FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Mitchell, CJ Getnet, D Kim, MS Manda, SS Kumar, P Huang, TC Pinto, SM Nirujogi, RS Iwasaki, M Shaw, PG Wu, XY Zhong, J Chaerkady, R Marimuthu, A Muthusamy, B Sahasrabuddhe, NA Raju, R Bowman, C Danilova, L Cutler, J Kelkar, DS Drake, CG Prasad, TSK Marchionni, L Murakami, PN Scott, AF Shi, LM Thierry-Mieg, J Thierry-Mieg, D Irizarry, R Cope, L Ishihama, Y Wang, C Gowda, H Pandey, A AF Mitchell, Christopher J. Getnet, Derese Kim, Min-Sik Manda, Srikanth S. Kumar, Praveen Huang, Tai-Chung Pinto, Sneha M. Nirujogi, Raja Sekhar Iwasaki, Mio Shaw, Patrick G. Wu, Xinyan Zhong, Jun Chaerkady, Raghothama Marimuthu, Arivusudar Muthusamy, Babylakshmi Sahasrabuddhe, Nandini A. Raju, Rajesh Bowman, Caitlyn Danilova, Ludmila Cutler, Jevon Kelkar, Dhanashree S. Drake, Charles G. Prasad, T. S. Keshava Marchionni, Luigi Murakami, Peter N. Scott, Alan F. Shi, Leming Thierry-Mieg, Jean Thierry-Mieg, Danielle Irizarry, Rafael Cope, Leslie Ishihama, Yasushi Wang, Charles Gowda, Harsha Pandey, Akhilesh TI A multi-omic analysis of human naive CD4+T cells SO BMC SYSTEMS BIOLOGY LA English DT Article DE Whole genome sequencing; Epigenomics; Transcriptomics; Proteomics; Phosphoproteomics; Integrativeomics; Innate immunity ID SPECTROMETRY-BASED PROTEOMICS; KAPPA-B ACTIVATION; RNA-SEQ DATA; MASS-SPECTROMETRY; T-CELLS; GENE-EXPRESSION; PHOSPHORYLATION; DIFFERENTIATION; TRANSCRIPTOME; LYMPHOCYTES AB Background: Cellular function and diversity are orchestrated by complex interactions of fundamental biomolecules including DNA, RNA and proteins. Technological advances in genomics, epigenomics, transcriptomics and proteomics have enabled massively parallel and unbiased measurements. Such high-throughput technologies have been extensively used to carry out broad, unbiased studies, particularly in the context of human diseases. Nevertheless, a unified analysis of the genome, epigenome, transcriptome and proteome of a single human cell type to obtain a coherent view of the complex interplay between various biomolecules has not yet been undertaken. Here, we report the first multi-omic analysis of human primary naive CD4+ T cells isolated from a single individual. Results: Integrating multi-omics datasets allowed us to investigate genome-wide methylation and its effect on mRNA/protein expression patterns, extent of RNA editing under normal physiological conditions and allele specific expression in naive CD4+ T cells. In addition, we carried out a multi-omic comparative analysis of naive with primary resting memory CD4+ T cells to identify molecular changes underlying T cell differentiation. This analysis provided mechanistic insights into how several molecules involved in T cell receptor signaling are regulated at the DNA, RNA and protein levels. Phosphoproteomics revealed downstream signaling events that regulate these two cellular states. Availability of multi-omics data from an identical genetic background also allowed us to employ novel proteogenomics approaches to identify individual-specific variants and putative novel protein coding regions in the human genome. Conclusions: We utilized multiple high-throughput technologies to derive a comprehensive profile of two primary human cell types, naive CD4+ T cells and memory CD4+ T cells, from a single donor. Through vertical as well as horizontal integration of whole genome sequencing, methylation arrays, RNA-Seq, miRNA-Seq, proteomics, and phosphoproteomics, we derived an integrated and comparative map of these two closely related immune cells and identified potential molecular effectors of immune cell differentiation following antigen encounter. C1 [Mitchell, Christopher J.; Getnet, Derese; Kim, Min-Sik; Huang, Tai-Chung; Shaw, Patrick G.; Wu, Xinyan; Zhong, Jun; Chaerkady, Raghothama; Bowman, Caitlyn; Cutler, Jevon; Scott, Alan F.; Pandey, Akhilesh] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21218 USA. [Manda, Srikanth S.; Kumar, Praveen; Pinto, Sneha M.; Nirujogi, Raja Sekhar; Marimuthu, Arivusudar; Muthusamy, Babylakshmi; Sahasrabuddhe, Nandini A.; Raju, Rajesh; Kelkar, Dhanashree S.; Prasad, T. S. Keshava; Gowda, Harsha; Pandey, Akhilesh] Int Tech Pk, Inst Bioinformat, Bangalore, Karnataka, India. [Iwasaki, Mio; Ishihama, Yasushi] Kyoto Univ, Dept Mol & Cellular BioAnal, Kyoto, Japan. [Murakami, Peter N.] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Danilova, Ludmila; Drake, Charles G.; Marchionni, Luigi; Cope, Leslie] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Shi, Leming] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Thierry-Mieg, Jean; Thierry-Mieg, Danielle] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Irizarry, Rafael] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Wang, Charles] Loma Linda Univ, Ctr Genom, Loma Linda, CA 92350 USA. [Wang, Charles] Loma Linda Univ, Div Microbiol & Mol Genet, Loma Linda, CA 92350 USA. [Pandey, Akhilesh] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. [Pandey, Akhilesh] Johns Hopkins Univ, Sch Med, Dept Pathol & Oncol, Baltimore, MD USA. RP Pandey, A (reprint author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21218 USA. EM pandey@jhmi.edu RI Ishihama, Yasushi/B-3101-2016; Kim, Min-Sik/M-3488-2016; Zhong, Jun/D-1662-2010; THIERRY-MIEG, Jean/F-1975-2017; OI Ishihama, Yasushi/0000-0001-7714-203X; Kim, Min-Sik/0000-0001-7317-5360; Zhong, Jun/0000-0003-3148-4143; THIERRY-MIEG, Jean/0000-0002-0396-6789; Huang, Tai-Chung/0000-0002-1625-7295 FU NIH [U54GM103520]; NCI's Clinical Proteomic Tumor Analysis Consortium initiative [U24CA160036]; National Heart, Lung and Blood Institute (NHLBI) [HHSN268201000032C]; Department of Biotechnology (DBT), Government of India FX We thank Dr. Barbara Migeon, Dr. Drew Pardoll, and Dr. Robert Siliciano for helpful discussions. We thank the Proteomics Core Facility at the Johns Hopkins University School of Medicine for data acquisition. This work was supported by a NIH roadmap grant for Technology Centers of Networks and Pathways (TCNP) (U54GM103520), NCI's Clinical Proteomic Tumor Analysis Consortium initiative (U24CA160036) and a contract (HHSN268201000032C) from the National Heart, Lung and Blood Institute (NHLBI). Harsha Gowda is a Wellcome Trust/DBT India Alliance Early Career Fellow. This work is also supported by research grants from the Department of Biotechnology (DBT), Government of India. NR 52 TC 3 Z9 3 U1 3 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD NOV 6 PY 2015 VL 9 AR 75 DI 10.1186/s12918-015-0225-4 PG 16 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA CV5BK UT WOS:000364280300001 PM 26542228 ER PT J AU Sun, C Tian, X Lee, YS Gunti, S Lipsky, A Herman, SEM Salem, D Stetler-Stevenson, M Yuan, C Kardava, L Moir, S Maric, I Valdez, J Soto, S Marti, GE Farooqui, MZ Notkins, AL Wiestner, A Aue, G AF Sun, Clare Tian, Xin Lee, Yuh Shan Gunti, Sreenivasulu Lipsky, Andrew Herman, Sarah E. M. Salem, Dalia Stetler-Stevenson, Maryalice Yuan, Constance Kardava, Lela Moir, Susan Maric, Irina Valdez, Janet Soto, Susan Marti, Gerald E. Farooqui, Mohammed Z. Notkins, Abner L. Wiestner, Adrian Aue, Georg TI Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib SO BLOOD LA English DT Article ID BRUTONS TYROSINE KINASE; B-CELL MALIGNANCIES; INITIAL THERAPY; TUMOR PROLIFERATION; OPEN-LABEL; BAFF; RITUXIMAB; CYCLOPHOSPHAMIDE; FLUDARABINE; EXPRESSION AB Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections and morbidity. Ibrutinib, a covalent inhibitor of Bruton tyrosinekinase (BTK), inhibits B-cell receptor signaling and is an effective, US Food and Drug Administration (FDA)-approved treatment of CLL. Inactivating germline mutations in BTK cause a severe B-cell defect and agammaglobulinemia. Therefore, we assessed the impact of ibrutinib on immunoglobulin levels, normal B cells, and infection rate in patients with CLL treated with single-agent ibrutinib on a phase 2 investigator-initiated trial. Consistent with previous reports, immunoglobulin G (IgG) levels remained stable during the first 6 months on treatment, but decreased thereafter. In contrast, there were a transient increase in IgM and a sustained increase in IgA (median increase 45% at 12 months, P < .0001). To distinguish the effects on clonal B cells from normal B cells, we measured serum free light chains (FLCs). In kappa-clonal CLL cases, clonal (kappa) FLCs were elevated at baseline and normalized by 6 months. Nonclonal (lambda) FLCs, which were often depressed at baseline, increased, suggesting the recovery of normal B cells. Consistently, we observed normal B-cell precursors in the bone marrow and an increase in normal B-cell numbers in the peripheral blood. Patients with superior immune reconstitution, as defined by an increase in serum IgA of >= 50% from baseline to 12 months, had a significantly lower rate of infections (P = .03). These data indicate that ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL. C1 [Sun, Clare; Lee, Yuh Shan; Lipsky, Andrew; Herman, Sarah E. M.; Valdez, Janet; Soto, Susan; Farooqui, Mohammed Z.; Wiestner, Adrian; Aue, Georg] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Tian, Xin] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Gunti, Sreenivasulu; Notkins, Abner L.] Natl Inst Dent & Craniofacial Res, Lab Sensory Biol, Expt Med Sect, Bethesda, MD USA. [Salem, Dalia; Stetler-Stevenson, Maryalice; Yuan, Constance] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Kardava, Lela; Moir, Susan] NIAID, Lab Immunoregulat, Bethesda, MD 20892 USA. [Maric, Irina] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Marti, Gerald E.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10,CRC 3-5140, Bethesda, MD 20892 USA. EM wiestnea@nhlbi.nih.gov RI Salem, Dalia/R-9314-2016 OI Salem, Dalia/0000-0002-4209-2260 FU Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health. NR 50 TC 15 Z9 15 U1 3 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD NOV 5 PY 2015 VL 126 IS 19 BP 2213 EP 2219 DI 10.1182/blood-2015-04-639203 PG 7 WC Hematology SC Hematology GA CY4PP UT WOS:000366390900011 PM 26337493 ER PT J AU Sack, C Vonderbrink, J Smoker, M Smith, RE AF Sack, Chris Vonderbrink, John Smoker, Michael Smith, Robert E. TI Determination of Acid Herbicides Using Modified QuEChERS with Fast Switching ESI+/ESI- LC-MS/MS SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article; Proceedings Paper CT 1st ACS-AGFD and ACSThailand Chapter Joint Symposium CY MAR 04-05, 2014 CL Bangkok, THAILAND DE acid herbicides; imidazolinone herbicides; chlorophenoxy acid herbicides; QuEChERS; LC-MS/MS ID TANDEM MASS-SPECTROMETRY; SOLID-PHASE EXTRACTION; LIQUID-CHROMATOGRAPHY; PESTICIDE-RESIDUES; PHENOXYACID HERBICIDES; MULTIRESIDUE METHOD; SURFACE-WATER; FRUITS; METABOLITES; QUANTITATION AB A method for the determination of 35 acid herbicides in food matrices was developed, validated, and implemented. It utilizes a modified QuEChERS extraction procedure coupled with quantitation by liquid chromatography tandem mass spectrometry (LC-MS/MS). The acid herbicides analyzed are all organic carboxylic acids, including the older chlorophenoxy acid herbicides such as 2,4-dichlorophenoxyacetic acid (2,4-D), dicamba, 4-chlorophenoxyacetic acid (4-CPA), quindorac, and many of the newer imidazolinone herbicides such as imazethapyr and imazaquin. In the procedure, 10 mL of water is added to 5 g of sample and then extracted with 1% formic acid in acetonitrile for 1 min. The acetonitrile phase is salted out of the extract by adding sodium chloride and magnesium sulfate, followed by centrifugation. The acetonitrile is diluted 1:1 with water to enable quantitation by LC-MS/MS using fast switching between positive and negative electrospray ionization modes. The average recoveries for all the compounds except aminocydopyrachlor were 95% with a precision of 8%. The method detection limits for all residues were less than 10 ng/g, and the correlation coefficients for the calibration curves was greater than 0.99 for all but two compounds tested. The method was used successfully for the quantitation of acid herbicides in the FDA's total diet study. The procedure proved to be accurate, precise, linear, sensitive, and rugged. C1 [Sack, Chris; Vonderbrink, John; Smoker, Michael; Smith, Robert E.] US FDA, Lenexa, KS 66224 USA. RP Smith, RE (reprint author), US FDA, 11510 West 80th St, Lenexa, KS 66224 USA. EM Robert.smith@fda.hhs.gov NR 51 TC 7 Z9 7 U1 5 U2 40 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD NOV 4 PY 2015 VL 63 IS 43 BP 9657 EP 9665 DI 10.1021/acs.jafc.5604093 PG 9 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA CV6BM UT WOS:000364355700035 PM 26473587 ER PT J AU Ambrose, BK Day, HR Rostron, B Conway, KP Borek, N Hyland, A Villanti, AC AF Ambrose, Bridget K. Day, Hannah R. Rostron, Brian Conway, Kevin P. Borek, Nicolette Hyland, Andrew Villanti, Andrea C. TI Flavored Tobacco Product Use Among US Youth Aged 12-17 Years, 2013-2014 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Ambrose, Bridget K.; Day, Hannah R.; Rostron, Brian; Borek, Nicolette] US FDA, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. [Conway, Kevin P.] NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. [Hyland, Andrew] Roswell Pk Canc Inst, Dept Hlth Behav, Buffalo, NY 14263 USA. [Villanti, Andrea C.] Truth Initiat, Schroeder Inst Tobacco Res & Policy Studies, Washington, DC USA. RP Ambrose, BK (reprint author), US FDA, Off Sci, Ctr Tobacco Prod, 10903 New Hampshire Ave,Bldg 75,Room 4432, Silver Spring, MD 20993 USA. EM bridget.ambrose@fda.hhs.gov OI Conway, Kevin/0000-0002-7638-339X; Villanti, Andrea/0000-0003-3104-966X FU PHS HHS [HHSN271201100027C] NR 5 TC 19 Z9 19 U1 1 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD NOV 3 PY 2015 VL 314 IS 17 BP 1871 EP 1873 DI 10.1001/jama.2015.13802 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CV0RO UT WOS:000363960200022 PM 26502219 ER PT J AU Draganova, EB Akbas, N Adrian, SA Lukat-Rodgers, GS Collins, DP Dawson, JH Allen, CE Schmitt, MP Rodgers, KR Dixon, DW AF Draganova, Elizabeth B. Akbas, Neval Adrian, Seth A. Lukat-Rodgers, Gudrun S. Collins, Daniel P. Dawson, John H. Allen, Courtni E. Schmitt, Michael P. Rodgers, Kenton R. Dixon, Dabney W. TI Heme Binding by Corynebacterium diphtheriae HmuT: Function and Heme Environment SO BIOCHEMISTRY LA English DT Article ID MAGNETIC CIRCULAR-DICHROISM; RESONANCE RAMAN-SPECTRA; CYTOCHROME-C PEROXIDASE; SITE-DIRECTED MUTAGENESIS; H-BONDING INTERACTIONS; ALLENE OXIDE SYNTHASE; BOVINE LIVER CATALASE; HOST IRON SOURCES; STAPHYLOCOCCUS-AUREUS; ACTIVE-SITE AB The heme uptake pathway (hmu) of Corynebacterium diphtheriae utilizes multiple proteins to bind and transport heme into the cell. One of these proteins, HmuT, delivers heme to the ABC transporter Hmut.W. In this study, the axial ligation of the heme in ferric HmuT is probed by examination of wild-type (WT) HmuT and a series of conserved heme pocket residue mutants, H136A, Y235A, and M292A. Characterization by UV-visible, resonance Raman, and magnetic circular dichroism spectroscopies indicates that H136 and Y235 are the axial ligands in ferric HmuT. Consistent with this assignment of axial ligands, ferric WT and H136A HmuT are difficult to reduce while Y235A is reduced readily in the presence of dithionite. The FeCO Raman shifts in WT, H136A, and Y235A HmuT CO complexes provide further evidence of the axial ligand assignments. Additionally, these frequencies provide insight into the nonbonding environment of the heme pocket. Ferrous Y235A and the Y235A CO complex reveal that the imidazole of H136 exists in two forms, one neutral and one with imidazolate character, consistent with a hydrogen bond acceptor on the H136 side of the heme. The ferric fluoride complex of Y235A reveals the presence of at least one hydrogen bond donor on the Y235 side of the heme. Hemoglobin utilization assays showed that the axial Y235 ligand is required for heme uptake in HmuT. C1 [Draganova, Elizabeth B.; Akbas, Neval; Dixon, Dabney W.] Georgia State Univ, Dept Chem, Atlanta, GA 30302 USA. [Adrian, Seth A.; Lukat-Rodgers, Gudrun S.; Rodgers, Kenton R.] N Dakota State Univ, Dept Chem & Biochem, Fargo, ND 58108 USA. [Collins, Daniel P.; Dawson, John H.] Univ S Carolina, Dept Chem & Biochem, Columbia, SC 29208 USA. [Allen, Courtni E.; Schmitt, Michael P.] Ctr Biol Evaluat & Res Food & Drug Adm, Div Bacterial Parasit & Allergen Prod, Lab Resp & Special Pathogens, Silver Spring, MD 20993 USA. RP Rodgers, KR (reprint author), N Dakota State Univ, Dept Chem & Biochem, Fargo, ND 58108 USA. EM kent.rodgers@ndsu.edu; ddixon@gsu.edu FU National Institutes of Health [AI072719, GM26730, GM094039]; Research Corp. FX This work was supported by National Institutes of Health Grants AI072719 (to K.R.R.), GM26730 (to J.H.D.), GM094039 (to G.S.L.-R) and the Research Corp. (to D.W.D.). NR 95 TC 5 Z9 5 U1 8 U2 35 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD NOV 3 PY 2015 VL 54 IS 43 BP 6598 EP 6609 DI 10.1021/acs.biochem.5b00666 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CV6BC UT WOS:000364354700005 PM 26478504 ER PT J AU Hayward, DG AF Hayward, Douglas G. TI Comment on Comparison of Atmospheric Pressure Ionization Gas Chromatography-Triple Quadrupole Mass Spectrometry to Traditional High-Resolution Mass Spectrometry for the Identification and Quantification of Halogenated Dioxins and Furans SO ANALYTICAL CHEMISTRY LA English DT Editorial Material C1 US FDA, College Pk, MD 20740 USA. RP Hayward, DG (reprint author), US FDA, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Douglas.hayward@fda.hhs.gov NR 2 TC 0 Z9 0 U1 1 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD NOV 3 PY 2015 VL 87 IS 21 BP 11164 EP 11165 DI 10.1021/acs.analchem.5b02689 PG 2 WC Chemistry, Analytical SC Chemistry GA CV6BE UT WOS:000364354900072 PM 26389693 ER PT J AU Edwards, GB AF Edwards, G. B. TI Freyinae, a major new subfamily of Neotropical jumping spiders (Araneae: Salticidae) SO ZOOTAXA LA English DT Article DE new terminology ID NEW-SPECIES ARANEAE; CAPORIACCO ARANEAE; ECUADOR ARANEAE; GENUS; PHYLOGENY; REVISION; REDESCRIPTION; BIOGEOGRAPHY; MORPHOLOGY; BRAZIL AB Freyinae, new subfamily, is described for a group of genera of Neotropical jumping spiders that can be distinguished from other non-ant mimic salticoid Neotropical salticids by having the following three morphological features: a slightly more elongate carapace, a distinctive prolateral tibial macrosetae arrangement (medially placed subdistal and subproximal macrosetae, with a subdorsal medial macroseta in some males), and an unusual dorsoventrally thick tegulum basal division (although one or two of these features are sometimes lost). It includes 20 genera previously considered valid, of which 19 are retained: Akela Peckham & Peckham, 1896, Aphirape C.L. Koch, 1850, Asaracus C.L. Koch, 1846, Capidava Simon, 1902, Chira Peckham & Peckham, 1896, Edilemma Ruiz & Brescovit, 2006, Eustiromastix Simon, 1902, Freya C.L. Koch, 1850, Frigga C.L. Koch, 1850, Kalcerrytus Galiano, 2000, Nycerella Galiano, 1982, Onofre Ruiz & Brescovit, 2007, Pachomius Peckham & Peckham, 1896, Phiale C.L. Koch, 1846, Rishaschia Makhan, 2006, Sumampattus Galiano, 1983, Trydarssus Galiano, 1995, Tullgrenella Mello-Leitao, 1941, and Wedoquella Galiano, 1984. Romitia Caporiacco, 1947 (and its synonym Uspachus Galiano, 1995) is synonymized with Pachomius, new synonymy. New genera described in the subfamily are: Drizztius, Leptofreya, Megafreya, Philira, Tarkas, Triggella, and Xanthofreya. The following nomenclatorial changes are made: New synonyms: Freya demarcata Chamberlin & Ivie, 1936 = Freya (sub Cyrene) albosignata (F.O.P.-Cambridge, 1901); Freya (sub Cyrene) grisea (F.O.P.-Cambridge, 1901) = Freya (sub Cyrene) infuscata (F.O.P.-Cambridge, 1901); Freya (sub Cyrene) emarginata (F.O.P.-Cambridge, 1901) and Nycerella (sub Heraclea) sanguinea paradoxa (Peckham & Peckham, 1896) = Nycerella (sub Heraclea) sanguinea (Peckham & Peckham, 1896); Pachomius (sub Phiale) maculosus (Chickering, 1946) = Phiale (sub Cyrene) bilobata (F.O.P.-Cambridge, 1901); Phiale (sub Cyrene) mediocava (F.O.P.-Cambridge, 1901) = Freya (sub Cyrene) maculatipes (F.O.P.-Cambridge, 1901); Phiale (sub Cyrene) simplicicava (F.O.P.-Cambridge, 1901) = Freya (sub Cyrene) bifurcata (F.O.P.-Cambridge, 1901). New combinations: Capidava rufithorax Simon, 1902 = Drizztius rufithorax; Freya frontalis Banks, 1929 = Eustiromastix frontalis; Chira (sub Attus) spinipes (Taczanowski, 1872) = Eustiromastix spinipes; Freya (sub Euophrys) ambigua (C.L. Koch, 1846) = Leptofreya ambigua; Freya (sub Cyrene) bifurcata (F.O.P.-Cambridge, 1901) = Leptofreya bifurcata; Freya (sub Cyrene) laticava (F.O.P.-Cambridge, 1901) = Leptofreya laticava; Freya (sub Cyrene) longispina (F.O.P.-Cambridge, 1901) = Leptofreya longispina; Phiale (sub Cyrene) bilobata (F.O.P.-Cambridge, 1901) = Pachomius bilobatus; Phiale (sub Cyrene) hieroglyphica (F.O.P.-Cambridge, 1901) = Pachomius hieroglyphicus; Phiale (sub Cyrene) niveoguttata (F.O.P.-Cambridge, 1901) = Pachomius niveoguttatus; Romitia (sub Euophrys) albipalpis (Taczanowski, 1878) = Pachomius albipalpis; Romitia (sub Euophrys) andina (Taczanowski, 1878) = Pachomius andinus; Romitia (sub Uspachus) bahiensis (Galiano, 1995) = Pachomius bahiensis; Romitia (sub Uspachus) columbiana (Galiano, 1995) = Pachomius columbianus; Romitia (sub Uspachus) juquiaensis (Galiano, 1995) = Pachomius juquiaensis; Romitia (sub Phiale) ministerialis (C.L. Koch, 1846) = Pachomius ministerialis; Romitia (sub Uspachus) misionensis (Galiano, 1995) = Pachomius misionensis; Romitia nigra Caporiacco, 1947 = Pachomius nigrus; Romitia (sub Uspachus) patellaris (Galiano, 1995) = Pachomius patellaris; Chira (sub Diagondas) micans (Simon, 1902) = Philira micans; Chira superba Caporiacco, 1947 = Philira superba; Freya (sub Cyrene) maculatipes (F.O.P.-Cambridge, 1901) = Tarkas maculatipes; Freya (sub Cyrene) bifida (F.O.P.-Cambridge, 1901) = Triggella bifida; Freya infuscata (F.O.P.-Cambridge, 1901) = Triggella infuscata; Freya (sub Cyrene) minuta (F.O.P.-Cambridge, 1901) = Triggella minuta; Freya (sub Cyrene) albosignata (F.O.P.-Cambridge, 1901) = Xanthofreya albosignata; Freya arraijanica Chickering, 1946 = Xanthofreya arraijanica; Phiale (sub Cyrene) bicuspidata (F.O.P.-Cambridge, 1901) = Xanthofreya bicuspidata; Freya chionopogon Simon, 1902 = Xanthofreya chionopogon; Freya (sub Heraclea) rustica (Peckham & Peckham, 1896) = Xanthofreya rustica. Combinations restored: Phiale (sub Pachomius) flavescens (Peckham & Peckham, 1896) = Pachomius flavescens; Phiale (sub Pachomius) similis (Peckham & Peckham, 1896) = Pachomius similis. Invalid name: Freya dyali Roewer 1951 is an invalid replacement name for Euophrys trifasciata "Dyal 1935", which was a redescription of Euophrys trifasciata C.L. Koch, 1846, not a homonym. New species: Drizztius geminensis. First female descriptions and transfers of mismatched females: First descriptions for Asaracus megacephalus C.L. Koch, 1846, Capidava biuncata Simon, 1902, and Phiale formosa (Banks, 1909); the true female of Eustiromastix spinipes is described, and its mismatched female is identified as the female of Eustiromastix falcatus Galiano, 1981; the mismatched female of Freya (sub Cyrene) prominens (F.O.P.-Cambridge, 1901) is identified as the female of Xanthofreya rustica; the misidentified female of X. rustica is identified as the female of Leptofreya bifurcata. Lectotypes: designated for Cyrene bifida F.O.P.-Cambridge, 1901 and Cyrene formosa Banks, 1909. New synapomorphy: a constricted proximal end of the cymbium of the male palp is an apparent new synapomorphy for Salticoida. C1 Florida State Collect Arthropods, FDACS, Div Plant Ind, Arachnida & Myriapoda, Gainesville, FL 32614 USA. RP Edwards, GB (reprint author), Florida State Collect Arthropods, FDACS, Div Plant Ind, Arachnida & Myriapoda, POB 147100, Gainesville, FL 32614 USA. EM GB.Edwards@freshfromflorida.com FU United States National Science Foundation FX This work is dedicated to Dra. Maria Elena Galiano, whose pioneering work on many of the genera included here greatly facilitated subsequent analysis of the subfamily. Thanks are due the following for their valuable contributions. Wayne Maddison and Gustavo Ruiz shared numerous discussions on salticids and insights on freyines. Martin Ramirez consulted on palpal terminology. Diomedes Quintero shared data from the Museo de Invertebrados G.B. Fairchild (MIUP), Panama. H. Don Cameron advised on the formation of new names. Gita Bodner co-collected many freyines and other salticids in Costa Rica during our visits as collaborators with the Arthropods of La Selva (ALAS) Project; trips were funded by the United States National Science Foundation. John Longino coordinated the ALAS field trips. Jerzy Proszynski's (2005, 2007, 2013, 2014) online Salticidae (Araneae) of the World was helpful for identifications. Heiko Metzner's (2014) recent reformatting of the world salticid illustrations improved access to and usability of the data. A special thanks is given to Laura Liebensperger for her cheerful assistance in obtaining loans on multiple occasions over many years. Elizabeth Jakob and James Carrel (former President and Editor-in-Chief, respectively, American Arachnological Society and Journal of Arachnology), Cristina Scioscia (former editor, Physis; Museo Argentino de Ciencias Naturales), and Mary deJong (Reference Librarian, American Museum of Natural History) clarified copyright issues for using the published figures of the late Maria Elena Galiano and their designation as orphaned works. Dra Scioscia is also heir to the scientific works of Dra Galiano and gave her permission to use the figures from these works. Paul Selden (editor, Bulletin of the British Arachnological Society) gave permission to use the figures of Onofre. I would also like to congratulate the editorial board of the journal Revista Brasileira de Zoologia (RBZ) for their foresight in releasing the journal's publications under a Creative Commons Attribution License, allowing the use of the figures of Edilemma foraminifera and Pachomius (sub Romitia) nigrus. Illustrations of the latter three taxa and one of the Leptofreya figures were by Gustavo Ruiz. All figures not of my creation used in this paper are covered under one of the aforementioned methods. All photographs of living specimens (and of the same specimens after preservation) are given photographer credit with the photograph, and remain copyright of those persons unless otherwise indicated in the Methods. Other than myself, photographers include Gita Bodner, John Koerner, Wayne Maddison, and Joe Warfel. I am especially grateful to Wayne Maddison for the use of multiple previously unpublished images under a Creative Commons license, for access to a preliminary molecular analysis of about 15 freyine genera (which helped clarify some relationships and inclusion of Asaracus), and for his pre-submission review. NR 123 TC 6 Z9 8 U1 0 U2 3 PU MAGNOLIA PRESS PI AUCKLAND PA PO BOX 41383, AUCKLAND, ST LUKES 1030, NEW ZEALAND SN 1175-5326 EI 1175-5334 J9 ZOOTAXA JI Zootaxa PD NOV 2 PY 2015 VL 4036 IS 1 BP 1 EP 87 PG 87 WC Zoology SC Zoology GA CU8QM UT WOS:000363808100001 PM 26624463 ER PT J AU Luo, S Zhang, BL AF Luo, Shen Zhang, Baolin TI Dextrose-mediated aggregation of therapeutic monoclonal antibodies in human plasma: Implication of isoelectric precipitation of complement proteins SO MABS LA English DT Article DE aggregation; complement proteins; compatibility; diluent; therapeutic proteins; isoelectric point; monoclonal antibodies; plasma; product formulation ID INACTIVATION; TRASTUZUMAB; NEONATE; SERUM AB Many therapeutic monoclonal antibodies (mAbs) are clinically administered through intravenous infusion after mixing with a diluent, e.g., saline, 5% dextrose. Such a clinical setting increases the likelihood of interactions among mAb molecules, diluent, and plasma components, which may adversely affect product safety and efficacy. Avastin (R) (bevacizumab) and Herceptin (R) (trastuzumab), but not Remicade (R) (infliximab), were shown to undergo rapid aggregation upon dilution into 5% dextrose when mixed with human plasma in vitro; however, the biochemical pathways leading to the aggregation were not clearly defined. Here, we show that dextrose-mediated aggregation of Avastin or Herceptin in plasma involves isoelectric precipitation of complement proteins. Using mass spectrometry, we found that dextrose-induced insoluble aggregates were composed of mAb itself and multiple abundant plasma proteins, namely complement proteins C3, C4, factor H, fibronectin, and apolipoprotein. These plasma proteins, which are characterized by an isoelectronic point of 5.5-6.7, lost solubility at the resulting pH in the mixture with formulated Avastin (pH 6.2) and Herceptin (pH 6.0). Notably, switching formulation buffers for Avastin (pH 6.2) and Remicade (pH 7.2) reversed their aggregation profiles. Avastin formed little, if any, insoluble aggregates in dextrose-plasma upon raising the buffer pH to 7.2 or above. Furthermore, dextrose induced pH-dependent precipitation of plasma proteins, with massive insoluble aggregates being detected at pH 6.5-6.8. These data show that isoelectric precipitation of complement proteins is a prerequisite of dextrose-induced aggregation of mAb in human plasma. This finding highlights the importance of assessing the compatibility of a therapeutic mAb with diluent and human plasma during product development. C1 [Luo, Shen; Zhang, Baolin] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Zhang, BL (reprint author), US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM baolin.zhang@fda.hhs.gov FU FDA FX We thank Drs. Bingjie Li, Qi Qiu, and Hui Xu for kindly providing human plasma and mouse serum samples. We also thank our labmates (Drs. William Bozza, Yaqin Zhang, Kory Hallett, William Hallett, and Julianne Twomey) for technical support and helpful discussions. This work was supported by FDA intramural funding. NR 23 TC 2 Z9 2 U1 0 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1942-0862 EI 1942-0870 J9 MABS-AUSTIN JI mAbs PD NOV 2 PY 2015 VL 7 IS 6 BP 1094 EP 1103 DI 10.1080/19420862.2015.1087636 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CU1QA UT WOS:000363295200009 PM 26338058 ER PT J AU Zhou, MW Gucinski, AC Boyne, MT AF Zhou, Mowei Gucinski, Ashley C. Boyne, Michael T. TI Performance metrics for evaluating system suitability in liquid chromatography-Mass spectrometry peptide mass mapping of protein therapeutics and monoclonal antibodies SO MABS LA English DT Article DE system suitability; protein therapeutics; liquid chromatography; mass spectrometry; quality control ID HIGH-RESOLUTION; IDENTIFICATION RATES; PROTEOMICS ANALYSES; DATA-ACQUISITION; ACCURACY; QUANTIFICATION; PARAMETERS; PRECISION; DIGESTION; PROTOCOL AB The use of liquid chromatography - mass spectrometry (LC-MS) for the characterization of proteins can provide a plethora of information related to their structure, including amino acid sequence determination and analysis of posttranslational modifications. The variety of LC-MS based applications has led to the use of LC-MS characterization of therapeutic proteins and monoclonal antibodies as an integral part of the regulatory approval process. However, the improper use of an LC-MS system, related to intrinsic instrument limitations, improper tuning parameters, or poorly optimized methods may result in the production of low quality data. Improper system performance may arise from subtle changes in operating conditions that limit the ability to detect low abundance species. To address this issue, we systematically evaluated LC-MS/MS operating parameters to identify a set of metrics that can be used in a workflow to determine if a system is suitable for its intended purpose. Development of this workflow utilized a bovine serum albumin (BSA) digest standard spiked with synthetic peptides present at 0.1% to 100% of the BSA digest peptide concentration to simulate the detection of low abundance species using a traditional bottom-up workflow and data-dependent MS2 acquisition. BSA sequence coverage, a commonly used indicator for instrument performance did not effectively identify settings that led to limited dynamic range or poorer absolute mass accuracy on 2 separate LC-MS systems. Additional metrics focusing on the detection limit and sensitivity for peptide identification were determined to be necessary to establish system suitability for protein therapeutic characterization by LC-MS. C1 [Zhou, Mowei; Gucinski, Ashley C.; Boyne, Michael T.] US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Pharmaceut Anal, St Louis, MO 63101 USA. RP Gucinski, AC (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Pharmaceut Anal, St Louis, MO 63101 USA. EM Ashley.Gucinski@fda.hhs.gov OI Zhou, Mowei/0000-0003-3575-3224 FU FDA Center for Drug Evaluation and Research Critical Path program FX This study was supported in part by an appointment to the Research Participation Program at the FDA Center for Drug Evaluation and Research, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA (MZ). This work was funded by the FDA Center for Drug Evaluation and Research Critical Path program (MTB). NR 34 TC 1 Z9 1 U1 2 U2 13 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1942-0862 EI 1942-0870 J9 MABS-AUSTIN JI mAbs PD NOV 2 PY 2015 VL 7 IS 6 BP 1104 EP 1117 DI 10.1080/19420862.2015.1074364 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CU1QA UT WOS:000363295200010 PM 26218711 ER PT J AU Alosh, M Huque, MF Koch, GG AF Alosh, Mohamed Huque, Mohammad F. Koch, Gary G. TI STATISTICAL PERSPECTIVES ON SUBGROUP ANALYSIS: TESTING FOR HETEROGENEITY AND EVALUATING ERROR RATE FOR THE COMPLEMENTARY SUBGROUP SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Complementary subgroup error rate; Supportive assessment; Targeted subgroup; Testing for interaction ID QUALITATIVE INTERACTIONS; CLINICAL-TRIALS; POWER AB Substantial heterogeneity in treatment effects across subgroups can cause significant findings in the overall population to be driven predominantly by those of a certain subgroup, thus raising concern on whether the treatment should be prescribed for the least benefitted subgroup. Because of its low power, a nonsignificant interaction test can lead to incorrectly prescribing treatment for the overall population. This article investigates the power of the interaction test and its implications. Also, it investigates the probability of prescribing the treatment to a nonbenefitted subgroup on the basis of a nonsignificant interaction test and other recently proposed criteria. C1 [Alosh, Mohamed] US FDA, Div Biometr 3, Off Biostat, OTS,CDER, Silver Spring, MD 20993 USA. [Huque, Mohammad F.] US FDA, OTS, Off Biostat, CDER, Silver Spring, MD 20993 USA. [Koch, Gary G.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. RP Alosh, M (reprint author), US FDA, Div Biometr 3, Off Biostat, OTS,CDER, 10903 New Hampshire Ave,Bldg 21,Room 3625, Silver Spring, MD 20993 USA. EM Mohamed.Alosh@fda.hhs.gov NR 20 TC 1 Z9 1 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PD NOV 2 PY 2015 VL 25 IS 6 BP 1161 EP 1178 DI 10.1080/10543406.2014.971169 PG 18 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA CT2NB UT WOS:000362637800003 PM 25331097 ER PT J AU O'Donoghue, AC Boudewyns, V Aikin, KJ Geisen, E Betts, KR Southwell, BG AF O'Donoghue, Amie C. Boudewyns, Vanessa Aikin, Kathryn J. Geisen, Emily Betts, Kevin R. Southwell, Brian G. TI Awareness of the Food and Drug Administration's Bad Ad Program and Education Regarding Pharmaceutical Advertising: A National Survey of Prescribers in Ambulatory Care Settings SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID MEDICAL-STUDENTS; REPRESENTATIVES; PROMOTION; ATTITUDES; NURSES AB The U.S. Food and Drug Administration's Bad Ad program educates health care professionals about false or misleading advertising and marketing and provides a pathway to report suspect materials. To assess familiarity with this program and the extent of training about pharmaceutical marketing, a sample of 2,008 health care professionals, weighted to be nationally representative, responded to an online survey. Approximately equal numbers of primary care physicians, specialists, physician assistants, and nurse practitioners answered questions concerning Bad Ad program awareness and its usefulness, as well as their likelihood of reporting false or misleading advertising, confidence in identifying such advertising, and training about pharmaceutical marketing. Results showed that fewer than a quarter reported any awareness of the Bad Ad program. Nonetheless, a substantial percentage (43%) thought it seemed useful and 50% reported being at least somewhat likely to report false or misleading advertising in the future. Nurse practitioners and physician assistants expressed more openness to the program and reported receiving more training about pharmaceutical marketing. Bad Ad program awareness is low, but opportunity exists to solicit assistance from health care professionals and to help health care professionals recognize false and misleading advertising. Nurse practitioners and physician assistants are perhaps the most likely contributors to the program. C1 [O'Donoghue, Amie C.; Aikin, Kathryn J.; Betts, Kevin R.] US FDA, Silver Spring, MD 20993 USA. [Boudewyns, Vanessa; Geisen, Emily; Southwell, Brian G.] RTI Int, Res Triangle Pk, NC USA. RP O'Donoghue, AC (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 51,Room 3236, Silver Spring, MD 20993 USA. EM amie.odonoghue@fda.hhs.gov OI Southwell, Brian/0000-0001-5091-8782 NR 22 TC 0 Z9 0 U1 0 U2 8 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PD NOV 2 PY 2015 VL 20 IS 11 BP 1330 EP 1336 DI 10.1080/10810730.2015.1018649 PG 7 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA CS3PG UT WOS:000361986100010 PM 26176326 ER PT J AU Joshi, BH Suzuki, A Fujisawa, T Leland, P Varrichio, F Lababidi, S Lloyd, R Kasperbauer, J Puri, RK AF Joshi, Bharat H. Suzuki, Akiko Fujisawa, Toshio Leland, Pamela Varrichio, FrederIck Lababidi, Samir Lloyd, Ricardo Kasperbauer, Jan Puri, Raj K. TI Identification, Characterization, and Targeting of IL-4 Receptor by IL-4-Pseudomonas Exotoxin in Mouse Models of Anaplastic Thyroid Cancer SO DISCOVERY MEDICINE LA English DT Article ID RENAL-CELL CARCINOMA; CIRCULARLY PERMUTED INTERLEUKIN-4; CD4(+) T-CELLS; PSEUDOMONAS EXOTOXIN; CHIMERIC PROTEIN; PULMONARY METASTASIS; AUTOCRINE PRODUCTION; CYTOTOXIN THERAPY; MALIGNANT GLIOMA; SARCOMA-CELLS AB Thyroid cancer is a rapidly increasing endocrine cancer. Since interleukin-4 receptor (IL4R) is overexpressed in human solid cancer, we examined expression of IL-4R in 50 cases of anaplastic thyroid cancer (ATC), 37 well-differentiated papillary cancer (WDPC), 35 well-differentiated follicular cancer of thyroid (WDFC), and 37 normal thyroid specimens by immunohistochemistry (IHC) and in-situ hybridization (ISH) techniques. We demonstrated that IL-4R alpha was overexpressed in 36/50 (72%) ATC, 20/35 (57%) WDFC, and 11/37 (30%) WDPC tumors. Other two subunits of IL-4R, interleukin-13 receptor alpha 1 (IL-13R alpha 1) and interleukin-2 receptor gamma (IL-2R gamma C), were either weakly expressed or absent. As ATC is a highly aggressive cancer with higher incidence of IL-4R alpha expression, we characterized IL-4R in 3 ATC cell lines. RT-qPCR and IFA results showed that IL-4R alpha is overexpressed while IL-13R alpha 1 is weakly expressed. Control human umbilical vein endothelial cell line (HUVEC) showed weak expression of IL-4R alpha. Binding and competition studies with 125I-IL-4 in ATC cell lines demonstrated that IL-4 specifically bound to IL-4R alpha on cell surface. ATC cell lines were highly sensitive to a chimeric fusion cytotoxin consisting of circularly permuted IL-4 and truncated Pseudomonas exotoxin (IL-4-PE), which killed them in a concentration dependent manner. IL-4-PE also blocked colony formation of ATC cell lines in clonogenic assays. IL-4-PE mediated a significant antitumor activity in mouse models of ATC. Intratumoral administration of IL-4-PE caused significant regression of established tumors in a dose dependent manner and increased the overall survival without any visible toxicity. Thus, IL-4R alpha in ATC may represent a novel therapeutic target and IL-4-PE may serve as an investigational therapeutic option for ATC. C1 [Joshi, Bharat H.; Suzuki, Akiko; Fujisawa, Toshio; Leland, Pamela; Varrichio, FrederIck; Puri, Raj K.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Off Cellular Tissue & Gene Therapies,Ctr Biol Eva, Silver Spring, MD 20993 USA. [Lababidi, Samir] Mayo Clin, Off Biostat & Epidemiol, Rochester, MN 55905 USA. [Lloyd, Ricardo] Mayo Clin, Dept Pathol, Rochester, MN 55905 USA. [Kasperbauer, Jan] Mayo Clin, Dept Otolaryngol, Rochester, MN 55905 USA. RP Joshi, BH (reprint author), US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Off Cellular Tissue & Gene Therapies,Ctr Biol Eva, Silver Spring, MD 20993 USA. EM raj.puri@fda.hhs.gov NR 51 TC 0 Z9 0 U1 0 U2 0 PU DISCOVERY MEDICINE PI TIMONIUM PA 10 GERARD AVE, STE 201, TIMONIUM, MD 21093 USA SN 1539-6509 EI 1944-7930 J9 DISCOV MED JI Discov. Med. PD NOV PY 2015 VL 20 IS 111 BP 273 EP 284 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CY3MH UT WOS:000366313400002 PM 26645899 ER PT J AU Henry, LM Larkin, ME Pike, ER AF Henry, Leslie Meltzer Larkin, Megan E. Pike, Elizabeth R. TI Just compensation: a no-fault proposal for research-related injuries SO JOURNAL OF LAW AND THE BIOSCIENCES LA English DT Article DE clinical trial; compensation; compensatory justice; no-fault compensation; research injury; remedy ID RESEARCH PARTICIPANTS; CLINICAL-RESEARCH AB Biomedical research, no matter how well designed and ethically conducted, carries uncertainties and exposes participants to risk of injury. Research injuries can range from the relatively minor to those that result in hospitalization, permanent disability, or even death. Participants might also suffer a range of economic harms related to their injuries. Unlike the vast majority of developed countries, which have implemented no-fault compensation systems, the United States continues to rely on the tort system to compensate injured research participants-an approach that is no longer morally defensible. Despite decades of US advisory panels advocating for no-fault compensation, little progress has been made. Accordingly, this article proposes a novel and necessary no-fault compensation system, grounded in the ethical notion of compensatory justice. This first-of-its-kind concrete proposal aims to treat like cases alike, offer fair compensation, and disburse compensation with maximum efficiency and minimum administrative cost. It also harmonizes national and international approaches-an increasingly important goal as research becomes more globalized, multi-site trials grow in number, and institutions and sponsors in the United States move to single-IRB review. C1 [Henry, Leslie Meltzer] Univ Maryland, Carey Sch Law, Baltimore, MD 21201 USA. [Henry, Leslie Meltzer] Johns Hopkins Berman Inst Bioeth, Baltimore, MD 21205 USA. [Larkin, Megan E.] US FDA, Off Chief Counsel, Silver Spring, MD USA. [Larkin, Megan E.] US FDA, Off Gen Counsel, Dept Hlth & Human Serv, Silver Spring, MD USA. [Pike, Elizabeth R.] Presidential Commiss Study Bioeth Issues, Washington, DC 20005 USA. RP Henry, LM (reprint author), Univ Maryland, Carey Sch Law, Baltimore, MD 21201 USA. EM lhenry@law.umaryland.edu OI Henry, Leslie/0000-0002-3697-7521 NR 72 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2053-9711 J9 J LAW BIOSCI JI J. Law Biosci. PD NOV PY 2015 VL 2 IS 3 BP 645 EP 668 DI 10.1093/jlb/lsv034 PG 24 WC Law SC Government & Law GA DJ8XO UT WOS:000374497800008 PM 27774216 ER PT J AU Pishko, G Oliveri, CM Zhang, J Bhullar, AS Ohara, MD Dill, DB Jung, WC Miller, DL AF Pishko, G. Oliveri, C. M. Zhang, J. Bhullar, A. S. Ohara, M. D. Dill, D. B. Jung, W. C. Miller, D. L. TI A Three-Layered Approach to Radiation Therapy Software Recall Analysis SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY OCT 18-21, 2015 CL San Antonio, TX SP Amer Soc Radiat Oncol C1 [Pishko, G.; Oliveri, C. M.; Zhang, J.; Bhullar, A. S.; Ohara, M. D.; Dill, D. B.; Jung, W. C.; Miller, D. L.] US FDA, Silver Spring, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 1 PY 2015 VL 93 IS 3 SU S MA 3245 BP E498 EP E499 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DI0VL UT WOS:000373215301312 ER PT J AU Graessle, DH Dorr, H Bennett, A Shapiro, A Farese, AM MacVittie, TJ Meineke, V AF Graessle, Dieter H. Doerr, Harald Bennett, Alexander Shapiro, Alla Farese, Ann M. MacVittie, Thomas J. Meineke, Viktor TI COMPARING THE HEMATOPOETIC SYNDROME TIME COURSE IN THE NHP ANIMAL MODEL TO RADIATION ACCIDENT CASES FROM THE DATABASE SEARCH SO HEALTH PHYSICS LA English DT Article DE accidents; nuclear; modelling; dose assessment; radiation damage; radiation effects ID COLONY-STIMULATING FACTOR; BODY IRRADIATION; EXPOSURE; FILGRASTIM; RESPONSES; SEVERITY AB Since controlled clinical studies on drug administration for the acute radiation syndrome are lacking, clinical data of human radiation accident victims as well as experimental animal models are the main sources of information. This leads to the question of how to compare and link clinical observations collected after human radiation accidents with experimental observations in non-human primate (NHP) models. Using the example of granulocyte counts in the peripheral blood following radiation exposure, approaches for adaptation between NHP and patient databases on data comparison and transformation are introduced. As a substitute for studying the effects of administration of granulocyte-colony stimulating factor (G-CSF) in human clinical trials, the method of mathematical modeling is suggested using the example of G-CSF administration to NHP after total body irradiation. C1 [Graessle, Dieter H.; Doerr, Harald; Meineke, Viktor] Univ Ulm, Bundeswehr Inst Radiobiol, Munich, Germany. [Bennett, Alexander; Farese, Ann M.; MacVittie, Thomas J.] Univ Maryland, Sch Med, Dept Radiat Oncol, Baltimore, MD 21201 USA. [Shapiro, Alla] US FDA, FDA CDER, Silver Spring, MD USA. RP Graessle, DH (reprint author), Ulmenweg 3, D-89428 Syrgenstein, Germany. EM dieter.graessle@arcor.de FU National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272201000046C] FX Contract Nr: HHSN272201000046C awarded to the University of Maryland, Baltimore (UMB) by National Institute of Allergy and Infectious Diseases (NIAID) for the project titled, "Radiation/Nuclear Medical Countermeasure Product Development Support Services." NR 17 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD NOV PY 2015 VL 109 IS 5 BP 493 EP 501 DI 10.1097/HP.0000000000000355 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA DC2VE UT WOS:000369075100013 PM 26425908 ER PT J AU Mindaye, ST Lo Surdo, J Bauer, SR Alterman, MA AF Mindaye, Samuel T. Lo Surdo, Jessica Bauer, Steven R. Alterman, Michail A. TI System-wide survey of proteomic responses of human bone marrow stromal cells (hBMSCs) to in vitro cultivation SO STEM CELL RESEARCH LA English DT Article ID MESENCHYMAL STEM-CELLS; CYCLIN D1 EXPRESSION; PYRUVATE-KINASE M2; OSTEOGENIC DIFFERENTIATION; CANCER-CELLS; REPLICATIVE SENESCENCE; UP-REGULATION; SELF-RENEWAL; PROLIFERATION; METABOLISM AB Human bone marrow stromal cells (hBMSCs, also loosely called bone marrow-derived mesenchymal stem cells) are the subject of increasing numbers of clinical trials and laboratory research. Our group recently reported on the optimization of a workflow for a sensitive proteomic study of hBMSCs. Here, we couple this workflow with a label-free protein quantitation method to investigate the molecular responses of hBMSCs to long-term in vitro passaging. We explored the proteomic responses of hBMSCs by assessing the expression levels of proteins at early passage (passage 3, P3) and late passage (P7). We used multiple biological as well as technical replicates to ensure that the detected proteomic changes are repeatable between cultures and thus likely to be biologically relevant Over 1700 proteins were quantified at three passages and a list of differentially expressed proteins was compiled. Bioinformatics-based network analysis and term enrichment revealed that metabolic pathways are largely altered, where many proteins in the glycolytic, pentose phosphate, and TCA pathways were shown to be largely upregulated in late passages. We also observed significant proteomic alterations in functional categories including apoptosis, and ER-based protein processing and sorting following in vitro cell aging. We posit that the comprehensive map outlined in this report of affected phenotypes as well as the underpinning molecular factors tremendously benefit the effort to uncovering targets that are not just used only to monitor cell fitness but can be employed to slowdown the in vitro aging process in hBMSCs and hence ensure manufacturing of cells with known quality, efficacy and stability. Published by Elsevier B.V. C1 [Mindaye, Samuel T.; Alterman, Michail A.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Lo Surdo, Jessica; Bauer, Steven R.] US FDA, Cellular & Tissue Therapies Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Alterman, MA (reprint author), US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD USA. EM Michail.Alterman@fda.hhs.gov NR 69 TC 1 Z9 1 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1873-5061 EI 1876-7753 J9 STEM CELL RES JI Stem Cell Res. PD NOV PY 2015 VL 15 IS 3 BP 655 EP 664 DI 10.1016/j.scr.2015.09.013 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA DC2GY UT WOS:000369036400027 PM 26523674 ER PT J AU Shokati, T Bodenberger, N Gadpaille, H Schniedewind, B Vinks, AA Jiang, WL Alloway, RR Christians, U AF Shokati, Touraj Bodenberger, Nicholas Gadpaille, Holly Schniedewind, Bjoern Vinks, Alexander A. Jiang, Wenlei Alloway, Rita R. Christians, Uwe TI Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Medicine; Issue 105; Tacrolimus; dried blood spots; high-performance liquid chromatography; tandem mass spectrometry; LC-MS/MS; column switching; online extraction; therapeutic drug monitoring; home monitoring; adherence monitoring ID TANDEM MASS-SPECTROMETRY; CYCLOSPORINE-A; ALLOGRAFT-REJECTION; TRANSPLANT RECIPIENTS; FK-506; SAMPLES; LIVER; FK506; STREPTOMYCES; VALIDATION AB The calcineurin inhibitor tacrolimus is the cornerstone of most immunosuppressive treatment protocols after solid organ transplantation in the United States. Tacrolimus is a narrow therapeutic index drug and as such requires therapeutic drug monitoring and dose adjustment based on its whole blood trough concentrations. To facilitate home therapeutic drug and adherence monitoring, the collection of dried blood spots is an attractive concept. After a finger stick, the patient collects a blood drop on filter paper at home. After the blood is dried, it is mailed to the analytical laboratory where tacrolimus is quantified using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) in combination with a simple manual protein precipitation step and online column extraction. For tacrolimus analysis, a 6-mm disc is punched from the saturated center of the blood spot. The blood spot is homogenized using a bullet blender and then proteins are precipitated with methanol/0.2 M ZnSO4 containing the internal standard D-2, C-13-tacrolimus. After vortexing and centrifugation, 100 mu l of supernatant is injected into an online extraction column and washed with 5 ml/min of 0.1 formic acid/acetonitrile (7: 3, v: v) for 1 min. Hereafter, the switching valve is activated and the analytes are back-flushed onto the analytical column (and separated using a 0.1% formic acid/acetonitrile gradient). Tacrolimus is quantified in the positive multi reaction mode (MRM) using a tandem mass spectrometer. The assay is linear from 1 to 50 ng/ml. Inter-assay variability (3.6%-6.1%) and accuracy (91.7%-101.6%) as assessed over 20 days meet acceptance criteria. Average extraction recovery is 95.5%. There are no relevant carry-over, matrix interferences and matrix effects. Tacrolimus is stable in dried blood spots at RT and at +4 degrees C for 1 week. Extracted samples in the autosampler are stable at +4 degrees C for at least 72 hr. C1 [Shokati, Touraj; Bodenberger, Nicholas; Gadpaille, Holly; Schniedewind, Bjoern; Christians, Uwe] Univ Colorado, Clin Res & Dev iC42, Anschutz Med Campus, Boulder, CO 80309 USA. [Vinks, Alexander A.] Cincinnati Childrens Hosp Med Ctr, Div Clin Pharmacol, Cincinnati, OH 45229 USA. [Jiang, Wenlei] US FDA, Ctr Drug Evaluat Res, Off Gener Drugs, Rockville, MD 20857 USA. [Alloway, Rita R.] Univ Cincinnati, Transplant Clin Res, Cincinnati, OH 45221 USA. RP Christians, U (reprint author), Univ Colorado, Clin Res & Dev iC42, Anschutz Med Campus, Boulder, CO 80309 USA. EM Uwe.Christians@ucdenver.edu FU United States Federal Drug Administration (FDA) [HHSF223201310224C]; United States National Institutes of Health/FDA [1U01FD004573-01] FX This work was supported by the United States Federal Drug Administration (FDA) contract HHSF223201310224C and the United States National Institutes of Health/FDA grant 1U01FD004573-01. NR 50 TC 1 Z9 1 U1 7 U2 11 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD NOV PY 2015 IS 105 AR e52424 DI 10.3791/52424 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB5SM UT WOS:000368573900007 PM 26575262 ER PT J AU Levin, VA Tonge, PJ Gallo, JM Birtwistle, MR Dar, AC Iavarone, A Paddison, PJ Heffron, TP Elmquist, WF Lachowicz, JE Johnson, TW White, FM Sul, J Smith, QR Shen, W Sarkaria, JN Samala, R Wen, PY Berry, DA Petter, RC AF Levin, Victor A. Tonge, Peter J. Gallo, James M. Birtwistle, Marc R. Dar, Arvin C. Iavarone, Antonio Paddison, Patrick J. Heffron, Timothy P. Elmquist, William F. Lachowicz, Jean E. Johnson, Ted W. White, Forest M. Sul, Joohee Smith, Quentin R. Shen, Wang Sarkaria, Jann N. Samala, Ramakrishna Wen, Patrick Y. Berry, Donald A. Petter, Russell C. TI CNS Anticancer Drug Discovery and Development Conference White Paper SO NEURO-ONCOLOGY LA English DT Article DE brain metastasis; chemotherapy; glioma; medulloblastoma; pharmacokinetics; pharmacology ID PHASE-II TRIAL; RECURRENT GLIOBLASTOMA-MULTIFORME; BRAIN-TUMOR CONSORTIUM; CENTRAL-NERVOUS-SYSTEM; HIGH-DOSE METHOTREXATE; CANCER-TREATMENT GROUP; HIGH-GRADE GLIOMAS; FRACTIONATION RADIATION-THERAPY; RADIOTHERAPY PLUS PROCARBAZINE; PROGRESSION-FREE SURVIVAL AB Following the first CNS Anticancer Drug Discovery and Development Conference, the speakers from the first 4 sessions and organizers of the conference created this White Paper hoping to stimulate more and better CNS anticancer drug discovery and development. The first part of the White Paper reviews, comments, and, in some cases, expands on the 4 session areas critical to new drug development: pharmacological challenges, recent drug approaches, drug targets and discovery, and clinical paths. Following this concise review of the science and clinical aspects of new CNS anticancer drug discovery and development, we discuss, under the rubric "Accelerating Drug Discovery and Development for Brain Tumors," further reasons why the pharmaceutical industry and academia have failed to develop new anticancer drugs for CNS malignancies and what it will take to change the current status quo and develop the drugs so desperately needed by our patients with malignant CNS tumors. While this White Paper is not a formal roadmap to that end, it should be an educational guide to clinicians and scientists to help move a stagnant field forward. C1 [Levin, Victor A.] Kaiser Permanente, Redwood City, CA USA. [Levin, Victor A.; Berry, Donald A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Levin, Victor A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Tonge, Peter J.] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Gallo, James M.; Birtwistle, Marc R.; Dar, Arvin C.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Iavarone, Antonio] Columbia Univ, Inst Canc Genet, New York, NY USA. [Paddison, Patrick J.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Heffron, Timothy P.] Genentech Inc, San Francisco, CA 94080 USA. [Elmquist, William F.] Univ Minnesota, Sch Pharm, Minneapolis, MN USA. [Lachowicz, Jean E.] Angiochem Inc, Montreal, PQ, Canada. [Johnson, Ted W.] Pfizer Oncol, San Diego, CA USA. [White, Forest M.] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Sul, Joohee] US FDA, Silver Spring, MD USA. [Smith, Quentin R.; Samala, Ramakrishna] Texas Tech Univ, Sch Pharm, Amarillo, TX USA. [Shen, Wang] NewGen Therapeut Inc, Menlo Pk, CA USA. [Sarkaria, Jann N.] Mayo Clin, Rochester, MN USA. [Wen, Patrick Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Petter, Russell C.] Celgene Avil Res, Bedford, MA USA. RP Levin, VA (reprint author), Kaiser Permanente, Redwood City, CA USA. EM vlevin11@gmail.com FU Genentech; American Brain Tumor Association; Society for Neuro-Oncology; Bristol-Myers Squibb; Celgene; Novartis FX This manuscript was the product of the first CNS Anticancer Drug Discovery and Development Conference, which was supported by Genentech (a member of the Roche Group), the American Brain Tumor Association, the Society for Neuro-Oncology, Bristol-Myers Squibb, Celgene, and Novartis. NR 201 TC 3 Z9 3 U1 0 U2 4 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 NOV PY 2015 VL 17 SU 6 BP 1 EP 26 DI 10.1093/neuonc/nov169 PG 26 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DB3OH UT WOS:000368420500001 ER PT J AU Rathore, AS Kumar Singh, S Pathak, M Read, EK Brorson, KA Agarabi, CD Khan, M AF Rathore, Anurag S. Kumar Singh, Sumit Pathak, Mili Read, Erik K. Brorson, Kurt A. Agarabi, Cyrus D. Khan, Mansoor TI Fermentanomics: Relating Quality Attributes of a Monoclonal Antibody to Cell Culture Process Variables and Raw Materials Using Multivariate Data Analysis SO BIOTECHNOLOGY PROGRESS LA English DT Article DE quality attributes; monoclonal antibody; cell culture media; chemometrics; multivariate analysis; multiway-PLS; batch modeling; amino acid supplementation; glycosylation ID HAMSTER OVARY CELLS; CHO-CELLS; DISSOLVED-OXYGEN; GLYCOSYLATION; BATCH; GLYCOPROTEINS; BIOPHARMACEUTICALS; OLIGOSACCHARIDES; ERYTHROPOIETIN; BIOTECHNOLOGY AB Fermentanomics is an emerging field of research and involves understanding the underlying controlled process variables and their effect on process yield and product quality. Although major advancements have occurred in process analytics over the past two decades, accurate real-time measurement of significant quality attributes for a biotech product during production culture is still not feasible. Researchers have used an amalgam of process models and analytical measurements for monitoring and process control during production. This article focuses on using multivariate data analysis as a tool for monitoring the internal bioreactor dynamics, the metabolic state of the cell, and interactions among them during culture. Quality attributes of the monoclonal antibody product that were monitored include glycosylation profile of the final product along with process attributes, such as viable cell density and level of antibody expression. These were related to process variables, raw materials components of the chemically defined hybridoma media, concentration of metabolites formed during the course of the culture, aeration-related parameters, and supplemented raw materials such as glucose, methionine, threonine, tryptophan, and tyrosine. This article demonstrates the utility of multivariate data analysis for correlating the product quality attributes (especially glycosylation) to process variables and raw materials (especially amino acid supplements in cell culture media). The proposed approach can be applied for process optimization to increase product expression, improve consistency of product quality, and target the desired quality attribute profile. (C) 2015 American Institute of Chemical Engineers C1 [Rathore, Anurag S.; Kumar Singh, Sumit; Pathak, Mili] Indian Inst Technol, Dept Chem Engn, New Delhi 110016, India. [Read, Erik K.; Brorson, Kurt A.] US FDA, Div Monoclonal Antibodies, Off Biotechnol Prod, Silver Spring, MD 20903 USA. [Agarabi, Cyrus D.; Khan, Mansoor] US FDA, Div Prod Qual Res, Off Testing & Res, Silver Spring, MD 20903 USA. RP Rathore, AS (reprint author), Indian Inst Technol, Dept Chem Engn, New Delhi 110016, India. EM asrathore@biotechcmz.com NR 46 TC 4 Z9 4 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8756-7938 EI 1520-6033 J9 BIOTECHNOL PROGR JI Biotechnol. Prog. PD NOV-DEC PY 2015 VL 31 IS 6 BP 1586 EP 1599 DI 10.1002/btpr.2155 PG 14 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA DA9OZ UT WOS:000368140300017 PM 26280800 ER PT J AU Yang, SJ Wang, SJ Ji, Y AF Yang, Shengjie Wang, Sue-Jane Ji, Yuan TI An integrated dose-finding tool for phase I trials in oncology SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE 3+3; Bayesian design; CRM; mTPI; Next-generation dose finding; Webtool ID CONTINUAL REASSESSMENT METHOD; CLINICAL-TRIALS; DESIGN; TOXICITY AB In the past 25 years, the 3 + 3 design has been the most popular approach for planning phase! dose-finding trials in oncology. During the same time period, major development of more efficient model-based designs has been made by statistical researchers aiming to improve the clinical practice of dose finding in oncology. Despite the effort, 3 + 3 is still the most frequently used designs in practice. Part of the reason is due to the lack of software tools that allow comparison of different designs, including 3 + 3 and other model-based methods, in a head-to-head and easy-to-use fashion. To this end, we introduce NextGen-DF, a next-generation tool for designing oncology dose-finding trials that allows for construction, comparison, and calibration of multiple designs via internet, in real time, and independent of computer operating systems. Through NextGen-DF, we present massive and user-generated comparison results based on over 4 million simulated trials, which clearly indicate the inferiority of 3 + 3. To our knowledge, the reported crowd-sourcing results are the largest and most objective comparison across major dose-finding methods to date. NextGen-DF is expected to improve patient care and drug development by providing safer and more efficient designs for phase I oncology trials. NextGen-DF is available at www.compgenome.org/NGDF. (C) 2015 Elsevier Inc. All rights reserved. C1 [Yang, Shengjie; Ji, Yuan] Northshore Univ HealthSyst, Program Computat Genom & Med, Chicago, IL USA. [Wang, Sue-Jane] US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Ji, Yuan] Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA. RP Ji, Y (reprint author), 1001 Univ Pl, Evanston, IL 60201 USA. EM koaeraser@gmail.com FU NIH [2R01 CA132897-06] FX Yuan Ji's research is partly supported by NIH 2R01 CA132897-06. NR 23 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD NOV PY 2015 VL 45 BP 426 EP 434 DI 10.1016/j.cct.2015.09.019 PN B PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DA4FJ UT WOS:000367755200040 PM 26419937 ER PT J AU Langley, G Austin, CP Balapure, AK Birnbaum, LS Bucher, JR Fentem, J Fitzpatrick, SC Fowle, JR Kavlock, RJ Kitano, H Lidbury, BA Muotri, AR Peng, SQ Sakharov, D Seidle, T Trez, T Tonevitsky, A van De Stolpe, A Whelan, M Willett, C AF Langley, Gill Austin, Christopher P. Balapure, Anil K. Birnbaum, Linda S. Bucher, John R. Fentem, Julia Fitzpatrick, Suzanne C. Fowle, John R. Kavlock, Robert J. Kitano, Hiroaki Lidbury, Brett A. Muotri, Alysson R. Peng, Shuang-Qing Sakharov, Dmitry Seidle, Troy Trez, Thales Tonevitsky, Alexander van de Stolpe, Anja Whelan, Maurice Willett, Catherine TI Lessons from Toxicology: Developing a 21st-Century Paradigm for Medical Research SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID PLURIPOTENT STEM-CELLS; ALZHEIMERS-DISEASE; MODELS; PATHWAYS; PROTEIN AB Biomedical developments in the 21st century provide an unprecedented opportunity to gain a dynamic systems-level and human-specific understanding of the causes and pathophysiologies of disease. This understanding is a vital need, in view of continuing failures in health research, drug discovery, and clinical translation. The full potential of advanced approaches may not be achieved within a 20th-century conceptual framework dominated by animal models. Novel technologies are being integrated into environmental health research and are also applicable to disease research, but these advances need a new medical research and drug discovery paradigm to gain maximal benefits. We suggest a new conceptual framework that repurposes the 21st-century transition underway in toxicology. Human disease should be conceived as resulting from integrated extrinsic and intrinsic causes, with research focused on modern human-specific models to understand disease pathways at multiple biological levels that are analogous to adverse outcome pathways in toxicology. Systems biology tools should be used to integrate and interpret data about disease causation and pathophysiology. Such an approach promises progress in overcoming the current roadblocks to understanding human disease and successful drug discovery and translation. A discourse should begin now to identify and consider the many challenges and questions that need to be solved. C1 [Langley, Gill] Humane Soc Int, Res & Toxicol Dept, London N1 7LY, England. [Austin, Christopher P.] NIH, Natl Ctr Adv Translat Sci, US Dept HHS, Bethesda, MD 20892 USA. [Balapure, Anil K.] CSIR Cent Drug Res Inst, Div Biochem, Lucknow, Uttar Pradesh, India. [Birnbaum, Linda S.] NIEHS, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NIH, NTP, DHHS, Res Triangle Pk, NC USA. [Bucher, John R.] NIEHS, Div NTP, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Fentem, Julia] Unilever R&D, SEAC, Sharnbrook, Beds, England. [Fitzpatrick, Suzanne C.] US FDA, Off Ctr Director, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. [Fowle, John R.] Sci Inform LLC, Pittsboro, NC USA. [Kavlock, Robert J.] US EPA, Off Res & Dev, Washington, DC 20460 USA. [Kitano, Hiroaki] Syst Biol Inst, Tokyo, Japan. [Lidbury, Brett A.] Australian Natl Univ, John Curtin Sch Med Res, Genom & Predict Med, Canberra, ACT 2601, Australia. [Muotri, Alysson R.] Univ Calif San Diego, Sch Med, Dept Pediat, Rady Childrens Hosp San Diego,Dept Cellular & Mol, La Jolla, CA 92093 USA. [Peng, Shuang-Qing] Acad Mil Med Sci, Inst Dis Control & Prevent, Evaluat & Res Ctr Toxicol, Beijing, Peoples R China. [Sakharov, Dmitry] Sci Res Ctr Bioclinicum, Moscow, Russia. [Seidle, Troy] Humane Soc Int, Res & Toxicol Dept, Montreal, PQ, Canada. [Trez, Thales] Univ Fed Alfenas, Inst Sci & Technol, Alfenas, Brazil. [Tonevitsky, Alexander] Natl Ctr Med Radiol Res, Obninsk, Russia. [van de Stolpe, Anja] Philips Res, Eindhoven, Netherlands. [Whelan, Maurice] Commiss European Communities, Joint Res Ctr, Inst Hlth & Consumer Protect, I-21020 Ispra, Italy. [Willett, Catherine] Humane Soc United States, Regulatory Toxicol Risk Assessment & Alternat, Washington, DC USA. RP Langley, G (reprint author), Humane Soc Int, 5 Underwood St, London N1 7LY, England. EM glangley@hsi.org OI Seidle, Troy/0000-0002-1341-2181; Tonevitsky, Alexander/0000-0002-7079-7145 NR 41 TC 11 Z9 12 U1 6 U2 9 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD NOV PY 2015 VL 123 IS 11 BP A268 EP A272 DI 10.1289/ehp.1510345 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DA1VW UT WOS:000367584600001 PM 26523530 ER PT J AU Goldberg, B Sichtig, H Geyer, C Ledeboer, N Weinstock, GM AF Goldberg, Brittany Sichtig, Heike Geyer, Chelsie Ledeboer, Nathan Weinstock, George M. TI Making the Leap from Research Laboratory to Clinic: Challenges and Opportunities for Next-Generation Sequencing in Infectious Disease Diagnostics SO MBIO LA English DT Review ID STAPHYLOCOCCUS-AUREUS; ESCHERICHIA-COLI; OUTBREAK; MICROBIOLOGY; ENCEPHALITIS; RESISTANCE; STANDARDS; STRAIN AB Next-generation DNA sequencing (NGS) has progressed enormously over the past decade, transforming genomic analysis and opening up many new opportunities for applications in clinical microbiology laboratories. The impact of NGS on microbiology has been revolutionary, with new microbial genomic sequences being generated daily, leading to the development of large databases of genomes and gene sequences. The ability to analyze microbial communities without culturing organisms has created the ever-growing field of metagenomics and microbiome analysis and has generated significant new insights into the relation between host and microbe. The medical literature contains many examples of how this new technology can be used for infectious disease diagnostics and pathogen analysis. The implementation of NGS in medical practice has been a slow process due to various challenges such as clinical trials, lack of applicable regulatory guidelines, and the adaptation of the technology to the clinical environment. In April 2015, the American Academy of Microbiology (AAM) convened a colloquium to begin to define these issues, and in this document, we present some of the concepts that were generated from these discussions. C1 [Goldberg, Brittany] Childrens Natl Med Ctr, Div Pediat Infect Dis, Washington, DC 20010 USA. [Sichtig, Heike] US FDA, Div Microbiol Devices, Off In Vitro Diagnost & Radiol Hlth, Silver Spring, MD USA. [Geyer, Chelsie] Amer Soc Microbiol, Washington, DC USA. [Ledeboer, Nathan] Med Coll Wisconsin, Dept Pathol, Milwaukee, WI 53226 USA. [Weinstock, George M.] Jackson Lab Genom Med, Farmington, CT 06032 USA. RP Weinstock, GM (reprint author), Jackson Lab Genom Med, Farmington, CT 06032 USA. EM George.Weinstock@jax.org NR 36 TC 15 Z9 16 U1 4 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2015 VL 6 IS 6 AR e01888-15 DI 10.1128/mBio.01888-15 PG 10 WC Microbiology SC Microbiology GA DA0YY UT WOS:000367524700056 PM 26646014 ER PT J AU Sahu, SC AF Sahu, Saura C. TI Nanotoxicology and Nanomedicine: A special issue of the Food and Chemical Toxicology SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Editorial Material C1 [Sahu, Saura C.] US FDA, Ctr Food Safety & Appl Nutr, Div Toxicol, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. RP Sahu, SC (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Toxicol, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. EM saura.sahu@fda.hhs.gov NR 0 TC 0 Z9 0 U1 2 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD NOV PY 2015 VL 85 BP 1 EP 1 DI 10.1016/j.fct.2015.07.014 PG 1 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA CZ2RC UT WOS:000366951300001 PM 26248127 ER PT J AU Sussman, EM Jayanti, P Dair, BJ Casey, BJ AF Sussman, Eric M. Jayanti, Priyanka Dair, Benita J. Casey, Brendan J. TI Assessment of total silver and silver nanoparticle extraction from medical devices SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Medical device; Silver nanoparticle; Extraction; Exposure assessment ID PLASMA-MASS SPECTROMETRY; IN-VIVO; INTRATRACHEAL INSTILLATION; NANO-SILVER; RELEASE; DRESSINGS; TOXICITY; VITRO; MECHANISMS; SUBSTRATE AB There is concern over the release of silver nanoparticles (AgNPs) from medical devices due to their potential toxicological consequences inside the body. Towards developing the exposure component of a risk assessment model, the purpose of this study was to determine the amount and physical form of silver released from medical devices. Scanning electron microscopy was used to confirm that three of five marketed medical devices contained nanosilver coatings (mean feature sizes 115-341 nm). Aqueous device extracts (water, saline and human plasma) were analyzed with inductively coupled plasma mass spectrometry, ultraviolet visible spectroscopy, dynamic light scattering, transmission electron microscopy, and nanoparticle tracking analysis. The amount of silver extracted from the devices ranged from 1 x 10(-1) to 1 x 10(6) ng/cm(2) (conditions ranged from 37 to 50 degrees C, over one hour to seven days). The results further indicated that one of the five devices (labeled MD1) released significantly more AgNPs than the other devices. This data suggests that some but not all devices that are formulated with nanosilver may release detectable levels of AgNPs upon extraction. Further work is underway to quantitate the proportion of silver released as AgNPs and to incorporate this data into a risk assessment for AgNP exposure from medical devices. Published by Elsevier Ltd. C1 [Sussman, Eric M.; Jayanti, Priyanka; Dair, Benita J.; Casey, Brendan J.] US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Biol Chem & Mat Sci, Silver Spring, MD 20993 USA. [Jayanti, Priyanka] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. RP Casey, BJ (reprint author), US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Biol Chem & Mat Sci, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM brendan.casey@fda.hhs.gov FU University of Maryland NanoCenter and its Nanoscale Imaging Spectroscopy and Properties Laboratory (NispLab) for FESEM imaging FX The authors would like to acknowledge the FDA White Oak Nanotechnology Core Facility for instrument use, scientific and technical assistance. Additionally, authors acknowledge the support of the University of Maryland NanoCenter and its Nanoscale Imaging Spectroscopy and Properties Laboratory (NispLab) for FESEM imaging. This project was supported in part by an appointment to the Research Participation Program administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 44 TC 7 Z9 7 U1 6 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD NOV PY 2015 VL 85 BP 10 EP 19 DI 10.1016/j.fct.2015.08.013 PG 10 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA CZ2RC UT WOS:000366951300003 PM 26282371 ER PT J AU Kumar, G Degheidy, H Casey, BJ Goering, PL AF Kumar, Girish Degheidy, Heba Casey, Brendan J. Goering, Peter L. TI Flow cytometry evaluation of in vitro cellular necrosis and apoptosis induced by silver nanoparticles SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Flow cytometry; Nanotoxicology; Silver nanoparticles; Cytotoxicity; Apoptosis ID CARBON NANOTUBES; DEATH; CELLS; TOXICITY; ASSAYS; LIGHT AB Particles possess unique properties in the nanoscale, e.g., enhanced catalytic activity, high surface area, and light emission/absorption properties, that might result in interference with calorimetric in vitro cytotoxicity assays such as MTT, XTT or MTS. Alternatively, assays that do not use spectrophotometric detection, such as trypan blue exclusion or flow cytometry (FC) based assays, are less likely to be influenced by nanoparticle interference. The aim of this study was to evaluate FC assays to assess the cytotoxicity of three different sizes (10, 100, or 200 nm) of silver nanoparticles (AgNPs) at different mass concentrations (1, 25, or 50 ug/ml) in L-929 fibroblast cells. After 4 h and 24 h exposure, cell necrosis and apoptosis were assessed using 7-AAD and Annexin V dyes, respectively, with FC. The data indicate that cell necrosis and apoptosis in AgNP-exposed fibroblasts depends on dose, exposure time, and AgNP size. The data indicate that AgNPs produced a dose- and time-dependent decrease in cell viability; however, 10 nm AgNPs were significantly more toxic than larger-sized particles. Thus, standard FC assays can be utilized to assess apoptosis and necrosis in response to nanomaterial exposure. Published by Elsevier Ltd. C1 [Kumar, Girish; Casey, Brendan J.; Goering, Peter L.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Degheidy, Heba] US FDA, Ctr Biol Evaluat & Res, Off Cellular Tissue & Gene Therapies, Silver Spring, MD 20993 USA. RP Goering, PL (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. EM Peter.Goering@fda.hhs.gov NR 25 TC 3 Z9 4 U1 4 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD NOV PY 2015 VL 85 BP 45 EP 51 DI 10.1016/j.fct.2015.06.012 PG 7 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA CZ2RC UT WOS:000366951300006 PM 26115599 ER PT J AU Katz, LM Dewan, K Bronaugh, RL AF Katz, Linda M. Dewan, Kapal Bronaugh, Robert L. TI Nanotechnology in cosmetics SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Nanomaterials; Cosmetics; Safety of nanomaterials in cosmetics; Skin absorption ID IN-VITRO; SKIN PENETRATION; TITANIUM-DIOXIDE; ZINC-OXIDE; SUNSCREEN FORMULATIONS; LIPID NANOPARTICLES; RIGID VESICLES; QUANTUM DOTS; INTACT SKIN; SIZE AB Nanomaterials are being used in cosmetic products for various effects. However, their use also raises potential safety concerns. Some of these concerns can be addressed by determining the type of nanomaterials used, as well as stability, potential for skin absorption, route of exposure, and how they are formulated in cosmetic products. There has been considerable effort internationally to harmonize approaches in order to address definitional issues and safety concerns related to the use of nanomaterials in cosmetic products. Published by Elsevier Ltd. C1 [Katz, Linda M.; Dewan, Kapal; Bronaugh, Robert L.] US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Dewan, K (reprint author), US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM Kapal.Dewan@fda.hhs.gov NR 41 TC 4 Z9 4 U1 14 U2 38 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD NOV PY 2015 VL 85 BP 127 EP 137 DI 10.1016/j.fct.2015.06.020 PG 11 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA CZ2RC UT WOS:000366951300016 PM 26159063 ER PT J AU Perez-Gonzalez, M Vu, N Harp, BP AF Perez-Gonzalez, Marianita Vu, Nga Harp, Bhakti Petigara TI Ultra-Performance Liquid Chromatographic Determination of Manufacturing Intermediates and Subsidiary Colors in D&C Red No. 6, D&C Red No. 7, and Their Lakes SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID 28 PHLOXINE-B; SOLID-PHASE MICROEXTRACTION; 1,3,6-PYRENETRISULFONIC ACID; MASS-SPECTROMETRY; TRISODIUM SALT; NOS. 27; FD; PRODUCTS; QUANTIFICATION; IDENTIFICATION AB An ultra-performance LC (UPLC) method was developed to determine the manufacturing intermediates and subsidiary colors in the monosulfo monoazo color additives D&C Red No. 6 and D&C Red No. 7 and their lakes. This method is intended for use in batch certification of the color additives by the U.S. Food and Drug Administration to ensure that each lot meets published specifications for coloring drugs and cosmetics. The intermediates are 2-amino-5-methylbenzenesulfonic acid (PTMS) and 3-hydroxy-2-naphthalenecarboxylic acid (3-hydroxy-2-naphthoic acid). The subsidiary colors are 3-hydroxy-4-[(4-methylphenyfiazo]-2-naphthalenecarboxylic acid (unsulfonated subsidiary color) and 1-[(4-methylphenyl) azo]-2-naphthalenol (4-methyl Sudan I). The analytes were identified by comparing their UPLC retention times and UV-Vis absorption spectra with those of standards. Validation studies showed that calibration curves were linear (average R-2 = 0.9994), and recoveries were 96-106%. Average LOD was 0.0014-0.0061% and average LOQ was 0.0047-0.020%. Results for RSD at the specification levels ranged from 0.67 to 5.79%. Survey analyses of 42 samples from 14 domestic and foreign manufacturers yielded results by the new UPLC method and a previously reported HPLC method that were consistent within experimental error. The new UPLC method provided increased sensitivity, faster analysis times, and improved separations compared to the HPLC method. C1 [Perez-Gonzalez, Marianita; Vu, Nga; Harp, Bhakti Petigara] US FDA, Off Cosmet & Colors, College Pk, MD 20740 USA. RP Harp, BP (reprint author), US FDA, Off Cosmet & Colors, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Bhakti.Petigara@fda.hhs.gov NR 27 TC 0 Z9 0 U1 0 U2 3 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 EI 1944-7922 J9 J AOAC INT JI J. AOAC Int. PD NOV-DEC PY 2015 VL 98 IS 6 BP 1752 EP 1759 DI 10.5740/jaoacint.15-125 PG 8 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA CZ6JH UT WOS:000367206700033 PM 26651589 ER PT J AU Hollerhage, M Rosler, TW Berjas, M Luo, RS Tran, K Richards, KM Sabaa-Srur, AU Maia, JGS de Moraes, MR Godoy, HT Hoglinger, GU Smith, RE AF Hoellerhage, Matthias Roesler, Thomas W. Berjas, Magda Luo, Rensheng Tran, Kevin Richards, Kristy M. Sabaa-Srur, Armando U. Maia, Jose Guilherme S. de Moraes, Maria Rosa Godoy, Helena T. Hoeglinger, Guenter U. Smith, Robert E. TI Neurotoxicity of Dietary Supplements from Annonaceae Species SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Article DE annonaceae; graviola; pawpaw; dietary supplements; neurotoxicity ID MITOCHONDRIAL COMPLEX-I; ATYPICAL PARKINSONISM; CANCER-CELLS; ALPHA-SYNUCLEIN; PAW PAW; ACETOGENINS; GUADELOUPE; INHIBITOR; APOPTOSIS; EXTRACT AB Dietary supplements containing plant materials of Annonaceae species (Annona muricata L., A. squamosa L., A. mucosa JACQ., A. squamosa x cherimola Mabb.) were extracted by hot, pressurized ethyl acetate and analyzed for their effect in vitro on Lund human mesencephalic neurons. Cell viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell death was determined by lactate dehydrogenase levels. Three supplements strongly decreased the cell viability at extract concentrations of 1 mu g/mL, of which 1 decreased cell viability at 0.1 mu g/mu L. Also, strong neuronal toxicities of these supplements were found. Cell death was observed at concentrations of 10 mu g/mL. The degree of toxicity was comparable to the ones found in Annonaceous fruit extracts. Two fruit pulps of Annonaceae (A. muricata and A. squamosa) showed a reduction in cell viability at lower concentrations. The fruit pulp extract of A. muricata revealed the strongest neurotoxic effect, with 67% cell death at a concentration of 1 mu g/mL. A high reduction in cell viability coupled with pronounced cell death was found at 0.1 mu g/mL for an Annonaceous seed extract. These results demonstrate that the intake of dietary supplements containing plant material from Annonaceae may be hazardous to health in terms of neurotoxicity. C1 [Hoellerhage, Matthias; Hoeglinger, Guenter U.] Tech Univ Munich, Dept Neurol, D-80290 Munich, Germany. [Hoellerhage, Matthias; Roesler, Thomas W.; Berjas, Magda; Hoeglinger, Guenter U.] German Ctr Neurodegenerat Dis DZNE, Munich, Germany. [Luo, Rensheng] Univ Missouri, St Louis, MO 63121 USA. [Tran, Kevin; Richards, Kristy M.] US FDA, Lenexa, KS 66214 USA. [Sabaa-Srur, Armando U.] Fed Rural Univ, Rio De Janeiro, Brazil. [Maia, Jose Guilherme S.] Univ Fed Oeste Para, Santarem, PA, Brazil. [de Moraes, Maria Rosa; Godoy, Helena T.] Univ Estadual Campinas, UNICAMP, Sao Paulo, Brazil. RP Smith, RE (reprint author), US FDA, 11510W 80th St, Lenexa, KS 66214 USA. EM robert.smith@fda.hhs.gov FU German Research Foundation (DFG) [HO2402/6-2]; CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico do Brasil); FAPERJ (Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro); FAPESPA (Fundacao de Amparo a Pesquisa do Estado do Para) FX We acknowledge support by the German Research Foundation (DFG, HO2402/6-2), the CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico do Brasil), FAPERJ (Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro), and FAPESPA (Fundacao de Amparo a Pesquisa do Estado do Para). NR 35 TC 2 Z9 2 U1 1 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD NOV-DEC PY 2015 VL 34 IS 6 BP 543 EP 550 DI 10.1177/1091581815602252 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CZ1HP UT WOS:000366857000007 PM 26405269 ER PT J AU Przepiorka, D Deisseroth, A Farrell, AT AF Przepiorka, Donna Deisseroth, Albert Farrell, Ann T. TI Acute Myeloid Leukemia Response Measures Other Than Complete Remission SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Przepiorka, Donna; Deisseroth, Albert; Farrell, Ann T.] US FDA, Silver Spring, MD 20993 USA. RP Przepiorka, D (reprint author), US FDA, Silver Spring, MD 20993 USA. NR 1 TC 2 Z9 2 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 1 PY 2015 VL 33 IS 31 BP 3675 EP + DI 10.1200/JCO.2015.62.0864 PG 2 WC Oncology SC Oncology GA CX9IU UT WOS:000366019800032 PM 26282653 ER PT J AU Hossen, V Solino, L Leroy, P David, E Velge, P Dragacci, S Krys, S Quintana, HF Diogene, J AF Hossen, Virginie Solino, Lucia Leroy, Patricia David, Eric Velge, Pierre Dragacci, Sylviane Krys, Sophie Quintana, Harold Flores Diogene, Jorge TI Contribution to the risk characterization of ciguatoxins: LOAEL estimated from eight ciguatera fish poisoning events in Guadeloupe (French West Indies) SO ENVIRONMENTAL RESEARCH LA English DT Article DE Ciguatera fish poisoning; Ciguatoxins; Mouse bioassay; Neuro-2A cell-based assay; LOAEL; Guadeloupe ID CARIBBEAN CIGUATOXINS; PACIFIC; TOXINS; CHEMISTRY; EXTRACTS; ISLANDS AB From 2010 to 2012, 35 ciguatera fish poisoning (CFP) events involving 87 individuals who consumed locally-caught fish were reported in Guadeloupe (French West Indies). For 12 of these events, the presence of ciguatoxins (CTXs) was indicated in meal remnants and in uncooked fish by the mouse bioassay (MBA). Caribbean ciguatoxins (C-CTXs) were confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Using a cell-based assay (CBA), and the only available standard Pacific ciguatoxin-1 (P-CTX-1), the lowest toxins level detected in fish samples causing CFP was 0.022 mu g P-CTX-1 equivalent (eq.).kg(-1) fish. Epidemiological and consumption data were compiled for most of the individuals afflicted, and complete data for establishing the lowest observable adverse effects level (LOAEL) were obtained from 8 CFP events involving 21 individuals. Based on toxin intakes, the LOAEL was estimated at 4.2 ng P-CTX-1 eq./individual corresponding to 48.4 pg P-CTX-1 eq. kg(-1) body weight (bw). Although based on limited data, these results are consistent with the conclusions of the European Food Safety Authority (EFSA) opinion which indicates that a level of 0.01 mu g P-CTX-1 eq. kg(-1) fish, regardless of source, should not exert effects in sensitive individuals when consuming a single meal. The calculated LOAEL is also consistent with the U.S. Food and Drug Administration guidance levels for CTXs (0.1 mu g C-CTX-1 eq. kg(-1) and 0.01 mu g P-CTX-1 eq. kg(-1) fish). (C) 2015 Elsevier Inc. All rights reserved. C1 [Hossen, Virginie; Leroy, Patricia; Dragacci, Sylviane; Krys, Sophie] Univ Paris Est, ANSES Lab Food Safety, Natl Reference Lab Control Marine biotoxins, F-94701 Maisons Alfort, France. [Solino, Lucia; Diogene, Jorge] IRTA, San Carlos de la Rapita, Spain. [David, Eric] Minist Agr, Direct Alimentat Agr & Foret Guadeloupe, Abymes, France. [Velge, Pierre] Minist Agr, Gen Directorate Food, Paris, France. [Quintana, Harold Flores] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. RP Dragacci, S (reprint author), Natl Reference Lab Control Marine Biotoxins, ANSES Lab Food Safety, 14 Rue Pierre & Marie Curie, F-94701 Maisons Alfort, France. EM Sylviane.dragacci@anses.fr FU European Union Seventh Framework Programme (FP7) under the ECsafeSEAFOOD project [311820] FX The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under the ECsafeSEAFOOD project (Grant agreement no. 311820). URV-IRTA-Banco de Santander also has delivered a PhD. Grant to Lucia Solino, one of the co-authors. NR 30 TC 2 Z9 2 U1 6 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD NOV PY 2015 VL 143 SI SI BP 100 EP 108 DI 10.1016/j.envres.2015.09.014 PN B PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA CX8CX UT WOS:000365931300013 PM 26409497 ER PT J AU Larkins, E Scepura, B Blumenthal, GM Bloomquist, E Tang, SH Biable, M Kluetz, P Keegan, P Pazdur, R AF Larkins, Erin Scepura, Barbara Blumenthal, Gideon M. Bloomquist, Erik Tang, Shenghui Biable, Missiratch Kluetz, Paul Keegan, Patricia Pazdur, Richard TI US Food and Drug Administration Approval Summary: Ramucirumab for the Treatment of Metastatic Non-Small Cell Lung Cancer Following Disease Progression On or After Platinum-Based Chemotherapy SO ONCOLOGIST LA English DT Article DE Ramucirumab; Non-small cell lung cancer; FDA; Vascular endothelial growth factor; VEGFR-2 ID PHASE-III TRIAL; ELDERLY-PATIENTS; BEVACIZUMAB; CARBOPLATIN; PACLITAXEL; DOCETAXEL; SELECTION; EFFICACY; AFFINITY; SAFETY AB On December 12, 2014, the U.S. Food and Drug Administration (FDA) approved ramucirumab for use in combination with docetaxel for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab. This approval was based on an improvement in overall survival (OS) with an acceptable toxicity profile in a randomized, multicenter, double-blinded, placebo-controlled trial of 1,253 patients with metastatic NSCLC previously treated with a platinum-based combination therapy. Patients were randomized 1:1 to receive either ramucirumab in combination with docetaxel or placebo in combination with docetaxel. The primary endpoint was OS. Patients who received ramucirumab in combination with docetaxel had improved OS (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.75, 0.98). Median OS was 10.5 months on the ramucirumab plus docetaxel arm versus 9.1 months on the placebo plus docetaxel arm. The most frequent (>= 30%) adverse reactions in ramucirumab treated patients were fatigue, neutropenia, and diarrhea. The most frequent (>= 5%) grade 3 and 4 adverse reactions in the ramucirumab arm were fatigue, neutropenia, febrile neutropenia, leukopenia, and hypertension. C1 [Larkins, Erin; Scepura, Barbara; Blumenthal, Gideon M.; Bloomquist, Erik; Tang, Shenghui; Biable, Missiratch; Kluetz, Paul; Keegan, Patricia; Pazdur, Richard] US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Larkins, E (reprint author), US FDA, White Oak Campus,10903 New Hampshire Ave,Bldg 22, Silver Spring, MD 20993 USA. EM erin.larkins@fda.hhs.gov NR 20 TC 3 Z9 4 U1 0 U2 4 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD NOV PY 2015 VL 20 IS 11 BP 1320 EP 1325 DI 10.1634/theoncologist.2015-0221 PG 6 WC Oncology SC Oncology GA CX9RS UT WOS:000366043600016 PM 26446239 ER PT J AU Berrier, KL Kazi, ZB Prater, SN Bali, DS Goldstein, J Stefanescu, MC Rehder, CW Botha, EG Ellaway, C Bhattacharya, K Tylki-Szymanska, A Karabul, N Rosenburg, AS Kishnani, PS AF Berrier, Kathryn L. Kazi, Zoheb B. Prater, Sean N. Bali, Deeksha S. Goldstein, Jennifer Stefanescu, Mihaela C. Rehder, Catherine W. Botha, Eleanor G. Ellaway, Carolyn Bhattacharya, Kaustuv Tylki-Szymanska, Anna Karabul, Nesrin Rosenburg, Amy S. Kishnani, Priya S. TI CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy SO GENETICS IN MEDICINE LA English DT Article DE alglucosidase alfa; antibodies; enzyme replacement therapy; immune tolerance; Pompe disease ID ENZYME REPLACEMENT THERAPY; SATISFACTORY CLINICAL-OUTCOMES; ACID ALPHA-GLUCOSIDASE; ALGLUCOSIDASE ALPHA; ANTIBODIES; CHILDREN AB Purpose: Enzyme replacement therapy (ERT) with recombinant human acid a-glucosidase (rhGAA) prolongs survival in infantile Pompe disease (IPD). However, the majority of cross-reactive immunologic material (CRIM)-negative (CN) patients have immune responses with significant clinical decline despite continued ERT. We aimed to characterize immune responses in CN patients with IPD receiving ERT monotherapy. Methods: A chart review identified 20 CN patients with IPD treated with ERT monotherapy for >= 6 months. Patients were stratified by anti-rhGAA antibody titers: high sustained antibody titers (HSAT; >= 51,200) at least twice; low titers (LT; <6,400) throughout treatment; or sustained intermediate titers (SIT; 6,400-25,600). Results: Despite early initiation of treatment, the majority (85%) of CN patients developed significant antibody titers, most with HSAT associated with invasive ventilation and death. Nearly all patients with HSAT had at least one nonsense GAA mutation, whereas the LT group exclusively carried splice-site or frameshift mutations. Only one patient in the HSAT group is currently alive after successful immune modulation in the entrenched setting. Conclusion: Immunological responses are a significant risk in CN IPD; thus induction of immune tolerance in the naive setting should strongly be considered. Further exploration of factors influencing immune responses is required, particularly with the advent of newborn screening for Pompe disease. C1 [Berrier, Kathryn L.; Kazi, Zoheb B.; Prater, Sean N.; Bali, Deeksha S.; Goldstein, Jennifer; Stefanescu, Mihaela C.; Kishnani, Priya S.] Duke Univ, Med Ctr, Dept Pediat, Div Med Genet, Durham, NC 27710 USA. [Rehder, Catherine W.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Botha, Eleanor G.] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. [Ellaway, Carolyn; Bhattacharya, Kaustuv] Childrens Hosp Westmead, Western Sydney Genet Program, Sydney, NSW, Australia. [Tylki-Szymanska, Anna] Childrens Mem Hlth Inst, Dept Pediat Nutr & Metab Dis, Warsaw, Poland. [Karabul, Nesrin] Univ Med Ctr, Ctr Pediat & Adolescent Med, Mainz, Germany. [Rosenburg, Amy S.] US FDA, Ctr Drug Evaluat & Res, Div Therapeut Prot, Silver Spring, MD USA. RP Kishnani, PS (reprint author), Duke Univ, Med Ctr, Dept Pediat, Div Med Genet, Durham, NC 27710 USA. EM priya.kishnani@duke.edu OI Berrier, Kathryn/0000-0003-3510-6836; Kazi, Zoheb/0000-0002-0447-2764 FU Genzyme Corporation; Sanofi Company (Cambridge, MA); Lysosomal Disease Network, a part of National Institutes of Health (NIH) Rare Diseases Clinical Research Network (RDCRN); NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS) [U54NS065768]; National Institute of Neurological Disorders and Stroke (NINDS) [U54NS065768]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U54NS065768] FX This research was supported by a grant from the Genzyme Corporation, a Sanofi Company (Cambridge, MA), and in part by the Lysosomal Disease Network, a part of National Institutes of Health (NIH) Rare Diseases Clinical Research Network (RDCRN). The Lysosomal Disease Network (U54NS065768) is supported through collaboration between the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS), the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The authors are grateful to the patients and their families who participated in this study. They thank Jian Dai for providing western blot results and the local physicians and clinical care team for their collaboration, including Stephanie DeArmey, David Viskochil, Jennifer Propst, Virginia Proud, and Mary-Alice Abbott. NR 20 TC 5 Z9 5 U1 1 U2 4 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 NOV PY 2015 VL 17 IS 11 BP 912 EP 918 DI 10.1038/gim.2015.6 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA CX8TL UT WOS:000365977000011 PM 25741864 ER PT J AU Toro, M Rump, LV Cao, G Meng, J Brown, EW Gonzalez-Escalona, N AF Toro, M. Rump, L. V. Cao, G. Meng, J. Brown, E. W. Gonzalez-Escalona, N. TI Simultaneous Presence of Insertion Sequence Excision Enhancer and Insertion Sequence IS629 Correlates with Increased Diversity and Virulence in Shiga Toxin-Producing Escherichia coli SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID STEPWISE EVOLUTIONARY MODEL; COMPLETE GENOME SEQUENCE; O157-H7; INFECTIONS; OUTBREAK; TRANSPOSITION; PREVALENCE; STRAINS; EMERGENCE; O157/H7 AB Although new serotypes of enterohemorrhagic Escherichia coli (EHEC) emerge constantly, the mechanisms by which these new pathogens arise and the reasons emerging serotypes tend to carry more virulence genes than other E. coli are not understood. An insertion sequence (IS) excision enhancer (IEE) was discovered in EHEC O157:H7 that promoted the excision of IS3 family members and generating various genomic deletions. One IS3 family member, IS629, actively transposes and proliferates in EHEC O157: H7 and enterotoxigenic E. coli (ETEC) O139 and O149. The simultaneous presence of the IEE and IS629 (and other IS3 family members) may be part of a system promoting not only adaptation and genome diversification in E. coli O157: H7 but also contributing to the development of pathogenicity among predominant serotypes. Prevalence comparisons of these elements in 461 strains, representing 72 different serotypes and 5 preassigned seropathotypes (SPT) A to E, showed that the presence of these two elements simultaneously was serotype specific and associated with highly pathogenic serotypes (O157 and top non-O157 Shiga toxin-producing Escherichia coli [STEC]) implicated in outbreaks and sporadic cases of human illness (SPT A and B). Serotypes lacking one or both elements were less likely to have been isolated from clinical cases. Our comparisons of IEE sequences showed sequence variations that could be divided into at least three clusters. Interestingly, the IEE sequences from O157 and the top 10 non-O157 STEC serotypes fell into clusters I and II, while less commonly isolated serotypes O5 and O174 fell into cluster III. These results suggest that IS629 and IEE elements may be acting synergistically to promote genome plasticity and genetic diversity among STEC strains, enhancing their abilities to adapt to hostile environments and rapidly take up virulence factors. C1 [Toro, M.; Rump, L. V.; Cao, G.; Meng, J.] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Cao, G.; Meng, J.] US FDA, Joint Inst Food Safety & Appl Nutr, College Pk, MD USA. [Brown, E. W.; Gonzalez-Escalona, N.] US FDA, Div Microbiol, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Gonzalez-Escalona, N (reprint author), US FDA, Div Microbiol, Ctr Food Safety & Appl Nutr, College Pk, MD USA. EM narjol.gonzalez-escalona@fda.hhs.gov RI Toro, Magaly/F-6525-2011; OI Toro, Magaly/0000-0002-6280-2215; Gonzalez-Escalona, Narjol/0000-0003-4568-0022 FU FDA Foods Program Intramural Funds; ORISE fellowship program FX The study was supported by the FDA Foods Program Intramural Funds and the ORISE fellowship program. NR 47 TC 2 Z9 2 U1 0 U2 6 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 NOV PY 2015 VL 53 IS 11 BP 3466 EP 3473 DI 10.1128/JCM.01349-15 PG 8 WC Microbiology SC Microbiology GA CX3UY UT WOS:000365626200014 PM 26292302 ER PT J AU Rappaport, BA Suresh, S Hertz, S Evers, AS Orser, BA AF Rappaport, B. A. Suresh, S. Hertz, S. Evers, A. S. Orser, B. A. TI Re: Anesthetic Neurotoxicity-Clinical Implications of Animal Models SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Rappaport, B. A.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. Northwestern Univ Feinberg, Sch Med, Chicago, IL USA. Washington Univ, Sch Med, St Louis, MO USA. Univ Toronto, Dept Anesthesia & Physiol, Toronto, ON, Canada. RP Rappaport, BA (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. NR 0 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD NOV PY 2015 VL 194 IS 5 BP 1425 EP 1425 DI 10.1016/j.juro.2015.08.024 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA CX9FT UT WOS:000366011100005 ER PT J AU Echbarthi, M Zonca, M Mellwig, R Schwab, Y Kaplan, G DeKruyff, RH Roda-Navarro, P Casasnovas, JM AF Echbarthi, Meriem Zonca, Manuela Mellwig, Rachel Schwab, Yannick Kaplan, Gerardo DeKruyff, Rosemarie H. Roda-Navarro, Pedro Casasnovas, Jose M. TI Distinct Trafficking of Cell Surface and Endosomal TIM-1 to the Immune Synapse SO TRAFFIC LA English DT Article DE immune synapse; microscopy; protein sorting; structural immunology; T-cell; TIM family ID HEPATITIS-A VIRUS; APOPTOTIC CELLS; T-CELLS; PHOSPHATIDYLSERINE RECEPTOR; IMMUNOLOGICAL SYNAPSE; ACTIVATION; IDENTIFICATION; FAMILY; DOMAIN; IG AB The T-cell/transmembrane, mucin and immunoglobulin domain protein 1 (TIM-1) is a phosphatidlyserine (PtdSer) receptor and a T-cell costimulatory molecule linked to the development of atopic diseases. TIM-1 locates preferentially in intracellular compartments. Here we show that in human and mouse lymphoid cells, TIM-1 localizes in different types of endosomes and that its domain structure is important for protein sorting to intracellular vesicles. The BALB/c mouse TIM-1 protein, which has a longer mucin domain, is sorted more efficiently to endosomes than the shorter C57BL/6 variant. High affinity ligands such as PtdSer increase the amount of cell surface TIM-1; the protein also polarizes toward cell contacts with apoptotic cells. The large pool of intracellular TIM-1 translocates to the immune synapse (IS) with the CD3-TCR (T-cell receptor) complex and colocalizes to the central supramolecular activation cluster (cSMAC). In contrast, cell surface TIM-1 does not traffic to the IS, but is located away from it. The bipolar TIM-1 sorting observed during IS formation is determined by differences in its subcellular location, and might modulate antigen-driven immune responses. C1 [Echbarthi, Meriem; Zonca, Manuela; Casasnovas, Jose M.] CNB CSIC, Macromol Struct, Ctr Nacl Biotecnol, Madrid 28049, Spain. [Mellwig, Rachel; Schwab, Yannick] EMBL Heidelberg, D-69117 Heidelberg, Germany. [Kaplan, Gerardo] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [DeKruyff, Rosemarie H.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Roda-Navarro, Pedro] Univ Complutense, Sch Med, Dept Immunol, Octubre Hlth Res Inst 12, E-28040 Madrid, Spain. RP Casasnovas, JM (reprint author), CNB CSIC, Macromol Struct, Ctr Nacl Biotecnol, Madrid 28049, Spain. EM jcasasnovas@cnb.csic.es RI Casasnovas, Jose/L-6299-2014; OI Casasnovas, Jose/0000-0002-2873-6410; Schwab, Yannick/0000-0001-8027-1836 FU Spanish Ministry of Sciences; Ramon y Cajal program [RYC-2011-08664]; US National Institutes of Health [P01AI054456] FX We thank I. Merida and F. Sanchez-Madrid for materials, S. Gutierrez for confocal services, the CNB cytometry unit and C. Mark for editorial assistance. M. E. received a FPI fellowship from the Spanish Ministry of Sciences. P. R. N. is supported by the Ramon y Cajal program (RYC-2011-08664). This research was supported by a grant from the US National Institutes of Health (P01AI054456 to J. M. C., R. D. K. and G. K.). NR 42 TC 0 Z9 0 U1 2 U2 6 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 NOV PY 2015 VL 16 IS 11 BP 1193 EP 1207 DI 10.1111/tra.12329 PG 15 WC Cell Biology SC Cell Biology GA CX0UB UT WOS:000365411300004 PM 26332704 ER PT J AU Anez, G Jiang, Z Heisey, DAR Kerby, S Rios, M AF Anez, G. Jiang, Z. Heisey, D. A. R. Kerby, S. Rios, M. CA Chikungunya Virus Collaborative St TI Collaborative study for the characterization of a chikungunya virus RNA reference reagent for use in nucleic acid testing SO VOX SANGUINIS LA English DT Article DE chikungunya virus; nucleic acid amplification tests; reference standards ID PHOTOCHEMICAL INACTIVATION; INTERNATIONAL STANDARD; AMERICA; EPIDEMIC; SYSTEM; ASSAYS; FEVER; RISK AB Background and Objectives Infections with the mosquito-borne chikungunya virus (CHIKV) can cause febrile illness or be asymptomatic. Laboratory diagnosis of CHIKV is often made with laboratory-developed nucleic acid amplification technology (NAT) assays because there are no U.S. Food and Drug Administration (FDA)-approved diagnostic or blood screening assays. We aimed to produce a well-characterized CHIKV RNA reference reagent (CHIKV-RR) for use in NAT assays. Materials and Methods A CHIKV RNA-RR consisting of cell culture-grown, heat-inactivated CHIKV diluted in human plasma was assessed by 8 laboratories in a collaborative study. The participants were asked to test the CHIKV-RR using their NAT assay(s) by qualitative testing (determination of RNA end-point by testing log and half-log dilutions followed by calculation of estimated NAT-detectable units/ml, after adjustment for the sample volume used for testing), and by quantitative testing, when available. Results Results from the testing showed that the CHIKV-RR had an estimated overall mean of 7.56 log(10) detectable units/ml, ranging from 6.2 log(10) to 8.6 log(10). Conclusions The Center for Biologics for Evaluation and Research/FDA CHIKV RNA-RR for NAT was established with a concentration of 7.56 log(10) detectable units/ml. C1 [Anez, G.; Heisey, D. A. R.; Kerby, S.; Rios, M.] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Jiang, Z.] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Rios, M (reprint author), 10903 New Hampshire Ave,Bldg 52-72,Room 5308, Silver Spring, MD 20993 USA. EM maria.rios@fda.hhs.gov OI Anez, German/0000-0001-5361-3001; Zink, Steven/0000-0002-3271-0192; Langsjoen, Rose/0000-0001-9008-425X FU U.S. Food and Drug Administration, Center for Biologics Evaluation and Research; FDA Medical Countermeasures Initiative (MCMi) FX This project was internally funded by the U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, and by the FDA Medical Countermeasures Initiative (MCMi). NR 26 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0042-9007 EI 1423-0410 J9 VOX SANG JI Vox Sang. PD NOV PY 2015 VL 109 IS 4 BP 312 EP 318 DI 10.1111/vox.12297 PG 7 WC Hematology SC Hematology GA CX0UU UT WOS:000365413400002 PM 26014282 ER PT J AU Verrill, L Bruns, R Luccioli, S AF Verrill, Linda Bruns, Richard Luccioli, Stefano TI Prevalence of self-reported food allergy in US adults: 2001, 2006, and 2010 SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article ID QUALITY-OF-LIFE; DIAL TELEPHONE SURVEY; TREE NUT ALLERGY; UNITED-STATES; NATIONAL-HEALTH; PEANUT ALLERGY; RISK-FACTORS; ANAPHYLAXIS; EPIDEMIOLOGY; CHILDREN AB Background: Epidemiologic evidence indicates that food allergies are increasing in the population. Information on a change in self-reported food allergy (srFA) in adults over time is lacking. Objective: To report the prevalence of srFA and compare differences at three time points over a decade. Methods: We analyzed srFA and reported physician-diagnosed food allergy in >4000 U.S. adults who participated in the 2010 U.S. Food and Drug Administration Food Safety Survey. Information on causative food(s), reaction severity characteristics, and various diagnostic factors was also analyzed. We compared 2010 Food Safety Survey data with 2006 and 2001 data, and highlighted relevant differences. Results: SrFA prevalence increased significantly, to 13% in 2010 and 14.9% in 2006 compared with 9.1% in 2001 (p < 0.001). Physician diagnosed food allergy was 6.5% in 2010, which was not significantly different compared with 7.6% in 2006 and 5.3% in 2001. SrFA increased in both men and women, non-Hispanic white and black adults, 50-59 year olds, and in adults with a high school or lower education. In 2010, milk, shellfish, and fruits were the most commonly reported food allergens, similar to 2001. Also, in 2010, 15% of reactions reportedly required a hospital visit and 8.4% were treated with epinephrine. Minor differences in reaction severity characteristics were noted among the surveys. Conclusions: Analysis of survey results indicates that the prevalence of srFA increased among U.S. adults from 2001 to 2010 and that adults are increasingly self-reporting FAs without obtaining medical diagnosis. Improved education about food allergies is needed for this risk group. C1 [Verrill, Linda] US FDA, Ctr Food Safety & Appl Nutr, Div Publ Hlth Informat & Analyt, Consumer Studies Branch, College Pk, MD 20740 USA. [Bruns, Richard] US FDA, Off Commissioner, Off Policy Planning Legislat & Anal, Off Planning, College Pk, MD 20740 USA. [Luccioli, Stefano] US FDA, Ctr Food Safety & Appl Nutr, Off Food Addit Safety, College Pk, MD 20740 USA. RP Verrill, L (reprint author), US FDA, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM linda.verrill@fda.hhs.gov FU U.S. Food and Drug Administration FX The research was funded by the U.S. Food and Drug Administration NR 42 TC 8 Z9 8 U1 4 U2 14 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 EI 1539-6304 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD NOV-DEC PY 2015 VL 36 IS 6 BP 458 EP 467 DI 10.2500/aap.2015.36.3895 PG 10 WC Allergy SC Allergy GA CW4VE UT WOS:000364993900013 PM 26453524 ER PT J AU Rogstad, S Pang, E Sommers, C Hu, M Jiang, XH Keire, DA Boyne, MT AF Rogstad, Sarah Pang, Eric Sommers, Cynthia Hu, Meng Jiang, Xiaohui Keire, David A. Boyne, Michael T., II TI Modern analytics for synthetically derived complex drug substances: NMR, AFFF-MALS, and MS tests for glatiramer acetate SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Glatiramer acetate; Mass spectrometry; Nuclear magnetic resonance; Asymmetric field flow fractionation with multi-angle light scattering ID REMITTING MULTIPLE-SCLEROSIS; PRINCIPAL-COMPONENTS; MOLECULAR-WEIGHT; CHEMICAL-SHIFTS; MECHANISMS; PROTIRAMER; SAFETY AB Glatiramer acetate (GA) is a mixture of synthetic copolymers consisting of four amino acids (glutamic acid, lysine, alanine, and tyrosine) with a labeled molecular weight range of 5000 to 9000 Da. GA is marketed as Copaxone (TM) by Teva for the treatment of multiple sclerosis. Here, the agency has evaluated the structure and composition of GA and a commercially available comparator, Copolymer-1. Modern analytical technologies which can characterize these complex mixtures are desirable for analysis of their comparability and structural "sameness." In the studies herein, a molecular fingerprinting approach is taken using mass-accurate mass spectrometry (MS) analysis, nuclear magnetic resonance (NMR) (1D-H-1-NMR, 1D-C-13-NMR, and 2D NMR), and asymmetric field flow fractionation (AFFF) coupled with multi-angle light scattering (MALS) for an in-depth characterization of three lots of the marketplace drug and a formulated sample of the comparator. Statistical analyses were applied to the MS and AFFF-MALS data to assess these methods' ability to detect analytical differences in the mixtures. The combination of multiple orthogonal measurements by liquid chromatography coupled with MS (LC-MS), AFFF-MALS, and NMR on the same sample set was found to be fit for the intended purpose of distinguishing analytical differences between these complex mixtures of peptide chains. C1 [Rogstad, Sarah; Pang, Eric; Sommers, Cynthia; Keire, David A.; Boyne, Michael T., II] US FDA, Div Pharmaceut Anal, Off Testing & Res, Ctr Drug Evaluat & Res, St Louis, MO 63110 USA. [Hu, Meng; Jiang, Xiaohui] US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Keire, DA (reprint author), US FDA, Div Pharmaceut Anal, Off Testing & Res, Ctr Drug Evaluat & Res, 645 S Newstead Ave, St Louis, MO 63110 USA. EM david.keire@fda.hhs.gov FU CDER Critical Path Program FX Funding and support for this work was provided by the CDER Critical Path Program and is gratefully acknowledged. NR 23 TC 3 Z9 3 U1 5 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 NOV PY 2015 VL 407 IS 29 BP 8647 EP 8659 DI 10.1007/s00216-015-9057-8 PG 13 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CW7HS UT WOS:000365169500002 PM 26458562 ER PT J AU Keire, D Mulloy, B Chase, C Al-Hakim, A Cairatti, D Gray, E Hogwood, J Morris, T Mourao, PAS Soares, MDC Szajek, A AF Keire, David Mulloy, Barbara Chase, Christina Al-Hakim, Ali Cairatti, Damian Gray, Elaine Hogwood, John Morris, Tina Mourao, Paulo A. S. Soares, Monica da Luz Carvalho Szajek, Anita TI Diversifying the Global Heparin Supply Chain: Reintroduction of Bovine Heparin in the United States? SO BIOPHARM INTERNATIONAL LA English DT Article ID ANTIBODIES; SURGERY C1 [Keire, David] US FDA, Div Pharmaceut Anal, Branch 1, Rockville, MD 20857 USA. [Al-Hakim, Ali] US FDA, Div New Drug API, Rockville, MD 20857 USA. [Mourao, Paulo A. S.] Univ Fed Rio de Janeiro, BR-21941 Rio De Janeiro, Brazil. RP Keire, D (reprint author), US FDA, Div Pharmaceut Anal, Branch 1, Rockville, MD 20857 USA. NR 17 TC 1 Z9 1 U1 2 U2 5 PU ADVANSTAR COMMUNICATIONS INC PI DULUTH PA 131 W 1ST STREET, DULUTH, MN 55802 USA SN 1542-166X EI 1939-1862 J9 BIOPHARM INT JI Biopharm. Int. PD NOV PY 2015 VL 28 IS 11 BP 36 EP 42 PG 7 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA CX1NQ UT WOS:000365463300008 ER PT J AU Eitan, E Hutchison, ER Greig, NH Tweedie, D Celik, H Ghosh, S Fishbein, KW Spencer, RG Sasaki, CY Ghosh, P Das, S Chigurapati, S Raymick, J Sarkar, S Chigurupati, S Seal, S Mattson, MP AF Eitan, Erez Hutchison, Emmette R. Greig, Nigel H. Tweedie, David Celik, Hasan Ghosh, Soumita Fishbein, Kenneth W. Spencer, Richard G. Sasaki, Carl Y. Ghosh, Paritosh Das, Soumen Chigurapati, Susheela Raymick, James Sarkar, Sumit Chigurupati, Srinivasulu Seal, Sudipta Mattson, Mark P. TI Combination therapy with lenalidomide and nanoceria ameliorates CNS autoimmunity SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Cerebral ventricles; Cerium oxide nanoparticles; Demyelination; EAE; Multiple sclerosis ID CERIUM OXIDE NANOPARTICLES; PROGRESSIVE MULTIPLE-SCLEROSIS; GLATIRAMER ACETATE; MOUSE MODEL; THALIDOMIDE; ENCEPHALOMYELITIS; MECHANISM; DISEASE; NEURODEGENERATION; DEMYELINATION AB Objective: Multiple sclerosis (MS) is a debilitating neurological disorder involving an autoimmune reaction to oligodendrocytes and degeneration of the axons they ensheath in the CNS. Because the damage to oligodendrocytes and axons involves local inflammation and associated oxidative stress, we tested the therapeutic efficacy of combined treatment with a potent anti-inflammatory thalidomide analog (lenalidomide) and novel synthetic anti-oxidant cerium oxide nanoparticles (nanoceria) in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Methods: C57BL/6 mice were randomly assigned to a control (no EAE) group, or one of the four myelin oligodendrocyte glycoprotein-induced EAE groups: vehicle, lenalidomide, nanoceria, or lenalidomide plus nanoceria. During a 23 day period, clinical EAE symptoms were evaluated daily, and MRI brain scans were performed at 11-13 days and 20-22 days. Histological and biochemical analyses of brain tissue samples were performed to quantify myelin loss and local inflammation. Results: Lenalidomide treatment alone delayed symptom onset, while nanoceria treatment had no effect on symptom onset or severity, but did promote recovery; lenalidomide and nanoceria each significantly attenuated white matter pathology and associated inflammation. Combined treatment with lenalidomide and nanoceria resulted in a near elimination of EAE symptoms, and reduced white matter pathology and inflammatory cell responses to a much greater extent than either treatment alone. Interpretation: By suppressing inflammation and oxidative stress, combined treatment with lenalidomide and nanoceria can reduce demyelination and associated neurological symptoms in EAE mice. Our preclinical data suggest a potential application of this combination therapy in MS. Published by Elsevier Inc. C1 [Eitan, Erez; Hutchison, Emmette R.; Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Greig, Nigel H.; Tweedie, David] NIA, Translat Gerontol Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Celik, Hasan; Ghosh, Soumita; Fishbein, Kenneth W.; Spencer, Richard G.] NIA, Lab Clin Invest, Intramural Res Program, Baltimore, MD 21224 USA. [Das, Soumen] Univ Cent Florida, Mat Sci & Engn Coll Med, Orlando, FL 32816 USA. [Sasaki, Carl Y.; Ghosh, Paritosh] NIA, Immunol Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Chigurapati, Susheela] US FDA, Arkansas Reg Lab, Off Regulatory Affairs, Jefferson, AR 72079 USA. [Raymick, James; Sarkar, Sumit; Chigurupati, Srinivasulu] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Seal, Sudipta] Univ Cent Florida, Mech Mat Aerosp Engn, Nanosci Technol Ctr, Adv Mat Proc & Anal Ctr, Orlando, FL 32816 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov OI Fishbein, Kenneth/0000-0002-6353-4603 FU National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institute on Aging. NR 41 TC 4 Z9 4 U1 1 U2 6 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 NOV PY 2015 VL 273 BP 151 EP 160 DI 10.1016/j.expneurol.2015.08.008 PG 10 WC Neurosciences SC Neurosciences & Neurology GA CW7BB UT WOS:000365151800014 PM 26277686 ER PT J AU Santillo, MF Liu, YT AF Santillo, Michael F. Liu, Yitong TI A fluorescence assay for measuring acetylcholinesterase activity in rat blood and a human neuroblastoma cell line (SH-SY5Y) SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Article DE 10-Acetyl-3,7-dihydroxyphenoxazine; Acetylcholinesterase (AChE); Amplex Red; Blood; Cell assay; Enzyme inhibitors; Enzyme kinetics; Fluorescence; In vitro; Neurotoxicity ID THROUGHPUT SCREENING ASSAYS; CHLORPYRIFOS-OXON; IN-VITRO; CHOLINESTERASE ACTIVITY; INHIBITION; BUTYRYLCHOLINESTERASE; ESTERASE; PHYSOSTIGMINE; RESORUFIN; KINETICS AB Acetylcholinesterase (AChE) is an enzyme responsible for metabolism of the neurotransmitter acetylcholine, and inhibition of AChE can have therapeutic applications (e.g., drugs for Alzheimer's disease) or neurotoxic consequences (e.g., pesticides). A common absorbance-based AChE activity assay that uses 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) can have limited sensitivity and be prone to interference. Therefore, an alternative assay was developed, in which AChE activity was determined by measuring fluorescence of resorufin produced from coupled enzyme reactions involving acetylcholine and Amplex Red (10-acetyl-3,7-dihydroxyphenoxazine). The Amplex Red assay was used for two separate applications. First, AChE activity was measured in rat whole blood, which is a biomarker for exposure to AChE inhibitor pesticides. Activity was quantified from a 10(5)-fold dilution of whole blood, and there was a linear correlation between Amplex Red and DTNB assays. For the second application, Amplex Red assay was used to measure AChE inhibition potency in a human neuroblastoma cell line (SH-SY5Y), which is important for assessing pharmacological and toxicological potential of AChE inhibitors including drugs, phytochemicals, and pesticides. Five known reversible inhibitors were evaluated (IC50, 7-225 nM), along with irreversible inhibitors chlorpyrifos-oxon (k(i) = 1.01nM(-1) h(-1)) and paraoxon (k(i) = 0.16 nM(-1) h(-1)). Lastly, in addition to inhibition, AChE reactivation was measured in SH-SY5Y cells incubated with pralidoxime chloride (2-PAM). The Amplex Red assay is a sensitive, specific, and reliable fluorescence method for measuring AChE activity in both rat whole blood and cultured SH-SY5Y cells. Published by Elsevier Inc. C1 [Santillo, Michael F.; Liu, Yitong] US FDA, Div Toxicol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Santillo, MF (reprint author), US FDA, Div Toxicol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM michael.santillo@fda.hhs.gov RI Santillo, Michael/B-5081-2009; OI Santillo, Michael/0000-0001-8087-5859; Liu, Yitong/0000-0002-4300-4349 FU U.S. Food and Drug Administration (FDA) FX This work was funded by the U.S. Food and Drug Administration (FDA). The authors thank Drs. Paddy L. Wiesenfeld, Robert L. Sprando, and Marianna D. Solomotis for reviewing the manuscript. NR 44 TC 0 Z9 0 U1 7 U2 49 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD NOV-DEC PY 2015 VL 76 BP 15 EP 22 DI 10.1016/j.vascn.2015.07.002 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CW6JJ UT WOS:000365103400003 PM 26165232 ER PT J AU Amiri-Kordestani, L Beaver, JA Cortazar, P AF Amiri-Kordestani, Laleh Beaver, Julia A. Cortazar, Patricia TI Neoadjuvant Therapy As a Platform for Drug Development: Current Controversies and Regulatory Perspectives SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID PATHOLOGICAL COMPLETE RESPONSE; SURGICAL ADJUVANT BREAST; TUMOR-INFILTRATING LYMPHOCYTES; PARALLEL HER2-NEGATIVE COHORT; CONTROLLED SUPERIORITY TRIAL; BOWEL PROJECT B-18; PREOPERATIVE CHEMOTHERAPY; PIK3CA MUTATIONS; OPEN-LABEL; CANCER C1 [Amiri-Kordestani, Laleh; Beaver, Julia A.; Cortazar, Patricia] US FDA, Ctr Drug Evaluat & Res, White Oak, MD 20993 USA. RP Amiri-Kordestani, L (reprint author), US FDA, Ctr Drug Evaluat & Res, White Oak, MD 20993 USA. NR 42 TC 1 Z9 1 U1 2 U2 3 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 NOV PY 2015 VL 29 IS 11 BP 843 EP + PG 3 WC Oncology SC Oncology GA CW6ZJ UT WOS:000365147100007 PM 26573064 ER PT J AU Botsis, T Scott, J Woo, EJ Ball, R AF Botsis, Taxiarchis Scott, John Woo, Emily Jane Ball, Robert TI Identifying Similar Cases in Document Networks Using Cross-Reference Structures SO IEEE JOURNAL OF BIOMEDICAL AND HEALTH INFORMATICS LA English DT Article DE Classification; clustering; document networks; postmarketing product surveillance; similarity ID TEXT MINING SYSTEM; ADVERSE; CLASSIFICATION; FEATURES; MEDDRA AB Our objective was to explore the creation of document networks based on different thresholds of shared information and different clustering algorithms on those networks to identify document clusters describing similar clinical cases. We created networks from vaccine adverse event report sets using seven approaches for linking reports. We then applied three clustering algorithms [ visualization of similarities (VOS), Louvain, k-means] to these networks and evaluated their ability to identify known clusters. The report sets included one simulated set and three sets from the Vaccine Adverse Event Reporting System; each was split into training and testing subsets. Training subsets were used to estimate parameter values for the clustering algorithms and testing subsets to evaluate clusters. We created the networks by linking reports based on shared information in the form either of individual-Medical Dictionary for Regulatory Activities Preferred Terms (PTs) or of dyads, triplets, quadruplets, quintuplets, and sextuplets of PTs; we created another network by weighting the single PT network connections by Lin's information theoretic approach to similarity. We then repeated this entire process using networks based on text mining output rather than structured data. We evaluated report clustering using recall, precision, and f-measure. The VOS algorithm outperformed Louvain and k-means in general. The best weighting scheme appeared to be related to the complexity of the known cluster. For example, singleton weighting performed best for an intussusception cluster driven by a single PT. We observed marginal differences between the code-and textual-based clustering. In conclusion, our approach supported identification of similar nodes in a document network. C1 [Botsis, Taxiarchis; Scott, John; Woo, Emily Jane; Ball, Robert] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Botsis, Taxiarchis] Univ Tromso, Dept Comp Sci, N-9019 Tromso, Norway. RP Botsis, T (reprint author), US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Taxiarchis.Botsis@fda.hhs.gov; John.Scott@fda.hhs.gov; Jane.Woo@fda.hhs.gov; Robert.Ball@fda.hhs.gov OI Scott, John/0000-0002-9116-948X NR 37 TC 0 Z9 0 U1 1 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2168-2194 J9 IEEE J BIOMED HEALTH JI IEEE J. Biomed. Health Inform. PD NOV PY 2015 VL 19 IS 6 BP 1906 EP 1917 DI 10.1109/JBHI.2014.2345873 PG 12 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Medical Informatics SC Computer Science; Mathematical & Computational Biology; Medical Informatics GA CW2XS UT WOS:000364857000015 PM 25122604 ER PT J AU Stewart, D Shieh, YC Tortorello, M Kukreja, A Shazer, A Schlesser, J AF Stewart, Diana Shieh, Y-Carol Tortorello, Mary Kukreja, Ankush Shazer, Arlette Schlesser, Joseph TI Quantitation of viable Coxiella burnetii in milk using an integrated cell culture-polymerase chain reaction (ICC-PCR) assay SO JOURNAL OF DAIRY RESEARCH LA English DT Article DE Coxiella burnetii; ICC-PCR; quantitation; milk ID REAL-TIME PCR; UNITED-STATES; Q-FEVER; PASTEURIZATION; SALMONELLA AB The obligate intracellular pathogen Coxiella burnetii has long been considered the most heat resistant pathogen in raw milk, making it the reference pathogen for determining pasteurisation conditions for milk products. New milk formulations and novel non-thermal processes require validation of effectiveness which requires a more practical method for analysis than using the currently used animal model for assessing Coxiella survival. Also, there is an interest in better characterising thermal inactivation of Coxiella in various milk formulations. To avoid the use of the guinea pig model for evaluating Coxiella survival, an Integrated Cell Culture-PCR (ICC-PCR) method was developed for determining Coxiella viability in milk. Vero cell cultures were directly infected from Coxiella-contaminated milk in duplicate 24-well plates. Viability of the Coxiella in milk was shown by a >= 0.5 log genome equivalent (ge)/ml increase in the quantity of IS111a gene from the baseline post-infection (day 0) level after 9-11 d propagation. Coxiella in skim, 2%, and whole milk, and half and half successfully infected Vero cells and increased in number by at least 2 logs using a 48-h infection period followed by 9-d propagation time. As few as 125 Coxiella ge/ml in whole milk was shown to infect and propagate at least 2 logs in the optimised ICC-PCR assay, though variable confirmation of propagation was shown for as low as 25 Coxiella ge/ml. Applicability of the ICC-PCR method was further proven in an MPN format to quantitate the number of viable Coxiella remaining in whole milk after 60 degrees C thermal treatment at 0, 20, 40, 60 and 90 min. C1 [Stewart, Diana; Shieh, Y-Carol; Tortorello, Mary; Shazer, Arlette; Schlesser, Joseph] US FDA, Div Food Proc Sci & Technol, Bedford Pk, IL 60501 USA. [Kukreja, Ankush] IIT, Inst Food Sci & Hlth, Bedford Pk, IL 60501 USA. RP Stewart, D (reprint author), US FDA, Div Food Proc Sci & Technol, Bedford Pk, IL 60501 USA. EM diana.stewart@fda.hhs.gov FU U.S. Food and Drug Administration [5U01FD003801] FX This study was supported in part by grant number 5U01FD003801 from the U.S. Food and Drug Administration to the Institute for Food Safety and Health of the Illinois Institute of Technology. The authors thank Songchuan Ma and Jiaojie Zheng for their technical assistance. NR 20 TC 0 Z9 0 U1 0 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0022-0299 EI 1469-7629 J9 J DAIRY RES JI J. Dairy Res. PD NOV PY 2015 VL 82 IS 4 BP 478 EP 484 DI 10.1017/S0022029915000400 PG 7 WC Agriculture, Dairy & Animal Science; Food Science & Technology SC Agriculture; Food Science & Technology GA CW4GK UT WOS:000364949200013 PM 26143937 ER PT J AU Galeotti, L van Dam, PM Johannesen, L Vicente, J Strauss, DG AF Galeotti, Loriano van Dam, Peter M. Johannesen, Lars Vicente, Jose Strauss, David G. TI Computer simulations to investigate the causes of T-wave notching SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE ECG; Simulation; T-wave notch; hERG block; Action potential; M-cells ID DRUG-INDUCED PROARRHYTHMIA; HEART; REPOLARIZATION; RANOLAZINE; FORMS; BLOCK AB Drugs that cause strong hERG potassium channel block (e.g., dofetilide, quinidine) cause T-wave notching. It has been suggested that this is due to prolongation of mid-myocardial (M) cells' action potential duration relative to endocardial and epicardial cells. However, the role of M cells in intact human hearts is debated. We simulated 2025 electrocardiograms representing changes in ventricular action potentials using the equivalent double layer mode that does not include M-cells. Action potential changes included prolongation, triangularization, squaring, and bumps in late repolarization, which have been observed experimentally and in single cell models with block of the hERG potassium channel. Changes were applied globally and spatially dispersed. Action potential bumps (slowing in late repolarization) produced T-wave notching similar to that observed clinically in healthy subjects receiving dofetilide or quinidine. Conversely, all other action potential changes (i.e., prolongation, triangularization, squaring), either global or spatially dispersed, resulted in T-wave changes, but did not cause T-wave notching. This study demonstrates that M-cells are not required to simulate T-wave notching. Published by Elsevier Inc. C1 [Galeotti, Loriano; Johannesen, Lars; Vicente, Jose; Strauss, David G.] US FDA, Silver Spring, MD USA. [van Dam, Peter M.] Radboud Univ Nijmegen, NL-6525 ED Nijmegen, Netherlands. [van Dam, Peter M.] Univ Calif Los Angeles, Los Angeles, CA USA. [Johannesen, Lars] Karolinska Inst, Dept Clin Physiol, S-10401 Stockholm, Sweden. [Johannesen, Lars] Karolinska Univ Hosp, Stockholm, Sweden. [Vicente, Jose] Univ Zaragoza, BSICoS Grp, I3A, IIS Aragon, Zaragoza, Spain. RP Galeotti, L (reprint author), 10903 New Hampshire Ave,W062-1111, Silver Spring, MD 20993 USA. EM Loriano.galeotti@fda.hhs.gov OI Vicente, Jose/0000-0001-9963-1205 FU US Food and Drug Administration (FDA)'s Critical Path Initiative; FDA's Office of Women's Health FX This project was supported in part by US Food and Drug Administration (FDA)'s Critical Path Initiative, FDA's Office of Women's Health, and appointments to the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and FDA. QTGuard+/12SL library was used under a Material Transfer Agreement between GE Healthcare and FDA. No official support or endorsement by FDA is intended nor should be inferred. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by FDA. NR 17 TC 1 Z9 1 U1 0 U2 2 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD NOV-DEC PY 2015 VL 48 IS 6 BP 927 EP 932 DI 10.1016/j.jelectrocard.2015.08.012 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CW3MQ UT WOS:000364896800002 PM 26341648 ER PT J AU Guldenring, D Finlay, DD Bond, RR Kennedy, A McLaughlin, J Galeotti, L Strauss, DG AF Guldenring, Daniel Finlay, Dewar D. Bond, Raymond R. Kennedy, Alan McLaughlin, James Galeotti, Loriano Strauss, David G. TI The derivation of the spatial QRS-T angle and the spatial ventricular gradient using the Mason-Likar 12-lead electrocardiogram SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE Linear lead transformations; Estimation of the Frank VCG; Derivation of the Frank VCG; Spatial ventricular gradient; Spatial QRS-T angle; Mason-Likar 12-lead ECG ID ISCHEMIC-HEART-DISEASE; SURFACE POTENTIAL MAPS; VECTORCARDIOGRAM; RECONSTRUCTION; VARIABILITY; SYSTEM; MATRIX; ECG AB Research has shown that the 'spatial QRS-T angle' (SA) and the 'spatial ventricular gradient' (SVG) have clinical value in a number of different applications. The determination of the SA and the SVG requires vectorcardiographic data. Such data is seldom recorded in clinical practice. The SA and the SVG are therefore frequently derived from 12-lead electrocardiogram (ECG) data using linear lead transformation matrices. This research compares the performance of two previously published linear lead transformation matrices (Kors and ML2VCG) in deriving the SA and the SVG from Mason-Likar (ML) 12-lead ECG data. This comparison was performed through an analysis of the estimation errors that are made when deriving the SA and the SVG for all 181 subjects in the study population. The estimation errors were quantified as the systematic error (mean difference) and the random error (span of the Bland-Altman 95% limits of agreement). The random error was found to be the dominating error component for both the Kors and the ML2VCG matrix. The random error [ML2VCG; Kors; result of the paired, two-sided Pitman-Morgan test for statistical significance of differences in the error variance between ML2VCG and Kors] for the vectorcardiographic parameters SA, magnitude of the SVG, elevation of the SVG and azimuth of the SVG were found to be [37.33 degrees; 50.52 degrees; p < 0.001], [30.17 mV ms; 39.09 mV ms; p < 0.001], [36.77 degrees; 47.62 degrees ; p = 0.001] and [63.45 degrees; 80.32 degrees; p < 0.001] respectively. The findings of this research indicate that in comparison to the Kors matrix the ML2VCG provides greater precision for estimating the SA and SVG from ML 12-lead ECG data. (C) 2015 Elsevier Inc. All rights reserved. C1 [Guldenring, Daniel; Finlay, Dewar D.; Bond, Raymond R.; Kennedy, Alan; McLaughlin, James] Univ Ulster, Belfast BT37 0QB, Antrim, North Ireland. [Galeotti, Loriano; Strauss, David G.] US FDA, CDRH, Off Sci & Engn Labs, Silver Spring, MD USA. RP Guldenring, D (reprint author), Univ Ulster, Belfast BT37 0QB, Antrim, North Ireland. EM guldenring-d2@email.ulster.ac.uk OI McLaughlin, James/0000-0001-6026-8971; Guldenring, Daniel/0000-0002-8847-2744 FU Northern Ireland Connected Health Innovation Centre - Invest Northern Ireland Competence Centre programme; engineering research institute of the Ulster University FX This work was supported in parts by the Northern Ireland Connected Health Innovation Centre, funded by the Invest Northern Ireland Competence Centre programme and the engineering research institute of the Ulster University. NR 25 TC 2 Z9 2 U1 0 U2 3 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD NOV-DEC PY 2015 VL 48 IS 6 BP 1045 EP 1052 DI 10.1016/j.jelectrocard.2015.08.009 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CW3MQ UT WOS:000364896800022 PM 26381798 ER PT J AU Vicente, J Johannesen, L Mason, JW Pueyo, E Stockbridge, N Strauss, DG AF Vicente, Jose Johannesen, Lars Mason, Jay W. Pueyo, Esther Stockbridge, Norman Strauss, David G. TI Sex differences in drug-induced changes in ventricular repolarization SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE Sex differences; QTc prolongation; T wave morphology; Torsade de pointes; Drugs; hERG block ID INDUCED QT PROLONGATION; QUINIDINE; DOFETILIDE; INTERVAL; WOMEN; RISK; AGE; ELECTROCARDIOGRAMS; MECHANISMS; BLOCK AB Introduction: Heart rate corrected QT (QTc) interval prolongation is a predictor of drug-induced torsade de pointes, a potentially fatal ventricular arrhythmia that disproportionately affects women. This study assesses whether there are sex differences in the ECG changes induced by four different hERG potassium channel blocking drugs. Methods and results: Twenty-two healthy subjects (11 women) received a single oral dose of dofetilide, quinidine, ranolazine, verapamil and placebo in a double-blind 5-period crossover study. ECGs and plasma drug concentrations were obtained at pre-dose and at 15 time-points post-dose. Dofetilide, quinidine and ranolazine prolonged QTc. There were no sex differences in QTc prolongation for any drug, after accounting for differences in exposure. Sex differences in any ECG biomarker were observed only with dofetilide, which caused greater J-T(peak)c prolongation (p = 0.045) but lesser T-peak-T-end prolongation (p = 0.006) and lesser decrease of T wave amplitude (p = 0.003) in women compared to men. Conclusions: There were no sex differences in QTc prolongation for any of the studied drugs. Moreover, no systematic sex differences in other drug-induced ECG biomarker changes were observed in this study. This study suggests that the higher torsade risk in women compared to men is not due to a larger concentration-dependent QTc prolongation. (C) 2015 Elsevier Inc. All rights reserved. C1 [Vicente, Jose; Johannesen, Lars; Strauss, David G.] US FDA, CDRH, Off Sci & Engn Labs, Silver Spring, MD USA. [Vicente, Jose; Stockbridge, Norman] US FDA, CDER, Off New Drugs, Div Cardiovasc & Renal Prod, Silver Spring, MD USA. [Johannesen, Lars] Karolinska Inst, Dept Clin Physiol, S-10401 Stockholm, Sweden. [Johannesen, Lars] Karolinska Univ Hosp, Stockholm, Sweden. [Mason, Jay W.] Spaulding Clin Res, West Bend, WI USA. [Pueyo, Esther] Biomed Res Networking Ctr Bioengn Biomat & Nanome, Barcelona, Spain. [Vicente, Jose] Univ Zaragoza, BSICoS Grp, Aragon Inst Engn Res I3A, IIS Aragon, Zaragoza, Spain. RP Vicente, J (reprint author), US FDA, 10903 New Hampshire Ave,WO62-1125B, Silver Spring, MD 20993 USA. EM jose.vicente@fda.hhs.gov OI Vicente, Jose/0000-0001-9963-1205 FU U.S. Food and Drug Administration's Critical Path Initiative; U.S. Food and Drug Administration's Office of Women's Health; Ministerio de Economia y Competitividad (MINECO), Spain [TIN2013-41998-R]; Grupo Consolidado BSICoS from DGA (Aragon); European Social Fund (EU) FX This study was supported by U.S. Food and Drug Administration's Critical Path Initiative, U.S. Food and Drug Administration's Office of Women's Health and appointments to the Research Participation Program at the Center for Devices and Radiological Health and the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. E.P. is funded by Ministerio de Economia y Competitividad (MINECO), Spain, under project TIN2013-41998-R and by Grupo Consolidado BSICoS from DGA (Aragon) and European Social Fund (EU). QTGuard + was provided by GE Healthcare through a material transfer agreement. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the U.S. Department of Health and Human Services. NR 29 TC 1 Z9 1 U1 1 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD NOV-DEC PY 2015 VL 48 IS 6 BP 1081 EP 1087 DI 10.1016/j.jelectrocard.2015.08.004 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CW3MQ UT WOS:000364896800028 PM 26324176 ER PT J AU Drew, BJ Sommargren, CE Tolan, GD Macfarlane, PW Wagner, GS Strauss, DG Burke, MC Kligfield, PD Rowlandson, I Lux, RL AF Drew, Barbara J. Sommargren, Claire E. Tolan, Gil D. Macfarlane, Peter W. Wagner, Galen S. Strauss, David G. Burke, Martin C. Kligfield, Paul D. Rowlandson, Ian Lux, Robert L. TI In memoriam: A tribute to the work and lives of Ron Selvester and Rory Childers SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE Electrocardiogram; Educators; Medical scientists; Clinical electrophysiology ID BUNDLE-BRANCH BLOCK; HEART; SCAR AB At the April, 2015 International Society for Computerized Electrocardiology (ISCE) Annual Conference in San Jose, CA, a special session entitled Remembering Ron & Rory was held to pay tribute to the extraordinary work and lives of two experts in electrocardiology. The session was well attended by conference attendees, Childers' family members and friends, and additional colleagues who traveled to San Jose solely to participate in this session. The purpose of the present paper is to document the spirit of this special session as faithfully as possible using the words of the session speakers. (C) 2015 Elsevier Inc. All rights reserved. C1 [Drew, Barbara J.; Sommargren, Claire E.] Univ Calif San Francisco, Dept Physiol Nursing, San Francisco, CA 94143 USA. [Tolan, Gil D.] Univ Texas San Antonio, Hlth Sci Ctr, San Antonio, TX USA. [Macfarlane, Peter W.] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8QQ, Lanark, Scotland. [Wagner, Galen S.] Duke Univ, Duke Clin Res Inst, Durham, NC USA. [Strauss, David G.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Burke, Martin C.] Univ Chicago, Heart Rhythm Ctr, Chicago, IL 60637 USA. [Kligfield, Paul D.] Weill Cornell Med Coll, New York, NY USA. [Rowlandson, Ian] GE Healthcare, Wauwatosa, WI USA. [Lux, Robert L.] Univ Utah, Nora Eccles Harrison Cardiovasc Res & Trainin Ins, Salt Lake City, UT USA. RP Sommargren, CE (reprint author), Univ Calif San Francisco, Dept Physiol Nursing, San Francisco, CA 94143 USA. EM claire.sommargren@ucsf.edu NR 14 TC 2 Z9 2 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD NOV-DEC PY 2015 VL 48 IS 6 BP 1088 EP 1098 DI 10.1016/j.jelectrocard.2015.08.037 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CW3MQ UT WOS:000364896800029 PM 26422547 ER PT J AU Goodwin, AK Hiranita, T Paule, MG AF Goodwin, Amy K. Hiranita, Takato Paule, Merle G. TI The Reinforcing Effects of Nicotine in Humans and Nonhuman Primates: A Review of Intravenous Self-Administration Evidence and Future Directions for Research SO NICOTINE & TOBACCO RESEARCH LA English DT Review ID SCHEDULE-CONTROLLED BEHAVIOR; ABUSE LIABILITY ASSESSMENT; SQUIRREL-MONKEYS; SEX-DIFFERENCES; CIGARETTE-SMOKE; RHESUS-MONKEYS; TOBACCO ALKALOIDS; FEMALE RATS; LABORATORY-ANIMALS; UNITED-STATES AB Cigarette smoking is largely driven by the reinforcing properties of nicotine. Intravenous (IV) self-administration procedures are the gold standard for investigating the reinforcing effects of psychoactive drugs. The goal of this review was to examine the results of published investigations of the reinforcing effects of nicotine measured using IV self-administration procedures in humans and nonhuman primates. The body of literature using nonhuman primate subjects indicates nicotine functions as a positive reinforcer when available for self-administration via IV catheters. However, it can also be difficult to establish IV nicotine self-administration in nonhuman primates and sometimes supplemental strategies have been required (e.g., priming injections or food deprivation) before subjects acquire the behavior. Although the body of literature using human subjects is limited, the evidence indicates nicotine functions as a reinforcer via the IV route of administration in adult cigarette smokers. Rates of nicotine self-injection can be variable across subjects and responding is sometimes inconsistent across sessions in both humans and nonhuman primates. The Family Smoking Prevention and Tobacco Control Act, enacted in 2009, gave the Food and Drug Administration regulatory authority over the manufacture, marketing, and distribution of tobacco products. Research examining the threshold reinforcing doses for initiation and maintenance of nicotine self-administration, comparisons of the reinforcing effects of nicotine in adolescent versus adult subjects, investigations of gender differences in the reinforcing effects of nicotine, and studies of the abuse liability of non-nicotine tobacco product constituents and their ability to alter the reinforcing effects of nicotine will inform potential tobacco regulatory actions. C1 [Goodwin, Amy K.; Hiranita, Takato; Paule, Merle G.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Goodwin, AK (reprint author), US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd HFT 132, Jefferson, AR 72079 USA. EM Amy.Goodwin@fda.hhs.gov FU U.S. Food and Drug Administration/Center for Tobacco Products (NCTR) [Protocol E07537-01] FX U.S. Food and Drug Administration/Center for Tobacco Products (NCTR Protocol E07537-01). NR 111 TC 6 Z9 6 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD NOV PY 2015 VL 17 IS 11 BP 1297 EP 1310 DI 10.1093/ntr/ntv002 PG 14 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA CW1SU UT WOS:000364772500002 PM 25673111 ER PT J AU Glier, H Simak, J Panigaj, M Gelderman, MP Vostal, JG Holada, K AF Glier, Hana Simak, Jan Panigaj, Martin Gelderman, Monique P. Vostal, Jaroslav G. Holada, Karel TI Expression of the cellular prion protein affects posttransfusion recovery and survival of red blood cells in mice SO TRANSFUSION LA English DT Article ID PRPC; TRANSFUSION; DEFICIENT; DISEASE AB BACKGROUNDCellular prion protein (PrPC) is expressed on various cell types including red blood cells (RBCs). The PrPC plays a key role in the pathogenesis of prion diseases, but its physiologic function remains unclear. PrPC is expressed on CD34+ hematopoietic stem cells and its expression is regulated during blood cell differentiation including the erythroid line. STUDY DESIGN AND METHODSWe investigated the role of PrPC in RBC survival in circulation by transfusing a mix of biotin-labeled RBCs from wild-type (WT) and PrP knockout (KO) mice to groups of recipient mice (WT and KO). The proportion of biotinylated RBCs in peripheral blood was estimated by flow cytometry. RESULTSKO RBCs displayed a markedly higher first-day posttransfusion recovery but had a decreased survival in circulation when compared to WT RBCs. Similar results were obtained in all groups of transfused mice, irrespective of RBCs biotinylation level. In addition, we confirmed this finding in an analogous study using Tga20 mice overexpressing PrPC and KO mice of a different genetic background. CONCLUSIONOur results demonstrate that PrPC expression affects RBC recovery and survival in circulation. C1 [Glier, Hana; Panigaj, Martin; Holada, Karel] Charles Univ Prague, Fac Med 1, Inst Microbiol & Immunol, Prague 12820 2, Czech Republic. [Simak, Jan; Gelderman, Monique P.; Vostal, Jaroslav G.] Food & Drug Adm, Ctr Biol Evaluat & Res, Lab Cellular Hematol, Silver Spring, MD USA. RP Holada, K (reprint author), Charles Univ Prague, Fac Med 1, Inst Microbiol & Immunol, Studnickova 7, Prague 12820 2, Czech Republic. EM karel.holada@lf1.cuni.cz RI Panigaj, Martin/G-6492-2013 FU Czech Science Foundation [GACR P303/12/1791]; Grant Agency of Charles University [GAUK 86408]; Charles University [PRVOUK-P24/LF1/3] FX This work was supported by grants from the Czech Science Foundation (GACR P303/12/1791) and the Grant Agency of Charles University (GAUK 86408). KH was supported by project of Charles University PRVOUK-P24/LF1/3. These findings and conclusions have not been formally disseminated by FDA and should not be construed to represent any Agency determination or policy. NR 20 TC 0 Z9 0 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD NOV PY 2015 VL 55 IS 11 BP 2590 EP 2596 DI 10.1111/trf.13190 PG 7 WC Hematology SC Hematology GA CW3EZ UT WOS:000364876100010 PM 26033638 ER PT J AU Sarachana, T Kulkarni, S Atreya, CD AF Sarachana, Tewarit Kulkarni, Sandhya Atreya, Chintamani D. TI Evaluation of small noncoding RNAs in ex vivo stored human mature red blood cells: changes in noncoding RNA levels correlate with storage lesion events SO TRANSFUSION LA English DT Article ID IN-VITRO; DEATH; APOPTOSIS; EXPRESSION; MICRORNAS; TARGETS; ERYTHROCYTES; RESTORATION; INHIBITION; MIR-196A AB BACKGROUNDWhile biomarkers of storage lesions (SLs) for red blood cells (RBCs) abound, the physiologic consequences of SLs and associated important events are poorly understood. Previously we have identified differentially expressed regulatory small noncoding RNAs (ncRNAs) in stored RBCs, suggesting their role in the RBC SL process and their potential as quality biomarkers of stored RBCs. STUDY DESIGN AND METHODSComprehensive ncRNA expression analysis of RBCs stored for up to 56 days was performed on RNAs collected from enriched mature RBCs on Days 0, 7, 14, 28, 42, and 56. Three known RBC SL processes, that is, mature RBCs' suicidal death (eryptosis), ATP loss, and changes in RBC indices, were correlated with differentially expressed ncRNAs to gain knowledge on the SL molecular processes. RESULTSThe analysis identified four ncRNAs whose changes in the expression levels were correlated with the selected three SL processes. Differential expression on Days 14 and 28 of the four selected ncRNAs was confirmed by TaqMan quantitative reverse transcription-polymerase chain reaction analysis. Bioinformatics analysis identified potential targets and biologic functions of these ncRNAs. Overexpression of one such ncRNA, hsa-miR-196a, in a human erythroblast cell line confirmed its protective effects against the cell death and ATP loss. CONCLUSIONOverall, this study demonstrates that changes in the levels of small ncRNAs of stored RBCs correlate with some of the SL events and thus they have the potential to serve as the storage quality markers. C1 [Sarachana, Tewarit; Kulkarni, Sandhya; Atreya, Chintamani D.] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Atreya, CD (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 52-72, Silver Spring, MD 20993 USA. EM Tewarit.Sa@chula.ac.th; chintamani.atreya@fda.hhs.gov FU Center for Biologics Evaluation and Research (CBER) FX The authors acknowledge Dr Valerie W. Hu, The George Washington University (GWU), Washington, DC, for the Affymetrix Workstation and bioinformatics software used in the study. TS was a recipient of a postdoctoral fellowship at the Center for Biologics Evaluation and Research (CBER) administered by the Oak Ridge Institute for Science and Education (ORISE) through an intra-agency agreement between the US Department of Energy and the US Food and Drug Administration. NR 32 TC 4 Z9 4 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD NOV PY 2015 VL 55 IS 11 BP 2672 EP 2683 DI 10.1111/trf.13235 PG 12 WC Hematology SC Hematology GA CW3EZ UT WOS:000364876100022 PM 26174076 ER PT J AU Calvo, MS Lamberg-Allardt, CJ AF Calvo, Mona S. Lamberg-Allardt, Christel J. TI Phosphorus SO ADVANCES IN NUTRITION LA English DT Editorial Material ID HEALTH IMPACT; POPULATION C1 [Calvo, Mona S.] US FDA, Ctr Food Safety & Appl Nutr, Off Foods & Vet Med, Washington, DC 20204 USA. [Lamberg-Allardt, Christel J.] Univ Helsinki, Calcium Res Unit, Dept Food & Environm Sci, Helsinki, Finland. RP Calvo, MS (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Foods & Vet Med, Washington, DC 20204 USA. EM mona.calvo@fda.hhs.gov OI Lamberg-Allardt, Christel/0000-0001-7326-1904 NR 12 TC 0 Z9 0 U1 1 U2 3 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD NOV PY 2015 VL 6 IS 6 BP 860 EP 862 DI 10.3945/an.115.008516 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CV8ZQ UT WOS:000364577400020 PM 26567206 ER PT J AU Slatko, GH AF Slatko, Gary H. TI Risk Evaluation and Mitigation Strategy (REMS): FDA Perspective on What Physicians Need to Know SO AMERICAN FAMILY PHYSICIAN LA English DT Editorial Material C1 [Slatko, Gary H.] US FDA, Silver Spring, MD USA. RP Slatko, GH (reprint author), US FDA, Silver Spring, MD USA. EM Gary.Slatko@fda.hhs.gov NR 1 TC 1 Z9 1 U1 0 U2 0 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 NOV 1 PY 2015 VL 92 IS 9 BP 771 EP 772 PG 2 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA CV9PT UT WOS:000364619800001 PM 26554468 ER PT J AU Eshera, N Itana, H Zhang, L Soon, G Fadiran, EO AF Eshera, Noha Itana, Hawi Zhang, Lei Soon, Greg Fadiran, Emmanuel O. TI Demographics of Clinical Trials Participants in Pivotal Clinical Trials for New Molecular Entity Drugs and Biologics Approved by FDA From 2010 to 2012 SO AMERICAN JOURNAL OF THERAPEUTICS LA English DT Article DE FDA reviews; pivotal clinical trials; demographics; sex analysis; PPR ID WOMEN; SEX; PHARMACODYNAMICS; PHARMACOKINETICS; THERAPY AB To fully assess the safety and efficacy of therapeutics before approval, the US Food and Drug Administration (FDA) has encouraged adequate representation and assessment of demographic subgroups in clinical trials through guidance documents and regulations. This study aimed to survey the demographics of participants in pivotal clinical trials, as well as the presence of analyses by sex on efficacy and safety for FDA-approved new drug applications (NDAs) and biologics license applications (BLAs) from 2010 to 2012. Medical and statistical reviews for new molecular entity drugs and biological products approved during this period were obtained from Drugs@FDA. All pivotal clinical trials referenced in the FDA reviews were evaluated for the participation of different demographic subgroups (such as sex, race/ethnicity, and age). Pivotal trials were defined as those phase 2 and/or phase 3 trials described in the labeling or the FDA medical reviews in support of the drug/biological approval. Eighty-three new molecular entities (66 NDAs and 17 BLAs) were approved by the FDA from 2010 to 2012. Overall, women constituted 45% of trial participants for NDAs and 65% for BLAs. Sex analysis related to safety and efficacy was reported in 92% of the surveyed FDA medical and statistical reviews. Most NDAs and BLAs (82%) had a study population that was representative of the sex distribution for the intended patient population; however, most study participants were whites (77%), and minority racial/ethnic groups had lower participation rates in the study population than would be representative of the US racial group populations. C1 [Eshera, Noha; Itana, Hawi; Fadiran, Emmanuel O.] US FDA, Off Womens Hlth, Off Commissioner, Silver Spring, MD 20993 USA. [Zhang, Lei] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Soon, Greg] US FDA, Off Biostat, OTS, CDER, Silver Spring, MD 20993 USA. RP Fadiran, EO (reprint author), US FDA, Off Womens Hlth, Bldg 32,Room 2312,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM emmanuel.fadiran@fda.hhs.gov NR 28 TC 4 Z9 4 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1075-2765 EI 1536-3686 J9 AM J THER JI Am. J. Ther. PD NOV-DEC PY 2015 VL 22 IS 6 BP 435 EP 455 DI 10.1097/MJT.0000000000000177 PG 21 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CW1SW UT WOS:000364772700006 PM 25621972 ER PT J AU Beaver, JA Amiri-Kordestani, L Charlab, R Chen, W Palmby, T Tilley, A Zirkelbach, JF Yu, JY Liu, Q Zhao, L Crich, J Chen, XH Hughes, M Bloomquist, E Tang, SH Sridhara, R Kluetz, PG Kim, G Ibrahim, A Pazdur, R Cortazar, P AF Beaver, Julia A. Amiri-Kordestani, Laleh Charlab, Rosane Chen, Wei Palmby, Todd Tilley, Amy Zirkelbach, Jeanne Fourie Yu, Jingyu Liu, Qi Zhao, Liang Crich, Joyce Chen, Xiao Hong Hughes, Minerva Bloomquist, Erik Tang, Shenghui Sridhara, Rajeshwari Kluetz, Paul G. Kim, Geoffrey Ibrahim, Amna Pazdur, Richard Cortazar, Patricia TI FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID KINASE 4/6 INHIBITOR; TAMOXIFEN; LETROZOLE; EFFICACY; THERAPY; WOMEN AB On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319-0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2. (C)2015 AACR. C1 [Beaver, Julia A.; Amiri-Kordestani, Laleh; Charlab, Rosane; Chen, Wei; Palmby, Todd; Tilley, Amy; Zirkelbach, Jeanne Fourie; Yu, Jingyu; Liu, Qi; Zhao, Liang; Crich, Joyce; Chen, Xiao Hong; Hughes, Minerva; Bloomquist, Erik; Tang, Shenghui; Sridhara, Rajeshwari; Kluetz, Paul G.; Kim, Geoffrey; Ibrahim, Amna; Pazdur, Richard; Cortazar, Patricia] US FDA, Ctr Drug Evaluat & Res, White Oak, MD USA. RP Beaver, JA (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Julia.Beaver@fda.hhs.gov NR 10 TC 35 Z9 35 U1 7 U2 19 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 NOV 1 PY 2015 VL 21 IS 21 BP 4760 EP 4766 DI 10.1158/1078-0432.CCR-15-1185 PG 7 WC Oncology SC Oncology GA CV7WW UT WOS:000364488100005 PM 26324739 ER PT J AU Hampton, D Tarver, ME Jacobs, DS Szczotka-Flynn, L Steinemann, T Dhaliwal, D Duenas, MR Jeng, BH Eydelman, M AF Hampton, Denise Tarver, Michelle E. Jacobs, Deborah S. Szczotka-Flynn, Loretta Steinemann, Thomas Dhaliwal, Deepinder Duenas, Michael R. Jeng, Bennie H. Eydelman, Malvina TI Special Commentary: Food and Drug Administration, American Academy of Ophthalmology, American Academy of Optometry, American Optometric Association and the Contact Lens Association of Ophthalmologists Cosponsored Workshop: Revamping Microbiological Test Methods for Contact Lenses, Products, and Accessories to Protect Health and Ensure Safety SO Eye & Contact Lens-Science and Clinical Practice LA English DT Editorial Material ID SOLUTION DISINFECTION ACTIVITY; MICROBIAL KERATITIS; CARE SOLUTIONS; ACANTHAMOEBA; AUSTRALIA; EFFICACY; CYSTS C1 [Hampton, Denise; Tarver, Michelle E.; Eydelman, Malvina] US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Silver Spring, MD USA. [Jacobs, Deborah S.] Boston Fdn Sight, Needham, MA USA. [Szczotka-Flynn, Loretta; Steinemann, Thomas] Case Western Reserve Univ, Dept Ophthalmol & Visual Sci, Cleveland, OH 44106 USA. [Steinemann, Thomas] Metrohlth Med Ctr, Div Ophthalmol, Cleveland, OH USA. [Dhaliwal, Deepinder] Univ Pittsburgh, Dept Ophthalmol, Sch Hlth Sci, UPMC, Pittsburgh, PA 15260 USA. [Duenas, Michael R.] Amer Optometr Assoc, St Louis, MO USA. [Jeng, Bennie H.] Univ Maryland, Sch Med, Dept Ophthalmol & Visual Sci, Baltimore, MD 21201 USA. RP Eydelman, M (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM malvina.eydelman@fda.hhs.gov NR 30 TC 0 Z9 0 U1 4 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1542-2321 EI 1542-233X J9 EYE CONTACT LENS JI Eye Contact Lens-Sci. Clin. Pra. PD NOV PY 2015 VL 41 IS 6 BP 329 EP 333 DI 10.1097/ICL.0000000000000205 PG 5 WC Ophthalmology SC Ophthalmology GA CV6LF UT WOS:000364381000001 PM 26469524 ER PT J AU Hickerson, WL Ryan, CM Conlon, KM Harrington, DT Foster, K Schwartz, S Iyer, N Jeschke, M Haller, HL Faucher, LD Arnoldo, BD Jeng, JC AF Hickerson, William L. Ryan, Colleen M. Conlon, Kathe M. Harrington, David T. Foster, Kevin Schwartz, Suzanne Iyer, Narayan Jeschke, Marc Haller, Herbert L. Faucher, Lee D. Arnoldo, Brett D. Jeng, James C. TI What's in a Name? Recent Key Projects of the Committee on Organization and Delivery of Burn Care SO Journal of Burn Care & Research LA English DT Article ID PLAN AB The Committee for the Organization and Delivery of Burn Care (ODBC) was charged by President Palmieri and the American Burn Association (ABA) Board of Directors with presenting a plenary session at the 45th Meeting of the ABA in Palm Springs, CA, in 2013. The objective of the plenary session was to inform the membership about the wide range of the activities performed by the ODBC committee. The hope was that this session would encourage active involvement within the ABA as a means to improve the delivery of future burn care. Selected current activities were summarized by key leaders of each project and highlighted in the plenary session. The history of the committee, current projects in disaster management, regionalization, best practice guidelines, federal partnerships, product development, new technologies, electronic medical records, and manpower issues in the burn workforce were summarized. The ODBC committee is a keystone committee of the ABA. It is tasked by the ABA leadership with addressing and leading progress in many areas that constitute current challenges in the delivery of burn care. C1 [Hickerson, William L.] Univ Tennessee, Ctr Hlth Sci, Reg Med Ctr, Firefighters Reg Burn Ctr, Memphis, TN 38163 USA. [Ryan, Colleen M.] Harvard Univ, Sch Med, Shriners Hosp Children Boston, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. [Conlon, Kathe M.] St Barnabas Hosp, Burn Ctr, Livingston, NJ USA. [Harrington, David T.] Rhode Isl Hosp, Providence, RI USA. [Foster, Kevin] Maricopa Cty Gen Hosp, Arizona Burn Ctr, Phoenix, AZ USA. [Schwartz, Suzanne] US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. [Iyer, Narayan] US Dept HHS, Div CBRN Countermeasures, Biomed Adv Res & Dev Author, Washington, DC USA. Univ Toronto, Sunnybrook Hlth Sci Ctr, Ross Tilley Burn Ctr, Toronto, ON, Canada. [Haller, Herbert L.] Unfallkrankenhaus Linz, Linz, Austria. [Faucher, Lee D.; Arnoldo, Brett D.] Univ Wisconsin, Med Ctr, Madison, WI 53706 USA. [Jeng, James C.] George Washington Univ, Medstar Washington Hosp Ctr, Washington, DC USA. RP Hickerson, WL (reprint author), Univ Tennessee, Ctr Hlth Sci, Reg Med Ctr, Firefighters Reg Burn Ctr, Memphis, TN 38163 USA. EM whicker1@uthsc.edu FU American Burn Association FX This study was supported by the American Burn Association. NR 7 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1559-047X EI 1559-0488 J9 J BURN CARE RES JI J. Burn Care Res. PD NOV-DEC PY 2015 VL 36 IS 6 BP 619 EP 625 DI 10.1097/BCR.0000000000000189 PG 7 WC Emergency Medicine; Dermatology; Surgery SC Emergency Medicine; Dermatology; Surgery GA CV5UZ UT WOS:000364338000007 PM 25423435 ER PT J AU Choi, D Chon, JW Kim, HS Kim, DH Lim, JS Yim, JH Seo, KH AF Choi, Dasom Chon, Jung-Whan Kim, Hong-Seok Kim, Dong-Hyeon Lim, Jong-Soo Yim, Jin-Hyeok Seo, Kun-Ho TI Incidence, Antimicrobial Resistance, and Molecular Characteristics of Nontyphoidal Salmonella Including Extended-Spectrum beta-Lactamase Producers in Retail Chicken Meat SO JOURNAL OF FOOD PROTECTION LA English DT Article ID ENTERICA SEROTYPE ENTERITIDIS; ESCHERICHIA-COLI; ANTIBIOTIC-RESISTANCE; QUINOLONE RESISTANCE; UNITED-STATES; SOUTH-KOREA; PREVALENCE; POULTRY; FOOD; ENTEROBACTERIACEAE AB The present study was undertaken to determine the prevalence of Salmonella in 100 chicken carcass samples from five integrated broiler operation brands in Korea. Serotypes, antibiotic resistance patterns, extended-spectrum P-lactamase (ESBL) genotype, and clonal divergence using multilocus sequence typing of the isolated strains were analyzed. A total of 42 chicken samples were contaminated with nontyphoidal Salmonella (NTS) isolates: 16 isolates (38%) were Salmonella Virchow, 9 (21%) were Salmonella Bareilly, and 8 (19%) were Salmonella Infantis. A multidrug resistance. (MDR; resistant to more than three classes of antibiotics) phenotype was observed in 29% of the isolates, which were resistant to five or more classes of antibiotics. The dominant MDR type was resistance to classes of penicillin, cephalosporins, aminoglycosides, quinolones, and tetracyclines. All the MDR isolates were positive for ESBL producers, and all but one (with the CTX-M-1 genotype) had the CTX-M-15 genotype. Multilocus sequence typing of the isolates revealed ST16 as the dominant sequence type; Salmonella Virchow, Salmonella Infantis, and Salmonella Richmond were all ST16, indicating a close genetic relationship between these serovars. This is the first study in Korea showing the CTX-M-1 type of NTS and the prevalence of ESBL-producing strains among NTS isolated from retail chicken meat. Our findings suggest that MDR Salmonella contamination is widely prevalent in retail chicken meat, and consumption of inadequately cooked products could lead to dissemination of NTS, which is hazardous to human health. C1 [Choi, Dasom; Kim, Hong-Seok; Kim, Dong-Hyeon; Lim, Jong-Soo; Yim, Jin-Hyeok; Seo, Kun-Ho] Konkuk Univ, Coll Vet Med, Ctr Food Safety, Seoul 143701, South Korea. [Chon, Jung-Whan] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. RP Seo, KH (reprint author), Konkuk Univ, Coll Vet Med, Ctr Food Safety, Seoul 143701, South Korea. EM bracstu3@konkuk.ac.kr FU National Research Foundation of Korea - Korea government (MSIP) [2015R1A2A2A05001288]; Bio-industry Technology Development Program of iPET - Ministry for Food, Agriculture, Forestry, and Fisheries [112137-3] FX This work was supported by the National Research Foundation of Korea grant funded by the Korea government (MSIP) (2015R1A2A2A05001288), and by the Bio-industry Technology Development Program of iPET (No. 112137-3) funded by the Ministry for Food, Agriculture, Forestry, and Fisheries. NR 50 TC 6 Z9 6 U1 0 U2 8 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD NOV PY 2015 VL 78 IS 11 BP 1932 EP 1937 DI 10.4315/0362-028X.JFP-15-145 PG 6 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CV8CB UT WOS:000364503000001 PM 26555514 ER PT J AU Gradl, DR Sun, LX Larkin, EL Chirtel, SJ Keller, SE AF Gradl, Dana R. Sun, Lingxiang Larkin, Emily L. Chirtel, Stuart J. Keller, Susanne E. TI Survival of Salmonella during Drying of Fresh Ginger Root (Zingiber officinale) and Storage of Ground Ginger SO JOURNAL OF FOOD PROTECTION LA English DT Article ID ESCHERICHIA-COLI; WATER ACTIVITY; UNITED-STATES; SPICES; FOODS; RESISTANCE; PEPPER; BLACK AB The survival of Salmonella on fresh ginger root (Zingiber officinale) during drying was examined using both a laboratory oven at 51 and 60 degrees C with two different fan settings and a small commercially available food dehydrator. The survival of Salmonella in ground ginger stored at 25 and 37 degrees C at 33% (low) and 97% (high) relative humidity (RH) was also examined. To inoculate ginger, a four-serovar cocktail of Salmonella was collected by harvesting agar lawn cells. For drying experiments, ginger slices (1 +/- 0.5 mm thickness) were surface inoculated at a starting level of approximately 9 log CFU/g. Higher temperature (60 degrees C) coupled with a slow fan speed (nonstringent condition) to promote a slower reduction in the water activity (a(w)) of the ginger resulted in a 3- to 4-log reduction in Salmonella populations in the first 4 to 6 h with an additional 2- to 3-log reduction by 24 h. Higher temperature with a higher fan speed (stringent condition) resulted in significantly less destruction of Salmonella throughout the 24-h period (P < 0.001). Survival appeared related to the rate of reduction in the a(w). The a(w) also influenced Salmonella survival during storage of ground ginger. During storage at 97% RH, the maximum a(w) values were 0.85 at 25 degrees C and 0.87 at 37 degrees C; Salmonella was no longer detected after 25 and 5 days of storage, respectively, under these conditions. At 33% RH, the a(w) stabilized to approximately 0.35 at 25 degrees C and 0.31 at 37 degrees C. Salmonella levels remained relatively constant throughout the 365-day and 170-day storage periods for the respective temperatures. These results indicate a relationship between temperature and a(w) and the survival of Salmonella during both drying and storage of ginger. C1 [Gradl, Dana R.; Larkin, Emily L.; Keller, Susanne E.] US FDA, Ctr Food Safety & Appl Nutr, Bedford Pk, IL 60501 USA. [Sun, Lingxiang] IIT, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. [Chirtel, Stuart J.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Keller, SE (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM susanne.keller@fda.hhs.gov FU U.S. Department of Energy, Oak Ridge Institute of Science and Education; U.S. Food and Drug Administration, Center for Applied Safety and Nutrition Research Participation Program FX This research was supported by an agreement between the U.S. Food and Drug Administration, Center for Applied Safety and Nutrition Research Participation Program and the U.S. Department of Energy, Oak Ridge Institute of Science and Education. NR 22 TC 4 Z9 4 U1 5 U2 15 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD NOV PY 2015 VL 78 IS 11 BP 1954 EP 1959 DI 10.4315/0362-028X.JFP-15-153 PG 6 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CV8CB UT WOS:000364503000004 PM 26555517 ER PT J AU Melton-Celsa, AR O'Brien, AD Feng, PCH AF Melton-Celsa, Angela R. O'Brien, Alison D. Feng, Peter C. H. TI Virulence Potential of Activatable Shiga Toxin 2d-Producing Escherichia coli Isolates from Fresh Produce SO JOURNAL OF FOOD PROTECTION LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; INTESTINAL MUCUS; STRAINS; CYTOTOXICITY; GENES; MOUSE; IDENTIFICATION; SUBTYPES; CLONING; HUMANS AB Shiga toxin (Stx)-producing Escherichia coli (STEC) strains are food- and waterborne pathogens that are often transmitted via beef products or fresh produce. STEC strains cause both sporadic infections and outbreaks, which may result in hemorrhagic colitis and hemolytic uremic syndrome. STEC strains may elaborate Stx1, Stx2, and/or subtypes of those toxins. Epidemiological evidence indicates that STEC that produce subtypes Stx2a, Stx2c, and/or Stx2d are more often associated with serious illness. The Stx2d subtype becomes more toxic to Vero cells after incubation with intestinal mucus or elastase, a process named "activation." Stx2d is not generally found in the E. coli serotypes most commonly connected to STEC outbreaks. However, STEC strains that are stx(2d) positive can be isolated from foods, an occurrence that gives rise to the question of whether those food isolates are potential human pathogens. In this study, we examined 14 STEC strains from fresh produce that were stx(2d) positive and found that they all produced the mucus-activatable Stx2d and that a subset of the strains tested were virulent in streptomycin-treated mice. C1 [Melton-Celsa, Angela R.; O'Brien, Alison D.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Feng, Peter C. H.] US FDA, Div Microbiol, College Pk, MD 20740 USA. RP Melton-Celsa, AR (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. EM angela.melton-celsa.ctr@usuhs.edu FU NIH [R37AI020148] FX This work was supported in part by NIH grant R37AI020148 to A.D.O. NR 32 TC 0 Z9 0 U1 0 U2 1 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD NOV PY 2015 VL 78 IS 11 BP 2085 EP 2088 DI 10.4315/0362-028X.JFP-15-180 PG 4 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CV8CB UT WOS:000364503000020 PM 26555533 ER PT J AU Hockman, DB Dong, M Grigorenko, E Duncan, R AF Hockman, D. B. Dong, M. Grigorenko, E. Duncan, R. TI Validation of Methods for Producing Spiked Blood and Plasma Samples for Use in Sensitivity and Reproducibility Studies Required for FDA Clearance of Diagnostic Devices SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 05-07, 2015 CL Austin, TX SP Assoc Mol Pathol C1 [Hockman, D. B.; Grigorenko, E.] Diatherix Labs, Huntsville, AL USA. [Dong, M.; Duncan, R.] US FDA, Silver Spring, MD USA. RI Hockman, Donna/D-7237-2017 OI Hockman, Donna/0000-0002-1790-0895 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2015 VL 17 IS 6 MA ID40 BP 788 EP 788 PG 1 WC Pathology SC Pathology GA CU8YM UT WOS:000363830000162 ER PT J AU Gutierrez, B Badano, A Samuelson, F AF Gutierrez, Benjamin Badano, Aldo Samuelson, Frank TI Analytic variance estimates of Swank and Fano factors (vol 41, 072102, 2014) SO MEDICAL PHYSICS LA English DT Correction C1 [Gutierrez, Benjamin; Badano, Aldo; Samuelson, Frank] US FDA, Silver Spring, MD 20993 USA. RP Gutierrez, B (reprint author), US FDA, Silver Spring, MD 20993 USA. EM frank.samuelson@fda.hhs.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD NOV PY 2015 VL 42 IS 11 BP 6769 EP 6769 DI 10.1118/1.4932369 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CV6SY UT WOS:000364402100063 PM 26520767 ER PT J AU Troutman, JA Rick, DL Stuard, SB Fisher, J Bartels, MJ AF Troutman, John A. Rick, David L. Stuard, Sharon B. Fisher, Jeffrey Bartels, Michael J. TI Development of a physiologically-based pharmacokinetic model of 2-phenoxyethanol and its metabolite phenoxyacetic acid in rats and humans to address toxicokinetic uncertainty in risk assessment SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Dosimetry; Ethylene glycol phenyl ether; PBPK; Pharmacokinetics; Toxicokinetics; Uncertainty factors ID GLYCOL ETHERS; PARTITION-COEFFICIENTS; EXPOSURE; ETHYLENE; DRINKING; RABBITS AB 2-Phenoxyethanol (PhE) has been shown to induce hepatotoxicity, renal toxicity, and hemolysis at dosages >= 400 mg/kg/day in subchronic and chronic studies in multiple species. To reduce uncertainty associated with interspecies extrapolations and to evaluate the margin of exposure (MOE) for use of PhE in cosmetics and baby products, a physiologically-based pharmacokinetic (PBPK) model of PhE and its metabolite 2-phenoxyacetic acid (PhAA) was developed. The PBPK model incorporated key kinetic processes describing the absorption, distribution, metabolism and excretion of PhE and PhAA following oral and dermal exposures. Simulations of repeat dose rat studies facilitated the selection of systemic AUC as the appropriate dose metric for evaluating internal exposures to PhE and PhAA in rats and humans. Use of the PBPK model resulted in refinement of the total default UF for extrapolation of the animal data to humans from 100 to 25. Based on very conservative assumptions for product composition and aggregate product use, model-predicted exposures to PhE and PhAA resulting from adult and infant exposures to cosmetic products are significantly below the internal dose of PhE observed at the NOAEL dose in rats. Calculated MOEs for all exposure scenarios were above the PBPK-refined UF of 25. (C) 2015 Elsevier Inc. All rights reserved. C1 [Troutman, John A.; Stuard, Sharon B.] Procter & Gamble Co, Cent Prod Safety, Cincinnati, OH 45202 USA. [Rick, David L.; Bartels, Michael J.] Dow Chem Co USA, Toxicol & Environm Res & Consulting, Midland, MI 48674 USA. [Fisher, Jeffrey] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Troutman, JA (reprint author), Procter & Gamble Co, Cent Prod Safety, Cincinnati, OH 45202 USA. EM troutman.ja@pg.com; LRick@dow.com; stuard.sb@pg.com; jeffrey.fisher@fda.hhs.gov; MJBartels@dow.com NR 35 TC 1 Z9 1 U1 8 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD NOV PY 2015 VL 73 IS 2 BP 530 EP 543 DI 10.1016/j.yrtph.2015.07.012 PG 14 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA CV9OY UT WOS:000364617700007 PM 26188115 ER PT J AU Sun, DJD Lee, PI AF Sun, Dajun D. Lee, Ping I. TI Haste Makes Waste: The Interplay Between Dissolution and Precipitation of Supersaturating Formulations SO AAPS JOURNAL LA English DT Editorial Material DE amorphous formulation; kinetic solubility; nonsink dissolution testing; poorly water-soluble drug; supersaturation rate ID AMORPHOUS SOLID DISPERSIONS; POLY(2-HYDROXYETHYL METHACRYLATE) HYDROGELS; WATER-SOLUBLE DRUGS; GASTROINTESTINAL ABSORPTION; EUTECTIC MIXTURES; RELEASE; RATES; PHARMACEUTICALS; GRISEOFULVIN; SOLUBILITY AB Contrary to the early philosophy of supersaturating formulation design for oral solid dosage forms, current evidence shows that an exceedingly high rate of supersaturation generation could result in a suboptimal in vitro dissolution profile and subsequently could reduce the in vivo oral bioavailability of amorphous solid dispersions. In this commentary, we outline recent research efforts on the specific effects of the rate and extent of supersaturation generation on the overall kinetic solubility profiles of supersaturating formulations. Additional insights into an appropriate definition of sink versus nonsink dissolution conditions and the solubility advantage of amorphous pharmaceuticals are also highlighted. The interplay between dissolution and precipitation kinetics should be carefully considered in designing a suitable supersaturating formulation to best improve the dissolution behavior and oral bioavailability of poorly water-soluble drugs. C1 [Sun, Dajun D.; Lee, Ping I.] Univ Toronto, Leslie Dan Fac Pharm, Dept Pharmaceut Sci, Toronto, ON M5S 3M2, Canada. [Sun, Dajun D.] US FDA, Silver Spring, MD 20993 USA. RP Lee, PI (reprint author), Univ Toronto, Leslie Dan Fac Pharm, Dept Pharmaceut Sci, 144 Coll St, Toronto, ON M5S 3M2, Canada. EM ping.lee@utoronto.ca RI Lee, Ping/E-5066-2010 NR 33 TC 3 Z9 3 U1 4 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD NOV PY 2015 VL 17 IS 6 BP 1317 EP 1326 DI 10.1208/s12248-015-9825-6 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CV2RJ UT WOS:000364104100001 PM 26338234 ER PT J AU Wen, H Jung, HJ Li, XH AF Wen, Hong Jung, Huijeong Li, Xuhong TI Drug Delivery Approaches in Addressing Clinical Pharmacology-Related Issues: Opportunities and Challenges SO AAPS JOURNAL LA English DT Review DE absorption, distribution, metabolism, and elimination (ADME); adverse effects; bioequivalence; clinical pharmacology; drug delivery; formulation design; local delivery; long-acting release; modified release; personalized medicine; pharmacokinetic profiles; prodrug; quality; regulatory; targeted delivery; therapeutic performance ID ORAL BIOAVAILABILITY; SOLID DISPERSION; WATER SOLUBILITY; CYCLOSPORINE-A; DESIGN; ABSORPTION; PRODRUGS; DISSOLUTION; SYSTEMS; FORMULATION AB Various drug delivery approaches can be used to maximize therapeutic efficacy and minimize side effects, by impacting absorption, distribution, metabolism, and elimination (ADME) of a drug compound. For those drugs with poor water solubility or low permeability, techniques such as amorphous solid dispersion, liposomes, and complexations have been used to improve their oral bioavailability. Modified release (MR) formulations have been widely used to improve patient compliance, as well as to reduce side effects, especially for those drugs with short half-lives or narrow therapeutic windows. More than ten drugs using sterile long-acting release (LAR) formulations with clear clinical benefit have been successfully marketed. Furthermore, drug delivery systems have been used in delaying drug clearance processes. Additionally, modifying the in vivo drug distribution using targeted delivery systems has significantly improved oncology treatments. All the drug delivery approaches have their advantages and limitations. For both brand and generic drugs, the achievement of consistent quality and therapeutic performance using drug delivery systems can also pose serious challenges in developing a drug for the market, which requires close collaboration among industry, academia, and regulatory agencies. With the advent of personalized medicines, there will be great opportunities and challenges in utilizing drug delivery systems to provide better products and services for patients. C1 [Wen, Hong; Jung, Huijeong] US FDA, Off Gener Drugs, CDER, Silver Spring, MD 20993 USA. [Li, Xuhong] US FDA, Off Pharmaceut Qual, CDER, Silver Spring, MD 20993 USA. RP Wen, H (reprint author), US FDA, Off Gener Drugs, CDER, Silver Spring, MD 20993 USA. EM hong.wen@fda.hhs.gov NR 117 TC 1 Z9 1 U1 6 U2 23 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD NOV PY 2015 VL 17 IS 6 BP 1327 EP 1340 DI 10.1208/s12248-015-9814-9 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CV2RJ UT WOS:000364104100002 PM 26276218 ER PT J AU Levy, MJ Boyneii, MT Rogstad, S Skanchy, DJ Jiang, XH Geerlof-Vidavsky, I AF Levy, Michaella J. Boyneii, Michael T. Rogstad, Sarah Skanchy, David J. Jiang, Xiaohui Geerlof-Vidavsky, Ilan TI Marketplace Analysis of Conjugated Estrogens: Determining the Consistently Present Steroidal Content with LC-MS SO AAPS JOURNAL LA English DT Article DE conjugated estrogens; mass spectrometry; steroidal content ID LIQUID-CHROMATOGRAPHY; EQUINE ESTROGENS; SEPARATION; EFFICACY; WOMEN; MASS AB Conjugated estrogens purified from pregnant mares urine has been used as estrogen hormone replacement therapy since 1942. Previously, methods were proposed to identify and quantify the components of this complex mixture but ultimately were withdrawn due to incomplete characterization of the product and difficulties in transferring the method between laboratories. The aim of the current study is to develop a LC method that can reliably detect multiple steroidal components in conjugated estrogen tablets and measure their relative amount. The method developed was optimized for UHPLC columns, and the elution profile was analyzed using high-resolution mass spectrometry. A total of 60 steroidal components were identified using their exact m/z, product ion spectra of known, and predicted conjugated estrogen structures. These components were consistently present in 23 lots of Premarin tablets spanning two production years. The ten conjugated estrogens identified in the USP monograph and other additional estrogens reported elsewhere are among the 60 steroidal components reported here. The LC-MS method was tested in different laboratories using multiple samples, and the obtained results were reproducible among laboratories. C1 [Levy, Michaella J.; Boyneii, Michael T.; Rogstad, Sarah; Geerlof-Vidavsky, Ilan] US FDA, Div Pharmaceut Anal, Off Testing & Res, Ctr Drug Evaluat & Res, St Louis, MO 63110 USA. [Skanchy, David J.] US FDA, Off New Drug Prod, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Jiang, Xiaohui] US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Geerlof-Vidavsky, I (reprint author), US FDA, Div Pharmaceut Anal, Off Testing & Res, Ctr Drug Evaluat & Res, 645 S Newstead Ave, St Louis, MO 63110 USA. EM ilan.geerlof-vidavsky@fda.hhs.gov NR 15 TC 1 Z9 1 U1 3 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD NOV PY 2015 VL 17 IS 6 BP 1438 EP 1445 DI 10.1208/s12248-015-9805-x PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CV2RJ UT WOS:000364104100012 PM 26242210 ER PT J AU Jiang, WL Makhlouf, F Schuirmann, DJ Zhang, XY Zheng, N Conner, D Yu, LX Lionberger, R AF Jiang, Wenlei Makhlouf, Fairouz Schuirmann, Donald J. Zhang, Xinyuan Zheng, Nan Conner, Dale Yu, Lawrence X. Lionberger, Robert TI A Bioequivalence Approach for Generic Narrow Therapeutic Index Drugs: Evaluation of the Reference-Scaled Approach and Variability Comparison Criterion (vol 17, pg 891, 2015) SO AAPS JOURNAL LA English DT Correction C1 [Jiang, Wenlei; Zhang, Xinyuan; Zheng, Nan; Conner, Dale; Lionberger, Robert] US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Makhlouf, Fairouz; Schuirmann, Donald J.] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Yu, Lawrence X.] US FDA, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Lionberger, R (reprint author), US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM robert.lionberger@fda.hhs.gov NR 1 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD NOV PY 2015 VL 17 IS 6 BP 1519 EP 1519 DI 10.1208/s12248-015-9786-9 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CV2RJ UT WOS:000364104100022 PM 25975618 ER PT J AU Chang, RK Raw, A Lionberger, R Yu, L AF Chang, Rong-Kun Raw, Andre Lionberger, Robert Yu, Lawrence TI Generic Development of Topical Dermatologic Products: Formulation Development, Process Development, and Testing of Topical Dermatologic Products (vol 15, pg 41, 2013) SO AAPS JOURNAL LA English DT Correction C1 [Chang, Rong-Kun; Raw, Andre; Lionberger, Robert; Yu, Lawrence] US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Rockville, MD 20855 USA. RP Raw, A (reprint author), US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, 7500 Standish Pl, Rockville, MD 20855 USA. EM andre.raw@fda.hhs.gov NR 1 TC 0 Z9 0 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD NOV PY 2015 VL 17 IS 6 BP 1522 EP 1522 DI 10.1208/s12248-015-9823-8 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CV2RJ UT WOS:000364104100024 PM 26338233 ER PT J AU Hartman, LJ Heinrich, ML Zovanyi, AM Ingram, MF Hobson, JP Kulesh, DA Craw, PD Jaissle, JG Norwood, DA Minogue, TD AF Hartman, Laurie J. Heinrich, Megan L. Zovanyi, Ashley M. Ingram, Michael F. Hobson, J. Peyton Kulesh, David A. Craw, Philip D. Jaissle, James G. Norwood, David A. Minogue, Timothy D. TI Demonstration of the Pre-Emergency Use Authorization Path Using 3 Minor Groove Binder-Hydrolysis Probe Assays to Detect Escherichia coli O104:H4 SO CLINICAL CHEMISTRY LA English DT Article ID MOLECULAR-PATHOLOGY; TESTS AB BACKGROUND: The Department of Defense (DoD) and the Food and Drug Administration (FDA) have collaboratively worked on a pre-Emergency Use Authorization (pre-EUA) process for in vitro diagnostic (IVD) devices, using FDA's regulatory flexibilities under the EUA authorities. The pre-EUA process enables FDA review of data in anticipation of a request for an EUA, advancing US government public health emergency preparedness efforts. METHODS: The IVD device developed to detect Escherichia coli O104:H4, for which an EUA has not been issued, serves as an example to illustrate that process. Specifically, DoD designed real-time PCR assays to target the virulent E. coli strain O104:H4 (etiological agent of the 2011 German outbreak) including: fliC (flagellin), Agg3C (AAF), and rfb (wbwC) on the basis of the published sequences. RESULTS: After development and optimization of these 3 specific assays, a defined protocol was followed to determine and document the sensitivity and specificity of each assay analytically. CONCLUSIONS: FDA reviewed these data and returned commentary on additional required experiments to complete the pre-EUA process and expedite the use of the device should there be an emergency need for an IVD device to detect this virulent E. coli strain before such a test is cleared by FDA. (C) 2015 American Association for Clinical Chemistry C1 [Hartman, Laurie J.; Heinrich, Megan L.; Zovanyi, Ashley M.; Ingram, Michael F.; Kulesh, David A.; Craw, Philip D.; Jaissle, James G.; Norwood, David A.; Minogue, Timothy D.] US Army Med Res Inst Infect Dis, Diagnost Syst Div, Ft Detrick, MD USA. [Hartman, Laurie J.] Clin RM, Hinckley, OH USA. [Hobson, J. Peyton] Food & Drug Adm, Silver Spring, MD USA. RP Minogue, TD (reprint author), 1425 Porter St, Frederick, MD 21702 USA. EM timothy.d.minogue.civ@mail.mil NR 13 TC 0 Z9 0 U1 1 U2 2 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD NOV PY 2015 VL 61 IS 11 BP 1391 EP 1398 DI 10.1373/clinchem.2015.242750 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA CV2UH UT WOS:000364112200012 PM 26384353 ER PT J AU Yamazaki, M Dwyer, K Sobhan, M Davis, D Kim, MJ Soule, L Willett, G Yu, C AF Yamazaki, Michiyo Dwyer, Kate Sobhan, Mahboob Davis, Daniel Kim, Myong-Jin Soule, Lisa Willett, Gerald Yu, Chongwoo TI Effect of obesity on the effectiveness of hormonal contraceptives: an individual participant data meta-analysis SO CONTRACEPTION LA English DT Article DE Obesity; Body mass index; Contraceptive effectiveness; Meta-analysis; Hazard ratio ID ORAL-CONTRACEPTIVES; EMERGENCY CONTRACEPTION; ULIPRISTAL ACETATE; SYSTEMATIC REVIEWS; RANDOMIZED-TRIALS; NATIONAL-SURVEY; FAMILY GROWTH; NORMAL-WEIGHT; PATIENT DATA; WOMEN AB Objective: The objective of this investigation was to assess the potential effect of obesity on the effectiveness of hormonal contraceptives (HCs). Study Design: A meta-analysis was conducted using individual participant data directly from the Phase 3 clinical trials of combination oral contraceptives (COCs) rather than extracting summary data from literature. Trials selected were reviewed by the US Food and Drug Administration (FDA) between 2000 and 2012, conducted in North America, had more than six 28-day cycle equivalents of exposure, and had readily retrievable participant-level data. Contraceptive effectiveness was measured by the Pearl Index (PI: the number of pregnancies per 100 woman-years) in women aged 18-35 at risk of unintended pregnancy. The incidence rate ratio (IRR), a ratio of PIs for obese women (defined as body mass index [BMI] >= 30 kg/m(2)) compared to non-obese women (BMI <30 kg/m(2)) was calculated. A Cox proportional-hazard regression model with fixed and random-effects were used to estimate hazard ratios (HRs) for unintended pregnancy in obese women compared to non-obese women. Results: Seven clinical trials with COCs (N=14,024: 2707 obese and 11,317 non-obese women) met the inclusion criteria for the meta-analysis. The PI for each trial varied: 2.05-5.08 for obese and 1.84-3.80 for non-obese women. The pooled PI estimated using direct weighted average method was 3.14 (95% CI: 2.33-4.22) for obese and 2.53 (95% CI: 1.88-3.41) for non-obese women. The pooled IRRs estimated using direct weighted average and Mantel-Haenszel adjustment methods were comparable: 1.37 (95% CI: 1.02-1.84) and 1.43 (95% CI: 1.07-1.92), respectively. The overall HR of 1.44 (95% CI: 1.06-1.95; p=.018) in the meta-analysis suggested a 44% higher pregnancy rate during COC use for obese women after adjusting for age and race. Implications Statement: Obesity may increase the risk of unintended pregnancy in women using COCs; more data on obese women from ongoing and future Phase 3 clinical trials are necessary to allow further evaluation of this topic. Conclusions: Results of this meta-analysis suggest that obese women may have a higher pregnancy rate during COC use compared to non-obese women. Future analysis should assess differences in pharmacodynamics or compliance that could potentially account for the observed difference in unintended pregnancy rates. Published by Elsevier Inc. C1 [Yamazaki, Michiyo; Kim, Myong-Jin; Yu, Chongwoo] US FDA, Div Clin Pharmacol 3, Off Clin Pharmacol, OTS,CDER, Silver Spring, MD 20993 USA. [Dwyer, Kate; Sobhan, Mahboob] US FDA, Div Biostat 3, Off Biostat, OTS,CDER, Silver Spring, MD 20993 USA. [Davis, Daniel; Soule, Lisa; Willett, Gerald] US FDA, Div Bone Reprod & Urol Prod, Off New Drugs, CDER, Silver Spring, MD 20993 USA. RP Yu, C (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM chongwoo.yu@fda.hhs.gov FU Intramural Research Science Program of the Office of Women's Health (OWH) at the U.S. Food and Drug Administration (FDA) FX Funding for this study was provided through the Intramural Research Science Program of the Office of Women's Health (OWH) at the U.S. Food and Drug Administration (FDA). NR 39 TC 8 Z9 8 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0010-7824 EI 1879-0518 J9 CONTRACEPTION JI Contraception PD NOV PY 2015 VL 92 IS 5 BP 445 EP 452 DI 10.1016/j.contraception.2015.07.016 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CV4YY UT WOS:000364273600004 PM 26247330 ER PT J AU Swisher, JFA Feldman, GM AF Swisher, Jennifer F. A. Feldman, Gerald M. TI The many faces of FcRI: implications for therapeutic antibody function SO IMMUNOLOGICAL REVIEWS LA English DT Review DE FcRI; immune complexes; therapeutic antibodies ID C-REACTIVE PROTEIN; GAMMA-RI CD64; TUMOR-ASSOCIATED MACROPHAGES; HIGH-AFFINITY RECEPTOR; PERSISTENT VIRAL-INFECTION; COLONY-STIMULATING FACTOR; MYELIN BASIC-PROTEIN; IGG IMMUNE-COMPLEXES; IFN-GAMMA; MONOCLONAL-ANTIBODY AB Fc receptor I (FcRI or CD64) is the sole human Fc receptor with high affinity for monovalent IgG. While it contains an immunoreceptor tyrosine-based activation motif in its cytoplasmic domain, binding of FcRI can result in a complex array of activating and inhibitory outcomes. For instance, binding of monomeric IgG provides a low-intensity tonic signal through FcRI that is necessary for full interferon receptor signaling in the same cell. Interaction of FcRI with larger high-avidity complexes can result in phagocytosis, the generation of reactive oxygen species, as well as the synthesis and release of inflammatory cytokines. However, numerous reports also document potent anti-inflammatory effects brought about by FcRI engagement with immune complexes such as the inhibition of IFN and TLR4 signaling, and secretion of interleukin-10. This has led to conflicting hypotheses regarding the function of FcRI, especially with regard to its role in the efficacy of several therapeutic monoclonal antibodies. While many of these issues are still unclear, continued characterization of the regulation and context dependence of FcRI function, as well as the molecular mechanisms responsible for these various outcomes, will improve our understanding of FcRI biology as well as the therapeutic strategies designed to harness or constrain its actions. C1 [Swisher, Jennifer F. A.; Feldman, Gerald M.] Ctr Drug Evaluat & Res Food & Drug Adm, Immunobiol Lab, Div Biotechnol Res & Review 4, Off Biotechnol Prod, Silver Spring, MD 20993 USA. RP Swisher, JFA (reprint author), Ctr Drug Evaluat & Res Food & Drug Adm, Immunobiol Lab, Div Biotechnol Res & Review 4, Off Biotechnol Prod, WO52-72 Rm 2326,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jennifer.swisher@fda.hhs.gov NR 138 TC 5 Z9 5 U1 3 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD NOV PY 2015 VL 268 IS 1 SI SI BP 160 EP 174 DI 10.1111/imr.12334 PG 15 WC Immunology SC Immunology GA CU9TJ UT WOS:000363887900011 PM 26497519 ER PT J AU Nagaraja, S Palepu, V Peck, JH Helgeson, MD AF Nagaraja, Srinidhi Palepu, Vivek Peck, Jonathan H. Helgeson, Melvin D. TI Impact of screw location and endplate preparation on pullout strength for anterior plates and integrated fixation cages SO SPINE JOURNAL LA English DT Article DE Anterior plate; End plate thickness; Integrated fixation; Intervertebral cageScrew pullout; Spine ID LUMBAR INTERBODY FUSION; BONE-MINERAL DENSITY; BIOMECHANICAL ANALYSIS; ASYMPTOMATIC SUBJECTS; INSERTION TORQUE; PILOT HOLE; DISABILITY; DEVICE; SPINE; PAIN AB BACKGROUND CONTEXT: Numerous integrated fixation cages (IFCs) have recently been introduced to the market with "zero-profile" designs that incorporate screw fixation through the vertebral endplate. It is unclear whether differences in bone quality and quantity in this insertion location may affect fixation compared with screws used in traditional anterior plate (AP) fixation. Moreover, endplate preparation for IFC implantation may affect fixation strength. PURPOSE: This study aimed to compare pullout strength of screws used in IFCs with screws used for AP implantations. STUDY DESIGN: A biomechanical cadaveric study. METHODS: T-12 and L-1 vertebrae from 13 human cadaver spines were prepared for pullout testing. End plates in T12 vertebrae were scraped according to surgical practice for fusion procedures. Conversely, endplates in L1 vertebrae were kept intact (unscraped). Integrated fixation cage screws were implanted at a 45 degrees angle into the endplate and AP screws were implanted horizontally into the same vertebral body. Pullout testing was performed on all screws, and peak pullout force (PPF) and work were compared between groups to determine fixation strength. In addition, micro-CT imaging was used to assess bone quantity and quality parameters such as trabecular bone volume fraction, endplate and anterior cortex thickness at screw insertion location, endplate mineralization, and anterior cortex mineralization. RESULTS: Peak pullout force for IFC screws (176 +/- 68 N) with scraped endplates was similar (p=.26) to AP screws (192 +/- 84 N). However, PPF for IFC screws (231 +/- 75 N) with unscraped endplates was significantly greater (p<.01) than AP screws (176 +/- 50 N). Peak pullout force for IFC screws with scraped endplates was significantly lower (p=.03) than IFC screws with unscraped endplates. Scraped endplates group (0.17 +/- 0.05 mm) were thinner (p=.05) than unscraped endplates (0.21 +/- 0.06 mm) by approximately 40 mu on average. CONCLUSIONS: These data indicate that IFC and AP screws exhibited similar fixation behavior when the endplate is prepared according to common surgical practices. However, endplate scraping reduces endplate thickness by 20% on average, resulting in a decrease in fixation strength when compared with the unscraped endplates and provides bounds for IFC screw fixation strength. Published by Elsevier Inc. C1 [Nagaraja, Srinidhi; Palepu, Vivek] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Appl Mech, Silver Spring, MD 20993 USA. [Peck, Jonathan H.] US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Div Orthoped Devices, Silver Spring, MD 20993 USA. [Helgeson, Melvin D.] Walter Reed Natl Mil Med Ctr, Dept Orthopaed Surg, Bethesda, MD 20889 USA. RP Nagaraja, S (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Build796 9932, Rockville, MD 20857 USA. EM srinidhi.nagaraja@fda.hhs.gov RI Palepu, Vivek/P-5446-2016; OI NAGARAJA, SRINIDHI/0000-0001-7394-7164 FU FDA's Office of Women's Health FX This study was funded by a grant through the FDA's Office of Women's Health. The authors would like to thank Valerie Elliott and David Baer, PhD, at United States Department of Agriculture for aid with DEXA measurements, and David Hwang at FDA for aid in study design. NR 26 TC 1 Z9 1 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1529-9430 EI 1878-1632 J9 SPINE J JI Spine Journal PD NOV 1 PY 2015 VL 15 IS 11 BP 2425 EP 2432 DI 10.1016/j.spinee.2015.07.454 PG 8 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA CV3QO UT WOS:000364173900039 PM 26235470 ER PT J AU Buckler, AJ Danagoulian, J Johnson, K Peskin, A Gavrielides, MA Petrick, N Obuchowski, NA Beaumont, H Hadjiiski, L Jarecha, R Kuhnigk, JM Mantri, N McNitt-Gray, M Moltz, JH Nyiri, G Peterson, S Terve, P Tietjen, C von Lavante, E Ma, XN St Pierre, S Athelogou, M AF Buckler, Andrew J. Danagoulian, Jovanna Johnson, Kjell Peskin, Adele Gavrielides, Marios A. Petrick, Nicholas Obuchowski, Nancy A. Beaumont, Hubert Hadjiiski, Lubomir Jarecha, Rudresh Kuhnigk, Jan-Martin Mantri, Ninad McNitt-Gray, Michael Moltz, Jan H. Nyiri, Gergely Peterson, Sam Terve, Pierre Tietjen, Christian von Lavante, Etienne Ma, Xiaonan St Pierre, Samantha Athelogou, Maria TI Inter-Method Performance Study of Tumor Volumetry Assessment on Computed Tomography Test-Retest Data SO ACADEMIC RADIOLOGY LA English DT Article DE CT; volumetry; lung cancer; quantitative imaging; segmentation ID QUANTITATIVE IMAGING BIOMARKERS; NODULE SIZE ESTIMATION; PULMONARY NODULES; THORACIC CT; AIDED VOLUMETRY; DATA SETS; PHANTOM; RECONSTRUCTION; VARIABILITY; ERROR AB Rationale and objectives: Tumor volume change has potential as a biomarker for diagnosis, therapy planning, and treatment response. Precision was evaluated and compared among semiautomated lung tumor volume measurement algorithms from clinical thoracic computed tomography data sets. The results inform approaches and testing requirements for establishing conformance with the Quantitative Imaging Biomarker Alliance (QIBA) Computed Tomography Volumetry Profile. Materials and Methods: Industry and academic groups participated in a challenge study. Intra-algorithm repeatability and inter-algorithm reproducibility were estimated. Relative magnitudes of various sources of variability were estimated using a linear mixed effects model. Segmentation boundaries were compared to provide a basis on which to optimize algorithm performance for developers. Results: Intra-algorithm repeatability ranged from 13% (best performing) to 100% (least performing), with most algorithms demonstrating improved repeatability as the tumor size increased. Inter-algorithm reproducibility was determined in three partitions and was found to be 58% for the four best performing groups, 70% for the set of groups meeting repeatability requirements, and 84% when all groups but the least performer were included. The best performing partition performed markedly better on tumors with equivalent diameters greater than 40 mm. Larger tumors benefitted by human editing but smaller tumors did not. One-fifth to one-half of the total variability came from sources independent of the algorithms. Segmentation boundaries differed substantially, not ony in overall volume but also in detail. Conclusions: Nine of the 12 participating algorithms pass precision requirements similar to what is indicated in the QIBA Profile, with the caveat that the present study was not designed to explicitly evaluate algorithm profile conformance. Change in tumor volume can be measured with confidence to within +/- 14% using any of these nine algorithms on tumor sizes greater than 10 mm. No partition of the algorithms was able to meet the QIBA requirements for interchangeability down to 10 mm, although the partition comprising best performing algorithms did meet this requirement for a tumor size of greater than approximately 40 mm. C1 [Buckler, Andrew J.; Danagoulian, Jovanna; Ma, Xiaonan; St Pierre, Samantha] Elucid Bioimaging Inc, Wenham, MA 01984 USA. [Johnson, Kjell] Arbor Analyt LLC, Ann Arbor, MI USA. [Peskin, Adele] NIST, Boulder, CO USA. [Gavrielides, Marios A.; Petrick, Nicholas] US FDA, Silver Spring, MD USA. [Obuchowski, Nancy A.] Cleveland Clin, Cleveland, OH 44106 USA. [Beaumont, Hubert] MEDIAN Technol, Valbonne, France. [Hadjiiski, Lubomir] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Jarecha, Rudresh] Sundew Properties SEZ Pvt Ltd Mindspace, Percept Informat, Hyderabad, Andhra Pradesh, India. [Kuhnigk, Jan-Martin; Moltz, Jan H.] Fraunhofer MEVIS, Inst Med Image Comp, Bremen, Germany. [Mantri, Ninad] ICON Med Imaging, Warrington, PA USA. [McNitt-Gray, Michael] Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA USA. [Nyiri, Gergely] GE Healthcare, Buc, France. [Peterson, Sam] Vital Images Inc, Los Angeles, CA USA. [Terve, Pierre] KEOSYS, St Herblain, France. [Tietjen, Christian] Siemens AG, Imaging & Therapy Div, Healthcare Sect, Forchheim, Germany. [von Lavante, Etienne] Mirada Med Ltd, Oxford Ctr Innovat, Oxford, England. [Athelogou, Maria] Definiens AG, Munich, Germany. RP Buckler, AJ (reprint author), Elucid Bioimaging Inc, 225 Main St, Wenham, MA 01984 USA. EM andrew.buckler@elucidbio.com OI Buckler, Andrew/0000-0002-0786-4835 FU National Institute of Biomedical Imaging and Bioengineering (NIBIB) [HHSN268201300071C] FX The challenge study could not have taken place without the active participation by the organizations that submitted data. We also acknowledge the crucial logistical support from the RSNA staff in administering the application process, which included anonymized interactions among participating study groups, funding provided by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) to defray statistical analysis costs (specifically, this manuscript was prepared in compliance with contract number HHSN268201300071C), and of course the groups themselves as without their effort to produce the submissions there would have been no project. NR 46 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD NOV PY 2015 VL 22 IS 11 BP 1393 EP 1408 DI 10.1016/j.acra.2015.08.007 PG 16 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CU5WG UT WOS:000363602100009 PM 26376841 ER PT J AU Raney, SG Franz, TJ Lehman, PA Lionberger, R Chen, ML AF Raney, Sam G. Franz, Thomas J. Lehman, Paul A. Lionberger, Robert Chen, Mei-Ling TI Pharmacokinetics-Based Approaches for Bioequivalence Evaluation of Topical Dermatological Drug Products SO CLINICAL PHARMACOKINETICS LA English DT Review ID BETAMETHASONE DIPROPIONATE; PERCUTANEOUS PENETRATION; GENERIC DEVELOPMENT; DOSAGE REGIMENS; BIOAVAILABILITY; SKIN; MICRODIALYSIS; DERMATOPHARMACOKINETICS; FORMULATIONS; ABSORPTION AB The pharmacokinetic approach has accelerated the development of high-quality generic medicines with extraordinary cost savings, transforming the pharmaceutical industry and healthcare system in the USA. While this is true for systemically absorbed drug products, the availability of generic versions of topical dermatological products remains constrained due to the limited methods accepted for bioequivalence evaluation of these products. The current review explores the possibility of developing appropriate bioequivalence approaches based on pharmacokinetic principles for topical dermatological products. This review focuses on the strengths and limitations of the three most promising pharmacokinetics-based methods to evaluate the performance and bioequivalence of topical dermatological products, which include in vivo skin stripping, in vivo microdialysis, and in vitro permeation testing (IVPT) with excised human skin. It is hoped that recent advances in pharmaceutical and regulatory science will facilitate the development of robust bioequivalence approaches for these dosage forms, enable more efficient methodologies to compare the performance of new drug products in certain pre-approval or post-approval change situations, and promote the availability of high-quality generic versions of topical dermatological products. C1 [Raney, Sam G.; Lionberger, Robert] US FDA, Off Res & Stand, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Lehman, Paul A.] QPS Holdings LLC, Newark, DE USA. [Chen, Mei-Ling] US FDA, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Raney, SG (reprint author), US FDA, Off Res & Stand, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Sameersingh.Raney@fda.hhs.gov NR 63 TC 5 Z9 5 U1 3 U2 27 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0312-5963 EI 1179-1926 J9 CLIN PHARMACOKINET JI Clin. Pharmacokinet. PD NOV PY 2015 VL 54 IS 11 BP 1095 EP 1106 DI 10.1007/s40262-015-0292-0 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CU7MJ UT WOS:000363723600002 PM 26063051 ER PT J AU Li, DC Mackowiak, B Brayman, TG Mitchell, M Zhang, L Huang, SM Wang, HB AF Li, Daochuan Mackowiak, Bryan Brayman, Timothy G. Mitchell, Michael Zhang, Lei Huang, Shiew-Mei Wang, Hongbing TI Genome-wide analysis of human constitutive androstane receptor (CAR) transcriptome in wild-type and CAR-knockout HepaRG cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE HepaRG; CAR; Gene knockout; RNA-seq; Phenobarbital; CITCO ID PREGNANE-X-RECEPTOR; PRIMARY HUMAN HEPATOCYTES; NUCLEAR RECEPTORS; DRUG-METABOLISM; CYTOCHROMES P450; GENE-EXPRESSION; ENHANCER MODULE; HEPG2 CELLS; CYP2B GENE; LIVER AB The constitutive androstane receptor (CAR) modulates the transcription of numerous genes involving drug metabolism, energy homeostasis, and cell proliferation. Most functions of CAR however were defined from animal studies. Given the known species difference of CAR and the significant cross-talk between CAR and the pregnane X receptor (PXR), it is extremely difficult to decipher the exact role of human CAR (hCAR) in gene regulation, relying predominantly on pharmacological manipulations. Here, utilizing a newly generated hCAR-knockout (KO) HepaRG cell line, we carried out RNA-seq analysis of the global transcriptomes in wild-type (WT) and hCAR-KO HepaRG cells treated with CITCO, a selective hCAR agonist, phenobarbital (PB), a dual activator of hCAR and hPXR, or vehicle control. Real-time PCR assays in separate experiments were used to validate RNA-seq findings. Our results indicate that genes encoding drug-metabolizing enzymes are among the main clusters altered by both CITCO and PB. Specifically, CITCO significantly changed the expression of 135 genes in an hCAR-dependent manner, while PB altered the expression of 227 genes in WT cells of which 94 were simultaneously modulated in both cell lines reflecting dual effects of PB on hCAR/PXR. Notably, we found that many genes promoting cell proliferation and tumorigenesis were up-regulated in hCAR-KO cells, suggesting that hCAR may play an important role in cell growth that differs from mouse CAR. Together, our results reveal both novel and known targets of hCAR and support the role of hCAR in maintaining the homeostasis of metabolism and cell proliferation in the liver. (C) 2015 Elsevier Inc. All rights reserved. C1 [Li, Daochuan; Mackowiak, Bryan; Wang, Hongbing] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Brayman, Timothy G.; Mitchell, Michael] Sigma Life Sci, St Louis, MO 63103 USA. [Zhang, Lei; Huang, Shiew-Mei] Food & Drug Adm, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20901 USA. RP Wang, HB (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, 20 Penn St, Baltimore, MD 21201 USA. EM hwang@rx.umaryland.edu FU National Institutes of Health [DK061652, GM107058]; FDA Oak Ridge Institute for Science and Education (ORISE) postdoctoral fellowship FX The authors thank Sigma-Aldrich for providing the Wild-type and hCAR-KO HepaRG cells. This work was partly supported by the National Institutes of Health grants DK061652 and GM107058. DL is supported by the FDA Oak Ridge Institute for Science and Education (ORISE) postdoctoral fellowship. NR 56 TC 8 Z9 8 U1 2 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD NOV 1 PY 2015 VL 98 IS 1 BP 190 EP 202 DI 10.1016/j.bcp.2015.08.087 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CU2LG UT WOS:000363354400017 PM 26275810 ER PT J AU Yu, DAK Green, B Tolleson, WH Jin, YQ Mei, N Guo, YL Deng, HL Pogribny, I Ning, BT AF Yu, Dianke Green, Bridgett Tolleson, William H. Jin, Yaqiong Mei, Nan Guo, Yongli Deng, Helen Pogribny, Igor Ning, Baitang TI MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE hsa-miR-29a-3p; CYP2C19; Drug metabolizing enzymes; Pharmacogenomics; Inter-individual variability; microRNA ID DRUG-METABOLISM; GENE-EXPRESSION; ASSOCIATION; RIFAMPICIN; RECEPTOR; IDENTIFICATION; POLYMORPHISM; INDUCTION; TRANSPORT; GENOTYPE AB Cytochrome P450 2C19 (CYP2C19) is involved in the metabolism of many drugs. Extensive studies have demonstrated that genetic variants and endogenous and environmental factors play important roles in the expression of CYP2C19. However, the role of microRNAs (miRNAs) in controlling CYP2C19 expression has not been investigated completely. In the present study, we performed in silico analysis to rank putative miRNA/CYP2C19 hybrids with regards to the predicted stabilities of their duplexes and then we applied a series of biochemical and molecular assays to elucidate the underlying functional mechanisms for the regulation of CYP2C19 by miRNAs. In silico analysis indicated that hsa-miR-23a-3p and hsa-miR-29a-3p target the coding region of CYP2C19 with hybrid stabilities of -27.5 kcal/mol and -23.3 kcal/mol, respectively. RNA electrophoresis mobility shift assays showed that both hsa-miR-23a-3p and hsa-miR-29a-3p miRNAs were able to bind directly to their cognate targets in the CYP2C19 transcript. Further, a significant inverse correlation was found between chemically-induced up-regulation of hsa-miR-29a-3p and CYP2C19 expression in HepaRG cells. In addition, inverse correlations were also observed in human liver tissue samples between the level of CYP2C19 mRNA expression and both hsa-miR-23a-3p and hsa-miR-29a-3p levels. All these results demonstrated the suppressing role of hsa-miR-29a-3p on CYP2C19 expression. Published by Elsevier Inc. C1 [Yu, Dianke; Green, Bridgett; Tolleson, William H.; Mei, Nan; Pogribny, Igor; Ning, Baitang] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Jin, Yaqiong; Guo, Yongli] Capital Med Univ, Beijing Pediat Res Inst, Beijing Childrens Hosp, Beijing Key Lab Pediat Dis Otolaryngol Head & Nec, Beijing 100045, Peoples R China. [Deng, Helen] Arkansas Dept Hlth, Little Rock, AR 72205 USA. RP Ning, BT (reprint author), Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 100, Jefferson, AR 72079 USA. EM baitang.ning@fda.hhs.gov OI MEI, NAN/0000-0002-3501-9014; Jin, Ya-Qiong/0000-0002-9318-6531 FU National Center for Toxicological Research, U.S. Food and Drug Administration [E0752601] FX This study was supported and funded by the National Center for Toxicological Research (Project E0752601), U.S. Food and Drug Administration. NR 38 TC 10 Z9 10 U1 1 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD NOV 1 PY 2015 VL 98 IS 1 BP 215 EP 223 DI 10.1016/j.bcp.2015.08.094 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CU2LG UT WOS:000363354400019 PM 26296572 ER PT J AU Pignatti, F Ashby, D Brass, EP Eichler, HG Frey, P Hillege, HL Hori, A Levitan, B Liberti, L Loefstedt, RE McAuslane, N Micaleff, A Noel, RA Postmus, D Renn, O Sabourin, BJ Salmonson, T Walker, S AF Pignatti, F. Ashby, D. Brass, E. P. Eichler, H-G Frey, P. Hillege, H. L. Hori, A. Levitan, B. Liberti, L. Loefstedt, R. E. McAuslane, N. Micaleff, A. Noel, R. A. Postmus, D. Renn, O. Sabourin, B. J. Salmonson, T. Walker, S. TI Structured Frameworks to Increase the Transparency of the Assessment of Benefits and Risks of Medicines: Current Status and Possible Future Directions SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Review ID NONPRESCRIPTION DRUGS; DECISION-MAKING AB Structured frameworks for benefit-risk analysis in drug licensing decisions are being implemented across a number of regulatory agencies worldwide. The aim of these frameworks is to aid the analysis and communication of the benefit-risk assessment throughout the development, evaluation, and supervision of medicines. In this review, authors from regulatory agencies, pharmaceutical companies, and academia share their views on the different frameworks and discuss future directions. C1 [Pignatti, F.; Eichler, H-G; Postmus, D.] European Med Agcy, London, England. [Ashby, D.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Brass, E. P.] Harbor UCLA Med Ctr, Dept Med, Torrance, CA 90509 USA. [Frey, P.] Food & Drug Adm, Silver Spring, MD USA. [Hillege, H. L.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Hori, A.] Pharmaceut & Med Devices Agcy, Tokyo, Japan. [Levitan, B.] Janssen Pharmaceut Res & Dev, Titusville, NJ USA. [Liberti, L.; McAuslane, N.; Walker, S.] CIRS, London, England. [Loefstedt, R. E.] Univ Surrey, Risk Res Grp, Ctr Environm Strategy, Guildford GU2 5XH, Surrey, England. [Micaleff, A.] Merck Serono, Geneva, Switzerland. [Noel, R. A.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Renn, O.] Univ Stuttgart, Inst Sozialwissensch, D-70174 Stuttgart, Germany. [Sabourin, B. J.] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Salmonson, T.] Lakemedelsverket, Uppsala, Sweden. RP Pignatti, F (reprint author), European Med Agcy, London, England. EM francesco.pignatti@ema.europa.eu NR 42 TC 6 Z9 6 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD NOV PY 2015 VL 98 IS 5 BP 522 EP 533 DI 10.1002/cpt.203 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CU3DU UT WOS:000363405000022 PM 26261064 ER PT J AU Fan, RZ Amos, CI Wang, YF Weeks, D Li, Y Ren, HB Lobach, I Xiong, MM Moore, JH Boehnke, M AF Fan, Ruzong Amos, Christopher I. Wang, Yifan Weeks, Daniel Li, Yun Ren, Haobo Lobach, Iryna Xiong, Momiao Moore, Jason H. Boehnke, Michael TI Meta-analysis of Complex Diseases at Gene Level by Functional Regression Models SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Fan, Ruzong] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockville, MD USA. [Amos, Christopher I.; Moore, Jason H.] Univ Dartmouth, Hanover, NH USA. [Wang, Yifan] FDA, Silver Spring, MD USA. [Weeks, Daniel] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Li, Yun] Univ N Carolina, Chapel Hill, NC 27515 USA. [Ren, Haobo] Regeneron Pharmaceut Inc, Tarrytown, NY USA. [Lobach, Iryna] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Xiong, Momiao] Univ Texas Houston, Houston, TX USA. [Boehnke, Michael] Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 49 BP 547 EP 548 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500053 ER PT J AU Jiang, Y Xu, YJ Zhang, HP AF Jiang, Yuan Xu, Yaji Zhang, Heping TI Genetic Effect and Association Test for Covariance Heterogeneity in Multiple Trait Comorbidity SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Jiang, Yuan] Oregon State Univ, Corvallis, OR 97331 USA. [Xu, Yaji] US FDA, Rockville, MD 20857 USA. [Zhang, Heping] Yale Univ, New Haven, CT 06520 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 78 BP 559 EP 559 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500082 ER PT J AU Lontok, E Harrington, P Howe, A Kieffer, T Lennerstrand, J Lenz, O McPhee, F Mo, HM Parkin, N Pilot-Matias, T Miller, V AF Lontok, Erik Harrington, Patrick Howe, Anita Kieffer, Tara Lennerstrand, Johan Lenz, Oliver McPhee, Fiona Mo, Hongmei Parkin, Neil Pilot-Matias, Tami Miller, Veronica TI Hepatitis C virus drug resistance-associated substitutions: State of the art summary SO HEPATOLOGY LA English DT Review ID GENOTYPE 1 INFECTION; TREATMENT-NAIVE PATIENTS; NS3/4A PROTEASE INHIBITOR; ACTING ANTIVIRAL AGENTS; INTERFERON-ALPHA 2A; NS5A INHIBITOR; IN-VITRO; PEGYLATED INTERFERON; PLUS RIBAVIRIN; POLYMERASE INHIBITOR AB Hepatitis C virus (HCV) drug development has resulted in treatment regimens composed of interferon-free, all-oral combinations of direct-acting antivirals. While the new regimens are potent and highly efficacious, the full clinical impact of HCV drug resistance, its implications for retreatment, and the potential role of baseline resistance testing remain critical research and clinical questions. In this report, we discuss the viral proteins targeted by HCV direct-acting antivirals and summarize clinically relevant resistance data for compounds that have been approved or are currently in phase 3 clinical trials. Conclusion: This report provides a comprehensive, systematic review of all resistance information available from sponsors' trials as a tool to inform the HCV drug development field. (Hepatology 2015;62:1623-1632) C1 [Lontok, Erik; Miller, Veronica] Univ Calif Berkeley, Forum Collaborat HIV Res, Washington, DC USA. [Harrington, Patrick] Ctr Drug Evaluat & Res, US FDA, Off Antimicrobial Prod, Div Antiviral Prod, Silver Spring, MD USA. [Howe, Anita] Merck Res Labs, West Point, PA USA. [Kieffer, Tara] Vertex Pharmaceut Inc, Boston, MA USA. [Lennerstrand, Johan] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Lenz, Oliver] Janssen Infect Dis, Beerse, Belgium. [McPhee, Fiona] Bristol Myers Squibb Co, Res & Dev, Wallingford, CT 06492 USA. [Mo, Hongmei] Gilead Sci Inc, Foster City, CA 94404 USA. [Parkin, Neil] Data First Consulting Inc, Belmont, CA USA. [Pilot-Matias, Tami] AbbVie Inc, Chicago, IL USA. RP Miller, V (reprint author), Forum Collaborat HIV Res, 1608 Rhode Isl Ave NW,Suite 212, Washington, DC 20036 USA. EM veronicam@berkeley.edu FU Forum for Collaborative HIV Research for the HCV Drug Development Advisory Group Project FX Supported by unrestricted grants received by the Forum for Collaborative HIV Research for the HCV Drug Development Advisory Group Project (to E.L., V.M.). NR 76 TC 56 Z9 59 U1 5 U2 11 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 NOV PY 2015 VL 62 IS 5 BP 1623 EP 1632 DI 10.1002/hep.27934 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CU1EZ UT WOS:000363264100031 PM 26095927 ER PT J AU Lian, CG Xu, SY Guo, WM Yan, J Frank, MYM Liu, R Liu, C Chen, Y Murphy, GF Chen, T AF Lian, Christine Guo Xu, Shuyun Guo, Weimin Yan, Jian Frank, Maximilian Y. M. Liu, Robert Liu, Cynthia Chen, Ying Murphy, George F. Chen, Tao TI Decrease of 5-hydroxymethylcytosine in rat liver with subchronic exposure to genotoxic carcinogens riddelliine and aristolochic acid SO MOLECULAR CARCINOGENESIS LA English DT Article DE 5-hydroxymethylcytosine; mutagenesis; carcinogenesis; riddelliine; aristolochic acid; ten-eleven translocation ID BIG BLUE RATS; MUTATIONS; GENE; MICE AB The level of 5-hydroxymethylcytosine (5-hmC) converted by ten-eleven translocation (TET) family is decreased in cancers. However, whether 5-hmC level is perturbed in early stages of carcinogenesis caused by genotoxic carcinogens is not defined. 5-hmC levels and TET2 expression were measured in liver of rats treated with genotoxic carcinogens, riddelliine, or aristolochic acid. Levels of 5-hmC and TET2 expression decreased in the liver of the carcinogens-treated rats. Loss of 5-hmC correlates well with documented induction of genetic mutations by the carcinogens, suggesting that TET2-mediated 5-hydroxymethylation plays an epigenetic role in early state of carcinogenesis. (c) 2014 Wiley Periodicals, Inc. C1 [Lian, Christine Guo; Xu, Shuyun; Guo, Weimin; Frank, Maximilian Y. M.; Liu, Robert; Liu, Cynthia; Murphy, George F.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Program Dermatopathol,Dept Pathol, Boston, MA 02115 USA. [Yan, Jian; Chen, Ying; Chen, Tao] Natl Ctr Toxicol Res, Food & Drug Adm, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. RP Lian, CG (reprint author), Brigham & Womens Hosp, Dept Pathol, Div Dermatopathol, 221 Longwood Ave, Boston, MA 02115 USA. FU [R01 HL84815]; [R01 CA158467] FX Grant sponsor: (GFM); Grant number: R01 HL84815; Grant sponsor: (GFM); Grant number: R01 CA158467 NR 21 TC 3 Z9 3 U1 0 U2 3 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 NOV PY 2015 VL 54 IS 11 BP 1503 EP 1507 DI 10.1002/mc.22201 PG 5 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA CU0PX UT WOS:000363220700024 PM 25154389 ER PT J AU Mohan, N Wu, WJ AF Mohan, Nishant Wu, Wen Jin TI Trastuzumab is not a tyrosine kinase inhibitor SO NATURE REVIEWS CARDIOLOGY LA English DT Letter ID BREAST-CANCER CELLS; THERAPY C1 [Mohan, Nishant; Wu, Wen Jin] US FDA, Div Biotechnol Res & Review 1, Off Biotechnol Prod, Ctr Drug Evaluat & Res,Off Pharmaceut Qual, Silver Spring, MD 20993 USA. RP Wu, WJ (reprint author), US FDA, Div Biotechnol Res & Review 1, Off Biotechnol Prod, Ctr Drug Evaluat & Res,Off Pharmaceut Qual, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM wen.wu@fda.hhs.gov NR 11 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5002 EI 1759-5010 J9 NAT REV CARDIOL JI Nat. Rev. Cardiol. PD NOV PY 2015 VL 12 IS 11 DI 10.1038/nrcardio.2015.135 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU4CN UT WOS:000363474000007 PM 26416004 ER PT J AU Wang, J Lon, HK Lee, SL Burckart, GJ Pisetsky, DS AF Wang, Jian Lon, Hoi-Kei Lee, Shwu-Luan Burckart, Gilbert J. Pisetsky, David S. TI Oligonucleotide-Based Drug Development: Considerations for Clinical Pharmacology and Immunogenicity SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Review DE antisense oligonucleotides; clinical pharmacology; immunogenicity; pharmacokinetics; drug interactions; pharmacodynamics ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; ANTI-DNA ANTIBODIES; KINASE-C-ALPHA; PHASE-II TRIAL; ANTISENSE OLIGONUCLEOTIDE; PROSTATE-CANCER; MESSENGER-RNA; PHARMACOKINETIC INTERACTION; NUCLEIC-ACIDS; SOLID TUMORS AB The field of oligonucleotide (OGN)-based therapeutics has been growing dramatically in the past decade, providing innovative platforms to develop agents for the treatment of a wide variety of clinical conditions. OGN agents have unique physicochemical properties and pharmacokinetic/pharmacodynamic characteristics. This review considers findings from the literature and information on new molecular entities submitted to the US Food and Drug Administration as OGN-based therapeutics. In addition, the article discusses several challenging issues from the perspective of clinical pharmacology, emphasizing the potential of immunogenicity, the effect of renal impairment on OGN exposure, drug-drug interactions, and the utility of pharmacokinetic/pharmacodynamic modeling. The field of OGN-based therapeutics is in evolution and will benefit from further studies as well as clinical experience to formulate guidelines and promote the development of this class of agents. C1 [Wang, Jian; Lon, Hoi-Kei; Burckart, Gilbert J.] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. [Lon, Hoi-Kei] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. [Lee, Shwu-Luan] US FDA, Off Hematol & Oncol Prod, Off New Drugs, Silver Spring, MD USA. [Pisetsky, David S.] Durham VA Med Ctr, Med Res Serv, Durham, NC USA. [Pisetsky, David S.] Duke Univ, Med Ctr, Durham, NC USA. RP Pisetsky, DS (reprint author), 508 Fulton St,151G, Durham, NC 27705 USA. EM david.pisetsky@duke.edu FU US FDA; Oak Ridge Institute for Science and Education FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was partially supported by the US FDA Regulatory Science and Review Enhancement funding and fellowship support for Dr Lon from Oak Ridge Institute for Science and Education. NR 66 TC 0 Z9 0 U1 2 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD NOV PY 2015 VL 49 IS 6 BP 861 EP 868 DI 10.1177/2168479015592195 PG 8 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA CU2DE UT WOS:000363332100011 ER PT J AU Li, YH Xue, MY Sheng, X Yu, H Zeng, J Thon, V Wang, PG Chen, X AF Li, Yanhong Xue, Mengyang Sheng, Xue Yu, Hai Zeng, Jie Thon, Vireak Wang, Peng G. Chen, Xi TI Substrate promiscuities of beta 1-3-N-acetylglucosaminyltransferases and beta 1-4-galactosyltransferases SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology on Glycobiology - Accelerating Impact across the Biomedical Sciences CY DEC 01-04, 2015 CL San Francisco, CA SP Soc Glycobiol C1 [Li, Yanhong; Xue, Mengyang; Sheng, Xue; Yu, Hai; Zeng, Jie; Thon, Vireak; Chen, Xi] Univ Calif Davis, Davis, CA USA. [Xue, Mengyang] Shandong Univ, Jinan, Shandong, Peoples R China. [Thon, Vireak; Wang, Peng G.] Georgia State Univ, Atlanta, GA 30303 USA. [Thon, Vireak] US FDA, Rockville, MD 20857 USA. [Zeng, Jie] Henan Inst Sci & Technol, Luoyang, Henan, Peoples R China. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2015 VL 25 IS 11 MA 93 BP 1259 EP 1259 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CT7JR UT WOS:000362991500087 ER PT J AU Trainor, EA Nicholson, TL Merkel, TJ AF Trainor, Elizabeth A. Nicholson, Tracy L. Merkel, Tod J. TI Bordetella pertussis transmission SO PATHOGENS AND DISEASE LA English DT Review DE Animal models; Bordetella pertussis; Bordetella bronchiseptica; Whooping cough; aerosol transmission ID VIRULENCE CONTROL-SYSTEM; NONHUMAN PRIMATE MODEL; LYMPHOID-TISSUE NALT; III SECRETION SYSTEM; WHOLE-CELL; HOUSEHOLD EXPOSURE; AIRBORNE TRANSMISSION; RESPIRATORY-INFECTION; BRONCHISEPTICA; VACCINE AB Bordetella pertussis and B. bronchiseptica are Gram-negative bacterial respiratory pathogens. Bordetella pertussis is the causative agent of whooping cough and is considered a human-adapted variant of B. bronchiseptica. Bordetella pertussis and B. bronchiseptica share mechanisms of pathogenesis and are genetically closely related. However, despite the close genetic relatedness, these Bordetella species differ in several classic fundamental aspects of bacterial pathogens such as host range, pathologies and persistence. The development of the baboon model for the study of B. pertussis transmission, along with the development of the swine and mouse model for the study of B. bronchiseptica, has enabled the investigation of different aspects of transmission including the route, attack rate, role of bacterial and host factors, and the impact of vaccination on transmission. This review will focus on B. pertussis transmission and how animal models of B. pertussis transmission and transmission models using the closely related B. bronchiseptica have increased our understanding of B. pertussis transmission. C1 [Trainor, Elizabeth A.; Merkel, Tod J.] US FDA, Ctr Biol Evaluat & Res, Div Bacterial Parasit & Allergen Prod, Bethesda, MD 20892 USA. [Nicholson, Tracy L.] USDA ARS, Natl Anim Dis Ctr, Ames, IA 50010 USA. RP Merkel, TJ (reprint author), US FDA, CBER, DBPAP, Lab Resp & Special Pathogens, Bldg 72,Room 3308,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM tod.merkel@fda.hhs.gov NR 59 TC 1 Z9 1 U1 1 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2049-632X J9 PATHOG DIS JI Pathog. Dis. PD NOV PY 2015 VL 73 IS 8 AR ftv068 DI 10.1093/femspd/ftv068 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CT7FA UT WOS:000362978200013 PM 26374235 ER PT J AU Landgren, O Shim, YK Michalek, J Costello, R Burton, D Ketchum, N Calvo, KR Caporaso, N Raveche, E Middleton, D Marti, G Vogt, RF AF Landgren, Ola Shim, Youn K. Michalek, Joel Costello, Rene Burton, Debra Ketchum, Norma Calvo, Katherine R. Caporaso, Neil Raveche, Elizabeth Middleton, Dan Marti, Gerald Vogt, Robert F., Jr. TI Agent Orange Exposure and Monoclonal Gammopathy of Undetermined Significance An Operation Ranch Hand Veteran Cohort Study SO JAMA ONCOLOGY LA English DT Article ID EARLY TREATMENT STRATEGIES; PRECEDES MULTIPLE-MYELOMA; AGRICULTURAL-WORKERS; BIOLOGICAL INSIGHTS; PESTICIDE EXPOSURE; SIGNIFICANCE MGUS; CANCER INCIDENCE; UNITED-STATES; LIGHT-CHAINS; IOWA FARMERS AB IMPORTANCE Multiple myeloma has been classified as exhibiting "limited or suggestive evidence" of an association with exposure to herbicides in Vietnam War veterans. Occupational studies have shown that other pesticides (ie, insecticides, herbicides, fungicides) are associated with excess risk of multiple myeloma and its precursor state, monoclonal gammopathy of undetermined significance (MGUS); however, to our knowledge, no studies have uncovered such an association in Vietnam War veterans. OBJECTIVE To examine the relationship between MGUS and exposure to Agent Orange, including its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in Vietnam War veterans. DESIGN, SETTING, AND PARTICIPANTS This was a prospective cohort study conducted in 2013 to 2014, testing for MGUS in serum specimens collected and stored in 2002 by the Air Force Health Study (AFHS). The relevant exposure data collected by the AFHS was also used. We tested all specimens in 2013 without knowledge of the exposure status. The AFHS included former US Air Force personnel who participated in Operation Ranch Hand (Ranch Hand veterans) and other US Air Force personnel who had similar duties in Southeast Asia during the same time period (1962 to 1971) but were not involved in herbicide spray missions (comparison veterans). Agent Orange was used by the US Air Force personnel who conducted aerial spray missions of herbicides (Operation Ranch Hand) in Vietnam from 1962 to 1971. We included 479 Ranch Hand veterans and 479 comparison veterans who participated in the 2002 follow-up examination of AFHS. EXPOSURES Agent Orange and TCDD. Serum TCDD levels were measured in 1987, 1992, 1997, and 2002. MAIN OUTCOMES AND MEASURES Risk of MGUS measured by prevalence, odds ratios (ORs), and 95% CIs. RESULTS The 479 Ranch Hand veterans and 479 comparison veterans had similar demographic and lifestyle characteristics and medical histories. The crude prevalence of overall MGUS was 7.1%(34 of 479) in Ranch Hand veterans and 3.1% (15 of 479) in comparison veterans. This translated into a 2.4-fold increased risk for MGUS in Ranch Hand veterans than comparison veterans after adjusting for age, race, BMI in 2002, and the change in BMI between 2002 and the time of blood draw for TCDD measurement (adjusted OR, 2.37; 95% CI, 1.27-4.44; P =.007). CONCLUSIONS AND RELEVANCE Operation Ranch Hand veterans have a significantly increased risk of MGUS, supporting an association between Agent Orange exposure and multiple myeloma. C1 [Landgren, Ola; Costello, Rene; Burton, Debra; Caporaso, Neil] NCI, NIH, Bethesda, MD 20892 USA. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Shim, Youn K.; Middleton, Dan] Agcy Tox Subst & Dis Registry, Atlanta, GA USA. [Michalek, Joel; Ketchum, Norma] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Calvo, Katherine R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Raveche, Elizabeth] Rutgers New Jersey Med Sch, Dept Pathol & Lab Med, Newark, NJ USA. [Marti, Gerald] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Vogt, Robert F., Jr.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. RP Landgren, O (reprint author), Mem Sloan Kettering Canc Ctr, Myeloma Serv, 1275 York Ave, New York, NY 10065 USA. EM landgrec@mskcc.org FU Intramural Program at the Agency for Toxic Substances and Disease Registry; Intramural Program at the National Cancer Institute; Air Force Health Study (AFHS) Assets Research Program at the Institute of Medicine FX This study was supported by the Intramural Program at the Agency for Toxic Substances and Disease Registry, the Intramural Program at the National Cancer Institute, and the Air Force Health Study (AFHS) Assets Research Program at the Institute of Medicine through an award to the Centers for Disease Control and Prevention (CDC) Foundation. NR 50 TC 4 Z9 5 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD NOV PY 2015 VL 1 IS 8 BP 1061 EP 1068 DI 10.1001/jamaoncol.2015.2938 PG 8 WC Oncology SC Oncology GA DW5IO UT WOS:000383677700010 PM 26335650 ER PT J AU Bennett, R Hait, J AF Bennett, Reginald Hait, Jennifer TI Recovery of Staphylococcal Enterotoxin in Multiple Phase Foods SO JOURNAL OF FOOD SAFETY LA English DT Article ID ILLNESS; GENES AB Lipids are soluble in organic solvents and staphylococcal enterotoxins are water-soluble. This recognized feature can assist in the recovery of these toxins. Partitioning studies were conducted using a toxin-insoluble organic solvent (CHCl3) treatment for the extraction of toxins from the lipid portion of the tested food products. Enterotoxin serotypes A, B and D were added at toxin concentrations of 2ng/mL to five brands each of whole milk, 1% low fat milk, half and half, eggs, and two kinds of salad dressings. Pre-partition and post-partition extracts from the foods were assayed for toxin recovery using an enzyme-linked immunosorbent assay-based serological method. While the toxin was detected by traditional extraction procedures, toxin levels were retained in the precipitate of the food products. This study demonstrates that CHCl3 treatment in conjunction with concentrating the extract is beneficial when low levels of enterotoxin need to be identified. Practical ApplicationsTraditional extraction methods work well in most low-fat containing foods; however, multiple CHCl3 extractions are advantageous when testing high-lipid containing foods or foods that may contain small traces of enterotoxin. This method proved valuable when extracting small quantities of staphylococcal enterotoxin from the lipid fraction of foods. C1 [Bennett, Reginald; Hait, Jennifer] US FDA, College Pk, MD 20740 USA. RP Bennett, R (reprint author), US FDA, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM reginald.bennett@fda.hhs.gov NR 15 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0149-6085 EI 1745-4565 J9 J FOOD SAFETY JI J. Food Saf. PD NOV PY 2015 VL 35 IS 4 BP 429 EP 439 DI 10.1111/jfs.12191 PG 11 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CT3FU UT WOS:000362693400001 ER PT J AU Donnelly, RP Sheikh, F Dickensheets, H Ramalingam, T Helming, L Gordon, S AF Donnelly, Raymond P. Sheikh, Faruk Dickensheets, Harold Ramalingam, Thirumalai Helming, Laura Gordon, Siamon TI The IL-13 receptor-alpha 1 chain is essential for induction of the alternative macrophage activation pathway by IL-13 but not IL-4 SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Donnelly, Raymond P.; Sheikh, Faruk; Dickensheets, Harold] US FDA, Rockville, MD 20857 USA. [Ramalingam, Thirumalai] NIAID, Bethesda, MD USA. [Helming, Laura] Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-80290 Munich, Germany. [Gordon, Siamon] Univ Oxford, Oxford OX1 2JD, England. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD NOV PY 2015 VL 76 IS 1 MA 43 BP 72 EP 72 DI 10.1016/j.cyto.2015.08.073 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400070 ER PT J AU Shokralla, S Hellberg, RS Handy, SM King, I Hajibabaei, M AF Shokralla, Shadi Hellberg, Rosalee S. Handy, Sara M. King, Ian Hajibabaei, Mehrdad TI A DNA Mini-Barcoding System for Authentication of Processed Fish Products SO SCIENTIFIC REPORTS LA English DT Article ID SPECIES IDENTIFICATION; COMMERCIAL MARKET; SEAFOOD; SUBSTITUTION; GENERATION; GENETICS; IDENTIFY; ORDERS; TUNA AB Species substitution is a form of seafood fraud for the purpose of economic gain. DNA barcoding utilizes species-specific DNA sequence information for specimen identification. Previous work has established the usability of short DNA sequences-mini-barcodes-for identification of specimens harboring degraded DNA. This study aims at establishing a DNA mini-barcoding system for all fish species commonly used in processed fish products in North America. Six mini-barcode primer pairs targeting short (127-314 bp) fragments of the cytochrome c oxidase I (CO1) DNA barcode region were developed by examining over 8,000 DNA barcodes from species in the U.S. Food and Drug Administration (FDA) Seafood List. The mini-barcode primer pairs were then tested against 44 processed fish products representing a range of species and product types. Of the 44 products, 41 (93.2%) could be identified at the species or genus level. The greatest mini-barcoding success rate found with an individual primer pair was 88.6% compared to 20.5% success rate achieved by the full-length DNA barcode primers. Overall, this study presents a mini-barcoding system that can be used to identify a wide range of fish species in commercial products and may be utilized in high throughput DNA sequencing for authentication of heavily processed fish products. C1 [Shokralla, Shadi; King, Ian; Hajibabaei, Mehrdad] Univ Guelph, Biodivers Inst Ontario, Guelph, ON N1G 2W1, Canada. [Shokralla, Shadi; King, Ian; Hajibabaei, Mehrdad] Univ Guelph, Dept Integrat Biol, Guelph, ON N1G 2W1, Canada. [Shokralla, Shadi] Mansoura Univ, Dept Microbiol, Mansoura 35516, Egypt. [Hellberg, Rosalee S.] Chapman Univ, Schmid Coll Sci & Technol, Orange, CA 92866 USA. [Handy, Sara M.] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Shokralla, S (reprint author), Univ Guelph, Biodivers Inst Ontario, Guelph, ON N1G 2W1, Canada. EM sshokral@uoguelph.ca RI Handy, Sara/C-6195-2008 FU Government of Canada through Genome Canada; Ontario Genomics Institute [OGI-050]; Natural Sciences and Engineering Research Council of Canada FX Thanks to Michael Kawalek and Khanh Van at the FDA Pacific Regional Laboratory Southwest for help with sample processing and to Jonathan Deeds at the FDA Center for Food Safety and Applied Nutrition for critical reads of the manuscript. This research was funded through grants from the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-050) and by a Discovery Grant from Natural Sciences and Engineering Research Council of Canada to M.H. NR 43 TC 2 Z9 3 U1 8 U2 37 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 30 PY 2015 VL 5 AR 15894 DI 10.1038/srep15894 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU8GF UT WOS:000363778900001 PM 26516098 ER PT J AU Battistel, MD Azurmendi, HF Frank, M Freedberg, DI AF Battistel, Marcos D. Azurmendi, Hugo F. Frank, Martin Freedberg, Daron I. TI Uncovering Nonconventional and Conventional Hydrogen Bonds in Oligosaccharides through NMR Experiments and Molecular Modeling: Application to Sialyl Lewis-X SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID AQUEOUS-SOLUTION; DYNAMICS; ANTIGEN; COMPLEX; SURFACE AB We describe the direct NMR detection of a C-H center dot center dot center dot O nonconventional hydrogen bond (Hbond) and provide experimental and theoretical evidence for conventional Hbonds in the pentasaccharide sialyl Lewis-X (sLe(X)-5) between 5 and 37 degrees C in water. Extensive NMR structural studies together with molecular dynamics simulations offer strong evidence for significant local dynamics in the Le(X) core and for previously undetected conventional Hbonds in rapid equilibrium that modulate structure. These NMR studies also showed temperature-dependent H-1 and C-13 line broadening. The resulting model emerging from this study is more complex than a simple rigid core description of Le(X)-like molecules and improves our understanding of stabilizing interactions in glycans. C1 [Battistel, Marcos D.; Azurmendi, Hugo F.; Freedberg, Daron I.] US FDA, Lab Bacterial Polysaccharides, Silver Spring, MD 20903 USA. [Frank, Martin] Biognos AB, S-41705 Gothenburg, Sweden. RP Freedberg, DI (reprint author), US FDA, Lab Bacterial Polysaccharides, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM daron.freedberg@fda.hhs.gov NR 23 TC 5 Z9 5 U1 3 U2 22 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD OCT 28 PY 2015 VL 137 IS 42 BP 13444 EP 13447 DI 10.1021/jacs.5b03824 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA CV0DC UT WOS:000363916600002 PM 26426963 ER PT J AU Ravi, A Avershina, E Foley, SL Ludvigsen, J Storro, O Oien, T Johnsen, R McCartney, AL L'Abee-Lund, TM Rudi, K AF Ravi, Anuradha Avershina, Ekaterina Foley, Steven L. Ludvigsen, Jane Storro, Ola Oien, Torbjorn Johnsen, Roar McCartney, Anne L. L'Abee-Lund, Trine M. Rudi, Knut TI The commensal infant gut meta-mobilome as a potential reservoir for persistent multidrug resistance integrons SO SCIENTIFIC REPORTS LA English DT Article ID ANTIBIOTIC-RESISTANCE; SUPER-INTEGRONS; GENE CASSETTES; MICROBIOTA; DIVERSITY; BACTERIA; COHORT; EVOLUTION; RESOURCE; DATABASE AB Despite the accumulating knowledge on the development and establishment of the gut microbiota, its role as a reservoir for multidrug resistance is not well understood. This study investigated the prevalence and persistence patterns of an integrase gene (int1), used as a proxy for integrons (which often carry multiple antimicrobial resistance genes), in the fecal microbiota of 147 mothers and their children sampled longitudinally from birth to 2 years. The study showed the int1 gene was detected in 15% of the study population, and apparently more persistent than the microbial community structure itself. We found int1 to be persistent throughout the first two years of life, as well as between mothers and their 2-year-old children. Metagenome sequencing revealed integrons in the gut meta-mobilome that were associated with plasmids and multidrug resistance. In conclusion, the persistent nature of integrons in the infant gut microbiota makes it a potential reservoir of mobile multidrug resistance. C1 [Ravi, Anuradha; Avershina, Ekaterina; Ludvigsen, Jane; Rudi, Knut] Norwegian Univ Life Sci, Chem Biotechnol & Food Sci Dept IKBM, N-1432 As, Norway. [Foley, Steven L.] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. [Storro, Ola; Oien, Torbjorn; Johnsen, Roar] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, N-9491 Trondheim, Norway. [McCartney, Anne L.] Univ Reading, Dept Food & Nutr Sci, Microbial Ecol & Hlth Grp, Reading, Berks, England. [L'Abee-Lund, Trine M.] Norwegian Univ Life Sci, Dept Food Safety & Infect Biol, N-0454 Oslo, Norway. RP Rudi, K (reprint author), Norwegian Univ Life Sci, Chem Biotechnol & Food Sci Dept IKBM, Campus As, N-1432 As, Norway. EM knut.rudi@nmbu.no FU Quota scholarship; Norwegian University of Life Sciences, As, Norway; Norwegian University of Science and Technology, Trondheim, Norway FX This work was supported by Quota scholarship and funding from Norwegian University of Life Sciences, As, Norway and Norwegian University of Science and Technology, Trondheim, Norway. NR 45 TC 1 Z9 1 U1 3 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 28 PY 2015 VL 5 AR 15317 DI 10.1038/srep15317 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU4SF UT WOS:000363519600001 PM 26507767 ER PT J AU Parra, M Liu, X Derrick, SC Yang, A Molina-Cruz, A Barillas-Mury, C Zheng, H Pham, PT Sedegah, M Belmonte, A Litilit, DD Waldmann, TA Kumar, S Morris, SL Perera, LP AF Parra, Marcela Liu, Xia Derrick, Steven C. Yang, Amy Molina-Cruz, Alvaro Barillas-Mury, Carolina Zheng, Hong Phuong Thao Pham Sedegah, Martha Belmonte, Arnel Litilit, Dianne D. Waldmann, Thomas A. Kumar, Sanjai Morris, Sheldon L. Perera, Liyanage P. TI Co-expression of Interleukin-15 Enhances the Protective Immune Responses Induced by Immunization with a Murine Malaria MVA-Based Vaccine Encoding the Circumsporozoite Protein SO PLOS ONE LA English DT Article AB Malaria remains a major global public health problem with an estimated 200 million cases detected in 2012. Although the most advanced candidate malaria vaccine (RTS,S) has shown promise in clinical trials, its modest efficacy and durability have created uncertainty about the impact of RTS, S immunization (when used alone) on global malaria transmission. Here we describe the development and characterization of a novel modified vaccinia virus Ankara (MVA)-based malaria vaccine which co-expresses the Plasmodium yoelii circumsporozoite protein (CSP) and IL-15. Vaccination/challenge studies showed that C57BL/6 mice immunized with the MVA-CSP/IL15 vaccine were protected significantly better against a P. yoelii 17XNL sporozoite challenge than either mice immunized with an MVA vaccine expressing only CSP or naive controls. Importantly, the levels of total anti-CSP IgG were elevated about 100-fold for the MVA-CSP/IL15 immunized group compared to mice immunized with the MVA-CSP construct that does not express IL-15. Among the IgG subtypes, the IL-15 expressing MVA-CSP vaccine induced levels of IgG1 (8 fold) and IgG2b (80 fold) higher than the MVA-CSP construct. The significantly enhanced humoral responses and protection detected after immunization with the MVA-CSP/IL-15 vaccine suggest that this IL-15 expressing MVA construct could be considered in the development of future malaria immunization strategies. C1 [Parra, Marcela; Liu, Xia; Derrick, Steven C.; Yang, Amy; Zheng, Hong; Kumar, Sanjai; Morris, Sheldon L.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Molina-Cruz, Alvaro; Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, Rockville, MD 20852 USA. [Phuong Thao Pham; Sedegah, Martha; Belmonte, Arnel; Litilit, Dianne D.] Naval Med Res Ctr, Silver Spring, MD 20910 USA. [Waldmann, Thomas A.; Perera, Liyanage P.] NCI, Bethesda, MD 20892 USA. RP Perera, LP (reprint author), NCI, Bethesda, MD 20892 USA. EM pereral@mail.nih.gov FU Intramural Research Programs of the National Cancer Institute, Center for Cancer Research, NIH; Food and Drug Administration FX Funding was provided by the Intramural Research Programs of the National Cancer Institute, Center for Cancer Research, NIH (T.A.W and L.P.P) and the Food and Drug Administration. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 0 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2015 VL 10 IS 10 AR e0141141 DI 10.1371/journal.pone.0141141 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU8PC UT WOS:000363804200032 PM 26505634 ER PT J AU Ferguson, SA Paule, MG He, Z AF Ferguson, Sherry A. Paule, Merle G. He, Zhen TI Pre- and postnatal bisphenol A treatment does not alter the number of tyrosine hydroxylase-positive cells in the anteroventral periventricular nucleus (AVPV) of weanling male and female rats SO BRAIN RESEARCH LA English DT Article DE Bisphenol A; Anteroventral paraventricular nucleus (AVPV); Tyrosine hydroxylase (TH); Prenatal; Postnatal; Rat ID ESTROGEN-RECEPTOR-BETA; SPRAGUE-DAWLEY RATS; SEXUALLY DIMORPHIC NUCLEUS; PREOPTIC AREA; DEVELOPMENTAL TREATMENT; ETHINYL ESTRADIOL; SEX-DIFFERENCES; GONADAL-STEROIDS; RODENT DIETS; DIFFERENTIATION AB Exposure to Bisphenol A (BPA) may interfere with brain sexual differentiation. Altered numbers of tyrosine hydroxylase (TH) cells in the rodent anteroventral petiventricular nucleus (AVPV) after developmental BPA treatment have been reported; however, definitive conclusions are lacking. The current study incorporated many of the guidelines suggested for endocrine disrupter research. Specifically, ethinyl estradiol (EE2) served as a reference estrogen, exogenous environmental estrogen exposure was controlled, BPA was administered orally, and subjects consumed a low phytoestrogen diet. Here, on gestational days 6-21, Sprague-Dawley rats (10-15/group) were gavaged with 2.5 or 25.0 mu g BPA/kg/day or 5.0 or 10.0 mu g EE2/kg/day or the vehicle (5 ml of 0.3% aqueous carboxymethylcellulose/kg/day). A naive control group was weighed and restrained, but not gavaged. Beginning on postnatal day (PND) 1 and continuing until PND 21, the 4 pups/sex/litter were orally treated with the same dose their dam had received. On PND 21, 1/sex/litter was perfused and the brain removed. TH immunoreactivity (TH-ir) was counted in 8 images/pup by a technician blind to treatment status. ANOVA results indicated significantly higher TH-ir cells/mm(2) in females (main effect of sex: p<0.01); however, there was no significant effect of treatment or a significant interaction of treatment with sex. In a separate untreated group of PND 21 Sprague-Dawley pups, AVPV volume was quantified and no significant sexual dimorphism was apparent Similar to our reported results of behavioral assessments, the BPA treatment paradigm used here (2.5 or 25.0 mu g BPA/kg/day administered orally) does not appear to cause significant alterations in AVPV TH-ir. Published by Elsevier B.V. C1 [Ferguson, Sherry A.; Paule, Merle G.; He, Zhen] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Ferguson, SA (reprint author), Natl Ctr Toxicol Res, HFT 132,3900 NCTR Rd, Jefferson, AR 72079 USA. EM Sherry.Ferguson@fda.hhs.gov; Merle.Paule@fda.hhs.gov; Zhen.He@fda.hhs.gov FU National Center for Toxicological Research/Food and Drug Administration [P00706, P00710] FX This work was supported by the National Center for Toxicological Research/Food and Drug Administration [Protocol #P00706 to S.A.F. and Protocol #P00710 to Z.H.]. The authors are grateful for the technical expertise provided by the animal care staff of the Priority One Corporation and appreciate the careful study supervision by Mr. C. Delbert Law of the Division of Neurotoxicology. We are especially indebted to Ms. Tina Williams of Toxicologic Pathology Associates for her meticulous and conscientious cell counting abilities. NR 53 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD OCT 22 PY 2015 VL 1624 BP 1 EP 8 DI 10.1016/j.brainres.2015.07.013 PG 8 WC Neurosciences SC Neurosciences & Neurology GA CW5PY UT WOS:000365050100001 PM 26206302 ER PT J AU Pightling, AW Petronella, N Pagotto, F AF Pightling, Arthur W. Petronella, Nicholas Pagotto, Franco TI The Listeria monocytogenes Core-Genome Sequence Typer (LmCGST): a bioinformatic pipeline for molecular characterization with next-generation sequence data SO BMC MICROBIOLOGY LA English DT Article DE Listeria monocytogenes; Typing; Molecular characterization; Next-generation sequencing; Pulsed-field gel electrophoresis; PFGE; Multi-locus sequence typing; MLST; wgMLST; cgMLST ID FIELD GEL-ELECTROPHORESIS; TYPING METHODS; PAN-GENOME; WALLACE COEFFICIENT; STRAINS; PHYLOGENIES; IDENTIFICATION; CONCORDANCE; COMPONENTS; DIVERSITY AB Background: Next-generation sequencing provides a powerful means of molecular characterization. However, methods such as single-nucleotide polymorphism detection or whole-chromosome sequence analysis are computationally expensive, prone to errors, and are still less accessible than traditional typing methods. Here, we present the Listeria monocytogenes core-genome sequence typing method for molecular characterization. This method uses a high-confidence core (HCC) genome, calculated to ensure accurate identification of orthologs. We also developed an evolutionarily relevant nomenclature based upon phylogenetic analysis of HCC genomes. Finally, we created a pipeline (LmCGST; https://sourceforge.net/projects/lmcgst/files/) that takes in raw next-generation sequencing reads, calculates a subject HCC profile, compares it to an expandable database, assigns a sequence type, and performs a phylogenetic analysis. Results: We analyzed 29 high-quality, closed Listeria monocytogenes chromosome sequences and identified loci that are reliable targets for automated molecular characterization methods. We identified 1013 open-reading frames that comprise our high-confidence core (HCC) genome. We then populated a database with HCC profiles from 114 taxa. We sequenced 84 randomly selected isolates from the Listeriosis Reference Service for Canada's collection and analysed them with the LmCGST pipeline. In addition, we generated pulsed-field gel electrophoresis, ribotyping, and in silico multi-locus sequence typing (MLST) data for the 84 isolates and compared the results to those obtained using the CGST method. We found that all of the methods yielded results that are generally congruent. However, due to the increased numbers of categories, the CGST method provides much greater discriminatory power than the other methods tested here. Conclusions: We show that the CGST method provides increased discriminatory power relative to typing methods such as pulsed-field gel electrophoresis, ribotyping, and multi-locus sequence typing while it addresses several shortcomings of other methods of molecular characterization with next-generation sequence data. It uses discrete, well-defined groupings (types) of organisms that are phylogenetically relevant and easily interpreted. In addition, the CGST scheme can be expanded to include additional loci and HCC profiles in the future. In total, the CGST method provides an approach to the molecular characterization of Listeria monocytogenes with next-generation sequence data that is highly reproducible, easily standardized, portable, and accessible. C1 [Pightling, Arthur W.; Pagotto, Franco] US FDA, Off Analyt & Outreach, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Petronella, Nicholas] Hlth Canada, Hlth Prod & Food Branch, Biostat & Modelling Div, Food Directorate,Bur Food Surveillance & Sci Inte, Ottawa, ON K1A 0K9, Canada. RP Pightling, AW (reprint author), US FDA, Off Analyt & Outreach, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Arthur.Pightling@fda.hhs.gov FU Genomics R&D Initiative (GRDI) grant [4500834] FX This work was funded by Genomics R&D Initiative (GRDI) grant #4500834, awarded to FP. The authors are grateful to Karine Hebert and Kevin Tyler for access to their serotyping, pulsed-field gel electrophoresis, and ribotyping database. We thank Robyn Kenwell for running the Illumina MiSeq sequencer. We also thank two anonymous reviewers whose insightful comments greatly improved the quality of this manuscript. NR 58 TC 9 Z9 9 U1 5 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD OCT 22 PY 2015 VL 15 AR 224 DI 10.1186/s12866-015-0526-1 PG 11 WC Microbiology SC Microbiology GA CT8WQ UT WOS:000363098000002 PM 26490433 ER PT J AU Robinson, BL Dumas, M Paule, MG Ali, SF Kanungo, J AF Robinson, Bonnie L. Dumas, Melanie Paule, Merle G. Ali, Syed F. Kanungo, Jyotshna TI Opposing effects of ketamine and acetyl L-carnitine on the serotonergic system of zebrafish SO NEUROSCIENCE LETTERS LA English DT Article DE Ketamine; Zebrafish; Acetyl L-carnitine; Serotonin; Metabolism; HPLC/EC ID RAT-BRAIN; IN-VIVO; SUBANESTHETIC KETAMINE; INDUCED NEUROTOXICITY; PARKINSONS-DISEASE; GENE-EXPRESSION; OLD DRUG; TOXICITY; EMBRYOS; MODEL AB Ketamine, a pediatric anesthetic, is a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist. Studies show that ketamine is neurotoxic in developing mammals and zebrafish. In both mammals and zebrafish, acetyl L-carnitine (ALCAR) has been shown to be protective against ketamine toxicity. Ketamine is known to modulate the serotonergic system in mammals. Here, we measured the levels of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in the embryos exposed to ketamine in the presence and absence of ALCAR. Ketamine, at lower doses, did not produce significant changes in the 5-HT or 5-HIAA levels in 3 dpf (day post-fertilization) embryos. However, 2 mM ketamine (internal embryo exposure levels comparable to human anesthetic plasma concentration) significantly reduced 5-HT level, and 5-HIAA was not detectable indicating that 5-HT metabolism was abolished. In the presence or absence of 2 mM ketamine, ALCAR by itself did not significantly alter 5-HT or 5-HIAA levels compared to the control. Ratios of metabolite/5-HT indicated that 2 mM ketamine inhibited 5-HT metabolism to 5-HIAA whereas lower doses (0.1-0.3 mM) of ketamine did not have any effect. ALCAR reversed the effects of 2 mM ketamine not only by restoring 5-HT and 5-HIAA levels but also 5-HT turnover rate to control levels. Whole mount immunohistochemical studies showed that 2 mM ketamine reduced the serotonergic area in the brain whereas ALCAR expanded it with increased axonal sprouting and branching. These results indicate that ketamine and ALCAR have opposing effects on the zebrafish serotonergic system. Published by Elsevier Ireland Ltd. C1 [Robinson, Bonnie L.; Dumas, Melanie; Paule, Merle G.; Ali, Syed F.; Kanungo, Jyotshna] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Kanungo, J (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM jyotshnabala.kanungo@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 53 TC 3 Z9 3 U1 1 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD OCT 21 PY 2015 VL 607 BP 17 EP 22 DI 10.1016/j.neulet.2015.09.006 PG 6 WC Neurosciences SC Neurosciences & Neurology GA CW3KK UT WOS:000364891000004 PM 26365406 ER PT J AU Zitomer, N Rybak, ME Li, Z Walters, MJ Holman, MR AF Zitomer, Nicholas Rybak, Michael E. Li, Zhong Walters, Matthew J. Holman, Matthew R. TI Determination of Aflatoxin B-1 in Smokeless Tobacco Products by Use of UHPLC-MS/MS SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE aflatoxins; smokeless tobacco; chewing tobacco; UHPLC-MS/MS; immunoaffinity column chromatography ID CHROMATOGRAPHY/TANDEM MASS-SPECTROMETRY; SOLID-PHASE EXTRACTION; LIQUID-CHROMATOGRAPHY; ISOTOPE-DILUTION; CLEANUP AB This work developed a UHPLC-MS/MS method for the detection and quantitation of aflatoxins in smokeless tobacco products, which was then used to determine aflatoxin B-1 concentrations in 32 smokeless tobacco products commercially available in the United States. Smokeless tobacco products were dried, milled, and amended with C-13(17)-labeled internal standards, extracted in water/methanol solution in the presence of a surfactant, isolated through use of immunoaffinity column chromatography, and reconstituted in mobile phase prior to UHPLC-MS/MS analysis. The method was capable of baseline separation of aflatoxins B-1, B-2, G(1), and G(2) in a 2.5 min run by use of a fused core C-18 column and a water/methanol gradient. MS/MS transition (m/z) 313.3 -> 241.2 was used for aflatoxin B-1 quantitation, with 313.3 -> 285.1 used for confirmation. The limit of detection (LOD) for aflatoxin B-1 was 0.007 parts per billion (ppb). Method imprecision for aflatoxin B1 (expressed as coefficient of variation) ranged from 5.5 to 9.4%. Spike recoveries were 105-111%. Aflatoxin B-1, concentrations in the smokeless tobacco products analyzed ranged from 50% reduction in HAI post-vaccination geometric mean titers against epidemic H3 isolates from those against egg-grown H3 vaccine strain A/Texas/50/2012 (TX/12e). The 2014-15 NH vaccines, regardless of production type, failed to further extend HAI cross-reactivity against H3 epidemic strains from previous seasonal vaccines. Head-to-head comparison between ferret and human antisera derived antigenic maps revealed different antigenic patterns among representative egg-and cell-grown H3 viruses characterized. Molecular modeling indicated that the mutations of epidemic H3 strains were mainly located in antibody-binding sites A and B as compared with TX/12e. To improve vaccine strain selection, human serologic testing on vaccination-induced cross-reactivity need be emphasized along with virus antigenic characterization by ferret model. C1 [Xie, Hang; Ye, Zhiping; Plant, Ewan P.; Zhao, Yangqing; Li, Xing; Finch, Courtney; Kawano, Toshiaki; Zoueva, Olga; Chiang, Meng-Jung; Jing, Xianghong; Lin, Zhengshi; Zhang, Anding; Zhu, Yanhong] US FDA, Lab Resp Viral Dis, Div Viral Prod, Off Vaccines Res & Review,CBER, Silver Spring, MD 20993 USA. [Wan, Xiu-Feng; Xu, Yifei; Zhao, Nan] Mississippi State Univ, Coll Vet Med, Dept Basic Sci, Wise Ctr 240, Mississippi State, MS 39762 USA. RP Xie, H (reprint author), US FDA, Lab Resp Viral Dis, Div Viral Prod, Off Vaccines Res & Review,CBER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Hang.Xie@fda.hhs.gov; Wan@cvm.msstate.edu RI Zhao, Nan/K-4015-2015; OI Zhao, Nan/0000-0002-7897-2374; Plant, Ewan/0000-0003-0166-5939 FU CBER/FDA; NIH [R01AI116744] FX We sincerely appreciate Dr. Xiyan Xu, Influenza Division, Centers for Diseases Control and Prevention, for providing egg- and cell-grown influenza viruses and ferret antisera. We also thank Dr. Marian Major, Division of Viral Products, Office of Vaccine Research and Review, and Dr. Shyh-Ching Lo, Division of Cellular and Gene Therapies, Office of Cellular, Tissue, and Gene Therapies, CBER/FDA, for critical review of this manuscript. This project was supported by the intramural research fund of CBER/FDA. X-F Wan, N Zhao, and Y Xu were supported by NIH grant R01AI116744 to X-F Wan. NR 44 TC 6 Z9 6 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 16 PY 2015 VL 5 AR 15279 DI 10.1038/srep15279 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CT5XI UT WOS:000362884000002 PM 26472175 ER PT J AU Bates, SE Berry, DA Balasubramaniam, S Bailey, S LoRusso, PM Rubin, EH AF Bates, Susan E. Berry, Donald A. Balasubramaniam, Sanjeeve Bailey, Stuart LoRusso, Patricia M. Rubin, Eric H. TI Advancing Clinical Trials to Streamline Drug Development SO CLINICAL CANCER RESEARCH LA English DT Article ID HER2-POSITIVE BREAST-CANCER; DOSE-ESCALATION; OPEN-LABEL; PHASE-III; DESIGN; APPROVAL; CHEMOTHERAPY; PERTUZUMAB; THERAPY AB The last decade in oncology has been marked by the identification of numerous new potential cancer targets and even more agents designed to inhibit them. The matrix of new targets, new agents, and the companion diagnostics required to identify the right patient for the right drug has created a major challenge for the clinical trial process. This has been compounded by the addition of new immunomodulators targeting the host immune system rather than the tumor. Recognizing the need for new approaches, industry, investigators, and regulators have responded to this challenge. New clinical trial designs are being evaluated to incorporate the genomic sequence data being obtained almost routinely after cancer diagnosis. New dose-finding approaches are being proposed to identify the maximum effective dose rather than the maximum tolerated dose. The FDA is involved in the drug approval process from points early in development and has accepted registration quality data from expansion cohorts in support of drug approval. Despite progress on several fronts, many challenges remain, including the lack of predictability of preclinical data for clinical results and phase II data for phase III results, an infrastructure that can be an obstacle to clinical trial development and implementation, and the increasing use of contracted clinical research organizations that limit a fit-for-purpose approach to clinical trial execution. Perhaps most challenging and important of all are the difficulties with clinical trial accrual that can prevent study completion. Both the innovations and the challenges highlight the important role of process in progress in clinical oncology. (C) 2015 AACR. C1 [Bates, Susan E.] NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. [Berry, Donald A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Balasubramaniam, Sanjeeve] FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, Silver Spring, MD USA. [Bailey, Stuart] Novartis Inst BioMed Res, Cambridge, MA USA. [LoRusso, Patricia M.] Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT USA. [Rubin, Eric H.] Merck Res Labs, N Wales, PA USA. RP Bates, SE (reprint author), Columbia Univ, Med Ctr, Div Hematol Oncol, Herbert Irving Pavill,9th Floor, New York, NY 10032 USA. EM seb2227@cumc.columbia.edu OI Balasubramaniam, Sanjeeve/0000-0002-0643-2117 FU Astex Pharmaceuticals; Genentech; Novartis FX D.A. Berry is an employee of and a consultant/advisory board member for Berry Consultants. P.M. LoRusso reports receiving commercial research support from Astex Pharmaceuticals, Genentech, and Novartis; speakers bureau honoraria from Genentech; and is a consultant/advisory board member for Pfizer. No potential conflicts of interest were disclosed by the other authors. NR 42 TC 6 Z9 6 U1 0 U2 7 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 OCT 15 PY 2015 VL 21 IS 20 BP 4527 EP 4535 DI 10.1158/1078-0432.CCR-15-0039 PG 9 WC Oncology SC Oncology GA CV7WH UT WOS:000364486300007 PM 26473188 ER PT J AU Theoret, MR Pai-Scherf, LH Chuk, MK Prowell, TM Balasubramaniam, S Kim, T Kim, G Kluetz, PG Keegan, P Pazdur, R AF Theoret, Marc R. Pai-Scherf, Lee H. Chuk, Meredith K. Prowell, Tatiana M. Balasubramaniam, Sanjeeve Kim, Tamy Kim, Geoffrey Kluetz, Paul G. Keegan, Patricia Pazdur, Richard TI Expansion Cohorts in First-in-Human Solid Tumor Oncology Trials SO CLINICAL CANCER RESEARCH LA English DT Article ID CANCER; PEMBROLIZUMAB AB In 1962, the passage of the Kefauver-Harris Amendment to the 1938 Food, Drug, and Cosmetic Act required that sponsors seeking approval of new drugs demonstrate the drug's efficacy, in addition to its safety, through a formal process that includes "adequate and well-controlled" clinical trials as the basis to support claims of effectiveness. As a result of this amendment, FDA formalized in regulation the definitions of various phases of clinical investigations (i.e., phase I, phase II, and phase III). The clinical drug development paradigm for anticancer drugs intended to support marketing approval has historically followed this "phased" approach with sequential, stand-alone trials, with an increasing number of patients exposed to an investigational drug with each trial in order to fulfill the objectives of that particular stage in development. Increasingly, it is the Office of Hematology and Oncology Products' experience that commercial sponsors of solid tumor oncology drug development programs are amending ongoing phase I trials to add expansion cohorts designed to evaluate study objectives typical of later-phase trials. For investigational anticancer drugs that demonstrate preliminary clinical evidence of substantial antitumor activity early in clinical testing, use of expansion cohorts as a component of the solid tumor oncology drug development pathway, with appropriate measures to mitigate the risks of this approach, may fit in well with the goals and concepts described by FDA's expedited programs for serious conditions. (C) 2015 AACR. C1 [Theoret, Marc R.; Pai-Scherf, Lee H.; Chuk, Meredith K.; Prowell, Tatiana M.; Balasubramaniam, Sanjeeve; Kim, Tamy; Kim, Geoffrey; Kluetz, Paul G.; Keegan, Patricia; Pazdur, Richard] US FDA, OHOP, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Theoret, MR (reprint author), US FDA, Bldg 22,Room 2165,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Marc.Theoret@fda.hhs.gov OI Balasubramaniam, Sanjeeve/0000-0002-0643-2117 NR 12 TC 5 Z9 5 U1 0 U2 1 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 OCT 15 PY 2015 VL 21 IS 20 BP 4545 EP 4551 DI 10.1158/1078-0432.CCR-14-3244 PG 7 WC Oncology SC Oncology GA CV7WH UT WOS:000364486300009 PM 26473190 ER PT J AU Menis, M Forshee, RA Kumar, S McKean, S Warnock, R Izurieta, HS Gondalia, R Johnson, C Mintz, PD Walderhaug, MO Worrall, CM Kelman, JA Anderson, SA AF Menis, Mikhail Forshee, Richard A. Kumar, Sanjai McKean, Stephen Warnock, Rob Izurieta, Hector S. Gondalia, Rahul Johnson, Chris Mintz, Paul D. Walderhaug, Mark O. Worrall, Christopher M. Kelman, Jeffrey A. Anderson, Steven A. TI Babesiosis Occurrence among the Elderly in the United States, as Recorded in Large Medicare Databases during 2006-2013 SO PLOS ONE LA English DT Article ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; NEW-YORK-STATE; LYME-DISEASE; PHYSICAL-ACTIVITY; LEISURE-TIME; BLOOD-TRANSFUSION; IXODES-SCAPULARIS; MICROTI; USA AB Background Human babesiosis, caused by intraerythrocytic protozoan parasites, can be an asymptomatic or mild-to-severe disease that may be fatal. The study objective was to assess babesiosis occurrence among the U.S. elderly Medicare beneficiaries, ages 65 and older, during 2006-2013. Methods Our retrospective claims-based study utilized large Medicare administrative databases. Babesiosis occurrence was ascertained by recorded ICD-9-CM diagnosis code. The study assessed babesiosis occurrence rates (per 100,000 elderly Medicare beneficiaries) overall and by year, age, gender, race, state of residence, and diagnosis months. Results A total of 10,305 elderly Medicare beneficiaries had a recorded babesiosis diagnosis during the eight-year study period, for an overall rate of about 5 per 100,000 persons. Study results showed a significant increase in babesiosis occurrence over time (p < 0.05), with the largest number of cases recorded in 2013 (N = 1,848) and the highest rates (per 100,000) in five Northeastern states: Connecticut (46), Massachusetts (45), Rhode Island (42), New York (27), and New Jersey (14). About 75% of all cases were diagnosed from May through October. Babesiosis occurrence was significantly higher among males vs. females and whites vs. non-whites. Conclusion Our study reveals increasing babesiosis occurrence among the U.S. elderly during 20062013, with highest rates in the babesiosis-endemic states. The study also shows variation in babesiosis occurrence by age, gender, race, state of residence, and diagnosis months. Overall, our study highlights the importance of large administrative databases in assessing the occurrence of emerging infections in the United States. C1 [Menis, Mikhail; Forshee, Richard A.; Kumar, Sanjai; Izurieta, Hector S.; Mintz, Paul D.; Walderhaug, Mark O.; Anderson, Steven A.] US FDA, Silver Spring, MD 20993 USA. [McKean, Stephen; Warnock, Rob; Gondalia, Rahul; Johnson, Chris] Acumen LLC, Burlingame, CA USA. [Worrall, Christopher M.; Kelman, Jeffrey A.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. RP Menis, M (reprint author), US FDA, Silver Spring, MD 20993 USA. EM Mikhail.Menis@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Biologics Evaluation and Research; FDA FX This study was internally funded by the U.S. Food and Drug Administration, Center for Biologics Evaluation and Research. Acumen LLC is a CMS contractor funded by FDA to conduct analyses of CMS data. All authors made substantial contributions to research design, or the acquisition, analysis or interpretation of data and were involved in drafting of the paper or revising it critically. NR 58 TC 2 Z9 2 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 15 PY 2015 VL 10 IS 10 AR e0140332 DI 10.1371/journal.pone.0140332 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU0CX UT WOS:000363184600042 PM 26469785 ER PT J AU Geller, AI Shehab, N Weidle, NJ Lovegrove, MC Wolpert, BJ Timbo, BB Mozersky, RP Budnitz, DS AF Geller, Andrew I. Shehab, Nadine Weidle, Nina J. Lovegrove, Maribeth C. Wolpert, Beverly J. Timbo, Babgaleh B. Mozersky, Robert P. Budnitz, Daniel S. TI Emergency Department Visits for Adverse Events Related to Dietary Supplements SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HERBAL MEDICINES; UNITED-STATES; SURVEILLANCE; MEDICATIONS; SYSTEM; HEALTH AB BACKGROUND Dietary supplements, such as herbal or complementary nutritional products and micronutrients (vitamins and minerals), are commonly used in the United States, yet national data on adverse effects are limited. METHODS We used nationally representative surveillance data from 63 emergency departments obtained from 2004 through 2013 to describe visits to U.S. emergency departments because of adverse events related to dietary supplements. RESULTS On the basis of 3667 cases, we estimated that 23,005 (95% confidence interval [CI], 18,611 to 27,398) emergency department visits per year were attributed to adverse events related to dietary supplements. These visits resulted in an estimated 2154 hospitalizations (95% CI, 1342 to 2967) annually. Such visits frequently involved young adults between the ages of 20 and 34 years (28.0% of visits; 95% CI, 25.1 to 30.8) and unsupervised children (21.2% of visits; 95% CI, 18.4 to 24.0). After the exclusion of unsupervised ingestion of dietary supplements by children, 65.9% (95% CI, 63.2 to 68.5) of emergency department visits for single-supplement-related adverse events involved herbal or complementary nutritional products; 31.8% (95% CI, 29.2 to 34.3) involved micronutrients. Herbal or complementary nutritional products for weight loss (25.5%; 95% CI, 23.1 to 27.9) and increased energy (10.0%; 95% CI, 8.0 to 11.9) were commonly implicated. Weight-loss or energy products caused 71.8% (95% CI, 67.6 to 76.1) of supplement-related adverse events involving palpitations, chest pain, or tachycardia, and 58.0% (95% CI, 52.2 to 63.7) involved persons 20 to 34 years of age. Among adults 65 years of age or older, choking or pill-induced dysphagia or globus caused 37.6% (95% CI, 29.1 to 46.2) of all emergency department visits for supplement-related adverse events; micronutrients were implicated in 83.1% (95% CI, 73.3 to 92.9) of these visits. CONCLUSIONS An estimated 23,000 emergency department visits in the United States every year are attributed to adverse events related to dietary supplements. Such visits commonly involve cardiovascular manifestations from weight-loss or energy products among young adults and swallowing problems, often associated with micronutrients, among older adults. C1 [Geller, Andrew I.; Shehab, Nadine; Lovegrove, Maribeth C.; Budnitz, Daniel S.] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA USA. [Weidle, Nina J.] Chenega Govt Consulting, Atlanta, GA USA. [Wolpert, Beverly J.; Timbo, Babgaleh B.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Wolpert, Beverly J.; Timbo, Babgaleh B.] US FDA, Div Publ Hlth Informat & Analyt, College Pk, MD USA. [Mozersky, Robert P.] US FDA, Div Dietary Supplement Programs, College Pk, MD USA. RP Geller, AI (reprint author), CDC, Div Healthcare Qual Promot, 1825 Century Blvd NE,Mailstop D-26, Atlanta, GA 30345 USA. EM ageller@cdc.gov FU Department of Health and Human Services FX Funded by the Department of Health and Human Services. NR 32 TC 32 Z9 34 U1 4 U2 18 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 15 PY 2015 VL 373 IS 16 BP 1531 EP 1540 DI 10.1056/NEJMsa1504267 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CT5VX UT WOS:000362880300009 PM 26465986 ER PT J AU Teeguarden, JG Twaddle, NC Churchwell, MI Yang, XX Fisher, JW Seryak, LM Doerge, DR AF Teeguarden, Justin G. Twaddle, Nathan C. Churchwell, Mona I. Yang, Xiaoxia Fisher, Jeffrey W. Seryak, Liesel M. Doerge, Daniel R. TI 24-hour human urine and serum profiles of bisphenol A: Evidence against sublingual absorption following ingestion in soup SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Bisphenol A; Pharmacokinetics; Exposure; Oral; Endocrine disruptors; Sublingual ID ROUTE DEPENDENT DOSIMETRY; TANDEM MASS-SPECTROMETRY; SPRAGUE-DAWLEY RATS; LIQUID-CHROMATOGRAPHY; UNITED-STATES; HUMAN BLOOD; EXPOSURE; BPA; SAMPLES; POPULATION AB Extensive first-pass metabolism of ingested bisphenol A (BPA) in the gastro-intestinal tract and liver restricts blood concentrations of bioactive BPA to <1% of total BPA in humans and non-human primates. Absorption of ingested BPA through non-metabolizing tissues of the oral cavity, recently demonstrated in dogs, could lead to the higher serum BPA concentrations reported in some human biomonitoring studies. We hypothesized that the extensive interaction with the oral mucosa by a liquid matrix, like soup, relative to solid food or capsules, might enhance absorption through non-metabolizing oral cavity tissues in humans, producing higher bioavailability and higher serum BPA concentrations. Concurrent serum and urine concentrations of d6-BPA, and its glucuronide and sulfate conjugates, were measured over a 24 hour period in 10 adult male volunteers following ingestion of 30 mu g d6-BPA/kg body weight in soup. Absorption of d6-BPA was rapid (t(1/2) = 0.45 h) and elimination of the administered dose was complete 24 h post-ingestion, evidence against any tissue depot for BPA. The maximum serum d6-BPA concentration was 0.43 nM at 1.6 h after administration and represented <0.3% of total d6-BPA. Pharmacokinetic parameters, pharmacokinetic model simulations, and the significantly faster appearance half-life of d6-BPA-glucuronide compared to d6-BPA (0.29 h vs 0.45 h) were evidence against meaningful absorption of BPA in humans through any non-metabolizing tissue (<1%). This study confirms that typical exposure to BPA in food produces picomolar to subpicomolar serum BPA concentrations in humans, not nM concentrations reported in some biomonitoring studies. Published by Elsevier Inc. C1 [Teeguarden, Justin G.] Pacific NW Natl Lab, Hlth Effects & Exposure Sci, Richland, WA 99352 USA. [Teeguarden, Justin G.] Oregon State Univ, Dept Environm & Mol Toxicol, Corvallis, OR 97331 USA. [Twaddle, Nathan C.; Churchwell, Mona I.; Yang, Xiaoxia; Fisher, Jeffrey W.; Doerge, Daniel R.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Seryak, Liesel M.] Ohio State Univ, Div Epidemiol, Coll Publ Hlth, Columbus, OH 43210 USA. RP Teeguarden, JG (reprint author), Pacific NW Natl Lab, Hlth Effects & Exposure Sci, Richland, WA 99352 USA. EM jt@pnl.gov; nathan.twaddle@fda.hhs.gov; mona.churchwell@fda.hhs.gov; xiaoxia.yang@fda.hhs.gov; jeffrey.fisher@fda.hhs.gov; seryak.2@osu.edu; daniel.doerge@fda.hhs.gov FU American Chemistry Council, Polycarbonate/BPA Global Group [63289]; U.S. Food and Drug Administration; CDC - NIOSH [R21OH010332]; National Center for Advancing Translational Sciences [UL1TR000090] FX Funding for this research was provided by a grant from the American Chemistry Council, Polycarbonate/BPA Global Group (Grant 63289). ACC and member affiliates did not contribute to the study design, data analysis, reporting, or writing and review of the manuscript. The NCTR laboratory activities were supported by U.S. Food and Drug Administration funding. The views expressed in this manuscript do not necessarily reflect those of the U.S. Food and Drug Administration. Research on the material composition of blood collection devices reported in this publication was supported by Grant Number R21OH010332 from CDC - NIOSH and Grant Number UL1TR000090 from the National Center for Advancing Translational Sciences. Its content is solely the responsibility of the authors and does not necessarily represent the official views of CDC - NIOSH or NCATS or the National Institutes of Health. NR 65 TC 10 Z9 10 U1 2 U2 13 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 OCT 15 PY 2015 VL 288 IS 2 BP 131 EP 142 DI 10.1016/j.taap.2015.01.009 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CS9DL UT WOS:000362389200001 PM 25620055 ER PT J AU Grayzel, SE Bender, JB Glore, RP Gumley, N Sykes, JE Whichard, JM Papich, MG Watts, JL Barlam, TF Murphy, MJ Hoang, C AF Grayzel, Sharon E. Bender, Jeff B. Glore, Reilly P. Gumley, Nigel Sykes, Jane E. Whichard, Jean M. Papich, Mark G. Watts, Jeffrey L. Barlam, Tamar F. Murphy, Michael J. Hoang, Christine CA AVMA Task Force Antimicrobial Stew TI Understanding companion animal practitioners' attitudes toward antimicrobial stewardship SO JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION LA English DT Editorial Material ID DRUG-USE; GUIDELINES; DOGS C1 [Grayzel, Sharon E.] Columbia Vet Ctr, Vancouver, WA 98665 USA. [Bender, Jeff B.] Univ Minnesota, Coll Vet Med, Dept Vet Populat Med, St Paul, MN 55108 USA. [Glore, Reilly P.] Brady Vet Hosp, Montesano, WA 98563 USA. [Gumley, Nigel] Canadian Vet Med Assoc, Ottawa, ON K1R 7K1, Canada. [Sykes, Jane E.] Univ Calif Davis, Sch Vet Med, Dept Med & Epidemiol, Davis, CA 95616 USA. [Whichard, Jean M.] CDC, Atlanta, GA 30329 USA. [Papich, Mark G.] N Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC 27607 USA. [Watts, Jeffrey L.] Anti Infect Res VMRD, Kalamazoo, MI 49009 USA. [Barlam, Tamar F.] Boston Med Ctr, Infect Dis Sect, Boston, MA 02118 USA. [Murphy, Michael J.] US FDA, Ctr Vet Med, Rockville, MD 20855 USA. [Hoang, Christine] AVMA, Schaumburg, IL 60173 USA. RP Grayzel, SE (reprint author), Columbia Vet Ctr, 5106 NE 78th St, Vancouver, WA 98665 USA. EM sgrayzel@comcast.net NR 6 TC 0 Z9 0 U1 4 U2 6 PU AMER VETERINARY MEDICAL ASSOC PI SCHAUMBURG PA 1931 N MEACHAM RD SUITE 100, SCHAUMBURG, IL 60173-4360 USA SN 0003-1488 EI 1943-569X J9 JAVMA-J AM VET MED A JI JAVMA-J. Am. Vet. Med. Assoc. PD OCT 15 PY 2015 VL 247 IS 8 BP 883 EP 884 PG 2 WC Veterinary Sciences SC Veterinary Sciences GA CS6QY UT WOS:000362207300036 ER PT J AU Xu, XM Al-Ghabeish, M Krishnaiah, YSR Rahman, Z Khan, MA AF Xu, Xiaoming Al-Ghabeish, Manar Krishnaiah, Yellela S. R. Rahman, Ziyaur Khan, Mansoor A. TI Kinetics of drug release from ointments: Role of transient-boundary layer SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Ointment; Acyclovir; In vitro drug release; Kinetics; Transient-boundary; Logarithmic time release; Higuchi model ID SEMISOLID DOSAGE FORMS; ACYCLOVIR; DELIVERY; SYSTEMS; BASES AB In the current work, an in vitro release testing method suitable for ointment formulations was developed using acyclovir as a model drug. Release studies were carried out using enhancer cells on acyclovir ointments prepared with oleaginous, absorption, and water-soluble bases. Kinetics and mechanism of drug release was found to be highly dependent on the type of ointment bases. In oleaginous bases, drug release followed a unique logarithmic-time dependent profile; in both absorption and water-soluble bases, drug release exhibited linearity with respect to square root of time (Higuchi model) albeit differences in the overall release profile. To help understand the underlying cause of logarithmic-time dependency of drug release, a novel transient-boundary hypothesis was proposed, verified, and compared to Higuchi theory. Furthermore, impact of drug solubility (under various pH conditions) and temperature on drug release were assessed. Additionally, conditions under which deviations from logarithmic-time drug release kinetics occur were determined using in situ UV fiber-optics. Overall, the results suggest that for oleaginous ointments containing dispersed drug particles, kinetics and mechanism of drug release is controlled by expansion of transient boundary layer, and drug release increases linearly with respect to logarithmic time. Published by Elsevier B.V. C1 [Xu, Xiaoming; Al-Ghabeish, Manar; Krishnaiah, Yellela S. R.; Rahman, Ziyaur; Khan, Mansoor A.] US FDA, Div Prod Qual Res, OTR OPQ, Silver Spring, MD 20993 USA. RP Khan, MA (reprint author), US FDA, Div Prod Qual Res, OTR OPQ, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Xiaoming.Xu@fda.hhs.gov; Manar.Al-Ghabeish@fda.hhs.gov; Krishnaiah.Yellela@fda.hhs.gov; Ziyaur.Rahman@fda.hhs.gov; Mansoor.khan@fda.hhs.gov OI Rahman, Ziyaur/0000-0002-0402-825X NR 28 TC 5 Z9 5 U1 0 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD OCT 15 PY 2015 VL 494 IS 1 BP 31 EP 39 DI 10.1016/j.ijpharm.2015.07.077 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CR9BX UT WOS:000361649300005 PM 26241753 ER PT J AU Ricks, TK Chiu, HJ Ison, G Kim, G Mckee, AE Kluetz, P Pazdur, R AF Ricks, Tiffany K. Chiu, Haw-Jyh Ison, Gwynn Kim, Geoffrey Mckee, Amy E. Kluetz, Paul Pazdur, Richard TI Successes and challenges of PARP inhibitors in cancer therapy SO FRONTIERS IN ONCOLOGY LA English DT Article DE PARP inhibitor; cancer; drug resistance; BRCA1; BRCA2; homologous recombination ID ADP-RIBOSE POLYMERASE; 0 CLINICAL-TRIAL; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS RECOMBINATION; DNA-REPAIR; SECONDARY MUTATIONS; EXCISION-REPAIR; HISTONE H2AX; BMN 673; RESISTANCE C1 [Ricks, Tiffany K.; Chiu, Haw-Jyh; Ison, Gwynn; Kim, Geoffrey; Mckee, Amy E.; Kluetz, Paul; Pazdur, Richard] US FDA, OHOP, OND, CDER, Silver Spring, MD USA. RP Ricks, TK (reprint author), US FDA, OHOP, OND, CDER, Silver Spring, MD USA. EM tiffany.ricks@fda.hhs.gov NR 43 TC 6 Z9 8 U1 1 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD OCT 14 PY 2015 VL 5 AR 222 DI 10.3389/fonc.2015.00222 PG 5 WC Oncology SC Oncology GA CX5JD UT WOS:000365737000002 PM 26528434 ER PT J AU Smith, SK Selig, W Harker, M Roberts, JN Hesterlee, S Leventhal, D Klein, R Patrick-Lake, B Abernethy, AP AF Smith, Sophia K. Selig, Wendy Harker, Matthew Roberts, Jamie N. Hesterlee, Sharon Leventhal, David Klein, Richard Patrick-Lake, Bray Abernethy, Amy P. TI Patient Engagement Practices in Clinical Research among Patient Groups, Industry, and Academia in the United States: A Survey SO PLOS ONE LA English DT Article ID DUCHENNE MUSCULAR-DYSTROPHY; CAREGIVER PREFERENCES; ORGANIZATIONS; COMMUNITY AB Objective Patient-centered clinical trial design and execution is becoming increasingly important. No best practice guidelines exist despite a key stakeholder declaration to create more effective engagement models. This study aims to gain a better understanding of attitudes and practices for engaging patient groups so that actionable recommendations may be developed. Methods Individuals from industry, academic institutions, and patient groups were identified through Clinical Trials Transformation Initiative and Drug Information Association rosters and mailing lists. Objectives, practices, and perceived barriers related to engaging patient groups in the planning, conduct, and interpretation of clinical trials were reported in an online survey. Descriptive and inferential statistical analysis of survey data followed a literature review to inform survey questions. Results Survey respondents (n = 179) valued the importance of involving patient groups in research; however, patient group respondents valued their contributions to research protocol development, funding acquisition, and interpretation of study results more highly than those contributions were valued by industry and academic respondents (all p < .001). Patient group respondents placed higher value in open communications, clear expectations, and detailed contract execution than did non-patient group respondents (all p < .05). Industry and academic respondents more often cited internal bureaucratic processes and reluctance to share information as engagement barriers than did patient group respondents (all p < .01). Patient groups reported that a lack of transparency and understanding of the benefits of collaboration on the part of industry and academia were greater barriers than did non-patient group respondents (all p < .01). Conclusions Despite reported similarities among approaches to engagement by the three stakeholder groups, key differences exist in perceived barriers and benefits to partnering with patient groups among the sectors studied. This recognition could inform the development of best practices for patient-centered clinical trial design and execution. Additional research is needed to define and optimize key success factors. C1 [Smith, Sophia K.] Duke Univ, Sch Nursing, Durham, NC 27708 USA. [Selig, Wendy] WS Collaborat, Mclean, VA USA. [Harker, Matthew; Roberts, Jamie N.; Patrick-Lake, Bray] Duke Clin Res Inst, Clin Trials Transformat Initiat, Durham, NC USA. [Hesterlee, Sharon] Parent Project Muscular Dystrophy, Hackensack, NJ USA. [Leventhal, David] Pfizer Worldwide Res & Dev, Groton, CT USA. [Klein, Richard] US FDA, Silver Spring, MD USA. [Abernethy, Amy P.] Flatiron Hlth, New York, NY USA. RP Smith, SK (reprint author), Duke Univ, Sch Nursing, Durham, NC 27708 USA. EM sophia.smith@duke.edu FU Food and Drug Administration [R18FD005292, U19FD003800]; Clinical Trials Transformation Initiative's member organizations FX Funding for this manuscript was made possible, in part, by the Food and Drug Administration through grant R18FD005292 and cooperative agreement U19FD003800. The views expressed in written materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organizations imply endorsement by the United States Government. Partial funding was also provided by pooled membership fees from the Clinical Trials Transformation Initiative's member organizations. The funder provided support in the form of salaries for authors (MH, JNR, BP) but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the Author Contributions section. NR 18 TC 6 Z9 6 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 14 PY 2015 VL 10 IS 10 AR e0140232 DI 10.1371/journal.pone.0140232 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU0CK UT WOS:000363183100092 PM 26465328 ER PT J AU Han, B Compton, WM Jones, CM Cai, R AF Han, Beth Compton, Wilson M. Jones, Christopher M. Cai, Rong TI Nonmedical Prescription Opioid Use and Use Disorders Among Adults Aged 18 Through 64 Years in the United States, 2003-2013 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID EMERGENCY-DEPARTMENT VISITS; PAIN RELIEVERS; ANALGESIC ABUSE; OVERDOSE DEATHS; TRENDS; FREQUENCY; EPIDEMIC AB IMPORTANCE Since 1999, the United States has experienced increases in morbidity and mortality associated with nonmedical use of prescription opioids. OBJECTIVE To assess national trends in and characteristics of nonmedical prescription opioid use and use disorders and the national trend in related mortality. DESIGN, SETTING, AND PARTICIPANTS Prevalence of nonmedical use and use disorders and related risk factors were based on data from 472 200 persons aged 18 through 64 years who participated in the 2003-2013 National Surveys on Drug Use and Health. Mortality was based on the 2003-2013 National Vital Statistics System's Multiple Cause of Death Files. EXPOSURES Prevalence of nonmedical use of prescription opioids. MAIN OUTCOMES AND MEASURES Nonmedical prescription opioid use and use disorders. RESULTS Among adults aged 18 through 64 years, the prevalence of nonmedical use of prescription opioids decreased from 5.4% (95% CI, 5.08%-5.70%) in 2003 to 4.9% (95% CI, 4.58%-5.22%) in 2013 (absolute difference, -0.5%; 95% CI, -0.11% to -0.89%), but the prevalence of prescription opioid use disorders increased from 0.6% (95% CI, 0.54%-0.76%) in 2003 to 0.9% (95% CI, 0.75%-1.01%) in 2013 (absolute difference, 0.3%; 95% CI, 0.03%-0.43%). The 12-month prevalence of high-frequency use (>= 200 days) also increased from 0.3% (95% CI, 0.19%-0.35%) in 2003 to 0.4% (95% CI, 0.31%-0.48%) in 2013 (absolute difference, 0.1%; 95% CI, 0.01%-0.29%). Mortality assessed by drug overdose death rates involving prescription opioids increased from 4.5 per 100 000 (95% CI, 4.42-4.61) in 2003 to 7.8 per 100 000 (95% CI, 7.64-7.89) in 2013 (absolute difference, 3.3; 95% CI, 3.09-3.41) among adults aged 18 through 64 years. The mean number of days of nonmedical use of prescription opioids increased from 2.1 (95% CI, 1.83-2.37) in 2003 to 2.6 (95% CI, 2.27-2.85) in 2013 (absolute difference, 0.5, 95% CI, 0.05-0.86). The model-adjusted prevalence of having prescription opioid use disorders among nonmedical users increased to 15.7% (95% CI, 13.87%-17.67%) in 2010,16.1% (95% CI, 14.36%-17.99%) in 2011, 17.0% (95% CI, 15.07%-19.12%) in 2012, and 16.9% (95% CI, 14.95%-19.03%) in 2013 from 12.7% (95% CI, 11.04%-14.53%) in 2003. CONCLUSIONS AND RELEVANCE During the 2003-2013 years, among adults aged 18 through 64 years, the percentage of nonmedical use of prescription opioids decreased. In contrast, the prevalence of prescription opioid use disorders, frequency of use, and related mortality increased. C1 [Han, Beth; Cai, Rong] Subst Abuse & Mental Hlth Serv Adm, Rockville, MD 20857 USA. [Compton, Wilson M.] NIDA, NIH, Bethesda, MD USA. [Jones, Christopher M.] US FDA, Silver Spring, MD USA. RP Han, B (reprint author), Subst Abuse & Mental Hlth Serv Adm, One Choke Cherry Rd,Room 2-1079, Rockville, MD 20857 USA. EM beth.han@samhsa.hhs.gov FU Substance Abuse and Mental Health Services Administration; National Institute on Drug Abuse; US Food and Drug Administration FX This study was jointly sponsored by the Substance Abuse and Mental Health Services Administration, the National Institute on Drug Abuse, and the US Food and Drug Administration. The National Surveys on Drug Use and Health were supported by contracts from the Substance Abuse and Mental Health Services Administration. NR 37 TC 37 Z9 37 U1 3 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 13 PY 2015 VL 314 IS 14 BP 1468 EP 1478 DI 10.1001/jama.2015.11859 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CT2QI UT WOS:000362647800014 PM 26461997 ER PT J AU Lee, JM Hwang, D Park, J Kim, KJ Park, KW Ahn, C Koo, BK AF Lee, Joo Myung Hwang, Doyeon Park, Jonghanne Kim, Kyung-Jin Park, Kyung Woo Ahn, Chul Koo, Bon-Kwon TI Percutaneous Coronary Intervention at Centers With and Without On-Site Surgical Backup: An Updated Meta-analysis of 23 Studies SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 27th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 11-15, 2015 CL San Francisco, CA DE Clinical outcomes; Meta-analysis; Percutaneous coronary intervention C1 [Lee, Joo Myung; Hwang, Doyeon; Park, Jonghanne; Kim, Kyung-Jin] Seoul Natl Univ Hosp, Seoul 110744, South Korea. [Park, Kyung Woo] Seoul Natl Univ Hosp, Dept Internal Med, Seoul 110744, South Korea. [Park, Kyung Woo] Seoul Natl Univ Hosp, Cardiovasc Ctr, Seoul 110744, South Korea. [Ahn, Chul] US FDA, Silver Spring, MD USA. [Koo, Bon-Kwon] Seoul Natl Univ, Seoul, South Korea. NR 0 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 13 PY 2015 VL 66 IS 15 SU S MA TCT-449 BP B184 EP B184 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CF UT WOS:000363329000399 ER PT J AU Wood, S Hancock, G Tesfamariam, B AF Wood, Steven Hancock, Galen Tesfamariam, Belay TI Bioresorbable polymers and paclitaxel impair endothelial regeneration by induction of autophagy SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 27th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 11-15, 2015 CL San Francisco, CA DE Biodegradation polymer coating; DES; Endothelialization C1 [Wood, Steven; Hancock, Galen] Ctr Devices & Radiolol Hlth, Silver Spring, MD USA. [Tesfamariam, Belay] Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 13 PY 2015 VL 66 IS 15 SU S MA TCT-511 BP B209 EP B209 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU2CF UT WOS:000363329000459 ER PT J AU Blaus, A Madabushi, R Pacanowski, M Rose, M Schuck, RN Stockbridge, N Temple, R Unger, EF AF Blaus, Alison Madabushi, Rajanikanth Pacanowski, Michael Rose, Martin Schuck, Robert N. Stockbridge, Norman Temple, Robert Unger, Ellis F. TI Personalized Cardiovascular Medicine Today A Food and Drug Administration/Center for Drug Evaluation and Research Perspective SO CIRCULATION LA English DT Article DE biological markers; cardiology; clinical trial; individualized medicine; pharmacogenetics ID CHRONIC HEART-FAILURE; INHERITED CARDIAC-ARRHYTHMIA; HIGH-RISK; MORTALITY; DISEASE; EVENTS; HYPERTENSION; CLOPIDOGREL; WARFARIN; POLYMORPHISMS AB Over the past decade, personalized medicine has received considerable attention from researchers, drug developers, and regulatory agencies. Personalized medicine includes identifying patients most likely to benefit and those most likely to experience adverse reactions in response to a drug, and tailoring therapy based on pharmacokinetics or pharmacodynamic response, as well. Perhaps most exciting is finding ways to identify likely responders through genetic, proteomic, or other tests, so that only likely responders will be treated. However, less precise methods such as identifying historical, demographic, or other indicators of increased or reduced responsiveness are also important aspects of personalized medicine. The cardiovascular field has not used many genetic or proteomic markers, but has regularly used prognostic variables to identify likely responders. The development of biomarker-based approaches to personalized medicine in cardiovascular disease has been challenging, in part, because most cardiovascular therapies treat acquired syndromes, such as acute coronary syndrome and heart failure, which develop over many decades and represent the end result of several pathophysiological mechanisms. More precise disease classification and greater understanding of individual variations in disease pathology could drive the development of targeted therapeutics. Success in designing clinical trials for personalized medicine will require the selection of patient populations with attributes that can be targeted or that predict outcome, and the use of appropriate enrichment strategies once such attributes are identified. Here, we describe examples of personalized medicine in cardiovascular disease, discuss its impact on clinical trial design, and provide insight into the future of personalized cardiovascular medicine from a regulatory perspective. C1 [Blaus, Alison; Rose, Martin; Stockbridge, Norman; Temple, Robert; Unger, Ellis F.] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Madabushi, Rajanikanth; Pacanowski, Michael; Schuck, Robert N.] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Schuck, RN (reprint author), US FDA, Off Clin Pharmacol, 10903 New Hampshire Ave,White Oak,Bldg 51,Rm 3104, Silver Spring, MD 20993 USA. EM robert.schuck@fda.hhs.gov NR 41 TC 8 Z9 9 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 13 PY 2015 VL 132 IS 15 BP 1425 EP 1432 DI 10.1161/CIRCULATIONAHA.114.009761 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CT1MY UT WOS:000362563800008 PM 26459078 ER PT J AU Sarkar, S Gough, B Raymick, J Beaudoin, MA Ali, SF Virmani, A Binienda, ZK AF Sarkar, S. Gough, B. Raymick, J. Beaudoin, M. A. Ali, S. F. Virmani, A. Binienda, Z. K. TI Histopathological and electrophysiological indices of rotenone-evoked dopaminergic toxicity: Neuroprotective effects of acetyl-L-carnitine SO NEUROSCIENCE LETTERS LA English DT Article DE Rotenone; Midbrain; Tyrosine hydroxylase; Dopamine transporter (DAT); Peripheral nerves ID PARKINSONS-DISEASE; MITOCHONDRIAL DYSFUNCTION; PERIPHERAL NEUROPATHY; OXIDATIVE STRESS; RATS; MODELS; DAMAGE; VULNERABILITY; STRIATUM; FEATURES AB Exposure to the natural pesticide, rotenone, a potent mitochondrial toxin, leads to degeneration in striatal nerve terminals and nigral neurons. Rotenone-induced behavioral, neurochemical and neuropathological changes in rats mimic those observed in Parkinson's disease (PD). Here, protective effects of acetyl-L-carnitine (ALC) in the brain dopaminergic toxicity after a prolonged exposure to rotenone were evaluated using electrophysiological and immunolabeling methods. Adult, male Sprague Dawley rats were injected i.p. with rotenone alone (1 mg/kg) or rotenone with ALC (either 10 or 100 mg/kg; ALC10 or ALC100, respectively) once daily on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, 33 and 37. Control rats received either 100 mg/kg ALC or vehicle (30% Solutol HS 15 in 0.9% saline) injections. Animals were weighed on injection days and monitored daily. Motor nerve conduction velocity (MCV) was assessed within two days after treatment using compound muscle action potentials (CMAP) detected from the tail muscle through surface receiver electrodes installed around the distal part of the tail. Rats were perfused immediately after testing with 4% paraformaldehyde and immunohistochemical analysis of dopamine transporter (DAT), tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and microglial CD11 b marker was performed in the caudate-putamen (CPu) and the substantia nigra pars compacta (SNc) in order to estimate dopaminergic neuronal and transporter damage. Additionally, effects of ALC on preventing microglial or astrocytic hypertrophy were also evaluated. In rats exposed to rotenone and rotenone/ACL10, a significant increases in both proximal (S1) and distal (S2) motor latency and a decrease in MCV were detected in tail nerves (p<0.05). The conduction parameters in rats co-treated with rotenone/ACL100 were not different from control. It was found that 100 mg/kg ALC prevented loss of TH and a decline of DAT level in the midbrain and also prevented the activation of both microglia and astroglia after rotenone treatment. Data indicate neuroprotective effects of ALC in rotenone-evoked dopaminergic neurotoxicity. Published by Elsevier Ireland Ltd. C1 [Sarkar, S.; Gough, B.; Raymick, J.; Ali, S. F.; Binienda, Z. K.] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Beaudoin, M. A.] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Virmani, A.] Sigma Tau BV, Innovat Res & Dev Nutraceut & Carnitines Int Div, NL-3500 GB Utrecht, Netherlands. [Virmani, A.] Sigma Tau HealthSci BV, NL-3500 GB Utrecht, Netherlands. RP Binienda, ZK (reprint author), US FDA, DNT, NCTR, HFT 132,3900 NCTR Dr, Jefferson, AR 72079 USA. EM zbigniew.binienda@fda.hhs.gov NR 22 TC 2 Z9 2 U1 2 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD OCT 8 PY 2015 VL 606 BP 53 EP 59 DI 10.1016/j.neulet.2015.08.044 PG 7 WC Neurosciences SC Neurosciences & Neurology GA CU2IJ UT WOS:000363346900010 PM 26321151 ER PT J AU Khurana, T Dobrovolskaia, E Shartouny, JR Slater, JE AF Khurana, Taruna Dobrovolskaia, Ekaterina Shartouny, Jessica R. Slater, Jay E. TI Multiplex Assay for Protein Profiling and Potency Measurement of German Cockroach Allergen Extracts SO PLOS ONE LA English DT Article ID DIAGNOSIS; CHILDREN; SYSTEM; ASTHMA AB Background German cockroach (GCr) allergens induce IgE responses and may cause asthma. Commercial GCr allergen extracts are variable and existing assays may not be appropriate for determining extract composition and potency. Objective Our aim was to develop a multiplex antibody/bead-based assay for assessment of GCr allergen extracts. Methods Single chain fragment variable (scFv) antibodies against GCr were obtained by screening libraries derived from naive human lymphocytes and hyperimmunized chicken splenocytes and bone marrow. Selected clones were sequenced and characterized by immunoblotting. Eighteen scFv antibodies (17 chicken, 1 human) coupled to polystyrene beads were used in this suspension assay; binding of targeted GCr allergens to antibody-coated beads was detected using rabbit antisera against GCr, and against specific allergens rBla g 1, rBla g 2, and rBla g 4. The assay was tested for specificity, accuracy, and precision. Extracts were also compared by IgE competition ELISA. Results Chicken scFv's generated eight different binding patterns to GCr proteins from 14 to 150 kDa molecular weight. Human scFv's recognized a 100 kDa GCr protein. The multiplex assay was found to be specific and reproducible with intra-assay coefficient of variation (CV) of 2.64% and inter-assay CV of 10.0%. Overall potencies of various GCr extracts were calculated using mean logEC50s for eight selected scFvs. Overall potency measures were also analyzed by assessing the contributions to potency of each target. Conclusions An scFv antibody-based multiplex assay has been developed capable of simultaneously measuring different proteins in a complex mixture, and to determine the potencies and compositions of allergen extracts. C1 [Khurana, Taruna; Dobrovolskaia, Ekaterina; Shartouny, Jessica R.; Slater, Jay E.] US FDA, Lab Immunobiochem, Div Bacterial Parasit & Allergen Prod, Silver Spring, MD 20993 USA. RP Slater, JE (reprint author), US FDA, Lab Immunobiochem, Div Bacterial Parasit & Allergen Prod, Silver Spring, MD 20993 USA. EM jay.slater@fda.hhs.gov FU intramural FDA FX All work was funded by intramural FDA research support. NR 19 TC 1 Z9 1 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 7 PY 2015 VL 10 IS 10 AR e0140225 DI 10.1371/journal.pone.0140225 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CT0TS UT WOS:000362510600152 PM 26444288 ER PT J AU Dutta, DK Rhodes, K Wood, SC AF Dutta, Debargh K. Rhodes, Kelly Wood, Steven C. TI In silico prediction of Ebola Zaire GP(1,2) immuno-dominant epitopes for the Balb/c mouse SO BMC IMMUNOLOGY LA English DT Article DE Ebola; GP(1,2); Immunodominant epitopes; CTL; Tetramer ID T-CELL RESPONSES; VIRUS INFECTION; NONHUMAN-PRIMATES; IMMUNE-RESPONSES; VIRAL-INFECTION; PROTECTION; ANTIBODY; VACCINE; IMMUNIZATION; MICE AB Background: Ebola is a Filovirus (FV) that induces a highly communicable and deadly hemorrhagic fever. Currently, there are no approved vaccines to treat FV infections. Protection from FV infection requires cell mediated and humoral immunity. Glycoprotein GP(1,2) Fc Zaire, a recombinant FV human Fc fusion protein, has been shown to confer protection against mouse adapted Zaire Ebola virus. The present studies are focused upon identifying immunodominant epitopes using in silico methods and developing tetramers as a diagnostic reagent to detect cell mediated immune responses to GP(1,2) Fc. Methods: The GP(1,2) Ebola Zaire sequence from the 1976 outbreak was analyzed by both BIMAS and SYFPEITHI algorithms to identify potential immuno-dominant epitopes. Several peptides were synthesized and screened in flow-based MHC stability studies. Three candidate peptides, P8, P9 and P10, were identified and, following immunization in Balb/c mice, all three peptides induced IFN-gamma as detected by ELISpot and intracellular staining. Results: Significantly, P8, P9 and P10 generated robust cytotoxic T-cell responses (CTL) as determined by a flow cytometry-based Caspase assay. Antigen specific cells were also detected, using tetramers. Both P9 and P10 have sequence homology with highly conserved regions of several strains of FV. Conclusions: In sum, three immunodominant sequences of the Ebola GP(1,2) have been identified using in silico methods that may confer protection against mouse adapted Ebola Zaire. The development of tetramer reagents will provide unique insight into the potency and durability of medical countermeasure vaccines for known bioterrorism threat agents in preclinical models. C1 [Dutta, Debargh K.; Rhodes, Kelly; Wood, Steven C.] US FDA, Div Biol Chem & Mat Sci, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Dutta, Debargh K.] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. [Rhodes, Kelly] Univ Maryland, College Pk, MD 20742 USA. RP Dutta, DK (reprint author), US FDA, Div Biol Chem & Mat Sci, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM debargh.dutta@gmail.com RI Dutta, Debargh/J-6086-2015 OI Dutta, Debargh/0000-0003-1517-0670 FU CDRH/FDA - NIAID/NIH from the Medical countermeasures initiative (MCMI) [224-10-6010, 1075469]; Food and Drug Administration; Biomedical Advanced Research and Development Authority (BARDA); Defense Advanced Research Projects Agency (DARPA) FX This work was supported by CDRH/FDA - NIAID/NIH Interagency Agreement: 224-10-6010 (req. # 1075469), grants from the Medical countermeasures initiative (MCMI), intramural funding from the Food and Drug Administration, Biomedical Advanced Research and Development Authority (BARDA) and Defense Advanced Research Projects Agency (DARPA). This article reflects the views of the author and should not be construed to represent FDA's views or policies. NR 35 TC 0 Z9 0 U1 2 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD OCT 6 PY 2015 VL 16 AR 59 DI 10.1186/s12865-015-0126-8 PG 10 WC Immunology SC Immunology GA CS9HP UT WOS:000362401300001 PM 26445317 ER PT J AU Ruan, JQ Gao, H Li, N Xue, JY Chen, J Ke, CQ Ye, Y Fu, PPC Zheng, J Wang, JY Lin, G AF Ruan, Jianqing Gao, Hong Li, Na Xue, Junyi Chen, Jie Ke, Changqiang Ye, Yang Fu, Peter Pi-Cheng Zheng, Jiang Wang, Jiyao Lin, Ge TI Blood Pyrrole-Protein Adducts-A Biomarker of Pyrrolizidine Alkaloid-Induced Liver Injury in Humans SO JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH PART C-ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS LA English DT Review DE hepatic sinusoidal obstruction syndrome; hepatotoxicity; pyrrolizidine alkaloids; pyrrole-protein adducts ID SINUSOIDAL-OBSTRUCTION SYNDROME; HEPATIC VENOOCCLUSIVE DISEASE; METABOLIC-ACTIVATION; HEPATOTOXICITY; TOXICITY; EXPOSURE; GENOTOXICITY; FAILURE; ARTICLE AB Pyrrolizidine alkaloids (PAs) induce liver injury (PA-ILI) and is very likely to contribute significantly to drug-induced liver injury (DILI). In this study we used a newly developed ultra-high performance liquid chromatography-triple quadrupole-mass spectrometry (UHPLC-MS)-based method to detect and quantitate blood pyrrole-protein adducts in DILI patients. Among the 46 suspected DILI patients, 15 were identified as PA-ILI by the identification of PA-containing herbs exposed. Blood pyrrole-protein adducts were detected in all PA-ILI patients (100%). These results confirm that PA-ILI is one of the major causes of DILI and that blood pyrrole-protein adducts quantitated by the newly developed UHPLC-MS method can serve as a specific biomarker of PA-ILI. C1 [Ruan, Jianqing; Li, Na; Xue, Junyi; Lin, Ge] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Gao, Hong; Chen, Jie; Wang, Jiyao] Fudan Univ, Div Gastroenterol, Zhongshan Hosp, Shanghai 200433, Peoples R China. [Xue, Junyi; Ke, Changqiang; Ye, Yang; Lin, Ge] Chinese Acad Sci, Joint Res Lab Promoting Globalizat Tradit Chinese, Hong Kong, Hong Kong, Peoples R China. [Xue, Junyi; Ke, Changqiang; Ye, Yang; Lin, Ge] Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Ke, Changqiang; Ye, Yang] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Beijing 100864, Peoples R China. [Ke, Changqiang; Ye, Yang] Chinese Acad Sci, Shanghai Inst Mat Med, Nat Prod Chem Dept, Beijing 100864, Peoples R China. [Fu, Peter Pi-Cheng] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Zheng, Jiang] Univ Washington, Dept Pediat, Seattle Childrens Res Inst, Ctr Dev Therapeut,Div Gastroenterol, Washington, DC USA. [Zheng, Jiang] Shenyang Pharmaceut Univ, Minist Educ, Key Lab Struct Based Drug Design & Discovery, Shenyang, Peoples R China. RP Lin, G (reprint author), Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. EM wang.jiyao@zs-hospital.sh.cn; linge@cuhk.edu.hk FU Research Grant Council of Hong Kong SAR [469712, 471013, 2140898]; CUHK [4054134, 4054215]; CUHK School of Biomedical Sciences - Seed Fund for Joint Establishments, Shanghai Committee of Science and Technology, P.R. China [12401907400]; Ministry of Education in China [KEF152006]; National Natural Science Foundation of China [81430086, 81373471] FX The present studies were supported by Research Grant Council of Hong Kong SAR (GRF Grants, Project No.: 469712, 471013 and 2140898), CUHK (Direct Grants: 4054134 and 4054215), CUHK School of Biomedical Sciences - Seed Fund for Joint Establishments, Shanghai Committee of Science and Technology, P.R. China (Grant no. 12401907400), Scientific research fund for returned overseas researchers from the Ministry of Education in China (Grant No. KEF152006), and also in part by the National Natural Science Foundation of China (Grants 81430086 and 81373471). NR 49 TC 8 Z9 8 U1 7 U2 15 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1059-0501 EI 1532-4095 J9 J ENVIRON SCI HEAL C JI J. Environ. Sci. Health Pt. C-Environ. Carcinog. Ecotoxicol. Rev. PD OCT 2 PY 2015 VL 33 IS 4 BP 404 EP 421 DI 10.1080/10590501.2015.1096882 PG 18 WC Oncology; Environmental Sciences; Toxicology SC Oncology; Environmental Sciences & Ecology; Toxicology GA CX4QD UT WOS:000365684500002 PM 26398275 ER PT J AU Neff, LJ Arrazola, RA Caraballo, RS Corey, CG Cox, S King, BA Choiniere, CJ Husten, CG AF Neff, Linda J. Arrazola, Rene A. Caraballo, Ralph S. Corey, Catherine G. Cox, Shanna King, Brian A. Choiniere, Conrad J. Husten, Corinne G. TI Frequency of Tobacco Use Among Middle and High School Students - United States, 2014 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID NICOTINE DEPENDENCE; ONSET; RISK C1 [Neff, Linda J.; Arrazola, Rene A.; Caraballo, Ralph S.; Cox, Shanna; King, Brian A.] CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Corey, Catherine G.; Choiniere, Conrad J.; Husten, Corinne G.] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Neff, LJ (reprint author), CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. EM len2@cdc.gov NR 8 TC 7 Z9 7 U1 0 U2 3 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD OCT 2 PY 2015 VL 64 IS 38 BP 1061 EP 1065 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CS5DF UT WOS:000362095900001 PM 26422781 ER PT J AU Corey, CG Ambrose, BK Apelberg, BJ King, BA AF Corey, Catherine G. Ambrose, Bridget K. Apelberg, Benjamin J. King, Brian A. TI Flavored Tobacco Product Use Among Middle and High School Students - United States, 2014 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID YOUTH C1 [Corey, Catherine G.; Ambrose, Bridget K.; Apelberg, Benjamin J.] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. [King, Brian A.] CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. RP Corey, CG (reprint author), US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. EM catherine.corey@fda.hhs.gov NR 9 TC 11 Z9 11 U1 1 U2 6 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD OCT 2 PY 2015 VL 64 IS 38 BP 1066 EP 1070 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CS5DF UT WOS:000362095900002 PM 26421418 ER PT J AU Gupta, S Tatouli, IP Rosen, LB Hasni, S Alevizos, I Manna, ZG Rivera, J Jiang, C Siegel, RM Holland, SM Moutsopoulos, HM Browne, SK AF Gupta, Sarthak Tatouli, Ioanna P. Rosen, Lindsey B. Hasni, Sarfaraz Alevizos, Illias Manna, Zerai G. Rivera, Juan Jiang, Chao Siegel, Richard M. Holland, Steven M. Moutsopoulos, Haralampos M. Browne, Sarah K. TI Anti-Interferon Autoantibodies in Systemic Lupus Erythematosus Are Biologically Active and Have Distinct Functions SO ARTHRITIS & RHEUMATOLOGY LA English DT Meeting Abstract C1 [Gupta, Sarthak; Rosen, Lindsey B.; Holland, Steven M.; Browne, Sarah K.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Gupta, Sarthak; Hasni, Sarfaraz; Manna, Zerai G.; Rivera, Juan; Jiang, Chao] NIAMSD, NIH, Bethesda, MD 20892 USA. [Tatouli, Ioanna P.; Moutsopoulos, Haralampos M.] Natl Univ Athens, Sch Med, Dept Pathophysiol, Athens, Greece. [Alevizos, Illias] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Jiang, Chao] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Siegel, Richard M.] NIAMS, Immunoregulat Sect, Autoimmun Branch, Bethesda, MD USA. [Browne, Sarah K.] US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD OCT PY 2015 VL 67 SU 10 MA 1859 PG 3 WC Rheumatology SC Rheumatology GA DE8BG UT WOS:000370860203265 ER PT J AU Gupta, S Patel, SK Blake, M Gadina, MG Tsai, WXL Carette, S Cuthbertson, D Hoffman, GS Khalidi, NA Koening, CL Langford, CA McAlear, CA Moreland, LW Monach, PA Pagnoux, C Seo, P Specks, U Sreih, AG Ytterberg, SR Browne, SK Holland, SM Kaplan, MJ Merkel, PA Grayson, PC AF Gupta, Sarthak Patel, Seema K. Blake, Mary Gadina, Massimo G. Tsai, Wanxia L. Carette, Simon Cuthbertson, David Hoffman, Gary S. Khalidi, Nader A. Koening, Curry L. Langford, Carol A. McAlear, Carol A. Moreland, Larry W. Monach, Paul A. Pagnoux, Christian Seo, Philip Specks, Ulrich Sreih, Antoine G. Ytterberg, Steven R. Browne, Sarah K. Holland, Steven M. Kaplan, Mariana J. Merkel, Peter A. Grayson, Peter C. CA Vasculitis Clinical Res Consortium TI Anticytokine Autoantibody Profiling in Five Types of Systemic Vasculitis SO ARTHRITIS & RHEUMATOLOGY LA English DT Meeting Abstract C1 [Gupta, Sarthak; Browne, Sarah K.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Gupta, Sarthak; Patel, Seema K.; Blake, Mary; Gadina, Massimo G.; Tsai, Wanxia L.; Kaplan, Mariana J.; Grayson, Peter C.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Carette, Simon; Pagnoux, Christian] Univ Toronto, Mt Sinai Hosp, Div Rheumatol, Toronto, ON M5G 1X5, Canada. [Cuthbertson, David] Univ S Florida, Dept Pediat, Biostat & Informat, Tampa, FL 33620 USA. [Hoffman, Gary S.; Langford, Carol A.] Cleveland Clin, Rheumatol, Cleveland, OH 44106 USA. [Khalidi, Nader A.] McMaster Univ, Div Rheumatol, St Josephs Hlth Care, Hamilton, ON, Canada. [Koening, Curry L.] Univ Utah, Div Rheumatol, Salt Lake City, UT USA. [McAlear, Carol A.] Univ Penn, Div Rheumatol, Philadelphia, PA 19104 USA. [Moreland, Larry W.] Univ Pittsburgh, Rheumatol & Clin Immunol, Pittsburgh, PA USA. [Monach, Paul A.] Boston Univ, Sch Med, Rheumatol, Boston, MA 02118 USA. [Seo, Philip] Johns Hopkins Univ, Div Rheumatol, Baltimore, MD USA. [Specks, Ulrich] Mayo Clin, Coll Med, Div Pulm & Crit Care Med, Rochester, MN USA. [Sreih, Antoine G.] Univ Penn, Dept Rheumatol, Philadelphia, PA 19104 USA. [Ytterberg, Steven R.] Mayo Clin, Div Rheumatol, Rochester, MN USA. [Browne, Sarah K.] US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Merkel, Peter A.] Univ Penn, Div Rheumatol, Penn Vasculitis Ctr, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD OCT PY 2015 VL 67 SU 10 MA 864 PG 2 WC Rheumatology SC Rheumatology GA DE8BG UT WOS:000370860202130 ER PT J AU Beadling, CW Burkle, FM Koenig, KL Sharp, TW AF Beadling, Charles W. Burkle, Frederick M., Jr. Koenig, Kristi L. Sharp, Trueman W. TI Ebola Virus and Public Health (Part 2) INTRODUCTION SO DISASTER MEDICINE AND PUBLIC HEALTH PREPAREDNESS LA English DT Editorial Material C1 [Beadling, Charles W.] Uniformed Serv Univ Hlth Sci, Ctr Disaster & Humanitarian Assistance Med, Bethesda, MD 20814 USA. [Burkle, Frederick M., Jr.] Harvard Univ, Harvard Humanitarian Initiat, Cambridge, MA 02138 USA. [Burkle, Frederick M., Jr.] Woodrow Wilson Int Ctr Scholars, Washington, DC 20560 USA. [Koenig, Kristi L.] Univ Calif Irvine, Ctr Disaster Med Sci, Orange, CA 92668 USA. [Sharp, Trueman W.] US FDA, CDER OGD DCR, Silver Spring, MD USA. RP Beadling, CW (reprint author), Uniformed Serv Univ Hlth Sci, Ctr Disaster & Humanitarian Assistance Med, Bethesda, MD 20814 USA. NR 2 TC 0 Z9 0 U1 5 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1935-7893 EI 1938-744X J9 DISASTER MED PUBLIC JI Dis. Med. Public Health Prep. PD OCT PY 2015 VL 9 IS 5 BP 521 EP 521 DI 10.1017/dmp.2015.120 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DF0NK UT WOS:000371035600012 PM 26668864 ER PT J AU Gonzalez-Jimenez, A Suzuki, A Stephens, C Chen, MJ Medina-Caliz, I Diaz, MR Prieto, M Soriano, G Montane, E Aldea, A Andrade, RJ Lucena, MI AF Gonzalez-Jimenez, Andres Suzuki, Ayako Stephens, C. Chen, Minjun Medina-Caliz, I. Robles Diaz, Mercedes Prieto, Martin Soriano, German Montane, Eva Aldea, A. Andrade, Raul J. Lucena, M. I. TI The influence of drug properties and host factors on delayed onset in hepatotoxicity: An analysis of the cohort included in the Spanish DILI Registry SO HEPATOLOGY LA English DT Meeting Abstract CT 66th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 13-17, 2015 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 [Gonzalez-Jimenez, Andres; Stephens, C.; Medina-Caliz, I.; Robles Diaz, Mercedes; Andrade, Raul J.; Lucena, M. I.] Univ Malaga, Hosp Univ Virgen de la Victoria, Inst Invest Biomed Malaga IBIMA, E-29071 Malaga, Spain. [Suzuki, Ayako] Univ Arkansas Med Sci, Dept Med, Little Rock, AR 72205 USA. [Chen, Minjun] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Stephens, C.; Medina-Caliz, I.; Robles Diaz, Mercedes; Prieto, Martin; Soriano, German] CIBERehd, Barcelona, Spain. [Prieto, Martin] Hosp Univ La Fe, Hepatogastroenterol Serv, Valencia, Spain. [Soriano, German] Univ Barcelona, Hosp Santa Creu & St Pau, Gastroenterol Serv, Barcelona, Spain. [Montane, Eva] Hosp Badalona Germans Trias & Pujol, Clin Pharmacol, Badalona, Spain. [Aldea, A.] Hosp Univ Canarias, Dept Clin Pharmacol, Canarias, Spain. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2015 VL 62 SU 1 SI SI MA 596 BP 504A EP 505A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DB2YA UT WOS:000368375401479 ER PT J AU Cui, QW Zubkova, I Murphy, T Schillie, SF Major, ME AF Cui, Qingwen Zubkova, Iryna Murphy, Trudy Schillie, Sarah F. Major, Marian E. TI Assessing the impact of hepatitis B immune globulin (HBIG) on responses to the hepatitis B vaccine during co-administration SO HEPATOLOGY LA English DT Meeting Abstract CT 66th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 13-17, 2015 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 [Cui, Qingwen; Zubkova, Iryna; Major, Marian E.] US FDA, CBER, Alexandria, VA USA. [Murphy, Trudy; Schillie, Sarah F.] Ctr Dis Control & Prevent, Div Viral Hepatitis, Atlanta, GA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2015 VL 62 SU 1 SI SI MA 1546 BP 964A EP 964A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DB2YA UT WOS:000368375403338 ER PT J AU Cui, QW Gufraind, A Boodram, B Cotler, S Dahari, H Major, ME AF Cui, Qingwen Gufraind, Alexander Boodram, Basmattee Cotler, Scott Dahari, Harel Major, Marian E. TI Modeling the probability of hepatitis C virus transmission in injecting drug users as a function of viral load SO HEPATOLOGY LA English DT Meeting Abstract CT 66th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 13-17, 2015 CL San Francisco, CA SP Amer Assoc Study Liver Dis C1 [Cui, Qingwen; Major, Marian E.] CBER FDA, Alexandria, VA USA. [Gufraind, Alexander; Cotler, Scott; Dahari, Harel] Loyola Univ, Dept Med, Maywood, IL 60153 USA. [Gufraind, Alexander; Boodram, Basmattee] Univ Illinois, Epidemiol & Biostat, Chicago, IL USA. [Dahari, Harel] Los Alamos Natl Lab, Theoret Biol & Biophys, Los Alamos, NM USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2015 VL 62 SU 1 SI SI MA 1854 BP 1114A EP 1114A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DB2YA UT WOS:000368375404100 ER PT J AU Brink, JA Miller, DL AF Brink, James A. Miller, Donald L. TI US National Diagnostic Reference Levels: Closing the Gap SO RADIOLOGY LA English DT Editorial Material C1 [Brink, James A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Diagnost Radiol, Boston, MA 02114 USA. [Miller, Donald L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Brink, JA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Diagnost Radiol, 175 Cambridge St,2nd Floor, Boston, MA 02114 USA. EM jabrink@partners.org NR 22 TC 3 Z9 3 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD OCT PY 2015 VL 277 IS 1 BP 3 EP 6 DI 10.1148/radiol.2015150971 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DB3TG UT WOS:000368434000002 PM 26115453 ER PT J AU Kim, H Fang, LY Choi, S Zhao, L Lionberger, R AF Kim, Hyewon Fang, Lanyan Choi, Stephanie Zhao, Liang Lionberger, Robert TI Exploration of Model-Based Bioequivalence (BE) Evaluation as an Alternative Approach for the Sparse Pharmacokinetic (PK) Sampling Design SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Kim, Hyewon; Fang, Lanyan; Choi, Stephanie; Zhao, Liang; Lionberger, Robert] US FDA, Off Gener Drug, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2015 VL 42 SU 1 MA M-36 BP S26 EP S27 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DA5KM UT WOS:000367842000036 ER PT J AU Lin, HP Dutcher, S Babiskin, A Liu, JZ Zhang, XY Zhao, L AF Lin, Ho-Pi Dutcher, Sarah Babiskin, Andrew Liu, Jinzhong Zhang, Xinyuan Zhao, Liang TI Combination of R "Shiny'' and Application Programming Interface (API) to Create a Browser Based Visualization Tool for FDA Public Database SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Lin, Ho-Pi; Dutcher, Sarah; Babiskin, Andrew; Liu, Jinzhong; Zhang, Xinyuan; Zhao, Liang] US FDA, Div Quantitat Methods & Modeling, Off Res & Stand, OGD, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2015 VL 42 SU 1 MA M-16 BP S17 EP S18 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DA5KM UT WOS:000367842000017 ER PT J AU Liu, C Florian, J Wang, YN Kim, MJ Bashaw, ED Sinha, V Marathe, D AF Liu, Chao Florian, Jeffry Wang, Yaning Kim, Myong-Jin Bashaw, Edward D. Sinha, Vikram Marathe, Dhananjay TI Utilizing Modeling and Simulation to Inform Dose Selection, Titration Algorithms, and Trial Design of Oral Testosterone (T) Products for Testosterone Replacement therapy (TRT) in Hypogonadal Men SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Liu, Chao; Florian, Jeffry; Wang, Yaning; Kim, Myong-Jin; Bashaw, Edward D.; Sinha, Vikram; Marathe, Dhananjay] OTS CDER FDA, Off Clin Pharmacol, Beaverton, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2015 VL 42 SU 1 MA W-02 BP S74 EP S75 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DA5KM UT WOS:000367842000141 ER PT J AU Liu, JZ Wang, YN Zhao, L AF Liu, Jinzhong Wang, Yaning Zhao, Liang TI Assessment of Exposure-Response (E-R) and Case-Control (C-C) Analyses in Oncology using Simulation Based Approach SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Liu, Jinzhong] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Wang, Yaning] US FDA, DPM OCP OTS CDER, Silver Spring, MD USA. [Zhao, Liang] US FDA, DQMM ORS OGD CDER, Silver Spring, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2015 VL 42 SU 1 MA W-34 BP S90 EP S90 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DA5KM UT WOS:000367842000173 ER PT J AU Liu, JZ Corrigan, B Flockhart, D Zhao, L AF Liu, Jinzhong Corrigan, Brian Flockhart, David Zhao, Liang TI SASR (Survival Analysis using "Shiny" R): A Browser Based Survival Analysis Visualization Tool using R "Shiny" SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Liu, Jinzhong; Flockhart, David] Indiana Univ Sch Med, Div Clin Pharmacol, Indianapolis, IN 46202 USA. [Corrigan, Brian] Pfizer Inc, Groton, CT 06340 USA. [Zhao, Liang] US FDA, Off Gener Drugs, Off Res & Stand, Div Quantitat Methods & Modeling, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2015 VL 42 SU 1 MA T-63 BP S70 EP S71 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DA5KM UT WOS:000367842000132 ER PT J AU Ma, XS Chien, JY Johnson, J Malone, J Sinha, V AF Ma, Xiaosu Chien, Jenny Y. Johnson, Jennal Malone, James Sinha, Vikram TI Simulation-Based Assessment of Insulin Lispro Dose Titration Algorithms Using a Model of Glucose-Insulin-Glucagon SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Ma, Xiaosu; Chien, Jenny Y.; Johnson, Jennal; Malone, James] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Sinha, Vikram] US FDA, Silver Spring, MD USA. NR 3 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2015 VL 42 SU 1 MA T-09 BP S46 EP S47 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DA5KM UT WOS:000367842000079 ER PT J AU Zheng, N Fang, L AF Zheng, Nan Fang, Lanyan (Lucy) TI Assessment of Partial AUC Requirement for Bioequivalence Evaluation of Methylphenidate Hydrochloride Extended-Release Oral Suspension SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Zheng, Nan; Fang, Lanyan (Lucy)] US FDA, Off Gener Drugs, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2015 VL 42 SU 1 MA T-23 BP S53 EP S53 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DA5KM UT WOS:000367842000093 ER PT J AU Liu, F Rainosek, SW Frisch-Daiello, JL Patterson, TA Paule, MG Slikker, W Wang, C Han, XL AF Liu, Fang Rainosek, Shuo W. Frisch-Daiello, Jessica L. Patterson, Tucker A. Paule, Merle G. Slikker, William, Jr. Wang, Cheng Han, Xianlin TI Potential Adverse Effects of Prolonged Sevoflurane Exposure on Developing Monkey Brain: From Abnormal Lipid Metabolism to Neuronal Damage SO TOXICOLOGICAL SCIENCES LA English DT Article DE sevoflurane; development; cytokines; lipid metabolism; neuronal degeneration ID MULTIDIMENSIONAL MASS-SPECTROMETRY; IN-SITU DERIVATIZATION; CENTRAL-NERVOUS-SYSTEM; DEVELOPING RAT-BRAIN; SHOTGUN LIPIDOMICS; ELECTROSPRAY-IONIZATION; DOCOSAHEXAENOIC ACID; ALZHEIMERS-DISEASE; BIOLOGICAL SAMPLES; GENE-EXPRESSION AB Sevoflurane is a volatile anesthetic that has been widely used in general anesthesia, yet its safety in pediatric use is a public concern. This study sought to evaluate whether prolonged exposure of infant monkeys to a clinically relevant concentration of sevoflurane is associated with any adverse effects on the developing brain. Infant monkeys were exposed to 2.5% sevoflurane for 9 h, and frontal cortical tissues were harvested for DNA microarray, lipidomics, Luminex protein, and histological assays. DNA microarray analysis showed that sevoflurane exposure resulted in a broad identification of differentially expressed genes (DEGs) in the monkey brain. In general, these genes were associated with nervous system development, function, and neural cell viability. Notably, a number of DEGs were closely related to lipid metabolism. Lipidomic analysis demonstrated that critical lipid components, (eg, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol) were significantly downregulated by prolonged exposure of sevoflurane. Luminex protein analysis indicated abnormal levels of cytokines in sevoflurane-exposed brains. Consistently, Fluoro-Jade C staining revealed more degenerating neurons after sevoflurane exposure. These data demonstrate that a clinically relevant concentration of sevoflurane (2.5%) is capable of inducing and maintaining an effective surgical plane of anesthesia in the developing nonhuman primate and that a prolonged exposure of 9h resulted in profound changes in gene expression, cytokine levels, lipid metabolism, and subsequently, neuronal damage. Generally, sevoflurane-induced neuronal damage was also associated with changes in lipid content, composition, or both; and specific lipid changes could provide insights into the molecular mechanism(s) underlying anesthetic-induced neurotoxicity and may be sensitive biomarkers for the early detection of anesthetic-induced neuronal damage. C1 [Liu, Fang; Patterson, Tucker A.; Paule, Merle G.; Wang, Cheng] US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. [Rainosek, Shuo W.] Univ Arkansas Med Sci, Dept Anesthesiol, Little Rock, AR 72205 USA. [Frisch-Daiello, Jessica L.; Han, Xianlin] Sanford Burnham Med Res Inst Lake Nona, Diabet & Obes Res Ctr, Orlando, FL 32827 USA. [Slikker, William, Jr.] US FDA, Natl Ctr Toxicol Res, Off Director, Jefferson, AR 72079 USA. RP Liu, F (reprint author), US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, HFT-132,3900 NCTR Rd, Jefferson, AR 72079 USA. EM Fang.liu@fda.hhs.gov FU National Center for Toxicological Research (NCTR)/US Food and Drug Administration (FDA); National Institute of General Medical Sciences [R01 GM105724] FX This work was supported by the National Center for Toxicological Research (NCTR)/US Food and Drug Administration (FDA) and National Institute of General Medical Sciences Grant R01 GM105724. No external funding and no competing interests declared. NR 64 TC 4 Z9 4 U1 2 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD OCT PY 2015 VL 147 IS 2 BP 562 EP 572 DI 10.1093/toxsci/kfv150 PG 11 WC Toxicology SC Toxicology GA CX2SO UT WOS:000365547300026 PM 26206149 ER PT J AU Huang, B Xie, T Rotstein, D Fang, H Frucht, DM AF Huang, Bruce Xie, Tao Rotstein, David Fang, Hui Frucht, David M. TI Passive Immunotherapy Protects against Enteric Invasion and Lethal Sepsis in a Murine Model of Gastrointestinal Anthrax SO TOXINS LA English DT Article DE gastrointestinal anthrax; anthrax toxin; protective antigen; monoclonal antibody; raxibacumab; lethal factor; edema factor ID T-LYMPHOCYTE ACTIVATION; BACILLUS-ANTHRACIS; INHALATIONAL ANTHRAX; UNITED-STATES; NORTH-DAKOTA; TOXIN; BIOTERRORISM; RECEPTOR; SPORES; CELLS AB The principal portal for anthrax infection in natural animal outbreaks is the digestive tract. Enteric exposure to anthrax, which is difficult to detect or prevent in a timely manner, could be exploited as an act of terror through contamination of human or animal food. Our group has developed a novel animal model of gastrointestinal (GI) anthrax for evaluation of disease pathogenesis and experimental therapeutics, utilizing vegetative Bacillus anthracis (Sterne strain) administered to A/J mice (a complement-deficient strain) by oral gavage. We hypothesized that a humanized recombinant monoclonal antibody (mAb) * that neutralizes the protective antigen (PA) component of B. anthracis lethal toxin (LT) and edema toxin (ET) could be an effective treatment. Although the efficacy of this anti-anthrax PA mAb has been shown in animal models of inhalational anthrax, its activity in GI infection had not yet been ascertained. We hereby demonstrate that passive immunotherapy with anti-anthrax PA mAb, administered at the same time as gastrointestinal exposure to B. anthracis, prevents lethal sepsis in nearly all cases (>90%), while a delay of up to forty-eight hours in treatment still greatly reduces mortality following exposure (65%). Moreover, passive immunotherapy protects against enteric invasion, associated mucosal injury and subsequent dissemination by gastrointestinal B. anthracis, indicating that it acts to prevent the initial stages of infection. * Expired raxibacumab being cycled off the Strategic National Stockpile; biological activity confirmed by in vitro assay. C1 [Huang, Bruce; Xie, Tao; Fang, Hui; Frucht, David M.] US FDA, Div Biotechnol Review & Res 2, Off Biotechnol Prod, Off Prod Qual,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Rotstein, David] US FDA, Div Compliance, Ctr Vet Med, Rockville, MD 20855 USA. RP Frucht, DM (reprint author), US FDA, Div Biotechnol Review & Res 2, Off Biotechnol Prod, Off Prod Qual,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM bruce.huang@fda.hhs.gov; tao.xie@fda.hhs.gov; david.rotstein@fda.hhs.gov; hui.fang@fda.hhs.gov; david.frucht@fda.hhs.gov FU FDA Medical Countermeasures Grant FX We thank Mate Tolnay, Jennifer Swisher and Odile Engel for critical review of the manuscript. We also thank Tod Merkel for critical reagents provided for our studies. This work was supported by an FDA Medical Countermeasures Grant. NR 62 TC 3 Z9 3 U1 0 U2 6 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2072-6651 J9 TOXINS JI Toxins PD OCT PY 2015 VL 7 IS 10 BP 3960 EP 3976 DI 10.3390/toxins7103960 PG 17 WC Toxicology SC Toxicology GA CW4KO UT WOS:000364960400009 PM 26426050 ER PT J AU Yue, M Han, XG De Masi, L Zhu, CH Ma, X Zhang, JJ Wu, RW Schmieder, R Kaushik, RS Fraser, GP Zhao, SH McDermott, PF Weill, FX Mainil, JG Arze, C Fricke, WF Edwards, RA Brisson, D Zhang, NR Rankin, SC Schifferli, DM AF Yue, Min Han, Xiangan De Masi, Leon Zhu, Chunhong Ma, Xun Zhang, Junjie Wu, Renwei Schmieder, Robert Kaushik, Radhey S. Fraser, George P. Zhao, Shaohua McDermott, Patrick F. Weill, Francois-Xavier Mainil, Jacques G. Arze, Cesar Fricke, W. Florian Edwards, Robert A. Brisson, Dustin Zhang, Nancy R. Rankin, Shelley C. Schifferli, Dieter M. TI Allelic variation contributes to bacterial host specificity SO NATURE COMMUNICATIONS LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; RECEPTOR-BINDING SPECIFICITY; SALMONELLA-ENTERICA; FIMH ADHESIN; MICROBIAL GENOMES; PROTEIN-STRUCTURE; POLYMORPHISM DATA; BIOFILM FORMATION; MAMMALIAN-CELLS; CRISPR-MVLST AB Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single-nucleotide polymorphisms (nsSNPs) has not been systematically evaluated. Here, our genome-wide analysis of core genes within Salmonella enterica serovar Typhimurium genomes reveals a high degree of allelic variation in surface-exposed molecules, including adhesins that promote host colonization. Subsequent multinomial logistic regression, MultiPhen and Random Forest analyses of known/ suspected adhesins from 580 independent Typhimurium isolates identifies distinct host-specific nsSNP signatures. Moreover, population and functional analyses of host-associated nsSNPs for FimH, the type 1 fimbrial adhesin, highlights the role of key allelic residues in host-specific adherence in vitro. Together, our data provide the first concrete evidence that functional differences between allelic variants of bacterial proteins likely contribute to pathoadaption to diverse hosts. C1 [Yue, Min; Han, Xiangan; De Masi, Leon; Zhu, Chunhong; Ma, Xun; Zhang, Junjie; Wu, Renwei; Rankin, Shelley C.; Schifferli, Dieter M.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Schmieder, Robert; Edwards, Robert A.] San Diego State Univ, Coll Sci, Dept Comp Sci, San Diego, CA 92182 USA. [Kaushik, Radhey S.] S Dakota State Univ, Dept Vet & Biomed Sci, Brookings, SD 57007 USA. [Kaushik, Radhey S.] S Dakota State Univ, Dept Biol & Microbiol, Brookings, SD 57007 USA. [Fraser, George P.] Bur Labs, Penn Dept Hlth, Exton, PA 19341 USA. [Zhao, Shaohua; McDermott, Patrick F.] US FDA, Div Anim & Food Microbiol, Ctr Vet Med, Res Off, Laurel, MD 20708 USA. [Weill, Francois-Xavier] Inst Pasteur, Unite Bacteries Pathogenes Enter, F-75724 Paris 15, France. [Mainil, Jacques G.] Univ Liege, Fac Vet Med, Dept Infect Dis, Bacteriol, B-4000 Liege, Belgium. [Mainil, Jacques G.] Univ Liege, Inst Fundamental & Appl Res Anim Hlth FARAH, B-4000 Liege, Belgium. [Arze, Cesar; Fricke, W. Florian] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Inst Genome Sci, Baltimore, MD 21201 USA. [Edwards, Robert A.] Argonne Natl Lab, Math & Comp Sci Div, Argonne, IL 60439 USA. [Brisson, Dustin] Univ Penn, Sch Art & Sci, Dept Biol, Philadelphia, PA 19104 USA. [Zhang, Nancy R.] Univ Penn, Wharton Sch, Dept Stat, Philadelphia, PA 19104 USA. RP Schifferli, DM (reprint author), Univ Penn, Sch Vet Med, Dept Pathobiol, 3800 Spruce St, Philadelphia, PA 19104 USA. EM dmschiff@vet.upenn.edu OI Weill, Francois-Xavier/0000-0001-9941-5799; Yue, Min/0000-0002-6787-0794 FU NIH [AI098041]; USDA [2013-67015-21285]; University of Pennsylvania Veterinary Center for Infectious Disease; University of Pennsylvania Center for Host-Microbial Interactions; China Scholarship Council (CSC) FX The study makes use of data generated by the DECIPHER Consortium. A full list of centres that contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. We thank all the contributors for sharing their Salmonella genomic data, Jason P. Folster and Jean Whichard, Division of Foodborne, Waterborne and Environmental Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA, for strains, Jeff Washeleski, Pennsylvania Department of Health, for technical help, and Suzanne Loret, Ernst Heinen and Guy Dandrifosse, University of Liege, Belgium, for their help with bovine cell cultures. We appreciate the critical reading and helpful comments on the manuscript made by Leslie King. This work was funded by NIH grant AI098041, USDA grant 2013-67015- 21285 and funds from the University of Pennsylvania Veterinary Center for Infectious Disease and the Center for Host-Microbial Interactions to D.M.S.; X.H., C.Z., X.M. and J.Z. were supported by the China Scholarship Council (CSC). NR 61 TC 3 Z9 3 U1 2 U2 19 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 OCT PY 2015 VL 6 AR 8754 DI 10.1038/ncomms9754 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CW4CT UT WOS:000364939600001 PM 26515720 ER PT J AU Liu, YT Flynn, TJ Xia, MH Wiesenfeld, PL Ferguson, MS AF Liu, Yitong Flynn, Thomas J. Xia, Menghang Wiesenfeld, Paddy L. Ferguson, Martine S. TI Evaluation of CYP3A4 inhibition and hepatotoxicity using DMSO-treated human hepatoma HuH-7 cells SO CELL BIOLOGY AND TOXICOLOGY LA English DT Article DE HuH-7 cells; DMSO; CYP3A4; Inhibition; Induction; Hepatotoxicity ID PRIMARY HUMAN HEPATOCYTES; DRUG-METABOLISM; LIVER-INJURY; IN-VITRO; CYTOCHROME-P450 ACTIVITY; DIMETHYL-SULFOXIDE; LINES; PREDICTION; TOXICITY; INDUCERS AB A human hepatoma cell line (HuH-7) was evaluated as a metabolically competent cell model to investigate cytochrome P450 3A4 (CYP3A4) inhibition, induction, and hepatotoxicity. First, CYP3A4 gene expression and activity were determined in HuH-7 cells under three culture conditions: 1-week culture, 3-week culture, or 1 % dimethyl sulfoxide (DMSO) treatment. HuH-7 cells treated with DMSO for 2 weeks after confluence expressed the highest CYP3A4 gene expression and activity compared to the other two culture conditions. Furthermore, CYP3A4 activity in DMSO-treated HuH-7 cells was compared to that in a human hepatoma cell line (HepG2/C3A) and human bipotent progenitor cell line (HepaRG), which yielded the following ranking: HepaRG > DMSO-treated HuH-7 >> HepG2/C3A cells. The effects of three known CYP3A4 inhibitors were evaluated using DMSO-treated HuH-7 cells. CYP3A4 enzyme inhibition in HuH-7 cells was further compared to human recombinant CYP3A4, indicating similar potency for reversible inhibitors (IC (50) within 2.5-fold), but different potency for the irreversible inhibitor. Next, induction of CYP3A4 activity was compared between DMSO-treated HuH-7 and HepaRG cells using two known inducers. DMSO-treated HuH-7 cells yielded minimal CYP3A4 induction compared to that in the HepaRG cells after 48-h treatments. Finally, the cytotoxicity of five known hepatotoxicants was evaluated in DMSO-treated HuH-7, HepG2/C3A, and HepaRG cells, and significant differences in cytotoxic sensitivity were observed. Overall, DMSO-treated HuH-7 cells are a valuable model for medium- or high-throughput screening of chemicals for CYP3A4 inhibition and hepatotoxicity. C1 [Liu, Yitong; Flynn, Thomas J.; Wiesenfeld, Paddy L.] US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Div Toxicol, Laurel, MD 20708 USA. [Xia, Menghang] NIH, Div Pre Clin Innovat, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Ferguson, Martine S.] US FDA, Ctr Food Safety & Appl Nutr, Off Analyt & Outreach, Div Publ Hlth Informat & Analyt, College Pk, MD USA. RP Liu, YT (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Div Toxicol, Laurel, MD 20708 USA. EM yitong.liu@fda.hhs.gov OI Liu, Yitong/0000-0002-4300-4349; Flynn, Thomas/0000-0002-7248-0643 FU US Food and Drug Administration FX The authors thank Dr. Michael F. Santillo for image processing and critical review of the paper. The authors thank Ms. Shelia PughBishop for technical assistance. This research was supported by the US Food and Drug Administration. This research report is not an official US Food and Drug Administration guidance or policy statement. No official support or endorsement by the US Food and Drug Administration is intended, nor should it be inferred. NR 31 TC 1 Z9 1 U1 3 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0742-2091 EI 1573-6822 J9 CELL BIOL TOXICOL JI Cell Biol. Toxicol. PD OCT PY 2015 VL 31 IS 4-5 BP 221 EP 230 DI 10.1007/s10565-015-9306-9 PG 10 WC Cell Biology; Toxicology SC Cell Biology; Toxicology GA CV4EU UT WOS:000364220000003 PM 26377104 ER PT J AU Kurtz, SL Elkins, KL AF Kurtz, Sherry L. Elkins, Karen L. TI Correlates of Vaccine-Induced Protection against Mycobacterium tuberculosis Revealed in Comparative Analyses of Lymphocyte Populations SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID CD8(+) T-CELLS; CHRONIC PULMONARY TUBERCULOSIS; CALMETTE-GUERIN INFECTION; NITRIC-OXIDE SYNTHASE; NECROSIS-FACTOR-ALPHA; IN-VIVO; INTERFERON-GAMMA; ACTIVE TUBERCULOSIS; HEME OXYGENASE-1; IMMUNE-RESPONSE AB A critical hindrance to the development of a novel vaccine against Mycobacterium tuberculosis is a lack of understanding of protective correlates of immunity and of host factors involved in a successful adaptive immune response. Studies from our group and others have used a mouse-based in vitro model system to assess correlates of protection. Here, using this coculture system and a panel of whole-cell vaccines with varied efficacy, we developed a comprehensive approach to understand correlates of protection. We compared the gene and protein expression profiles of vaccine-generated immune peripheral blood lymphocytes (PBLs) to the profiles found in immune splenocytes. PBLs not only represent a clinically relevant cell population, but comparing the expression in these populations gave insight into compartmentally specific mechanisms of protection. Additionally, we performed a direct comparison of host responses induced when immune cells were cocultured with either the vaccine strain Mycobacterium bovis BCG or virulent M. tuberculosis. These comparisons revealed host-specific and bacterium-specific factors involved in protection against virulent M. tuberculosis. Most significantly, we identified a set of 13 core molecules induced in the most protective vaccines under all of the conditions tested. Further validation of this panel of mediators as a predictor of vaccine efficacy will facilitate vaccine development, and determining how each promotes adaptive immunity will advance our under-standing of antimycobacterial immune responses. C1 [Kurtz, Sherry L.; Elkins, Karen L.] US FDA, Lab Mucosal Pathogens & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Elkins, KL (reprint author), US FDA, Lab Mucosal Pathogens & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. EM karen.elkins@fda.hhs.gov NR 82 TC 2 Z9 2 U1 5 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD OCT PY 2015 VL 22 IS 10 BP 1096 EP 1108 DI 10.1128/CVI.00301-15 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU8SR UT WOS:000363814100003 PM 26269537 ER PT J AU Wang, W DeFeo, CJ Alvarado-Facundo, E Vassell, R Weiss, CD AF Wang, Wei DeFeo, Christopher J. Alvarado-Facundo, Esmeralda Vassell, Russell Weiss, Carol D. TI Intermonomer Interactions in Hemagglutinin Subunits HA1 and HA2 Affecting Hemagglutinin Stability and Influenza Virus Infectivity SO JOURNAL OF VIROLOGY LA English DT Article ID VIRAL MEMBRANE-FUSION; CONFORMATIONAL-CHANGE; RECEPTOR-BINDING; A VIRUSES; LOW-PH; HISTIDINE-RESIDUES; LENTIVIRAL VECTOR; PEPTIDE MUTANTS; DISULFIDE BONDS; GENE DELIVERY AB Influenza virus hemagglutinin (HA) mediates virus entry by binding to cell surface receptors and fusing the viral and endosomal membranes following uptake by endocytosis. The acidic environment of endosomes triggers a large-scale conformational change in the transmembrane subunit of HA (HA2) involving a loop (B loop)-to-helix transition, which releases the fusion peptide at the HA2 N terminus from an interior pocket within the HA trimer. Subsequent insertion of the fusion peptide into the endosomal membrane initiates fusion. The acid stability of HA is influenced by residues in the fusion peptide, fusion peptide pocket, coiled-coil regions of HA2, and interactions between the surface (HA1) and HA2 subunits, but details are not fully understood and vary among strains. Current evidence suggests that the HA from the circulating pandemic 2009 H1N1 influenza A virus [ A(H1N1)pdm09] is less stable than the HAs from other seasonal influenza virus strains. Here we show that residue 205 in HA1 and residue 399 in the B loop of HA2 (residue 72, HA2 numbering) in different monomers of the trimeric A(H1N1) pdm09 HA are involved in functionally important intermolecular interactions and that a conserved histidine in this pair helps regulate HA stability. An arginine-lysine pair at this location destabilizes HA at acidic pH and mediates fusion at a higher pH, while a glutamate-lysine pair enhances HA stability and requires a lower pH to induce fusion. Our findings identify key residues in HA1 and HA2 that interact to help regulate H1N1 HA stability and virus infectivity. IMPORTANCE Influenza virus hemagglutinin (HA) is the principal antigen in inactivated influenza vaccines and the target of protective antibodies. However, the influenza A virus HA is highly variable, necessitating frequent vaccine changes to match circulating strains. Sequence changes in HA affect not only antigenicity but also HA stability, which has important implications for vaccine production, as well as viral adaptation to hosts. HA from the pandemic 2009 H1N1 influenza A virus is less stable than other recent seasonal influenza virus HAs, but the molecular interactions that contribute to HA stability are not fully understood. Here we identify molecular interactions between specific residues in the surface and transmembrane subunits of HA that help regulate the HA conformational changes needed for HA stability and virus entry. These findings contribute to our understanding of the molecular mechanisms controlling HA function and antigen stability. C1 [Wang, Wei; DeFeo, Christopher J.; Alvarado-Facundo, Esmeralda; Vassell, Russell; Weiss, Carol D.] US FDA, Immunoregulat Lab, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Wang, W (reprint author), US FDA, Immunoregulat Lab, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM wei.wang@fda.hhs.gov; carol.weiss@fda.hhs.gov FU U.S. Food and Drug Administration FX This work was funded by the U.S. Food and Drug Administration. NR 59 TC 2 Z9 2 U1 1 U2 12 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 OCT PY 2015 VL 89 IS 20 BP 10602 EP 10611 DI 10.1128/JVI.00939-15 PG 10 WC Virology SC Virology GA CU3ZG UT WOS:000363464700038 PM 26269180 ER PT J AU Kim, G Ison, G Mckee, AE Zhang, H Tang, SH Gwise, T Sridhara, R Lee, E Tzou, A Philip, R Chiu, HJ Ricks, TK Palmby, T Russell, AM Ladouceur, G Pfuma, E Li, HS Zhao, L Liu, Q Venugopal, R Ibrahim, A Pazdur, R AF Kim, Geoffrey Ison, Gwynn Mckee, Amy E. Zhang, Hui Tang, Shenghui Gwise, Thomas Sridhara, Rajeshwari Lee, Eunice Tzou, Abraham Philip, Reena Chiu, Haw-Jyh Ricks, Tiffany K. Palmby, Todd Russell, Anne Marie Ladouceur, Gaetan Pfuma, Elimika Li, Hongshan Zhao, Liang Liu, Qi Venugopal, Rajesh Ibrahim, Amna Pazdur, Richard TI FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy SO CLINICAL CANCER RESEARCH LA English DT Article ID 3RD-LINE CHEMOTHERAPY; RECURRENT OVARIAN; MAINTENANCE THERAPY; PLATINUM-RESISTANT; FALLOPIAN-TUBE; CARCINOMA; MUTATIONS; SURVIVAL; BREAST; TRIAL AB On December 19, 2014, the FDA approved olaparib capsules (Lynparza; AstraZeneca) for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The BRACAnalysis CDx (Myriad Genetic Laboratories, Inc.) was approved concurrently. An international multicenter, single-arm trial enrolled 137 patients with measurable gBRCAm-associated ovarian cancer treated with three or more prior lines of chemotherapy. Patients received olaparib at a dose of 400 mg by mouth twice daily until disease progression or unacceptable toxicity. The objective response rate (ORR) was 34% with median response duration of 7.9 months in this cohort. The most common adverse reactions (>= 20%) in patients treated with olaparib were anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/upper respiratory infection, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash, and abdominal pain/discomfort. Myelodysplatic syndrome and/or acute myeloid leukemia occurred in 2% of the patients enrolled on this trial. (C) 2015 AACR. C1 [Kim, Geoffrey; Ison, Gwynn; Mckee, Amy E.; Chiu, Haw-Jyh; Ricks, Tiffany K.; Palmby, Todd; Venugopal, Rajesh; Ibrahim, Amna; Pazdur, Richard] US FDA, OHOP, Silver Spring, MD USA. [Zhang, Hui; Tang, Shenghui; Gwise, Thomas; Sridhara, Rajeshwari] US FDA, Off Biostat, Silver Spring, MD USA. [Lee, Eunice; Tzou, Abraham; Philip, Reena] US FDA, Off Vitro Diagnost & Radiol Hlth, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Russell, Anne Marie; Ladouceur, Gaetan] US FDA, New Drug Qual Assessment, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Pfuma, Elimika; Li, Hongshan; Zhao, Liang; Liu, Qi] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. RP Kim, G (reprint author), US FDA, 10903 New Hampshire Ave, White Oak, MD 20993 USA. EM Geoffrey.Kim@fda.hhs.gov NR 19 TC 48 Z9 48 U1 4 U2 18 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 OCT 1 PY 2015 VL 21 IS 19 BP 4257 EP 4261 DI 10.1158/1078-0432.CCR-15-0887 PG 5 WC Oncology SC Oncology GA CU2CQ UT WOS:000363330500005 PM 26187614 ER PT J AU McCune, JS Reynolds, KS AF McCune, Jeannine S. Reynolds, Kellie S. TI Developing and Using Therapeutics for Emerging Infections SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID MEASLES; PHARMACOLOGY; VIRUS AB This issue of Clinical Pharmacology & Therapeutics focuses on emerging infections. The outbreaks of the vaccine-preventable diseases (e.g., measles) and the emerging pathogens (e.g., Ebola) show us how small the world has become. These outbreaks also show the pressing need for effective public education and development of novel therapies. This issue covers various aspects of relevant therapeutic topics ranging from preclinical models, pharmacokinetics, pharmacodynamics, pharmacogenomics, and clinical trial results, to education efforts in this area. Pharmacokinetic/dynamic modeling had an appreciable role in reducing the morbidity and mortality associated with human immunodeficiency virus and hepatitis C virus, recent emerging infections. However, these gains could be lessened by poor adherence to therapies, which has contributed to the development of multidrug-resistant tuberculosis. We must not forget lessons from previous infections, or they may reemerge. C1 [McCune, Jeannine S.] Univ Washington, Dept Pharm, Seattle, WA 98195 USA. [Reynolds, Kellie S.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP McCune, JS (reprint author), Univ Washington, Dept Pharm, Seattle, WA 98195 USA. EM jmccune@u.washington.edu OI McCune, Jeannine/0000-0002-0795-497X NR 25 TC 0 Z9 0 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD OCT PY 2015 VL 98 IS 4 BP 346 EP 351 DI 10.1002/cpt.183 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CU3DW UT WOS:000363405200001 PM 26179402 ER PT J AU Bergman, KL AF Bergman, K. L. TI The Animal Rule: The Role of Clinical Pharmacology in Determining an Effective Dose in Humans SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article C1 US FDA, Silver Spring, MD USA. RP Bergman, KL (reprint author), US FDA, Silver Spring, MD USA. EM kimberly.bergman@fda.hhs.gov NR 4 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD OCT PY 2015 VL 98 IS 4 BP 365 EP 368 DI 10.1002/cpt.172 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CU3DW UT WOS:000363405200018 PM 26082064 ER PT J AU Florian, J Mishra, P Arya, V Harrington, P Connelly, S Reynolds, KS Sinha, V AF Florian, J. Mishra, P. Arya, V. Harrington, P. Connelly, S. Reynolds, K. S. Sinha, V. TI Direct-Acting Antiviral Drugs for the Treatment of Chronic Hepatitis C Virus Infection: Interferon Free Is Now SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID SUSTAINED VIROLOGICAL RESPONSE; GENOTYPE 1 INFECTION; ALL-CAUSE MORTALITY; DYNAMICS IN-VIVO; UNITED-STATES; VIRAL DYNAMICS; HCV; PREVALENCE; THERAPY; ASSOCIATION AB Chronic hepatitis C (CHC) is a global, serious, and life-threatening disease. Virologic response at 12 weeks post-treatment (SVR12) signifies a durable virologic response and is currently the primary efficacy endpoint used in registrational trials. This change led to more rapid clinical development and earlier approvals of highly effective and well-tolerated therapies, facilitating access to those in need. Hepatitis C virus (HCV) infection is a therapeutic area where mathematical modeling has proven helpful in understanding the drug mechanism and characterizing viral kinetics to inform therapy decisions. The availability of direct-acting antivirals (DAAs) provides various treatment options for HIV/HCV coinfected patients, but the complexity of predicting and managing drug-drug interactions presents a unique challenge. Real-world experience or noninterventional studies can provide insight regarding the safety and use of therapeutics that may not be readily available from traditional clinical trials. This article provides a brief overview of the development of promising drugs for the treatment of CHC. C1 [Florian, J.; Arya, V.; Reynolds, K. S.; Sinha, V.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Mishra, P.; Harrington, P.; Connelly, S.] US FDA, Div Antiviral Prod, Off Antimicrobial Prod, Off New Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Sinha, V (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM Vikram.Sinha@fda.hhs.gov NR 45 TC 5 Z9 5 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD OCT PY 2015 VL 98 IS 4 BP 394 EP 402 DI 10.1002/cpt.185 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CU3DW UT WOS:000363405200022 PM 26179495 ER PT J AU Dobrovolsky, VN Revollo, J Pearce, MG Pacheco-Martinez, MM Lin, HX AF Dobrovolsky, Vasily N. Revollo, Javier Pearce, Mason G. Monserrat Pacheco-Martinez, M. Lin, Haixia TI CD48-deficient T-lymphocytes from DMBA-treated rats have de novo mutations in the endogenous Pig-a gene SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE glycosylphosphatidylinositol (GPI) anchor; flow cytometry; cell sorting; sequencing ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; RED-BLOOD-CELLS; FLOW-CYTOMETRIC DETECTION; ANCHOR-SYNTHESIS PATHWAY; IN-VIVO MUTATION; CAUSE HYPERPHOSPHATASIA; MENTAL-RETARDATION; PERIPHERAL-BLOOD; SOMATIC MUTATION; ASSAY AB A major question concerning the scientific and regulatory acceptance of the rodent red blood cell-based Pig-a gene mutation assay is the extent to which mutants identified by their phenotype in the assay are caused by mutations in the Pig-a gene. In this study, we identified T-lymphocytes deficient for the glycosylphosphatidylinositol-anchored surface marker, CD48, in control and 7,12-dimethylbenz[a]anthracene (DMBA)-treated rats using a flow cytometric assay and determined the spectra of mutations in the endogenous Pig-a gene in these cells. CD48-deficient T-cells were seeded by sorting at one cell per well into 96-well plates, expanded into clones, and exons of their genomic Pig-a were sequenced. The majority (78%) of CD48-deficient T-cell clones from DMBA-treated rats had mutations in the Pig-a gene. The spectrum of DMBA-induced Pig-a mutations was dominated by mutations at A:T, with the mutated A being on the nontranscribed strand and AT transversion being the most frequent change. The spectrum of Pig-a mutations in DMBA-treated rats was different from the spectrum of Pig-a mutations in N-ethyl-N-nitrosourea (ENU)-treated rats, but similar to the spectrum of DMBA mutations for another endogenous X-linked gene, Hprt. Only 15% of CD48-deficient mutants from control animals contained Pig-a mutations; T-cell biology may be responsible for a relatively large fraction of false Pig-a mutant lymphocytes in control animals. Among the verified mutants from control rats, the most common were frameshifts and deletions. The differences in the spectra of spontaneous, DMBA-, and ENU-induced Pig-a mutations suggest that the flow cytometric Pig-a assay detects de novo mutation in the endogenous Pig-a gene. Environ. Mol. Mutagen. 56:674-683, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Dobrovolsky, Vasily N.; Revollo, Javier; Pearce, Mason G.; Lin, Haixia] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Monserrat Pacheco-Martinez, M.] Univ Autonoma Metropolitana Iztapalapa, Dept Ciencias Salud, Mexico City 09340, DF, Mexico. RP Dobrovolsky, VN (reprint author), Div Genet & Mol Toxicol, 3900 NCTR Rd,HFT-120, Jefferson, AR 72079 USA. EM vasily.dobrovolsky@fda.hhs.gov NR 40 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD OCT PY 2015 VL 56 IS 8 BP 674 EP 683 DI 10.1002/em.21959 PG 10 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CU0LV UT WOS:000363209100004 PM 26033714 ER PT J AU Tyson, GH McDermott, PF Li, C Chen, Y Tadesse, DA Mukherjee, S Bodeis-Jones, S Kabera, C Gaines, SA Loneragan, GH Edrington, TS Torrence, M Harhay, DM Zhao, SH AF Tyson, Gregory H. McDermott, Patrick F. Li, Cong Chen, Yuansha Tadesse, Daniel A. Mukherjee, Sampa Bodeis-Jones, Sonya Kabera, Claudine Gaines, Stuart A. Loneragan, Guy H. Edrington, Tom S. Torrence, Mary Harhay, Dayna M. Zhao, Shaohua TI WGS accurately predicts antimicrobial resistance in Escherichia coli SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article ID UNITED-STATES; PLASMID; GENES; SALMONELLA; ENTEROBACTERIACEAE; SUSCEPTIBILITY; MUTATIONS; INTEGRONS; ANIMALS; STRAINS AB Objectives: The objective of this study was to determine the effectiveness of WGS in identifying resistance genotypes of MDR Escherichia coli and whether these correlate with observed phenotypes. Methods: Seventy-six E. coli strains were isolated from farm cattle and measured for phenotypic resistance to 15 antimicrobials with the Sensititre(R) system. Isolates with resistance to at least four antimicrobials in three classes were selected for WGS using an Illumina MiSeq. Genotypic analysis was conducted with in-house Perl scripts using BLAST analysis to identify known genes and mutations associated with clinical resistance. Results: Over 30 resistance genes and a number of resistance mutations were identified among the E. coli isolates. Resistance genotypes correlated with 97.8% specificity and 99.6% sensitivity to the identified phenotypes. The majority of discordant results were attributable to the aminoglycoside streptomycin, whereas there was a perfect genotype-phenotype correlation for most antibiotic classes such as tetracyclines, quinolones and phenicols. WGS also revealed information about rare resistance mechanisms, such as structural mutations in chromosomal copies of ampC conferring third-generation cephalosporin resistance. Conclusions: WGS can provide comprehensive resistance genotypes and is capable of accurately predicting resistance phenotypes, making it a valuable tool for surveillance. Moreover, the data presented here showing the ability to accurately predict resistance suggest that WGS may be used as a screening tool in selecting anti-infective therapy, especially as costs drop and methods improve. C1 [Tyson, Gregory H.; McDermott, Patrick F.; Li, Cong; Chen, Yuansha; Tadesse, Daniel A.; Mukherjee, Sampa; Bodeis-Jones, Sonya; Kabera, Claudine; Gaines, Stuart A.; Zhao, Shaohua] US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, Laurel, MD USA. [Loneragan, Guy H.] Texas Tech Univ, Dept Anim & Food Sci, Int Ctr Food Ind Excellence, Lubbock, TX 79409 USA. [Edrington, Tom S.] USDA ARS, Food & Feed Safety Res Unit, College Stn, TX USA. [Torrence, Mary] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Harhay, Dayna M.] USDA ARS, US Meat Anim Res Ctr, Clay Ctr, NE 68933 USA. RP Zhao, SH (reprint author), US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, Laurel, MD USA. EM shaohua.zhao@fda.hhs.gov FU US Food and Drug Administration; Research Participation Program at the Center for Veterinary Medicine FX This work was supported by the US Food and Drug Administration with internal funds as part of routine work. This project was also supported in part by an appointment to the Research Participation Program at the Center for Veterinary Medicine administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and US Food and Drug Administration. NR 29 TC 19 Z9 19 U1 5 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 EI 1460-2091 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD OCT PY 2015 VL 70 IS 10 BP 2763 EP 2769 DI 10.1093/jac/dkv186 PG 7 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA CU0ZZ UT WOS:000363249800012 PM 26142410 ER PT J AU Winnenburg, R Sorbello, A Ripple, A Harpaz, R Tonning, J Szarfman, A Francis, H Bodenreider, O AF Winnenburg, Rainer Sorbello, Alfred Ripple, Anna Harpaz, Rave Tonning, Joseph Szarfman, Ana Francis, Henry Bodenreider, Olivier TI Leveraging MEDLINE indexing for pharmacovigilance - Inherent limitations and mitigation strategies SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE MEDLINE indexing; Pharmacovigilance; Adverse drug events ID ADVERSE DRUG EVENTS; SAFETY; RECORDS; DESIGN; ADULTS AB Background: Traditional approaches to pharmacovigilance center on the signal detection from spontaneous reports, e.g., the U.S. Food and Drug Administration (FDA) adverse event reporting system (FAERS). In order to enrich the scientific evidence and enhance the detection of emerging adverse drug events that can lead to unintended harmful outcomes, pharmacovigilance activities need to evolve to encompass novel complementary data streams, for example the biomedical literature available through MEDLINE. Objectives: (1) To review how the characteristics of MEDLINE indexing influence the identification of adverse drug events (ADEs); (2) to leverage this knowledge to inform the design of a system for extracting ADEs from MEDLINE indexing; and (3) to assess the specific contribution of some characteristics of MEDLINE indexing to the performance of this system. Methods: We analyze the characteristics of MEDLINE indexing. We integrate three specific characteristics into the design of a system for extracting ADEs from MEDLINE indexing. We experimentally assess the specific contribution of these characteristics over a baseline system based on co-occurrence between drug descriptors qualified by adverse effects and disease descriptors qualified by chemically induced. Results: Our system extracted 405,300 ADEs from 366,120 MEDLINE articles. The baseline system accounts for 297,093 ADEs (73%). 85,318 ADEs (21%) can be extracted only after integrating specific pre-coordinated MeSH descriptors and additional qualifiers. 22,889 ADEs (6%) can be extracted only after considering indirect links between the drug of interest and the descriptor that bears the ADE context. Conclusions: In this paper, we demonstrate significant improvement over a baseline approach to identifying ADEs from MEDLINE indexing, which mitigates some of the inherent limitations of MEDLINE indexing for pharmacovigilance. ADEs extracted from MEDLINE indexing are complementary to, not a replacement for, other sources. Published by Elsevier Inc. C1 [Winnenburg, Rainer; Ripple, Anna; Bodenreider, Olivier] US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. [Sorbello, Alfred; Tonning, Joseph; Szarfman, Ana; Francis, Henry] US FDA, Ctr Drug Evaluat & Res, Off Translat Sci, Silver Spring, MD 20993 USA. [Harpaz, Rave] Oracle Hlth Sci GBU, Bedford, MA 01730 USA. RP Bodenreider, O (reprint author), US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM olivier.bodenreider@nih.gov FU Intramural Research Program of the NIH, National Library of Medicine (NLM); US Food and Drug Administration (FDA) through the Center for Drug Evaluation and Research (CDER) Critical Path Program [XLM12011 001]; Office of Translational Sciences at CDER; U.S. Department of Energy; National Library of Medicine; NIH [U54-HG004028]; NIGMS [GM101430- 01A1] FX This work was supported by the Intramural Research Program of the NIH, National Library of Medicine (NLM). This work also received support from the US Food and Drug Administration (FDA) through the Center for Drug Evaluation and Research (CDER) Critical Path Program [interagency agreement with NLM (XLM12011 001)] and from the Office of Translational Sciences at CDER. RW was supported by an appointment to the NLM Research Participation Program administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the National Library of Medicine. RH was employed by Stanford University while conducting this research, and acknowledges support by NIH grant U54-HG004028 for the National Center for Biomedical Ontology and by NIGMS grant GM101430- 01A1. NR 31 TC 4 Z9 4 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 EI 1532-0480 J9 J BIOMED INFORM JI J. Biomed. Inform. PD OCT PY 2015 VL 57 BP 425 EP 435 DI 10.1016/j.jbi.2015.08.022 PG 11 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA CU3PO UT WOS:000363437500036 PM 26342964 ER PT J AU Giovenco, DP Hammond, D Corey, CG Ambrose, BK Delnevo, CD AF Giovenco, Daniel P. Hammond, David Corey, Catherine G. Ambrose, Bridget K. Delnevo, Cristine D. TI E-Cigarette Market Trends in Traditional US Retail Channels, 2012-2013 SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID AWARENESS; ADULTS AB Introduction: E-cigarette sales continue to increase in the United States. To date, little surveillance research has documented the specific product attributes driving growth. This study uses national market scanner data to describe sales trends in traditional U.S. tobacco retail channels between 2012 and 2013 and identifies product features associated with sales increases. Methods: Data on e-cigarette sales in convenience stores, drug stores, grocery stores, and mass merchandisers in the United States were obtained from the Nielsen Company. Each product was coded for attributes such as brand, flavor, and unit size. Total sales volume, market share, and percent growth were calculated for various product attributes. Results: E-cigarette sales more than doubled between 2012 and 2013, from $273.6 million to $636.2 million, respectively. Growth was particularly strong in the convenience store channel. Blu eCigs quickly emerged as the best-selling brand and in 2013 constituted nearly half (44.1%) of overall sales. Although fruit-flavored and other flavored products experienced marked growth, unflavored and menthol e-cigarettes overwhelmingly dominated the market. Sales of single unit products (likely disposable e-cigarettes) increased by 216.4%, a much faster rate than multi-unit packs and cartridge refills. Conclusions: In traditional U.S. retail channels, particularly the convenience store channel, sales of e-cigarettes continue to grow, with brands like blu and disposable products as the likely drivers. Given the rapidly-changing market, expanded surveillance is needed to monitor sales not only in traditional retail locations, but sales online and in specialty "vape shops," as well. C1 [Giovenco, Daniel P.; Delnevo, Cristine D.] Rutgers State Univ, Sch Publ Hlth, Ctr Tobacco Studies, New Brunswick, NJ 08903 USA. [Hammond, David] Univ Waterloo, Dept Hlth Studies, Sch Publ Hlth & Hlth Syst, Waterloo, ON N2L 3G1, Canada. [Corey, Catherine G.; Ambrose, Bridget K.] US FDA, Ctr Tobacco Prod, Silver Spring, MD USA. RP Giovenco, DP (reprint author), Rutgers State Univ, Sch Publ Hlth, Ctr Tobacco Studies, 335 George St,Suite 2100, New Brunswick, NJ 08903 USA. EM d.giovenco@rutgers.edu FU Federal funds from the National Institute on Drug Abuse, National Institutes of Health; Food and Drug Administration, Department of Health and Human Services [HHSN271201100027C] FX This project has been funded in part with Federal funds from the National Institute on Drug Abuse, National Institutes of Health, and the Food and Drug Administration, Department of Health and Human Services, under contract no. HHSN271201100027C. The views and opinions expressed in this paper are those of the authors only and do not necessarily represent the views, official policy or position of the U.S. Department of Health and Human Services or any of its affiliated institutions or agencies. NR 19 TC 15 Z9 15 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD OCT PY 2015 VL 17 IS 10 BP 1279 EP 1283 DI 10.1093/ntr/ntu282 PG 5 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA CT9ZQ UT WOS:000363175500014 PM 25542918 ER PT J AU Kawai, AT Martin, D Kulldorff, M Li, LL Cole, DV McMahill-Walraven, CN Selvam, N Selvan, MS Lee, GM AF Kawai, Alison Tse Martin, David Kulldorff, Martin Li, Lingling Cole, David V. McMahill-Walraven, Cheryl N. Selvam, Nandini Selvan, Mano S. Lee, Grace M. TI Febrile Seizures After 2010-2011 Trivalent Inactivated Influenza Vaccine SO PEDIATRICS LA English DT Article ID SAFETY MONITORING PROGRAM; ACELLULAR PERTUSSIS-VACCINE; IMMUNIZATION PRACTICES ACIP; UNITED-STATES; ADVISORY-COMMITTEE; DATALINK PROJECT; CHILDREN; RISK; RECOMMENDATIONS; PREVENTION AB OBJECTIVES: In the Post-Licensure Rapid Immunization Safety Monitoring Program, we examined risk of febrile seizures (FS) after trivalent inactivated influenza vaccine (TIV) and 13-valent pneumococcal conjugate vaccine (PCV13) during the 2010-2011 influenza season, adjusted for concomitant diphtheria tetanus acellular pertussis-containing vaccines (DTaP). Assuming children would receive both vaccines, we examined whether same-day TIV and PCV13 vaccination was associated with greater FS risk when compared with separate-day vaccination. METHODS: We used a self-controlled risk interval design, comparing the FS rate in a risk interval (0-1 days) versus control interval (14-20 days). Vaccinations were identified in claims and immunization registry data. FS were confirmed with medical records. RESULTS: No statistically significant TIV-FS associations were found in unadjusted or adjusted models (incidence rate ratio [IRR] adjusted for age, seasonality, and concomitant PCV13 and DTaP: 1.36, 95% confidence interval [CI] 0.78 to 2.39). Adjusted for age and seasonality, PCV13 was significantly associated with FS (IRR 1.74, 95% CI 1.06 to 2.86), but not when further adjusting for concomitant TIV and DTaP (IRR 1.61, 95% CI 0.91 to 2.82). Same-day TIV and PCV13 vaccination was not associated with excess risk of FS when compared with separate-day vaccination (1.08 fewer FS per 100 000 with same day administration, 95% CI 25.68 to 6.09). CONCLUSIONS: No statistically significant increased risk of FS was found for 2010-2011 TIV or PCV13, when adjusting for concomitant vaccines. Same-day TIV and PCV13 vaccination was not associated with more FS compared with separate-day vaccination. C1 [Kawai, Alison Tse; Kulldorff, Martin; Li, Lingling; Cole, David V.; Lee, Grace M.] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Kawai, Alison Tse; Kulldorff, Martin; Li, Lingling; Cole, David V.; Lee, Grace M.] Harvard Pilgrim Hlth Care Inst, Boston, MA 02215 USA. [Martin, David] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [McMahill-Walraven, Cheryl N.] Aetna, Blue Bell, PA USA. [Selvam, Nandini] HealthCore, Wilmington, DE USA. [Selvan, Mano S.] Humana Inc, Comprehens Hlth Insights, Louisville, KY USA. [Lee, Grace M.] Boston Childrens Hosp, Div Infect Dis, Boston, MA USA. RP Kawai, AT (reprint author), Harvard Pilgrim Hlth Care Inst, Dept Populat Med, 133 Brookline Ave,6th Floor, Boston, MA 02215 USA. EM Alison_Kawai@harvardpilgrim.org FU Food and Drug Administration, through the Department of Health and Human Services [HHSF223200910006I] FX Supported by funding from the Food and Drug Administration, through the Department of Health and Human Services, for the Mini-Sentinel and PRISM programs (contract HHSF223200910006I). NR 19 TC 2 Z9 2 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD OCT PY 2015 VL 136 IS 4 BP E848 EP E855 DI 10.1542/peds.2015-0635 PG 8 WC Pediatrics SC Pediatrics GA CT6TC UT WOS:000362944300009 PM 26371192 ER PT J AU Califf, RM Sugarman, J AF Califf, Robert M. Sugarman, Jeremy TI Exploring the ethical and regulatory issues in pragmatic clinical trials SO CLINICAL TRIALS LA English DT Article DE Clinical trials; cluster-randomized trial; ethics; evidence-based medicine; learning health-care system; patient-centered outcomes research; pragmatic clinical trial ID SCIENTIFIC EVIDENCE; PRACTICE GUIDELINES; RANDOMIZED-TRIALS; AMERICAN-COLLEGE; PART II; RECOMMENDATIONS; PRINCIPLES; WAREHOUSE; RELEVANT AB The need for high-quality evidence to support decision making about health and health care by patients, physicians, care providers, and policy-makers is well documented. However, serious shortcomings in evidence persist. Pragmatic clinical trials that use novel techniques including emerging information and communication technologies to explore important research questions rapidly and at a fraction of the cost incurred by more traditional research methods promise to help close this gap. Nevertheless, while pragmatic clinical trials can bridge clinical practice and research, they may also raise difficult ethical and regulatory challenges. In this article, the authors briefly survey the current state of evidence that is available to inform clinical care and other health-related decisions and discuss the potential for pragmatic clinical trials to improve this state of affairs. They then propose a new working definition for pragmatic research that centers upon fitness for informing decisions about health and health care. Finally, they introduce a project, jointly undertaken by the National Institutes of Health Health Care Systems Research Collaboratory and the National Patient-Centered Clinical Research Network (PCORnet), which addresses 11 key aspects of current systems for regulatory and ethical oversight of clinical research that pose challenges to conducting pragmatic clinical trials. In the series of articles commissioned on this topic published in this issue of Clinical Trials, each of these aspects is addressed in a dedicated article, with a special focus on the interplay between ethical and regulatory considerations and pragmatic clinical research aimed at informing real-world choices about health and health care. C1 [Califf, Robert M.] Duke Univ, Sch Med, Dept Med, Div Cardiol, Durham, NC 27706 USA. [Califf, Robert M.] Duke Univ, Duke Translat Med Inst, Durham, NC USA. [Sugarman, Jeremy] Johns Hopkins Univ, Berman Inst Bioeth, Baltimore, MD USA. [Sugarman, Jeremy] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Califf, RM (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 1,Room 2314, Silver Spring, MD 20993 USA. EM Robert.Califf@fda.hhs.gov FU National Institutes of Health (NIH) from the Office of Strategic Coordination within the Office of the NIH Director [U54 AT007748]; Patient-Centered Outcomes Research Institute (PCORI) Award for development of the National Patient-Centered Clinical Research Network (PCORnet) FX This work was supported by the National Institutes of Health (NIH) Common Fund, through a cooperative agreement (U54 AT007748) from the Office of Strategic Coordination within the Office of the NIH Director. Additional support was provided by the Patient-Centered Outcomes Research Institute (PCORI) Award for development of the National Patient-Centered Clinical Research Network (PCORnet). The views presented here are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or of the Patient-Centered Outcomes Research Institute (PCORI), its Board of Governors or Methodology Committee, or other participants in PCORnet. NR 44 TC 20 Z9 20 U1 5 U2 11 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD OCT PY 2015 VL 12 IS 5 BP 436 EP 441 DI 10.1177/1740774515598334 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CS9YM UT WOS:000362450000002 PM 26374676 ER PT J AU Rodriguez-Pena, AB Gomez-Rodriguez, J Kortum, RL Palmer, DC Yu, Z Guittard, GC Wohlfert, EA Silver, PB Misplon, JA Sommers, CL Feigenbaum, L Epstein, SL Caspi, RR Belkaid, Y Restifo, NP Samelson, LE Balagopalan, L AF Rodriguez-Pena, A. B. Gomez-Rodriguez, J. Kortum, R. L. Palmer, D. C. Yu, Z. Guittard, G. C. Wohlfert, E. A. Silver, P. B. Misplon, J. A. Sommers, C. L. Feigenbaum, L. Epstein, S. L. Caspi, R. R. Belkaid, Y. Restifo, N. P. Samelson, L. E. Balagopalan, L. TI Enhanced T-cell activation and differentiation in lymphocytes from transgenic mice expressing ubiquitination-resistant 2KR LAT molecules SO GENE THERAPY LA English DT Article ID SUPERIOR ANTITUMOR IMMUNITY; ADOPTIVE IMMUNOTHERAPY; NAIVE RATHER; EFFECTOR; RECEPTOR; UBIQUITYLATION; AUTOIMMUNITY; INFECTION; PROTEIN; KINASE AB Linker for activation of T cells (LAT) is critical for the propagation of T-cell signals upon T-cell receptor (TCR) activation. Previous studies demonstrated that substitution of LAT lysines with arginines (2KR LAT) resulted in decreased LAT ubiquitination and elevated T-cell signaling, indicating that LAT ubiquitination is a molecular checkpoint for attenuation of T-cell signaling. To investigate the role of LAT ubiquitination in vivo, we have generated transgenic mice expressing WT and ubiquitin-defective 2KR LAT. On TCR stimulation of T cells from these mice, proximal signaling and cytokine production was elevated in 2KR versus wildtype (WT) LAT mice. Enhanced cytolytic activity as well as T-helper responses were observed on LAT expression, which were further elevated by 2KR LAT expression. Despite greater T-effector function, WT or 2KR LAT expression did not have any effect on clearance of certain pathogens or tumors. Our data support the model that lack of tumor clearance is due to increased differentiation and acquisition of effector phenotype that is associated with suboptimal immunity in an immunotherapy model. Thus, our data further reinforce the role of LAT ubiquitination in TCR signaling and uncovers a novel role for LAT in driving T-cell differentiation. C1 [Rodriguez-Pena, A. B.; Kortum, R. L.; Guittard, G. C.; Sommers, C. L.; Samelson, L. E.; Balagopalan, L.] NIH, Cellular & Mol Biol Lab, Ctr Canc Res, NCI, Bethesda, MD 20892 USA. [Rodriguez-Pena, A. B.] Ctr Invest Cacn, Salamanca, Spain. [Rodriguez-Pena, A. B.] Univ Salamanca, Inst Biol Mol & Celular Canc, Consejo Super Invest Cientif, E-37008 Salamanca, Spain. [Gomez-Rodriguez, J.] NIH, Cell Signaling & Immun Sect, NHGRI, Bethesda, MD 20892 USA. [Kortum, R. L.] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. [Palmer, D. C.; Yu, Z.; Restifo, N. P.] NIH, Tumor Immunol Sect, Ctr Canc Res, NCI, Bethesda, MD 20892 USA. [Wohlfert, E. A.; Belkaid, Y.] NIAID, Immun Barrier Sites Initiat, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Wohlfert, E. A.; Belkaid, Y.] NIAID, Parasit Dis Lab, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA. [Wohlfert, E. A.] SUNY Buffalo, Dept Microbiol & Immunol, Sch Med & Biomed Sci, Buffalo, NY 14260 USA. [Silver, P. B.; Caspi, R. R.] NIH, Immunoregulat Sect, NEI, Bethesda, MD 20892 USA. [Misplon, J. A.; Epstein, S. L.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Feigenbaum, L.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Anim Sci Program, Frederick, MD USA. RP Balagopalan, L (reprint author), NIH, Cellular & Mol Biol Lab, Ctr Canc Res, NCI, Bldg 37,Rm 2064, Bethesda, MD 20892 USA. EM balagopl@mail.nih.gov OI Restifo, Nicholas P./0000-0003-4229-4580; Caspi, Rachel/0000-0002-7140-7671; Guittard, Geoffrey/0000-0002-6061-8553 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Spain FX We thank Paul Love for providing the dLck expression vector, Wenmei Li and Terri Stull for technical support, F Zhao, Jennifer Cannons and Kristina Lu for helpful advice in cytotoxicity and immunization experiments, The EL4 mouse thymoma (H-2Kb) cell line was a kind gift from Carol Clayberger. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Ana B Rodriguez-Pena was additionally supported by Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Spain. NR 47 TC 3 Z9 3 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 EI 1476-5462 J9 GENE THER JI Gene Ther. PD OCT PY 2015 VL 22 IS 10 BP 781 EP 792 DI 10.1038/gt.2015.48 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CT1BT UT WOS:000362532800002 PM 26018935 ER PT J AU Bhattacharya, P Dey, R Dagur, PK Kruhlak, M Ismail, N Debrabant, A Joshi, AB Akue, A Kukuruga, M Takeda, K Selvapandiyan, A McCoy, JP Nakhasi, HL AF Bhattacharya, Parna Dey, Ranadhir Dagur, Pradeep K. Kruhlak, Michael Ismail, Nevien Debrabant, Alain Joshi, Amritanshu B. Akue, Adovi Kukuruga, Mark Takeda, Kazuyo Selvapandiyan, Angamuthu McCoy, John Philip, Jr. Nakhasi, Hira L. TI Genetically Modified Live Attenuated Leishmania donovani Parasites Induce Innate Immunity through Classical Activation of Macrophages That Direct the Th1 Response in Mice SO INFECTION AND IMMUNITY LA English DT Article ID EXPERIMENTAL VISCERAL LEISHMANIASIS; CENTRIN DELETED PARASITES; ARGINASE-I INDUCTION; ANTIGEN PRESENTATION; DENDRITIC CELLS; NITRIC-OXIDE; INFECTED MACROPHAGES; PROTECTIVE IMMUNITY; MEMBRANE-FLUIDITY; TH1/TH2 PARADIGM AB Visceral leishmaniasis (VL) causes significant mortality and there is no effective vaccine. Previously, we have shown that genetically modified Leishmania donovani parasites, here described as live attenuated parasites, induce a host protective adaptive immune response in various animal models. In this study, we demonstrate an innate immune response upon infection with live attenuated parasites in macrophages from BALB/c mice both in vitro and in vivo. In vitro infection of macrophages with live attenuated parasites (compared to that with wild-type [WT] L. donovani parasites) induced significantly higher production of proinflammatory cytokines (tumor necrosis factor alpha [TNF-alpha], interleukin-12 [IL-12], gamma interferon [IFN-gamma], and IL-6), chemokines (monocyte chemoattractant protein 1/CCL-2, macrophage inflammatory protein 1 alpha/CCL-3, and IP-10), reactive oxygen species (ROS), and nitric oxide, while concomitantly reducing anti-inflammatory cytokine IL-10 and arginase-1 activities, suggesting a dominant classically activated/M1 macrophage response. The classically activated response in turn helps in presenting antigen to T cells, as observed with robust CD4(+) T cell activation in vitro. Similarly, parasitized splenic macrophages from live attenuated parasite-infected mice also demonstrated induction of an M1 macrophage phenotype, indicated by upregulation of IL-1 beta, TNF-alpha, IL-12, and inducible nitric oxide synthase 2 and downregulation of genes associated with the M2 phenotype, i.e., the IL-10, YM1, Arg-1, and MRC-1 genes, compared to WT L. donovani-infected mice. Furthermore, an ex vivo antigen presentation assay showed macrophages from live attenuated parasite-infected mice induced higher IFN-alpha and IL-2 but significantly less IL-10 production by ovalbumin-specific CD4(+) T cells, resulting in proliferation of Th1 cells. These data suggest that infection with live attenuated parasites promotes a state of classical activation (M1 dominant) in macrophages that leads to the generation of protective Th1 responses in BALB/c mice. C1 [Bhattacharya, Parna; Dey, Ranadhir; Ismail, Nevien; Debrabant, Alain; Joshi, Amritanshu B.; Nakhasi, Hira L.] US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Dagur, Pradeep K.; McCoy, John Philip, Jr.] NHLBI, Flow Cytometry Core, NIH, Bethesda, MD 20892 USA. [Kruhlak, Michael] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Akue, Adovi; Kukuruga, Mark; Takeda, Kazuyo] US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Selvapandiyan, Angamuthu] Inst Mol Med, New Delhi, India. RP Nakhasi, HL (reprint author), US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Hira.Nakhasi@fda.hhs.gov FU Critical Path Initiative of the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration FX Funding for these studies was provided by intramural funds and the Critical Path Initiative of the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. NR 67 TC 6 Z9 7 U1 2 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD OCT PY 2015 VL 83 IS 10 BP 3800 EP 3815 DI 10.1128/IAI.00184-15 PG 16 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CT0NJ UT WOS:000362492600005 PM 26169275 ER PT J AU Moitra, P Zheng, H Anantharaman, V Banerjee, R Takeda, K Kozakai, Y Lepore, T Krause, PJ Aravind, L Kumar, S AF Moitra, Prasun Zheng, Hong Anantharaman, Vivek Banerjee, Rajdeep Takeda, Kazuyo Kozakai, Yukiko Lepore, Timothy Krause, Peter J. Aravind, L. Kumar, Sanjai TI Expression, Purification, and Biological Characterization of Babesia microti Apical Membrane Antigen 1 SO INFECTION AND IMMUNITY LA English DT Article ID MALARIA VACCINE CANDIDATE; ERYTHROCYTE-BINDING ACTIVITY; HOST-CELL INVASION; RED-BLOOD-CELLS; PLASMODIUM-FALCIPARUM; TOXOPLASMA-GONDII; PROTEINS; RECEPTOR; BOVIS; PARASITES AB The intraerythrocytic apicomplexan Babesia microti, the primary causative agent of human babesiosis, is a major public health concern in the United States and elsewhere. Apicomplexans utilize a multiprotein complex that includes a type I membrane protein called apical membrane antigen 1 (AMA1) to invade host cells. We have isolated the full-length B. microti AMA1 (BmAMA1) gene and determined its nucleotide sequence, as well as the amino acid sequence of the AMA1 protein. This protein contains an N-terminal signal sequence, an extracellular region, a transmembrane region, and a short conserved cytoplasmic tail. It shows the same domain organization as the AMA1 orthologs from piroplasm, coccidian, and haemosporidian apicomplexans but differs from all other currently known piroplasmida, including other Babesia and Theileria species, in lacking two conserved cysteines in highly variable domain III of the extracellular region. Minimal polymorphism was detected in BmAMA1 gene sequences of parasite isolates from six babesiosis patients from Nantucket. Immunofluorescence microscopy studies showed that BmAMA1 is localized on the cell surface and cytoplasm near the apical end of the parasite. Native BmAMA1 from parasite lysate and refolded recombinant BmAMA1 (rBmAMA1) expressed in Escherichia coli reacted with a mouse anti-BmAMA1 antibody using Western blotting. In vitro binding studies showed that both native BmAMA1 and rBmAMA1 bind to human red blood cells (RBCs). This binding is trypsin and chymotrypsin treatment sensitive but neuraminidase independent. Incubation of B. microti parasites in human RBCs with a mouse anti-BmAMA1 antibody inhibited parasite growth by 80% in a 24-h assay. Based on its antigenically conserved nature and potential role in RBC invasion, BmAMA1 should be evaluated as a vaccine candidate. C1 [Moitra, Prasun; Zheng, Hong; Banerjee, Rajdeep; Kozakai, Yukiko; Kumar, Sanjai] US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Off Blood Res & Review,Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Anantharaman, Vivek; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Takeda, Kazuyo] US FDA, Microscopy & Imaging Core Facil, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Lepore, Timothy] Nantucket Cottage Hosp, Nantucket, MA USA. [Krause, Peter J.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Krause, Peter J.] Yale Univ, Sch Med, New Haven, CT USA. RP Kumar, S (reprint author), US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Off Blood Res & Review,Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Sanjai.Kumar@fda.hhs.gov OI Anantharaman, Vivek/0000-0001-8395-0009 FU funds of the Intramural Research Programs of the U.S. Food and Drug Administration; National Library of Medicine, National Institutes of Health (NIH) FX This research was supported by the funds of the Intramural Research Programs of the U.S. Food and Drug Administration and the National Library of Medicine, National Institutes of Health (NIH). NR 65 TC 5 Z9 5 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD OCT PY 2015 VL 83 IS 10 BP 3890 EP 3901 DI 10.1128/IAI.00168-15 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CT0NJ UT WOS:000362492600013 PM 26195550 ER PT J AU Beaton, DE Terwee, CB Singh, JA Hawker, GA Patrick, DL Burke, LB Toupin-April, K Tugwell, PS AF Beaton, Dorcas E. Terwee, Caroline B. Singh, Jasvinder A. Hawker, Gillian A. Patrick, Donald L. Burke, Laurie B. Toupin-April, Karine Tugwell, Peter S. TI A Call for Evidence-based Decision Making When Selecting Outcome Measurement Instruments for Summary of Findings Tables in Systematic Reviews: Results from an OMERACT Working Group SO JOURNAL OF RHEUMATOLOGY LA English DT Review DE EVIDENCE BASED; OUTCOME MEASUREMENT; REPRODUCIBILITY OF RESULTS; HEALTH STATUS INDICATORS; SYSTEMATIC REVIEWS ID PATIENT-CENTERED OUTCOMES; METHODOLOGICAL QUALITY; CLINICAL-TRIALS; INTERNATIONAL DELPHI; COSMIN CHECKLIST; FILTER 2.0; OSTEOARTHRITIS; KNEE; PAIN; RESPONSIVENESS AB Objective. Systematic reviews often struggle with how to combine information when more than 1 instrument is used across studies being synthesized. Different techniques have been suggested based on frequency of use in the literature, or on consensus. We explore an approach blending 2 initiatives: OMERACT (Outcome Measurement in Rheumatology) and COSMIN (Consensus On Selection of Measurement Instruments), and investigate the effects of an evidence-based measurement approach on selection of outcomes. Methods. Readings were circulated to attendees registered for a preconference workshop on pain measurement. Three instruments were considered and exercises conducted to engage people in the content and measurement performance of these tools. Consensus was sought that an evidence-based approach could be created for selection of instruments for summary of findings (SoF) tables. Results. The blending of COSMIN and OMERACT approaches led to an evidence-based approach that depended both on a clear definition of target concept and a review of measurement performance of the instrument. Participants emphasized that conceptual clarity and practical considerations should come before measurement property results. Conclusion. Evidence-based approaches can be adopted for selection of instruments for SoF tables. A research agenda was formulated. C1 St Michaels Hosp, Li Ka Shing Knowledge Inst, Musculoskeletal Hlth & Outcomes Res, Toronto, ON M5B 1W8, Canada. [Beaton, Dorcas E.] Inst Work & Hlth, Toronto, ON, Canada. [Beaton, Dorcas E.; Hawker, Gillian A.] Univ Toronto, Toronto, ON, Canada. [Terwee, Caroline B.] Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands. [Terwee, Caroline B.] EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Singh, Jasvinder A.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. [Hawker, Gillian A.] Womens Coll Hosp, Inst Clin Evaluat Sci, Toronto, ON, Canada. [Patrick, Donald L.] Univ Washington, Seattle Qual Life Grp, Ctr Disabil Policy & Res, Seattle, WA 98195 USA. US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Toupin-April, Karine] Univ Ottawa, Fac Med, Dept Epidemiol & Community Med, Ottawa, ON, Canada. Ottawa Hosp, Res Inst, Fac Med, Dept Med, Ottawa, ON, Canada. Univ Ottawa, Clin Epidemiol Program, Ottawa, ON, Canada. Univ Ottawa, Fac Med, Inst Populat Hlth, Dept Epidemiol & Community Med, Ottawa, ON, Canada. RP Beaton, DE (reprint author), St Michaels Hosp, 30 Bond St, Toronto, ON M5B 1W8, Canada. EM beatond@smh.ca OI Tugwell, Peter/0000-0001-5062-0556 FU Agency for Health Quality and Research Center for Education and Research on Therapeutics (AHRQ CERTs) [U19 HS021110]; US National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) [P50 AR060772, U34 AR062891]; National Institute of Aging [U01 AG018947]; National Cancer Institute [U10 CA149950]; Patient Centered Outcomes Research Institute [CE-1304-6631]; Takeda; Savient; Regeneron; Allergan FX Supported through the OMERACT premeeting conference on pain measurement. JAS is supported by grants from the Agency for Health Quality and Research Center for Education and Research on Therapeutics (AHRQ CERTs) U19 HS021110, US National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) P50 AR060772 and U34 AR062891, National Institute of Aging U01 AG018947, National Cancer Institute U10 CA149950, the resources and the use of facilities at the VA Medical Center at Birmingham, Alabama and research contract CE-1304-6631 from the Patient Centered Outcomes Research Institute. JAS has received research grants from Takeda and Savient and consultant fees from Savient, Takeda, Regeneron, and Allergan. JAS is a member of the American College of Rheumatology's Guidelines Subcommittee of the Quality of Care Committee; and a member of the Veterans Affairs Rheumatology Field Advisory Committee. JAS, DEB, and PT are members of the executive of OMERACT, an organization that develops outcome measures in rheumatology and receives arms-length funding from 36 companies. NR 45 TC 1 Z9 1 U1 2 U2 5 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X EI 1499-2752 J9 J RHEUMATOL JI J. Rheumatol. PD OCT PY 2015 VL 42 IS 10 BP 1954 EP 1961 DI 10.3899/jrheum.141446 PG 8 WC Rheumatology SC Rheumatology GA CS7AC UT WOS:000362234900036 PM 26373567 ER PT J AU Pratt, AC Dewage, SW Pang, AH Biswas, T Barnard-Britson, S Cisneros, GA Tsodikov, OV AF Pratt, Andrew C. Dewage, Sajeewa W. Pang, Allan H. Biswas, Tapan Barnard-Britson, Sandra Cisneros, G. Andres Tsodikov, Oleg V. TI Structural and computational dissection of the catalytic mechanism of the inorganic pyrophosphatase from Mycobacterium tuberculosis SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Crystallography; Enzyme catalysis; Phosphatase; Molecular dynamics; Structure-function ID ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; YEAST PYROPHOSPHATASE; DIRECTED MUTAGENESIS; STRUCTURE VALIDATION; ACTIVE-SITE; SIMULATIONS; NUCLEOTIDE; INHIBITORS; HYDROLYSIS AB Family I inorganic pyrophosphatases (PPiases) are ubiquitous enzymes that are critical for phosphate metabolism in all domains of life. The detailed catalytic mechanism of these enzymes, including the identity of the general base, is not fully understood. We determined a series of crystal structures of the PPiase from Mycobacterium tuberculosis (Mtb PPiase) bound to catalytic metals, inorganic pyrophosphate (PPi; the reaction substrate) and to one or two inorganic phosphate ions (P-i; the reaction product), ranging in resolution from 1.85 to 3.30 angstrom. These structures represent a set of major kinetic intermediates in the catalytic turnover pathway for this enzyme and suggest an order of association and dissociation of the divalent metals, the substrate and the two products during the catalytic turnover. The active site of Mtb PPiase exhibits significant structural differences from the well characterized Escherichia coil PPiase in the vicinity of the bound PPi substrate. Prompted by these differences, quantum mechanics/molecular mechanics (QM/MM) analysis yielded an atomic description of the hydrolysis step for Mtb PPiase and, unexpectedly, indicated that Asp89, rather than Asp54 that was proposed for E. coli PPiase, can abstract a proton from a water molecule to activate it for a nucleophilic attack on the PPi substrate. Mutagenesis studies of the key Asp residues of Mtb PPiase supported this mechanism. This combination of structural and computational analyses clarifies our understanding of the mechanism of family I PPiases and has potential utility for rational development of drugs targeting this enzyme. (C) 2015 Elsevier Inc. All rights reserved. C1 [Pang, Allan H.; Tsodikov, Oleg V.] Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40536 USA. [Pratt, Andrew C.] Univ Michigan, Coll Pharm, Dept Med Chem, Ann Arbor, MI 48109 USA. [Dewage, Sajeewa W.; Cisneros, G. Andres] Wayne State Univ, Dept Chem, Detroit, MI 48202 USA. [Biswas, Tapan] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. [Barnard-Britson, Sandra] Food & Drug Adm, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Cisneros, GA (reprint author), Wayne State Univ, Dept Chem, Detroit, MI 48202 USA. EM andres@chem.wayne.edu; oleg.tsodikov@uky.edu NR 55 TC 1 Z9 1 U1 2 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 EI 1095-8657 J9 J STRUCT BIOL JI J. Struct. Biol. PD OCT PY 2015 VL 192 IS 1 BP 76 EP 87 DI 10.1016/j.jsb.2015.08.010 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CT2HT UT WOS:000362623300008 PM 26296329 ER PT J AU Sechopoulos, I Ali, ESM Badal, A Badano, A Boone, JM Kyprianou, LS Mainegra-Hing, E McMillan, KL McNitt-Gray, MF Rogers, DWO Samei, E Turner, AC AF Sechopoulos, Ioannis Ali, Elsayed S. M. Badal, Andreu Badano, Aldo Boone, John M. Kyprianou, Lacovos S. Mainegra-Hing, Ernesto McMillan, Kyle L. McNitt-Gray, Michael F. Rogers, D. W. O. Samei, Ehsan Turner, Adam C. TI Monte Carlo reference data sets for imaging research: Executive summary of the report of AAPM Research Committee Task Group 195 SO MEDICAL PHYSICS LA English DT Article DE Monte Carlo simulation; diagnostic imaging; PENELOPE4; GEANT4; EGSnrc; MCNP; x-rays; test cases ID SIMULATION; VALIDATION; PENELOPE; GEANT4; TRANSPORT; SYSTEM AB The use of Monte Carlo simulations in diagnostic medical imaging research is widespread due to its flexibility and ability to estimate quantities that are challenging to measure empirically. However, any new Monte Carlo simulation code needs to be validated before it can be used reliably. The type and degree of validation required depends on the goals of the research project, but, typically, such validation involves either comparison of simulation results to physical measurements or to previously published results obtained with established Monte Carlo codes. The former is complicated due to nuances of experimental conditions and uncertainty, while the latter is challenging due to typical graphical presentation and lack of simulation details in previous publications. In addition, entering the field of Monte Carlo simulations in general involves a steep learning curve. It is not a simple task to learn how to program and interpret a Monte Carlo simulation, even when using one of the publicly available code packages. This Task Group report provides a common reference for benchmarking Monte Carlo simulations across a range of Monte Carlo codes and simulation scenarios. In the report, all simulation conditions are provided for six different Monte Carlo simulation cases that involve common x-ray based imaging research areas. The results obtained for the six cases using four publicly available Monte Carlo software packages are included in tabular form. In addition to a full description of all simulation conditions and results, a discussion and comparison of results among the Monte Carlo packages and the lessons learned during the compilation of these results are included. This abridged version of the report includes only an introductory description of the six cases and a brief example of the results of one of the cases. This work provides an investigator the necessary information to benchmark his/her Monte Carlo simulation software against the reference cases included here before performing his/her own novel research. In addition, an investigator entering the field of Monte Carlo simulations can use these descriptions and results as a self-teaching tool to ensure that he/she is able to perform a specific simulation correctly. Finally, educators can assign these cases as learning projects as part of course objectives or training programs. (C) 2015 American Association of Physicists in Medicine. C1 [Sechopoulos, Ioannis] Emory Univ, Dept Radiol & Imaging Sci, Atlanta, GA 30322 USA. [Ali, Elsayed S. M.] Carleton Univ, Dept Phys, Carleton Lab Radiotherapy Phys, Ottawa, ON K1S 5B6, Canada. [Badal, Andreu; Badano, Aldo; Kyprianou, Lacovos S.] US FDA, Silver Spring, MD 20993 USA. [Boone, John M.] Univ Calif Davis, Dept Radiol, Sacramento, CA 95817 USA. [Boone, John M.] Univ Calif Davis, Dept Biomed Engn, Sacramento, CA 95817 USA. [Mainegra-Hing, Ernesto] Natl Res Council Canada, Ottawa, ON K1S 5B6, Canada. [McMillan, Kyle L.; McNitt-Gray, Michael F.; Turner, Adam C.] Univ Calif Los Angeles, Dept Biomed Phys, Los Angeles, CA 90024 USA. [McMillan, Kyle L.; McNitt-Gray, Michael F.; Turner, Adam C.] Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA 90024 USA. [Rogers, D. W. O.] Carleton Univ, Carleton Lab Radiotherapy Phys, Dept Phys, Ottawa, ON K1A 0R6, Canada. [Samei, Ehsan] Duke Univ, Dept Radiol, Carl E Ravin Adv Imaging Labs, Durham, NC 27705 USA. RP Sechopoulos, I (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Radiol & Nucl Med, POB 9101, NL-6500 HB Nijmegen 766, Netherlands. EM ioannis.sechopoulos@radboudumc.nl RI Sechopoulos, Ioannis/B-4762-2016; OI McNItt-Gray, Michael/0000-0003-3004-4613; badano, aldo/0000-0003-3712-6670 FU U.S. Department of Energy [DE-AC02-76SF00515] FX The TG would like to thank Samir Abboud, Cecilia Marini Bettolo, Bahaa Ghammraoui, Sebastien Incerti, Vladimir Ivantchenko, Alfonso Mantero, Luciano Pandola, Joseph Perl, and Yakun Zhang for their contributions to this work, Eric Jablonowski for his contributions to the figures, and Karen MacFarland, Lisa Giove, Corbi Foster, and Debbie Gilley from the AAPM for assisting with administrative issues throughout the TG's work. Work by I.S. supported in part by the U.S. Department of Energy under Contract No. DE-AC02-76SF00515. NR 25 TC 6 Z9 6 U1 0 U2 4 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD OCT PY 2015 VL 42 IS 10 BP 5679 EP 5691 DI 10.1118/1.4928676 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CT1OY UT WOS:000362570100011 PM 26429242 ER PT J AU Colin-Gonzalez, AL Ali, SF Tunez, I Santamaria, A AF Laura Colin-Gonzalez, Ana Ali, Syed F. Tunez, Isaac Santamaria, Abel TI On the antioxidant, neuroprotective and anti-inflammatory properties of S-allyl cysteine: An update SO NEUROCHEMISTRY INTERNATIONAL LA English DT Review DE Garlic-derived organosulfur compounds; Neuroprotection; S-allyl cysteine; Neuroinflammation; Oxidative stress ID TOLL-LIKE RECEPTOR-4; NF-KAPPA-B; ENDOPLASMIC-RETICULUM STRESS; ACID-INDUCED NEUROTOXICITY; LONG-TERM POTENTIATION; TUMOR-NECROSIS-FACTOR; RAT DENTATE GYRUS; ALZHEIMERS-DISEASE; NEURONAL DEATH; PPAR-GAMMA AB Therapeutic approaches based on isolated compounds obtained from natural products to handle central and peripheral disorders involving oxidative stress and inflammation are more common nowadays. The validation of nutraceutics vs. pharmaceutics as tools to induce preventive and protective profiles in human health alterations is still far of complete acceptance, but the basis to start more solid experimental and clinical protocols with natural products has already begun. S-allyl cysteine (SAC) is a promising garlic-derived organosulfur compound exhibiting a considerable number of positive actions in cell models and living systems. An update, in the form of review, is needed from time to time to get access to the state-of-the-art on this topic. In this review we visited recent and refreshing evidence of new already proven and potential targets to explain the benefits of using SAC against toxic and pathological conditions. The broad spectrum of protective actions covered by this molecule comprises antioxidant, redox modulatory and anti-inflammatory activities, accompanied by anti-apoptotic, pro-energetic and signaling capacities. Herein, we detail the evidence on these aspects to provide the reader a more complete overview on the promising aspects of SAC in research. Published by Elsevier Ltd. C1 [Laura Colin-Gonzalez, Ana; Santamaria, Abel] Inst Nacl Neurol & Neurocirugia Manuel Velasco Su, SSA, Lab Aminoacidos Excitadores, Mexico City, DF, Mexico. [Ali, Syed F.] US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Tunez, Isaac] Univ Cordoba, Hosp Univ Reina Sofia, Inst Maimonides Invest Biomed Cordoba IMIBIC, Dept Bioquim & Biol Mol,Fac Med, Cordoba, Spain. [Tunez, Isaac] Red Temat Invest Cooperat Envejecimiento & Fragil, Madrid, Spain. RP Ali, SF (reprint author), US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Syed.ali@fda.hhs.gov; absada@yahoo.com NR 81 TC 12 Z9 12 U1 3 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 EI 1872-9754 J9 NEUROCHEM INT JI Neurochem. Int. PD OCT PY 2015 VL 89 BP 83 EP 91 DI 10.1016/j.neuint.2015.06.011 PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CT2CO UT WOS:000362609800009 PM 26122973 ER PT J AU Boorman, GA Foster, JR Laast, VA Francke, S AF Boorman, Gary A. Foster, John R. Laast, Victoria A. Francke, Sabine TI Regulatory Forum Opinion Piece*: The Value of Publishing Negative Scientific Study Data SO TOXICOLOGIC PATHOLOGY LA English DT Article DE positive-outcome bias; research evaluation; bias; regulatory science; publishing; negative data ID FREQUENCY MAGNETIC-FIELDS; TOXICITY ONCOGENICITY EVALUATION; CHILDHOOD LEUKEMIA; PUBLICATION BIAS; LONG-TERM; CARCINOGENICITY; EXPOSURE; RODENTS; CANCER; PREDICTION AB Historically it has been easier to publish positive scientific results than negative data not supporting the research hypothesis. This appears to be increasing, with fewer negative studies appearing in the literature across many disciplines. Failure to recognize the value of negative results has important implications for the toxicology community. Implications include perpetuating scientific fields based upon selective or occasionally erroneous, positive results. One example is decreased vaccination rates and increased measles infections that can lead to childhood mortality following one erroneous positive study linking vaccination to adverse effects despite multiple negative studies. Publication of negative data that challenges existing paradigms enhances progress by stopping further investment in scientifically barren topics, decreases the use of animals, and focuses research in more fruitful areas. The National Toxicology Program (NTP) publishes both positive and negative rodent data. Retrospective analysis of the NTP database has provided insights on the carcinogenic process and in the gradual acceptance of using fewer animals in safety studies. This article proposes that careful publication of both positive and negative data can enhance product safety assessment, add robustness to safety determinations in the regulatory decision-making process, and should be actively encouraged by those determining journal editorial policy. C1 [Boorman, Gary A.] Covance Labs Inc, Chantilly, VA 20151 USA. [Foster, John R.] ToxPath Sci Ltd, Congelton, Cheshire, England. [Laast, Victoria A.] Covance Labs, Shanghai, Peoples R China. [Francke, Sabine] US FDA, US Off Facil & Adm Serv, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Boorman, GA (reprint author), Covance Labs Inc, 14500 Av Pkwy,Suite 125, Chantilly, VA 20151 USA. EM gary.boorman@Covance.com NR 40 TC 1 Z9 1 U1 1 U2 7 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 OCT PY 2015 VL 43 IS 7 BP 901 EP 906 DI 10.1177/0192623315595884 PG 6 WC Pathology; Toxicology SC Pathology; Toxicology GA CS9ZO UT WOS:000362453500001 PM 26269614 ER PT J AU Fikes, JD Patrick, DJ Francke, S Frazier, KS Reindel, JF Romeike, A Spaet, RH Tomlinson, L Schafer, KA AF Fikes, James D. Patrick, Daniel J. Francke, Sabine Frazier, Kendall S. Reindel, James F. Romeike, Annette Spaet, Robert H. Tomlinson, Lindsay Schafer, Kenneth A. TI Scientific and Regulatory Policy Committee Review: Review of the Organisation for Economic Co-operation and Development (OECD) Guidance on the GLP Requirements for Peer Review of Histopathology SO TOXICOLOGIC PATHOLOGY LA English DT Article DE OECD; GLP; guidance; histopathology; pathology; peer review; regulatory AB In 2014, the Organisation for Economic Co-operation and Development (OECD) issued guidance no. 16, Guidance on the GLP Requirements for Peer Review of Histopathology. The stated purpose of the guidance document is to provide guidance to pathologists, test facility management, study directors and quality assurance personnel on how the peer review of histopathology should be planned, managed, documented, and reported in order to meet Good Laboratory Practice (GLP) expectations and requirements. On behalf of and in collaboration with the global societies of toxicologic pathology, the Society of Toxicologic Pathology initiated a review of OECD guidance no. 16. The objectives of this review are to provide a unified interpretation of the guidance, to recommend compliant processes for organizations to implement, and to avoid inconsistent process adaptations across the industry. This review of the guidance document is the product of a global collaboration with other societies of toxicologic pathology and provides a section-by-section international consensus view and interpretation of the OECD guidance on peer review. C1 [Fikes, James D.] Biogen Inc, Cambridge, MA 02142 USA. [Patrick, Daniel J.] MPI Res, Mattawan, MI USA. [Francke, Sabine] US FDA, College Pk, MD USA. [Frazier, Kendall S.] GlaxoSmithKline, King Of Prussia, PA USA. [Reindel, James F.] Amgen Inc, Seattle, WA USA. [Romeike, Annette] Covance Labs, Porcheville, France. [Spaet, Robert H.] RSPathologics, Granby, CO USA. [Tomlinson, Lindsay] Pfizer Inc, Andover, MA USA. [Schafer, Kenneth A.] Vet Path Serv Inc, Mason, OH USA. RP Fikes, JD (reprint author), Biogen Inc, 14 Cambridge Ctr, Cambridge, MA 02142 USA. EM jim.fikes@biogen.com NR 7 TC 0 Z9 0 U1 1 U2 1 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 OCT PY 2015 VL 43 IS 7 BP 907 EP 914 DI 10.1177/0192623315596382 PG 8 WC Pathology; Toxicology SC Pathology; Toxicology GA CS9ZO UT WOS:000362453500002 PM 26208968 ER PT J AU Frazier, KS Engelhardt, JA Fant, P Guionaud, S Henry, SP Leach, MW Louden, C Scicchitano, MS Weaver, JL Zabka, TS AF Frazier, Kendall S. Engelhardt, Jeffery A. Fant, Pierluigi Guionaud, Silvia Henry, Scott P. Leach, Michael W. Louden, Calvert Scicchitano, Marshall S. Weaver, James L. Zabka, Tanja S. CA Soc Toxicologic Pathology Vasc Inj TI Scientific and Regulatory Policy Committee Points-to-consider Paper*: Drug-induced Vascular Injury Associated with Nonsmall Molecule Therapeutics in Preclinical Development: Part I. Biotherapeutics SO TOXICOLOGIC PATHOLOGY LA English DT Article DE cardiovascular system; pharmaceutical development; products; preclinical safety-assessment; risk management; biomarkers; biotherapeutics; nonhuman primate; vascular injury ID CIRCULATING ENDOTHELIAL-CELLS; RECOMBINANT HUMAN INTERLEUKIN-4; ANTIBODY-ASSOCIATED VASCULITIS; SPRAGUE-DAWLEY RATS; MONKEYS MACACA-FASCICULARIS; ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY; SPONTANEOUSLY HYPERTENSIVE-RAT; ANCA-ASSOCIATED VASCULITIS; INHIBITOR SCH 351591; CYNOMOLGUS MONKEYS AB Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. Although DIVI in laboratory animal species has been well characterized for vasoactive small molecules, there is little available information regarding DIVI associated with biotherapeutics such as peptides/proteins or antibodies. Because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans and the lack of robust biomarkers of DIVI, preclinical DIVI findings can cause considerable delays in or even halt development of promising new drugs. This review discusses standard terminology, characteristics, and mechanisms of DIVI associated with biotherapeutics. Guidance and points to consider for the toxicologist and pathologist facing preclinical cases of biotherapeutic-related DIVI are outlined, and examples of regulatory feedback for each of the mechanistic types of DIVI are included to provide insight into risk assessment. C1 [Frazier, Kendall S.; Scicchitano, Marshall S.] GlaxoSmithKline Safety Assessment, King Of Prussia, PA 19406 USA. [Engelhardt, Jeffery A.; Henry, Scott P.] ISIS Pharmaceut, Carlsbad, CA 92008 USA. [Fant, Pierluigi] WIL Res Europe, St Germain En Laye, France. [Guionaud, Silvia] MedImmune, Cambridge, England. [Leach, Michael W.] Pfizer Drug Safety Res & Dev, Andover, MA USA. [Louden, Calvert] Raritan, Somerset, NJ USA. [Weaver, James L.] US FDA, CDER, Silver Spring, MD USA. [Zabka, Tanja S.] Genentech Inc, San Francisco, CA USA. RP Frazier, KS (reprint author), GlaxoSmithKline Safety Assessment, 709 Swedeland Rd,UE0376 POB 1539, King Of Prussia, PA 19406 USA. EM kendall.s.frazier@gsk.com NR 202 TC 0 Z9 0 U1 2 U2 4 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 OCT PY 2015 VL 43 IS 7 BP 915 EP 934 DI 10.1177/0192623315570340 PG 20 WC Pathology; Toxicology SC Pathology; Toxicology GA CS9ZO UT WOS:000362453500003 PM 25722122 ER PT J AU Engelhardt, JA Fant, P Guionaud, S Henry, SP Leach, MW Louden, C Scicchitano, MS Weaver, JL Zabka, TS Frazier, KS AF Engelhardt, Jeffery A. Fant, Pierluigi Guionaud, Silvia Henry, Scott P. Leach, Michael W. Louden, Calvert Scicchitano, Marshall S. Weaver, James L. Zabka, Tanja S. Frazier, Kendall S. CA Soc Toxicologic Pathology Vasc Inj TI Scientific and Regulatory Policy Committee Points-to-consider Paper*: Drug-induced Vascular Injury Associated with Nonsmall Molecule Therapeutics in Preclinical Development: Part 2. Antisense Oligonucleotides SO TOXICOLOGIC PATHOLOGY LA English DT Article DE biomarkers; preclinical safety-assessment; risk management; nonhuman primate; cardiovascular system; antisense oligonucleotide; vascular injury ID PHOSPHOROTHIOATE OLIGONUCLEOTIDE; MACACA-FASCICULARIS; CYNOMOLGUS MACAQUE; NONCLINICAL SAFETY; BIOMARKERS; MONKEYS; TOXICITY; OLIGODEOXYNUCLEOTIDE; COMPLEMENT; ACTIVATION AB Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. In recent years, DIVI has been occasionally observed in nonhuman primates given RNA-targeting therapeutics such as antisense oligonucleotide therapies (ASOs) during chronic toxicity studies. While DIVI in laboratory animal species has been well characterized for vasoactive small molecules, and immune-mediated responses against large molecule biotherapeutics have been well described, there is little published information regarding DIVI induced by ASOs to date. Preclinical DIVI findings in monkeys have caused considerable delays in development of promising new ASO therapies, because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans, and the lack of robust biomarkers of DIVI. This review of DIVI discusses clinical and microscopic features of vasculitis in monkeys, their pathogenic mechanisms, and points to consider for the toxicologist and pathologist when confronted with ASO-related DIVI. Relevant examples of regulatory feedback are included to provide insight into risk assessment of ASO therapies. C1 [Engelhardt, Jeffery A.; Henry, Scott P.] ISIS Pharmaceut, Carlsbad, CA 92008 USA. [Fant, Pierluigi] WIL Res Europe, St Germain En Laye, France. [Guionaud, Silvia] MedImmune, Cambridge, England. [Leach, Michael W.] Pfizer Drug Safety Res & Dev, Andover, MA USA. [Scicchitano, Marshall S.; Frazier, Kendall S.] GlaxoSmithKline Safety Assessment, King Of Prussia, PA 19406 USA. [Weaver, James L.] US FDA, CDER, Silver Spring, MD USA. [Zabka, Tanja S.] Genentech Inc, San Francisco, CA 94080 USA. RP Frazier, KS (reprint author), GlaxoSmithKline Safety Assessment, 709 Swedeland Rd,UE0376 POB 1539, King Of Prussia, PA 19406 USA. EM kendall.s.frazier@gsk.com NR 51 TC 0 Z9 0 U1 1 U2 5 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 OCT PY 2015 VL 43 IS 7 BP 935 EP 944 DI 10.1177/0192623315570341 PG 10 WC Pathology; Toxicology SC Pathology; Toxicology GA CS9ZO UT WOS:000362453500004 PM 25717082 ER PT J AU Mishra, P Murray, J Birnkrant, D AF Mishra, Poonam Murray, Jeffrey Birnkrant, Debra TI Direct-acting antiviral drug approvals for treatment of chronic hepatitis C virus infection: Scientific and regulatory approaches to clinical trial designs SO HEPATOLOGY LA English DT Article ID SUSTAINED VIROLOGICAL RESPONSE; ALL-CAUSE MORTALITY; ASSOCIATION; FIBROSIS; UPDATE AB Therapeutic options for treatment of chronic hepatitis C have improved substantially since the approval of direct-acting antiviral agents (DAAs). Several interferon (IFN)-free or IFN- and ribavirin (RBV)-free treatment regimens with shorter durations and improved efficacy and safety profiles are now available. The U.S. Food and Drug Administration (FDA) used several scientific approaches and regulatory mechanisms, such as (1) use of a validated surrogate (sustained virological response) for a primary endpoint, (2) shortening the time point for measuring the surrogate by 12 weeks, (3) use of historical controls when clinically appropriate, and (4) use of modeling when scientifically sound to extend treatment indications to subpopulations not fully evaluated in clinical trials, which had an impact on DAA development and subsequent approvals. This article intends to provide increased transparency about the FDA's scientific approaches and regulatory processes that supported drug development and marketing approval of DAAs for treatment of hepatitis C, a serious, life-threatening infection. (Hepatology 2015;62:1298-1303) C1 [Mishra, Poonam; Murray, Jeffrey; Birnkrant, Debra] US FDA, Ctr Drug Evaluat & Res, Off Antimicrobial Prod, Div Antiviral Prod, Silver Spring, MD 20993 USA. RP Mishra, P (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Antimicrobial Prod, Div Antiviral Prod, 10903 New Hampshire Ave,Bldg 22,Room 6365, Silver Spring, MD 20993 USA. EM Poonam.mis-hra@fda.hhs.gov NR 20 TC 6 Z9 6 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 OCT PY 2015 VL 62 IS 4 BP 1298 EP 1303 DI 10.1002/hep.27880 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CS6TJ UT WOS:000362214800031 PM 25953139 ER PT J AU Sun, H Como, PG Downey, LC Murphy, D Ariagno, RL Rodriguez, W AF Sun, H. Como, P. G. Downey, L. C. Murphy, D. Ariagno, R. L. Rodriguez, W. TI Infant formula and neurocognitive outcomes: impact of study end-point selection SO JOURNAL OF PERINATOLOGY LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; HEALTHY TERM INFANTS; RANDOMIZED CONTROLLED-TRIAL; PRETERM INFANTS; DOCOSAHEXAENOIC ACID; COGNITIVE FUNCTION; VISUAL-ATTENTION; CLINICAL-TRIALS; DOUBLE-BLIND; SUPPLEMENTATION AB OBJECTIVES: Assessing validity and reliability of end points used in docosahexanoic and arachidonic acids (DHA and ARA) infant formula supplementation trials as an example for addressing the impact of end-point selection and critical need for well-defined, reliable and validated clinical outcome assessments for neurocognitive assessment in neonates and infants. STUDY DESIGN: We searched eight electronic databases and reviewed all randomized, controlled human trials using DHA/ARA supplements with neurodevelopment clinical outcomes. We systematically evaluated the validity and reliability of end-point measures based on the criteria for studying nutritional additives recommended by the Institute of Medicine, criteria described in the Food and Drug Administration guidance for clinical outcome assessment, development and literature review. RESULTS: We identified 29 articles that met the selection criteria. The end points that were used for neurodevelopment measures in 23 out of 29 original short-term studies included the Bayley Scale of Infant Development (BSID)-I and -II (n = 12), Brunet-Lezine test (n = 2), videotape infant's movements (n = 1), record time to milestones including sitting, crawling, standing and walking (n = 1), problem-solving test (n = 2), brainstem auditory-evoked potential (n = 1), Touwen examination (n = 1), Fagan test of infant intelligence (n = 2) and visual habituation protocol (n = 1). None of these end points have a long-term predictive property for neurocognitive assessment. Compared with standard infant formula, the beneficial effects of DHA/ARA supplementation on neurodevelopment were reported in 2 out of 12 studies using BSID vs 8 out of 11 studies using other end-point measures. In addition, 6 out of 29 long-term follow-up studies used the end points including Stanford-Binet IQ test (n = 1), Wechsler Preschool and Primary Scale of Intelligence (n = 4) and Bracken Basic Concept Scale (n = 1), which are generally scales of intellectual ability and typically do not change substantively in the short term. None of these long-term follow-up studies demonstrated beneficial effects of DHA/ARA supplementation on neurodevelopment. CONCLUSION: The choice of end-point measures affects the outcomes of DHA/ARA-supplemented infant formula trials. Available data are currently inadequate to conclude that DHA/ARA supplementation has a clinically meaningful beneficial effect upon neurological development. Although BSID is validated to assess early developmental delays, it is not designed to predict long-term neurocognitive outcome. A well-defined, valid and reliable clinical outcome assessment that measures neurocognitive function in neonates and infants is essential to provide the scientific evidence required for future clinical trials. C1 [Sun, H.; Como, P. G.; Murphy, D.; Ariagno, R. L.; Rodriguez, W.] US FDA, Off Pediat Therapeut, Off Commissioner, Silver Spring, MD 20993 USA. [Downey, L. C.] Wake Forest Sch Med, Dept Pediat, Div Neonatol, Winston Salem, NC USA. [Ariagno, R. L.] Stanford Univ, Sch Med, Dept Pediat, Div Neonatol, Palo Alto, CA 94304 USA. RP Sun, H (reprint author), US FDA, Off Pediat Therapeut, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM sun.haihao@fda.hhs.gov NR 43 TC 3 Z9 3 U1 8 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0743-8346 EI 1476-5543 J9 J PERINATOL JI J. Perinatol. PD OCT PY 2015 VL 35 IS 10 BP 867 EP 874 DI 10.1038/jp.2015.87 PG 8 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA CS2KI UT WOS:000361899100019 PM 26248129 ER PT J AU Schick, A Miller, KL Lanthier, M Woodcock, J AF Schick, Andreas Miller, Kathleen L. Lanthier, Michael Woodcock, Janet TI REGULATORY WATCH What drives differences in review times among CDER divisions? SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material C1 [Schick, Andreas; Miller, Kathleen L.; Lanthier, Michael] US FDA, Off Commissioner, Silver Spring, MD 20993 USA. [Woodcock, Janet] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Schick, A (reprint author), US FDA, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Andreas.Schick@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD OCT PY 2015 VL 14 IS 10 BP 670 EP U21 DI 10.1038/nrd4724 PG 2 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA CS6LT UT WOS:000362191100004 PM 26294264 ER PT J AU Dahiya, N Sarachana, T Vu, L Becker, KG Wood, WH Zhang, YQ Atreya, CD AF Dahiya, Neetu Sarachana, Tewarit Vu, Long Becker, Kevin G. Wood, William H., III Zhang, Yongqing Atreya, Chintamani D. TI Platelet MicroRNAs: An Overview SO TRANSFUSION MEDICINE REVIEWS LA English DT Review DE MicroRNA; Blood disorders; Platelets; Signaling pathways ID MEGAKARYOCYTIC DIFFERENTIATION; ACTIVATED PLATELETS; K562 CELLS; MICROPARTICLES; MEGAKARYOPOIESIS; EXPRESSION; APOPTOSIS; PATHWAY; STORAGE AB MicroRNAs (miRNAs) are short similar to 22-nucleotide noncoding RNA that have been found to influence the expression of many genes and cellular processes by either repressing translation or degrading messenger RNA transcripts. Platelet miRNA expression has been shown to be perturbed during ex vivo storage of platelets and in platelet-associated disorders. Although bioinformatics-based miRNA target predictions have been established, direct experimental validation of the role of miRNAs in platelet biology has been rather slow. Target prediction studies are, nonetheless, valuable in directing the design of appropriate experiments to test specific miRNA:messenger RNA interactions relevant to the underlying mechanisms of platelet function in general and in disease as well as in ex vivo storage-associated "storage lesions," a collective term used to include physiologic, biochemical, and morphologic changes that occur in stored platelets. This brief review will focus on emerging human platelet miRNA studies to emphasize their potential role relevant to transfusion medicine field in terms of regulating platelet signaling pathways, markers of platelet associated disorders, and remote impactors of gene expression (intercellular biomodulators) as well as potential platelet quality markers of storage and pathogen reduction treatments. Published by Elsevier Inc. C1 [Dahiya, Neetu; Vu, Long; Atreya, Chintamani D.] US FDA, Sect Cell Biol, Lab Cellular Hematol, Div Hematol Res & Review,Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Sarachana, Tewarit] Chulalongkorn Univ, Dept Clin Chem, Fac Allied Hlth Sci, Bangkok, Thailand. [Becker, Kevin G.; Wood, William H., III; Zhang, Yongqing] NIA, Genet Lab, Baltimore, MD 21224 USA. RP Atreya, CD (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 71,Room 4236, Silver Spring, MD 20993 USA. EM chintamani.atreya@fda.hhs.gov FU Center for Biologics Evaluation and Research, US Food and Drug Administration; Center for Biologics Evaluation and Research; Intramural Research Program FX CDA received funding for this study from the Center for Biologics Evaluation and Research, US Food and Drug Administration. ND and LV are recipients of a postdoctoral fellowship at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. The collaborative work performed by the coauthors KGB, WHW, and YZ at the National Institute on Aging, NIH, was supported by their Intramural Research Program. We would like to thank Dr Valerie W. Hu from the Department of Biochemistry and Molecular Biology, The George Washington University School of Medicine and Health Sciences, for allowing us to use the Ingenuity Pathway Analysis software. NR 44 TC 1 Z9 2 U1 3 U2 15 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0887-7963 EI 1532-9496 J9 TRANSFUS MED REV JI Transf. Med. Rev. PD OCT PY 2015 VL 29 IS 4 BP 215 EP 219 DI 10.1016/j.tmrv.2015.08.002 PG 5 WC Hematology SC Hematology GA CS4LT UT WOS:000362048000001 PM 26341586 ER PT J AU Ferguson, SA Law, CD Sarkar, S AF Ferguson, Sherry A. Law, C. Delbert Sarkar, Sumit TI Chronic MPTP treatment produces hyperactivity in male mice which is not alleviated by concurrent trehalose treatment SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Parkinson's disease; MPTP; Probenecid; Behavior; Locomotor activity; Mice ID CHRONIC MOUSE MODEL; INDUCED PARKINSONS-DISEASE; DOPAMINERGIC NEURONAL LOSS; BEHAVIORAL-CHANGES; C57BL/6 MICE; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE; INFLAMMATION; NEURODEGENERATION; METHAMPHETAMINE; SUSCEPTIBILITY AB The chronic MPTP + probenecid treatment paradigm has been used to successfully model the neurochemical, neuropathological, and behavioral effects associated with Parkinson's disease. Here, adult male C57Bl/6 mice were injected ip with 25 mg/kg MPTP and 250 mg/kg probenecid (MPTPp) or saline twice weekly for a total of 10 injections. Behavioral assessments included motor coordination, grip strength, spatial learning/memory, locomotor activity, and anhedonia. Those assessments were repeated up to 8 weeks post-treatment. In a subsequent experiment, adult male mice were treated with saline or MPTPp as described above. One-half of each group was allowed access to 1% trehalose in the water bottle. Trehalose intake averaged 1.90-2.34g/kg. Behavioral assessments included locomotor activity, olfaction, motor coordination, grip strength, and exploratory behavior. Those assessments were repeated 4 weeks post-treatment. The strongest MPTPp effect was hyperactivity as exhibited in the open field. This increased activity was apparent in both experiments and occurred at all time points post-treatment. Assessments of grip strength, water maze performance, olfaction, and exploratory behavior did not indicate MPTPp-related alterations. When the specifications for the motor coordination test were made somewhat easier in the second experiment, there were deficits exhibited by the MPTPp group, the MPTPp + trehalose group and the trehalose group. The addition of trehalose did not alleviate any of the MPTPp-induced behavioral alterations; however, trehalose treatment significantly attenuated the striatal decreases in DA, DOPAC, HVA and 5-HIAA. These results provide a more comprehensive description of the behavioral alterations resulting from the chronic MPTPp treatment regimen and suggest that trehalose at this concentration does not act as a complete neuroprotectant. Published by Elsevier B.V. C1 [Ferguson, Sherry A.; Law, C. Delbert; Sarkar, Sumit] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Ferguson, SA (reprint author), HFT-132 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Sherry.Ferguson@fda.hhs.gov; Charies.Law@fda.hhs.gov; Sumit.Sarkar@fda.hhs.gov FU National Center for Toxicological Research/Food and Drug Administration [E7451] FX This work was supported by the National Center for Toxicological Research/Food and Drug Administration [Protocol # E7451 to S.S.]. The authors are grateful for the technical expertise provided by the animal care staff of the Priority One Corporation. We especially are indebted to expert statistician Mr. Robert Paul Felton of the Division of Bioinformatics and Biostatistics for his careful analyses. NR 51 TC 2 Z9 2 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD OCT 1 PY 2015 VL 292 BP 68 EP 78 DI 10.1016/j.bbr.2015.05.057 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CR8EI UT WOS:000361583500009 PM 26111725 ER PT J AU Tian, G Hindle, M Lee, S Longest, PW AF Tian, Geng Hindle, Michael Lee, Sau Longest, P. Worth TI Validating CFD Predictions of Pharmaceutical Aerosol Deposition with In Vivo Data SO PHARMACEUTICAL RESEARCH LA English DT Article DE airway dosimetry predictions; computational fluid dynamics (CFD); pharmaceutical aerosols; predictions of aerosol deposition; respiratory drug delivery ID SOFT MIST(TM) INHALER; DRY POWDER INHALERS; PATH SIP MODEL; EXCIPIENT SUBMICROMETER PARTICLES; COMPUTATIONAL FLUID-DYNAMICS; RESPIRATORY-TRACT DEPOSITION; METERED-DOSE INHALERS; LARGE-EDDY SIMULATION; HUMAN-LUNG; AIRWAY MODEL AB CFD provides a powerful approach to evaluate the deposition of pharmaceutical aerosols; however, previous studies have not compared CFD results of deposition throughout the lungs with in vivo data. The in vivo datasets selected for comparison with CFD predictions included fast and slow clearance of monodisperse aerosols as well as 2D gamma scintigraphy measurements for a dry powder inhaler (DPI) and softmist inhaler (SMI). The CFD model included the inhaler, a characteristic model of the mouth-throat (MT) and upper tracheobronchial (TB) airways, stochastic individual pathways (SIPs) representing the remaining TB region, and recent CFD-based correlations to predict pharmaceutical aerosol deposition in the alveolar airways. For the monodisperse aerosol, CFD predictions of total lung deposition agreed with in vivo data providing a percent relative error of 6% averaged across aerosol sizes of 1-7 mu m. With the DPI and SMI, deposition was evaluated in the MT, central airways (bifurcations B1-B7), and intermediate plus peripheral airways (B8 through alveoli). Across these regions, CFD predictions produced an average relative error < 10% for each inhaler. CFD simulations with the SIP modeling approach were shown to accurately predict regional deposition throughout the lungs for multiple aerosol types and different in vivo assessment methods. C1 [Tian, Geng; Longest, P. Worth] Virginia Commonwealth Univ, Dept Mech & Nucl Engn, Richmond, VA 23284 USA. [Hindle, Michael; Longest, P. Worth] Virginia Commonwealth Univ, Dept Pharmaceut, Richmond, VA 23284 USA. [Lee, Sau] US FDA, Off Pharmaceut Qual, Ctr Drug Evaluat Res, Silver Spring, MD USA. RP Longest, PW (reprint author), Virginia Commonwealth Univ, Dept Mech & Nucl Engn, 401 West Main St,POB 843015, Richmond, VA 23284 USA. EM pwlongest@vcu.edu FU US FDA [U01 FD004570]; National Heart, Lung, and Blood Institute [R01 HL107333] FX Katharina Bormann and Xiangyin Wei are acknowledged for their assistance in measuring the initial size of the Novolizer DPI. Navvab Dalasm is credited with creating the alveolar model shown in Fig. 3 while at VCU. This study was supported by Award U01 FD004570 from the US FDA and Award R01 HL107333 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US FDA, the National Heart, Lung, and Blood Institute or the National Institutes of Health. NR 100 TC 6 Z9 6 U1 0 U2 15 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 EI 1573-904X J9 PHARM RES-DORDR JI Pharm. Res. PD OCT PY 2015 VL 32 IS 10 BP 3170 EP 3187 DI 10.1007/s11095-015-1695-1 PG 18 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA CS0BC UT WOS:000361720700005 PM 25944585 ER PT J AU Ho, MP Gonzalez, JM Lerner, HP Neuland, CY Whang, JM McMurry-Heath, M Hauber, AB Irony, T AF Ho, Martin P. Gonzalez, Juan Marcos Lerner, Herbert P. Neuland, Carolyn Y. Whang, Joyce M. McMurry-Heath, Michelle Hauber, A. Brett Irony, Telba TI Incorporating patient-preference evidence into regulatory decision making SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES LA English DT Article DE Patient preferences; Weight-loss devices; Obesity treatment; FDA; Benefit-risk assessment; Regulatory-approval decisions ID EXPERIMENTAL-DESIGN; TASK-FORCE AB Background Patients have a unique role in deciding what treatments should be available for them and regulatory agencies should take their preferences into account when making treatment approval decisions. This is the first study designed to obtain quantitative patient-preference evidence to inform regulatory approval decisions by the Food and Drug Administration Center for Devices and Radiological Health. Methods Five-hundred and forty United States adults with body mass index (BMI) >= 30 kg/m(2) evaluated tradeoffs among effectiveness, safety, and other attributes of weight-loss devices in a scientific survey. Discrete-choice experiments were used to quantify the importance of safety, effectiveness, and other attributes of weight-loss devices to obese respondents. A tool based on these measures is being used to inform benefit-risk assessments for premarket approval of medical devices. Results Respondent choices yielded preference scores indicating their relative value for attributes of weight-loss devices in this study. We developed a tool to estimate the minimum weight loss acceptable by a patient to receive a device with a given risk profile and the maximum mortality risk tolerable in exchange for a given weight loss. For example, to accept a device with 0.01 % mortality risk, a risk tolerant patient will require about 10 % total body weight loss lasting 5 years. Conclusions Patient preference evidence was used make regulatory decision making more patient-centered. In addition, we captured the heterogeneity of patient preferences allowing market approval of effective devices for risk tolerant patients. CDRH is using the study tool to define minimum clinical effectiveness to evaluate new weight-loss devices. The methods presented can be applied to a wide variety of medical products. This study supports the ongoing development of a guidance document on incorporating patient preferences into medical-device premarket approval decisions. C1 [Ho, Martin P.; Lerner, Herbert P.; Neuland, Carolyn Y.; Whang, Joyce M.; McMurry-Heath, Michelle; Irony, Telba] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Gonzalez, Juan Marcos; Hauber, A. Brett] RTI Hlth Solut, Durham, NC USA. RP Irony, T (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 66,Room 2232, Silver Spring, MD 20993 USA. EM martin.ho@fda.hhs.gov; jgonzalez@rti.org; herbert.lerner@fda.hhs.gov; carolyn.neuland@fda.hhs.gov; joyce.whang@fda.hhs.gov; michelle.mcmurry-heath@fda.hhs.gov; abhauber@rti.org; telba.irony@fda.hhs.gov NR 10 TC 18 Z9 18 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0930-2794 EI 1432-2218 J9 SURG ENDOSC JI Surg. Endosc. PD OCT PY 2015 VL 29 IS 10 BP 2984 EP 2993 DI 10.1007/s00464-014-4044-2 PG 10 WC Surgery SC Surgery GA CS1EN UT WOS:000361805500017 PM 25552232 ER PT J AU Xia, QS Chiang, HM Yin, JJ Chen, SJ Cai, LN Yu, HT Fu, PP AF Xia, Qingsu Chiang, Hsiu-Mei Yin, Jun-Jie Chen, Shoujun Cai, Lining Yu, Hongtao Fu, Peter P. TI UVA photoirradiation of benzo[a]pyrene metabolites: induction of cytotoxicity, reactive oxygen species, and lipid peroxidation SO TOXICOLOGY AND INDUSTRIAL HEALTH LA English DT Article DE Polycyclic aromatic hydrocarbons (PAHs); Benzo[a]pyrene; metabolite; lipid peroxidation; reactive oxygen species (ROS) ID POLYCYCLIC AROMATIC-HYDROCARBONS; SINGLET OXYGEN; ULTRAVIOLET-RADIATION; RETINYL PALMITATE; DNA-DAMAGE; LIGHT; PHOTOTOXICITY; RADICALS; CLEAVAGE; AZULENE AB Benzo[a]pyrene (BaP) is a prototype for studying carcinogenesis of polycyclic aromatic hydrocarbons (PAHs). We have long been interested in studying the phototoxicity of PAHs. In this study, we determined that metabolism of BaP by human skin HaCaT keratinocytes resulted in six identified phase I metabolites, for example, BaP trans-7,8-dihydrodiol (BaP t-7,8-diol), BaP t-4,5-diol, BaP t-9,10-diol, 3-hydroxybenzo[a]pyrene (3-OH-BaP), BaP (7,10/8,9)tetrol, and BaP (7/8,9,10)tetrol. The photocytotoxicity of BaP, 3-OH-BaP, BaP t-7,8-diol, BaP trans-7,8-diol-anti-9,10-epoxide (BPDE), and BaP (7,10/8,9)tetrol in the HaCaT keratinocytes was examined. When irradiated with 1.0 J/cm(2) UVA light, these compounds when tested at doses of 0.1, 0.2, and 0.5 M, all induced photocytotoxicity in a dose-dependent manner. When photoirradiation was conducted in the presence of a lipid (methyl linoleate), BaP metabolites, BPDE, and three related PAHs, pyrene, 7,8,9,10-tetrahydro-BaP trans-7,8-diol, and 7,8,9,10-tetrahydro-BaP trans-9,10-diol, all induced lipid peroxidation. The formation of lipid peroxides by BaP t-7,8-diol was inhibited by NaN3 and enhanced by deuterated methanol, which suggests that singlet oxygen may be involved in the generation of lipid peroxides. The formation of lipid hydroperoxides was partially inhibited by superoxide dismutase (SOD). Electron spin resonance spin trapping experiments indicated that both singlet oxygen and superoxide radical anion were generated from UVA photoirradiation of BPDE in a light dose responding manner. C1 [Xia, Qingsu; Chiang, Hsiu-Mei; Chen, Shoujun; Fu, Peter P.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Chiang, Hsiu-Mei] China Med Univ, Dept Cosmecut, Taichung, Taiwan. [Yin, Jun-Jie] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Cai, Lining] Biotranex LLC, Monmouth Jct, NJ USA. [Yu, Hongtao] Jackson State Univ, Dept Chem & Biochem, Jackson, MS USA. RP Fu, PP (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM peter.fu@fda.hhs.gov RI Yin, Jun Jie /E-5619-2014; Chiang, Hsiu-Mei/L-8150-2013 NR 61 TC 0 Z9 0 U1 4 U2 22 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0748-2337 EI 1477-0393 J9 TOXICOL IND HEALTH JI Toxicol. Ind. Health PD OCT PY 2015 VL 31 IS 10 BP 898 EP 910 DI 10.1177/0748233713484648 PG 13 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA CS2LO UT WOS:000361902600004 PM 23552265 ER PT J AU Jones, CM McAninch, JK AF Jones, Christopher M. McAninch, Jana K. TI Emergency Department Visits and Overdose Deaths From Combined Use of Opioids and Benzodiazepines SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID UNITED-STATES; PRESCRIPTION; PAIN; RISK; THERAPY; TRENDS; ABUSE AB Introduction: Opioid analgesics and benzodiazepines are the prescription drugs most commonly associated with drug overdose deaths. This study was conducted to assess trends in nonmedical use related emergency department (ED) visits and drug overdose deaths that involved both opioid analgesics and benzodiazepines in the U.S. from 2004 to 2011. Methods: Opioid analgesic and benzodiazepine nonmedical use related ED visits from the Drug Abuse Warning Network and drug overdose deaths from the National Vital Statistics System were analyzed for 2004-2011 to determine trends and demographic-specific rates. Data were analyzed from March 2014 to June 2014. Results: From 2004 to 2011, the rate of nonmedical use-related ED visits involving both opioid analgesics and benzodiazepines increased from 11.0 to 34.2 per 100,000 population (p-trend <0.0001). During the same period, drug overdose deaths involving both drugs increased from 0.6 to 1.7 per 100,000 (p-trend <0.0001). Statistically significant increases in ED visits occurred among males and females, non-Hispanic whites, non-Hispanic blacks, and Hispanics, and all age groups except 12- to 17-year-olds. For overdose deaths, statistically significant increases were seen in, males and females, all three race/ethnicity groups, and all age groups except 12- to 17-year-olds. Benzodiazepine involvement in opioid analgesic overdose deaths increased each year, increasing from 18% of opioid analgesic overdose deaths in 2004 to 31% in 2011 (p-trend <0.0001). Conclusions: ED visits and drug overdose deaths involving both opioid analgesics and benzodiazepines increased significantly between 2004 and 2011. Interventions to improve the appropriate prescribing and use of these medications are needed. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Jones, Christopher M.] US FDA, Off Commissioner, Silver Spring, MD 20993 USA. [McAninch, Jana K.] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Jones, CM (reprint author), US FDA, Off Publ Hlth Strategy & Anal, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM christopher.m.jones@fda.hhs.gov NR 28 TC 20 Z9 20 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2015 VL 49 IS 4 BP 493 EP 501 DI 10.1016/j.amepre.2015.03.040 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CR5YV UT WOS:000361421200001 PM 26143953 ER PT J AU Barber, C Amberg, A Custer, L Dobo, KL Dobo, KL Van Gompel, J Gutsell, S Harvey, J Honma, M Kenyon, MO Kruhlak, N Muster, W Stavitskaya, L Teasdale, A Vessey, J Wichard, J AF Barber, Chris Amberg, Alexander Custer, Laura Dobo, Krista L. Glowienke, Susanne Van Gompel, Jacky Gutsell, Steve Harvey, Jim Honma, Masamitsu Kenyon, Michelle O. Kruhlak, Naomi Muster, Wolfgang Stavitskaya, Lidiya Teasdale, Andrew Vessey, Jonathan Wichard, Joerg TI Establishing best practise in the application of expert review of mutagenicity under ICH M7 SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE ICH M7; Ames; Genotoxicity; Mutagenicity; Expert rule-based; Statistical; In silico ID IN-SILICO SYSTEMS; APPLICABILITY DOMAIN; IMPURITIES; KNOWLEDGE; GENOTOXICITY; METABOLITES; PREDICTION; ADENINE; DNA AB The ICH M7 guidelines for the assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals allows for the consideration of in silico predictions in place of in vitro studies. This represents a significant advance in the acceptance of (Q)SAR models and has resulted from positive interactions between modellers, regulatory agencies and industry with a shared purpose of developing effective processes to minimise risk. This paper discusses key scientific principles that should be applied when evaluating in silico predictions with a focus on accuracy and scientific rigour that will support a consistent and practical route to regulatory submission. (C) 2015 Elsevier Inc. All rights reserved. C1 [Barber, Chris; Vessey, Jonathan] Lhasa Ltd, Leeds LS11 5PS, W Yorkshire, England. [Amberg, Alexander] Sanofi Aventis Deutschland GmbH, DSAR Preclin Safety, Frankfurt, Germany. [Custer, Laura] Bristol Myers Squibb, Drug Safety Evaluat, New Brunswick, NJ USA. [Dobo, Krista L.; Kenyon, Michelle O.] Pfizer, Drug Safety Res & Dev, Groton, CT USA. [Glowienke, Susanne] Novartis Inst Biomed Res, Dept Preclin Safety, Basel, Switzerland. [Van Gompel, Jacky] Janssen, Drug Safety Sci, Beerse, Belgium. [Gutsell, Steve] Unilever, Safety & Environm Assurance Ctr, Colworth, Beds, England. [Harvey, Jim] GlaxoSmithkline, Computat Toxicol, Ware, Herts, England. [Honma, Masamitsu] Natl Inst Hlth Sci, Tokyo, Japan. [Kruhlak, Naomi; Stavitskaya, Lidiya] FDA Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Muster, Wolfgang] F Hoffmann La Roche Ltd, Pharma Res & Early Dev, Basel, Switzerland. [Teasdale, Andrew] AstraZeneca, Macclesfield, Cheshire, England. [Wichard, Joerg] Bayer, HealthCare, Genet Toxicol, Berlin, Germany. RP Barber, C (reprint author), Lhasa Ltd, Granary Wharf House,2 Canal Wharf, Leeds LS11 5PS, W Yorkshire, England. EM chris.barber@lhasalimited.org OI Barber, Chris/0000-0003-4220-1137 NR 29 TC 6 Z9 6 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD OCT PY 2015 VL 73 IS 1 BP 367 EP 377 DI 10.1016/j.yrtph.2015.07.018 PG 11 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA CR5UU UT WOS:000361410700039 PM 26248005 ER PT J AU Thayer, KA Doerge, DR Hunt, D Schurman, SH Twaddle, NC Churchwell, MI Garantziotis, S Kissling, GE Easterling, MR Bucher, JR Birnbaum, LS AF Thayer, Kristina A. Doerge, Daniel R. Hunt, Dawn Schurman, Shepherd H. Twaddle, Nathan C. Churchwell, Mona I. Garantziotis, Stavros Kissling, Grace E. Easterling, Michael R. Bucher, John R. Birnbaum, Linda S. TI Pharmacokinetics of bisphenol A in humans following a single oral administration SO ENVIRONMENT INTERNATIONAL LA English DT Article DE Deuterated bisphenol A; Endocrine disruptor; ADME; Bioavailability; Metabolism; Excretion ID SPRAGUE-DAWLEY RATS; HUMAN EXPOSURE; RHESUS-MONKEYS; HUMAN SERUM; BPA; URINE; POPULATION; ADULT; CONTAMINATION; CHEMICALS AB Background: Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA. Objective: To reduce uncertainties about the metabolism and excretion of BPA in humans following oral administration. Methods: We exposed six men and eight women to 100 mu g/kg bw of deuterated BPA (d6-BPA) by oral administration and conducted blood and urine analysis over a three day period. The use of d6-BPA allowed administered d6-BPA to be distinguished from background native (unlabeled) BPA. We calculated the rate of oral absorption, serum elimination, half-life, area under the curve (AUC), urinary excretion, and metabolism to glucuronide and sulfate conjugates. Results: Mean serum total (unconjugated and conjugated) d6-BPA C-max of 1711 nM (390 ng/ml) was observed at T-max of 1.1 +/- 0.50 h. Unconjugated d6-BPA appeared in serum within 5-20 min of dosing with a mean C-max of 6.5 nM (1.5 ng/ml) observed at T-max of 1.3 +/- 0.52 h. Detectable blood levels of unconjugated or total d6-BPA were observed at 48 h in some subjects at concentrations near the LOD (0.001-0.002 ng/ml). The half-times for terminal elimination of total d6-BPA and unconjugated d6-BPA were 6.4 +/- 2.0 hand 6.2 +/- 2.6 h, respectively. Recovery of total administered d6-BPA in urine was 84-109%. Most subjects (10 of 14) excreted >90% as metabolites within 24 h. Conclusions: Using more sensitive methods, our study expands the findings of other human oral pharmacokinetic studies. Conjugation reactions are rapid and nearly complete with unconjugated BPA comprising less than 1% of the total d6-BPA in blood at all times. Elimination of conjugates into urine largely occurs within 24 h. Published by Elsevier Ltd C1 [Thayer, Kristina A.; Bucher, John R.] NIEHS, Div Natl Toxicol Program, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Doerge, Daniel R.; Twaddle, Nathan C.; Churchwell, Mona I.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Hunt, Dawn; Schurman, Shepherd H.; Garantziotis, Stavros] NIEHS, Clin Res Unit, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Easterling, Michael R.] Social & Sci Syst Inc, Durham, NC 27703 USA. [Birnbaum, Linda S.] NCI, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Birnbaum, LS (reprint author), NCI, NIH, US Dept HHS, POB 12233,Mail Drop B2-01, Res Triangle Pk, NC 27709 USA. EM thayer@niehs.nih.gov; daniel.doerge@fda.hhs.gov; dawnhunt2233@outlook.com; schurmansh@niehs.nih.gov; Nathan.Twaddle@fda.hhs.gov; Mona.Churchwell@fda.hhs.gov; garantziotis@niehs.nih.gov; kissling@niehs.nih.gov; MEasterling@s-3.com; bucher@niehs.nih.gov; birnbaumls@niehs.nih.gov RI Garantziotis, Stavros/A-6903-2009; OI Garantziotis, Stavros/0000-0003-4007-375X; Schurman, Shepherd/0000-0002-9133-7906 FU intramural research program of the National Institute of Environmental Health Sciences; intramural research program of the National Cancer Institute, National Institutes of Health FX We gratefully acknowledge the contributions of Gail McCarver and Karthika Divakaran (Medical College of Wisconsin, Milwaukee, Wisconsin, USA) for conducting genotype analyses and Mike DeVito, Jeffrey Fisher, Jerry Heindel, and Matthew Longnecker for reviewing a draft version of the manuscript. Funding: This research was supported by the intramural research programs of the National Institute of Environmental Health Sciences and the National Cancer Institute, National Institutes of Health. NR 48 TC 23 Z9 23 U1 9 U2 41 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 OCT PY 2015 VL 83 BP 107 EP 115 DI 10.1016/j.envint.2015.06.008 PG 9 WC Environmental Sciences SC Environmental Sciences & Ecology GA CR2LN UT WOS:000361161300010 PM 26115537 ER PT J AU Gajendran, J Kramer, J Shah, VP Langguth, P Polli, J Mehta, M Groot, DW Cristofoletti, R Abrahamsson, B Dressman, JB AF Gajendran, Jayachandar Kraemer, Johannes Shah, Vinod P. Langguth, Peter Polli, James Mehta, Mehul Groot, D. W. Cristofoletti, Rodrigo Abrahamsson, Bertil Dressman, Jennifer B. TI Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Nifedipine SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE nifedipine; absorption; bioavailability; bioequivalence; soft gelatin capsules; tablets; solubility; permeability; dissolution ID BIOPHARMACEUTICS CLASSIFICATION-SYSTEM; ELECTRON-CAPTURE DETECTION; SOFT GELATIN CAPSULES; IN-VITRO; CALCIUM-ANTAGONISTS; ESSENTIAL-HYPERTENSION; LIQUID-CHROMATOGRAPHY; BIOAVAILABILITY; PHARMACOKINETICS; DISSOLUTION AB Literature data relevant to the biopharmaceutical properties of the active pharmaceutical ingredient (API) nifedipine are reviewed to evaluate whether a waiver of invivo bioequivalence (BE) testing of immediate-release (IR) dosage forms formulated as tablets and soft gelatin capsules is warranted. Nifedipine's solubility and permeability, its therapeutic use and index, pharmacokinetics, food drug interactions, and any reported BE/bioavailability problems were all taken into consideration. Solubility and BA data indicate conclusively that nifedipine is a class II substance of biopharmaceutics classification system (BCS) and that the formulation of drug product plays a key role on the dissolution characteristics of the API. Therefore, a BCS biowaiver-based approval of nifedipine containing IR oral dosage forms cannot be recommended for reformulated/new multisource drug products or for major scale-up and postapproval changes to the existing drug products. (c) 2015 Wiley Periodicals, Inc. C1 [Gajendran, Jayachandar; Kraemer, Johannes] PHAST GmbH, Homburg, Germany. [Gajendran, Jayachandar; Langguth, Peter] Johannes Gutenberg Univ Mainz, Dept Pharmaceut Technol & Biopharmaceut, D-55122 Mainz, Germany. [Shah, Vinod P.] Int Pharmaceut Federat, The Hague, Netherlands. [Polli, James] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Mehta, Mehul] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Rockville, MD 20857 USA. [Groot, D. W.] RIVM Natl Inst Publ Hlth & Environm, Bilthoven, Netherlands. [Cristofoletti, Rodrigo] Brazilian Hlth Surveillance Agcy Anvisa, Div Bioequivalence, Brasilia, DF, Brazil. [Abrahamsson, Bertil] AstraZeneca R&D, Molndal, Sweden. [Dressman, Jennifer B.] Goethe Univ Frankfurt, Inst Pharmaceut Technol, D-60054 Frankfurt, Germany. RP Dressman, JB (reprint author), Goethe Univ Frankfurt, Inst Pharmaceut Technol, D-60054 Frankfurt, Germany. EM dressman@em.uni-frankfurt.de RI Fachbereich14, Dekanat/C-8553-2015 NR 88 TC 2 Z9 2 U1 0 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD OCT PY 2015 VL 104 IS 10 BP 3289 EP 3298 DI 10.1002/jps.24560 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA CR0EP UT WOS:000360991400003 PM 26149619 ER PT J AU Knolhoff, AM Zheng, J McFarland, MA Luo, Y Callahan, JH Brown, EW Croley, TR AF Knolhoff, Ann M. Zheng, Jie McFarland, Melinda A. Luo, Yan Callahan, John H. Brown, Eric W. Croley, Timothy R. TI Identification and Structural Characterization of Naturally-Occurring Broad-Spectrum Cyclic Antibiotics Isolated from Paenibacillus SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article DE Paenibacillus; Cyclic peptide; Non-ribosomal peptide; Antibiotic; Cyclic lipopeptides; Mass spectrometry; Bacteria; Identification ID PEPTIDE ANTIBIOTICS; NONRIBOSOMAL PEPTIDES; ADENYLATION DOMAINS; MASS-SPECTROMETRY; AMINO-ACID; PREDICTION; BIOSYNTHESIS; LIPOPEPTIDES; SPECIFICITY; POLYKETIDE AB The rise of antimicrobial resistance necessitates the discovery and/or production of novel antibiotics. Isolated strains of Paenibacillus alvei were previously shown to exhibit antimicrobial activity against a number of pathogens, such as E. coli, Salmonella, and methicillin-resistant Staphylococcus aureus (MRSA). The responsible antimicrobial compounds were isolated from these Paenibacillus strains and a combination of low and high resolution mass spectrometry with multiple-stage tandem mass spectrometry was used for identification. A group of closely related cyclic lipopeptides was identified, differing primarily by fatty acid chain length and one of two possible amino acid substitutions. Variation in the fatty acid length resulted in mass differences of 14 Da and yielded groups of related MSn spectra. Despite the inherent complexity of MS/MS spectra of cyclic compounds, straightforward analysis of these spectra was accomplished by determining differences in complementary product ion series between compounds that differ in molecular weight by 14 Da. The primary peptide sequence assignment was confirmed through genome mining; the combination of these analytical tools represents a workflow that can be used for the identification of complex antibiotics. The compounds also share amino acid sequence similarity to a previously identified broad-spectrum antibiotic isolated from Paenibacillus. The presence of such a wide distribution of related compounds produced by the same organism represents a novel class of broad-spectrum antibiotic compounds. C1 [Knolhoff, Ann M.; Zheng, Jie; McFarland, Melinda A.; Luo, Yan; Callahan, John H.; Brown, Eric W.; Croley, Timothy R.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Knolhoff, AM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, HFS-707,5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Ann.Knolhoff@fda.hhs.gov NR 35 TC 0 Z9 0 U1 1 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1044-0305 EI 1879-1123 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD OCT PY 2015 VL 26 IS 10 BP 1768 EP 1779 DI 10.1007/s13361-015-1190-2 PG 12 WC Biochemical Research Methods; Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA CR1GP UT WOS:000361073200015 PM 26250559 ER PT J AU Durmowicz, AG AF Durmowicz, Anthony G. TI REGULATORY CONSIDERATIONS APPLICABLE TO THE DEVELOPMENT OF CFTR MODULATOR THERAPIES SO PEDIATRIC PULMONOLOGY LA English DT Meeting Abstract C1 [Durmowicz, Anthony G.] US FDA, Div Pulm Allergy & Rheumatol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD OCT PY 2015 VL 50 SU 41 MA S9.4 BP 139 EP 139 PG 1 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA CQ7NS UT WOS:000360791500031 ER PT J AU Jadhav, PR Cook, J Sinha, V Zhao, P Rostami-Hodjegan, A Sahasrabudhe, V Stockbridge, N Powell, JR AF Jadhav, Pravin R. Cook, Jack Sinha, Vikram Zhao, Ping Rostami-Hodjegan, Amin Sahasrabudhe, Vaishali Stockbridge, Norman Powell, J. Robert TI A proposal for scientific framework enabling specific population drug dosing recommendations SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Editorial Material DE clinical pharmacology; specific populations; dosing and administration; labeling; drug development; drug approval; modeling and simulation ID SUBMISSIONS; EXPOSURE; RISK AB Over the last 3 decades, there has been little change in the paradigm to derive dosing recommendations for specific populations (e.g., renal failure, elderly, or obese patients) despite better understanding of clearance pathways in these groups and availability of modeling and simulation tools. Dosing recommendations for specific populations are often incomplete or unavailable at the time of drug approval. Currently, there is no regulatory framework to incorporate model-based dosing recommendations for specific populations. This paper proposes a scientific framework for using modeling and simulation to support specific population dosing recommendations. This framework creates a knowledgebase of drug and population attributes where model-based approaches can be developed to inform dosing recommendations. The framework may benefit patients by having reliable dosing information at the time of drug approval. Patients with conditions where studies are difficult to perform would benefit from dosing based on state-of-the-art knowledge. Industry and regulators would benefit from a scientific and efficient approach to improve specific population prediction. A research approach to determine specific population dose prediction is discussed along with challenges and risks. We hope to initiate a dialogue to explore the role of modeling based on data for drugs with similar clearance mechanisms to predict drug dosing. C1 [Jadhav, Pravin R.] Merck & Co Inc, Quantitat Pharmacol & Pharmacometr, Kenilworth, NJ 07033 USA. [Cook, Jack; Sahasrabudhe, Vaishali] Pfizer Inc, Clin Pharmacol, Groton, CT 06340 USA. [Sinha, Vikram; Zhao, Ping] US FDA, Ctr Drug Evaluat & Res, Off Translat Sci, Off Clin Pharmacol,Div Pharmacometr, Silver Spring, MD USA. [Rostami-Hodjegan, Amin] Univ Manchester, Syst Pharmacol, Manchester, Lancs, England. [Stockbridge, Norman] US FDA, Ctr Drug Evaluat & Res, Off New Drugs, Silver Spring, MD USA. RP Jadhav, PR (reprint author), Merck & Co Inc, Quantitat Pharmacol & Pharmacometr, 2000 Galloping Hill Rd, Kenilworth, NJ 07033 USA. EM Pravin.Jadhav@merck.com NR 15 TC 7 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD OCT PY 2015 VL 55 IS 10 BP 1073 EP 1078 DI 10.1002/jcph.579 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CQ8BS UT WOS:000360831700001 PM 26109076 ER PT J AU Wang, J Edginton, AN Avant, D Burckart, GJ AF Wang, Jian Edginton, Andrea N. Avant, Debbie Burckart, Gilbert J. TI Predicting neonatal pharmacokinetics from prior data using population pharmacokinetic modeling SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE neonates; pharmacokinetics; population PK ID PRETERM INFANTS; MEDICATION USE; CHILDREN; EFFICACY AB Selection of the first dose for neonates in clinical trials is very challenging. The objective of this analysis was to assess if a population pharmacokinetic (PK) model developed with data from infants to adults is predictive of neonatal clearance and to evaluate what age range of prior PK data is needed for informative modeling to predict neonate exposure. Two sources of pharmacokinetic data from 8 drugs were used to develop population models: (1) data from all patients > 2 years of age, and (2) data from all nonneonatal patients aged > 28 days. The prediction error based on the models using data from subjects > 2 years of age showed bias toward overprediction, with median average fold error (AFE) for CL predicted/CLobserved greater than 1.5. The bias for predicting neonatal PK was improved when using all prior PK data including infants as opposed to an assessment without infant PK data, with the median AFE 0.91. As an increased number of pediatric trials are conducted in neonates under the Food and Drug Administration Safety and Innovation Act, dose selection should be based on the best estimates of neonatal pharmacokinetics and pharmacodynamics prior to conducting efficacy and safety studies in neonates. C1 [Wang, Jian; Burckart, Gilbert J.] US FDA, Pediat Clin Pharmacol Staff, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Edginton, Andrea N.] Univ Waterloo, Waterloo, ON N2L 3G1, Canada. [Avant, Debbie] US FDA, Off Pediat Therapeut, Commissioners Off, Silver Spring, MD USA. RP Wang, J (reprint author), Bldg 51,Rm 2154,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jian.wang@fda.hhs.gov NR 27 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD OCT PY 2015 VL 55 IS 10 BP 1175 EP 1183 DI 10.1002/jcph.524 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CQ8BS UT WOS:000360831700014 PM 25907280 ER PT J AU Kim, T Jancel, T Kumar, P Freeman, AF AF Kim, T. Jancel, T. Kumar, P. Freeman, A. F. TI Drug-drug interaction between isavuconazole and tacrolimus: a case report indicating the need for tacrolimus drug-level monitoring SO JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS LA English DT Article DE drug-drug interaction; new antifungal agent; therapeutic drug monitoring AB What is known and objectiveDespite the known significant drug-drug interaction between isavuconazole and tacrolimus, there are no recommendations on dose adjustment when these drugs are given concomitantly. We report on a patient with amediastinal Aspergillus fumigatus infection resistant to posaconazole and describe how she was successfully managed with tacrolimus therapeutic drug-level monitoring. Case summaryOur patient presented with a mediastial Aspergillus fumigatus infection, 2years after lung transplantation. A.fumigatus was resistant to posaconazole, and the patient had intolerance to voriconazole shown by elevated transaminases. The patient was given isavuconazole with drug-level monitoring. She was managed successfully with no adverse events. Tacrolimus concentration continued to increase after more than 2weeks of therapy and required a further reduction to 72% of the usual dose to maintain the target concentrations over a 8-week period. What is new and conclusionWhen isavuconazole is given to patients on tacrolimus, the dose of the latter will need considerable reduction. We would suggest an initial 50% reduction and recommend close weekly monitoring of tacrolimus concentration. Further dose decreases of 25-50% may be required. C1 [Kim, T.; Kumar, P.] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. [Jancel, T.] US FDA, Off Safety & Epidemiol, Silver Spring, MD USA. [Freeman, A. F.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Kim, T (reprint author), NIH, 10 Ctr Dr,Bldg 10 Room 1C240, Bethesda, MD 20892 USA. EM tiffany.kim@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX The views expressed in this article are those of the authors and do not reflect the official policy of the U.S. Government. This research was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. NR 4 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-4727 EI 1365-2710 J9 J CLIN PHARM THER JI J. Clin. Pharm. Ther. PD OCT PY 2015 VL 40 IS 5 BP 609 EP 611 DI 10.1111/jcpt.12308 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CQ8FW UT WOS:000360842900023 ER PT J AU Yin, LL Coelho, SG Valencia, JC Ebsen, D Mahns, A Smuda, C Miller, SA Beer, JZ Kolbe, L Hearing, VJ AF Yin, Lanlan Coelho, Sergio G. Valencia, Julio C. Ebsen, Dominik Mahns, Andre Smuda, Christoph Miller, Sharon A. Beer, Janusz Z. Kolbe, Ludger Hearing, Vincent J. TI Identification of Genes Expressed in Hyperpigmented Skin Using Meta-Analysis of Microarray Data Sets SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID PIGMENTATION; UVB AB More than 375 genes have been identified that are involved in regulating skin pigmentation and these act during development, survival, differentiation, and/or responses of melanocytes to the environment. Many of these genes have been cloned, and disruptions of their functions are associated with various pigmentary diseases; however, many remain to be identified. We have performed a series of microarray analyses of hyperpigmented compared with less pigmented skin to identify genes responsible for these differences. The rationale and goal for this study was to perform a meta-analysis on these microarray databases to identify genes that may be significantly involved in regulating skin phenotype either directly or indirectly that might not have been identified due to subtle differences by any of these individual studies alone. The meta-analysis demonstrates that 1,271 probes representing 921 genes are differentially expressed at significant levels in the 5 microarray data sets compared, providing new insights into the variety of genes involved in determining skin phenotype. Immunohistochemistry was used to validate two of these markers at the protein level (TRIM63 and QPCT), and we discuss the possible functions of these genes in regulating skin physiology. C1 [Yin, Lanlan; Coelho, Sergio G.; Valencia, Julio C.; Ebsen, Dominik; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Mahns, Andre; Smuda, Christoph; Kolbe, Ludger] Beiersdorf AG, R&D Skin Res, D-20245 Hamburg, Germany. [Miller, Sharon A.; Beer, Janusz Z.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Kolbe, L (reprint author), Beiersdorf AG, R&D Skin Res, D-20245 Hamburg, Germany. EM Ludger.Kolbe@Beiersdorf.com FU Intramural NIH HHS [Z01 BC010785-01] NR 21 TC 3 Z9 3 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2015 VL 135 IS 10 BP 2455 EP 2463 DI 10.1038/jid.2015.179 PG 9 WC Dermatology SC Dermatology GA CR0GD UT WOS:000360995600018 PM 25950827 ER PT J AU Virmani, A Pinto, L Bauermann, O Zerelli, S Diedenhofen, A Binienda, ZK Ali, SF van der Leij, FR AF Virmani, Ashraf Pinto, Luigi Bauermann, Otto Zerelli, Saf Diedenhofen, Andreas Binienda, Zbigniew K. Ali, Syed F. van der Leij, Feike R. TI The Carnitine Palmitoyl Transferase (CPT) System and Possible Relevance for Neuropsychiatric and Neurological Conditions SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Oxidative phosphorylation; AMP-activated; protein kinase; Nutrition; Malonyl-CoA; Metabolic-cognitive syndrome ID FATTY-ACID-METABOLISM; ACETYL-L-CARNITINE; ENDOPLASMIC-RETICULUM STRESS; REGULATES FOOD-INTAKE; PALMITOYLTRANSFERASE-I; OXIDATIVE STRESS; INSULIN-RESISTANCE; MITOCHONDRIAL DYSFUNCTION; PARKINSONS-DISEASE; ENERGY HOMEOSTASIS AB The carnitine palmitoyl transferase (CPT) system is a multiprotein complex with catalytic activity localized within a core represented by CPT1 and CPT2 in the outer and inner membrane of the mitochondria, respectively. Two proteins, the acyl-CoA synthase and a translocase also form part of this system. This system is crucial for the mitochondrial beta-oxidation of long-chain fatty acids. CPT1 has two well-known isoforms, CPT1a and CPT1b. CPT1a is the hepatic isoform and CPT1b is typically muscular; both are normally utilized by the organism for metabolic processes throughout the body. There is a strong evidence for their involvement in various disease states, e.g., metabolic syndrome, cardiovascular diseases, and in diabetes mellitus type 2. Recently, a new, third isoform of CPT was described, CPT1c. This is a neuronal isoform and is prevalently localized in brain regions such as hypothalamus, amygdala, and hippocampus. These brain regions play an important role in control of food intake and neuropsychiatric and neurological diseases. CPT activity has been implicated in several neurological and social diseases mainly related to the alteration of insulin equilibrium in the brain. These pathologies include Parkinson's disease, Alzheimer's disease, and schizophrenia. Evolution of both Parkinson's disease and Alzheimer's disease is in some way linked to brain insulin and related metabolic dysfunctions with putative links also with the diabetes type 2. Studies show that in the CNS, CPT1c affects ceramide levels, endocannabionoids, and oxidative processes and may play an important role in various brain functions such as learning. C1 [Virmani, Ashraf; Pinto, Luigi; Bauermann, Otto; Zerelli, Saf] Sigma Tau Hlth Sci Int BV, Res Innovat & Dev, Utrecht, Netherlands. [Virmani, Ashraf; Pinto, Luigi; Bauermann, Otto; Diedenhofen, Andreas] Sigma Tau Pharmaceut Co, Pomezia, Rome, Italy. [Binienda, Zbigniew K.] US FDA, Neurophysiol Lab, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Ali, Syed F.] US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [van der Leij, Feike R.] Van Hall Larenstein & NHL Univ Appl Sci, NL-8901 BV Leeuwarden, Netherlands. RP Virmani, A (reprint author), Sigma Tau Hlth Sci Int BV, Res Innovat & Dev, Utrecht, Netherlands. EM ashraf.virmani@sigma-tau.it NR 87 TC 3 Z9 3 U1 2 U2 9 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD OCT PY 2015 VL 52 IS 2 SI SI BP 826 EP 836 DI 10.1007/s12035-015-9238-7 PG 11 WC Neurosciences SC Neurosciences & Neurology GA CQ6AQ UT WOS:000360687200003 PM 26041663 ER PT J AU Imam, SZ Lantz-McPeak, SM Cuevas, E Rosas-Hernandez, H Liachenko, S Zhang, YB Sarkar, S Ramu, J Robinson, BL Jones, Y Gough, B Paule, MG Ali, SF Binienda, ZK AF Imam, Syed Z. Lantz-McPeak, Susan M. Cuevas, Elvis Rosas-Hernandez, Hector Liachenko, Serguei Zhang, Yongbin Sarkar, Sumit Ramu, Jaivijay Robinson, Bonnie L. Jones, Yvonne Gough, Bobby Paule, Merle G. Ali, Syed F. Binienda, Zbigniew K. TI Iron Oxide Nanoparticles Induce Dopaminergic Damage: In vitro Pathways and In Vivo Imaging Reveals Mechanism of Neuronal Damage SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Iron-oxide nanoparticles; Fe-NPs; Neuroblastoma cells; Neurotoxicity; Dopamine; Mitochondria; Magnetic resonance imaging ID BLOOD-BRAIN-BARRIER; MICROVESSEL ENDOTHELIAL-CELLS; INDUCED OXIDATIVE STRESS; NITRIC-OXIDE; DNA-DAMAGE; NEUROTOXICITY; APOPTOSIS; RATS; NEURODEGENERATION; PEROXYNITRITE AB Various iron-oxide nanoparticles have been in use for a long time as therapeutic and imaging agents and for supplemental delivery in cases of iron-deficiency. While all of these products have a specified size range of similar to 40 nm and above, efforts are underway to produce smaller particles, down to similar to 1 nm. Here, we show that after a 24-h exposure of SHSY-5Y human neuroblastoma cells to 10 mu g/ml of 10 and 30 nm ferric oxide nanoparticles (Fe-NPs), cellular dopamine content was depleted by 68 and 52 %, respectively. Increases in activated tyrosine kinase c-Abl, a molecular switch induced by oxidative stress, and neuronal alpha-synuclein expression, a protein marker associated with neuronal injury, were also observed (55 and 38 % percent increases, respectively). Inhibition of cell-proliferation, significant reductions in the number of active mitochondria, and a dose-dependent increase in reactive oxygen species (ROS) were observed in neuronal cells. Additionally, using a rat in vitro blood-brain barrier (BBB) model, a dose-dependent increase in ROS accompanied by increased fluorescein efflux demonstrated compromised BBB integrity. To assess translational implications, in vivo Fe-NP-induced neurotoxicity was determined using in vivo MRI and post-mortem neurochemical and neuropathological correlates in adult male rats after exposure to 50 mg/kg of 10 nm Fe-NPs. Significant decrease in T (2) values was observed. Dynamic observations suggested transfer and retention of Fe-NPs from brain vasculature into brain ventricles. A significant decrease in striatal dopamine and its metabolites was also observed, and neuropathological correlates provided additional evidence of significant nerve cell body and dopaminergic terminal damage as well as damage to neuronal vasculature after exposure to 10 nm Fe-NPs. These data demonstrate a neurotoxic potential of very small size iron nanoparticles and suggest that use of these ferric oxide nanoparticles may result in neurotoxicity, thereby limiting their clinical application. C1 [Imam, Syed Z.; Lantz-McPeak, Susan M.; Cuevas, Elvis; Rosas-Hernandez, Hector; Liachenko, Serguei; Sarkar, Sumit; Ramu, Jaivijay; Robinson, Bonnie L.; Gough, Bobby; Paule, Merle G.; Ali, Syed F.; Binienda, Zbigniew K.] US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. [Zhang, Yongbin; Jones, Yvonne] US FDA, Natl Ctr Toxicol Res, NCTR ORA Nanotechnol Core Facil, Jefferson, AR 72079 USA. RP Imam, SZ (reprint author), US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. EM Syed.Imam@fda.hhs.gov; Zbigniew.Binienda@fda.hhs.gov OI Rosas-Hernandez, Hector/0000-0002-2736-8302 FU NCTR/FDA [E-07394.01] FX The research reported here was funded by the NCTR/FDA protocol # E-07394.01. This document has been reviewed in accordance with US Food and Drug Administration (FDA) policy and approved for publication. Approval does not signify that the contents necessarily reflect the position or opinions of the FDA nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the FDA. NR 49 TC 3 Z9 3 U1 3 U2 16 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD OCT PY 2015 VL 52 IS 2 SI SI BP 913 EP 926 DI 10.1007/s12035-015-9259-2 PG 14 WC Neurosciences SC Neurosciences & Neurology GA CQ6AQ UT WOS:000360687200010 PM 26099304 ER PT J AU He, Z Cui, L Paule, MG Ferguson, SA AF He, Zhen Cui, Li Paule, Merle G. Ferguson, Sherry A. TI Estrogen Selectively Mobilizes Neural Stem Cells in the Third Ventricle Stem Cell Niche of Postnatal Day 21 Rats SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Doublecortin; Ethinyl estradiol; Nestin; Mitosis; Ki-67; Perinatal oral exposure; Phosphohistone; H3; Proliferation ID FOCAL CEREBRAL-ISCHEMIA; ADULT NEUROGENESIS; HIPPOCAMPAL NEUROGENESIS; SUBVENTRICULAR ZONE; MAMMALIAN BRAIN; BISPHENOL-A; LIFE-SPAN; PROLIFERATION; HYPOTHALAMUS; EXPRESSION AB The neuroprotective properties of stem cells have been described for various pathophysiological states. Here, we determined the effects of exogenous perinatal estrogen treatment on endogenous neural stem cell activity in the third ventricle stem cell niche (3VSCN) and the caudal third ventricle (C3V). Pregnant Sprague-Dawley rats were gavaged with ethinyl estradiol (EE2, 10 mu g/kg/day) or vehicle on gestational days 6-21, and their offspring were similarly treated from birth to weaning on postnatal day 21. At weaning, neural stem cell activity was investigated using the stem cell markers nestin, Ki-67, phosphohistone H3 (PHH3), and doublecortin (DCX). The 3VSCN was characterized by nestin labeling, but little DCX labeling, while both the subventricular (SVZ) and subgranular zones (SGZ) displayed robust DCX expression. Ki-67 cell counts in the 3VSCN were 2.2 to 6.4 times those of the C3V. In the 3VSCN, EE2 treatment significantly increased Ki-67, PHH3, and co-labeled cell counts by 135-207 %, effects which appeared stronger in females. EE2 treatment had only marginally significant effects in the C3V, mildly increasing PHH3 and co-labeled cell counts. Perinatal estrogen treatment selectively increased and mobilized proliferative cells in the 3VSCN at weaning, potentially providing increased neuroprotection. Because PHH3 cells are thought to be in the mitotic phase of the cell cycle and Ki-67 cells can be found in most phases of the cycle, the effect of estrogen treatment on 3VSCN cells appears to involve enhancement of mitosis. C1 [He, Zhen; Paule, Merle G.; Ferguson, Sherry A.] Natl Ctr Toxicol Res, FDA, Div Neurotoxicol, HFT 132, Jefferson, AR 72079 USA. [He, Zhen; Cui, Li] UAMS, Dept Neurol, Little Rock, AR USA. RP Ferguson, SA (reprint author), Natl Ctr Toxicol Res, FDA, Div Neurotoxicol, HFT 132, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Zhen.He@fda.hhs.gov; licuimdphd@hotmail.com; Merle.Paule@fda.hhs.gov; Sherry.Ferguson@fda.hhs.gov FU National Center for Toxicological Research/Food and Drug Administration [P00706, P00710]; University of Arkansas for Medical Sciences institutional in-house Hornick Awards FX This work was supported by the National Center for Toxicological Research/Food and Drug Administration [Protocol # P00706 to S. A. F. and Protocol # P00710 to Z.H.]. L.C. was supported by the University of Arkansas for Medical Sciences institutional in-house Hornick Awards. The authors are grateful for the technical expertise provided by the animal care staff of the Priority One Corporation and the careful reviews of this manuscript by Dr. Amy Inselman and Tucker Patterson. NR 43 TC 1 Z9 1 U1 3 U2 8 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD OCT PY 2015 VL 52 IS 2 SI SI BP 927 EP 933 DI 10.1007/s12035-015-9244-9 PG 7 WC Neurosciences SC Neurosciences & Neurology GA CQ6AQ UT WOS:000360687200011 PM 26041664 ER PT J AU Slikker, W Liu, F Rainosek, SW Patterson, TA Sadovova, N Hanig, JP Paule, MG Wang, C AF Slikker, William, Jr. Liu, Fang Rainosek, Shuo W. Patterson, Tucker A. Sadovova, Natalya Hanig, Joseph P. Paule, Merle G. Wang, Cheng TI Ketamine-Induced Toxicity in Neurons Differentiated from Neural Stem Cells SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Ketamine; N-methyl-D-aspartate (NMDA) receptors; Development; Differentiation; Neurons; Neurodegeneration ID DEVELOPING RAT-BRAIN; D-ASPARTATE RECEPTOR; INDUCED APOPTOSIS; NEUROTOXICITY; CULTURE; DEATH; NEURODEGENERATION; BLOCKADE; EXPOSURE; MONKEY AB Ketamine is used as a general anesthetic, and recent data suggest that anesthetics can cause neuronal damage when exposure occurs during development. The precise mechanisms are not completely understood. To evaluate the degree of ketamine-induced neuronal toxicity, neural stem cells were isolated from gestational day 16 rat fetuses. On the eighth day in culture, proliferating neural stem cells were exposed for 24 h to ketamine at 1, 10, 100, and 500 mu M. To determine the effect of ketamine on differentiated stem cells, separate cultures of neural stem cells were maintained in transition medium (DIV 6) for 1 day and kept in differentiation medium for another 3 days. Differentiated neural cells were exposed for 24 h to 10 mu M ketamine. Markers of cellular proliferation and differentiation, mitochondrial health, cell death/damage, and oxidative damage were monitored to determine: (1) the effects of ketamine on neural stem cell proliferation and neural stem cell differentiation; (2) the nature and degree of ketamine-induced toxicity in proliferating neural stem cells and differentiated neural cells; and (3) to provide information regarding receptor expression and possible mechanisms underlying ketamine toxicity. After ketamine exposure at a clinically relevant concentration (10 mu M), neural stem cell proliferation was not significantly affected and oxidative DNA damage was not induced. No significant effect on mitochondrial viability (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay) in neural stem cell cultures (growth medium) was observed at ketamine concentrations up to 500 mu M. However, quantitative analysis shows that the number of differentiated neurons was substantially reduced in 10 mu M ketamine-exposed cultures in differentiation medium, compared with the controls. No significant changes in the number of GFAP-positive astrocytes and O4-positive oligodendrocytes (in differentiation medium) were detected from ketamine-exposed cultures. The discussion focuses on: (1) the doses and time-course over which ketamine is associated with damage of neural cells; (2) how ketamine directs or signals neural stem cells/neural cells to undergo apoptosis or necrosis; (3) how functional neuronal transmitter receptors affect neurotoxicity induced by ketamine; and (4) advantages of using neural stem cell models to study critical issues related to ketamine anesthesia. C1 [Liu, Fang; Patterson, Tucker A.; Sadovova, Natalya; Paule, Merle G.; Wang, Cheng] Natl Ctr Toxicol Res, Food & Drug Adm, Div Neurotoxicol, HFT 132, Jefferson, AR 72079 USA. [Rainosek, Shuo W.] Univ Arkansas Med Sci, Dept Anesthesiol, Little Rock, AR 72205 USA. [Hanig, Joseph P.] Food & Drug Adm, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Slikker, William, Jr.] Natl Ctr Toxicol Res, Food & Drug Adm, Off Director, Jefferson, AR 72079 USA. RP Slikker, W (reprint author), Natl Ctr Toxicol Res, Food & Drug Adm, Off Director, Jefferson, AR 72079 USA. EM William.slikker@fda.hhs.gov; Cheng.wang@fda.hhs.gov NR 29 TC 2 Z9 2 U1 1 U2 25 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD OCT PY 2015 VL 52 IS 2 SI SI BP 959 EP 969 DI 10.1007/s12035-015-9248-5 PG 11 WC Neurosciences SC Neurosciences & Neurology GA CQ6AQ UT WOS:000360687200015 PM 26055230 ER PT J AU Sahu, SC Zheng, JW Yourick, JJ Sprando, RL Gao, XG AF Sahu, Saura C. Zheng, Jiwen Yourick, Jeffrey J. Sprando, Robert L. Gao, Xiugong TI Toxicogenomic responses of human liver HepG2 cells to silver nanoparticles SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE Silver nanoparticles; toxicogenomics; DNA microarray; gene expression; HepG2 cells; oxidative stress; DNA damage; genotoxicity; carcinogenicity; alternative model ID COLON CACO2 CELLS; GENE-EXPRESSION ANALYSIS; PROBE LEVEL DATA; COMPARATIVE GENOTOXICITY; TOXICOLOGICAL-RESEARCH; TISSUE DISTRIBUTION; DNA MICROARRAY; TOXICITY; NANOSILVER; MODEL AB The increased use of silver nanoparticles (AgNPs) in foods and cosmetics has raised public safety concerns. However, only limited knowledge exists on the effect of AgNPs on the cellular transcriptome. This study evaluated global gene expression profiles of human liver HepG2 cells exposed to 20 and 50nm AgNPs for 4 and 24h at 2.5 mu gml(-1). Exposure to 20nm AgNPs resulted in 811 altered genes after 4h, but much less after 24h. Exposure to 50nm AgNPs showed minimal altered genes at both exposure times. The HepG2 cells responded to the toxic insult of AgNPs by transiently upregulating stress response genes such as metallothioneins and heat shock proteins. Functional analysis of the altered genes showed more than 20 major biological processes were affected, of which metabolism, development, cell differentiation and cell death were the most dominant categories. Several cellular pathways were also impacted by AgNP exposure, including the p53 signaling pathway and the NRF2-mediated oxidative stress response pathway, which may lead to increased oxidative stress and DNA damage in the cell and potentially result in genotoxicity and carcinogenicity. Together, these results indicate that HepG2 cells underwent a multitude of cellular processes in response to the toxic insult of AgNP exposure, and suggest that toxicogenomic characterization of human HepG2 cells could serve as an alternative model for assessing toxicities of NPs. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Sahu, Saura C.; Yourick, Jeffrey J.; Sprando, Robert L.; Gao, Xiugong] US FDA, Ctr Food Safety & Appl Nutr, Div Toxicol, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. [Zheng, Jiwen] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Chem & Mat Sci, Silver Spring, MD USA. RP Sahu, SC (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Toxicol, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. EM saura.sahu@fda.hhs.gov NR 51 TC 6 Z9 6 U1 2 U2 33 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0260-437X EI 1099-1263 J9 J APPL TOXICOL JI J. Appl. Toxicol. PD OCT PY 2015 VL 35 IS 10 BP 1160 EP 1168 DI 10.1002/jat.3170 PG 9 WC Toxicology SC Toxicology GA CP4LW UT WOS:000359854500009 PM 26014281 ER PT J AU Gutfraind, A Boodram, B Prachand, N Hailegiorgis, A Dahari, H Major, ME AF Gutfraind, Alexander Boodram, Basmattee Prachand, Nikhil Hailegiorgis, Atesmachew Dahari, Harel Major, Marian E. TI Agent-Based Model Forecasts Aging of the Population of People Who Inject Drugs in Metropolitan Chicago and Changing Prevalence of Hepatitis C Infections SO PLOS ONE LA English DT Article ID YOUNG ADULTS-MASSACHUSETTS; NONINJECTING HEROIN USERS; VIRUS-INFECTION; UNITED-STATES; HUMAN IMMUNODEFICIENCY; VIRAL-HEPATITIS; SOCIAL NETWORKS; RISK BEHAVIORS; TRANSMISSION; MORTALITY AB People who inject drugs (PWID) are at high risk for blood-borne pathogens transmitted during the sharing of contaminated injection equipment, particularly hepatitis C virus (HCV). HCV prevalence is influenced by a complex interplay of drug-use behaviors, social networks, and geography, as well as the availability of interventions, such as needle exchange programs. To adequately address this complexity in HCV epidemic forecasting, we have developed a computational model, the Agent-based Pathogen Kinetics model (APK). APK simulates the PWID population in metropolitan Chicago, including the social interactions that result in HCV infection. We used multiple empirical data sources on Chicago PWID to build a spatial distribution of an in silico PWID population and modeled networks among the PWID by considering the geography of the city and its suburbs. APK was validated against 2012 empirical data (the latest available) and shown to agree with network and epidemiological surveys to within 1%. For the period 2010-2020, APK forecasts a decline in HCV prevalence of 0.8% per year from 44(+/- 2)% to 36(+/- 5)%, although some sub-populations would continue to have relatively high prevalence, including Non-Hispanic Blacks, 48(+/- 5)%. The rate of decline will be lowest in Non-Hispanic Whites and we find, in a reversal of historical trends, that incidence among non-Hispanic Whites would exceed incidence among Non-Hispanic Blacks (0.66 per 100 per years vs 0.17 per 100 person years). APK also forecasts an increase in PWID mean age from 35(+/- 1) to 40(+/- 2) with a corresponding increase from 59 (+/- 2)% to 80(+/- 6)% in the proportion of the population >30 years old. Our studies highlight the importance of analyzing subpopulations in disease predictions, the utility of computer simulation for analyzing demographic and health trends among PWID and serve as a tool for guiding intervention and prevention strategies in Chicago, and other major cities. C1 [Gutfraind, Alexander; Boodram, Basmattee] Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, Chicago, IL 60064 USA. [Gutfraind, Alexander; Dahari, Harel] Loyola Univ, Med Ctr, Dept Med, Program Expt & Theoret Modeling, Maywood, IL 60153 USA. [Gutfraind, Alexander; Major, Marian E.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Prachand, Nikhil] Chicago Dept Publ Hlth, STI HIV Surveillance, Chicago, IL USA. [Hailegiorgis, Atesmachew] George Mason Univ, Dept Computat Social Sci, Fairfax, VA 22030 USA. [Dahari, Harel] Los Alamos Natl Lab, Div Theoret, Los Alamos, NM USA. RP Gutfraind, A (reprint author), Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, Chicago, IL 60064 USA. EM agutfrai@uic.edu; marian.major@fda.hhs.gov FU National Institutes of Health [P20-GM103452, R01-AI078881]; Food and Drug Administration (FDA) Center for Biologics Evaluation and Research (CBER); University of Illinois at Chicago (UIC) Areas of Excellence Award; National Science Foundation [OCI-1053575]; U.S. Department of Energy [DE-AC52-06NA25396]; TACC at the University of Texas at Austin FX Support was provided by National Institutes of Health [http://www.nih.gov/] grant P20-GM103452 and R01-AI078881 to HD, Food and Drug Administration (FDA) Center for Biologics Evaluation and Research (CBER) intramural research funds [http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTo bacco/CBER/default.htm] to MM, University of Illinois at Chicago (UIC) Areas of Excellence Award [http://www.uic.edu/uic/] to BB. Computational experiments were supported through the National Science Foundation's [www.nsf.gov] XSEDE supercomputing system through grant number OCI-1053575 to AG. Portion of this work were done under the auspices of the U.S. Department of Energy under contract DE-AC52-06NA25396. Additional computing training and resources were awarded by TACC at the University of Texas at Austin to AG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 2 Z9 2 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 30 PY 2015 VL 10 IS 9 AR e0137993 DI 10.1371/journal.pone.0137993 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS6GF UT WOS:000362175700024 PM 26421722 ER PT J AU Xi, JX Zhao, WZ Yuan, JE Kim, J Si, XH Xu, XW AF Xi, Jinxiang Zhao, Weizhong Yuan, Jiayao Eddie Kim, JongWon Si, Xiuhua Xu, Xiaowei TI Detecting Lung Diseases from Exhaled Aerosols: Non-Invasive Lung Diagnosis Using Fractal Analysis and SVM Classification SO PLOS ONE LA English DT Article ID UPPER TRACHEOBRONCHIAL AIRWAYS; BREATH CONDENSATE; OXIDATIVE STRESS; BRONCHIAL TREE; IMAGE-ANALYSIS; DEPOSITION; CANCER; MODEL; NANOPARTICLE; PARTICLES AB Background Each lung structure exhales a unique pattern of aerosols, which can be used to detect and monitor lung diseases non-invasively. The challenges are accurately interpreting the exhaled aerosol fingerprints and quantitatively correlating them to the lung diseases. Objective and Methods In this study, we presented a paradigm of an exhaled aerosol test that addresses the above two challenges and is promising to detect the site and severity of lung diseases. This paradigm consists of two steps: image feature extraction using sub-regional fractal analysis and data classification using a support vector machine (SVM). Numerical experiments were conducted to evaluate the feasibility of the breath test in four asthmatic lung models. A highfidelity image-CFD approach was employed to compute the exhaled aerosol patterns under different disease conditions. Findings By employing the 10-fold cross-validation method, we achieved 100% classification accuracy among four asthmatic models using an ideal 108-sample dataset and 99.1% accuracy using a more realistic 324-sample dataset. The fractal-SVM classifier has been shown to be robust, highly sensitive to structural variations, and inherently suitable for investigating aerosol-disease correlations. Conclusion For the first time, this study quantitatively linked the exhaled aerosol patterns with their underlying diseases and set the stage for the development of a computer-aided diagnostic system for non-invasive detection of obstructive respiratory diseases. C1 [Xi, Jinxiang; Yuan, Jiayao Eddie] Cent Michigan Univ, Sch Engn & Technol, Mt Pleasant, MI 48859 USA. [Zhao, Weizhong] Xiangtan Univ, Coll Informat Engn, Xiangtan, Hunan, Peoples R China. [Zhao, Weizhong] Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Kim, JongWon] Univ Georgia, Coll Engn, Athens, GA 30602 USA. [Si, Xiuhua] Calif Baptist Univ, Dept Mech Engn, Riverside, CA USA. [Xu, Xiaowei] Univ Arkansas, Dept Informat Sci, Little Rock, AR 72204 USA. RP Xi, JX (reprint author), Cent Michigan Univ, Sch Engn & Technol, Mt Pleasant, MI 48859 USA. EM xi1j@cmich.edu FU Central Michigan University Early Career Grant [P62242] FX Jinxiang Xi was supported by the Central Michigan University Early Career Grant P62242 [https://www.cmich.edu/office_provost/ORSP/Pages/default.aspx]. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 2 Z9 2 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 30 PY 2015 VL 10 IS 9 AR e0139511 DI 10.1371/journal.pone.0139511 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS6GF UT WOS:000362175700125 PM 26422016 ER PT J AU Zhang, ZH Chen, S Mei, H Xuan, JK Guo, XQ Couch, L Dobrovolsky, VN Guo, L Mei, N AF Zhang, Zhuhong Chen, Si Mei, Hu Xuan, Jiekun Guo, Xiaoqing Couch, Letha Dobrovolsky, Vasily N. Guo, Lei Mei, Nan TI Ginkgo biloba leaf extract induces DNA damage by inhibiting topoisomerase II activity in human hepatic cells SO SCIENTIFIC REPORTS LA English DT Article ID PLACEBO-CONTROLLED TRIAL; HERB-DRUG INTERACTIONS; EGB 761(R); HEALTHY-VOLUNTEERS; INFANT LEUKEMIA; CANCER-THERAPY; DOUBLE-BLIND; HEPG2 CELLS; GENOTOXICITY; FLAVONOIDS AB Ginkgo biloba leaf extract has been shown to increase the incidence in liver tumors in mice in a 2-year bioassay conducted by the National Toxicology Program. In this study, the DNA damaging effects of Ginkgo biloba leaf extract and many of its constituents were evaluated in human hepatic HepG2 cells and the underlying mechanism was determined. A molecular docking study revealed that quercetin, a flavonoid constituent of Ginkgo biloba, showed a higher potential to interact with topoisomerase II (Topo II) than did the other Ginkgo biloba constituents; this in silico prediction was confirmed by using a biochemical assay to study Topo II enzyme inhibition. Moreover, as measured by the Comet assay and the induction of gamma-H2A. X, quercetin, followed by keampferol and isorhamnetin, appeared to be the most potent DNA damage inducer in HepG2 cells. In Topo II knockdown cells, DNA damage triggered by Ginkgo biloba leaf extract or quercetin was dramatically decreased, indicating that DNA damage is directly associated with Topo II. DNA damage was also observed when cells were treated with commercially available Ginkgo biloba extract product. Our findings suggest that Ginkgo biloba leaf extract- and quercetin-induced in vitro genotoxicity may be the result of Topo II inhibition. C1 [Zhang, Zhuhong; Guo, Xiaoqing; Dobrovolsky, Vasily N.; Mei, Nan] Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Chen, Si; Xuan, Jiekun; Couch, Letha; Guo, Lei] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Mei, Hu] Chongqing Univ, Coll Bioengn, Chongqing 400044, Peoples R China. RP Guo, L (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM Lei.Guo@fda.hhs.gov; Nan.Mei@fda.hhs.gov OI MEI, NAN/0000-0002-3501-9014 NR 54 TC 4 Z9 4 U1 3 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD SEP 30 PY 2015 VL 5 AR 14633 DI 10.1038/srep14633 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS3BF UT WOS:000361945400001 PM 26419945 ER PT J AU Duke, SP Bancken, F Crowe, B Soukup, M Botsis, T Forshee, R AF Duke, Susan P. Bancken, Fabrice Crowe, Brenda Soukup, Mat Botsis, Taxiarchis Forshee, Richard TI Seeing is believing: good graphic design principles for medical research SO STATISTICS IN MEDICINE LA English DT Article; Proceedings Paper CT 7th International-French-Society-of-Statistics Meeting on Statistical Methods in Biopharmacy - Emerging Topics for Statistical Methodology in Clinical Drug Development CY SEP, 2013 CL Paris, FRANCE SP Int French Soc Stat DE graphics; communication; visualization; visual perception ID ROTAVIRUS VACCINATION; STATISTICAL GRAPHICS; INTUSSUSCEPTION; EVENTS; VAERS; RISK AB Have you noticed when you browse a book, journal, study report, or product label how your eye is drawn to figures more than to words and tables? Statistical graphs are powerful ways to transparently and succinctly communicate the key points of medical research. Furthermore, the graphic design itself adds to the clarity of the messages in the data. The goal of this paper is to provide a mechanism for selecting the appropriate graph to thoughtfully construct quality deliverables using good graphic design principles. Examples are motivated by the efforts of a Safety Graphics Working Group that consisted of scientists from the pharmaceutical industry, Food and Drug Administration, and academic institutions. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Duke, Susan P.] GlaxoSmithKline, Res Triangle Pk, NC 27709 USA. [Bancken, Fabrice] Novartis AG, Drug Safety & Epidemiol, CH-4056 Basel, Switzerland. [Crowe, Brenda] Eli Lilly & Co, Lilly Corp Ctr, Global Stat Sci, Indianapolis, IN 46285 USA. [Soukup, Mat] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Botsis, Taxiarchis; Forshee, Richard] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Duke, SP (reprint author), GlaxoSmithKline, Res Triangle Pk, NC 27709 USA. EM susan.p.duke@gsk.com OI Duke, Susan/0000-0001-9302-8579 NR 41 TC 3 Z9 3 U1 3 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD SEP 30 PY 2015 VL 34 IS 22 SI SI BP 3040 EP 3059 DI 10.1002/sim.6549 PG 20 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA CQ7EI UT WOS:000360765300006 PM 26112209 ER PT J AU Siddiqui, A Rahman, Z Korang-Yeboah, M Khan, MA AF Siddiqui, Akhtar Rahman, Ziyaur Korang-Yeboah, Maxwell Khan, Mansoor A. TI Development and validation of X-ray diffraction method for quantitative determination of crystallinity in warfarin sodium products SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Warfarin; XRPD; Analytical method; Quality control; Validation; Amorphous ID QUANTIFICATION AB The objective of this study was to develop and validate XRPD analytical method for the estimation of percent crystalline warfarin sodium present in drug products. Warfarin sodium (WS) is a clathrate containing Isopropyl alcohol entrapped in the crystalline structure. Four types of WS-excipient mixtures were prepared and used to make four formulations: M1 containing lactose monohydrate (WS: excipient 1:9), M2 containing anhydrous lactose (WS: excipient 1:9), M3 containing lactose monohydrate (WS: excipient 1:21.5), M4 containing lactose anhydrous (WS: excipient 1:21.5). Thoroughly mixed powders were packed in the XRD sample holders and diffractogram were collected. Diffractogram in the 7-9 2 theta were found to be distinctive as the peak intensity grows with increasing percent crystalline WS. This peak region was, therefore, used to validate the XRPD method. Validation parameters were evaluated for accuracy, precision, linearity, limit of detection (LOD), and limit of quantitation (LOQ). LOD and LOQ for M1, M2, M3, and M4 were 3.04, 3.17, 4.17, 4.49% and 9.21, 9.62,12.65,13.30%, respectively. The method was found to be linear with R-2 > 0.99. With changing scan speed, X-ray power output, and type of sample holder, the method was found to be robust. Prediction of the % crystalline content of the WS sample with known crystallinity showed close agreement between actual and predicted value. In summary, XRPD method was validated, which can be used as a quantitative method for the estimation of % crystalline WS present in a drug product. Published by Elsevier B.V. C1 [Siddiqui, Akhtar; Rahman, Ziyaur; Korang-Yeboah, Maxwell; Khan, Mansoor A.] FDA, Div Prod Qual Res, Off Testing & Res, OPS,CDER, Jefferson, AR USA. RP Khan, MA (reprint author), FDA CDER DPQR White Oak, LS Bldg 64,Room 1070 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Mansoor.Khan@fda.hhs.gov OI Rahman, Ziyaur/0000-0002-0402-825X NR 8 TC 3 Z9 3 U1 0 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD SEP 30 PY 2015 VL 493 IS 1-2 BP 1 EP 6 DI 10.1016/j.ijpharm.2015.07.051 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CQ3HF UT WOS:000360492000001 PM 26209072 ER PT J AU Xu, XM Al-Ghabeish, M Rahman, Z Krishnaiah, YSR Yerlikaya, F Yang, Y Manda, P Hunt, RL Khan, MA AF Xu, Xiaoming Al-Ghabeish, Manar Rahman, Ziyaur Krishnaiah, Yellela S. R. Yerlikaya, Firat Yang, Yang Manda, Prashanth Hunt, Robert L. Khan, Mansoor A. TI Formulation and process factors influencing product quality and in vitro performance of ophthalmic ointments SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Ophthalmic ointments; Acyclovir; In vitro release testing; Corneal drug permeation; Rheology; Yield stress; Equivalence evaluation; Multivariate analysis; Design of experiments (DoE) AB Owing to its unique anatomical and physiological functions, ocular surface presents special challenges for both design and performance evaluation of the ophthalmic ointment drug products formulated with a variety of bases. The current investigation was carried out to understand and identify the appropriate in vitro methods suitable for quality and performance evaluation of ophthalmic ointment, and to study the effect of formulation and process variables on its critical quality attributes (CQA). The evaluated critical formulation variables include API initial size, drug percentage, and mineral oil percentage while the critical process parameters include mixing rate, temperature, time and cooling rate. The investigated quality and performance attributes include drug assay, content uniformity, API particle size in ointment, rheological characteristics, in vitro drug release and in vitro transcorneal drug permeation. Using design of experiments (DoE) as well as a novel principle component analysis approach, five of the quality and performance attributes (API particle size, storage modulus of ointment, high shear viscosity of ointment, in vitro drug release constant and in vitro transcorneal drug permeation rate constant) were found to be highly influenced by the formulation, in particular the strength of API, and to a lesser degree by processing variables. Correlating the ocular physiology with the physicochemical characteristics of acyclovir ophthalmic ointment suggested that in vitro quality metrics could be a valuable predictor of its in vivo performance. Published by Elsevier B.V. C1 [Xu, Xiaoming; Al-Ghabeish, Manar; Rahman, Ziyaur; Krishnaiah, Yellela S. R.; Yerlikaya, Firat; Yang, Yang; Manda, Prashanth; Hunt, Robert L.; Khan, Mansoor A.] US FDA, CDER, OPQ, OTR,DPQR, Silver Spring, MD 20993 USA. RP Khan, MA (reprint author), US FDA, CDER, OPQ, OTR,DPQR, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Mansoor.Khan@fda.hhs.gov RI Manda, Prashanth/A-9950-2016; OI Manda, Prashanth/0000-0001-5667-3528; Rahman, Ziyaur/0000-0002-0402-825X NR 0 TC 3 Z9 3 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD SEP 30 PY 2015 VL 493 IS 1-2 BP 412 EP 425 DI 10.1016/j.ijpharm.2015.07.066 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CQ3HF UT WOS:000360492000045 PM 26231106 ER PT J AU Luo, H Ye, H Ng, HW Shi, LM Tong, WD Mattes, W Mendrick, D Hong, HX AF Luo, Heng Ye, Hao Ng, Hui Wen Shi, Leming Tong, Weida Mattes, William Mendrick, Donna Hong, Huixiao TI Understanding and predicting binding between human leukocyte antigens (HLAs) and peptides by network analysis SO BMC BIOINFORMATICS LA English DT Article; Proceedings Paper CT 12th Annual Conference of the MidSouth-Computational-Biology-and-Bioinformatics-Society (MCBIOS) CY MAR 13-14, 2015 CL Little Rock, AR SP MidSouth Computat Biol & Bioinformat Soc ID MAJOR HISTOCOMPATIBILITY COMPLEX; STEVENS-JOHNSON-SYNDROME; CLASS-I MOLECULES; DRUG HYPERSENSITIVITY; T-CELLS; SEQUENCE; HLA-B-ASTERISK-5701; ABACAVIR; DATABASE; PROTEIN AB Background: As the major histocompatibility complex (MHC), human leukocyte antigens (HLAs) are one of the most polymorphic genes in humans. Patients carrying certain HLA alleles may develop adverse drug reactions (ADRs) after taking specific drugs. Peptides play an important role in HLA related ADRs as they are the necessary co-binders of HLAs with drugs. Many experimental data have been generated for understanding HLA-peptide binding. However, efficiently utilizing the data for understanding and accurately predicting HLA-peptide binding is challenging. Therefore, we developed a network analysis based method to understand and predict HLA-peptide binding. Methods: Qualitative Class I HLA-peptide binding data were harvested and prepared from four major databases. An HLA-peptide binding network was constructed from this dataset and modules were identified by the fast greedy modularity optimization algorithm. To examine the significance of signals in the yielded models, the modularity was compared with the modularity values generated from 1,000 random networks. The peptides and HLAs in the modules were characterized by similarity analysis. The neighbor-edges based and unbiased leverage algorithm (Nebula) was developed for predicting HLA-peptide binding. Leave-one-out (LOO) validations and twofold cross-validations were conducted to evaluate the performance of Nebula using the constructed HLA-peptide binding network. Results: Nine modules were identified from analyzing the HLA-peptide binding network with a highest modularity compared to all the random networks. Peptide length and functional side chains of amino acids at certain positions of the peptides were different among the modules. HLA sequences were module dependent to some extent. Nebula archived an overall prediction accuracy of 0.816 in the LOO validations and average accuracy of 0.795 in the two-fold cross-validations and outperformed the method reported in the literature. Conclusions: Network analysis is a useful approach for analyzing large and sparse datasets such as the HLA-peptide binding dataset. The modules identified from the network analysis clustered peptides and HLAs with similar sequences and properties of amino acids. Nebula performed well in the predictions of HLA-peptide binding. We demonstrated that network analysis coupled with Nebula is an efficient approach to understand and predict HLA-peptide binding interactions and thus, could further our understanding of ADRs. C1 [Luo, Heng; Ye, Hao; Ng, Hui Wen; Tong, Weida; Mattes, William; Mendrick, Donna; Hong, Huixiao] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Luo, Heng] Univ Arkansas Med Sci, Univ Arkansas Little Rock, Bioinformat Grad Program, Little Rock, AR 72201 USA. [Shi, Leming] Fudan Univ, Ctr Pharmacogenom, Sch Pharm, Shanghai 201203, Peoples R China. RP Mendrick, D (reprint author), US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Donna.Menderick@fda.hhs.gov; Huixiao.Hong@fda.hhs.gov RI Luo, Heng/D-3616-2016 OI Luo, Heng/0000-0001-5192-8878 FU NCRR NIH HHS [P20RR016460]; NIGMS NIH HHS [P20 GM103429] NR 39 TC 7 Z9 7 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD SEP 25 PY 2015 VL 16 SU 13 AR S9 DI 10.1186/1471-2105-16-S13-S9 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DA5YU UT WOS:000367879400009 PM 26424483 ER PT J AU Wren, JD Thakkar, S Homayouni, R Johann, DJ Dozmorov, MG AF Wren, Jonathan D. Thakkar, Shraddha Homayouni, Ramin Johann, Donald J. Dozmorov, Mikhail G. TI Proceedings of the 2015 midsouth computational biology and bioinformatics society (MCBIOS) conference INTRODUCTION SO BMC BIOINFORMATICS LA English DT Editorial Material ID PRECISION MEDICINE C1 [Wren, Jonathan D.] Oklahoma Med Res Fdn, Arthritis & Clin Immunol Res Program, Oklahoma City, OK 73104 USA. [Wren, Jonathan D.] Univ Oklahoma, Hlth Sci Ctr, Biochem & Mol Biol Dept, Norman, OK 73019 USA. [Wren, Jonathan D.] Univ Oklahoma, Hlth Sci Ctr, Stephenson Canc Ctr, Norman, OK 73019 USA. [Wren, Jonathan D.] Univ Oklahoma, Hlth Sci Ctr, Dept Geriatr Med, Norman, OK 73019 USA. [Thakkar, Shraddha] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Homayouni, Ramin] Univ Memphis, Dept Biol sci, Memphis, TN 38152 USA. [Homayouni, Ramin] Univ Memphis, Bioinformat Program, Memphis, TN 38152 USA. [Johann, Donald J.] Myeloma Inst, Univ Arkansas Med Sci, Little Rock, AR USA. [Johann, Donald J.] Dept Biomed Informat, Little Rock, AR USA. [Dozmorov, Mikhail G.] Virginia Commonwealth Univ, Richmond Acad Med, Dept Biostat, Richmond, VA 23284 USA. RP Wren, JD (reprint author), Oklahoma Med Res Fdn, Arthritis & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM jonathan-wren@omrf.org NR 16 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD SEP 25 PY 2015 VL 16 SU 13 AR S1 DI 10.1186/1471-2105-16-S13-S1 PG 4 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DA5YU UT WOS:000367879400001 PM 26424691 ER PT J AU Zhao, WZ Chen, JJ Perkins, R Liu, ZC Ge, WG Ding, YJ Zou, W AF Zhao, Weizhong Chen, James J. Perkins, Roger Liu, Zhichao Ge, Weigong Ding, Yijun Zou, Wen TI A heuristic approach to determine an appropriate number of topics in topic modeling SO BMC BIOINFORMATICS LA English DT Article; Proceedings Paper CT 12th Annual Conference of the MidSouth-Computational-Biology-and-Bioinformatics-Society (MCBIOS) CY MAR 13-14, 2015 CL Little Rock, AR SP MidSouth Computat Biol & Bioinformat Soc ID LATENT DIRICHLET ALLOCATION; SEMANTIC ANALYSIS AB Background: Topic modelling is an active research field in machine learning. While mainly used to build models from unstructured textual data, it offers an effective means of data mining where samples represent documents, and different biological endpoints or omics data represent words. Latent Dirichlet Allocation (LDA) is the most commonly used topic modelling method across a wide number of technical fields. However, model development can be arduous and tedious, and requires burdensome and systematic sensitivity studies in order to find the best set of model parameters. Often, time-consuming subjective evaluations are needed to compare models. Currently, research has yielded no easy way to choose the proper number of topics in a model beyond a major iterative approach. Methods and results: Based on analysis of variation of statistical perplexity during topic modelling, a heuristic approach is proposed in this study to estimate the most appropriate number of topics. Specifically, the rate of perplexity change (RPC) as a function of numbers of topics is proposed as a suitable selector. We test the stability and effectiveness of the proposed method for three markedly different types of grounded-truth datasets: Salmonella next generation sequencing, pharmacological side effects, and textual abstracts on computational biology and bioinformatics (TCBB) from PubMed. Conclusion: The proposed RPC-based method is demonstrated to choose the best number of topics in three numerical experiments of widely different data types, and for databases of very different sizes. The work required was markedly less arduous than if full systematic sensitivity studies had been carried out with number of topics as a parameter. We understand that additional investigation is needed to substantiate the method's theoretical basis, and to establish its generalizability in terms of dataset characteristics. C1 [Zhao, Weizhong; Chen, James J.; Perkins, Roger; Liu, Zhichao; Ge, Weigong; Ding, Yijun; Zou, Wen] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Zhao, Weizhong] Xiangtan Univ, Coll Informat Engn, Xiangtan, Hunan, Peoples R China. RP Zou, W (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. EM wen.zou@fda.hhs.gov NR 18 TC 2 Z9 2 U1 3 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD SEP 25 PY 2015 VL 16 SU 13 AR S8 DI 10.1186/1471-2105-16-S13-S8 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DA5YU UT WOS:000367879400008 PM 26424364 ER PT J AU Majid, L Zagorodnyaya, T Plant, EP Petrovskaya, S Bidzhieva, B Ye, ZP Simonyan, V Chumakov, K AF Majid, Laassri Zagorodnyaya, Tatiana Plant, Ewan P. Petrovskaya, Svetlana Bidzhieva, Bella Ye, Zhiping Simonyan, Vahan Chumakov, Konstantin TI Deep Sequencing for Evaluation of Genetic Stability of Influenza A/California/07/2009 (H1N1) Vaccine Viruses SO PLOS ONE LA English DT Article ID RECEPTOR-BINDING PROPERTIES; LIVE VIRAL VACCINES; A VIRUS; GEL-ELECTROPHORESIS; SIALIC-ACID; HEMAGGLUTININ; NEURAMINIDASE; RNA; SPECIFICITY; POPULATIONS AB Virus growth during influenza vaccine manufacture can lead to mutations that alter antigenic properties of the virus, and thus may affect protective potency of the vaccine. Different reassortants of pandemic "swine" H1N1 influenza A vaccine (121XP, X-179A and X-181) viruses as well as wild type A/California/07/2009(H1N1) and A/PR/8/34 strains were propagated in embryonated eggs and used for DNA/RNA Illumina HiSeq and MiSeq sequencing. The RNA sequences of these viruses published in NCBI were used as references for alignment of the sequencing reads generated in this study. Consensus sequences of these viruses differed from the NCBI-deposited sequences at several nucleotides. 121XP stock derived by reverse genetics was more heterogeneous than X-179A and X-181 stocks prepared by conventional reassortant technology. Passaged 121XP virus contained four non-synonymous mutations in the HA gene. One of these mutations (Lys(226)Glu) was located in the Ca antigenic site of HA (present in 18% of the population). Two non-synonymous mutations were present in HA of viruses derived from X-179A: Pro(314)Gln (18%) and Asn(146)Asp (78%). The latter mutation located in the Sa antigenic site was also detected at a low level (11%) in the wild-type A/California/07/2009(H1N1) virus, and was present as a complete substitution in X-181 viruses derived from X-179A virus. In the passaged X-181 viruses, two mutations emerged in HA: a silent mutation A(1398)G (31%) in one batch and G(756)T (Glu(252)Asp, 47%) in another batch. The latter mutation was located in the conservative region of the antigenic site Ca. The protocol for RNA sequencing was found to be robust, reproducible, and suitable for monitoring genetic consistency of influenza vaccine seed stocks. C1 [Majid, Laassri; Zagorodnyaya, Tatiana; Plant, Ewan P.; Petrovskaya, Svetlana; Bidzhieva, Bella; Ye, Zhiping; Simonyan, Vahan; Chumakov, Konstantin] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Majid, L (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM majid.laassri@fda.hhs.gov OI Plant, Ewan/0000-0003-0166-5939 NR 42 TC 1 Z9 1 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 25 PY 2015 VL 10 IS 9 AR e0138650 DI 10.1371/journal.pone.0138650 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS1CR UT WOS:000361800700064 ER PT J AU Hayward, DG Wong, JW Park, HY AF Hayward, Douglas G. Wong, Jon W. Park, Hoon Y. TI Determinations for Pesticides on Black, Green, Oolong, and White Teas by Gas Chromatography Triple-Quadrupole Mass Spectrometry SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE multiresidue pesticide analysis; tea; GCB/PSA SPE; GC-MS/MS ID SOLID-PHASE EXTRACTION; THROUGHPUT ANALYTICAL TECHNIQUES; ORGANOCHLORINE PESTICIDES; CHEMICAL-POLLUTANTS; SAMPLE PREPARATION; RESIDUES; MULTIRESIDUE; PERSISTENCE; INFUSION; DICOFOL AB Black, green, white, and Oolong teas, all derived from leaves of Camellia sinensis, are widely consumed throughout the world and represent a significant part of the beverages consumed by Americans. A gas chromatography-triple quadrupolebased method, previously validated for pesticides on dried botanical dietary supplements, including green tea, was used to measure pesticides fortified into black and green teas at 10, 25, 100, and 500 mu g/kg. Teas from 18 vendors of tea products were then surveyed for pesticides. Of 62 black, green, white, and Oolong tea products, 31 (50%) had residues of pesticides for which no United States Environmental Protection Agency tolerances are established for tea. The following pesticides were identified on tea leaves, with concentrations between 1 and 3200 mu g/kg: anthraquinone, azoxystrobin, bifenthrin, buprofesin, chlorpyrifos, cyhalothrin, cypermethrin, DDE-p,p', DDT-o,p, DDT-p,p', deltamethrin, endosulfan, fenvalerate, heptachlor, hexachlorocydohexanes (alpha,beta,gamma,delta), phenylphenol, pyridaben, tebuconazole, tebufenpyrad, and triazophos. DDT-p,p' was found at much higher concentrations than DDE-p,p' or DDT-o,p' in 9 of 10 teas with DDTs. A comparison between three commercially available solid-phase extraction (SPE) column brands of the same type revealed that two brands of SPE columns could be interchanged without modification of the tea method. C1 [Hayward, Douglas G.; Wong, Jon W.; Park, Hoon Y.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Hayward, DG (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy,HFS 706, College Pk, MD 20740 USA. EM douglas.hayward@fda.hhs.gov; jon.wong@fda.hhs.gov NR 30 TC 4 Z9 4 U1 15 U2 76 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD SEP 23 PY 2015 VL 63 IS 37 BP 8116 EP 8124 DI 10.1021/acs.jafc.5b02860 PG 9 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA CS2VM UT WOS:000361930100004 PM 26209005 ER PT J AU Liao, CD Wong, JW Zhang, K Yang, P Wittenberg, JB Trucksess, MW Hayward, DG Lee, NS Chang, JS AF Liao, Chia-Ding Wong, Jon W. Zhang, Kai Yang, Paul Wittenberg, James B. Trucksess, Mary W. Hayward, Douglas G. Lee, Nathaniel S. Chang, James S. TI Multi-mycotoxin Analysis of Finished Grain and Nut Products Using Ultrahigh-Performance Liquid Chromatography and Positive Electrospray Ionization-Quadrupole Orbital Ion Trap High-Resolution Mass Spectrometry SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE multi-mycotoxin analysis; ultrahigh-performance liquid chromatography/quadrupole orbital ion trap high-resolution mass spectrometry; finished cereal and nut products ID ERGOT ALKALOIDS; LC-MS/MS; METABOLITE IDENTIFICATION; SCREENING METHOD; FOOD; MS; VALIDATION; VEGETABLES; FRUITS; TIME AB Ultrahigh-performance liquid chromatography using positive electrospray ionization and quadrupole orbital ion trap high-resolution mass spectrometry was evaluated for analyzing mycotoxins in finished cereal and nut products. Optimizing the orbital ion trap mass analyzer in full-scan mode using mycotoxin-fortified matrix extracts gave mass accuracies, delta(M), of <+/- 2.0 ppm at 70 000 full width at half maximum (FWHM) mass resolution (R-FWHM). The limits of quantitation were matrix- and mycotoxin-dependent, ranging from 0.02 to 11.6 mu g/kg. Mean recoveries and standard deviations for mycotoxins from acetonitrile/water extraction at their relevant fortification levels were 91 +/- 10, 94 +/- 10, 98 +/- 12, 91 +/- 13, 99 +/- 15, and 93 +/- 17% for corn, rice, wheat, almond, peanut, and pistachio, respectively. Nineteen mycotoxins with concentrations ranging from 0.3 (aflatoxin B-1 in peanut and almond) to 1175 mu g/kg (fumonisin B-1 in corn flour) were found in 35 of the 70 commercial grain and nut samples surveyed. Mycotoxins could be identified at delta(M) < +/- 5 ppm by identifying the precursor and product ions in full-scan MS and data-dependent MS/MS modes. This method demonstrates a new analytical approach for monitoring mycotoxins in finished grain and nut products. C1 [Liao, Chia-Ding; Wong, Jon W.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Liao, Chia-Ding] Minist Hlth & Welf, Food & Drug Adm, Taipei 115, Taiwan. [Yang, Paul] Ontario Minist Environm, Lab Serv Branch, Etobicoke, ON M9P 3V6, Canada. [Lee, Nathaniel S.] Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 USA. [Chang, James S.] ThermoFisher Sci, San Jose, CA 95134 USA. RP Liao, CD (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM cdliao@fda.gov.tw; jon.wong@fda.hhs.gov FU FDA/CFSAN FX We thank Drs. Timothy D. Norden, Thomas A Weber, and Jason Vanfossan of the United States Department of Agriculture, Grain Inspection, Packers and Stockyards Administration, Technology and Science Division (Kansas City, MO) for providing reference materials, suggestions and technical expertise. We also thank Dr. Dipankar Ghosh and Mr. Charles Yang of Thermo Fisher Scientific (San Jose, CA) for providing available software to process and analyze the data. C.-D.L. and J.B.W. acknowledge the support of the FDA/CFSAN post-doctoral positions administered through the Oak Ridge Institute for Science and Education (ORISE) program. NR 45 TC 6 Z9 6 U1 7 U2 57 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD SEP 23 PY 2015 VL 63 IS 37 BP 8314 EP 8332 DI 10.1021/jf505049a PG 19 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA CS2VM UT WOS:000361930100030 PM 25531669 ER PT J AU Maggio, S Takeda, K Stark, F Meierovics, AI Yabe, I Cowley, SC AF Maggio, Savannah Takeda, Kazuyo Stark, Felicity Meierovics, Anda I. Yabe, Idalia Cowley, Siobhan C. TI Control of Francisella tularensis Intracellular Growth by Pulmonary Epithelial Cells SO PLOS ONE LA English DT Article ID SYNTHASE GENE-EXPRESSION; NITRIC-OXIDE; REACTIVE NITROGEN; IFN-GAMMA; II CELLS; MURINE MACROPHAGES; IN-VITRO; SCHU S4; LUNG; ACTIVATION AB The virulence of F. tularensis is often associated with its ability to grow in macrophages, although recent studies show that Francisella proliferates in multiple host cell types, including pulmonary epithelial cells. Thus far little is known about the requirements for killing of F. tularensis in the non-macrophage host cell types that support replication of this organism. Here we sought to address this question through the use of a murine lung epithelial cell line (TC-1 cells). Our data show that combinations of the cytokines IFN-gamma, TNF, and IL-17A activated murine pulmonary epithelial cells to inhibit the intracellular growth of the F. tularensis Live Vaccine Strain (LVS) and the highly virulent F. tularensis Schu S4 strain. Although paired combinations of IFN-gamma, TNF, and IL-17A all significantly controlled LVS growth, simultaneous treatment with all three cytokines had the greatest effect on LVS growth inhibition. In contrast, Schu S4 was more resistant to cytokine-induced growth effects, exhibiting significant growth inhibition only in response to all three cytokines. Since one of the main antimicrobial mechanisms of activated macrophages is the release of reactive nitrogen intermediates (RNI) via the activity of iNOS, we investigated the role of RNI and iNOS in Francisella growth control by pulmonary epithelial cells. NOS2 gene expression was significantly up-regulated in infected, cytokine-treated pulmonary epithelial cells in a manner that correlated with LVS and Schu S4 growth control. Treatment of LVS-infected cells with an iNOS inhibitor significantly reversed LVS killing in cytokine-treated cultures. Further, we found that mouse pulmonary epithelial cells produced iNOS during in vivo respiratory LVS infection. Overall, these data demonstrate that lung epithelial cells produce iNOS both in vitro and in vivo, and can inhibit Francisella intracellular growth via reactive nitrogen intermediates. C1 [Maggio, Savannah; Meierovics, Anda I.; Cowley, Siobhan C.] US FDA, Lab Mucosal Pathogens & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Takeda, Kazuyo] US FDA, Microscopy & Imaging Core Facil, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Stark, Felicity] Natl Res Council Canada, Human Hlth Therapeut Portfolio, Ottawa, ON K1A 0R6, Canada. [Yabe, Idalia] NHLBI, NIH, Bethesda, MD 20892 USA. RP Cowley, SC (reprint author), US FDA, Lab Mucosal Pathogens & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM siobhan.cowley@fda.hhs.gov FU FDA Medical Countermeasures Initiative FX This work was supported by the FDA Medical Countermeasures Initiative. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 0 Z9 0 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 17 PY 2015 VL 10 IS 9 AR e0138565 DI 10.1371/journal.pone.0138565 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS0RH UT WOS:000361769400110 PM 26379269 ER PT J AU Przepiorka, D Ko, CW Deisseroth, A Yancey, CL Candau-Chacon, R Chiu, HJ Gehrke, BJ Gomez-Broughton, C Kane, RC Kirshner, S Mehrotra, N Ricks, TK Schmiel, D Song, PF Zhao, P Zhou, Q Farrell, AT Pazdur, R AF Przepiorka, Donna Ko, Chia-Wen Deisseroth, Albert Yancey, Carolyn L. Candau-Chacon, Reyes Chiu, Haw-Jyh Gehrke, Brenda J. Gomez-Broughton, Candace Kane, Robert C. Kirshner, Susan Mehrotra, Nitin Ricks, Tiffany K. Schmiel, Deborah Song, Pengfei Zhao, Ping Zhou, Qing Farrell, Ann T. Pazdur, Richard TI FDA Approval: Blinatumomab SO CLINICAL CANCER RESEARCH LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE LYMPHOCYTIC-LEUKEMIA; STEM-CELL TRANSPLANTATION; MINIMAL RESIDUAL DISEASE; SALVAGE THERAPY; CHEMOTHERAPY; ADULTS AB On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager. The basis for the approval was a single-arm trial with 185 evaluable adults with R/R ALL. The complete remission (CR) rate was 32%[95% confidence interval (CI), 26%-40%], and the median duration of response was 6.7 months. A minimal residual disease response was achieved by 31% (95% CI, 25%-39%) of all patients. Cytokine release syndrome and neurologic events were serious toxicities that occurred. Other common (>20%) adverse reactions were pyrexia, headache, edema, febrile neutropenia, nausea, tremor, and rash. Neutropenia, thrombocytopenia, and elevated transaminases were the most common (>10%) laboratory abnormalities related to blinatumomab. A randomized trial is required in order to confirm clinical benefit. (C)2015 AACR. C1 [Przepiorka, Donna; Ko, Chia-Wen; Deisseroth, Albert; Yancey, Carolyn L.; Candau-Chacon, Reyes; Chiu, Haw-Jyh; Gehrke, Brenda J.; Gomez-Broughton, Candace; Kane, Robert C.; Kirshner, Susan; Mehrotra, Nitin; Ricks, Tiffany K.; Schmiel, Deborah; Song, Pengfei; Zhao, Ping; Zhou, Qing; Farrell, Ann T.; Pazdur, Richard] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Przepiorka, D (reprint author), US FDA, Div Hematol Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM donna.przepiorka@fda.hhs.gov NR 19 TC 22 Z9 22 U1 1 U2 7 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 SEP 15 PY 2015 VL 21 IS 18 BP 4035 EP 4039 DI 10.1158/1078-0432.CCR-15-0612 PG 5 WC Oncology SC Oncology GA CU2CN UT WOS:000363329900004 PM 26374073 ER PT J AU Harrington, PR Fleischer, R Connelly, SM Lewis, LL Murray, J AF Harrington, Patrick R. Fleischer, Russell Connelly, Sarah M. Lewis, Linda L. Murray, Jeffrey TI Ribavirin Reduces Absolute Lymphocyte Counts in Hepatitis C Virus-Infected Patients Treated With Interferon-Free, Direct-Acting Antiviral Regimens SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HCV; ribavirin; lymphocytes; direct-acting antiviral agents ID GENOTYPE 1 INFECTION; HCV; SOFOSBUVIR AB In clinical trials of interferon-free, direct-acting antiviral treatment of chronic hepatitis C, subjects who received ribavirin had reduced lymphocyte levels (median decline of approximately 0.4-0.5 x 10(9) cells/L). A modest decline in CD4(+) T cells was observed in subjects with human immunodeficiency virus type 1 coinfection without documented opportunistic infections. C1 [Harrington, Patrick R.; Fleischer, Russell; Connelly, Sarah M.; Lewis, Linda L.; Murray, Jeffrey] US FDA, Div Antiviral Prod, Off Antimicrobial Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Harrington, PR (reprint author), FDA CDER OAP DAVP, 10903 New Hampshire Ave,Bldg 22,Rm 6336, Silver Spring, MD 20993 USA. EM patrick.harrington@fda.hhs.gov FU AbbVie Inc; Gilead Sciences Inc FX The data analyzed for this report were submitted in the New Drug Applications (NDAs) for ombitasvir/paritaprevir/ritonavir plus dasabuvir (Viekira Pak) and ledipasvir/sofosbuvir (Harvoni). The analyses are documented in the US Food and Drug Administration (FDA) Clinical Virology review of NDA 206619 for Viekira Pak, and are posted on the Drugs@FDA website (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206619Orig1s000M icroR.pdf). The authors acknowledge the study sponsors (AbbVie Inc and Gilead Sciences Inc), investigators, and study volunteers as the source of these data. NR 12 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2015 VL 61 IS 6 BP 974 EP 977 DI 10.1093/cid/civ419 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CR6OY UT WOS:000361468200021 PM 26021996 ER PT J AU Jang, H Pfefer, TJ Chen, Y AF Jang, Hyounguk Pfefer, T. Joshua Chen, Yu TI Solid hemoglobin-polymer phantoms for evaluation of biophotonic systems SO OPTICS LETTERS LA English DT Article ID OPTICAL-PROPERTIES; FLUORESCENCE SPECTROSCOPY; DESIGN; BLOOD AB Stable tissue phantoms that incorporate the spectral absorption properties of hemoglobin would benefit a wide range of biophotonic technologies. Toward this end, we have developed and validated a novel polymer material incorporating hemoglobin. Our solid hemoglobin-polymer (SHP) material is fabricated by mixing liquid silicone base with a hemoglobin solution, followed by sonication and low temperature curing. The optical properties of samples were determined over 450-1000 nm using the inverse adding-doubling method and the Beer-Lambert law. Measurements indicated SHP optical stability over four months. Near-infrared spectroscopy and hyperspectral imaging measurements of SHP samples were performed to demonstrate the utility of this approach. SHP materials have the potential to improve tissue-simulating phantoms used for development, evaluation, and standardization of optical devices for oximetry and other applications. (C) 2015 Optical Society of America C1 [Jang, Hyounguk; Chen, Yu] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [Jang, Hyounguk; Pfefer, T. Joshua] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20902 USA. RP Chen, Y (reprint author), Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. EM yuchen@umd.edu FU National Science Foundation (NSF) [CBET-1343641] FX National Science Foundation (NSF) (CBET-1343641). NR 16 TC 1 Z9 1 U1 2 U2 10 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 EI 1539-4794 J9 OPT LETT JI Opt. Lett. PD SEP 15 PY 2015 VL 40 IS 18 BP 4321 EP 4324 DI 10.1364/OL.40.004321 PG 4 WC Optics SC Optics GA CR7UJ UT WOS:000361556700034 PM 26371926 ER PT J AU Weaver, JL Boyne, M Pang, E Chimalakonda, K Howard, KE AF Weaver, James L. Boyne, Michael Pang, Eric Chimalakonda, Krishna Howard, Kristina E. TI Nonclinical evaluation of the potential for mast cell activation by an erythropoietin analog SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Peginesatide; Mast cells; Phenol; Anaphylactoid ID INDUCED HISTAMINE-RELEASE; IMMUNE-RESPONSES; VANCOMYCIN; DEGRANULATION; MEDIATOR AB The elythropoietin analog peginesatide was withdrawn from marketing due to unexpected severe anaphylactic reactions associated with administration of the multi-use formulation. The adverse events occurred rapidly following the first ever administration of the drug with most affected patients becoming symptomatic in less than 30 min. This is most consistent with an anaphylactoid reaction due to direct activation of mast cells. Laboratory evaluation was undertaken using rat peritoneal mast cells as the model system. Initial studies showed that high concentrations of the formulated drug as well as formulated vehicle alone could cause mast cell degranulation as measured by histamine release. The purified active drug was not able to cause histamine release whereas the vehicle filtrate and lab created drug vehicle were equally potent at causing histamine release. Individual formulations of vehicle leaving one component out showed that histamine release was due to phenol. Dose response studies with phenol showed a very sharp dose response curve that was similar in three buffer systems. Cellular analysis by flow cytometry showed that the histamine release was not due to cell death, and that changes in light scatter parameters consistent with degranulation were rapidly observed. Limited testing with primary human mast cells showed a similar dose response of histamine release with exposure to phenol. To provide in vivo confirmation, rats were injected with vehicle formulated with various concentrations of phenol via a jugular vein cannula. Significant release of histamine was detected in blood samples taken 2 min after dosing at the highest concentrations tested. Published by Elsevier Inc. C1 [Weaver, James L.; Pang, Eric; Chimalakonda, Krishna; Howard, Kristina E.] US FDA, Div Appl Regulatory Sci, OCP, OTS,CDER, Silver Spring, MD 20993 USA. [Boyne, Michael] US FDA, Div Pharmaceut Anal, OTR, OPQ,CDER, Silver Spring, MD 20993 USA. RP Weaver, JL (reprint author), US FDA, Div Appl Regulatory Sci, OCP, CDER, Bldg 64,Room 2064,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM James.Weaver@fda.hhs.gov; mboyne@biotechlogic.com; Eric.Pang@fda.hhs.gov; Krishna.Chimalakonda@fda.hhs.gov; Kristina.Howard@fda.hhs.gov FU Product Quality and Clinical Omontys working groups, CDER, FDA FX We would like to acknowledge the Product Quality and Clinical Omontys working groups, CDER, FDA for the extensive background information and support during this project. We thank Jose Austin, Carlos Gonzalez and Sharron Stewart for providing technical support. NR 23 TC 6 Z9 6 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 15 PY 2015 VL 287 IS 3 BP 246 EP 252 DI 10.1016/j.taap.2015.06.009 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CQ2IG UT WOS:000360422800007 PM 26079829 ER PT J AU Khan, SA DeGrasse, JA Yakes, BJ Croley, TR AF Khan, Sadia Afrin DeGrasse, Jeffrey A. Yakes, Betsy Jean Croley, Timothy R. TI Rapid and sensitive detection of cholera toxin using gold nanoparticle-based simple colorimetric and dynamic light scattering assay SO ANALYTICA CHIMICA ACTA LA English DT Article DE Cholera toxin; Gold nanoparticle; Colorimetric assay; Dynamic light scattering assay ID SURFACE-PLASMON RESONANCE; COMPETITION ASSAY; AQUEOUS-SOLUTION; VIBRIO-CHOLERAE; HEAT-LABILE; REAL-TIME; CANCER; GANGLIOSIDE; IMMUNOASSAY; PROBES AB Herein, a rapid and simple gold nanoparticle based colorimetric and dynamic light scattering (DLS) assay for the sensitive detection of cholera toxin has been developed. The developed assay is based on the distance dependent properties of gold nanoparticles which cause aggregation of antibody-conjugated gold nanoparticles in the presence of cholera toxin resulting discernible color change. This aggregation induced color change caused a red shift in the plasmon band of nanoparticles which was measured by UV-Vis spectroscopy. In addition, we employed DLS assay to monitor the extent of aggregation in the presence of different concentration of cholera toxin. Our assay can visually detect as low as 10 nM of cholera toxin which is lower than the previously reported colorimetric methods. The reported assay is very fast and showed an excellent specificity against other diarrhetic toxins. Moreover, we have demonstrated the feasibility of our method for cholera toxin detection in local lake water. Published by Elsevier B.V. C1 [Khan, Sadia Afrin; DeGrasse, Jeffrey A.; Yakes, Betsy Jean; Croley, Timothy R.] US FDA, CFSAN, College Pk, MD 20740 USA. RP Khan, SA (reprint author), US FDA, CFSAN, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM sadia.khan@fda.hhs.gov NR 42 TC 6 Z9 6 U1 5 U2 42 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0003-2670 EI 1873-4324 J9 ANAL CHIM ACTA JI Anal. Chim. Acta PD SEP 10 PY 2015 VL 892 BP 167 EP 174 DI 10.1016/j.aca.2015.08.029 PG 8 WC Chemistry, Analytical SC Chemistry GA CR9AZ UT WOS:000361646900018 PM 26388488 ER PT J AU Borio, L Cox, E Lurie, N AF Borio, Luciana Cox, Edward Lurie, Nicole TI Combating Emerging Threats - Accelerating the Availability of Medical Therapies SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Borio, Luciana] US FDA, Off Commissioner, Silver Spring, MD 20993 USA. [Cox, Edward] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Lurie, Nicole] US Dept HHS, Off Assistant Secretary Preparedness & Response, Washington, DC 20201 USA. RP Borio, L (reprint author), US FDA, Off Commissioner, Silver Spring, MD 20993 USA. NR 5 TC 12 Z9 12 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 10 PY 2015 VL 373 IS 11 BP 993 EP 995 DI 10.1056/NEJMp1508708 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CQ9TV UT WOS:000360959000004 PM 26244879 ER PT J AU Liu, Y Wu, HH Chong, Y Wamer, WG Xia, QS Cai, LN Nie, ZH Fu, PP Yin, JJ AF Liu, Yi Wu, Haohao Chong, Yu Wamer, Wayne G. Xia, Qingsu Cai, Lining Nie, Zhihong Fu, Peter P. Yin, Jun-Jie TI Platinum Nanoparticles: Efficient and Stable Catechol Oxidase Mimetics SO ACS APPLIED MATERIALS & INTERFACES LA English DT Article DE platinum nanoparticles; heterogeneous catalysts; enzyme mimetics; catechol oxidase-like activity; oxidation of polyphenols ID SURFACE-PLASMON RESONANCE; PEROXIDASE-LIKE ACTIVITY; SPIN-LABEL OXIMETRY; MUSHROOM TYROSINASE; GOLD NANOPARTICLES; CATALYTIC-ACTIVITY; HYDROGEN-PEROXIDE; CRYSTAL-STRUCTURE; DIFFERENT SHAPES; ACTIVE-SITE AB Although enzyme-like nanomaterials have been extensively investigated over the past decade, most research has focused on the peroxidaselike, catalase-like, or SOD-like activity of these nanomaterials. Identifying nanomaterials having oiddase-like activities has received less attention. In this study, we demonstrate that platinum nanopartides (Pt NPs) exhibit catechol oiddase-like activity, oxidizing polyphenols into the corresponding o-quinones. Four unique approaches are employed to demonstrate the catechol oxidase-like activity exerted by Pt NPs. First, UV vis spectroscopy is used to monitor the oxidation of polyphenols catalyzed by Pt NPs. Second, the oxidized products of polyphenols are identified by ultrahigh-performance liquid chromatography (UHPLC) separation followed by high-resolution mass spectrometry (HRMS) identification. Third, electron spin resonance (ESR) oximetry techniques are used to confirm the O-2 consumption during the oxidation reaction. Fourth, the intermediate products of semiquinone radicals formed during the oxidation of polyphenols are determined by ESR using spin stabilization. These results indicate Pt NPs possess catechol oxidase-like activity. Because polyphenols and related bioactive substances have been explored as potent antioxidants that could be useful for the prevention of cancer and cardiovascular diseases, and Pt NPs have been widely used in the chemical industry and medical science, it is essential to understand the potential effects of Pt NPs for altering or influencing the antioxidant activity of polyphenols. C1 [Liu, Yi; Wu, Haohao; Chong, Yu; Wamer, Wayne G.; Yin, Jun-Jie] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, Div Analyt Chem, College Pk, MD 20740 USA. [Liu, Yi; Nie, Zhihong] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Xia, Qingsu; Fu, Peter P.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Cai, Lining] Biotranex LLC, Monmouth Jct, NJ 08852 USA. RP Fu, PP (reprint author), US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM peter.fu@fda.hhs.gov; junjie.yin@fda.hhs.gov RI Yin, Jun Jie /E-5619-2014; Nie, Zhihong/D-7495-2011; OI Nie, Zhihong/0000-0001-9639-905X; Wu, Haohao/0000-0003-3852-2608 FU NSF [DMR-1255377]; University of Maryland; Joint Institute for Food Safety and Nutrition, University of Maryland, College Park, MD - FDA [5U01FD001418]; FDA Nanotechnology CORES Program FX This work is supported by the NSF career award (DMR-1255377), startup funds from the University of Maryland, and the Joint Institute for Food Safety and Nutrition, University of Maryland, College Park, MD through a cooperative agreement funded by the FDA, Grant no. 5U01FD001418 (LY). Support was also received through a regulatory science grant under the FDA Nanotechnology CORES Program. We gratefully acknowledge Wanlong Zhou and Perry Wang (Office of Regulatory Science, Center for Food Safety and Applied Nutrition/FDA) for their expert assistance in performing UHPLC-HRMS analyses. We are also grateful to Lili Fox Velez for her editorial support. This paper is not an official U.S. FDA guidance or policy statement. No official support or endorsement by the U.S. FDA is intended or should be inferred. NR 68 TC 8 Z9 8 U1 18 U2 75 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1944-8244 J9 ACS APPL MATER INTER JI ACS Appl. Mater. Interfaces PD SEP 9 PY 2015 VL 7 IS 35 BP 19709 EP 19717 DI 10.1021/acsami.5b05180 PG 9 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA CR3SC UT WOS:000361252400024 PM 26305170 ER PT J AU Li, Q Kappil, MA Li, A Dassanayake, PS Darrah, TH Friedman, AE Friedman, M Lambertini, L Landrigan, P Stodgell, CJ Xia, YL Nanes, JA Aagaard, KM Schadt, EE Murray, JC Clark, EB Dole, N Culhane, J Swanson, J Varner, M Moye, J Kasten, C Miller, RK Chen, J AF Li, Qian Kappil, Maya A. Li, An Dassanayake, Priyanthi S. Darrah, Thomas H. Friedman, Alan E. Friedman, Michelle Lambertini, Luca Landrigan, Philip Stodgell, Christopher J. Xia, Yulin Nanes, Jessica A. Aagaard, Kjersti M. Schadt, Eric E. Murray, Jeff C. Clark, Edward B. Dole, Nancy Culhane, Jennifer Swanson, James Varner, Michael Moye, Jack Kasten, Carol Miller, Richard K. Chen, Jia TI Exploring the associations between microRNA expression profiles and environmental pollutants in human placenta from the National Children's Study (NCS) SO EPIGENETICS LA English DT Article DE environmental pollutants; placenta; birth cohort; microRNA; epigenetics ID POLYBROMINATED DIPHENYL ETHERS; PERSISTENT ORGANIC POLLUTANTS; PREGNANT-WOMEN; LEAD-EXPOSURE; POLYCHLORINATED-BIPHENYLS; MERCURY EXPOSURE; IN-UTERO; BLOOD; CELLS; FISH AB The placenta is the principal regulator of the in utero environment, and disruptions to this environment can result in adverse offspring health outcomes. To better characterize the impact of in utero perturbations, we assessed the influence of known environmental pollutants on the expression of microRNA (miRNA) in placental samples collected from the National Children's Study (NCS) Vanguard birth cohort. This study analyzed the expression of 654 miRNAs in 110 term placentas. Environmental pollutants measured in these placentas included dichlorodiphenyldichloroethylene (DDE), bisphenol A (BPA), polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), arsenic (As), mercury (Hg), lead (Pb), and cadmium (Cd). A moderated t-test was used to identify a panel of differentially expressed miRNAs, which were further analyzed using generalized linear models. We observed 112 miRNAs consistently expressed in >70% of the samples. Consistent with the literature, miRNAs located within the imprinted placenta-specific C19MC cluster, specifically mir-517a, mir-517c, mir-522, and mir-23a, are among the top expressed miRNA in our study. We observed a positive association between PBDE 209 and miR-188-5p and an inverse association between PBDE 99 and let-7c. Both PCBs and Cd were positively associated with miR-1537 expression level. In addition, multiple let-7 family members were downregulated with increasing levels of Hg and Pb. We did not observe DDE or BPA levels to be associated with placental miRNA expression. This is the first birth cohort study linking environmental pollutants and placental expression of miRNAs. Our results suggest that placental miRNA profiles may signal in utero exposures to environmental chemicals. C1 [Li, Qian; Kappil, Maya A.; Lambertini, Luca; Landrigan, Philip; Chen, Jia] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Li, Qian; Kappil, Maya A.; Lambertini, Luca; Landrigan, Philip; Chen, Jia] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA. [Li, Qian; Kappil, Maya A.; Lambertini, Luca; Landrigan, Philip; Chen, Jia] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Li, Qian; Kappil, Maya A.; Lambertini, Luca; Landrigan, Philip; Chen, Jia] Icahn Sch Med Mt Sinai, Dept Obstet Gynecol & Reprod Sci, New York, NY 10029 USA. [Li, An; Dassanayake, Priyanthi S.; Xia, Yulin; Nanes, Jessica A.] Univ Illinois, Sch Publ Hlth, Chicago, IL USA. [Darrah, Thomas H.; Stodgell, Christopher J.; Miller, Richard K.] Ohio State Univ, Sch Earth Sci, Columbus, OH 43210 USA. [Stodgell, Christopher J.; Miller, Richard K.] Univ Rochester, Sch Med & Dent, Dept Obs Gyn, Rochester, NY USA. [Stodgell, Christopher J.; Miller, Richard K.] Univ Rochester, Sch Med & Dent, Dept Environm Med, Rochester, NY USA. [Aagaard, Kjersti M.] Baylor Sch Med, Dept Obs Gyn, Houston, TX USA. [Schadt, Eric E.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci & Multiscale Biol, New York, NY 10029 USA. [Murray, Jeff C.] Univ Iowa, Dept Genet, Iowa City, IA USA. [Clark, Edward B.; Varner, Michael] Univ Utah, Dept Pediat & Obs Gyn, Salt Lake City, UT USA. [Dole, Nancy] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Culhane, Jennifer] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Swanson, James] Univ Calif Irvine, Dept Pediat, Irvine, CA 92717 USA. [Moye, Jack] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Kasten, Carol] US FDA, Div Pediat & Maternal Hlth, Silver Spring, MD USA. RP Chen, J (reprint author), Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. EM jia.chen@mssm.edu RI Darrah, Tom/I-2253-2016; Varner, Michael/K-9890-2013; OI Stodgell, Christopher/0000-0002-1666-5299; Varner, Michael/0000-0001-9455-3973; moye, john/0000-0001-9976-8586; , Maya/0000-0003-2913-2392 FU National Children's Study Placenta Consortium (NCS formative research project) [LOI2-BIO-18]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of the Director of the National Institutes of Health; NICHD [HHSN267200700027C, HHSN275201100002C, HHSN275200503396C] FX This work is part of the National Children's Study Placenta Consortium (NCS formative research project LOI2-BIO-18). This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and funded, through its appropriation, by the Office of the Director of the National Institutes of Health, with NICHD Contracts HHSN267200700027C, HHSN275201100002C, and HHSN275200503396C. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institutes of Health or the US Department of Health and Human Services. NR 69 TC 4 Z9 4 U1 2 U2 22 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1559-2294 EI 1559-2308 J9 EPIGENETICS-US JI Epigenetics PD SEP 2 PY 2015 VL 10 IS 9 BP 793 EP 802 DI 10.1080/15592294.2015.1066960 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CP9NW UT WOS:000360222200003 PM 26252056 ER PT J AU Williams, MS Golden, NJ Ebel, ED Crarey, ET Tate, HP AF Williams, Michael S. Golden, Neal J. Ebel, Eric D. Crarey, Emily T. Tate, Heather P. TI Temporal patterns of Campylobacter contamination on chicken and their relationship to campylobacteriosis cases in the United States SO INTERNATIONAL JOURNAL OF FOOD MICROBIOLOGY LA English DT Article DE Campylobacteriosis; Times series; Seasonality; Retail chicken ID FOODBORNE ILLNESSES; HUMAN SALMONELLOSIS; OUTBREAK DATA; RAW CHICKEN; JEJUNI; RETAIL; SEASONALITY; POULTRY; QUANTIFICATION; IDENTIFICATION AB The proportion of Campylobacter contaminated food and water samples collected by different surveillance systems often exhibit seasonal patterns. In addition, the incidence of foodborne campylobacteriosis also tends to exhibit strong seasonal patterns. Of the various product classes, the occurrence of Campylobacter contamination can be high on raw poultry products, and chicken is often thought to be one of the leading food vehicles for campylobacteriosis. Two different federal agencies in the United States collected samples of raw chicken products and tested them for the presence of Campylobacter. During the same time period, a consortium of federal and state agencies operated a nationwide surveillance system to monitor cases of campylobacteriosis in the United States. This study uses a common modeling approach to estimate trends and seasonal patterns in both the proportion of raw chicken product samples that test positive for Campylobacter and cases of campylobacteriosis. The results generally support the hypothesis of a weak seasonal increase in the proportion of Campylobacter positive chicken samples in the summer months, though the number of Campylobacter on test-positive samples is slightly lower during this time period. In contrast, campylobacteriosis cases exhibit a strong seasonal pattern that generally precedes increases in contaminated raw chicken. These results suggest that while contaminated chicken products may be responsible for a substantial number of campylobacteriosis cases, they are most likely not the primary driver of the seasonal pattern in human illness. Published by Elsevier B.V. C1 [Williams, Michael S.; Golden, Neal J.; Ebel, Eric D.] USDA, Off Publ Hlth Sci, Food Safety & Inspect Serv, Ft Collins, CO 80526 USA. [Crarey, Emily T.; Tate, Heather P.] US FDA, Ctr Vet Med, Natl Antimicrobial Resistance Monitoring Syst, Laurel, MD 20708 USA. RP Williams, MS (reprint author), USDA, Off Publ Hlth Sci, Food Safety & Inspect Serv, 2150 Ctr Ave,Bldg D, Ft Collins, CO 80526 USA. EM mike.williams@fsis.usda.gov NR 51 TC 4 Z9 4 U1 1 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1605 EI 1879-3460 J9 INT J FOOD MICROBIOL JI Int. J. Food Microbiol. PD SEP 2 PY 2015 VL 208 BP 114 EP 121 DI 10.1016/j.ijfoodmicro.2015.05.018 PG 8 WC Food Science & Technology; Microbiology SC Food Science & Technology; Microbiology GA CN5KE UT WOS:000358467400014 PM 26065728 ER PT J AU Zhang, WD Yan, L Li, M Zhao, RS Yang, X Ji, TJ Gu, ZJ Yin, JJ Gao, XF Nie, GJ AF Zhang, Wendi Yan, Liang Li, Meng Zhao, Ruisheng Yang, Xiao Ji, Tianjiao Gu, Zhanjun Yin, Jun-Jie Gao, Xingfa Nie, Guangjun TI Deciphering the underlying mechanisms of oxidation-state dependent cytotoxicity of graphene oxide on mammalian cells SO TOXICOLOGY LETTERS LA English DT Article DE Cytotoxicity; Graphene oxide (GO); Reactive oxygen species (ROS); Apoptosis; Electron spin resonance (ESR) spectrometry ID DRUG-DELIVERY; INDUCED TOXICITY; CAENORHABDITIS-ELEGANS; PHOTOTHERMAL THERAPY; LATERAL DIMENSION; IN-VITRO; STRESS; NANOPARTICLES; FIBROBLASTS; NANOPLATELETS AB The promising broad applications of graphene oxide (GO) derivatives in biomedicine have raised concerns about their safety on biological organisms. However, correlations between the physicochemical properties, especially oxidation degree of GOs and their toxicity, and the underlying mechanisms are not well understood. Herein, we evaluated the cytotoxicity of three GO samples with various oxidation degrees on mouse embryo fibroblasts (MEFs). Three samples can be internalized by MEFs observed via transmission electron microscopy (TEM), and were well tolerant by MEFs at lower doses (below 25 mu g/ ml) but significantly toxic at 50 and 100 mu g/ml via Cytell Imaging System. More importantly, as the oxidation degree decreased, GO derivatives led to a higher degree of cytotoxicity and apoptosis. Meanwhile, three GOs stimulated dramatic enhancement in reactive oxygen species (ROS) production in MEFs, where the less oxidized GO produced a higher level of ROS, suggesting the major role of oxidative stress in the oxidation- degree dependent toxicity of GOs. Results from electron spin resonance (ESR) spectrometry showed a strong association of the lower oxidation degree of GOs with their stronger indirect oxidative damage through facilitating H2O2 decomposition into (OH)-O-center dot and higher direct oxidativeabilities on cells. The theoretical simulation revealed the key contributions of carboxyl groups and aromatic domain size of nanosheets to varying the energy barrier of H2O2 decomposition reaction. These systematic explorations in the chemical mechanisms unravel the key physicochemical properties that would lead to the diverse toxic profiles of the GO nanosheets with different oxygenation levels, and offer us new clues in the molecular design of carbon nanomaterials for their safe applications in biomedicine. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Zhang, Wendi; Yang, Xiao; Ji, Tianjiao; Nie, Guangjun] Natl Ctr Nanosci & Technol, Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100190, Peoples R China. [Yan, Liang; Zhao, Ruisheng; Gu, Zhanjun; Gao, Xingfa] Chinese Acad Sci, Inst High Energy Phys, Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100049, Peoples R China. [Li, Meng; Yin, Jun-Jie] US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Nie, GJ (reprint author), Chinese Acad Sci, Natl Ctr Nanosci & Technol, 11 Beiyitiao Zhongguancun, Beijing 100190, Peoples R China. EM niegj@nanoctr.cn RI Yin, Jun Jie /E-5619-2014; Gu, Zhanjun/A-7592-2013; OI Gu, Zhanjun/0000-0003-3717-2423; nie, guangjun/0000-0001-5040-9793 FU MoST 973 [2012CB934004, 2011CB933400]; National Distinguished Young Scientists program [31325010]; Key Research Program of the Chinese Academy of Sciences [KGZD-EW-T06]; FDA Nanotechnology CORES Program FX The authors thank Hongda Guo for the assistance with TEM, Xiao Song for his guidance in flow cytometry-based apoptosis assays, and Ruifang Zhao, Drs. Hanqing Chen, Yi Yuan, Yiye Li and Yanping Ding for their kind suggestions for this work. This work was supported by MoST 973 (2012CB934004; 2011CB933400); National Distinguished Young Scientists program (31325010); the Key Research Program of the Chinese Academy of Sciences, Grant NO. KGZD-EW-T06; and was partially supported by a regulatory science grant under the FDA Nanotechnology CORES Program. This article is not an official U.S. FDA guidance or policy statement. No official support or endorsement by the U.S. FDA is intended or should be inferred. NR 56 TC 12 Z9 13 U1 12 U2 85 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 EI 1879-3169 J9 TOXICOL LETT JI Toxicol. Lett. PD SEP 2 PY 2015 VL 237 IS 2 BP 61 EP 71 DI 10.1016/j.toxlet.2015.05.021 PG 11 WC Toxicology SC Toxicology GA CM0TN UT WOS:000357391500001 PM 26047786 ER PT J AU Durmowicz, EL AF Durmowicz, Elizabeth L. TI Other Tobacco Products Electronic Devices/Water Pipes/Hookas SO JOURNAL OF THORACIC ONCOLOGY LA English DT Meeting Abstract DE Tobacco products; waterpipe; little cigars; electronic nicotine delivery systems C1 [Durmowicz, Elizabeth L.] US FDA, Ctr Tobacco Prod, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2015 VL 10 IS 9 SU 2 MA MS23.04 BP S131 EP S131 PG 1 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DE1CX UT WOS:000370365100129 ER PT J AU Kazandjian, D Blumenthal, G Khozin, S Zhang, LJ Tang, SH Keegan, P Pazdur, R AF Kazandjian, Diko Blumenthal, Gideon Khozin, Sean Zhang, Lijun Tang, Shenghui Keegan, Patricia Pazdur, Richard TI An Exploratory Responder Analysis of Best RECIST Response and Survival in Patients with Metastatic Squamous NSCLC Treated with Nivolumab SO JOURNAL OF THORACIC ONCOLOGY LA English DT Meeting Abstract DE NSCLC; PD-1 inhibitor; Nivolumab C1 [Kazandjian, Diko; Blumenthal, Gideon; Khozin, Sean; Keegan, Patricia; Pazdur, Richard] US FDA, Off Hematol Oncol Prod, Silver Spring, MD USA. [Zhang, Lijun; Tang, Shenghui] US FDA, Biostat, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2015 VL 10 IS 9 SU 2 MA ORAL31.06 BP S234 EP S234 PG 1 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DE1CX UT WOS:000370365100390 ER PT J AU Khozin, S Blumenthal, G Khomyanina, A Brodsky, B Fitzmartin, R Keegan, P Pazdur, R AF Khozin, Sean Blumenthal, Gideon Khomyanina, Alisa Brodsky, Boris Fitzmartin, Ronald Keegan, Patricia Pazdur, Richard TI Recommendations for Standardized Efficacy Data Specifications in Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Meeting Abstract DE lung cancer; FDA; data standards; health information technology C1 [Khozin, Sean; Blumenthal, Gideon; Keegan, Patricia; Pazdur, Richard] US FDA, Off Hematol & Oncol Prod, Silver Spring, MD USA. [Khomyanina, Alisa] IBM Corp, Armonk, NY USA. [Brodsky, Boris; Fitzmartin, Ronald] US FDA, Off Strateg Programs, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2015 VL 10 IS 9 SU 2 MA MINI29.09 BP S369 EP S371 PG 3 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DE1CX UT WOS:000370365101326 ER PT J AU Zeller, M AF Zeller, Mitch TI FDA Regulation of Tobacco Products in the US SO JOURNAL OF THORACIC ONCOLOGY LA English DT Meeting Abstract C1 [Zeller, Mitch] US FDA, Ctr Tobacco Prod, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2015 VL 10 IS 9 SU 2 MA MS06.03 BP S98 EP S98 PG 1 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DE1CX UT WOS:000370365100068 ER PT J AU Burcu, M Zito, JM McKean, S Warnock, R Herbert, P Verma, S Worrall, CM Chu, S Mohamadi, A AF Burcu, Mehmet Zito, Julie M. McKean, Stephen Warnock, Rob Herbert, Peter Verma, Sumit Worrall, Chris M. Chu, Steve Mohamadi, Ali TI The Effect of Medicaid Peer Review Prior Authorization Policies on Pediatric Use of Antipsychotic Medications SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Burcu, Mehmet; Zito, Julie M.] Univ Maryland, Pharmaceut Hlth Serv Res, Baltimore, MD 21201 USA. [McKean, Stephen; Warnock, Rob; Herbert, Peter; Verma, Sumit] Acumen LLC, Burlingame, CA USA. [Worrall, Chris M.; Chu, Steve] Ctr Medicare & Medicaid Serv, Washington, DC USA. [Mohamadi, Ali] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 SEP PY 2015 VL 24 SU 1 SI SI MA 28 BP 16 EP 17 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200029 ER PT J AU Wang, CL Kane, R Levenson, M Kelman, J Wernecke, M Lee, JY Worrall, C MaCurdy, T Graham, DJ AF Wang, Cunlin Kane, Robert Levenson, Mark Kelman, Jeffrey Wernecke, Mickel Lee, Joo-Yeon Worrall, Chris MaCurdy, Thomas Graham, David J. TI Risk of Major Adverse Cardiovascular Events and Transfusion Among US Hemodialysis Patients After CMS and FDA Policy Changes in 2011 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Wang, Cunlin; Kane, Robert; Levenson, Mark; Lee, Joo-Yeon; Graham, David J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Kelman, Jeffrey; Worrall, Chris] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. [Wernecke, Mickel; MaCurdy, Thomas] ACUMEN LLC, Burlingame, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 27 BP 16 EP 16 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200028 ER PT J AU Graham, DJ Howery, AE Major, JM Xie, DQ Bipat, V Moeny, D Voss, S Young, J Lan, L MaCurdy, TE Worrall, C Kelman, JA AF Graham, David J. Howery, Andrew E. Major, Jacqueline M. Xie, Diqiong Bipat, Vedita Moeny, David Voss, Stephen Young, Jessica Lan, Ling MaCurdy, Thomas E. Worrall, Chris Kelman, Jeffrey A. TI Risk of Esophageal or Gastric Cardia Cancer in Elderly Medicare Beneficiaries Treated with Oral Bisphosphonates SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Graham, David J.; Major, Jacqueline M.; Xie, Diqiong; Moeny, David; Voss, Stephen; Lan, Ling] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Howery, Andrew E.; Bipat, Vedita; Young, Jessica; MaCurdy, Thomas E.] Acumen LLC, Burlingame, CA USA. [MaCurdy, Thomas E.] Stanford Univ, Stanford, CA 94305 USA. [Worrall, Chris; Kelman, Jeffrey A.] Ctr Medicare Serv, Washington, DC USA. [Worrall, Chris; Kelman, Jeffrey A.] Ctr Medicaid Serv, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 51 BP 30 EP 31 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200052 ER PT J AU De Bruin, ML Ampadu, HH Hoekman, J Kurz, X Leufkens, HGM Sekine, S Dal Pan, G AF De Bruin, Marie L. Ampadu, Haggar H. Hoekman, Jarno Kurz, Xavier Leufkens, Hubert G. M. Sekine, Shohko Dal Pan, Gerald TI Data Driven Regulatory Science SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [De Bruin, Marie L.; Hoekman, Jarno; Leufkens, Hubert G. M.] Univ Utrecht, WHO Collaborating Ctr Pharmaceut Policy & Regulat, Utrecht, Netherlands. [Ampadu, Haggar H.] WHO Collaborating Ctr Advocacy & Training Pharmac, Accra, Ghana. [Kurz, Xavier] European Med Agcy, London, England. [Sekine, Shohko; Dal Pan, Gerald] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Sekine, Shohko] PMDA, Tokyo, Japan. RI Hoekman, Jarno/C-3287-2017 OI Hoekman, Jarno/0000-0002-2817-1229 NR 0 TC 0 Z9 0 U1 1 U2 1 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 SEP PY 2015 VL 24 SU 1 SI SI MA 78 BP 46 EP 46 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200079 ER PT J AU Ekezue, B Sridhar, G Forshee, R Selvam, N Anderson, S Menis, M AF Ekezue, Bola Sridhar, Gayathri Forshee, Richard Selvam, Nandini Anderson, Steven Menis, Mikhail TI Occurrence of Hemolytic Reactions (HRs) on the Same Day as Immune Globulin (IG) Product Administrations During 2008-2014 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Ekezue, Bola; Sridhar, Gayathri; Selvam, Nandini] HealthCore Inc, Govt & Acad Res, Alexandria, VA USA. [Forshee, Richard; Anderson, Steven; Menis, Mikhail] US FDA, CBER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 84 BP 49 EP 50 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200085 ER PT J AU Ekezue, B Sridhar, G Forshee, R Selvam, N Scott, D Anderson, S Menis, M AF Ekezue, Bola Sridhar, Gayathri Forshee, Richard Selvam, Nandini Scott, Dorothy Anderson, Steven Menis, Mikhail TI Occurrence of Acute Renal Failure (ARF) on the Same Day as Immune Globulin (IG) Product Administrations During 2008-2014 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Ekezue, Bola; Sridhar, Gayathri; Selvam, Nandini] HealthCore Inc, GAR, Alexandria, VA USA. [Forshee, Richard; Scott, Dorothy; Anderson, Steven; Menis, Mikhail] US FDA, CBER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 83 BP 49 EP 49 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200084 ER PT J AU Menis, M Anderson, SA McKean, S Warnock, R Ovanesov, MV Mintz, PD Verma, S Norton, N Kessler, Z Izurieta, HS Worrall, CM Kelman, JA Forshee, RA AF Menis, Mikhail Anderson, Steven A. McKean, Stephen Warnock, Rob Ovanesov, Mikhail V. Mintz, Paul D. Verma, Sumit Norton, Natalie Kessler, Zebulin Izurieta, Hector S. Worrall, Christopher M. Kelman, Jeffrey A. Forshee, Richard A. TI Clotting Factor Utilization Among the US Elderly as Recorded in Medicare Databases During 2008-2013 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Menis, Mikhail; Anderson, Steven A.; Ovanesov, Mikhail V.; Mintz, Paul D.; Izurieta, Hector S.; Forshee, Richard A.] US FDA, CBER, Silver Spring, MD USA. [McKean, Stephen; Warnock, Rob; Verma, Sumit; Norton, Natalie; Kessler, Zebulin] Acumen LLC, Burlingame, CA USA. [Worrall, Christopher M.; Kelman, Jeffrey A.] CMS, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 90 BP 53 EP 54 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200091 ER PT J AU Zhou, EH Kang, EM Seymour, S Goulding, M Iyasu, S AF Zhou, Esther H. Kang, Elizabeth M. Seymour, Sally Goulding, Margie Iyasu, Solomon TI The 2010 FDA Drug Safety Recommendations and LABA Dispensing Pattern Changes in Adult Asthma Patients During 2003-2012 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Zhou, Esther H.; Kang, Elizabeth M.; Goulding, Margie; Iyasu, Solomon] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Seymour, Sally] US FDA, Off New Drugs, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 120 BP 70 EP 70 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200120 ER PT J AU Segal, JB Daubresse, M Lee, CY Moechtar, M Duchter, S Jiang, WL Romanelli, R AF Segal, Jodi B. Daubresse, Matthew Lee, Chia-Ying Moechtar, Mischka Duchter, Sarah Jiang, Wenlei Romanelli, Robert TI Therapeutic class differences in generic usage SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Segal, Jodi B.; Daubresse, Matthew; Lee, Chia-Ying; Moechtar, Mischka] Johns Hopkins Univ, Baltimore, MD USA. [Romanelli, Robert] Palo Alto Med Fdn, Res Inst, Palo Alto, CA USA. [Duchter, Sarah; Jiang, Wenlei] US FDA, Off Gener Drugs, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 245 BP 137 EP 137 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200237 ER PT J AU Khokhar, B Park, Y Pradel, F Palumbo, F Kiptanui, Z Dutcher, S Jiang, WL Zuckerman, I AF Khokhar, Bilal Park, Yujin Pradel, Francoise Palumbo, Francis Kiptanui, Zippora Dutcher, Sarah Jiang, Wenlei Zuckerman, Ilene TI Patients' awareness of bioequivalence study methods supporting generic venlafaxine extended release (ER) tablet approval SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Khokhar, Bilal; Park, Yujin; Pradel, Francoise; Palumbo, Francis] Univ Maryland, Pharmaceut Hlth Serv, Baltimore, MD 21201 USA. [Kiptanui, Zippora; Zuckerman, Ilene] IMPAQ Int, Columbia, MD USA. [Dutcher, Sarah; Jiang, Wenlei] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 274 BP 153 EP 153 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200265 ER PT J AU Choi, Y Eworuke, E Segal, R AF Choi, Yoonyoung Eworuke, Efe Segal, Richard TI What explains the different rates of human papillomavirus vaccination among adolescent males and females in the United States? SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Choi, Yoonyoung; Eworuke, Efe; Segal, Richard] Univ Florida, Coll Pharm, Dept Pharmaceut Outcomes & Policy, Gainesville, FL USA. [Eworuke, Efe] US FDA, Div Epidemiol 2, Off Surveillance & Epidemiol, Off Pharmacovigilance & Epidemiol,Ctr Drug Evalua, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 309 BP 173 EP 173 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200300 ER PT J AU Hampp, C Greene, P Pinheiro, SP AF Hampp, Christian Greene, Patty Pinheiro, Simone P. TI Use of Prescription Drug Samples in the United States and Implications for Pharmacoepidemiologic Studies SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Hampp, Christian; Greene, Patty; Pinheiro, Simone P.] US FDA, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 364 BP 204 EP 205 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200355 ER PT J AU Schneeweiss, S Gagne, J Brown, J Rassen, J Eichler, HG Dal Pan, G Bartels, D AF Schneeweiss, Sebastian Gagne, Joshua Brown, Jeffrey Rassen, Jeremy Eichler, Hans-Georg Dal Pan, Geral Bartels, Dorothee TI Pragmatic Randomized Trials in Practice: How Can We Overcome the Hurdles? (Sponsored by the CER Special Interest Group) SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Schneeweiss, Sebastian; Gagne, Joshua] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pharmacoepidemiol, Boston, MA 02115 USA. [Brown, Jeffrey] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Rassen, Jeremy] Aetion Inc, New York, NY USA. [Eichler, Hans-Georg] European Med Agcy, London, England. [Dal Pan, Geral] US FDA, Off Surveillance & Epidemiol, Washington, DC 20204 USA. [Bartels, Dorothee] Boehringer Ingelheim KG, Pharmacoepidemiol, Ingelheim, Germany. RI Schneeweiss, Sebastian/C-2125-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 421 BP 238 EP 238 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200412 ER PT J AU Andrade, S Perez-Gutthann, S Hua, W Kawai, A Martin, D Reichman, M Toh, D AF Andrade, Susan Perez-Gutthann, Susana Hua, Wei Kawai, Alison Martin, David Reichman, Marsha Toh, Darren TI Building a Sustainable Surveillance System to Monitor the Use and Safety of Medical Products in Pregnancy SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Andrade, Susan] Meyers Primary Care Inst, Worcester, MA USA. [Perez-Gutthann, Susana] RTI Hlth Solut, Barcelona, Spain. [Hua, Wei; Reichman, Marsha] US FDA, Silver Spring, MD USA. [Kawai, Alison; Toh, Darren] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Kawai, Alison; Toh, Darren] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Martin, David] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 423 BP 239 EP 240 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200414 ER PT J AU Kelsh, M Ko, CW Chia, V Przepiorka, D Suissa, S AF Kelsh, Michael Ko, Chia-Wen Chia, Victoria Przepiorka, Donna Suissa, Samy TI Historical Comparator Studies: Strengths, Limitations, and Analytical Considerations in Using Historical Pooled Clinical Data for Evaluating Efficacy and Safety of New Therapies SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Kelsh, Michael; Chia, Victoria] Amgen Inc, Ctr Observat Res, Thousand Oaks, CA 91320 USA. [Ko, Chia-Wen; Przepiorka, Donna] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Suissa, Samy] McGill Univ, Montreal, PQ, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 424 BP 240 EP 240 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200415 ER PT J AU Knox, CA Dal Pan, GJ Coplan, PM Lanes, SF AF Knox, Caitlin A. Dal Pan, Gerald J. Coplan, Paul M. Lanes, Stephan F. TI Evaluating Risk Evaluation and Mitigation Strategies (REMS): Lessons Learned and Future Opportunities with a Focus on Opioid Analgesics SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Knox, Caitlin A.; Lanes, Stephan F.] HealthCore, Safety & Epidemiol, Andover, MA USA. [Dal Pan, Gerald J.] US FDA, Silver Spring, MD USA. [Coplan, Paul M.] Purdue Pharma LP, Stamford, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 427 BP 242 EP 242 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200418 ER PT J AU Pitts, MR Mott, K Reichman, ME Ceresa, C Andrade, SE Kieswetter, C Toh, S Houstoun, M Haffenreffer, K AF Pitts, Marilyn R. Mott, Katrina Reichman, Marsha E. Ceresa, Carrie Andrade, Susan E. Kieswetter, Caren Toh, Sengwee Houstoun, Monika Haffenreffer, Katherine TI Patterns of Anti-epileptic Drug (AED) Use during Pregnancy in the Mini-Sentinel Database (MSDD) among Women Delivering a Liveborn Infant SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Pitts, Marilyn R.; Mott, Katrina; Reichman, Marsha E.; Ceresa, Carrie; Kieswetter, Caren; Houstoun, Monika] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Andrade, Susan E.] Meyers Primary Care Inst, Worcester, MA USA. [Toh, Sengwee; Haffenreffer, Katherine] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 433 BP 245 EP 246 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200424 ER PT J AU Mott, K Reichman, ME Toh, D Houstoun, M Pitts, M Kieswetter, C Ceresa, C Haffenreffer, K Andrade, SE AF Mott, Katrina Reichman, Marsha E. Toh, Darren Houstoun, Monika Pitts, Marilyn Kieswetter, Caren Ceresa, Carrie Haffenreffer, Katherine Andrade, Susan E. TI Patterns of Antidiabetic Agent Use During Pregnancy among Women Delivering a Liveborn Infant in the Mini-Sentinel Database (MSDD) SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Mott, Katrina; Reichman, Marsha E.; Houstoun, Monika; Pitts, Marilyn; Kieswetter, Caren; Ceresa, Carrie] US FDA, Silver Spring, MD USA. [Toh, Darren; Haffenreffer, Katherine] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Toh, Darren; Haffenreffer, Katherine] Harvard Pilgrim Healthcare Inst, Boston, MA USA. [Andrade, Susan E.] Meyers Primary Care Inst, Worcester, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 438 BP 248 EP 249 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200429 ER PT J AU Knox, CA Hampp, C Brumback, B Xu, XH Segal, R Winterstein, AG AF Knox, Caitlin A. Hampp, Christian Brumback, Babette Xu, Xiaohui Segal, Richard Winterstein, Almut G. TI Risk of Preeclampsia among Live Births Exposed to Anti-diabetic Agents during the First Trimester of Pregnancy SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Knox, Caitlin A.; Segal, Richard; Winterstein, Almut G.] Univ Florida, Pharmaceut Outcomes & Policy, Gainesville, FL USA. [Knox, Caitlin A.] HealthCore, Safety & Epidemiol, Andover, MA USA. [Hampp, Christian] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Brumback, Babette] Univ Florida, Biostat, Gainesville, FL USA. [Xu, Xiaohui; Winterstein, Almut G.] Univ Florida, Epidemiol, Gainesville, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 440 BP 249 EP 250 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200431 ER PT J AU Knox, CA Hampp, C Brumback, B Xu, XH Segal, R Winterstein, AG AF Knox, Caitlin A. Hampp, Christian Brumback, Babette Xu, Xiaohui Segal, Richard Winterstein, Almut G. TI Risk of Preterm Delivery among Live Births Exposed to Anti-diabetic Agents during the First Trimester of Pregnancy SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Knox, Caitlin A.; Segal, Richard; Winterstein, Almut G.] Univ Florida, Pharmaceut Outcomes & Policy, Gainesville, FL USA. [Knox, Caitlin A.] HealthCore, Safety & Epidemiol, Andover, MA USA. [Hampp, Christian] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Brumback, Babette] Univ Florida, Biostat, Gainesville, FL USA. [Xu, Xiaohui; Winterstein, Almut G.] Univ Florida, Epidemiol, Gainesville, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 439 BP 249 EP 249 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200430 ER PT J AU Hansen, C Andrade, SE Freiman, H Dublin, S Haffenreffer, K Cooper, WO Cheetham, TC Toh, D Li, DK Raebel, MA Kuntz, JL Perrin, N Rosales, AG Carter, S Pawloski, PA Maloney, EM Graham, DJ Sahin, L Scott, PE Yap, J Davis, R AF Hansen, Craig Andrade, Susan E. Freiman, Heather Dublin, Sascha Haffenreffer, Katie Cooper, William O. Cheetham, T. Craig Toh, Darren Li, De-Kun Raebel, Marsha A. Kuntz, Jennifer L. Perrin, Nancy Rosales, A. Gabriela Carter, Shelley Pawloski, Pamala A. Maloney, Elizabeth M. Graham, David J. Sahin, Leyla Scott, Pamela E. Yap, John Davis, Robert TI Sulfonamide Use during the First Trimester of Pregnancy and Risk of Selected Congenital Anomalies among Live Births SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Andrade, Susan E.] Univ Massachusetts, Meyers Primary Care Inst, Med Sch Worcester, Worcester, MA 01605 USA. [Freiman, Heather] Emory Univ, Sch Med, Dept Emergency Med, Atlanta, GA USA. [Dublin, Sascha] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Haffenreffer, Katie; Toh, Darren] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Haffenreffer, Katie; Toh, Darren] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Cooper, William O.] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA. [Cooper, William O.] Vanderbilt Univ, Sch Med, Dept Hlth Policy, Nashville, TN 37212 USA. [Cheetham, T. Craig] Kaiser Permanente So Calif, Dept Res & Evaluat, Pasadena, CA 91101 USA. [Li, De-Kun] Kaiser Permanente, Div Res, Kaiser Fdn, Res Inst, Oakland, CA USA. [Raebel, Marsha A.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. [Kuntz, Jennifer L.; Perrin, Nancy; Rosales, A. Gabriela] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR USA. [Carter, Shelley] LCF Res, Albuquerque, NM USA. [Pawloski, Pamala A.] HealthPartners Inst Educ & Res, Minneapolis, MN USA. [Maloney, Elizabeth M.; Graham, David J.] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Sahin, Leyla] US FDA, Off New Drugs, Silver Spring, MD USA. [Scott, Pamela E.] US FDA, Off Womens Hlth, Silver Spring, MD USA. [Yap, John] US FDA, Off Biostat, Silver Spring, MD USA. [Davis, Robert] Univ Tennessee, Ctr Biomed Informat, Memphis, TN USA. [Davis, Robert] Univ Tennessee, Dept Pediat, Memphis, TN USA. [Hansen, Craig] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 442 BP 250 EP 251 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200433 ER PT J AU Knox, CA Hampp, C Brumback, B Xu, XH Segal, R Winterstein, AG AF Knox, Caitlin A. Hampp, Christian Brumback, Babette Xu, Xiaohui Segal, Richard Winterstein, Almut G. TI Risk of Cesarean Section Delivery among Live Births Exposed to Anti-Diabetic Agents during the First Trimester of Pregnancy SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Knox, Caitlin A.; Segal, Richard; Winterstein, Almut G.] Univ Florida, Pharmaceut Outcomes & Policy, Gainesville, FL USA. [Knox, Caitlin A.] HealthCore, Safety & Epidemiol, Andover, MA USA. [Hampp, Christian] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Brumback, Babette] Univ Florida, Biostat, Gainesville, FL USA. [Xu, Xiaohui; Winterstein, Almut G.] Univ Florida, Epidemiol, Gainesville, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 441 BP 250 EP 250 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200432 ER PT J AU Eworuke, E Moeny, DG AF Eworuke, Efe Moeny, David G. TI Risk Factors Associated with Early Intrauterine Device Insertion after Delivery SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Eworuke, Efe; Moeny, David G.] US FDA, Div Epidemiol 2, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol,Ctr Drug Evaluat & R, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 450 BP 256 EP 256 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200441 ER PT J AU Gelperin, K Hammad, H Bird, S Hampp, C Leishear, K Sahin, L Taylor, L AF Gelperin, Kate Hammad, Hoda Bird, Steven Hampp, Christian Leishear, Kira Sahin, Leyla Taylor, Lockwood TI Systematic Review of Pregnancy Exposure Registries: Fetal/Infant Outcomes, Target Sample Size, and Comparators SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Gelperin, Kate; Hammad, Hoda; Bird, Steven; Hampp, Christian; Leishear, Kira; Taylor, Lockwood] US FDA, Off Pharmacovigilance & Epidemiol, Silver Spring, MD USA. [Sahin, Leyla] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 475 BP 271 EP 271 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200466 ER PT J AU McMahon, AW Murphy, MD AF McMahon, Ann W. Murphy, M. Dianne TI Stratification, Hypothesis Testing, and Clinical Trial Simulation in Pediatric Drug Development SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [McMahon, Ann W.; Murphy, M. Dianne] US FDA, Off Pediat Therapeut, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 489 BP 279 EP 280 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200480 ER PT J AU Torosyan, Y Karapetyan, T Loyo-Berrios, N Marinac-Dabic, D AF Torosyan, Yelizaveta Karapetyan, Tigran Loyo-Berrios, Nilsa Marinac-Dabic, Danica TI NIS/AHRQ-derived Epidemiologic Evidence on Modifying Effects of Sex and Race on Arthroplasty-related Outcomes SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Torosyan, Yelizaveta; Karapetyan, Tigran; Loyo-Berrios, Nilsa; Marinac-Dabic, Danica] US FDA, Div Epidemiol, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 511 BP 292 EP 292 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200502 ER PT J AU Hoffman, SR Tang, EA Laschinger, JC AF Hoffman, Sarah R. Tang, Erika Avila Laschinger, John C. TI Extracorporeal Membrane Oxygenation (ECMO) Use among Children and Adults in the United States, 2009-2012 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Hoffman, Sarah R.; Tang, Erika Avila; Laschinger, John C.] US FDA, CDRH, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 523 BP 299 EP 299 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200514 ER PT J AU Reichman, ME Wernecke, M Yap, J Chillarige, Y Liao, JM Keeton, S Goulding, M Mott, K Kelman, JA Graham, DJ AF Reichman, Marsha E. Wernecke, Michael Yap, John Chillarige, Yoganand Liao, Jiemin Keeton, Stephine Goulding, Margie Mott, Katrina Kelman, Jeffrey A. Graham, David J. TI Drug-associated Angioedema: Effect Modification by Race SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Reichman, Marsha E.; Yap, John; Keeton, Stephine; Goulding, Margie; Mott, Katrina; Graham, David J.] US FDA, Silver Spring, MD USA. [Wernecke, Michael; Chillarige, Yoganand; Liao, Jiemin] Acumen LLC, Burlingame, CA USA. [Kelman, Jeffrey A.] Ctr Medicare & Medicaid Serv, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 546 BP 312 EP 312 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200537 ER PT J AU Chien, HC Yang, YHK Bai, JPF AF Chien, Hsu-Chih Yang, Yea-Huei Kao Bai, Jane P. F. TI Cardiotoxicity of Adjuvant Trastuzumab in Taiwan Breast Cancer Patients: A Population-based Study SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Chien, Hsu-Chih; Yang, Yea-Huei Kao] Natl Cheng Kung Univ, Inst Clin Pharm & Pharmaceu Sci, Tainan 701, Taiwan. [Yang, Yea-Huei Kao] Natl Cheng Kung Univ, Hlth Outcome Res Ctr, Tainan 701, Taiwan. [Bai, Jane P. F.] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 SEP PY 2015 VL 24 SU 1 SI SI MA 684 BP 390 EP 390 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980200674 ER PT J AU Louik, C Sahin, L Ephross, S Colvin, L Cooper, W AF Louik, Carol Sahin, Leyla Ephross, Sara Colvin, Lyn Cooper, William TI The New FDA Pregnancy Label-And How to Fill It (Sponsored by the Medications in Pregnancy Special Interest Group) SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Louik, Carol] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Sahin, Leyla] US FDA, Div Pediat & Maternal Hlth, Silver Spring, MD USA. [Ephross, Sara] GlaxoSmithKline, Worldwide Epidemiol, Res Triangle Pk, NC USA. [Colvin, Lyn] Telethon Kids Inst, Subiaco, WA, Australia. [Cooper, William] Vanderbilt Univ, Nashville, TN 37235 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 SEP PY 2015 VL 24 SU 1 SI SI MA 725 BP 413 EP 414 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980201017 ER PT J AU Arlett, P Kurz, X Schneeweiss, S Roddam, A Raine, J Dal Pan, G AF Arlett, Peter Kurz, Xavier Schneeweiss, Sebastian Roddam, Andrew Raine, June Dal Pan, Gerald TI Protecting and Promoting Public Health through Pharmacovigilance: Approaches for Measuring the Impact of Pharmacovigilance Systems SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Arlett, Peter; Kurz, Xavier] European Med Agcy, London, England. [Schneeweiss, Sebastian] Harvard Univ, Sch Med, Boston, MA USA. [Roddam, Andrew] GSK, Uxbridge, Middx, England. [Raine, June] MHRA, London, England. [Dal Pan, Gerald] US FDA, CDER, Silver Spring, MD USA. RI Schneeweiss, Sebastian/C-2125-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 728 BP 415 EP 416 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980201020 ER PT J AU Reichman, ME Bartels, D Carnahan, RM Chrischilles, EA Gagne, JJ Go, AS Toh, D AF Reichman, Marsha E. Bartels, Dorothee Carnahan, Ryan M. Chrischilles, Elizabeth A. Gagne, Joshua J. Go, Alan S. Toh, Darren TI Safety Surveillance of New Oral Anticoagulants within the Mini-Sentinel Program-Progress, Challenges, and Future Directions SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Reichman, Marsha E.] US FDA, Silver Spring, MD USA. [Bartels, Dorothee] Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany. [Carnahan, Ryan M.; Chrischilles, Elizabeth A.] Univ Iowa, Iowa City, IA USA. [Gagne, Joshua J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Go, Alan S.] Kaiser Permanente No Calif, Oakland, CA USA. [Toh, Darren] Harvard Univ, Sch Med, Boston, MA USA. [Toh, Darren] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 731 BP 417 EP 417 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980201023 ER PT J AU Stone, MB Crentsil, V AF Stone, Marc B. Crentsil, Victor TI Tempest in a TE-Cup: A Case of Publication Bias in Pharmacoepidemiology SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Stone, Marc B.; Crentsil, Victor] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 743 BP 424 EP 425 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980201035 ER PT J AU Graham, DJ Nelson, LM Yang, J Calia, K Wyman, J Howery, AE MaCurdy, TE Worrall, C Kelman, JA AF Graham, David J. Nelson, Lorene M. Yang, Jeff Calia, Katlyn Wyman, Jason Howery, Andrew E. MaCurdy, Thomas E. Worrall, Chris Kelman, Jeffrey A. TI Diabetes, Pancreatitis, and Pancreatic Cancer Risk: Implications for Study of Associations Between Diabetes Medications and Pancreatic Cancer SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Graham, David J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Nelson, Lorene M.; MaCurdy, Thomas E.] Stanford Univ, Stanford, CA 94305 USA. [Yang, Jeff; Calia, Katlyn; Wyman, Jason; Howery, Andrew E.; MaCurdy, Thomas E.] Acumen LLC, Burlingame, CA USA. [Worrall, Chris; Kelman, Jeffrey A.] Ctr Medicare Serv, Washington, DC USA. [Worrall, Chris; Kelman, Jeffrey A.] Ctr Medicaid Serv, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 751 BP 429 EP 429 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980201043 ER PT J AU Narayanan, S Rucker, NL Bullman, WR Alexander, GC Rausch, P AF Narayanan, S. Rucker, N. L. Bullman, W. R. Alexander, G. C. Rausch, P. TI Awareness of Medication Safety Warnings: Results from a Survey of Patients and Caregivers in the USA SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Narayanan, S.] Ipsos Healthcare, Evidence Generat Value & Access COE, Washington, DC USA. [Rucker, N. L.] Enhance Value, Bethesda, MD USA. [Bullman, W. R.] NCPIE, Rockville, MD USA. [Alexander, G. C.] Johns Hopkins Univ, Ctr Drug Safety & Effectiveness, Baltimore, MD USA. [Rausch, P.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 757 BP 432 EP 433 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980201049 ER PT J AU Narayanan, S Rucker, NL Alexander, GC Bullman, WR Rausch, P AF Narayanan, S. Rucker, N. L. Alexander, G. C. Bullman, W. R. Rausch, P. TI Perceptions about Medication Safety Warnings and Communication with Patients: Results from a Survey of Healthcare Providers in the USA SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Narayanan, S.] Ipsos Healthcare, Evidence Generat Value & Access COE, Washington, DC USA. [Rucker, N. L.] Enhance Value, Bethesda, MD USA. [Alexander, G. C.] Johns Hopkins Univ, Ctr Drug Safety & Effectiveness, Baltimore, MD USA. [Bullman, W. R.] NCPIE, Rockville, MD USA. [Rausch, P.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 758 BP 433 EP 434 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980201050 ER PT J AU Sekine, S Pinnow, EE Kurtzig, R Wu, E Marni, H Dal Pan, G AF Sekine, Shohko Pinnow, Ellen E. Kurtzig, Rebecca Wu, Eileen Marni, Hall Dal Pan, Gerald TI Impact of Scheduled Post-Marketing Safety Summary Analyses on Regulatory Actions SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Sekine, Shohko] Pharmaceut & Med Devices Agcy, Tokyo, Japan. [Pinnow, Ellen E.; Kurtzig, Rebecca; Wu, Eileen; Marni, Hall; Dal Pan, Gerald] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 776 BP 443 EP 444 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980201068 ER PT J AU Bohn, J Kortepeter, C Munoz, M Simms, K Montenegro, S Dal Pan, G AF Bohn, Justin Kortepeter, Cindy Munoz, Monica Simms, Kelley Montenegro, Susan Dal Pan, Gerald TI Patterns in Spontaneous Adverse Event Reporting Among Branded and Generic Antiepileptic Drugs SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Bohn, Justin] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Bohn, Justin] Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02115 USA. [Bohn, Justin] Harvard Univ, Sch Med, Boston, MA USA. [Bohn, Justin; Kortepeter, Cindy; Munoz, Monica; Simms, Kelley; Montenegro, Susan; Dal Pan, Gerald] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 791 BP 452 EP 452 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980201083 ER PT J AU Yih, WK Zichittella, L Sandhu, SK Nguyen, M Kulldorff, M Cole, DV Jin, R Kawai, AT McMahill-Walraven, CN Selvam, N Selvan, MS Lee, GM AF Yih, W. Katherine Zichittella, Lauren Sandhu, Sukhminder K. Nguyen, Michael Kulldorff, Martin Cole, David V. Jin, Robert Kawai, Alison T. McMahill-Walraven, Cheryl N. Selvam, Nandini Selvan, Mano S. Lee, Grace M. TI Using the Earliest Available Claims Data for Influenza Vaccine Safety Surveillance in Mini-Sentinel SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Yih, W. Katherine; Zichittella, Lauren; Kulldorff, Martin; Cole, David V.; Jin, Robert; Kawai, Alison T.; Lee, Grace M.] Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Yih, W. Katherine; Zichittella, Lauren; Kulldorff, Martin; Cole, David V.; Jin, Robert; Kawai, Alison T.; Lee, Grace M.] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Sandhu, Sukhminder K.; Nguyen, Michael] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [McMahill-Walraven, Cheryl N.] Aetna, Data Sci, Blue Bell, PA USA. [Selvam, Nandini] HealthCore, Govt & Acad Res, Alexandria, VA USA. [Selvan, Mano S.] Humana, Comprehens Hlth Insights, Louisville, KY USA. [Lee, Grace M.] Childrens Hosp Boston, Div Infect Dis, Boston, MA USA. [Lee, Grace M.] Childrens Hosp Boston, Dept Lab Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 798 BP 455 EP 456 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980201089 ER PT J AU West, SL Lefebvre, C McCormack, LA Taylor, O Rausch, P AF West, Suzanne L. Lefebvre, Craig McCormack, Lauren A. Taylor, Olivia Rausch, Paula TI Qualitative Research with Primary Care Clinicians and Neurologists Regarding Drug Safety Communications SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [West, Suzanne L.; Lefebvre, Craig; McCormack, Lauren A.; Taylor, Olivia] RTI Int, Res Triangle Pk, NC USA. [Rausch, Paula] US FDA, Div Hlth Commun, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2015 VL 24 SU 1 SI SI MA 816 BP 466 EP 467 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DD5QW UT WOS:000369980201107 ER PT J AU Menis, M Forshee, R McKean, S Warnock, R Verma, S Heeter, WA Kessler, Z Izurieta, HS Mintz, PD Worrall, CM Kelman, JA Anderson, SA AF Menis, M. Forshee, R. McKean, S. Warnock, R. Verma, S. Heeter, W. A. Kessler, Z. Izurieta, H. S. Mintz, P. D. Worrall, C. M. Kelman, J. A. Anderson, S. A. TI Transfusion-Related Acute Lung Injury (TRALI) Occurrence among Female Medicaid Beneficiaries of Childbearing Age, 10-55 Years Old, as Recorded by Large Administrative Databases, During 2007-2010 SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 24-27, 2015 CL Anaheim, CA SP AABB C1 [Menis, M.; Forshee, R.; Izurieta, H. S.; Mintz, P. D.; Anderson, S. A.] FDA CBER, Silver Spring, MD USA. [McKean, S.; Warnock, R.; Verma, S.; Heeter, W. A.; Kessler, Z.] Acumen LLC, Burlingame, CA USA. [Worrall, C. M.; Kelman, J. A.] CMS, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2015 VL 55 SU 3 SI SI MA S77-040B BP 40A EP 41A PG 2 WC Hematology SC Hematology GA DD5GS UT WOS:000369951500084 ER PT J AU Simonetti, A Ezzeldin, H Menis, M McKean, S Izurieta, HS Anderson, SA Forshee, R AF Simonetti, A. Ezzeldin, H. Menis, M. McKean, S. Izurieta, H. S. Anderson, S. A. Forshee, R. TI How Would Strategies for Transfusing Critically Ill Patients with Younger Blood Affect the US Blood Supply? SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 24-27, 2015 CL Anaheim, CA SP AABB C1 [Simonetti, A.; Ezzeldin, H.; Menis, M.; Izurieta, H. S.; Anderson, S. A.; Forshee, R.] US FDA, Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, Silver Spring, MD USA. [McKean, S.] Acumen LLC, Burlingame, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2015 VL 55 SU 3 SI SI MA SP299 BP 177A EP 178A PG 2 WC Hematology SC Hematology GA DD5GS UT WOS:000369951500389 ER PT J AU Lemke, RJ Burkholder, WJ Conway, CE Lando, AM Valcin, S AF Lemke, Robert J. Burkholder, William J. Conway, Charlotte E. Lando, Amy M. Valcin, Samuel TI An Analysis of Pet Food Label Usage SO JOURNAL OF CONSUMER AFFAIRS LA English DT Article ID ADULTS; CATS; DOGS AB We use the 2008 Health and Diet Survey to investigate the extent to which pet owners consult pet food labels. We find that pet food label usage has not penetrated shopping behavior to the degree that using the Nutrition Facts label has for human food purchases. While we find no gender difference in using pet food labels among dog owners, women may be less likely than men to consult labels among cat owners. The data also suggest that usage increases when at least three pets are owned; cat owners consult pet food labels less frequently than dog owners; and usage is not dependent on the type of product purchased. C1 [Lemke, Robert J.] Lake Forest Coll, Econ, Lake Forest, IL 60045 USA. [Valcin, Samuel] Lake Forest Coll, Lake Forest, IL USA. [Burkholder, William J.; Conway, Charlotte E.] US FDA, Ctr Vet Med, Rockville, MD 20857 USA. [Lando, Amy M.] US FDA, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. RP Lemke, RJ (reprint author), Lake Forest Coll, Econ, Lake Forest, IL 60045 USA. EM lemke@lakeforest.edu; william.burkholder@fda.hhs.gov; charlotte.conway@fda.hhs.gov; Amy.Lando@fda.hhs.gov; valcin@lakeforest.edu FU Richter Scholar Mentorship Program at Lake Forest College FX Robert J. Lemke (lemke@lakeforest.edu) is a Professor of Economics and Samuel Valcin (valcin@lakeforest.edu) is a Student, both at Lake Forest College. Charlotte E. Conway (charlotte.conway@fda.hhs.gov) is an Animal Scientist and William J. Burkholder (william.burkholder@fda.hhs.gov) is a Veterinary Medical Officer and Board Certified Veterinary Nutritionist, both at FDA Center for Veterinary Medicine. Amy M. Lando (Amy.Lando@fda.hhs.gov) is a Consumer Science Specialist at FDA Center for Food Safety and Applied Nutrition. The Richter Scholar Mentorship Program at Lake Forest College provided financial support to Lemke and Valcin. All errors are our own. NR 12 TC 0 Z9 0 U1 4 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-0078 EI 1745-6606 J9 J CONSUM AFF JI J. Consum. Aff. PD FAL PY 2015 VL 49 IS 3 BP 627 EP 638 DI 10.1111/joca.12076 PG 12 WC Business; Economics SC Business & Economics GA DA2WR UT WOS:000367658400007 ER PT J AU Gray, MD Leonard, SR Lacher, DW Lampel, KA Alam, MT Morris, JG Ali, A LaBreck, PT Maurelli, AT AF Gray, Miranda D. Leonard, Susan R. Lacher, David W. Lampel, Keith A. Alam, Meer T. Morris, J. Glenn, Jr. Ali, Afsar LaBreck, Patrick T. Maurelli, Anthony T. TI Stx-Producing Shigella Species From Patients in Haiti: An Emerging Pathogen With the Potential for Global Spread SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE bacteriophage; Haiti; Shiga toxin; Shigella ID HEMOLYTIC-UREMIC SYNDROME; SHIGA-TOXIN; FLEXNERI; TRAVEL; GENES AB Shiga toxins (Stx) are commonly produced by Shigella dysenteriae serotype 1 and Stx-producing Escherichia coli. However, the toxin genes have been detected in additional Shigella species. We recently reported the emergence of Stx-producing Shigella in travelers in the United States and France who had recently visited Hispaniola (Haiti and the Dominican Republic). In this study, we confirm this epidemiological link by identifying Stx-producing Shigella from Haitian patients attending clinics near Port-au-Prince. We also demonstrate that the bacteriophage encoding Stx is capable of dissemination to stx-negative Shigella species found in Haiti, suggesting that Stx-producing Shigella may become more widespread within that region. C1 [Gray, Miranda D.; LaBreck, Patrick T.; Maurelli, Anthony T.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Leonard, Susan R.; Lacher, David W.; Lampel, Keith A.] US FDA, Ctr Food Safety & Nutr, Laurel, MD USA. [Alam, Meer T.; Morris, J. Glenn, Jr.; Ali, Afsar] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. [Alam, Meer T.; Ali, Afsar] Univ Florida, Coll Publ Hlth & Hlth Profess, Dept Environm & Global Hlth, Gainesville, FL USA. RP Maurelli, AT (reprint author), Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. EM anthony.maurelli@usuhs.edu NR 15 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD FAL PY 2015 VL 2 IS 4 DI 10.1093/ofid/ofv134 PG 5 WC Infectious Diseases SC Infectious Diseases GA CX6BY UT WOS:000365787400011 ER PT J AU Chan, VC La Grenade, L Diak, IL Levin, RL AF Chan, Vicky C. La Grenade, Lois Diak, Ida-Lina Levin, Robert L. TI US Food and Drug Administration Warning About the Risk of Drug Reaction with Eosinophilia and Systemic Symptoms With Ziprasidone SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Letter DE Antipsychotics ID INDUCED HYPERSENSITIVITY SYNDROME; DRESS SYNDROME; RASH; UPDATE C1 [Chan, Vicky C.; La Grenade, Lois; Diak, Ida-Lina; Levin, Robert L.] US FDA, Div Pharmacovigilance, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Chan, VC (reprint author), US FDA, Div Pharmacovigilance, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM vicky.chan@fda.hhs.gov NR 15 TC 2 Z9 2 U1 0 U2 1 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD SEP PY 2015 VL 76 IS 9 BP E1138 EP E1139 DI 10.4088/JCP.15l09921 PG 2 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA CX0UM UT WOS:000365412500011 PM 26455682 ER PT J AU Skinner, C Zhang, GD Patfield, S He, XH AF Skinner, Craig Zhang, Guodong Patfield, Stephanie He, Xiaohua TI An In Vitro Combined Antibiotic-Antibody Treatment Eliminates Toxicity from Shiga Toxin-Producing Escherichia coli SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; LACTAMASE-PRODUCING ENTEROBACTERIACEAE; CLOSTRIDIUM-DIFFICILE INFECTION; UNITED-STATES; MONOCLONAL-ANTIBODIES; TIGECYCLINE; O157-H7; STRAINS; GENE; IDENTIFICATION AB Treating Shiga toxin-producing Escherichia coli (STEC) gastrointestinal infections is difficult. The utility of antibiotics for STEC treatment is controversial, since antibiotic resistance among STEC isolates is widespread and certain antibiotics dramatically increase the expression of Shiga toxins (Stxs), which are some of the most important virulence factors in STEC. Stxs contribute to life-threatening hemolytic uremic syndrome (HUS), which develops in considerable proportions of patients with STEC infections. Understanding the antibiotic resistance profiles of STEC isolates and the Stx induction potential of promising antibiotics is essential for evaluating any antibiotic treatment of STEC. In this study, 42 O157:H7 or non-O157 STEC isolates (including the "big six" serotypes) were evaluated for their resistance against 22 antibiotics by using an antibiotic array. Tigecycline inhibited the growth of all of the tested STEC isolates and also inhibited the production of Stxs (Stx2 in particular). In combination with neutralizing antibodies to Stx1 and Stx2, the tigecycline-antibody treatment fully protected Vero cells from Stx toxicity, even when the STEC bacteria and the Vero cells were cultured together. The combination of an antibiotic such as tigecycline with neutralizing antibodies presents a promising strategy for future STEC treatments. C1 [Skinner, Craig; Patfield, Stephanie; He, Xiaohua] ARS, Western Reg Res Ctr, USDA, Albany, CA 94710 USA. [Zhang, Guodong] US FDA, Ctr Food Safety & Appl Nutr, Div Microbiol, College Pk, MD USA. RP He, XH (reprint author), ARS, Western Reg Res Ctr, USDA, Albany, CA 94710 USA. EM xiaohua.he@ari.usda.gov FU USDA-ARS National Program [NP108, 5325-42000-048-00D] FX This project was supported by USDA-ARS National Program NP108 (CRIS project 5325-42000-048-00D). NR 44 TC 1 Z9 1 U1 0 U2 2 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 SEP PY 2015 VL 59 IS 9 BP 5435 EP 5444 DI 10.1128/AAC.00763-15 PG 10 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA CV5XD UT WOS:000364343900043 PM 26100707 ER PT J AU Green, MD AF Green, Martin D. TI Acute Phase Responses to Novel, Investigational Vaccines in Toxicology Studies: The Relationship Between C-Reactive Protein and Other Acute Phase Proteins SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Article DE C-reactive protein; acute-phase response; toxicology studies; rabbit ID SICKNESS BEHAVIOR; MECHANISMS; RABBITS; LESIONS AB The objective of this study was to determine the effects of investigational vaccine candidates on acute-phase proteins (APPs) as determined in GLP toxicology studies. Sixty-four GLP toxicity studies, which were submitted to the Food and Drug Administration from 2008 to 2012 in support of proposed clinical investigations, were reviewed and entered into a database. These studies employed the intramuscular route of injection and were conducted using New Zealand White rabbits. A retrospective review of these GLP toxicity studies was conducted to evaluate the changes in plasma levels of C-reactive protein (CRP), fibrinogen, and albumin as APPs following the administration of various investigational vaccines. The incidence and intensity of responses associated with acute-phase responses both positive and negative were observed to increase in animals when treated with vaccines containing more potent immunological components such as novel adjuvants that activate Toll-like receptors in the investigational vaccine products. Changes in plasma levels of CRP were prominent among these responses and provided a basis to propose a classification scheme of H, M, L, and N responding groups. These changes in plasma proteins reflect an activation of the acute-phase response and indicate increasing levels of systemic inflammation, which potentially may be correlated with important clinical adverse events. C1 [Green, Martin D.] US FDA, Div Vaccines & Related Prod Applicat, Off Vaccines, Ctr Biol Evaluat & Review, Rockville, MD 20993 USA. RP Green, MD (reprint author), US FDA, 10903 New Hampshire Ave W071,G112 Silver Spring, Rockville, MD 20993 USA. EM martin.green@fda.hhs.gov NR 11 TC 3 Z9 3 U1 5 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD SEP-OCT PY 2015 VL 34 IS 5 BP 379 EP 383 DI 10.1177/1091581815598750 PG 5 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CV0YF UT WOS:000363979100001 PM 26268767 ER PT J AU Junod, SW AF Junod, Suzanne White TI Toxicants, Health, and Regulation since 1945 SO ISIS LA English DT Book Review C1 [Junod, Suzanne White] US FDA, Rockville, MD 20857 USA. RP Junod, SW (reprint author), US FDA, Rockville, MD 20857 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0021-1753 EI 1545-6994 J9 ISIS JI Isis PD SEP PY 2015 VL 106 IS 3 BP 742 EP 743 DI 10.1086/683415 PG 3 WC History & Philosophy Of Science SC History & Philosophy of Science GA CV7BZ UT WOS:000364428500055 ER PT J AU Mosquera, A Braun, M Hulett, M Ryszka, L AF Mosquera, Alexis Braun, Michelle Hulett, Melissa Ryszka, Lauren TI US Public Health Service Response to the 2014-2015 Ebola Epidemic in West Africa: A Nursing Perspective SO PUBLIC HEALTH NURSING LA English DT Article DE epidemic; epidemiology; ethics; infectious diseases; public health nursing practice AB The 2014-2015 Ebola epidemic in West Africa has been the deadliest Ebola epidemic to date. In response to this deadly epidemic, the U.S. government declared this a top national security priority and members of the Commissioned Corps of the United States Public Health Service were tasked to provide direct patient care to Ebola virus disease patients. Commissioned Corps nurses provided the highest level of care under the most austere conditions. This article discusses the training, ethical dilemmas, and constant risk for potential exposure while working in an Ebola Treatment Unit. C1 [Mosquera, Alexis] USAMRMC, Congressionally Directed Med Res Programs, Ft Detrick, MD 21702 USA. [Braun, Michelle] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD USA. [Hulett, Melissa] US FDA, CDER OMP OMPI DMPP, Silver Spring, MD USA. [Ryszka, Lauren] US Marshals Serv Headquarters, Prisoner Operat Div, Washington, DC USA. RP Mosquera, A (reprint author), USAMRMC, Congressionally Directed Med Res Programs, 1077 Patchel St, Ft Detrick, MD 21702 USA. EM alexis.mosquera.mil@mail.mil NR 4 TC 1 Z9 1 U1 4 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0737-1209 EI 1525-1446 J9 PUBLIC HEALTH NURS JI Public Health Nurs. PD SEP-OCT PY 2015 VL 32 IS 5 BP 550 EP 554 DI 10.1111/phn.12217 PG 5 WC Public, Environmental & Occupational Health; Nursing SC Public, Environmental & Occupational Health; Nursing GA CV4EA UT WOS:000364217600019 PM 26207646 ER PT J AU Barr, RG Ferraioli, G Palmeri, ML Goodman, ZD Garcia-Tsao, G Rubin, J Garra, B Myers, RP Wilson, SR Rubens, D Levine, D AF Barr, Richard G. Ferraioli, Giovanna Palmeri, Mark L. Goodman, Zachary D. Garcia-Tsao, Guadalupe Rubin, Jonathan Garra, Brian Myers, Robert P. Wilson, Stephanie R. Rubens, Deborah Levine, Deborah TI Elastography Assessment of Liver Fibrosis: Society of Radiologists in Ultrasound Consensus Conference Statement SO RADIOLOGY LA English DT Article ID RADIATION FORCE IMPULSE; MAGNETIC-RESONANCE ELASTOGRAPHY; CHRONIC HEPATITIS-C; SHEAR-WAVE ELASTOGRAPHY; CHRONIC VIRAL-HEPATITIS; CONTROLLED TRANSIENT ELASTOGRAPHY; 1 BASIC PRINCIPLES; STIFFNESS MEASUREMENT; NONINVASIVE ASSESSMENT; ESOPHAGEAL-VARICES AB The Society of Radiologists in Ultrasound convened a panel of specialists from radiology, hepatology, pathology, and basic science and physics to arrive at a consensus regarding the use of elastography in the assessment of liver fibrosis in chronic liver disease. The panel met in Denver, Colo, on October 21-22, 2014, and drafted this consensus statement. The recommendations in this statement are based on analysis of current literature and common practice strategies and are thought to represent a reasonable approach to the noninvasive assessment of diffuse liver fibrosis. (C) RSNA, 2015 C1 [Barr, Richard G.] Northeastern Ohio Med Univ, Dept Radiol, Rootstown, OH 44272 USA. [Barr, Richard G.] Southwoods Imaging, Boardman, OH 44512 USA. [Ferraioli, Giovanna] Univ Pavia, Ultrasound Unit, Dept Infect Dis, Fdn IRCCS Policlin San Matteo, I-27100 Pavia, Italy. [Palmeri, Mark L.] Duke Univ, Pratt Sch Engn, Dept Biomed Engn, Durham, NC USA. [Goodman, Zachary D.] Inova Fairfax Hosp, Ctr Liver Dis, Falls Church, VA USA. [Garcia-Tsao, Guadalupe] Yale Univ, Dept Med, Sect Digest Dis, New Haven, CT 06520 USA. [Garcia-Tsao, Guadalupe] VA Connecticut Healthcare Syst, West Haven, CT USA. [Rubin, Jonathan] Univ Michigan, Med Ctr, Dept Radiol, Ann Arbor, MI 48109 USA. [Garra, Brian] Washington DC VA Med Ctr, Dept Radiol, Washington, DC USA. [Garra, Brian] US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Myers, Robert P.] Univ Calgary, Dept Hepatol, Calgary, AB, Canada. [Wilson, Stephanie R.] Univ Calgary, Dept Radiol, Calgary, AB, Canada. [Rubens, Deborah] Univ Rochester, Med Ctr, Dept Imaging Sci, Rochester, NY 14642 USA. [Rubens, Deborah] Univ Rochester, Med Ctr, Dept Oncol, Rochester, NY 14642 USA. [Rubens, Deborah] Univ Rochester, Med Ctr, Dept Biomed Engn, Rochester, NY 14642 USA. [Levine, Deborah] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. RP Barr, RG (reprint author), Northeastern Ohio Med Univ, Dept Radiol, Rootstown, OH 44272 USA. EM rgbarr@zoominternet.net RI Ferraioli, Giovanna/E-3075-2013 OI Ferraioli, Giovanna/0000-0002-6344-697X FU Society of Radiologists in Ultrasound Foundation FX Supported by the Society of Radiologists in Ultrasound Foundation. NR 117 TC 40 Z9 41 U1 9 U2 12 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD SEP PY 2015 VL 276 IS 3 BP 845 EP 861 DI 10.1148/radiol.2015150619 PG 17 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CV6EM UT WOS:000364363500024 PM 26079489 ER PT J AU Gronich, N Deftereos, SN Lavi, I Persidis, AS Abernethy, DR Rennert, G AF Gronich, Naomi Deftereos, Spyros N. Lavi, Idit Persidis, Andreas S. Abernethy, Darrell R. Rennert, Gad TI Hypothyroidism Is a Risk Factor for New-Onset Diabetes: A Cohort Study SO DIABETES CARE LA English DT Article ID STATIN THERAPY; SUBCLINICAL HYPOTHYROIDISM; INSULIN-RESISTANCE; METABOLIC SYNDROME; GLUCOSE-TRANSPORT; SKELETAL-MUSCLE; THYROID-HORMONE; DYSFUNCTION; EXPRESSION; LIVER AB OBJECTIVE To identify risk factors for the development of statin-associated diabetes mellitus (DM). RESEARCH DESIGN AND METHODS The study was conducted in two phases. Phase one involved high-throughput in silico processing of a large amount of biomedical data to identify risk factors for the development of statin-associated DM. In phase two, the most prominent risk factor identified was confirmed in an observational cohort study at Clalit, the largest health care organization in Israel. Time-dependent Poisson regression multivariable models were performed to assess rate ratios (RRs) with 95% CIs for DM occurrence. RESULTS A total of 39,263 statin nonusers were matched by propensity score to 20,334 highly compliant statin initiators in 2004-2005 and followed until the end of 2010. Within 59,597 statin users and nonusers in a multivariable model, hypothyroidism and subclinical hypothyroidism carried an increased risk for DM (RR 1.53 [95% CI 1.31-1.79] and 1.75 [1.40-2.18], respectively). Hypothyroidism increased DM risk irrespective of statin treatment (RR 2.06 [1.42-2.99] and 1.66 [1.05-2.64] in statin users and nonusers, respectively). Subclinical hypothyroidism risk for DM was prominent only upon statin use (RR 1.94 [1.13-3.34] and 1.20 [0.52-2.75] in statin users and nonusers, respectively). Patients with hypothyroidism treated with thyroid hormone replacement therapy were not at increased risk for DM. CONCLUSIONS Hypothyroidism is a risk factor for DM. Subclinical hypothyroidism-associated risk for DM is prominent only upon statin use. Identifying and treating hypothyroidism and subclinical hypothyroidism might reduce DM risk. Future clinical studies are needed to confirm the findings. C1 [Gronich, Naomi; Lavi, Idit; Rennert, Gad] Technion Israel Inst Technol, Pharmacoepidemiol & Pharmacogenet Unit, Dept Community Med & Epidemiol, Lady Davis Carmel Med Ctr, Haifa, Israel. [Gronich, Naomi; Lavi, Idit; Rennert, Gad] Technion Israel Inst Technol, Ruth & Bruce Rappaport Fac Med, Haifa, Israel. [Deftereos, Spyros N.; Persidis, Andreas S.] Biovista Inc, Charlottesville, VA USA. [Abernethy, Darrell R.] US FDA, Drug Safety Grp, Off Clin Pharmacol, Silver Spring, MD USA. [Rennert, Gad] Clalit Hlth Serv, Chief Phys Off, Tel Aviv, Israel. RP Gronich, N (reprint author), Technion Israel Inst Technol, Pharmacoepidemiol & Pharmacogenet Unit, Dept Community Med & Epidemiol, Lady Davis Carmel Med Ctr, Haifa, Israel. EM gronichn@clalit.org.il NR 35 TC 8 Z9 8 U1 1 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2015 VL 38 IS 9 BP 1657 EP 1664 DI 10.2337/dc14-2515 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CU3HZ UT WOS:000363416500019 PM 26070591 ER PT J AU Miller, PR Boehm, RD Skoog, SA Edwards, TL Rodriguez, M Brozik, S Brener, I Byrd, T Baca, JT Ashley, C Narayan, RJ Polsky, R AF Miller, Philip R. Boehm, Ryan D. Skoog, Shelby A. Edwards, Thayne L. Rodriguez, Mark Brozik, Susan Brener, Igal Byrd, Thomas Baca, Justin T. Ashley, Carlee Narayan, Roger J. Polsky, Ronen TI Electrodeposited Iron as a Biocompatible Material for Microneedle Fabrication SO ELECTROANALYSIS LA English DT Article DE Microneedle; Electroplating; Coating; Iron ID HOLLOW MICRONEEDLES; ELECTROFORMED IRON; INSERTION; ARRAY; SKIN; BIOMATERIAL; DEPOSITION; GROWTH; DRUG AB Electroplated iron was investigated as a novel material for microneedle fabrication due to its recent success as a biocompatible metal in other medical device applications. Hollow polymer microneedles were made using a laser direct write process that involved two-photon polymerization of a commercially available Class 2a biocompatible polymer and subsequent electroplating of this structure with iron. Electroplating bath and deposition conditions were shown to affect the mechanical properties of both iron plated microneedles and iron plated on planar polymer substrates. Conditions for depositing the iron coatings were investigated in terms of grain size, residual strain, and elemental composition for planar iron samples. Fracture strength and puncture mechanics into ex vivo porcine skin for iron coated hollow microneedles were examined. Biocompatibility testing was performed using the MTT assay against human epidermal keratinocytes with several concentrations of iron extract to investigate iron as a material used for transdermal applications. Iron coatings proved to significantly improve the strength of the hollow polymer microneedles and sustained structural integrity up to 7 insertions into porcine skin without bending. A commercially available device (Medtronic MiniMed Quick-Serter O) was used for controlled application of microneedles into porcine skin and estimations of insertion forces for the device were made. Plating conditions were optimized such that an adherent, uniform, and high purity iron coating was deposited onto polymer substrates and polymer microneedles without delamination or fracturing of the microneedles upon ex vivo insertion into porcine skin. C1 [Miller, Philip R.; Edwards, Thayne L.; Rodriguez, Mark; Brozik, Susan; Brener, Igal; Ashley, Carlee; Polsky, Ronen] Sandia Natl Labs, Albuquerque, NM 87185 USA. [Miller, Philip R.; Boehm, Ryan D.; Skoog, Shelby A.; Narayan, Roger J.] Univ N Carolina, Joint Dept Biomed Engn, Raleigh, NC 27695 USA. [Miller, Philip R.; Boehm, Ryan D.; Skoog, Shelby A.; Narayan, Roger J.] N Carolina State Univ, Raleigh, NC USA. [Skoog, Shelby A.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Brener, Igal] Sandia Natl Labs, Ctr Integrated Nanotechnol, Albuquerque, NM 87185 USA. [Byrd, Thomas; Baca, Justin T.] Univ New Mexico, Sch Med, Albuquerque, NM 87131 USA. [Baca, Justin T.] Univ New Mexico, Hlth Sci Ctr, Dept Emergency Med, Albuquerque, NM 87131 USA. RP Narayan, RJ (reprint author), Univ N Carolina, Joint Dept Biomed Engn, Raleigh, NC 27695 USA. EM roger_narayan@unc.edu; rpolsky@sandia.gov FU United States Department of Energy's National Nuclear Security Administration [DE-AC04449-4AL85000] FX We would like to thank Amy Allen for her help with the scanning electron micrographs, Graham Yelton for his insight with electroplating, as well as Steve Jett and Tamara Howard for access to the cyrosectioning system. Sandia is a multiprogram laboratory operated by Sandia Corporation, a Lockheed Martin Company, for the United States Department of Energy's National Nuclear Security Administration under Contract DE-AC04449-4AL85000. The authors acknowledge the Sandia National Laboratories' Laboratory Directed Research & Development (LDRD) program. NR 33 TC 0 Z9 0 U1 12 U2 35 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1040-0397 EI 1521-4109 J9 ELECTROANAL JI Electroanalysis PD SEP PY 2015 VL 27 IS 9 SI SI BP 2239 EP 2249 DI 10.1002/elan.201500199 PG 11 WC Chemistry, Analytical; Electrochemistry SC Chemistry; Electrochemistry GA CT6DL UT WOS:000362901800023 ER PT J AU Wu, HQ Read, E White, M Chavez, B Brorson, K Agarabi, C Khan, M AF Wu, Huiquan Read, Erik White, Maury Chavez, Brittany Brorson, Kurt Agarabi, Cyrus Khan, Mansoor TI Real time monitoring of bioreactor mAb IgG3 cell culture process dynamics via Fourier transform infrared spectroscopy: Implications for enabling cell culture process analytical technology SO FRONTIERS OF CHEMICAL SCIENCE AND ENGINEERING LA English DT Article DE process analytical technology (PAT); Fourier-transform infrared (FTIR) spectroscopy; partial least squares (PLS) regression; mouse IgG3; bioreactor cell culture process; real time process monitoring ID INTEGRATED PROCESS; PAT APPROACH; GLUCOSE; LACTATE AB Compared to small molecule process analytical technology (PAT) applications, biotechnology product PAT applications have certain unique challenges and opportunities. Understanding process dynamics of bioreactor cell culture process is essential to establish an appropriate process control strategy for biotechnology product PAT applications. Inline spectroscopic techniques for real time monitoring of bioreactor cell culture process have the distinct potential to develop PAT approaches in manufacturing biotechnology drug products. However, the use of inline Fourier transform infrared (FTIR) spectroscopic techniques for bioreactor cell culture process monitoring has not been reported. In this work, real time inline FTIR Spectroscopy was applied to a lab scale bioreactor mAb IgG3 cell culture fluid biomolecular dynamic model. The technical feasibility of using FTIR Spectroscopy for real time tracking and monitoring four key cell culture metabolites (including glucose, glutamine, lactate, and ammonia) and protein yield at increasing levels of complexity (simple binary system, fully formulated media, actual bioreactor cell culture process) was evaluated via a stepwise approach. The FTIR fingerprints of the key metabolites were identified. The multivariate partial least squares (PLS) calibration models were established to correlate the process FTIR spectra with the concentrations of key metabolites and protein yield of in-process samples, either individually for each metabolite and protein or globally for all four metabolites simultaneously. Applying the 2nd derivative pre-processing algorithm to the FTIR spectra helps to reduce the number of PLS latent variables needed significantly and thus simplify the interpretation of the PLS models. The validated PLS models show promise in predicting the concentration profiles of glucose, glutamine, lactate, and ammonia and protein yield over the course of the bioreactor cell culture process. Therefore, this work demonstrated the technical feasibility of real time monitoring of the bioreactor cell culture process via FTIR spectroscopy. Its implications for enabling cell culture PAT were discussed. C1 [Wu, Huiquan; White, Maury; Agarabi, Cyrus; Khan, Mansoor] US FDA, CDER, Fed Res Ctr White Oak, OPQ,OTR,DPQR,HFD 940, Silver Spring, MD 20993 USA. [Wu, Huiquan] US FDA, CDER, Fed Res Ctr White Oak, OPQ,OPF,DPA 1,Proc Assessment Branch 2, Silver Spring, MD 20993 USA. [Read, Erik; Chavez, Brittany; Brorson, Kurt] US FDA, CDER, Fed Res Ctr White Oak, OPQ,OBP,DBRR 2, Silver Spring, MD 20993 USA. RP Wu, HQ (reprint author), US FDA, CDER, Fed Res Ctr White Oak, OPQ,OTR,DPQR,HFD 940, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Huiquan.wu@fda.hhs.gov FU FDA Center for Drug Evaluation and Research (CDER) Regulatory Science and Review (RSR) [RSR-12-42, RSR-13-32]; FDA CDER Office of Testing and Research (OTR) Funding [Wu-12-PAT]; FDA CDER OBP's PAT Critical Path project [1500] FX This work was financially supported by FDA Center for Drug Evaluation and Research (CDER) Regulatory Science and Review (RSR) funding RSR-12-42, RSR-13-32, FDA CDER Office of Testing and Research (OTR) Funding Wu-12-PAT, and FDA CDER OBP's PAT Critical Path project 1500. The unmatched technical support from Mettler-Toledo AutoChem team including but not limited to Vaso Vlachos, Paul Scholl, Simon Rea, and Jack Sue in the aspects of ReactIR probe autoclaving and ReactIR system optimization is greatly acknowledged. H. Wu wishes to thank Dr. Jennifer Maguire, Dr. Rapti Madurawe, Dr. Christine Moore, Dr. Vincent Vilker (retired), Dr. Patrick Faustino, Dr. Lucinda Buhse, and Dr. Lawrence Yu at the Office of Process and Facilities (OPF), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), FDA for their management supports during the preparation and finalization of this manuscript. H. Wu is grateful to Prof. Jingkang Wang, Dr. Yingjin Yuan, Dr. Zhenhua Li at Tianjin University for the kind invitation, to Dr. Xiaowen Zhu for prompt communication and hard work, and to Yanni Li and Luli Cheng for their editorial assistance. NR 32 TC 2 Z9 2 U1 4 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 2095-0179 EI 2095-0187 J9 FRONT CHEM SCI ENG JI Front. Chem. Sci. Eng. PD SEP PY 2015 VL 9 IS 3 BP 386 EP 406 DI 10.1007/s11705-015-1533-3 PG 21 WC Engineering, Chemical SC Engineering GA CT5YX UT WOS:000362888300014 ER PT J AU Davenport, LL Hsieh, H Eppert, BL Carreira, VS Krishan, M Ingle, T Howard, PC Williams, MT Vorhees, CV Genter, MB AF Davenport, Laurie L. Hsieh, Heidi Eppert, Bryan L. Carreira, Vinicius S. Krishan, Mansi Ingle, Taylor Howard, Paul C. Williams, Michael T. Vorhees, Charles V. Genter, Mary Beth TI Systemic and behavioral effects of intranasal administration of silver nanoparticles SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Silver nanoparticles; Neurobehavioral effects; Autometallography; Intranasal instillation; Morris Water Maze ID OXIDATIVE STRESS; ADULT MICE; EXPOSURE; GLUTATHIONE; RATS; MOUSE; EXPRESSION; NANOSILVER; MEMORY; BRAIN AB Use of silver nanoparticles (AgNPs) for their antimicrobial properties is widespread. Much of the previous work on the toxicity of AgNPs has been conducted in vitro or following oral or intravenous administration in vivo. Intranasal (IN) instillation of AgNPs mimics inhalation exposure and allows further exploration of the toxicity of these particles via respiratory tract exposure. The present study involved 1) single-dose exposures to assess tissue distribution and toxicity and 2) repeated exposures to assess behavioral effects of IN AgNP exposure (nominally uncoated 25 nm AgNP). AgNP deposition was localized in the liver, gut-associated lymphoid tissue, and brain. Decrease cellularity in spleen follicles was observed in treated mice, along with changes in cell number and populations in the spleen. The splenic GSH:GSSG ratio was also reduced following AgNP exposure. Expression of the oxidative stress-responsive gene Hmox1 was elevated in the hippocampus, but not cortex of treated mice, as was the level of HMOX1 protein. Mice receiving 7 days of IN exposure to 50 mg/kg AgNPs exhibited similar learning- and memory-related behaviors to control mice, except that treated mice spent significantly less time in the target quadrant of the Morris Water Maze during the acquisition phase probe trial. These findings indicate systemic distribution and toxicity following IN administration of AgNPs. (C) 2015 Elsevier Inc All rights reserved. C1 [Davenport, Laurie L.; Hsieh, Heidi; Eppert, Bryan L.; Carreira, Vinicius S.; Krishan, Mansi; Genter, Mary Beth] Univ Cincinnati, Dept Environm Hlth, Cincinnati, OH 45267 USA. [Ingle, Taylor; Howard, Paul C.] Natl Ctr Toxicol Res, ORA Nanotechnol Core Facil, Jefferson, AR 72079 USA. [Williams, Michael T.; Vorhees, Charles V.] Cincinnati Childrens Res Fdn, Div Child Neurol MLC 7044, Cincinnati, OH 45229 USA. RP Genter, MB (reprint author), Univ Cincinnati, Dept Environm Hlth, ML 670056,160 Panzeca Way, Cincinnati, OH 45267 USA. EM Marybeth.genter@uc.edu OI Williams, Michael/0000-0001-9841-9683 FU NIEHS NIH HHS [NIH/NIEHSP30-ES006096, NIH/NIEHST32ES016646, P30 ES006096, T32 ES016646] NR 36 TC 5 Z9 6 U1 2 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD SEP-OCT PY 2015 VL 51 BP 68 EP 76 DI 10.1016/j.ntt.2015.08.006 PG 9 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA CT6LQ UT WOS:000362924900009 PM 26340819 ER PT J AU Xia, XJ Chaudhry, U Wieslander, B Borgquist, R Wagner, GS Strauss, DG Platonov, P Ugander, M Couderc, JP AF Xia, Xiaojuan Chaudhry, Uzma Wieslander, Bjorn Borgquist, Rasmus Wagner, Galen S. Strauss, David G. Platonov, Pyotr Ugander, Martin Couderc, Jean-Philippe TI Selvester scoring in patients with strict LBBB using the QUARESS software SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE Electrocardiography; Left bundle branch block; Myocardial infarction; Infarct size ID MYOCARDIAL INFARCT SIZE; CARDIAC RESYNCHRONIZATION THERAPY; QUANTITATIVE ANATOMIC FINDINGS; BUNDLE-BRANCH BLOCK; MAGNETIC-RESONANCE; PROGNOSTIC VALUE; SYSTEM; SCAR; CARDIOMYOPATHY; CONDUCTION AB Background: Estimation of the infarct size from body-surface ECGs in post-myocardial infarction patients has become possible using the Selvester scoring method. Automation of this scoring has been proposed in order to speed-up the measurement of the score and improving the inter-observer variability in computing a score that requires strong expertise in electrocardiography. In this work, we evaluated the quality of the QuAReSS software for delivering correct Selvester scoring in a set of standard 12-lead ECGs. Method: Standard 12-lead ECGs were recorded in 105 post-MI patients prescribed implantation of an implantable cardiodefibrillator (ICD). Amongst the 105 patients with standard clinical left bundle branch block (LBBB) patterns, 67 had a LBBB pattern meeting the strict criteria. The QuAReSS software was applied to these 67 tracings by two independent groups of cardiologists (from a clinical group and an ECG core laboratory) to measure the Selvester score semi-automatically. Using various level of agreement metrics, we compared the scores between groups and when automatically measured by the software. Results: The average of the absolute difference in Selvester scores measured by the two independent groups was 1.4 +/- 1.5 score points, whereas the difference between automatic method and the two manual adjudications were 1.2 +/- 1.2 and 1.3 +/- 1.2 points. Eighty-two percent score agreement was observed between the two independent measurements when the difference of score was within two point ranges, while 90% and 84% score agreements were reached using the automatic method compared to the two manual adjudications. Conclusion: The study confirms that the QuAReSS software provides valid measurements of the Selvester score in patients with strict LBBB with minimal correction from cardiologists. (C) 2015 Elsevier Inc. All rights reserved. C1 [Xia, Xiaojuan; Couderc, Jean-Philippe] Univ Rochester, Heart Res Follow Up Program, Rochester, NY USA. [Chaudhry, Uzma; Borgquist, Rasmus; Platonov, Pyotr] Lund Univ, Skane Univ Hosp, Arrhythmia clin, Lund, Sweden. [Wieslander, Bjorn; Ugander, Martin] Karolinska Inst, Dept Clin Physiol, Stockholm, Sweden. [Wieslander, Bjorn; Ugander, Martin] Karolinska Univ Hosp, Stockholm, Sweden. [Wagner, Galen S.] Duke Univ, Duke Clin Res Inst, Durham, NC USA. [Strauss, David G.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD USA. RP Xia, XJ (reprint author), Univ Rochester, Med Ctr, Div Cardiol, Heart Res Follow Up Program, 265 Crittenden Blvd,Box 653, Rochester, NY 14642 USA. EM heartjxx@heart.rochester.edu RI Chaudhry, Uzma/P-3421-2015; OI Chaudhry, Uzma/0000-0001-5186-0252; Ugander, Martin/0000-0003-3665-2038 NR 18 TC 3 Z9 3 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD SEP-OCT PY 2015 VL 48 IS 5 BP 763 EP 768 DI 10.1016/j.jelectrocard.2015.06.003 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CT2FI UT WOS:000362617000004 PM 26210409 ER PT J AU Walker, BN James, RH Calogero, D Ilev, IK AF Walker, Bennett N. James, Robert H. Calogero, Don Ilev, Ilko K. TI A novel full-angle scanning light scattering profiler to quantitatively evaluate forward and backward light scattering from intraocular lenses SO REVIEW OF SCIENTIFIC INSTRUMENTS LA English DT Article ID ASTIGMATISM CORRECTION; CATARACT PATIENTS; IMPACT; IMPLANTATION; GLISTENINGS; QUALITY; DEPTH; GLARE; EYES AB Glare, glistenings, optical defects, dysphotopsia, and poor image quality are a few of the known deficiencies of intraocular lenses (IOLs). All of these optical phenomena are related to light scatter. However, the specific direction that light scatters makes a critical difference between debilitating glare and a slightly noticeable decrease in image quality. Consequently, quantifying the magnitude and direction of scattered light is essential to appropriately evaluate the safety and efficacy of IOLs. In this study, we introduce a full-angle scanning light scattering profiler (SLSP) as a novel approach capable of quantitatively evaluating the light scattering from IOLs with a nearly 360 degrees view. The SLSP method can simulate in situ conditions by controlling the parameters of the light source including angle of incidence. This testing strategy will provide a more effective nonclinical approach for the evaluation of IOL light scatter. C1 [Walker, Bennett N.; James, Robert H.; Ilev, Ilko K.] US FDA, Opt Therapeut & Med Nanophoton Lab, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Walker, Bennett N.; Calogero, Don] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Walker, BN (reprint author), US FDA, Opt Therapeut & Med Nanophoton Lab, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. EM bennett.walker@fda.hhs.gov FU Oak Ridge Institute for Science and Education (ORISE) FX The authors would like to thank the companies for the access of their monofocal and multifocal IOLs. This work was supported by Oak Ridge Institute for Science and Education (ORISE) and their contributions are appreciated. In addition, the authors would like to thank Samuel Song for his contributions in the laboratory. NR 24 TC 0 Z9 0 U1 1 U2 3 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0034-6748 EI 1089-7623 J9 REV SCI INSTRUM JI Rev. Sci. Instrum. PD SEP PY 2015 VL 86 IS 9 AR 095004 DI 10.1063/1.4930179 PG 5 WC Instruments & Instrumentation; Physics, Applied SC Instruments & Instrumentation; Physics GA CT1PX UT WOS:000362573300051 PM 26429472 ER PT J AU Struble, E Fadiran, E Soule, L AF Struble, Evi Fadiran, Emmanuel Soule, Lisa TI Thrombosis during pregnancy: Risks, prevention, and treatment for mother and fetus SO BIRTH DEFECTS RESEARCH PART C-EMBRYO TODAY-REVIEWS LA English DT Editorial Material C1 [Struble, Evi] US FDA, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20903 USA. [Fadiran, Emmanuel] US FDA, Off Womens Hlth, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. [Soule, Lisa] US FDA, Div Bone Reprod & Urol Prod, Off Commissioner, Silver Spring, MD 20903 USA. RP Soule, L (reprint author), US FDA, Div Bone Reprod & Urol Prod, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM lisa.soule@fda.hhs.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-975X EI 1542-9768 J9 BIRTH DEFECTS RES C JI Birth Defects Res. Part C-Embryo Today-Rev. PD SEP PY 2015 VL 105 IS 3 BP 157 EP 158 DI 10.1002/bdrc.21110 PG 2 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA CS5OK UT WOS:000362127400001 PM 26412573 ER PT J AU Parunov, LA Soshitova, NP Ovanesov, MV Panteleev, MA Serebriyskiy, II AF Parunov, Leonid A. Soshitova, Natalia P. Ovanesov, Mikhail V. Panteleev, Mikhail A. Serebriyskiy, Ilya I. TI Epidemiology of venous thromboembolism (VTE) associated with pregnancy SO BIRTH DEFECTS RESEARCH PART C-EMBRYO TODAY-REVIEWS LA English DT Review DE venous thromboembolism; deep vein thrombosis; pulmonary embolism; pregnancy; pregnant women ID DEEP-VEIN THROMBOSIS; SEVERE MATERNAL MORBIDITY; MOLECULAR-WEIGHT HEPARIN; POPULATION-BASED COHORT; V-LEIDEN MUTATION; RISK-FACTORS; UNITED-STATES; HYPERTENSIVE DISORDERS; PULMONARY-EMBOLISM; POSTPARTUM PERIOD AB This review is focused on the epidemiology of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), associated with pregnancy. Superficial vein thrombosis, a less hazardous and less studied type of thrombosis in pregnant women, is beyond the scope of this review. This study discusses the VTE incidence rate in women from developed countries for both antepartum and postpartum periods and for subpopulations of women affected by additional risk factors, such as thrombophilias, circulatory diseases, preeclampsia of varying degrees of severity, and Caesarean section. To minimize bias due to historical changes in medical and obstetric practices, lifestyle, diet, etc., this review is generally limited to relatively recent studies, i.e., those that cover the last 35 years. The absolute risk or incidence rate was used to ascertain risk of VTE associated with pregnancy. For the studies where the direct incidence rates of VTE were not reported, we calculated an estimate of the observed but not reported absolute incidence rates using the data presented in respective articles. Birth Defects Research (Part C) 105:167-184, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Parunov, Leonid A.; Ovanesov, Mikhail V.] US FDA, Off Blood Res & Review, CBER, Silver Spring, MD 20993 USA. [Parunov, Leonid A.; Soshitova, Natalia P.; Serebriyskiy, Ilya I.] LLC Hematol Corp, Moscow, Russia. [Parunov, Leonid A.; Panteleev, Mikhail A.] Ctr Theoret Problems Physicochem Pharmacol, Moscow, Russia. [Panteleev, Mikhail A.] Fed Res & Clin Ctr Pediat Hematol, Oncol & Immunol, Moscow, Russia. RP Parunov, LA (reprint author), US FDA, Off Blood Res & Review, CBER, Silver Spring, MD 20993 USA. EM parunov@gmail.com RI Panteleev, Mikhail/H-5491-2012 OI Panteleev, Mikhail/0000-0002-8128-7757 FU Oak Ridge Institute for Science and Education (ORISE) through U.S. Department of Energy; Oak Ridge Institute for Science and Education (ORISE) through U.S. Food and Drug Administration FX Supported in part by a Postgraduate and Postbaccalaureate Research Fellowship Award (to L.A.P) from the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 80 TC 5 Z9 7 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-975X EI 1542-9768 J9 BIRTH DEFECTS RES C JI Birth Defects Res. Part C-Embryo Today-Rev. PD SEP PY 2015 VL 105 IS 3 BP 167 EP 184 DI 10.1002/bdrc.21105 PG 18 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA CS5OK UT WOS:000362127400003 PM 26406886 ER PT J AU Struble, E Harrouk, W DeFelice, A Tesfamariam, B AF Struble, Evi Harrouk, Wafa DeFelice, Albert Tesfamariam, Belay TI Nonclinical aspects of venous thrombosis in pregnancy SO BIRTH DEFECTS RESEARCH PART C-EMBRYO TODAY-REVIEWS LA English DT Review DE pregnancy; venous thrombosis; embryofetal toxicity assessment; drugs; biologics; biomarkers; nonclinical evaluation ID BLOOD PARAMETERS; D-DIMER; HEMOSTATIC SYSTEM; TISSUE FACTOR; PROTEIN-S; REFERENCE INTERVALS; VEIN-THROMBOSIS; ANIMAL-MODELS; WHITE-RABBITS; FACTOR-VIII AB Pregnancy is a hypercoagulable state which carries an excess risk of maternal venous thrombosis. Endothelial injury, alterations in blood flow and activation of the coagulation pathway are proposed to contribute to the hypercoagulability. The risk for thrombosis may be accentuated by certain drugs and device implants that directly or indirectly affect the coagulation pathway. To help ensure that these interventions do not result in adverse maternal or fetal outcomes during pregnancy, gravid experimental animals can be exposed to such treatments at various stages of gestation and over a dosage range that would identify hazards and inform risk assessment. Circulating soluble biomarkers can also be evaluated for enhancing the assessment of any increased risk of venous thrombosis during pregnancy. In addition to traditional in vivo animal testing, efforts are under way to incorporate reliable non-animal methods in the assessment of embryofetal toxicity and thrombogenic effects. This review summarizes hemostatic balance during pregnancy in animal species, embryofetal development, biomarkers of venous thrombosis, and alterations caused by drug-induced venous thrombosis. Birth Defects Research (Part C) 105:190-200, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Struble, Evi] US FDA, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Harrouk, Wafa] US FDA, Div Nonprescript Drug Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [DeFelice, Albert; Tesfamariam, Belay] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Struble, E (reprint author), US FDA, Lab Plasma Derivat, Div Hematol Res, CBER, 10903 New Hampshire Ave,Bldg 52-72,Rm 4218, Silver Spring, MD 20993 USA. EM evi.struble@fda.hhs.gov; belay.tesfamariam@fda.hhs.gov NR 71 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-975X EI 1542-9768 J9 BIRTH DEFECTS RES C JI Birth Defects Res. Part C-Embryo Today-Rev. PD SEP PY 2015 VL 105 IS 3 BP 190 EP 200 DI 10.1002/bdrc.21111 PG 11 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA CS5OK UT WOS:000362127400005 PM 26404176 ER PT J AU Authier, S Curtis, MJ Soloviev, M Redfern, WS Kallman, MJ Hamlin, RL Leishman, DJ Valentin, JP Koerner, JE Vargas, HM Botchway, A Correll, K Pugsley, MK AF Authier, Simon Curtis, Michael J. Soloviev, Maxim Redfern, Will S. Kallman, Mary Jeanne Hamlin, Robert L. Leishman, Derek J. Valentin, Jean-Pierre Koerner, John E. Vargas, Hugo M. Botchway, Alfred Correll, Krystle Pugsley, Michael K. TI The Diplomate in Safety Pharmacology (DSP) certification scheme SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Article DE Diplomate in Safety Pharmacology (DSP); Safety pharmacology (SP); ICH S7A; ICH S7B; ICH M3; Certification; Cardiovascular; Respiratory; Central nervous systems; Core battery ID SOCIETY; TOXICOLOGY AB As with other professional disciplines there is a growing need from within industry as well as global regulatory authorities for implementation of a certification process in order to assure that appropriate expertise is developed and quality standards are identified for professionals involved in the practice of Safety Pharmacology (SP). In order to meet this need, the Safety Pharmacology Society (SPS) has developed the Diplomate in Safety Pharmacology (DSP) certification process. There are many benefits to certification including authentication of the discipline within the overall pharmaceutical community and with regulatory authorities. It also encourages participation in SPS activities by other professionals (toxicologists, clinicians, academics) who wish to broaden their professional expertise. It provides an opportunity for candidates to strengthen their fundamental scientific knowledge, and stimulates the sharing of data, methods and model development in the form of publications and presentations on relevant topics in SP. Accreditation in SP occurs after candidates successfully complete a written certification examination conducted at the annual SPS meeting. The DSP exam consists primarily of material pertinent to the conduct of SP vital function core battery studies (i.e., cardiovascular, respiratory and central nervous systems), supplemental SP studies (i.e., renal/urinary, gastrointestinal, immunology, and hematology), Regulatory Guidelines (ICH Guidelines) as well as relevant cross-functional knowledge (e.g., physiology, pharmacology, toxicology, biochemistry, pathology, pharmacokinetics, dosing formulation, analytical methods, and statistics). Maintenance of the DSP certification results from the accrual of credits which are gained from a range of educational and scientific contributions. Eligibility requirements include a combination of at least a bachelor degree in science and two years of relevant professional SP experience and one poster presentation on a SP topic as first author at a recognized major scientific meeting. (C) 2015 Elsevier Inc. All rights reserved. C1 [Authier, Simon] CiToxLAB North Amer, Laval, PQ H7V 4B3, Canada. [Authier, Simon; Soloviev, Maxim; Redfern, Will S.; Kallman, Mary Jeanne; Hamlin, Robert L.; Leishman, Derek J.; Valentin, Jean-Pierre; Koerner, John E.; Vargas, Hugo M.; Botchway, Alfred; Correll, Krystle; Pugsley, Michael K.] Safety Pharmacol Soc, Reston, VA 20190 USA. [Curtis, Michael J.] Kings Coll London, Rayne Inst, Fac Life Sci & Med, Cardiovasc Div, London SE1 7EH, England. [Soloviev, Maxim] Incyte Corp, Wilmington, DE 19803 USA. [Redfern, Will S.] AstraZeneca R&D, Alderley Pk SK10 4TG, Cheshire, England. [Kallman, Mary Jeanne] COVANCE Labs Inc, Greenfield, IN 46140 USA. [Hamlin, Robert L.] QTest Labs, Columbus, OH 43235 USA. [Leishman, Derek J.] Eli Lilly & Co, Indianapolis, IN 46225 USA. [Valentin, Jean-Pierre] UCB BioPharma SPRL, Non Clin Dev, B-1420 Braine Lalleud, Belgium. [Koerner, John E.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Vargas, Hugo M.] Amgen Inc, Thousand Oaks, CA 91320 USA. [Botchway, Alfred] XenoMetrics LLC, Stilwell, KS 66085 USA. [Pugsley, Michael K.] Janssen Pharmaceut LLC, Raritan, NJ 08869 USA. RP Authier, S (reprint author), CiToxLAB North Amer, 445 Armand Frappier Blvd, Laval, PQ H7V 4B3, Canada. EM AUTHIERS@ca.citoxlab.com NR 23 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD SEP-OCT PY 2015 VL 75 BP 1 EP 4 DI 10.1016/j.vascn.2015.04.008 PG 4 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CS3KB UT WOS:000361971300001 PM 25959882 ER PT J AU Guth, BD Chiang, AY Doyle, J Engwall, MJ Guillon, JM Hoffmann, P Koerner, J Mittelstadt, S Ottinger, S Pierson, JB Pugsley, MK Rossman, EI Walisser, J Sarazan, D AF Guth, Brian D. Chiang, Alan Y. Doyle, Jennifer Engwall, Michael J. Guillon, Jean-Michel Hoffmann, Peter Koerner, John Mittelstadt, Scott Ottinger, Sean Pierson, Jennifer Beck Pugsley, Michael K. Rossman, Eric I. Walisser, Jacqueline Sarazan, Dustan TI The evaluation of drug-induced changes in cardiac inotropy in dogs: Results from a HESI-sponsored consortium SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Article DE Myocardial; Contractility; Left ventricular dP/dt; Beagle dog; Pimobendan; Atenolol; Itraconazole; Amrinone; Heart rate; Arterial blood pressure ID HEART-FAILURE; SAFETY ASSESSMENT; PRESSURE; CONTRACTILITY; ITRACONAZOLE; PIMOBENDAN; AMRINONE; MECHANISM AB Introduction: Drug-induced effects on the cardiovascular system remain a major cause of drug attrition. While hemodynamic (blood pressure (BP) and heart rate (HR)) and electrophysiological methods have been used in testing drug safety for years, animal models for assessing myocardial contractility are used less frequently and their translation to humans has not been established. The goal of these studies was to determine whether assessment of contractility and hemodynamics, when measured across different laboratories using the same protocol, could consistently detect drug-induced changes in the inotropic state of the heart using drugs known to have clinically relevant positive and negative effects on myocardial contractility. Methods: A 4 x 4 double Latin square design (n = 8) design using Beagle dogs was developed. Drugs were administrated orally. Arterial blood pressure, left ventricular pressure (LVP) and the electrocardiogram were assessed. Each of the six laboratories studied at least 2 drugs (one positive inotrope (pimobendan or amrinone) and one negative inotrope) (itraconazole or atenolol) at 3 doses selected to match clinical exposure data and a vehicle control. Animals were instrumented with an ITS telemetry system, DSI's D70-PCTP system or DSI's Physiotel Digital system. Data acquisition and analysis systems were Ponemah, Notocord or EMKA. Results: Derived parameters included: diastolic, systolic and mean arterial BP, peak systolic LVP, HR, end-diastolic LVP, and LVdP/dt(max) as the primary contractility index. Blood samples were drawn to confirm drug exposures predicted from independent pharmacokinetic studies. Across the laboratories, a consistent change in LVdP/dt(max) was captured despite some differences in the absolute values of some of the hemodynamic parameters prior to treatment. Discussion: These findings indicate that this experimental model, using the chronically instrumented conscious dog, can accurately and consistently detect changes in cardiac contractility, across multiple sites and instrumentation systems, and that data obtained in this model may also translate to clinical outcomes. (C) 2015 The Authors. Published by Elsevier Inc. C1 [Guth, Brian D.] Boehringer Ingelheim GmbH & Co KG, Biberach, Germany. [Chiang, Alan Y.] Eli Lilly & Co, Indianapolis, IN USA. [Doyle, Jennifer] Data Sci Int, Indianapolis, IN USA. [Engwall, Michael J.] Amgen Inc, Thousand Oaks, CA USA. [Guillon, Jean-Michel] Sanofi, Paris, France. [Hoffmann, Peter] Novartis, Paris, France. [Koerner, John] US FDA, Rockville, MD 20857 USA. [Mittelstadt, Scott] AbbVie, Lexington, MA USA. [Ottinger, Sean] Millennium, New York, NY USA. [Pierson, Jennifer Beck] HESI, New York, NY USA. [Sarazan, Dustan] Data Sci Int, New York, NY USA. RP Pierson, JB (reprint author), 1156 15th St,NW Suite 200, Washington, DC 20005 USA. NR 29 TC 9 Z9 9 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD SEP-OCT PY 2015 VL 75 BP 70 EP 90 DI 10.1016/j.vascn.2015.02.002 PG 21 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CS3KB UT WOS:000361971300010 PM 25843226 ER PT J AU Chittiboyina, AG Avonto, C Rua, D Khan, IA AF Chittiboyina, Amar G. Avonto, Cristina Rua, Diego Khan, Ikhlas A. TI Alternative Testing Methods for Skin Sensitization: NMR Spectroscopy for Probing the Reactivity and Classification of Potential Skin Sensitizers SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID ALLERGIC CONTACT-DERMATITIS; IN-VITRO PREDICTION; PEPTIDE REACTIVITY; MICHAEL ACCEPTORS; READ-ACROSS; GUINEA PIG; ASSAY; CHEMICALS; POTENCY; GLUTATHIONE AB Evaluating consumer products for potentially harmful side effects of chemical ingredients is important for the protection of both the consumer and those involved in the manufacturing process. In order to assess the risk potential of chemicals, regulatory agencies have encouraged the development of several in silico, in vitro, and in chemico methods as alternatives to eliminate or minimize the use of animals. To add structural information to the existing in chemico methods, an NMR-based method is proposed for probing the reactivity and classification of the potential electrophiles (E) using a model thiol, DCYA, as a nucleophile. The major advantage of the NMR method is the quantitation of the actual adduct, DCYA-E. The degree of reaction is here provided as a direct measurement of adduct formation and/or electrophile depletion, in contrast to other in chemico assays, e.g., ADRA and DPRA, where the reactivity is inferred from the quantification of the test nucleophile depletion. Moreover, the developed NMR method should serve as a qualitative and quantitative tool in understanding the site of reaction and other structural information associated with test sensitizer. This is particularly valuable and advantageous over methods encouraged by regulatory agencies, which merely provide quantification of the reaction but lack any structural information. Several compounds with multiple reaction sites were successfully tested with the proposed NMR method. Otherwise, these compounds have proven to be a challenge to identify and classify using existing alternative methods. C1 [Chittiboyina, Amar G.; Avonto, Cristina; Khan, Ikhlas A.] Univ Mississippi, Natl Ctr Nat Prod Res, University, MS 38677 USA. [Khan, Ikhlas A.] Univ Mississippi, Sch Pharm, Div Pharmacognosy, Dept Biomol Sci, University, MS 38677 USA. [Rua, Diego] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Khan, IA (reprint author), Univ Mississippi, Natl Ctr Nat Prod Res, University, MS 38677 USA. EM ikhan@olemiss.edu OI Avonto, Cristina/0000-0002-8209-6813 FU Science Based Authentication of Dietary Supplements - Food and Drug Administration [1U01FD004246-04]; United States Department of Agriculture, Agricultural Research Service [58-6408-1-603-04] FX This research was supported in part by "Science Based Authentication of Dietary Supplements" funded by the Food and Drug Administration grant number 1U01FD004246-04, the United States Department of Agriculture, Agricultural Research Service, Specific Cooperative Agreement No. 58-6408-1-603-04. NR 51 TC 4 Z9 4 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X EI 1520-5010 J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD SEP PY 2015 VL 28 IS 9 BP 1704 EP 1714 DI 10.1021/acs.chemrestox.5b00098 PG 11 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA CS1YR UT WOS:000361865300007 PM 26225548 ER PT J AU Ng, HW Shu, M Luo, H Ye, H Ge, WG Perkins, R Tong, WD Hong, HX AF Ng, Hui Wen Shu, Mao Luo, Heng Ye, Hao Ge, Weigong Perkins, Roger Tong, Weida Hong, Huixiao TI Estrogenic Activity Data Extraction and in Silico Prediction Show the Endocrine Disruption Potential of Bisphenol A Replacement Compounds SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; EASTMANS TRITAN(TM) COPOLYESTERS; HIV-1 INTEGRASE INHIBITORS; ADENOSINE A2A RECEPTOR; DIGLYCIDYL ETHER BFDGE; BINDING AFFINITIES; ANDROGEN RECEPTOR; ALPHA-FETOPROTEIN; 4-POINT PHARMACOPHORE; DIVERSE CHEMICALS AB Bisphenol A (BPA) replacement compounds are released to the environment and cause widespread human exposure. However, a lack of thorough safety evaluations on the BPA replacement compounds has raised public concerns. We assessed the endocrine disruption potential of BPA replacement compounds in the market to assist their safety evaluations. A literature search was conducted to ascertain the BPA replacement compounds in use. Available experimental estrogenic activity data of these compounds were extracted from the Estrogenic Activity Database (EADB) to assess their estrogenic potential. An in silico model was developed to predict the estrogenic activity of compounds lacking experimental data. Molecular dynamics (MD) simulations were performed to understand the mechanisms by which the estrogenic compounds bind to and activate the estrogen receptor (ER). Forty-five BPA replacement compounds were identified in the literature. Seven were more estrogenic and five less estrogenic than BPA, while six were nonestrogenic in EADB. A two-tier in silico model was developed based on molecular docking to predict the estrogenic activity of the 27 compounds lacking data. Eleven were predicted as ER binders and 16 as nonbinders. MD simulations revealed hydrophobic contacts and hydrogen bonds as the main interactions between ER and the estrogenic compounds. C1 [Ng, Hui Wen; Shu, Mao; Luo, Heng; Ye, Hao; Ge, Weigong; Perkins, Roger; Tong, Weida; Hong, Huixiao] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Hong, HX (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM huixiao.hong@fda.hhs.gov RI Luo, Heng/D-3616-2016 OI Luo, Heng/0000-0001-5192-8878 NR 70 TC 11 Z9 12 U1 3 U2 25 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X EI 1520-5010 J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD SEP PY 2015 VL 28 IS 9 BP 1784 EP 1795 DI 10.1021/acs.chemrestox.5b00243 PG 12 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA CS1YR UT WOS:000361865300015 PM 26308263 ER PT J AU Manjanatha, MG Shelton, SD Chen, Y Gaddameedhi, S Howard, PC Boudreau, MD AF Manjanatha, Mugimane G. Shelton, Sharon D. Chen, Ying Gaddameedhi, Shobhan Howard, Paul C. Boudreau, Mary D. TI Development and validation of a new transgenic hairless albino mouse as a mutational model for potential assessment of photocarcinogenicity SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE Transgenic Hairless albino mouse; gpt-Delta mouse; Spi(-) selection assay; Mutant frequency; Mutation frequency ID CYCLOBUTANE PYRIMIDINE DIMERS; SQUAMOUS-CELL CARCINOMA; UV-SIGNATURE MUTATIONS; INDUCED GPT MUTATIONS; SKIN-CANCER; RODENT CELLS; DIPYRIMIDINE SITES; ULTRAVIOLET-LIGHT; P53 MUTATIONS; MITOMYCIN-C AB Short-term phototoxicity testing is useful in selecting test agents for the longer and more expensive photocarcinogenesis safety tests; however, no validated short-term tests have been proven reliable in predicting the outcome of a photocarcinogenesis safety test. A transgenic, hairless, albino (THA) mouse model was developed that carries the gpt and red/gam [Spi(-)] genes from the gpt delta mouse background and the phenotypes from the SKH-1 mouse background to use as a short-term test in lieu of photocarcinogenesis safety tests. Validation of the THA mouse model was confirmed by exposing groups of male mice to sub-erythemal doses of ultraviolet B (UVB) irradiation for three consecutive days emitted from calibrated overhead, Kodacel-filtered fluorescent lamps and measuring the mutant frequencies (MFs) in the gpt and red/gam (Spi(-)) genes and types of mutations in the gpt gene. The doses or irradiation were monitored with broad-spectrum dosimeters that were calibrated to a NIST-traceable standard and cumulative CIE-weighted doses were 20.55 and 41.0 mJ/cm(2) (effective). Mice were sacrificed 14 days after the final UVB exposure and MFs in both the gpt and red/gam genes were evaluated in the epidermis. The exposure of mice to UVB induced significant ten- to twelve-fold increases in the gpt MF and three- to five-fold increases in the Spi(-) MF over their respective background MF, 26 +/- 3 x 10(-6) and 9 +/- 1 x 10(-6). The gpt mutation spectra were significantly different between that of the UVB-irradiated and that of non-irradiated mice although the mutation spectra of both groups were dominated by C -> T transitions (84% and 66%). In mice exposed to UVB, the C -> T transitions occurred almost exclusively at dipyrimidine sites (92%), whereas in non-irradiated control mice, the C -> T transitions occurred at CpG sites (86%). These results suggest that the newly developed THA mice are a useful and reliable model for testing UVB-induced mutagenicity in skin tissue. The application of this model for short-term prediction of solar-induced skin carcinogenicity is presently under investigation. Published by Elsevier B.V. C1 [Manjanatha, Mugimane G.; Shelton, Sharon D.; Chen, Ying] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Gaddameedhi, Shobhan] Washington State Univ, Coll Pharm, Dept Expt & Syst Pharmacol, Spokane, WA USA. [Howard, Paul C.] US FDA, Natl Ctr Toxicol Res, Off Sci Coordinat, Jefferson, AR 72079 USA. [Boudreau, Mary D.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Manjanatha, MG (reprint author), US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, HFT 120,3900 NCTR Rd, Jefferson, AR 72079 USA. EM Mugimane.manjanatha@fda.hhs.gov FU NIEHS NIH HHS [K99 ES022640, R00 ES022640] NR 64 TC 0 Z9 0 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 EI 1879-3592 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD SEP PY 2015 VL 791 BP 42 EP 52 DI 10.1016/j.mrgentox.2015.08.001 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA CS0US UT WOS:000361778300006 PM 26338542 ER PT J AU Avila, C Willins, JL Jackson, M Mathai, J Jabsky, M Kong, A Callaghan, F Ishkin, S Shroyer, ALW AF Avila, Cecilia Willins, Jennifer L. Jackson, Matthew Mathai, Jacob Jabsky, Marina Kong, Alex Callaghan, Fiona Ishkin, Selda Shroyer, A. Laurie W. TI Usefulness of Two Clinical Chorioamnionitis Definitions in Predicting Neonatal Infectious Outcomes: A Systematic Review SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Review DE chorioamnionitis; sepsis; fever; pregnancy complications ID PRETERM PREMATURE RUPTURE; INTRA-AMNIOTIC INFECTION; B STREPTOCOCCAL DISEASE; BIRTH-WEIGHT INFANTS; BIOPHYSICAL PROFILE; MEMBRANES; TERM; EPIDEMIOLOGY; PREVENTION; GUIDELINES AB Objective To assess the usefulness of two definitions of acute clinical chorioamnionitis (ACCA) in predicting risk of neonatal infectious outcomes (NIO) and mortality, the first definition requiring maternal fever alone (Fever), and the second requiring >= 1 Gibbs criterion besides fever (Fever + 1). Study Design PubMed, Web of Science, and the Cochrane Database of Systematic Reviews were searched from January 1, 1979 to April 9, 2013. Twelve studies were reviewed (of 316 articles identified): three studies with term patients, four with preterm premature rupture of membranes (PPROM) patients, and five mixed studies with mixed gestational ages and/or membrane status (intact and/or ruptured). Results Both definitions demonstrated an increased NIO risk for ACCA versus non-ACCA patients, with an odds ratio increase for the Fever + 1 definition that was about twofold larger than the Fever definition. Conclusion As the Fever definition demonstrated increased NIO risk for ACCA versus non-ACCA patients, the Fever alone ACCA definition should be used to trigger future clinical treatment in many clinical situations. C1 [Avila, Cecilia; Willins, Jennifer L.; Mathai, Jacob; Jabsky, Marina; Kong, Alex; Ishkin, Selda] SUNY Stony Brook, Sch Med, Dept Obstet Gynecol & Reprod Med, Stony Brook, NY 11794 USA. [Jackson, Matthew] US FDA, CDER OTS OB DB6, Silver Spring, MD USA. [Callaghan, Fiona] Natl Lib Med, Lister Hill Ctr Biomed Commun, NIH, Bethesda, MD USA. [Shroyer, A. Laurie W.] SUNY Stony Brook, Sch Med, Dept Surg, Stony Brook, NY 11794 USA. RP Avila, C (reprint author), SUNY Stony Brook, Sch Med, Dept Obstet & Gynecol, HSC T9-30,100 Nicholls Rd, Stony Brook, NY 11794 USA. EM Cecilia.Avila@stonybrookmedicine.edu RI Shroyer, Annie Laurie/B-8836-2016 OI Shroyer, Annie Laurie/0000-0001-6461-0623 FU Department of OB/GYN at Stony Brook University School of Medicine (Division of Maternal Fetal Medicine); Stony Brook University School of Medicine Dean's office Professional Development Program FX This study was supported by the Department of OB/GYN at Stony Brook University School of Medicine (Division of Maternal Fetal Medicine) and by the Stony Brook University School of Medicine Dean's office Professional Development Program (Dr. Avila, PDP Scholar; Dr. Shroyer, PDP Mentor). NR 37 TC 5 Z9 5 U1 1 U2 3 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 EI 1098-8785 J9 AM J PERINAT JI Am. J. Perinatol. PD SEP PY 2015 VL 32 IS 11 BP 1001 EP 1009 DI 10.1055/s-0035-1547325 PG 9 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA CR5UQ UT WOS:000361410300001 PM 26007317 ER PT J AU Bauer, K Esquilin, IO Cornier, AS Thomas, SJ del Rio, AIQ Bertran-Pasarell, J Ramirez, JOM Diaz, C Carlo, S Eckels, KH Tournay, E Toussaint, JF De La Barrera, R Fernandez, S Lyons, A Sun, W Innis, BL AF Bauer, Kristen Esquilin, Ines O. Cornier, Alberto Santiago Thomas, Stephen J. del Rio, Ana I. Quintero Bertran-Pasarell, Jorge Ramirez, Javier O. Morales Diaz, Clemente Carlo, Simon Eckels, Kenneth H. Tournay, Elodie Toussaint, Jean-Francois De La Barrera, Rafael Fernandez, Stefan Lyons, Arthur Sun, Wellington Innis, Bruce L. TI A Phase II, Randomized, Safety and Immunogenicity Trial of a Re-Derived, Live-Attenuated Dengue Virus Vaccine in Healthy Children and Adults Living in Puerto Rico SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article AB This was a double-blind, randomized, controlled, phase II clinical trial, two dose study of re-derived, live-attenuated, tetravalent dengue virus (TDEN) vaccine (two formulations) or placebo in subjects 1-50 years of age. Among the 636 subjects enrolled, 331 (52%) were primed, that is, baseline seropositive to at least one dengue virus (DENY) type. Baseline seropositivity prevalence increased with age (10% [< 2 years], 26% [2-4 years], 60% [5-20 years], and 93% [21-50 years]). Safety profiles of TDEN vaccines were similar to placebo regardless of priming status. No vaccine-related serious adverse events (SAEs) were reported. Among unprimed subjects, immunogenicity (geometric mean antibody titers [GMT] and seropositivity rates) for each DENV increased substantially in both TDEN vaccine groups with at least 74.6% seropositive for four DENV types. The TDEN vaccine candidate showed an acceptable safety and immunogenicity profile in children and adults ranging from 1 to 50 years of age, regardless of priming status. C1 [Thomas, Stephen J.] Walter Reed Army Inst Res, Viral Dis Branch, Silver Spring, MD USA. [Esquilin, Ines O.; Bertran-Pasarell, Jorge; Diaz, Clemente] Univ Puerto Rico, Sch Med, San Juan, PR 00936 USA. [Cornier, Alberto Santiago; Carlo, Simon] La Concepc Hosp, Dept Mol Med, San German, PR USA. [Cornier, Alberto Santiago] Ponce Sch Med, Dept Biochem, Ponce, PR USA. [del Rio, Ana I. Quintero] Ctr Reumatol Pediat Puerto Rico, San Juan, PR USA. [Ramirez, Javier O. Morales] Clin Res Puerto Rico Inc, San Juan, PR USA. [Eckels, Kenneth H.; De La Barrera, Rafael] Walter Reed Army Inst Res, Pilot Bioprod Facil, Silver Spring, MD USA. GSK Vaccines, Wavre, Belgium. [Innis, Bruce L.] GSK Vaccines, King Of Prussia, PA USA. [Bauer, Kristen] Landstuhl Reg Med Ctr, Landstuh, Germany. [Carlo, Simon] Dept Biochem & Pediat PSMHS, Ponce, PR USA. [Tournay, Elodie] GSK Vaccines, Vaccine Value & Hlth Sci, Biomed Data Sci, Wavre, Belgium. [Toussaint, Jean-Francois] GSK Vaccines, Vaccine Discovery & Dev, Viral Dis Area Program, Rixensart, Belgium. [Fernandez, Stefan] US Army Med Component Armed Forces Res Inst Med S, Bangkok, Thailand. [Lyons, Arthur] Army Pentagon, OTSG, Washington, DC USA. [Sun, Wellington] US FDA, Div Vaccines & Related Product Applicat, CBER, Rockville, MD 20857 USA. RP Thomas, SJ (reprint author), Walter Reed Army Inst Res, Operat, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM kristen.m.bauer.mil@mail.mil; ines.esquilin@upr.edu; scornier@psm.edu; stephen.j.thomas3.mil@mail.mil; anaquintero8293@msn.com; jorge.bertran@upr.edu; morales@clinicalresearchpr.com; clemente.diaz@upr.edu; simoncarlo3@yahoo.com; kenneth.h.eckels.civ@mail.mil; elodie.x.tournay@gsk.com; jean-francois.x.toussaint@gsk.com; rafael.a.delabarrera.ctr@mail.mil; stefan.femandez@afrims.org; arthur.g.lyons.mil@mail.mil; wellington.sun@fda.hhs.gov; bruce.2.innis@gsk.com FU U.S. Army Medical Research and Materiel Command (Fort Detrick, MD); GlaxoSmithKline Biologicals SA (Rixensart, Belgium) FX This work was funded by U.S. Army Medical Research and Materiel Command (Fort Detrick, MD) and GlaxoSmithKline Biologicals SA (Rixensart, Belgium) under a Cooperative Research and Development Agreement. GlaxoSmithKline Biologicals SA was involved in all stages of study conduct, including analysis of the data, in addition to costs related to the development of the publication of this manuscript. NR 17 TC 2 Z9 2 U1 0 U2 0 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 SEP PY 2015 VL 93 IS 3 BP 441 EP 453 DI 10.4269/ajtmh.14-0625 PG 13 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CR3TB UT WOS:000361254900005 PM 26175027 ER PT J AU Evans, SR Rubin, D Follmann, D Pennello, G Huskins, WC Powers, JH Schoenfeld, D Chuang-Stein, C Cosgrove, SE Fowler, VG Lautenbach, E Chambers, HF AF Evans, Scott R. Rubin, Daniel Follmann, Dean Pennello, Gene Huskins, W. Charles Powers, John H. Schoenfeld, David Chuang-Stein, Christy Cosgrove, Sara E. Fowler, Vance G., Jr. Lautenbach, Ebbing Chambers, Henry F. TI Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR) SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE DOOR; RADAR; antibiotic use strategies ID EQUIVALENCE TRIALS; ANTIMICROBIAL USE; NON-INFERIORITY; SAMPLE-SIZE AB Clinical trials that compare strategies to optimize antibiotic use are of critical importance but are limited by competing risks that distort outcome interpretation, complexities of noninferiority trials, large sample sizes, and inadequate evaluation of benefits and harms at the patient level. The Antibacterial Resistance Leadership Group strives to overcome these challenges through innovative trial design. Response adjusted for duration of antibiotic risk (RADAR) is a novel methodology utilizing a superiority design and a 2-step process: (1) categorizing patients into an overall clinical outcome (based on benefits and harms), and (2) ranking patients with respect to a desirability of outcome ranking (DOOR). DOORs are constructed by assigning higher ranks to patients with (1) better overall clinical outcomes and (2) shorter durations of antibiotic use for similar overall clinical outcomes. DOOR distributions are compared between antibiotic use strategies. The probability that a randomly selected patient will have a better DOOR if assigned to the new strategy is estimated. DOOR/RADAR represents a new paradigm in assessing the risks and benefits of new strategies to optimize antibiotic use. C1 [Evans, Scott R.] Harvard Univ, Boston, MA 02115 USA. [Rubin, Daniel] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Follmann, Dean] NIAID, NIH, Bethesda, MD 20892 USA. [Pennello, Gene] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Huskins, W. Charles] Mayo Clin, Div Pediat Infect Dis, Rochester, MN USA. [Powers, John H.] George Washington Univ, Sch Med, Washington, DC USA. [Powers, John H.] NIH, Leidos Biomed Res, Div Clin Res, Bethesda, MD 20892 USA. [Schoenfeld, David] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chuang-Stein, Christy] Pfizer Inc, Groton, CT 06340 USA. [Cosgrove, Sara E.] Johns Hopkins Univ, Baltimore, MD USA. [Fowler, Vance G., Jr.] Duke Univ, Durham, NC USA. [Lautenbach, Ebbing] Univ Penn, Philadelphia, PA 19104 USA. [Chambers, Henry F.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Evans, SR (reprint author), Harvard Univ, Sch Publ Hlth, CBAR Biostat, FXB 513,651 Huntington Ave, Boston, MA 02115 USA. EM evans@sdac.harvard.edu FU National Institute of Allergy and Infectious Diseases of the NIH [UM1AI104681]; National Cancer Institute, NIH [HHSN261200800001E] FX This work was supported by the National Institute of Allergy and Infectious Diseases of the NIH (award number UM1AI104681) and in part with federal funds from the National Cancer Institute, NIH (contract number HHSN261200800001E). NR 14 TC 16 Z9 16 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 1 PY 2015 VL 61 IS 5 BP 800 EP 806 DI 10.1093/cid/civ495 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CR6PD UT WOS:000361468700021 PM 26113652 ER PT J AU Adolf, JE Bachvaroff, TR Deeds, JR Place, AR AF Adolf, Jason E. Bachvaroff, Tsvetan R. Deeds, Jonathan R. Place, Allen R. TI Ichthyotoxic Karlodinium veneficum (Ballantine) J Larsen in the Upper Swan River Estuary (Western Australia): Ecological conditions leading to a fish kill SO HARMFUL ALGAE LA English DT Article DE Fish kill; Karlodinium veneficum; Karlotoxins; Swan River Estuary ID GYMNODINIOID DINOFLAGELLATES KARENIACEAE; PHYTOPLANKTON SUCCESSION; CRASSOSTREA-VIRGINICA; MICRUM DINOPHYCEAE; CHESAPEAKE BAY; ALGAL BLOOMS; EUTROPHICATION; TOXIN; KARLOTOXINS; STRAINS AB Ichthyotoxic Karlodinium veneficum has become a persistent problem in the eutrophic Swan River Estuary (SRE) near Perth, Western Australia. Karlotoxin (KmTx) concentrations and K. veneficum were sampled from March to July 2005, spanning a bloom confirmed by microscopy and genetics (ITS sequence), and a fish kill coincident with end of the bloom. The objective of this study was to investigate K. veneficum cell and toxin dynamics, and water quality conditions, leading up to the bloom and fish kill in this estuarine system. Abundance of K veneficum increased as diatom abundance decreased over a 3-month period (Jan-Mar) preceding the bloom. Low freshwater flow to the SRE characterized the bloom initiation period, while elevated seasonal flows altered water quality and preceded the end of the bloom and fish kill. The bloom of K. veneficum was localized over a bottom layer of hypoxic water in a stratified water column. Low nitrate levels, DIN:DIP (mol) near unity, and particulate C:N:P of K. veneficum-rich water samples were consistent with nitrogen limitation of phytoplankton. A KmTx 2 congener was present in the concentration range 0-1052 ng KmTx mL(-1), levels that were sufficient to kill larval fish in the laboratory within 4 h. A KmTx cell quota of 2.8 pg KmTx cell(-1) was estimated for the bloom, which is moderately high for the species. Gill histopathology of fish from this fish kill showed signs of damage similar to those caused by KmTx in the lab. Results from this study suggest that conditions in the SRE, including elevated K. veneficum abundance and KmTx cell quotas, as well as hypoxia in the upper SRE, likely contribute to seasonal fish kills observed in this system. (C) 2015 Elsevier B.V. All rights reserved. C1 [Adolf, Jason E.; Bachvaroff, Tsvetan R.; Place, Allen R.] Univ Maryland Ctr Environm Sci, Inst Marine & Environm Technol, Baltimore, MD 21202 USA. [Deeds, Jonathan R.] US FDA Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Adolf, JE (reprint author), Univ Hawaii Hilo, Dept Marine Sci, 200 W Kawili St, Hilo, HI 96720 USA. EM jadolf@hawaii.edu; bachvarofft@gmail.com; jonathan.deeds@fda.hhs.gov; place@umces.edu FU NOAA ECOHAB; NOAA CSCOR travel award; CDC FX The authors thank all the staff and crew of the WA DOE and SRT, particularly Ashrafi Begum, Wasele (Vas) Hosja, Tarren Reitsema, Petra Ringeltaube, Malcolm Robb, and Laura Cunningham for speedy delivery of phytoplankton count data. We thank Nancy Feissner who worked at University of Maryland COMB as a summer technician and processed the > 250 toxin samples received from Australia in that time period. Parts of this work have been supported by NOAA ECOHAB, CDC, and a NOAA CSCOR travel award. This is contribution #15-154 from University System of Maryland Institute of Marine and Environmental Technology, #5028 from UMCES, and contribution # 833 from the ECOHAB program.[SS] NR 66 TC 3 Z9 3 U1 6 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9883 EI 1878-1470 J9 HARMFUL ALGAE JI Harmful Algae PD SEP PY 2015 VL 48 BP 83 EP 93 DI 10.1016/j.hal.2015.07.006 PG 11 WC Marine & Freshwater Biology SC Marine & Freshwater Biology GA CR3RW UT WOS:000361251800010 PM 27642270 ER PT J AU Ma, L Zhao, HQ Xia, QS Cai, LN Fu, PP AF Ma, Liang Zhao, Hengqiang Xia, Qingsu Cai, Lining Fu, Peter P. TI Synthesis and phototoxicity of isomeric 7,9-diglutathione pyrrole adducts: Formation of reactive oxygen species and induction of lipid peroxidation SO JOURNAL OF FOOD AND DRUG ANALYSIS LA English DT Article DE 7,9-diGS-DHP adducts; DHP; LC-ES-MS/MS; pyrrolizidine alkaloid ID ALCOHOL GLUTATHIONE CONJUGATE; PYRROLIZIDINE ALKALOIDS; DNA-ADDUCTS; METABOLIC-ACTIVATION; IN-VIVO; MICROSOMAL FORMATION; DIETARY-SUPPLEMENTS; RETINYL PALMITATE; SINGLET OXYGEN; RAT-LIVER AB Pyrrolizidine alkaloids (PAs) are hepatotoxic, genotoxic, and carcinogenic in experimental animals. Because of their widespread distribution in the world, PA-containing plants are probably the most common poisonous plants affecting livestock, wildlife, and humans. Upon metabolism, PAs generate reactive dehydro-PAs and other pyrrolic metabolites that lead to toxicity. Dehydro-PAs are known to react with glutathione (GSH) to form 7-GSH(+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (7-GS-DHP) in vivo and in vitro and 7,9-diGS-DHP in vitro. To date, the phototoxicity of GS-DHP addUcts has not been well studied. In this study, we synthesized 7-GS-DHP, a tentatively assigned 9-GS-DHP, and two enantiomeric 7,9-diGS-DHP adducts by reaction of dehydromonocrotaline with GSH. The two 7,9-diGS-DHPs were separated by high performance liquid chromatography (HPLC) and their structures were characterized by H-1 nuclear magnetic resonance (NMR) and (H-1H)-H-1 correlation spectroscopy (COSY) NMR spectral analysis. Photoirradiation of 7-GS-DHP, 9-GS-DHP, and the two 7,9-diGS-DHPs as well as dehydromonocrotaline, dehydroheliotrine, and the 7-R enantiomer of DHP (DHR), by UVA light at 0 J/cm(2), 14 J/cm(2), and 35 J/cm(2) in the presence of a lipid, methyl linoleate, all resulted in lipid peroxidation in a light dose-responsive manner. The levels of lipid peroxidation induced by the two isomeric 7,9-diGS-DHPs were significantly higher than that by 7-GS-DHP and 9-GS-DHP. When 7,9-diGS-DHP was irradiated in the presence of sodium azide (NaN3), the level of lipid peroxidation decreased; lipid peroxidation was enhanced when methanol was replaced by deuterated methanol. These results suggest that singlet oxygen is a product induced by the irradiation of 7,9-diGS-DHP. When irradiated in the presence of superoxide dismutase (SOD), the level of lipid peroxidation decreased, indicating that lipid peroxidation is also mediated by superoxide. These results indicate that lipid peroxidation is mediated by reactive oxygen species (ROS). These results suggest that 7,9-diGS-DHPs are phototoxic, generating lipid peroxidation mediated by ROS. Copyright (c) 2015, Food and Drug Administration, Taiwan. Published by Elsevier Taiwan LLC. All rights reserved. C1 [Ma, Liang; Zhao, Hengqiang; Xia, Qingsu; Fu, Peter P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Cai, Lining] Biotranex LLC, Monmouth Jct, NJ 08852 USA. RP Ma, L (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM liangyu84@163.com; peter.fu@fda.hhs.gov FU National Center for Toxicological Research (NCTR) FX We thank Dr. Beland for critical review of this manuscript. This research was supported in part by appointments (L.M.; H.Z.) to the Postgraduate Research Program at the National Center for Toxicological Research (NCTR) administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the Food and Drug Administration (FDA). NR 40 TC 6 Z9 6 U1 1 U2 12 PU FOOD & DRUG ADMINSTRATION PI TAIPEI PA 161-2 KUNYANG STREET, NANGANG, TAIPEI, 00000, TAIWAN SN 1021-9498 J9 J FOOD DRUG ANAL JI J. Food Drug Anal. PD SEP PY 2015 VL 23 IS 3 BP 577 EP 586 DI 10.1016/j.jfda.2015.06.001 PG 10 WC Food Science & Technology; Pharmacology & Pharmacy SC Food Science & Technology; Pharmacology & Pharmacy GA CR3TV UT WOS:000361256900029 ER PT J AU An, YM McCullers, JA Alymova, I Parsons, LM Cipollo, JF AF An, Yanming McCullers, Jonathan A. Alymova, Irina Parsons, Lisa M. Cipollo, John F. TI Glycosylation Analysis of Engineered H3N2 Influenza A Virus Hemagglutinins with Sequentially Added Historically Relevant Glycosylation Sites SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE influenza; hemagglutinin; glycoprotein; glycan; mass spectrometry; glycopeptide; LC-MS; SP-D; antigenic site; H3N2 ID BIOLOGICAL-ACTIVITIES; RECEPTOR-BINDING; RECOGNITION; PREDICTION; INFECTION; ANTIBODY; GLYCANS; MICE AB The influenza virus surface glycoprotein hemagglutinin (HA) is the major target of host neutralizing antibodies. The oligosaccharides of HA can contribute to HA's antigenic characteristics. After a leap to humans from a zoonotic host, influenza can gain N-glycosylation sequons over time as part of its fitness strategy. This glycosylation expansion has not been studied at the structural level. Here we examine HA N-glycosylation of H3N2 virus strains that we have engineered to closely mimic glycosylation sites gained between 1968 through 2002 starting with pandemic A/Hong Kong/1/68 (H3N2: HK68). HAs studied include HK68 and engineered forms with 1, 2, and 4 added sites. We have used: nano-LC-MSE for glycopeptide composition, sequence and site occupancy analysis, and MALDI-TOF MS permethylation profiling for characterization of released glycans. Our study reveals that 1) the majority of N-sequons are occupied at >90%, 2) the class and complexity of the glycans varies by region over the landscape of the proteins, 3) Asn 165 and Asn 246, which are associated with interactions between HA and SP-D lung collectin, are exclusively high mannose type. Based on this study and previous reports we provide structural insight as to how the immune system responses may differ depending on HA glycosylation. C1 [An, Yanming; Parsons, Lisa M.; Cipollo, John F.] Food & Drug Adm, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [McCullers, Jonathan A.; Alymova, Irina] St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. [McCullers, Jonathan A.] Univ Tennessee, Hlth Sci Ctr, Dept Pediat, Memphis, TN 38103 USA. [Alymova, Irina] Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. RP Cipollo, JF (reprint author), Food & Drug Adm, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM john.cipollo@fda.hhs.gov FU ALSAC; CBER Pandemic Flu and Medical Counter Measures targeted internal funds FX This study was funded by ALSAC to J.A.M. and the CBER Pandemic Flu and Medical Counter Measures targeted internal funds to J.F.C. We would like to acknowledge Drs. Ian York and Terry Tumpey of the Influenza Division of the CDC for helpful discussions, and Shane Gansebom of the Infectious Disease Department of St. Jude Children's Research Hospital for technical assistance. NR 41 TC 10 Z9 11 U1 2 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD SEP PY 2015 VL 14 IS 9 BP 3957 EP 3969 DI 10.1021/acs.jproteome.5b00416 PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CR1LU UT WOS:000361087100049 PM 26202417 ER PT J AU Sul, J Krainak, DM AF Sul, Joohee Krainak, Daniel M. TI Brain tumor clinical trials imaging: a (well-standardized) picture is worth a thousand words SO NEURO-ONCOLOGY LA English DT Editorial Material C1 [Sul, Joohee] US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Krainak, Daniel M.] US FDA, Div Radiol Hlth, Off Vitro Diagnost & Radiol Hlth, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Sul, J (reprint author), US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,White Oak 22,Room 2331, Silver Spring, MD 20993 USA. EM joohee.sul@fda.hhs.gov NR 3 TC 0 Z9 0 U1 0 U2 1 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 SEP PY 2015 VL 17 IS 9 BP 1179 EP 1180 DI 10.1093/neuonc/nov158 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CR4MH UT WOS:000361306400001 PM 26293326 ER PT J AU Eworuke, E Zeng, QYL Winterstein, AG AF Eworuke, Efe Zeng, Qian Ya Lensa Winterstein, Almut G. TI Clinical and Sociodemographic Factors Associated With Attention-Deficit/Hyperactivity Disorder in Patients With Cystic Fibrosis SO PSYCHOSOMATICS LA English DT Article ID CHILDREN; ADOLESCENTS; PREVALENCE; DEPRESSION; ADHERENCE; SAMPLE AB Background: There is scarce evidence on the epidemiology of attention-deficit/hyperactivity disorder (ADHD) in patients with cystic fibrosis (CT). Objective: We employed stepwise logistic regression to examine the association between ADHD diagnosis and selected patient characteristics. Methods: This was a cross-sectional analysis of inpatient and outpatient billing data for Medicaid beneficiaries with CF ages 3-18 years to obtain A DJ-ID diagnosis prevalence and incidence estimates from 1999-2006. Results: Annual ADHD prevalence increased 1.55-fold from 5.26% (95% CI 5.25-5.27) to 8.16% (8.15-8.17), and annual ADHD incidence rose slightly from 1.70% (1.70 1.71) to 2.01% (2.00-2.01). As in the general population, males were significantly more likely to have a diagnosis of ADHD compared with females (odds ratio: 1.97 [CI: 1.49-260]), as were children with recent diagnoses of anxiety, emotional disorder, depression, adjustment disorder, and learning, motor, and communication disorders. Patients with ADHD diagnoses were also more likely to be in foster care (odds ratio = 4.36 [CI: 2.26-8.40]). Except for recent DNase use (odds ratio = 0.64 [CI 0.43-0.93), CF severity indicators and medications including pancreatic enzymes, inhaled tobramycin, inhaled or oral corticosteroids, inhaled bronchodilators, and oral antibiotics had no association with A DEW diagnosis. Conclusion: ADHD prevalence in CF increased during the study period. Clinical and sociodemographic determinants of ADHD diagnosis were similar to the general population, whereas treatment and severity of CF appeared to have little influence. Our findings warrant future research evaluating diagnostic protocols and assessment of safety and efficacy of ADHD treatment in children with CF. C1 [Eworuke, Efe; Zeng, Qian Ya Lensa; Winterstein, Almut G.] Univ Florida, Coll Pharm, Dept Pharmaceut Outcomes & Policy, Gainesville, FL USA. [Winterstein, Almut G.] Univ Florida, Coll Med, Dept Epidemiol, Gainesville, FL USA. [Winterstein, Almut G.] Univ Florida, Coll Publ Hlth & Hlth Profess, Dept Epidemiol, Gainesville, FL USA. RP Eworuke, E (reprint author), US FDA, Div Epidemiol 2, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol,Ctr Drug Evaluat & R, Silver Spring, MD 20993 USA. EM efe.eworuke@fda.hhs.gov NR 14 TC 0 Z9 0 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD SEP-OCT PY 2015 VL 56 IS 5 BP 495 EP 503 PG 9 WC Psychiatry; Psychology SC Psychiatry; Psychology GA CR0KD UT WOS:000361006500007 PM 25620567 ER PT J AU Sacks, LV AF Sacks, L. V. TI Creating a global community for clinical drug repurposing and development SO TROPICAL MEDICINE & INTERNATIONAL HEALTH LA English DT Meeting Abstract C1 [Sacks, L. V.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1360-2276 EI 1365-3156 J9 TROP MED INT HEALTH JI Trop. Med. Int. Health PD SEP PY 2015 VL 20 SU 1 SI SI BP 124 EP 124 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CQ7BW UT WOS:000360758800302 ER PT J AU Darpo, B Garnett, C Keirns, J Stockbridge, N AF Darpo, Borje Garnett, Christine Keirns, James Stockbridge, Norman TI Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14 SO DRUG SAFETY LA English DT Article ID ELECTROCARDIOGRAPHIC DATA QUALITY; EARLY QT ASSESSMENT; THOROUGH QT; CLINICAL-PHASE; QT/QTC; PROLONGATION; TRAFFICKING; INTERVAL; SAFETY; REPLACEMENT AB Exposure-response (ER) analysis has evolved as an important tool to evaluate the effect of a drug on cardiac repolarization, as reflected in the QTc interval. It has been suggested that careful electrocardiogram (ECG) evaluation in 'first-in-human' studies using ER analysis could replace or serve as an alternative to the E14 'thorough QT' study. This commentary shares and discusses the results of a recently conducted study with the objective to evaluate this approach. Six drugs with a well-characterized QT effect, five of which are known QT prolongers, were evaluated in a study design similar to a conventional single-ascending-dose study. Each drug was given to nine healthy subjects (six for placebo) in two dose levels, which for the positive drugs (ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide) were chosen with the intent to cause 10-12 ms and 15-20 ms QTc prolongation. Replicate 12-lead ECGs were extracted from continuous recordings pre-dose and serially after dosing and paired with drug concentration determinations. The ER criteria for the identification of a QT effect, a statistically significant positive ER slope and an effect above 10 ms, were met with all five positive drugs, and an effect exceeding 10 ms could be excluded at the supratherapeutic dose of the negative drug, levocetirizine. The study results thereby provided evidence to support that careful QT assessment in early phase clinical studies can be used as an alternative to the thorough QT study. Clinical and regulatory implications, as well as limitations of this approach, are discussed in the commentary. C1 [Darpo, Borje] Karolinska Inst, Danderyds Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden. [Darpo, Borje] ICardiac Technol Inc, Rochester, NY USA. [Garnett, Christine; Stockbridge, Norman] US FDA, Ctr Drug Evaluat & Res, Div Cardiovasc & Renal Prod, Silver Spring, MD USA. [Keirns, James] Astellas Pharma Global Dev Inc, Global Clin Pharmacol & Exploratory Dev, Northbrook, IL USA. RP Darpo, B (reprint author), Karolinska Inst, Danderyds Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden. EM borje.darpo@telia.com FU Consortium for Innovation and Quality in Pharmaceutical Development; Cardiac Safety Research Consortium; FDA; iCardiac Technologies, Rochester, New York, USA FX The IQ-CSRC study discussed in this commentary was supported by the Consortium for Innovation and Quality in Pharmaceutical Development, the Cardiac Safety Research Consortium, and by the FDA. The study was sponsored and funded by iCardiac Technologies, Rochester, New York, USA. No sources of funding were used to assist in the preparation of this manuscript. NR 42 TC 10 Z9 10 U1 0 U2 1 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0114-5916 EI 1179-1942 J9 DRUG SAFETY JI Drug Saf. PD SEP PY 2015 VL 38 IS 9 BP 773 EP 780 DI 10.1007/s40264-015-0325-5 PG 8 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA CQ9ME UT WOS:000360938200002 PM 26162419 ER PT J AU Kesselheim, AS Campbell, EG Schneeweiss, S Rausch, P Lappin, BM Zhou, EH Seeger, JD Brownstein, JS Woloshin, S Schwartz, LM Toomey, T Dal Pan, GJ Avorn, J AF Kesselheim, Aaron S. Campbell, Eric G. Schneeweiss, Sebastian Rausch, Paula Lappin, Brian M. Zhou, Esther H. Seeger, John D. Brownstein, John S. Woloshin, Steven Schwartz, Lisa M. Toomey, Timothy Dal Pan, Gerald J. Avorn, Jerry TI Methodological Approaches to Evaluate the Impact of FDA Drug Safety Communications (vol 38, pg 565, 2015) SO DRUG SAFETY LA English DT Correction C1 [Kesselheim, Aaron S.; Schneeweiss, Sebastian; Seeger, John D.; Toomey, Timothy; Avorn, Jerry] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Program Regulat Therapeut & Law PORTAL, Boston, MA 02120 USA. [Kesselheim, Aaron S.; Campbell, Eric G.; Schneeweiss, Sebastian; Seeger, John D.; Brownstein, John S.; Toomey, Timothy; Avorn, Jerry] Harvard Univ, Sch Med, Boston, MA 02120 USA. [Campbell, Eric G.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy Res, Boston, MA 02114 USA. [Rausch, Paula] Food & Drug Adm, Ctr Drug Evaluat & Res, Off Commun, Silver Spring, MD 20993 USA. [Lappin, Brian M.] Food & Drug Adm, Off Commissioner, Off Planning, Silver Spring, MD 20993 USA. [Zhou, Esther H.] Food & Drug Adm, Ctr Drug Evaluat & Res, Off Surveillance & Epidemiol, Silver Spring, MD 20993 USA. [Brownstein, John S.] Childrens Hosp, Childrens Hosp Epidemiol Grp, Boston, MA 02115 USA. [Woloshin, Steven; Schwartz, Lisa M.] Dartmouth Inst Hlth Policy & Clin Practice, Ctr Med & Media, Lebanon, NH USA. [Dal Pan, Gerald J.] Food & Drug Adm, Ctr Drug Evaluat & Res, Off Surveillance & Epidemiol, Silver Spring, MD 20993 USA. RP Kesselheim, AS (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Program Regulat Therapeut & Law PORTAL, Suite 3030,1620 Tremont St, Boston, MA 02120 USA. EM akesselheim@partners.org RI Schneeweiss, Sebastian/C-2125-2013 NR 1 TC 0 Z9 0 U1 0 U2 1 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0114-5916 EI 1179-1942 J9 DRUG SAFETY JI Drug Saf. PD SEP PY 2015 VL 38 IS 9 BP 845 EP 845 DI 10.1007/s40264-015-0329-1 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA CQ9ME UT WOS:000360938200009 PM 26201399 ER PT J AU Ciolino, LA AF Ciolino, Laura A. TI Quantitation of Synthetic Cannabinoids in Plant Materials Using High Performance Liquid Chromatography with UV Detection (Validated Method) SO JOURNAL OF FORENSIC SCIENCES LA English DT Article DE forensic science; synthetic cannabinoids; synthetic marijuana; synthetic cannabis; quantitative analysis; plant products; herbals; high performance liquid chromatography-ultraviolet detection; validated method ID IDENTIFICATION; RECEPTOR; SPICE; BLENDS; STATES; 1ST AB Plant based products laced with synthetic cannabinoids have become popular substances of abuse over the last decade. Quantitative analysis for synthetic cannabinoid content in the laced materials is necessary for health hazard assessments addressing overall exposure and toxicity when the products are smoked. A validated, broadly applicable HPLC-UV method for the determination of synthetic cannabinoids in plant materials is presented, using acetonitrile extraction and separation on a commercial phenylhexyl stationary phase. UV detection provides excellent sensitivity with limits of quantitation (LOQs) less than 10g/g for many cannabinoids. The method was validated for several structural classes (dibenzopyrans, cyclohexylphenols, naphthoylindoles, benzoylindoles, phenylacetylindoles, tetramethylcyclopropylindoles) based on spike recovery experiments in multiple plant materials over a wide cannabinoid contents range (0.1-81mg/g). Average recovery across 32 cannabinoids was 94% for marshmallow leaf, 95% for damiana leaf, and 92% for mullein leaf. The method was applied to a series of case-related products with determined amounts ranging from 0.2 to >100mg/g. C1 US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. RP Ciolino, LA (reprint author), US FDA, Forens Chem Ctr, 6751 Steger Dr, Cincinnati, OH 45237 USA. EM laura.ciolino@fda.hhs.gov NR 30 TC 1 Z9 1 U1 6 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-1198 EI 1556-4029 J9 J FORENSIC SCI JI J. Forensic Sci. PD SEP PY 2015 VL 60 IS 5 BP 1171 EP 1181 DI 10.1111/1556-4029.12795 PG 11 WC Medicine, Legal SC Legal Medicine GA CR0CE UT WOS:000360985000008 PM 26175160 ER PT J AU Wei, L Scott, J AF Wei, Lai Scott, John TI Association rule mining in the US Vaccine Adverse Event Reporting System (VAERS) SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE data mining; association rule discovery; signal detection; spontaneous reporting system; vaccine safety; pharmacoepidemiology ID SIGNAL-DETECTION; FEBRILE SEIZURES; SAFETY; DATABASE; RATIO; SURVEILLANCE; ALGORITHMS; GENERATION; RISK AB PurposeSpontaneous adverse event reporting systems are critical tools for monitoring the safety of licensed medical products. Commonly used signal detection algorithms identify disproportionate product-adverse event pairs and may not be sensitive to more complex potential signals. We sought to develop a computationally tractable multivariate data-mining approach to identify product-multiple adverse event associations. MethodsWe describe an application of stepwise association rule mining (Step-ARM) to detect potential vaccine-symptom group associations in the US Vaccine Adverse Event Reporting System. Step-ARM identifies strong associations between one vaccine and one or more adverse events. To reduce the number of redundant association rules found by Step-ARM, we also propose a clustering method for the post-processing of association rules. ResultsIn sample applications to a trivalent intradermal inactivated influenza virus vaccine and to measles, mumps, rubella, and varicella (MMRV) vaccine and in simulation studies, we find that Step-ARM can detect a variety of medically coherent potential vaccine-symptom group signals efficiently. In the MMRV example, Step-ARM appears to outperform univariate methods in detecting a known safety signal. ConclusionsOur approach is sensitive to potentially complex signals, which may be particularly important when monitoring novel medical countermeasure products such as pandemic influenza vaccines. The post-processing clustering algorithm improves the applicability of the approach as a screening method to identify patterns that may merit further investigation. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Wei, Lai; Scott, John] US FDA, Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, Div Biostat, Silver Spring, MD 20993 USA. RP Scott, J (reprint author), US FDA, Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, Div Biostat, 10903 New Hampshire Ave,Bldg 71 Rm 1018, Silver Spring, MD 20993 USA. EM John.Scott@fda.hhs.gov OI Scott, John/0000-0002-9116-948X NR 40 TC 1 Z9 1 U1 1 U2 5 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 SEP PY 2015 VL 24 IS 9 BP 922 EP 933 DI 10.1002/pds.3797 PG 12 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA CQ7DY UT WOS:000360764300004 PM 26045284 ER PT J AU Klontz, KC DeBeck, HJ LeBlanc, P Mogen, KM Wolpert, BJ Sabo, JL Salter, M Seelman, SL Lance, SE Monahan, C Steigman, DS Gensheimer, K AF Klontz, Karl C. DeBeck, Heidi J. LeBlanc, Pamela Mogen, Kathryn M. Wolpert, Beverly J. Sabo, Jonathan L. Salter, Monique Seelman, Sharon L. Lance, Susan E. Monahan, Caitlin Steigman, David S. Gensheimer, Kathleen TI The Role of Adverse Event Reporting in the FDA Response to a Multistate Outbreak of Liver Disease Associated with a Dietary Supplement SO PUBLIC HEALTH REPORTS LA English DT Article ID SAFETY; DEATH; DMAA AB Objective. Liver disease is a potential complication from using dietary supplements. This study investigated an outbreak of non-viral liver disease associated with the use of OxyELITE Pro (TM), a dietary supplement used for weight loss and/or muscle building. Methods. Illness details were ascertained from MedWatch reports submitted to the U.S. Food and Drug Administration (FDA) describing consumers who ingested OxyELITE Pro alone or in combination with other dietary supplements. FDA's Forensic Chemistry Center analyzed samples of OxyELITE Pro. Results. From February 2012 to February 2014, FDA received 114 reports of adverse events of all kinds involving consumers who ingested OxyELITE Pro. The onset of illness for the first report was December 2010 and for the last report was January 2014. Thirty-three states, two foreign nations, and Puerto Rico submitted reports. Fifty-five of the reports (48%) described liver disease in the absence of viral infection, gallbladder disease, autoimmune disease, or other known causes of liver damage. A total of 33 (60%) of these patients were hospitalized, and three underwent liver transplantation. In early 2013, OxyELITE Pro products entered the market with a formulation distinct from products sold previously. The new formulation replaced 1,3-dimethylamylamine with aegeline. However, the manufacturer failed to submit to FDA a required "new dietary ingredient" notice for the use of aegeline in OxyELITE Pro products. Laboratory analysis identified no drugs, poisons, pharmaceuticals, toxic metals, usnic acid, N-Nitroso-fenfluramine, pyrrolizidine alkaloids, aristocholic acid, or phenethylamines in the products. Conclusions. Vigilant surveillance is required for adverse events linked to the use of dietary supplements. C1 [Klontz, Karl C.; Wolpert, Beverly J.] US FDA, Ctr Food Safety & Appl Nutr, Off Analyt & Outreach, College Pk, MD 20742 USA. [DeBeck, Heidi J.; LeBlanc, Pamela; Salter, Monique; Seelman, Sharon L.; Lance, Susan E.; Monahan, Caitlin; Steigman, David S.; Gensheimer, Kathleen] US FDA, Off Foods & Vet Med, Coordinated Outbreak Response & Evaluat Network, College Pk, MD 20742 USA. [Mogen, Kathryn M.] US FDA, Off Regulatory Affairs, Silver Spring, MD USA. [Sabo, Jonathan L.] US FDA, Ctr Vet Med, Res Off, Laurel, MD USA. RP Klontz, KC (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Analyt & Outreach, 5100 Paint Branch Pkwy, College Pk, MD 20742 USA. EM karl.klontz@fda.hhs.gov NR 18 TC 8 Z9 8 U1 2 U2 8 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 SEP-OCT PY 2015 VL 130 IS 5 BP 526 EP 532 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CR1KX UT WOS:000361084800015 PM 26327730 ER PT J AU Lam, E Garhyan, P Linnebjerg, H Choi, S Knadler, MP Sinha, VP Sassenfeld, BM Nosek, L Heise, T AF Lam, E. Garhyan, P. Linnebjerg, H. Choi, S. Knadler, M. P. Sinha, V. P. Sassenfeld, B. M. Nosek, L. Heise, T. TI Reduced intra-subject variability of Basal Insulin peglispro (BIL) compared to insulin Glargine (GL) in patients with type 1 diabetes mellitus Abstracts SO DIABETOLOGIA LA English DT Meeting Abstract CT 51st Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD) CY SEP 14-18, 2015 CL Stockholm, SWEDEN SP European Assoc Study Diabet C1 [Lam, E.; Choi, S.] Lilly NUS Ctr Clin Pharmacol Pte Ltd, Singapore, Singapore. [Garhyan, P.; Linnebjerg, H.; Knadler, M. P.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Sinha, V. P.] US FDA, Silver Spring, MD USA. [Sassenfeld, B. M.; Nosek, L.; Heise, T.] Profil, Neuss, Germany. NR 0 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2015 VL 58 SU 1 MA 2 BP S1 EP S2 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CP3ZE UT WOS:000359820900003 ER PT J AU Linnebjerg, H Lam, E Choi, S Knadler, MP Porksen, N Sinha, VP Garhyan, P Klein, O Nosek, L Heise, T AF Linnebjerg, H. Lam, E. Choi, S. Knadler, M. P. Porksen, N. Sinha, V. P. Garhyan, P. Klein, O. Nosek, L. Heise, T. TI Effect of exercise on Pharmacokinetics (PK) of Basal Insulin peglispro (BIL) and insulin Glargine (GL) in type 1 diabetes mellitus patients SO DIABETOLOGIA LA English DT Meeting Abstract CT 51st Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD) CY SEP 14-18, 2015 CL Stockholm, SWEDEN SP European Assoc Study Diabet C1 [Linnebjerg, H.; Knadler, M. P.; Porksen, N.; Garhyan, P.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Lam, E.; Choi, S.] Lilly NUS Ctr Clin Pharmacol Pte Ltd, Singapore, Singapore. [Sinha, V. P.] US FDA, Silver Spring, MD USA. [Klein, O.; Nosek, L.; Heise, T.] Profil, Neuss, Germany. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2015 VL 58 SU 1 MA 325 BP S164 EP S164 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CP3ZE UT WOS:000359820901015 ER PT J AU Ting, TY Jiang, WL Lionberger, R Wong, J Jones, JW Kane, MA Krumholz, A Temple, R Polli, JE AF Ting, Tricia Y. Jiang, Wenlei Lionberger, Robert Wong, Jessica Jones, Jace W. Kane, Maureen A. Krumholz, Allan Temple, Robert Polli, James E. TI Generic lamotrigine versus brand-name Lamictal bioequivalence in patients with epilepsy: A field test of the FDA bioequivalence standard SO EPILEPSIA LA English DT Article DE Bioequivalence; Switchability; Lamotrigine; Generic-brittle; Narrow therapeutic index ID KIDNEY-TRANSPLANT RECIPIENTS; THERAPEUTIC INDEX DRUGS; ANTIEPILEPTIC DRUGS; IMMUNOSUPPRESSIVE DRUGS; ORGAN-TRANSPLANTATION; TACROLIMUS; SUBSTITUTION; PRODUCTS; SOCIETY; PROGRAF AB ObjectiveTo test the current U.S. Food and Drug Administration (FDA) bioequivalence standard in a comparison of generic and brand-name drug pharmacokinetic (PK) performance in generic-brittle patients with epilepsy under clinical use conditions. MethodsThis randomized, double-blind, multiple-dose, steady-state, fully replicated bioequivalence study compared generic lamotrigine to brand-name Lamictal in generic-brittle patients with epilepsy (n=34) who were already taking lamotrigine. Patients were repeatedly switched between masked Lamictal and generic lamotrigine. Intensive PK blood sampling at the end of each 2-week treatment period yielded two 12-h PK profiles for brand-name and generic forms for each patient. Steady-state area under the curve (AUC), peak plasma concentration (C-max), and minimum plasma concentration (C-min) data were subjected to conventional average bioequivalence (ABE) analysis, reference-scaled ABE analysis, and within-subject variability (WSV) comparisons. In addition, generic-versus-brand comparisons in individual patients were performed. Secondary clinical outcomes included seizure frequency and adverse events. ResultsGeneric demonstrated bioequivalence to brand. The 90% confidence intervals of the mean for steady-state AUC, C-max, and C-min for generic-versus-brand were 97.2-101.6%, 98.8-104.5%, and 93.4-101.0%, respectively. The WSV of generic and brand were also similar. Individual patient PK ratios for generic-versus-brand were similar but not identical, in part because brand-versus-brand profiles were not identical, even though subjects were rechallenged with the same product. Few subjects had seizure exacerbations or tolerability issues with product switching. One subject, however, reported 267 focal motor seizures, primarily on generic, although his brand and generic PK profiles were practically identical. SignificanceSome neurologists question whether bioequivalence in healthy volunteers ensures therapeutic equivalence of brand and generic antiepileptic drugs in patients with epilepsy, who may be at increased risk for problems with brand-to-generic switching. Bioequivalence results in generic-brittle patients with epilepsy under clinical conditions support the soundness of the FDA bioequivalence standards. Adverse events on generic were not related to the small, allowable PK differences between generic and brand. C1 [Ting, Tricia Y.; Krumholz, Allan] Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. [Jiang, Wenlei; Lionberger, Robert; Temple, Robert] US FDA, White Oak, MD USA. [Wong, Jessica; Jones, Jace W.; Kane, Maureen A.; Polli, James E.] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. RP Polli, JE (reprint author), Univ Maryland, Dept Pharmaceut Sci, 20 Penn St, Baltimore, MD 21201 USA. EM jpolli@rx.umaryland.edu FU FDA [HHSF223201010144A]; University of Maryland Clinical Translational Science Institute; University of Maryland General Clinical Research Center FX Supported by FDA contract HHSF223201010144A. This work was supported in part by the University of Maryland Clinical Translational Science Institute and the University of Maryland General Clinical Research Center. We thank Virginia Ganley for clinical research support. NR 42 TC 14 Z9 14 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD SEP PY 2015 VL 56 IS 9 BP 1415 EP 1424 DI 10.1111/epi.13095 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA CQ7PF UT WOS:000360795400017 PM 26201987 ER PT J AU Larson, BR Barrett, SC Hatcliff, J Zhang, Y Jones, PL AF Larson, Brian R. Barrett, Stephen C. Hatcliff, John Zhang, Yi Jones, Paul L. TI Enabling Safe Interoperation by Medical Device Virtual Integration SO IEEE DESIGN & TEST LA English DT Article C1 [Larson, Brian R.; Hatcliff, John] Kansas State Univ, Comp & Informat Sci Dept, Manhattan, KS 66502 USA. [Barrett, Stephen C.] Kansas State Univ, Manhattan, KS 66502 USA. [Zhang, Yi] US FDA, Ctr Devices & Radiol Hlth, White Oak, MD USA. [Jones, Paul L.] US FDA, White Oak, MD USA. RP Hatcliff, J (reprint author), Kansas State Univ, Comp & Informat Sci, Manhattan, KS 66502 USA. EM hatcliff@ksu.edu FU NSF/FDA Scholar in Residence [1355778, 1446544]; NSF CPS [1239543]; CIMIT/Massachusetts General Hospital as a sub-contract of a NIH/NIBIB Quantum grant FX This work was supported by NSF/FDA Scholar in Residence under Grant 1355778 and Grant 1446544, by NSF CPS under Grant 1239543, and by CIMIT/Massachusetts General Hospital as a sub-contract of a NIH/NIBIB Quantum grant. NR 18 TC 0 Z9 0 U1 0 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2168-2356 J9 IEEE DES TEST JI IEEE Des. Test PD SEP-OCT PY 2015 VL 32 IS 5 SI SI BP 74 EP 88 DI 10.1109/MDAT.2015.2464813 PG 15 WC Computer Science, Hardware & Architecture; Engineering, Electrical & Electronic SC Computer Science; Engineering GA CQ8GQ UT WOS:000360845300010 ER PT J AU Tesh, LD Shaeer, KM Cho, JC Estrada, SJ Huang, V Bland, CM DiMondi, VP Potter, AN Hussein, G Bookstaver, PB AF Tesh, Lauren D. Shaeer, Kristy M. Cho, Jonathan C. Estrada, Sandy J. Huang, Vanthida Bland, Christopher M. DiMondi, V. Paul Potter, Alicia N. Hussein, Gamal Bookstaver, P. Brandon TI Neisseria gonorrhoeae and fosfomycin: Past, present and future SO INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS LA English DT Review DE Neisseria gonorrhoeae; Fosfomycin; Gonorrhoea; Multidrug-resistant; In vitro ID INFECTIOUS-DISEASES-SOCIETY; IN-VITRO SYNERGY; BAD BUGS; RESISTANCE; AMERICA; PHOSPHONOMYCIN; CEFTRIAXONE; COMBINATION; UPDATE; DRUGS AB Drug-resistant Neisseria gonorrhoeae has become a global health concern that requires immediate attention. Due to increasing resistance to cephalosporins, pursuing novel alternatives for treating N. gonorrhoeae infections is paramount. Whilst new drug development is often cumbersome, reviving antiquated antibiotic agents for treatment of modern infections has become prevalent in clinical practice. Fosfomycin exhibits bactericidal activity through a unique mechanism of action, and a variety of organisms including N. gonorrhoeae are susceptible. In vitro studies have demonstrated that fosfomycin can retain activity against ceftriaxone-resistant N. gonorrhoeae; however, it remains unclear whether there is synergy between fosfomycin and other antibiotics. Clinical investigations evaluating fosfomycin for the treatment of N. gonorrhoeae infections are confounded by methodological limitations, none the less they do provide some perspective on its potential role in therapy. Future studies are needed to establish a safe, convenient and effective fosfomycin regimen for treating N. gonorrhoeae infections. Published by Elsevier B.V. on behalf of International Society of Chemotherapy. C1 [Tesh, Lauren D.] US FDA, Div Advisory Comm & Consultant Management, Off Execut Programs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Shaeer, Kristy M.] Univ S Florida, Coll Pharm, Dept Pharmacotherapeut & Clin Res, Tampa, FL 33612 USA. [Cho, Jonathan C.] Univ Texas Tyler, Coll Pharm, Dept Clin Sci, Tyler, TX 75799 USA. [Estrada, Sandy J.] Lee Mem Hlth Syst, Dept Pharm, Ft Myers, FL 33919 USA. [Huang, Vanthida] Midwestern Univ, Coll Pharm Glendale, Dept Pharm Practice, Glendale, AZ 85308 USA. [Bland, Christopher M.] Univ Georgia, Coll Pharm, Dept Clin & Adm Pharm, Savannah, GA 31405 USA. [DiMondi, V. Paul] Campbell Univ, Coll Pharm & Hlth Sci, Dept Pharm Practice, Buies Creek, NC 27506 USA. [Potter, Alicia N.; Hussein, Gamal] South Coll Sch Pharm, Dept Pharm Practice, Knoxville, TN 37922 USA. [Bookstaver, P. Brandon] Univ S Carolina, South Carolina Coll Pharm, Dept Clin Pharm & Outcomes Sci, Columbia, SC 29208 USA. RP Tesh, LD (reprint author), US FDA, Div Advisory Comm & Consultant Management, Off Execut Programs, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,WO31-2417, Silver Spring, MD 20993 USA. EM laurentesh@aol.com OI Tesh, Lauren/0000-0001-9674-8424 FU Actavis FX SJE has served on a speaker's bureau for Cubist Pharmaceuticals and on advisory boards for Cubist Pharmaceuticals and Theravance Pharmaceuticals; VH has served on a speaker's bureau/advisory board for Theravance Biopharma, Inc.; CMB has served on a speaker's bureau for Cubist Pharmaceuticals and on advisory boards for Cubist Pharmaceuticals and Theravance Pharmaceuticals; PBB has served on a research advisory board for and has received research funding from Durata Therapeutics, now Actavis. All other authors declare no competing interests. NR 37 TC 2 Z9 2 U1 2 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-8579 EI 1872-7913 J9 INT J ANTIMICROB AG JI Int. J. Antimicrob. Agents PD SEP PY 2015 VL 46 IS 3 BP 290 EP 296 DI 10.1016/j.ijantimicag.2015.05.007 PG 7 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA CQ6HT UT WOS:000360706000010 PM 26145201 ER PT J AU Meany, HJ Seibel, NL Krailo, M Villaluna, D Chen, ZJ Gaynon, P Neglia, JP Park, JR Hutchinson, R Sato, JK Wells, RJ Woods, WG Reaman, G AF Meany, Holly J. Seibel, Nita L. Krailo, Mark Villaluna, Doojduen Chen, Zhengjia Gaynon, Paul Neglia, Joseph P. Park, Julie R. Hutchinson, Raymond Sato, Judith K. Wells, Robert J. Woods, William G. Reaman, Gregory TI Feasibility Study of a Novel Experimental Induction Protocol Combining B43-PAP (Anti-CD19) Immunotoxin With Standard Induction Chemotherapy in Children and Adolescents With Relapsed B-Lineage ALL: A Report From the Children's Oncology Group SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE anti-CD19 immunotoxin; immunotherapy; relapsed B-lineage ALL ID ACUTE LYMPHOBLASTIC-LEUKEMIA; BONE-MARROW RELAPSE; POKEWEED ANTIVIRAL PROTEIN; CANCER-GROUP; INTENSIVE CHEMOTHERAPY; MONOCLONAL-ANTIBODY; LYMPHOMA CELL; IN-VITRO; P-GP; THERAPY AB Background:B43-pokeweed antiviral protein (B43-PAP) is a high-affinity anti-CD19 immunotoxin that is capable of causing apoptotic death in B-lineage leukemic cells with a drug-resistant phenotype. B43-PAP exhibited in vivo antileukemic activity in preclinical studies as well as on a single-agent phase I clinical trial. This pediatric phase I/II study evaluated the toxicity profile and efficacy of B43-PAP immunotoxin in combination with standard induction chemotherapy in children and adolescents with relapsed CD19-positive B-lineage acute lymphoblastic leukemia (B-ALL). Pharmacokinetic profile and immunogenicity of B43-PAP were assessed.Experimental Design:B43-PAP in combination with standard 3 and 4-drug induction chemotherapy was administered on days 9-13 and 21-25 of a 28-day treatment course with vincristine, prednisone, l-asparaginase, daunomycin, and intrathecal methotrexate. Thirty patients with relapsed B-ALL were enrolled on study CCG-0957.Results:Grade III/IV nonhematologic dose-limiting toxicities were encountered in 4 patients evaluable for toxicity and included myalgias, motor dysfunction, pulmonary toxicity, and elevated liver transaminase. Dose-limiting toxicities occurred only with the 4-drug regimen. Fourteen patients achieved a complete remission at the end of induction among the 20 patients evaluable for response.Conclusions:B43-PAP in combination with standard induction chemotherapy can be safely administered and exhibits clinical antileukemic activity against relapsed B-ALL. C1 [Meany, Holly J.] George Washington Univ, Childrens Natl Med Ctr, Sch Med & Publ Hlth, Dept Pediat Hematol Oncol, Washington, DC USA. [Seibel, Nita L.] NCI, Clin Invest Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Reaman, Gregory] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Krailo, Mark] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Gaynon, Paul] Childrens Hosp Los Angeles, Div Hematol Oncol, Los Angeles, CA 90027 USA. [Villaluna, Doojduen] Childrens Oncol Grp, Arcadia, CA USA. [Sato, Judith K.] City Hope Natl Med Ctr, Dept Pediat, Duarte, CA 91010 USA. [Chen, Zhengjia] Emory Univ, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Woods, William G.] Emory Univ, Childrens Healthcare Atlanta, Aflac Canc & Blood Disorder Ctr, Atlanta, GA 30322 USA. [Neglia, Joseph P.] Univ Minnesota, Sch Med, Dept Pediat, Minneapolis, MN 55455 USA. [Park, Julie R.] Univ Washington, Dept Pediat, Seattle Childrens Hosp, Seattle, WA 98195 USA. [Hutchinson, Raymond] Univ Michigan, CS Mott Childrens Hosp, Pediat Hematol Oncol, Ann Arbor, MI 48109 USA. [Wells, Robert J.] Univ Texas MD Anderson Canc Ctr, Childrens Canc Hosp, Div Pediat, Houston, TX 77030 USA. RP Meany, HJ (reprint author), Childrens Natl Med Ctr, Dept Pediat Hematol Oncol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM hmeany@childrensnational.org FU NCTN Operation Center Grant [CA180886]; Statistics and Data Center Grant [CA98413]; NCTN Statistics and Data Center Grant [CA180899]; [CA98543] FX Supported by study grants CA98543 (Chair's Grant), CA180886 (NCTN Operation Center Grant), CA98413 (Statistics and Data Center Grant), CA180899 (NCTN Statistics and Data Center Grant). NR 45 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1524-9557 EI 1537-4513 J9 J IMMUNOTHER JI J. Immunother. PD SEP PY 2015 VL 38 IS 7 BP 299 EP 305 DI 10.1097/CJI.0000000000000088 PG 7 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA CQ4QB UT WOS:000360588600006 PM 26261894 ER PT J AU Wittenberg, JB Canas, BJ Zhou, WL Wang, PG Rua, D Krynitsky, AJ AF Wittenberg, James B. Canas, Benjamin J. Zhou, Wanlong Wang, Perry G. Rua, Diego Krynitsky, Alexander J. TI Determination of methylisothiazolinone and methylchloroisothiazolinone in cosmetic products by ultra high performance liquid chromatography with tandem mass spectrometry SO JOURNAL OF SEPARATION SCIENCE LA English DT Article DE Cosmetics; Methylchloroisothiazolinone; Methylisothiazolinone; Preservatives ID KATHON-CG; ISOTHIAZOLINONE BIOCIDES; CONTACT ALLERGY; PRESERVATIVES; MATRICES AB Isothiazolinone biocides are broad-spectrum preservatives that are widely used in cosmetics, household, and industrial products. An increase in the number of cases of allergic contact dermatitis to isothiazolinone preservatives, namely, methylisothiazolinone and methylchloroisothiazolinone, have been recently noticed. The Food and Drug Administration relies on analytical methods to quantify levels of use of cosmetic ingredients and support enforcement action against products that are not in compliance with the law. In this study, an efficient ultra high performance liquid chromatography with tandem mass spectrometry method was developed and validated for the determination of methylisothiazolinone and methylchloroisothiazolinone in selected cosmetic products. The lower limit of quantitation was determined to be 0.1 mu g/g for both preservatives. A survey of 24 cosmetic products was conducted and found concentrations of methylisothiazolinone and methylchloroisothiazolinone ranging from not quantified, or below the lower limit of quantitation, to 89.64 mu g/g and not quantified to 10.31 mu g/g, respectively. C1 [Wittenberg, James B.; Canas, Benjamin J.; Zhou, Wanlong; Wang, Perry G.; Rua, Diego; Krynitsky, Alexander J.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Wittenberg, JB (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy,HFS-717, College Pk, MD 20740 USA. EM James.Wittenberg@fda.hhs.gov NR 20 TC 3 Z9 3 U1 10 U2 23 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1615-9306 EI 1615-9314 J9 J SEP SCI JI J. Sep. Sci. PD SEP PY 2015 VL 38 IS 17 BP 2983 EP 2988 DI 10.1002/jssc.201500365 PG 6 WC Chemistry, Analytical SC Chemistry GA CQ8BK UT WOS:000360830900008 PM 26103935 ER PT J AU Kontson, K Jennings, RJ AF Kontson, Kimberly Jennings, Robert J. TI Bowtie filters for dedicated breast CT: Analysis of bowtie filter material selection SO MEDICAL PHYSICS LA English DT Article DE breast CT; dynamic range; bowtie filters ID CONE-BEAM CT; X-RAY SCATTER; COMPUTED-TOMOGRAPHY; IMAGE QUALITY; SPECTRAL OPTIMIZATION; DETECTOR ARRAYS; RADIATION; FEASIBILITY; MAMMOGRAPHY; PROTOTYPE AB Purpose: For a given bowtie filter design, both the selection of material and the physical design control the energy fluence, and consequently the dose distribution, in the object. Using three previously described bowtie filter designs, the goal of this work is to demonstrate the effect that different materials have on the bowtie filter performance measures. Methods: Three bowtie filter designs that compensate for one or more aspects of the beam-modifying effects due to the differences in path length in a projection have been designed. The nature of the designs allows for their realization using a variety of materials. The designs were based on a phantom, 14 cm in diameter, composed of 40% fibroglandular and 60% adipose tissue. Bowtie design #1 is based on single material spectral matching and produces nearly uniform spectral shape for radiation incident upon the detector. Bowtie design #2 uses the idea of basis-material decomposition to produce the same spectral shape and intensity at the detector, using two different materials. With bowtie design #3, it is possible to eliminate the beam hardening effect in the reconstructed image by adjusting the bowtie filter thickness so that the effective attenuation coefficient for every ray is the same. Seven different materials were chosen to represent a range of chemical compositions and densities. After calculation of construction parameters for each bowtie filter design, a bowtie filter was created using each of these materials (assuming reasonable construction parameters were obtained), resulting in a total of 26 bowtie filters modeled analytically and in the PENELOPE Monte Carlo simulation environment. Using the analytical model of each bowtie filter, design profiles were obtained and energy fluence as a function of fan-angle was calculated. Projection images with and without each bowtie filter design were also generated using PENELOPE and reconstructed using FBP. Parameters such as dose distribution, noise uniformity, and scatter were investigated. Results: Analytical calculations with and without each bowtie filter show that some materials for a given design produce bowtie filters that are too large for implementation in breast CT scanners or too small to accurately manufacture. Results also demonstrate the ability to manipulate the energy fluence distribution (dynamic range) by using different materials, or different combinations of materials, for a given bowtie filter design. This feature is especially advantageous when using photon counting detector technology. Monte Carlo simulation results from PENELOPE. show that all studied material choices for bowtie design #2 achieve nearly uniform dose distribution, noise uniformity index less than 5%, and nearly uniform scatter-to-primary ratio. These same features can also be obtained using certain materials with bowtie designs #1 and #3. Conclusions: With the three bowtie filter designs used in this work, the selection of material is an important design consideration. An appropriate material choice can improve image quality, dose uniformity, and dynamic range. (C) 2015 American Association of Physicists in Medicine. C1 [Kontson, Kimberly] Univ Maryland, Dept Bioengn, College Pk, MD 20742 USA. US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Kontson, K (reprint author), Univ Maryland, Dept Bioengn, College Pk, MD 20742 USA. EM Kimberly.Kontson@fda.hhs.gov OI KONTSON, KIMBERLY/0000-0002-4978-6011 FU U.S. Food and Drug Administration's Office of Women's Health FX The authors would like to acknowledge funding from the U.S. Food and Drug Administration's Office of Women's Health and by appointments to the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 34 TC 1 Z9 1 U1 0 U2 3 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD SEP PY 2015 VL 42 IS 9 BP 5270 EP 5277 DI 10.1118/1.4928476 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CQ5LG UT WOS:000360645000027 PM 26328976 ER PT J AU Klein, MM Treister, R Raij, T Pascual-Leone, A Park, L Nurmikko, T Lenz, F Lefaucheur, JP Lang, M Hallett, M Fox, M Cudkowicz, M Costello, A Carr, DB Ayache, SS Oaklander, AL AF Klein, Max M. Treister, Roi Raij, Tommi Pascual-Leone, Alvaro Park, Lawrence Nurmikko, Turo Lenz, Fred Lefaucheur, Jean-Pascal Lang, Magdalena Hallett, Mark Fox, Michael Cudkowicz, Merit Costello, Ann Carr, Daniel B. Ayache, Samar S. Oaklander, Anne Louise TI Transcranial magnetic stimulation of the brain: guidelines for pain treatment research SO PAIN LA English DT Review DE Neuropathic pain; Neuromodulation; Treatment; Human; Device ID MOTOR CORTEX STIMULATION; SHAM-CONTROLLED TRIAL; SPINAL-CORD-INJURY; CHRONIC NEUROPATHIC PAIN; SYNDROME TYPE-I; THETA-BURST STIMULATION; CENTRAL POSTSTROKE PAIN; SMALL-FIBER NEUROPATHY; DOUBLE-BLIND; MULTIPLE-SCLEROSIS AB Recognizing that electrically stimulating the motor cortex could relieve chronic pain sparked development of noninvasive technologies. In transcranial magnetic stimulation (TMS), electromagnetic coils held against the scalp influence underlying cortical firing. Multiday repetitive transcranial magnetic stimulation (rTMS) can induce long-lasting, potentially therapeutic brain plasticity. Nearby ferromagnetic or electronic implants are contraindications. Adverse effects are minimal, primarily headaches. Single provoked seizures are very rare. Transcranial magnetic stimulation devices are marketed for depression and migraine in the United States and for various indications elsewhere. Although multiple studies report that high-frequency rTMS of the motor cortex reduces neuropathic pain, their quality has been insufficient to support Food and Drug Administration application. Harvard's Radcliffe Institute therefore sponsored a workshop to solicit advice from experts in TMS, pain research, and clinical trials. They recommended that researchers standardize and document all TMS parameters and improve strategies for sham and double blinding. Subjects should have common well-characterized pain conditions amenable to motor cortex rTMS and studies should be adequately powered. They recommended standardized assessment tools (eg, NIH's PROMIS) plus validated condition-specific instruments and consensus-recommended metrics (eg, IMMPACT). Outcomes should include pain intensity and qualities, patient and clinician impression of change, and proportions achieving 30% and 50% pain relief. Secondary outcomes could include function, mood, sleep, and/or quality of life. Minimum required elements include sample sources, sizes, and demographics, recruitment methods, inclusion and exclusion criteria, baseline and posttreatment means and SD, adverse effects, safety concerns, discontinuations, and medication-usage records. Outcomes should be monitored for at least 3 months after initiation with prespecified statistical analyses. Multigroup collaborations or registry studies may be needed for pivotal trials. C1 [Klein, Max M.; Treister, Roi; Lang, Magdalena; Fox, Michael; Cudkowicz, Merit; Oaklander, Anne Louise] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. [Raij, Tommi; Fox, Michael] Harvard Univ, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Dept Radiol,Med Sch, Boston, MA 02114 USA. [Pascual-Leone, Alvaro; Fox, Michael] Harvard Univ, Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, Dept Neurol,Med Sch, Boston, MA 02114 USA. [Park, Lawrence; Costello, Ann] US FDA, Ctr Devices & Radiol Hlth, Div Neurol & Phys Med Devices, Off Device Evaluat, Bethesda, MD 20014 USA. [Park, Lawrence] NIMH, US Natl Inst Hlth, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. [Nurmikko, Turo] Walton Ctr NHS Fdn Trust, Pain Res Inst, Neurosci Res Ctr, Liverpool, Merseyside, England. [Lenz, Fred] Johns Hopkins Med Inst, Dept Neurosurg, Baltimore, MD 21205 USA. [Lefaucheur, Jean-Pascal; Ayache, Samar S.] Henri Mondor Hosp, Assistance Publ Hop Paris, Dept Physiol, Creteil, France. [Lefaucheur, Jean-Pascal; Ayache, Samar S.] Paris Est Creteil Univ, Fac Med, Nerve Excitabil & Therapeut Team, EA 4391, Creteil, France. [Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Carr, Daniel B.] Tufts Univ, Sch Med, Dept Anesthesiol, Boston, MA 02111 USA. [Carr, Daniel B.] Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. [Carr, Daniel B.] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Oaklander, Anne Louise] Massachusetts Gen Hosp, Dept Pathol Neuropathol, Boston, MA 02114 USA. RP Klein, MM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, 275 Charles St Warren Bldg 310, Boston, MA 02114 USA. EM mklein@mgh.harvard.edu FU Radcliffe Institute for Advanced Study; Samuels Family Foundation; Public Health Service [K24NS059892, K23NS083741, NS38493, R01HD069776, R01NS073601, R21 MH099196, R21 NS082870, R21 NS085491, R21 HD07616, U01NS077179]; NINDS; UK National Institute of Health Research [PB-PG-0110-20321]; Hopkins Neurosurgery Pain Research Institute; American Academy of Neurology/American Brain Foundation; Sidney R. Baer Foundation; Harvard Catalyst-Clinical and Translational Science Center [UL1 RR025758] FX Supported in part by the Radcliffe Institute for Advanced Study and the Samuels Family Foundation, the Public Health Service (K24NS059892, K23NS083741, NS38493, R01HD069776, R01NS073601, R21 MH099196, R21 NS082870, R21 NS085491, R21 HD07616, and U01NS077179) and NINDS intramural support to M. Hallett, the UK National Institute of Health Research (PB-PG-0110-20321) to T. Nurmikko, the Hopkins Neurosurgery Pain Research Institute, the American Academy of Neurology/American Brain Foundation, the Sidney R. Baer Foundation, the Harvard Catalyst-Clinical and Translational Science Center (UL1 RR025758). NR 117 TC 16 Z9 16 U1 4 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD SEP PY 2015 VL 156 IS 9 BP 1601 EP 1614 DI 10.1097/j.pain.0000000000000210 PG 14 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA CQ4MQ UT WOS:000360579400007 PM 25919472 ER PT J AU Shur, J Saluja, B Lee, S Tibbatts, J Price, R AF Shur, Jagdeep Saluja, Bhawana Lee, Sau Tibbatts, James Price, Robert TI Effect of Device Design and Formulation on the In Vitro Comparability for Multi-Unit Dose Dry Powder Inhalers SO AAPS JOURNAL LA English DT Article DE aerosolization; computational fluid dynamics; device design; dry powder inhaler; in vitro comparability; in vitro performance ID PRIMARY CRYSTALLIZATION CONDITIONS; COHESIVE-ADHESIVE BALANCES; ATOMIC-FORCE MICROSCOPY; FLUTICASONE PROPIONATE; PERFORMANCE; INHALATION; LACTOSE; MORPHOLOGY; BEHAVIOR; CARRIERS AB The focus of this investigation was to understand the design space to achieve comparable in vitro performance of two multi-unit dose dry powder inhalers (DPIs)-Flixotider (R) Accuhaler (R) (reference product) and MultiHaler (R) (test product). Flow field, pressure drop and particle trajectories within the test and reference DPI devices were modelled via computational fluid dynamics (CFD). Micronized fluticasone propionate (FP) was characterized to determine particle size distribution (PSD), specific surface area (SSA) and surface interfacial properties using cohesive-adhesive balance (CAB). CFD simulations suggested that the pressure drop and airflow velocity in the MultiHaler (R) were greater than Accuhaler (R). Two modified test devices (MOD MH 1 and MOD MH 2) were manufactured with the introduction of by-pass channels in the airflow path, which achieved comparable specific resistance and airflow path between the test and reference devices. Assessment of reference product formulation in modified test devices suggested that MOD MH 2 achieved comparable in vitro performance to the reference product. CAB analysis suggested that adhesion of all FP batches to lactose was different, with batch D showing greatest and batch A least adhesion to lactose. Test DPI formulations were manufactured using four different batches of FP with milled or sieved lactose, and showed that batch A FP formulated with sieved lactose in MOD MH 2 device demonstrated the highest degree of similarity to the Accuhaler (R) in vitro deposition. Application of CFD modelling and material characterization of formulation raw materials enabled the modification of device and formulation critical material attributes to create an in vitro comparable device/formulation system to the reference product. C1 [Shur, Jagdeep; Tibbatts, James; Price, Robert] Univ Bath, Dept Pharm & Pharmacol, Pharmaceut Surface Sci Res Grp, Bath BA2 7AY, Avon, England. [Saluja, Bhawana] US FDA, Ctr Drug Evaluat & Res, Off Gener Drugs, Silver Spring, MD 20993 USA. [Lee, Sau] US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Qual, Silver Spring, MD 20993 USA. RP Saluja, B (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Gener Drugs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM bhawana.saluja@fda.hhs.gov NR 33 TC 2 Z9 2 U1 2 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD SEP PY 2015 VL 17 IS 5 BP 1105 EP 1116 DI 10.1208/s12248-015-9775-z PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CQ1NN UT WOS:000360364500006 PM 25956383 ER PT J AU Lee, SL Saluja, B Garcia-Arieta, A Santos, GML Li, Y Lu, S Hou, SG Rebello, J Vaidya, A Gogtay, J Purandare, S Lyapustina, S AF Lee, Sau L. Saluja, Bhawana Garcia-Arieta, Alfredo Lima Santos, Gustavo Mendes Li, Ying Lu, Sarah Hou, Shuguang Rebello, Juliet Vaidya, Abhijit Gogtay, Jaideep Purandare, Shrinivas Lyapustina, Svetlana TI Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU, Brazil, China, and India SO AAPS JOURNAL LA English DT Article DE bioequivalence; emerging markets; generics; pMDIs and DPIs; regulatory requirements ID METERED-DOSE INHALERS; DRY POWDER INHALERS; IN-VITRO PERFORMANCE; BECLOMETHASONE DIPROPIONATE; ASTHMATIC-PATIENTS; RELATIVE POTENCY; BIOEQUIVALENCE; BUDESONIDE; CORTICOSTEROIDS; FORMOTEROL AB This article describes regulatory approaches for approval of "generic" orally inhaled drug products (OIDPs) in the United States, European Union, Brazil, China and India. While registration of a generic OIDP in any given market may require some documentation of the formulation and device similarity to the "original" product as well as comparative testing of in vitro characteristics and in vivo performance, the specific documentation approaches, tests and acceptance criteria vary by the country. This divergence is due to several factors, including unique cultural, historical, legal and economic circumstances of each region; the diverse healthcare and regulatory systems; the different definitions of key terms such as "generic" and "reference" drug; the acknowledged absence of in vitro in vivo correlations for OIDPs; and the scientific and statistical issues related to OIDP testing (such as how best to account for the batch-to-batch variability of the Reference product, whether to use average bioequivalence or population bioequivalence in the statistical analysis of results, whether to use healthy volunteers or patients for pharmacokinetic studies, and which pharmacodynamic or clinical end-points should be used). As a result of this discrepancy, there are ample opportunities for the regulatory and scientific communities around the world to collaborate in developing more consistent, better aligned, science-based approaches. Moving in that direction will require both further research and further open discussion of the pros and cons of various approaches. C1 [Lee, Sau L.; Saluja, Bhawana] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Garcia-Arieta, Alfredo] Spanish Agcy Med & Hlth Care Prod, Pharmacokinet & Gener Serv, Madrid, Spain. [Lima Santos, Gustavo Mendes] Brazilian Hlth Surveillance Agcy Anvisa, Coordinat Therapeut EquivalenceHlth Surveillance, Brasilia, DF, Brazil. [Li, Ying] Merck, Resp Prod Dev, Rahway, NJ USA. [Lu, Sarah] Teva, Regulatory Affairs, Beijing, Peoples R China. [Hou, Shuguang] Sichuan Pur Pharmaceut Technol Co Ltd, Chengdu, Peoples R China. [Rebello, Juliet; Vaidya, Abhijit; Gogtay, Jaideep] Cipla, Div Clin Res, Vikhroli, India. [Purandare, Shrinivas] Cipla, Regulatory Affairs, Vikhroli, India. [Lyapustina, Svetlana] DBR, Pharmaceut Practice Grp, Washington, DC 20005 USA. [Lyapustina, Svetlana] Drinker Biddle & Reath LLP, Washington, DC 20005 USA. RP Lyapustina, S (reprint author), DBR, Pharmaceut Practice Grp, Washington, DC 20005 USA. EM svetlana.lyapustina@dbr.com NR 81 TC 6 Z9 6 U1 2 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD SEP PY 2015 VL 17 IS 5 BP 1285 EP 1304 DI 10.1208/s12248-015-9787-8 PG 20 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CQ1NN UT WOS:000360364500023 PM 26002510 ER PT J AU Hochhaus, G Davis-Cutting, C Oliver, M Lee, SL Lyapustina, S AF Hochhaus, Guenther Davis-Cutting, Craig Oliver, Martin Lee, Sau L. Lyapustina, Svetlana TI Current Scientific and Regulatory Approaches for Development of Orally Inhaled and Nasal Drug Products: Overview of the IPAC-RS/University of Florida Orlando Inhalation Conference SO AAPS JOURNAL LA English DT Article DE bioequivalence; emerging markets; generics; MDIs and DPIs; regulatory science AB This article summarizes discussions at the March 2014 conference organized by the University of Florida (UF) and International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS), entitled "Orlando Inhalation Conference: Approaches in International Regulation." The special focus of the conference was on global scientific and regulatory issues associated with the testing and demonstration of equivalence for the registration of orally inhaled drug products (OIDPs) in the United States, Europe, Brazil, China, and India. The scope included all types of OIDPs throughout their lifecycle, e.g., innovator/brand-name products, generics, modifications due to lifecycle management, device changes, etc. Details were presented for the U.S. "weight of evidence approach" for registration of generic products (which includes demonstration of in vitro and in vivo equivalence, as well as quantitative and qualitative sameness, and device similarity). The European "stepwise" approach was elucidated, and the thinking of regulatory agencies in the major emerging markets was clarified. The conference also highlighted a number of areas that would benefit from further research and discussion, especially around patient/device interface and human factor studies, statistical methods and criteria for demonstrating equivalence, the relative roles of in vivo and in vitro tests, and appropriate designs and metrics for in vivo studies of inhaled drugs. C1 [Hochhaus, Guenther] Univ Florida, Coll Pharm, Dept Pharmaceut, Gainesville, FL 32610 USA. [Davis-Cutting, Craig] Catalent Pharma Solut, Res & Dev, Morrisville, NC USA. [Oliver, Martin] Vectura Ltd, Chippenham, Wilts, England. [Lee, Sau L.] US FDA, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Lyapustina, Svetlana] Drinker Biddle & Reath LLP, Washington, DC 20005 USA. EM svetlana.lyapustina@dbr.com NR 10 TC 1 Z9 1 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD SEP PY 2015 VL 17 IS 5 BP 1305 EP 1311 DI 10.1208/s12248-015-9791-z PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CQ1NN UT WOS:000360364500024 PM 26033698 ER PT J AU Frey, J Guan, A Li, ZY Turtil, S Phillips, KS AF Frey, Justin Guan, Allan Li, Zhenyu Turtil, Steven Phillips, K. Scott TI Hemoglobin assay for validation and quality control of medical device reprocessing SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Hemoglobin; Medical device reprocessing; Reflectivity ID FLEXIBLE ENDOSCOPE CHANNELS; BLOOD AB Hemoglobin (Hb) is an important analyte in medicine, forensics, and research. One area of crucial need for real-world Hb quantitation is the validation and quality control (QC) of reprocessed medical device cleaning. Here, we show how a microplate reader and colorimetric blood test strips can be used to quantitate nanogram (ng) quantities of Hb in a 1-min assay. The assay had a linear range of 0-50 ng (0-370 ng on a log scale) for Hb, with a limit of detection (LOD) of 3.3 ng, which was similar to 500-fold more sensitive than the micro-BCA reagent (LOD = 1.6 mu g) and on the same order of magnitude as detection of labeled Hb with fluorescence (LOD = 1.9 ng). For validation of medical device cleaning, the assay was specific for Hb in the presence of artificial test soil and was unaffected by interferences from common cleaning reagents at 10 ppm. Lubricant and sodium dodecyl sulfate did not significantly affect the assay at 10 ppm but affected the assay at 1 % g/g. The method showed 100 % recovery of hemoglobin in extracted soils, with extraction from silicone having the greatest variability in recovery, while Teflon and stainless steel had < 10 % RSD. The assay makes it possible for medical device companies and health-care providers to obtain crucially needed information on the cleanliness of reused devices. C1 [Frey, Justin; Guan, Allan; Phillips, K. Scott] US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Biol Chem & Mat Sci, Silver Spring, MD 20993 USA. [Guan, Allan; Li, Zhenyu] George Washington Univ, Dept Biomed Engn, Washington, DC 20052 USA. [Turtil, Steven] US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, Off Device Evaluat,Div Orthoped Devices, Silver Spring, MD 20993 USA. RP Phillips, KS (reprint author), US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Biol Chem & Mat Sci, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM kenneth.phillips@fda.hhs.gov RI Phillips, Kenneth/A-2156-2013; OI Phillips, Kenneth/0000-0002-6552-0694; Guan, Allan/0000-0001-9292-4582 NR 15 TC 1 Z9 1 U1 0 U2 15 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 SEP PY 2015 VL 407 IS 22 BP 6885 EP 6889 DI 10.1007/s00216-015-8856-2 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CP9NJ UT WOS:000360220800031 PM 26173785 ER PT J AU Kane, RC AF Kane, Robert C. TI Routine Iron Supplementation and Screening for Iron Deficiency Anemia in Pregnancy SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 US FDA, Silver Spring, MD 20993 USA. RP Kane, RC (reprint author), US FDA, Silver Spring, MD 20993 USA. NR 1 TC 0 Z9 0 U1 0 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 1 PY 2015 VL 163 IS 5 BP 399 EP 400 DI 10.7326/L15-5132 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CQ0OM UT WOS:000360296000022 PM 26322707 ER PT J AU Beger, RD Bhattacharyya, S Yang, X Gill, PS Schnackenberg, LK Sun, JC James, LP AF Beger, Richard D. Bhattacharyya, Sudeepa Yang, Xi Gill, Pritmohinder S. Schnackenberg, Laura K. Sun, Jinchun James, Laura P. TI Translational biomarkers of acetaminophen-induced acute liver injury SO ARCHIVES OF TOXICOLOGY LA English DT Review DE Acetaminophen; MicroRNA; Proteomics; Metabolomics; Biomarkers ID GAP METABOLIC-ACIDOSIS; SERUM BILE-ACIDS; CHROMATOGRAPHY-MASS SPECTROMETRY; MITOCHONDRIAL PERMEABILITY TRANSITION; PERFORMANCE LIQUID-CHROMATOGRAPHY; 5-OXOPROLINE PYROGLUTAMIC ACID; GROUP BOX-1 PROTEIN; ANION GAP; INDUCED HEPATOTOXICITY; SAFETY BIOMARKERS AB Acetaminophen (APAP) is a commonly used analgesic drug that can cause liver injury, liver necrosis and liver failure. APAP-induced liver injury is associated with glutathione depletion, the formation of APAP protein adducts, the generation of reactive oxygen and nitrogen species and mitochondrial injury. The systems biology omics technologies (transcriptomics, proteomics and metabolomics) have been used to discover potential translational biomarkers of liver injury. The following review provides a summary of the systems biology discovery process, analytical validation of biomarkers and translation of omics biomarkers from the nonclinical to clinical setting in APAP-induced liver injury. C1 [Beger, Richard D.; Yang, Xi; Schnackenberg, Laura K.; Sun, Jinchun] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. [Bhattacharyya, Sudeepa; Gill, Pritmohinder S.; James, Laura P.] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. [Bhattacharyya, Sudeepa; Gill, Pritmohinder S.; James, Laura P.] Arkansas Childrens Hosp, Clin Pharmacol & Toxicol Sect, Little Rock, AR 72202 USA. RP Beger, RD (reprint author), US FDA, Natl Ctr Toxicol Res, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Richard.Beger@fda.hhs.gov NR 212 TC 12 Z9 12 U1 5 U2 27 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD SEP PY 2015 VL 89 IS 9 BP 1497 EP 1522 DI 10.1007/s00204-015-1519-4 PG 26 WC Toxicology SC Toxicology GA CQ2EP UT WOS:000360412500005 PM 25983262 ER PT J AU Morganroth, J Wang, YN Thorn, M Kumagai, Y Harris, S Stockbridge, N Kleiman, R Shah, R AF Morganroth, Joel Wang, Yaning Thorn, Michael Kumagai, Yuji Harris, Stuart Stockbridge, Norman Kleiman, Robert Shah, Rashmi TI Moxifloxacin-induced QT(c) interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study SO BRITISH JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE Caucasians; ethnicity; Japanese; moxifloxacin; QT(c) interval; thorough QT studies ID CARDIAC REPOLARIZATION; GENETIC SUSCEPTIBILITY; ETHNIC-DIFFERENCES; CHANNEL VARIANTS; LIABILITY; QT/QTC; WHITE AB AimWe investigated whether moxifloxacin-induced QT(c) prolongations in Japanese and Caucasian healthy male volunteers were significantly different. MethodsA two period, randomized, crossover, ICH-E14-compliant thorough QT (TQT) study compared placebo-corrected changes in QT(c) interval from baseline (QT(c)F) and concentration-effect relationships following administration of placebo and 400 mg moxifloxacin to 40 healthy male volunteers from each ethnic population. The point estimates of QT(c)F for each population, and the difference between the two, were calculated at a geometric mean C-max of moxifloxacin using a linear mixed effects model. The concentration-effect slopes of the two populations were also compared. Equivalence was concluded if the two-sided 90% confidence interval of the difference in QT(c)F was contained within -5 ms to +5 ms limits and the ratio of the slopes was between 0.5 and 2. ResultsThere were no statistically significant differences between the two populations studied, Japanese vs. Caucasians, respectively, for moxifloxacin C-max (3.27 0.6 vs. 2.98 +/- 0.7 mu g ml(-1)), QT(c)F (9.63 +/- 1.15 vs. 11.46 +/- 1.19 ms at C-max of 3.07 mu g ml(-1)) and concentration-response slopes (2.58 +/- 0.62 vs. 2.34 +/- 0.64 ms per mu g ml(-1)). The difference in the two QT(c)F of -1.8 (90% CI -4.6, 0.9) and the ratio of the two slopes (1.1; 90% CI 0.63, 1.82) were within pre-specified equivalence limits. ConclusionsMoxifloxacin-induced QT(c) prolongations did not differ significantly between the Japanese and Caucasian subjects. However, before our findings are more widely generalized, further studies in other populations and with other QT-prolonging drugs are needed to clarify whether inter-ethnic differences in QT sensitivity exist and whether ethnicity of the study population may affect the outcome of a TQT study. C1 [Morganroth, Joel; Kleiman, Robert] ERes Technol Inc, Philadelphia, PA USA. [Wang, Yaning] US FDA, Div Pharmacometr, Silver Spring, MD USA. [Thorn, Michael] Stat Resources Inc, Chapel Hill, NC USA. [Kumagai, Yuji] Kitasato Univ, East Hosp, Clin Res Ctr, Sagamihara, Kanagawa 228, Japan. [Harris, Stuart] SeaView Res Inc, Miami, FL USA. [Stockbridge, Norman] US FDA, Div Cardiovasc & Renal Prod, Silver Spring, MD USA. RP Shah, R (reprint author), 8 Birchdale, Gerrards Cross SL9 7JA, Bucks, England. EM clinical.safety@hotmail.co.uk NR 37 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0306-5251 EI 1365-2125 J9 BRIT J CLIN PHARMACO JI Br. J. Clin. Pharmacol. PD SEP PY 2015 VL 80 IS 3 BP 446 EP 459 DI 10.1111/bcp.12684 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CQ1QA UT WOS:000360371900013 PM 26011050 ER PT J AU Suzuki, A Leland, P Joshi, BH Puri, RK AF Suzuki, Akiko Leland, Pamela Joshi, Bharat H. Puri, Raj K. TI Targeting of IL-4 and IL-13 receptors for cancer therapy SO CYTOKINE LA English DT Review DE Interleukin-4; Interleukin-4 receptor; Interleukin-13; Interleukin-13 receptor; Receptor-targeted cancer therapy ID RENAL-CELL-CARCINOMA; HUMAN B-CELLS; PANCREATIC DUCTAL ADENOCARCINOMA; RECOMBINANT HUMAN INTERLEUKIN-4; HUMAN GLIOBLASTOMA-MULTIFORME; RECURRENT MALIGNANT GLIOMA; CHIMERIC FUSION PROTEINS; MURINE TUMOR-MODELS; CD4(+) T-CELLS; PHASE-II TRIAL AB The Th2 cytokines, interleukin (IL)-4 and -13, are structurally and functionally related. They regulate immune responses and the immune microenvironment, not only under normal physiological conditions, but also in cancer. Both cytokines bind to their high-affinity receptors and form various configurations of receptor subtypes. We and others have reported that IL-4 and IL-13 bind to IL-4R alpha and IL-13R alpha 1 chains, forming functional receptors in cancer cells. IL-13 also binds with high affinity to a private chain IL-13R alpha 2. After forming ligand-receptor complexes, both cytokines initiate signal transduction and mediate biological effects, such as tumor proliferation, cell survival, cell adhesion and metastasis. In certain cancers, the presence of these cytokine receptors may serve as biomarkers of cancer aggressiveness. In a series of studies, we reported that overexpression of IL-4 and IL-13 receptors on cancer cells provides targets for therapeutic agents for cancer therapy. In addition, both of these cytokines and their receptors have been shown to play important roles in modulating the immune system for tumor growth. IL-4, IL-13 and their receptors seem to play a role in cancer stem cells and provide unique targets to eradicate these cells. In this review article, we summarize some of the important attributes of IL-4 and IL-13 receptors in cancer biology and discuss pre-clinical and clinical studies pertaining to recombinant immunotoxins designed to target these receptors. Published by Elsevier Ltd. C1 [Suzuki, Akiko; Leland, Pamela; Joshi, Bharat H.; Puri, Raj K.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Puri, RK (reprint author), US FDA, Ctr Biol Evaluat & Res, Off Cellular Tissue & Gene Therapies, Div Cellular & Gene Therapies, New Hampshire Ave,WO Bldg 71,Room 5342, Silver Spring, MD 20993 USA. EM akiko.suzuki@fda.hhs.gov; pamela.dover@fda.hhs.gov; bharat.joshi@fda.hhs.gov; raj.puri@fda.hhs.gov NR 150 TC 12 Z9 14 U1 2 U2 13 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD SEP PY 2015 VL 75 IS 1 BP 79 EP 88 DI 10.1016/j.cyto.2015.05.026 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CQ3NZ UT WOS:000360510600011 PM 26088753 ER PT J AU Mannisto, T Mendola, P Grantz, KL Leishear, K Sundaram, R Sherman, S Ying, Q Liu, DP AF Mannisto, Tuija Mendola, Pauline Grantz, Katherine Laughon Leishear, Kira Sundaram, Rajeshwari Sherman, Seth Ying, Qi Liu, Danping TI Acute and recent air pollution exposure and cardiovascular events at labour and delivery SO HEART LA English DT Article ID HOSPITAL CARDIAC-ARREST; CASE-CROSSOVER ANALYSIS; MYOCARDIAL-INFARCTION; MORTALITY; PREGNANCY; INFLAMMATION; POLLUTANTS; DISEASE; STROKE; COHORT AB Objective To study the relationship between acute air pollution exposure and cardiovascular events during labour/delivery. Methods The Consortium on Safe Labor (2002-2008), an observational US cohort with 223 502 singleton deliveries provided electronic medical records. Air pollution exposure was estimated by modified Community Multiscale Air Quality models. Cardiovascular events (cardiac failure/arrest, stroke, myocardial infarcts and other events) were recorded in the hospital discharge records for 687 pregnancies (0.3%). Logistic regression with generalised estimating equations estimated the relationship between cardiovascular events and daily air pollutant levels for delivery day and the 7 days preceding delivery. Results Increased odds of cardiovascular events were observed for each IQR increase in exposure to nitric oxides at 5 and 6 days prior to delivery (OR= 1.17, 99% CI 1.04 to 1.30 and OR= 1.15, 1.03 to 1.28, respectively). High exposure to toxic air pollution species such as ethylbenzene (OR= 1.50, 1.08 to 2.09), m-xylene (OR= 1.54, 1.11 to 2.13), o-xylene (OR= 1.51, 1.09 to 2.09), p-xylene (OR= 1.43, 1.03 to 1.99) and toluene (OR= 1.42, 1.02 to 1.97) at 5 days prior to delivery were also associated with cardiovascular events. Decreased odds of events were observed with exposure to ozone. Conclusions Air pollution in the days prior to delivery, especially nitrogen oxides and some toxic air pollution species, was associated with increased risk of cardiovascular events during the labour/delivery admission. C1 [Mannisto, Tuija; Mendola, Pauline; Grantz, Katherine Laughon] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Mannisto, Tuija] Ctr NordLab, Northern Finland Lab, Oulu, Finland. [Mannisto, Tuija] Univ Oulu, Dept Clin Chem, Oulu, Finland. [Mannisto, Tuija] Oulu Univ Hosp, Med Res Ctr Oulu, Oulu, Finland. [Mannisto, Tuija] Univ Oulu, Oulu, Finland. [Mannisto, Tuija] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Oulu, Finland. [Leishear, Kira] Glotech Inc, Rockville, MD USA. [Leishear, Kira] US FDA, Silver Spring, MD USA. [Sundaram, Rajeshwari; Liu, Danping] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Sherman, Seth] EMMES Corp, Rockville, MD USA. [Ying, Qi] Texas A&M Univ, Zachry Dept Civil Engn, College Stn, TX USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,7B05, Rockville, MD 20852 USA. EM Pauline.Mendola@nih.gov OI Grantz, Katherine/0000-0003-0276-8534; Sherman, Seth/0000-0003-3667-9898; Mannisto, Tuija/0000-0002-6382-9153; Mendola, Pauline/0000-0001-5330-2844; Sundaram, Rajeshwari/0000-0002-6918-5002 NR 28 TC 1 Z9 1 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 EI 1468-201X J9 HEART JI Heart PD SEP PY 2015 VL 101 IS 18 BP 1491 EP 1498 DI 10.1136/heartjnl-2014-307366 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CQ0SP UT WOS:000360307600014 PM 26105036 ER PT J AU Teitelbaum, DH Guenter, P Griebel, D Abrams, SA Bark, S Baker, M Berry, KL Bistrian, BR Brenna, JT Bonnot, D Carpentier, YA Deckelbaum, RJ Hise, M Koletzko, B Mirtallo, JM Mulberg, AE O'Reilly, RC Shaffer, J von Kleist, E Zaloga, GP Ziegler, TR AF Teitelbaum, Daniel H. Guenter, Peggi Griebel, Donna Abrams, Steven A. Bark, Staffan Baker, Mary Berry, Karyn L. Bistrian, Bruce R. Brenna, J. Thomas Bonnot, Denis Carpentier, Yvon A. Deckelbaum, Richard J. Hise, Mary Koletzko, Berthold Mirtallo, Jay M. Mulberg, Andrew E. O'Reilly, Randall C. Shaffer, Jonathan von Kleist, Elke Zaloga, Gary P. Ziegler, Thomas R. TI Proceedings From FDA/ASPEN Public Workshop: Clinical Trial Design for Intravenous Fat Emulsion Products, October 29, 2013 SO JOURNAL OF PARENTERAL AND ENTERAL NUTRITION LA English DT Article DE fatty acids; research and diseases; lipids; nutrition ID RECEIVING PARENTERAL-NUTRITION; RANDOMIZED CONTROLLED-TRIALS; HOSPITALIZED ADULT PATIENTS; LONG-CHAIN TRIACYLGLYCEROL; DOSE DOCOSAHEXAENOIC ACID; CRITICALLY-ILL PATIENTS; CARE-UNIT PATIENTS; FISH-OIL; LIPID EMULSIONS; PRETERM INFANTS AB The development of intravenous fat emulsion (IVFE) is the culmination of physiological, biochemical, nutritional, and medical scientific advancements. IVFEs have the ability to deliver critical nutritional substrates to the patient. Recent literature purports that they may also play roles in modulation of immune functionality and pulmonary physiology, but data supporting these potential benefits are limited. While soybean-based IVFEs have comprised the dominant fat in U.S. markets, a number of other novel IVFEs may prove to optimize the care of children and adults in both hospitalized and home settings. The October 2013 U.S. Food and Drug Administration (FDA)/American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Public Workshop brought together scientists, researchers, and clinical experts to present updated clinical perspectives of IVFEs, including historical development, current state of usage throughout the world, and considerations for the regulatory approval of new IVFEs in the United States. C1 [Teitelbaum, Daniel H.] Univ Michigan, CS Mott Childrens Hosp, Ann Arbor, MI 48109 USA. [Guenter, Peggi] Amer Soc Parenteral & Enteral Nutr, Silver Spring, MD USA. [Griebel, Donna; Berry, Karyn L.; Mulberg, Andrew E.] US FDA, Div Gastroenterol & Inborn Error Prod, Off Drug Evaluat 3, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Abrams, Steven A.] Baylor Coll Med, Dept Pediat, Sect Neonatol, Houston, TX 77030 USA. [Abrams, Steven A.] Baylor Coll Med, USDA ARS, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Abrams, Steven A.] Texas Childrens Hosp, Houston, TX 77030 USA. [Bark, Staffan] Karolinska Inst, Dept Surg, Stockholm, Sweden. [Bark, Staffan] Visby Hosp, Dept Surg, Visby, Sweden. [Baker, Mary] Hospira Inc, Chicago, IL USA. [Bistrian, Bruce R.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Clin Nutr, Boston, MA 02215 USA. [Brenna, J. Thomas] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Bonnot, Denis] Fresenius Kabi Deutschland GmbH, Sci Affairs, Business Unit, Parenteral Nutr & Colloids, Bad Homburg, Germany. [Carpentier, Yvon A.] Univ Libre Bruxelles, Free Univ Brussels, Brussels, Belgium. [Carpentier, Yvon A.] Lipid Nutr Ctr, Brussels, Belgium. [Deckelbaum, Richard J.] Columbia Univ, Inst Human Nutr, Med Ctr, Dept Pediat & Epidemiol, New York, NY 10032 USA. [Hise, Mary; Zaloga, Gary P.] Baxter Healthcare, Deerfield, IL USA. [Koletzko, Berthold] Univ Munich, Med Ctr, Dr von Hauner Childrens Hosp, D-81377 Munich, Germany. [Mirtallo, Jay M.] Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. [O'Reilly, Randall C.] Univ Colorado, Boulder, CO 80309 USA. [Shaffer, Jonathan] Univ Manchester, Salford Royal Hosp, Intestinal Failure Unit, Manchester M13 9PL, Lancs, England. [von Kleist, Elke] B Braun Melsungen AG, Hosp Care Div, Melsungen, Germany. [Ziegler, Thomas R.] Emory Univ Hosp, Div Endocrinol Metab & Lipids, Atlanta, GA 30322 USA. [Ziegler, Thomas R.] Emory Univ Hosp, Emory Ctr Clin & Mol Nutr, Atlanta, GA 30322 USA. RP Teitelbaum, DH (reprint author), Univ Michigan, CS Mott Childrens Hosp, Ann Arbor, MI 48109 USA. EM dttlbm@med.umich.edu OI Mirtallo, Jay/0000-0003-0736-6171; Abrams, Steven/0000-0003-4972-9233 FU European Commission; European Research Council; German Federal Government; United States Food and Drug Administration; American Society for Parenteral and Enteral Nutrition; Fresenius-Kabi, Hospira FX Berthold Koletzko, MD PhD: The Ludwig Maximilians University of Munich Medical Centre and its employee B.K. have or have had scientific and educational collaborations with manufacturers of parenteral nutrition products, including Baxter, B. Braun, and Fresenius Kabi, and receive grant support from the European Commission, the European Research Council, and the German Federal Government. B.K. reports no conflict of interest which would represent "a set of circumstances that creates a risk that professional judgement or actions regarding a primary interest will be unduly influenced by a secondary interest," as defined by the US Institute of Medicine.; This meeting is cosponsored by the United States Food and Drug Administration and the American Society for Parenteral and Enteral Nutrition.; Educational grants were provided to A.S.P.E.N. to support this program from Fresenius-Kabi, Hospira, and B. Braun. NR 91 TC 3 Z9 3 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0148-6071 EI 1941-2444 J9 JPEN-PARENTER ENTER JI J. Parenter. Enter. Nutr. PD SEP PY 2015 VL 39 IS 7 BP 768 EP 786 DI 10.1177/0148607114560825 PG 19 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CQ2FB UT WOS:000360413700007 PM 25475623 ER PT J AU Caprioli, J Kim, JH Friedman, DS Kiang, T Moster, MR Parrish, RK Rorer, EM Samuelson, T Tarver, ME Singh, K Eydelman, MB AF Caprioli, Joseph Kim, Julie H. Friedman, David S. Kiang, Tina Moster, Marlene R. Parrish, Richard K., II Rorer, Eva M. Samuelson, Thomas Tarver, Michelle E. Singh, Kuldev Eydelman, Malvina B. TI Special Commentary: Supporting Innovation for Safe and Effective Minimally Invasive Glaucoma Surgery Summary of a Joint Meeting of the American Glaucoma Society and the Food and Drug Administration, Washington, DC, February 26, 2014 SO OPHTHALMOLOGY LA English DT Editorial Material ID SELECTIVE LASER TRABECULOPLASTY; COMPOSITE END-POINTS; OPEN-ANGLE GLAUCOMA; VISUAL-FIELD LOSS; RISK-FACTORS; PERSPECTIVES; PRESSURE; OUTFLOW; DESIGN; TRIAL C1 [Caprioli, Joseph] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. [Kim, Julie H.; Kiang, Tina; Rorer, Eva M.; Tarver, Michelle E.; Eydelman, Malvina B.] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Friedman, David S.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Moster, Marlene R.] Thomas Jefferson Univ, Jefferson Med Coll, Wills Eye Inst, Dept Ophthalmol, Philadelphia, PA 19107 USA. [Parrish, Richard K., II] Univ Miami, Dept Ophthalmol, Bascom Palmer Eye Inst, Miami, FL USA. [Samuelson, Thomas] Minnesota Eye Consultants, Minneapolis, MN USA. [Singh, Kuldev] Stanford Univ, Sch Med, Dept Ophthalmol, Palo Alto, CA 94304 USA. RP Eydelman, MB (reprint author), US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM malvina.eydelman@fda.hhs.gov NR 28 TC 2 Z9 2 U1 0 U2 0 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 SEP PY 2015 VL 122 IS 9 BP 1795 EP 1801 DI 10.1016/j.ophtha.2015.02.029 PG 7 WC Ophthalmology SC Ophthalmology GA CP8BU UT WOS:000360116900018 PM 25881513 ER PT J AU Offringa, M Davis, JM Turner, MA Ward, R Bax, R Maldonado, S Sinha, V McCune, SK Zajicek, A Benjamin, DK Bucci-Rechtweg, C Nelson, RM AF Offringa, Martin Davis, Jonathan M. Turner, Mark A. Ward, Robert Bax, Ralph Maldonado, Sam Sinha, Vikram McCune, Susan K. Zajicek, Anne Benjamin, Daniel K., Jr. Bucci-Rechtweg, Christina Nelson, Robert M. TI Applying Regulatory Science to Develop Safe and Effective Medicines for Neonates: Report of the US Food and Drug Administration First Annual Neonatal Scientific Workshop, October 28-29, 2014 SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE extrapolation; biomarkers; clinical outcomes; adaptive designs; pediatric trials ID PRETERM INFANTS; MEDICATION USE; BIOMARKERS; AGE; SURVIVAL; OUTCOMES; TRIALS; LIFE AB The First Annual Neonatal Scientific Workshop focused on the needs of the neonate by addressing the basic question: what information is required to inform decision making both at the regulatory level and at the bedside? Priority therapeutic areas include neonatal lung, brain, and gastrointestinal injury, retinopathy of prematurity, sepsis, and neonatal abstinence syndrome. Scientific progress in these therapeutic areas, regulatory standards, and the acceptable design and conduct of clinical trials must be aligned. This report will review potential approaches to enhancing neonatal drug development. C1 [Offringa, Martin] Hosp Sick Children, Child Hlth Evaluat Sci, Toronto, ON M5G 1X8, Canada. [Davis, Jonathan M.] Tufts Med Ctr, Floating Hosp Children, Dept Pediat, Boston, MA 02111 USA. [Davis, Jonathan M.] Tufts Med Ctr, Floating Hosp Children, Tufts Clin & Translat Sci Inst, Boston, MA 02111 USA. [Turner, Mark A.] Univ Liverpool, Inst Translat Med, Dept Womens & Childrens Hlth, Liverpool L69 3BX, Merseyside, England. [Ward, Robert] Univ Utah, Dept Pediat & Pharmacol Toxicol, Salt Lake City, UT USA. [Bax, Ralph] European Med Agcy, Prod Dev Sci Support Dept, Paediat Med, London, England. [Maldonado, Sam] CHILD Child Hlth Innovat Leadership Dept, Janssen Res & Dev, Raritan, NJ USA. [Sinha, Vikram] US FDA, Div Pharmacometr, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD USA. [McCune, Susan K.] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Zajicek, Anne] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Benjamin, Daniel K., Jr.] Duke Univ, Duke Clin Res Inst, Durham, NC USA. [Bucci-Rechtweg, Christina] Novartis Pharmaceut, E Hanover, NJ USA. [Nelson, Robert M.] US FDA, Off Pediat Therapeut, Silver Spring, MD USA. RP Davis, JM (reprint author), Tufts Med Ctr, Floating Hosp Children, Newborn Med, TMC 44,750 Washington St, Boston, MA 02111 USA. EM jdavis@tuftsmedicalcenter.org FU Burroughs Wellcome Fund; FDA grant [1U18FD005320-01] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The workshop was supported in part by the Burroughs Wellcome Fund and an FDA grant (no. 1U18FD005320-01) to the Critical Path Institute. NR 38 TC 3 Z9 3 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD SEP PY 2015 VL 49 IS 5 BP 623 EP 631 DI 10.1177/2168479015597730 PG 9 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA CQ2FG UT WOS:000360414200003 ER PT J AU Darpo, B Ferber, G Garnett, C Liu, J Stockbridge, N AF Darpo, Borje Ferber, Georg Garnett, Christine Liu, Jiang Stockbridge, Norman TI Topic of Timely InterestDecision Criteria for Negative QT Assessment Using Exposure Response Analysis of Data From Early-Phase Clinical Studies: Letter to the Editor SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Letter C1 [Darpo, Borje] Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden. [Darpo, Borje] iCardiac Technol Inc, Rochester, NY USA. [Ferber, Georg] Stat Georg Ferber GmbH, Riehen, Switzerland. [Garnett, Christine; Stockbridge, Norman] US FDA, Ctr Drug Evaluat & Res, Div Cardiovasc & Renal Prod, Silver Spring, MD USA. [Liu, Jiang] US FDA, Ctr Drug Evaluat andResearch, Off Clin Pharmacol, Div Pharmacometr, Silver Spring, MD USA. RP Darpo, B (reprint author), Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden. EM borje.darpo@telia.com NR 5 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 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD SEP PY 2015 VL 49 IS 5 BP 717 EP 719 DI 10.1177/2168479015596022 PG 3 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA CQ2FG UT WOS:000360414200013 ER PT J AU Miousse, IR Currie, R Datta, K Ellinger-Ziegelbauer, H French, JE Harrill, AH Koturbash, I Lawton, M Mann, D Meehan, RR Moggs, JG O'Lone, R Rasoulpour, RJ Pera, RAR Thompson, K AF Miousse, Isabelle R. Currie, Richard Datta, Kaushik Ellinger-Ziegelbauer, Heidrun French, John E. Harrill, Alison H. Koturbash, Igor Lawton, Michael Mann, Derek Meehan, Richard R. Moggs, Jonathan G. O'Lone, Raegan Rasoulpour, Reza J. Pera, Renee A. Reijo Thompson, Karol TI Importance of investigating epigenetic alterations for industry, and regulators: An appraisal of current efforts by the Health and Environmental Sciences Institute SO TOXICOLOGY LA English DT Review DE Epigenetics; Safety assessment; Models; Transgenerational effects; Stem cells; Biomarkers ID EPIGENOME-WIDE ASSOCIATION; PRIMORDIAL GERM-CELLS; EMBRYONIC STEM-CELLS; EPSTEIN-BARR-VIRUS; DNA METHYLATION; NATIONAL-HEALTH; TUMOR PROMOTION; RISK ASSESSMENT; MOUSE; CANCER AB Recent technological advances have led to rapid progress in the characterization of epigenetic modifications that control gene expression in a generally heritable way, and are likely involved in defining cellular phenotypes, developmental stages and disease status from one generation to the next. On November 18, 2013, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) held a symposium entitled "Advances in Assessing Adverse Epigenetic Effects of Drugs and Chemicals" in Washington, D.C. The goal of the symposium was to identify gaps in knowledge and highlight promising areas of progress that represent opportunities to utilize epigenomic profiling for risk assessment of drugs and chemicals. Epigenomic profiling has the potential to provide mechanistic information in toxicological safety assessments; this is especially relevant for the evaluation of carcinogenic or teratogenic potential and also for drugs that directly target epigenetic modifiers, like DNA methyltransferases or histone modifying enzymes. Furthermore, it can serve as an endpoint or marker for hazard characterization in chemical safety assessment. The assessment of epigenetic effects may also be approached with new model systems that could directly assess transgenerational effects or potentially sensitive stem cell populations. These would enhance the range of safety assessment tools for evaluating xenobiotics that perturb the epigenome. Here we provide a brief synopsis of the symposium, update findings since that time and then highlight potential directions for future collaborative efforts to incorporate epigenetic profiling into risk assessment. (C) 2015 The Authors. Published by Elsevier Ireland Ltd. C1 [Miousse, Isabelle R.; Harrill, Alison H.; Koturbash, Igor] Univ Arkansas Med Sci, Dept Environm & Occupat Hlth, Little Rock, AR 72205 USA. [Currie, Richard] Syngenta Jealotts Hill Int Res Ctr, Bracknell, Berks, England. [Datta, Kaushik] Celgene Corp, Summit, NJ USA. [Ellinger-Ziegelbauer, Heidrun] Bayer Pharma AG, Toxicol, Wuppertal, Germany. [French, John E.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Lawton, Michael] Pfizer Inc, Groton, CT 06340 USA. [Mann, Derek] Newcastle Univ, Inst Cellular Med, Fibrosis Res Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Meehan, Richard R.] Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland. [Moggs, Jonathan G.] Novartis Inst Biomed Res, Preclin Safety, Discovery & Invest Safety, Basel, Switzerland. [O'Lone, Raegan] ILSI Hlth & Environm Sci Inst, Washington, DC 20036 USA. [Rasoulpour, Reza J.] Dow Chem Co USA, Toxicol Environm Res & Consulting, Midland, MI 48674 USA. [Pera, Renee A. Reijo] Montana State Univ, Bozeman, MT 59717 USA. [Thompson, Karol] US FDA, Div Appl Regulatory Sci, OCP, CDER, Silver Spring, MD USA. RP O'Lone, R (reprint author), ILSI Hlth & Environm Sci Inst, Washington, DC 20036 USA. RI Meehan, Richard/B-5556-2012 FU ILSI HESI FX The symposium and manuscript are activities of the ILSI HESI technical committee on the Application of Genomics to Mechanism-Based Risk Assessment and funded by ILSI HESI. NR 85 TC 5 Z9 6 U1 0 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD SEP 1 PY 2015 VL 335 BP 11 EP 19 DI 10.1016/j.tox.2015.06.009 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CQ3QM UT WOS:000360517600002 PM 26134581 ER PT J AU Levy, B Paulozzi, L Mack, KA Jones, CM AF Levy, Benjamin Paulozzi, Leonard Mack, Karin A. Jones, Christopher M. TI Trends in Opioid Analgesic-Prescribing Rates by Specialty, US, 2007-2012 SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID CHRONIC NONCANCER PAIN; UNITED-STATES AB Introduction: Opioid analgesic prescriptions are driving trends in drug overdoses, but little is known about prescribing patterns among medical specialties. We conducted this study to examine the opioid-prescribing patterns of the medical specialties over time. Methods: IMS Health's National Prescription Audit (NPA) estimated the annual counts of pharmaceutical prescriptions dispensed in the U.S. during 2007-2012. We grouped NPA prescriber specialty data by practice type for ease of analysis, and measured the distribution of total prescriptions and opioid prescriptions by specialty. We calculated the percentage of all prescriptions dispensed that were opioids, and evaluated changes in that rate by specialty during 2007-2012. The analysis was conducted in 2013. Results: In 2012, U.S. pharmacies and long-term care facilities dispensed 4.2 billion prescriptions, 289 million (6.8%) of which were opioids. Primary care specialties accounted for nearly half of all dispensed opioid prescriptions. The rate of opioid prescribing was highest for specialists in pain medicine (48.6%); surgery (36.5%); and physical medicine/rehabilitation (35.5%). The rate of opioid prescribing rose during 2007-2010 but leveled thereafter as most specialties reduced opioid use. The greatest percentage increase in opioid-prescribing rates during 2007-2012 occurred among physical medicine/rehabilitation specialists (+12.0%). The largest percentage drops in opioid-prescribing rates occurred in emergency medicine (-8.9%) and dentistry (-5.7%). Conclusions: The data indicate diverging trends in opioid prescribing among medical specialties in the U.S. during 2007-2012. Engaging the medical specialties individually is critical for continued improvement in the safe and effective treatment of pain. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Levy, Benjamin; Paulozzi, Leonard] CDC, Div Unintent Injury Prevent, Natl Ctr Injury Prevent & Control, Atlanta, GA 30333 USA. [Mack, Karin A.] CDC, Div Anal Res & Practice Integrat, Natl Ctr Injury Prevent & Control, Atlanta, GA 30333 USA. [Jones, Christopher M.] US FDA, Off Publ Hlth Strategy & Anal, Off Commissioner, Silver Spring, MD USA. RP Levy, B (reprint author), CDC, Div Unintent Injury Prevent, 4770 Buford Highway MS-F62, Chamblee, GA 30341 USA. EM xew6@cdc.gov FU CDC FX CDC funded this study and supported the staff responsible for the design and conduct of the study; the collection, analysis, and interpretation of the data; and the preparation, review, and approval of the manuscript. The views expressed in this article are those of the authors and do not necessarily reflect the official position of CDC or the U.S. Food and Drug Administration. NR 9 TC 21 Z9 22 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2015 VL 49 IS 3 BP 409 EP 413 DI 10.1016/j.amepre.2015.02.020 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CP5VX UT WOS:000359954200010 PM 25896191 ER PT J AU Roth-Cline, M Nelson, RM AF Roth-Cline, M. Nelson, R. M. TI Microdosing Studies in Children: A US Regulatory Perspective SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB Microdosing studies in children are used to obtain pharmacokinetic information, to study the ontogeny of metabolic enzymes, or to study drug disposition. C1 [Roth-Cline, M.; Nelson, R. M.] US FDA, Off Pediat Therapeut, Silver Spring, MD 20993 USA. RP Roth-Cline, M (reprint author), US FDA, Off Pediat Therapeut, Silver Spring, MD 20993 USA. EM Michelle.Roth-Cline@fda.hhs.gov NR 5 TC 2 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD SEP PY 2015 VL 98 IS 3 BP 232 EP 233 DI 10.1002/cpt.165 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CP6RD UT WOS:000360014700002 PM 26095312 ER PT J AU Momper, JD Mulugeta, Y Burckart, GJ AF Momper, J. D. Mulugeta, Y. Burckart, G. J. TI Failed Pediatric Drug Development Trials SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID ADOLESCENTS; CHILDREN AB Pediatric product development initiatives have stimulated the development of therapies for children, resulting in improved product labeling, increased identification of adverse events, and development of new pediatric formulations. However, 42% of recently completed pediatric trials have failed to establish either safety or efficacy, leading to an inability to label the product for use in children.(1) Characterizing these failed trials, including common contributing factors, is imperative to designing better pediatric trials in the future. C1 [Momper, J. D.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. [Mulugeta, Y.; Burckart, G. J.] US FDA, Off Clin Pharmacol, Off Translat Sci, Silver Spring, MD 20993 USA. RP Burckart, GJ (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Silver Spring, MD 20993 USA. EM gilbert.burckart@fda.hhs.gov NR 5 TC 10 Z9 11 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD SEP PY 2015 VL 98 IS 3 BP 245 EP 251 DI 10.1002/cpt.142 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CP6RD UT WOS:000360014700006 PM 25963725 ER PT J AU Wang, J Avant, D Green, D Seo, S Fisher, J Mulberg, AE McCune, SK Burckart, GJ AF Wang, J. Avant, D. Green, D. Seo, S. Fisher, J. Mulberg, A. E. McCune, S. K. Burckart, G. J. TI A Survey of Neonatal Pharmacokinetic and Pharmacodynamic Studies in Pediatric Drug Development SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID GASTROESOPHAGEAL-REFLUX DISEASE; CLINICAL-PHARMACOLOGY; INFANTS; DIAGNOSIS AB Conducting clinical trials in neonates is challenging, and knowledge gaps in neonatal clinical pharmacology exist. We surveyed the US Food and Drug Administration databases and identified 43 drugs studied in neonates or referring to neonates between 1998 and 2014. Twenty drugs were approved in neonates. For 10 drugs, approval was based on efficacy data in neonates, supplemented by pharmacokinetic data for four drugs. Approval for neonates was based on full extrapolation from older patients for six drugs, and partial extrapolation was the basis of approval for four drugs. Dosing recommendations differed from older patients for most drugs, and used body-size based adjustment in neonates. Trial failures were associated with various factors including inappropriate dose selection. Successful drug development in neonates could be facilitated by an improved understanding of the natural history and pathophysiology of neonatal diseases and identification and validation of clinically relevant biomarkers. C1 [Wang, J.; Green, D.; Seo, S.; Burckart, G. J.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Avant, D.] US FDA, Off Pediat Therapeut, Commissioners Off, Silver Spring, MD USA. [Fisher, J.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Mulberg, A. E.] Ctr Drug Evaluat & Res, Div Gastroenterol & Inborn Errors Prod, Off Drug Evaluat 3, Silver Spring, MD USA. [Mulberg, A. E.] US FDA, Silver Spring, MD USA. [McCune, S. K.] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Wang, J (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM jian.wang@fda.hhs.gov NR 17 TC 6 Z9 7 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD SEP PY 2015 VL 98 IS 3 BP 328 EP 335 DI 10.1002/cpt.149 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CP6RD UT WOS:000360014700013 PM 25975723 ER PT J AU Donovan, MD Polli, JE Langguth, P Tamai, I Vig, B Yu, LX AF Donovan, Maureen D. Polli, James E. Langguth, Peter Tamai, Ikumi Vig, Balvinder Yu, Lawrence X. TI Gordon L. Amidon: Very Sustained Drug Absorption SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Editorial Material DE absorption; active transport; Biopharmaceutics Classification System (BCS); gastrointestinal; intestinal absorption; membrane transport; prodrugs ID ACID ESTER PRODRUGS; BIOPHARMACEUTICS CLASSIFICATION-SYSTEM; INTESTINAL-MEMBRANE PERMEABILITY; BETA-LACTAM ANTIBIOTICS; ALPHA-METHYLDOPA ABSORPTION; HUMAN DIPEPTIDE TRANSPORTER; HUMAN JEJUNAL PERMEABILITY; HUMAN PEPTIDE TRANSPORTER; BOUNDARY-LAYER APPROACH; HYDROLASE-LIKE PROTEIN C1 [Donovan, Maureen D.] Univ Iowa, Coll Pharm, Iowa City, IA 52242 USA. [Polli, James E.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. [Langguth, Peter] Johannes Gutenberg Univ Mainz, Inst Pharm, D-55122 Mainz, Germany. [Tamai, Ikumi] Kanazawa Univ, Fac Pharm, Kanazawa, Ishikawa, Japan. [Vig, Balvinder] Bristol Myers Squibb, New Brunswick, NJ USA. [Yu, Lawrence X.] US FDA, Rockville, MD 20857 USA. RP Polli, JE (reprint author), Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. EM jpolli@rx.umaryland.edu RI TAMAI, Ikumi/D-8412-2015 NR 151 TC 0 Z9 0 U1 1 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD SEP PY 2015 VL 104 IS 9 BP 2650 EP 2663 DI 10.1002/jps.24523 PG 14 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA CP4MV UT WOS:000359857200002 PM 26053319 ER PT J AU Petrusevska, M Berglez, S Krisch, I Legen, I Megusar, K Peternel, L Abrahamsson, B Cristofoletti, R Groot, DW Kopp, S Langguth, P Mehta, M Polli, JE Shah, VP Dressman, J AF Petrusevska, Marija Berglez, Sandra Krisch, Igor Legen, Igor Megusar, Klara Peternel, Luka Abrahamsson, Bertil Cristofoletti, Rodrigo Groot, D. W. Kopp, Sabine Langguth, Peter Mehta, Mehul Polli, James E. Shah, Vinod P. Dressman, Jennifer TI Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Levetiracetam SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Editorial Material DE absorption; bioavailability; bioequivalence; biopharmaceutical classification system (BCS); biowaiver; levetiracetam; pharmacokinetics; permeability; solubility ID PHARMACOKINETICS; BIOAVAILABILITY; BIOEQUIVALENCE; EPILEPSY; DRUGS; MODEL; VOLUNTEERS; ABSORPTION; PHENYTOIN; INTESTINE AB Literature and experimental data relevant for the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levetiracetam are reviewed. Data on solubility and permeability suggest that levetiracetam belongs to class I of the biopharmaceutical classification system (BCS). Levetiracetam's therapeutic use, its wide therapeutic index, and its favorable pharmacokinetic properties make levetiracetam a valid candidate for the BCS-based biowaiver approach. Further, no BE studies with levetiracetam IR formulations in which the test formulation failed to show BE with the comparator have been reported in the open literature. On the basis of the overall evidence, it appears unlikely that a BCS-based biowaiver approach for levetiracetam IR solid oral dosage forms formulated with established excipients would expose patients to undue risks. Thus, the BCS-based biowaiver approach procedure is recommended for IR solid oral dosage form containing levetiracetam, provided the excipients in the formulation are also present in products that have been approved in countries belonging to or associated with the International Committee on Harmonization and are used in their usual quantities, and provided the dissolution profiles of the test and reference product comply with the current requirements for BCS-based biowaivers. (c) 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2676-2687, 2015 C1 [Petrusevska, Marija] Inst Preclin & Clin Pharmacol & Toxicol, Fac Med, Skopje, Macedonia. [Berglez, Sandra; Krisch, Igor; Legen, Igor; Megusar, Klara; Peternel, Luka] Lek Pharmaceut DD, SDC Slovenia, Ljubljana 1529, Slovenia. [Abrahamsson, Bertil] AstraZeneca, R&D, Molndal, Sweden. [Cristofoletti, Rodrigo] Brazilian Hlth Surveillance Agcy Anvisa, Div Bioequivalence, Brasilia, DF, Brazil. [Groot, D. W.] RIVM, Natl Inst Publ Hlth & Environm, Bilthoven, Netherlands. [Kopp, Sabine] WHO, CH-1211 Geneva, Switzerland. [Langguth, Peter] Johannes Gutenberg Univ Mainz, Inst Pharm Biopharmaceut & Pharmaceut Technol, D-55122 Mainz, Germany. [Mehta, Mehul] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Polli, James E.] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Shah, Vinod P.] FIP, The Hague, Netherlands. [Dressman, Jennifer] Goethe Univ Frankfurt, Inst Pharmaceut Technol, D-60054 Frankfurt, Germany. RP Dressman, J (reprint author), Goethe Univ Frankfurt, Inst Pharmaceut Technol, D-60054 Frankfurt, Germany. EM dressman@em.uni-frankfurt.de RI Fachbereich14, Dekanat/C-8553-2015 FU World Health Organization [001] NR 46 TC 0 Z9 1 U1 2 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD SEP PY 2015 VL 104 IS 9 BP 2676 EP 2687 DI 10.1002/jps.24350 PG 12 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA CP4MV UT WOS:000359857200004 PM 25663270 ER PT J AU Babiskin, AH Zhang, XY AF Babiskin, Andrew H. Zhang, Xinyuan TI Application of Physiologically Based Absorption Modeling for Amphetamine Salts Drug Products in Generic Drug Evaluation SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE physiological model; absorption; bioequivalence; bioavailability; clinical trial simulation; modified release ID FORMULATIONS; SIMULATION; TRANSIT; RELEASE AB Amphetamine (AMP) salts-based extended-release (ER) drug products are widely used for the treatment of attention deficit hyperactivity disorder. We developed physiologically based absorption models for mixed AMP salts ER capsules and dextroamphetamine sulfate ER capsules to address specific questions raised during generic drug postmarketing surveillance and bioequivalence (BE) guidance development. The models were verified against several data sets. Virtual BE simulations were conducted to assess BE in various populations other than normal healthy subjects where BE studies are generally conducted for approval. The models were also used to predict pharmacokinetics (PK) for hypothetical formulations having dissolution profiles falling within specification after the development of in vitro-in vivo relation. Finally, we demonstrated how to use the models to test sensitivity of PK metrics to the changes in formulation variables. (c) 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3170-3182, 2015 C1 [Babiskin, Andrew H.; Zhang, Xinyuan] US FDA, Div Quantitat Methods & Modeling, Off Res & Stand, Off Gener Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Babiskin, AH (reprint author), US FDA, Div Quantitat Methods & Modeling, Off Res & Stand, Off Gener Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM andrew.babiskin@fda.hhs.gov NR 18 TC 2 Z9 2 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD SEP PY 2015 VL 104 IS 9 BP 3170 EP 3182 DI 10.1002/jps.24474 PG 13 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA CP4MV UT WOS:000359857200049 PM 25973928 ER PT J AU Parshikov, IA Woodling, KA Sutherland, JB AF Parshikov, Igor A. Woodling, Kellie A. Sutherland, John B. TI Biotransformations of organic compounds mediated by cultures of Aspergillus niger SO APPLIED MICROBIOLOGY AND BIOTECHNOLOGY LA English DT Review DE Arenes; Aspergillus niger; Biotransformation; Hydrocarbons; Organic compounds ID SOLID-STATE FERMENTATION; MICROBIAL TRANSFORMATION; FUNGAL DETOXICATION; ENANTIOSELECTIVE HYDROLYSIS; METABOLISM; ACID; BIODEGRADATION; REDUCTION; MICROORGANISMS; HYDROXYLATION AB Many different organic compounds may be converted by microbial biotransformation to high-value products for the chemical and pharmaceutical industries. This review summarizes the use of strains of Aspergillus niger, a well-known filamentous fungus used in numerous biotechnological processes, for biochemical transformations of organic compounds. The substrates transformed include monocyclic, bicyclic, and polycyclic aromatic hydrocarbons; azaarenes, epoxides, chlorinated hydrocarbons, and other aliphatic and aromatic compounds. The types of reactions performed by A. niger, although not unique to this species, are extremely diverse. They include hydroxylation, oxidation of various functional groups, reduction of double bonds, demethylation, sulfation, epoxide hydrolysis, dechlorination, ring cleavage, and conjugation. Some of the products may be useful as new investigational drugs or chemical intermediates. C1 [Parshikov, Igor A.] Russian Acad Sci, Inst Appl Mech, Moscow 119991, Russia. [Woodling, Kellie A.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Sutherland, John B.] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. RP Sutherland, JB (reprint author), US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. EM john.sutherland@fda.hhs.gov OI Parshikov, Igor/0000-0003-1466-1128 NR 80 TC 3 Z9 3 U1 10 U2 58 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0175-7598 EI 1432-0614 J9 APPL MICROBIOL BIOT JI Appl. Microbiol. Biotechnol. PD SEP PY 2015 VL 99 IS 17 BP 6971 EP 6986 DI 10.1007/s00253-015-6765-0 PG 16 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA CP2WY UT WOS:000359739600002 PM 26162670 ER PT J AU Gonzalez, Y Pokrzywinski, KL Rosen, ET Mog, S Aryal, B Chehab, LM Vijay, V Moland, CL Desai, VG Dickey, JS Rao, VA AF Gonzalez, Yanira Pokrzywinski, Kaytee L. Rosen, Elliot T. Mog, Steven Aryal, Baikuntha Chehab, Leena M. Vijay, Vikrant Moland, Carrie L. Desai, Varsha G. Dickey, Jennifer S. Rao, V. Ashutosh TI Reproductive hormone levels and differential mitochondria-related oxidative gene expression as potential mechanisms for gender differences in cardiosensitivity to Doxorubicin in tumor-bearing spontaneously hypertensive rats SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Doxorubicin; Gender differences; Cardiotoxicity; Apoptosis; Testosterone; Estradiol; Dexrazoxane; Adriamycin ID ANTHRACYCLINE-INDUCED CARDIOTOXICITY; IN-VIVO; INDUCED CARDIOMYOPATHY; CARDIAC TOXICITY; CELL-DEATH; ESTROGEN; HEART; TESTOSTERONE; ADRIAMYCIN; CHILDREN AB Chemotherapy with doxorubicin (Dox) causes dose-limiting cardiotoxicity. We investigated the role that gender has on cardiosensitivity to Dox treatment by evaluating reproductive hormone levels in male, castrated male (c-male), female and ovariectomized female (o-female) adult spontaneously hypertensive rats (SHRs) and expression of mitochondria-related genes in male and female adult SHRs. SST-2 breast tumor-bearing SHRs were treated with saline, Dox, dexrazoxane (Drz) or both Dox and Drz and monitored for 14 days. Tumor size was used to monitor anticancer activity. Heart weight, cardiac lesion score and serum levels of cardiac troponin T (cTnT) were used to determine cardiotoxicity. Serum estradiol (E2) and testosterone were evaluated using electrochemiluminescence immunoassays. Expression of mitochondria-related genes was profiled in heart by MitoChip array analyses. Dox significantly reduced tumor volume (+/- Drz) and increased heart weight in all genders (13-30 % vs. control). Higher heart lesion scores were observed in reproductively normal animals (male 2.9, female 2.2) than in hormone-deficient animals (c-male 1.7, o-female 1.9). Lesion score and cTnT inversely correlated with hormone levels. Reduced levels of both sex hormones were observed after Dox treatment. Gene expression analyses of Dox-treated hearts showed significant differential expression of oxidative stress genes in male hearts and apoptotic genes in both male and female hearts. Our results demonstrate that adult tumor-bearing male SHRs are more cardiosensitive to Dox than female or hormone-deficient animals. We provide evidence to suggest that reproductive hormones negatively regulate or are inhibited by Dox-induced cardiotoxicity and the selective cytotoxic mechanism likely functions through the greater activation of oxidative stress and apoptosis in male SHRs. C1 [Gonzalez, Yanira; Pokrzywinski, Kaytee L.; Rosen, Elliot T.; Aryal, Baikuntha; Chehab, Leena M.; Rao, V. Ashutosh] US FDA, Chem Lab, Div Therapeut Prot, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Mog, Steven] US FDA, Ctr Food Safety & Appl Nutr, Silver Spring, MD 20993 USA. [Vijay, Vikrant; Moland, Carrie L.; Desai, Varsha G.] US FDA, Personalized Med Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Dickey, Jennifer S.] US FDA, Div Mol Genet & Pathol, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Rao, VA (reprint author), US FDA, Chem Lab, Div Therapeut Prot, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave Bldg 52-72 Rm 2212, Silver Spring, MD 20993 USA. EM ashutosh.rao@fda.hhs.gov RI Vijay, Vikrant/E-7651-2010 OI Vijay, Vikrant/0000-0001-8425-1285 FU United States Food and Drug Administration Office of Women's Health FX We would like to acknowledge Eugene Herman (FDA/CDER) and Rodney Levine (NIH/NHLBI) for helpful discussions, and Karlecia Corbett and Raissa Dantas (FDA/CDER) for assistance with animal procedures. We gratefully acknowledge funding support by the United States Food and Drug Administration Office of Women's Health grant. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the United States Food and Drug Administration and the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the United States Government. NR 44 TC 4 Z9 4 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD SEP PY 2015 VL 76 IS 3 BP 447 EP 459 DI 10.1007/s00280-015-2786-8 PG 13 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA CP3YC UT WOS:000359817800002 PM 26108538 ER PT J AU Myers, MJ Martinez, M Li, H Qiu, JS Troutman, L Sharkey, M Yancy, HF AF Myers, Michael J. Martinez, Marilyn Li, Hui Qiu, Junshan Troutman, Lisa Sharkey, Michele Yancy, Haile F. TI Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID NT230(DEL4) MDR1 MUTATION; HUMAN LIVER-MICROSOMES; P-GLYCOPROTEIN; GENE-EXPRESSION; BLOOD-BRAIN; IVERMECTIN SENSITIVITY; INTESTINAL METABOLISM; EPIGENETIC REGULATION; EFFLUX TRANSPORTER; BREED DISTRIBUTION AB Thirty-three Collies (14 male and 19 female) were used in a dose-escalation study to determine the impact of ABCB1 genotype on loperamide pharmacokinetics (PK) and pharmacodynamics (PD). Loperamide was orally administered in four ascending doses (0.01, 0.05, 0.1, or 0.2 mg/kg) over a 4-wk period to fasted Collies. Comparisons were made within each dose to genotype, phenotype, and whether Collies received three (3D) or four (4D) loperamide doses. The 3D and 4D groupings had statistically significant differences in systemic drug exposure (defined by the area under the concentration-versus-time profile estimated from time zero to the last quantifiable drug concentration, AUC0- last). In contrast, statistical differences in AUC0- last only occurred in the comparison between wild-type (WT) Collies versus homozygous mutant (Mut) Collies administered 0.1 mg/kg. Statistical differences in the proportionality relationship were observed when comparing 3D to 4D Collies, and the WT to Mut Collies. Intersubject variability in drug exposure tended to be twice as high between Mut and WT Collies. Associations were observed between systemic drug exposure and ataxia or depression but not between systemic drug exposure and mydriasis or salivation. Thus, Collies expressing the greatest sensitivity to CNS-associated effects of loperamide (Mut) tended to have higher drug exposure compared with those less sensitive to the adverse effects of loperamide. Genotype and phenotype only partially explained differences in loperamide PK and PD, suggesting this relationship may not be straightforward and that other factors need to be considered. Accordingly, the PD and PK of one P-glycoprotein substrate only partially predicted the likelihood of adverse responses to unrelated substrates. C1 [Myers, Michael J.; Yancy, Haile F.] US FDA, Res Off, Div Appl Vet Res, Ctr Vet Med, Silver Spring, MD USA. [Qiu, Junshan] US FDA, Off New Anim Drug Evaluat, Div Sci Support, Ctr Vet Med, Silver Spring, MD USA. [Martinez, Marilyn] US FDA, Off New Anim Drug Evaluat, Ctr Vet Med, Silver Spring, MD USA. [Li, Hui] US FDA, Res Off, Div Residue Chem, Ctr Vet Med, Silver Spring, MD USA. [Troutman, Lisa; Sharkey, Michele] US FDA, Off New Anim Drug Evaluat, Div Therapeut Drugs Nonfood Anim, Ctr Vet Med, Silver Spring, MD USA. RP Myers, MJ (reprint author), US FDA, Ctr Vet Med, Res Off, Div Appl Vet Res, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM michael.myers@fda.hhs.gov NR 50 TC 3 Z9 3 U1 0 U2 0 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 SEP PY 2015 VL 43 IS 9 BP 1392 EP 1407 DI 10.1124/dmd.115.063735 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CO2LR UT WOS:000358988300014 PM 26153274 ER PT J AU Lee, SL O'Connor, TF Yang, XC Cruz, CN Chatterjee, S Madurawe, RD Moore, CMV Yu, LX Woodcock, J AF Lee, Sau L. O'Connor, Thomas F. Yang, Xiaochuan Cruz, Celia N. Chatterjee, Sharmista Madurawe, Rapti D. Moore, Christine M. V. Yu, Lawrence X. Woodcock, Janet TI Modernizing Pharmaceutical Manufacturing: from Batch to Continuous Production SO JOURNAL OF PHARMACEUTICAL INNOVATION LA English DT Review DE Continuous processing; Quality by design; Process analytical technology; Control strategy; Traceability ID HOT-MELT EXTRUSION; TRACEABILITY; PERSPECTIVE; INDUSTRY AB The Food and Drug Administration (FDA) regulates pharmaceutical drug products to ensure a continuous supply of high-quality drugs in the USA. Continuous processing has a great deal of potential to address issues of agility, flexibility, cost, and robustness in the development of pharmaceutical manufacturing processes. Over the past decade, there have been significant advancements in science and engineering to support the implementation of continuous pharmaceutical manufacturing. These investments along with the adoption of the quality-by-design (QbD) paradigm for pharmaceutical development and the advancement of process analytical technology (PAT) for designing, analyzing, and controlling manufacturing have progressed the scientific and regulatory readiness for continuous manufacturing. The FDA supports the implementation of continuous manufacturing using science- and risk-based approaches. C1 [Lee, Sau L.; O'Connor, Thomas F.; Yang, Xiaochuan; Cruz, Celia N.; Chatterjee, Sharmista; Madurawe, Rapti D.; Moore, Christine M. V.; Yu, Lawrence X.; Woodcock, Janet] US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Qual, Silver Spring, MD 20993 USA. RP Yu, LX (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Qual, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Lawrence.Yu@fda.hhs.gov RI Yu, Lawrence/L-6280-2016; OI Yang, Xiaochuan/0000-0001-7003-444X NR 42 TC 22 Z9 23 U1 18 U2 67 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1872-5120 EI 1939-8042 J9 J PHARM INNOV JI J. Pharm. Innov. PD SEP PY 2015 VL 10 IS 3 BP 191 EP 199 DI 10.1007/s12247-015-9215-8 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CO2WZ UT WOS:000359019000001 ER PT J AU Chudasama, VL Ovacik, MA Abernethy, DR Mager, DE AF Chudasama, Vaishali L. Ovacik, Meric A. Abernethy, Darrell R. Mager, Donald E. TI Logic-Based and Cellular Pharmacodynamic Modeling of Bortezomib Responses in U266 Human Myeloma Cells SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NF-KAPPA-B; PROTEASOME INHIBITOR PS-341; XENOGRAFT MOUSE MODEL; MULTIPLE-MYELOMA; DRUG DEVELOPMENT; SIGNALING NETWORKS; INDUCED APOPTOSIS; BREAST-CANCER; STAT3; SYSTEMS AB Systems models of biological networks show promise for informing drug target selection/qualification, identifying lead compounds and factors regulating disease progression, rationalizing combinatorial regimens, and explaining sources of intersubject variability and adverse drug reactions. However, most models of biological systems are qualitative and are not easily coupled with dynamical models of drug exposure-response relationships. In this proof-of-concept study, logic-based modeling of signal transduction pathways in U266 multiple myeloma (MM) cells is used to guide the development of a simple dynamical model linking bortezomib exposure to cellular outcomes. Bortezomib is a commonly used first-line agent in MM treatment; however, knowledge of the signal transduction pathways regulating bortezomib-mediated cell cytotoxicity is incomplete. A Boolean network model of 66 nodes was constructed that includes major survival and apoptotic pathways and was updated using responses to several chemical probes. Simulated responses to bortezomib were in good agreement with experimental data, and a reduction algorithm was used to identify key signaling proteins. Bortezomib-mediated apoptosis was not associated with suppression of nuclear factor kappa B (NF kappa B) protein inhibition in this cell line, which contradicts a major hypothesis of bortezomib pharmacodynamics. A pharmacodynamic model was developed that included three critical proteins (phospho-NF kappa B, BclxL, and cleaved poly (ADP ribose) polymerase). Model-fitted protein dynamics and cell proliferation profiles agreed with experimental data, and the model-predicted IC50 (3.5 nM) is comparable to the experimental value (1.5 nM). The cell-based pharmacodynamic model successfully links bortezomib exposure to MM cellular proliferation via protein dynamics, and this model may show utility in exploring bortezomib-based combination regimens. C1 [Chudasama, Vaishali L.; Ovacik, Meric A.; Mager, Donald E.] SUNY Buffalo, Dept Pharmaceut Sci, Buffalo, NY 14214 USA. [Abernethy, Darrell R.] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. RP Mager, DE (reprint author), SUNY Buffalo, Dept Pharmaceut Sci, 431 Kapoor Hall, Buffalo, NY 14214 USA. EM dmager@buffalo.edu FU National Institutes of Health National Institute of General Medical Sciences [R01-GM57980]; University at Buffalo-Pfizer strategic alliance; Daiichi Sankyo Pharma Development; American Foundation for Pharmaceutical Education predoctoral fellowship FX This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM57980] (to D.E.M.); the University at Buffalo-Pfizer strategic alliance (D.E.M.); an unrestricted training grant from Daiichi Sankyo Pharma Development (to D.E.M.); and an American Foundation for Pharmaceutical Education predoctoral fellowship (to V.L.C.). NR 50 TC 2 Z9 2 U1 4 U2 5 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 SEP PY 2015 VL 354 IS 3 BP 448 EP 458 DI 10.1124/jpet.115.224766 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CO2PU UT WOS:000358999900022 PM 26163548 ER PT J AU Hariharan, P D'Souza, G Horner, M Malinauskas, RA Myers, MR AF Hariharan, Prasanna D'Souza, Gavin Horner, Marc Malinauskas, Richard A. Myers, Matthew R. TI Verification Benchmarks to Assess the Implementation of Computational Fluid Dynamics Based Hemolysis Prediction Models SO JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LA English DT Article DE computational fluid dynamics; shear stress; power-law hemolysis models; verification and validation ID INDUCED PLATELET ACTIVATION; MECHANICAL HEART-VALVE; BLOOD DAMAGE; FLOW; STRESS; DEVICES; PUMP; SHEARING; TRAUMA AB As part of an ongoing effort to develop verification and validation (V&V) standards for using computational fluid dynamics (CFD) in the evaluation of medical devices, we have developed idealized flow-based verification benchmarks to assess the implementation of commonly cited power-law based hemolysis models in CFD. The verification process ensures that all governing equations are solved correctly and the model is free of user and numerical errors. To perform verification for power-law based hemolysis modeling, analytical solutions for the Eulerian power-law blood damage model (which estimates hemolysis index (HI) as a function of shear stress and exposure time) were obtained for Couette and inclined Couette flow models, and for Newtonian and non-Newtonian pipe flow models. Subsequently, CFD simulations of fluid flow and HI were performed using Eulerian and three different Lagrangian-based hemolysis models and compared with the analytical solutions. For all the geometries, the blood damage results from the Eulerian-based CFD simulations matched the Eulerian analytical solutions within similar to 1%, which indicates successful implementation of the Eulerian hemolysis model. Agreement between the Lagrangian and Eulerian models depended upon the choice of the hemolysis power-law constants. For the ommonly used values of power-law constants (alpha = 1.9-2.42 and beta = 0.65-0.80), in the absence of flow acceleration, most of the Lagrangian models matched the Eulerian results within 5%. In the presence of flow acceleration (inclined Couette flow), moderate differences (similar to 10%) were observed between the Lagrangian and Eulerian models. This difference increased to greater than 100% as the beta exponent decreased. These simplified flow problems can be used as standard benchmarks for verifying the implementation of blood damage predictive models in commercial and open-source CFD codes. The current study used only a power-law model as an illustrative example to emphasize the need for model verification. Similar verification problems could be developed for other types of hemolysis models (such as strain-based and energy dissipation-based methods). And since the current study did not include experimental validation, the results from the verified models do not guarantee accurate hemolysis predictions. This verification step must be followed by experimental validation before the hemolysis models can be used for actual device safety evaluations. C1 [Hariharan, Prasanna; D'Souza, Gavin; Malinauskas, Richard A.; Myers, Matthew R.] US FDA, Silver Spring, MD 20993 USA. [Horner, Marc] ANSYS Inc, Evanston, IL 60201 USA. RP Hariharan, P (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Prasanna.hariharan@fda.hhs.gov NR 41 TC 2 Z9 2 U1 2 U2 17 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 0148-0731 EI 1528-8951 J9 J BIOMECH ENG-T ASME JI J. Biomech. Eng.-Trans. ASME PD SEP PY 2015 VL 137 IS 9 AR 094501 DI 10.1115/1.4030823 PG 10 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA CN9VO UT WOS:000358798500010 ER PT J AU Bellmann, S Carlander, D Fasano, A Momcilovic, D Scimeca, JA Waldman, WJ Gombau, L Tsytsikova, L Canady, R Pereira, DIA Lefebvre, DE AF Bellmann, Susann Carlander, David Fasano, Alessio Momcilovic, Dragan Scimeca, Joseph A. Waldman, W. James Gombau, Lourdes Tsytsikova, Lyubov Canady, Richard Pereira, Dora I. A. Lefebvre, David E. TI Mammalian gastrointestinal tract parameters modulating the integrity, surface properties, and absorption of food-relevant nanomaterials SO WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY LA English DT Review ID INTESTINAL BARRIER FUNCTION; IN-VITRO DIGESTION; MUCUS GEL LAYER; TITANIUM-DIOXIDE; ENGINEERED NANOMATERIALS; M-CELLS; SILICA NANOPARTICLES; LIPID NANOPARTICLES; OXIDE NANOPARTICLES; TIO2 NANOPARTICLES AB Many natural chemicals in food are in the nanometer size range, and the selective uptake of nutrients with nanoscale dimensions by the gastrointestinal (GI) tract is a normal physiological process. Novel engineered nanomaterials (NMs) can bring various benefits to food, e.g., enhancing nutrition. Assessing potential risks requires an understanding of the stability of these entities in the GI lumen, and an understanding of whether or not they can be absorbed and thus become systemically available. Data are emerging on the mammalian in vivo absorption of engineered NMs composed of chemicals with a range of properties, including metal, mineral, biochemical macromolecules, and lipid-based entities. In vitro and in silico fluid incubation data has also provided some evidence of changes in particle stability, aggregation, and surface properties following interaction with luminal factors present in the GI tract. The variables include physical forces, osmotic concentration, pH, digestive enzymes, other food, and endogenous biochemicals, and commensal microbes. Further research is required to fill remaining data gaps on the effects of these parameters on NM integrity, physicochemical properties, and GI absorption. Knowledge of the most influential luminal parameters will be essential when developing models of the GI tract to quantify the percent absorption of food-relevant engineered NMs for risk assessment. WIREs Nanomed Nanobiotechnol 2015, 7:609-622. doi: 10.1002/wnan.1333 For further resources related to this article, please visit the . C1 [Bellmann, Susann] TNO, Utrecht, Netherlands. [Carlander, David] Nanotechnol Ind Assoc, Brussels, Belgium. [Fasano, Alessio] Harvard Univ, Sch Med, Massachusetts Gen Hosp Children, Boston, MA USA. [Momcilovic, Dragan] US FDA, Dept Hlth & Human Serv, Silver Spring, MD USA. [Scimeca, Joseph A.] Cargill Inc, Minneapolis, MN USA. [Waldman, W. James] Ohio State Univ, Columbus, OH 43210 USA. [Gombau, Lourdes] Leitat Technol Ctr, Barcelona, Spain. [Tsytsikova, Lyubov; Canady, Richard] ILSI Res Fdn, Ctr Risk Sci Innovat & Applicat, Washington, DC USA. [Pereira, Dora I. A.] MRC Human Nutr Res, Elsie Widdowson Lab, Cambridge, England. [Lefebvre, David E.] Hlth Canada, Food Directorate, Regulatory Toxicol Res Div, Ottawa, ON K1A 0L2, Canada. RP Lefebvre, DE (reprint author), Hlth Canada, Food Directorate, Regulatory Toxicol Res Div, Ottawa, ON K1A 0L2, Canada. EM david.lefebvre@hc-sc.gc.ca RI Pereira, Dora/D-4634-2012 OI Pereira, Dora/0000-0001-5688-4448 FU Pew Charitable Trusts; US Food and Drug Administration; Health Canada; ILSI North America; Coca-Cola Company; Illinois Institute of Technology's Institute for Food Safety and Health; ILSI Research Foundation; Nanotechnology Industries Association; UK Medical Research Council [U105960399] FX The authors are grateful to the following individuals for their expert input: Vicki Stone (Heriot-Watt University, UK), John Milner (Agricultural Research Service, US Department of Agriculture), Bruce Hamaker (Purdue University, USA), Brian Lee (GE Global Research, USA), Jozef Kokini (University of Illinois, USA), Bevan Pearce, Joel Rotstein, Jesse Bertinato, and Rekha Mehta (Health Canada). We also thank Molly Bloom and Elyse Lee (Center for Risk Science Innovation and Application, ILSI Research Foundation, USA) for assistance with the management of the NanoRelease Food Additive project. We acknowledge the NanoRelease Food Additive Steering Committee, which operates as an independent public-private partnership (http://www.ilsi.org/ResearchFoundation/RSIA/Pages/FoodAdditiveSteeringC ommittee.aspx), for convening the authors and for developing the initial framing concepts for the review. The initial steering phase of the NanoRelease Food Additive project was funded by the Pew Charitable Trusts, the US Food and Drug Administration, Health Canada, ILSI North America, the Coca-Cola Company, the Illinois Institute of Technology's Institute for Food Safety and Health, and the ILSI Research Foundation. Substantial in-kind support was provided by the Nanotechnology Industries Association and by the UK Medical Research Council (U105960399). This article has been reviewed in accordance with the US FDA's peer and administrative review policies and approved for publication. Mention of trade names or commercial products does not constitute an endorsement or recommendation for use by the US FDA. The statements made in this report do not necessarily represent the official position of the employers or affiliated organizations of the authors. NR 115 TC 8 Z9 8 U1 7 U2 40 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1939-5116 EI 1939-0041 J9 WIRES NANOMED NANOBI JI Wiley Interdiscip. Rev.-Nanomed. Nanobiotechnol. PD SEP-OCT PY 2015 VL 7 IS 5 BP 609 EP 622 DI 10.1002/wnan.1333 PG 14 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA CN7LR UT WOS:000358616500001 PM 25641962 ER PT J AU Tyner, KM Zou, P Yang, XC Zhang, HL Cruz, CN Lee, SL AF Tyner, Katherine M. Zou, Peng Yang, Xiaochuan Zhang, Hailing Cruz, Celia N. Lee, Sau L. TI Product quality for nanomaterials: current US experience and perspective SO WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY LA English DT Review ID RESONANCE ENERGY-TRANSFER; VITRO DRUG-RELEASE; IN-VITRO; FORMULATION OPTIMIZATION; GOLD NANOPARTICLES; CRITICAL VARIABLES; DESIGN APPROACH; LIPOSOMES; DELIVERY; NANOTECHNOLOGY AB In recent years, there has been an increased focus on developing novel drug delivery systems and targeted therapies through the use of nanotechnology and nanomaterials. Such focus is translating to an increasing number of investigational new drug (IND) applications, new drug applications (NDAs), and abbreviated new drug applications (ANDAs) for drug products containing nanomaterials to the United States Food and Drug Administration (FDA). Although subject to the same rigorous regulatory standards and regulatory pathways as any drug product, unique properties that arise from the small size, large surface area, and polydispersity of nanomaterials may lead to additional scientific considerations when following current FDA guidelines and practices for drug evaluation. This review article will discuss these scientific considerations based on the experience with FDA-approved drug products containing nanomaterials. WIREs Nanomed Nanobiotechnol 2015, 7:640-654. doi: 10.1002/wnan.1338 For further resources related to this article, please visit the . C1 [Tyner, Katherine M.; Zou, Peng; Yang, Xiaochuan; Zhang, Hailing; Cruz, Celia N.; Lee, Sau L.] US FDA, CDER OPQ SRS, Silver Spring, MD 20993 USA. RP Tyner, KM (reprint author), US FDA, CDER OPQ SRS, Silver Spring, MD 20993 USA. EM katherine.tyner@fda.hhs.gov RI Zou, Peng/J-9300-2015; OI Yang, Xiaochuan/0000-0001-7003-444X NR 68 TC 5 Z9 5 U1 4 U2 32 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1939-5116 EI 1939-0041 J9 WIRES NANOMED NANOBI JI Wiley Interdiscip. Rev.-Nanomed. Nanobiotechnol. PD SEP-OCT PY 2015 VL 7 IS 5 BP 640 EP 654 DI 10.1002/wnan.1338 PG 15 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA CN7LR UT WOS:000358616500003 PM 25641690 ER PT J AU Shen, JL Rump, L Ju, WT Shao, JD Zhao, SH Brown, E Meng, JH AF Shen, Jinling Rump, Lydia Ju, Wenting Shao, Jingdong Zhao, Shaohua Brown, Eric Meng, Jianghong TI Virulence characterization of non-O157 Shiga toxin-producing Escherichia coli isolates from food, humans and animals SO FOOD MICROBIOLOGY LA English DT Article DE STEC; Shiga toxin subtype; eae subtype; Vero cell cytotoxicity ID HEMOLYTIC-UREMIC SYNDROME; EPITHELIAL-CELLS; UNITED-STATES; INTIMIN TYPES; MOLECULAR CHARACTERIZATION; INTESTINAL MUCUS; GENE-CLUSTER; STRAINS; IDENTIFICATION; VARIANTS AB A total of 359 non-O157 STEC isolates from food, humans and animals were examined for serotypes, Shiga toxin subtypes and intimin subtypes. Isolates solely harboring stx(2) from the three sources were selected for Vero cell cytotoxicity test. stx subtypes in eae negative isolates were more diverse than in eae positive isolates primarily carrying stx(2a). Four eae subtypes (eae(beta), eae(epsilon 1), eae(gamma 1) and eae(gamma 2/theta)) were observed and correlated with serotypes and flagella. Food isolates showed more diverse serotypes, virulence factors and cell cytotoxicities than human isolates. Some isolates from produce belonged to serotypes that have been implicated in human diseases, carried stx(2a) or/and stx(2dact) and exhibited high cell cytotoxicity similar to human isolates. This indicates that foods can be contaminated with potentially pathogenic STEC isolates that may cause human diseases. Given the increased produce consumption and growing burden of foodborne outbreaks due to produce, produce safety should be given great importance. (C) 2015 Published by Elsevier Ltd. C1 [Shen, Jinling; Shao, Jingdong] Technol Ctr Zhangjiagang Entry Exit Inspect, Zhangjiagang 215600, Jiangsu, Peoples R China. [Shen, Jinling; Shao, Jingdong] Quarantine Bur Peoples Republ China, Zhangjiagang 215600, Jiangsu, Peoples R China. [Shen, Jinling; Rump, Lydia; Ju, Wenting; Meng, Jianghong] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Zhao, Shaohua] US FDA, Ctr Vet Med, Laurel, MD 20708 USA. [Brown, Eric] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Meng, JH (reprint author), Univ Maryland, Dept Nutr & Food Sci, 0112 Skinner Bldg, College Pk, MD 20742 USA. EM jmeng@umd.edu NR 60 TC 6 Z9 6 U1 1 U2 39 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0740-0020 EI 1095-9998 J9 FOOD MICROBIOL JI Food Microbiol. PD SEP PY 2015 VL 50 BP 20 EP 27 DI 10.1016/j.fm.2015.02.007 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA CI5FI UT WOS:000354778800004 PM 25998811 ER PT J AU Yan, QQ Jarvis, KG Chase, HR Hebert, K Trach, LH Lee, C Sadowski, J Lee, B Hwang, S Sathyamoorthy, V Mullane, N Pava-Ripoll, M Iversen, C Pagotto, F Fanning, S Tall, BD AF Yan, Qiongqiong Jarvis, Karen G. Chase, Hannah R. Hebert, Karine Trach, Larisa H. Lee, Chloe Sadowski, Jennifer Lee, Boram Hwang, Seongeun Sathyamoorthy, Venugopal Mullane, Niall Pava-Ripoll, Monica Iversen, Carol Pagotto, Franco Fanning, Seamus Tall, Ben D. TI A proposed harmonized LPS molecular-subtyping scheme for Cronobacter species SO FOOD MICROBIOLOGY LA English DT Article DE Cronobacter; LPS; Molecular serotyping; SDS-PAGE ID LIPOPOLYSACCHARIDE O-ANTIGEN; ENTEROBACTER-SAKAZAKII; GENE; IDENTIFICATION; SEROTYPE; SPP.; POLYSACCHARIDE; TRANSPORTERS; CONDIMENTI; LACTARIDI AB Cronobacter are opportunistic pathogens, which cause infections in all age groups. To aid the characterization of Cronobacter in foods and environments a harmonized LPS identification scheme for molecular serotyping is needed. To this end, we studied 409 Cronobacter isolates representing the seven Cronobacter species using two previously reported molecular serotyping schemes, described here as Mullane-Jarvis (M-J) and Sun schemes. PCR analysis revealed many overlapping results that were obtained when independently applying the two serotyping schemes. There were complete agreements between the two PCR schemes for Cronobacter sakazakii (Csak) O:1, Csak O:3, and Csak O:7 serotypes. However, only thirty-five of 41 Csak O:4 strains, identified using the M-J scheme, were PCR-positive with the Sun scheme primers. Also the Sun scheme Csak O:5 primers failed to identify this serotype in any of the C. sakazakii strains tested, but did recognize seven Cronobacter turicensis strains, which were identified as Ctur O:3 using the M-J scheme. Similarly, the Sun scheme Csak O:6 primers recognized 30 Cronobacter malonaticus O:2 strains identified with the M-J scheme, but failed to identify this serotype in any C. sakazakii strain investigated. In this report, these findings are summarized and a harmonized molecular-serotyping scheme is proposed which is predicated on the correct identification of Cronobacter species, prior to serotype determination. In summary, fourteen serotypes were identified using the combined protocol, which consists of Csak O:1-O:4, and Csak O:7; Cmal O:1-O:2; Cdub O:1-O:2, Cmuy O:1-O:2, Cuni O:1, as well as Ctur O:1 and Ctur O:3. Published by Elsevier Ltd. C1 [Yan, Qiongqiong; Fanning, Seamus] Univ Coll Dublin, Ctr Food Safety, WHO Collaborating Ctr Res Reference & Training Cr, Dublin 4, Ireland. [Jarvis, Karen G.; Chase, Hannah R.; Trach, Larisa H.; Lee, Chloe; Sadowski, Jennifer; Lee, Boram; Hwang, Seongeun; Sathyamoorthy, Venugopal; Tall, Ben D.] US FDA, CFSAN, Laurel, MD 20708 USA. [Mullane, Niall] Mead Johnson Nutr, Evansville, IN USA. [Pava-Ripoll, Monica] US FDA, CFSAN, College Pk, MD USA. [Iversen, Carol] Univ Dundee, Coll Life Sci, Dundee DD1 4HN, Scotland. [Hebert, Karine; Pagotto, Franco] Bur Microbial Hazards Hlth Canada, Food Directorate, Ottawa, ON, Canada. RP Tall, BD (reprint author), US FDA, Virulence Mech Branch, Div Virulence Assessment, OARSA,Ctr Food Safety & Appl Nutr, Lab 3408,MOD 1 Facil,HFS 025,8301 Muirkirk Rd, Laurel, MD 20708 USA. EM ben.tall@fda.hhs.gov OI Fanning, Seamus/0000-0002-1922-8836; Tall, Ben/0000-0003-0399-3629 NR 37 TC 5 Z9 5 U1 4 U2 27 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0740-0020 EI 1095-9998 J9 FOOD MICROBIOL JI Food Microbiol. PD SEP PY 2015 VL 50 BP 38 EP 43 DI 10.1016/j.fm.2015.03.003 PG 6 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA CI5FI UT WOS:000354778800006 PM 25998813 ER PT J AU Mueller, S Handy, SM Deeds, JR George, GO Broadhead, WJ Pugh, SE Garrett, SD AF Mueller, Steffen Handy, Sara M. Deeds, Jonathan R. George, Gideon O. Broadhead, Wendy J. Pugh, Sian E. Garrett, Stephen D. TI Development of a COX1 based PCR-RFLP method for fish species identification SO FOOD CONTROL LA English DT Article DE Species identification; Fish; COX1; PCR-RFLP; Microfluidics; Capillary electrophoresis ID CHIP CAPILLARY-ELECTROPHORESIS; DNA; SEAFOOD; ADULTERATION; MARKET AB Economically motivated adulteration and species substitution of certain types of seafood are of concern within the global food supply chain. Complex multinational supply chains, price pressure, as well as resource limitations for certain food commodities invite substitution of higher value ingredients with lower value species or varieties. Due to these issues, the seafood market is particularly susceptible to fraud and substitution. In the past polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) methods based on a mitochondrial CytB target have been developed and are in routine use. The aim of this work was to develop a faster method with higher sample throughput using microfluidics based capillary electrophoresis and a target within the COX1 barcoding region. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Mueller, Steffen] Agilent Technol, D-76337 Waldbronn, Germany. [Handy, Sara M.; Deeds, Jonathan R.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. [George, Gideon O.; Broadhead, Wendy J.; Pugh, Sian E.; Garrett, Stephen D.] Campden BRI, Chipping Campden GL55 6LD, Glos, England. RP Mueller, S (reprint author), Agilent Technol, Hewlett Packard Str 8, D-76337 Waldbronn, Germany. EM steffen.mueller@agilent.com RI Handy, Sara/C-6195-2008 NR 20 TC 6 Z9 6 U1 2 U2 32 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-7135 EI 1873-7129 J9 FOOD CONTROL JI Food Control PD SEP PY 2015 VL 55 BP 39 EP 42 DI 10.1016/j.foodcont.2015.02.026 PG 4 WC Food Science & Technology SC Food Science & Technology GA CH2JC UT WOS:000353850500005 ER PT J AU Bartz, JA Yuk, HG Mahovic, MJ Warren, BR Sreedharan, A Schneider, KR AF Bartz, Jerry A. Yuk, Hyun-Gyun Mahovic, Michael J. Warren, Benjamin R. Sreedharan, Aswathy Schneider, Keith R. TI Internalization of Salmonella enterica by tomato fruit SO FOOD CONTROL LA English DT Review DE Salmonellosis; Tomato; Infiltration; Disinfectant; Internalization ID CAROTOVORA SUBSP CAROTOVORA; BACTERIAL SOFT-ROT; CHLORINATED WATER; RAW TOMATOES; MULTISTATE OUTBREAK; IRRIGATION WATER; HEALTHY TOMATOES; UNITED-STATES; SURVIVAL; PLANTS AB Since 1990, several outbreaks of foodborne illness have been associated with the consumption of raw tomatoes. Various serovars of the bacterial pathogen, Salmonella enterica, were responsible for these illnesses. Fruits and vegetables are not a normal niche for mammalian pathogens. Hypotheses concerning introduction of Salmonella into tomatoes range from contamination in the field or greenhouse to direct or cross-contamination during harvest handling and preparation of tomato as a raw agricultural commodity. Many different reports have shown that Salmonella can not only survive in tomato fruit but also proliferate from small, relatively inconsequential populations to numbers known to incite illness even in healthy individuals. Herein, production, harvest and handling of fresh market tomatoes are evaluated in terms of how Salmonella might contaminate this crop. Physical principles are emphasized, whereas biological factors are included where appropriate. Salmonella is viewed as a bacterium that is affected by the same physical principles affecting bacteria naturally occurring in the environment surrounding tomato fruit as well as tomato plants during production, harvest and handling. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Sreedharan, Aswathy; Schneider, Keith R.] Univ Florida, Dept Food Sci & Human Nutr, Gainesville, FL 32611 USA. [Bartz, Jerry A.] Univ Florida, Dept Plant Pathol, Gainesville, FL 32611 USA. [Mahovic, Michael J.] US FDA, College Pk, MD 20740 USA. [Warren, Benjamin R.] Land OLakes Inc, Arden Hills, MN 55126 USA. [Yuk, Hyun-Gyun] Natl Univ Singapore, Dept Chem, Food Sci & Technol Programme, Singapore 117543, Singapore. RP Bartz, JA (reprint author), Univ Florida, Dept Plant Pathol, POB 110680, Gainesville, FL 32611 USA. EM softbart@ufl.edu NR 91 TC 6 Z9 6 U1 6 U2 55 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-7135 EI 1873-7129 J9 FOOD CONTROL JI Food Control PD SEP PY 2015 VL 55 BP 141 EP 150 DI 10.1016/j.foodcont.2015.02.046 PG 10 WC Food Science & Technology SC Food Science & Technology GA CH2JC UT WOS:000353850500019 ER PT J AU Hu, N Huang, L Tiwari, RC AF Hu, Na Huang, Lan Tiwari, Ram C. TI Signal detection in FDA AERS database using Dirichlet process SO STATISTICS IN MEDICINE LA English DT Article DE reporting rates; information component; false discovery rate; pseudo-maximum likelihood; pseudo-Bayes factor; zero-inflated Poisson model ID PROBABILITY RATIO TESTS; DRUG SAFETY DATA; PHARMACOVIGILANCE; GENERATION; SURVEILLANCE; MODELS; PRIORS AB In the recent two decades, data mining methods for signal detection have been developed for drug safety surveillance, using large post-market safety data. Several of these methods assume that the number of reports for each drug-adverse event combination is a Poisson random variable with mean proportional to the unknown reporting rate of the drug-adverse event pair. Here, a Bayesian method based on the Poisson-Dirichlet process (DP) model is proposed for signal detection from large databases, such as the Food and Drug Administration's Adverse Event Reporting System (AERS) database. Instead of using a parametric distribution as a common prior for the reporting rates, as is the case with existing Bayesian or empirical Bayesian methods, a nonparametric prior, namely, the DP, is used. The precision parameter and the baseline distribution of the DP, which characterize the process, are modeled hierarchically. The performance of the Poisson-DP model is compared with some other models, through an intensive simulation study using a Bayesian model selection and frequentist performance characteristics such as type-I error, false discovery rate, sensitivity, and power. For illustration, the proposed model and its extension to address a large amount of zero counts are used to analyze statin drugs for signals using the 2006-2011 AERS data. Copyright (c) 2015John Wiley & Sons, Ltd. C1 [Hu, Na] Univ Missouri, Dept Stat, Columbia, MO 65201 USA. [Huang, Lan; Tiwari, Ram C.] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Huang, L (reprint author), US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM lan.huang@fda.hhs.gov NR 37 TC 1 Z9 1 U1 3 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD AUG 30 PY 2015 VL 34 IS 19 BP 2725 EP 2742 DI 10.1002/sim.6510 PG 18 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA CM4YP UT WOS:000357693100004 PM 25924820 ER PT J AU Krause, PR AF Krause, Philip R. TI Interim results from a phase 3 Ebola vaccine study in Guinea SO LANCET LA English DT Editorial Material C1 US FDA, Ctr Biol Evaluat & Res, Off Vaccines Res & Review, Silver Spring, MD 20993 USA. RP Krause, PR (reprint author), US FDA, Ctr Biol Evaluat & Res, Off Vaccines Res & Review, Silver Spring, MD 20993 USA. EM philip.krause@fda.hhs.gov NR 4 TC 11 Z9 12 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD AUG 29 PY 2015 VL 386 IS 9996 BP 831 EP 833 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CQ0MJ UT WOS:000360290000004 PM 26335862 ER PT J AU Ji, YC Gray, RA Fenton, FH AF Ji, Yanyan Claire Gray, Richard A. Fenton, Flavio H. TI Implementation of Contraction to Electrophysiological Ventricular Myocyte Models, and Their Quantitative Characterization via Post-Extrasystolic Potentiation SO PLOS ONE LA English DT Article ID CARDIAC RESYNCHRONIZATION THERAPY; HEART-FAILURE; ELECTRICAL ALTERNANS; CALCIUM KINETICS; MODULATION; MUSCLE; DYNAMICS; SIMULATION; DEPENDENCE; EFFICACY AB Heart failure (HF) affects over 5 million Americans and is characterized by impairment of cellular cardiac contractile function resulting in reduced ejection fraction in patients. Electrical stimulation such as cardiac resynchronization therapy (CRT) and cardiac contractility modulation (CCM) have shown some success in treating patients with HF. Computer simulations have the potential to help improve such therapy (e.g. suggest optimal lead placement) as well as provide insight into the underlying mechanisms which could be beneficial. However, these myocyte models require a quantitatively accurate excitation-contraction coupling such that the electrical and contraction predictions are correct. While currently there are close to a hundred models describing the detailed electrophysiology of cardiac cells, the majority of cell models do not include the equations to reproduce contractile force or they have been added ad hoc. Here we present a systematic methodology to couple first generation contraction models into electrophysiological models via intracellular calcium and then compare the resulting model predictions to experimental data. This is done by using a post-extrasystolic pacing protocol, which captures essential dynamics of contractile forces. We found that modeling the dynamic intracellular calcium buffers is necessary in order to reproduce the experimental data. Furthermore, we demonstrate that in models the mechanism of the post-extrasystolic potentiation is highly dependent on the calcium released from the Sarcoplasmic Reticulum. Overall this study provides new insights into both specific and general determinants of cellular contractile force and provides a framework for incorporating contraction into electrophysiological models, both of which will be necessary to develop reliable simulations to optimize electrical therapies for HF. C1 [Ji, Yanyan Claire; Fenton, Flavio H.] Georgia Inst Technol, Dept Phys, Atlanta, GA 30332 USA. [Gray, Richard A.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Ji, YC (reprint author), Georgia Inst Technol, Dept Phys, Atlanta, GA 30332 USA. EM yji47@gatech.edu FU National Science Foundation [1347015] FX The authors acknowledge the National Science Foundation grant number: 1347015, http://www.nsf.gov/.FHF received the grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 2 Z9 2 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 28 PY 2015 VL 10 IS 8 AR e0135699 DI 10.1371/journal.pone.0135699 PG 35 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CQ0PO UT WOS:000360299100042 PM 26317204 ER PT J AU Shimabukuro, TT Nguyen, M Martin, D DeStefano, F AF Shimabukuro, Tom T. Nguyen, Michael Martin, David DeStefano, Frank TI Safety monitoring in the Vaccine Adverse Event Reporting System (VAERS) SO VACCINE LA English DT Review DE Vaccination; Vaccine adverse event; Adverse event following immunization; Adverse reaction; Adverse effect; Spontaneous reporting; Passive surveillance; Vaccine safety; Vaccine Adverse Event Reporting System (VAERS) ID HUMAN-PAPILLOMAVIRUS VACCINE; A H1N1 2009; UNITED-STATES; FEBRILE SEIZURES; ROTAVIRUS VACCINATION; MONOVALENT VACCINES; IMMUNIZATION SAFETY; INFLUENZA VACCINE; SURVEILLANCE; SIGNAL AB The Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA) conduct post-licensure vaccine safety monitoring using the Vaccine Adverse Event Reporting System (VAERS), a spontaneous (or passive) reporting system. This means that after a vaccine is approved, CDC and FDA continue to monitor safety while it is distributed in the marketplace for use by collecting and analyzing spontaneous reports of adverse events that occur in persons following vaccination. Various methods and statistical techniques are used to analyze VAERS data, which CDC and FDA use to guide further safety evaluations and inform decisions around vaccine recommendations and regulatory action. VAERS data must be interpreted with caution due to the inherent limitations of passive surveillance. VAERS is primarily a safety signal detection and hypothesis generating system. Generally, VAERS data cannot be used to determine if a vaccine caused an adverse event. VAERS data interpreted alone or out of context can lead to erroneous conclusions about cause and effect as well as the risk of adverse events occurring following vaccination. CDC makes VAERS data available to the public and readily accessible online. We describe fundamental vaccine safety concepts, provide an overview of VAERS for healthcare professionals who provide vaccinations and might want to report or better understand a vaccine adverse event, and explain how CDC and FDA analyze VAERS data. We also describe strengths and limitations, and address common misconceptions about VAERS. Information in this review will be helpful for healthcare professionals counseling patients, parents, and others on vaccine safety and benefit-risk balance of vaccination. Published by Elsevier Ltd. C1 [Shimabukuro, Tom T.; DeStefano, Frank] Ctr Dis Control & Prevent, Natl Ctr Emerging & Zoonot Infect Dis, Div Hlth Care Qual Promot, Immunizat Safety Off, Atlanta, GA 30329 USA. [Nguyen, Michael; Martin, David] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Shimabukuro, TT (reprint author), Ctr Dis Control & Prevent, Immunizat Safety Off, 1600 Clifton Rd NE,MS D-26, Atlanta, GA 30329 USA. EM TShimabukuro@cdc.gov FU Intramural CDC HHS [CC999999] NR 69 TC 14 Z9 14 U1 1 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD AUG 26 PY 2015 VL 33 IS 36 BP 4398 EP 4405 DI 10.1016/j.vaccine.2015.07.035 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CQ8OK UT WOS:000360867500008 PM 26209838 ER PT J AU Leonard, SR Lacher, DW Lampel, KA AF Leonard, Susan R. Lacher, David W. Lampel, Keith A. TI Acquisition of the lac operon by Salmonella enterica SO BMC MICROBIOLOGY LA English DT Article ID LACTOSE-FERMENTING SALMONELLA; TYPHOID-FEVER; TYPHIMURIUM; VIRULENCE; OUTBREAK; NEWPORT; MODELS AB Background: Classical bacteriological characteristics of Salmonella enterica indicate that the members of this species are unable to utilize lactose as a carbon source. However, lactose-fermenting (Lac+) strains of several Salmonella serovars have been isolated from different foodborne outbreaks as well as different geographical regions worldwide. In the present study, we sequenced the genomes of 13 Lac + S. enterica isolates and characterized the lac region, comparing it to the lac region in other enteric bacterial species. Results: Genetic analysis of the lac operons in the S. enterica genomes revealed that they all contain intact lacI, lacZ, and lacY genes. However, lacA was truncated in all of the S. enterica subsp. enterica isolates, encoding a 56 amino acid peptide rather than the full length 220 amino acid LacA protein. Molecular analyses of the 13 isolates revealed that the lac operon resided on a plasmid in some strains and in others was integrated into the bacterial chromosome. In most cases, an insertion sequence flanked at least one end of the operon. Interestingly, the S. enterica Montevideo and S. enterica Senftenberg isolates were found to harbor a plasmid with a high degree of sequence similarity to a plasmid from Klebsiella pneumoniae strain NK29 that also harbors the lac operon. In addition, two S. enterica Tennessee isolates carried two copies of the lac operon. Phylogenetic analysis based on lacIZY gene sequences determines distinct clusters, and reveals a greater correlation between lacIZY sequence and flanking organization than with either bacterial species or genomic location. Conclusions: Our results indicate that the lac region is highly mobile among Enterobacteriaceae and demonstrate that the Lac + S. enterica subsp. enterica serovars acquired the lac region through parallel events. The acquisition of the lac operon by several S. enterica serovars may be indicative of environmental adaptation by these bacteria. C1 [Leonard, Susan R.; Lacher, David W.; Lampel, Keith A.] US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD 20993 USA. RP Lampel, KA (reprint author), US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD 20993 USA. EM Keith.Lampel@fda.hhs.gov FU Oak Ridge Institute for Science Education FX We thank Rebecca Dievart at BIO-RAD Laboratories, France, for the Lac + Salmonella isolates. One of us (KAL) is indebted to Monica Riley whose work on genome comparisons decades ago inspired this work. This research was funded in part by the Oak Ridge Institute for Science Education. NR 27 TC 0 Z9 0 U1 7 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD AUG 25 PY 2015 VL 15 AR 173 DI 10.1186/s12866-015-0511-8 PG 8 WC Microbiology SC Microbiology GA CP6FK UT WOS:000359980200001 PM 26303940 ER PT J AU Echevarria, D Gutfraind, A Boodram, B Major, M Del Valle, S Cotler, SJ Dahari, H AF Echevarria, Desarae Gutfraind, Alexander Boodram, Basmattee Major, Marian Del Valle, Sara Cotler, Scott J. Dahari, Harel TI Mathematical Modeling of Hepatitis C Prevalence Reduction with Antiviral Treatment Scale-Up in Persons Who Inject Drugs in Metropolitan Chicago SO PLOS ONE LA English DT Article ID HIV-ASSOCIATED BEHAVIORS; DIRECT-ACTING ANTIVIRALS; VIRUS-INFECTION; UNITED-STATES; RISK BEHAVIORS; YOUNG-ADULTS; USERS; METAANALYSIS; REINFECTION; PEOPLE AB Background/Aim New direct-acting antivirals (DAAs) provide an opportunity to combat hepatitis C virus (HCV) infection in persons who inject drugs (PWID). Here we use a mathematical model to predict the impact of a DAA-treatment scale-up on HCV prevalence among PWID and the estimated cost in metropolitan Chicago. Methods To estimate the HCV antibody and HCV-RNA (chronic infection) prevalence among the metropolitan Chicago PWID population, we used empirical data from three large epidemiological studies. Cost of DAAs is assumed $50,000 per person. Results Approximately 32,000 PWID reside in metropolitan Chicago with an estimated HCV-RNA prevalence of 47% or 15,040 cases. Approximately 22,000 PWID (69% of the total PWID population) attend harm reduction (HR) programs, such as syringe exchange programs, and have an estimated HCV-RNA prevalence of 30%. There are about 11,000 young PWID (<30 years old) with an estimated HCV-RNA prevalence of 10% (PWID in these two subpopulations overlap). The model suggests that the following treatment scale-up is needed to reduce the baseline HCV-RNA prevalence by one-half over 10 years of treatment [cost per year, min-max in millions]: 35 per 1,000 [$50-$77] in the overall PWID population, 19 per 1,000 [$20-$26] for persons in HR programs, and 5 per 1,000 [$3-$4] for young PWID. Conclusions Treatment scale-up could dramatically reduce the prevalence of chronic HCV infection among PWID in Chicago, who are the main reservoir for on-going HCV transmission. Focusing treatment on PWID attending HR programs and/or young PWID could have a significant impact on HCV prevalence in these subpopulations at an attainable cost. C1 [Echevarria, Desarae; Gutfraind, Alexander; Cotler, Scott J.; Dahari, Harel] Loyola Univ Chicago, Med Ctr, Program Expt & Theoret Modeling, Div Hepatol,Dept Med, Maywood, IL 60526 USA. [Gutfraind, Alexander; Boodram, Basmattee] Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, Chicago, IL USA. [Major, Marian] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Del Valle, Sara] Los Alamos Natl Lab, Energy & Infrastruct Anal Grp, Los Alamos, NM USA. [Dahari, Harel] Los Alamos Natl Lab, Theoret & Biophys Grp, Los Alamos, NM USA. RP Dahari, H (reprint author), Loyola Univ Chicago, Med Ctr, Program Expt & Theoret Modeling, Div Hepatol,Dept Med, Maywood, IL 60526 USA. EM hdahari@lumc.edu FU NIH [P20-GM103452, R01-AI078881]; U.S. Department of Energy [DE-AC52-06NA25396]; UIC Award of Excellence FX This study was supported by NIH grants P20-GM103452 and R01-AI078881, the U.S. Department of Energy contract DE-AC52-06NA25396 and UIC Award of Excellence. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 0 Z9 0 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 21 PY 2015 VL 10 IS 8 AR e0135901 DI 10.1371/journal.pone.0135901 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CP5MR UT WOS:000359926900048 PM 26295805 ER PT J AU Nguyen, CP Hirsch, MS Moeny, D Kaul, S Mohamoud, M Joffe, HV AF Christine P. Nguyen Hirsch, Mark S. Moeny, David Kaul, Suresh Mohamoud, Mohamed Joffe, Hylton V. TI Testosterone and "Age-Related Hypogonadism" - FDA Concerns SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Christine P. Nguyen; Hirsch, Mark S.; Moeny, David; Kaul, Suresh; Mohamoud, Mohamed; Joffe, Hylton V.] Food & Drug Adm, Silver Spring, MD 20993 USA. RP Nguyen, CP (reprint author), Food & Drug Adm, Silver Spring, MD 20993 USA. NR 4 TC 27 Z9 27 U1 1 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 20 PY 2015 VL 373 IS 8 BP 689 EP 691 DI 10.1056/NEJMp1506632 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CP2LU UT WOS:000359709400003 PM 26287846 ER PT J AU Rosas-Hernandez, H Ramirez, M Ramirez-Lee, MA Ali, SF Gonzalez, C AF Rosas-Hernandez, H. Ramirez, M. Ramirez-Lee, M. A. Ali, S. F. Gonzalez, C. TI INHIBITION OF PROLACTIN WITH BROMOCRIPTINE FOR 28 DAYS INCREASES BLOOD-BRAIN BARRIER PERMEABILITY IN THE RAT SO NEUROSCIENCE LA English DT Article DE prolactin; blood-brain barrier; lipopolysaccharide; tight junctions; permeability ID TIGHT JUNCTION; GROWTH-HORMONE; MAMMARY EPITHELIUM; PARKINSONS-DISEASE; ENDOTHELIAL-CELLS; EDEMA FORMATION; MILK SECRETION; LIPOPOLYSACCHARIDE; DOPAMINE; EXPRESSION AB The blood-brain barrier (BBB) is necessary for the proper function of the brain. Its maintenance is regulated by endogenous factors. Recent evidences suggest prolactin (PRL) regulates the BBB properties in vitro, nevertheless no evidence of these effects have been reported in vivo. The aim of this study was to evaluate the role of PRL in the maintenance of the BBB in the rat. Male Wistar rats were treated with Bromocriptine (Bromo) to inhibit PRL production for 28 days in the absence or presence of lipopolysaccharide (LPS). BBB permeability was evaluated through the Evans Blue dye and fluorescein-dextran extravasation as well as through edema formation. The expression of claudin-5, occludin, glial fibrillary acidic protein (GFAP) and the PRL receptor (PRLR) was evaluated through western blot. Bromo reduced the physiological levels of PRL at 28 days. At the same time, Bromo increased BBB permeability and edema formation associated with a decrement in claudin-5 and occludin and potentiated the increase in BBB permeability induced by LPS. However, no neuroinflammation was detected, since the expression of GFAP was unchanged, as well as the expression of the PRLR. These data provide the first evidence that inhibition of PRL with Bromo affects the maintenance of the BBB through modulating the expression of tight junction proteins in vivo. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Rosas-Hernandez, H.; Ramirez, M.; Ramirez-Lee, M. A.; Gonzalez, C.] Univ Autonoma San Luis Potosi, Fac Ciencias Quim, Lab Fisiol Celular, San Luis Potosi 78210, Slp, Mexico. [Ali, S. F.] Natl Ctr Toxicol Res, Div Neurotoxicol, Neurochem Lab, Jefferson, AR 72079 USA. RP Gonzalez, C (reprint author), Univ Autonoma San Luis Potosi, Fac Ciencias Quim, Lab Fisiol Celular, Av Manuel Nava 6, San Luis Potosi 78210, Slp, Mexico. EM cgonzalez.uaslp@gmail.com RI Hector, Rosas-Hernandez/J-5130-2015; OI Rosas-Hernandez, Hector/0000-0002-2736-8302 FU Consejo Nacional de Ciencia y Tecnologia CONACYT-Mexico (CONACYT Ciencias Basicas) [134595]; CONACYT [317768, 318669] FX This study was supported by the Consejo Nacional de Ciencia y Tecnologia CONACYT-Mexico (CONACYT Ciencias Basicas 134595). We thank CONACYT for the fellowships of Hector Rosas-Hernandez (317768) and Manuel A. Ramirez-Lee (318669). NR 60 TC 2 Z9 2 U1 1 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD AUG 20 PY 2015 VL 301 BP 61 EP 70 DI 10.1016/j.neuroscience.2015.05.066 PG 10 WC Neurosciences SC Neurosciences & Neurology GA CM7MO UT WOS:000357877800006 PM 26047726 ER PT J AU Harrison, LM AF Harrison, Lisa M. TI Beyond Campylobacter jejuni: understanding Campylobacter coli infections in a systemic model of disease SO VIRULENCE LA English DT Editorial Material ID INTESTINAL EPITHELIAL-CELLS; BACTEREMIA; ADHERENCE; VIRULENCE; INVASION C1 [Harrison, Lisa M.] US FDA, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Harrison, LM (reprint author), US FDA, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. EM lisa.plemons@fda.hhs.gov NR 13 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 2150-5594 EI 2150-5608 J9 VIRULENCE JI Virulence PD AUG 18 PY 2015 VL 6 IS 6 BP 564 EP 565 DI 10.1080/21505594.2015.1060397 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CW4FB UT WOS:000364945600008 PM 26083465 ER PT J AU Li, HL Wickramasekara, S Nemes, P AF Li, Hongli Wickramasekara, Samanthi Nemes, Peter TI One-Hour Screening of Adulterated Heparin by Simplified Peroxide Digestion and Fast RPIP-LC-MS2 SO ANALYTICAL CHEMISTRY LA English DT Article ID POLYACRYLAMIDE-GEL ELECTROPHORESIS; CHROMATOGRAPHY-MASS-SPECTROMETRY; OVERSULFATED CHONDROITIN SULFATE; ADVERSE CLINICAL EVENTS; MAGNETIC-RESONANCE-SPECTROSCOPY; CAPILLARY-ELECTROPHORESIS; DERMATAN SULFATE; RADICAL DEPOLYMERIZATION; UNFRACTIONATED HEPARIN; CONTAMINATED HEPARIN AB Early detection of potential contaminants in heparin, an extensively used anticoagulant in drug formulations and medical devices, is critical to ensuring public health. In response to heparin adulteration by oversulfated chondroitin sulfates (OSCS) that was associated with adverse events including deaths in 2007-2008, many methods have been developed to detect OSCS in heparin. However, an analytical challenge for quality screenings has been to speed up these measurements to address the complex distribution scheme of heparin in today's global market. Here an approach based on mass spectrometry is described that enables the measurement of adulterated heparin in 1 h, significantly shortening the time frame of screening for potential contaminants. The methodology is based on simplified peroxide digestion that rapidly depolymerizes large polysaccharide chains to small oligosaccharides followed by fast liquid chromatography mass spectrometry to determine sample purity. We find that rapid peroxide digestion generates abundant C- and Y-type oligosaccharides that can be used to differentiate parent glycosaminoglycans via unsupervised multivariate analysis, including heparin, chondroitin sulfate A, dermatan sulfate, and the infamous OSCS. With quantitation demonstrated at 1% (w/w), or 50 ng, OSCS in heparin and the lower limit of detection estimated at similar to 0.20% (w/w), or similar to 10 ng, OSCS in heparin, the technology was sufficiently sensitive to differentiate real-life, "authentic" adulterated heparin samples and to quantify this contaminant with an error <10% relative standard deviation. The methodologies presented here are deliberately simple to foster adoption and increase the analytical throughput of mass spectrometric screening in the routine quality assessment of heparin and other types of compounds of this molecular family. C1 [Li, Hongli; Wickramasekara, Samanthi; Nemes, Peter] US FDA, CDRH OSEL DBCMS, Silver Spring, MD 20993 USA. [Nemes, Peter] George Washington Univ, Dept Chem, Washington, DC 20052 USA. RP Nemes, P (reprint author), US FDA, CDRH OSEL DBCMS, Silver Spring, MD 20993 USA. EM petern@gwu.edu RI Nemes, Peter/C-3145-2008 FU Medical Countermeasure Initiative [2J260T4]; Medical Countermeasure Initiative Challenge Grant [MCM2J277MW]; George Washington University Department of Chemistry Start-Up Funds FX This work was supported by the Medical Countermeasure Initiative under award number 2J260T4 (to P.N.), the Medical Countermeasure Initiative Challenge Grant under award number MCM2J277MW (to P.N.), and the George Washington University Department of Chemistry Start-Up Funds (to P.N.). At FDA, we thank David A. Keire for the generous sharing of the authentic heparin samples and scientific discussions related to this work, as well as Jason Brookbank, Benita J. Dair, and Dinesh V. Patwardhan for advising on regulatory matters. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either actual or implied endorsement of such products by the Department of Health and Human Service. NR 37 TC 2 Z9 2 U1 4 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD AUG 18 PY 2015 VL 87 IS 16 BP 8424 EP 8432 DI 10.1021/acs.analchem.5b01788 PG 9 WC Chemistry, Analytical SC Chemistry GA CP4ZW UT WOS:000359892100057 PM 26168275 ER PT J AU de Claro, RA McGinn, KM Verdun, N Lee, SL Chiu, HJ Saber, H Brower, ME Chang, CJG Pfuma, E Habtemariam, B Bullock, J Wang, Y Nie, L Chen, XH Lu, DH Al-Hakim, A Kane, RC Kaminskas, E Justice, R Farrell, AT Pazdur, R AF de Claro, R. Angelo McGinn, Karen M. Verdun, Nicole Lee, Shwu-Luan Chiu, Haw-Jyh Saber, Haleh Brower, Margaret E. Chang, C. J. George Pfuma, Elimika Habtemariam, Bahru Bullock, Julie Wang, Yun Nie, Lei Chen, Xiao-Hong Lu, Donghao (Robert) Al-Hakim, Ali Kane, Robert C. Kaminskas, Edvardas Justice, Robert Farrell, Ann T. Pazdur, Richard TI FDA Approval: Ibrutinib for Patients with Previously Treated Mantle Cell Lymphoma and Previously Treated Chronic Lymphocytic Leukemia SO CLINICAL CANCER RESEARCH LA English DT Article ID TYROSINE KINASE; TARGETING BTK; BORTEZOMIB; WORKSHOP; THERAPY AB On November 13, 2013, the FDA granted accelerated approval to ibrutinib (IMBRUVICA capsules; Pharmacyclics, Inc.) for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. On February 12, 2014, the FDA granted accelerated approval for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Ibrutinib is a first-in-class Bruton's tyrosine kinase (BTK) inhibitor that received all four expedited programs of the FDA: Fast-Track designation, Breakthrough Therapy designation, Priority Review, and Accelerated Approval. Both approvals were based on overall response rate (ORR) and duration of response (DOR) in single-arm clinical trials in patients with prior treatment. In MCL (N = 111), the complete and partial response rates were 17.1% and 48.6%, respectively, for an ORR of 65.8% [95% confidence interval (CI), 56.2%-74.5%]. The median DOR was 17.5 months (95% CI, 15.8-not reached). In CLL (N = 48), the ORR was 58.3% (95% CI, 43.2%-72.4%), and the DOR ranged from 5.6 to 24.2 months. The most common adverse reactions (>= 30% in either trial) were thrombocytopenia, diarrhea, neutropenia, bruising, upper respiratory tract infection, anemia, fatigue, musculoskeletal pain, peripheral edema, and nausea. (C)2015 AACR. C1 [de Claro, R. Angelo; McGinn, Karen M.; Verdun, Nicole; Lee, Shwu-Luan; Chiu, Haw-Jyh; Saber, Haleh; Brower, Margaret E.; Chang, C. J. George; Kane, Robert C.; Kaminskas, Edvardas; Justice, Robert; Farrell, Ann T.; Pazdur, Richard] US FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, Off New Drugs, Silver Spring, MD USA. [Pfuma, Elimika; Habtemariam, Bahru; Bullock, Julie] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Silver Spring, MD USA. [Wang, Yun; Nie, Lei] US FDA, Ctr Drug Evaluat & Res, Off Biostat, Silver Spring, MD USA. [Chen, Xiao-Hong; Lu, Donghao (Robert); Al-Hakim, Ali] US FDA, Ctr Drug Evaluat & Res, Off New Drug Qual Assessment, Silver Spring, MD USA. RP de Claro, RA (reprint author), FDA, WO22-2173 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM romeo.declaro@fda.hhs.gov NR 19 TC 10 Z9 10 U1 1 U2 5 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 AUG 15 PY 2015 VL 21 IS 16 BP 3586 EP 3590 DI 10.1158/1078-0432.CCR-14-2225 PG 5 WC Oncology SC Oncology GA CS2NX UT WOS:000361909100005 PM 26275952 ER PT J AU Panozzo, CA Hampp, C AF Panozzo, Catherine A. Hampp, Christian TI Can a Reduced-Dose Prophylaxis Schedule Provide Adequate Coverage Against Respiratory Syncytial Virus Infection? SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material DE respiratory syncytial virus; RSV; palivizumab; clinical guideline; seasonality ID PALIVIZUMAB PROPHYLAXIS; CHILDREN; INFANTS C1 [Panozzo, Catherine A.] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA 02115 USA. [Panozzo, Catherine A.] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Hampp, Christian] US FDA, Div Epidemiol 1, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol,Ctr Drug Evaluat & R, Silver Spring, MD USA. RP Panozzo, CA (reprint author), Dept Populat Med, 133 Brookline Ave,6th Flr, Boston, MA 02215 USA. EM Catherine_Panozzo@harvardpilgrim.org NR 9 TC 1 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2015 VL 61 IS 4 BP 515 EP 516 DI 10.1093/cid/civ336 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CO7MT UT WOS:000359344200006 PM 25904371 ER PT J AU Harrington, PR Deming, DJ Komatsu, TE Naeger, LK AF Harrington, Patrick R. Deming, Damon J. Komatsu, Takashi E. Naeger, Lisa K. TI Hepatitis C Virus RNA Levels During Interferon-Free Combination Direct-Acting Antiviral Treatment in Registrational Trials SO CLINICAL INFECTIOUS DISEASES LA English DT Letter C1 [Harrington, Patrick R.; Deming, Damon J.; Komatsu, Takashi E.; Naeger, Lisa K.] US FDA, Div Antiviral Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Harrington, PR (reprint author), FDA CDER OND OAP DAVP, 10903 New Hampshire Ave,Bldg 22,Rm 6336, Silver Spring, MD 20993 USA. EM patrick.harrington@fda.hhs.gov NR 5 TC 5 Z9 5 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2015 VL 61 IS 4 BP 666 EP 667 DI 10.1093/cid/civ402 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CO7MT UT WOS:000359344200031 PM 26002846 ER PT J AU Chilukuri, D McMaster, O Bergman, K Colangelo, P Snow, K Toerner, JG AF Chilukuri, Dakshina McMaster, Owen Bergman, Kimberly Colangelo, Philip Snow, Kerry Toerner, Joseph G. TI The Hollow Fiber System Model in the Nonclinical Evaluation of Antituberculosis Drug Regimens SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE tuberculosis; antimycobacterial; in vitro C1 [Chilukuri, Dakshina; Bergman, Kimberly; Colangelo, Philip] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Off Translat Sci, Silver Spring, MD 20993 USA. [McMaster, Owen; Snow, Kerry; Toerner, Joseph G.] US FDA, Off New Drugs, Silver Spring, MD 20993 USA. RP Toerner, JG (reprint author), US FDA, Off Antimicrobial Prod, CDER Off New Drugs, 10903 New Hampshire Ave,White Oak Bldg 22,Rm 6244, Silver Spring, MD 20993 USA. EM joseph.toerner@fda.hhs.gov FU Critical Path to TB Drug Regimens (CPTR) Initiative FX This article was published as part of a supplement entitled "An Evidence-Based Drug Development Tool for TB Regimens: The Hollow Fiber System Model," initiated and sponsored by the Critical Path to TB Drug Regimens (CPTR) Initiative. NR 8 TC 5 Z9 5 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2015 VL 61 SU 1 BP S32 EP S33 DI 10.1093/cid/civ460 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CO7NA UT WOS:000359344900006 PM 26224770 ER PT J AU Gao, XG Sprando, RL Yourick, JJ AF Gao, Xiugong Sprando, Robert L. Yourick, Jeffrey J. TI Thalidomide induced early gene expression perturbations indicative of human embryopathy in mouse embryonic stem cells SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Thalidomide; Transcriptomics; Embryonic stem cell; Developmental toxicity; Differentiation; Microarray; Mouse ID IN-VITRO; DEVELOPMENTAL TOXICITY; LIMB DEFECTS; RABBITS; ANGIOGENESIS; CULTURES; MODEL; RATS AB Developmental toxicity testing has traditionally relied on animal models which are costly, time consuming, and require the sacrifice of large numbers of animals. In addition, there are significant disparities between human beings and animals in their responses to chemicals. Thalidomide is a species-specific developmental toxicant that causes severe limb malformations in humans but not in mice. Here, we used microarrays to study transcriptomic changes induced by thalidomide in an in vitro model based on differentiation of mouse embryonic stem cells (mESCs). C57BL/6 mESCs were allowed to differentiate spontaneously and RNA was collected at 24, 48, and 72 h after exposure to 0.25 mM thalidomide. Global gene expression analysis using microarrays revealed hundreds of differentially expressed genes upon thalidomide exposure that were enriched in gene ontology (GO) terms and canonical pathways associated with embryonic development and differentiation. In addition, many genes were found to be involved in small GTPases-mediated signal transduction, heart development, and inflammatory responses, which coincide with clinical evidences and may represent critical embryotoxicities of thalidomide. These results demonstrate that transcriptomics in combination with mouse embryonic stem cell differentiation is a promising alternative model for developmental toxicity assessment. Published by Elsevier Inc. C1 [Gao, Xiugong; Sprando, Robert L.; Yourick, Jeffrey J.] US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Div Toxicol, Laurel, MD USA. RP Gao, XG (reprint author), 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM xiugong.gao@fda.hhs.gov FU U.S. Food and Drug Administration FX This research is funded by internal funds of the U.S. Food and Drug Administration. The findings and conclusions presented in this article are those of the authors and do not necessarily represent views, opinions, or policies of the U.S. Food and Drug Administration. NR 40 TC 1 Z9 1 U1 1 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 AUG 15 PY 2015 VL 287 IS 1 BP 43 EP 51 DI 10.1016/j.taap.2015.05.009 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CM5ZB UT WOS:000357766400006 PM 26006729 ER PT J AU Hamade, AK Deglin, SE McLaughlin, JB Deeds, JR Handy, SM Knolhoff, AM AF Hamade, Ali K. Deglin, Sandrine E. McLaughlin, Joe B. Deeds, Jonathan R. Handy, Sara M. Knolhoff, Ann M. TI Suspected Palytoxin Inhalation Exposures Associated with Zoanthid Corals in Aquarium Shops and Homes - Alaska, 2012-2014 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Deeds, Jonathan R.; Handy, Sara M.; Knolhoff, Ann M.] US FDA, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. EM ali.hamade@alaska.gov RI Handy, Sara/C-6195-2008 NR 8 TC 4 Z9 4 U1 0 U2 7 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD AUG 14 PY 2015 VL 64 IS 31 BP 852 EP 855 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CO9DD UT WOS:000359471900004 PM 26270061 ER PT J AU Cokic, VP Mossuz, P Han, J Socoro, N Beleslin-Cokic, BB Mitrovic, O Suboticki, T Diklic, M Lekovic, D Gotic, M Puri, RK Noguchi, CT Schechter, AN AF Cokic, Vladan P. Mossuz, Pascal Han, Jing Socoro, Nuria Beleslin-Cokic, Bojana B. Mitrovic, Olivera Suboticki, Tijana Diklic, Milos Lekovic, Danijela Gotic, Mirjana Puri, Raj K. Noguchi, Constance Tom Schechter, Alan N. TI Microarray and Proteomic Analyses of Myeloproliferative Neoplasms with a Highlight on the mTOR Signaling Pathway SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; POLYCYTHEMIA-VERA; ESSENTIAL THROMBOCYTHEMIA; MAMMALIAN TARGET; BREAST-CANCER; MEGAKARYOCYTE PROGENITORS; HEMATOPOIETIC STEM; RHEB GTPASE; CELLS; PROLIFERATION AB The gene and protein expression profiles in myeloproliferative neoplasms (MPNs) may reveal gene and protein markers of a potential clinical relevance in diagnosis, treatment and prediction of response to therapy. Using cDNA microarray analysis of 25,100 unique genes, we studied the gene expression profile of CD34(+) cells and granulocytes obtained from peripheral blood of subjects with essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). The microarray analyses of the CD34(+) cells and granulocytes were performed from 20 de novo MPN subjects: JAK2 positive ET, PV, PMF subjects, and JAK2 negative ET/PMF subjects. The granulocytes for proteomic studies were pooled in 4 groups: PV with JAK2 mutant allele burden above 80%, ET with JAK2 mutation, PMF with JAK2 mutation and ET/PMF with no JAK2 mutation. The number of differentially regulated genes was about two fold larger in CD34(+) cells compared to granulocytes. Thirty-six genes (including RUNX1, TNFRSF19) were persistently highly expressed, while 42 genes (including FOXD4, PDE4A) were underexpressed both in CD34(+) cells and granulocytes. Using proteomic studies, significant up-regulation was observed for MAPK and PI3K/AKT signaling regulators that control myeloid cell apoptosis and proliferation: RAC2, MNDA, S100A8/9, CORO1A, and GNAI2. When the status of the mTOR signaling pathway related genes was analyzed, PI3K/AKT regulators were preferentially up-regulated in CD34(+) cells of MPNs, with down-regulated major components of the protein complex EIF4F. Molecular profiling of CD34(+) cells and granulocytes of MPN determined gene expression patterns beyond their recognized function in disease pathogenesis that included dominant up-regulation of PI3K/AKT signaling. C1 [Cokic, Vladan P.; Mitrovic, Olivera; Suboticki, Tijana; Diklic, Milos] Univ Belgrade, Inst Med Res, Belgrade, Serbia. [Mossuz, Pascal] CHU Grenoble, Inst Biol & Pathol, Dept Hematol, F-38043 Grenoble, France. [Han, Jing; Puri, Raj K.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Socoro, Nuria] Fac Med Grenoble, Lab TIMC IMAG, Grenoble, France. [Beleslin-Cokic, Bojana B.] Clin Ctr Serbia, Clin Endocrinol Diabet & Dis Metab, Belgrade, Serbia. [Lekovic, Danijela; Gotic, Mirjana] Clin Ctr Serbia, Clin Hematol, Belgrade, Serbia. [Gotic, Mirjana] Univ Belgrade, Fac Med, Belgrade, Serbia. [Noguchi, Constance Tom; Schechter, Alan N.] Natl Inst Diabet & Digest & Kidney Dis, Mol Med Branch, NIH, Bethesda, MD USA. RP Cokic, VP (reprint author), Univ Belgrade, Inst Med Res, Belgrade, Serbia. EM vl@imi.bg.ac.rs FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health; Serbian Ministry of Education, Science and Technological Development [175053] FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institutes of Health and by a grant from the Serbian Ministry of Education, Science and Technological Development [175053]. NR 41 TC 2 Z9 2 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 14 PY 2015 VL 10 IS 8 AR e0135463 DI 10.1371/journal.pone.0135463 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CO9KD UT WOS:000359493600068 PM 26275051 ER PT J AU Pettengill, JB AF Pettengill, James B. TI The Time to Most Recent Common Ancestor Does Not (Usually) Approximate the Date of Divergence SO PLOS ONE LA English DT Article ID MODEL AB With the advent of more sophisticated models and increase in computational power, an ever-growing amount of information can be extracted from DNA sequence data. In particular, recent advances have allowed researchers to estimate the date of historical events for a group of interest including time to most recent common ancestor (TMRCA), dates of specific nodes in a phylogeny, and the date of divergence or speciation date. Here I use coalescent simulations and re-analyze an empirical dataset to illustrate the importance of taxon sampling, in particular, on correctly estimating such dates. I show that TMRCA of representatives of a single taxon is often not the same as divergence date due to issues such as incomplete lineage sorting. Of critical importance is when estimating divergence or speciation dates a representative from a different taxonomic lineage must be included in the analysis. Without considering these issues, studies may incorrectly estimate the times at which historical events occurred, which has profound impacts within both research and applied (e.g., those related to public health) settings. C1 US FDA, Div rPubl Hlth Informat & Analyt, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Pettengill, JB (reprint author), US FDA, Div rPubl Hlth Informat & Analyt, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM james.pettengill@fda.hhs.gov NR 14 TC 0 Z9 0 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 14 PY 2015 VL 10 IS 8 AR e0128407 DI 10.1371/journal.pone.0128407 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CO9KD UT WOS:000359493600002 PM 26273822 ER PT J AU Takeda, K Adhikari, R Yamada, KM Dhawan, S AF Takeda, Kazuyo Adhikari, Rewati Yamada, Kenneth M. Dhawan, Subhash TI Hemin activation of innate cellular response blocks human immunodeficiency virus type-1-induced osteoclastogenesis SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE HIV-1; Hemin; Heme oxygenase-1; Osteoclasts ID BONE-MINERAL DENSITY; MULTINUCLEATED GIANT-CELLS; HIV-INFECTION; OXYGENASE-1 INDUCTION; PROTEASE INHIBITORS; RISK-FACTORS; DISEASE; OSTEOPOROSIS; RANKL; PATHOGENESIS AB The normal skeletal developmental and homeostatic process termed osteoclastogenesis is exacerbated in numerous pathological conditions and causes excess bone loss. In cancer and HIV-1-infected patients, this disruption of homeostasis results in osteopenia and eventual osteoporesis. Counteracting the factors responsible for these metabolic disorders remains a challenge for preventing or minimizing this comorbidity associated with these diseases. In this report, we demonstrate that a hemin-induced host protection mechanism not only suppresses HIV-1 associated osteoclastogenesis, but it also exhibits anti-osteoclastogenic activity for non-infected cells. Since the mode of action of hemin is both physiological and pharmacological through induction of heme oxygenase-1 (HO-1), an endogenous host protective response to an FDA-licensed therapeutic used to treat another disease, our study suggests an approach to developing novel, safe and effective therapeutic strategies for treating bone disorders, because hemin administration in humans has previously met required FDA safety standards. Published by Elsevier Inc. C1 [Adhikari, Rewati; Dhawan, Subhash] US FDA, Ctr Biol Evaluat & Res, Div Transfus Transmitted Dis, Bethesda, MD 20993 USA. [Takeda, Kazuyo] US FDA, Ctr Biol Evaluat & Res, Microscopy & Imaging Core Facil, Silver Spring, MD USA. [Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Dhawan, S (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Transfus Transmitted Dis, Bethesda, MD 20993 USA. EM subhash.dhawan@fda.hhs.gov FU FDA; NIDCR Intramural Research Programs FX S.D.: conceptualized, designed, performed, analyzed experiments, and wrote the paper; K.T. performed confocal microscopy and analyzed experiments; R.A. performed TRAP activity experiments; K.M.Y. analyzed experiments. We thank Dr. Zu-Xi Yu, National Heart, Lung and Blood Institute, NIH, for his expertise in microscopy. The findings and conclusions in this paper have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. This work was supported by FDA and NIDCR Intramural Research Programs. NR 49 TC 0 Z9 0 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 14 PY 2015 VL 464 IS 1 BP 7 EP 12 DI 10.1016/j.bbrc.2015.05.037 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CO5AY UT WOS:000359173200002 PM 25998388 ER PT J AU Liu, W Zhang, B Zhang, ZW Tao, J Branscum, AJ AF Liu, Wei Zhang, Bo Zhang, Zhiwei Tao, Jian Branscum, Adam J. TI Model selection in finite mixture of regression models: a Bayesian approach with innovative weighted g priors and reversible jump Markov chain Monte Carlo implementation SO JOURNAL OF STATISTICAL COMPUTATION AND SIMULATION LA English DT Article DE reversible jump algorithm; weighted prior; Metropolis-Hastings algorithm; finite normal mixtures; Bayesian variable selection ID VARIABLE SELECTION; CRITERION; NUMBER AB Finite mixture of regression (FMR) models are aimed at characterizing subpopulation heterogeneity stemming from different sets of covariates that impact different groups in a population. We address the contemporary problem of simultaneously conducting covariate selection and determining the number of mixture components from a Bayesian perspective that can incorporate prior information. We propose a Gibbs sampling algorithm with reversible jump Markov chain Monte Carlo implementation to accomplish concurrent covariate selection and mixture component determination in FMR models. Our Bayesian approach contains innovative features compared to previously developed reversible jump algorithms. In addition, we introduce component-adaptive weighted g priors for regression coefficients, and illustrate their improved performance in covariate selection. Numerical studies show that the Gibbs sampler with reversible jump implementation performs well, and that the proposed weighted priors can be superior to non-adaptive unweighted priors. C1 [Liu, Wei] Harbin Inst Technol, Dept Math, Harbin 150001, Peoples R China. [Zhang, Bo; Zhang, Zhiwei] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Tao, Jian] NE Normal Univ, Sch Math & Stat, Changchun 130024, Jilin, Peoples R China. [Branscum, Adam J.] Oregon State Univ, Sch Biol & Populat Hlth Sci, Coll Publ Hlth & Human Sci, Corvallis, OR 97331 USA. RP Zhang, B (reprint author), US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM bo.zhang@fda.hhs.gov FU 'Fundamental Research Funds for the Central Universities' [HIT.NSRIF.2012063]; National Natural Science Foundation of China [11171059] FX DrWei Liu's research was partially supported by the 'Fundamental Research Funds for the Central Universities' through Grant [HIT.NSRIF.2012063]. Dr Jian Tao's research was supported by the National Natural Science Foundation of China (Grant No. 11171059). NR 19 TC 1 Z9 1 U1 2 U2 11 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0094-9655 EI 1563-5163 J9 J STAT COMPUT SIM JI J. Stat. Comput. Simul. PD AUG 13 PY 2015 VL 85 IS 12 BP 2456 EP 2478 DI 10.1080/00949655.2014.931584 PG 23 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA CI0YG UT WOS:000354465400008 ER PT J AU Jarvis, KG White, JR Grim, CJ Ewing, L Ottesen, AR Beaubrun, JJG Pettengill, JB Brown, E Hanes, DE AF Jarvis, Karen G. White, James R. Grim, Christopher J. Ewing, Laura Ottesen, Andrea R. Beaubrun, Junia Jean-Gilles Pettengill, James B. Brown, Eric Hanes, Darcy E. TI Cilantro microbiome before and after nonselective pre-enrichment for Salmonella using 16S rRNA and metagenomic sequencing SO BMC MICROBIOLOGY LA English DT Article ID BACTERIAL DIVERSITY; SOFT-ROT; ALIGNMENT; IDENTIFICATION; PHYLLOSPHERE; COMMUNITIES; CLOSTRIDIA; TAXONOMY; ENTERICA; ECOLOGY AB Background: Salmonella enterica is a common cause of foodborne gastroenteritis in the United States and is associated with outbreaks in fresh produce such as cilantro. Salmonella culture-based detection methods are complex and time consuming, and improvments to increase detection sensitivity will benefit consumers. In this study, we used 16S rRNA sequencing to determine the microbiome of cilantro. We also investigated changes to the microbial community prior to and after a 24-hour nonselective pre-enrichment culture step commonly used by laboratory analysts to resuscitate microorganisms in foods suspected of contamination with pathogens. Cilantro samples were processed for Salmonella detection according to the method in the United States Food and Drug Administration Bacteriological Analytical Manual. Genomic DNA was extracted from culture supernatants prior to and after a 24-hour nonselective pre-enrichment step and 454 pyrosequencing was performed on 16S rRNA amplicon libraries. A database of Enterobacteriaceae 16S rRNA sequences was created, and used to screen the libraries for Salmonella, as some samples were known to be culture positive. Additionally, culture positive cilantro samples were examined for the presence of Salmonella using shotgun metagenomics on the Illumina MiSeq. Results: Time zero uncultured samples had an abundance of Proteobacteria while the 24-hour enriched samples were composed mostly of Gram-positive Firmicutes. Shotgun metagenomic sequencing of Salmonella culture positive cilantro samples revealed variable degrees of Salmonella contamination among the sequenced samples. Conclusions: Our cilantro study demonstrates the use of high-throughput sequencing to reveal the microbiome of cilantro, and how the microbiome changes during the culture-based protocols employed by food safety laboratories to detect foodborne pathogens. Finding that culturing the cilantro shifts the microbiome to a predominance of Firmicutes suggests that changing our culture-based methods will improve detection sensitivity for foodborne enteric pathogens. C1 [Jarvis, Karen G.; Grim, Christopher J.; Ewing, Laura; Beaubrun, Junia Jean-Gilles; Hanes, Darcy E.] US FDA, Ctr Food Safety & Appl Nutr, OARSA, Laurel, MD 20708 USA. [White, James R.; Grim, Christopher J.] Oak Ridge Inst Sci & Technol, Oak Ridge, TN USA. [Ottesen, Andrea R.; Pettengill, James B.; Brown, Eric] US FDA, Ctr Food Safety & Appl Nutr, ORS, College Pk, MD USA. RP Jarvis, KG (reprint author), US FDA, Ctr Food Safety & Appl Nutr, OARSA, Laurel, MD 20708 USA. EM karen.jarvis@fda.hhs.gov FU Department of Energy FX C. J. Grim and J. R. White are Oak Ridge Institute for Science and Education fellows, and we thank the Department of Energy for their support. We also thank Charles Wang for his guidance and support with the 454 pyrosequencing. NR 42 TC 5 Z9 5 U1 4 U2 27 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD AUG 12 PY 2015 VL 15 AR 160 DI 10.1186/s12866-015-0497-2 PG 13 WC Microbiology SC Microbiology GA CO7NQ UT WOS:000359346600002 PM 26264042 ER PT J AU Tumipseed, SB Storey, JM Andersen, WC Filigenzi, MS Heise, AS Lohne, JJ Madson, MR Ceric, O Reimschuessel, R AF Tumipseed, Sherri B. Storey, Joseph M. Andersen, Wendy C. Filigenzi, Michael S. Heise, Andrea S. Lohne, Jack J. Madson, Mark R. Ceric, Olgica Reimschuessel, Renate TI Determination and Confirmation of the Antiviral Drug Amantadine and Its Analogues in Chicken Jerky Pet Treats SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE amantadine; antiviral compounds; chicken jerky pet treats; LC-MS ID MASS-SPECTROMETRY; MUSCLE; RIMANTADINE; EXTRACTION; UHPLC AB In this study, we investigated two methods for the detection of antiviral compounds in chicken jerky pet treats. Initially, a screening method developed to detect many different chemical contaminants indicated the presence of amantadine, 1, in some pet treats analyzed. A second antiviral-specific method was then developed for amantadine and its analogues, rimantadine, 2, and memantine, 3. Both methods used an acidic water/acetonitrile extraction. The antiviral-specific method also included a dispersive sorbent cleanup. Analytes were detected and identified by LC-MS (ion trap and Orbitrap) instruments. The antiviral-specific method was validated by analyzing matrix blanks and fortified samples (2.5-50 mu g/kg levels). Average recoveries for amantadine (using a deuterated internal standard) in fortified samples ranged from 76 to 123% with relative standard deviations of <= 12%. Amantadine was detected and identified in suspect chicken jerky pet treat samples at levels ranging from <2.5 mu g/kg to over 600 mu g/kg. Rimantadine and memantine were not detected in any samples. C1 [Tumipseed, Sherri B.; Storey, Joseph M.; Andersen, Wendy C.; Lohne, Jack J.; Madson, Mark R.] US FDA, Anim Drugs Res Ctr, Denver Fed Ctr, Denver, CO 80225 USA. [Filigenzi, Michael S.] Univ Calif Davis, Calif Anim Hlth & Food Safety Lab, Davis, CA 95616 USA. [Heise, Andrea S.; Madson, Mark R.] US FDA, Denver Lab, Denver, CO 80225 USA. [Ceric, Olgica; Reimschuessel, Renate] US FDA, Vet Lab Invest & Response Network Vet LIRN, Ctr Vet Med, Laurel, MD 20708 USA. RP Tumipseed, SB (reprint author), US FDA, Anim Drugs Res Ctr, Denver Fed Ctr, Bldg 20, Denver, CO 80225 USA. EM sherri.turnipseed@fda.hhs.gov NR 15 TC 0 Z9 0 U1 4 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD AUG 12 PY 2015 VL 63 IS 31 BP 6968 EP 6978 DI 10.1021/acs.jafc.5b02416 PG 11 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA CP1CL UT WOS:000359613400015 ER PT J AU Rosenberg, AS Puig, M Nagaraju, K Hoffman, EP Villalta, SA Rao, VA Wakefield, LM Woodcock, J AF Rosenberg, Amy S. Puig, Montserrat Nagaraju, Kanneboyina Hoffman, Eric P. Villalta, S. Armando Rao, V. Ashutosh Wakefield, Lalage M. Woodcock, Janet TI Immune-mediated pathology in Duchenne muscular dystrophy SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Review ID REGULATORY T-CELLS; GROWTH-FACTOR-BETA; MDX MOUSE MODEL; TOLL-LIKE RECEPTORS; SKELETAL-MUSCLE; TGF-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; INFLAMMATORY RESPONSE; DISEASE PROGRESSION; DEFICIENT SKELETAL AB Immunological and inflammatory processes downstream of dystrophin deficiency as well asmetabolic abnormalities, defective autophagy, and loss of regenerative capacity all contribute to muscle pathology in Duchenne muscular dystrophy (DMD). These downstream cascades offer potential avenues for pharmacological intervention. Modulating the inflammatory response and inducing immunological tolerance to de novo dystrophin expression will be critical to the success of dystrophin-replacement therapies. This Review focuses on the role of the inflammatory response in DMD pathogenesis and opportunities for clinical intervention. C1 [Rosenberg, Amy S.; Puig, Montserrat; Rao, V. Ashutosh; Woodcock, Janet] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Nagaraju, Kanneboyina; Hoffman, Eric P.] Childrens Natl Med Ctr, Ctr Genet Med Res, Washington, DC 20010 USA. [Villalta, S. Armando] Univ Calif Irvine, Dept Physiol & Biophys, Inst Immunol, Irvine, CA 92697 USA. [Wakefield, Lalage M.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Rosenberg, AS (reprint author), US FDA, Ctr Drug Evaluat & Res, Bldg 71-2238, Silver Spring, MD 20993 USA. EM amy.rosenberg@fda.hhs.gov FU NINDS NIH HHS [R01 NS029525] NR 109 TC 8 Z9 9 U1 3 U2 12 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD AUG 5 PY 2015 VL 7 IS 299 AR 299rv4 DI 10.1126/scitranslmed.aaa7322 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CQ9MX UT WOS:000360940300006 PM 26246170 ER PT J AU He, WW Jia, HM Yang, DF Xiao, P Fan, XL Zheng, Z Kim, HK Warner, WG Yin, JJ AF He, Weiwei Jia, Huimin Yang, Dongfang Xiao, Pin Fan, Xiaoli Zheng, Zhi Kim, Hyun-Kyung Warner, Wayne G. Yin, Jun-Jie TI Composition Directed Generation of Reactive Oxygen Species in Irradiated Mixed Metal Sulfides Correlated with Their Photocatalytic Activities SO ACS APPLIED MATERIALS & INTERFACES LA English DT Article DE reactive oxygen species; mixed metal sulfides; ESR; photocatalytic; antibacterial ID VISIBLE-LIGHT IRRADIATION; MICRO-NANO STRUCTURES; ANTIBACTERIAL ACTIVITY; HYBRID NANOSTRUCTURES; HYDROGEN-PEROXIDE; OXIDATIVE STRESS; CHARGE-CARRIERS; SINGLET OXYGEN; NANOPARTICLES; DEGRADATION AB The ability of nanostructures to facilitate the generation of reactive oxygen species and charge carriers underlies many of their chemical and biological activities. Elucidating which factors are essential and how these influence the production of various active intermediates is fundamental to understanding potential applications of these nanostructures, as well as potential risks. Using electron spin resonance spectroscopy coupled with spin trapping and spin labeling techniques, we assessed 3 mixed metal sulfides of varying compositions for their abilities to generate reactive oxygen species, photogenerate electrons, and consume oxygen during photoirradiation. We found these irradiated mixed metal sulfides exhibited composition dependent generation of ROS: ZnIn2S4 can generate .OH, O-2(-.) and O-1(2); CdIn2S4 can produce O-2(-.) and O-1(2), while AgInS2 only produces O-2(-.). Our characterizations of the reactivity of the photogenerated electrons and consumption of dissolved oxygen, performed using spin labeling, showed the same trend in activity: ZnIn2S4 > CdIn2S4 > AgInS2. These intrinsic abilities to generate ROS and the reactivity of charge carriers correlated closely with the photocatalytic degradation and photoassisted antibacterial activities of these nanomaterials. C1 [He, Weiwei; Jia, Huimin; Yang, Dongfang; Zheng, Zhi] Xuchang Univ, Inst Surface Micro & Nano Mat, Key Lab Micronano Mat Energy Storage & Convers He, Xuchang 461000, Henan, Peoples R China. [He, Weiwei; Warner, Wayne G.; Yin, Jun-Jie] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, Div Bioanalyt Chem, College Pk, MD 20740 USA. [He, Weiwei; Warner, Wayne G.; Yin, Jun-Jie] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, Div Analyt Chem, College Pk, MD 20740 USA. [Xiao, Pin; Fan, Xiaoli] Northwestern Polytech Univ, State Key Lab Solidificat Proc, Sch Mat Sci & Engn, Xian 710072, Shaanxi, Peoples R China. [Kim, Hyun-Kyung] Minist Food & Drug Safety, Food Safety Bur, Cheongju 363700, South Korea. RP He, WW (reprint author), Xuchang Univ, Inst Surface Micro & Nano Mat, Key Lab Micronano Mat Energy Storage & Convers He, Xuchang 461000, Henan, Peoples R China. EM heweiweixcu@gmail.com; zhengzhi99999@gmail.com; junjie.yin@fda.hhs.gov RI Yin, Jun Jie /E-5619-2014 FU National Natural Science Foundation of China [21303153, 61204009]; Program for Science & Technology Innovation Talents in Universities of Henan Province [14HASTIT008]; Innovation Scientists and Technicians Troop Construction Projects of Henan Province [144200510014]; FDA Nanotechnology CORES Program; Office of Cosmetics and Colors, CFSAN/FDA FX This work was supported by National Natural Science Foundation of China (Grant No. 21303153 and 61204009), Program for Science & Technology Innovation Talents in Universities of Henan Province (14HASTIT008), Innovation Scientists and Technicians Troop Construction Projects of Henan Province (Grant No. 144200510014), and a regulatory science grant under the FDA Nanotechnology CORES Program and by the Office of Cosmetics and Colors, CFSAN/FDA. The authors thank Dr. Lili Fox Velez for editorial and scientific writing support. NR 38 TC 6 Z9 7 U1 10 U2 53 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1944-8244 J9 ACS APPL MATER INTER JI ACS Appl. Mater. Interfaces PD AUG 5 PY 2015 VL 7 IS 30 BP 16440 EP 16449 DI 10.1021/acsami.5b03626 PG 10 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA CO6PY UT WOS:000359279800039 PM 26158231 ER PT J AU Bueno, J Long, D Kauffman, JF Arzhantsev, S AF Bueno, Justin Long, Dianna Kauffman, John F. Arzhantsev, Sergey TI Deep-Ultraviolet Resonance Raman (DUVRR) Spectroscopy of Therapeutic Monoclonal Antibodies Subjected to Thermal Stress SO ANALYTICAL CHEMISTRY LA English DT Article ID PROTEIN SECONDARY STRUCTURE; STRUCTURAL-CHARACTERIZATION; AGGREGATION; TOOL AB The structural assessment of Rituximab, an IgG1 mAb, was investigated with deep-ultraviolet resonance Raman (DUVRR) spectroscopy. DUVRR spectroscopy was used to monitor the changes to the secondary structure of Rituximab under thermal stress. DUVRR spectra showed obvious changes from 22 to 72 degrees C. Specifically, changes in the amide I vibrational mode were assigned to an increase in unordered structure (random coil). Structural changes in samples heated to 72 degrees C were related to loss in drug potency via a complement dependent cytotoxicity (CDC) bioassay. The DUVRR spectroscopic method shows promise as a tool for the quality assessment of mAb drug products and would represent an improvement over current methodology in terms of analysis time and sample preparation. To determine the scope of the method, protein pharmaceuticals of different molecular weights (ranging from 4 to 143 kDa) and secondary structure (beta-sheet, alpha-helix and unordered structure) were analyzed. The model illustrated the methods sensitivity for the analysis of protein drug products of different secondary structure. Results show promise for DUVRR spectroscopy as a rapid screening tool of a variety of formulated protein pharmaceuticals. C1 [Bueno, Justin; Long, Dianna; Kauffman, John F.; Arzhantsev, Sergey] US FDA, Div Pharmaceut Anal, Off Testing & Res, Ctr Drug Evaluat & Res, St Louis, MO 63110 USA. RP Bueno, J (reprint author), US FDA, Div Pharmaceut Anal, Off Testing & Res, Ctr Drug Evaluat & Res, 645 S Newstead Ave, St Louis, MO 63110 USA. EM Justin.Bueno@fda.hhs.gov FU CDER Critical Path Program FX Funding for this work was provided by the CDER Critical Path Program. NR 24 TC 2 Z9 2 U1 2 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD AUG 4 PY 2015 VL 87 IS 15 BP 7880 EP 7886 DI 10.1021/acs.analchem.5601606 PG 7 WC Chemistry, Analytical SC Chemistry GA CO6PF UT WOS:000359277900054 PM 26132464 ER PT J AU Lee, JM Hwang, D Park, J Kim, KJ Ahn, C Koo, BK AF Lee, Joo Myung Hwang, Doyeon Park, Jonghanne Kim, Kyung-Jin Ahn, Chul Koo, Bon-Kwon TI Percutaneous Coronary Intervention at Centers With and Without On-Site Surgical Backup An Updated Meta-Analysis of 23 Studies SO CIRCULATION LA English DT Article DE meta-analysis; mortality; onsite coronary artery bypass graft (CABG); outcome assessment (health care); percutaneous coronary intervention; STEMI; thoracic surgery ID ELEVATION MYOCARDIAL-INFARCTION; BYPASS GRAFT-SURGERY; CARDIAC-SURGERY; ST-SEGMENT; OUTCOMES; HOSPITALS; ANGIOPLASTY; REGARDLESS; EXPERIENCE; FACILITIES AB Background Emergency coronary artery bypass grafting for unsuccessful percutaneous coronary intervention (PCI) is now rare. We aimed to evaluate the current safety and outcomes of primary PCI and nonprimary PCI at centers with and without on-site surgical backup. Methods and Results We performed an updated systematic review and meta-analysis by using mixed-effects models. We included 23 high-quality studies that compared clinical outcomes and complication rates of 1 101 123 patients after PCI at centers with or without on-site surgery. For primary PCI for ST-segment-elevation myocardial infarction (133 574 patients), all-cause mortality (without on-site surgery versus with on-site surgery: observed rates, 4.8% versus 7.2%; pooled odds ratio [OR], 0.99; 95% confidence interval, 0.91-1.07; P=0.729; I-2=3.4%) or emergency coronary artery bypass grafting rates (observed rates, 1.5% versus 2.4%; pooled OR, 0.76; 95% confidence interval, 0.56-1.01; P=0.062; I-2=42.5%) did not differ by presence of on-site surgery. For nonprimary PCI (967 549 patients), all-cause mortality (observed rates, 1.6% versus 2.1%; pooled OR, 1.15; 95% confidence interval, 0.94-1.41; P=0.172; I-2=67.5%) and emergency coronary artery bypass grafting rates (observed rates, 0.5% versus 0.8%; pooled OR, 1.14; 95% confidence interval, 0.62-2.13; P=0.669; I-2=81.7%) were not significantly different. PCI complication rates (cardiogenic shock, stroke, aortic dissection, tamponade, recurrent infarction) also did not differ by on-site surgical capability. Cumulative meta-analysis of nonprimary PCI showed a temporal decrease of the effect size (OR) for all-cause mortality after 2007. Conclusions Clinical outcomes and complication rates of PCI at centers without on-site surgery did not differ from those with on-site surgery, for both primary and nonprimary PCI. Temporal trends indicated improving clinical outcomes in nonprimary PCI at centers without on-site surgery. C1 [Lee, Joo Myung; Hwang, Doyeon; Park, Jonghanne; Kim, Kyung-Jin; Koo, Bon-Kwon] Seoul Natl Univ Hosp, Dept Internal Med, Seoul 110744, South Korea. [Lee, Joo Myung; Hwang, Doyeon; Park, Jonghanne; Kim, Kyung-Jin; Koo, Bon-Kwon] Seoul Natl Univ Hosp, Cardiovasc Ctr, Seoul 110744, South Korea. [Ahn, Chul] US FDA, Div Biostat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Koo, Bon-Kwon] Seoul Natl Univ, Inst Aging, Seoul 151, South Korea. RP Koo, BK (reprint author), Seoul Natl Univ Hosp, Dept Internal Med, 101 Daehang Ro, Seoul 110744, South Korea. EM bkkoo@snu.ac.kr FU Medical Research Collaborating Center, Seoul National University Hospital, Republic of Korea [23-2015-0070] FX This study was supported by the Meta-Analysis Research Grants from the Medical Research Collaborating Center, Seoul National University Hospital, Republic of Korea (23-2015-0070). NR 33 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD AUG 4 PY 2015 VL 132 IS 5 BP 388 EP 401 DI 10.1161/CIRCULATIONAHA.115.016137 PG 14 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CP1WF UT WOS:000359667000005 PM 26152708 ER PT J AU Clark, SB Storey, JM Carr, JR Madson, M AF Clark, Susan B. Storey, Joseph M. Carr, Justin R. Madson, Mark TI Analysis of lasalocid residues in grease and fat using liquid chromatography-mass spectrometry SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE animal feed; contamination; LC-MS analysis; lasalocid grease ID ANTIBIOTICS; IONOPHORES; FEEDS AB A method for the determination of lasalocid, an antibiotic and coccidiostat, in grease and fat is described. The manufacture of lasalocid produces a grease-like residue as a waste byproduct. Recently this byproduct has been shown to have been illegally introduced into the animal feed chain. Therefore, a quantitative and confirmatory procedure to analyse for lasalocid in this matrix is needed. A portion of grease/oil sample was extracted into hexane-washed acetonitrile, and a portion of the extract was then applied to a carboxylic acid solid-phase extraction (SPE) column for concentration and clean-up. The SPE column was washed with additional hexane-washed acetonitrile and ethyl acetate/methanol, after which lasalocid was eluted with 10% ammoniated methanol. The eluate was evaporated to dryness, redissolved in (1:1) acetonitrile-water and filtered through a PTFE syringe filter. Confirmation and quantitation of lasalocid in the final extract employed a triple quadrupole LC-MS/MS. The method was applied to grease and oil samples containing from 0.02 to 34000mgkg(-1) of lasalocid. C1 [Clark, Susan B.; Carr, Justin R.; Madson, Mark] US FDA, Denver Lab, Denver, CO USA. [Storey, Joseph M.; Madson, Mark] US FDA, Anim Drugs Res Ctr, Denver, CO 80237 USA. RP Storey, JM (reprint author), US FDA, Anim Drugs Res Ctr, Denver, CO 80237 USA. EM joseph.storey@fda.hhs.gov NR 15 TC 0 Z9 0 U1 4 U2 12 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PD AUG 3 PY 2015 VL 32 IS 8 BP 1243 EP 1248 DI 10.1080/19440049.2015.1052572 PG 6 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA CP3DZ UT WOS:000359758700004 PM 26054429 ER PT J AU Valentin, A Li, JY Rosati, M Kulkarni, V Patel, V Jalah, R Alicea, C Reed, S Sardesai, N Berkower, I Pavlakis, GN Felber, BK AF Valentin, Antonio Li, Jinyao Rosati, Margherita Kulkarni, Viraj Patel, Vainav Jalah, Rashmi Alicea, Candido Reed, Steven Sardesai, Niranjan Berkower, Ira Pavlakis, George N. Felber, Barbara K. TI Dose-dependent inhibition of Gag cellular immunity by Env in SIV/HIV DNA vaccinated macaques SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Article; Proceedings Paper CT DNA Vaccine 2014 Conference CY JUL 21-23, 2014 CL San Diego, CA DE cellular immunity; DNA electroporation; HIV vaccines; humoral immunity; vaccine optimization ID IMMUNODEFICIENCY-VIRUS TYPE-1; RHESUS MACAQUES; CO-IMMUNIZATION; SIVMAC251 CHALLENGE; PLASMID IL-12; VIRAL LOAD; T-CELLS; RESPONSES; ELECTROPORATION; INTERLEUKIN-12 AB The induction of a balanced immune response targeting the major structural proteins, Gag and Env of HIV, is important for the development of an efficacious vaccine. The use of DNA plasmids expressing different antigens offers the opportunity to test in a controlled manner the influence of different vaccine components on the magnitude and distribution of the vaccine-induced cellular and humoral immune responses. Here, we show that increasing amounts of env DNA results in greatly enhanced Env antibody titers without significantly affecting the levels of anti-Env cellular immune responses. Co-immunization with Env protein further increased antibody levels, indicating that vaccination with DNA only is not sufficient for eliciting maximal humoral responses against Env. In contrast, under high env:gag DNA plasmid ratio, the development of Gag cellular responses was significantly reduced by either SIV or HIV Env, whereas Gag humoral responses were not affected. Our data indicate that a balanced ratio of the 2 key HIV/SIV vaccine components, Gag and Env, is important to avoid immunological interference and to achieve both maximal humoral responses against Env to prevent virus acquisition and maximal cytotoxic T cell responses against Gag to prevent virus spread. C1 [Valentin, Antonio; Li, Jinyao; Rosati, Margherita; Patel, Vainav; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. [Kulkarni, Viraj; Jalah, Rashmi; Alicea, Candido; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. [Reed, Steven] Infect Dis Res Inst, Seattle, WA USA. [Sardesai, Niranjan] Inovio Pharmaceut, Plymouth Meeting, PA USA. [Berkower, Ira] US FDA, Lab Immunoregulat, Div Viral Prod, Off Vaccines,Ctr Biol, Silver Spring, MD USA. RP Felber, BK (reprint author), NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. EM Barbara.felber@nih.gov FU Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH); Bill and Melinda Gates Foundation [42387] FX This work was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH) (BKF, GNP), and Bill and Melinda Gates Foundation Grant #42387 (SGR). NR 43 TC 1 Z9 1 U1 1 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 2164-5515 EI 2164-554X J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD AUG 3 PY 2015 VL 11 IS 8 BP 2005 EP 2011 DI 10.1080/21645515.2015.1016671 PG 7 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA CP1AQ UT WOS:000359608600025 PM 26125521 ER PT J AU Chaisaingmongkol, J Budhu, A Dang, H Rabibhadana, S Pupacdi, B Forgues, M Bhudhisawasdi, V Lertprasertsuke, N Chotirosniramit, A Pairojkul, C Auewarakul, CU Sricharunrat, T Phornphutkul, K Sangrajrang, S Cam, M He, P Hewitt, SM Wu, XL Thorgeirsson, SS Meltzer, PS Loffredo, CA Wiltrout, RH Harris, CC Mahidol, C Ruchirawat, M Wang, XW AF Chaisaingmongkol, Jittiporn Budhu, Anuradha Dang, Hien Rabibhadana, Siritida Pupacdi, Benjarath Forgues, Marshonna Bhudhisawasdi, Vajarabhongsa Lertprasertsuke, Nirush Chotirosniramit, Anon Pairojkul, Chawalit Auewarakul, Chirayu U. Sricharunrat, Thaniya Phornphutkul, Kannika Sangrajrang, Suleeporn Cam, Maggie He, Ping Hewitt, Stephen M. Wu, Xiaolin Thorgeirsson, Snorri S. Meltzer, Paul S. Loffredo, Christopher A. Wiltrout, Robert H. Harris, Curtis C. Mahidol, Chulabhorn Ruchirawat, Mathuros Wang, Xin W. TI The Thailand initiative in genomics and expression research for liver cancer (TIGER-LC): Defining novel subtypes of hepatocellular carcinoma and cholangiocarcinoma SO CANCER RESEARCH LA English DT Meeting Abstract CT 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 18-22, 2015 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Chaisaingmongkol, Jittiporn; Budhu, Anuradha; Dang, Hien; Forgues, Marshonna; Cam, Maggie; Hewitt, Stephen M.; Wu, Xiaolin; Thorgeirsson, Snorri S.; Meltzer, Paul S.; Wiltrout, Robert H.; Harris, Curtis C.; Wang, Xin W.] NCI, Bethesda, MD 20892 USA. [Rabibhadana, Siritida; Pupacdi, Benjarath; Mahidol, Chulabhorn; Ruchirawat, Mathuros] Chulabhorn Res Inst, Bangkok, Thailand. [Bhudhisawasdi, Vajarabhongsa; Pairojkul, Chawalit] Khon Kaen Univ, Khon Kaen, Thailand. [Lertprasertsuke, Nirush; Chotirosniramit, Anon] Chiang Mai Univ, Chiang Mai 50000, Thailand. [Auewarakul, Chirayu U.; Sricharunrat, Thaniya] Chulabhorn Hosp, Bangkok, Thailand. [Phornphutkul, Kannika] Rajavej Hosp, Chiang Mai, Thailand. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand. [He, Ping] US FDA, Bethesda, MD 20014 USA. [Loffredo, Christopher A.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 AUG 1 PY 2015 VL 75 SU 15 MA LB-173 DI 10.1158/1538-7445.AM2015-LB-173 PG 2 WC Oncology SC Oncology GA DF8HA UT WOS:000371597100273 ER PT J AU Cope, JU Reaman, GH Tonning, JM AF Cope, Judith U. Reaman, Gregory H. Tonning, Joseph M. TI Medication exposures and subsequent development of Ewing sarcoma: a review of FDA adverse event reports SO CANCER RESEARCH LA English DT Meeting Abstract CT 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 18-22, 2015 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Cope, Judith U.; Reaman, Gregory H.; Tonning, Joseph M.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG 1 PY 2015 VL 75 SU 15 MA 5579 DI 10.1158/1538-7445.AM2015-5579 PG 2 WC Oncology SC Oncology GA DF8HA UT WOS:000371597106237 ER PT J AU Joseph, SJ Osborne, T Word, B Lyn-Cook, B AF Joseph, Stancy J. Osborne, Taylor Word, Beverly Lyn-Cook, Beverly TI Metformin upregulates hENT1 expression and enhances gemcitabine efficacy in pancreatic cancer cells SO CANCER RESEARCH LA English DT Meeting Abstract CT 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 18-22, 2015 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Joseph, Stancy J.; Osborne, Taylor; Word, Beverly; Lyn-Cook, Beverly] US FDA, NCTR, Jefferson, AR USA. NR 0 TC 1 Z9 1 U1 1 U2 1 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 AUG 1 PY 2015 VL 75 SU 15 MA 4436 DI 10.1158/1538-7445.AM2015-4436 PG 1 WC Oncology SC Oncology GA DF8HA UT WOS:000371597104066 ER PT J AU Karagiannis, K Chumakov, K Simonyan, V Mazumder, R AF Karagiannis, Konstantinos Chumakov, Konstantin Simonyan, Vahan Mazumder, Raja TI Detection of genetically distinct subclones in cancer: a novel NGS algorithm with high spatial and genetic resolution SO CANCER RESEARCH LA English DT Meeting Abstract CT 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 18-22, 2015 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Karagiannis, Konstantinos; Mazumder, Raja] George Washington Univ, Dept Biochem & Mol Biol, Washington, DC USA. [Chumakov, Konstantin; Simonyan, Vahan] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG 1 PY 2015 VL 75 SU 15 MA 4860 DI 10.1158/1538-7445.AM2015-4860 PG 2 WC Oncology SC Oncology GA DF8HA UT WOS:000371597105045 ER PT J AU Lyn-Cook, BD Osborne, T Joseph, S Word, B Pang, L Hammons, G AF Lyn-Cook, Beverly D. Osborne, Taylor Joseph, Stancy Word, Beverly Pang, Li Hammons, George TI Metformin effects on ABCB1 expression and proliferation in pancreatic cancer cell lines with different ABCB1 genotypes/haplotypes SO CANCER RESEARCH LA English DT Meeting Abstract CT 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 18-22, 2015 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Lyn-Cook, Beverly D.; Joseph, Stancy; Word, Beverly; Pang, Li; Hammons, George] FDA NCTR, Jefferson, AR USA. [Osborne, Taylor] Univ Arkansas Pine Bluff, Jefferson, AR USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 AUG 1 PY 2015 VL 75 SU 15 MA 4428 DI 10.1158/1538-7445.AM2015-4428 PG 1 WC Oncology SC Oncology GA DF8HA UT WOS:000371597104059 ER PT J AU Pokrzywinski, KL Rao, VA AF Pokrzywinski, Kaytee L. Rao, V. Ashutosh TI microRNA regulation of Nrf2: A link between autophagy and oxidative stress SO CANCER RESEARCH LA English DT Meeting Abstract CT 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 18-22, 2015 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Pokrzywinski, Kaytee L.; Rao, V. Ashutosh] US FDA, Div Therapeut Proteins, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG 1 PY 2015 VL 75 SU 15 MA LB-291 DI 10.1158/1538-7445.AM2015-LB-291 PG 2 WC Oncology SC Oncology GA DF8HA UT WOS:000371597100383 ER PT J AU Rosen, ET Kryndushkin, D Gonzalez, Y Aryal, B Chehab, L Dickey, J Rao, A AF Rosen, Elliot T. Kryndushkin, Dmitry Gonzalez, Yanira Aryal, Baikuntha Chehab, Leena Dickey, Jennifer Rao, Ashutosh TI Mitigating long-term cardiac adverse effects of radiation exposure: Emerging opportunities in protein oxidation and autophagy modulation SO CANCER RESEARCH LA English DT Meeting Abstract CT 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 18-22, 2015 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Rosen, Elliot T.; Kryndushkin, Dmitry; Gonzalez, Yanira; Aryal, Baikuntha; Chehab, Leena; Dickey, Jennifer; Rao, Ashutosh] FDA CDER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG 1 PY 2015 VL 75 SU 15 MA 3328 DI 10.1158/1538-7445.AM2015-3328 PG 1 WC Oncology SC Oncology GA DF8HA UT WOS:000371597101357 ER PT J AU Aryal, BP Jeong, J Rao, VA AF Aryal, Baikuntha P. Jeong, Jinsook Rao, V. Ashutosh TI Carbonylation and degradation of cardiac myosin binding protein C serves as an indicator doxorubicin-induced cardiotoxicity SO CANCER RESEARCH LA English DT Meeting Abstract CT 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 18-22, 2015 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Aryal, Baikuntha P.; Jeong, Jinsook; Rao, V. Ashutosh] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG 1 PY 2015 VL 75 SU 15 MA 1825 DI 10.1158/1538-7445.AM2015-1825 PG 1 WC Oncology SC Oncology GA DF8AH UT WOS:000371578503310 ER PT J AU Kindrat, I Tryndyak, V de Conti, A Shpyleva, S Erstenyuk, A Beland, FA Pogribny, I AF Kindrat, Iryna Tryndyak, Volodymyr de Conti, Aline Shpyleva, Svitlana Erstenyuk, Anna Beland, Frederick A. Pogribny, Igor TI Mechanism of the transferrin receptor 1 dysregulation in hepatocarcinogenesis SO CANCER RESEARCH LA English DT Meeting Abstract CT 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 18-22, 2015 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Kindrat, Iryna; Tryndyak, Volodymyr; de Conti, Aline; Shpyleva, Svitlana; Beland, Frederick A.; Pogribny, Igor] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Erstenyuk, Anna] Ivano Frankivsk Natl Med Univ, Ivano Frankivsk, Ukraine. NR 0 TC 1 Z9 1 U1 0 U2 0 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 AUG 1 PY 2015 VL 75 SU 15 MA 920 DI 10.1158/1538-7445.AM2015-920 PG 2 WC Oncology SC Oncology GA DF8AH UT WOS:000371578501371 ER PT J AU Mohan, N Shen, Y Wu, WJ AF Mohan, Nishant Shen, Yi Wu, Wen Jin TI Role of autophagy as potential molecular mechanism in trastuzumab-induced cardiotoxicity SO CANCER RESEARCH LA English DT Meeting Abstract CT 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 18-22, 2015 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Mohan, Nishant; Shen, Yi; Wu, Wen Jin] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG 1 PY 2015 VL 75 SU 15 MA 991 DI 10.1158/1538-7445.AM2015-991 PG 1 WC Oncology SC Oncology GA DF8AH UT WOS:000371578502037 ER PT J AU Myers, MB Banda, M McKim, KL Parsons, BL AF Myers, Meagan B. Banda, Malathi McKim, Karen L. Parsons, Barbara L. TI Subclonal structure of breast cancer subtypes determined by quantitative analyses of activating mutations SO CANCER RESEARCH LA English DT Meeting Abstract CT 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 18-22, 2015 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Myers, Meagan B.; Banda, Malathi; McKim, Karen L.; Parsons, Barbara L.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG 1 PY 2015 VL 75 SU 15 MA 1119 DI 10.1158/1538-7445.AM2015-1119 PG 1 WC Oncology SC Oncology GA DF8AH UT WOS:000371578502161 ER PT J AU Pokrzywinski, KL Gonzalez, Y Chehab, LM Rosen, ET Vijay, V Desai, V Dickey, JS Rao, VA AF Pokrzywinski, Kaytee L. Gonzalez, Yanira Chehab, Leena M. Rosen, Elliot T. Vijay, Vikrant Desai, Varsha Dickey, Jennifer S. Rao, V. Ashutosh TI Doxorubicin induced gender differences in tumor-bearing spontaneously hypertensive rats, with an emphasis on cardiotoxicity SO CANCER RESEARCH LA English DT Meeting Abstract CT 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 18-22, 2015 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Pokrzywinski, Kaytee L.; Gonzalez, Yanira; Chehab, Leena M.; Rosen, Elliot T.; Dickey, Jennifer S.; Rao, V. Ashutosh] US FDA, Div Therapeut Prot, Silver Spring, MD USA. [Vijay, Vikrant; Desai, Varsha] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG 1 PY 2015 VL 75 SU 15 MA 2554 DI 10.1158/1538-7445.AM2015-2554 PG 2 WC Oncology SC Oncology GA DF8AH UT WOS:000371578505146 ER PT J AU Guo, N Duan, HY Kachko, A Krause, BW Major, ME Krause, PR AF Guo, Nini Duan, Hongying Kachko, Alla Krause, Benjamin W. Major, Marian E. Krause, Philip R. TI Reverse Engineering of Vaccine Antigens Using High Throughput Sequencing-enhanced mRNA Display SO EBIOMEDICINE LA English DT Article DE mRNA display; Vaccine reverse-engineering ID HEPATITIS-C VIRUS; IN-VITRO SELECTION; ANTIBODIES; PROTEIN; DESIGN; NEUTRALIZATION; IDENTIFICATION; LIBRARIES AB Vaccine reverse engineering is emerging as an important approach to vaccine antigen identification, recently focusing mainly on structural characterization of interactions between neutralizing monoclonal antibodies (mAbs) and antigens. Using mAbs that bind unknown antigen structures, we sought to probe the intrinsic features of antibody antigen-binding sites with a high complexity peptide library, aiming to identify conformationally optimized mimotope antigens that capture mAb-specific epitopes. Using a high throughput sequencing-enhanced messenger ribonucleic acid (mRNA) display approach, we identified high affinity binding peptides for a hepatitis C virus neutralizing mAb. Immunization with the selected peptides induced neutralizing activity similar to that of the original mAb. Antibodies elicited by the most commonly selected peptides were predominantly against specific epitopes. Thus, using mRNA display to interrogate mAbs permits high resolution identification of functional peptide antigens that direct targeted immune responses, supporting its use in vaccine reverse engineering for pathogens against which potent neutralizing mAbs are available. Research in Context: We used a large number of randomly produced small proteins ("peptides") to identify peptides containing specific protein sequences that bind efficiently to an antibody that can prevent hepatitis C virus infection in cell culture. After the identified peptides were injected into mice, the mice produced their own antibodies with characteristics similar to the original antibody. This approach can provide previously unavailable information about antibody binding and could also be useful in developing new vaccines. (C) 2015 Published by Elsevier B.V. C1 [Guo, Nini; Duan, Hongying; Kachko, Alla; Krause, Benjamin W.; Major, Marian E.; Krause, Philip R.] US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Krause, PR (reprint author), US FDA, CBER, WO71 RM3234 HFM 457,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Philip.Krause@fda.hhs.gov NR 22 TC 0 Z9 0 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD AUG PY 2015 VL 2 IS 8 BP 859 EP 867 DI 10.1016/j.ebiom.2015.06.021 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CX8LT UT WOS:000365955900025 PM 26425692 ER PT J AU Hebert, A Bishop, M Bhattacharyya, D Gleason, K Torosian, S AF Hebert, Amanda Bishop, Michelle Bhattacharyya, Dhiman Gleason, Karen Torosian, Stephen TI Assessment by Ames test and comet assay of toxicity potential of polymer used to develop field-capable rapid-detection device to analyze environmental samples SO APPLIED NANOSCIENCE LA English DT Article DE Biosensor; Cytotoxicity; oCVD; P(EDO-Tco-3TE) ID TEST SYSTEM; DNA DAMAGE; CELLS; S9; CARCINOGENS; MUTAGENS AB There is need for devices that decrease detection time of food-borne pathogens from days to real-time. In this study, a rapid-detection device is being developed and assessed for potential cytotoxicity. The device is comprised of melt-spun polypropylene coupons coated via oxidative chemical vapor deposition (oCVD) with 3,4-Ethylenedioxythiophene (EDOT), for conductivity and 3-Thiopheneethanol (3TE), allowing antibody attachment. The Ames test and comet assay have been used in this study to examine the toxicity potentials of EDOT, 3TE, and polymerized EDOT-co-3TE. For this study, Salmonella typhimurium strain TA1535 was used to assess the mutagenic potential of EDOT, 3TE and the copolymer. The average mutagenic potential of EDOT, 3TE and copolymer was calculated to be 0.86, 0.56, and 0.92, respectively. For mutagenic potential, on a scale from 0 to 1, close to 1 indicates low potential for toxicity, whereas a value of 0 indicates a high potential for toxicity. The comet assay is a single-cell gel electrophoresis technique that is widely used for this purpose. This assay measures toxicity based on the area or intensity of the comet-like shape that DNA fragments produce when DNA damage has occurred. Three cell lines were assessed; FRhK-4, BHK-21, and Vero cells. After averaging the results of all three strains, the tail intensity of the copolymer was 8.8 % and tail moment was 3.0, and is most similar to the untreated control, with average tail intensity of 5.7 % and tail moment of 1.7. The assays conducted in this study provide evidence that the copolymer is non-toxic to humans. C1 [Hebert, Amanda; Torosian, Stephen] US FDA, Winchester Engn & Analyt Ctr, Winchester, MA 01890 USA. [Bishop, Michelle] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Bhattacharyya, Dhiman; Gleason, Karen] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. RP Torosian, S (reprint author), US FDA, Winchester Engn & Analyt Ctr, Winchester, MA 01890 USA. EM stephen.torosian@fda.hhs.gov NR 23 TC 0 Z9 0 U1 1 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2190-5509 EI 2190-5517 J9 APPL NANOSCI JI Appl. Nanosci. PD AUG PY 2015 VL 5 IS 6 BP 763 EP 769 DI 10.1007/s13204-014-0373-7 PG 7 WC Nanoscience & Nanotechnology SC Science & Technology - Other Topics GA CW6WB UT WOS:000365138000014 ER PT J AU Jones, CM Campopiano, M Baldwin, G McCance-Katz, E AF Jones, Christopher M. Campopiano, Melinda Baldwin, Grant McCance-Katz, Elinore TI National and State Treatment Need and Capacity for Opioid Agonist Medication-Assisted Treatment SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID HEPATITIS-C VIRUS; UNITED-STATES; PRESCRIBING BUPRENORPHINE; ADDICTION TREATMENT; TREATMENT PROGRAMS; OVERDOSE DEATHS; PAIN RELIEVERS; HEROIN USE; ABUSE; PHYSICIANS AB Objectives. We estimated national and state trends in opioid agonist medication-assisted treatment (OA-MAT) need and capacity to identify gaps and inform policy decisions. Methods. We generated national and state rates of past-year opioid abuse or dependence, maximum potential buprenorphine treatment capacity, number of patients receiving methadone from opioid treatment programs (OTPs), and the percentage of OTPs operating at 80% capacity or more using Substance Abuse and Mental Health Services Administration data. Results. Nationally, in 2012, the rate of opioid abuse or dependence was 891.8 per 100 000 people aged 12 years or older compared with national rates of maximum potential buprenorphine treatment capacity and patients receiving methadone in OTPs of, respectively, 420.3 and 119.9. Among states and the District of Columbia, 96% had opioid abuse or dependence rates higher than their buprenorphine treatment capacity rates; 37% had a gap of at least 5 per 1000 people. Thirty-eight states (77.6%) reported at least 75% of their OTPs were operating at 80% capacity or more. Conclusions. Significant gaps between treatment need and capacity exist at the state and national levels. Strategies to increase the number of OA-MAT providers are needed. C1 [Jones, Christopher M.] US FDA, Off Publ Hlth Strategy & Anal, Off Commissioner, Silver Spring, MD 20993 USA. [Campopiano, Melinda] Subst Abuse & Mental Hlth Serv Adm, Div Pharmacol Therapies, Ctr Subst Abuse Treatment, Rockville, MD USA. [Baldwin, Grant] Ctr Dis Control & Prevent, Div Unintent Injury Prevent, Natl Ctr Injury Prevent & Control, Atlanta, GA USA. [McCance-Katz, Elinore] Subst Abuse & Mental Hlth Serv Adm, Off Policy Planning & Innovat, Rockville, MD USA. RP Jones, CM (reprint author), US FDA, Off Publ Hlth Strategy & Anal, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM christopher.m.jones@fda.hhs.gov NR 60 TC 29 Z9 30 U1 9 U2 18 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2015 VL 105 IS 8 BP E55 EP E63 DI 10.2105/AJPH.2015.302664 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CT6VL UT WOS:000362950400014 PM 26066931 ER PT J AU Eydelman, MB Saha, A Tarver, ME AF Eydelman, Malvina B. Saha, Anindita Tarver, Michelle E. TI Tapping Into Valuable Expertise From Private Practitioners and Academicians Casting a Wider Net SO JAMA OPHTHALMOLOGY LA English DT Editorial Material C1 [Eydelman, Malvina B.; Saha, Anindita; Tarver, Michelle E.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Eydelman, MB (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM malvina.eydelman@fda.hhs.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD AUG PY 2015 VL 133 IS 8 BP 865 EP 866 DI 10.1001/jamaophthalmol.2015.1310 PG 2 WC Ophthalmology SC Ophthalmology GA CR5IP UT WOS:000361374800005 PM 25996586 ER PT J AU Casak, SJ Fashoyin-Aje, I Lemery, SJ Zhang, LL Jin, RY Li, HS Zhao, L Zhao, H Zhang, H Chen, HY He, K Dougherty, M Novak, R Kennett, S Khasar, S Helms, W Keegan, P Pazdur, R AF Casak, Sandra J. Fashoyin-Aje, Ibilola Lemery, Steven J. Zhang, Lillian Jin, Runyan Li, Hongshan Zhao, Liang Zhao, Hong Zhang, Hui Chen, Huanyu He, Kun Dougherty, Michele Novak, Rachel Kennett, Sarah Khasar, Sachia Helms, Whitney Keegan, Patricia Pazdur, Richard TI FDA Approval Summary: Ramucirumab for Gastric Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID PHASE-3 TRIAL; DOUBLE-BLIND; CHEMOTHERAPY AB The FDA approved ramucirumab (CYRAMZA; Eli Lilly and Company) for previously treated patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma initially as monotherapy (April 21, 2014) and subsequently as combination therapy with paclitaxel (November 5, 2014). In the monotherapy trial, 355 patients in the indicated population were randomly allocated (2:1) to receive ramucirumab or placebo, 8 mg/kg intravenously every 2 weeks. In the combination trial, 665 patients were randomly allocated (1:1) to receive ramucirumab or placebo, 8 mg/kg intravenously every 2 weeks, in combination with paclitaxel, 80 mg/m(2) on days 1, 8, and 15 of 28-day cycles. Overall survival (OS) was increased in patients who received ramucirumab in both the monotherapy [HR, 0.78; 95% confidence interval (CI), 0.60-0.998; log rank P = 0.047] and combination trials (HR, 0.81; 95% CI, 0.68-0.96; P = 0.017). The most common adverse reactions were hypertension and diarrhea in the monotherapy trial and fatigue, neutropenia, diarrhea, and epistaxis in the combination trial. Because of concerns about the robustness of the monotherapy trial results, FDA approved the original application after receiving the results of the combination trial confirming the OS effect. Based on exploratory exposure-response analyses, there is residual uncertainty regarding the optimal dose of ramucirumab. (C)2015 AACR. C1 [Casak, Sandra J.; Fashoyin-Aje, Ibilola; Lemery, Steven J.; Khasar, Sachia; Helms, Whitney; Keegan, Patricia] US FDA, Off Hematol & Oncol Prod, Off New Drugs, Silver Spring, MD 20993 USA. [Zhang, Lillian; Jin, Runyan; Li, Hongshan; Zhao, Liang; Zhao, Hong] US FDA, Off Clin Pharmacol, Silver Spring, MD 20993 USA. [Zhang, Hui; Chen, Huanyu; He, Kun; Pazdur, Richard] US FDA, Off Biostat, Off Translat Sci, Silver Spring, MD 20993 USA. [Dougherty, Michele; Novak, Rachel; Kennett, Sarah] US FDA, Off Biotechnol Prod, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Casak, SJ (reprint author), US FDA, Div Oncol Prod 2, Off Hematol & Oncol Prod, WO22-2387,10993 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Sandra.Casak@fda.hhs.gov NR 7 TC 8 Z9 10 U1 2 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 1 PY 2015 VL 21 IS 15 BP 3372 EP 3376 DI 10.1158/1078-0432.CCR-15-0600 PG 5 WC Oncology SC Oncology GA CS2NK UT WOS:000361907800004 PM 26048277 ER PT J AU Aydanian, A Tang, L Chen, YS Morris, JG Olsen, P Johnson, JA Nair, GB Stine, OC AF Aydanian, Antonina Tang, Li Chen, Yuansha Morris, J. Glenn, Jr. Olsen, Peter Johnson, Judith A. Nair, G. Balakrish Stine, O. Colin TI Genetic relatedness of selected clinical and environmental non-O1/O139 Vibrio cholerae SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Vibrio cholerae; Recombination; Subpopulations; Phylogenetically related ID SEQUENCE; O1; EPIDEMIOLOGY; INFERENCE; PATHOGEN; CALCUTTA; CLONES; GENOME; INDIA AB Background: In an attempt to better understand the non-O1/O139 isolates of Vibrio cholerae, a systematic study of clinical and environmental isolates collected from various geographical locations between the years 1932 and 1998 was conducted. Methods: Ninety-nine V. cholerae isolates collected from clinical and environmental sources from various geographical regions between 1932 and 1998 were studied by sequencing seven housekeeping genes. Genetic relatedness was defined by multiple methods that allow for the observed high levels of recombination. Results: Four V. cholerae subpopulations were determined. One subpopulation contained mostly environmental isolates, a second contained the cholera toxin-positive serogroup O1/O139 isolates, and the other two subpopulations were enriched for non-O1/O139 clinical isolates that were frequently clonally related to each other. Conclusions: The data suggest that many of these non-O1/O139 clinical isolates were phylogenetically related to common ancestors, even though the isolates had been collected up to 36 years apart and from different countries or continents. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). C1 [Aydanian, Antonina] US FDA, Bethesda, MD 20014 USA. [Tang, Li; Chen, Yuansha; Stine, O. Colin] Univ Maryland, Coll Med, Baltimore, MD 21201 USA. [Morris, J. Glenn, Jr.; Johnson, Judith A.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. [Olsen, Peter] Univ Maryland Baltimore Cty, Dept Comp Sci, Catonsville, MD USA. [Nair, G. Balakrish] Translat Hlth Sci & Technol Inst, Gurgaon, Haryana, India. RP Aydanian, A (reprint author), US FDA, Bethesda, MD 20014 USA. FU NIAID NIH HHS [R01 AI039129] NR 24 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 EI 1878-3511 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD AUG PY 2015 VL 37 BP 152 EP 158 DI 10.1016/j.ijid.2015.07.001 PG 7 WC Infectious Diseases SC Infectious Diseases GA CS1SC UT WOS:000361847000032 PM 26164777 ER PT J AU Kronstein, PD Ishida, E Khin, NA Chang, E Hung, HMJ Temple, RJ Yang, PL AF Kronstein, Phillip D. Ishida, Eiji Khin, Ni A. Chang, Eric Hung, H. M. James Temple, Robert J. Yang, Peiling TI Summary of Findings From the FDA Regulatory Science Forum on Measuring Sexual Dysfunction in Depression Trials SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Review ID FUNCTIONING QUESTIONNAIRE CSFQ; PAROXETINE-CONTROLLED TRIAL; DOUBLE-BLIND; ANTIDEPRESSANT EFFICACY; SUSTAINED-RELEASE; PLACEBO; DULOXETINE; DISORDER; RELIABILITY; BUPROPION AB Objective: Sexual dysfunction is a significant treatment-emergent adverse reaction to the serotonergic antidepressants (selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]). However, the rate of sexual dysfunction is often underestimated in registration trials, which have relied on unsolicited reports. We conducted a literature search to examine the rates of sexual dysfunction with SSRIs/SNRIs when these rates were ascertained by structured questionnaires or standardized instruments. Additionally, we conducted exploratory analyses of major depressive disorder (MDD) registration trial data. Data Sources: For the literature search, we used the PubMed and EMBASE databases, with a cutoff date of April 1, 2011. We included all the SSRIs and SNRIs that at the time had been approved for the treatment of MDD. For each of these drugs, a search was conducted with the following terms: sexual dysfunction, SD, sexual adverse effects, desire, arousal, excitement, and orgasm. For the exploratory analyses of US Food and Drug Administration in-house trial data, we searched our database for short-term (6-8 weeks), randomized, placebo-controlled MDD monotherapy trials of approved drugs included in New Drug Application submissions that used a standardized instrument to assess sexual function. Study Selection: For the literature search, we initially found a total of 123 nonduplicate articles, some of which included multiple studies. After screening based on our inclusion/exclusion criteria (and to remove duplicate trial-level data), we were left with 7 articles representing 11 unique studies in which sexual dysfunction was assessed with direct questioning or standardized instruments. The Changes in Sexual Functioning Questionnaire-Short-Form (CSFQ-14) and Arizona Sexual Experiences Scale (ASEX) were the only instruments represented. For the exploratory analyses of in-house MDD trial data, we found controlled studies using either the CSFQ-14 (6 trials) or ASEX (5 trials). Data Extraction: For the literature search, we were able to pool the results for the studies that included direct questioning. For the studies that used standardized instruments to assess sexual function, we simply describe our findings. For the exploratory analyses of in-house MDD trial data, we constructed a dataset containing all subject-level CSFQ-14 or ASEX item scores for each of the trials as well as demographic and other relevant variables. For each treatment or placebo group, analyses were performed on pooled data, including multiple studies, and on individual studies. Results: For our literature search, regardless of which method was used to assess sexual function, the data from these articles were informative and showed the expected effects on sexual function with SSRIs/SNRIs. However, for our exploratory analyses, no trend was observed in CSFQ-14 or ASEX results for individual drugs or drug classes. Conclusions: These results raise the question as to why the CSFQ-14 and ASEX appeared to perform well in the published studies but not in our exploratory analyses of in-house MDD trial data. We discuss possible reasons and solutions. (C) Copyright 2015 Physicians Postgraduate Press, Inc. C1 [Kronstein, Phillip D.; Khin, Ni A.; Chang, Eric] US FDA, Div Psychiat Prod, Off Drug Evaluat 1, Off New Drugs,Ctr Drug Evaluat & Res CDER, Silver Spring, MD 20993 USA. [Ishida, Eiji; Hung, H. M. James; Yang, Peiling] US FDA, Div Biometr 1, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res CDER, Silver Spring, MD 20993 USA. [Temple, Robert J.] US FDA, Off Drug Evaluat 1, Off New Drugs, Ctr Drug Evaluat & Res CDER, Silver Spring, MD 20993 USA. [Temple, Robert J.] US FDA, Off Ctr Director, Ctr Drug Evaluat & Res CDER, Silver Spring, MD 20993 USA. RP Kronstein, PD (reprint author), US FDA, Div Clin Compliance Evaluat, Off Sci Invest, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg WO51,Rm 5222, Silver Spring, MD 20993 USA. EM phillip.kronstein@fda.hhs.gov FU FDA Office of Women's Health; University of California San Francisco FX The forum, and some of the research necessary in preparing for it, was made possible by a grant from the FDA Office of Women's Health. Mr Chang, who assisted with the literature search portion of this project during his summer internship at FDA, was supported by University of California San Francisco. NR 21 TC 2 Z9 2 U1 2 U2 8 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2015 VL 76 IS 8 BP 1050 EP 1059 DI 10.4088/JCP.14r09699 PG 10 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA CR8IE UT WOS:000361593800015 PM 26335083 ER PT J AU Khin, NA Kronstein, PD Yang, PL Ishida, E Hung, HMJ Mathis, MV Unger, EF Temple, RJ AF Khin, Ni A. Kronstein, Phillip D. Yang, Peiling Ishida, Eiji Hung, H. M. James Mathis, Mitchell V. Unger, Ellis F. Temple, Robert J. TI Regulatory and Scientific Issues in Studies to Evaluate Sexual Dysfunction in Antidepressant Drug Trials SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID RELIABILITY; DEPRESSION; VALIDITY; PREVALENCE; SCALE AB Objective: Sexual dysfunction is an important side effect of serotonergic antidepressants, as it often leads to treatment nonadherence. However, sexual dysfunction is often underestimated in clinical trials submitted in support of drug approval. This is because such assessments are based mainly on unsolicited reporting. As a result, the characterization of sexual adverse events has become an important component of many of the development programs for new antidepressants. The purpose of this article is to discuss US Food and Drug Administration's (FDA's) current thinking on possible approaches to characterizing the effects of drugs on sexual function in depression drug trials. Participants: FDA's Division of Psychiatry Products, together with the Division of Biometrics I, in particular the authors of this article. Evidence: The above-referenced FDA divisions conducted a regulatory science forum on measuring sexual dysfunction in depression trials. Consensus Process: Considering the evidence presented and discussed at the forum, we developed our preliminary regulatory views on the scientific issues with regard to study design, study population, use of available scales, testing strategy, and statistical analysis plans. Conclusions: Sexual dysfunction associated with antidepressants is an important entity that should be adequately assessed during clinical trials with the use of available instruments and described in product labels. It is important to appreciate the need for a positive control to establish assay sensitivity for any trial evaluating the impact of antidepressant medications on sexual function. Methodological improvement and additional data as well as experience with these approaches will be needed prior to further consideration of a formal regulatory guidance document by the FDA. (C) Copyright 2015 Physicians Postgraduate Press, Inc. C1 [Khin, Ni A.; Kronstein, Phillip D.; Mathis, Mitchell V.] US FDA, Div Psychiat Prod, Off Drug Evaluat 1, Off New Drugs,Ctr Drug Evaluat & Res CDER, Silver Spring, MD 20993 USA. [Yang, Peiling; Ishida, Eiji; Hung, H. M. James] US FDA, Div Biometr 1, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res CDER, Silver Spring, MD 20993 USA. [Unger, Ellis F.; Temple, Robert J.] US FDA, Off Drug Evaluat 1, Off New Drugs, Ctr Drug Evaluat & Res CDER, Silver Spring, MD 20993 USA. [Temple, Robert J.] US FDA, Off Ctr Director, Ctr Drug Evaluat & Res CDER, Silver Spring, MD 20993 USA. RP Kronstein, PD (reprint author), US FDA, Div Clin Compliance Evaluat, Off Sci Invest, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg WO51,Rm 5222, Silver Spring, MD 20993 USA. EM phillip.kronstein@fda.hhs.gov NR 22 TC 5 Z9 5 U1 0 U2 3 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2015 VL 76 IS 8 BP 1060 EP 1063 DI 10.4088/JCP.14cs09700 PG 4 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA CR8IE UT WOS:000361593800016 PM 26214346 ER PT J AU McDermott, M Chatterjee, S Hu, XL Ash-Shakoor, A Avery, R Belyaeva, A Cruz, C Hughes, M Leadbetter, J Merkle, C Moot, T Parvinian, S Patwardhan, D Saylor, D Tang, N Zhang, TN AF McDermott, Martin Chatterjee, Sharmista Hu, Xiaoli Ash-Shakoor, Ariel Avery, Reginald Belyaeva, Anastasiya Cruz, Celia Hughes, Minerva Leadbetter, Joanne Merkle, Conrad Moot, Taylor Parvinian, Sepideh Patwardhan, Dinesh Saylor, David Tang, Nancy Zhang, Tina TI Application of Quality by Design (QbD) Approach to Ultrasonic Atomization Spray Coating of Drug-Eluting Stents SO AAPS PHARMSCITECH LA English DT Article DE biodegradable polymers; coating; drug-eluting stents; processing; quality by design ID CONFOCAL RAMAN MICROSCOPY; RELEASE KINETICS; FILMS; FABRICATION; POLYMERS; OPTIMIZATION; DELIVERY; RECEPTOR; IMPACT; CELLS AB The drug coating process for coated drug-eluting stents (DES) has been identified as a key source of inter-and intra-batch variability in drug elution rates. Quality-by-design (QbD) principles were applied to gain an understanding of the ultrasonic spray coating process of DES. Statistically based design of experiments (DOE) were used to understand the relationship between ultrasonic atomization spray coating parameters and dependent variables such as coating mass ratio, roughness, drug solid state composite microstructure, and elution kinetics. Defect-free DES coatings composed of 70% 85:15 poly(DL-lactide-co-glycolide) and 30% everolimus were fabricated with a constant coating mass. The drug elution profile was characterized by a mathematical model describing biphasic release kinetics. Model coefficients were analyzed as a DOE response. Changes in ultrasonic coating processing conditions resulted in substantial changes in roughness and elution kinetics. Based on the outcome from the DOE study, a design space was defined in terms of the critical coating process parameters resulting in optimum coating roughness and drug elution. This QbD methodology can be useful to enhance the quality of coated DES. C1 [McDermott, Martin; Hu, Xiaoli; Ash-Shakoor, Ariel; Avery, Reginald; Belyaeva, Anastasiya; Leadbetter, Joanne; Merkle, Conrad; Moot, Taylor; Parvinian, Sepideh; Patwardhan, Dinesh; Saylor, David; Tang, Nancy; Zhang, Tina] US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Chatterjee, Sharmista; Cruz, Celia; Hughes, Minerva] US FDA, Off New Drug Qual Assessment, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP McDermott, M (reprint author), US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Martin.McDermott@fda.hhs.gov; sharmista.chatterjee@fda.hhs.gov FU CDER RSR (Regulatory Science and Review Enhancement Program) [12-29]; ONDQA/FDA research funds FX We wish to thank our coworkers Dr. Kasturi Srinivasachar and Dr. Monica Cooper in the Office of New Drug Quality Assessment at CDER/FDA for their advice throughout this project. In addition, we would also like to thank our coworkers in the Division of Biology, Chemistry and Materials Sciences in CDRH/FDA for their help and support and the machine shop for manufacturing fixtures. Funding for this project was provided by CDER RSR (Regulatory Science and Review Enhancement Program) project 12-29 and ONDQA/FDA research funds. NR 41 TC 1 Z9 1 U1 1 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-9932 J9 AAPS PHARMSCITECH JI AAPS PharmSciTech PD AUG PY 2015 VL 16 IS 4 BP 811 EP 823 DI 10.1208/s12249-014-0266-9 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CR1NW UT WOS:000361093100008 PM 25563817 ER PT J AU Wu, Y Freed, A Lavrich, D Raghavachari, R Huynh-Ba, K Shah, K Alasandro, M AF Wu, Yan Freed, Anita Lavrich, David Raghavachari, Ramesh Huynh-Ba, Kim Shah, Ketan Alasandro, Mark TI Strategies of Bringing Drug Product Marketing Applications to Meet Current Regulatory Standards SO AAPS PHARMSCITECH LA English DT Article AB In the past decade, many guidance documents have been issued through collaboration of global organizations and regulatory authorities. Most of these are applicable to new products, but there is a risk that currently marketed products will not meet the new compliance standards during audits and inspections while companies continue to make changes through the product life cycle for continuous improvement or market demands. This discussion presents different strategies to bringing drug product marketing applications to meet current and emerging standards. It also discusses stability and method designs to meet process validation and global development efforts. C1 [Wu, Yan; Lavrich, David] Merck & Co Inc, Kenilworth, NJ USA. [Freed, Anita] Pfizer, Groton, CT USA. [Raghavachari, Ramesh] US FDA, Silver Spring, MD USA. [Huynh-Ba, Kim] Pharmalytik, Newark, DE 19711 USA. [Shah, Ketan] Biogen, Cambridge, MA USA. [Alasandro, Mark] Allergan, Irvine, CA USA. RP Huynh-Ba, K (reprint author), Pharmalytik, Newark, DE 19711 USA. EM kim.huynhba@pharmalytik.com NR 1 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-9932 J9 AAPS PHARMSCITECH JI AAPS PharmSciTech PD AUG PY 2015 VL 16 IS 4 BP 986 EP 991 DI 10.1208/s12249-015-0334-9 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CR1NW UT WOS:000361093100025 PM 26024722 ER PT J AU Warfel, JM Edwards, KM AF Warfel, Jason M. Edwards, Kathryn M. TI Pertussis vaccines and the challenge of inducing durable immunity SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID DEFICIENT BORDETELLA-PERTUSSIS; NONHUMAN PRIMATE MODEL; WHOLE-CELL VACCINE; TETANUS-DIPHTHERIA; CONTROLLED TRIAL; WANING IMMUNITY; UNITED-STATES; RESPONSES; CHILDREN; INFANTS AB Pertussis has re-emerged as an important public health concern. In the 1990s whole-cell pertussis vaccines were replaced with less reactogenic acellular vaccines consisting of purified pertussis components. However, recent data show that protection from acellular pertussis vaccines is not longlasting. Antibody levels wane rapidly following vaccination, likely a result of the inability of acellular pertussis antigens to stimulate long-lasting B cell memory. In addition, T cell responses to acellular pertussis vaccines are mixed Th2/Th1, while whole-cell pertussis vaccination and infection stimulate Th17 responses, important for host defense against extracellular mucosal pathogens. Consistent with this T cell skewing, acellular vaccines did not prevent colonization or transmission following challenge in nonhuman primates while whole-cell vaccinated and previously infected animals cleared the infection more rapidly. C1 [Warfel, Jason M.] FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Edwards, Kathryn M.] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37232 USA. [Edwards, Kathryn M.] Vanderbilt Univ, Vanderbilt Vaccine Res Program, Nashville, TN 37232 USA. RP Edwards, KM (reprint author), Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37232 USA. EM kathryn.edwards@vanderbilt.edu NR 64 TC 15 Z9 15 U1 2 U2 8 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 EI 1879-0372 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 2015 VL 35 BP 48 EP 54 DI 10.1016/j.coi.2015.05.008 PG 7 WC Immunology SC Immunology GA CR1HB UT WOS:000361074400009 PM 26091979 ER PT J AU Siegel, JA Sacks, B Feinendegen, LE Welsh, JS Fornalski, KW Miller, M Mahn, J Gomez, L Stabin, MG Lewis, P Esposito, VJ Strupczewski, A Pennington, CW Cuttler, JM Rangacharyulu, C Davey, C Sutou, S AF Siegel, Jeffry A. Sacks, Bill Feinendegen, Ludwig E. Welsh, James S. Fornalski, Krzysztof W. Miller, Mark Mahn, Jeffrey Gomez, Leo Stabin, Michael G. Lewis, Patricia Esposito, Vincent J. Strupczewski, Andrzej Pennington, Charles W. Cuttler, Jerry M. Rangacharyulu, Chary Davey, Chris Sutou, Shizuyo TI Comment on "Background Ionizing Radiation and the Risk of Childhood Cancer: A Census-Based Nationwide Cohort Study" SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 [Siegel, Jeffry A.] Nucl Phys Enterprises, Marlton, NJ 08053 USA. [Sacks, Bill] US FDA, Washington, DC 20204 USA. [Feinendegen, Ludwig E.] Univ Dusseldorf, Dusseldorf, Germany. [Welsh, James S.] Loyola Univ, Stritch Sch Med, Chicago, IL 60611 USA. [Fornalski, Krzysztof W.] Polish Nucl Soc, Warsaw, Poland. [Miller, Mark; Mahn, Jeffrey; Gomez, Leo] Sandia Natl Labs, Albuquerque, NM 87185 USA. [Stabin, Michael G.] Vanderbilt Univ, Nashville, TN 37235 USA. [Lewis, Patricia] Free Enterprise Radon Hlth Mine, Boulder, MT USA. [Esposito, Vincent J.] Univ Pittsburgh, Pittsburgh, PA USA. [Strupczewski, Andrzej] Natl Ctr Nucl Res, Warsaw, Poland. [Pennington, Charles W.] NAC Int, Norcross, GA USA. [Cuttler, Jerry M.] Cuttler & Associates, Mississauga, ON, Canada. [Rangacharyulu, Chary] Univ Saskatchewan, Saskatoon, SK, Canada. [Davey, Chris] King Abdullah Univ Sci & Technol, Jeddah, Saudi Arabia. [Sutou, Shizuyo] Shujitsu Univ, Okayama, Japan. RP Siegel, JA (reprint author), Nucl Phys Enterprises, 4 Wedgewood Dr, Marlton, NJ 08053 USA. EM nukephysics@comcast.net NR 3 TC 0 Z9 2 U1 1 U2 1 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 2015 VL 123 IS 8 BP A200 EP A200 DI 10.1289/ehp.1510111 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CQ6CX UT WOS:000360693100004 PM 26230545 ER PT J AU Walker, BN James, RH Calogero, D Ilev, IK AF Walker, Bennett N. James, Robert H. Calogero, Don Ilev, Ilko K. TI Quantifying the Multiwavelength Dispersion Effect on Dioptric Power Measurement of Intraocular Lenses SO IEEE PHOTONICS JOURNAL LA English DT Article DE Optics; biophotonics; intraocular lens; confocal microscopy; wavelength of light ID LASER METHOD; ABERRATION AB Improving technology and high demand has prompted a rapidly evolving intraocular lens (IOL) industry. To keep up with the improved designs, optical property evaluation techniques need to be adapted quickly to ensure IOL safety and efficacy. Identifying critical parameters are essential in evaluating IOL optical properties, which include temperature, medium, and test light characteristics. Here, we present a novel preclinical quantitative study of the dispersion effect that the wavelength of exposed test light has on IOL optical properties, specifically dioptric power. Dioptric power levels of IOLs were measured using a confocal laser method (CLM) when exposed to various wavelengths throughout the visible spectrum. Results showed statistically significant yet minimal focal point shift and, therefore, dioptric power changes (similar to 0.15D) due to the effect of test light wavelength, similar to known wavelength-dependent relationships associated with changes in refractive index. Further evaluation of critical parameters can lead to an improvement of IOL product designs and overall public health. C1 [Walker, Bennett N.; James, Robert H.; Ilev, Ilko K.] US FDA, Opt Therapeut & Med Nanophoton Lab, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Walker, Bennett N.; Calogero, Don] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Walker, BN (reprint author), US FDA, Opt Therapeut & Med Nanophoton Lab, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. EM Bennett.Walker@fda.hhs.gov FU Oak Ridge Institute for Science and Education (ORISE) FX The author would like to acknowledge the financial support from Oak Ridge Institute for Science and Education (ORISE) as well as the laboratory assistance from S. Song, who helped facilitate the experiments. NR 20 TC 0 Z9 0 U1 2 U2 2 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1943-0655 EI 1943-0647 J9 IEEE PHOTONICS J JI IEEE Photonics J. PD AUG PY 2015 VL 7 IS 4 AR 6802607 DI 10.1109/JPHOT.2015.2460119 PG 7 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA CR1FL UT WOS:000361069900038 ER PT J AU Groopman, AM Katz, JI Holland, MR Fujita, F Matsukawa, M Mizuno, K Wear, KA Miller, JG AF Groopman, Amber M. Katz, Jonathan I. Holland, Mark R. Fujita, Fuminori Matsukawa, Mami Mizuno, Katsunori Wear, Keith A. Miller, James G. TI Conventional, Bayesian, and Modified Prony's methods for characterizing fast and slow waves in equine cancellous bone SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID BAND ULTRASONIC-ATTENUATION; KRAMERS-KRONIG RELATIONSHIP; PHASE CANCELLATION; NEGATIVE DISPERSION; IN-VITRO; LIMITED DECONVOLUTION; ACOUSTIC ANISOTROPY; PROBABILITY-THEORY; FREQUENCY RANGE; TRABECULAR BONE AB Conventional, Bayesian, and the modified least-squares Prony's plus curve-fitting (MLSP + CF) methods were applied to data acquired using 1 MHz center frequency, broadband transducers on a single equine cancellous bone specimen that was systematically shortened from 11.8 mm down to 0.5 mm for a total of 24 sample thicknesses. Due to overlapping fast and slow waves, conventional analysis methods were restricted to data from sample thicknesses ranging from 11.8 mm to 6.0 mm. In contrast, Bayesian and MLSP + CF methods successfully separated fast and slow waves and provided reliable estimates of the ultrasonic properties of fast and slow waves for sample thicknesses ranging from 11.8 mm down to 3.5 mm. Comparisons of the three methods were carried out for phase velocity at the center frequency and the slope of the attenuation coefficient for the fast and slow waves. Good agreement among the three methods was also observed for average signal loss at the center frequency. The Bayesian and MLSP + CF approaches were able to separate the fast and slow waves and provide good estimates of the fast and slow wave properties even when the two wave modes overlapped in both time and frequency domains making conventional analysis methods unreliable. (C) 2015 Acoustical Society of America. C1 [Groopman, Amber M.; Katz, Jonathan I.; Miller, James G.] Washington Univ, Dept Phys, St Louis, MO 63130 USA. [Holland, Mark R.] Indiana Univ Purdue Univ, Sch Med, Dept Radiol & Imaging Sci, Indianapolis, IN 46202 USA. [Fujita, Fuminori; Matsukawa, Mami] Doshisha Univ, Res Ctr Wave Elect, Lab Ultrason Elect, Kyotanabe, Kyoto 6100321, Japan. [Mizuno, Katsunori] Univ Tokyo, Underwater Technol Res Ctr, Meguro Ku, Tokyo 1538505, Japan. [Wear, Keith A.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Groopman, AM (reprint author), Washington Univ, Dept Phys, St Louis, MO 63130 USA. EM nelsonam@wustl.edu FU NIH [R01 AR057433, R01 HL040302]; Ministry of Education, Culture, Sports, and Technology, Japan; Japan Society for Promotion of Science FX This study was supported, in part, by NIH Grant No. R01 AR057433, NIH Grant No. R01 HL040302, and by the Regional Innovation Strategy Support Program of the Ministry of Education, Culture, Sports, and Technology, Japan, and a Grant-in Aid for Scientific Research (B) from the Japan Society for Promotion of Science. NR 44 TC 0 Z9 0 U1 1 U2 2 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 EI 1520-8524 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD AUG PY 2015 VL 138 IS 2 BP 594 EP 604 DI 10.1121/1.4923366 PG 11 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA CQ5NV UT WOS:000360652900017 PM 26328678 ER PT J AU Ning, YM Brave, M Maher, VE Zhang, LJ Tang, SH Sridhara, R Kim, G Ibrahim, A Pazdur, R AF Ning, Yang-Min Brave, Michael Maher, V. Ellen Zhang, Lijun Tang, Shenghui Sridhara, Rajeshwari Kim, Geoffrey Ibrahim, Amna Pazdur, Richard TI US Food and Drug Administration Approval Summary: Enzalutamide for the Treatment of Patients With Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer SO ONCOLOGIST LA English DT Article DE Metastatic castration-resistant prostate cancer; Enzalutamide; Androgen receptor inhibitor; Chemotherapy-naive ID PLACEBO PLUS PREDNISONE; DOUBLE-BLIND; ABIRATERONE ACETATE; SIPULEUCEL-T; DOCETAXEL; SURVIVAL; IMMUNOTHERAPY; COMBINATION; MULTICENTER; THERAPY AB The U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). At the prespecified interim analysis, a statistically significant improvement in overall survival was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm. The overall benefit-risk profile supports the expanded indication for enzalutamide. On September 10, 2014, the U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Enzalutamide was initially approved in 2012 for use in patients with mCRPC who had previously received docetaxel. The current approval was based on the results of a randomized, placebo-controlled, double-blind trial conducted in 1,717 asymptomatic or minimally symptomatic patients with chemotherapy-naive mCRPC. Patients were assigned to receive either enzalutamide 160 mg or placebo orally once daily. The coprimary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS), which was assessed by independent central radiology review. At the prespecified interim analysis, a statistically significant improvement in OS was demonstrated for patients in the enzalutamidearm compared with patients in the placebo arm (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.60-0.84). The median OS was 32.4 and 30.2 months in the enzalutamide and placebo arms, respectively. A statistically significant prolongation of rPFS was observed in patients in the enzalutamidearm(HR, 0.17; 95% CI, 0.14-0.21). In addition, the time to initiation of cytotoxic chemotherapy was prolonged in the enzalutamide arm (HR, 0.35; 95% CI, 0.30-0.40), with median times of 28.0 and 10.8 months in the enzalutamide and placebo arms, respectively. The safety profile was similar to that previously reported for enzalutamide. Adverse reactions of interest included seizure, hypertension, and falls. Enzalutamide should be discontinued if a seizure occurs during treatment. The overall benefit-risk profile supports the expanded indication for enzalutamide. C1 [Ning, Yang-Min; Brave, Michael; Maher, V. Ellen; Zhang, Lijun; Tang, Shenghui; Sridhara, Rajeshwari; Kim, Geoffrey; Ibrahim, Amna; Pazdur, Richard] US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Ning, YM (reprint author), US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 22,Room 2139, Silver Spring, MD 20993 USA. EM ningy@cder.fda.gov NR 20 TC 7 Z9 7 U1 0 U2 5 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD AUG PY 2015 VL 20 IS 8 BP 960 EP 966 DI 10.1634/theoncologist.2015-0166 PG 7 WC Oncology SC Oncology GA CQ9YR UT WOS:000360973500021 PM 26070917 ER PT J AU Ali, S Rosas-Hernandez, H Cuevas, E Lantz-McPeak, S Paule, M Gonzalez, C Rice, K Gannon, B Fantegrossi, W AF Ali, S. Rosas-Hernandez, H. Cuevas, E. Lantz-McPeak, S. Paule, M. Gonzalez, C. Rice, K. Gannon, B. Fantegrossi, W. TI Methamphetamine, MDMA and bath salts induce cytotoxic effects in bovine brain microvessel endothelial cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 25th Biennial Meeting of the International-Society-for-Neurochemistry Jointly with the 13th Meeting of the Asian-Pacific-Society-for-Neurochemistry in Conjunction with the 35th Meeting of the Australasian-Neuroscience-Society CY AUG 23-27, 2015 CL Cairns, AUSTRALIA SP Int Soc Neurochemistry, Asian Pacific Soc Neurochemistry, Australasian Neuroscience Soc C1 [Ali, S.; Cuevas, E.; Lantz-McPeak, S.; Paule, M.] Natl Ctr Toxicol Res, Div Neuroroxicol HFT 132, Jefferson, AR 72079 USA. [Rosas-Hernandez, H.; Gonzalez, C.] Univ Autonoma San Luis Potosi, Fac Ciencias Quim, Slp, Mexico. [Rice, K.] NIAAA, NIDA, Chem Biol Res Br Drug Design & Synth Sect, Baltimore, MD USA. [Gannon, B.; Fantegrossi, W.] UAMS, Dept Pharmacol, Little Rock, AR USA. NR 0 TC 0 Z9 0 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2015 VL 134 SU 1 SI SI MA MTU12-26 BP 220 EP 220 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CP9IA UT WOS:000360206300539 ER PT J AU Butler, KS Casey, BJ Peeler, DJ Dair, BJ Elespuru, RK AF Butler, K. S. Casey, B. J. Peeler, D. J. Dair, B. J. Elespuru, R. K. TI Genotoxicity of Nanomaterials: Probing the Responses of the Bacterial Assays SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Butler, K. S.; Casey, B. J.; Peeler, D. J.; Dair, B. J.; Elespuru, R. K.] US FDA, CDRH, Div Biol Chem & Mat Sci, Silver Spring, MD USA. RI Peeler, David/M-2673-2014 OI Peeler, David/0000-0003-2441-6409 NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P89 BP S79 EP S79 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400196 ER PT J AU Dan, M Balsam, J Tang, X Li, B Elespuru, R AF Dan, M. Balsam, J. Tang, X. Li, B. Elespuru, R. TI Assembly of a PCR-Based DNA Diagnostic System for use in the Field (Independent of a Lab) SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Dan, M.; Tang, X.; Elespuru, R.] US FDA, CDRH, OSEL, DBCMS, Silver Spring, MD USA. [Balsam, J.] US FDA, CDRH, OIR, DCT, Silver Spring, MD USA. [Li, B.] US FDA, CDRH, OARSA, College Pk, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P56 BP S71 EP S71 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400163 ER PT J AU Demir, E Li, Y Qin, T Zhang, Y Guo, X Ingle, T Yan, J Orza, AI Biris, A Chen, T AF Demir, E. Li, Y. Qin, T. Zhang, Y. Guo, X. Ingle, T. Yan, J. Orza, A., I Biris, A. Chen, T. TI Genotoxicity of Cadmium Oxide Nanoparticles Evaluated Using In Vitro Assays SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Demir, E.; Li, Y.; Qin, T.; Guo, X.; Yan, J.; Chen, T.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Zhang, Y.; Ingle, T.] US FDA, Nanotechnol Core Facil, Natl Ctr Toxicol Res, Jefferson, AR USA. [Orza, A., I; Biris, A.] Univ Arkansas, Ctr Integrat Nanotechnol Sci, Little Rock, AR 72204 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P58 BP S71 EP S71 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400165 ER PT J AU Dobrovolsky, VN Ding, W Pearce, M AF Dobrovolsky, V. N. Ding, W. Pearce, M. TI Evaluation of In Vivo Genotoxicity of Acrylamide and Glycidyl Methacrylate SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Dobrovolsky, V. N.; Ding, W.; Pearce, M.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P69 BP S74 EP S74 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400176 ER PT J AU Elespuru, RK AF Elespuru, R. K. TI New Challenges for Genetic Toxicity Testing and Cancer Risk Assessment in the Medical Device Arena. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Elespuru, R. K.] US FDA, CDRH, OSEL, Div Biol Chem & Mat Sci, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA S52 BP S44 EP S44 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400052 ER PT J AU Fuscoe, JC Vijay, V Han, T Wang, K Desai, VG AF Fuscoe, J. C. Vijay, V. Han, T. Wang, K. Desai, V. G. TI Whole Genome Gene Expression Profiling of Hearts from Mice Exposed to Doxorubicin-Effect of Pretreatment with Dexrazoxane SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Fuscoe, J. C.; Vijay, V.; Han, T.; Wang, K.; Desai, V. G.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P95 BP S81 EP S81 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400202 ER PT J AU Guo, X Heflich, RH Dial, SL De, M Richter, PA Mei, N AF Guo, X. Heflich, R. H. Dial, S. L. De, M. Richter, P. A. Mei, N. TI Quantitative Analysis of In Vitro Mutagenicity Induced by Five Chemical Constituents of Tobacco Smoke. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Guo, X.; Heflich, R. H.; Dial, S. L.; Mei, N.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [De, M.] Ctr Tobacco Prod, Rockville, MD USA. [Richter, P. A.] Ctr Dis Control & Prevent, Atlanta, GA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA 20 BP S54 EP S54 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400097 ER PT J AU Heflich, RH AF Heflich, R. H. TI A Case for Mutagenicity As an Apical Endpoint to Derive Permissible Exposure Levels SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Heflich, R. H.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA S28 BP S38 EP S38 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400028 ER PT J AU Kabir, F Balsam, J Elespuru, R AF Kabir, F. Balsam, J. Elespuru, R. TI Mutation Dynamics during Mutant Colony Development of Salmonella typhimurium TA100 lux SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Kabir, F.; Elespuru, R.] US FDA, CDRH, OSEL, DBCMS, Silver Spring, MD USA. [Balsam, J.] US FDA, CDRH, OIR, DCT, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P91 BP S80 EP S80 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400198 ER PT J AU Manjanatha, MG Shelton, SD Chen, Y Gaddameedhi, S Howard, PC Boudreau, MD AF Manjanatha, M. G. Shelton, S. D. Chen, Y. Gaddameedhi, S. Howard, P. C. Boudreau, M. D. TI Development and Validation of a New Transgenic Hairless Albino Mouse Model for Photocarcinogenicity Studies SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Manjanatha, M. G.; Shelton, S. D.; Chen, Y.; Howard, P. C.; Boudreau, M. D.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Gaddameedhi, S.] Washington State Univ, Spokane, WA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P47 BP S69 EP S69 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400154 ER PT J AU McGovern, TJ AF McGovern, T. J. TI Recent Changes in Genetic Toxicology Testing of Pharmaceuticals. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [McGovern, T. J.] US FDA, CDER, Off New Drugs, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA S49 BP S43 EP S43 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400049 ER PT J AU Mei, N Guo, X Zhang, Z Dial, SL Dobrovolsky, VN Chen, S Guo, L AF Mei, N. Guo, X. Zhang, Z. Dial, S. L. Dobrovolsky, V. N. Chen, S. Guo, L. TI Mechanistic Study of TEMPO-Associated Oxidative Stress and Genotoxicity. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Mei, N.; Guo, X.; Zhang, Z.; Dial, S. L.; Dobrovolsky, V. N.; Chen, S.; Guo, L.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P4 BP S58 EP S58 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400111 ER PT J AU Myers, MB Mckim, KL Parsons, BL AF Myers, M. B. Mckim, K. L. Parsons, B. L. TI Relating Spontaneous Levels of PIK3CA Mutations to Organ-Specific Carcinogenesis SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Myers, M. B.; Mckim, K. L.; Parsons, B. L.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P108 BP S84 EP S84 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400215 ER PT J AU Parsons, BL Banda, M Myers, MB Mckim, KL Ortiz, L Luderer, U AF Parsons, B. L. Banda, M. Myers, M. B. Mckim, K. L. Ortiz, L. Luderer, U. TI Levels of Kras Codon 12 Mutations in Mouse Ovary Measured by ACB-PCR Were Not Increased by Transplacental Exposure to benzo[a]pyrene or Impacted by Gclm Genotype SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Parsons, B. L.; Banda, M.; Myers, M. B.; Mckim, K. L.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Ortiz, L.; Luderer, U.] Univ Calif Irvine, Irvine, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P107 BP S84 EP S84 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400214 ER PT J AU Petibone, DM Mustafa, T Shawn, B Lafont, A Ding, W Watanabe, F Casciano, DI Biris, AS Dobrovolsky, VN Morris, SM AF Petibone, D. M. Mustafa, T. Shawn, Bourdo Lafont, A. Ding, W. Watanabe, F. Casciano, D., I Biris, A. S. Dobrovolsky, V. N. Morris, S. M. TI Oxidized Graphene Toxicity Depends on p53 Functional Status in Human B-Lymphoblast Cell Lines SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Petibone, D. M.; Ding, W.; Dobrovolsky, V. N.; Morris, S. M.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Mustafa, T.; Shawn, Bourdo; Lafont, A.; Watanabe, F.; Casciano, D., I; Biris, A. S.] Univ Arkansas, Little Rock, AR 72204 USA. [Mustafa, T.] Univ Baghdad, Baghdad, Iraq. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P70 BP S74 EP S74 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400177 ER PT J AU Revollo, J Crabtree, N Pearce, M Dobrovolsky, V AF Revollo, J. Crabtree, N. Pearce, M. Dobrovolsky, V TI Mutational Analysis with Random DNA Identifiers (MARDI), a High-Fidelity NGS Approach That Simultaneously Identifies Gene Marker Mutations from Heterogeneous Mutant Cell Populations. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Revollo, J.; Pearce, M.; Dobrovolsky, V] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Crabtree, N.] Univ Arkansas, Little Rock, AR 72204 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA 10 BP S52 EP S52 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400087 ER PT J AU Thompson, CM Suh, M Proctor, DM Haws, LC Hixon, JG Wolf, JC Young, RR Elbekai, RH O'Brien, TJ Parsons, BL Seiter, JM Chappell, MA Harris, MA AF Thompson, C. M. Suh, M. Proctor, D. M. Haws, L. C. Hixon, J. G. Wolf, J. C. Young, R. R. Elbekai, R. H. O'Brien, T. J. Parsons, B. L. Seiter, J. M. Chappell, M. A. Harris, M. A. TI Follow-Up Assessment of In Vivo Genotoxicity in Target Organs of Relevant Species Identified from a Two-Year Cancer Bioassay: Case Study with Hexavalent Chromium. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Thompson, C. M.; Harris, M. A.] ToxStrategies Inc, Katy, TX USA. [Suh, M.; Proctor, D. M.] ToxStrategies Inc, Mission Viejo, CA USA. [Haws, L. C.; Hixon, J. G.] ToxStrategies Inc, Austin, TX USA. [Wolf, J. C.] Expt Pathol Labs, Sterling, VA USA. [Young, R. R.; Elbekai, R. H.] BioReliance, Rockville, MD USA. [O'Brien, T. J.] George Washington Univ, Med Ctr, Washington, DC 20037 USA. [Parsons, B. L.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Seiter, J. M.; Chappell, M. A.] US Army Engineer Res & Dev Ctr, Vicksburg, MS USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA 12 BP S52 EP S52 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400089 ER PT J AU Townsend, TA Bishop, ME Shelton, SD Manjanatha, MG AF Townsend, T. A. Bishop, M. E. Shelton, S. D. Manjanatha, M. G. TI The Development of a Modified Comet Assay for Assessment of Global and Region-Specific DNA Methylation Status. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Townsend, T. A.; Bishop, M. E.; Shelton, S. D.; Manjanatha, M. G.] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Townsend, T. A.] US FDA, Off Commissioner, Off Chief Scientist, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA 15 BP S53 EP S53 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400092 ER PT J AU Zhang, Z Li, H Manjanatha, MG Chen, T Mei, N AF Zhang, Z. Li, H. Manjanatha, M. G. Chen, T. Mei, N. TI Neonatal Exposure of 17 beta-estradiol Has No Effects on Mutagenicity of 7,12-dimethylbenz[a]anthracene in Reproductive Tissues of Adult Mice SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract C1 [Zhang, Z.; Li, H.; Manjanatha, M. G.; Chen, T.; Mei, N.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD AUG PY 2015 VL 56 SU 1 MA P45 BP S68 EP S68 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA CP9PJ UT WOS:000360226400152 ER PT J AU Huang, X Zheng, JF Wu, X Kono, M Hozono, H Kainz, W Yang, F Chen, J AF Huang, Xin Zheng, Jianfeng Wu, Xin Kono, Mari Hozono, Hideki Kainz, Wolfgang Yang, Fan Chen, Ji TI MRI Heating Reduction for External Fixation Devices Using Absorption Material SO IEEE TRANSACTIONS ON ELECTROMAGNETIC COMPATIBILITY LA English DT Article; Proceedings Paper CT IEEE International Symposium on Electromagnetic Compatibility CY AUG, 2014 CL Raleigh, NC SP IEEE DE Absorption material; external fixation; RF heating reduction; response surface methodology (RSM) AB This paper presents a novel approach to minimize the radio frequency (RF)-induced heating from external fixation devices under magnetic resonance imaging (MRI) procedure. With proper placement and selection of absorption material, one can alter the electromagnetic field and current distributions around and/or on medical devices so that the MRI RF field-induced heating can be reduced. The absorption-material-based RF heating reduction schemes are analyzed and validated. Numerical and experimental studies are conducted to illustrate the potentials of reducing the RF heating for external fixation devices. A design strategy based on response surface methodology is presented for material selection, and it is shown that absorption materials can significantly reduce the RF heating effects from 645 to 172 W/kg in terms of 1-g spatial-averaged SAR for the device under this investigation. C1 [Huang, Xin; Zheng, Jianfeng; Chen, Ji] Univ Houston, Dept Elect & Comp Engn, Houston, TX 77204 USA. [Wu, Xin] Molex Co Ltd, Lisle, IL 60532 USA. [Kainz, Wolfgang] Ctr Devices & Radiol Hlth Food & Drug Adm, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Yang, Fan] Tsinghua Univ, Dept Elect Engn, Beijing 100084, Peoples R China. RP Huang, X (reprint author), Univ Houston, Dept Elect & Comp Engn, Houston, TX 77204 USA. EM xhuang12@uh.edu; jzheng4@central.uh.edu; xin.wu@lorom.com; mari.kono@molex.co.jp; hideki.hozono@molex.co.jp; wolfgang.kainz@fda.hhs.gov; fan_yang@tsinghua.edu.cn; jchen23@central.uh.edu FU NSF-IIP [1440107] FX This paper was supported by NSF-IIP 1440107. This paper is an expanded version of the paper presented at the 2014 IEEE International Symposium on EMC, Raleigh, NC, USA, August 3-8 2014. NR 9 TC 1 Z9 1 U1 1 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9375 EI 1558-187X J9 IEEE T ELECTROMAGN C JI IEEE Trans. Electromagn. Compat. PD AUG PY 2015 VL 57 IS 4 SI SI BP 635 EP 642 DI 10.1109/TEMC.2015.2407318 PG 8 WC Engineering, Electrical & Electronic; Telecommunications SC Engineering; Telecommunications GA CP6RI UT WOS:000360015200004 ER PT J AU Li, DW Zheng, JF Liu, Y Pan, CW Kainz, W Yang, F Wu, W Chen, J AF Li, Dawei Zheng, Jianfeng Liu, Yan Pan, Changwang Kainz, Wolfgang Yang, Fan Wu, Wen Chen, Ji TI An Efficient Approach to Estimate MRI RF Field Induced In Vivo Heating for Small Medical Implants SO IEEE TRANSACTIONS ON ELECTROMAGNETIC COMPATIBILITY LA English DT Article; Proceedings Paper CT IEEE International Symposium on Electromagnetic Compatibility CY AUG, 2014 CL Raleigh, NC SP IEEE DE In vivo heating estimation; medical implants; MRI safety; RF-induced heating; scaling approach ID COMPUTATIONAL ELECTROMAGNETICS CEM; SELECTIVE VALIDATION FSV; PACEMAKER LEADS; DEVICES; SAFETY AB In this paper, a quick and efficient approach is proposed to estimate in vivo RF-induced heating from small medical implants under MRI procedure. An efficient methodology is developed to correlate the incident electric field to the induced temperature rise for stents of arbitrary shapes. A 10-cm-long titanium rod and a 6-cm-long intestine stent are used as examples to validate the approach under in vitro testing conditions. In vivo temperature rise estimations are then performed on an anatomically corrected adult male model. Numerical and experimental studies demonstrate the efficiency and accuracy of the proposed method. C1 [Li, Dawei; Zheng, Jianfeng; Chen, Ji] Univ Houston, Dept Elect & Comp Engn, Houston, TX 77204 USA. [Liu, Yan] Univ Houston, Houston, TX 77204 USA. [Pan, Changwang] Microtech Co Ltd, Nanjing 210061, Jiangsu, Peoples R China. [Kainz, Wolfgang] Ctr Devices & Radiol Hlth Food & Drug Adm, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Yang, Fan] Tsinghua Univ, Dept Elect Engn, Beijing 100084, Peoples R China. [Wu, Wen] Nanjing Univ Sci & Technol, Sch Elect Engn & Photoelect Technol, Nanjing 210094, Jiangsu, Peoples R China. RP Li, DW (reprint author), Univ Houston, Dept Elect & Comp Engn, Houston, TX 77204 USA. EM dli15@central.uh.edu; jzheng3@uh.edu; yan.liu@cgg.com; pcw@micro-tech.com.cn; wolfgang.kainz@fda.hhs.gov; fan_yang@tsinghua.edu.cn; wuwen@mail.njust.edu.cn; jchen23@central.uh.edu NR 26 TC 2 Z9 2 U1 0 U2 7 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9375 EI 1558-187X J9 IEEE T ELECTROMAGN C JI IEEE Trans. Electromagn. Compat. PD AUG PY 2015 VL 57 IS 4 SI SI BP 643 EP 650 DI 10.1109/TEMC.2015.2435519 PG 8 WC Engineering, Electrical & Electronic; Telecommunications SC Engineering; Telecommunications GA CP6RI UT WOS:000360015200005 ER PT J AU Yu, LX Woodcock, J AF Yu, Lawrence X. Woodcock, Janet TI FDA pharmaceutical quality oversight SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Review DE Pharmaceutical quality; Quality by design; Quality manufacturing systems; Integrated quality assessment; Facility investigations; Pharmaceutical surveillance AB The launch of the Center for Drug Evaluation and Research (CDER) Office of Pharmaceutical Quality (OPQ) is a milestone in FDA's efforts to assure that quality medicines are available to the American public. As a new super-office within CDER, OPQ is strategically organized to streamline regulatory processes, advance regulatory standards, align areas of expertise, and originate surveillance of drug quality. Supporting these objectives will be an innovative and systematic approach to product quality knowledge management and informatics. Concerted strategies will bring parity to the oversight of innovator and generic drugs as well as domestic and international facilities. OPQ will promote and encourage the adoption of emerging pharmaceutical technology to enhance pharmaceutical quality and potentially reinvigorate the pharmaceutical manufacturing sector in the United States. With a motto of "One Quality Voice," OPQ embodies the closer integration of review, inspection, surveillance, policy, and research for the purpose of strengthening pharmaceutical quality on a global scale. Published by Elsevier B.V. C1 [Yu, Lawrence X.; Woodcock, Janet] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Yu, LX (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM lawrence.yu@fda.hhs.gov NR 1 TC 6 Z9 6 U1 2 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD AUG 1 PY 2015 VL 491 IS 1-2 BP 2 EP 7 DI 10.1016/j.ijpharm.2015.05.066 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CP1EM UT WOS:000359619100002 PM 26027494 ER PT J AU Manjanatha, MG Shelton, SD Haber, L Gollapudi, B MacGregor, JA Rajendran, N Moore, MM AF Manjanatha, Mugimane G. Shelton, Sharon D. Haber, Lynne Gollapudi, Bhaskar MacGregor, Judith A. Rajendran, Narayanan Moore, Martha M. TI Evaluation of cII mutations in lung of male Big Blue mice exposed by inhalation to vanadium pentoxide for up to 8 weeks SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE Vanadium pentoxide mutagenicity in lungs by inhalation study; cII mutagenicity in Big Blue mice; Mutagenic mode of action for the carcinogenicity of vanadium pentoxide ID OXIDATIVE DNA-DAMAGE; INHALED PARTICLES; F344/N RATS; MECHANISMS; CANCER; MORTALITY AB Chronic inhalation of vanadium pentoxide (V2O5) increases the incidence of alveolar/bronchiolar tumors in male and female B6C3F1 mice at 1, 2, or 4 mg/m(3). The genotoxicity of V2O5 has been extensively investigated in the literature with mixed results. ln general, tests for gene mutations have been negative. Both positive and negative results were reported for clastogenicity in vitro with some reports suggesting aneugenic potential. In vivo, V2O5 was negative in the mouse micronucleus test (erythrocyte) and comet assay (lung). Previously, K-ras mutations have been detected in the lung tumors in mice exposed to V2O5. Recently, a short-term inhalation study in B6C3F1 mice reported slight induction of 8-oxodGuo DNA lesions in lungs. Because 8-oxodGuo DNA lesions can lead to gene mutations if not repaired or if misrepaired, we have used groups of transgenic Big Blue (BB) mice (B6C3F1) to test whether V2O5 has mutagenic potential in vivo in the tumor target tissue under the conditions of the bioassay. Groups of six male BB mice were exposed to particulate aerosols containing 0, 0.1, or 1 mg/m3 (tumorigenic concentration) V2O5 for 4 or 8 weeks (6 h/day, 5 days/week) and cII mutant frequencies (MFs) were evaluated in the right lungs. A significant increase in lung weight was noted in mice exposed to 1 mg/m(3) V2O5 (P <= 0.05) compared to sham control, confirming exposure to an inflammatory level of the test material. The mean MFs (x10(-6)) of mice in the 4-week exposure groups were 30 (sham control), 39 (0.1 mg/m(3)), and 24 (1 mg/m(3)) while the corresponding values in the 8-week exposure groups were 29, 48, and 17, respectively. None of these cll MFs measured at any time point was significantly higher than the corresponding control MFs (P >= 0.1). Overall, these results suggest that mutagenicity is not likely to be an initial key event in the lung tumorigenicity of V2O5. Published by Elsevier B.V. C1 [Manjanatha, Mugimane G.; Shelton, Sharon D.; Moore, Martha M.] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Haber, Lynne] Toxicol Excellence Risk Assessment, Cincinnati, OH USA. [Gollapudi, Bhaskar] Exponent Inc, Ctr Toxicol & Mechanist Biol, Midland, MI USA. [MacGregor, Judith A.] Toxicol Consulting Serv, Bonita Springs, FL USA. [Rajendran, Narayanan] IIT, Res Inst, Chicago, IL 60616 USA. RP Manjanatha, MG (reprint author), US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, HFT 120,3900 NCTR Rd, Jefferson, AR 72079 USA. EM Mugimane.manjanatha@fda.hhs.gov FU Vanadium Producers & Reclaimers Association; Toxicology Excellence for Risk Assessment; US FDA; U.S. Department of Defense (DOD) under U.S. Army Medical Research and Materiel Command (USAMRMC) Fort Detrick, Maryland [W81XWH-09-2-006] FX Funding for Dr. Haber's scientific input was provided by the Vanadium Producers & Reclaimers Association. Research funding was provided via a Cooperative Research and Development Agreement between Toxicology Excellence for Risk Assessment and the US FDA. Funding for project planning and scientific oversight by Drs. Gollapudi and MacGregor was provided by the U.S. Department of Defense (DOD) under a cooperative agreement that was awarded and administered by the U.S. Army Medical Research and Materiel Command (USAMRMC) Fort Detrick, Maryland 21702, under Contract Number: W81XWH-09-2-006. The results and conclusion presented in this manuscript are neither a formal dissemination of information by FDA nor do they represent agency position or policy. NR 28 TC 0 Z9 0 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 EI 1879-3592 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD AUG PY 2015 VL 789 BP 46 EP 52 DI 10.1016/j.mrgentox.2015.06.014 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA CP5XV UT WOS:000359959600005 PM 26232257 ER PT J AU Banda, M Mckim, KL Haber, LT MacGregor, JA Gollapudi, BB Parsons, BL AF Banda, Malathi McKim, Karen L. Haber, Lynne T. MacGregor, Judith A. Gollapudi, B. Bhaskar Parsons, Barbara L. TI Quantification of Kras mutant fraction in the lung DNA of mice exposed to aerosolized particulate vanadium pentoxide by inhalation SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE Mutation; Mode of action; Carcinogenesis; Vanadium pentoxide ID ACB-PCR MEASUREMENT; OXIDATIVE STRESS; MAP KINASE; ACTIVATION; SENESCENCE; CELLS; MYOFIBROBLASTS; VANADATE; MUTATION; NOX4 AB This study investigated whether Kras mutation is an early event in the development of lung tumors induced by inhalation of particulate vanadium pentoxide (VP) aerosols. A National Toxicology Program tumor bioassay of inhaled particulate VP aerosols established that VP-induced alveolar/bronchiolar carcinomas of the B6C3F1 mouse lung carried Kras mutations at a higher frequency than observed in spontaneous mouse lung tumors. Therefore, this study sought to: (1) characterize any Kras mutational response with respect to VP exposure concentration, and (2) investigate the possibility that amplification of preexisting Kras mutation is an early event in VP-induced mouse lung tumorigenesis. Male Big Blue B6C3F1 mice (6 mice/group) were exposed to aerosolized particulate VP by inhalation, 6 h/day, 5 days/week for 4 or 8 weeks, using VP exposure concentrations of 0, 0.1, and 1 mg/m(3). The levels of two different Kras codon 12 mutations [GGT -> GAT (G12D) and GGT -> GIT (G12V)] were measured in lung DNAs by Allele-specific Competitive Blocker PCR (ACB-PCR). For both exposure concentrations (0.1 and 1.0 mg/m(3)) and both time points (4 and 8 weeks), the mutant fractions observed in VP-exposed mice were not significantly different from the concurrent controls. Given that 8 weeks of inhalation of a tumorigenic concentration of particulate aerosols of VP did not result in a significant change in levels of lung Kras mutation, the data do not support either a direct genotoxic effect of VP on Kras or early amplification of preexisting mutation as being involved in the genesis of VP-induced mouse lung tumors under the exposure conditions used. Rather, the data suggest that accumulation of Kras mutation occurs later with chronic VP exposure and is likely not an early event in VP-induced mouse lung carcinogenesis. Published by Elsevier B.V. C1 [Banda, Malathi; McKim, Karen L.; Parsons, Barbara L.] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Haber, Lynne T.] Toxicol Excellence Risk Assessment, Cincinnati, OH USA. [MacGregor, Judith A.] Toxicol Consulting Serv, Bonita Springs, FL USA. [Gollapudi, B. Bhaskar] Exponent, Midland, MI USA. RP Parsons, BL (reprint author), US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, HFT 120,3900 NCTR Rd, Jefferson, AR 72079 USA. EM barbara.parsons@fda.hhs.gov FU Vanadium Producers 82 Reclaimers Association; Toxicology Excellence for Risk Assessment; US FDA; U.S. Department of Defense (DOD) under U.S. Army Medical Research and Materiel Command (USAMRMC) Fort Detrick, Maryland [W81XWH-09-2-006] FX Funding for Dr. Haber's scientific input was provided by the Vanadium Producers 82 Reclaimers Association. Research funding was provided via a Cooperative Research and Development Agreement between Toxicology Excellence for Risk Assessment and the US FDA. Funding for project planning and scientific oversight was provided by the U.S. Department of Defense (DOD) under a cooperative agreement that is awarded and administered by the U.S. Army Medical Research and Materiel Command (USAMRMC) Fort Detrick, Maryland 21702, under Contract Number: W81XWH-09-2-006. The information in these materials is not a formal dissemination of information by FDA and does not represent agency position or policy. NR 37 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 EI 1879-3592 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD AUG PY 2015 VL 789 BP 53 EP 60 DI 10.1016/j.mrgentox.2015.07.003 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA CP5XV UT WOS:000359959600006 PM 26232258 ER PT J AU Tassinari, MS Sahin, L Yao, LP AF Tassinari, Melissa S. Sahin, Leyla Yao, Lynne P. TI Assessing congenital malformation risk from medications used in pregnancy: The contribution of NBDPS in pregnancy labeling of prescription drug products SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article DE NBDPS; FDA; pregnancy labeling ID BIRTH-DEFECTS-PREVENTION AB BackgroundObtaining human pregnancy data to inform product labeling is important for drug and biological products. MethodsCollection and analyses of safety data on their use during pregnancy is usually performed after approval. ResultsThe Centers for Disease Control National Birth Defects Prevention Study has provided important data on the relationship between drug use in pregnancy and birth defects. ConclusionThe Pregnancy and Lactation Labeling Rule will set new and improved standards for the inclusion of information about the use of prescription drugs and biological products during pregnancy; the National Birth Defects Prevention Study, along with other data sources, will be critical for providing safety data to inform product labeling. Birth Defects Research (Part A) 103:718-720, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Tassinari, Melissa S.; Sahin, Leyla; Yao, Lynne P.] US FDA, Div Pediat & Maternal Hlth, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Tassinari, MS (reprint author), 10903 New Hampshire Ave,WO Bldg 22 Room 6410, Silver Spring, MD 20993 USA. EM melissa.tassinari@fda.hhs.gov NR 12 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD AUG PY 2015 VL 103 IS 8 BP 718 EP 720 DI 10.1002/bdra.23403 PG 3 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CP2XJ UT WOS:000359740800009 PM 26223007 ER PT J AU Vu, AT Taylor, KM Holman, MR Ding, YS Hearn, B Watson, CH AF Vu, An T. Taylor, Kenneth M. Holman, Matthew R. Ding, Yan S. Hearn, Bryan Watson, Clifford H. TI Polycyclic Aromatic Hydrocarbons in the Mainstream Smoke of Popular US Cigarettes SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID TOTAL PARTICULATE MATTER; TOBACCO-SMOKE; BENZO(A)PYRENE AB The mainstream smoke yields of 14 polycyclic aromatic hydrocarbons (PAHs) were determined for 50 commercial U.S. cigarettes using a validated GC/MS method with the International Organization of Standardization (ISO) and Canadian Intense (CI) smoking machine regimens. PAN mainstream smoke deliveries vary widely among the commercial cigarettes with the ISO smoking regimen primarily because of differing filter ventilation. The more abundant, lower molecular weight PAHs such as naphthalene, fluorene, and phenanthrene predominantly comprise the total PAN yields. In contrast, delivery yields of high molecular weight PAHs such as benzo [b]fluoranthene, benzo[e]pyrene, benzo[k]fluoranthene, and benzo[a]pyrene (BaP) are much lower. Comparative analysis of PAHs deliveries shows brand specific differences. Correlation analysis shows strong positive associations between BaP and most of the other PAHs as well as total PAHs. The results suggest that BaP may be a representative marker for other PAN constituents in cigarette smoke generated from similarly blended tobacco, particularly those PAHs with similar molecular weights and chemical structures. C1 [Vu, An T.; Taylor, Kenneth M.; Holman, Matthew R.] US FDA, Off Sci, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. [Ding, Yan S.; Hearn, Bryan; Watson, Clifford H.] Ctr Dis Control & Prevent, Tobacco & Volatiles Branch, Div Sci Lab, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. RP Taylor, KM (reprint author), US FDA, Off Sci, Ctr Tobacco Prod, 10903 New Hampshire Ave,Bldg 32, Silver Spring, MD 20993 USA. EM Kenneth.Taylor@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Tobacco Products FX This research was funded by the U.S. Food and Drug Administration, Center for Tobacco Products. NR 21 TC 5 Z9 5 U1 5 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X EI 1520-5010 J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD AUG PY 2015 VL 28 IS 8 BP 1616 EP 1626 DI 10.1021/acs.chemrestox.5b00190 PG 11 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA CP4AL UT WOS:000359824300012 PM 26158771 ER PT J AU Laschinger, JC Ibrahim, NG Zuckerman, BD AF Laschinger, John C. Ibrahim, Nicole G. Zuckerman, Bram D. TI Mitral Valve Academic Research Consortium consensus report: the US Food and Drug Administration perspective SO EUROPEAN HEART JOURNAL LA English DT Editorial Material ID TRIAL DESIGN PRINCIPLES; END-POINT DEFINITIONS; DOCUMENT; REPAIR AB This editorial refers to 'Clinical trial design principles and endpoint definitions for transcatheter mitral valve repair and replacement: part 1: clinical trial design principles'(dagger), by G.W. Stone et al., on page 1851 and 'Clinical trial design principles and endpoint definitions for transcatheter mitral valve repair and replacement: part 2: endpoint definitions'(double dagger), by G.W. Stone et al., on page 1878. C1 [Laschinger, John C.] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Struct Heart Device Branch, Silver Spring, MD 20993 USA. RP Laschinger, JC (reprint author), US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Struct Heart Device Branch, 10903 New Hampshire Ave,WO66,Room 1266, Silver Spring, MD 20993 USA. EM John.Laschinger@fda.hhs.gov NR 2 TC 1 Z9 1 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG 1 PY 2015 VL 36 IS 29 BP 1849 EP 1850 DI 10.1093/eurheartj/ehv334 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP1XB UT WOS:000359669800006 PM 26170469 ER PT J AU Wang, YY Li, ZG Chen, T Zhao, XM AF Wang, Yin-Ying Li, Zhiguang Chen, Tao Zhao, Xing-Ming TI Understanding the aristolochic acid toxicities in rat kidneys with regulatory networks SO IET SYSTEMS BIOLOGY LA English DT Article DE kidney; toxicology; genetics; RNA; molecular biophysics; cancer; bioinformatics; aristolochic acid toxicities; rat kidneys; regulatory networks; acne; gastritis; acute renal failures; chronic renal failures; Chinese herbs; gene regulatory network; microRNA-gene regulatory network; molecular dynamics; nephrotoxicity; carcinogenicity ID GENE-EXPRESSION; CANCER; CELLS; PROTEINS; BIOMARKERS; DISEASES; DATABASE; REVEALS; HERBS AB The natural products containing aristolochic acid (AA) have been widely used for acne, gastritis and so on. Recently, it is becoming accepted that AA may be responsible for acute and chronic renal failures as the side effects of Chinese herbs. However, it is unclear what happens in the cells after the AA treatment. In this study, the authors built a gene regulatory network as well as a microRNA-gene regulatory network to investigate the molecular dynamics induced by AA from a systematic perspective. With the regulatory networks, they detected some important pathways and biological processes that were affected by AA treatment, which can help explain the nephrotoxicity and carcinogenicity of AA. They found some important regulators and genes responding to AA treatment, and these genes have been reported to be related to the kidney functions, indicating their important roles in the toxicity of AA. C1 [Wang, Yin-Ying] Shanghai Univ, Inst Syst Biol, Shanghai 200444, Peoples R China. [Wang, Yin-Ying] Shanghai Univ, Sch Commun & Informat Engn, Shanghai 200444, Peoples R China. [Li, Zhiguang] Dalian Med Univ, Ctr Canc, Inst Canc Stem Cell, Dalian 116044, Liaoning, Peoples R China. [Chen, Tao] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Zhao, Xing-Ming] Tongji Univ, Sch Elect & Informat Engn, Dept Comp Sci, Shanghai 201804, Peoples R China. RP Zhao, XM (reprint author), Tongji Univ, Sch Elect & Informat Engn, Dept Comp Sci, Shanghai 201804, Peoples R China. EM xm_zhao@tongji.edu.cn FU Strategic Priority Research Program of the Chinese Academy of Sciences [XDB13040700]; National Nature Science Foundation of China [91130032, 61103075]; Shanghai Municipal Education Commission [13ZZ072]; Shanghai Pujiang Program [13PJD032] FX This work is partly supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB13040700), National Nature Science Foundation of China (91130032, 61103075), Innovation Program of Shanghai Municipal Education Commission (13ZZ072) and Shanghai Pujiang Program (13PJD032). The views presented in this article do not necessarily reflect those of the Food and Drug Administration. NR 42 TC 2 Z9 2 U1 2 U2 6 PU INST ENGINEERING TECHNOLOGY-IET PI HERTFORD PA MICHAEL FARADAY HOUSE SIX HILLS WAY STEVENAGE, HERTFORD SG1 2AY, ENGLAND SN 1751-8849 EI 1751-8857 J9 IET SYST BIOL JI IET Syst. Biol. PD AUG PY 2015 VL 9 IS 4 SI SI BP 141 EP 146 DI 10.1049/iet-syb.2014.0057 PG 6 WC Cell Biology; Mathematical & Computational Biology SC Cell Biology; Mathematical & Computational Biology GA CO9IH UT WOS:000359487900007 PM 26243830 ER PT J AU Shahverdi, AR Mirzaie, S Rafii, F Kakavand, M Foroumadi, A AF Shahverdi, Ahmad R. Mirzaie, Sako Rafii, Fatemeh Kakavand, Marjan Foroumadi, Alireza TI Monoterpenes as nitrofurantoin resistance modulating agents: minimal structural requirements, molecular dynamics simulations, and the effect of piperitone on the emergence of nitrofurantoin resistance in Enterobacteriaceae SO JOURNAL OF MOLECULAR MODELING LA English DT Article DE Molecular dynamics; Monoterpenes; Nitrofurantoin; Resistance modulating activity; Structural activity relationships ID PROTEIN-LIGAND COMPLEXES; ESCHERICHIA-COLI; ANTIMICROBIAL ACTIVITY; STAPHYLOCOCCUS-AUREUS; BACTERIAL-RESISTANCE; INHIBITOR BINDING; NITROREDUCTASE; SUBSTRATE; MUTANTS; CLOACAE AB The effects of different monoterpenes and 2-cyclohexen-1-one on the antibacterial activity of nitrofurantoin against resistant Enterobacter cloacae, were compared and the minimal structural component of monoterpene required for the highest level of resistance-modulating activity was determined. Subinhibitory concentrations of all compounds tested enhanced the antibacterial activity of nitrofurantoin against E. cloacae to different extents. The highest synergistic effect was observed for the monoterpenes, like piperitone, which contained a conjugated ketone and C=C bond in their carbon ring structure. Piperitone also suppressed the emergence of nitrofurantoin-resistant strains of Enterobacteriaceae that were mutagenized by ethyl methanesulfonate. The modes of interaction of carvone, piperitone, and an enzyme inhibitor, benzoate, with nitroreductase were investigated by molecular docking and molecular dynamic (MD) simulation for 20 ns. MD simulation supported greater stability of the benzoate and monoterpene-nitroreductase (NR) complexes than of free NR. The results of this investigation are promising for the synthesis of more effective lead compounds to enhance the antibacterial activity of nitro drugs against resistant Enterobacter strains. C1 [Shahverdi, Ahmad R.; Kakavand, Marjan] Univ Tehran Med Sci, Fac Pharm, Dept Pharmaceut Biotechnol, Tehran 1417614411, Iran. [Shahverdi, Ahmad R.; Kakavand, Marjan] Univ Tehran Med Sci, Biotechnol Res Ctr, Dept Pharmaceut Biotechnol, Tehran 1417614411, Iran. [Mirzaie, Sako] Islamic Azad Univ, Sanandaj Branch, Dept Biochem, Sanandaj, Iran. [Rafii, Fatemeh] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. [Foroumadi, Alireza] Univ Tehran Med Sci, Drug Design & Dev Res Ctr, Fac Pharm, Tehran 1417614411, Iran. RP Mirzaie, S (reprint author), Islamic Azad Univ, Sanandaj Branch, Dept Biochem, Sanandaj, Iran. EM shahverd@sina.tums.ac.ir; sako.biochem@gmail.com OI mirzaie, sako/0000-0003-4080-9210 FU Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran [10320] FX This work was supported by a grant (No. 10320) by Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran. The authors are grateful to the School of Computer Science, Institute for Research in Fundamental Science (IPM), Tehran, Iran, for professional technical assistance. The views presented in this manuscript do not necessarily reflect those of the U.S. Food and Drug Administration. In addition, no conflict of interest is declared. NR 40 TC 1 Z9 1 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1610-2940 EI 0948-5023 J9 J MOL MODEL JI J. Mol. Model. PD AUG PY 2015 VL 21 IS 8 AR 198 DI 10.1007/s00894-015-2741-y PG 12 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Multidisciplinary; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Chemistry; Computer Science GA CP0BB UT WOS:000359539700022 PM 26174760 ER PT J AU Ghods, MP Schmid, IT Pamer, CA Lappin, BM Slavin, DC AF Ghods, Mary P. Schmid, Ian T. Pamer, Carol A. Lappin, Brian M. Slavin, Dale C. TI Developing and Initiating Validation of a Model Opioid Patient-Prescriber Agreement as a Tool for Patient-Centered Pain Treatment SO PATIENT-PATIENT CENTERED OUTCOMES RESEARCH LA English DT Article ID CHRONIC NONCANCER PAIN; MANAGEMENT; CONTRACTS; GUIDELINES; PHYSICIANS; THERAPY AB Opioid treatment agreements generally are used in pain treatment to delineate the terms and consequences of opioid use and abuse. The US Food and Drug Administration (FDA) Safe Use Initiative convened a multi-disciplinary working group with outside experts to draft a patient-centered, model opioid treatment agreement named the Model Patient-Prescriber Agreement (model PPA). The model PPA was evaluated for readability and usability in two tests that sampled both healthcare professional and non-healthcare professional FDA employees. In a survey sent to FDA employees in the Center for Drug Evaluation and Research (CDER), 209 respondents assessed the quality of the content and the level of difficulty in reading and understanding the model PPA. Ten other FDA employees participated in usability testing to assess the effectiveness of the model PPA as an educational and decision-making tool. The majority of the 209 CDER employee survey respondents indicated the model PPA was neutral in tone (67.5 %) and easy or somewhat easy to understand (90.4 %). Usability study participants generally thought the model PPA would facilitate discussion between patient and prescriber and that the content was informative, thorough, and clear. These studies suggest that the working group was able to develop an opioid PPA that may be acceptable and usable among a diverse population of stakeholders. A follow-up pilot study using the model PPA in medical facilities in the USA with patients is underway and will facilitate this determination. C1 [Ghods, Mary P.; Schmid, Ian T.; Pamer, Carol A.; Slavin, Dale C.] US FDA, Ctr Drug Evaluat & Res Safe Use Initiat, Silver Spring, MD 20993 USA. [Lappin, Brian M.] US FDA, Silver Spring, MD 20993 USA. RP Ghods, MP (reprint author), US FDA, Ctr Drug Evaluat & Res Safe Use Initiat, Silver Spring, MD 20993 USA. EM mary.ghods@fda.hhs.gov NR 24 TC 2 Z9 2 U1 1 U2 2 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 1178-1653 EI 1178-1661 J9 PATIENT JI Patient PD AUG PY 2015 VL 8 IS 4 BP 349 EP 358 DI 10.1007/s40271-014-0094-8 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CO7ZR UT WOS:000359384000007 PM 25344927 ER PT J AU Rouse, R AF Rouse, Rodney TI Regulatory Forum Opinion Piece*: Blinding and Binning in Histopathology Methods in the Biomarker Qualification Process SO TOXICOLOGIC PATHOLOGY LA English DT Article DE biomarker assessment; biomarker qualification; histopathology methods; blinded evaluations; knowledge bias; data binning or filtering AB Both, the Society of Toxicologic Pathology (STP) and the U.S. Food and Drug Administration (FDA) have released documents discussing histopathology methods in biomarker qualification studies. These documents appear to disagree on two critical and controversial aspects of methodology; blinding of pathologists and binning of data (Burkhardt et al. 2011; U.S. FDA 2011). Upon closer examination, however, both documents propose that blinded evaluation of biomarker studies is appropriate under similar strict criteria. However, they differ in their recommendations on the binning of data (i.e., individual binning of all changes vs. common binning of changes observed in control animals), seemingly based on different perceptions of study objectives and the role of the pathologist. This article offers a personal opinion on blinded evaluations and data binning in the context of biomarker qualification studies. C1 [Rouse, Rodney] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Div Appl Regulatory Sci,Off Translat Sci, Silver Spring, MD 20993 USA. RP Rouse, R (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Sci, Off Testing & Res,Div Drug Safety Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM rodney.rouse@fda.hhs.gov NR 5 TC 0 Z9 0 U1 0 U2 1 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 AUG PY 2015 VL 43 IS 6 BP 757 EP 759 DI 10.1177/0192623315574780 PG 3 WC Pathology; Toxicology SC Pathology; Toxicology GA CO3WI UT WOS:000359091500001 PM 25755101 ER PT J AU Wood, CE Hukkanen, RR Sura, R Jacobson-Kram, D Nolte, T Odin, M Cohen, SM AF Wood, Charles E. Hukkanen, Renee R. Sura, Radhakrishna Jacobson-Kram, David Nolte, Thomas Odin, Marielle Cohen, Samuel M. TI Scientific and Regulatory Policy Committee (SRPC) Review*: Interpretation and Use of Cell Proliferation Data in Cancer Risk Assessment SO TOXICOLOGIC PATHOLOGY LA English DT Article DE cell proliferation; carcinogenesis; mode of action; Ki-67; BrdU; PCNA ID PARAFFIN-EMBEDDED TISSUE; HUMAN RELEVANCE ANALYSIS; ANDROSTANE RECEPTOR CAR; FORMALIN-FIXED TISSUE; MOUSE LUNG-TUMORS; NUCLEAR ANTIGEN; BREAST-CANCER; MONOCLONAL-ANTIBODY; DNA-REPLICATION; F344 RATS AB Increased cell proliferation is a central key event in the mode of action for many non-genotoxic carcinogens, and quantitative cell proliferation data play an important role in the cancer risk assessment of many pharmaceutical and environmental compounds. Currently, there is limited unified information on assay standards, reference values, targeted applications, study design issues, and quality control considerations for proliferation data. Here, we review issues in measuring cell proliferation indices, considerations for targeted studies, and applications within current risk assessment frameworks. As the regulatory environment moves toward more prospective evaluations based on quantitative pathway-based models, standardization of proliferation assays will become an increasingly important part of cancer risk assessment. To help address this development, we also discuss the potential role for proliferation data as a component of alternative carcinogenicity testing models. This information should improve consistency of cell proliferation methods and increase efficiency of targeted testing strategies. C1 [Wood, Charles E.] US EPA, Res Triangle Pk, NC 27709 USA. [Hukkanen, Renee R.; Sura, Radhakrishna] Dow Chem Co USA, Midland, MI 48674 USA. [Jacobson-Kram, David] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Nolte, Thomas] Boehringer Ingelheim Pharma GmbH & Co KG, KG Dev, Biberach An Der Riss, Germany. [Odin, Marielle] Roche Diagnost GmbH, PLBT, Penzberg, Germany. [Cohen, Samuel M.] Univ Nebraska Med Ctr, Omaha, NE USA. RP Wood, CE (reprint author), US EPA, Mail Code B105-03,109 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM wood.charles@epa.gov NR 128 TC 6 Z9 6 U1 2 U2 8 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 AUG PY 2015 VL 43 IS 6 BP 760 EP 775 DI 10.1177/0192623315576005 PG 16 WC Pathology; Toxicology SC Pathology; Toxicology GA CO3WI UT WOS:000359091500002 PM 25903269 ER PT J AU Jensen, V Throckmorton, DC AF Jensen, Valerie Throckmorton, Douglas C. TI Shortage of Peritoneal Dialysis Solution and the Food and Drug Administration's Response SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article AB Although the number of new drug shortages has been lower in recent years than in the past, severe shortages have occurred that have affected large numbers of patients. A new law entitled the Food and Drug Administration Safety and Innovation Act was enacted in July of 2012, which requires companies to notify the Food and Drug Administration of anticipated shortages. This notification requirement has allowed the Food and Drug Administration to work closely with manufacturers earlier to mitigate and, often, prevent shortages. However, not all shortages are able to be prevented, and the shortage of peritoneal dialysis solution is one that has had a significant effect on patients. The Food and Drug Administration continues to use all available tools to address this shortage with manufacturers, including temporary availability of imported peritoneal dialysis solution from Ireland. Mitigating shortages is a top priority for the Food and Drug Administration, and communication with all stakeholders is essential. C1 [Jensen, Valerie; Throckmorton, Douglas C.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Jensen, V (reprint author), Room 6204,Bldg 22,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Valerie.Jensen@fda.hhs.gov NR 3 TC 1 Z9 1 U1 1 U2 6 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD AUG PY 2015 VL 10 IS 8 BP 1484 EP 1486 DI 10.2215/CJN.12061214 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA CO5AU UT WOS:000359172800024 PM 25896999 ER PT J AU Drawz, PE Archdeacon, P McDonald, CJ Powe, NR Smith, KA Norton, J Williams, DE Patel, UD Narva, A AF Drawz, Paul E. Archdeacon, Patrick McDonald, Clement J. Powe, Neil R. Smith, Kimberly A. Norton, Jenna Williams, Desmond E. Patel, Uptal D. Narva, Andrew TI CKD as a Model for Improving Chronic Disease Care through Electronic Health Records SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; INCIDENT HEMODIALYSIS-PATIENTS; INFORMATION-TECHNOLOGY; CONTROLLED-TRIAL; AMBULATORY-CARE; CLINICAL-TRIALS; CHRONIC ILLNESS; BLOOD-PRESSURE; UNITED-STATES; MORTALITY AB Electronic health records have the potential to improve the care of patients with chronic medical conditions. CKD provides a unique opportunity to show this potential: the disease is common in the United States, there is significant room to improve CKD detection and management, CKD and its related conditions are defined primarily by objective laboratory data, CKD care requires collaboration by a diverse team of health care professionals, and improved access to CKD-related data would enable identification of a group of patients at high risk for multiple adverse outcomes. However, to realize the potential for improvement in CKD-related care, electronic health records will need to provide optimal functionality for providers and patients and interoperability across multiple health care settings. The goal of the National Kidney Disease Education Program Health Information Technology Working Group is to enable and support the widespread interoperability of data related to kidney health among health care software applications to optimize CKD detection and management. Over the course of the last 2 years, group members met to identify general strategies for using electronic health records to improve care for patients with CKD. This paper discusses these strategies and provides general goals for appropriate incorporation of CKD-related data into electronic health records and corresponding design features that may facilitate (1) optimal care of individual patients with CKD through improved access to clinical information and decision support, (2) clinical quality improvement through enhanced population management capabilities, (3) CKD surveillance to improve public health through wider availability of population-level CKD data, and (4) research to improve CKD management practices through efficiencies in study recruitment and data collection. Although these strategies may be most effectively applied in the setting of CKD, because it is primarily defined by laboratory abnormalities and therefore, an ideal computable electronic health record phenotype, they may also apply to other chronic diseases. C1 [Drawz, Paul E.] Univ Minnesota, Div Renal Dis & Hypertens, Minneapolis, MN USA. [Archdeacon, Patrick] US FDA, Off Med Policy, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [McDonald, Clement J.] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD USA. [Powe, Neil R.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Smith, Kimberly A.] Ctr Medicare & Medicaid Serv, Ctr Clin Stand & Qual, Baltimore, MD USA. [Norton, Jenna; Narva, Andrew] NIDDK, Natl Kidney Dis Educ Program, Bethesda, MD 20892 USA. [Williams, Desmond E.] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Patel, Uptal D.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. RP Narva, A (reprint author), NIDDK, Natl Kidney Dis Educ Program, NIH, Bldg 31,Room 9A27 MSC 2560,31 Ctr Dr, Bethesda, MD 20892 USA. EM narvaa@niddk.nih.gov FU National Institutes of Health (NIH) [R01-DK093938, R34-DK102166]; NKDEP HIT Intern FX U.D.P. was supported by National Institutes of Health (NIH) Grants R01-DK093938 and R34-DK102166.; Thanks for support from the NKDEP HIT Intern, Jessica Pereira. NR 56 TC 1 Z9 1 U1 1 U2 7 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD AUG PY 2015 VL 10 IS 8 BP 1488 EP 1499 DI 10.2215/CJN.00940115 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA CO5AU UT WOS:000359172800025 PM 26111857 ER PT J AU Kim, DH Chon, JW Kim, H Seo, KH AF Kim, Dong-Hyeon Chon, Jung-Whan Kim, Hyunsook Seo, Kun-Ho TI Modulation of intestinal microbiota in mice by kefir administration SO FOOD SCIENCE AND BIOTECHNOLOGY LA English DT Article DE kefir; probiotic; improvement; intestinal microbiota; qPCR ID REAL-TIME PCR; LACTIC-ACID BACTERIA; GUT MICROBIOTA; ENUMERATION; POULTRY; DISEASE; FECES; LACTOBACILLUS; COLONIZATION; COMMUNITIES AB Kefir is a multi-species probiotic consisting of lactic and acetic acid bacteria and yeast. The modulatory effects of kefir on gut microfloral profiles of mice were investigated using group-specific quantitative real-time polymerase chain reaction. At the end of 3 week oral kefir administration period, the numbers of Firmicutes, Proteobacteria, and Enterobacteriaceae were significantly (p < 0.05) decreased, and the numbers of Bacteroidetes, Lactobacillus, and Lactococcus, and total yeast were significantly (p < 0.05) increased in the kefir group, compared with the control group. Kefir consumption significantly (p < 0.05) suppressed proliferation of the opportunistic pathogen Enterobacteriaceae, compared with saline administration, with an increased proportion of Lactobacillus and Lactococcus to total bacteria, suggesting lactobacilli-Enterobacteriaceae antagonism. Kefir consumption significantly (p < 0.05) reduced the Firmicutes/Bacteroidetes (F/B) ratio, compared with controls, suggesting oral administration of kefir could be beneficial in the treatment of obesity. C1 [Kim, Dong-Hyeon; Kim, Hyunsook; Seo, Kun-Ho] Konkuk Univ, Coll Vet Med, KU Ctr Food Safety, Seoul 143701, South Korea. [Chon, Jung-Whan] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Seo, Kun-Ho] Konkuk Univ, Sensorgen Inc, Seoul 143701, South Korea. RP Seo, KH (reprint author), Konkuk Univ, Coll Vet Med, KU Ctr Food Safety, Seoul 143701, South Korea. EM bracstu3@konkuk.ac.kr FU High Value-added Food Technology Development Program of iPET - Ministry of Agriculture, Food and Rural Affairs [114110-1] FX This research was supported by the High Value-added Food Technology Development Program of iPET (No. 114110-1) funded by the Ministry of Agriculture, Food and Rural Affairs. NR 35 TC 1 Z9 1 U1 7 U2 27 PU KOREAN SOCIETY FOOD SCIENCE & TECHNOLOGY-KOSFOST PI SEOUL PA #605, KOREA SCI TECHNOL CENT, 635-4 YEOKSAM-DONG, KANGNAM-GU, SEOUL, 135-703, SOUTH KOREA SN 1226-7708 EI 2092-6456 J9 FOOD SCI BIOTECHNOL JI Food Sci. Biotechnol. PD AUG PY 2015 VL 24 IS 4 BP 1397 EP 1403 DI 10.1007/s10068-015-0179-8 PG 7 WC Food Science & Technology SC Food Science & Technology GA CN9WO UT WOS:000358801400028 ER PT J AU Ma, YQ Klontz, KC DiNovi, MJ Edwards, AJ Hennes, RF AF Ma, Yinqing Klontz, Karl C. DiNovi, Michael J. Edwards, Alison J. Hennes, Robert F. TI Evaluation of the Level of Food Safety Protection Provided by the US Grade "A" Pasteurized Milk Ordinance and Its Associated Cooperative Grade "A" Milk Safety Program SO JOURNAL OF FOOD PROTECTION LA English DT Article ID UNITED-STATES; OUTBREAK AB The present study was conducted to evaluate the level of food safety protection provided to consumers of Grade "A" milk and milk products in the United States by the National Conference on Interstate Milk Shipments (NCIMS) Grade "A" Milk Safety Program through its implementation and enforcement of the U.S. Grade "A" Pasteurized Milk Ordinance (PMO). The number of reported illnesses associated with Grade "A" milk and milk products in the United States was obtained from state and federal agencies and published articles. The consumption of Grade "A" milk and milk products in the United States was estimated from food consumption survey data for individuals. The level of food safety protection was measured quantitatively using the metric of annual illness attack rate. During a 15-year period (1999 through 2013), the estimated annual illness attack rate was 0.41 reported illnesses per 1 billion exposures (estimated using person-day intake data) or 0.52 reported illnesses per 1 billion lb (454 million kg) of Grade "A" milk and milk products consumed. Food safety protection provided to consumers of Grade "A" milk and milk products by the NCIMS through its implementation and enforcement of the PMO is important given the common consumption of Grade "A" milk and milk products in the United States. C1 [Ma, Yinqing; Klontz, Karl C.; DiNovi, Michael J.; Edwards, Alison J.; Hennes, Robert F.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Ma, YQ (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM yinqing.ma@fda.hhs.gov NR 24 TC 1 Z9 1 U1 1 U2 7 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD AUG PY 2015 VL 78 IS 8 BP 1428 EP 1433 DI 10.4315/0362-028X.JFP-15-078 PG 6 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CO3CQ UT WOS:000359034600001 PM 26219354 ER PT J AU Skinner, GE Fleischman, GJ Balster, F Reineke, K Reddy, NR Larkin, JW AF Skinner, Guy E. Fleischman, Gregory J. Balster, Fran Reineke, Karl Reddy, N. Rukma Larkin, John W. TI Effect of Fill Temperature on Clostridium botulinum Type A Toxin Activity during the Hot Filling of Juice Bottles SO JOURNAL OF FOOD PROTECTION LA English DT Article ID MOUSE BIOASSAY; INACTIVATION; BEEF; FOOD AB The potential threat of terrorist attacks against the United States food supply using neurotoxin produced by Clostridium botulinum (BoNT) has resulted in the need for studying the effect of various food process operations on the bioavailability of this toxin. The objective of this study was to evaluate C. botulinum type A neurotoxin bioavailability after a simulated hot fill juice bottling operation. C. botulinum type A acid mud toxin (similar to 10(6) mouse lethal dose [MLD50]/ml) was deposited into juice bottles at an experimentally determined fastest cooling spot. Bottles (12 or 20 oz [355 and 592 ml.]) were filled with either apple juice or an orange drink, at 80 or 85 C, in either upright or inverted orientations. Toxicity of the juice was evaluated as a function of holding time (1 to 2 min) by the mouse bioassay. The fastest cooling point in the upright orientation was determined to be at a bottle's bottom rim. In the inverted orientation, the fastest cooling point was in the bottle cap region. With respect to these two points, the upright bottle cooled faster than the inverted bottle, which was reflected in a higher inactivation of BoNT in the latter. For the orange drink (pH 2.9) toxicity was reduced by 0.5 x 10(6) MILD50/ml to a nondetectable level after 1 min in all bottle sizes, orientations, and temperatures as measured by the mouse bioassay. This indicates that there was at least a 0.5 x 10(6) MLD50/ml reduction in activity. Inactivation in apple juice (pH 4.0), to the same degree as in the orange drink, was found only for the inverted orientation at 85 C. Complete inactivation in apple juice for all conditions was found at a lower added toxin level of 0.25 x 10(5) MLD50/ml. In general, bottle inversion and filling at 85 C provided complete inactivation of BoNT to the 0.5 x 10(6) MLD50/ml level. All experiments resulted in the inactivation of 2.5 x 10(4) MLD50/ml of BoNT regardless of juice type, fill temperature, or bottle orientation and size. C1 [Skinner, Guy E.; Fleischman, Gregory J.; Reineke, Karl; Reddy, N. Rukma; Larkin, John W.] US FDA, Bedford Pk, IL 60501 USA. [Skinner, Guy E.; Fleischman, Gregory J.; Balster, Fran; Reineke, Karl; Reddy, N. Rukma; Larkin, John W.] IFSH, Bedford Pk, IL 60501 USA. [Balster, Fran] IIT, Bedford Pk, IL 60501 USA. RP Skinner, GE (reprint author), US FDA, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM guy.skinner@fda.hhs.gov NR 18 TC 0 Z9 0 U1 1 U2 7 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD AUG PY 2015 VL 78 IS 8 BP 1506 EP 1511 DI 10.4315/0362-028X.JFP-14-378 PG 6 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CO3CQ UT WOS:000359034600011 PM 26219364 ER PT J AU Kinsey, TP Lydon, KA Bowers, JC Jones, JL AF Kinsey, Thomas P. Lydon, Keri A. Bowers, John C. Jones, Jessica L. TI Effects of Dry Storage and Resubmersion of Oysters on Total Vibrio vulnificus and Total and Pathogenic (tdh plus /trh plus ) Vibrio parahaemolyticus Levels SO JOURNAL OF FOOD PROTECTION LA English DT Article ID UNITED-STATES; SHELLSTOCK OYSTERS; CRASSOSTREA-VIRGINICA; SURVIVAL; TIME; EPIDEMIOLOGY; PURIFICATION; TEMPERATURE; MERCENARIA; HEMOLYSIN AB Vibrio vulnificus (Vv) and Vibrio parahaemolyticus (Vp) are the two leading causes of bacterial illnesses associated with raw shellfish consumption. Levels of these pathogens in oysters can increase during routine antifouling aquaculture practices involving dry storage in ambient air conditions. After storage, common practice is to resubmerge these stored oysters to reduce elevated Vv and Vp levels, but evidence proving the effectiveness of this practice is lacking. This study examined the changes in Vv and in total and pathogenic (thermostable direct hemolysin gene and the tdh-related hemolysin gene, tdh+ and trh+) Vp levels in oysters after 5 or 24 h of dry storage (28 to 32 degrees C), followed by resubmersion (27 to 32 degrees C) for 14 days. For each trial, replicate oyster samples were collected at initial harvest, after dry storage, after 7 days, and after 14 days of resubmersion. Oysters not subjected to dry storage were collected and analyzed to determine natural undisturbed vibrio levels (background control). Vibrio levels were measured using a most-probable-number enrichment followed by real-time PCR. After storage, vibrio levels (excluding tdh+ and trh+ Vp during 5-h storage) increased significantly (P < 0.001) from initial levels. After 7 days of resubmersion, Vv and total Vp levels (excluding total Vp in oysters stored for 5 h) were not significantly different (P > 0.1) from levels in background oysters. Vv and total and pathogenic Vp levels were not significantly different (P > 0.1) from levels in background oysters after 14 days of resubmersion, regardless of dry storage time. These data demonstrate that oyster resubmersion after dry storage at elevated ambient temperatures allows vibrio levels to return to those of background control samples. These results can be used to help minimize the risk of Vv and Vp illnesses and to inform the oyster industry on the effectiveness of routine storing and resubmerging of aquaculture oysters. C1 [Kinsey, Thomas P.] Interstate Shellfish Sanitat Conf, Columbia, SC 29223 USA. [Kinsey, Thomas P.; Lydon, Keri A.; Jones, Jessica L.] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. [Bowers, John C.] US FDA, Biostat & Bioinformat Staff, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Jones, JL (reprint author), US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. EM Jessica.Jones@fda.hhs.gov FU Interstate Shellfish Sanitation Conference FX Special thanks to George Doup for collecting oysters for this project and for making the biological media throughout. Thanks to the Interstate Shellfish Sanitation Conference for financial support of this project. NR 38 TC 1 Z9 1 U1 3 U2 8 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD AUG PY 2015 VL 78 IS 8 BP 1574 EP 1580 DI 10.4315/0362-028X.JFP-15-017 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CO3CQ UT WOS:000359034600020 PM 26219373 ER PT J AU Parunov, LA Surov, SS Tucker, E Ovanesov, MV AF Parunov, L. A. Surov, S. S. Tucker, E. Ovanesov, M. V. TI The effect of corn trypsin inhibitor and inhibiting antibodies for FXIa and FXIIa on coagulation of plasma and whole blood: comment SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Letter ID FACTOR-XIA; THROMBIN GENERATION; ACTIVATION C1 [Parunov, L. A.; Surov, S. S.; Ovanesov, M. V.] US FDA, Off Blood Res & Review, CBER, Silver Spring, MD 20993 USA. [Tucker, E.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Ovanesov, MV (reprint author), US FDA, 10903 New Hampshire Ave,White Oak Bldg 52-72, Silver Spring, MD 20993 USA. EM mikhail.ovanesov@fda.hhs.gov NR 16 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD AUG PY 2015 VL 13 IS 8 BP 1527 EP 1530 DI 10.1111/jth.13028 PG 4 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CN8LC UT WOS:000358690900025 PM 26094623 ER PT J AU Liu, YX Hilakivi-Clarke, L Zhang, YK Wang, X Pan, YX Xuan, JH Fleck, SC Doerge, DR Helferich, WG AF Liu, Yunxian Hilakivi-Clarke, Leena Zhang, Yukun Wang, Xiao Pan, Yuan-Xiang Xuan, Jianhua Fleck, Stefanie C. Doerge, Daniel R. Helferich, William G. TI Isoflavones in soy flour diet have different effects on whole-genome expression patterns than purified isoflavone mix in human MCF-7 breast tumors in ovariectomized athymic nude mice SO MOLECULAR NUTRITION & FOOD RESEARCH LA English DT Article DE Breast cancer; Isoflavones; MCF-7; Soy; Whole-genome expression ID ESTROGEN-RECEPTOR-ALPHA; CELLS IN-VITRO; CANCER CELLS; GENE-EXPRESSION; DATA SETS; GROWTH; RISK; KEY; MICRONUTRIENTS; TUMORIGENESIS AB ScopeSoy flour diet (MS) prevented isoflavones from stimulating MCF-7 tumor growth in athymic nude mice, indicating that other bioactive compounds in soy can negate the estrogenic properties of isoflavones. The underlying signal transduction pathways to explain the protective effects of soy flour consumption were studied here. Methods and resultsOvariectomized athymic nude mice inoculated with MCF-7 human breast cancer cells were fed either Soy flour diet (MS) or purified isoflavone mix diet (MI), both with equivalent amounts of genistein. Positive controls received estradiol pellets and negative controls received sham pellets. GeneChip Human Genome U133 Plus 2.0 Array platform was used to evaluate gene expressions, and results were analyzed using bioinformatics approaches. Tumors in MS-fed mice exhibited higher expression of tumor growth suppressing genes ATP2A3 and BLNK and lower expression of oncogene MYC. Tumors in MI-fed mice expressed a higher level of oncogene MYB and a lower level of MHC-I and MHC-II, allowing tumor cells to escape immunosurveillance. MS-induced gene expression alterations were predictive of prolonged survival among estrogen-receptor-positive breast cancer patients, whilst MI-induced gene changes were predictive of shortened survival. ConclusionOur findings suggest that dietary soy flour affects gene expression differently than purified isoflavones, which may explain why soy foods prevent isoflavones-induced stimulation of MCF-7 tumor growth in athymic nude mice. C1 [Liu, Yunxian; Zhang, Yukun; Pan, Yuan-Xiang; Helferich, William G.] Univ Illinois, Dept Food Sci & Human Nutr, Urbana, IL 61801 USA. [Hilakivi-Clarke, Leena] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Wang, Xiao; Xuan, Jianhua] Virginia Polytech Inst & State Univ, Bradley Dept Elect & Comp Engn, Arlington, VA USA. [Fleck, Stefanie C.; Doerge, Daniel R.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Helferich, WG (reprint author), Univ Illinois, Dept Food Sci & Human Nutr, Urbana, IL 61801 USA. EM helferic@illinois.edu FU NIH from the National Center for Complementary and Alternative Medicines (NCCAM) [P50AT006268]; Office of Dietary Supplements (ODS); National Cancer Institute (NCI) FX This work was supported by the NIH [P50AT006268] (WGH) from the National Center for Complementary and Alternative Medicines (NCCAM), the Office of Dietary Supplements (ODS), and the National Cancer Institute (NCI). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM, ODS, NCI, or the National Institutes of Health. The views expressed in this paper do not necessarily reflect those of the U.S. Food and Drug Administration (FDA). NR 59 TC 3 Z9 3 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1613-4125 EI 1613-4133 J9 MOL NUTR FOOD RES JI Mol. Nutr. Food Res. PD AUG PY 2015 VL 59 IS 8 BP 1419 EP 1430 DI 10.1002/mnfr.201500028 PG 12 WC Food Science & Technology SC Food Science & Technology GA CO3KS UT WOS:000359056700001 PM 25820259 ER PT J AU McMahon, AW Wharton, GT Bonnel, R DeCelle, M Swank, K Testoni, D Cope, JU Smith, PB Wu, E Murphy, MD AF McMahon, Ann W. Wharton, Gerold T. Bonnel, Renan DeCelle, Mary Swank, Kimberley Testoni, Daniela Cope, Judith U. Smith, Phillip Brian Wu, Eileen Murphy, Mary Dianne TI Pediatric post-marketing safety systems in North America: assessment of the current status SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Review DE FDA; Pediatrix; adverse events; drug safety; active surveillance; octreotide; infliximab; etanercept; adalimumab; meropenem; imipenem; cilastatin; electronic medical record; passive surveillance; retrospective chart review; pharmacoepidemiology ID ADVERSE EVENT DETECTION; CHILDRENS HOSPITALS; DRUG-DEVELOPMENT; VACCINE SAFETY; SURVEILLANCE AB PurposeIt is critical to have pediatric post-marketing safety systems that contain enough clinical and epidemiological detail to draw regulatory, public health, and clinical conclusions. The pediatric safety surveillance workshop (PSSW), coordinated by the Food and Drug Administration (FDA), identified these pediatric systems as of 2010. This manuscript aims to update the information from the PSSW and look critically at the systems currently in use. MethodsWe reviewed North American pediatric post-marketing safety systems such as databases, networks, and research consortiums found in peer-reviewed journals and other online sources. We detail clinical examples from three systems that FDA used to assess pediatric medical product safety. ResultsOf the 59 systems reviewed for pediatric content, only nine were pediatric-focused and met the inclusion criteria. Brief descriptions are provided for these nine. The strengths and weaknesses of three systems (two of the nine pediatric-focused and one including both children and adults) are illustrated with clinical examples. ConclusionsSystems reviewed in this manuscript have strengths such as clinical detail, a large enough sample size to capture rare adverse events, and/or a patient denominator internal to the database. Few systems include all of these attributes. Pediatric drug safety would be better informed by utilizing multiple systems to take advantage of their individual characteristics. C1 [McMahon, Ann W.; Wharton, Gerold T.; Bonnel, Renan; DeCelle, Mary; Cope, Judith U.; Murphy, Mary Dianne] US FDA, Off Pediat Therapeut, Off Commissioner, Silver Spring, MD 20993 USA. [Swank, Kimberley; Wu, Eileen] US FDA, Off Pharmacovigilance & Epidemiol, Silver Spring, MD 20993 USA. [Testoni, Daniela; Smith, Phillip Brian] Duke Sch Med, Duke Clin Res Inst, Durham, NC USA. RP McMahon, AW (reprint author), US FDA, Off Pediat Therapeut, Off Commissioner, 10903 New Hampshire Ave,Bldg 32,Room 5158, Silver Spring, MD 20993 USA. EM ann.mcmahon@fda.hhs.gov NR 25 TC 2 Z9 2 U1 0 U2 1 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 AUG PY 2015 VL 24 IS 8 BP 785 EP 792 DI 10.1002/pds.3813 PG 8 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA CO3NI UT WOS:000359064400001 PM 26098297 ER PT J AU Guha, S Mejia-Alfaro, A Hariharan, P Myers, MR AF Guha, Suvajyoti Mejia-Alfaro, Andres Hariharan, Prasanna Myers, Matthew R. TI Effectiveness of facemasks for pediatric populations against submicron-sized aerosols SO AMERICAN JOURNAL OF INFECTION CONTROL LA English DT Article DE Surgical masks; Respirators; Bioterror; Pandemics; N95 ID FILTERING-FACEPIECE RESPIRATORS; FILTRATION PERFORMANCE; N95 RESPIRATORS; SURGICAL MASKS; PARTICLE-SIZE; INFLUENZA; VIRUS; PROTECTION AB Background: In the event of a public-health threat involving bioaerosols, such as a terrorist attack or pandemic, options for devices to protect the pediatric population are limited. One strategy involves deployment of facemasks meant for the pediatric population, although protection against bioaerosols was not an intended use of such masks and little is known about their effectiveness. Methods: We chose 3 brands of facemasks for pediatric use for characterizing penetration. To validate our experimental technique, 2 N95 respirator brands were also tested. All barriers were subjected to neutralized polydispersed sodium chloride aerosols, and their intrinsic penetration was evaluated in the submicron size range at different flow rates. Results: As expected, the N95 brands had low penetration (5% or less) at the highest flow rates. However, for the facemasks for pediatric use, penetration varied significantly amongst brands at the highest flow rates (similar to 15%->50%). Studies with isopropanol-dipped respirators and facemasks demonstrated that not all brands of facemasks for pediatric use have electret layers. Conclusions: Our bench tests suggest that the intrinsic penetration through facemasks for pediatric use can be high in the submicron size range. These data can be used in risk-assessment models to determine the extent to which facemasks for pediatric use reduce the likelihood of infection in emergency situations. Copyright (C) 2015 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved. C1 [Guha, Suvajyoti; Mejia-Alfaro, Andres; Hariharan, Prasanna; Myers, Matthew R.] US FDA, Div Appl Mech, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20933 USA. RP Guha, S (reprint author), US FDA, Div Appl Mech, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,WO62,Room 2233, Silver Spring, MD 20933 USA. EM Suvajyoti.Guha@fda.hhs.gov FU Office of Counterterrorism and Emerging Threats of the US Food and Drug Administration, Silver Spring, Md [MCM2DXXXXX205, MCM2JXXXXX270HT] FX This study was funded by 2 Medical Countermeasures Initiative projects (MCM2DXXXXX205 and MCM2JXXXXX270HT) from the Office of Counterterrorism and Emerging Threats of the US Food and Drug Administration, Silver Spring, Md. Dr. Guha is a research participant in the Food and Drug Administration via Oak Ridge Associated Universities. The contents of this article do not necessarily represent policy of the US Food and Drug Administration or the Department of Health and Human Services. NR 36 TC 1 Z9 1 U1 1 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-6553 EI 1527-3296 J9 AM J INFECT CONTROL JI Am. J. Infect. Control PD AUG 1 PY 2015 VL 43 IS 8 BP 871 EP 877 DI 10.1016/j.ajic.2015.03.032 PG 7 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA CN9WY UT WOS:000358802400020 PM 26022658 ER PT J AU Martin, PJ Lee, SJ Przepiorka, D Horowitz, MM Koreth, J Vogelsang, GB Walker, I Carpenter, PA Griffith, LM Akpek, G Mohty, M Wolff, D Pavletic, SZ Cutler, CS AF Martin, Paul J. Lee, Stephanie J. Przepiorka, Donna Horowitz, Mary M. Koreth, John Vogelsang, Georgia B. Walker, Irwin Carpenter, Paul A. Griffith, Linda M. Akpek, Gorgun Mohty, Mohamad Wolff, Daniel Pavletic, Steven Z. Cutler, Corey S. TI National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: VI. The 2014 Clinical Trial Design Working Group Report SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host disease; Allogeneic hematopoietic cell transplantation; Clinical trials; Design; Consensus; Guidelines ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; MEASURING THERAPEUTIC RESPONSE; REFRACTORY CHRONIC GVHD; FAILURE-FREE SURVIVAL; ACTIVITY INDEX; EXTRACORPOREAL PHOTOPHERESIS; MARROW-TRANSPLANTATION; PRELIMINARY DEFINITION; RHEUMATOID-ARTHRITIS; AMERICAN-COLLEGE AB Treatment of chronic graft-versus-host disease is intended to produce a sustainable benefit by reducing symptom burden, controlling objective manifestations of disease activity, preventing damage and impairment, and improving overall survival without causing disproportionate harms related to the treatment itself. Successful management can control the disease until systemic treatment is no longer needed. The complexity of the disease, the extended duration of follow-up needed to observe disease resolution and withdrawal of immunosuppressive treatment, and the lack of fully developed shorter term endpoints impede progress in the field. Identification and characterization of primary endpoints demonstrating clinical benefit without requiring years of follow-up is urgently needed, with the understanding that clinical benefit encompasses not only the self-evident benefit of the primary endpoint but also any other associated benefits. This report discusses regulatory considerations, eligibility criteria, the value of controlled trial designs, the merits of proposed primary endpoints, and key considerations elaborated from experience and progress during the past decade. The report concludes by mapping an overall approach that could support and lead to maximally informative clinical trials, especially those that seek to demonstrate clinical benefit along a pathway to regulatory review and approval. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Martin, Paul J.; Lee, Stephanie J.; Carpenter, Paul A.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Przepiorka, Donna] US FDA, Ctr Drug Evaluat Res, Silver Spring, MD USA. [Horowitz, Mary M.] Med Coll Wisconsin, Div Hematol & Oncol, Milwaukee, WI 53226 USA. [Koreth, John; Cutler, Corey S.] Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA 02115 USA. [Vogelsang, Georgia B.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Walker, Irwin] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Griffith, Linda M.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Akpek, Gorgun] Banner MD Anderson Canc Ctr, Stem Cell Transplant Program, Gilbert, AZ USA. [Mohty, Mohamad] Univ Paris 06, Hop St Antoine, INSERM, Clin Hematol & Cellular Therapy Dept,U938, Paris, France. [Wolff, Daniel] Univ Regensburg, Dept Internal Med 3, D-93053 Regensburg, Germany. [Pavletic, Steven Z.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Martin, PJ (reprint author), Fred Hutchinson Canc Res Ctr, D2-100,POB 19024, Seattle, WA 98109 USA. EM pmartin@fredhutch.org OI Martin, Paul/0000-0001-9051-1215 FU NIH: National Cancer Institute (NCI), Center for Cancer Research, Intramural Research Program and Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program; Office of Rare Disease Research (ORD), National Center for Advancing Translational Sciences; Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases; National Heart, Lung and Blood Institute, Division of Blood Diseases and Resources; NCI, NIH [CA118953, CA18029]; U.S. Department of Health and Human Services FX This project was supported by the NIH: National Cancer Institute (NCI), Center for Cancer Research, Intramural Research Program and Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program; Office of Rare Disease Research (ORD), National Center for Advancing Translational Sciences; Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases; National Heart, Lung and Blood Institute, Division of Blood Diseases and Resources. Supported by grants CA118953 and CA18029 from the NCI, NIH, and U.S. Department of Health and Human Services (to P.J.M. and S.J.L.). The opinions expressed are those of the authors and do not represent the position of the NCI, the National Heart, Lung and Blood Institute, the National Institute of Allergy and Infectious Diseases, the NIH, the FDA, or the US Government. NR 71 TC 11 Z9 12 U1 0 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 AUG PY 2015 VL 21 IS 8 BP 1343 EP 1359 DI 10.1016/j.bbmt.2015.05.004 PG 17 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CN6PW UT WOS:000358557700003 PM 25985921 ER PT J AU Aikin, KJ Betts, KR O'Donoghue, AC Rupert, DJ Lee, PK Amoozegar, JB Southwell, BG AF Aikin, Kathryn J. Betts, Kevin R. O'Donoghue, Amie C. Rupert, Douglas J. Lee, Philip K. Amoozegar, Jacqueline B. Southwell, Brian G. TI Correction of Overstatement and Omission in Direct-to-Consumer Prescription Drug Advertising SO JOURNAL OF COMMUNICATION LA English DT Article DE Misinformation; DTC Advertising; Prescription Drugs; Corrective Advertising; Television Advertising ID STATEMENTS; BELIEFS; SMOKING; FTC AB Little experimental evidence exists regarding corrective television advertising as a remedy for misleading direct-to-consumer prescription drug ads. We examined how exposure to an ad for a fictitious prescription drug that appeared to offer benefits and risks superior to normative standards for asthma medication (i.e., a simulated violative ad) and a corresponding corrective ad shaped viewer perceptions, understanding, and intended behavior. Through an experiment with 1,057 participants, we found that a corrective ad counteracted viewer belief of an overstatement of efficacy claim, but was less successful in counteracting omission of risk. Corrective ad exposure also affected general viewer perceptions of, and intended behaviors toward, the drug. C1 [Aikin, Kathryn J.; Betts, Kevin R.; O'Donoghue, Amie C.] US FDA, Off Prescript Drug Promot, Silver Spring, MD 20993 USA. [Rupert, Douglas J.; Lee, Philip K.; Amoozegar, Jacqueline B.; Southwell, Brian G.] RTI Int, Ctr Commun Sci, Res Triangle Pk, NC 27709 USA. RP Aikin, KJ (reprint author), US FDA, Off Prescript Drug Promot, Silver Spring, MD 20993 USA. EM Kathryn.Aikin@fda.hhs.gov OI Southwell, Brian/0000-0001-5091-8782 NR 23 TC 2 Z9 2 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9916 EI 1460-2466 J9 J COMMUN JI J. Commun. PD AUG PY 2015 VL 65 IS 4 BP 596 EP 618 DI 10.1111/jcom.12167 PG 23 WC Communication SC Communication GA CN8MT UT WOS:000358695900003 ER PT J AU Zhang, W Soika, V Meehan, J Su, Z Ge, W Ng, HW Perkins, R Simonyan, V Tong, W Hong, H AF Zhang, W. Soika, V. Meehan, J. Su, Z. Ge, W. Ng, H. W. Perkins, R. Simonyan, V. Tong, W. Hong, H. TI Quality control metrics improve repeatability and reproducibility of single-nucleotide variants derived from whole-genome sequencing SO PHARMACOGENOMICS JOURNAL LA English DT Article ID SHORT READ ALIGNMENT; WIDE ASSOCIATION; HAPMAP SAMPLES; RISK LOCI; CANCER; DNA; DISEASES; TRAITS; TOOL AB Although many quality control (QC) methods have been developed to improve the quality of single-nucleotide variants (SNVs) in SNV-calling, QC methods for use subsequent to single-nucleotide polymorphism-calling have not been reported. We developed five QC metrics to improve the quality of SNVs using the whole-genome-sequencing data of a monozygotic twin pair from the Korean Personal Genome Project. The QC metrics improved both repeatability between the monozygotic twin pair and reproducibility between SNV-calling pipelines. We demonstrated the QC metrics improve reproducibility of SNVs derived from not only whole-genome-sequencing data but also whole-exome-sequencing data. The QC metrics are calculated based on the reference genome used in the alignment without accessing the raw and intermediate data or knowing the SNV-calling details. Therefore, the QC metrics can be easily adopted in downstream association analysis. C1 [Zhang, W.; Meehan, J.; Su, Z.; Ge, W.; Ng, H. W.; Perkins, R.; Tong, W.; Hong, H.] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Soika, V.; Simonyan, V.] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Hong, H (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM huixiao.hong@fda.hhs.gov FU Research Participation Program at National Center for Toxicological Research; Center for Biologics Evaluation and Research FX This research was supported in part by an appointment to the Research Participation Program at the National Center for Toxicological Research (WZ and HWN) and at the Center for Biologics Evaluation and Research (VS) administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration (FDA). We thank Mike Mikailov of FDA's Center for Devices and Radiological Health for his technical support on the data analysis conducted on the high-performance computation cluster Betsy in the White Oak Data Center of FDA. We acknowledge Critical Assessment of Massive Data Analysis consortium for providing us the raw data, as well as the mapping and SNVs calling results from KPGP. The findings and conclusions in this article have not been formally disseminated by the US FDA and should not be construed to represent any agency determination or policy. NR 52 TC 2 Z9 2 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1470-269X EI 1473-1150 J9 PHARMACOGENOMICS J JI Pharmacogenomics J. PD AUG PY 2015 VL 15 IS 4 BP 298 EP 309 DI 10.1038/tpj.2014.70 PG 12 WC Genetics & Heredity; Pharmacology & Pharmacy SC Genetics & Heredity; Pharmacology & Pharmacy GA CN5CY UT WOS:000358448500002 PM 25384574 ER PT J AU Galeotti, L Scully, CG Vicente, J Johannesen, L Strauss, DG AF Galeotti, Loriano Scully, Christopher G. Vicente, Jose Johannesen, Lars Strauss, David G. TI Robust algorithm to locate heart beats from multiple physiological waveforms by individual signal detector voting SO PHYSIOLOGICAL MEASUREMENT LA English DT Article DE heart beat detection; fusion algorithms; electrocardiograph; blood pressure ID QRS DETECTION ALGORITHM; DATABASE AB Alarm fatigue is a top medical device hazard in patient monitoring that could be reduced by merging physiological information from multiple sensors, minimizing the impact of a single sensor failing. We developed a heart beat detection algorithm that utilizes multi-modal physiological signals (e.g. electrocardiogram, blood pressure, stroke volume, photoplethysmogram and electro-encephalogram) by merging the heart beats obtained from signal-specific detectors. We used the PhysioNet/Computing in Cardiology Challenge 2014 training set to develop the algorithm, and we refined it with a mix of signals from the multiparameter intelligent monitoring in intensive care (MIMIC II) database and artificially disrupted waveforms. The algorithm had an average sensitivity of 95.67% and positive predictive value (PPV) of 92.28% when applied to the PhysioNet/Computing in Cardiology Challenge 2014 200 record training set. On a refined dataset obtained by removing 5 records with arrhythmias and inconsistent reference annotations we obtained an average sensitivity of 97.43% and PPV of 94.17%. Algorithm performance was assessed with the Physionet Challenge 2014 test set that consisted of 200 records (each up to 10 min length) containing multiple physiological signals and reference annotations verified by the PhysioNet/Computing in Cardiology Challenge 2014 organizers. Our algorithm had a sensitivity of 92.74% and PPV of 87.37% computed over all annotated beats, and a record average sensitivity of 91.08%, PPV of 86.96% and an overall score (average of all 4 measures) of 89.53%. Our algorithm is an example of a data fusion approach that can improve patient monitoring and reduce false alarms by reducing the effect of individual signal failures. C1 [Galeotti, Loriano; Scully, Christopher G.; Vicente, Jose; Johannesen, Lars; Strauss, David G.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Johannesen, Lars] Karolinska Inst, Dept Clin Physiol, S-10401 Stockholm, Sweden. [Johannesen, Lars] Karolinska Univ Hosp, Stockholm, Sweden. [Vicente, Jose] Univ Zaragoza, BSICoS Grp, Aragon Inst Engn Res I3A, IIS Aragon, Zaragoza, Aragon, Spain. RP Galeotti, L (reprint author), US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM loriano.galeotti@fda.hhs.gov OI Vicente, Jose/0000-0001-9963-1205 FU FDA's Critical Path Initiative, Office of Women's Health, Medical Countermeasures Initiative; Department of Energy; FDA FX This project was supported in part by FDA's Critical Path Initiative, Office of Women's Health, Medical Countermeasures Initiative and appointments to the Research Participation Programs at the Oak Ridge Institute for Science and Education through an interagency agreement between the Department of Energy and FDA. NR 20 TC 4 Z9 4 U1 1 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0967-3334 EI 1361-6579 J9 PHYSIOL MEAS JI Physiol. Meas. PD AUG PY 2015 VL 36 IS 8 BP 1705 EP 1716 DI 10.1088/0967-3334/36/8/1705 PG 12 WC Biophysics; Engineering, Biomedical; Physiology SC Biophysics; Engineering; Physiology GA CN8TQ UT WOS:000358716900006 PM 26218439 ER PT J AU Solino, L Widgy, S Pautonnier, A Turquet, J Loeffler, CR Quintana, HAF Diogene, J AF Solino, Lucia Widgy, Saha Pautonnier, Anthony Turquet, Jean Loeffler, Christopher R. Quintana, Harold A. Flores Diogene, Jorge TI Prevalence of ciguatoxins in lionfish (Pterois spp.) from Guadeloupe, Saint Martin, and Saint Barthelmy Islands (Caribbean) SO TOXICON LA English DT Article DE Ciguatera; Ciguatoxin; Lionfish; Pterois spp.; Caribbean; Guadeloupe ID CELL-BASED ASSAY; INDIAN-OCEAN; FLORIDA-KEYS; CIGUATERA; FISH; TOXICITY; PACIFIC; ECOLOGY; TOXINS; PATTERNS AB Lionfish (Pterois spp.) are invasive species that have recently spread throughout the Caribbean. Lionfish are available for purchase in local markets for human consumption in several islands of the region. We examined the prevalence of ciguatoxins (CTXs) in lionfish from the French Antilles, a ciguatera-endemic region. The neuroblastoma-2a (N2a) cell assay was used to assess composite cytotoxicity in 120 fish samples collected from the surrounding waters of Guadeloupe (n = 60), Saint Barthelemy Islands (n = 55) and Saint Martin (n = 5). Twenty-seven of these samples exhibited CTX-like activity by the N2a assay. Ciguatoxin (CTX) was confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in multiple samples that presented highest composite toxicity levels by N2a. Those fish found to contain CTXs were all from Saint Barthelemy. Lionfish from Guadeloupe and Saint Martin did not exhibit toxin activity, although the sample size from Saint Martin was insufficient to draw any conclusions as to the incidence of CTXs. In this study, we provide information about the potential hazard of ciguatera associated with the consumption of lionfish from known endemic areas. We also demonstrate the utility of the cell-based assay combined with LC-MS/MS to assess activity and to provide structural confirmation of CTXs respectively. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Solino, Lucia; Diogene, Jorge] IRTA, E-43540 San Carlos de la Rapita, Spain. [Widgy, Saha; Pautonnier, Anthony] CRPMEM, Pointe A Pitre 97110, Guadeloupe. [Turquet, Jean] CIROY, ARDA & ARVAM, St Clotilde 97490, Reunion. [Loeffler, Christopher R.; Quintana, Harold A. Flores] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. RP Diogene, J (reprint author), IRTA, Ctra Poble Nou Km 5-5, E-43540 San Carlos de la Rapita, Spain. EM jorge.diogene@irta.cat FU European Union Seventh Framework Programme (FP7) under the ECsafeSEAFOOD project [311820] FX The authors acknowledge Universitat Rovira i Virgili, Banco de Santander and IRTA for the PhD grant to Lucia Solino. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under the ECsafeSEAFOOD project (grant agreement no 311820). NR 45 TC 1 Z9 1 U1 5 U2 35 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 AUG PY 2015 VL 102 BP 62 EP 68 DI 10.1016/j.toxicon.2015.05.015 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CN4ID UT WOS:000358392900009 PM 26026621 ER PT J AU Sauder, CJ Ngo, L Simonyan, V Cong, Y Zhang, C Link, M Malik, T Rubin, SA AF Sauder, Christian J. Ngo, Laurie Simonyan, Vahan Cong, Yu Zhang, Cheryl Link, Malen Malik, Tahir Rubin, Steven A. TI Generation and propagation of recombinant mumps viruses exhibiting an additional U residue in the homopolymeric U tract of the F gene-end signal SO VIRUS GENES LA English DT Article DE Mumps virus; Rule of six; F gene-end signal; Homopolymeric tract; High-throughput sequencing ID MESSENGER-RNA; PARAMYXOVIRUS; REPLICATION; TRANSCRIPTION; RULE; IDENTIFICATION; NEUROVIRULENCE; POLYMERASE; VACCINES; PROTEIN AB As a member of the family paramyxoviridae, subfamily paramyxovirinae, the genome of mumps virus (MuV) is postulated to be polyhexameric in length in order to be able to replicate efficiently. While all natural MuV strains sequenced so far obey to this "rule of six," we describe here the isolation of recombinant MuVs that appeared to contain an additional U residue in the homopolymeric tract of the F gene-end signal, resulting in a genome length of 6n + 1. Sequencing of several plaque-purified viruses from these preparations did not reveal the existence of length-correcting mutations, suggesting that they are violators of the rule of six. Employing high-throughput sequencing technology, we provide evidence that the insertion of an additional U residue is mainly the result of the rescue system used that relies on T7 RNA polymerase. Limited in vitro and in vivo testing of the viruses did not reveal any significant impact of the longer genome on virus replication or virulence, suggesting that the rule of six is not a strict requirement for MuV replication. C1 [Sauder, Christian J.; Ngo, Laurie; Cong, Yu; Zhang, Cheryl; Link, Malen; Malik, Tahir; Rubin, Steven A.] US FDA, CBER, OVRR, DVP, Silver Spring, MD 20993 USA. [Simonyan, Vahan] US FDA, CBER, OD, Silver Spring, MD 20993 USA. RP Sauder, CJ (reprint author), US FDA, CBER, OVRR, DVP, 10903 New Hampshire Ave,Bldg 52-72, Silver Spring, MD 20993 USA. EM christian.sauder@fda.hhs.gov FU Oak Ridge Institute for Science and Education FX Salary support for L.N., C.Z, Y.C., and M.L. was provided by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. We wish to thank Shen Rongfong and Rong Wang (FDA/CBER) for helpful discussion about HTS; U. Buchholz (NIH, Bethesda, MD) for providing the BHK BSR-T7/5 cells, P. Duprex for providing pMuV(MPBS). We are grateful to Ewan Plant and Konstantin Chumakov (FDA/CBER) for critically reading the manuscript. NR 24 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-8569 EI 1572-994X J9 VIRUS GENES JI Virus Genes PD AUG PY 2015 VL 51 IS 1 BP 12 EP 24 DI 10.1007/s11262-015-1204-y PG 13 WC Genetics & Heredity; Virology SC Genetics & Heredity; Virology GA CN6MI UT WOS:000358548500002 PM 25962759 ER PT J AU Karnaukhova, E AF Karnaukhova, Elena TI Protein-Ligand Interactions: heme binding to proteins with Therapeutic Potential SO AMINO ACIDS LA English DT Meeting Abstract C1 [Karnaukhova, Elena] US FDA, Lab Biochem & Vasc Biol, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0939-4451 EI 1438-2199 J9 AMINO ACIDS JI Amino Acids PD AUG PY 2015 VL 47 IS 8 BP 1654 EP 1654 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CN1JH UT WOS:000358175100134 ER PT J AU Karnaukhova, E AF Karnaukhova, Elena TI Therapeutic proteins and peptides: recent advances in the research and development for hereditary angioedema SO AMINO ACIDS LA English DT Meeting Abstract C1 [Karnaukhova, Elena] US FDA, Lab Biochem & Vasc Biol, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0939-4451 EI 1438-2199 J9 AMINO ACIDS JI Amino Acids PD AUG PY 2015 VL 47 IS 8 BP 1695 EP 1695 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CN1JH UT WOS:000358175100259 ER PT J AU Wu, YF Beland, FA Chen, S Fang, JL AF Wu, Yuanfeng Beland, Frederick A. Chen, Si Fang, Jia-Long TI Extracellular signal-regulated kinases 1/2 and Akt contribute to triclosan-stimulated proliferation of JB6 Cl 41-5a cells SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Triclosan; JB6 cells; Cell proliferation; Extracellular signal-regulated kinases 1/2; Akt ID ACTIVATED PROTEIN-KINASE; EPIDERMAL-GROWTH-FACTOR; XENOBIOTIC METABOLISM CAPACITIES; CYCLIN-DEPENDENT KINASES; IN-VITRO ALTERNATIVES; SKIN MODELS; AP-1 TRANSACTIVATION; MAMMALIAN-CELLS; RISK-ASSESSMENT; EGF RECEPTOR AB Triclosan is a broad spectrum anti-bacterial agent widely used in many personal care products, household items, medical devices, and clinical settings. Human exposure to triclosan is mainly through oral and dermal routes. In previous studies, we found that sub-chronic dermal exposure of B6C3F1 mice to triclosan induced epidermal hyperplasia and focal necrosis; however, the mechanisms for these responses remain elusive. In this study, using mouse epidermis-derived JB6 Cl 41-5a cells, we found that triclosan stimulated cell growth in a concentration- and time-dependent manner. Enhanced cell proliferation was demonstrated by a substantial increase in the percentage of BrdU-positive cells, an elevation in the protein levels of cyclin D1 and cyclin A, and a reduction in the protein level of p27(Kip1). Western blotting analysis revealed that triclosan induced the activation of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK), p38, and Akt. Pre-treatment of the cells with PD184352, an inhibitor of the upstream kinase MEK1/2, or with wortmannin, an inhibitor of phosphoinositide 3-kinase, blocked triclosan-mediated phosphorylation of ERK1/2 and Akt, respectively, and substantially suppressed triclosan-stimulated cell proliferation, whereas the JNK inhibitor SP600125 or the p38 inhibitor SB203580 had little to no effect on triclosan-stimulated cell proliferation. The phosphorylation activation of ERK1/2 and Akt was further confirmed on the skin of mice dermally administered triclosan. These data suggest that the activation of ERK1/2 and Akt is involved in triclosan-stimulated proliferation of JB6 Cl 41-5a cells. C1 [Wu, Yuanfeng; Beland, Frederick A.; Chen, Si; Fang, Jia-Long] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Fang, JL (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM jia-long.fang@fda.hhs.gov FU National Center for Toxicological Research, U.S. Food and Drug Administration (FDA) [FDA IAG: 224-07-0007, NIH Y1ES1027]; National Toxicology Program, National Institute of Environmental Health Sciences [FDA IAG: 224-07-0007, NIH Y1ES1027] FX Yuanfeng Wu and Si Chen were supported by an appointment to the Postgraduate Research in the Division of Biochemical Toxicology at the National Center for Toxicological Research administered by Oak Ridge Institute for Science Education through an interagency agreement between the U.S. Department of Energy and the U.S. FDA. This research was supported through an interagency agreement between the National Center for Toxicological Research, U.S. Food and Drug Administration (FDA) and the National Toxicology Program, National Institute of Environmental Health Sciences. (FDA IAG: 224-07-0007; NIH Y1ES1027). NR 57 TC 3 Z9 3 U1 1 U2 7 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD AUG PY 2015 VL 89 IS 8 BP 1297 EP 1311 DI 10.1007/s00204-014-1308-5 PG 15 WC Toxicology SC Toxicology GA CN2GF UT WOS:000358238100011 PM 25033989 ER PT J AU Berlin, NL Ferrucci, LM Cartmel, B Wang, SY Leffell, DJ McNiff, JM Mayne, ST AF Berlin, Nicholas L. Ferrucci, Leah M. Cartmel, Brenda Wang, Shi-yi Leffell, David J. McNiff, Jennifer M. Mayne, Susan T. TI Subsequent skin cancer in patients with early-onset basal cell carcinoma SO AUSTRALASIAN JOURNAL OF DERMATOLOGY LA English DT Letter ID TRENDS C1 [Berlin, Nicholas L.; Ferrucci, Leah M.; Cartmel, Brenda; Wang, Shi-yi; Mayne, Susan T.] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Ferrucci, Leah M.; Cartmel, Brenda; Wang, Shi-yi; Leffell, David J.; Mayne, Susan T.] Yale Canc Ctr, New Haven, CT USA. [Leffell, David J.; McNiff, Jennifer M.] Yale Univ, Sch Med, New Haven, CT USA. [Leffell, David J.; McNiff, Jennifer M.] US FDA, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. RP Berlin, NL (reprint author), Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-8380 EI 1440-0960 J9 AUSTRALAS J DERMATOL JI Australas. J. Dermatol. PD AUG PY 2015 VL 56 IS 3 BP 236 EP 237 DI 10.1111/ajd.12338 PG 2 WC Dermatology SC Dermatology GA CN4UL UT WOS:000358425700030 PM 26201376 ER PT J AU Vargas, HM Bass, AS Koerner, J Matis-Mitchell, S Pugsley, MK Skinner, M Burnham, M Bridgland-Taylor, M Pettit, S Valentin, JP AF Vargas, Hugo M. Bass, Alan S. Koerner, John Matis-Mitchell, Sherri Pugsley, Michael K. Skinner, Matthew Burnham, Matthew Bridgland-Taylor, Matthew Pettit, Syril Valentin, Jean-Pierre TI Evaluation of drug-induced QT interval prolongation in animal and human studies: a literature review of concordance SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Review ID TORSADES-DE-POINTES; NONCLINICAL MODELS; SAFETY EVALUATION; PREDICTIVE-VALUE; CONSCIOUS DOG; HEART-RATE; IN-VITRO; REPOLARIZATION; PHARMACOLOGY; PRODACT AB Evaluating whether a new medication prolongs QT intervals is a critical safety activity that is conducted in a sensitive animal model during non-clinical drug development. The importance of QT liability detection has been reinforced by non-clinical [International Conference on Harmonization (ICH) S7B] and clinical (ICH E14) regulatory guidance from the International Conference on Harmonization. A key challenge for the cardiovascular safety community is to understand how the finding from a non-clinical in vivoQT assay in animals predicts the outcomes of a clinical QT evaluation in humans. The Health and Environmental Sciences Institute Pro-Arrhythmia Working Group performed a literature search (1960-2011) to identify both human and non-rodent animal studies that assessed QT signal concordance between species and identified drugs that prolonged or did not prolong the QT interval. The main finding was the excellent agreement between QT results in humans and non-rodent animals. Ninety-one percent (21 of 23) of drugs that prolonged the QT interval in humans also did so in animals, and 88% (15 of 17) of drugs that did not prolong the QT interval in humans had no effect on animals. This suggests that QT interval data derived from relevant non-rodent models has a 90% chance of predicting QT findings in humans. Disagreement can occur, but in the limited cases of QT discordance we identified, there appeared to be plausible explanations for the underlying disconnect between the human and non-rodent animal QT outcomes. C1 [Vargas, Hugo M.] Amgen Inc, Integrated Discovery & Safety Pharmacol, Thousand Oaks, CA 91320 USA. [Bass, Alan S.] Merck Res Labs, Safety Assessment, Boston, MA USA. [Koerner, John] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Matis-Mitchell, Sherri] AstraZeneca R&D, Discovery Informat, Wilmington, DE USA. [Pugsley, Michael K.] Janssen R&D, Safety & Exploratory Pharmacol, Raritan, NJ USA. [Skinner, Matthew; Burnham, Matthew; Bridgland-Taylor, Matthew; Valentin, Jean-Pierre] AstraZeneca R&D, Safety Assessment, Macclesfield, Cheshire, England. [Pettit, Syril] Hlth & Environm Sci Inst, Washington, DC USA. RP Vargas, HM (reprint author), Amgen Inc, Integrated Discovery & Safety Pharmacol, One Amgen Ctr Dr, Thousand Oaks, CA 91320 USA. EM hvargas@amgen.com OI Skinner, Matt/0000-0002-9677-3352 NR 37 TC 6 Z9 6 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD AUG PY 2015 VL 172 IS 16 BP 4002 EP 4011 DI 10.1111/bph.13207 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CN5FB UT WOS:000358454100005 PM 26031452 ER PT J AU Barrett, TD Palomino, HL Brondstetter, TI Kanelakis, KC Wu, XD Yan, W Merton, KP Schoetens, F Ma, JY Skaptason, J Gao, JJ Tran, DT Venkatesan, H Rosen, MD Shankley, NP Rabinowitz, MH AF Barrett, Terrance D. Palomino, Heather L. Brondstetter, Theresa I. Kanelakis, Kimon C. Wu, Xiaodong Yan, Wen Merton, Katherine P. Schoetens, Freddy Ma, Jing Ying Skaptason, Judy Gao, Jingjin Da-Thao Tran Venkatesan, Hariharan Rosen, Mark D. Shankley, Nigel P. Rabinowitz, Michael H. TI Prolyl hydroxylase inhibition corrects functional iron deficiency and inflammation-induced anaemia in rats SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article ID CONCISE GUIDE; HIF-ALPHA; PHARMACOLOGY; DISEASE; FAMILY; MICE AB Background and PurposeSmall-molecule inhibitors of prolyl hydroxylase (PHD) enzymes are a novel target for the treatment of anaemia and functional iron deficiency (FID). Other than being orally bioavailable, the differentiation of PHD inhibitors from recombinant human erythropoietin (rhEPO) has not been demonstrated. Experimental ApproachJNJ-42905343 was identified and characterized as a novel inhibitor of PHD and its action was compared with rhEPO in healthy rats and in a rat model of inflammation-induced anaemia and FID [peptidoglycan-polysaccharide (PGPS) model]. Key ResultsOral administration of JNJ-42905343 to healthy rats increased the gene expression of cytochrome b (DcytB) and divalent metal-ion transporter 1 (DMT1) in the duodenum, and increased plasma EPO. Repeated administration of JNJ-42905343 for 28 days increased blood haemoglobin, mean corpuscular haemoglobin (MCH) and mean corpuscular volume (MCV). The serum iron concentration was increased with low doses (0.3mgkg(-1)) but reduced at high doses (6mgkg(-1)). In PGPS-treated rats, administration of JNJ-42905343 for 28 days corrected FID and anaemia, as reflected by increased blood haemoglobin, MCH and MCV. Increased expression of DcytB and DMT1 genes in the duodenum resulting in increased iron availability was defined as the mechanism for these effects. rhEPO did not affect DcytB and DMT1 and was not effective in PGPS-treated rats. Conclusions and ImplicationsPHD inhibition has a beneficial effect on iron metabolism in addition to stimulating the release of EPO. Small-molecule inhibitors of PHD such as JNJ-42905343 represent a mechanism distinct from rhEPO to treat anaemia and FID. C1 [Barrett, Terrance D.; Wu, Xiaodong; Merton, Katherine P.; Schoetens, Freddy; Ma, Jing Ying; Skaptason, Judy; Gao, Jingjin; Da-Thao Tran; Venkatesan, Hariharan] Janssen Pharmaceut Co Johnson & Johnson, Cardiovasc Metab Res, San Diego, CA 92121 USA. [Palomino, Heather L.] Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. [Yan, Wen] Arcturus Therapeut, San Diego, CA USA. [Rosen, Mark D.; Rabinowitz, Michael H.] Aetheria Therapeut, San Diego, CA USA. [Brondstetter, Theresa I.] Covenant Care, Palo Alto, CA USA. [Kanelakis, Kimon C.] US FDA, Off Foods & Vet Med, Rockville, MD 20857 USA. [Shankley, Nigel P.] Higher Todsworthy Farm, Gunnislake, Cornwall, England. RP Barrett, TD (reprint author), Janssen Pharmaceut Co Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121 USA. EM TBarret1@its.jnj.com FU Janssen Pharmaceutical Research and Development FX All studies were funded by Janssen Pharmaceutical Research and Development. We would like to acknowledge the contribution of the La Jolla bio-analytic group, micro-array core and Dr. Kevin Sharp. NR 28 TC 3 Z9 3 U1 5 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD AUG PY 2015 VL 172 IS 16 BP 4078 EP 4088 DI 10.1111/bph.13188 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CN5FB UT WOS:000358454100011 PM 25988595 ER PT J AU Reynnells, R Callahan, MT Handy, ET Roberts, C Felton, G Ingram, DT Millner, PD Sharma, M AF Reynnells, Russell Callahan, Mary Theresa Handy, Eric T. Roberts, Cheryl Felton, Gary Ingram, David T. Millner, Patricia D. Sharma, Manan TI Evaluation of Two Immunomagnetic Separation Techniques for the Detection and Recovery of Escherichia coli O157:H7 from Finished Composts SO FOOD ANALYTICAL METHODS LA English DT Article DE Immunomagnetic; Compost; E. coli O157:H7; Real time PCR; Soil amendments ID BOVINE; MANURE; SALMONELLA; O157-H7 AB Two rapid immunomagnetic separation (IMS) protocols were evaluated to recover inoculated Escherichia coli O157:H7 (1-2 log colony-forming unit (CFU)/g) from 30 different commercial, finished compost samples. Both protocols detected E. coli O157:H7 in compost samples; PCR techniques required the removal of inhibitors to reduce possibility of a false negative result. C1 [Reynnells, Russell; Callahan, Mary Theresa; Handy, Eric T.; Roberts, Cheryl; Millner, Patricia D.; Sharma, Manan] ARS, USDA, Environm Microbial & Food Safety Lab, Henry A Wallace Beltsville Area Res Ctr, Beltsville, MD 20705 USA. [Felton, Gary] Univ Maryland, Environm Sci & Technol Dept, Anim Sci Agr Engn 1433, College Pk, MD 20742 USA. [Ingram, David T.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Sharma, M (reprint author), ARS, USDA, Environm Microbial & Food Safety Lab, Henry A Wallace Beltsville Area Res Ctr, Bldg 201,Rm 103,10300 Baltimore Ave, Beltsville, MD 20705 USA. EM rreynn555@aol.com; callahan.maryt@gmail.com; eric.handy@ars.usda.gov; cheryl.roberts@ars.usda.gov; gfelton@umd.edu; david.ingram@fda.hhs.gov; pat.millner@ars.usda.gov; manan.sharma@ars.usda.gov FU Center for Produce Safety grant; USDA-ARS "Microbial Ecology & Safety of Fresh on-Farm Organically Grown Produce" project FX Funding was provided by the Center for Produce Safety grant "Validation of testing methods for the detection and quantification of Escherichia coli O157:H7, Salmonella spp., fecal coliforms and nonpathogenic Escherichia coli in compost" and the USDA-ARS "Microbial Ecology & Safety of Fresh on-Farm Organically Grown Produce" project. NR 13 TC 0 Z9 0 U1 2 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1936-9751 EI 1936-976X J9 FOOD ANAL METHOD JI Food Anal. Meth. PD AUG PY 2015 VL 8 IS 7 BP 1812 EP 1814 DI 10.1007/s12161-014-0068-4 PG 3 WC Food Science & Technology SC Food Science & Technology GA CN3LC UT WOS:000358326700022 ER PT J AU Vallelian, F Garcia-Rubio, I Puglia, M Kahraman, A Deuel, JW Engelsberger, WR Mason, RP Buehler, PW Schaer, DJ AF Vallelian, Florence Garcia-Rubio, Ines Puglia, Michele Kahraman, Abdullah Deuel, Jeremy W. Engelsberger, Wolfgang R. Mason, Ronald P. Buehler, Paul W. Schaer, Dominik J. TI Spin trapping combined with quantitative mass spectrometry defines free radical redistribution within the oxidized hemoglobin: haptoglobin complex SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Hemoglobin; Haptoglobin; Radical; Spin trapping; Oxidative stress; Oxidation; Electron paramagnetic resonance (EPR); Mass spectrometry ID GUINEA-PIGS; CYSTEINE RESIDUE; IN-VIVO; PEROXIDE; IDENTIFICATION; THERAPEUTICS; MECHANISMS; DECREASES; HEMOLYSIS; PROTEINS AB Extracellular or free hemoglobin (Hb) accumulates during hemolysis, tissue damage, and inflammation. Heme-triggered oxidative reactions can lead to diverse structural modifications of lipids and proteins, which contribute to the propagation of tissue damage. One important target of Hb's peroxidase reactivity is its own globin structure. Amino acid oxidation and crosslinking events destabilize the protein and ultimately cause accumulation of proinflammatory and cytotoxic Hb degradation products. The Hb scavenger haptoglobin (Hp) attenuates oxidation induced Hb degradation. In this study we show that in the presence of hydrogen peroxide (H2O2), Hb and the Hb:Hp complex share comparable peroxidative reactivity and free radical generation. While oxidation of both free Hb and Hb:Hp complex generates a common tyrosine based free radical, the spin-trapping reaction with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) yields dissimilar paramagnetic products in Hb and Hb:Hp, suggesting that radicals are differently redistributed within the complex before reacting with the spin trap. With LC-MS2 mass spectrometry we assigned multiple known and novel DMPO adduct sites. Quantification of these adducts suggested that the Hb:Hp complex formation causes extensive delocalization of accessible free radicals with drastic reduction of the major tryptophan and cysteine modifications in the beta-globin chain of the Hb:Hp complex, including decreased beta Cys93 DMPO adduction. In contrast, the quantitative changes in DMPO adduct formation on Hb:Hp complex formation were less pronounced in the Hb alpha-globin chain. In contrast to earlier speculations, we found no evidence that free Hb radicals are delocalized to the Hp chain of the complex. The observation that Hb:Hp complex formation alters free radical distribution in Hb may help to better understand the structural basis for Hp as an antioxidant protein. (C) 2015 Elsevier Inc. All rights reseived, C1 [Vallelian, Florence; Puglia, Michele; Deuel, Jeremy W.; Engelsberger, Wolfgang R.; Schaer, Dominik J.] Univ Zurich Hosp, Div Internal Med, CH-8091 Zurich, Switzerland. [Garcia-Rubio, Ines] Swiss Fed Inst Technol, Lab Phys Chem, Zurich, Switzerland. [Garcia-Rubio, Ines] Ctr Univ Def, Zaragoza, Spain. [Puglia, Michele] Univ Zurich, Funct Genom Ctr, CH-8006 Zurich, Switzerland. [Kahraman, Abdullah] Univ Zurich, Inst Mol & Life Sci, CH-8006 Zurich, Switzerland. [Mason, Ronald P.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Buehler, Paul W.] Food & Drug Adm, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Schaer, Dominik J.] Univ Zurich, Inst Evolutionary Med, CH-8006 Zurich, Switzerland. RP Schaer, DJ (reprint author), Univ Zurich Hosp, Div Internal Med, CH-8091 Zurich, Switzerland. EM dominik.schaer@usz.ch OI Deuel, Jeremy/0000-0002-5409-7712; Kahraman, Abdullah/0000-0003-3523-4467 FU Swiss National Science Foundation [310030/120658, 31003A/138500]; University of Zurich Research Priority Program "Integrative Human Physiology"; University of Zurich program "Research Time"; Swiss Federal Commission for Technology and Innovation (CTI) FX This work was supported by the Swiss National Science Foundation (Grants 310030/120658 and 31003A/138500 to D.J.S.), the University of Zurich Research Priority Program "Integrative Human Physiology," the University of Zurich program "Research Time," and the Swiss Federal Commission for Technology and Innovation (CTI). NR 33 TC 5 Z9 5 U1 9 U2 27 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG PY 2015 VL 85 BP 259 EP 268 DI 10.1016/j.freeradbiomed.2015.04.023 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CN1RO UT WOS:000358198000025 PM 25933590 ER PT J AU Zhou, D Li, HS Wang, YN Hochhaus, G Sinha, V Zhao, L AF Zhou, Di Li, Hongshan Wang, Yaning Hochhaus, Guenther Sinha, Vikram Zhao, Liang TI Quantitative characterization of circadian rhythm of pulmonary function in asthmatic patients treated with inhaled corticosteroids SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Article DE Circadian rhythm; Asthma; FEV1; Pharmacodynamic model; Drug development ID NOCTURNAL ASTHMA; MODEL; SMOKING; FEV1; METAANALYSIS; AGONISTS; DECLINE; FEV(1); NONMEM; CLOCK AB The aim of this study was to characterize the circadian rhythm observed for forced expiratory volume in 1 s (FEV1) in patients with persistent asthma being treated with inhaled corticosteroids. The database included 3379 FEV1 measurements from 189 patients with mild to moderate asthma. A model using the sum of two Sine functions with periods of 12 and 24 h and a constant component of mean circadian rhythm adequately described the circadian rhythm in FEV1 measurements over time. The model adequateness was evaluated by various approaches including visual predictive check (VPC), prediction-corrected VPC, standardized VPC and normalized prediction distribution error. Covariates tested included age, body weight, height, body mass index, baseline FEV1, and sex. Age and height were found to have significant effects on the mean FEV1 level and no covariate was found to have an effect on the magnitude and timing of circadian rhythm. The model predicted that a minimum FEV1 occurred in the early morning and maximum FEV1 occurred in the early afternoon, with a population mean fluctuation of 170 mL, which is consistent with the finding that asthma symptoms usually exacerbate in the early morning for patients with persistent asthma. This developed model provides the first quantitative approach to describing FEV1 circadian rhythm with ICS background treatment and provided insight in designing future registration trials for asthma drug development. C1 [Zhou, Di; Hochhaus, Guenther] Univ Florida, Coll Pharm, Dept Pharmaceut, Gainesville, FL 32610 USA. [Li, Hongshan; Wang, Yaning; Sinha, Vikram; Zhao, Liang] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Zhao, L (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM liang.zhao@fda.hhs.gov NR 37 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD AUG PY 2015 VL 42 IS 4 BP 391 EP 399 DI 10.1007/s10928-015-9420-6 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CN1EN UT WOS:000358160100005 PM 26099861 ER PT J AU Ilinykh, PA Lubaki, NM Widen, SG Renn, LA Theisen, TC Rabin, RL Wood, TG Bukreyev, A AF Ilinykh, Philipp A. Lubaki, Ndongala M. Widen, Steven G. Renn, Lynnsey A. Theisen, Terence C. Rabin, Ronald L. Wood, Thomas G. Bukreyev, Alexander TI Different Temporal Effects of Ebola Virus VP35 and VP24 Proteins on Global Gene Expression in Human Dendritic Cells SO JOURNAL OF VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; DOUBLE-STRANDED-RNA; VIRAL HEMORRHAGIC-FEVER; CYNOMOLGUS MACAQUES; T-CELLS; TRANSCRIPTIONAL REGULATION; KARYOPHERIN ALPHA-1; CLUSTER FORMATION; MARBURG VIRUSES; NUCLEAR IMPORT AB Ebola virus (EBOV) causes a severe hemorrhagic fever with a deficient immune response, lymphopenia, and lymphocyte apoptosis. Dendritic cells (DC), which trigger the adaptive response, do not mature despite EBOV infection. We recently demonstrated that DC maturation is unblocked by disabling the innate response antagonizing domains (IRADs) in EBOV VP35 and VP24 by the mutations R312A and K142A, respectively. Here we analyzed the effects of VP35 and VP24 with the IRADs disabled on global gene expression in human DC. Human monocyte-derived DC were infected by wild-type (wt) EBOV or EBOVs carrying the mutation in VP35 (EBOV/VP35m), VP24 (EBOV/VP24m), or both (EBOV/VP35m/VP24m). Global gene expression at 8 and 24 h was analyzed by deep sequencing, and the expression of interferon (IFN) subtypes up to 5 days postinfection was analyzed by quantitative reverse transcription-PCR (qRT-PCR). wt EBOV induced a weak global gene expression response, including markers of DC maturation, cytokines, chemokines, chemokine receptors, and multiple IFNs. The VP35 mutation unblocked the expression, resulting in a dramatic increase in expression of these transcripts at 8 and 24 h. Surprisingly, DC infected with EBOV/ VP24m expressed lower levels of many of these transcripts at 8 h after infection, compared to wt EBOV. In contrast, at 24 h, expression of the transcripts increased in DC infected with any of the three mutants, compared to wt EBOV. Moreover, sets of genes affected by the two mutations only partially overlapped. Pathway analysis demonstrated that the VP35 mutation unblocked pathways involved in antigen processing and presentation and IFN signaling. These data suggest that EBOV IRADs have profound effects on the host adaptive immune response through massive transcriptional downregulation of DC. IMPORTANCE This study shows that infection of DC with EBOV, but not its mutant forms with the VP35 IRAD and/or VP24 IRAD disabled, causes a global block in expression of host genes. The temporal effects of mutations disrupting the two IRADs differ, and the lists of affected genes only partially overlap such that VP35 and VP24 IRADs each have profound effects on antigen presentation by exposed DC. The global modulation of DC gene expression and the resulting lack of their maturation represent a major mechanism by which EBOV disables the T cell response and suggests that these suppressive pathways are a therapeutic target that may unleash the T cell responses during EBOV infection. C1 [Ilinykh, Philipp A.; Lubaki, Ndongala M.; Bukreyev, Alexander] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Widen, Steven G.; Wood, Thomas G.] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. [Bukreyev, Alexander] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. [Ilinykh, Philipp A.; Lubaki, Ndongala M.; Bukreyev, Alexander] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Renn, Lynnsey A.; Theisen, Terence C.; Rabin, Ronald L.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Bukreyev, A (reprint author), Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. EM alexander.bukreyev@utmb.edu FU John Sealy Memorial Endowment Fund pilot grant (Mechanisms of "Immune Paralysis" in Ebola Infections); University of Texas Medical Branch; McLaughlin Fellowship; UTMB Institute of Human Infections and Immunity; NIH [U19 AI109945-01] FX This study was supported by a John Sealy Memorial Endowment Fund pilot grant (Mechanisms of "Immune Paralysis" in Ebola Infections) (A.B.), a departmental startup grant from the University of Texas Medical Branch (A.B.), a McLaughlin Fellowship (M.L.), seed funds for pathogen genomics and other infectious disease and immunology initiatives involving next-generation sequencing from the UTMB Institute of Human Infections and Immunity (A.B.), and NIH grant U19 AI109945-01 (Molecular Basis for Ebola Virus Immune Paralysis) (A.B.). NR 61 TC 10 Z9 10 U1 2 U2 11 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 AUG PY 2015 VL 89 IS 15 BP 7567 EP 7583 DI 10.1128/JVI.00924-15 PG 17 WC Virology SC Virology GA CN2UP UT WOS:000358277800011 PM 25972536 ER PT J AU Fuentes, S Coyle, EM Golding, H Khurana, S AF Fuentes, Sandra Coyle, Elizabeth M. Golding, Hana Khurana, Surender TI Nonglycosylated G-Protein Vaccine Protects against Homologous and Heterologous Respiratory Syncytial Virus (RSV) Challenge, while Glycosylated G Enhances RSV Lung Pathology and Cytokine Levels SO JOURNAL OF VIROLOGY LA English DT Article ID ATTACHMENT G-PROTEIN; CD8 T-CELLS; BALB/C MICE; PULMONARY EOSINOPHILIA; FUSION PROTEIN; G-GLYCOPROTEIN; UNITED-STATES; SUBSTANCE-P; ANTIBODIES; INFECTION AB New efforts are under way to develop a vaccine against respiratory syncytial virus (RSV) that will provide protective immunity without the potential for vaccine-associated disease enhancement such as that observed in infants following vaccination with formalin-inactivated RSV vaccine. In addition to the F fusion protein, the G attachment surface protein is a target for neutralizing antibodies and thus represents an important vaccine candidate. However, glycosylated G protein expressed in mammalian cells has been shown to induce pulmonary eosinophilia upon RSV infection in a mouse model. In the current study, we evaluated in parallel the safety and protective efficacy of the RSV A2 recombinant unglycosylated G protein ectodomain (amino acids 67 to 298) expressed in Escherichia coli (REG) and those of glycosylated G produced in mammalian cells (RMG) in a mouse RSV challenge model. Vaccination with REG generated neutralizing antibodies against RSV A2 in 7/11 BALB/c mice, while RMG did not elicit neutralizing antibodies. Total serum binding antibodies against the recombinant proteins (both REG and RMG) were measured by surface plasmon resonance (SPR) and were found to be > 10-fold higher for REG-than for RMG-vaccinated animals. Reduction of lung viral loads to undetectable levels after homologous (RSV-A2) and heterologous (RSV-B1) viral challenge was observed in 7/8 animals vaccinated with REG but not in RMG-vaccinated animals. Furthermore, enhanced lung pathology and elevated Th2 cytokines/chemokines were observed exclusively in animals vaccinated with RMG (but not in those vaccinated with REG or phosphate-buffered saline [PBS]) after homologous or heterologous RSV challenge. This study suggests that bacterially produced unglycosylated G protein could be developed alone or as a component of a protective vaccine against RSV disease. IMPORTANCE New efforts are under way to develop vaccines against RSV that will provide protective immunity without the potential for disease enhancement. The G attachment protein represents an important candidate for inclusion in an effective RSV vaccine. In the current study, we evaluated the safety and protective efficacy of the RSV A2 recombinant unglycosylated G protein ectodomain produced in E. coli (REG) and those of glycosylated G produced in mammalian cells (RMG) in a mouse RSV challenge model (strains A2 and B1). The unglycosylated G generated high protective immunity and no lung pathology, even in animals that lacked anti-RSV neutralizing antibodies prior to RSV challenge. Control of viral loads correlated with antibody binding to the G protein. In contrast, the glycosylated G protein provided poor protection and enhanced lung pathology after RSV challenge. Therefore, bacterially produced unglycosylated G protein holds promise as an economical approach to a protective vaccine against RSV. C1 [Fuentes, Sandra; Coyle, Elizabeth M.; Golding, Hana; Khurana, Surender] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Silver Spring, MD 20993 USA. RP Khurana, S (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Silver Spring, MD 20993 USA. EM Surender.Khurana@fda.hhs.gov NR 61 TC 4 Z9 4 U1 2 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 AUG PY 2015 VL 89 IS 16 BP 8193 EP 8205 DI 10.1128/JVI.00133-15 PG 13 WC Virology SC Virology GA CN2UT UT WOS:000358278200010 PM 26018164 ER PT J AU Rahardja, D Yang, Y AF Rahardja, Dewi Yang, Ying TI Maximum likelihood estimation of a binomial proportion using one-sample misclassified binary data SO STATISTICA NEERLANDICA LA English DT Article DE binary data; double sampling; identifiability; misclassification; contingency table ID FALSE-POSITIVE MISCLASSIFICATION; CONFIDENCE-INTERVALS; BAYESIAN-APPROACH; SUBJECT; SCHEME AB In this article, we construct two likelihood-based confidence intervals (CIs) for a binomial proportion parameter using a double-sampling scheme with misclassified binary data. We utilize an easy-to-implement closed-form algorithm to obtain maximum likelihood estimators of the model parameters by maximizing the full-likelihood function. The two CIs are a naive Wald interval and a modified Wald interval. Using simulations, we assess and compare the coverage probabilities and average widths of our two CIs. Finally, we conclude that the modified Wald interval, unlike the naive Wald interval, produces close-to-nominal CIs under various simulations and, thus, is preferred in practice. Utilizing the expressions derived, we also illustrate our two CIs for a binomial proportion parameter using real-data example. C1 [Rahardja, Dewi; Yang, Ying] US FDA, Silver Spring, MD 20993 USA. RP Rahardja, D (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM rahardja@gmail.com NR 7 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0039-0402 EI 1467-9574 J9 STAT NEERL JI Stat. Neerl. PD AUG PY 2015 VL 69 IS 3 BP 272 EP 280 DI 10.1111/stan.12058 PG 9 WC Statistics & Probability SC Mathematics GA CN4CR UT WOS:000358377200004 ER PT J AU Hung, HMJ Inoue, L Pickering, E Zee, J Kattan, M Shaw, P Weisberg, H Huang, Y Baker, S Mietlowski, WL Wang, SB Ellenberg, S Taylor, J AF Hung, H. M. James Inoue, Lurdes Pickering, Eve Zee, Jarcy Kattan, Michael Shaw, Pamela Weisberg, Herbert Huang, Ying Baker, Stuart Mietlowski, William L. Wang, Songbai Ellenberg, Susan Taylor, Jeremy TI University of Pennsylvania 7th annual conference on statistical issues in clinical trials: Current issues regarding the use of biomarkers and surrogate endpoints in clinical trials (afternoon panel discussion session) SO CLINICAL TRIALS LA English DT Editorial Material C1 [Hung, H. M. James] US FDA, Rockville, MD 20857 USA. [Inoue, Lurdes] Univ Washington, Seattle, WA 98195 USA. [Pickering, Eve] Pfizer Inc, New York, NY USA. [Zee, Jarcy; Shaw, Pamela; Ellenberg, Susan] Univ Penn, Philadelphia, PA 19104 USA. [Kattan, Michael] Cleveland Clin, Cleveland, OH USA. [Huang, Ying] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Baker, Stuart] NCI, Bethesda, MD 20892 USA. [Taylor, Jeremy] Univ Michigan, Ann Arbor, MI 48109 USA. RP Hung, HMJ (reprint author), US FDA, Rockville, MD 20857 USA. NR 12 TC 0 Z9 0 U1 1 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD AUG PY 2015 VL 12 IS 4 BP 365 EP 373 DI 10.1177/1740774515590089 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CN0DA UT WOS:000358081800010 PM 26178573 ER PT J AU Parrett, M AF Parrett, Matt TI Beauty and the feast: Examining the effect of beauty on earnings using restaurant tipping data SO JOURNAL OF ECONOMIC PSYCHOLOGY LA English DT Article DE Wage gap; Beauty; Restaurant tipping; Discrimination ID PHYSICAL ATTRACTIVENESS; LABOR-MARKET; SOCIAL NORM; DISCRIMINATION; GENDER; DETERMINANTS; WAITRESSES; GAME AB This paper looks at the effect of beauty on earnings using restaurant tipping data. Customers were surveyed as they left a set of five Virginia restaurants about the dining experience, their server, and themselves, including about their tip and their server's beauty and productivity. I find that attractive servers earn approximately $1261 more per year in tips than unattractive servers, the primary driver of which is female customers tipping attractive females more than unattractive females. Potential explanations of this earnings gap are drawn from both the labor and experimental economics literatures, the most compelling of which is customer taste-based discrimination. (C) 2015 Elsevier B.V. All rights reserved. C1 [Parrett, Matt] US FDA, Rockville, MD 20857 USA. RP Parrett, M (reprint author), 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM mbparrett@gmail.com FU National Science Foundation [SBE-0241935] FX The opinions and conclusions expressed in this article are solely the views of the author and do not necessarily reflect those of the Food and Drug Administration. Funding for this research was provided by the National Science Foundation (SBE-0241935). I want to thank Sissy Parrett for survey data collection assistance. I want to thank Catherine Eckel, Art Goldsmith, and Phil Grossman for their thoughtful and detailed comments on earlier versions of this paper. Finally, I want to thank the three anonymous referees, as well as the Editor, Ofer Azar, for their insightful comments and suggestions. The usual disclaimer applies. This paper is dedicated to my late father, John Parrett, who saw beauty in everyone and everything, as well as to my late, beautiful daughter, Faith Lexington Parrett. NR 42 TC 0 Z9 0 U1 10 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4870 EI 1872-7719 J9 J ECON PSYCHOL JI J. Econ. Psychol. PD AUG PY 2015 VL 49 BP 34 EP 46 DI 10.1016/j.joep.2015.04.002 PG 13 WC Economics; Psychology, Multidisciplinary SC Business & Economics; Psychology GA CM5XS UT WOS:000357762900003 ER PT J AU Chen, MJ Suzuki, A Borlak, J Andrade, RJ Lucena, MI AF Chen, Minjun Suzuki, Ayako Borlak, Juergen Andrade, Raul J. Lucena, M. Isabel TI Drug-induced liver injury: Interactions between drug properties and host factors SO JOURNAL OF HEPATOLOGY LA English DT Review DE Drug-induced liver injury; Drug physicochemical properties; Host factors; Drug-host Interaction; Pharmacogenetics; Drug metabolism; Drug clearance; Clinical toxicology ID SALT EXPORT PUMP; CELL-DEATH; IDIOSYNCRATIC HEPATOTOXICITY; OXIDATIVE STRESS; ORAL MEDICATIONS; UNITED-STATES; RAT-LIVER; ACETAMINOPHEN HEPATOTOXICITY; SUPEROXIDE-DISMUTASE; INDUCED CHOLESTASIS AB Idiosyncratic drug-induced liver injury (DILI) is a common cause for drug withdrawal from the market and although infrequent, DILI can result in serious clinical outcomes including acute liver failure and the need for liver transplantation. Eliminating the iatrogenic "harm'' caused by a therapeutic intent is a priority in patient care. However, identifying culprit drugs and individuals at risk for DILI remains challenging. Apart from genetic factors predisposing individuals at risk, the role of the drugs' physicochemical and toxicological properties and their interactions with host and environmental factors need to be considered. The influence of these factors on mechanisms involved in DILI is multi-layered. In this review, we summarize current knowledge on 1) drug properties associated with hepatotoxicity, 2) host factors considered to modify an individuals' risk for DILI and clinical phenotypes, and 3) drug-host interactions. We aim at clarifying knowledge gaps needed to be filled in as to improve risk stratification in patient care. We therefore broadly discuss relevant areas of future research. Emerging insight will stimulate new investigational approaches to facilitate the discovery of clinical DILI risk modifiers in the context of disease complexity and associated interactions with drug properties, and hence will be able to move towards safety personalized medicine. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Chen, Minjun] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Suzuki, Ayako] Cent Arkansas Vet Healthcare Syst, Gastroenterol, Little Rock, AR USA. [Suzuki, Ayako] Univ Arkansas Med Sci, Dept Med, Little Rock, AR 72205 USA. [Borlak, Juergen] Hannover Med Sch, Ctr Pharmacol & Toxicol, Hannover, Germany. [Andrade, Raul J.; Lucena, M. Isabel] Univ Malaga, Hosp Univ Virgen de la Victoria, Unidad Gest Clin Enfermedades Digest, Serv Farmacol Clin,Inst Invest Biomed Malaga IBIM, E-29071 Malaga, Spain. [Andrade, Raul J.] CIBERehd, Madrid, Spain. RP Andrade, RJ (reprint author), Fac Med, Dept Med, Blvd Louis Pasteur 32, Malaga 29071, Spain. EM andrade@uma.es FU Agencia Espanola del Medicamento y Productos Sanitarios (AEMPS); Instituto de Salud Carlos III; Virtual Liver Network of the German Federal Ministry of Education and Research (BMBF) [031 6154]; Lower Saxony Ministry of Culture and Sciences; Volkswagen Foundation, Germany [25A.5-7251-99-3/00]; [P10-CTS-6470]; [PI12-00620]; [PI12-00378] FX This study was supported by the research grant P10-CTS-6470, PI12-00620, PI12-00378 and the Agencia Espanola del Medicamento y Productos Sanitarios (AEMPS). CIBERehd is funded by Instituto de Salud Carlos III.r Author JB gratefully acknowledges support from The Virtual Liver Network (grant 031 6154) of the German Federal Ministry of Education and Research (BMBF). Part of this work was also funded by the Lower Saxony Ministry of Culture and Sciences and the Volkswagen Foundation, Germany to JB. Grant number: 25A.5-7251-99-3/00. NR 141 TC 30 Z9 30 U1 5 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD AUG PY 2015 VL 63 IS 2 BP 503 EP 514 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CM8YX UT WOS:000357991700029 PM 25912521 ER PT J AU Schiel, JE Rogstad, SM Boyne, MT AF Schiel, John E. Rogstad, Sarah M. Boyne, Michael T., II TI Comparison of Traditional 2-AB Fluorescence LC-MS/MS and Automated LC-MS for the Comparative Glycan Analysis of Monoclonal Antibodies SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE Mass spectrometry; Fluorescence spectroscopy; Glycosylation; Monoclonal antibody; LC-MS ID MASS-SPECTROMETRY; IMMUNOGLOBULIN-G; IDENTIFICATION; GLYCOSYLATION; GLYCOPROTEINS; AFFINITY; BINDING AB Monoclonal antibody therapeutics are a heterogeneous mixture of glycoforms. Multiple methods exist for defining the glycan composition and relative abundance of species present. In the current report, two MS-based methods were compared for their ability to both identify glycans and monitor differences in the glycoprofile. Gross changes in the glycoprofile can be identified either by visual inspection of fluorescence profiles and correlated to glycan identities when coupled with online MS/MS (LC-F-MS/MS) or through extracted ion chromatograms using LC-MS. In the present study, both an LC-F-MS/MS method and an automated LC-MS label free approach were able to identify minor differences in low abundance glycoforms, and data indicate a disparity in glycosylation between the analyzed batches of US and foreign-sourced mAb X. Thus, either method may be useful in characterizing monoclonal antibody therapeutics products and could serve as a potential screening test for understanding process, comparability, similarity, and possibly detecting counterfeit agents. Published 2015. This article is a U.S. Government work and is in the public domain in the USA 104:2464-2472, 2015 C1 [Schiel, John E.] NIST, Biomol Measurement Div, Gaithersburg, MD 20899 USA. [Rogstad, Sarah M.; Boyne, Michael T., II] US FDA, Div Pharmaceut Res, Off Testing & Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Rogstad, SM (reprint author), US FDA, Div Pharmaceut Res, Off Testing & Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Sarah.Rogstad@fda.hhs.gov NR 19 TC 4 Z9 4 U1 4 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD AUG PY 2015 VL 104 IS 8 BP 2464 EP 2472 DI 10.1002/jps.24522 PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA CM9EM UT WOS:000358009700008 PM 26053232 ER PT J AU Rahman, Z Mohammad, A Akhtar, S Siddiqui, A Korang-Yeboah, M Khan, MA AF Rahman, Ziyaur Mohammad, Adil Akhtar, Sohail Siddiqui, Akhtar Korang-Yeboah, Maxwell Khan, Mansoor A. TI Chemometric Model Development and Comparison of Raman and C-13 Solid-State Nuclear Magnetic Resonance-Chemometric Methods for Quantification of Crystalline/Amorphous Warfarin Sodium Fraction in the Formulations SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE crystallinity; amorphous; Raman spectroscopy; solid state NMR; partial least squares ID QUANTITATIVE-ANALYSIS; PHARMACEUTICAL SOLIDS; SPECTROSCOPY; DISPERSION; POLYMORPHS; TACROLIMUS; TABLETS; FORMS AB Warfarin sodium (WS) exists in multiple solid-state forms. The solid-state forms differ in physicochemical properties, and crystalline changes in the drug formulation may influence on the drug product quality and/or clinical performance. It is, therefore, critically important to have a good and reliable analytical method to monitor and quantitate this transformation during stability studies. The aim of the present research was to investigate Raman spectroscopy and solid-state nuclear magnetic resonance (C-13 ssNMR) methods in conjunction with chemometry to quantitate the amorphous and crystalline WS fractions in the drug products. Compositionally identical formulations of amorphous and crystalline WS were prepared, and mixed in various proportions to make 0%-100% amorphous/crystalline sample matrices. Raman and C-13 ssNMR spectra were collected and subjected to partial-least-squares and principle component regressions after mathematical treatment of the data. The model performance parameters such as root-mean-square error of prediction, standard error of prediction, and bias were low for Raman models in comparison to C-13 ssNMR models. Models predicted values of the independent sample matrices match closely with the actual values at high level of crystalline WS. Thus, the developed methods provide means to control and quantitate the WS forms fraction in the drug product. Published 2015. This article is a U.S. Government work and is in the public domain in the USA 104:2550-2558, 2015 C1 [Rahman, Ziyaur; Mohammad, Adil; Akhtar, Sohail; Siddiqui, Akhtar; Korang-Yeboah, Maxwell; Khan, Mansoor A.] US FDA, Div Prod Qual & Res, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Khan, MA (reprint author), US FDA, Div Prod Qual & Res, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. EM Mansoor.Khan@fda.hhs.gov OI Rahman, Ziyaur/0000-0002-0402-825X NR 29 TC 7 Z9 7 U1 1 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD AUG PY 2015 VL 104 IS 8 BP 2550 EP 2558 DI 10.1002/jps.24524 PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA CM9EM UT WOS:000358009700017 PM 26096869 ER PT J AU Gray, MD Lacher, DW Leonard, SR Abbott, J Zhao, S Lampel, KA Prothery, E Gouali, M Weill, FX Maurelli, AT AF Gray, M. D. Lacher, D. W. Leonard, S. R. Abbott, J. Zhao, S. Lampel, K. A. Prothery, E. Gouali, M. Weill, F. -X. Maurelli, A. T. TI Prevalence of Shiga toxin-producing Shigella species isolated from French travellers returning from the Caribbean: an emerging pathogen with international implications SO CLINICAL MICROBIOLOGY AND INFECTION LA English DT Article DE Dominican Republic; Haiti; Shiga toxin; Shigella ID HEMOLYTIC-UREMIC SYNDROME; POLYMERASE-CHAIN-REACTION; ESCHERICHIA-COLI; VEROTOXIN GENES; SEQUENCE; RELEASE AB Shiga toxins (Stxs) are potent cytotoxins that inhibit host cell protein synthesis, leading to cell death. Classically, these toxins are associated with intestinal infections due to Stx-producing Escherichia coli or Shigella dysenteriae serotype 1, and infections with these strains can lead to haemolytic-uraemic syndrome. Over the past decade, there has been increasing recognition that Stx is produced by additional Shigella species. We recently reported the presence and expression of stx genes in Shigella flexneri 2a clinical isolates. The toxin genes were carried by a new stx-encoding bacteriophage, and infection with these strains correlated with recent travel to Haiti or the Dominican Republic. In this study, we further explored the epidemiological link to this region by utilizing the French National Reference Centre for Escherichia coli, Shigella and Salmonella collection to survey the frequency of Stx-producing Shigella species isolated from French travellers returning from the Caribbean. Approximately 21% of the isolates tested were found to encode and produce Stx. These isolates included strains of S. flexneri 2a, S. flexneri Y, and S. dysenteriae 4. All of the travellers who were infected with Stx-producing Shigella had recently travelled to Haiti, the Dominican Republic, or French Guiana. Furthermore, whole genome sequencing showed that the toxin genes were encoded by a prophage that was highly identical to the phage that we identified in our previous study. These findings demonstrate that this new stx-encoding prophage is circulating within that geographical area, has spread to other continents, and is capable of spreading to multiple Shigella serogroups. Clinical Microbiology and Infection published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. C1 [Gray, M. D.; Maurelli, A. T.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Lacher, D. W.; Leonard, S. R.; Abbott, J.; Zhao, S.; Lampel, K. A.] US FDA, Laurel, MD USA. [Prothery, E.; Gouali, M.; Weill, F. -X.] Ctr Natl Reference Escherichia Coli Shigella & Sa, Unite Bacteries Pathogenes Enter, Inst Pasteur, Paris, France. RP Maurelli, AT (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. EM anthony.maurelli@usuhs.edu OI Weill, Francois-Xavier/0000-0001-9941-5799 FU Institut de Veille Sanitaire; French Government's Investissement d'Avenir program [ANR-10-LABX-62-IBEID]; National Institute of Allergy and Infectious Diseases [R01A124656] FX We thank all of the corresponding laboratories of the FNRC-ESS network. We thank I. Carle, M. Lejay-Collin, C. Ruckly, S. Darnell and R. Fernandez for their excellent technical assistance. The FNRC-ESS is co-funded by the Institut de Veille Sanitaire. The Unite des Bacteries Pathogenes Enteriques belongs to the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence funded by the French Government's Investissement d'Avenir program (grant no. ANR-10-LABX-62-IBEID). This work was also supported by grant R01A124656 from the National Institute of Allergy and Infectious Diseases. The results included herein were previously presented at the 49th US-Japan Conference on Cholera and Other Enteric Bacterial Infections and the 2015 Mid-Atlantic Microbial Pathogenesis Meeting. The opinions or assertions contained herein are the private ones of the authors, and are not to be construed as official or reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences. NR 20 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1198-743X EI 1469-0691 J9 CLIN MICROBIOL INFEC JI Clin. Microbiol. Infect. PD AUG PY 2015 VL 21 IS 8 AR 765.e9 DI 10.1016/j.cmi.2015.05.006 PG 6 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA DU2BC UT WOS:000382014500009 PM 25980352 ER PT J AU Gurev, V Pathmanathan, P Fattebert, JL Wen, HF Magerlein, J Gray, RA Richards, DF Rice, JJ AF Gurev, Viatcheslav Pathmanathan, Pras Fattebert, Jean-Luc Wen, Hui-Fang Magerlein, John Gray, Richard A. Richards, David F. Rice, J. Jeremy TI A high-resolution computational model of the deforming human heart SO BIOMECHANICS AND MODELING IN MECHANOBIOLOGY LA English DT Article DE Cardiac mechanics; Soft tissue mechanics; Parallel computations; Ventricular model ID HUMAN LEFT-VENTRICLE; INDEFINITE LINEAR-SYSTEMS; ELASTICITY PROBLEMS; CARDIAC TISSUE; STRAIN; CONTRACTION; SIMULATION; ALGORITHM; ELECTROPHYSIOLOGY; ELECTROMECHANICS AB Modeling of the heart ventricles is one of the most challenging tasks in soft tissue mechanics because cardiac tissue is a strongly anisotropic incompressible material with an active component of stress. In most current approaches with active force, the number of degrees of freedom (DOF) is limited by the direct method of solution of linear systems of equations. We develop a new approach for high-resolution heart models with large numbers of DOF by: (1) developing a hex-dominant finite element mixed formulation and (2) developing a Krylov subspace iterative method that is able to solve the system of linearized equations for saddle-point problems with active stress. In our approach, passive cardiac tissue is modeled as a hyperelastic, incompressible material with orthotropic properties, and mixed pressure-displacement finite elements are used to enforce incompressibility. Active stress is generated by a model with force dependence on length and velocity of muscle shortening. The ventricles are coupled to a lumped circulatory model. For efficient solution of linear systems, we use Flexible GMRES with a nonlinear preconditioner based on block matrix decomposition involving the Schur complement. Three methods for approximating the inverse of the Schur complement are evaluated: inverse of the pressure mass matrix; least squares commutators; and sparse approximate inverse. The sub-matrix corresponding to the displacement variables is preconditioned by a V-cycle of hybrid geometric-algebraic multigrid followed by correction with several iterations of GMRES preconditioned by sparse approximate inverse. The overall solver is demonstrated on a high-resolution two ventricle mesh based on a human anatomy with roughly 130 K elements and 1.7 M displacement DOF. Effectiveness of the numerical method for active contraction is shown. To the best of our knowledge, this solver is the first to efficiently model ventricular contraction using an iterative linear solver for the mesh size demonstrated and therefore opens the possibility for future very high-resolution models. In addition, several relatively simple benchmark problems are designed for a verification exercise to show that the solver is functioning properly and correctly solves the underlying mathematical model. Here, the output of the newly designed solver is compared to that of the mechanics component of Chaste ('Cancer, Heart and Soft Tissue Environment'). These benchmark tests may be used by other researchers to verify their newly developed methods and codes. C1 [Gurev, Viatcheslav; Wen, Hui-Fang; Magerlein, John; Rice, J. Jeremy] IBM Res, Thomas J Watson Res Ctr, Yorktown Hts, NY 10598 USA. [Pathmanathan, Pras; Gray, Richard A.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Fattebert, Jean-Luc; Richards, David F.] Lawrence Livermore Natl Lab, Livermore, CA 94551 USA. RP Pathmanathan, P (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM vgurev@us.ibm.com; pras.pathmanathan@fda.hhs.gov; fattebert1@llnl.gov; hfwen@us.ibm.com; mager@us.ibm.com; richard.gray@fda.hhs.gov; richards12@llnl.gov; johnrice@us.ibm.com FU US Department of Energy by Lawrence Livermore National Laboratory [DE-AC52-07NA27344] FX We thank Tzanio Kolev and Ulrike Meier Yang from the Hypre team at Lawrence Livermore National Laboratory for very informative discussions. The work of J.-L. Fattebert and D. F. Richards was performed under the auspices of the US Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. NR 59 TC 7 Z9 7 U1 1 U2 12 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1617-7959 EI 1617-7940 J9 BIOMECH MODEL MECHAN JI Biomech. Model. Mechanobiol. PD AUG PY 2015 VL 14 IS 4 BP 829 EP 849 DI 10.1007/s10237-014-0639-8 PG 21 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA CL9ZZ UT WOS:000357339300011 PM 25567753 ER PT J AU Dykstra, K Mehrotra, N Tornoe, CW Kastrissios, H Patel, B Al-Huniti, N Jadhav, P Wang, YN Byon, W AF Dykstra, Kevin Mehrotra, Nitin Tornoe, Christoffer Wenzel Kastrissios, Helen Patel, Bela Al-Huniti, Nidal Jadhav, Pravin Wang, Yaning Byon, Wonkyung TI Reporting guidelines for population pharmacokinetic analyses SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE Population pharmacokinetics; Best practices; PK reporting; Regulatory submission ID MODEL AB The purpose of this work was to develop a consolidated set of guiding principles for the reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting, and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (in which population PK frequently serves as preparatory analysis for exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider 2 main purposes of population PK reports: (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified 2 main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results; and (2) a scientifically literate but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with 6 questions that need to be addressed throughout the report. We recommend 8 sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step toward industrialization of the field of pharmacometrics such that a nontechnical audience also understands the role of pharmacometric analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports including pharmacokinetics/pharmacodynamics and simulation reports. C1 [Dykstra, Kevin] qPharmetra LLC, Andover, MA 01810 USA. [Mehrotra, Nitin; Wang, Yaning] US FDA, Div Pharmacometr, Silver Spring, MD USA. [Tornoe, Christoffer Wenzel] Clin Reporting, Copenhagen, Denmark. [Kastrissios, Helen] Novo Nordisk AS, Pharsight Consulting Serv, St Louis, MO USA. [Patel, Bela] GlaxoSmithKline, Quantitat Sci, Clin Pharmacol, King Of Prussia, PA USA. [Al-Huniti, Nidal] AstraZeneca, Quantitat Clin Pharmacol, Waltham, MA USA. [Jadhav, Pravin] Merck & Co Inc, Quantitat Pharmacol & Pharmacometr, Whitehouse Stn, NJ USA. [Byon, Wonkyung] Pfizer Inc, Global Innovat Pharma Business Clin Pharmacol, Groton, CT 06340 USA. RP Dykstra, K (reprint author), qPharmetra LLC, 9 Nollet, Andover, MA 01810 USA. EM kevin.dykstra@qpharmetra.com NR 11 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD AUG PY 2015 VL 55 IS 8 BP 875 EP 887 DI 10.1002/jcph.532 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CM2BY UT WOS:000357485800006 PM 26148467 ER PT J AU Presse, N Potvin, S Bertrand, B Calvo, MS Ferland, G AF Presse, Nancy Potvin, Stephanie Bertrand, Benoit Calvo, Mona S. Ferland, Guylaine TI Phylloquinone content of herbs, spices and seasonings SO JOURNAL OF FOOD COMPOSITION AND ANALYSIS LA English DT Article DE Food composition; Food analysis; Culinary herbs; Phylloquinone; Seasonings; Spices; Vitamin K; Nutrient databases ID DIETARY VITAMIN-K; CULINARY HERBS; FOOD SOURCES; VEGETABLES; THERAPY; ADULTS AB Culinary herbs and spices contain a variety of bioactive compounds including phylloquinone, the most common dietary form of vitamin K. In this study, we analyzed the phylloquinone content of a large number of commonly available culinary herbs, spices, and seasonings. Samples of fresh herbs (n = 19), dried herbs (n = 28), spices and seeds (n = 26), seasoning blends (n = 9), and other flavor enhancers (n = 11) were purchased in Montreal (Quebec, Canada) and Washington (DC, USA). All samples were analyzed in quadruplicate using standardized HPLC procedures. Most fresh herbs contained between 450 and 1200 mu g of phylloquinone/100 g. Dried herbs were even richer with some (cilantro, marjoram, parsley) showing concentrations of approximate to 13000 mu g/100 g. Phylloquinone content of spices and seeds was relatively low (5-250 mu g/100 g), while being highly variable among seasoning blends (2.3-1878 mu g/100 g). According to our results, portions of only 3 g of herbs can increase daily intakes of phylloquinone by up to 100 mu g, contributing significantly to the daily vitamin K intake. Herbs can thus be important food sources of phylloquinone and should be accounted for when assessing vitamin K intakes in research or in patients treated with vitamin K antagonists. Future research should focus on the bioavailability of phylloquinone in these products. (C) 2015 Elsevier Inc. All rights reserved. C1 [Presse, Nancy; Ferland, Guylaine] Inst Univ Geriatrie Montreal, Ctr Rech, Montreal, PQ, Canada. [Potvin, Stephanie; Bertrand, Benoit; Ferland, Guylaine] Univ Montreal, Fac Med, Dept Nutr, Montreal, PQ H3C 3J7, Canada. [Calvo, Mona S.] US FDA, Div Toxicol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD USA. [Ferland, Guylaine] Hop Sacre Coeur, Ctr Rech, Montreal, PQ H4J 1C5, Canada. RP Ferland, G (reprint author), Hop Sacre Coeur, Ctr Rech, 5400 Boul Gouin Ouest, Montreal, PQ H4J 1C5, Canada. EM guylaine.ferland@umontreal.ca OI Bertrand, Benoit/0000-0002-1374-1743 NR 29 TC 1 Z9 1 U1 4 U2 21 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1575 EI 1096-0481 J9 J FOOD COMPOS ANAL JI J. Food Compos. Anal. PD AUG PY 2015 VL 41 BP 15 EP 20 DI 10.1016/j.jfca.2014.12.020 PG 6 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA CK4IP UT WOS:000356187800002 ER PT J AU Wycoff, W Luo, RS Schauss, AG Neal-Kababick, J Sabaa-Srur, AUO Maia, JGS Tran, K Richards, KM Smith, RE AF Wycoff, Wei Luo, Rensheng Schauss, Alexander G. Neal-Kababick, James Sabaa-Srur, Armando U. O. Maia, Jose Guilherme S. Tran, Kevin Richards, Kristy M. Smith, Robert E. TI Chemical and nutritional analysis of seeds from purple and white acai (Euterpe oleracea Mart.) SO JOURNAL OF FOOD COMPOSITION AND ANALYSIS LA English DT Article DE Acai; Acai seeds; Euterpe oleracea Mart.; NMR; Triglycerides; Fats; Phytochemical composition; Polyphenols; Emphysema; Food composition; Food analysis ID AMAZONIAN PALM BERRY; PROTON NMR; CAPACITY; JUICE; OILS AB Seeds from the purple and the white fruit produced by the Amazonian palm, Euterpe oleracea Mart., commonly called "acai", were analyzed by solid state H-1-decoupled C-13 CPMAS and MAS NMR, solution NMR and LC-MS/MS. The goal was to distinguish the seeds from each colored fruit and determine their spectra for the first time. The seeds of each variety contained primarily glycosidic carbons, due to their cellulose and hemicellulose content. They also contained carbons due to C=O, C=C, as well as aliphatic carbons. The insoluble fiber found in acai pulp is distinguishable from the seed of the fruit by its unique solid state H-1-decoupled C-13 CPMAS NMR spectra. The seed also contains fats (0.22-0.33%) not previously reported. The seed contains a mixture of saturated and unsaturated fats. There are also 3.38-4.70% total methanolic extractables, with no detectable cyanidin 3-O-glucoside or cyanidin 3-O-rutinoside, unlike the pulp which contains both cyanidins. When the NMR spectra of the white and purple acai seeds are compared, it was possible to observe differences between these two acai varieties, as well as differences between the composition of pulp of the fruit and its seed. Published by Elsevier Inc. C1 [Wycoff, Wei] Univ Missouri, Columbia, MO 65211 USA. [Luo, Rensheng] Univ Missouri, St Louis, MO 63121 USA. [Schauss, Alexander G.] AIBMR Life Sci, Nat & Med Prod Res, Puyallup, WA 98373 USA. [Neal-Kababick, James] Flora Res Labs, Unit B, Grants Pass, OR 97526 USA. [Sabaa-Srur, Armando U. O.] Univ Fed Rural Rio de Janeiro, Programa Posgrad Ciencia & Tecnol Alimento, BR-23851970 Seropedica, RJ, Brazil. [Maia, Jose Guilherme S.] Fed Univ Para, Programa Posgrad Quim, BR-66075900 Belem, Pa, Brazil. [Tran, Kevin; Richards, Kristy M.; Smith, Robert E.] US FDA, Total Diet & Pesticide Res Ctr, Lenexa, KS 66214 USA. RP Smith, RE (reprint author), US FDA, Total Diet & Pesticide Res Ctr, 11510 W 80th St, Lenexa, KS 66214 USA. EM robert.smith@fda.hhs.gov NR 25 TC 2 Z9 3 U1 5 U2 58 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1575 EI 1096-0481 J9 J FOOD COMPOS ANAL JI J. Food Compos. Anal. PD AUG PY 2015 VL 41 BP 181 EP 187 DI 10.1016/j.jfca.2015.01.021 PG 7 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA CK4IP UT WOS:000356187800025 ER PT J AU Spindel, S Balsam, J Mattay, G Sapsford, KE AF Spindel, Samantha Balsam, Joshua Mattay, Govind Sapsford, Kim E. TI Investigating low volume planar surface fluorescent immunoassays with QDs for spatial and spectral multiplexing SO SENSORS AND ACTUATORS B-CHEMICAL LA English DT Article DE Point-of-care; Quantum dot; Evanescent; Waveguide; Multiplex; SEB ID RESONANCE ENERGY-TRANSFER; STAPHYLOCOCCAL-ENTEROTOXIN; QUANTUM DOTS; BIOSENSORS; SAMPLES; ELISA AB The simultaneous detection of two analytes, chicken IgY (IgG) and Staphylococcal enterotoxin B (SEB), in a single spot of a planar surface fluorescent immunoassay was demonstrated using luminescent semiconductor quantum dot nanocrystal (QD) tracers. This spectral multiplexing is made possible by employing one laser to serve as the excitation source for detecting two distinct QD signals from different analytes. Spatial multiplexing - detection of two analytes in different regions of the planar surface - was also demonstrated using fluid handling constructs that allowed for very low solution volumes when performing the assay. The limits of detection for detecting both chicken IgG and SEB within a single spot were 25 ng/mL and 1.6 ng/mL, respectively. A novel slide reading detection platform involving evanescent wave excitation of a planar surface was created in-house for assay measurement. This platform is potentially more amenable to a point-of-care (POC) environment than conventional slide readers because of its modular design architecture and lack of moving parts. The result is a platform which is simple to repair using primarily off-the-shelf consumer components. Published by Elsevier BM. C1 [Spindel, Samantha; Balsam, Joshua; Sapsford, Kim E.] US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Mattay, Govind] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. RP Spindel, S (reprint author), US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Samantha.spindel@fda.hhs.gov; joshua.balsam@fda.hhs.gov; mattayg@seas.upenn.edu; kim.sapsford@fda.hhs.gov FU Division of Biology, Chemistry, and Materials Science FX The authors acknowledge the support from Dr. Marilyn Light-foote and Dr. Benjamin Fisher and the Division of Biology, Chemistry, and Materials Science for financial support. The authors appreciate the review of this article by Megan Young. The authors also thank eBiosciences for QD materials. NR 19 TC 1 Z9 1 U1 2 U2 22 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0925-4005 J9 SENSOR ACTUAT B-CHEM JI Sens. Actuator B-Chem. PD AUG PY 2015 VL 215 BP 396 EP 404 DI 10.1016/j.snb.2015.03.061 PG 9 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation SC Chemistry; Electrochemistry; Instruments & Instrumentation GA CH6FG UT WOS:000354131200052 ER PT J AU Pava-Ripoll, M Pearson, REG Miller, AK Tall, BD Keys, CE Ziobro, GC AF Pava-Ripoll, Monica Pearson, Rachel E. Goeriz Miller, Amy K. Tall, Ben D. Keys, Christine E. Ziobro, George C. TI Ingested Salmonella enterica, Cronobacter sakazakii, Escherichia coli O157:H7, and Listeria monocytogenes: transmission dynamics from adult house flies to their eggs and first filial (F-1) generation adults SO BMC MICROBIOLOGY LA English DT Article ID MUSCA-DOMESTICA DIPTERA; REGULATORY ACTION CRITERIA; CALCITRANS L. DIPTERA; ENTEROBACTER-SAKAZAKII; STOMOXYS-CALCITRANS; BACTERIAL SYMBIONTS; TEMPOROSPATIAL FATE; STABLE FLIES; CATTLE FARM; FILTH FLIES AB Background: The mechanical transmission of pathogenic bacteria by synanthropic filth flies is widely recognized. While many studies report the fate and the temporospatial distribution of ingested foodborne bacteria by filth flies, there is little evidence about the transmission dynamics of ingested foodborne bacteria by adult house flies (Musca domestica) to their progeny. In this study, we fed parental house fly adults with food contaminated with low, medium, and high concentrations of Salmonella enterica, Cronobacter sakazakii, Escherichia coli O157:H7, and Listeria monocytogenes and evaluated the probability of transmission of these pathogens to house fly eggs and the surface and the alimentary canal of their first filial (F-1) generation adults. Results: All foodborne pathogens were present in samples containing pooled house fly eggs. The probability of transmission was higher after parental house flies ingested food containing medium bacterial loads. Cronobacter sakazakii was 16, 6, and 3 times more likely to be transmitted to house fly eggs than S. enterica, E. coli O157: H7, and L. monocytogenes, respectively. Only S. enterica and C. sakazakii were transmitted to F-1 generation adults and their presence was 2.4 times more likely on their body surfaces than in their alimentary canals. The highest probabilities of finding S. enterica (60 %) and C. sakazakii (28 %) on newly emerged F-1 adults were observed after parental house flies ingested food containing medium and high levels of these pathogens, respectively. Conclusion: Our study demonstrates that adult house flies that fed from food contaminated with various levels of foodborne bacteria were able to transmit those pathogens to their eggs and some were further transmitted to newly emerged F-1 generation adults, enhancing the vector potential of these insects. Understanding the type of associations that synanthropic filth flies establish with foodborne pathogens will help to elucidate transmission mechanisms and possible ways to mitigate the spread of foodborne pathogens. C1 [Pava-Ripoll, Monica; Pearson, Rachel E. Goeriz; Miller, Amy K.; Ziobro, George C.] US FDA, Ctr Food Safety & Appl Nutr, Off Food Safety, College Pk, MD 20740 USA. [Tall, Ben D.] US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. [Keys, Christine E.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. RP Pava-Ripoll, M (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Food Safety, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Monica.Pava-Ripoll@fda.hhs.gov NR 72 TC 0 Z9 1 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD JUL 31 PY 2015 VL 15 AR 150 DI 10.1186/s12866-015-0478-5 PG 12 WC Microbiology SC Microbiology GA CN9JH UT WOS:000358762600001 PM 26228457 ER PT J AU McFarland, HI Berkson, JD Lee, JP Elkahloun, AG Mason, KP Rosenberg, AS AF McFarland, Hugh I. Berkson, Julia D. Lee, Jay P. Elkahloun, Abdel G. Mason, Karen P. Rosenberg, Amy S. TI Rescue of CD8+T cell vaccine memory following sublethal gamma irradiation SO VACCINE LA English DT Article ID IONIZING-RADIATION; LISTERIA-MONOCYTOGENES; T-CELLS; LYMPHOCYTES; INDUCTION; RESPONSES; EXPOSURE; RADIOSENSITIVITY; TRANSPLANTATION; EXPRESSION AB Sublethal gamma irradiation eliminates CD8+ T cell mediated memory responses. In this work, we explored how these memory responses could be rescued in the aftermath of such exposure. We utilized two models of CD8+ T cell mediated immunity: a mouse model of Listeria monocytogenes (LM) infection in which CD8+ T cells specific for LM expressed antigens (Listeriolysin 0, LLO) can be tracked, and a murine skin graft model in which CD8+ T cells mediate rejection across a MHC class I (D-d) disparity. In the LM immunized mice, LLO specific CD8+ T memory cells were lost on irradiation, preserved with rapid revaccination with an attenuated strain 1-3 days post-irradiation (PI), and these mice survived a subsequent wild type LM challenge. A genetic "signature of rescue" identified a group of immune-associated mRNA maintained or upregulated following irradiation and rescue. A number of these factors, including IL-36 gamma, dectin-2 (Clec4n), and mir101c are upregulated rapidly after exposure of mice to sublethal gamma radiation alone and are sustained by early, but not later rescue. Such factors will be evaluated as potential therapeutics to replace individual vaccines for global rescue of CD8+ T memory cell responses following sublethal gamma irradiation. The skin allograft model mirrored that of the LM model in that the accelerated D-d skin allograft rejection response was lost in mice exposed to sublethal gamma radiation, but infusion of allogeneic D-d expressing bone marrow cells 1-4 days PI preserved the CD8+ T memory mediated accelerated rejection response, further suggesting that innate immune responses may not always be essential to rescue of CD8+ memory T cells following gamma irradiation. Published by Elsevier Ltd. C1 [McFarland, Hugh I.; Berkson, Julia D.; Lee, Jay P.; Mason, Karen P.; Rosenberg, Amy S.] US FDA, Div Res & Review 3, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Elkahloun, Abdel G.] NHGRI, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. [Lee, Jay P.] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20037 USA. [Mason, Karen P.] NIAID, Intramural Adm Branch, NIH, Bethesda, MD 20892 USA. RP McFarland, HI (reprint author), US FDA, Div Res & Review 3, Off Biotechnol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM hugh.mcfarland@fda.hhs.gov; julia.berkson@fda.hhs.gov; jlee17@gwmail.gwu.edu; abdel@nhgri.nih.gov; karen.mason2@nih.gov; amy.rosenberg@fda.hhs.gov RI McFarland, Hugh/K-1503-2016 OI McFarland, Hugh/0000-0002-3322-038X FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; U.S. Food and Drug Administration Medical Countermeasures Initiative FX We wish to thank Dr. Sing Sing Way and Dr. Karen Elkins for kindly providing the Listeria monocytogenes strains, Weiwei Wu for microarray technical assistance, and Drs. Michael Norcross and Daniela Verthelyi for advice and careful reading of the manuscript. This research was supported [in part] by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, and the U.S. Food and Drug Administration Medical Countermeasures Initiative. NR 26 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUL 31 PY 2015 VL 33 IS 32 BP 3865 EP 3872 DI 10.1016/j.vaccine.2015.06.070 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CN5HN UT WOS:000358460500013 PM 26122582 ER PT J AU Chung, KY Coyle, EM Jani, D King, LR Bhardwaj, R Fries, L Smith, G Glenn, G Golding, H Khurana, S AF Chung, Ka Yan Coyle, Elizabeth M. Jani, Dewal King, Lisa R. Bhardwaj, Rukmini Fries, Louis Smith, Gale Glenn, Gregory Golding, Hana Khurana, Surender TI ISCOMATRIX (TM) adjuvant promotes epitope spreading and antibody affinity maturation of influenza A H7N9 virus like particle vaccine that correlate with virus neutralization in humans SO VACCINE LA English DT Article DE H7N9; Pandemic; Influenza; Vaccine; Phage display; Antibody affinity; Neutralization; Virus; Adjuvant; Epitope; ISCOMATRIX (ISCO); Hemagglutinin; H7N7 ID PROTECTIVE IMMUNE-RESPONSES; RANDOMIZED CLINICAL-TRIAL; T-CELL RESPONSES; AVIAN INFLUENZA; THERAPEUTIC VACCINES; RECEPTOR-BINDING; ANTIGEN DELIVERY; MF59 ADJUVANT; H5N1 VIRUS; FERRETS AB In a previously reported phase I clinical trial, subjects vaccinated with two doses of an unadjuvanted H7N9 virus like particle (VLP) vaccine responded poorly (15.6% seroconversion rates with 45 mu g hemagglutinin (HA) dose). In contrast, 80.6% of subjects receiving H7N9 VLP vaccine (5 mu g HA) with ISCOMATRIX (TM) adjuvant developed hemagglutination-inhibition (HI) responses. To better understand the role of adjuvant, complete antibody epitope repertoires of post-vaccination sera were investigated using Whole Genome Fragment Phage Display Library (GFPDL). In addition, antibody affinity maturation following vaccination was measured against HA1 and HA2 antigenic domains using real time Surface Plasmon Resonance (SPR) based kinetic assays. Unadjuvanted H7N9-VLP vaccine generated primarily antibodies targeting the C-terminus of the HA1 domain, predicted to be mostly buried on the native HA spikes, while adjuvanted VLP vaccine generated antibodies against large epitopes in the HA1 spanning the receptor binding domain (RBD). SPR analysis using a functional H7-HA1 domain demonstrated that sera from adjuvanted H7N9-VLP vaccine induced higher total binding antibodies and significantly higher antibody affinity maturation to HA1 compared to sera from unadjuvanted vaccine. Total antibody binding and affinity to the HA1 (but not HA2) domain correlated with HI and neutralization titers. This study demonstrates that ISCOMATRIX (TM) adjuvanted vaccine promotes higher quality antibody immune response against avian influenza in naive humans. Published by Elsevier Ltd. C1 [Chung, Ka Yan; Coyle, Elizabeth M.; King, Lisa R.; Bhardwaj, Rukmini; Golding, Hana; Khurana, Surender] FDA, Div Viral Prod, CBER, Silver Spring, MD 20993 USA. [Jani, Dewal; Fries, Louis; Smith, Gale; Glenn, Gregory] Novavax, Gaithersburg, MD 20878 USA. RP Khurana, S (reprint author), FDA, Div Viral Prod, CBER, Silver Spring, MD 20993 USA. EM surender.khurana@fda.hhs.gov FU internal FDA/CBER PANFLU funds; Novavax FX All the data in the current study were generated at CBER. This work was supported by internal FDA/CBER PANFLU funds. The Phase I clinical trial [14] was funded by Novavax. NR 38 TC 8 Z9 8 U1 1 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUL 31 PY 2015 VL 33 IS 32 BP 3953 EP 3962 DI 10.1016/j.vaccine.2015.06.047 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CN5HN UT WOS:000358460500027 PM 26093202 ER PT J AU de Puig, H Tam, JO Yen, CW Gehrke, L Hamad-Schifferli, K AF de Puig, Helena Tam, Justina O. Yen, Chun-Wan Gehrke, Lee Hamad-Schifferli, Kimberly TI Extinction Coefficient of Gold Nanostars SO JOURNAL OF PHYSICAL CHEMISTRY C LA English DT Article ID OPTICAL-PROPERTIES; METAL NANOPARTICLES; RAMAN-SCATTERING; NANORODS; SIZE; SHAPE; ABSORPTION; SPECTRA; BINDING; IGG AB Gold nanostars (NStars) are highly attractive for biological applications due to their surface Chemistry, facile synthesis, and optical properties. Here, we synthesize NStars in HEPES buffer at different HEPES/Au ratios, producing NStars of different sies and shapes and therefore varying optical properties. We measure the extinction coefficient of the synthesized NStars at their maximum surface plasmon resonances (SPIks), which range from 5.7 x 10(8) to 26.8 X 10(8) M-1 cm(-1). Measured values correlate with those obtained from theoretical models of the NStars using the discrete dipole approximation (DDA), which we use to simulate the extinction spectra of the nariostars. Finally, because NStars are typically used in biological applications, we conjugate DNA and antibodies to the NStars. and calculate the footprint of the bound biomolecules. C1 [de Puig, Helena; Hamad-Schifferli, Kimberly] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Tam, Justina O.; Yen, Chun-Wan; Gehrke, Lee] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Hamad-Schifferli, Kimberly] Univ Massachusetts, Dept Engn, Boston, MA 02125 USA. [Tam, Justina O.; Yen, Chun-Wan] US FDA, Winchester Engn Analyt Ctr, Winchester, MA 01890 USA. [Gehrke, Lee] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. RP Hamad-Schifferli, K (reprint author), MIT, Dept Mech Engn, Cambridge, MA 02139 USA. EM lgehrke@mit.edu; schiffer@mit.edu FU NIH NIAID [AI100190]; MIT-SUTD IDC; Rafael del Pino Fellowship FX Funding was from NIH NIAID (AI100190). HdP was funded by MIT-SUTD IDC and a Rafael del Pino Fellowship. The authors would like to thank the CMSE at MIT for the use of their equipment facilities. Authors would like to thank Dr. Vlad Liberman for advice on the simulations and Prof. Kim Vandiver and Prof. Sunho Park for fruitful discussions. NR 47 TC 13 Z9 13 U1 16 U2 39 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1932-7447 J9 J PHYS CHEM C JI J. Phys. Chem. C PD JUL 30 PY 2015 VL 119 IS 30 BP 17408 EP 17415 DI 10.1021/acs.jpcc.5b03624 PG 8 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA CO3BP UT WOS:000359031900042 PM 28018519 ER PT J AU Allman, WR Dey, R Liu, LH Siddiqui, S Coleman, AS Bhattacharya, P Yano, M Uslu, K Takeda, K Nakhasi, HL Akkoyunlu, M AF Allman, Windy R. Dey, Ranadhir Liu, Lunhua Siddiqui, Shafiuddin Coleman, Adam S. Bhattacharya, Parna Yano, Masahide Uslu, Kadriye Takeda, Kazuyo Nakhasi, Hira L. Akkoyunlu, Mustafa TI TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility to Leishmania infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE TACI; BAFF; APRIL; macrophage; Leishmania ID NF-KAPPA-B; CUTANEOUS LEISHMANIASIS; MAJOR INFECTION; BAFF; EXPRESSION; CELLS; MICE; RECEPTOR; APRIL; POLARIZATION AB The TNF family member, transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), is a key molecule for plasma cell maintenance and is required in infections where protection depends on antibody response. Here, we report that compared with WT mouse, TACI KO M phi s expressed lower levels of Toll-like receptors (TLRs), CD14, myeloid differentiation primary response protein 88, and adaptor protein Toll/IL-1 receptor domaincontaining adapter-inducing IFN-beta and responded poorly to TLR agonists. Analysis of M phi phenotype revealed that, in the absence of TACI, M phi s adapt the alternatively activated (M2) phenotype. Steady-state expression levels for M2 markers IL-4R alpha, CD206, CCL22, IL-10, Arg1, IL1RN, and FIZZ1 were significantly higher in TACI KO M phi than in WT cells. Confirming their M2 phenotype, TACI-KO M phi s were unable to control Leishmania major infection in vitro, and intradermal inoculation of Leishmania resulted in a more severe manifestation of disease than in the resistant C57BL/6 strain. Transfer of WT M phi s to TACI KO mice was sufficient to significantly reduce disease severity. TACI is likely to influence M phi phenotype by mediating B cell-activating factor belonging to the TNF family (BAFF) and a proliferation inducing ligand (APRIL) signals because both these ligands down-regulated M2 markers in WT but not in TACI-deficient M phi s. Moreover, treatment of M phi s with BAFF or APRIL enhanced the clearance of Leishmania from cells only when TACI is expressed. These findings may have implications for understanding the shortcomings of host response in newborns where TACI expression is reduced and in combined variable immunodeficiency patients where TACI signaling is ablated. C1 [Allman, Windy R.; Liu, Lunhua; Siddiqui, Shafiuddin; Coleman, Adam S.; Yano, Masahide; Uslu, Kadriye; Akkoyunlu, Mustafa] US FDA, Lab Bacterial Polysaccharides, Div Bacterial Parasit & Allergen Prod, Silver Spring, MD 20993 USA. [Dey, Ranadhir; Bhattacharya, Parna; Nakhasi, Hira L.] US FDA, Div Emerging & Transfus Transmitted Dis, Silver Spring, MD 20993 USA. [Takeda, Kazuyo] US FDA, Microscopy & Imaging Core Facil, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Akkoyunlu, M (reprint author), US FDA, Lab Bacterial Polysaccharides, Div Bacterial Parasit & Allergen Prod, Silver Spring, MD 20993 USA. EM mustafa.akkoyunlu@fda.hhs.gov FU US Food and Drug Administration; Oak Ridge Institute for Science and Education (Oak Ridge, TN) FX We thank Dr. Alain Debrabant (Center for Biologics Evaluation and Research/US Food and Drug Administration) for providing L. major RFP parasites. This project is supported by intramural funds from the US Food and Drug Administration. W.R.A., A.S.C., K.U., and M.Y. were supported by postdoctoral fellowships from the Oak Ridge Institute for Science and Education (Oak Ridge, TN). NR 52 TC 2 Z9 2 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 28 PY 2015 VL 112 IS 30 BP E4094 EP E4103 DI 10.1073/pnas.1421580112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN7ZW UT WOS:000358656500017 PM 26170307 ER PT J AU Yang, Y Manda, P Pavurala, N Khan, MA Krishnaiah, YSR AF Yang, Yang Manda, Prashanth Pavurala, Naresh Khan, Mansoor A. Krishnaiah, Yellela S. R. TI Development and validation of in vitro-in vivo correlation (IVIVC) for estradiol transdermal drug delivery systems SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE In vitro-in vivo correlation (IVIVC); Estradiol; Transdermal; Permeation; Absorption; Validation ID STRATUM-CORNEUM; PERMEATION; SKIN; BIOAVAILABILITY; CLASSIFICATION; MENOREST(R); ABSORPTION; CLIMARA(R); WATER AB The objective of this studywas to develop a level A in vitro-in vivo correlation (IVIVC) for drug-in-adhesive (DIA) type estradiol transdermal drug delivery systems (TDDS). In vitro drug permeation studies across human skin were carried out to obtain the percent of estradiol permeation from marketed products. The in vivo time versus plasma concentration data of three estradiol TDDS at drug loadings of 2.0, 3.8 and 7.6 mg (delivery rates of 25, 50 and 100 mu g/day, respectively) was deconvoluted usingWagner-Nelson method to obtain percent of in vivo drug absorption in postmenopausal women. The IVIVC between the in vitro percent of drug permeation (X) and in vivo percent of drug absorption (Y) for these three estradiol TDDS was constructed using GastroPlus software. There was a high correlation (R-2= 1.0) with a polynomial regression of Y = -0.227X(2) + 0.331X - 0.001. These three estradiol TDDS were used for internal validation whereas another two products of the same formulation design (with delivery rates of 60 and 100 mu g/day) were used for external validation. The predicted estradiol serum concentrations (convoluted from in vitro skin permeation data) were compared with the observed serum concentrations for the respective products. The developed IVIVC model passed both the internal and external validations as the prediction errors (% PE) for C-max and AUC were less than 15%. When anothermarketed estradiol TDDS with a delivery rate of 100 mu g/day but with a slight variation in formulation design was chosen, it did not pass external validation indicating the product-specific nature of IVIVC model. Results suggest that the IVIVC model developed in this study can be used to successfully predict the in vivo performance of the same estradiol TDDS with in vivo delivery rates ranging from 25 to 100 mu g/day. Published by Elsevier B.V. C1 [Yang, Yang; Manda, Prashanth; Pavurala, Naresh; Khan, Mansoor A.; Krishnaiah, Yellela S. R.] US FDA, DPQR, OTR, OPQ,CDER, Silver Spring, MD 20993 USA. RP Krishnaiah, YSR (reprint author), US FDA, DPQR, OTR, OPQ,CDER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM krishnaiah.yellela@fda.hhs.gov RI Manda, Prashanth/A-9950-2016 OI Manda, Prashanth/0000-0001-5667-3528 FU CDER's Regulatory Science and Review Enhancement Grant [RSR 13-25]; National Cancer Institute FX The authors acknowledge the funding support from the CDER's Regulatory Science and Review Enhancement Grant (Grant # RSR 13-25). Surgically discarded human skin samples were provided by the Cooperative Human Tissue Network which is funded by the National Cancer Institute. Other investigators may have received the specimens from the same subjects. NR 37 TC 11 Z9 11 U1 5 U2 28 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 EI 1873-4995 J9 J CONTROL RELEASE JI J. Control. Release PD JUL 28 PY 2015 VL 210 BP 58 EP 66 DI 10.1016/j.jconrel.2015.05.263 PG 9 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA CK5CC UT WOS:000356238700007 PM 25979329 ER PT J AU Wang, Z Wu, NB Tesfaye, A Feinstone, S Kumar, A AF Wang, Zhao Wu, Ningbin Tesfaye, Abeba Feinstone, Stephen Kumar, Ajit TI HCV infection-associated hepatocellular carcinoma in humanized mice SO INFECTIOUS AGENTS AND CANCER LA English DT Article DE HCV Infection-associated HCC ID LIPID PHOSPHATASE-ACTIVITY; PTEN TUMOR-SUPPRESSOR; C VIRUS-REPLICATION; LIVER-CANCER; IN-VIVO; NUCLEAR PTEN; STEM-CELLS; HEPATITIS; MICRORNA; PROTEIN AB Background and Aims: Hepatitis C virus (HCV) infection is a major risk factor for chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). Our aim is to explore molecular changes that underlie HCV infection-associated HCC in a humanized mouse model, in order to identify markers of HCC progression. Methods: Liver proteins from human hepatocyte-engrafted and HCV-infected MUP-uPA/SCID/Bg mice were compared with either uninfected controls or HCV-infected but HCC-negative mice by Western blotting. MicroRNA markers of HCC positive or uninfected mouse liver were analyzed by RT-PCR. Results: We describe the depletion of tumor suppressor proteins and induction of oncoproteins and oncogenic microRNAs (oncomiRs) in HCV-infection associated HCC. Similar depletion of PTEN protein in both HCC-positive and HCV-infected but HCC-negative liver suggests that PTEN depletion is an early, precancerous marker of HCC. By contrast, induction of oncoprotein cMyc, oncomiRs (miR21, miR221 and miR141) and inflammatory response proteins correspond to HCC progression. Conclusions: While the loss of PTEN is important for the initiation of HCV infection-associated HCC, PTEN depletion by itself is insufficient for tumor progression. Liver tumor progression requires induction of oncoproteins and oncomiRs. Overall, human hepatocyte-engrafted (MUP-uPA/SCID/Bg) mice provide a suitable small animal model for studying the effects of oncogenic changes that promote HCV infection associated HCC. C1 [Wang, Zhao; Wu, Ningbin; Feinstone, Stephen; Kumar, Ajit] George Washington Univ, Dept Biochem & Mol Med, Washington, DC 20037 USA. [Tesfaye, Abeba; Feinstone, Stephen] FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD 20892 USA. [Kumar, Ajit] George Washington Univ, Biochem & Mol Med, Washington, DC 20037 USA. RP Kumar, A (reprint author), George Washington Univ, Dept Biochem & Mol Med, Washington, DC 20037 USA. EM akumar@gwu.edu FU GWU Katzen Cancer Research funds; McCormick Genomics Research funds in Biochemistry FX The research was supported in part from GWU Katzen Cancer Research funds and the McCormick Genomics Research funds in Biochemistry. We thank Alison Kaufmann for reading the manuscript. NR 50 TC 1 Z9 1 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-9378 J9 INFECT AGENTS CANCER JI Infect. Agents Cancer PD JUL 27 PY 2015 VL 10 AR 24 DI 10.1186/s13027-015-0018-9 PG 9 WC Oncology; Immunology SC Oncology; Immunology GA CN5MR UT WOS:000358473900001 PM 26217396 ER PT J AU Awotwe-Otoo, D Agarabi, C Read, EK Lute, S Brorson, KA Khan, MA AF Awotwe-Otoo, David Agarabi, Cyrus Read, Erik K. Lute, Scott Brorson, Kurt A. Khan, Mansoor A. TI Product and process understanding to relate the effect of freezing method on glycation and aggregation of lyophilized monoclonal antibody formulations SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Lyophilization; Glycation; Monoclonal antibody; Super-cooling; Controlled nucleation; Uncontrolled nucleation ID PROTEIN FORMULATIONS; PRACTICAL ADVICE; NUCLEATION; SUCROSE; DESIGN AB The objective of the study was to analyze the effect of controlled and uncontrolled freezing step of a lyophilization process on the extent of non-enzymatic glycation and aggregation of an IgG1 formulation at two concentrations (1 mg/ml and 20 mg/ml). The degree of glycation (%) was determined through boronate affinity chromatography and its effect on the formation of soluble aggregates and higher molecular weight species was studied using dynamic light scattering (DLS) and size exclusion chromatography with multi-angle light scattering (SEC-MALS). The effect of non-enzymatic glycation on the secondary structure of the formulations was also studied using circular dichroism (CD) spectroscopy and Fourier transform infrared (FT-IR) spectroscopy. Results indicated that controlled nucleation yielded higher residual moisture contents and significantly lower specific surface areas for the two monoclonal antibody concentrations compared with uncontrolled nucleation cycle (p < 0.05). For the two concentrations, uncontrolled nucleation resulted in significantly higher levels of glycation compared with controlled nucleation samples (p < 0.05). Further, it was observed that higher storage temperatures (25 degrees C/60% RH) versus 5 degrees C resulted in higher glycation. Even though SEC-MALS analyses of the low concentrated formulations did not reveal the formation of higher molecular weight species, DLS analyses at two storage conditions revealed increases in the hydrodynamic radii and polydispersity index of the reconstituted formulations, suggesting the onset of formation of smaller species in the formulations. CD spectroscopy did not reveal any differences in the secondary structure of the mAb for the two concentrations after lyophilization. In conclusion, the freezing step method impacted the extent of glycation in lyophilized samples and the hydrolyzed component of sucrose was critical for increasing glycation. Even though some level of glycation was observed in lyophilized samples, the native structure of the protein was not affected. Further, it was demonstrated that storage of both lyophilized cakes and reconstituted formulations at higher temperatures could increase the extent of glycation in monoclonal antibody formulations. Published by Elsevier B.V. C1 [Awotwe-Otoo, David; Agarabi, Cyrus; Khan, Mansoor A.] CDER, FDA, OPS, Div Prod Qual Res,Off Testing & Res, Rockville, MD 20857 USA. [Read, Erik K.; Lute, Scott; Brorson, Kurt A.] CDER, FDA, OPS, Div Monoclonal Antibodies,Off Biotechnol Prod, Rockville, MD USA. RP Khan, MA (reprint author), CDER, FDA, OPS, Div Prod Qual Res,Off Testing & Res, Rockville, MD 20857 USA. EM Mansoor.Khan@fda.hhs.gov NR 20 TC 1 Z9 1 U1 1 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD JUL 25 PY 2015 VL 490 IS 1-2 BP 341 EP 350 DI 10.1016/j.ijpharm.2015.03.056 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CL3FV UT WOS:000356836700039 PM 25835267 ER PT J AU James, L Yan, K Pence, L Simpson, P Bhattacharyya, S Gill, P Letzig, L Kearns, G Beger, R AF James, Laura Yan, Ke Pence, Lisa Simpson, Pippa Bhattacharyya, Sudeepa Gill, Pritmohinder Letzig, Lynda Kearns, Gregory Beger, Richard TI Comparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity SO PLOS ONE LA English DT Article ID ACUTE LIVER-FAILURE; INDUCED HEPATOTOXICITY; LIQUID-CHROMATOGRAPHY; DRUG-METABOLISM; HEPATIC-INJURY; NITRIC-OXIDE; OVERDOSE; SERUM; TAURINE; HEPATOCYTES AB Metabolomics approaches have enabled the study of new mechanisms of liver injury in experimental models of drug toxicity. Disruption of bile acid homeostasis is a known mechanism of drug induced liver injury. The relationship of individual bile acids to indicators of oxidative drug metabolism (acetaminophen protein adducts) and liver injury was examined in children with acetaminophen overdose, hospitalized children with low dose exposure to acetaminophen, and children with no recent exposure to acetaminophen. Nine bile acids were quantified through targeted metabolomic analysis in the serum samples of the three groups. Bile acids were compared to serum levels of acetaminophen protein adducts and alanine aminotransferase. Glycodeoxycholic acid, taurodeoxycholic acid, and glycochenodeoxycholic acid were significantly increased in children with acetaminophen overdose compared to healthy controls. Among patients with acetaminophen overdose, bile acids were higher in subjects with acetaminophen protein adduct values > 1.0 nmol/mL and modest correlations were noted for three bile acids and acetaminophen protein adducts as follows: taurodeoxycholic acid (R=0.604; p<0.001), glycodeoxycholic acid (R=0.581; p<0.001), and glycochenodeoxycholic acid (R=0.571; p<0.001). Variability in bile acids was greater among hospitalized children receiving low doses of acetaminophen than in healthy children with no recent acetaminophen exposure. Compared to bile acids, acetaminophen protein adducts more accurately discriminated among children with acetaminophen overdose, children with low dose exposure to acetaminophen, and healthy control subjects. In children with acetaminophen overdose, elevations of conjugated bile acids were associated with specific indicators of acetaminophen metabolism and non-specific indicators of liver injury. C1 [James, Laura; Bhattacharyya, Sudeepa; Gill, Pritmohinder; Letzig, Lynda] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72202 USA. [James, Laura; Bhattacharyya, Sudeepa; Gill, Pritmohinder; Letzig, Lynda] Arkansas Childrens Hosp, Res Inst, Little Rock, AR 72202 USA. [Yan, Ke; Simpson, Pippa] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Pence, Lisa; Beger, Richard] Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. [Kearns, Gregory] Childrens Mercy Hosp, Div Pediat Pharmacol Med Toxicol & Therapeut Inno, Kansas City, MO 64108 USA. RP James, L (reprint author), Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72202 USA. EM jameslaurap@uams.edu FU National Institutes of Diabetes, Digestive and Kidney Diseases of the United States Department of Health and Human Services [DK75936]; Arkansas Biosciences Institute; Arkansas Tobacco Settlement Funds FX This work was funded in part by a grant (DK75936 to LJ) from the National Institutes of Diabetes, Digestive and Kidney Diseases of the United States Department of Health and Human Services and the Arkansas Biosciences Institute which is funded by Arkansas Tobacco Settlement Funds. NR 43 TC 2 Z9 2 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 24 PY 2015 VL 10 IS 7 AR e0131010 DI 10.1371/journal.pone.0131010 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN7NT UT WOS:000358622000014 PM 26208104 ER PT J AU Levy, MJ Gucinski, AC Boyne , MT AF Levy, Michaella J. Gucinski, Ashley C. Boyne, Michael T., II TI Primary Sequence Confirmation of a Protein Therapeutic Using Top Down MS/MS and MS3 SO ANALYTICAL CHEMISTRY LA English DT Article AB Mass spectrometry has gained widespread acceptance for the characterization of protein therapeutics as a part of the regulatory approval process. Improvements in mass spectrometer sensitivity, resolution, and mass accuracy have enabled more detailed and confident analysis of larger biomolecules for confirming amino acid sequences, assessing sequence variants, and characterizing post translational modifications. This work demonstrates the suitability of a combined approach using intact MS and multistage top down MS/MS analyses for the characterization of a protein therapeutic drug. The protein therapeutic granulocyte-colony stimulating factor was analyzed using a Thermo Fusion Tribrid mass spectrometer using a multistage top down MS approach. Intact mass analysis identified the presence of two disulfide bonds based on exact mass shifts while a combined collision induced dissociation (CID), higher-energy collisional dissociation (HCD), and electron transfer dissociation (ETD) MS/MS approach obtained 80% protein sequence coverage. Isolating MS/MS fragments for MS3 analysis using HCD or CID increased the sequence coverage to 89%. 95% sequence coverage was obtained by reducing human granulocyte-colony stimulating factor (G-CSF) prior to MS/MS and MS3 analysis to specifically target the residues between the disulfide bonds. The use of this combined intact MS and multistage top down MS approach allows for rapid and accurate determination of the primary sequence of a protein therapeutic drug product. C1 [Levy, Michaella J.; Gucinski, Ashley C.; Boyne, Michael T., II] US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Pharmaceut Anal, St Louis, MO 63110 USA. RP Gucinski, AC (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Pharmaceut Anal, 645 S Newstead Ave, St Louis, MO 63110 USA. EM Ashley.gucinski@fda.hhs.gov NR 0 TC 2 Z9 2 U1 1 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD JUL 21 PY 2015 VL 87 IS 14 BP 6995 EP 6999 DI 10.1021/acs.analchem.5b01113 PG 5 WC Chemistry, Analytical SC Chemistry GA CN6PE UT WOS:000358555900003 PM 26086621 ER PT J AU Mudalige, TK Qu, HO Linder, SW AF Mudalige, Thilak K. Qu, Haiou Linder, Sean W. TI Asymmetric Flow-Field Flow Fractionation Hyphenated ICP-MS as an Alternative to Cloud Point Extraction for Quantification of Silver Nanoparticles and Silver Speciation: Application for Nanoparticles with a Protein Corona SO ANALYTICAL CHEMISTRY LA English DT Article ID ENVIRONMENTAL WATERS; ANTIBACTERIAL PRODUCTS; TRACE SILVER; SEPARATION; NANOMATERIALS; IONS AB Production and application of nanoparticles in consumer products is at an all-time high due to the emerging field of nanotechnology. Direct detection and quantification of trace levels of nanoparticles within consumer products is very challenging and problematic. Although multiple methodologies are available for this purpose, each method has its own set of limitations. Herein, we developed an analytical platform consisting of asymmetric flow-field flow fractionation (AF4) coupled with inductively coupled plasma mass spectroscopy (ICP-MS) for the speciation and quantification of silver ions and silver nanoparticles at the ng/kg level (ppt). AF4 is utilized to concentrate the nanoparticles, and ICP-MS acts as the detector. The protein corona that forms upon exposure of nanoparticles to bovine serum albumin was utilized as a nanoparticle stabilization and AF4 recovery enhancement mechanism. Speciation of silver ions and nanoparticles was achieved with the assistance of penicillamine as a complexation ligand. The effect of nanoparticle size, surface coating, and ionization state toward the detection and quantification of the developed methodology was evaluated. The detection limit was found to be 4 ng/kg with the application of a 5 mL sample loop. Further application of this developed methodology on environmentally relevant samples was demonstrated by the analysis of Arkansas River water spiked with silver nanoparticles and nanoparticle spiked into humic acid solution (50 mg/L) at an environmentally relevant level. C1 [Mudalige, Thilak K.; Qu, Haiou; Linder, Sean W.] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, Jefferson, AR 72079 USA. RP Mudalige, TK (reprint author), US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM thilak.mudalige@fda.hhs.gov; sean.linder@fda.hhs.gov NR 31 TC 14 Z9 15 U1 8 U2 59 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD JUL 21 PY 2015 VL 87 IS 14 BP 7395 EP 7401 DI 10.1021/acs.analchem.5b01595 PG 7 WC Chemistry, Analytical SC Chemistry GA CN6PE UT WOS:000358555900056 PM 26095720 ER PT J AU Laschinger, JC Ibrahim, NG Zuckerman, BD AF Laschinger, John C. Ibrahim, Nicole G. Zuckerman, Bram D. TI Mitral Valve Academic Research Consortium Consensus Report The US Food and Drug Administration Perspective SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE heart failure; mitral regurgitation; mitral valve; valve intervention; valve surgery C1 [Laschinger, John C.; Ibrahim, Nicole G.; Zuckerman, Bram D.] Food & Drug Adm, Off Device Evaluat, Ctr Devices & Radiol Hlth, Struct Heart Device Branch, Silver Spring, MD 20993 USA. RP Laschinger, JC (reprint author), Food & Drug Adm, Off Device Evaluat, Ctr Devices & Radiol Hlth, Struct Heart Device Branch, 10903 New Hampshire Ave,WO66,Room 1266, Silver Spring, MD 20993 USA. EM John.Laschinger@fda.hhs.gov NR 2 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 21 PY 2015 VL 66 IS 3 BP 322 EP 323 DI 10.1016/j.jacc.2015.05.045 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CN2PH UT WOS:000358263700013 PM 26184624 ER PT J AU Blinova, K Stohlman, J Chan, D Hortigon, M Rodriquez, VZ Smith, G Crumb, W Pang, L Lyn-Cook, B Vicente, J Johannesen, L Stockbridge, N Stockbridge, N Strauss, D AF Blinova, Ksenia Stohlman, Jayna Chan, Dulciana Hortigon, Maria Rodriquez, Victor Z. Smith, Godfrey Crumb, William Pang, Li Lyn-Cook, Beverly Vicente, Jose Johannesen, Lars Stockbridge, Norman Stockbridge, Norman Strauss, David TI Assessing Proarrhythmic Potential of Drugs Using Human Induced Pluripotent Stem Cell Derived Cardiomyocytes and Optical Recordings With Voltage-sensitive Dyes SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT American-Stroke-Association/American-Heart-Association Basic Cardiovascular Sciences Scientific Sessions - Pathways to Cardiovascular Therapeutics CY JUL 13-16, 2015 CL New Orleans, LA SP Amer Stroke Assoc, Amer Heart Assoc, Council Basic Cardiovascular Sci DE translational research; drug-induced arrhythmias; induced pluripotent stem cell cardiomyocytes C1 [Blinova, Ksenia; Stohlman, Jayna; Chan, Dulciana; Vicente, Jose; Johannesen, Lars; Stockbridge, Norman; Stockbridge, Norman; Strauss, David] US FDA, Silver Spring, MD USA. [Hortigon, Maria; Rodriquez, Victor Z.] Clyde Biosci, Glasgow, Lanark, Scotland. [Smith, Godfrey] Univ Glasgow, Glasgow, Lanark, Scotland. [Crumb, William] Zenas Technol, Metairie, LA USA. [Pang, Li; Lyn-Cook, Beverly] US FDA, Jefferson, AR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JUL 17 PY 2015 VL 117 SU 1 MA 245 PG 2 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DJ9SI UT WOS:000374552800218 ER PT J AU Donaldson, FE Nyman, E Coburn, JC AF Donaldson, Finn E. Nyman, Edward, Jr. Coburn, James C. TI Prediction of contact mechanics in metal-on-metal Total Hip Replacement for parametrically comprehensive designs and loads SO JOURNAL OF BIOMECHANICS LA English DT Article DE Total Hip Arthroplasty; Wear; Contact mechanics; Metal-on-Metal; Finite element analysis; Surrogate models ID ELASTOHYDRODYNAMIC LUBRICATION; ACETABULAR COMPONENT; POLYETHYLENE WEAR; BEARING SURFACE; ION LEVELS; PROSTHESES; CUP; ARTHROPLASTY; IMPLANT; FORMULATION AB Manufacturers and investigators of Total Hip Replacement (THR) bearings require tools to predict the contact mechanics resulting from diverse design and loading parameters. This study provides contact mechanics solutions for metal-on-metal (MoM) bearings that encompass the current design space and could aid pre-clinical design optimization and evaluation. Stochastic finite element (FE) simulation was used to calculate the head-on-cup contact mechanics for five thousand combinations of design and loading parameters. FE results were used to train a Random Forest (RF) surrogate model to rapidly predict the contact patch dimensions, contact area, pressures and plastic deformations for arbitrary designs and loading. In addition to widely observed polar and edge contact, FE results included ring-polar, asymmetric-polar, and transitional categories which have previously received limited attention. Combinations of design and load parameters associated with each contact category were identified. Polar contact pressures were predicted in the range of 0-200 MPa with no permanent deformation. Edge loading (with subluxation) was associated with pressures greater than 500 MPa and induced permanent deformation in 83% of cases. Transitional-edge contact (with little subluxation) was associated with intermediate pressures and permanent deformation in most cases, indicating that, even with ideal anatomical alignment, bearings may face extreme wear challenges. Surrogate models were able to accurately predict contact mechanics 18,000 times faster than FE analyses. The developed surrogate models enable rapid prediction of MoM bearing contact mechanics across the most comprehensive range of loading and designs to date, and may be useful to those performing bearing design optimization or evaluation. Published by Elsevier Ltd. C1 [Donaldson, Finn E.; Nyman, Edward, Jr.; Coburn, James C.] US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth,Off Med Prod & Tobacco, Silver Spring, MD 20993 USA. RP Donaldson, FE (reprint author), US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Rm 1202A,Bldg 62,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Finn.Donaldson@fda.hhs.gov FU Critical Path Initiative from the Center for Devices and Radiological Health of the FDA; Office of Women's Health of the FDA FX The authors would like to acknowledge the Critical Path Initiative from the Center for Devices and Radiological Health, and the Office of Women's Health, both of the FDA, for funding this work. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the U.S. Department of Health and Human Services. NR 43 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 EI 1873-2380 J9 J BIOMECH JI J. Biomech. PD JUL 16 PY 2015 VL 48 IS 10 BP 1828 EP 1835 DI 10.1016/j.jbiomech.2015.04.037 PG 8 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA CN5HG UT WOS:000358459800021 PM 25980556 ER PT J AU Bowyer, JF Tranter, KM Hanig, JP Crabtree, NM Schleimer, RP George, NI AF Bowyer, John F. Tranter, Karen M. Hanig, Joseph P. Crabtree, Nathaniel M. Schleimer, Robert P. George, Nysia I. TI Evaluating the Stability of RNA-Seq Transcriptome Profiles and Drug-Induced Immune-Related Expression Changes in Whole Blood SO PLOS ONE LA English DT Article ID SICKLE-CELL-DISEASE; GENE-EXPRESSION; ADHESION MOLECULES; DENDRITIC CELLS; INFLAMMATION; PATHOGENESIS; MECHANISMS; IDENTITY; SYSTEM; ARRAYS AB Methods were developed to evaluate the stability of rat whole blood expression obtained from RNA sequencing (RNA-seq) and assess changes in whole blood transcriptome profiles in experiments replicated over time. Expression was measured in globin-depleted RNA extracted from the whole blood of Sprague-Dawley rats, given either saline (control) or neurotoxic doses of amphetamine (AMPH). The experiment was repeated four times (paired control and AMPH groups) over a 2-year span. The transcriptome of the control and AMPH-treated groups was evaluated on: 1) transcript levels for ribosomal protein subunits; 2) relative expression of immune-related genes; 3) stability of the control transcriptome over 2 years; and 4) stability of the effects of AMPH on immune-related genes over 2 years. All, except one, of the 70 genes that encode the 80s ribosome had levels that ranked in the top 5% of all mean expression levels. Deviations in sequencing performance led to significant changes in the ribosomal transcripts. The overall expression profile of immune-related genes and genes specific to monocytes, T-cells or B-cells were well represented and consistent within treatment groups. There were no differences between the levels of ribosomal transcripts in time-matched control and AMPH groups but significant differences in the expression of immune-related genes between control and AMPH groups. AMPH significantly increased expression of some genes related to monocytes but down-regulated those specific to T-cells. These changes were partially due to changes in the two types of leukocytes present in blood, which indicate an activation of the innate immune system by AMPH. Thus, the stability of RNA-seq whole blood transcriptome can be verified by assessing ribosomal protein subunits and immune-related gene expression. Such stability enables the pooling of samples from replicate experiments to carry out differential expression analysis with acceptable power. C1 [Bowyer, John F.; Tranter, Karen M.; Crabtree, Nathaniel M.] US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. [George, Nysia I.] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Hanig, Joseph P.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Schleimer, Robert P.] Northwestern Feinberg Sch Med, Div Allergy & Immunol, Chicago, IL USA. RP Bowyer, JF (reprint author), US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. EM john.bowyer@fda.hhs.gov FU NCTR/FDA [E7295, E7519]; National Institute of General Medical Sciences under the Institutional Development Award (IDeA) Program of the National Institutes of Health (NIH); NIH [R37HL068546, R01HL078860, U19AI106683]; Ernest S. Bazley Foundation FX Research animals, their housing and reagents were funded under NCTR/FDA protocols E7295 and E7519. Nathan Crabtree is a graduate student in Bioinformatics, Department of Information Science, at the University of Arkansas Little Rock and his research is supported by E7519 and Arkansas IDeA Network of Biomedical Research Excellence (Arkansas INBRE) which received funds from the National Institute of General Medical Sciences under the Institutional Development Award (IDeA) Program of the National Institutes of Health (NIH). Dr. Schleimer was supported by NIH grants R37HL068546, R01HL078860 and U19AI106683 from the NIH and by the Ernest S. Bazley Foundation. NR 66 TC 1 Z9 1 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 15 PY 2015 VL 10 IS 7 AR e0133315 DI 10.1371/journal.pone.0133315 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1RL UT WOS:000358197600241 PM 26177368 ER PT J AU Sarachana, T Dahiya, N Simhadri, VL Pandey, GS Saini, S Guelcher, C Guerrera, MF Kimchi-Sarfaty, C Sauna, ZE Atreya, CD AF Sarachana, Tewarit Dahiya, Neetu Simhadri, Vijaya L. Pandey, Gouri Shankar Saini, Surbhi Guelcher, Christine Guerrera, Michael F. Kimchi-Sarfaty, Chava Sauna, Zuben E. Atreya, Chintamani D. TI Small ncRNA Expression-Profiling of Blood from Hemophilia A Patients Identifies miR-1246 as a Potential Regulator of Factor 8 Gene SO PLOS ONE LA English DT Article ID FACTOR-VIII; MUTATION; MICRORNAS; RNAS AB Hemophilia A (HA) is a bleeding disorder caused by deficiency of functional plasma clotting factor VIII (FVIII). Genetic mutations in the gene encoding FVIII (F8) have been extensively studied. Over a thousand different mutations have been reported in the F8 gene. These span a diverse range of mutation types, namely, missense, splice-site, deletions of single and multiple exons, inversions, etc. There is nonetheless evidence that other molecular mechanisms, in addition to mutations in the gene encoding the FVIII protein, may be involved in the pathobiology of HA. In this study, global small ncRNA expression profiling analysis of whole blood from HA patients, and controls, was performed using high-throughput ncRNA microarrays. Patients were further sub-divided into those that developed neutralizing-anti-FVIII antibodies (inhibitors) and those that did not. Selected differentially expressed ncRNAs were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. We identified several ncRNAs, and among them hsa-miR-1246 was significantly up-regulated in HA patients. In addition, miR-1246 showed a six-fold higher expression in HA patients without inhibitors. We have identified an miR-1246 target site in the noncoding region of F8 mRNA and were able to confirm the suppressory role of hsa-miR-1246 on F8 expression in a stable lymphoblastoid cell line expressing FVIII. These findings suggest several testable hypotheses vis-a-vis the role of nc-RNAs in the regulation of F8 expression. These hypotheses have not been exhaustively tested in this study as they require carefully curated clinical samples. C1 [Sarachana, Tewarit; Dahiya, Neetu; Atreya, Chintamani D.] US FDA, Lab Cellular Hematol, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Sarachana, Tewarit] Chulalongkorn Univ, Fac Allied Hlth Sci, Dept Clin Chem, Bangkok 10330, Thailand. [Simhadri, Vijaya L.; Pandey, Gouri Shankar; Saini, Surbhi; Kimchi-Sarfaty, Chava; Sauna, Zuben E.] US FDA, Lab Hemostasis, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Saini, Surbhi; Guelcher, Christine; Guerrera, Michael F.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Guerrera, Michael F.] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20037 USA. RP Sauna, ZE (reprint author), US FDA, Lab Hemostasis, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM zuben.sauna@fda.hhs.gov; chintamani.atreya@fda.hhs.gov FU Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, D. C; CBER, FDA intramural funding FX Research conducted in the laboratories of CDA and ZES is funded by the CBER, FDA intramural funding. SS received a fellowship from the Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, D. C. NR 25 TC 1 Z9 1 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 15 PY 2015 VL 10 IS 7 AR e0132433 DI 10.1371/journal.pone.0132433 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1RL UT WOS:000358197600112 PM 26176629 ER PT J AU Calif, RM Ostrof, S AF Calif, Robert M. Ostrof, Stephen TI FDA as a catalyst for translation SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material C1 [Calif, Robert M.] US FDA, Med Prod & Tobacco, US Dept HHS, Silver Spring, MD 20993 USA. [Ostrof, Stephen] US FDA, US Dept HHS, Silver Spring, MD 20993 USA. RP Calif, RM (reprint author), US FDA, Med Prod & Tobacco, US Dept HHS, Silver Spring, MD 20993 USA. EM robert.calif@fda.hhs.gov NR 6 TC 1 Z9 1 U1 0 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 15 PY 2015 VL 7 IS 296 AR 296ed9 DI 10.1126/scitranslmed.aab2404 PG 4 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CN9AQ UT WOS:000358738400001 PM 26180098 ER PT J AU Basarab, GS Kern, GH McNulty, J Mueller, JP Lawrence, K Vishwanathan, K Alm, RA Barvian, K Doig, P Galullo, V Gardner, H Gowravaram, M Huband, M Kimzey, A Morningstar, M Kutschke, A Lahiri, SD Perros, M Singh, R Schuck, VJA Tommasi, R Walkup, G Newman, JV AF Basarab, Gregory S. Kern, Gunther H. McNulty, John Mueller, John P. Lawrence, Kenneth Vishwanathan, Karthick Alm, Richard A. Barvian, Kevin Doig, Peter Galullo, Vincent Gardner, Humphrey Gowravaram, Madhusudhan Huband, Michael Kimzey, Amy Morningstar, Marshall Kutschke, Amy Lahiri, Sushmita D. Perros, Manos Singh, Renu Schuck, Virna J. A. Tommasi, Ruben Walkup, Grant Newman, Joseph V. TI Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases SO SCIENTIFIC REPORTS LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; SERIOUSLY ILL-PATIENTS; DNA GYRASE INHIBITOR; NEISSERIA-GONORRHOEAE; QUINOLONE RESISTANCE; ESCHERICHIA-COLI; INFECTION MODELS; PHARMACODYNAMICS; MULTIDRUG; THERAPY AB With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors. Organisms resistant to other topoisomerase inhibitors were not cross-resistant with ETX0914 nor were spontaneous resistant mutants to ETX0914 cross-resistant with other topoisomerase inhibitor classes, including the widely used fluoroquinolone class. Preclinical evaluation of ETX0914 pharmacokinetics and pharmacodynamics showed distribution into vascular tissues and efficacy in a murine Staphylococcus aureus infection model that served as a surrogate for predicting efficacious exposures for the treatment of Neisseria gonorrhoeae infections. A wide safety margin to the efficacious exposure in toxicological evaluations supported progression to Phase 1. Dosing ETX0914 in human volunteers showed sufficient exposure and minimal adverse effects to expect a highly efficacious anti-gonorrhea therapy. C1 [Basarab, Gregory S.; Singh, Renu] Univ Cape Town, Dept Chem, Drug Discovery & Dev Ctr, ZA-7701 Rondebosch, South Africa. [Kern, Gunther H.; Vishwanathan, Karthick; Alm, Richard A.; Doig, Peter; Galullo, Vincent; Kimzey, Amy; Kutschke, Amy; Lahiri, Sushmita D.; Walkup, Grant; Newman, Joseph V.] AstraZeneca R&D Boston, Infect iMed, Waltham, MA 02415 USA. [McNulty, John; Perros, Manos; Tommasi, Ruben] Shire Pharmaceut, Lexington, MA 02421 USA. [Mueller, John P.; Lawrence, Kenneth] Entasis Therapeut, Waltham, MA 02415 USA. [Barvian, Kevin] Albany Mol Res Inc, Albany, NY 12203 USA. [Gowravaram, Madhusudhan] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Huband, Michael] JMI Labs, North Liberty, IA 52317 USA. [Morningstar, Marshall] Broad Inst, Cambridge, MA 02142 USA. [Schuck, Virna J. A.] Norvartis Pharmaceut Corp, E Hanover, NJ 07936 USA. RP Basarab, GS (reprint author), Univ Cape Town, Dept Chem, Drug Discovery & Dev Ctr, ZA-7701 Rondebosch, South Africa. EM gbasarab@gmail.com NR 66 TC 17 Z9 18 U1 5 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 14 PY 2015 VL 5 AR 11827 DI 10.1038/srep11827 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CM7IT UT WOS:000357865900001 PM 26168713 ER PT J AU Hoinka, J Berezhnoy, A Dao, P Sauna, ZE Gilboa, E Przytycka, TM AF Hoinka, Jan Berezhnoy, Alexey Phuong Dao Sauna, Zuben E. Gilboa, Eli Przytycka, Teresa M. TI Large scale analysis of the mutational landscape in HT-SELEX improves aptamer discovery SO NUCLEIC ACIDS RESEARCH LA English DT Article ID THROUGHPUT SEQUENCE-ANALYSIS; RNA APTAMERS; ESCHERICHIA-COLI; SELECTION; LIGANDS; IDENTIFICATION; OPTIMIZATION; GENERATION; IL-10 AB High-Throughput (HT) SELEX combines SELEX (Systematic Evolution of Ligands by EXponential Enrichment), a method for aptamer discovery, with massively parallel sequencing technologies. This emerging technology provides data for a global analysis of the selection process and for simultaneous discovery of a large number of candidates but currently lacks dedicated computational approaches for their analysis. To close this gap, we developed novel in-silico methods to analyze HT-SELEX data and utilized them to study the emergence of polymerase errors during HT-SELEX. Rather than considering these errors as a nuisance, we demonstrated their utility for guiding aptamer discovery. Our approach builds on two main advancements in aptamer analysis: AptaMut--a novel technique allowing for the identification of polymerase errors conferring an improved binding affinity relative to the 'parent' sequence and AptaCluster--an aptamer clustering algorithm which is to our best knowledge, the only currently available tool capable of efficiently clustering entire aptamer pools. We applied these methods to an HT-SELEX experiment developing aptamers against Interleukin 10 receptor alpha chain (IL-10RA) and experimentally confirmed our predictions thus validating our computational methods. C1 [Hoinka, Jan; Phuong Dao; Przytycka, Teresa M.] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Berezhnoy, Alexey; Gilboa, Eli] Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Miami, FL 33101 USA. [Sauna, Zuben E.] US FDA, Lab Hemostasis, Div Hematol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Przytycka, TM (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM przytyck@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine; Laboratory of Hemostasis; Center for Biologics Evaluation and Research, Food and Drug Administration's Chief Scientist Challenge Grant; Dodson estate; Sylvester Comprehensive Cancer Center, Medical School, University of Miami; National Institutes of Health FX Intramural Research Program of the National Institutes of Health, National Library of Medicine [J.H., P.D., T.M.P., in part]; Laboratory of Hemostasis and the Center for Biologics Evaluation and Research, Food and Drug Administration's Chief Scientist Challenge Grant [Z.E.S., in part]; Dodson estate and the Sylvester Comprehensive Cancer Center, Medical School, University of Miami [A.B., E.G., in part]. Funding for open access charge: National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. NR 41 TC 18 Z9 18 U1 5 U2 18 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 JUL 13 PY 2015 VL 43 IS 12 BP 5699 EP 5707 DI 10.1093/nar/gkv308 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CP3JM UT WOS:000359775200009 PM 25870409 ER PT J AU Weng, ZQ Wang, KJ Li, HB Shi, Q AF Weng, Zuquan Wang, Kejian Li, Haibo Shi, Qiang TI A comprehensive study of the association between drug hepatotoxicity and daily dose, liver metabolism, and lipophilicity using 975 oral medications SO ONCOTARGET LA English DT Article DE Pathology Section; hepatotoxicity; metabolism; lipophilicity; dose; oral ID INJURY; RISK AB It was recently suggested that daily dose, liver metabolism and lipophilicity were associated with an oral drug's potential to cause hepatotoxicity, but this has not been widely accepted. A likely reason is that published data lack comprehensiveness, as they were based on only about one third of all FDA approved single-active-ingredient oral prescription drugs. Here the 975 oral drugs used worldwide which have a Defined Daily Dose (DDD) designated in the World Health Organization's Anatomical Therapeutic Chemical classification system and whose hADRs potential and metabolism data are available in the Micromedex Drugdex (R) compendium were studied, with their lipophilicity calculated by the partition coefficient LogP. Of the 975 drugs examined, 49% (478) have the potential to induce at least one type of hepatic adverse drug reactions (hADRs) such as fatal hepatotoxicity, acute liver failure, significant ALT/AST elevation, hepatitis, and jaundice. By single factor analysis, a higher DDD (>= 100 mg) was found to be associated with all types of hADRs, and extensive liver metabolism (>= 50%) was associated with a subset of hADRs including fatal hADRs, hepatitis and jaundice, while LogP showed no relation to any types of hADRs. Contrary to previous reports, none of the combination, neither DDD and liver metabolism, nor DDD and LogP, was found to be more predictive of hADRs than using DDD or liver metabolism alone. These data provide convincing evidence that a higher daily dose and extensive liver metabolism, but not lipophilicity, are independent but not synergistic risk factors for oral drugs to induce hepatotoxicity. C1 [Weng, Zuquan; Wang, Kejian; Shi, Qiang] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Li, Haibo] Nantong Maternal & Child Hlth Hosp, Dept Clin Lab Med, Nantong 226018, Jiangsu, Peoples R China. RP Shi, Q (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM qiang.shi@fda.hhs.gov FU U.S. FDA's Office of Women's Health; International Cooperation and Exchanges Program from Department of Health in Jiangsu Province, China; Research Participation Program at the National Center for Toxicological Research FX This project is supported by the U.S. FDA's Office of Women's Health. Drs. Zuquan Weng and Kejian Wang are supported by the Research Participation Program at the National Center for Toxicological Research administrated by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. FDA. Dr. Haibo Li is supported by the International Cooperation and Exchanges (2012) program from the Department of Health in Jiangsu Province, China. NR 16 TC 10 Z9 10 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 10 PY 2015 VL 6 IS 19 BP 17031 EP 17038 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2VB UT WOS:000359013600037 PM 26220713 ER PT J AU Jones, CM Logan, J Gladden, M Bohm, MK AF Jones, Christopher M. Logan, Joseph Gladden, Matthew Bohm, Michele K. TI Vital Signs: Demographic and Substance Use Trends Among Heroin Users - United States, 2002-2013 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID INJECTION-DRUG USE; INCREASES AB Background: Heroin use and overdose deaths have increased significantly in the United States. Assessing trends in heroin use among demographic and particular substance-using groups can inform prevention efforts. Methods: FDA and CDC analyzed data from the National Survey on Drug Use and Health and National Vital Statistics System reported during 2002-2013. Trends in heroin use among demographic and substance using groups were compared for 2002-2004, 2005-2007, 2008-2010, and 2011-2013. A multivariable logistic regression model was used to identify characteristics associated with heroin abuse or dependence. Results: Annual average rates of past-year heroin use increased from 1.6 per 1,000 persons aged >= 12 years in 2002-2004 to 2.6 per 1,000 in 2011-2013. Rates of heroin abuse or dependence were strongly positively correlated with rates of heroin-related overdose deaths over time. For the combined data years 2011-2013, the odds of past-year heroin abuse or dependence were highest among those with past-year cocaine or opioid pain reliever abuse or dependence. Conclusions: Heroin use has increased significantly across most demographic groups. The increase in heroin abuse or dependence parallels the increase in heroin-related overdose deaths. Heroin use is occurring in the context of broader poly-substance use. Implications for Public Health Practice: Further implementation of a comprehensive response that targets the wider range of demographic groups using heroin and addresses the key risk factors for heroin abuse and dependence is needed. Specific response needs include reducing inappropriate prescribing and use of opioids through early identification of persons demonstrating problematic use, stronger prescription drug monitoring programs, and other clinical measures; improving access to, and insurance coverage for, evidence-based substance abuse treatment, including medication-assisted treatment for opioid use disorders; and expanding overdose recognition and response training and access to naloxone to treat opioid pain reliever and heroin overdoses. C1 [Jones, Christopher M.] US FDA, Off Commissioner, Off Publ Hlth Strategy & Anal, Rockville, MD 20857 USA. [Logan, Joseph] CDC, Natl Ctr Injury Prevent & Control, Div Violence Prevent, Atlanta, GA 30333 USA. [Gladden, Matthew; Bohm, Michele K.] CDC, Natl Ctr Injury Prevent & Control, Div Unintent, Atlanta, GA 30333 USA. RP Jones, CM (reprint author), US FDA, Off Commissioner, Off Publ Hlth Strategy & Anal, Rockville, MD 20857 USA. EM Christopher.M.Jones@fda.hhs.gov NR 15 TC 52 Z9 52 U1 4 U2 19 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD JUL 10 PY 2015 VL 64 IS 26 BP 719 EP 725 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CN5ET UT WOS:000358453300003 PM 26158353 ER PT J AU Allec, N Choi, M Yesupriya, N Szychowski, B White, MR Kann, MG Garcin, ED Daniel, MC Badano, A AF Allec, Nicholas Choi, Mina Yesupriya, Nikhil Szychowski, Brian White, Michael R. Kann, Maricel G. Garcin, Elsa D. Daniel, Marie-Christine Badano, Aldo TI Small-angle X-ray scattering method to characterize molecular interactions: Proof of concept SO SCIENTIFIC REPORTS LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; ENERGY-TRANSFER BRET; GOLD NANOPARTICLES; BIOLOGICAL MACROMOLECULES; STRUCTURAL-CHANGES; SIZE; DNA; DISTRIBUTIONS; TOMOGRAPHY; NANOTECHNOLOGY AB Characterizing biomolecular interactions is crucial to the understanding of biological processes. Existing characterization methods have low spatial resolution, poor specificity, and some lack the capability for deep tissue imaging. We describe a novel technique that relies on small-angle X-ray scattering signatures from high-contrast molecular probes that correlate with the presence of biomolecular interactions. We describe a proof-of-concept study that uses a model system consisting of mixtures of monomer solutions of gold nanoparticles (GNPs) as the non-interacting species and solutions of GNP dimers linked with an organic molecule (dimethyl suberimidate) as the interacting species. We report estimates of the interaction fraction obtained with the proposed small-angle X-ray scattering characterization method exhibiting strong correlation with the known relative concentration of interacting and non-interacting species. C1 [Allec, Nicholas; Choi, Mina; Yesupriya, Nikhil; Badano, Aldo] US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Choi, Mina] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [Szychowski, Brian; White, Michael R.; Garcin, Elsa D.; Daniel, Marie-Christine] Univ Maryland, Dept Chem & Biochem, College Pk, MD USA. [Kann, Maricel G.] Univ Maryland, Dept Biol Sci, College Pk, MD USA. RP Badano, A (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM aldo.badano@fda.hhs.gov RI Garcin, Elsa/C-1556-2013; OI Garcin, Elsa/0000-0003-0501-8421; badano, aldo/0000-0003-3712-6670 FU Center for Devices and Radiological Health (CDRH); Fischell Fellowship in Biomedical Engineering; National Science Foundation/FDA Scholars-in-Residence Grant [1238292]; FDA Medical Countermeasures Initiative (MCMi) FX The authors (N.A. and N.Y.) acknowledge funding by appointments to the Research Participation Program at the Center for Devices and Radiological Health (CDRH) administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration (FDA). M.C. was supported by the Fischell Fellowship in Biomedical Engineering. This work was supported by a National Science Foundation/FDA Scholars-in-Residence Grant (1238292) and the FDA Medical Countermeasures Initiative (MCMi). We are grateful to B. Casey and J. Zheng (CDRH/FDA) for technical assistance with DLS and TEM. The authors would like to acknowledge the FDA White Oak Nanotechnology Core Facility for instrument use, scientific and technical assistance. The mention of commercial products herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. This is a contribution of the U.S. Food and Drug Administration and is not subject to copyright. NR 54 TC 1 Z9 1 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 10 PY 2015 VL 5 AR 12085 DI 10.1038/srep12085 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CM5GZ UT WOS:000357716400001 PM 26160052 ER PT J AU Califf, RM Ostroff, S AF Califf, Robert M. Ostroff, Stephen TI Sunscreen and the FDA SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID ADVANCED MELANOMA C1 [Califf, Robert M.; Ostroff, Stephen] US FDA, Silver Spring, MD 20993 USA. RP Califf, RM (reprint author), US FDA, Silver Spring, MD 20993 USA. EM robert.califf@fda.hhs.gov NR 5 TC 0 Z9 0 U1 1 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 9 PY 2015 VL 373 IS 2 BP 197 EP 197 DI 10.1056/NEJMc1507737 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CM3QP UT WOS:000357598600028 PM 26154807 ER PT J AU Rajaiah, R Perkins, DJ Ireland, DDC Vogel, SN AF Rajaiah, Rajesh Perkins, Darren J. Ireland, Derek D. C. Vogel, Stefanie N. TI CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE TLR4 endocytosis; agonistic antibody; small-molecule ligands; Eritoran; endotoxin tolerance ID RECEPTOR 4; ADAPTIVE IMMUNITY; CUTTING EDGE; LIPOPOLYSACCHARIDE; COMPLEX; ACTIVATION; LPS; INFLAMMATION; MACROPHAGES; PATHWAYS AB Dimerization of Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD2) heterodimers is critical for both MyD88- and TIR-domain-containing adapter-inducing IFN-beta (TRIF)-mediated signaling pathways. Recently, Zanoni et al. [(2011) Cell 147(4):868-880] reported that cluster of differentiation 14 (CD14) is required for LPS-/Escherichia coli-induced TLR4 internalization into endosomes and activation of TRIF-mediated signaling in macrophages. We confirmed their findings with LPS but report here that CD14 is not required for receptor endocytosis and downstream signaling mediated by TLR4/MD2 agonistic antibody (UT12) and synthetic small-molecule TLR4 ligands (1Z105) in murine macrophages. CD14 deficiency completely ablated the LPS-induced TBK1/IRF3 signaling axis that mediates production of IFN-beta in murine macrophages without affecting MyD88-mediated signaling, including NF-kappa B, MAPK activation, and TNF-alpha and IL-6 production. However, neither the MyD88-nor TRIF-signaling pathways and their associated cytokine profiles were altered in the absence of CD14 in UT12- or 1Z105-treated murine macrophages. Eritoran (E5564), a lipid A antagonist that binds the MD2 "pocket," completely blocked LPS- and 1Z105-driven, but not UT12-induced, TLR4 dimerization and endocytosis. Furthermore, TLR4 endocytosis is induced in macrophages tolerized by exposure to either LPS or UT12 and is independent of CD14. These data indicate that TLR4 receptor endocytosis and the TRIF-signaling pathway are dissociable and that TLR4 internalization in macrophages can be induced by UT12, 1Z105, and during endotoxin tolerance in the absence of CD14. C1 [Rajaiah, Rajesh; Perkins, Darren J.; Vogel, Stefanie N.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Ireland, Derek D. C.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Vogel, SN (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. EM svogel@som.umaryland.edu FU National Institutes of Health [AI018797] FX We thank Dr. Dennis Carson and Dr. Tomoko Hayashi (University of California at San Diego Moores Cancer Center) for providing synthetic small TLR4 ligands. This work was supported by National Institutes of Health Grant AI018797 (to S.N.V.). NR 42 TC 9 Z9 9 U1 6 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 7 PY 2015 VL 112 IS 27 BP 8391 EP 8396 DI 10.1073/pnas.1424980112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CM2QU UT WOS:000357527600070 PM 26106158 ER PT J AU Baek, JH Zhang, XY Williams, MC Hicks, W Buehler, PW D'Agnillo, F AF Baek, Jin Hyen Zhang, Xiaoyuan Williams, Matthew C. Hicks, Wayne Buehler, Paul W. D'Agnillo, Felice TI Sodium nitrite potentiates renal oxidative stress and injury in hemoglobin exposed guinea pigs SO TOXICOLOGY LA English DT Article DE Hemoglobin; Nitrite; Kidney; Biomarkers; Heme; Oxidative stress ID HEME OXYGENASE; IN-VIVO; HAPTOGLOBIN THERAPY; BURN INJURY; NITRATE; HEMOLYSIS; PROTEINS; FAILURE; DISEASE; KIDNEY AB Methemoglobin-forming drugs, such as sodium nitrite (NaNO2), may exacerbate oxidative toxicity under certain chronic or acute hemolytic settings. In this study, we evaluated markers of renal oxidative stress and injury in guinea pigs exposed to extracellular hemoglobin (Hb) followed by NaNO2 at doses sufficient to simulate clinically relevant acute methemoglobinemia. NaNO2 induced rapid and extensive oxidation of plasma Hb in this model. This was accompanied by increased renal expression of the oxidative response effectors nuclear factor erythroid 2-derived-factor 2 (Nrf-2) and heme oxygenase-1 (HO-1), elevated non-heme iron deposition, lipid peroxidation, interstitial inflammatory cell activation, increased expression of tubular injury markers kidney injury-1 marker (KIM-1) and liver-fatty acid binding protein (L-FABP), podocyte injury, and cell death. Importantly, these indicators of renal oxidative stress and injury were minimal or absent following infusion of Hb or NaNO2 alone. Together, these results suggest that the exposure to NaNO2 in settings associated with increased extracellular Hb may potentiate acute renal toxicity via processes that are independent of NaNO2 induced erythrocyte methemoglobinemia. Published by Elsevier Ireland Ltd. C1 [Baek, Jin Hyen; Zhang, Xiaoyuan; Williams, Matthew C.; Hicks, Wayne; Buehler, Paul W.; D'Agnillo, Felice] US FDA, Ctr Biol Evaluat & Res, Div Hematol Res & Review, Lab Biochem & Vasc Biol, Silver Spring, MD 20993 USA. RP D'Agnillo, F (reprint author), US FDA, Ctr Biol Evaluat & Res, Fed Res Ctr, White Oak Bldg 52-72,Room 4110,10903 New, Silver Spring, MD 20993 USA. EM felice.dagnillo@fda.hhs.gov FU Critical Path Initiative; Modernizing Science funds from the Center for Biologics Evaluation and Research, Food and Drug Administration FX This work was supported by Critical Path Initiative and Modernizing Science funds from the Center for Biologics Evaluation and Research, Food and Drug Administration. We would like to thank Dr. Andre F. Palmer, Department of Chemical and Biomedical Engineering, The Ohio State University, for providing the purified human hemoglobin. We thank Dr. Abdu Alayash, Center for Biologics Evaluation and Research, Food and Drug Administration for critical review of the manuscript. NR 58 TC 3 Z9 4 U1 2 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD JUL 3 PY 2015 VL 333 BP 89 EP 99 DI 10.1016/j.tox.2015.04.007 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CL8MG UT WOS:000357228200009 PM 25891524 ER PT J AU Prestin, A Vieux, SN Chou, WYS AF Prestin, Abby Vieux, Sana N. Chou, Wen-ying Sylvia TI Is Online Health Activity Alive and Well or Flat lining? Findings From 10 Years of the Health Information National Trends Survey SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID DIGITAL DIVIDE; CARE PROVIDERS; SUPPORT GROUPS; UNITED-STATES; INTERNET; RACE; COMMUNICATION; PHYSICIAN; SEEKING; ACCESS AB The Internet increasingly enables diverse health communication activities, from information seeking to social media interaction. Up-to-date reporting is needed to document the national prevalence, trends, and user profiles of online health activities so that these technologies can be best used in health communication efforts. This study identifies prevalence, trend, and factors associated with seeking health information, e-mailing health care providers, and using social media for health purposes. Four iterations of HINTS survey data, collected in 2003, 2005, 2008, and 2012, were analyzed to assess population-level trends over the last decade, and current prevalence of Internet-based health communication activities. Sociodemographic and health correlates were explored through weighted logistic regression modeling. Findings demonstrated that Internet use has steadily increased, with 78% of U.S. adults online in 2012; however several digital divide factorsamong them education, age, and race/ethnicitystill predict access. Once online, 70% of adults use the Internet as their first source for health information, and while 19% have e-mailed health care providers, engagement in health communication on social media is still relatively low. Distinct user profiles characterize each type of communication, with age, population density, and gender emerging as important predictors across online health activities. These findings have important implications for health communication research and practice. C1 [Prestin, Abby; Vieux, Sana N.; Chou, Wen-ying Sylvia] NCI, Div Canc Control & Populat Sci, NIH, Rockville, MD 20892 USA. [Prestin, Abby] US FDA, Off Sci, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Chou, WYS (reprint author), NCI, Hlth Commun & Informat Res Branch, Div Canc Control & Populat Sci, 9609 Med Ctr Dr 3E614, Rockville, MD 20892 USA. EM chouws@mail.nih.gov NR 43 TC 13 Z9 13 U1 7 U2 24 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PD JUL 3 PY 2015 VL 20 IS 7 BP 790 EP 798 DI 10.1080/10810730.2015.1018590 PG 9 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA CL6QS UT WOS:000357092700007 PM 26042588 ER PT J AU Loeffler, CR Richlen, ML Brandt, ME Smith, TB AF Loeffler, Christopher R. Richlen, Mindy L. Brandt, Marilyn E. Smith, Tyler B. TI Effects of grazing, nutrients, and depth on the ciguatera-causing dinoflagellate Gambierdiscus in the US Virgin Islands SO MARINE ECOLOGY PROGRESS SERIES LA English DT Article DE Ciguatera fish poisoning; Gambierdiscus; Caging; Grazing; St. Thomas; Coral reefs; Fish survey; Management ID CORAL-REEF; EPILITHIC ALGAL; WATER MOTION; DINOPHYCEAE; TOXICUS; GROWTH; FISH; TEMPERATURE; SEASONALITY; SALINITY AB Ciguatera fish poisoning in humans is a serious and widespread syndrome associated with the consumption of reef fishes that have accumulated lipid-soluble toxins known as cigua toxins. These toxins are piscine metabolites of ciguatoxin precursors produced by benthic dino flagellates in the genus Gambierdiscus. This investigation employed a novel experimental approach to identify and characterize the environmental factors and their interactions that influence the dynamic balance between cellular growth and loss of Gambierdiscus populations in situ. Field studies were conducted in St. Thomas (US Virgin Islands) at 3 sites and 2 depths (10 and 20 m). At each site and depth, Gambierdiscus was subjected to treatments designed to reduce grazing pressure (disturbance and removal) and elevate nutrient availability to elicit a population abundance response attributable to one of these treatments. We hypothesized that Gambierdiscus abundance would respond positively to increased nutrient availability, increasing depth (reduced water motion), and decreased grazing pressures. We found communities of Gambierdiscus were significantly higher by, on average, 138% when the effects of grazing were limited (p = 0.0002). Among sites, the effects of depth and nutrients on Gambierdiscus populations were not significant. The significant effect of grazing and disturbance observed in this study suggests that changes in reef herbivore and detritivore feeding selectivity and grazing rates may have large impacts on the areal density of Gambierdiscus in natural systems. Whether or not reduced grazing rates or disturbances translate into higher cell (toxin) ingestion rates for consumers and ultimately cause changes in toxicity for humans is unknown and in need of further investigation. C1 [Loeffler, Christopher R.; Brandt, Marilyn E.; Smith, Tyler B.] Univ Virgin Isl, Ctr Marine & Environm Studies, St Thomas, VI 00802 USA. [Richlen, Mindy L.] Woods Hole Oceanog Inst, Woods Hole, MA 02543 USA. RP Loeffler, CR (reprint author), US FDA, CFSAN, Off Food Safety, Gulf Coast Seafood Lab,Ctr Seafood Safety, 1 Iberville Dr, Dauphin Isl, AL 36528 USA. EM christopher.loeffler@fda.hhs.gov FU Centers for Disease Control and Prevention [U01 EH000421]; US FDA [F223201000060C]; NOAA NOS [NA11NOS4780060, NA11NOS4780028]; Lana Vento Trust Foundation; National Science Foundation S-STEM fellowship; National Harmful Algal Blooms Committee (made possible by NOAA Center for Sponsored Coastal Ocean Research); Virgin Islands EPSCoR program; WHOI Nutrient Facility; UVI FX Funding for this work was provided by the Centers for Disease Control and Prevention (U01 EH000421), US FDA (F223201000060C), a NOAA NOS (Cooperative Agreement NA11NOS4780060, NA11NOS4780028), The Lana Vento Trust Foundation, the National Science Foundation S-STEM fellowship, the travel award subcommittee of the National Harmful Algal Blooms Committee (made possible by NOAA Center for Sponsored Coastal Ocean Research), the Virgin Islands EPSCoR program, the WHOI Nutrient Facility, and the Research Assistantships and Teaching Assistantships provided by UVI. We also thank divers L. Henderson and R. Brewer for their field sampling assistance, as well as J. Liefer and A. Robertson for their suggestions to improve the manuscript and support during writing. This is publication #117 from the Center for Marine and Environmental Studies and is ECOHAB publication #806. NR 27 TC 2 Z9 2 U1 7 U2 31 PU INTER-RESEARCH PI OLDENDORF LUHE PA NORDBUNTE 23, D-21385 OLDENDORF LUHE, GERMANY SN 0171-8630 EI 1616-1599 J9 MAR ECOL PROG SER JI Mar. Ecol.-Prog. Ser. PD JUL 2 PY 2015 VL 531 BP 91 EP 104 DI 10.3354/meps11310 PG 14 WC Ecology; Marine & Freshwater Biology; Oceanography SC Environmental Sciences & Ecology; Marine & Freshwater Biology; Oceanography GA CN5BR UT WOS:000358445000007 ER PT J AU Arya, V Au, S Belew, Y Miele, P Struble, K AF Arya, Vikram Au, Stanley Belew, Yodit Miele, Peter Struble, Kimberly TI Regulatory challenges in developing long-acting antiretrovirals for treatment and prevention of HIV infection SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE antiretroviral therapy; HIV preexposure prophylaxis; HIV; AIDS; long-acting ID PREEXPOSURE PROPHYLAXIS; AFRICAN WOMEN AB Purpose of reviewTo outline some of the regulatory challenges inherent to the development of long-acting antiretrovirals (ARVs) for the treatment or prevention of HIV infection.Recent findingsDespite advances in drug development that have reduced ARV dosing to once daily, suboptimal drug adherence remains an obstacle to successful HIV treatment. Further, large randomized trials of once daily oral ARVs for preexposure prophylaxis (PrEP) have shown that drug adherence correlates strongly with prophylactic effect and study outcomes. Thus, the prospect of developing long-acting ARVs, which may mitigate drug adherence issues, has attracted considerable attention lately.SummaryBecause of their pharmacokinetic properties, the development of long-acting ARVs can present novel regulatory challenges. Chief among them is determining the appropriate dosing regimen, the need for an oral lead-in, and whether existing data with an approved oral agent, if available, can be leveraged for a treatment or prevention indication. For PrEP, because validated biomarkers are lacking, additional nonclinical studies and evaluation of tissue concentrations in multiple compartments may be necessary to identify optimal dosages. Study design and choice of controls for registrational trials of new long-acting PrEP agents might also prove challenging following the availability of an oral PrEP drug. C1 [Arya, Vikram; Au, Stanley] US FDA, Off Clin Pharmacol, Off Translat Sci, Div Clin Pharmacol 4, Silver Spring, MD USA. [Belew, Yodit; Miele, Peter; Struble, Kimberly] US FDA, Ctr Drug Evaluat & Res, Off New Drugs, Div Antiviral Prod, Silver Spring, MD USA. RP Miele, P (reprint author), FDA CDER OND DAVP, 10903 New Hampshire Ave,Bldg 22,Room 6380, Silver Spring, MD 20993 USA. EM peter.miele@fda.hhs.gov NR 7 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD JUL PY 2015 VL 10 IS 4 BP 278 EP 281 DI 10.1097/COH.0000000000000163 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CY4DC UT WOS:000366357800011 PM 26049954 ER PT J AU Vicente, J Simlund, J Johannesen, L Sundh, F Florian, J Ugander, M Wagner, GS Woosley, RL Strauss, DG AF Vicente, Jose Simlund, Jacob Johannesen, Lars Sundh, Frida Florian, Jeffry Ugander, Martin Wagner, Galen S. Woosley, Raymond L. Strauss, David G. TI Investigation of potential mechanisms of sex differences in quinidine-induced torsade de pointes risk SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE QTc prolongation; Quinidine; Torsade de pointes; Sex differences; T wave notching ID CARDIAC REPOLARIZATION; CELLULAR BASIS; QT INTERVAL; WOMEN; BLOCK; TESTOSTERONE; PROLONGATION; GENDER; DRUGS; HEART AB Introduction: The electrocardiographic index T-peak-T-end has been proposed as a marker of dispersion of repolarization and may be a stronger predictor of torsade de pointes risk than QTc prolongation. Methods and results: We assessed whether quinidine-induced T-peak-T-end prolongation is greater in women than men. The relationship between QTc prolongation and quinidine concentration was greater in women than men (38 +/- 10 vs. 28 +/- 9 ms/mu g/ml, p = 0.02), but there was no difference for T-peak-T-end prolongation (39 +/- 13 vs. 32 +/- 13 ms/mu g/ml, p = 0.21). There was a delay (hysteresis) between peak concentration and both maximum QTc and T-peak-T-end prolongation and a trend toward higher serum quinidine concentration in men than women. Analysis controlling for hysteresis showed no sex difference for QTc (55 +/- 18 vs. 43 +/- 19 ms/mu g/ml, p = 0.14), without changing the lack of sex difference with T-peak-T-end (61 +/- 22 vs. 55 +/- 21 ms/mu g/ml, p = 0.49). Conclusions: Women do not have a greater quinidine-induced T-peak-T-end prolongation than men. Sex differences in hysteresis and serum quinidine concentration in this study may have contributed to sex differences in quinidine-induced QTc prolongation. (C) Published by Elsevier Inc. C1 [Vicente, Jose; Johannesen, Lars; Strauss, David G.] US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Device & Radiol Hlth, Silver Spring, MD 20993 USA. [Vicente, Jose] US FDA, Div Cardiovasc & Renal Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Vicente, Jose] Univ Zaragoza, IIS Aragon, Aragon Inst Engn Res I3A, BSICoS Grp, Zaragoza, Spain. [Simlund, Jacob; Sundh, Frida; Wagner, Galen S.] Duke Clin Res Inst, Durham, NC USA. [Simlund, Jacob; Johannesen, Lars; Sundh, Frida; Ugander, Martin; Strauss, David G.] Karolinska Inst, Dept Clin Physiol, S-10401 Stockholm, Sweden. [Simlund, Jacob; Johannesen, Lars; Sundh, Frida; Ugander, Martin; Strauss, David G.] Karolinska Univ Hosp, Stockholm, Sweden. [Florian, Jeffry] US FDA, Div Pharmacometr, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Woosley, Raymond L.] AZCERT Inc, Oro Valley, AZ USA. RP Strauss, DG (reprint author), US FDA, 10903 New Hampshire Ave,WO62-1126, Silver Spring, MD 20993 USA. EM david.strauss@fda.hhs.gov OI Woosley, Raymond L./0000-0002-2588-328X; Ugander, Martin/0000-0003-3665-2038; Vicente, Jose/0000-0001-9963-1205 FU FDA's Critical Path Initiative, FDA's Office of Women's Health FX This study was supported by FDA's Critical Path Initiative, FDA's Office of Women's Health and appointments to the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the U.S. Department of Health and Human Services. NR 28 TC 5 Z9 5 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD JUL-AUG PY 2015 VL 48 IS 4 BP 533 EP 538 DI 10.1016/j.jelectrocard.2015.03.011 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU3OG UT WOS:000363434100010 PM 25796102 ER PT J AU Almer, J Zusterzeel, R Strauss, DG Tragardh, E Maynard, C Wagner, GS Engblom, H AF Almer, Jakob Zusterzeel, Robbert Strauss, David G. Tragardh, Elin Maynard, Charles Wagner, Galen S. Engblom, Henrik TI Prevalence of manual Strauss LBBB criteria in patients diagnosed with the automated Glasgow LBBB criteria SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE ECG; LBBB; CRT; Diagnostic criteria ID BUNDLE-BRANCH-BLOCK; CARDIAC-RESYNCHRONIZATION THERAPY; CONDUCTION DISTURBANCES; HEART-FAILURE; ACTIVATION; MORPHOLOGY; ECG AB Introduction: About one-third of patients undergoing cardiac resynchronization therapy because of left bundle branch block (LBBB) and heart failure do not improve. Strauss et al. have developed strict criteria to more accurately define complete LBBB in this patient group. The aim of this study was to investigate the prevalence of the manual application of the Strauss criteria for LBBB (QRS >= 140 ms in men, >= 130 ms in women, along with mid-QRS notching/slurring) in consecutive patients who have been diagnosed with LBBB by the automated Glasgow criteria (QRS >= 120 ms). Method: In 158 consecutive patients (78 females) diagnosed with LBBB according to the automated Glasgow criteria, the manual Strauss criteria were applied. Results & conclusion: A majority of patients (87%) diagnosed with LBBB using the Glasgow criteria were positive for the Strauss criteria. In 70% (13/20) of the cases of disagreement the reason for disagreement was short QRS duration. (C) 2015 Elsevier Inc. All rights reserved. C1 [Almer, Jakob; Tragardh, Elin; Engblom, Henrik] Skane Univ Hosp, Dept Clin Physiol & Nucl Med, S-22185 Lund, Sweden. [Almer, Jakob; Tragardh, Elin; Engblom, Henrik] Lund Univ, Lund, Sweden. [Zusterzeel, Robbert; Strauss, David G.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Maynard, Charles] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Wagner, Galen S.] Duke Clin Res Inst, Durham, NC USA. RP Engblom, H (reprint author), Skane Univ Hosp, Dept Clin Physiol & Nucl Med, S-22185 Lund, Sweden. EM henrik.engblom@med.lu.se RI Maynard, Charles/N-3906-2015 OI Maynard, Charles/0000-0002-1644-7814 FU Swedish Heart and Lung foundation; Region of Scania; Medical Faculty of Lund University; Oak Ridge Institute of Science and Education FX We wish to acknowledge the technical expertise and ECG processing provided by Britt-Marie Gunnarsson (engineer, Skane University Hospital Lund). The study has been supported by the Swedish Heart and Lung foundation, Region of Scania and the Medical Faculty of Lund University. This study was supported by a research fellowship from the Oak Ridge Institute of Science and Education through an interagency agreement between the U.S. Department of Energy and the FDA. NR 21 TC 3 Z9 3 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD JUL-AUG PY 2015 VL 48 IS 4 BP 558 EP 564 DI 10.1016/j.jelectrocard.2015.01.008 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU3OG UT WOS:000363434100014 PM 25705035 ER PT J AU Hannink, LGJ Wagner, GS Kisslo, J Alenezi, FAM Shaw, LK Hofrnann, P Zusterzeel, R Phelan, M Velazquez, EJ Gorgels, APM AF Hannink, Laura G. J. Wagner, Galen S. Kisslo, Joseph Alenezi, Fawaz Abdulaziz M. Shaw, Linda K. Hofrnann, Paul Zusterzeel, Robbert Phelan, Matthew Velazquez, Eric J. Gorgels, Anton P. M. TI Influence of QRS infarct score and QRS duration prior to transcatheter aortic valve replacement on follow-up left ventricular end systolic volume in patients with new persistent left bundle branch block SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE Transcatheter aortic valve replacement; Left bundle branch block; Selvester QRS-score; QRS duration; TAVR; LBBB ID IMPLANTATION; QUANTIFICATION; PREDICTORS; OUTCOMES; STENOSIS; ANATOMY; IMPACT; RISK AB Background: New-onset left bundle branch block (LBBB) is a known complication during Transcatheter Aortic Valve Replacement (TAVR). This study evaluated the influence of pre-TAVR cardiac conditions on left ventricular functions in patients with new persistent LBBB post-TAVR. Methods: Only 11 patients qualified for this study because of the strict inclusion criteria. Pre-TAVR electrocardiograms were evaluated for Selvester QRS infarct score and QRS duration, and left ventricular end-systolic volume (LVESV) was used as outcome variable. Results: There was a trend towards a positive correlation between QRS score and LVESV of r = 0.59 (p = 0.058), while there was no relationship between QRS duration and LVESV (r = 0.18[p = 0.59]). Conclusion: This study showed that patients with new LBBB and higher pre-TAVR QRS infarct score may have worse post-TAVR left ventricular function, however, pre-TAVR QRS duration has no such predictive value. Because of the small sample size these results should be interpreted with caution and assessed in a larger study population. (C) 2015 Elsevier Inc. All rights reserved. C1 [Hannink, Laura G. J.; Gorgels, Anton P. M.] Maastricht Univ, Med Ctr, Dept Cardiol, NL-6202 AZ Maastricht, Netherlands. [Hannink, Laura G. J.] Duke Clin Res Inst, Durham, NC USA. [Wagner, Galen S.; Kisslo, Joseph; Alenezi, Fawaz Abdulaziz M.; Velazquez, Eric J.] Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA. [Shaw, Linda K.; Hofrnann, Paul; Phelan, Matthew] Duke Clin Res Inst, Dept Stat, Durham, NC USA. [Zusterzeel, Robbert] US FDA, Silver Spring, MD USA. RP Hannink, LGJ (reprint author), Maastricht Univ, Med Ctr, Dept Cardiol, Postbus 5800, NL-6202 AZ Maastricht, Netherlands. EM lgj.hannink@student.maasrichuniversity.nl FU Oak Ridge Institute of Science and Education FX This study was supported by a research fellowship from the Oak Ridge Institute of Science and Education through an interagency agreement between the U.S. Department of Energy and the FDA. NR 22 TC 4 Z9 4 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD JUL-AUG PY 2015 VL 48 IS 4 BP 637 EP 642 DI 10.1016/j.jelectrocard.2015.04.010 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU3OG UT WOS:000363434100025 PM 25959263 ER PT J AU Klein, MR Sundh, F Simlund, J Harrison, JK Jackson, KP Hughes, GC Wagner, GS Risum, N Sogaard, P Strauss, DG Kisslo, J AF Klein, Michael R. Sundh, Frida Simlund, Jacob Harrison, J. Kevin Jackson, Kevin P. Hughes, G. Chad Wagner, Galen S. Risum, Niels Sogaard, Peter Strauss, David G. Kisslo, Joseph TI Immediate mechanical effects of acute left bundle branch block by speckle tracked strain SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE Left bundle branch block; Cardiac resynchronization therapy; Regional longitudinal strain; Congestive heart failure; Dyssynchrony ID CARDIAC RESYNCHRONIZATION THERAPY; AORTIC-VALVE IMPLANTATION; CONDUCTION ABNORMALITIES; PACED HEART; ACTIVATION; CARDIOMYOPATHY; REPLACEMENT; STENOSIS; MRI AB Introduction: Left bundle branch block (LBBB) is a known complication of transcatheter aortic valve replacement (TAVR) and has been shown to predict worsened outcomes in TAVR patients. A regional longitudinal strain pattern, termed the "classic" pattern of left ventricular (LV) dyssynchrony, which is thought to be due to LBBB, is highly predictive of response to cardiac resynchronization therapy. Whether LBBB causes this "classic" pattern is not known. Methods: We retrospectively studied patients undergoing TAVR who also underwent pre- and post-TAVR strain analysis to determine if the "classic" pattern arose in those who developed TAVR-induced true LBBB. After removing patients with baseline conduction abnormalities or insufficient studies 9 patients had sufficient data for analysis. Six patients developed LBBB after TAVR and 3 patients did not develop LBBB after TAVR. ECGs were analyzed for the new onset of LBBB after TAVR. Global longitudinal strain (GLS) and regional longitudinal strain patterns were analyzed for changes between pre- and immediately post-TAVR examinations. Results: Patients who did not develop LBBB showed no significant changes in their regional longitudinal strain pattern. Those patients who did develop LBBB showed significant increase in their difference of time-to-onset of contraction between the septal and lateral walls post-TAVR (22 +/- 14 ms vs 111 +/- 49 ms; p = 0.003) and in their difference of time-to-peak contraction between the septal and lateral walls post-TAVR (63 +/- 56 ms vs 133 +/- 46 ms; p = 0.002). Early lateral wall pre-stretch and delayed lateral wall peak contraction emerged in all patients with LBBB but early septal peak contraction meeting the established criteria was present in only one patient. Discussion: The onset of LBBB led to acute, measurable changes in the regional longitudinal strain pattern consisting of early lateral wall pre-stretch and delayed lateral wall peak contraction. These represent 2 of the 3 findings in the "classic" pattern of LV dyssynchrony. Early termination of septal wall contraction meeting established criteria was not routinely found. Time and/or other factors may be required to develop the full "classic" pattern. (C) 2015 Elsevier Inc. All rights reserved. C1 [Klein, Michael R.; Sundh, Frida; Simlund, Jacob; Harrison, J. Kevin; Jackson, Kevin P.; Wagner, Galen S.; Kisslo, Joseph] Duke Univ, Sch Med, Div Cardiol, Durham, NC 27710 USA. [Sundh, Frida; Simlund, Jacob] Karolinska Inst, Dept Clin Physiol, S-10401 Stockholm, Sweden. [Sundh, Frida; Simlund, Jacob] Karolinska Univ Hosp, Stockholm, Sweden. [Hughes, G. Chad] Duke Univ, Sch Med, Div Cardiovasc & Thorac Surg, Durham, NC 27710 USA. [Risum, Niels] Hvidorve Hosp, Dept Cardiol, Copenhagen, Denmark. [Sogaard, Peter] Aalborg Univ Hosp, Heart Ctr & Clin Inst, Aalborg, Denmark. [Strauss, David G.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Klein, MR (reprint author), Duke Univ, Med Ctr, Div Cardiovasc Dis, DUMC Box 3845, Durham, NC 27710 USA. EM Michael.Klein@dm.duke.edu NR 19 TC 4 Z9 4 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD JUL-AUG PY 2015 VL 48 IS 4 BP 643 EP 651 DI 10.1016/j.jelectrocard.2015.05.005 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU3OG UT WOS:000363434100026 PM 26002227 ER PT J AU Sanjar, F Rusconi, B Hazen, TH Koenig, SSK Mammel, MK Feng, PCH Rasko, DA Eppinger, M AF Sanjar, Fatemeh Rusconi, Brigida Hazen, Tracy H. Koenig, Sara S. K. Mammel, Mark K. Feng, Peter C. H. Rasko, David A. Eppinger, Mark TI Characterization of the pathogenome and phylogenomic classification of enteropathogenic Escherichia coli of the O157:non-H7 serotypes SO PATHOGENS AND DISEASE LA English DT Article DE enteropathogenic E. coli (EPEC); O157:non-H7; pathogenome evolution; genotyping ID COMPARATIVE GENOMICS; CLONAL ANALYSIS; III SECRETION; UIDA GENE; STRAINS; VIRULENCE; O157-H7; DIARRHEA; SEQUENCE; IDENTIFICATION AB Escherichia coli of the O157 serogroup are comprised of a diverse collection of more than 100 O157:non-H7 serotypes that are found in the environment, animal reservoir and infected patients and some have been linked to severe outbreaks of human disease. Among these, the enteropathogenic E. coli O157: non-H7 serotypes carry virulence factors that are hallmarks of enterohemorrhagic E. coli, such as causing attaching and effacing lesions during human gastrointestinal tract infections. Given the shared virulence gene pool between O157: H7 and O157: non-H7 serotypes, our objective was to examine the prevalence of virulence traits of O157: non-H7 serotypes within and across their H-serotype and when compared to other E. coli pathovars. We sequenced six O157: non-H7 genomes complemented by four genomes from public repositories in an effort to determine their virulence state and genetic relatedness to the highly pathogenic enterohemorrhagic O157: H7 lineage and its ancestral O55: H7 serotype. Whole-genome-based phylogenomic analysis and molecular typing is indicative of a non-monophyletic origin of the heterogeneous O157: non-H7 serotypes that are only distantly related to the O157: H7 serotype. The availability of multiple genomes enables robust phylogenomic placement of these strains into their evolutionary context, and the assessment of the pathogenic potential of the O157: non-H7 strains in causing human disease. C1 [Sanjar, Fatemeh; Rusconi, Brigida; Koenig, Sara S. K.; Eppinger, Mark] Univ Texas San Antonio, Dept Biol, San Antonio, TX 78249 USA. [Sanjar, Fatemeh; Rusconi, Brigida; Koenig, Sara S. K.; Eppinger, Mark] Univ Texas San Antonio, South Texas Ctr Emerging Infect Dis, San Antonio, TX 78249 USA. [Hazen, Tracy H.; Rasko, David A.] Univ Maryland, IGS, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21021 USA. [Mammel, Mark K.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Feng, Peter C. H.] US FDA, Div Microbiol, College Pk, MD 20740 USA. RP Eppinger, M (reprint author), Univ Texas San Antonio, Dept Biol, San Antonio, TX 78249 USA. EM mark.eppinger@utsa.edu FU South Texas Center of Emerging Infectious Diseases (STCEID), Department of Biology and Computational System Biology Core at the University of Texas at San Antonio; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900007C]; High Performance Computing Center/Computational Bioinformatics Initiative (HPC/CBI) [2G12RR013646-12]; Army Research Office of the Department of Defense [W911NF-11-1-0136]; South Texas Center for Emerging Infectious Diseases (STCEID); University Teaching Fellowship (UTF); Swiss National Science Foundation (SNSF) [P2LAP3-151770] FX This work received support from the South Texas Center of Emerging Infectious Diseases (STCEID), Department of Biology and Computational System Biology Core at the University of Texas at San Antonio, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under contract HHSN272200900007C, the High Performance Computing Center/Computational Bioinformatics Initiative (HPC/CBI) under contract 2G12RR013646-12. This project is supported by the Army Research Office of the Department of Defense under Contract No. W911NF-11-1-0136. FS is supported by the South Texas Center for Emerging Infectious Diseases (STCEID) and an University Teaching Fellowship (UTF). BR is supported by the Swiss National Science Foundation (SNSF) Early.Postdoc.Mobility Fellowship (P2LAP3-151770). NR 69 TC 4 Z9 4 U1 2 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2049-632X J9 PATHOG DIS JI Pathog. Dis. PD JUL PY 2015 VL 73 IS 5 AR ftv033 DI 10.1093/femspd/ftv033 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CT1QB UT WOS:000362573900014 ER PT J AU Ragupathy, V Setty, MKHG Kostov, Y Ge, XD Uplekar, S Hewlett, I Rao, G AF Ragupathy, Viswanath Setty, Mohan Kumar Hayuri Giri Kostov, Yordan Ge, Xudong Uplekar, Shaunak Hewlett, Indira Rao, Govind TI Non-Invasive Optical Sensor Based Approaches for Monitoring Virus Culture to Minimize BSL3 Laboratory Entry SO SENSORS LA English DT Article DE virus cell culture; BSL3 use; monitoring; optical sensor ID MAMMALIAN-CELL CULTURE; DISSOLVED-OXYGEN; HIV; SYSTEM; PANEL; PH AB High titers of infectious viruses for vaccine and diagnostic reference panel development are made by infecting susceptible mammalian cells. Laboratory procedures are strictly performed in a Bio-Safety Level-3 (BSL3) laboratory and each entry and exit involves the use of disposable Personnel Protective Equipment (PPE) to observe cell culture conditions. Routine PPE use involves significant recurring costs. Alternative non-invasive optical sensor based approaches to remotely monitor cell culture may provide a promising and cost effective approach to monitor infectious virus cultures resulting in lower disruption and costs. We report here the monitoring of high titer cultures of Human Immunodeficiency Virus-1 (HIV-1) and Herpes Simplex Virus-2 (HSV-2) remotely with the use of optical oxygen sensors aseptically placed inside the cell culture vessel. The replacement of culture media for cell and virus propagation and virus load monitoring was effectively performed using this fluorescent sensor and resulted in half the number of visits to the BSL3 lab (five versus ten). C1 [Ragupathy, Viswanath; Setty, Mohan Kumar Hayuri Giri; Hewlett, Indira] US FDA, LMV, DETTD, OBRR,CBER, Silver Spring, MD 20993 USA. [Kostov, Yordan; Ge, Xudong; Uplekar, Shaunak; Rao, Govind] Univ Maryland Baltimore Cty, Ctr Adv Sensor Technol, Baltimore, MD 21250 USA. [Kostov, Yordan; Ge, Xudong; Uplekar, Shaunak; Rao, Govind] Univ Maryland Baltimore Cty, Dept Chem Biochem & Environm Engn, Baltimore, MD 21250 USA. RP Hewlett, I (reprint author), US FDA, LMV, DETTD, OBRR,CBER, Silver Spring, MD 20993 USA. EM viswanath.ragupathy@fda.hhs.gov; Mohan.Haleyurgirisetty@fda.hhs.gov; kostov@umbc.edu; xge1@umbc.edu; shaunak1@umbc.edu; Indira.Hewlett@fda.hhs.gov; grao@umbc.edu FU CBER FX The authors wish to acknowledge Xue Wang and Krishnakumar Devadas for review of the manuscript. This work was supported by an intramural grant from CBER. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration, and should not be construed to represent any Agency determination or policy. NR 14 TC 1 Z9 1 U1 1 U2 1 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1424-8220 J9 SENSORS-BASEL JI Sensors PD JUL PY 2015 VL 15 IS 7 BP 14864 EP 14870 DI 10.3390/s150714864 PG 7 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation SC Chemistry; Electrochemistry; Instruments & Instrumentation GA CS0YN UT WOS:000361788200003 PM 26115456 ER PT J AU Miousse, IR Chalbot, MCG Lumen, A Ferguson, A Kavouras, IG Koturbash, I AF Miousse, Isabelle R. Chalbot, Marie-Cecile G. Lumen, Annie Ferguson, Alesia Kavouras, Ilias G. Koturbash, Igor TI Response of transposable elements to environmental stressors SO MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH LA English DT Article DE Air pollution; DNA methylation; Environmental stressors; Ionizing radiation; Metals; Retrotransposition ID GENOMIC DNA METHYLATION; PERSISTENT ORGANIC POLLUTANTS; ENDOGENOUS RETROVIRUS-K; PARTICULATE AIR-POLLUTION; SQUAMOUS-CELL CARCINOMA; ACUTE MYELOID-LEUKEMIA; OXYGEN SPECIES ROS; LOW-LEVEL EXPOSURE; X-RAY-IRRADIATION; L1 RETROTRANSPOSITION AB Transposable elements (TEs) comprise a group of repetitive sequences that bring positive, negative, as well as neutral effects to the host organism. Earlier considered as "junk DNA," TEs are now well-accepted driving forces of evolution and critical regulators of the expression of genetic information. Their activity is regulated by epigenetic mechanisms, including methylation of DNA and histone modifications. The loss of epigenetic control over TEs, exhibited as loss of DNA methylation and decondensation of the chromatin structure, may result in TEs reactivation, initiation of their insertional mutagenesis (retrotransposition) and has been reported in numerous human diseases, including cancer. Accumulating evidence suggests that these alterations are not the simple consequences of the disease, but often may drive the pathogenesis, as they can be detected early during disease development. Knowledge derived from the in vitro, in vivo, and epidemiological studies, clearly demonstrates that exposure to ubiquitous environmental stressors, many of which are carcinogens or suspected carcinogens, are capable of causing alterations in methylation and expression of TEs and initiate retrotransposition events. Evidence summarized in this review suggests that TEs are the sensitive endpoints for detection of effects caused by such environmental stressors, as ionizing radiation (terrestrial, space, and UV-radiation), air pollution (including particulate matter [PM]-derived and gaseous), persistent organic pollutants, and metals. Furthermore, the significance of these effects is characterized by their early appearance, persistence and presence in both, target organs and peripheral blood. Altogether, these findings suggest that TEs may potentially be introduced into safety and risk assessment and serve as biomarkers of exposure to environmental stressors. Furthermore, TEs also show significant potential to become invaluable surrogate biomarkers in clinic and possible targets for therapeutic modalities for disease treatment and prevention. (C) 2015 Elsevier B.V. All rights reserved. C1 [Miousse, Isabelle R.; Chalbot, Marie-Cecile G.; Ferguson, Alesia; Kavouras, Ilias G.; Koturbash, Igor] Univ Arkansas Med Sci, Fay W Boozman Coll Publ Hlth, Dept Environm & Occupat Hlth, Little Rock, AR 72205 USA. [Lumen, Annie] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Koturbash, I (reprint author), Univ Arkansas Med Sci, Fay W Boozman Coll Publ Hlth, Dept Environm & Occupat Hlth, Little Rock, AR 72205 USA. EM iracinemiousse@uams.edu; mgchalbot@uams.edu; annie.lumen@fda.hhs.gov; aferguson@uams.edu; ikavouras@uams.edu; ikoturbash@uams.edu OI Kavouras, Ilias/0000-0003-0342-5306 FU NIH/UAMS Clinical and Translational Science Award [UL1TR000039, KL2TR000063]; National Space Biomedical Research Institute through National Aeronautics and Space Administration [RE03701, NCC 9-58]; Arkansas Biosciences Institute; EPA [NE-00F65601-0, X8-00F10401-1] FX We are thankful to Drs. Frederick A. Beland, Yuri Dubrova, Kristy Kutanzi, and Luisa Camacho for critical reading and Rebecca Helm for editing this manuscript. We apologize to our colleagues whose research was not mentioned here owing to the focus on specific models and space limitations. The research in Koturbash' Lab is supported, in part, by the NIH/UAMS Clinical and Translational Science Award [UL1TR000039 and KL2TR000063], National Space Biomedical Research Institute (RE03701) through National Aeronautics and Space Administration NCC 9-58, and the Arkansas Biosciences Institute. The research in Fergusons' Lab is supported, in part, by EPA NE-00F65601-0 and X8-00F10401-1 grants. NR 249 TC 12 Z9 12 U1 7 U2 32 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5742 EI 1388-2139 J9 MUTAT RES-REV MUTAT JI Mutat. Res.-Rev. Mutat. Res. PD JUL-SEP PY 2015 VL 765 BP 19 EP 39 DI 10.1016/j.mrrev.2015.05.003 PG 21 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA CR3VH UT WOS:000361260700003 PM 26281766 ER PT J AU Dankwa-Mullan, I Bull, J Sy, F AF Dankwa-Mullan, Irene Bull, Jonca Sy, Francisco TI Precision Medicine and Health Disparities: Advancing the Science of Individualizing Patient Care SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Dankwa-Mullan, Irene] NIMHD, Bethesda, MD USA. [Bull, Jonca] US FDA, Off Minor Hlth, Rockville, MD 20857 USA. [Sy, Francisco] NIMHD, Off Community Based Participatory Res & Collabora, Bethesda, MD USA. RP Dankwa-Mullan, I (reprint author), NIMHD, Bethesda, MD USA. NR 0 TC 1 Z9 2 U1 1 U2 8 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2015 VL 105 SU 3 BP S368 EP S368 DI 10.2105/AJPH.2015.302755 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CQ9LH UT WOS:000360935700011 PM 26039545 ER PT J AU Frank, GM Angeletti, D Ince, WL Gibbs, JS Khurana, S Wheatley, AK Max, EE McDermott, AB Golding, H Stevens, J Bennink, JR Yewdell, JW AF Frank, Gregory M. Angeletti, Davide Ince, William L. Gibbs, James S. Khurana, Surender Wheatley, Adam K. Max, Edward E. McDermott, Adrian B. Golding, Hana Stevens, James Bennink, Jack R. Yewdell, Jonathan W. TI A Simple Flow-Cytometric Method Measuring B Cell Surface Immunoglobulin Avidity Enables Characterization of Affinity Maturation to Influenza A Virus SO MBIO LA English DT Article ID ANTIBODY-RESPONSE; IMMUNE-RESPONSE; PLASMA-CELLS; MEMORY; HEMAGGLUTININ; INFECTION; ANTIGEN; EXPRESSION; RECEPTOR; VACCINES AB Antibody (Ab) affinity maturation enables an individual to maintain immunity to an increasing number of pathogens within the limits of a total Ig production threshold. A better understanding of this process is critical for designing vaccines that generate optimal Ab responses to pathogens. Our study describes a simple flow-cytometric method that enumerates virus-specific germinal center (GC) B cells as well as their AC(50), a measure of Ab avidity, defined as the antigen concentration required to detect 50% of specific B cells. Using a model of mouse Ab responses to the influenza A virus hemagglutinin (IAV HA), we obtained data indicating that AC(50) decreases with time postinfection in an affinity maturation-dependent process. As proof of principle of the utility of the method, our data clearly show that relative to intranasal IAV infection, intramuscular immunization against inactivated IAV in adjuvant results in a diminished GC HA B cell response, with increased AC(50) correlating with an increased serum Ab off-rate. Enabling simultaneous interrogation of both GC HA B cell quantity and quality, this technique should facilitate study of affinity maturation and rational vaccine design. IMPORTANCE Though it was first described 50 years ago, little is known about how antibody affinity maturation contributes to immunity. This question is particularly relevant to developing more effective vaccines for influenza A virus (IAV) and other viruses that are difficult vaccine targets. Limitations in methods for characterizing antigen-specific B cells have impeded progress in characterizing the quality of immune responses to vaccine and natural immunogens. In this work, we describe a simple flow cytometry-based approach that measures both the number and affinity of IAV-binding germinal center B cells specific for the IAV HA, the major target of IAV-neutralizing antibodies. Using this method, we showed that the route and form of immunization significantly impacts the quality and quantity of B cell antibody responses. This method provides a relatively simple yet powerful tool for better understanding the contribution of affinity maturation to viral immunity. C1 [Frank, Gregory M.; Angeletti, Davide; Ince, William L.; Gibbs, James S.; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Khurana, Surender; Golding, Hana] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Wheatley, Adam K.; McDermott, Adrian B.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Max, Edward E.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Stevens, James] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Influenza Div, Atlanta, GA USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jyewdell@mail.nih.gov OI Wheatley, Adam/0000-0002-5593-9387; Angeletti, Davide/0000-0002-5256-1972 FU National Institute of Allergy and Infectious Diseases Division of Intramural Research; Food and Drug Administration Centers for Drug Evaluation and Research FX This work was generously supported by the National Institute of Allergy and Infectious Diseases Division of Intramural Research and Food and Drug Administration Centers for Drug Evaluation and Research. NR 49 TC 2 Z9 2 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2015 VL 6 IS 4 AR e01156-15 DI 10.1128/mBio.01156-15 PG 11 WC Microbiology SC Microbiology GA CQ8EN UT WOS:000360839400046 PM 26242629 ER EF