FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Rahman, Z Siddiqui, A Bykadi, S Khan, MA AF Rahman, Ziyaur Siddiqui, Akhtar Bykadi, Srikant Khan, Mansoor A. TI Determination of tacrolimus crystalline fraction in the commercial immediate release amorphous solid dispersion products by a standardized X-ray powder diffraction method with chemometrics SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Tacrolimus; Amorphous solid dispersion; X-ray powder diffraction; Partial least square regression; Principle component regression ID PHARMACEUTICAL SOLIDS; MOLECULAR MOBILITY; TECHNOLOGIES; SPECTROSCOPY; FORMULATION; STABILITY; DRUG AB Clinical performance of an amorphous solid dispersion (ASD) drug product is related to the amorphous drug content because of the greater bioavailability of this form of the drug than its crystalline form. Therefore, it is paramount to monitor the amorphous and the crystalline fractions in the ASD products. The objective of the present investigation was to study the feasibility of using a standardized X-ray powder diffraction (XRPD) in conjunction with chemometric methods to quantitate the amorphous and crystalline fraction of the drug in several tacrolimus ASD products. Three ASD products were prepared in which drug to excipients ratios ranged from 1:19 to 1:49. The amorphous and crystalline drug products were mixed in various proportions so that amorphous/crystalline tacrolimus in the samples vary from 0 to 100%. XRPD of the samples of the drug products were collected, and PLSR and PCR chemometric methods were applied to the data. The R-2 was greater than '0.987' for all the models and bias in the models were statistically insignificant (p > 0.05). RMSEP and SEP values were smaller for PLSR models than PCR models. The models prediction capabilities were good and can predict as low as 10% when drug to excipient ratio is as high as 1: 49. In summary, XRPD and chemometric provide powerful analytical tools to monitor the crystalline fractions of the drug in the ASD products. Published by Elsevier B.V. C1 [Rahman, Ziyaur; Siddiqui, Akhtar; Bykadi, Srikant; Khan, Mansoor A.] US FDA, Div Prod Qual & Res, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Khan, MA (reprint author), FDA CDER DPQR, White Oak LS Bldg 64,Room 1070, Silver Spring, MD 20993 USA. EM Mansoor.Khan@fda.hhs.gov OI Rahman, Ziyaur/0000-0002-0402-825X NR 22 TC 2 Z9 2 U1 2 U2 18 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 NOV 20 PY 2014 VL 475 IS 1-2 BP 462 EP 470 DI 10.1016/j.ijpharm.2014.08.050 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AU0FR UT WOS:000345299500048 PM 25173870 ER PT J AU Wu, YF Wu, QG Beland, FA Ge, P Manjanatha, MG Fang, JL AF Wu, Yuanfeng Wu, Qiangen Beland, Frederick A. Ge, Peter Manjanatha, Mugimane G. Fang, Jia-Long TI Differential effects of triclosan on the activation of mouse and human peroxisome proliferator-activated receptor alpha SO TOXICOLOGY LETTERS LA English DT Article DE Triclosan; PPAR alpha; DNA synthesis; Apoptosis ID PPAR-ALPHA; DNA-SYNTHESIS; APOPTOSIS; DYNAMICS; TRANSCRIPTION; METABOLISM; RAT; RESPONSIVENESS; IDENTIFICATION; HEPATOCYTES AB Triclosan is an anti-bacterial agent used in many personal care products, household items, medical devices, and clinical settings. Liver tumors occur in mice exposed to triclosan, a response attributed to peroxisome proliferator-activated receptor alpha (PPAR alpha) activation; however, the effects of triclosan on mouse and human PPARa have not been fully evaluated. We compared the effects of triclosan on mouse and human PPARa using PPARa reporter assays and on downstream events of PPARa activation using mouse hepatoma Hepa1c1c7 cells and human hepatoma HepG2 cells. PPARa transcriptional activity was increased by triclosan in a mouse PPARa reporter assay and decreased in a human PPARa reporter assay. Concentrations of triclosan inhibiting 50% cell growth were similar in both human and mouse hepatoma cells. Western blotting analysis showed that triclosan increased acyl-coenzyme A oxidase (ACOX1), a PPARa target, in Hepa1c1c7 cells but decreased the level in HepG2 cells. Treatment of Hepa1c1c7 cells with triclosan enhanced DNA synthesis and suppressed transforming growth factor beta-mediated apoptosis. This did not occur in HepG2 cells. These data demonstrate that triclosan had similar cytotoxicity in Hepa1c1c7 and HepG2 cells, but differential effects on the activation of PPARa, the expression of ACOX1, and downstream events including DNA synthesis and apoptosis. Published by Elsevier Ireland Ltd. C1 [Wu, Yuanfeng; Wu, Qiangen; Beland, Frederick A.; Ge, Peter; Fang, Jia-Long] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Manjanatha, Mugimane G.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Fang, JL (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 110, Jefferson, AR 72079 USA. EM jia-long.fang@fda.hhs.gov FU Division of Biochemical Toxicology at the National Center for Toxicological Research FX Yuanfeng Wu and Qiangen Wu were supported by an appointment to the Postgraduate Research Program 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. Food and Drug Administration. NR 45 TC 5 Z9 5 U1 1 U2 22 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 NOV 18 PY 2014 VL 231 IS 1 BP 17 EP 28 DI 10.1016/j.toxlet.2014.09.001 PG 12 WC Toxicology SC Toxicology GA AT1LU UT WOS:000344696100003 PM 25193434 ER PT J AU Colin-Gonzalez, AL Maya-Lopez, M Pedraza-Chaverri, J Ali, SF Chavarria, A Santamaria, A AF Laura Colin-Gonzalez, Ana Maya-Lopez, Marisol Pedraza-Chaverri, Jose Ali, Syed F. Chavarria, Anahi Santamaria, Abel TI The Janus faces of 3-hydroxykynurenine: Dual redox modulatory activity and lack of neurotoxicity in the rat striatum SO BRAIN RESEARCH LA English DT Article DE Redox activity; Oxidative stress; Antioxidant systems; Cell preservation; Kynurenine pathway ID NEURONAL CELL-DEATH; HUNTINGTONS-DISEASE; KYNURENINE PATHWAY; OXIDATIVE STRESS; 3-HYDROXYANTHRANILIC ACID; TRYPTOPHAN-METABOLITES; HYDROGEN-PEROXIDE; QUINOLINIC ACID; MITOCHONDRIAL DYSFUNCTION; BRAIN 3-HYDROXYKYNURENINE AB 3-Hydroxykynurenine (3-HK), an intermediate metabolite of the kynurenine pathway, has been largely hypothesized as a neurotoxic molecule contributing to neurodegeneration in several experimental and clinical conditions. Interestingly, the balance in literature points to a dual role of this molecule in the CNS: in vitro studies describe neurotoxic and/or antioxidant properties, whereas in vivo studies suggest a role of this metabolite as a weak neurotoxin. This work was designed to investigate, under different experimental conditions, whether or not 3-HK is toxic to cells, and if the redox activity exerted by this molecule modulates its actions in the rat striatum. In order to evaluate these effects, 3-HK was administered in vitro to isolated striatal slices, and in vivo to the striatum of rats. In striatal slices, 3-HK exerted a concentration- and time-dependent effect on lipid peroxidation, inducing both pro-oxidant actions at low (5-20) micromolar concentrations, and antioxidant activity at a higher concentration (100 mu M). Interestingly, while 3-HK was unable to induce mitochondrial dysfunction in slices, at the same range of concentrations it prevented the deleterious effects exerted by the neurotoxin and related metabolite quinolinic acid (QUIN), the mitochondrial toxin 3-nitropropionic acid, and the pro-oxidant compound iron sulfate. These protective actions were related to the stimulation of glutathione S-transferase (GST) and superoxide dismutase (SOD) activities. In addition, 3-HK stimulated the protein content of the transcription factor and antioxidant regulator Nrf2, and some of its related proteins. Accordingly, 3-HK, but not QUIN, exhibited reductive properties at high concentrations. The striatal tissue of animals infused with 3-HK exhibited moderate levels of lipid and protein oxidation at short times post-lesion (h), but these endpoints were substantially decreased at longer times (days). These effects were correlated with an early increase in glutathione reductase (GR) and GST activities. However, these changes were likely to be merely compensatory as 3-HK-infused animals did not display behavioral (rotation) alterations or morphological changes in their injected striata. Altogether, these findings suggest that, despite 3-HK might exert pro-oxidant actions under certain conditions, these changes serve to evoke a redox modulatory activity that, in turn, could decrease the risk of cell damage. In light of this evidence, 3-HK seems to be more a redox modulatory molecule than a neurotoxic metabolite. (C) 2014 Elsevier B.V. All rights reserved. C1 [Laura Colin-Gonzalez, Ana; Maya-Lopez, Marisol; Santamaria, Abel] SSA, Inst Nacl Neurol & Neurocirugia, Lab Aminoacidos Excitadores, Mexico City 14269, DF, Mexico. [Pedraza-Chaverri, Jose] Univ Nacl Autonoma Mexico, Fac Quim, Dept Biol, Mexico City 04510, DF, Mexico. [Ali, Syed F.] FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Chavarria, Anahi] Univ Nacl Autonoma Mexico, Fac Med, Dept Expt Med, Mexico City 04510, DF, Mexico. RP Santamaria, A (reprint author), SSA, Inst Nacl Neurol & Neurocirugia, Lab Aminoacidos Excitadores, Mexico City 14269, DF, Mexico. EM absada@yahoo.com OI Chavarria, Anahi/0000-0002-6412-0461 FU CONACyT Grant [205648]; CONACyT-Mexico [239954] FX This work was supported by CONACyT Grant 205648 (A.S.). Ana Laura Colin-Gonzalez is scholarship holder of CONACyT-Mexico (239954). Authors wish to thank Dr. Irma Gonzalez-Herrera for her technical support and to Dr. Enrique Pinzon and Dr. Ismael Torres for the technical assistance with the experimental animals. NR 54 TC 7 Z9 7 U1 1 U2 7 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 NOV 17 PY 2014 VL 1589 BP 1 EP 14 DI 10.1016/j.brainres.2014.09.034 PG 14 WC Neurosciences SC Neurosciences & Neurology GA AU6SR UT WOS:000345732600001 PM 25251594 ER PT J AU Wang, W Mocca, B Johnson, C AF Wang, Wei Mocca, Brian Johnson, Candice TI NO-mediated interkingdom signaling in bacterial pathogenesis and controversies SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract DE NO-signaling; Nitrite reduction; Bacterial-host cell interaction; Bacterial pathogenesis ID MORAXELLA-CATARRHALIS C1 [Wang, Wei; Mocca, Brian; Johnson, Candice] US FDA, Rockville, MD 20857 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD NOV 15 PY 2014 VL 42 MA P207 BP 149 EP 150 DI 10.1016/j.niox.2014.09.148 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU7XZ UT WOS:000345812900155 ER PT J AU Liu, JK Du, BC Zhang, PH Haleyurgirisetty, M Zhao, J Ragupathy, V Lee, S Devoe, DL Hewlett, IK AF Liu, Jikun Du, Bingchen Zhang, Panhe Haleyurgirisetty, Mohan Zhao, Jiangqin Ragupathy, Viswanath Lee, Sherwin DeVoe, Don L. Hewlett, Indira K. TI Development of a microchip Europium nanoparticle immunoassay for sensitive point-of-care HIV detection SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE Europium nanoparticles; Microchip; Point-of-care diagnostics; HIV; Resource-limited settings ID HUMAN-IMMUNODEFICIENCY-VIRUS; IMMUNE-RESPONSES; DEVELOPING-WORLD; ANALYSIS SYSTEMS; ASSAY; DIAGNOSTICS; AMPLIFICATION; TESTS; OPPORTUNITIES; PERFORMANCE AB Rapid, sensitive and specific diagnostic assays play an indispensable role in determination of HIV infection stages and evaluation of efficacy of antiretroviral therapy. Recently, our laboratory developed a sensitive Europium nanoparticle-based microtiter-plate immunoassay capable of detecting target analytes at subpicogram per milliliter levels without the use of catalytic enzymes and signal amplification processes. Encouraged by its sensitivity and simplicity, we continued to miniaturize this assay to a microchip platform for the purpose of converting the benchtop assay technique to a point-of-care test. It was found that detection capability of the microchip platform could be readily improved using Europium nanoparticle probes. We were able to routinely detect 5 pg/mL (4.6 attomoles) of HIV-1 p24 antigen at a signal-to-blank ratio of 1.5, a sensitivity level reasonably close to that of microtiter-plate Europium nanoparticle assay. Meanwhile, use of the microchip platform effectively reduced sample/reagent consumption 4.5 fold and shortened total assay time 2 fold in comparison with microtiter plate assays. Complex matrix substance in plasma negatively affected the microchip assays and the effects could be minimized by diluting the samples before loading. With further improvements in sensitivity, reproducibility, usability, assay process simplification, and incorporation of portable time-resolved fluorescence reader, Europium nanoparticle immunoassay technology could be adapted to meet the challenges of point-of-care diagnosis of HIV or other health-threatening pathogens at bedside or in resource-limited settings. (C) 2014 Elsevier B.V. All rights reserved. C1 [Liu, Jikun; Du, Bingchen; Zhang, Panhe; Haleyurgirisetty, Mohan; Zhao, Jiangqin; Ragupathy, Viswanath; Lee, Sherwin; Hewlett, Indira K.] US FDA, CBER, Mol Virol Lab, Bethesda, MD 20892 USA. [DeVoe, Don L.] Univ Maryland, Dept Mech Engn, College Pk, MD 20842 USA. RP Liu, JK (reprint author), US FDA, CBER, Mol Virol Lab, Bldg 29B Room 4NN16 8800 Rockville Pike, Bethesda, MD 20892 USA. EM jikunliu@fda.hhs.gov; Indira.Hewlett@fda.hhs.gov RI DeVoe, Don/A-2891-2011 OI DeVoe, Don/0000-0002-7740-9993 FU National Heart, Lung and Blood Institute (NHLBI) [Nano IAA-Y1-HB-8027-01]; Oak Ridge Institute for Science and Education (ORISE) FX This work was supported financially by the National Heart, Lung and Blood Institute (NHLBI, Nano IAA-Y1-HB-8027-01) and Oak Ridge Institute for Science and Education (ORISE). We would like to thank Drs. Xue Wang and Krishnakumar Devadas for review 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 43 TC 15 Z9 15 U1 3 U2 96 PU ELSEVIER ADVANCED TECHNOLOGY PI OXFORD PA OXFORD FULFILLMENT CENTRE THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-5663 EI 1873-4235 J9 BIOSENS BIOELECTRON JI Biosens. Bioelectron. PD NOV 15 PY 2014 VL 61 BP 177 EP 183 DI 10.1016/j.bios.2014.04.057 PG 7 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA AM2PE UT WOS:000339692500026 PM 24880655 ER PT J AU Arrazola, RA Neff, LJ Kennedy, SM Holder-Hayes, E Jones, CD AF Arrazola, Rene A. Neff, Linda J. Kennedy, Sara M. Holder-Hayes, Enver Jones, Christopher D. TI Tobacco Use Among Middle and High School Students - United States, 2013 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Arrazola, Rene A.; Neff, Linda J.; Jones, Christopher D.] CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Kennedy, Sara M.] RTI Int, Dept Biostat & Epidemiol, Res Triangle Pk, NC USA. [Holder-Hayes, Enver] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Arrazola, RA (reprint author), CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. EM rarrazola@cdc.gov NR 9 TC 60 Z9 61 U1 0 U2 5 PU CENTER DISEASE CONTROL & PREVENTION PI ATLANTA PA MAILSTOP E-90, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD NOV 14 PY 2014 VL 63 IS 45 BP 1021 EP 1026 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT6DW UT WOS:000345030400001 PM 25393220 ER PT J AU Khurana, S Coyle, EM Verma, S King, LR Manischewitz, J Crevar, CJ Carter, DM Ross, TM Golding, H AF Khurana, Surender Coyle, Elizabeth M. Verma, Swati King, Lisa R. Manischewitz, Jody Crevar, Corey J. Carter, Donald M. Ross, Ted M. Golding, Hana TI H5 N-terminal beta sheet promotes oligomerization of H7-HA1 that induces better antibody affinity maturation and enhanced protection against H7N7 and H7N9 viruses compared to inactivated influenza vaccine SO VACCINE LA English DT Article DE Influenza; Vaccine; Hemagglutinin; HA1; Antibody; Affinity; Immune Response; Ferrets; Bacteria; protein; Pandemic; H7N7; H7N9 ID AVIAN INFLUENZA; TRANSMISSION; FERRETS; HEMAGGLUTININ; POULTRY; HUMANS; FARMS AB Initiation of mass vaccination is critical in response to influenza pandemic. There is an urgent need of a simple, rapid method for production of influenza vaccine that is more effective than current traditional influenza vaccines. Recent H7N9 transmissions to humans in China with high morbidity/mortality initiated extensive vaccine evaluation. We produced the HA1 domains (amino acids 1-320) from H7N9 and H7N7 strains in E. coli. Both were found to contain primarily monomers/trimers with low oligomeric content. However, when residues from the N-terminal beta sheet (first 8 amino acid) of H7 HA1 domains were swapped with the corresponding amino acids from H5N1, functional oligomeric H7 HA1 were produced (HA1-DS), demonstrating strong receptor binding and hemagglutination. In rabbits, the HA1-DS from either H7N9 or H7N7 generated high neutralization titers against both homologous and heterologous H7 strains, superior to the unmodified H7 HA1 proteins. In ferrets, HA1-DS from H7N7 elicited higher (and faster) HI titers, better protected ferrets from lethality, weight loss, and reduced viral loads following challenge with wild-type highly pathogenic H7N7 virus compared with inactivated H7N7 subunit vaccine. HA1-DS vaccinated ferrets were also better protected from weight loss after challenge with the heterologous H7N9 virus compared with inactivated H7N7 subunit vaccine. Importantly, the H7N7 HA1-DS vaccine induced antibody affinity maturation far superior to the inactivated H7N7 subunit vaccine, which strongly correlated with control of viral loads in the nasal washes after challenge with either H7N7 or H7N9 strains. We conclude that N-terminus p sheet domain-swap can be used to produce stable functional oligomeric forms of better recombinant HA1 vaccines in simple, inexpensive bacterial system for rapid response to emerging pandemic threat for the global population. Published by Elsevier Ltd. C1 [Khurana, Surender; Coyle, Elizabeth M.; Verma, Swati; King, Lisa R.; Manischewitz, Jody; Golding, Hana] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20903 USA. [Crevar, Corey J.; Carter, Donald M.; Ross, Ted M.] Vaccine & Gene Therapy Inst Florida, Miami, FL USA. RP Khurana, S (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20903 USA. EM Surender.Khurana@fda.hhs.gov; Hana.Golding@fda.hhs.gov FU CBER, FDA FX We are thankful to Carol Weiss and Zhiping Ye for thorough review of the manuscript. The H7N3 containing the H7 hemagglutinin from H7N7-A/Netherlands/02/2003 was kind gift from Maryna Eichelberger, CBER, FDA. The research was funded by CBER, FDA. NR 20 TC 8 Z9 8 U1 0 U2 3 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 NOV 12 PY 2014 VL 32 IS 48 BP 6421 EP 6432 DI 10.1016/j.vaccine.2014.09.049 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AU2SY UT WOS:000345469000017 PM 25284811 ER PT J AU Haber, P Moro, PL McNeil, MM Lewis, P Woo, EJ Hughes, H Shimabukuro, TT AF Haber, Penina Moro, Pedro L. McNeil, Michael M. Lewis, Paige Woo, Emily Jane Hughes, Hayley Shimabukuro, Tom T. TI Post-licensure surveillance of trivalent live attenuated influenza vaccine in adults, United States, Vaccine Adverse Event Reporting System (VAERS), July 2005-June 2013 SO VACCINE LA English DT Article DE Vaccine safety; Post-licensure surveillance; Live attenuated influenza vaccine ID GUILLAIN-BARRE-SYNDROME; IMMUNIZATION PRACTICES ACIP; ADVISORY-COMMITTEE; SMALLPOX VACCINATION; SEASONAL INFLUENZA; SAFETY DATA; RECOMMENDATIONS; PREVENTION; GUIDELINES; COLLECTION AB Background: Trivalent live attenuated influenza vaccine (LAIV3) was licensed and recommended for use in 2003 in children and adults 2-49 years of age. Post-licensure safety data have been limited, particularly in adults. Methods: We searched Vaccine Adverse Event Reporting System (VAERS) for US reports after LAIV3 from July 1,2005-June 30, 2013 (eight influenza seasons) in adults aged >= 18 years old. We conducted descriptive analyses and clinically reviewed serious reports (i.e., death, life-threatening illness, hospitalization, prolonged hospitalization, or permanent disability) and reports of selected conditions of interest. We used empirical Bayesian data mining to identify adverse events (AEs) that were reported more frequently than expected. We calculated crude AE reporting rates to VAERS by influenza season. Results: During the study period, VAERS received 1207 LAIV3 reports in adults aged 18-49 years old; 107 (8.9%) were serious, including four death reports. The most commonly reported events were expired drug administered (n = 207, 17%), headache (n = 192, 16%), and fever (n = 133, 11%). The most common diagnostic categories for non-fatal serious reports were neurological (n = 40, 39%), cardiovascular (n = 14, 14%), and other non-infectious conditions (n = 20, 19%). We noted a higher proportion of Guillain-Barre syndrome (GBS) and cardiovascular reports in the Department of Defense (DoD) population compared to the civilian population. Data mining detected disproportional reporting of ataxia (n = 15); clinical review revealed that ataxia was a component of diverse clinical entities including GBS. Conclusions: Review of VAERS reports are reassuring, the only unexpected safety concern for LAIV3 identified was a higher than expected number of GBS reports in the DoD population, which is being investigated. Reports of administration of expired LAIV3 represent administration errors and indicate the need for education, training and screening regarding the approved indications. Published by Elsevier Ltd. C1 [Haber, Penina; Moro, Pedro L.; McNeil, Michael M.; Lewis, Paige; Shimabukuro, Tom T.] Ctr Dis Control & Prevent, Immunizat Safety Off, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis,CDC, Atlanta, GA 30333 USA. [Woo, Emily Jane] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Hughes, Hayley] Mil Vaccine Agcy MILVAX, Safety & Evaluat Div, Falls Church, VA 22042 USA. RP Haber, P (reprint author), Ctr Dis Control & Prevent, Immunizat Safety Off, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis,CDC, 1600 Clifton Rd NE, Atlanta, GA 30333 USA. EM pyh0@cdc.gov NR 31 TC 7 Z9 7 U1 0 U2 2 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 NOV 12 PY 2014 VL 32 IS 48 BP 6499 EP 6504 DI 10.1016/j.vaccine.2014.09.018 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AU2SY UT WOS:000345469000028 PM 25258101 ER PT J AU Huque, MF Valappil, T Soon, G AF Huque, Mohammad F. Valappil, Thamban Soon, Guoxing (Greg) TI Hierarchical nested trial design (HNTD) for demonstrating treatment efficacy of new antibacterial drugs in patient populations with emerging bacterial resistance SO STATISTICS IN MEDICINE LA English DT Article DE hierarchical nested trial design; noninferiority; superiority testing; group sequential procedure; unmet medical need; antibacterial drug resistance ID CLINICAL-TRIALS AB In the last decade or so, pharmaceutical drug development activities in the area of new antibacterial drugs for treating serious bacterial diseases have declined, and at the same time, there are worries that the increased prevalence of antibiotic-resistant bacterial infections, especially the increase in drug-resistant Gram-negative infections, limits available treatment options . A recent CDC report, Antibiotic Resistance Threats in the United States', indicates that antimicrobial resistance is one of our most serious health threats. However, recently, new ideas have been proposed to change this situation. An idea proposed in this regard is to conduct randomized clinical trials in which some patients, on the basis of a diagnostic test, may show presence of bacterial pathogens that are resistant to the control treatment, whereas remaining patients would show pathogens that are susceptible to the control. The control treatment in such trials can be the standard of care or the best available therapy approved for the disease. Patients in the control arm with resistant pathogens can have the option for rescue therapies if their clinical signs and symptoms worsen. A statistical proposal for such patient populations is to use a hierarchical noninferiority-superiority nested trial design that is informative and allows for treatment-to-control comparisons for the two subpopulations without any statistical penalty. This design can achieve in the same trial dual objectives: (i) to show that the new drug is effective for patients with susceptible pathogens on the basis of a noninferiority test and (ii) to show that it is superior to the control in patients with resistant pathogens. This paper addresses statistical considerations and methods for achieving these two objectives for this design. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Huque, Mohammad F.] US FDA, Off Biostat, OTS, CDER, Silver Spring, MD 20993 USA. [Valappil, Thamban; Soon, Guoxing (Greg)] US FDA, Div Biometr 4, OB, OTS,CDER, Silver Spring, MD USA. RP Huque, MF (reprint author), US FDA, Off Biostat, OTS, CDER, Silver Spring, MD 20993 USA. EM Mohammad.Huque@fda.hhs.gov NR 20 TC 1 Z9 1 U1 0 U2 8 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 NOV 9 PY 2014 VL 33 IS 25 BP 4321 EP 4336 DI 10.1002/sim.6233 PG 16 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 AQ6DK UT WOS:000342898500001 PM 24957660 ER PT J AU Zhang, ZW Liu, CL Kim, S Liu, AY AF Zhang, Zhiwei Liu, Chunling Kim, Sungduk Liu, Aiyi TI Prevalence estimation subject to misclassification: the mis-substitution bias and some remedies SO STATISTICS IN MEDICINE LA English DT Article DE dilution effect; group testing; maximum likelihood; optimal design; pooled testing; sensitivity; specificity; test error ID HUMAN-IMMUNODEFICIENCY-VIRUS; GROUP-TESTING PROCEDURE; REGRESSION-ANALYSIS; INFECTION-RATES; VARIABLE SIZE; BLOOD-DONORS; RARE DISEASE; POOLED SERA; MODELS; HIV AB We consider the problem of estimating the prevalence of a disease under a group testing framework. Because assays are usually imperfect, misclassification of disease status is a major challenge in prevalence estimation. To account for possible misclassification, it is usually assumed that the sensitivity and specificity of the assay are known and independent of the group size. This assumption is often questionable, and substitution of incorrect values of an assay's sensitivity and specificity can result in a large bias in the prevalence estimate, which we refer to as the mis-substitution bias. In this article, we propose simple designs and methods for prevalence estimation that do not require known values of assay sensitivity and specificity. If a gold standard test is available, it can be applied to a validation subsample to yield information on the imperfect assay's sensitivity and specificity. When a gold standard is unavailable, it is possible to estimate assay sensitivity and specificity, either as unknown constants or as specified functions of the group size, from group testing data with varying group size. We develop methods for estimating parameters and for finding or approximating optimal designs, and perform extensive simulation experiments to evaluate and compare the different designs. An example concerning human immunodeficiency virus infection is used to illustrate the validation subsample design. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Zhang, Zhiwei] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Liu, Chunling] Hong Kong Polytech Univ, Dept Appl Math, Hong Kong, Hong Kong, Peoples R China. [Kim, Sungduk; Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. RP Zhang, ZW (reprint author), US FDA, DBS, OSB, CDRH, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM zhiwei.zhang@fda.hhs.gov RI Liu, Chunling/A-4827-2015; OI Liu, Chunling/0000-0003-3410-445X; Liu, Aiyi/0000-0002-6618-5082 FU Hong Kong research grant [BQ25U]; National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We thank three anonymous reviewers for their insightful and constructive comments that have improved the manuscript greatly. Dr. Chunling Liu's research was partially supported by Hong Kong research grant BQ25U. The research of Drs. Aiyi Liu and Sung-Duk Kim was supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. The views expressed in this article do not represent the official position of the US Food and Drug Administration. NR 43 TC 3 Z9 3 U1 0 U2 2 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 NOV 9 PY 2014 VL 33 IS 25 BP 4482 EP 4500 DI 10.1002/sim.6268 PG 19 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 AQ6DK UT WOS:000342898500011 PM 25043925 ER PT J AU Meseda, CA Srinivasan, K Wise, J Catalano, J Yamada, KM Dhawan, S AF Meseda, Clement A. Srinivasan, Kumar Wise, Jasen Catalano, Jennifer Yamada, Kenneth M. Dhawan, Subhash TI Non-coding RNAs and heme oxygenase-1 in vaccinia virus infection SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Vaccinia; Non-coding RNAs; Heme oxygenase-1; Host defense; Gene expression ID INDUCTION; REPLICATION; MALARIA AB Small nuclear RNAs (snRNAs) are <200 nucleotide non-coding uridylate-rich RNAs. Although the functions of many snRNAs remain undetermined, a population of snRNAs is produced during the early phase of infection of cells by vaccinia virus. In the present study, we demonstrate a direct correlation between expression of the cytoprotective enzyme heme oxygenase-1 (HO-1), suppression of selective snRNA expression, and inhibition of vaccinia virus infection of macrophages. Hemin induced HO-1 expression, completely reversed virus-induced host snRNA expression, and suppressed vaccinia virus infection. This involvement of specific virus-induced snRNAs and associated gene clusters suggests a novel HO-1-dependent host-defense pathway in poxvirus infection. Published by Elsevier Inc. C1 [Srinivasan, Kumar; Dhawan, Subhash] US FDA, Ctr Biol Evaluat & Res, Div Transfus Transmitted Dis, Bethesda, MD 20014 USA. [Meseda, Clement A.] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD 20014 USA. [Wise, Jasen] Qiagen, Frederick, MD USA. [Catalano, Jennifer] US FDA, Ctr Tobacco Prod, Bethesda, MD 20014 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 20014 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; C.A.M., K.S. and J.W., performed and analyzed experiments; J.C. and K.M.Y. analyzed experiments. We thank Dr. Jerry Weir for supporting this study. This paper is dedicated to the memory of Dr. Kumar Srinivasan. 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 15 TC 1 Z9 1 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD NOV 7 PY 2014 VL 454 IS 1 BP 84 EP 88 DI 10.1016/j.bbrc.2014.10.035 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AX1FN UT WOS:000346693500015 PM 25450361 ER PT J AU Mbondji-Wonje, C Ragupathy, V Zhao, JQ Nanfack, A Lee, S Torimiro, J Nyambi, P Hewlett, IK AF Mbondji-Wonje, Christelle Ragupathy, Viswanath Zhao, Jiangqin Nanfack, Aubin Lee, Sherwin Torimiro, Judith Nyambi, Phillipe Hewlett, Indira K. TI Genotypic Prediction of Tropism of Highly Diverse HIV-1 Strains from Cameroon SO PLOS ONE LA English DT Article ID VIRUS TYPE-1 GP120; NON-B SUBTYPES; GENETIC DIVERSITY; INTERSUBTYPE RECOMBINANTS; CCR5 ANTAGONISTS; BLOOD-DONORS; V3 LOOP; PREVALENCE; CRF02-AG; CXCR4 AB Background: The use of CCR5 antagonists involves determination of HIV-1 tropism prior to initiation of treatment. HIV-1 tropism can be assessed either by phenotypic or genotypic methods. Genotypic methods are extensively used for tropism prediction. However, their validation in predicting tropism of viral isolates belonging to group M non-B subtypes remains challenging. In Cameroon, the genetic diversity of HIV-1 strains is the broadest reported worldwide. To facilitate the integration of CCR5 antagonists into clinical practice in this region, there is a need to evaluate the performance of genotypic methods for predicting tropism of highly diverse group M HIV-1 strains. Methods: Tropism of diverse HIV-1 strains isolated from PBMCs from Cameroon was determined using the GHOST cell assay. Prediction, based on V3 sequences from matched plasma samples, was determined using bioinformatics algorithms and rules based on position 11/25 and net charge applied independently or combined according to Delobel's and Garrido's rules. Performance of genotypic methods was evaluated by comparing prediction generated with tropism assigned by the phenotypic assay. Results: Specificity for predicting R5-tropic virus was high, ranging from 83.7% to 97.7% depending on the genotypic methods used. Sensitivity for X4-tropic viruses was fairly low, ranging from 33.3% to 50%. In our study, overall, genotypic methods were less able to accurately predict X4-tropic virus belonging to subtype CRF02_AG. In addition, it was found that of the methods we used the Garrido rule has the highest sensitivity rate of over 50% with a specificity of 93%. Conclusion: Our study demonstrated that overall, genotypic methods were less sensitive for accurate prediction of HIV-1 tropism in settings where diverse HIV-1 strains co-circulate. Our data suggest that further optimization of genotypic methods is needed and that larger studies to determine their utility for tropism prediction of diverse HIV-1 strains may be warranted. C1 [Mbondji-Wonje, Christelle; Ragupathy, Viswanath; Zhao, Jiangqin; Lee, Sherwin; Hewlett, Indira K.] Ctr Biol Evaluat & Res, Div Emerging & Transmiss Transmitted Dis, Mol Virol Lab, Off Blood Review & Res,Food & Drug Adm, Silver Spring, MD 20993 USA. [Mbondji-Wonje, Christelle] Univ Douala, Fac Med Pharm & Biomed Sci, Douala, Cameroon. [Nanfack, Aubin; Torimiro, Judith] Chantal Biya Int Reference Ctr, Yaounde, Cameroon. [Nanfack, Aubin] NYU, Sch Med, Dept Pathol, New York, NY USA. RP Mbondji-Wonje, C (reprint author), Ctr Biol Evaluat & Res, Div Emerging & Transmiss Transmitted Dis, Mol Virol Lab, Off Blood Review & Res,Food & Drug Adm, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM christelle.mbondji@fda.hhs.gov FU National Heart, Lung and Blood Institute [BY1-HB-5026-01]; Center for Biologics Evaluation and Research intramural funding program (CBER/FDA) FX For this work the authors received the funding support of the National Heart, Lung and Blood Institute for funding part of this work through the Inter-Agency Agreement BY1-HB-5026-01, www.nhlbi.nih.gov; and of the Center for Biologics Evaluation and Research intramural funding program (CBER/FDA), www.fda.gov. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 1 Z9 1 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 NOV 7 PY 2014 VL 9 IS 11 AR e112434 DI 10.1371/journal.pone.0112434 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT3WF UT WOS:000344863100091 PM 25379669 ER PT J AU Shaffer, S Yang, KJ Vargas, J Di Prima, MA Voit, W AF Shaffer, Steven Yang, Kejia Vargas, Juan Di Prima, Matthew A. Voit, Walter TI On reducing anisotropy in 3D printed polymers via ionizing radiation SO POLYMER LA English DT Article DE Radiation crosslinking; 3D printing; Anisotropy ID SHAPE-MEMORY POLYMERS; MECHANICAL-PROPERTIES; CROSS-LINKING; BIOMEDICAL APPLICATIONS; LAYER ORIENTATION; MORPHOLOGY; RECONSTRUCTION; TEMPERATURE; IRRADIATION; FABRICATION AB The mechanical properties of materials printed using fused filament fabrication (FFF) 3D printers typically rely only on adhesion among melt processed thermoplastic polymer strands. This dramatically limits the utility of FFF systems today for a host of manufacturing and consumer products and severely limits the toughness in 3D printed shape memory polymers. To improve the interlayer adhesion in 3D printed parts, we introduce crosslinks among the polymer chains by exposing 3D printed copolymer blends to ionizing radiation to strengthen the parts and reduce anisotropy. A series polymers blended with specific radiation sensitizers, such as trimethylolpropane triacrylate (TMPTA) and triallyisocyanurate (TAIC), were prepared and irradiated by gamma rays. Differential scanning calorimetry (DSC), tensile testing, dynamic mechanical analysis (DMA) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) were employed to characterize the thermomechanical properties and the chemical structure of the various polymers. TAIC was shown to be a very effective radiation sensitizer for 3D printed sensitized polylactic acid (PLA). The results further revealed that crosslinks induced by radiation temperatures near T-g of shape memory systems have prominently enhanced the thermomechanical properties of the 3D printed polymers, as well as the solvent resistance. This enables us to deliver a new generation of inexpensive 3D printable, crosslinked parts with robust thermomechanical properties. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Shaffer, Steven; Voit, Walter] Univ Texas Dallas, Dept Mech Engn, Richardson, TX 75080 USA. [Yang, Kejia; Voit, Walter] Univ Texas Dallas, Dept Chem, Richardson, TX 75080 USA. [Di Prima, Matthew A.] US FDA, CDRH OSEL DSFM, Silver Spring, MD 20993 USA. [Vargas, Juan; Voit, Walter] Univ Texas Dallas, Dept Mat Sci & Engn, Richardson, TX 75080 USA. [Voit, Walter] Syzygy Memory Plast, Dallas, TX 75252 USA. RP Voit, W (reprint author), Univ Texas Dallas, Dept Mech Engn, Richardson, TX 75080 USA. EM walter.voit@utdallas.edu OI Di Prima, Matthew/0000-0003-1623-1324 FU DARPA Young Faculty Award Program [D13AP00049]; US FDA Medical Countermeasures Program [FDA-11-1092096]; University of Texas at Dallas Biomedical Device Center [TXMDC55002]; Center for Engineering Innovation [CEI30003] FX We would like to thank Nordion's Gamma Center of Excellence and Sterilization team including Fatima Hasanain and Harold Walker for their contributions on the gamma irradiation experiments. We would like to acknowledge funding from the DARPA Young Faculty Award Program (D13AP00049), the US FDA Medical Countermeasures Program via FDA-11-1092096 "Expanded Emergency Capacity of Medical Device Production through 3D Printing of Radiation Cross Linked Polymers" and support from the University of Texas at Dallas Biomedical Device Center (TXMDC55002) and from Center for Engineering Innovation (CEI30003). NR 91 TC 22 Z9 22 U1 19 U2 126 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0032-3861 EI 1873-2291 J9 POLYMER JI Polymer PD NOV 5 PY 2014 VL 55 IS 23 SI SI BP 5969 EP 5979 DI 10.1016/j.polymer.2014.07.054 PG 11 WC Polymer Science SC Polymer Science GA AU0JW UT WOS:000345310100015 ER PT J AU Jones, CM Lurie, P Woodcock, J AF Jones, Christopher M. Lurie, Peter Woodcock, Janet TI Addressing Prescription Opioid Overdose Data Support a Comprehensive Policy Approach SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID MORTALITY; DEATHS C1 [Jones, Christopher M.; Lurie, Peter] US FDA, Off Commissioner, Silver Spring, MD 20993 USA. [Woodcock, Janet] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Jones, CM (reprint author), US FDA, Off Commissioner, 10903 New Hampshire Ave,WO32 RM4220, Silver Spring, MD 20993 USA. EM Christopher.M.Jones@fda.hhs.gov NR 10 TC 12 Z9 12 U1 2 U2 9 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 5 PY 2014 VL 312 IS 17 BP 1733 EP 1734 DI 10.1001/jama.2014.13480 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AS3QX UT WOS:000344194500006 PM 25275855 ER PT J AU de Conti, A Tryndyak, V Churchwell, MI Melnyk, S Latendresse, JR Muskhelishvili, L Beland, FA Pogribny, IP AF de Conti, Aline Tryndyak, Volodymyr Churchwell, Mona I. Melnyk, Stepan Latendresse, John R. Muskhelishvili, Levan Beland, Frederick A. Pogribny, Igor P. TI Genotoxic, epigenetic, and transcriptomic effects of tamoxifen in mouse liver SO TOXICOLOGY LA English DT Article DE Tamoxifen; Mouse; Liver; DNA adducts; Epigenetics; Gene expression ID INDUCED RAT HEPATOCARCINOGENESIS; ACTIVATED RECEPTOR-GAMMA; BREAST-CANCER PATIENTS; NONALCOHOLIC STEATOHEPATITIS; HEPATIC STEATOSIS; DNA-ADDUCTS; ENDOMETRIAL CANCER; ADJUVANT TAMOXIFEN; MICE; EXPOSURE AB Tamoxifen is a non-steroidal anti-estrogenic drug widely used for the treatment and prevention of breast cancer in women; however, there is evidence that tamoxifen is hepatocarcinogenic in rats, but not in mice. Additionally, it has been reported that tamoxifen may cause non-alcoholic fatty liver disease (NAFLD) in humans and experimental animals. The goals of the present study were to (i) investigate the mechanisms of the resistance of mice to tamoxifen-induced hepatocarcinogenesis, and (ii) clarify effects of tamoxifen on NAFLD-associated liver injury. Feeding female WSB/EiJ mice a 420 p.p.m. tamoxifen-containing diet for 12 weeks resulted in an accumulation of tamoxifen-DNA adducts, (E)-alpha-(deoxyguanosin-N-2-yl)-tamoxifen (dG-TAM) and (E)-alpha-(deoxyguanosin-N-2-yl)-N-desmethyltamoxifen (dG-DesMeTAM), in the livers. The levels of hepatic dG-TAM and dG-DesMeTAM DNA adducts in tamoxifen-treated mice were 578 and 340 adducts/108 nucleotides, respectively, while the extent of global DNA and repetitive elements methylation and histone modifications did not differ from the values in control mice. Additionally, there was no biochemical or histopathological evidence of NAFLD-associated liver injury in mice treated with tamoxifen. A transcriptomic analysis of differentially expressed genes demonstrated that tamoxifen caused predominantly down-regulation of hepatic lipid metabolism genes accompanied by a distinct over-expression of the lipocalin 13 (Lcn13) and peroxisome proliferator receptor gamma (Ppar gamma), which may prevent the development of NAFLD. The results of the present study demonstrate that the resistance of mice to tamoxifen-induced liver carcinogenesis may be associated with its ability to induce genotoxic alterations only without affecting the cellular epigenome and an inability of tamoxifen to induce the development of NAFLD. Published by Elsevier Ireland Ltd. C1 [de Conti, Aline; Tryndyak, Volodymyr; Churchwell, Mona I.; Beland, Frederick A.; Pogribny, Igor P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Melnyk, Stepan] Univ Arkansas Med Sci Hosp, Dept Pediat, Little Rock, AR 72202 USA. [Latendresse, John R.; Muskhelishvili, Levan] US FDA, Toxicol Pathol Associates, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov NR 36 TC 3 Z9 3 U1 5 U2 24 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 NOV 5 PY 2014 VL 325 BP 12 EP 20 DI 10.1016/j.tox.2014.08.004 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AR7UO UT WOS:000343785400002 PM 25123088 ER PT J AU Guo, DY Dexheimer, TS Pommier, Y Nash, HA AF Guo, DongYu Dexheimer, Thomas S. Pommier, Yves Nash, Howard A. TI Neuroprotection and repair of 3 '-blocking DNA ends by glaikit (gkt) encoding Drosophila tyrosyl-DNA phosphodiesterase 1 (TDP1) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aging; neuroscience; DNA repair; topoisomerase; fly ID STRAND BREAK REPAIR; TOPOISOMERASE-I COMPLEXES; SPINOCEREBELLAR ATAXIA; LIFE-SPAN; COVALENT COMPLEXES; CLEAVAGE COMPLEXES; AXONAL NEUROPATHY; NERVOUS-SYSTEM; HUMAN-CELLS; DAMAGE AB Tyrosyl-DNA phosphodiesterase (TDP1) is a phylogenetically conserved enzyme critical for the removal of blocking lesions at the 3' ends of DNA or RNA. This study analyzes the Drosophila TDP1 gene ortholog glaikit (gkt) and its possible role(s) in the repair of endogenous DNA lesions and neuroprotection. To do so, we studied a homozygous PiggyBac insertion (c03958) that disrupts the 5' UTR of gkt. Protein extracts of c03958 flies were defective in hydrolyzing 3'-DNA-tyrosyl residues, demonstrating that gkt is the Drosophila TDP1. Although the mutant is generally healthy and fertile, females exhibit reduced lifespan and diminished climbing ability. This phenotype was rescued by neuronal expression of TDP1. In addition, when c03958 larvae were exposed to bleomycin, an agent that produces oxidative DNA damage, or topoisomerase I-targeted drugs (camptothecin and a noncamptothecin indenoisoquinoline derivative, LMP-776), survivors displayed rough eye patches, which were rescued by neuronal expression of TDP1. Our study establishes that gkt is the Drosophila TDP1 gene, and that it is critical for neuroprotection, normal longevity, and repair of damaged DNA. C1 [Guo, DongYu; Nash, Howard A.] NIMH, Sect Mol Genet, Mol Biol Lab, Bethesda, MD 20892 USA. [Dexheimer, Thomas S.; Pommier, Yves] NCI, Lab Mol Pharmacol, Dev Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Guo, DY (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM dongyu.guo@fda.hhs.gov; pommier@nih.gov FU NIH Intramural Program, National Institute of Diabetes and Digestive and Kidney Diseases; Center for Cancer Research of the National Cancer Institute [Z01 BC 006161] FX The authors thank Dr. Alena Naumova and Dr. Christophe Marchand (Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch) for help in running the TDP1 activity experiments. They also thank Dr. Shar-yin N. Huang (Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch) and Benjamin H. White (Neural Function Section, National Institute of Mental Health) for critical reading and editing of the manuscript and for constructive suggestions. This work was supported by the NIH Intramural Program, National Institute of Diabetes and Digestive and Kidney Diseases, and the Center for Cancer Research of the National Cancer Institute (Z01 BC 006161). NR 56 TC 6 Z9 6 U1 1 U2 13 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 NOV 4 PY 2014 VL 111 IS 44 BP 15816 EP 15820 DI 10.1073/pnas.1415011111 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS2CY UT WOS:000344088100053 PM 25331878 ER PT J AU Mattes, W Davis, K Fabian, E Greenhaw, J Herold, M Looser, R Mellert, W Groeters, S Marxfeld, H Moeller, N Montoya-Parra, G Prokoudine, A van Ravenzwaay, B Strauss, V Walk, T Kamp, H AF Mattes, W. Davis, K. Fabian, E. Greenhaw, J. Herold, M. Looser, R. Mellert, W. Groeters, S. Marxfeld, H. Moeller, N. Montoya-Parra, G. Prokoudine, A. van Ravenzwaay, B. Strauss, V. Walk, T. Kamp, H. TI Detection of hepatotoxicity potential with metabolite profiling (metabolomics) of rat plasma SO TOXICOLOGY LETTERS LA English DT Article DE Hepatotoxicity; Metabolomic; Rat plasma ID INDUCED LIVER-INJURY; DRUG-INDUCED HEPATOTOXICITY; TOXICITY; MECHANISMS; BIOMARKERS; NEPHROTOXICITY; ZIDOVUDINE; HISTOPATHOLOGY; DOXORUBICIN; STRATEGIES AB While conventional parameters used to detect hepatotoxicity in drug safety assessment studies are generally informative, the need remains for parameters that can detect the potential for hepatotoxicity at lower doses and/or at earlier time points. Previous work has shown that metabolite profiling (metabonomics/metabolomics) can detect signals of potential hepatotoxicity in rats treated with doxorubicin at doses that do not elicit hepatotoxicity as monitored with conventional parameters. The current study extended this observation to the question of whether such signals could be detected in rats treated with compounds that can elicit hepatotoxicity in humans (i.e., drug-induced liver injury, DILI) but have not been reported to do so in rats. Nine compounds were selected on the basis of their known DILI potential, with six other compounds chosen as negative for DILI potential. A database of rat plasma metabolite profiles, MetaMape (R) Tox (developed by metanomics GmbH and BASF SE) was used for both metabolite profiles and mode of action (MoA) metabolite signatures for a number of known toxicities. Eight of the nine compounds with DILI potential elicited metabolite profiles that matched with MoA patterns of various rat liver toxicities, including cholestasis, oxidative stress, acetaminophen-type toxicity and peroxisome proliferation. By contrast, only one of the six non-DILI compounds showed a weak match with rat liver toxicity. These results suggest that metabolite profiling may indeed have promise to detect signals of hepatotoxicity in rats treated with compounds having DILI potential. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Mattes, W.] PharmPoint Consulting, Poolesville, MD 20837 USA. [Davis, K.] Toxicol Pathol Associates, Jefferson, AR USA. [Greenhaw, J.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Fabian, E.; Mellert, W.; Groeters, S.; Marxfeld, H.; Montoya-Parra, G.; van Ravenzwaay, B.; Strauss, V.; Kamp, H.] BASF SE, Ludwigshafen, Germany. [Herold, M.; Looser, R.; Prokoudine, A.; Walk, T.] Metanomics GmbH, Berlin, Germany. [Moeller, N.] Metan Hlth GmbH, Berlin, Germany. RP van Ravenzwaay, B (reprint author), BASF SE, Ludwigshafen, Germany. EM bennard.ravenzwaay@basf.com NR 59 TC 13 Z9 15 U1 10 U2 75 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 NOV 4 PY 2014 VL 230 IS 3 BP 467 EP 478 DI 10.1016/j.toxlet.2014.07.021 PG 12 WC Toxicology SC Toxicology GA AR8SY UT WOS:000343845800011 PM 25086301 ER PT J AU Chang, YW Tsong, Y Dong, XY Zhao, ZG AF Chang, Yu-Wei Tsong, Yi Dong, Xiaoyu Zhao, Zhigen TI Sample Size Determination for a Three-Arm Equivalence Trial of Normally Distributed Responses SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Superiority; Equivalence test; Power; Three-arm clinical trial; Sample size AB The equivalence assessment is often conducted through a three-arm clinical trial (namely, test, reference, and placebo) and it usually consists of three tests. The first two tests are to demonstrate the superiority of the test and the reference treatment to the placebo, and they are followed by an equivalence test between the test treatment and the reference treatment. When the response variable is continuous, equivalence is commonly defined in terms of mean difference, mean ratio, or ratio of mean differences, that is, the mean difference of the test and the placebo to the mean difference of the reference and the placebo. These equivalence tests can be performed with both a hypothesis-testing approach and a confidence-interval approach. The advantage of applying the equivalence test by ratio of mean differences is that it can test both superiority of the test treatment over placebo and equivalence between the test and the reference simultaneously through a single hypothesis. In this article, we derive the test statistics and the power function for the ratio of mean differences hypothesis and solve the required sample size for a three-arm clinical trial. Examples of required sample size are given in this article, and are compared with the required sample size by the traditional mean difference equivalence test. After a careful examination, we suggest increasing the power of the ratio of mean differences approach by appropriately adjusting the lower limit of the equivalence interval. C1 [Chang, Yu-Wei; Zhao, Zhigen] Temple Univ, Dept Stat, Philadelphia, PA 19122 USA. [Tsong, Yi; Dong, Xiaoyu] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Chang, YW (reprint author), Temple Univ, Dept Stat, Mitten Hall Lower Level 043-79,1913 N Broad St, Philadelphia, PA 19122 USA. EM changvick@gmail.com NR 9 TC 1 Z9 1 U1 1 U2 4 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 2014 VL 24 IS 6 SI SI BP 1190 EP 1202 DI 10.1080/10543406.2014.948552 PG 13 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA AR9QR UT WOS:000343910400006 PM 25098678 ER PT J AU Sun, AN Dong, XY Tsong, Y AF Sun, Anna Dong, Xiaoyu Tsong, Yi TI Sample Size Determination for Equivalence Assessment with Multiple Endpoints SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Sample size; Crossover design; Power; Multiple comparisons; Bioequivalence; Two one-sided tests AB Equivalence assessment between a reference and test treatment is often conducted by two one-sided tests (TOST). The corresponding power function and sample size determination can be derived from a joint distribution of the sample mean and sample variance. When an equivalence trial is designed with multiple endpoints, it often involves several sets of two one-sided tests. A naive approach for sample size determination in this case would select the largest sample size required for each endpoint. However, such a method ignores the correlation among endpoints. With the objective to reject all endpoints and when the endpoints are uncorrelated, the power function is the production of all power functions for individual endpoints. With correlated endpoints, the sample size and power should be adjusted for such a correlation. In this article, we propose the exact power function for the equivalence test with multiple endpoints adjusted for correlation under both crossover and parallel designs. We further discuss the differences in sample size for the naive method without and with correlation adjusted methods and illustrate with an in vivo bioequivalence crossover study with area under the curve (AUC) and maximum concentration (Cmax) as the two endpoints. C1 [Sun, Anna; Dong, Xiaoyu; Tsong, Yi] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Sun, AN (reprint author), US FDA, Div Biometr 6, Off Biostat, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM anna.sun@fda.hhs.gov NR 12 TC 1 Z9 1 U1 2 U2 7 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 2014 VL 24 IS 6 SI SI BP 1203 EP 1214 DI 10.1080/10543406.2014.941986 PG 12 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA AR9QR UT WOS:000343910400007 PM 25032845 ER PT J AU Dong, XY Tsong, Y AF Dong, Xiaoyu Tsong, Yi TI Equivalence Assessment for Interchangeability Based on Two-Sided Tests SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Two-sided tolerance interval; Power; Type I error rate; Interchangeability; Sample size ID FOLLOW-ON BIOLOGICS; INDIVIDUAL BIOEQUIVALENCE; VARIABILITY AB Interchangeability was originally developed in order to assess drug bioequivalence beyond average bioequivalence. In 2003, the Food and Drug Administration (FDA) published a Guidance documenting the procedures on using in vivo bioequivalence crossover trial to assess interchangeability between test and reference products. In general, this FDA Guidance describes interchangeability in terms of population and individual bioequivalence. The Guidance procedures were criticized for their lack of sampling distribution of the test statistics. As a result, the critical points were generated from simulation studies without adjusting for sample size. Further more, they lack consistency with average bioequivalence required in the 1992 FDA Guidance. Alternative interchangeability or interchangeability procedures were proposed to measure the probability of individual response difference under two treatments within prespecified lower and upper limits. Interchangeability is claimed if this probability is greater than a prespecified threshold. Tse et al. (2006) proposed an approximate distribution of the estimated probability based on the second-order Taylor expansion. For the same interchangeability probability hypothesis, Liu and Chow (1997) and Tsong and Shen (2007) also proposed a tolerance interval-based approach that can be extended to clinical trials with parallel arm design under the normality assumption. In this article, we first generalized the two-sided tolerance interval based interchangeability without equal sample size and variance assumption. We also derived a power function for the proposed method, and performed simulation studies to compare the type I error rate, power, and sample size between the Tse approximated test and the generalized tolerance interval approach for interchangeability assessment. C1 [Dong, Xiaoyu; Tsong, Yi] US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Dong, XY (reprint author), US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 21,Room 3617, Silver Spring, MD 20993 USA. EM xiaoyu.dong@fda.hhs.gov NR 14 TC 3 Z9 3 U1 4 U2 6 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 2014 VL 24 IS 6 SI SI BP 1312 EP 1331 DI 10.1080/10543406.2014.941988 PG 20 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA AR9QR UT WOS:000343910400015 PM 25032976 ER PT J AU Dong, XY Tsong, Y Shen, MY AF Dong, Xiaoyu Tsong, Yi Shen, Meiyu TI Equivalence Tests for Interchangeability Based on Two One-Sided Probabilities SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE TOST; Interchangeability; Type I error rate; Sample size; Power ID INDIVIDUAL BIOEQUIVALENCE AB A test treatment is considered to be interchangeable with its reference treatment if they are equivalent and expected to produce the same clinical result in any given patient. To assess interchangeability, FDA Draft Guidance (1999) and Guidance for Industry (2001, 2003) recommend using individual bioequivalence (IBE) and population bioequivalence (PBE) procedures. Chow (1999) and Chow and Liu (1999) gave a discussion on the limitation of the aggregate criteria of the IBE and PBE proposed therein. They mentioned that it is not clear whether IBE or PBE can imply average bioequivalence. Alternative approaches have been proposed to address the weakness of IBE and PBE. Dong et al. (2014) discuss the tolerance interval method and an approximate test for interchangeability defined by a two-sided probability. These tests may not be able to test for the two one-sided tests (TOST) with asymmetric margins around the true mean difference. In addition, the tests of two-sided probability provide no direction when failing the equivalence in interchangeability. Thus, we reexamine the statistical properties of the two one-sided tolerance interval approaches proposed by Tsong and Shen (2007, 2008). In this project, we extend their approach for parallel arms trials and paired/crossover data without the assumption of equal sample sizes and variances. We also develop the exact power function and assess the type I error rate of our proposed approach. In addition, we study the sample size determination based on the interchangeability testing utilizing the tolerance interval method. C1 [Dong, Xiaoyu; Tsong, Yi; Shen, Meiyu] US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Dong, XY (reprint author), US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 21,Room 3617, Silver Spring, MD 20993 USA. EM xiaoyu.dong@fda.hhs.gov NR 16 TC 2 Z9 2 U1 0 U2 0 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 2014 VL 24 IS 6 SI SI BP 1332 EP 1348 DI 10.1080/10543406.2014.941987 PG 17 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA AR9QR UT WOS:000343910400016 PM 25033074 ER PT J AU Roth-Cline, M Nelson, R AF Roth-Cline, Michelle Nelson, Robert TI FDA Implementation of the Expanded Access Program in the United States SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material C1 [Roth-Cline, Michelle; Nelson, Robert] US FDA, Silver Spring, MD 20993 USA. RP Nelson, R (reprint author), US FDA, Off Pediat Therapeut, 10903 New Hampshire Ave,WO32,Room 5126, Silver Spring, MD 20993 USA. EM Robert.nelson@fda.hhs.gov NR 1 TC 4 Z9 4 U1 0 U2 3 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD NOV 2 PY 2014 VL 14 IS 11 BP 17 EP 19 DI 10.1080/15265161.2014.957418 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA AQ9XG UT WOS:000343211500006 PM 25325803 ER PT J AU Avigan, MI Bjornsson, ES Pasanen, M Cooper, C Andrade, RJ Watkins, PB Lewis, JH Merz, M AF Avigan, Mark I. Bjornsson, Einar S. Pasanen, Markku Cooper, Charles Andrade, Raul J. Watkins, Paul B. Lewis, James H. Merz, Michael TI Liver Safety Assessment: Required Data Elements and Best Practices for Data Collection and Standardization in Clinical Trials SO DRUG SAFETY LA English DT Review AB A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. In a breakout session, workshop attendees discussed necessary data elements and standards for the accurate measurement of DILI risk associated with new therapeutic agents in clinical trials. There was agreement that in order to achieve this goal the systematic acquisition of protocol-specified clinical measures and lab specimens from all study subjects is crucial. In addition, standard DILI terms that address the diverse clinical and pathologic signatures of DILI were considered essential. There was a strong consensus that clinical and lab analyses necessary for the evaluation of cases of acute liver injury should be consistent with the US Food and Drug Administration (FDA) guidance on pre-marketing risk assessment of DILI in clinical trials issued in 2009. A recommendation that liver injury case review and management be guided by clinicians with hepatologic expertise was made. Of note, there was agreement that emerging DILI signals should prompt the systematic collection of candidate pharmacogenomic, proteomic and/or metabonomic biomarkers from all study subjects. The use of emerging standardized clinical terminology, CRFs and graphic tools for data review to enable harmonization across clinical trials was strongly encouraged. Many of the recommendations made in the breakout session are in alignment with those made in the other parallel sessions on methodology to assess clinical liver safety data, causality assessment for suspected DILI, and liver safety assessment in special populations (hepatitis B, C, and oncology trials). Nonetheless, a few outstanding issues remain for future consideration. C1 [Avigan, Mark I.] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Bjornsson, Einar S.] Natl Univ Hosp Iceland, Reykjavik, Iceland. [Pasanen, Markku] Univ Eastern Finland, Sch Pharm Kuopio, Fac Hlth Sci, Kuopio, Finland. [Cooper, Charles] Becton Dickenson, Franklin Lakes, NJ USA. [Andrade, Raul J.] Univ Malaga, Gastroenterol Serv, E-29071 Malaga, Spain. [Andrade, Raul J.] Univ Malaga, Univ Hosp Virgen de la Victoria, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Inst Invest Biomed Malaga IBIMA,Liver Unit, E-29071 Malaga, Spain. [Watkins, Paul B.] Hamner Univ North Carolina, Inst Drug Safety Sci, Res Triangle Pk, NC 27709 USA. [Watkins, Paul B.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Watkins, Paul B.] Univ N Carolina, Sch Pharm, Chapel Hill, NC USA. [Watkins, Paul B.] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [Lewis, James H.] Georgetown Univ, Washington, DC USA. [Merz, Michael] Novartis Inst BioMed Res, Discovery & Invest Safety, Basel, Switzerland. RP Avigan, MI (reprint author), US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM mark.avigan@fda.hhs.gov; pwatkins@thehamner.org NR 13 TC 6 Z9 7 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 NOV PY 2014 VL 37 SU 1 BP S19 EP S31 DI 10.1007/s40264-014-0183-6 PG 13 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA CP5SZ UT WOS:000359946000003 PM 25352325 ER PT J AU Senior, JR AF Senior, John R. TI Evolution of the Food and Drug Administration Approach to Liver Safety Assessment for New Drugs: Current Status and Challenges SO DRUG SAFETY LA English DT Review ID CAUSALITY ASSESSMENT; ADVERSE REACTIONS; INJURY; HEPATOTOXICITY; TROVAFLOXACIN; HEPATITIS; DIAGNOSIS; EVENTS; MODEL AB Prompted by approval in 1997 of troglitazone and bromfenac, two drugs that promptly began to show serious and sometimes fatal liver toxicity, we began at the Food and Drug Administration (FDA) a series of annual conferences in 1999 to consider issues of drug-induced liver injury (DILI). First inviting reviewers of new drug applications we opened the audiences in 2001 to pharmaceutical industry and academic consultants to industry and FDA, and slides shown at the meetings were posted on the internet to be available at the website of the American Association for the Study of Liver Diseases (AASLD)-go to (http://www.aasld.org/dili/Pages/default.aspx). Observations by Dr. Hyman J. Zimmerman that "drug-induced hepatocellular jaundice is a serious lesion'' with possible mortality formed a basis for developing a computer program to plot peak serum values for alanine aminotransferase (ALT) and total bilirubin (TBL) in an x-y log-log graph for all subjects enrolled in clinical trials. This program had the capability to show the time course of all liver tests for individuals who had both hepatocellular injury and reduced whole liver function, plus clinical narratives to diagnose the severity and most likely cause of the abnormalities. We called the program eDISH (for evaluation of Drug-Induced Serious Hepatotoxicity), and began in 2004 to use it to assess DILI in clinical trial subjects. From 2008, comments made by the presenters at the conferences about their slides and ensuing discussions have been added to the website. All this has raised awareness of the problem, and since 1997, the FDA has not had to withdraw a single drug because of post-marketing hepatotoxicity. Many issues still remain to be resolved; among the most controversial is the best method to estimate likelihood that a given liver injury was actually caused by the drug in question. On November 9, 2012, a workshop was convened to discuss the best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. C1 US FDA, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Senior, JR (reprint author), US FDA, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM john.senior@fda.hhs.gov NR 28 TC 16 Z9 16 U1 1 U2 6 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 NOV PY 2014 VL 37 SU 1 BP S9 EP S17 DI 10.1007/s40264-014-0182-7 PG 9 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA CP5SZ UT WOS:000359946000002 PM 25352324 ER PT J AU Watkins, PB Merz, M Avigan, MI Kaplowitz, N Regev, A Senior, JR AF Watkins, Paul B. Merz, Michael Avigan, Mark I. Kaplowitz, Neil Regev, Arie Senior, John R. TI The Clinical Liver Safety Assessment Best Practices Workshop: Rationale, Goals, Accomplishments and the Future SO DRUG SAFETY LA English DT Editorial Material ID ADVERSE EVENT; GENOME-WIDE; DRUG; HEPATOTOXICITY; TRIALS; INJURY C1 [Watkins, Paul B.] Hamner Univ North Carolina, Inst Drug Safety Sci, Res Triangle Pk, NC 27709 USA. [Watkins, Paul B.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Watkins, Paul B.] Univ N Carolina, Sch Pharm, Chapel Hill, NC USA. [Watkins, Paul B.] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [Merz, Michael] Novartis Inst BioMed Res, Discovery & Invest Safety, Basel, Switzerland. [Avigan, Mark I.] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Kaplowitz, Neil] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Res Ctr Liver Dis, Los Angeles, CA 90033 USA. [Regev, Arie] Eli Lilly & Co, Global Patient Safety, Indianapolis, IN 46285 USA. [Senior, John R.] US FDA, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Watkins, PB (reprint author), Hamner Univ North Carolina, Inst Drug Safety Sci, 6 Davis Dr,POB 12137, Res Triangle Pk, NC 27709 USA. EM pwatkins@thehamner.org NR 22 TC 5 Z9 5 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 NOV PY 2014 VL 37 SU 1 BP S1 EP S7 DI 10.1007/s40264-014-0181-8 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA CP5SZ UT WOS:000359946000001 PM 25352323 ER PT J AU Buehler, P Eigenberger, P Irwin, D Loomis, Z Maltzhan, J Anderson, M Lisk, C AF Buehler, Paul Eigenberger, Paul Irwin, David Loomis, Zoe Maltzhan, Joanne Anderson, Malcolm Lisk, Christina TI Hemoglobin Induced Vasoconstriction and Oxidative Stress are Prevented by Haptoglobin SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Buehler, Paul] US FDA, Ctr Biol Evaluat & Res, Lab Biochem & Vasc Biol, Div Hematol, Bethesda, MD USA. [Eigenberger, Paul; Irwin, David; Loomis, Zoe; Maltzhan, Joanne] Univ Colorado, Cardiovasc Pulm Res Grp, Boulder, CO 80309 USA. [Anderson, Malcolm] Childrens Hosp Colorado, Dept Crit Care, Colorado Springs, CO USA. [Lisk, Christina] Boston Univ, Sch Med, Program Biol Sci, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV PY 2014 VL 76 SU 1 MA 4 BP S14 EP S15 DI 10.1016/j.freeradbiomed.2014.10.490 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CO9WA UT WOS:000359525800024 ER PT J AU McNeill, K Iwamoto, F Kreisl, T Sul, J Shih, J Fine, H AF McNeill, Katharine Iwamoto, Fabio Kreisl, Teri Sul, Joohee Shih, Joanna Fine, Howard TI A RANDOMIZED PHASE II TRIAL OF VANDETANIB (ZD6474) IN COMBINATION WITH CARBOPLATIN VERSUS CARBOPLATIN ALONE IN ADULTS WITH RECURRENT GLIOBLASTOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract C1 [McNeill, Katharine; Fine, Howard] NYU, New York, NY USA. [Iwamoto, Fabio; Kreisl, Teri] Columbia Univ, New York, NY USA. [Sul, Joohee] NIH, Bethesda, MD 20892 USA. [Shih, Joanna] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 2014 VL 16 SU 5 MA AT-39 DI 10.1093/neuonc/nou237.38 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200068 ER PT J AU Ekezue, BF Sridhar, G Izurieta, HS Forshee, RA Selvam, N Ovanesov, MV Jain, N Mintz, PD Anderson, SA Menis, M AF Ekezue, B. F. Sridhar, G. Izurieta, H. S. Forshee, R. A. Selvam, N. Ovanesov, M., V Jain, N. Mintz, P. D. Anderson, S. A. Menis, M. TI CLOTTING FACTOR (CF) PRODUCT USE AND SAME-DAY RISK FOR THROMBOTIC ADVERSE EVENTS (TES), AS RECORDED IN LARGE HEALTH CARE DATABASE DURING 2008-2013 STUDY PERIOD SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Ekezue, B. F.; Sridhar, G.; Selvam, N.] HealthCore Inc, Alexandria, VA USA. [Izurieta, H. S.; Forshee, R. A.; Ovanesov, M., V; Jain, N.; Mintz, P. D.; Anderson, S. A.; Menis, M.] US FDA, Silver Spring, MD USA. FU NCI NIH HHS [P30 CA016672] NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD NOV PY 2014 VL 17 IS 7 MA PCV4 BP A473 EP A473 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA AX4QT UT WOS:000346917301097 PM 27201359 ER PT J AU Woods, TO Angelone, LM Delfino, JG AF Woods, Terry O. Angelone, Leonardo M. Delfino, Jana G. TI Assessment of MRI Issues at 7 T SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Letter C1 [Woods, Terry O.; Angelone, Leonardo M.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Delfino, Jana G.] US FDA, Off In Vitro Diagnost & Radiol Hlth, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Woods, TO (reprint author), US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. OI Angelone, Leonardo/0000-0002-1105-021X NR 3 TC 1 Z9 1 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD NOV PY 2014 VL 203 IS 5 BP W560 EP W560 DI 10.2214/AJR.14.12956 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AY2JM UT WOS:000347415700021 PM 25341179 ER PT J AU Jarvis, KG Grim, CJ Beaubrun, JJ Ewing, L Dudley, K Ottesen, A Wang, C Pettengill, J Brown, E Hanes, D AF Jarvis, K. G. Grim, C. J. Beaubrun, J. J. Ewing, L. Dudley, K. Ottesen, A. Wang, C. Pettengill, J. Brown, E. Hanes, D. TI Evaluation of a metagenomics approach for the early detection of Salmonella in cilantro SO PHYTOPATHOLOGY LA English DT Meeting Abstract CT APS-CPS Joint Meeting CY AUG 09-13, 2014 CL Minneapolis, MN SP APS, CPS C1 [Jarvis, K. G.; Beaubrun, J. J.; Ewing, L.; Dudley, K.; Ottesen, A.; Hanes, D.] US FDA, Laurel, MD USA. [Grim, C. J.] Oak Ridge Inst Sci & Technol, Oak Ridge, TN USA. [Wang, C.; Pettengill, J.; Brown, E.] US FDA, College Pk, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER PHYTOPATHOLOGICAL SOC PI ST PAUL PA 3340 PILOT KNOB ROAD, ST PAUL, MN 55121 USA SN 0031-949X EI 1943-7684 J9 PHYTOPATHOLOGY JI Phytopathology PD NOV PY 2014 VL 104 IS 11 SU 3 BP 55 EP 55 PG 1 WC Plant Sciences SC Plant Sciences GA AW5GG UT WOS:000346303300310 ER PT J AU Ottesen, A White, JR Gorham, S Reed, E Newell, M Burrows, E Mahovic, M Brown, E AF Ottesen, A. White, J. R. Gorham, S. Reed, E. Newell, M. Burrows, E. Mahovic, M. Brown, E. TI Phyllosphere envirosphere SO PHYTOPATHOLOGY LA English DT Meeting Abstract CT APS-CPS Joint Meeting CY AUG 09-13, 2014 CL Minneapolis, MN SP APS, CPS C1 [Ottesen, A.; White, J. R.; Gorham, S.; Reed, E.; Burrows, E.; Mahovic, M.; Brown, E.] FDA CFSAN, College Pk, MD USA. [Newell, M.] Univ Maryland, Wye Res & Educ Ctr, Queenstown, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER PHYTOPATHOLOGICAL SOC PI ST PAUL PA 3340 PILOT KNOB ROAD, ST PAUL, MN 55121 USA SN 0031-949X EI 1943-7684 J9 PHYTOPATHOLOGY JI Phytopathology PD NOV PY 2014 VL 104 IS 11 SU 3 BP 87 EP 88 PG 2 WC Plant Sciences SC Plant Sciences GA AW5GG UT WOS:000346303300499 ER PT J AU Rideout, SL Gu, G Reiter, MS Zheng, J Brown, EW AF Rideout, S. L. Gu, G. Reiter, M. S. Zheng, J. Brown, E. W. TI Salmonella contamination and persistence in tomato fields as affected by irrigation, fertilization and cultivation practices SO PHYTOPATHOLOGY LA English DT Meeting Abstract CT APS-CPS Joint Meeting CY AUG 09-13, 2014 CL Minneapolis, MN SP APS, CPS C1 [Rideout, S. L.; Reiter, M. S.] Virginia Tech, Painter, VA USA. [Gu, G.] Virginia Tech, Ellicott City, MD USA. [Zheng, J.; Brown, E. W.] US FDA, College Pk, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER PHYTOPATHOLOGICAL SOC PI ST PAUL PA 3340 PILOT KNOB ROAD, ST PAUL, MN 55121 USA SN 0031-949X EI 1943-7684 J9 PHYTOPATHOLOGY JI Phytopathology PD NOV PY 2014 VL 104 IS 11 SU 3 BP 98 EP 98 PG 1 WC Plant Sciences SC Plant Sciences GA AW5GG UT WOS:000346303300557 ER PT J AU Schultz-Cherry, S Webby, RJ Webster, RG Kelso, A Barr, IG McCauley, JW Daniels, RS Wang, D Shu, Y Nobusawa, E Itamura, S Tashiro, M Harada, Y Watanabe, S Odagiri, T Ye, Z Grohmann, G Harvey, R Engelhardt, O Smith, D Hamilton, K Claes, F Dauphink, G AF Schultz-Cherry, S. Webby, R. J. Webster, R. G. Kelso, A. Barr, I. G. McCauley, J. W. Daniels, R. S. Wang, D. Shu, Y. Nobusawa, E. Itamura, S. Tashiro, M. Harada, Y. Watanabe, S. Odagiri, T. Ye, Z. Grohmann, G. Harvey, R. Engelhardt, O. Smith, D. Hamilton, K. Claes, F. Dauphink, G. TI Influenza Gain-of-Function Experiments: Their Role in Vaccine Virus Recommendation and Pandemic Preparedness SO MBIO LA English DT Editorial Material ID RECEPTOR-BINDING SPECIFICITY; HUMAN COINFECTION; A VIRUSES; HEMAGGLUTININ; FERRETS; IDENTIFICATION; TRANSMISSION; ANTIBODY; MUTANTS; CHINA AB In recent years, controversy has arisen regarding the risks and benefits of certain types of gain-of-function (GOF) studies involving avian influenza viruses. In this article, we provide specific examples of how different types of data, including information garnered from GOF studies, have helped to shape the influenza vaccine production process-from selection of candidate vaccine viruses (CVVs) to the manufacture and stockpiling of safe, high-yield prepandemic vaccines for the global community. The article is not written to support a specific pro-or anti-GOF stance but rather to inform the scientific community about factors involved in vaccine virus selection and the preparation of prepandemic influenza vaccines and the impact that some GOF information has had on this process. C1 [Schultz-Cherry, S.; Webby, R. J.; Webster, R. G.] St Jude Childrens Res Hosp, Dept Infect Dis, WHO Collaborating Ctr Studies Ecol Influenza Anim, Memphis, TN 38105 USA. [Kelso, A.; Barr, I. G.] Peter Doherty Inst Infect & Immun, WHO Collaborating Ctr Reference & Res Influenza, Melbourne, Vic, Australia. [McCauley, J. W.; Daniels, R. S.] MRC Natl Inst Med Res, Div Virol, WHO Collaborating Ctr Reference & Res Influenza, London, England. [Wang, D.; Shu, Y.] CDC, Natl Inst Viral Dis Control & Prevent China, Chinese Natl Influenza Ctr, WHO Collaborating Ctr Reference & Res Influenza, Beijing, Peoples R China. [Nobusawa, E.; Itamura, S.; Tashiro, M.; Harada, Y.; Watanabe, S.; Odagiri, T.] Natl Inst Infect Dis, WHO Collaborating Ctr Reference & Res Influenza, Lab Influenza Virus Surveillance, Influenza Virus Res Ctr, Tokyo, Japan. [Ye, Z.] US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Grohmann, G.] Therapeut Goods Adm Labs, Woden, ACT, Australia. [Harvey, R.; Engelhardt, O.] Med & Healthcare Prod Regulatory Agcy, Natl Inst Biol Stand & Control, Potters Bar, Herts, England. [Smith, D.] Univ Cambridge, WHO CC Modeling Evolut & Control Emerging Infect, Dept Zool, Ctr Pathogen Evolut, Cambridge, England. [Hamilton, K.] OIE, OIE Sci & Tech Dept, Paris, France. [Claes, F.; Dauphink, G.] FAO, Anim Hlth Serv, OFFLU EMPRES Lab Unit, I-00100 Rome, Italy. RP Schultz-Cherry, S (reprint author), St Jude Childrens Res Hosp, Dept Infect Dis, WHO Collaborating Ctr Studies Ecol Influenza Anim, 332 N Lauderdale St, Memphis, TN 38105 USA. EM Stacey.schultz-cherry@stjude.org OI Barr, Ian/0000-0002-7351-418X NR 38 TC 10 Z9 10 U1 0 U2 17 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 2014 VL 5 IS 6 AR e02430-14 DI 10.1128/mBio.02430-14 PG 7 WC Microbiology SC Microbiology GA AX7CE UT WOS:000347073600068 ER PT J AU Deeds, JR Handy, SM Fry, F Granade, H Williams, JT Powers, M Shipp, R Weigt, LA AF Deeds, Jonathan R. Handy, Sara M. Fry, Frederick, Jr. Granade, Hudson Williams, Jeffrey T. Powers, Monica Shipp, Robert Weigt, Lee A. TI Protocol for Building a Reference Standard Sequence Library for DNA-Based Seafood Identification SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID BARCODES; FISH AB With the recent adoption of a DNA sequencing-based method for the species identification for seafood products by the U.S. Food and Drug Administration (FDA), a library of standard sequences derived from reference specimens with authoritative taxonomic authentication was required. Provided here are details of how the FDA and its collaborators are building this reference standard sequence library that will be used to confirm the accurate labeling of seafood products sold in interstate commerce in the United States. As an example data set from this library, information for 117 fish reference standards, representing 94 species from 43 families in 15 orders, collected over a 4-year period from the Gulf of Mexico, U.S., that are now stored at the Smithsonian Museum Support Center in Suitland, MD, are provided. C1 [Deeds, Jonathan R.; Handy, Sara M.; Fry, Frederick, Jr.] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Granade, Hudson] US FDA, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. [Williams, Jeffrey T.] Smithsonian Inst, Natl Museum Nat Hist, Div Fishes, Museum Support Ctr, Suitland, MD 20746 USA. [Powers, Monica; Shipp, Robert] Univ S Alabama, Dept Marine Sci, Mobile, AL 36688 USA. [Weigt, Lee A.] Smithsonian Inst, Natl Museum Nat Hist, Labs Analyt Biol, Museum Support Ctr, Suitland, MD 20746 USA. RP Deeds, JR (reprint author), US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM jonathan.deeds@fda.hhs.gov RI Handy, Sara/C-6195-2008 NR 11 TC 4 Z9 4 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 2014 VL 97 IS 6 BP 1626 EP 1633 DI 10.5740/jaoacint.14-111 PG 8 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA AX3DF UT WOS:000346820000015 PM 25230794 ER PT J AU Shah, R De Jager, LS Begley, TH AF Shah, Romina De Jager, Lowri S. Begley, Timothy H. TI Development and Single-Laboratory Validation of an Improved Method for the Determination of Cyclamate in Foods Using Liquid Chromatography/Tandem Mass Spectrometry SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID SOLID-PHASE EXTRACTION AB A fast and reliable LC-MS/MS method for thedetermination of cyclamate in a variety of food matrices was developed and validated. This method provides both quantitation and qualitative mass spectral determination important for analysis of regulatory samples. Utilization of a cyclamate-d(11) internal standard corrects for potential matrix interferences during sample injection and allows minimal sample preparation. Seventeen commercially available food products were fortified at 250 mu g/mL and tested as part of the method validation. Recoveries ranged from 72 to 110%, with RSDs ranging from 3 to 15%. The linear range spanned 0.010-1.00 mu g/mL. LODs were 0.1 and 0.6 ng/mL, determined in pomegranate juice and dried fig, respectively. LOQs were 0.3 and 1.6 ng/mL, which are significantly lower than needed to measure cyclamate when used as a food additive. The interday and intraday accuracy and precision data are presented. This method was validated for analysis of a variety of commonly adulterated products, including drinks, dried fruits, jams, and hard candies. C1 [Shah, Romina; De Jager, Lowri S.; Begley, Timothy H.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Shah, R (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM romina.shah@fda.hhs.gov NR 14 TC 1 Z9 1 U1 1 U2 9 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 2014 VL 97 IS 6 BP 1651 EP 1655 DI 10.5740/jaoacint.14-042 PG 5 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA AX3DF UT WOS:000346820000018 PM 25632440 ER PT J AU Du, DY McKean, S Kelman, JA Laschinger, J Johnson, C Warnock, R Worrall, CM Sedrakyan, A Encinosa, W MaCurdy, TE Izurieta, HS AF Du, Dongyi (Tony) McKean, Stephen Kelman, Jeffrey A. Laschinger, John Johnson, Chris Warnock, Rob Worrall, Chris M. Sedrakyan, Art Encinosa, William MaCurdy, Thomas E. Izurieta, Hector S. TI Early Mortality After Aortic Valve Replacement With Mechanical Prosthetic vs Bioprosthetic Valves Among Medicare Beneficiaries A Population-Based Cohort Study SO JAMA INTERNAL MEDICINE LA English DT Article ID PROPENSITY SCORE; HEART-VALVE; SOCIETY; DISEASE; SURGERY AB IMPORTANCE Early mortality for patients who undergo aortic valve replacement (AVR) may differ between mechanical and biological prosthetic (hereinafter referred to as bioprosthetic) valves. Clinical trials may have difficulty addressing this issue owing to limited sample sizes and low mortality rates. OBJECTIVE To compare early mortality after AVR between the recipients of mechanical and bioprosthetic aortic valves. DESIGN, SETTING, AND PARTICIPANTS A retrospective analysis of patients 65 years or older in the Medicare databases who underwent AVR from July 1, 2006, through December 31, 2011. In the mixed-effects models adjusting for physician and hospital random effects, we estimated odds ratios (OR) of early mortality to compare mechanical vs bioprosthetic valves. EXPOSURES Mechanical or bioprosthetic aortic valve replacement. MAIN OUTCOMES AND MEASURES Early mortalitywas measured as death on the date of surgery, death within 1 to 30 or 31 to 365 days after the date of surgery, death within 30 days after the date of hospital discharge, and operative mortality (death within 30 days after surgery or at discharge, whichever is longer). RESULTS Of the 66 453 Medicare beneficiaries who met inclusion criteria, 19 190 (28.88%) received a mechanical valve and 47 263 (71.12%) received a bioprosthetic valve. The risk for death on the date of surgery was 60% higher for recipients of mechanical valves than recipients of bioprosthetic valves (OR, 1.61 [95% CI, 1.27-2.04; P <.001]; risk ratio [RR], 1.60). The risk difference decreased to 16% during the 30 days after the date of surgery (OR, 1.18 [95% CI, 1.09-1.28; P < .001]; RR, 1.16). We found no differences within 31 to 365 days after the date of surgery and within the 30 days after discharge. The risk for operative mortality was 19% higher for recipients of mechanical compared with bioprosthetic valves (OR, 1.21 [95% CI, 1.13-1.30; P < .001]; RR, 1.19). The number needed to treat with mechanical valves to observe 1 additional death on the surgery date was 290; to observe 1 additional death within 30 days of surgery, 121. Consistent findings were observed in subgroup analyses of patients who underwent concurrent AVR and coronary artery bypass graft, but not in the subgroup undergoing isolated AVR. CONCLUSIONS AND RELEVANCE In this cohort analysis of Medicare beneficiaries, use of mechanical aortic valves was associated with a higher risk for death on the date of surgery and within the 30 days after surgery compared with bioprosthetic aortic valves among patients who underwent concurrent AVR and coronary artery bypass graft but not isolated AVR. C1 [Du, Dongyi (Tony); Izurieta, Hector S.] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Du, Dongyi (Tony)] US FDA, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [McKean, Stephen; Warnock, Rob; MaCurdy, Thomas E.] Acumen LLC, Burlingame, CA USA. [Kelman, Jeffrey A.; Worrall, Chris M.] Ctr Medicare & Medicaid Serv, Washington, DC USA. [Laschinger, John] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Sedrakyan, Art] Weill Cornell Med Coll, Patient Ctr Comparat Effectiveness Program, New York, NY USA. [Sedrakyan, Art] Weill Cornell Med Coll, MDEpiNet Sci & Infrastruct Ctr, New York, NY USA. [Encinosa, William] Agcy Healthcare Res & Qual, Ctr Delivery Org & Markets, Rockville, MD USA. [MaCurdy, Thomas E.] Stanford Univ, Dept Econ, Stanford, CA 94305 USA. RP Du, DY (reprint author), Ctr Devices & Radiol Hlth Food & Drug Adm, Off Surveillance & Biometr, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM dongyi.du@fda.hhs.gov FU SafeRx Project, Centers for Medicare & Medicaid Services; SafeRx Project, US Food and Drug Administration FX This study was performed as part of the SafeRx Project, a joint initiative of the Centers for Medicare & Medicaid Services and the US Food and Drug Administration. NR 37 TC 7 Z9 7 U1 1 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD NOV PY 2014 VL 174 IS 11 BP 1788 EP 1795 DI 10.1001/jamainternmed.2014.4300 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AU9KA UT WOS:000345909900018 PM 25221895 ER PT J AU Shiels, MS Katki, HA Freedman, ND Purdue, MP Wentzensen, N Trabert, B Kitahara, CM Furr, M Li, Y Kemp, TJ Goedert, JJ Chang, CM Engels, EA Caporaso, NE Pinto, LA Hildesheim, A Chaturvedi, AK AF Shiels, Meredith S. Katki, Hormuzd A. Freedman, Neal D. Purdue, Mark P. Wentzensen, Nicolas Trabert, Britton Kitahara, Cari M. Furr, Michael Li, Yan Kemp, Troy J. Goedert, James J. Chang, Cindy M. Engels, Eric A. Caporaso, Neil E. Pinto, Ligia A. Hildesheim, Allan Chaturvedi, Anil K. TI Cigarette Smoking and Variations in Systemic Immune and Inflammation Markers SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTOR; LUNG-CANCER; BIOMARKERS; ACTIVATION; MORTALITY; EXPOSURE; PROSTATE; TOBACCO; SMOKERS; TRIAL AB Background A comprehensive characterization of the effects of cigarette smoke on systemic soluble immune/inflammatory markers may provide insight into the mechanisms through which smoking causes disease. Methods Levels of 78 inflammation, immune, and metabolic markers were measured using multiplex immune assays in 1819 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) participants aged 55 to 74 years from three existing nested case-control studies. These data were made representative of the entire PLCO screening arm through reweighting with weights estimated in logistic regression models. We assessed associations between smoking status, cigarettes smoked per day, and time since quitting with dichotomized marker levels using adjusted weighted logistic regression models. Results Current smoking was associated with 10 inflammation markers after correcting for multiple testing, encompassing several components of the immune/inflammation response. Levels of seven of these markers (interleukin [IL]-15, IL-1RA, IL-1 beta, IL-16, stem cell factor, soluble interleukin 6 receptor, and soluble vascular endothelial growth factor receptor 3) were lower among current smokers (n = 414) when compared with never smokers (n = 548), with odds ratios (ORs) ranging from 0.44 to 0.27, while levels of CC motif ligand (CCL)/thymus and activation regulated chemokine (CCL17/TARC) (OR = 4.08, 95% confidence interval [CI] = 2.01 to 8.25), CCL11/EOTAXIN (OR = 2.57, 95% CI = 1.45 to 4.55), and C-reactive protein (CRP) (OR = 2.54, 95% CI = 1.29 to 4.98) were elevated. These markers were not associated with cigarettes per day among current smokers, but there were trends in IL-15, IL-1RA, IL-1 beta, CCL17/TARC, CCL11/EOTAXIN, and CRP levels across categories of years since quitting smoking. Conclusions Smoking is associated with a broad range of alterations in systemic immune and inflammation marker levels among older, long-term smokers. Smoking cessation may result in marker levels reverting back to those of never smokers over time. C1 [Shiels, Meredith S.; Katki, Hormuzd A.; Freedman, Neal D.; Purdue, Mark P.; Wentzensen, Nicolas; Trabert, Britton; Kitahara, Cari M.; Goedert, James J.; Engels, Eric A.; Caporaso, Neil E.; Hildesheim, Allan] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Furr, Michael] Informat Management Serv Inc, Rockville, MD USA. [Li, Yan] Univ Maryland, Joint Program Survey Methodol, College Pk, MD 20742 USA. [Kemp, Troy J.; Pinto, Ligia A.] Leidos Biomed Res Inc, Frederick, MD USA. [Chang, Cindy M.] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Shiels, MS (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E-218 MSC 9767, Bethesda, MD 20892 USA. EM shielsms@mail.nih.gov RI Katki, Hormuzd/B-4003-2015; Hildesheim, Allan/B-9760-2015; Freedman, Neal/B-9741-2015; Purdue, Mark/C-9228-2016; Trabert, Britton/F-8051-2015; Chaturvedi, Anil/J-2024-2015; Kitahara, Cari/R-8267-2016 OI Hildesheim, Allan/0000-0003-0257-2363; Freedman, Neal/0000-0003-0074-1098; Purdue, Mark/0000-0003-1177-3108; Chaturvedi, Anil/0000-0003-2696-8899; FU Intramural Research Program of the National Cancer Institute FX This work was supported by the Intramural Research Program of the National Cancer Institute. NR 27 TC 16 Z9 16 U1 1 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD NOV PY 2014 VL 106 IS 11 AR dju294 DI 10.1093/jnci/dju294 PG 8 WC Oncology SC Oncology GA AU7IG UT WOS:000345773500012 ER PT J AU Chen, S Dobrovolsky, VN Liu, F Wu, YF Zhang, ZH Mei, N Guo, L AF Chen, Si Dobrovolsky, Vasily N. Liu, Fang Wu, Yuanfeng Zhang, Zhuhong Mei, Nan Guo, Lei TI The Role of Autophagy in Usnic Acid-Induced Toxicity in Hepatic Cells SO TOXICOLOGICAL SCIENCES LA English DT Article DE usnic acid; liver toxicity; autophagy; apoptosis; MAPK pathway ID ACETAMINOPHEN-INDUCED HEPATOTOXICITY; HEPATOCELLULAR-CARCINOMA CELLS; ENDOPLASMIC-RETICULUM STRESS; ISOLATED RAT HEPATOCYTES; MITOCHONDRIAL-FUNCTION; CANCER-CELLS; HEPG2 CELLS; WEIGHT-LOSS; APOPTOSIS; ACTIVATION AB The use of usnic acid and usnic acid-containing products is associated with acute liver failure; however, mechanistic studies of hepatotoxicity caused by usnic acid are limited. In this study, we investigated and characterized the possible mechanisms, especially the role of autophagy in usnic acid's toxicity in human HepG2 cells. Usnic acid caused apoptosis as demonstrated by an increased caspase-3/7 activity and an increased subdiploid nucleus formation. Usnic acid-induced autophagy as demonstrated by the conversion of LC3B-I to LC3B-II, degradation of P62, and an increased number of puncta. Inhibition of autophagy by treating cells with autophagy inhibitors (3-methyladenine or chloroquine) or by small interfering RNA against Atg7 aggravated usnic acid-induced apoptosis and decreased cell viability, indicating that autophagy plays a protective role against usnic acid-induced toxicity. Moreover, usnic acid activated the MAPK signaling pathway. Usnic acid-elicited apoptosis was enhanced and autophagy was decreased when JNK was suppressed by a specific inhibitor. Additionally, inhibition of autophagy decreased the activity of JNK. Taken together, our results suggest that usnic acid perturbs various interrelated signaling pathways and that autophagy induction is a defensive mechanism against usnic acid-induced cytotoxicity. C1 [Chen, Si; Wu, Yuanfeng; Guo, Lei] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Dobrovolsky, Vasily N.; Zhang, Zhuhong; Mei, Nan] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Liu, Fang] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Guo, L (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, HFT 110,3900 NCTR Rd, Jefferson, AR 72079 USA. EM lei.guo@fda.hhs.gov OI MEI, NAN/0000-0002-3501-9014 FU U.S. Department of Energy; U.S. Food and Drug Administration FX S.C., Y.W., and Z.H.Z. were supported by appointments to the Postgraduate Research Program at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. We thank Dr William Melchior for his critical review of this manuscript. NR 52 TC 7 Z9 8 U1 0 U2 19 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 NOV PY 2014 VL 142 IS 1 BP 33 EP 44 DI 10.1093/toxsci/kfu154 PG 12 WC Toxicology SC Toxicology GA AU8IT UT WOS:000345840600006 PM 25078063 ER PT J AU Taliaferro, LP Galvin, TA Ma, HL Shaheduzzaman, S Williams, DK Glasner, DR Khan, AS AF Taliaferro, Lanyn P. Galvin, Teresa A. Ma, Hailun Shaheduzzaman, Syed Williams, Dhanya K. Glasner, Dustin R. Khan, Arifa S. TI Evaluation of the Broad-Range PCR-Electrospray Ionization Mass Spectrometry (PCR/ESI-MS) System and Virus Microarrays for Virus Detection (vol 6, pg 1876, 2014) SO VIRUSES-BASEL LA English DT Correction C1 [Taliaferro, Lanyn P.; Galvin, Teresa A.; Ma, Hailun; Shaheduzzaman, Syed; Williams, Dhanya K.; Glasner, Dustin R.; Khan, Arifa S.] US FDA, Lab Retroviruses, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Khan, AS (reprint author), US FDA, Lab Retroviruses, Div Viral Prod, Ctr Biol Evaluat & Res, 8800 Rockville Pike,HFM-454, Bethesda, MD 20892 USA. EM lanyn.taliaferro@fda.hhs.gov; teresa.galvin@fda.hhs.gov; hailun.ma@fda.hhs.gov; syed.shaheduzzaman@fda.hhs.gov; dhanya.williams@fda.hhs.gov; drglasner@berkeley.edu; arifa.khan@fda.hhs.gov NR 1 TC 0 Z9 0 U1 1 U2 5 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD NOV PY 2014 VL 6 IS 11 BP 4664 EP 4665 DI 10.3390/v6114664 PG 2 WC Virology SC Virology GA AU4FL UT WOS:000345565200030 PM 25427296 ER PT J AU Guan, A Li, ZY Phillips, KS AF Guan, Allan Li, Zhenyu Phillips, K. Scott TI The Effect of Fluorescent Labels on Protein Sorption in Polymer Hydrogels SO JOURNAL OF FLUORESCENCE LA English DT Article DE Hydrogel; Fluorophore; Fluorescent label; Sorption; Biofouling; Protein; Labeling; Interference; Contact lens; Medical device; Adsorption; Absorption; Fluorescence; Fluorescence recovery after photobleaching (FRAP); Photobleaching; Intrinsic fluorescence; UV fluorescence; Residues; Microplate; Structure; Lysozyme; Ionic; Hydrohobic; BCA assay; Calibration; Response; Transparent; (Hydroxyethyl) methacrylate (HEMA); Silicone; Bicinchoninic acid; Polymer ID BOVINE SERUM-ALBUMIN; CAPILLARY-ELECTROPHORESIS; ULTRAVIOLET FLUORESCENCE; MEDICAL DEVICES; CONTACT-LENSES; SURFACES; ADSORPTION; BEHAVIOR; ACID AB Hydrogels are an increasingly important class of medical device materials that enable diverse and unique function, but can also be subject to significant biofouling and contamination. Although it is challenging to accurately quantify protein biofouling in hydrogels, spectroscopic detection of fluorescently labeled proteins is one method with the potential to provide direct, sensitive quantitation in transparent materials. Therefore, it is important to understand how fluorophores can affect protein-material interactions in hydrogels. This work uses an independent method, native ultraviolet fluorescence (native UV) of proteins, in conjunction with labeled protein fluorescence and the bicinchoninic acid assay (BCA), to assess the effect of fluorescent labels on protein sorption in polymer hydrogels. Bovine serum albumin (BSA) and lysozyme (LY) were labeled with two common but structurally different fluorophores and used as model biofouling proteins in three contact lens hydrogel materials. Native UV was used to directly measure both labeled and unlabeled protein sorption, while orthogonal measurements were performed with extrinsic fluorescence and BCA assay to compare with the native UV results. Sorption of labeled proteins was found to be < 2-fold higher than unlabeled proteins on most protein-material combinations, while differences of up to 10-fold were observed for labeled BSA in more hydrophobic hydrogels. Fluorescence recovery after photobleaching (FRAP) also showed that the fluorescent label chemistry can significantly affect surface adsorption of sorbed proteins on the internal surfaces of hydrogels. This study reveals the complex nature of fluorophore-protein-material interactions and shows the potential of native UV for investigating unlabeled protein biofouling in hydrogels. C1 [Guan, Allan; Li, Zhenyu] George Washington Univ, Dept Biomed Engn, Washington, DC 20052 USA. [Guan, Allan; Phillips, K. Scott] US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Chem & Mat Sci, 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 Chem & Mat Sci, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM kenneth.phillips@fda.hhs.gov RI phillips, kenneth/F-7560-2014; Phillips, Kenneth/A-2156-2013; OI phillips, kenneth/0000-0002-6552-0694; Phillips, Kenneth/0000-0002-6552-0694; Guan, Allan/0000-0001-9292-4582 NR 46 TC 6 Z9 6 U1 7 U2 42 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1053-0509 EI 1573-4994 J9 J FLUORESC JI J. Fluoresc. PD NOV PY 2014 VL 24 IS 6 BP 1639 EP 1650 DI 10.1007/s10895-014-1450-8 PG 12 WC Biochemical Research Methods; Chemistry, Analytical; Chemistry, Physical SC Biochemistry & Molecular Biology; Chemistry GA AU5JP UT WOS:000345643200010 PM 25209202 ER PT J AU Ding, W Bishop, ME Pearce, MG Davis, KJ White, GA Lyn-Cook, LE Manjanatha, MG AF Ding, Wei Bishop, Michelle E. Pearce, Mason G. Davis, Kelly J. White, Gene A. Lyn-Cook, Lascelles E. Manjanatha, Mugimane G. TI Sex-specific dose-response analysis of genotoxicity in cyproterone acetate-treated F344 rats SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE Cyproterone acetate (CPA); In vivo Comet assay; Liver; DNA damage; Oxidative DNA damage; Sex-specific genotoxicity ID GLUTATHIONE-PEROXIDASE ACTIVITY; NO-EFFECT LEVEL; COMET ASSAY; DNA-ADDUCTS; IN-VIVO; MUTAGENIC-ACTIVITY; OXIDATIVE DAMAGE; GENE-MUTATIONS; CANCER-RISK; LIVER AB Cyproterone acetate (CPA), a synthetic hormonal drug, induces rat liver tumors in a sex-specific manner, with five-fold higher doses needed to induce liver tumors in male rats compared to females. In order to evaluate the potential of the in vivo alkaline Comet assay to predict the sex-specific carcinogenicity of CPA, CPA-induced direct DNA damage (DNA strand breaks and alkali-labile sites) were evaluated in the livers of both male and female F344 rats. In addition, secondary oxidative DNA damage was measured concurrently utilizing the human 8-oxoguanine-DNA-N-glycosylase (hOGG1) and EndonucleaseIII (EndoIII)-modified in vivo alkaline Comet assays and the reticulocyte micronucleus (MN) frequency was analyzed in peripheral blood. Groups of 5 seven-week-old male and female F344 rats received olive oil or 10, 25, 50 or 100 mg/kg bw CPA in olive oil by gavage at 0, 24, and 45 h and were sacrificed at 48 h. CPA-induced direct DNA damage in rat liver showed the same sex-specific pattern as its hepatotumorigenicity: a five-fold-higher dose of CPA was needed to induce a statistically significant increase in direct DNA damage in livers of males compared to females. However, peripheral blood MN frequency was weak in both sexes and CPA-induced oxidative DNA damage was generally greater in male than female rat livers. Taken together, our results demonstrate concordance in the sex-specificity of CPA in the in vivo alkaline Comet assay and cancer bioassay, while the induction of oxidative DNA damage by CPA was not directly correlated with its tumorigenicity. Published by Elsevier By. C1 [Ding, Wei; Bishop, Michelle E.; Pearce, Mason G.; Lyn-Cook, Lascelles E.; Manjanatha, Mugimane G.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Davis, Kelly J.; White, Gene A.] US FDA, Toxicol Pathol Associates, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Ding, W (reprint author), US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Wei.Ding@fda.hhs.gov FU US Food and Drug Administration FX This work was supported by the US Food and Drug Administration. The views presented in this paper are not necessarily those of the U.S. FDA. NR 47 TC 2 Z9 2 U1 0 U2 6 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 NOV 1 PY 2014 VL 774 BP 1 EP 7 DI 10.1016/j.mrgentox.2014.08.005 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA AU3XH UT WOS:000345543500001 PM 25440904 ER PT J AU Hunsinger, M Smith, SM Rothstein, D McKeown, A Parkhurst, M Hertz, S Katz, NP Lin, AH McDermott, MP Rappaport, BA Turk, DC Dworkin, RH AF Hunsinger, Matthew Smith, Shannon M. Rothstein, Daniel McKeown, Andrew Parkhurst, Melissa Hertz, Sharon Katz, Nathaniel P. Lin, Allison H. McDermott, Michael P. Rappaport, Bob A. Turk, Dennis C. Dworkin, Robert H. TI Adverse event reporting in nonpharmacologic, noninterventional pain clinical trials: ACTTION systematic review SO PAIN LA English DT Review DE Harms reporting; Safety reporting; Adverse events; Complementary and alternative medical treatments ID RANDOMIZED CONTROLLED-TRIALS; PSYCHOLOGICAL TREATMENTS; IMMPACT RECOMMENDATIONS; DRUG-SAFETY; HARMS; MANAGEMENT; STATEMENT; SYMPTOMS AB Assessment of treatment safety is 1 of the primary goals of clinical trials. Organizations and working groups have created reporting guidelines for adverse events (AEs). Previous research examining AE reporting for pharmacologic clinical trials of analgesics in major pain journals found many reporting inadequacies, suggesting that analgesic trials are not adhering to existing AE reporting guidelines. The present systematic review documented AE reporting in 3 main pain journals for nonpharmacologic, non-interventional (NP/NI) trials examining pain treatments. To broaden our pool of nonpharmacologic trials, we also included trials examining acupuncture, leech therapy, and noninvasive stimulation techniques (eg, transcutaneous electrical nerve stimulation). We documented AE reporting at 2 levels of specificity using coding manuals based on the Consolidated Standards of Reporting Trials (CONSORT) harms reporting standards and Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) AE reporting checklist. We identified a number of inadequacies in AE reporting across the 3 journals. For example, using the ACTTION coding manual, we found that less than one-half of the trials reported specific AE assessment methods; approximately one-third of the trials reported withdrawals due to AEs for each study arm; and about one-fourth of the trials reported all specific AEs. We also examined differences in AE reporting across several trial characteristics, finding that AE reporting was generally more detailed in trials with patients versus those using healthy volunteers undergoing experimentally evoked pain. These results suggest that investigators conducting and reporting NP/NI clinical trials are not adequately describing the assessment and occurrence of AEs. (C) 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 [Hunsinger, Matthew] Univ Pacific, Sch Profess Psychol, Hillsboro, OR 97123 USA. [Smith, Shannon M.; Rothstein, Daniel; McKeown, Andrew; Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Dept Anesthesiol, Rochester, NY USA. [Parkhurst, Melissa] Univ Rochester, Sch Med & Dent, Dept Psychiat, Rochester, NY 14642 USA. [Hertz, Sharon; Lin, Allison H.; Rappaport, Bob A.] US FDA, Silver Spring, MD USA. [Katz, Nathaniel P.] Analges Solut, Natick, MA USA. [Katz, Nathaniel P.] Tufts Univ, Boston, MA 02111 USA. [McDermott, Michael P.] Univ Rochester, Sch Med & Dent, Dept Biostat & Computat Biol, Rochester, NY USA. [Turk, Dennis C.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. RP Hunsinger, M (reprint author), Univ Pacific, Sch Profess Psychol, 190 SE 8th Ave, Hillsboro, OR 97123 USA. EM matthewh@pacificu.edu FU ACTTION; FDA FX Financial support for this project was provided by the ACTTION public-private partnership with the FDA, which has received research grants or other revenue from the FDA, various pharmaceutical companies, and other sources. The views expressed in this article are those of the authors and no official endorsement by the FDA or the pharmaceutical companies that have provided unrestricted grants to support the activities of ACTTION should be inferred. NR 30 TC 5 Z9 5 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD NOV PY 2014 VL 155 IS 11 BP 2253 EP 2262 DI 10.1016/j.pain.2014.08.004 PG 10 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA AU1YM UT WOS:000345413400008 PM 25123543 ER PT J AU Ilyushina, NA Donnelly, RP AF Ilyushina, Natalia A. Donnelly, Raymond P. TI In vitro anti-influenza A activity of interferon (IFN)-lambda 1 combined with IFN-beta or oseltamivir carboxylate SO ANTIVIRAL RESEARCH LA English DT Article DE Influenza A virus; IFN-beta; IFN-lambda; Oseltamivir carboxylate; Combination therapy ID VIRUSES ISOLATED WORLDWIDE; CHRONIC HEPATITIS-C; A H3N2 VIRUSES; INFLUENZA-VIRUSES; ANTIVIRAL AGENTS; COMBINATIONS; INFECTIONS; LAMBDA; NEURAMINIDASE; RESISTANCE AB Influenza viruses, which can cross species barriers and adapt to new hosts, pose a constant potential threat to human health. The influenza pandemic of 2009 highlighted the rapidity with which an influenza virus can spread worldwide. Currently available antivirals have a number of limitations against influenza, and novel antiviral strategies, including novel drugs and drug combinations, are urgently needed. Here, we evaluated the in vitro effects of interferon (IFN)-beta, IFN-lambda 1, oseltamivir carboxylate (a neuraminidase (NA) inhibitor), and combinations of these agents against two seasonal (i.e., H1N1 and H3N2) influenza A viruses. We observed that A/California/04/09 (H1N1) and A/Panama/2007/99 (H3N2) isolates were equally sensitive to the antiviral activity of IFN-beta and oseltamivir carboxylate in A549 and Calu-3 cells. In contrast, IFN-lambda 1 exhibited substantially lower protective potential against the H1N1 strain (64-1030-fold down arrow, P < 0.05), and was ineffective against H3N2 virus in both cell lines. Three dimensional analysis of drug-drug interactions revealed that IFN-lambda 1 interacted with IFN-beta and oseltamivir carboxylate in an additive or synergistic manner, respectively, to inhibit influenza A virus replication in human airway epithelial cells. Overall, the present study demonstrated that anti-influenza agents with different mechanisms of action (e.g., a NA inhibitor combined with IFN-lambda 1) exerted a significantly greater (P < 0.05) synergistic effect compared to co-treatment with drugs that target the same signaling pathway (i.e., IFN-beta plus IFN-lambda 1) in vitro. Our findings provide support for the combined use of interferon plus oseltamivir as a potential means for treating influenza infections. (C) 2014 Elsevier B.V. All rights reserved. C1 [Ilyushina, Natalia A.; Donnelly, Raymond P.] US FDA, Ctr Drug Evaluat & Res, Div Therapeut Proteins, Silver Spring, MD 20993 USA. RP Ilyushina, NA (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Therapeut Proteins, Silver Spring, MD 20993 USA. EM Natalia.Ilyushina@fda.hhs.gov FU Oak Ridge Institute for Science and Education (ORISE); FDA Medical Countermeasures Initiative program FX This study was supported in part by a Senior Postgraduate Research Fellowship Award to N.A.I. 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. This study was also supported by a grant from the FDA Medical Countermeasures Initiative program to R.P.D. NR 47 TC 1 Z9 1 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD NOV PY 2014 VL 111 BP 112 EP 120 DI 10.1016/j.antiviral.2014.09.008 PG 9 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA AT8LP UT WOS:000345185100016 PM 25245230 ER PT J AU Simhadri, VR Mariano, JL Zenarruzabeitia, O Seroogy, CM Holland, SM Kuehn, HS Rosenzweig, SD Borrego, F AF Simhadri, Venkateswara R. Mariano, John L. Zenarruzabeitia, Olatz Seroogy, Christine M. Holland, Steven M. Kuehn, Hye Sun Rosenzweig, Sergio D. Borrego, Francisco TI Intact IL-12 signaling is necessary for the generation of human natural killer cells with enhanced effector function after restimulation SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID NK CELLS; MEMORY C1 [Simhadri, Venkateswara R.; Mariano, John L.; Borrego, Francisco] Food & Drug Adm, Ctr Drug Evaluat & Res, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Bethesda, MD 20993 USA. [Zenarruzabeitia, Olatz; Borrego, Francisco] BioCruces Hlth Res Inst, Baracaldo, Spain. [Seroogy, Christine M.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Rosenzweig, Sergio D.] NIAID, Primary Immuno Deficiency Clin, NIH, Bethesda, MD 20892 USA. [Kuehn, Hye Sun] Ctr Clin, Serv Immunol, Dept Lab Med, NIH, Bethesda, MD USA. [Borrego, Francisco] Basque Fdn Sci, Ikerbasque, Bilbao, Spain. RP Simhadri, VR (reprint author), Food & Drug Adm, Ctr Drug Evaluat & Res, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Bethesda, MD 20993 USA. EM francisco.borregorabasco@osakidetza.net FU Intramural NIH HHS [Z99 CL999999] NR 10 TC 5 Z9 5 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2014 VL 134 IS 5 BP 1190 EP 1193 DI 10.1016/j.jaci.2014.06.006 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA AT4UN UT WOS:000344938900026 PM 25065718 ER PT J AU Das, S Chigurupati, S Dowding, J Munusamy, P Baer, DR McGinnis, JF Mattson, MP Self, W Seal, S AF Das, Soumen Chigurupati, Srinivasulu Dowding, Janet Munusamy, Prabhakaran Baer, Donald R. McGinnis, James F. Mattson, Mark P. Self, William Seal, Sudipta TI Therapeutic potential of nanoceria in regenerative medicine SO MRS BULLETIN LA English DT Article ID CERIUM OXIDE NANOPARTICLES; OXIDATIVE STRESS; CEO2 NANOPARTICLES; NEURONAL SURVIVAL; CELLS; RADIATION; PROTECT; MICE; NANOSTRUCTURES; PROLIFERATION AB Tissue engineering and regenerative medicine aim to achieve functional restoration of tissue or cells damaged through disease, aging, or trauma. Advancement of tissue engineering requires innovation in the field of three-dimensional scaffolding and functionalization with bioactive molecules. Nanotechnology offers advanced materials with patterned nano-morphologies for cell growth and different molecular substrates that can support cell survival and functions. Cerium oxide nanoparticles (nanoceria) can control intracellular as well as extracellular reactive oxygen and nitrogen species. Recent findings suggest that nanoceria can enhance long-term cell survival, enable cell migration and proliferation, and promote stem cell differentiation. Moreover, the self-regenerative property of nanoceria permits a small dose to remain catalytically active for an extended time. This review summarizes the possibilities and applications of nanoceria in the field of tissue engineering and regenerative medicine. C1 [Das, Soumen] Univ Cent Florida, Nanosci Technol Ctr, Adv Mat Proc Anal Ctr, Orlando, FL 32816 USA. [Chigurupati, Srinivasulu] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Rockville, MD 20857 USA. [Dowding, Janet] Univ Cent Florida, Burnett Sch Biomed Sci, Orlando, FL 32816 USA. [Munusamy, Prabhakaran; Baer, Donald R.] Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. [McGinnis, James F.] Univ Oklahoma, Hlth Sci Ctr, Dept Ophthalmol, Norman, OK 73019 USA. [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Self, William] Univ Cent Florida, Burnett Sch Biomed Sci, Orlando, FL 32816 USA. [Seal, Sudipta] Univ Cent Florida, Adv Mat Proc & Anal Ctr, Nanosci & Technol Ctr, Coll Med, Orlando, FL 32816 USA. RP Das, S (reprint author), Univ Cent Florida, Nanosci Technol Ctr, Adv Mat Proc Anal Ctr, Orlando, FL 32816 USA. EM soumen.das@ucf.edu; srinivasulu.chigurupati@fda.hhs.gov; jdowding42q@gmail.com; prabhakaran.munusamy@pnnl.gov; don.baer@pnnl.gov; James-McGinnis@ouhsc.edu; MattsonM@grc.nia.nih.gov; william.self@ucf.edu; Sudipta.Seal@ucf.edu RI Baer, Donald/J-6191-2013; Self, William/A-6704-2008 OI Baer, Donald/0000-0003-0875-5961; FU National Institute on Aging; NIH NEI [COBRE-P20 RR017703, P30-EY 12190, R21EY018306, R01EY18724, R01EY022111]; National Science Foundation [CBET-0708172]; NIEHS Center [U19 ES019544]; US Department of Energy, Biological and Environmental Research and located at PNNL FX This work was supported, in part, by the intramural research program of the National Institute on Aging. The work by J.F.M. was supported by NIH NEI Grant COBRE-P20 RR017703, P30-EY 12190, R21EY018306, R01EY18724, R01EY022111; National Science Foundation: CBET-0708172; and Research to Prevent Blindness. D.R.B. was supported by the NIEHS Center Grant U19 ES019544. Part of this work was performed using EMSL, a national scientific user facility sponsored by the US Department of Energy, Biological and Environmental Research and located at PNNL. S.S. and W.S. acknowledge NSF and NIH for various aspects of nano-biotechnology research. NR 50 TC 5 Z9 5 U1 3 U2 20 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0883-7694 EI 1938-1425 J9 MRS BULL JI MRS Bull. PD NOV PY 2014 VL 39 IS 11 BP 976 EP 983 DI 10.1557/mrs.2014.221 PG 8 WC Materials Science, Multidisciplinary; Physics, Applied SC Materials Science; Physics GA AT7ML UT WOS:000345121300017 ER PT J AU Graham, DJ By, K McKean, S Mosholder, A Kornegay, C Racoosin, JA Young, J Levenson, M MaCurdy, TE Worrall, C Kelman, JA AF Graham, David J. By, Kunthel McKean, Stephen Mosholder, Andrew Kornegay, Cynthia Racoosin, Judith A. Young, Jessica Levenson, Mark MaCurdy, Thomas E. Worrall, Chris Kelman, Jeffrey A. TI Cardiovascular and mortality risks in older Medicare patients treated with varenicline or bupropion for smoking cessation: an observational cohort study SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE varenicline; bupropion; cardiovascular risk; mortality; pharmacoepidemiology ID POSITIVE PREDICTIVE-VALUE; ACUTE MYOCARDIAL-INFARCTION; CORONARY-HEART-DISEASE; ADMINISTRATIVE DATA; CAUSAL INFERENCE; CODING ACCURACY; PARTIAL AGONIST; EVENTS; METAANALYSIS; DEPENDENCE AB PurposeTo compare cardiovascular and mortality risks in elderly patients treated with varenicline or bupropion for smoking cessation. MethodsElderly Medicare beneficiaries were entered into new-user cohorts of varenicline or bupropion for smoking cessation and followed on therapy for primary outcomes of acute myocardial infarction (AMI), stroke, mortality, and a composite of any of these events. Secondary outcomes were unstable angina, coronary revascularization, and a composite of any primary or secondary outcome event. Propensity score stratification was used to adjust for baseline differences in potential confounding factors. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards, with bupropion as reference. ResultsIn cohorts of 74824 varenicline and 14133 bupropion users, there were 164 AMI, 96 stroke, 87 death, 317 primary composite, and 814 secondary composite events while on therapy. The HRs (95%CI) were 0.79 (0.50-1.24) for AMI, 1.27 (0.63-2.55) for stroke, 0.58 (0.30-1.13) for death, 0.84 (0.58-1.23) for the primary composite, and 0.92 (0.73-1.14) for the secondary composite. The risk of AMI or the primary composite outcome did not differ in subgroups defined by age, diabetes status, or presence of underlying ischemic heart disease. Only 30% of patients remained on either study drug beyond their first prescription. ConclusionCardiovascular and mortality risks were not increased in older patients treated with varenicline compared with bupropion for smoking cessation. A potential increase in the risk of stroke with varenicline could not be excluded. Treatment persistence with either drug was low. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Graham, David J.; Mosholder, Andrew; Kornegay, Cynthia] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD 20993 USA. [By, Kunthel; Levenson, Mark] US FDA, Off Biostat, Silver Spring, MD 20993 USA. [McKean, Stephen; Young, Jessica; MaCurdy, Thomas E.] Acumen LLC, Burlingame, CA USA. [Racoosin, Judith A.] US FDA, Off New Drugs, Silver Spring, MD 20993 USA. [MaCurdy, Thomas E.] Stanford Univ, Stanford, CA 94305 USA. [Worrall, Chris; Kelman, Jeffrey A.] Ctr Medicare & Medicaid Serv, Washington, DC USA. RP Graham, DJ (reprint author), US FDA, Off Surveillance & Epidemiol, 10903 New Hampshire Ave,Bldg 22,Room 4314, Silver Spring, MD 20993 USA. EM david.graham1@fda.hhs.gov FU Centers for Medicare & Medicaid Services; FDA FX This study was funded through an intraagency agreement between the Centers for Medicare & Medicaid Services and the FDA. NR 37 TC 3 Z9 3 U1 0 U2 3 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 NOV PY 2014 VL 23 IS 11 BP 1205 EP 1212 DI 10.1002/pds.3678 PG 8 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AT6WA UT WOS:000345076200012 PM 25044169 ER PT J AU Bell, C Chakravarty, A Gruber, S Heckbert, SR Levenson, M Martin, D Nelson, JC Pinheiro, S Psaty, BM Reich, CG Schneeweiss, S Shoaibi, A Toh, S Walker, AM AF Bell, Carlos Chakravarty, Aloka Gruber, Susan Heckbert, Susan R. Levenson, Mark Martin, David Nelson, Jennifer C. Pinheiro, Simone Psaty, Bruce M. Reich, Christian G. Schneeweiss, Sebastian Shoaibi, Azadeh Toh, Sengwee Walker, Alexander M. TI Characteristics of study design and elements that may contribute to the success of electronic safety monitoring systems SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Editorial Material DE safety surveillance; insurance claims; electronic medical records; pharmacoepidemiology ID ANGIOEDEMA; RISK C1 [Bell, Carlos; Shoaibi, Azadeh] US FDA, Off Med Policy, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Chakravarty, Aloka; Levenson, Mark] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Gruber, Susan] US FDA, Reagan Udall Fdn, Washington, DC 20204 USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Heckbert, Susan R.; Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Martin, David] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Nelson, Jennifer C.] Univ Washington, Dept Biostat, Grp Hlth Res Inst, Biostat Unit, Seattle, WA 98195 USA. [Pinheiro, Simone] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA 98195 USA. [Reich, Christian G.] AstraZeneca PLC, Res & Dev Informat, Waltham, MA USA. [Schneeweiss, Sebastian] Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02115 USA. [Schneeweiss, Sebastian] Harvard Univ, Sch Med, Boston, MA USA. [Toh, Sengwee] Harvard Univ, Dept Populat Med, Sch Med, Boston, MA USA. [Toh, Sengwee] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Walker, Alexander M.] WHISCON, Newton, MA USA. RP Walker, AM (reprint author), World Hlth Informat Sci Consultants, Riverside Ctr, Suite 2-400,275 Grove St, Newton, MA 02466 USA. EM Alec.Walker@WHISCON.com RI Schneeweiss, Sebastian/C-2125-2013; Toh, Sengwee/D-7567-2017 OI Toh, Sengwee/0000-0002-5160-0810 NR 6 TC 2 Z9 2 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 NOV PY 2014 VL 23 IS 11 BP 1223 EP 1225 DI 10.1002/pds.3712 PG 3 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AT6WA UT WOS:000345076200014 PM 25263307 ER PT J AU O'Donoghue, AC Williams, PA Sullivan, HW Boudewyns, V Squire, C Willoughby, JF AF O'Donoghue, Amie C. Williams, Pamela A. Sullivan, Helen W. Boudewyns, Vanessa Squire, Claudia Willoughby, Jessica Fitts TI Effects of comparative claims in prescription drug direct-to-consumer advertising on consumer perceptions and recall SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE United States; Direct-to-consumer (DTC) advertisements; Prescription drugs; Marketing; Comparative advertising; Perceived risk; Communication ID INFORMATION; PREFERENCES; NEED AB Although pharmaceutical companies cannot make comparative claims in direct-to-consumer (DTC) ads for prescription drugs without substantial evidence, the U.S. Food and Drug Administration permits some comparisons based on labeled attributes of the drug, such as dosing. Researchers have examined comparative advertising for packaged goods; however, scant research has examined comparative DTC advertising. We conducted two studies to determine if comparative claims in DTC ads influence consumers' perceptions and recall of drug information. In Experiment 1, participants with osteoarthritis (n = 1934) viewed a fictitious print or video DTC ad that had no comparative claim or made an efficacy comparison to a named or unnamed competitor. Participants who viewed print (but not video) ads with named competitors had greater efficacy and lower risk perceptions than participants who viewed unnamed competitor and noncomparative ads. In Experiment 2, participants with high cholesterol or high body mass index (n = 5317) viewed a fictitious print or video DTC ad that had no comparative claim or made a comparison to a named or unnamed competitor. We varied the type of comparison (of indication, dosing, or mechanism of action) and whether the comparison was accompanied by a visual depiction. Participants who viewed print and video ads with named competitors had greater efficacy perceptions than participants who viewed unnamed competitor and noncomparative ads. Unlike Experiment 1, named competitors in print ads resulted in higher risk perceptions than unnamed competitors. In video ads, participants who saw an indication comparison had greater benefit recall than participants who saw dosing or mechanism of action comparisons. In addition, visual depictions of the comparison decreased risk recall for video ads. Overall, the results suggest that comparative claims in DTC ads could mislead consumers about a drug's efficacy and risk; therefore, caution should be used when presenting comparative claims in DTC ads. Published by Elsevier Ltd. C1 [O'Donoghue, Amie C.; Sullivan, Helen W.] US FDA, Off Prescript Drug Promot, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Williams, Pamela A.; Boudewyns, Vanessa; Squire, Claudia; Willoughby, Jessica Fitts] RTI Int, Res Triangle Pk, NC 27709 USA. RP O'Donoghue, AC (reprint author), US FDA, Off Prescript Drug Promot, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3236, Silver Spring, MD 20993 USA. EM amie.odonoghue@fda.hhs.gov RI Boudewyns, PhD, Vanessa/G-5713-2013; OI Boudewyns, PhD, Vanessa/0000-0002-1777-290X; Willoughby, Jessica/0000-0002-1118-9502 FU Center for Drug Evaluation and Research, Food and Drug Administration (FDA) FX The Center for Drug Evaluation and Research, Food and Drug Administration (FDA) provided research funding for this study. The OMB Control No. for this study is 0910-0707. The authors thank Susan McRitchie and Katherine Cullen for research assistance. NR 37 TC 2 Z9 2 U1 2 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD NOV PY 2014 VL 120 BP 1 EP 11 DI 10.1016/j.socscimed.2014.08.039 PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA AT8JU UT WOS:000345180600001 PM 25194471 ER PT J AU Vicente, J Johannesen, L Galeotti, L Strauss, DG AF Vicente, Jose Johannesen, Lars Galeotti, Loriano Strauss, David G. TI Mechanisms of sex and age differences in ventricular repolarization in humans SO AMERICAN HEART JOURNAL LA English DT Article ID CARDIAC REPOLARIZATION; QT PROLONGATION; I-KS; MEN; ELECTROCARDIOGRAMS; TESTOSTERONE; GENDER; INTERVAL; HORMONES; RESERVE AB Introduction Corrected QT interval (QTc) is shorter in postpubertal men than in women; however, QTc lengthens as men age and testosterone levels decrease. Animal studies have demonstrated that testosterone decreases L-type calcium current and increases slow delayed rectifier potassium current; however, it is not known how these contribute to QTc differences by sex and age in humans. We separately analyzed early versus late repolarization duration and performed simulations of the effect of testosterone on the electrocardiogram (ECG) to examine the mechanism of sex and age differences in QTc in humans. Methods Twelve-lead ECGs from 2,235 healthy subjects (41% women) in Thorough QT studies were analyzed to characterize sex-and age-dependent differences in depolarization (QRS), early repolarization (J-T-peak), and late repolarization (T-peak-T-end). In addition, we simulated the effects of testosterone on calcium current, slow delayed rectifier potassium current, and surface ECG intervals. Results QTc was shorter in men than in women (394 +/- 16 vs 408 +/- 15 milliseconds, P < .001), which was due to shorter early repolarization (213 +/- 16 vs 242 +/- 16 milliseconds, P < .001), as men had longer depolarization (94 +/- 7 vs 89 +/- 7 milliseconds, P <.001) and longer late repolarization (87 +/- 10 vs 78 +/- 9 milliseconds, P<.001). Sex difference in QTc decreased with age and was due to changes in early repolarization. Simulations showed that the early repolarization changes were most influenced by testosterone's effect on calcium current. Conclusion Shorter QTc in men compared to women is explained by shorter early repolarization, and this difference decreases with age. These sex and age differences in repolarization appear to be caused by testosterone effects on calcium current. C1 [Vicente, Jose; Johannesen, Lars; Galeotti, Loriano; Strauss, David G.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Vicente, Jose] Univ Zaragoza, BSICoS Grp, Aragon Inst Engn Res I3A, IIS Aragon, Zaragoza, Aragon, Spain. [Johannesen, Lars] Karolinska Inst, Dept Clin Physiol, S-10401 Stockholm, Sweden. [Johannesen, Lars] Karolinska Univ Hosp, Stockholm, Sweden. RP Strauss, DG (reprint author), US FDA, 10903 New Hampshire Ave,WO62-1126, Silver Spring, MD 20993 USA. EM david.strauss@fda.hhs.gov RI GALEOTTI, LORIANO/N-4240-2014; OI GALEOTTI, LORIANO/0000-0002-3200-9080; Vicente, Jose/0000-0001-9963-1205 NR 38 TC 8 Z9 9 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD NOV PY 2014 VL 168 IS 5 BP 749 EP 756 DI 10.1016/j.ahj.2014.07.010 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AS7KE UT WOS:000344434300018 PM 25440804 ER PT J AU Wu, CF Kurtzman, SB Laschinger, J Johnson, T Aguel, F AF Wu, Changfu Kurtzman, Steven B. Laschinger, John Johnson, Terri Aguel, Fernando TI United States Food and Drug Administration Perspectives on the Update to the Objective Performance Criteria for Surgically Implanted Heart Valve Prostheses SO ANNALS OF THORACIC SURGERY LA English DT Letter C1 [Wu, Changfu; Kurtzman, Steven B.; Laschinger, John; Aguel, Fernando] US FDA, Div Cardiovasc Devices, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Johnson, Terri] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Wu, CF (reprint author), US FDA, Div Cardiovasc Devices, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM Changfu.Wu@fda.hhs.gov NR 2 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 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD NOV PY 2014 VL 98 IS 5 BP 1890 EP 1891 PG 4 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA AT2EZ UT WOS:000344746600110 PM 25441824 ER PT J AU Amiri-Kordestani, L Wedam, S Zhang, LJ Tang, SH Tilley, A Ibrahim, A Justice, R Pazdur, R Cortazar, P AF Amiri-Kordestani, Laleh Wedam, Suparna Zhang, Lijun Tang, Shenghui Tilley, Amy Ibrahim, Amna Justice, Robert Pazdur, Richard Cortazar, Patricia TI First FDA Approval of Neoadjuvant Therapy for Breast Cancer: Pertuzumab for the Treatment of Patients with HER2-Positive Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID PLUS TRASTUZUMAB; OPEN-LABEL; DOCETAXEL; COMBINATION; SURVIVAL; SAFETY; TRIAL AB On September 30, 2013, the FDA granted accelerated approval to pertuzumab (Perjecta; Genentech, Inc.) for use in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. The approval was based in part on a randomized multicenter trial in the indicated population that allocated 417 patients to neoadjuvant treatment with trastuzumab-docetaxel (TD), pertuzumab-trastuzumab-docetaxel (PTD), pertuzumab-trastuzumab, or pertuzumab-docetaxel. PTD was administered preoperatively every 3 weeks for four cycles. Following surgery patients received three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide every 3 weeks and trastuzumab every 3 weeks to complete 1 year of therapy. The pathologic complete response rates by the FDA-preferred definition [absence of invasive cancer in the breast and lymph nodes (ypT0/is ypN0)] were 39.3% and 21.5% in the PTD and the TD arms, respectively (P = 0.0063). The most common adverse reactions with PTD were alopecia, diarrhea, nausea, and neutropenia. This approval was based on the totality of evidence, particularly improved survival in the metastatic breast cancer trial, and a fully accrued confirmatory trial. (C) 2014 AACR. C1 [Amiri-Kordestani, Laleh; Wedam, Suparna; Zhang, Lijun; Tang, Shenghui; Tilley, Amy; Ibrahim, Amna; Justice, Robert; Pazdur, Richard; Cortazar, Patricia] US FDA, Ctr Drug Evaluat & Res, White Oak, MD USA. RP Amiri-Kordestani, L (reprint author), FDA, 10903 New Hampshire Ave,WO 22,Room 2115, Silver Spring, MD 20993 USA. EM Laleh.AmiriKordestani@fda.hhs.gov NR 12 TC 31 Z9 33 U1 0 U2 6 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 2014 VL 20 IS 21 BP 5359 EP 5364 DI 10.1158/1078-0432.CCR-14-1268 PG 6 WC Oncology SC Oncology GA AT2IU UT WOS:000344759100004 PM 25204553 ER PT J AU Deng, KP Wang, X Yen, LH Ding, HL Tortorello, ML AF Deng, Kaiping Wang, Xue Yen, Li-Han Ding, Hongliu Tortorello, Mary Lou TI Behavior of Shiga Toxigenic Escherichia coli Relevant to Lettuce Washing Processes and Consideration of Factors for Evaluating Washing Process Surrogates SO JOURNAL OF FOOD PROTECTION LA English DT Article ID FRESH-CUT LETTUCE; CROSS-CONTAMINATION; MULTISTATE OUTBREAK; COMMERCIAL SANITIZERS; CHLORINE EFFICACY; O157H7 INFECTION; MICROBIAL SAFETY; LEAFY GREENS; PRODUCE WASH; E.-COLI AB Postharvest processes for fresh produce commonly include washing in water containing antimicrobial chemicals, such as chlorine; however, if the antimicrobials are not present in sufficient levels, washing can promote the spread of contamination that might be present. To understand cross-contamination risk during washing, we tested a collection of Shiga toxigenic Escherichia colt (STEC), including O157:H7 and other non-O157 strains, for certain traits during washing of fresh-cut lettuce, i.e., sensitivity to sublethal chlorine levels and ability to cross-contaminate (detach from and attach to) lettuce in the presence of sublethal chlorine levels. Nonpathogenic E. colt Nissle 1917 (EcN) and Pediococcus pentosaceus lactic acid bacterial species (LAB) were included as potential washing process validation surrogates. As measured by extension of the lag phase of growth in media containing 0.15 ppm of chlorine, chlorine sensitivity varied among the STECs. Cross-contamination was assessed by evaluating transfer of bacteria from inoculated to uninoculated leaves during washing. Without chlorine, similar transfer to wash water and uninoculated leaves was shown. In 1 ppm of chlorine, cross-contamination was not detected with most strains, except for the substantial transfer by a STEC 0111 strain and EcN in some replicates. Strain 0111 and EcN showed less inactivation in 0.25 ppm of chlorine water compared with O157 (P < 0.05). LAB showed similar transfer and similar chlorine inactivation to O157. Considering together the sublethal chlorine sensitivity and detachment/attachment traits, neither EcN nor LAB displayed optimal characteristics as washing process surrogates for the STEC strains, although further evaluation is needed. This work demonstrated a range of behaviors of STEC strains during lettuce washing and may be helpful in hazard characterization, identifying factors to consider for evaluating washing process efficacy, and identifying phenotypic traits to select surrogates to validate washing processes. C1 [Deng, Kaiping; Ding, Hongliu; Tortorello, Mary Lou] US FDA, Div Food Proc Sci & Technol, Bedford Pk, IL 60501 USA. [Wang, Xue; Yen, Li-Han] IIT, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. RP Tortorello, ML (reprint author), US FDA, Div Food Proc Sci & Technol, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM mary.tortorello@fda.hhs.gov FU FDA; Oak Ridge Institute for Science and Education Research Participation Program FX This study was supported by a FDA cooperative agreement grant to the Institute of Food Safety and Health of the Illinois Institute of Technology. Kaiping Deng was sponsored by the Oak Ridge Institute for Science and Education Research Participation Program through a contract with the FDA. The authors thank Dr. Tong-Jen Fu for valuable discussions related to fresh produce washing processes. NR 55 TC 3 Z9 3 U1 1 U2 16 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 2014 VL 77 IS 11 BP 1860 EP 1867 DI 10.4315/0362-028X.JFP-14-220 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA AT1TS UT WOS:000344717400003 PM 25364918 ER PT J AU He, X Samuelson, F Zeng, RP Sahiner, B AF He, Xin Samuelson, Frank Zeng, Rongping Sahiner, Berkman TI Discovering intrinsic properties of human observers' visual search and mathematical observers' scanning SO JOURNAL OF THE OPTICAL SOCIETY OF AMERICA A-OPTICS IMAGE SCIENCE AND VISION LA English DT Article ID SIGNAL-DETECTION; LUMINANCE INCREMENT; LUMPY BACKGROUNDS; IDEAL OBSERVERS; SET-SIZE; ATTENTION; MODEL; UNCERTAINTY; STIMULUS; TASKS AB There is a lack of consensus in measuring observer performance in search tasks. To pursue a consensus, we set our goal to obtain metrics that are practical, meaningful, and predictive. We consider a metric practical if it can be implemented to measure human and computer observers' performance. To be meaningful, we propose to discover intrinsic properties of search observers and formulate the metrics to characterize these properties. If the discovered properties allow verifiable predictions, we consider them predictive. We propose a theory and a conjecture toward two intrinsic properties of search observers: rationality in classification as measured by the location-known-exactly (LKE) receiver operating characteristic (ROC) curve and location uncertainty as measured by the effective set size (M*). These two properties are used to develop search models in both single-response and free-response search tasks. To confirm whether these properties are "intrinsic," we investigate their ability in predicting search performance of both human and scanning channelized Hotelling observers. In particular, for each observer, we designed experiments to measure the LKE-ROC curve and M*, which were then used to predict the same observer's performance in other search tasks. The predictions were then compared to the experimentally measured observer performance. Our results indicate that modeling the search performance using the LKE-ROC curve and M* leads to successful predictions in most cases. C1 [He, Xin; Samuelson, Frank; Zeng, Rongping; Sahiner, Berkman] US FDA, Silver Spring, MD 20993 USA. RP He, X (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM xin.he@fda.hhs.gov NR 43 TC 3 Z9 3 U1 0 U2 4 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1084-7529 EI 1520-8532 J9 J OPT SOC AM A JI J. Opt. Soc. Am. A-Opt. Image Sci. Vis. PD NOV PY 2014 VL 31 IS 11 BP 2495 EP 2510 DI 10.1364/JOSAA.31.002495 PG 16 WC Optics SC Optics GA AT2RM UT WOS:000344782300022 PM 25401363 ER PT J AU Krais, AM Melis, JPM Speksnijder, EN Stiborova, M Singh, R da Costa, GG Luijten, M Phillips, DH Arlt, VM AF Krais, Annette M. Melis, Joost P. M. Speksnijder, Ewoud N. Stiborova, Marie Singh, Rajinder da Costa, Goncalo Gamboa Luijten, Mirjam Phillips, David H. Arlt, Volker M. TI Impact of p53 on DNA damage and metabolic activation of PhIP in Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice SO MUTAGENESIS LA English DT Meeting Abstract C1 [Krais, Annette M.; Phillips, David H.; Arlt, Volker M.] Kings Coll London, London WC2R 2LS, England. [Melis, Joost P. M.; Luijten, Mirjam] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Melis, Joost P. M.; Speksnijder, Ewoud N.] Leiden Univ, Med Ctr, NL-2300 RA Leiden, Netherlands. [Stiborova, Marie] Charles Univ Prague, Prague, Czech Republic. [Singh, Rajinder] Univ Leicester, Leicester LE1 7RH, Leics, England. [da Costa, Goncalo Gamboa] Natl Ctr Toxicol Res, Jefferson, AR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 EI 1464-3804 J9 MUTAGENESIS JI Mutagenesis PD NOV PY 2014 VL 29 IS 6 BP 522 EP 523 PG 2 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA AT0KI UT WOS:000344624700092 ER PT J AU Meier, KL Greenfield, DS Hilmantel, G Kahook, MY Lin, C Rorer, EM Singh, K Tarver, ME Weinreb, RN Eydelman, MB Liebmann, JM AF Meier, Kristen L. Greenfield, David S. Hilmantel, Gene Kahook, Malik Y. Lin, Carol Rorer, Eva M. Singh, Kuldev Tarver, Michelle E. Weinreb, Robert N. Eydelman, Malvina B. Liebmann, Jeffrey M. TI Special Commentary: Food and Drug Administration and American Glaucoma Society Co-sponsored Workshop The Validity, Reliability, and Usability of Glaucoma Imaging Devices SO OPHTHALMOLOGY LA English DT Article ID NERVE-FIBER LAYER; OPTICAL COHERENCE TOMOGRAPHY; SPECTRAL-DOMAIN OCT; CIRRUS HD-OCT; SCANNING-LASER-OPHTHALMOSCOPY; OPEN-ANGLE GLAUCOMA; VISUAL-FIELD LOSS; THICKNESS MEASUREMENTS; TIME-DOMAIN; DIAGNOSTIC-ACCURACY C1 [Meier, Kristen L.] US FDA, Ctr Devices & Radiol Hlth, Off Surveillance & Biometr, Silver Spring, MD USA. [Greenfield, David S.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Dept Ophthalmol, Palm Beach Gardens, FL USA. [Hilmantel, Gene; Lin, Carol; Rorer, Eva M.; Tarver, Michelle E.; Eydelman, Malvina B.] US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Silver Spring, MD 20993 USA. [Kahook, Malik Y.] Univ Colorado, Sch Med, Dept Ophthalmol, Aurora, CO USA. [Singh, Kuldev] Stanford Univ, Sch Med, Dept Ophthalmol, Palo Alto, CA 94304 USA. [Weinreb, Robert N.] Univ Calif San Diego, Dept Ophthalmol, La Jolla, CA 92093 USA. [Weinreb, Robert N.] Univ Calif San Diego, Hamilton Glaucoma Ctr, La Jolla, CA 92093 USA. [Liebmann, Jeffrey M.] NYU, Sch Med, Dept Ophthalmol, New York, NY USA. [Liebmann, Jeffrey M.] New York Eye & Ear Infirm, New York, NY 10003 USA. RP Eydelman, MB (reprint author), 10903 New Hampshire Ave,Bldg 66,Room 2410, Silver Spring, MD 20993 USA. EM malvina.eydelman@fda.hhs.gov FU Alcon; Allergan; AMO; Genentech; Regeneron; NIH [R01 EY013516]; Carl Zeiss Meditec Inc; Optovue Inc; Heidelberg Engineering; Meditec-Zeiss; Nidek; Optovue; Topcon; National Institutes of Health; New York Glaucoma Research Institute; Reichert FX The authors have made the following disclosures:; Malik Y. Kahook: Consultant-Alcon, Allergan, Aerie Pharma, AMO, ClarVista Medical; Research Support-Alcon, Allergan, AMO, Genentech, Regeneron; Intellectual Property-AMO, Oasis, New World Medical, ClarVista Medical, ShapeTech LLC, ShapeOphthalmics LLC.; David S. Greenfield: Consultant-Allergan Inc, Merz, Quark, SOLX, Biometric Imaging, Senju; Grant Support-NIH R01 EY013516, Carl Zeiss Meditec Inc, Optovue Inc, Heidelberg Engineering.; Robert N. Weinreb: Consultant-Meditec-Zeiss, Topcon; Grant/Research Support-Heidelberg Engineering, Meditec-Zeiss, Nidek, Optovue, Topcon. Jeffrey Liebmann: Consultant-Allergan, Alcon, Bausch & Lomb, Carl Zeiss Meditech, Diopsys, Merz, Quark; Grant/Research Support-National Institutes of Health, New York Glaucoma Research Institute, Heidelberg Engineering, Optovue, Reichert, Topcon. NR 89 TC 7 Z9 7 U1 0 U2 5 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 NOV PY 2014 VL 121 IS 11 BP 2116 EP 2123 DI 10.1016/j.ophtha.2014.05.024 PG 8 WC Ophthalmology SC Ophthalmology GA AS8DM UT WOS:000344480400015 PM 25085628 ER PT J AU Mezal, EH Bae, D Khan, AA AF Mezal, Ezat H. Bae, Dongryeoul Khan, Ashraf A. TI Detection and functionality of the CdtB, PltA, and PltB from Salmonella enterica serovar Javiana SO PATHOGENS AND DISEASE LA English DT Article DE cytolethal distending toxin; Salmonella Javiana; deletion mutants ID CYTOLETHAL DISTENDING TOXIN; CELL-CYCLE ARREST; RESISTANCE GENE CASSETTES; HAMSTER OVARY CELLS; IMPORTED SEAFOOD; MOLECULAR CHARACTERIZATION; ESCHERICHIA-COLI; CAMPYLOBACTER-JEJUNI; CLINICAL-SAMPLES; BACTERIAL GENOTOXIN AB Salmonella infection is one of the major foodborne illnesses in the United States. Several Gram-negative bacterial pathogens, including Salmonella Typhi, produce cytolethal distending toxin (CDT), which arrests growth, induces apoptosis of infected host cells and extends persistence of pathogenic bacteria in the host. The aim of this study was to characterize the functionality of CDT (cdtB, pltA and pltB) from nontyphoidal Salmonella isolates. Fifty Salmonella enterica serovar Javiana isolates from food, environmental, and clinical samples were screened for cdtB, pltA, and pltB genes by PCR, and all were positive for all three genes. Nucleotide sequence analysis of all amplified PCR products showed 100% identity to S.Typhi cdtB. To understand the roles of CdtB, PltA, and PltB in S.Javiana, cdtB, pltA, and pltB deletion mutants were constructed using a lambda Red-based recombination system. In vitro-cultured HeLa cell lines were infected with a wild-type strain and its isogenic cdtB, pltA, and pltB to determine whether the strains of S.Javiana are responsible for invasion and cytolethal distending intoxication, including cell cycle arrest, cytoplasmic distension, and nuclear enlargement of host target cells. The results showed that HeLa cells infected with S.Javiana wild type were arrested in G(2)/M and had distended cytoplasm and nuclei that were larger than those infected with S.Javiana cdtB and pltA strains. The S.Javiana pltB strain retained the ability to induce cytoplasmic distension and cell cycle arrest, whereas the complemented cdtB and pltA S.Javiana strains showed activity like the wild-type strains. CdtB and pltA from S.Javiana had apparent effects on the distension of both cytoplasm and nucleus as well as cell cycle arrest of HeLa cell lines after 72h of infection. Our data show a significant difference between the wild-type cdtB strain and its isogenic cdtB for invasion of the cell lines. Therefore, CdtB produced from S.Javiana strains may play an important role in pathogenesis in host cells. C1 [Mezal, Ezat H.; Bae, Dongryeoul; Khan, Ashraf A.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Mezal, Ezat H.] Univ Arkansas, Little Rock, AR 72204 USA. [Mezal, Ezat H.] Univ Thi Qar, Thi Qar, Iraq. RP Khan, AA (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Ashraf.khan@fda.hhs.gov NR 54 TC 10 Z9 12 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2049-632X J9 PATHOG DIS JI Pathog. Dis. PD NOV PY 2014 VL 72 IS 2 BP 95 EP 103 DI 10.1111/2049-632X.12191 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT7YZ UT WOS:000345151900002 PM 24891290 ER PT J AU Mahmood, I Staschen, CM Goteti, K AF Mahmood, Iftekhar Staschen, Carl-Michael Goteti, Kosalaram TI Prediction of Drug Clearance in Children: an Evaluation of the Predictive Performance of Several Models SO AAPS JOURNAL LA English DT Article DE allometry; clearance; exponents; models ID MORPHINE MATURATION MODEL; PEDIATRIC POPULATIONS; ALLOMETRIC EXPONENTS; PROPOFOL CLEARANCE; METABOLIC-RATES; BODY-WEIGHT; INFANTS; PHARMACOKINETICS; AGE; ONTOGENY AB The objective of this study is to evaluate the predictive performance of several models to predict drug clearance in children a parts per thousand currency sign5 years of age. Six models (allometric model (data-dependent exponent), fixed exponent of 0.75 model, maturation model, body weight-dependent model, segmented allometric model, and age-dependent exponent model) were evaluated in this study. From the literature, the clearance values for six drugs from neonates to adults were obtained. External data were used to evaluate the predictive performance of these models in children a parts per thousand currency sign5 years of age. With the exception of a fixed exponent of 0.75, the mean predicted clearance in most of the age groups was within a parts per thousand currency sign50% prediction error. Individual clearance prediction was erratic by all models and cannot be used reliably to predict individual clearance. Maturation, body weight-dependent, and segmented allometric models to predict clearances of drugs in children a parts per thousand currency sign5 years of age are of limited practical value during drug development due to the lack of availability of data. Age-dependent exponent model can be used for the selection of first-in-children dose during drug development. C1 [Mahmood, Iftekhar; Staschen, Carl-Michael] US FDA, Div Hematol, OBRR, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Goteti, Kosalaram] Medimmune Inc, Dept Pharmacokinet Pharmacodynam, Gaithersburg, MD 20878 USA. [Goteti, Kosalaram] Pfizer Inc, Quantitat Clin Sci, Biotherapeut Res, Cambridge, MA 02140 USA. RP Mahmood, I (reprint author), US FDA, Div Hematol, OBRR, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM iftekhar.mahmood@fda.hhs.gov NR 52 TC 6 Z9 6 U1 1 U2 1 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 2014 VL 16 IS 6 BP 1334 EP 1343 DI 10.1208/s12248-014-9667-7 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AS5ZN UT WOS:000344345000021 PM 25274608 ER PT J AU Ranieri, N Tabernero, P Green, MD Verbois, L Herrington, J Sampson, E Satzger, RD Phonlavong, C Thao, K Newton, PN Witkowski, MR AF Ranieri, Nicola Tabernero, Patricia Green, Michael D. Verbois, Leigh Herrington, James Sampson, Eric Satzger, R. Duane Phonlavong, Chindaphone Thao, Khamxay Newton, Paul N. Witkowski, Mark R. TI Evaluation of a New Handheld Instrument for the Detection of Counterfeit Artesunate by Visual Fluorescence Comparison SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID OFFSET RAMAN-SPECTROSCOPY; ANTIMALARIAL TABLETS; FAKE ARTESUNATE; SOUTHEAST-ASIA; DRUGS; QUALITY; AUTHENTICATION; MEDICINES; CAMBODIA; AFRICA AB There is an urgent need for accurate and inexpensive handheld instruments for the evaluation of medicine quality in the field. A blinded evaluation of the diagnostic accuracy of the Counterfeit Detection Device 3 (CD-3), developed by the US Food and Drug Administration Forensic Chemistry Center, was conducted in the Lao People's Democratic Republic. Two hundred three samples of the oral antimalarial artesunate were compared with authentic products using the CD-3 by a trainer and two trainees. The specificity (95% confidence interval [95% CI]), sensitivity (95% CI), positive predictive value (95% CI), and negative predictive value (95% CI) of the CD-3 for detecting counterfeit (falsified) artesunate were 100% (93.8-100%), 98.4% (93.8-99.7%), 100% (96.2-100%), and 97.4% (90.2-99.6%), respectively. Interobserver agreement for 203 samples of artesunate was 100%. The CD-3 holds promise as a relatively inexpensive and easy to use instrument for field evaluation of medicines, potentially empowering drug inspectors, customs agents, and pharmacists. C1 [Ranieri, Nicola; Satzger, R. Duane; Witkowski, Mark R.] US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. [Tabernero, Patricia; Newton, Paul N.] Mahosot Hosp, Microbiol Lab, Lao Oxford Mahosot Hosp Wellcome Trust Res Unit L, Viangchan, Laos. [Tabernero, Patricia; Newton, Paul N.] Univ Oxford, Nuffield Dept Clin Med, Worldwide Antimalarial Resistance Network WWARN, Oxford, England. [Tabernero, Patricia; Newton, Paul N.] Univ Oxford, Churchill Hosp, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England. [Green, Michael D.; Sampson, Eric] Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Atlanta, GA USA. [Verbois, Leigh; Sampson, Eric] US FDA, Off Int Programs, Off Global Regulatory Operat & Policy, Silver Spring, MD USA. [Herrington, James] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Phonlavong, Chindaphone] Govt Lao Peoples Democrat Republ, BIDI, Minist Hlth, Viangchan, Laos. [Thao, Khamxay] Govern Lao PDR, FDQCC, Minist Hlth, Viangchan, Laos. RP Ranieri, N (reprint author), US FDA, Forens Chem Ctr, 6751 Steger Dr, Cincinnati, OH 45237 USA. EM Nicola.Ranieri@fda.hhs.gov; Patricia.Tabernero@wwarn.org; mdg4@CDC.GOV; Leigh.Verbois@fda.hhs.gov; James.Herrington@nih.gov; ejs1@verizon.net; RD.Satzger@fda.hhs.gov; bfdi_chindaphone@yahoo.com; kham_xay@hotmail.com; paul@tropmedres.ac; Mark.Witkowski@fda.hhs.gov FU US Food and Drug Administration; Wellcome Trust of Great Britain; Institut de Recherche sur l'Asie du Sud-Est Contemporaine through French Ministry of Foreign and European Affairs (FSP [Fonds de Solidarite Prioritaire] Mekong Project); Bill and Melinda Gates Foundation FX This work was supported by the US Food and Drug Administration and the Wellcome Trust of Great Britain. The Antimalarial Quality Scientific Group of the Worldwide Antimalarial Resistance Network is supported by the Institut de Recherche sur l'Asie du Sud-Est Contemporaine through funding from the French Ministry of Foreign and European Affairs (FSP [Fonds de Solidarite Prioritaire] Mekong Project) and the Bill and Melinda Gates Foundation. NR 29 TC 9 Z9 9 U1 3 U2 20 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 NOV PY 2014 VL 91 IS 5 BP 920 EP 924 DI 10.4269/ajtmh.13-0644 PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA AS7PO UT WOS:000344447800013 PM 25266348 ER PT J AU Kumari, N Iordanskiy, S Kovalskyy, D Breuer, D Niu, XM Lin, XH Xu, M Gavrilenko, K Kashanchi, F Dhawan, S Nekhai, S AF Kumari, Namita Iordanskiy, Sergey Kovalskyy, Dmytro Breuer, Denitra Niu, Xiaomei Lin, Xionghao Xu, Min Gavrilenko, Konstantin Kashanchi, Fatah Dhawan, Subhash Nekhai, Sergei TI Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase I kappa B-alpha Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID LONG TERMINAL REPEAT; SMOOTH-MUSCLE-CELLS; P-TEFB; 7SK SNRNP; METHEMOGLOBIN FORMATION; POLYMERASE-II; CYCLE ARREST; TAT; ELONGATION; ACTIVATION AB HIV-1 transcription is activated by the Tat protein, which recruits CDK9/cyclin T1 to the HIV-1 promoter. CDK9 is phosphorylated by CDK2, which facilitates formation of the high-molecular-weight positive transcription elongation factor b (P-TEFb) complex. We previously showed that chelation of intracellular iron inhibits CDK2 and CDK9 activities and suppresses HIV-1 transcription, but the mechanism of the inhibition was not understood. In the present study, we tested a set of novel iron chelators for the ability to inhibit HIV-1 transcription and elucidated their mechanism of action. Novel phenyl-1-pyridin-2yl-ethanone (PPY)-based iron chelators were synthesized and examined for their effects on cellular iron, HIV-1 inhibition, and cytotoxicity. Activities of CDK2 and CDK9, expression of CDK9-dependent and CDK2-inhibitory mRNAs, NF-kappa B expression, and HIV-1- and NF-kappa B-dependent transcription were determined. PPY-based iron chelators significantly inhibited HIV-1, with minimal cytotoxicity, in cultured and primary cells chronically or acutely infected with HIV-1 subtype B, but they had less of an effect on HIV-1 subtype C. Iron chelators upregulated the expression of I kappa B-alpha, with increased accumulation of cytoplasmic NF-kappa B. The iron chelators inhibited CDK2 activity and reduced the amount of CDK9/cyclin T1 in the large P-TEFb complex. Iron chelators reduced HIV-1 Gag and Env mRNA synthesis but had no effect on HIV-1 reverse transcription. In addition, iron chelators moderately inhibited basal HIV-1 transcription, equally affecting HIV-1 and Sp1-or NF-kappa B-driven transcription. By virtue of their involvement in targeting several key steps in HIV-1 transcription, these novel iron chelators have the potential for the development of new therapeutics for the treatment of HIV-1 infection. C1 [Kumari, Namita; Niu, Xiaomei; Lin, Xionghao; Xu, Min; Nekhai, Sergei] Howard Univ, Dept Med, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Iordanskiy, Sergey; Kashanchi, Fatah] George Mason Univ, Sch Syst Biol, Natl Ctr Biodef & Infect Dis, Manassas, VA USA. [Kovalskyy, Dmytro; Gavrilenko, Konstantin] Natl Taras Shevchenko Univ, ChemBio Ctr, Kiev, Ukraine. [Breuer, Denitra; Dhawan, Subhash] US FDA, Viral Immunol Sect, Mol Virol Lab, Div Emerging & Transfus Transmitted Dis,Ctr Biol, Bethesda, MD 20014 USA. RP Nekhai, S (reprint author), Howard Univ, Dept Med, Ctr Sickle Cell Dis, Washington, DC 20059 USA. EM snekhai@howard.edu FU NIH [1SC1GM082325, 1P50HL118006-01, 1R01HL125005-01, U19AI109664-01, R01AI043894, R21AI114490, R21AI113140, 5G12MD007597]; District of Columbia Developmental Center for AIDS Research grant [P30AI087714] FX This work was supported by NIH research grants (1SC1GM082325, 1P50HL118006-01, 1R01HL125005-01, U19AI109664-01, R01AI043894, R21AI114490, R21AI113140, and 5G12MD007597) and a District of Columbia Developmental Center for AIDS Research grant (P30AI087714). NR 58 TC 1 Z9 1 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD NOV PY 2014 VL 58 IS 11 BP 6558 EP 6571 DI 10.1128/AAC.02918-14 PG 14 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AS3EF UT WOS:000344158600028 PM 25155598 ER PT J AU Fuss, IJ Joshi, B Yang, ZQ Degheidy, H Fichtner-Feigl, S de Souza, H Rieder, F Scaldaferri, F Schirbel, A Scarpa, M West, G Yi, CL Xu, LL Leland, P Yao, M Mannon, P Puri, RK Fiocchi, C Strober, W AF Fuss, Ivan J. Joshi, Bharat Yang, Zhiqiong Degheidy, Heba Fichtner-Feigl, Stefan de Souza, Heitor Rieder, Florian Scaldaferri, Franco Schirbel, Anja Scarpa, Melania West, Gail Yi, Chuli Xu, Lili Leland, Pamela Yao, Michael Mannon, Peter Puri, Raj K. Fiocchi, Claudio Strober, Warren TI IL-13R alpha 2-bearing, type II NKT cells reactive to sulfatide self-antigen populate the mucosa of ulcerative colitis SO GUT LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; T-CELLS; CROHNS-DISEASE; INTERLEUKIN-13; RECEPTOR; AUTOIMMUNITY; FIBROSIS; GLIOMA AB Objective Previous studies have shown that ulcerative colitis (UC) is associated with the presence of lamina propria non-invariant (Type II) NKT cells producing IL-13 and mediating epithelial cell cytotoxicity. Here we sought to define the antigen(s) stimulating the NKT cells and to quantitate these cells in the UC lamina propria. Design Detection of Type II NKT cells in UC lamina propria mononuclear cells (LPMC) with lyso-sulfatide loaded tetramer and quantum dot-based flow cytometry and staining. Culture of UC LPMCs with lyso-sulfatide glycolipid to determine sulfatide induction of epithelial cell cytotoxicity, IL-13 production and IL-13R alpha 2 expression. Blinded quantum dot-based phenotypic analysis to assess UC LPMC expression of IL-13R alpha 2, CD161 and IL-13. Results Approximately 36% of UC LPMC were lysosulfatide tetramer positive, whereas few, if any, control LPMCs were positive. When tested, the positive cells were also CD3 and IL-13R alpha 2 positive. Culture of UC LPMC with lyso-sulfatide glycolipid showed that sulfatide stimulates UC LPMC production of IL-13 and induces UC CD161 LPMC-mediated cytotoxicity of activated epithelial cells; additionally, lyso-sulfatide induces enhanced expression of IL-13R alpha 2. Finally, blinded phenotypic analysis of UC LP MC using multicolour quantum dot-staining technology showed that approximately 60% of the LPMC bear both IL-13R alpha 2 and CD161 and most of these cells also produce IL-13. Conclusions These studies show that UC lamina propria is replete with Type II NKT cells responsive to lyso-sulfatide glycolipid and bearing IL-13R alpha 2. Since lyso-sulfatide is a self-antigen, these data suggest that an autoimmune response is involved in UC pathogenesis. C1 [Fuss, Ivan J.; Yang, Zhiqiong; Yi, Chuli; Xu, Lili; Yao, Michael; Mannon, Peter; Strober, Warren] NIAID, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Joshi, Bharat; Degheidy, Heba; Leland, Pamela; Puri, Raj K.] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Fichtner-Feigl, Stefan] Univ Regensburg, Dept Surg, D-93053 Regensburg, Germany. [de Souza, Heitor; Rieder, Florian; Scaldaferri, Franco; Schirbel, Anja; Scarpa, Melania; West, Gail; Fiocchi, Claudio] Cleveland Clin Fdn, Dept Pathobiol, Cleveland, OH 44195 USA. RP Fuss, IJ (reprint author), NIH, Mucosal Immun Sect, LHD, 10 Ctr Dr,CRC Bldg,Room 5W-3864, Bethesda, MD 20892 USA. EM ifuss@niaid.nih.gov RI Scarpa, Melania/J-6912-2016 OI Scarpa, Melania/0000-0002-7055-635X FU NIAID, National Institutes of Health FX This work was supported by the Intramural Research Program of NIAID, National Institutes of Health. NR 21 TC 20 Z9 20 U1 1 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD NOV PY 2014 VL 63 IS 11 BP 1728 EP + DI 10.1136/gutjnl-2013-305671 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AR9YI UT WOS:000343933000013 PM 24515806 ER PT J AU Carpentier, A Tesfaye, A Chu, V Nimgaonkar, I Zhang, F Lee, SB Thorgeirsson, SS Feinstone, SM Liang, TJ AF Carpentier, Arnaud Tesfaye, Abeba Chu, Virginia Nimgaonkar, Ila Zhang, Fang Lee, Seung Bum Thorgeirsson, Snorri S. Feinstone, Stephen M. Liang, T. Jake TI Engrafted human stem cell-derived hepatocytes establish an infectious HCV murine model SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HEPATITIS-C-VIRUS; HUMAN FIBROBLASTS; IN-VITRO; EFFICIENT DIFFERENTIATION; DIRECTED DIFFERENTIATION; GENETIC-VARIATION; MOUSE-LIVER; LOW-DENSITY; CULTURE; ENDODERM AB The demonstrated ability to differentiate both human embryonic stem cells (hESCs) and patient-derived induced pluripotent stem cells (hiPSCs) into hepatocyte-like cells (HLCs) holds great promise for both regenerative medicine and liver disease research. Here, we determined that, despite an immature phenotype, differentiated HLCs are permissive to hepatitis C virus (HCV) infection and mount an interferon response to HCV infection in vitro. HLCs differentiated from hESCs and hiPSCs could be engrafted in the liver parenchyma of immune-deficient transgenic mice carrying the urokinase-type plasminogen activator gene driven by the major urinary protein promoter. The HLCs were maintained for more than 3 months in the livers of chimeric mice, in which they underwent further maturation and proliferation. These engrafted and expanded human HLCs were permissive to in vivo infection with HCV-positive sera and supported long-term infection of multiple HCV genotypes. Our study demonstrates efficient engraftment and in vivo HCV infection of human stem cell-derived hepatocytes and provides a model to study chronic HCV infection in patient-derived hepatocytes, action of antiviral therapies, and the biology of HCV infection. C1 [Carpentier, Arnaud; Tesfaye, Abeba; Chu, Virginia; Nimgaonkar, Ila; Zhang, Fang; Feinstone, Stephen M.; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Tesfaye, Abeba; Feinstone, Stephen M.] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD USA. [Lee, Seung Bum; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Liang, TJ (reprint author), NIDDK, Liver Dis Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 9B16, Bethesda, MD 20892 USA. EM arnaud.carpentier@nih.gov; jakel@bdg10.niddk.nih.gov FU Intramural Research Program of the NIDDK [Z01 DK54504, DK54505]; NIH Center for Regenerative Medicine; NIH [N01-DK-7-0004/HHSN26700700004C] FX We wish to thank Ronda Sapp, Frank Qisheng Li, Zhensheng Zhang, Zongyi Hu, Emmanuel Thomas, and Chen Du (all from NIDDK); Marian E. Major (FDA); Stephen Strom (Karolinska Institute); Hengli Tang (University of Florida); and the Flow Cytometry Core of National Heart, Lung, and Blood Institute for technical assistance and helpful discussions. This work was supported by the Intramural Research Program of the NIDDK (Z01 DK54504 and DK54505) and the NIH Center for Regenerative Medicine. PHHs were provided by the NIH-funded Liver Tissue Procurement and Cell Distribution System (N01-DK-7-0004/HHSN26700700004C). NR 64 TC 30 Z9 31 U1 0 U2 9 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2014 VL 124 IS 11 BP 4953 EP 4964 DI 10.1172/JCI75456 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AS3UK UT WOS:000344203300030 PM 25295540 ER PT J AU Momper, JD Karesh, A Green, DJ Hirsch, M Khurana, M Lee, J Kim, MJ Mulugeta, Y Sachs, HC Yao, L Burckart, GJ AF Momper, Jeremiah D. Karesh, Alyson Green, Dionna J. Hirsch, Mark Khurana, Mona Lee, Jinoo Kim, Myong-Jin Mulugeta, Yeruk Sachs, Hari C. Yao, Lynne Burckart, Gilbert J. TI Drug Development for Pediatric Neurogenic Bladder Dysfunction: Dosing, Endpoints, and Study Design SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE neurogenic bladder; clinical trial design; pharmacokinetics; pediatric urology ID N-OF-1 TRIALS; SPINA-BIFIDA; MANAGEMENT; CHILDREN AB Pediatric drug development is challenging when a product is studied for a pediatric disease that has a different underlying etiology and pathophysiology compared to the adult disease. Neurogenic bladder dysfunction (NBD) is such a therapeutic area with multiple unsuccessful development programs. The objective of this study was to critically evaluate clinical trial design elements that may have contributed to unsuccessful drug development programs for pediatric NBD. Trial design elements of drugs tested for pediatric NBD were identified from trials submitted to the U.S. Food and Drug Administration. Data were extracted from publically available FDA reviews and labeling and included trial design, primary endpoints, enrollment eligibilities, and pharmacokinetic data. A total of four products were identified. Although all four programs potentially provided clinically useful information, only one drug (oxybutynin) demonstrated efficacy in children with NBD. The lack of demonstrable efficacy for the remainder of the products illustrates that future trials should give careful attention to testing a range of doses, using objectively measured, clinically meaningful endpoints, and selecting clinical trial designs that are both interpretable and feasible. Compiling the drug development experience with pediatric NBD will facilitate an improved approach for future drug development for this, and perhaps other, therapeutic areas. C1 [Momper, Jeremiah D.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. [Karesh, Alyson; Sachs, Hari C.; Yao, Lynne] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. [Green, Dionna J.; Kim, Myong-Jin; Mulugeta, Yeruk; Burckart, Gilbert J.] US FDA, Off Clin Pharmacol, Off Translat Sci, CDER, Silver Spring, MD 20903 USA. [Hirsch, Mark] US FDA, Div Bone Reprod & Urol Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. [Khurana, Mona] US FDA, Div Nonprescript Regulat Dev, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. [Lee, Jinoo] Western Univ Hlth Sci, Coll Pharm, Pomona, CA USA. RP Burckart, GJ (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, CDER, White Oak Bldg 51,Room 3184, Silver Spring, MD 20903 USA. EM gilbert.burckart@fda.hhs.gov NR 14 TC 0 Z9 1 U1 1 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 NOV PY 2014 VL 54 IS 11 BP 1239 EP 1246 DI 10.1002/jcph.345 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AS1PC UT WOS:000344051600006 PM 24922179 ER PT J AU Goldsmith, JC AF Goldsmith, Jonathan C. TI Capsule Comment on Harrison et al., Assessing the Impact of Nurse Post-Discharge Telephone Calls on 30-day Hospital Readmission Rates SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Goldsmith, JC (reprint author), US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Jonathan.goldsmith@fda.hhs.gov NR 5 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2014 VL 29 IS 11 BP 1533 EP 1533 DI 10.1007/s11606-014-2972-0 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AS1ZC UT WOS:000344077900028 PM 25183474 ER PT J AU Selen, A Dickinson, PA Mullertz, A Crison, JR Mistry, HB Cruanes, MT Martinez, MN Lennernas, H Wigal, TL Swinney, DC Polli, JE Serajuddin, ATM Cook, JA Dressman, JB AF Selen, Arzu Dickinson, Paul A. Mullertz, Anette Crison, John R. Mistry, Hitesh B. Cruanes, Maria T. Martinez, Marilyn N. Lennernas, Hans Wigal, Tim L. Swinney, David C. Polli, James E. Serajuddin, Abu T. M. Cook, Jack A. Dressman, Jennifer B. TI The Biopharmaceutics Risk Assessment Roadmap for Optimizing Clinical Drug Product Performance SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE Quality by Design (QbD); bioavailability; biopharmaceutics classification system (BCS); clinical trial simulations; controlled delivery; in silico modeling; in vitro models; in vitro; in vivo correlations (IVIVC); oral drug delivery; pharmacokinetics; pharmacodynamics ID WATER-SOLUBLE DRUGS; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; ZOLPIDEM EXTENDED-RELEASE; ADVANCED SOLID TUMORS; IN-VIVO DISSOLUTION; UNDER-THE-CURVE; IMMEDIATE-RELEASE; ORAL ABSORPTION; DOSAGE FORM; PHARMACODYNAMIC-SEPARATION AB The biopharmaceutics risk assessment roadmap (BioRAM) optimizes drug product development and performance by using therapy-driven target drug delivery profiles as a framework to achieve the desired therapeutic outcome. Hence, clinical relevance is directly built into early formulation development. Biopharmaceutics tools are used to identify and address potential challenges to optimize the drug product for patient benefit. For illustration, BioRAM is applied to four relatively common therapy-driven drug delivery scenarios: rapid therapeutic onset, multiphasic delivery, delayed therapeutic onset, and maintenance of target exposure. BioRAM considers the therapeutic target with the drug substance characteristics and enables collection of critical knowledge for development of a dosage form that can perform consistently for meeting the patient's needs. Accordingly, the key factors are identified and in vitro, in vivo, and in silico modeling and simulation techniques are used to elucidate the optimal drug delivery rate and pattern. BioRAM enables (1) feasibility assessment for the dosage form, (2) development and conduct of appropriate learning and confirming studies, (3) transparency in decision-making, (4) assurance of drug product quality during lifecycle management, and (5) development of robust linkages between the desired clinical outcome and the necessary product quality attributes for inclusion in the quality target product profile. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3377-3397, 2014 C1 [Selen, Arzu] US FDA, Off New Drug Qual Assessment, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Dickinson, Paul A.] AstraZeneca, Quantitat Clin Pharmacol, Macclesfield, Cheshire, England. [Mullertz, Anette] Univ Copenhagen, Fac Pharmaceut Sci, Copenhagen, Denmark. [Crison, John R.] Bristol Myers Squibb Co, New Brunswick, NJ USA. [Mistry, Hitesh B.] Physiomics PLC, Oxford, England. [Cruanes, Maria T.] Merck & Co Inc, West Point, PA USA. [Martinez, Marilyn N.] US FDA CVM, Rockville, MD USA. [Lennernas, Hans] Uppsala Univ, Dept Pharm, Uppsala, Sweden. [Wigal, Tim L.] Univ Calif Irvine, Child Dev Ctr, Irvine, CA USA. [Swinney, David C.] iRND3, Mountain View, CA USA. [Polli, James E.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. [Serajuddin, Abu T. M.] St Johns Univ, Coll Pharm & Hlth Sci, Queens, NY USA. [Cook, Jack A.] Pfizer Inc, Groton, CT 06340 USA. [Dressman, Jennifer B.] Goethe Univ Frankfurt, Bioctr, Inst Pharmaceut Technol, D-60054 Frankfurt, Germany. RP Selen, A (reprint author), US FDA, Off New Drug Qual Assessment, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM arzu.selen@fda.hhs.gov RI Fachbereich14, Dekanat/C-8553-2015; OI Mistry, Hitesh/0000-0002-9683-1903; Mullertz, Anette/0000-0003-3020-8892 NR 169 TC 14 Z9 14 U1 8 U2 43 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 NOV PY 2014 VL 103 IS 11 BP 3377 EP 3397 DI 10.1002/jps.24162 PG 21 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA AS2ZO UT WOS:000344145200004 PM 25256402 ER PT J AU Doub, WH Shah, V Limb, S Guo, CN Liu, XF Ngo, D AF Doub, William H. Shah, Vibhakar Limb, Susan Guo, Changning Liu, Xiaofei Ngo, Diem TI Developing an In Vitro Understanding of Patient Experience with Hydrofluoroalkane-Metered Dose Inhalers SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE pulmonary drug delivery; aerosols; pulmonary; analysis; HPLC (high performance; pressure liquid chromatography); metered dose inhalers ID FORMULATION; HFA; PROPELLANT; REFORMULATION; EQUIVALENCE; BUDESONIDE; AEROSOL; ASTHMA AB As a result of the Montreal Protocol on Substances that Deplete the Ozone Layer, manufacturers of metered dose inhalers began reformulating their products to use hydrofluoroalkanes (HFAs) as propellants in place of chlorofluorocarbons (CFCs). Although the new products are considered safe and efficacious by the US Food and Drug Administration (FDA), a large number of complaints have been registered via the FDA's Adverse Events Reporting System (FAERS)more than 7000 as of May 2013. To develop a better understanding of the measurable parameters that may, in part, determine in vitro performance and thus patient compliance, we compared several CFC- and HFA-based products with respect to their aerodynamic performance in response to changes in actuator cleaning interval and interactuation delay interval. Comparison metrics examined in this study were: total drug delivered ex-actuator, fine particle dose (<5 m), mass median aerodynamic diameter, plume width, plume temperature, plume impaction force, and actuator orifice diameter. Overall, no single metric or test condition distinguishes HFA products from CFC products, but, for individual products tested, there were a combination of metrics that differentiated one from another. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3648-3656, 2014 C1 [Doub, William H.; Guo, Changning; Liu, Xiaofei; Ngo, Diem] US FDA OMPT CDER OPS OTR Div Pharmaceut Anal, St Louis, MO USA. [Shah, Vibhakar] US FDA OMPT CDER OC OMPQ DGMPA NDMAB, Silver Spring, MD USA. [Limb, Susan] US FDA OMPT CDER OND ODEII Div Pulm Allergy & Rhe, Silver Spring, MD USA. RP Doub, WH (reprint author), US FDA OMPT CDER OPS OTR Div Pharmaceut Anal, St Louis, MO USA. EM william.doub@fda.hhs.gov FU FDA/CDER RSR program FX The authors wish to thank the FDA/CDER RSR program for financial support of this project, and Kimberly Story and Shafiq Ahadi for assistance with the experimental work. NR 23 TC 1 Z9 1 U1 0 U2 3 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 NOV PY 2014 VL 103 IS 11 BP 3648 EP 3656 DI 10.1002/jps.24167 PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA AS2ZO UT WOS:000344145200032 PM 25228114 ER PT J AU Woodcock, J Brumfield, M Gill, D Zerhouni, E AF Woodcock, Janet Brumfield, Martha Gill, Dalvir Zerhouni, Elias TI The driving role of consortia on the critical path to innovative therapies SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material C1 [Woodcock, Janet] US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Brumfield, Martha] Crit Path Inst, Tucson, AZ USA. [Gill, Dalvir] TransCelerate BioPharma, King Of Prussia, PA USA. [Zerhouni, Elias] Sanofi, Global Res & Dev, Paris, France. RP Woodcock, J (reprint author), US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. EM janet.woodcock@fda.hhs.gov; MBrumfield@c-path.org; dalvir.gill@transceleratebiopharmainc.com; Elias.Zerhouni@sanofi.com NR 0 TC 1 Z9 1 U1 1 U2 2 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 NOV PY 2014 VL 13 IS 11 BP 781 EP 781 DI 10.1038/nrd4462 PG 1 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA AS4AR UT WOS:000344216500001 PM 25551158 ER PT J AU Woodcock, J AF Woodcock, Janet TI Paving the critical path of drug development: the CDER perspective SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material C1 US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Woodcock, J (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM janet.woodcock@fda.hhs.gov NR 0 TC 4 Z9 4 U1 0 U2 3 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 NOV PY 2014 VL 13 IS 11 BP 783 EP 784 DI 10.1038/nrd4435 PG 2 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA AS4AR UT WOS:000344216500002 PM 25359359 ER PT J AU Tenaerts, P Madre, L Archdeacon, P Califf, RM AF Tenaerts, Pamela Madre, Leanne Archdeacon, Patrick Califf, Robert M. TI The Clinical Trials Transformation Initiative: innovation through collaboration SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material C1 [Tenaerts, Pamela; Madre, Leanne] Duke Translat Med Inst, Clin Trials Transformat Initiat, Durham, NC 27701 USA. [Archdeacon, Patrick] US FDA, Off Med Policy, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Califf, Robert M.] Duke Translat Med Inst, Durham, NC 27710 USA. RP Tenaerts, P (reprint author), Duke Translat Med Inst, Clin Trials Transformat Initiat, 300 West Morgan St,Suite 800, Durham, NC 27701 USA. EM pamela.tenaerts@duke.edu NR 5 TC 7 Z9 8 U1 1 U2 3 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 NOV PY 2014 VL 13 IS 11 BP 797 EP 798 DI 10.1038/nrd4442 PG 2 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA AS4AR UT WOS:000344216500009 PM 25359366 ER PT J AU Gao, WY Mulberg, AE AF Gao, Wen-Yi Mulberg, Andrew E. TI Dependence of PERT Endpoint on Endogenous Lipase Activity SO PANCREAS LA English DT Article DE exocrine pancreatic insufficiency; pancreatic enzyme replacement therapy; cystic fibrosis; coefficient of fat absorption; clinical trials; efficacy analysis ID CYSTIC-FIBROSIS; COLONOPATHY; CHILDREN AB Objective: To clarify and to understand the potential for misinterpretation of change in fecal fat quantitation during pancreatic enzyme replacement therapy (PERT) trials for treatment of exocrine pancreatic insufficiency. Methods: Analysis of clinical trials submitted to the U. S. Food and Drug Administration (FDA) for approval of PERT that enrolled 123 cystic fibrosis adult and pediatric patients treated with Creon, Pertzye, Ultresa, and Zenpep. Results: (a) There was a strong negative dependence in measurement of coefficient of fat absorption (CFA%) between porcine pancreatic enzyme product-induced CFA improvement (PICI) and coexisting endogenous human pancreatic lipase activity (HPLA) (r = -0.92, P < 0.001, n = 123). (b) (1) Patients with HPLA greater than 75% had no measurable PICI; (2) patients with HPLA of 75% or less underestimated true PICI. Conclusions: The CFA% defines lipase activity as a percentage of converting substrate of "Total Daily Dietary Fat Intake." PERT trials performed to date have modified the definition to converting the "Shared Daily Fat Intake," generating "Partial CFA" for the exogenous lipase: the higher the activity of coexisting endogenous lipase, the lower the "Partial CFA" of exogenous measured. This review shows that "Partial CFA" is not CFA. Enrollment of patients with low HPLA during treatment may improve the interpretability of "Partial CFA" measured by PERT trials. C1 [Gao, Wen-Yi; Mulberg, Andrew E.] US FDA, Div Gastroenterol & Inborn Errors Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Gao, WY (reprint author), Div Gastroenterol Inborn Errors Prod, Bldg 22,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM wen-yi.gao@fda.hhs.gov NR 19 TC 0 Z9 0 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2014 VL 43 IS 8 BP 1232 EP 1238 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6GO UT WOS:000344362600016 PM 25102439 ER PT J AU Raebel, MA Penfold, R McMahon, AW Reichman, M Shetterly, S Goodrich, G Andrade, S Correll, CU Gerhard, T AF Raebel, Marsha A. Penfold, Robert McMahon, Ann W. Reichman, Marsha Shetterly, Susan Goodrich, Glenn Andrade, Susan Correll, Christoph U. Gerhard, Tobias TI Adherence to Guidelines for Glucose Assessment in Starting Second-Generation Antipsychotics SO PEDIATRICS LA English DT Article DE antipsychotic agents; second-generation antipsychotic; olanzapine; risperidone; aripiprazole; quetiapine; child adolescent; youth; glucose; hyperglycemia; glycosylated hemoglobin; monitoring; guideline adherence; retrospective studies ID HEALTH DATA-NETWORKS; MINI-SENTINEL; ATYPICAL ANTIPSYCHOTICS; CARDIOMETABOLIC RISK; NATIONAL TRENDS; CHILDREN; ADOLESCENTS; RISPERIDONE; WEIGHT; SAFETY AB OBJECTIVES: In 2003, the US Food and Drug Administration issued warnings about hyperglycemia and diabetes with second-generation antipsychotics (SGAs); guidelines have recommended metabolic screening since 2004. However, little is known of contemporary practices of glucose screening among youth initiating SGAs. Our objective was to evaluate baseline glucose assessment among youth in the Mini-Sentinel Distributed Database starting an SGA. METHODS: The cohort included youth ages 2 through 18 newly initiating SGAs January 1, 2006, through December 31, 2011, across 10 sites. Baseline glucose was defined as fasting/random glucose or hemoglobin A1c (GLU) measurement occurring relative to first SGA dispensing. Differences in GLU assessment were evaluated with chi(2) tests and logistic regression. RESULTS: The cohort included 16 304 youth; 60% boys; mean age 12.8 years. Risperidone was most commonly started (43%). Eleven percent (n = 1858) had GLU assessed between 90 days before and 3 days after first dispensing. Assessment varied across SGAs (olanzapine highest), sites (integrated health care systems higher), ages (16-18 highest), years (2007 highest), and gender (female higher; all P < .001). GLU assessment among those starting olanzapine was more likely than among those starting quetiapine (odds ratio [OR]: 1.72 [95% confidence interval (CI): 1.37-2.18]), aripiprazole (OR: 1.49 [95% CI: 1.18-1.87]), or risperidone (OR: 1.61 [95% CI: 1.28-2.03]). CONCLUSIONS: Few children and adolescents starting SGA have baseline glucose assessed. This is concerning because those at high diabetes risk may not be identified. Further, lack of screening impedes determining the contribution of SGAs to hyperglycemia development. C1 [Raebel, Marsha A.; Shetterly, Susan; Goodrich, Glenn] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO 80237 USA. [Penfold, Robert] Grp Hlth Res Inst, Seattle, WA USA. [McMahon, Ann W.] Off Commissioner, Off Pediat Therapeut, Silver Spring, MD USA. [Reichman, Marsha] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Andrade, Susan] Reliant Med Grp, Meyers Primary Care Inst, Worcester, MA USA. [Andrade, Susan] Univ Massachusetts, Sch Med, Worcester, MA USA. [Correll, Christoph U.] Zucker Hillside Hosp, Glen Oaks, NY USA. [Gerhard, Tobias] Rutgers State Univ, Inst Hlth Hlth Care Policy & Aging Res, New Brunswick, NJ 08903 USA. [Gerhard, Tobias] Ernest Mario Sch Pharm, Piscataway, NJ USA. RP Raebel, MA (reprint author), Kaiser Permanente Colorado, Inst Hlth Res, POB 378066, Denver, CO 80237 USA. EM marsha.a.raebel@kp.org FU US Food and Drug Administration (FDA) [HHSF22301004T-0009, HHSF22301007T-0004, HHSF22301007T-0006, HHSF2232009100061] FX This project was supported by Task Order HHSF22301004T-0009, HHSF22301007T-0004, and/or HHSF22301007T-0006 under Master Agreement HHSF2232009100061 from the US Food and Drug Administration (FDA). The FDA approved the study protocol including statistical analysis plan, and reviewed and approved this manuscript. Coauthors from the FDA participated in the results interpretation and in the preparation and decision to submit the manuscript for publication. The FDA had no role in data collection, management, or analysis. NR 34 TC 4 Z9 4 U1 1 U2 6 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 NOV PY 2014 VL 134 IS 5 BP E1308 EP E1314 DI 10.1542/peds.2014-0828 PG 7 WC Pediatrics SC Pediatrics GA AS6PU UT WOS:000344385900005 PM 25287454 ER PT J AU Link, WT De Felice, A AF Link, William T. De Felice, Albert TI An FDA overview of rodent carcinogenicity studies of angiotensin II AT-1 receptor blockers: Pulmonary adenomas and carcinomas SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Angiotensin II-AT1 receptor blockers; Lung tumors; RAS and angiogenesis ID ENDOTHELIAL GROWTH-FACTOR; VASCULAR-PERMEABILITY FACTOR; TRANSGENIC MOUSE MODELS; SMOOTH-MUSCLE-CELLS; TUMOR-GROWTH; TYPE-1 RECEPTOR; CHEMICAL CARCINOGENS; PROSTATE-CANCER; RAS ONCOGENES; ANGIOGENESIS AB Sipahi et al. (2010) performed a meta-analysis of 5 clinical trials (n = 68,402) of 3 Angiotensin II (AngII) receptor subtype AT-1 blockers (ARBs) in cardiovascular disease. It revealed excess new lung cancer diagnoses in the cohorts treated with an ARB and background therapy (0.9% vs. 0.7% in non-ARB control; RR: 1.25; CI: 1.05-1.49; p = 0.01). The FDA responded with a larger meta-analysis of 31 clinical trials (n = 155,816) of ARBs that found no evidence of any excess of site-specific cancer (lung, breast, prostate), solid/skin cancer or cancer death (FDA safety communication, 3 June 2011). The FDA then re-visited the 19 rodent carcinogenicity assays of 9 ARBs, starting with those for Losartan in 1994, for any evidence of dosage-related lung tumorigenicity in this class. Assays were performed in 5 strains of rats and 5 strains of wild-type and transgenic mice per protocols and dosages sanctioned by FDA's executive carcinogenicity assessment committee (eCAC). Duration was lifetime except for 26-week assays of azilsartan and olmesartan in transgenic Tg rasH2 mice, and an assay of olmesartan in p53(+/-) transgenic mice. The dosages provided exposures approximating, and in most cases up to 20-300 times greater than, that in patients. Depending on strain, up to 35% of untreated mice spontaneously developed lung tumors. Regression analysis of placebo-corrected mouse lung tumor incidence collapsed across strains, gender, and ARBs vs. multiples of human exposure revealed no excess lung neoplasia. The R-2 of <0.001 reflected the virtually identical number of treated cohorts with more tumors than its control cohort vs. those with less. Regardless of strain, both control and medicated rats were essentially devoid of lung tumors in the lifetime trials. Accordingly, there was neither promotion of background lung tumors in the mouse, nor initiation of de nova lung tumors in the rat. The negative lung findings in the mouse Tg rasH2 strain are also noteworthy given that, historically, the most prevalent spontaneous tumors in 26 week trials in that model are lung adenomas and carcinomas. The negative results of the 19, mostly lifetime, assays for cancer viewed en masse add to the results of the meta-analysis of the shorter clinical trials of ARBs that were benign regardless of statistical method used (random vs. fixed effect), comparator arm (with or without ACE-inhibitors) and major co-factors (smoking or cancer history). Published by Elsevier Inc. C1 [Link, William T.; De Felice, Albert] US FDA, Ctr Drug Evaluat & Res, Div Cardiovasc & Renal Drug Prod, Off New Drugs, Silver Spring, MD USA. RP Link, WT (reprint author), 10903 New Hampshire Ave,Bldg 22,Room 4130, Silver Spring, MD 20993 USA. EM William.link@fda.hhs.gov NR 74 TC 4 Z9 4 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 NOV PY 2014 VL 70 IS 2 BP 555 EP 563 DI 10.1016/j.yrtph.2014.09.002 PG 9 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA AS0FN UT WOS:000343953700015 PM 25223563 ER PT J AU Schreiner, CA Hoffman, GM Gudi, R Clark, CR AF Schreiner, Ceinwen A. Hoffman, Gary M. Gudi, Ramadevi Clark, Charles R. TI Health assessment of gasoline and fuel oxygenate vapors: Micronucleus and sister chromatid exchange evaluations SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Micronucleus; Micronucleated immature erythrocytes (MIE); Sister chromatid exchange (SCE); Methyl tert-butyl ether (MTBE); Ethyl tert butyl ether (ETBE); t-Amyl methyl ether (TAME); Diisopropyl ether (DIPE); t-Butyl alcohol (TBA); Ethanol (EtOH); Bromodeoxyuridine (BrdU) ID TERTIARY-BUTYL ETHER; GENOTOXICITY; TOXICITY AB Micronucleus and sister chromatid exchange (SCE) tests were performed for vapor condensate of baseline gasoline (BGVC), or gasoline with oxygenates, methyl tert-butyl ether (G/MTBE), ethyl tert butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), t-butyl alcohol (TBA), or ethanol (G/ EtOH). Sprague Dawley rats (the same 5/sex/group for both endpoints) were exposed to 0, 2000, 10,000, or 20,000 mg/m(3) of each condensate, 6 h/day, 5 days/week over 4 weeks. Positive controls (5/sex/test) were given cyclophosphamide IP, 24 h prior to sacrifice at 5 mg/kg (SCE test) and 40 mg/kg (micronucleus test). Blood was collected from the abdominal aorta for the SCE test and femurs removed for the micronucleus test. Blood cell cultures were treated with 5 mu g/ml bromodeoxyuridine (BrdU) for SCE evaluation. No significant increases in micronucleated immature erythrocytes were observed for any test material. Statistically significant increases in SCE were observed in rats given BGVC alone or in female rats given G/MTBE. G/TAME induced increased SCE in both sexes at the highest dose only. Although DNA perturbation was observed for several samples, DNA damage was not expressed as increased micronuclei in bone marrow cells. Inclusion of oxygenates in gasoline did not increase the effects of gasoline alone or produce a cytogenetic hazard. (C) 2014 Elsevier Inc. C1 [Schreiner, Ceinwen A.] C&C Consulting Toxicol, Meadowbrook, PA 19046 USA. [Hoffman, Gary M.] Huntingdon Life Sci Inc, E Millstone, NJ 08875 USA. [Gudi, Ramadevi] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Clark, Charles R.] Phillips 66 Co, Bartlesville, OK 74004 USA. RP Schreiner, CA (reprint author), C&C Consulting Toxicol, Meadowbrook, PA 19046 USA. EM castox@comcast.net; hoffmang@princeton.huntingdon.com; ramadevi.gudi@fda.hhs.gov; okietox@g-mail.com NR 32 TC 9 Z9 9 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 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD NOV 1 PY 2014 VL 70 IS 2 SU 1 BP S29 EP S34 DI 10.1016/j.yrtph.2014.05.014 PG 6 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA AS0FQ UT WOS:000343954000005 PM 24852491 ER PT J AU Epstein, J Ganz, PR Seitz, R Jutzi, M Schaerer, C Michaud, G Agbanyo, F Smith, G Prosser, I Heiden, M Saint-Marie, I Oualikene-Gonin, W Hamaguchi, I Yasuda, N AF Epstein, J. Ganz, P. R. Seitz, R. Jutzi, M. Schaerer, C. Michaud, G. Agbanyo, F. Smith, G. Prosser, I. Heiden, M. Saint-Marie, I. Oualikene-Gonin, W. Hamaguchi, I. Yasuda, N. TI A shared regulatory perspective on deferral from blood donation of men who have sex with men (MSM) SO VOX SANGUINIS LA English DT Article DE blood collection; donors; epidemiology; motivation; recruitment; transfusion medicine (in general) ID HAD SEX; RISK; ENGLAND; IMPACT; VIRUS; AUSTRALIA; BENEFITS; DONORS AB National Regulatory Authorities (NRAs) establish deferral criteria for donors with risk factors for transfusion transmissible infections (TTI). In most jurisdictions, epidemiological data show that men who have sex with men (MSM) have a significantly higher rate of TTI than the general population. Nevertheless, changes from an indefinite donor deferral for MSM have been considered in many countries in response to concerns over a perceived discrimination and questioning of the scientific need. Changes to MSM donor deferral criteria should be based on sound scientific evidence. Safety of transfusion recipients should be the first priority, and stakeholder input should be sought. C1 [Epstein, J.; Michaud, G.] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Ganz, P. R.; Agbanyo, F.] Hlth Canada, Ctr Blood & Tissues Evaluat, Biol & Genet Therapies Directorate, Ottawa, ON K1A 0L2, Canada. [Seitz, R.; Heiden, M.] Paul Ehrlich Inst, Div Haematol Transfus Med, Langen, Germany. [Jutzi, M.; Schaerer, C.] Swiss Agcy Therapeut Prod, Swissmed, Bern, Switzerland. [Smith, G.; Prosser, I.] Therapeut Goods Adm, Off Sci Evaluat, Woden, ACT, Australia. [Saint-Marie, I.; Oualikene-Gonin, W.] French Natl Agcy Med & Hlth Prod Safety, Div Adv Therapies Prod Human Origin & Vaccines, St Denis, France. [Hamaguchi, I.] Natl Inst Infect Dis, Dept Safety Res Blood & Biol Prod, Tokyo, Japan. [Yasuda, N.] Minist Hlth Labour & Welf, Chiyoda Ku, Tokyo, Japan. RP Epstein, J (reprint author), US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, WO71-4230,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jay.epstein@fda.hhs.gov NR 27 TC 3 Z9 3 U1 0 U2 9 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 2014 VL 107 IS 4 BP 416 EP 419 DI 10.1111/vox.12166 PG 4 WC Hematology SC Hematology GA AS4EY UT WOS:000344227100014 PM 24924302 ER PT J AU Vaclavik, L Krynitsky, AJ Rader, JI AF Vaclavik, Lukas Krynitsky, Alexander J. Rader, Jeanne I. TI Mass spectrometric analysis of pharmaceutical adulterants in products labeled as botanical dietary supplements or herbal remedies: a review SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Review DE Botanical dietary supplements; Herbal remedies; Adulteration; Pharmaceuticals; Mass spectrometry; LC-MS; GC-MS; Ambient ionization methods ID PERFORMANCE LIQUID-CHROMATOGRAPHY; TRADITIONAL CHINESE MEDICINES; FAST GAS-CHROMATOGRAPHY; MS SCREENING METHOD; ELECTROSPRAY-IONIZATION; WEIGHT-LOSS; NUTRITIONAL SUPPLEMENTS; PESTICIDE-RESIDUES; LC-MS/MS; CAPILLARY-ELECTROPHORESIS AB The increased availability and use of botanical dietary supplements and herbal remedies among consumers has been accompanied by an increased frequency of adulteration of these products with synthetic pharmaceuticals. Unscrupulous producers may add drugs and analogues of various classes, such as phosphodiesterase type 5 (PDE-5) inhibitors, weight loss, hypoglycemic, antihypertensive and anti-inflammatory agents, or anabolic steroids, to develop or intensify biological effects of dietary supplements or herbal remedies. The presence of such adulterated products in the marketplace is a worldwide problem and their consumption poses health risks to consumers. Analytical methods that allow rapid and reliable testing of dietary supplements for the presence of synthetic drugs are needed to address such fraudulent practices. Mass spectrometry (MS) and hyphenated techniques such as liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) have become primary tools in this endeavor. The present review critically assesses the role and summarizes the applications of MS in the analysis of pharmaceutical adulterants in botanical dietary supplements and herbal remedies. The uses of MS techniques in detection, confirmation, and quantification of known pharmaceutical adulterants as well as in screening for and structure elucidation of unexpected adulterants and novel designer drugs are discussed. C1 [Vaclavik, Lukas; Krynitsky, Alexander J.; Rader, Jeanne I.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. RP Vaclavik, L (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5100 Paint Branch Pkwy,HFS-717, College Pk, MD 20740 USA. EM Lukas.Vaclavik@fda.hhs.gov NR 109 TC 15 Z9 17 U1 9 U2 92 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 2014 VL 406 IS 27 BP 6767 EP 6790 DI 10.1007/s00216-014-8159-z PG 24 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AR8DG UT WOS:000343805100004 PM 25270866 ER PT J AU O'Brien, TR Prokunina-Olsson, L Donnelly, RP AF O'Brien, Thomas R. Prokunina-Olsson, Ludmila Donnelly, Raymond P. TI IFN-lambda 4: The Paradoxical New Member of the Interferon Lambda Family SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Review ID HEPATITIS-C VIRUS; GENOME-WIDE ASSOCIATION; GENETIC-VARIATION; SPONTANEOUS CLEARANCE; SIGNAL-TRANSDUCTION; ANTIVIRAL ACTIVITY; RIBAVIRIN THERAPY; HUMAN HEPATOCYTES; STIMULATED GENES; INTERLEUKIN 28B AB Interferons (IFNs) are generally considered antiviral cytokines, yet the newly discovered IFN-lambda 4 is linked with the failure to clear hepatitis C virus (HCV) infection either spontaneously or in response to treatment. IFN-lambda 4 can be generated only by individuals who carry the IFNL4-Delta G allele (rs368234815), which is the strongest known host factor for predicting clearance of HCV. The ancestral IFNL4-Delta G allele is the major variant in Africans while the minor variant in Asians, suggesting very strong negative genetic selection for this allele-most likely driven by an infectious agent other than HCV. IFN-lambda 4 most closely resembles IFN-lambda 3, but these proteins share only 29% amino-acid identity, and, in contrast to IFN-lambda 3, IFN-lambda 4 is only weakly secreted. Nevertheless, IFN-lambda 4 signals through the IFN-lambda receptor complex and induces expression of IFN-stimulated genes via the Janus kinase-signal transducer and activator of transcription signaling pathway. Although the IFNL4-Delta G variant is strongly associated with the failure to clear HCV infection, HCV-infected patients who carry this allele have lower baseline HCV RNA levels in the absence of treatment. Resolving the paradoxical functions of IFN-lambda 4, which appears to induce antiviral activity yet impair effective clearance of HCV, may yield critical new insights into the immunologic response to HCV infection and IFN biology. C1 [O'Brien, Thomas R.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Donnelly, Raymond P.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. RP O'Brien, TR (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,6E108 MSC 9767, Bethesda, MD 20892 USA. EM obrient@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 60 TC 36 Z9 37 U1 1 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 EI 1557-7465 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD NOV 1 PY 2014 VL 34 IS 11 BP 829 EP 838 DI 10.1089/jir.2013.0136 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA AS3EI UT WOS:000344158900001 PM 24786669 ER PT J AU Shon, J Abernethy, DR AF Shon, J. Abernethy, D. R. TI Application of Systems Pharmacology to Explore Mechanisms of Hepatotoxicity SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID INDUCED LIVER-INJURY; MATHEMATICAL-MODEL; IN-VITRO; TROGLITAZONE; VIVO AB Advances in systems biology have allowed the development of a highly characterized systems pharmacology model to study mechanisms of drug-induced hepatotoxicity. In this issue of CPT, Yang et al. describe a model, DILIsym, used to characterize mechanisms of hepatotoxicity of troglitazone. Their modeling approach has provided new insight into troglitazone-induced hepatotoxicity in humans but is not associated with hepatotoxicity in rats, consistent with preclinical data for this drug. C1 [Shon, J.; Abernethy, D. R.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Abernethy, DR (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Darrell.Abernethy@fda.hhs.gov NR 9 TC 3 Z9 3 U1 0 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 NOV PY 2014 VL 96 IS 5 BP 536 EP 537 DI 10.1038/clpt.2014.167 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AR5OE UT WOS:000343632900013 PM 25336266 ER PT J AU Johannesen, L Vicente, J Mason, JW Sanabria, C Waite-Labott, K Hong, M Guo, P Lin, J Sorensen, JS Galeotti, L Florian, J Ugander, M Stockbridge, N Strauss, DG AF Johannesen, L. Vicente, J. Mason, J. W. Sanabria, C. Waite-Labott, K. Hong, M. Guo, P. Lin, J. Sorensen, J. S. Galeotti, L. Florian, J. Ugander, M. Stockbridge, N. Strauss, D. G. TI Differentiating Drug-Induced Multichannel Block on the Electrocardiogram: Randomized Study of Dofetilide, Quinidine, Ranolazine, and Verapamil SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID LONG-QT SYNDROME; TORSADE-DE-POINTES; LATE SODIUM CURRENT; T-WAVE MORPHOLOGY; VENTRICULAR REPOLARIZATION; HEART-RATE; TRANSMURAL DISPERSION; INTERVAL PROLONGATION; NA+ CHANNEL; K+ CURRENT AB Block of the hERG potassium channel and prolongation of the QT interval are predictors of drug-induced torsade de pointes. However, drugs that block the hERG potassium channel may also block other channels that mitigate torsade risk. We hypothesized that the electrocardiogram can differentiate the effects of multichannel drug block by separate analysis of early repolarization (global J-T-peak) and late repolarization (global T-peak-T-end). In this prospective randomized controlled clinical trial, 22 subjects received a pure hERG potassium channel blocker (dofetilide) and three drugs that block hERG and either calcium or late sodium currents (quinidine, ranolazine, and verapamil). The results show that hERG potassium channel block equally prolongs early and late repolarization, whereas additional inward current block (calcium or late sodium) preferentially shortens early repolarization. Characterization of multichannel drug effects on human cardiac repolarization is possible and may improve the utility of the electrocardiogram in the assessment of drug-related cardiac electrophysiology. C1 [Johannesen, L.; Vicente, J.; Galeotti, L.; Ugander, M.; Strauss, D. G.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Johannesen, L.; Ugander, M.; Strauss, D. G.] Karolinska Inst, Dept Clin Physiol, S-10401 Stockholm, Sweden. [Johannesen, L.; Ugander, M.; Strauss, D. G.] Karolinska Univ Hosp, Stockholm, Sweden. [Vicente, J.] Univ Zaragoza, BSICoS Grp, Aragon Inst Engn Res I3A, IIS Aragon, Zaragoza, Aragon, Spain. [Mason, J. W.; Sanabria, C.; Waite-Labott, K.] Spaulding Clin Res, West Bend, WI USA. [Hong, M.; Guo, P.; Lin, J.] Frontage Labs, Exton, PA USA. [Sorensen, J. S.; Florian, J.] US FDA, Div Pharmacometr, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Stockbridge, N.] US FDA, Div Cardiovasc & Renal Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Strauss, DG (reprint author), US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM david.strauss@fda.hhs.gov RI GALEOTTI, LORIANO/N-4240-2014; OI GALEOTTI, LORIANO/0000-0002-3200-9080; Ugander, Martin/0000-0003-3665-2038; Vicente, Jose/0000-0001-9963-1205 FU Department of Energy; FDA; FDA's Critical Path Initiative; Office of Women's Health FX We thank Jill Coker, FDA extramural clinical studies coordinator, and staff at Spaulding Clinical Research for executing the study. This project was supported in part by 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 the FDA. The opinions presented here are those of the authors. No official support or endorsement by the 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 the FDA. This project was supported by the FDA's Critical Path Initiative and Office of Women's Health. NR 58 TC 36 Z9 36 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD NOV PY 2014 VL 96 IS 5 BP 549 EP 558 DI 10.1038/clpt.2014.155 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AR5OE UT WOS:000343632900016 PM 25054430 ER PT J AU Baird, LG Banken, R Eichler, HG Kristensen, FB Lee, DK Lim, JCW Lim, R Longson, C Pezalla, E Salmonson, T Samaha, D Tunis, S Woodcock, J Hirsch, G AF Baird, L. G. Banken, R. Eichler, H-G Kristensen, F. B. Lee, D. K. Lim, J. C. W. Lim, R. Longson, C. Pezalla, E. Salmonson, T. Samaha, D. Tunis, S. Woodcock, J. Hirsch, G. TI Accelerated Access to Innovative Medicines for Patients in Need SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID PROMISING HEALTH TECHNOLOGIES; EVIDENCE GENERATION; MEDICARE COVERAGE; POLICY; DRUGS AB There is broad agreement among health-care stakeholders that more must be done to ensure that patients have timely access to new and innovative medicines. Assuming that industry will continue to develop such medicines at a sustainable rate, regulators and payers become the gatekeepers. Regulators, starting in the late 1980s/early 1990s, and, more recently, payers have implemented a variety of early-access pathways or initiatives, and this practice is continuing even today. This article describes the specific approaches that have been taken in four economically developed regions, reviews their success rates, and suggests possible new directions. C1 [Baird, L. G.; Hirsch, G.] MIT, Ctr Biomed Innovat, Cambridge, MA 02139 USA. [Banken, R.; Samaha, D.] Inst Natl Excellence Sante & Serv Sociaux, Quebec City, PQ, Canada. [Eichler, H-G] European Med Agcy, London, England. [Kristensen, F. B.] Danish Hlth & Med Author, Copenhagen, Denmark. [Lee, D. K.; Lim, R.] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Lim, J. C. W.] Singapore Hlth Sci Author, Singapore, Singapore. [Longson, C.] Natl Inst Hlth & Care Excellence, London, England. [Pezalla, E.] Aetna, Hartford, CT USA. [Salmonson, T.] Swedish Med Prod Agcy, Uppsala, Sweden. [Tunis, S.] Ctr Med Technol Policy, Baltimore, MD USA. [Woodcock, J.] US FDA, Silver Spring, MD USA. RP Baird, LG (reprint author), MIT, Ctr Biomed Innovat, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM lbaird@mit.edu NR 26 TC 21 Z9 21 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 2014 VL 96 IS 5 BP 559 EP 571 DI 10.1038/clpt.2014.145 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AR5OE UT WOS:000343632900017 PM 25006877 ER PT J AU Minasian, L Rosen, O Auclair, D Rahman, A Pazdur, R Schilsky, RL AF Minasian, L. Rosen, O. Auclair, D. Rahman, A. Pazdur, R. Schilsky, R. L. TI Optimizing Dosing of Oncology Drugs SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Review ID APPROVAL; FOOD; CHEMOTHERAPY; OUTCOMES AB The purpose of this article is to acknowledge the challenges in optimizing the dosing of oncology drugs and to propose potential approaches to address these challenges in order to optimize effectiveness, minimize toxicity, and promote adherence in patients. These approaches could provide better opportunities to understand the sources of variability in drug exposure and clinical outcomes during the development and premarketing evaluation of investigational new drugs. C1 [Minasian, L.] NCI, Div Canc Prevent, Bethesda, MD 20892 USA. [Rosen, O.] Millennium Takeda Oncol Co, Cambridge, MA USA. [Auclair, D.] Multiple Myeloma Res Fdn, Norwalk, CT USA. [Rahman, A.; Pazdur, R.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Schilsky, R. L.] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. RP Schilsky, RL (reprint author), Amer Soc Clin Oncol, Alexandria, VA 22314 USA. EM Richard.Schilsky@asco.org NR 18 TC 12 Z9 12 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD NOV PY 2014 VL 96 IS 5 BP 572 EP 579 DI 10.1038/clpt.2014.153 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AR5OE UT WOS:000343632900018 PM 25105705 ER PT J AU Hellberg, RS Kawalek, MD Van, KT Shen, YL Williams-Hill, DM AF Hellberg, Rosalee S. Kawalek, Michael D. Van, Khanh T. Shen, Yuelian Williams-Hill, Donna M. TI Comparison of DNA Extraction and PCR Setup Methods for Use in High-Throughput DNA Barcoding of Fish Species SO FOOD ANALYTICAL METHODS LA English DT Article DE DNA barcoding; DNA extraction; Fish species identification; PCR; Sequencing ID SEAFOOD AB DNA barcoding is a sequencing-based method that can be used for the identification of fish species in a regulatory setting. The objective of this study was to compare modified versions of three DNA extraction kits (i.e., Qiagen DNeasy Blood and Tissue Kit, Sigma-Aldrich Extract-N-Amp Kit; and Life Technologies MagMax-96 DNA Multi-Sample Kit) and two polymerase chain reaction (PCR) setup methods (manual vs. automated) for use in DNA barcoding, with a focus on minimizing time, costs, and labor. DNA was extracted from 83 fish products using each of the three kits and the results were compared based on sequencing success and sequencing quality parameters. A subset of 14 fish products was also tested in triplicate to compare PCR setup methods. Initially, reduced sequencing success was observed with the MagMax Kit (88 %) compared to the other two kits (95-96 %); however, after PCR and sequencing were repeated for DNA samples that initially failed, all three methods showed very high sequencing success (98-99 %). Overall, the modified Extract-NAmpKit offered the greatest reduction in time and costs, while the DNeasy Blood and Tissue Kit produced sequences with the highest quality and highest initial success rates. Automation of the PCR setup process resulted in slightly greater success (100 %) compared to manual PCR setup (98 %), and reduced the potential for human error that may result from manual pipetting. The results of this study demonstrate the advantages of incorporating rapid and/or automated methods into the DNA barcoding workflow, especially with regard to high-throughput operations. C1 [Hellberg, Rosalee S.] Chapman Univ, Sch Earth & Environm Sci, Orange, CA 92866 USA. [Kawalek, Michael D.; Van, Khanh T.; Williams-Hill, Donna M.] US FDA, Off Regulatory Affairs, Pacific Reg Lab Southwest, Irvine, CA 92612 USA. [Shen, Yuelian] US FDA, Off Regulatory Affairs, Off Reg Operat, Div Field Sci, Rockville, MD 20857 USA. RP Hellberg, RS (reprint author), Chapman Univ, Sch Earth & Environm Sci, One Univ Dr, Orange, CA 92866 USA. EM hellberg@chapman.edu FU FDA Commissioner's Fellowship Program FX We thank the microbiology branch at the Food and Drug Administration (FDA) Pacific Regional Laboratory Southwest for setting aside fish tissue samples for this project. We also thank Jonathan R. Deeds and Sara M. Handy for critically reviewing the manuscript. This work was supported in part by the FDA Commissioner's Fellowship Program. NR 14 TC 2 Z9 2 U1 2 U2 29 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 NOV PY 2014 VL 7 IS 10 BP 1950 EP 1959 DI 10.1007/s12161-014-9865-z PG 10 WC Food Science & Technology SC Food Science & Technology GA AR6QD UT WOS:000343707100002 ER PT J AU Stingley, RL Liu, HL Mullis, LB Elkins, CA Hart, ME AF Stingley, Robin L. Liu, Huanli Mullis, Lisa B. Elkins, Christopher A. Hart, Mark E. TI Staphylococcus aureus toxic shock syndrome toxin-1 (TSST-1) production and Lactobacillus species growth in a defined medium simulating vaginal secretions SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Article DE Staphylococcus aureus; Lactobacillus species; Simulated genital tract secretion medium; TSST-1; Menstrual toxic shock syndrome; In vitro growth ID APERTURED FILM COVER; NUTRITIONAL-REQUIREMENTS; GENITAL-TRACT; BACTERIAL VAGINOSIS; PEROXIDE PRODUCTION; MENSTRUATING WOMEN; COMMERCIAL TAMPON; ANAEROBIC GROWTH; EPITHELIAL-CELLS; NONWOVEN FLEECE AB Lactobacillus species are commensal with the healthy vaginal environment and inhibit the growth of many pathogenic bacteria in the vaginal tract by a variety of mechanisms, such as the production of hydrogen peroxide, organic acids, and antimicrobial substances. Simulation of the vaginal environment is crucial for proper investigation of the effects of Lactobacillus species on pathogenic bacteria. In this study, we modified a medium used to simulate vaginal secretions to improve the growth of toxic shock syndrome toxin-1 (TSST-1)-producing Staphylococcus aureus clinical strains and Lactobacillus species so that interactions between these bacteria may be examined. A medium consisting of basal salts, vitamins, albumin, glycogen, mucin, urea, sodium bicarbonate, polyoxyethylene sorbitan monolaurate, and amino acids supported the growth of S. aureus and the production of TSST-1 as determined by Western analysis. Improved growth of the Lactobacillus species was seen when this same medium was supplemented with manganese chloride, sodium acetate, and an increase in glucose concentration. However, growth of S. aureus in the supplemented medium resulted in reduced levels of TSST-1. Production of TSST-1 was not detected in a medium routinely used for the growth of Lactobacillus species although S. aureus growth was not inhibited. The development of an improved genital tract secretion medium provides a more authentic environment in which to study the interactions of Lactobacillus species and vaginal pathogens, such as S. aureus. Published by Elsevier B.V. C1 [Stingley, Robin L.] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Liu, Huanli] US FDA, Off Regulatory Affairs, Arkansas Reg Labs, Jefferson, AR 72079 USA. [Mullis, Lisa B.; Hart, Mark E.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Elkins, Christopher A.] US FDA, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Jefferson, AR 72079 USA. [Hart, Mark E.] Univ Arkansas Med Sci, Dept Microbiol & Immunol, Little Rock, AR 72205 USA. RP Hart, ME (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, HFT-250,3900 NCTR Rd, Jefferson, AR 72079 USA. EM mark.hart@fda.hhs.gov FU Office of Women's Health of the U. S. Food and Drug Administration [E0725501, E0728601] FX R.L.S. and H.L. contributed equally to this study and were supported in part, by an appointment to the Postgraduate Research Program at the National Center for Toxicological 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. This study was funded by the Office of Women's Health of the U. S. Food and Drug Administration under protocols E0725501 and E0728601. We thank Dr. Paul D. Fey of the University of Nebraska Medical Center, Omaha, NE, for S. aureus isolates, Dr. Mark S. Smeltzer of the University of Arkansas for Medical Sciences, Little Rock, AR, for S. aureus UAMS-1, and Dr. Raoul F. Reiser of Toxin Technology, Inc., Sarasota, FL, for technical advice. We are indebted to Drs. Carl Cerniglia, Steve Foley, and John Sutherland for their careful evaluation of the manuscript. The views presented in this article do not necessarily reflect those of the Food and Drug Administration. NR 64 TC 1 Z9 1 U1 3 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7012 EI 1872-8359 J9 J MICROBIOL METH JI J. Microbiol. Methods PD NOV PY 2014 VL 106 BP 57 EP 66 DI 10.1016/j.mimet.2014.08.002 PG 10 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA AR1PX UT WOS:000343358200010 PM 25135489 ER PT J AU Johnson, DH Via, LE Kim, P Laddy, D Lau, CY Weinstein, EA Jain, S AF Johnson, Daniel H. Via, Laura E. Kim, Peter Laddy, Dominick Lau, Chuen-Yen Weinstein, Edward A. Jain, Sanjay TI Nuclear imaging: A powerful novel approach for tuberculosis SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Drug-resistance; PET; SPECT; Probe-design; Pharmacokinetics ID POSITRON-EMISSION-TOMOGRAPHY; METASTATIC BREAST-CANCER; XPERT MTB/RIF ASSAY; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; FDG PET/CT; THERAPEUTIC RESPONSE; LATENT TUBERCULOSIS; F-18-FDG PET/CT; BACTERIAL-INFECTIONS AB Nearly 20 years after the World Health Organization declared tuberculosis (TB) a global public health emergency, TB still remains a major global threat with 8.6 million new cases and 1.3 million deaths annually. Mycobacterium tuberculosis adapts to a quiescent physiological state, and is notable for complex interaction with the host, producing poorly-understood disease states ranging from latent infection to fully active disease. Of the approximately 2.5 billion people latently infected with M. tuberculosis, many will develop reactivation disease (relapse), years after the initial infection. While progress has been made on some fronts, the alarming spread of multidrug-resistant, extensively drug-resistant, and more recently totally-drug resistant strains is of grave concern. New tools are urgently needed for rapidly diagnosing TB, monitoring TB treatments and to allow unique insights into disease pathogenesis. Nuclear bioimaging is a powerful, noninvasive tool that can rapidly provide three-dimensional views of disease processes deep within the body and conduct noninvasive longitudinal assessments of the same patient. In this review, we discuss the application of nuclear bioimaging to TB, including the current state of the field, considerations for radioprobe development, study of TB drug pharmacokinetics in infected tissues, and areas of research and clinical needs that could be addressed by nuclear bioimaging. These technologies are an emerging field of research, overcome several fundamental limitations of current tools, and will have a broad impact on both basic research and patient care. Beyond diagnosis and monitoring disease, these technologies will also allow unique insights into understanding disease pathogenesis: and expedite bench-to-bedside translation of new therapeutics. Finally, since molecular imaging is readily available for humans, validated tracers will become valuable tools for clinical applications. Published by Elsevier Inc. C1 [Johnson, Daniel H.; Via, Laura E.; Kim, Peter; Lau, Chuen-Yen] NIAID, NIH, Bethesda, MD 20892 USA. [Laddy, Dominick] Aeras, Rockville, MD USA. [Weinstein, Edward A.] FDA CDER, Silver Spring, MD USA. [Jain, Sanjay] Johns Hopkins Univ, Sch Med, Ctr TB Res, Ctr Infect & Inflammat Imaging Res, Baltimore, MD USA. [Jain, Sanjay] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. RP Johnson, DH (reprint author), NIAID, DAIDS, NIH, 5601 Fisher Lane,Rm 9E39 MSC 9830, Rockville, MD 20852 USA. EM daniel.johnson@nih.gov OI Via, Laura/0000-0001-6074-9521 FU NIH [DP2-OD006492, R01-HL116316]; AIDS Clinical Trials Group Administrative Novel Formulations Supplement; NIH, NIAID FX This study was funded by the NIH Director's New Innovator Award DP2-OD006492 (S.K.J.), R01-HL116316 (S.K.J.), and AIDS Clinical Trials Group Administrative Novel Formulations Supplement (S.K.J.). We thank Dr. William Eckelman (Molecular Tracer LLC) for comments. The authors do not have a commercial or other association that might pose a conflict of interest. The views expressed in review are those of the authors and do not necessarily reflect the official policy or position of the U.S. Food and Drug Administration, the Department of Health and Human Services, or the United States Government, and should not be used for advertising or product endorsement purposes. Reference to any specific commercial products, process, or service by trade name, trademark, manufacturer, or otherwise, does not constitute or imply its approval, endorsement, recommendation, or favoring by the United States Government or any department, agency, office, or branch thereof. Funding for this work was provided (in part) by the Intramural Research Program of the NIH, NIAID. NR 108 TC 7 Z9 7 U1 2 U2 26 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 EI 1872-9614 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD NOV-DEC PY 2014 VL 41 IS 10 BP 777 EP 784 DI 10.1016/j.nucmedbio.2014.08.005 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AR5HE UT WOS:000343614800001 PM 25195017 ER PT J AU Guo, X Zhang, SH Dial, SL Boudreau, MD Xia, QS Fu, PP Levy, DD Moore, MM Mei, N AF Guo, Xiaoqing Zhang, Suhui Dial, Stacey L. Boudreau, Mary D. Xia, Qingsu Fu, Peter P. Levy, Dan D. Moore, Martha M. Mei, Nan TI In vitro investigation of the mutagenic potential of Aloe vera extracts SO TOXICOLOGY RESEARCH LA English DT Article ID MOUSE LYMPHOMA-CELLS; BARBADENSIS MILLER; MAMMALIAN-CELLS; LIPID-PEROXIDATION; TOPOISOMERASE-II; LEAF EXTRACT; GENOTOXICITY; EMODIN; ANTHRAQUINONES; SAFETY AB A 2-year cancer bioassay in rodents with a preparation of Aloe vera whole leaf extract administered in drinking water showed clear evidence of carcinogenic activity. To provide insight into the identity and mechanisms associated with mutagenic components of the Aloe vera extracts, we used the mouse lymphoma assay to evaluate the mutagenicity of the Aloe vera whole leaf extract (WLE) and Aloe vera decolorized whole leaf extract (WLD). The WLD extract was obtained by subjecting WLE to activated carbon-adsorption. HPLC analysis indicated that the decolorization process removed many components from the WLE extract, including anthraquinones. Both WLE and WLD extracts showed cytotoxic and mutagenic effects in mouse lymphoma cells but in different concentration ranges, and WLD induced about 3-fold higher levels of intracellular reactive oxygen species than WLE. Molecular analysis of mutant colonies from cells treated with WLE and WLD revealed that the primary type of damage from both treatments was largely due to chromosome mutations (deletions and/or mitotic recombination). The fact that the samples were mutagenic at different concentrations suggests that while some mutagenic components of WLE were removed by activated carbon filtration, components with pro-oxidant activity and mutagenic activity remained. The results demonstrate the utility of the mouse lymphoma assay as a tool to characterize the mutagenic activity of fractionated complex botanical mixtures to identify bioactive components. C1 [Guo, Xiaoqing; Zhang, Suhui; Dial, Stacey L.; Moore, Martha M.; Mei, Nan] Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Boudreau, Mary D.; Xia, Qingsu; Fu, Peter P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Levy, Dan D.] Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Zhang, Suhui] Shanghai Inst Food & Drug Control, Dept Pharmacol & Toxicol, Shanghai 201203, Peoples R China. RP Guo, X (reprint author), Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. EM Nan.Mei@fda.hhs.gov OI MEI, NAN/0000-0002-3501-9014 FU Office of International Programs, the U.S. Food and Drug Administration (FDA) FX Mrs Suhui Zhang from the Shanghai Institute for Food and Drug Control (Shanghai, China) participated in the International Scientist Exchange Program (ISEP) at the National Center for Toxicological Research receiving funding from the Office of International Programs, the U.S. Food and Drug Administration (FDA). The information given in this paper is not a formal dissemination of information by the U.S. FDA and does not represent the agency position or policy. NR 46 TC 2 Z9 2 U1 0 U2 10 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2045-452X EI 2045-4538 J9 TOXICOL RES-UK JI Toxicol. Res. PD NOV 1 PY 2014 VL 3 IS 6 BP 487 EP 496 DI 10.1039/c4tx00053f PG 10 WC Toxicology SC Toxicology GA AR6TQ UT WOS:000343716400009 ER PT J AU Woo, EJ AF Woo, Emily Jane TI Letter to the Editor: Editorial: When "Safe and Effective" Becomes Dangerous SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Letter C1 US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Woo, EJ (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jane.woo@fda.hhs.gov NR 8 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD NOV PY 2014 VL 472 IS 11 BP 3588 EP 3589 DI 10.1007/s11999-014-3923-0 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AQ9DO UT WOS:000343143900057 PM 25201092 ER PT J AU Yang, B Zhao, H Cui, S Wang, Y Xia, X Xi, M Wang, X Meng, J Ge, W AF Yang, B. Zhao, H. Cui, S. Wang, Y. Xia, X. Xi, M. Wang, X. Meng, J. Ge, W. TI Prevalence and characterization of Salmonella enterica in dried milk-related infant foods in Shaanxi, China SO JOURNAL OF DAIRY SCIENCE LA English DT Article DE Salmonella; infant food; antimicrobial resistance; pulsed-field gel electrophoresis ID MEDIATED QUINOLONE RESISTANCE; ENTEROBACTER-SAKAZAKII; UNITED-STATES; RETAIL MEATS; FORMULA; INFECTIONS; SEROTYPE; CONSUMPTION; SHIGELLA; PRODUCTS AB The aim of this study was to investigate the existence and characteristics of Salmonella enterica in dried milk-related infant foods. Twenty-four (3.4%) of 705 samples, including 5 (2.0%) of 246 powdered infant formula, 18 (4.0%) of 445 infant rice cereal, and 1 (7.1%) of 14 other infant foods, were positive for Salmonella. Fifteen serotypes were identified in 40 Salmonella isolates; Salmonella Duesseldorf (15.0%) and Salmonella Indiana (15.0%) were more frequently detected than other serotypes. Resistance to chloramphenicol (82.5%) was most common, followed by tetracycline (57.5%), ceftiofur (52.5%), kanamycin (52.5%), streptomycin (50.0%), gentamycin (45.0%), nalidixic acid (35.0%), ceftriaxone (32.5%), ciprofloxacin (25.0%), amikacin (20.0%), and cefoxitin (15.0%). Twenty-eight (70.0%) isolates were resistant to >= 8 antimicrobials, with 5 (12.5%) being resistant to 14 antimicrobials. Amino acid substitutions in gyrase A (GyrA) were most frequently detected as Ser83Arg/Asp87Glu and in p53-associated Parkin-like cytoplasmic protein (ParC), they were all Ser80Arg; the quinolone resistance gene qnrS (47.5%) was commonly detected as well as aminoglycoside acetyltransferase [aac(6')-Ib; 25.0%], qnrA (17.5%), and qnrB (15.0%) genes. Thirty distinct pulsed-field gel electrophoresis patterns were identified among 40 isolates; no identical pulsed-field gel electrophoresis pattern was detected among Salmonella isolates with the same serovar that was recovered in 2010 and 2012. Our results suggest that dried milk-related infant foods could be contaminated with Salmonella and highlight that the dangers to infant health should not be neglected. C1 [Yang, B.; Zhao, H.; Wang, Y.; Xia, X.; Xi, M.; Wang, X.; Meng, J.; Ge, W.] Northwest A&F Univ, Coll Food Sci & Engn, Yangling 712100, Shaanxi, Peoples R China. [Cui, S.] Natl Inst Food & Drug Control, Beijing 100050, Peoples R China. [Meng, J.] Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 USA. [Meng, J.] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. RP Ge, W (reprint author), Northwest A&F Univ, Coll Food Sci & Engn, Yangling 712100, Shaanxi, Peoples R China. EM josephge@nwsuaf.edu.cn FU National Key Technology Research and Development Program of the Ministry of Science and Technology (Beijing, China) [2011BAD28B05]; National Key Spark Program of China [2013GA85003] FX This study was supported by the National Key Technology Research and Development Program of the Ministry of Science and Technology (Beijing, China; 2011BAD28B05) and the National Key Spark Program of China (2013GA85003). NR 27 TC 2 Z9 2 U1 4 U2 29 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-0302 EI 1525-3198 J9 J DAIRY SCI JI J. Dairy Sci. PD NOV PY 2014 VL 97 IS 11 BP 6754 EP 6760 DI 10.3168/jds.2014-8292 PG 7 WC Agriculture, Dairy & Animal Science; Food Science & Technology SC Agriculture; Food Science & Technology GA AQ8JN UT WOS:000343071900013 PM 25218754 ER PT J AU Donnelly, RP Sheikh, F Dickensheets, H Gamero, AM Vogel, SN AF Donnelly, Raymond P. Sheikh, Faruk Dickensheets, Harold Gamero, Ana M. Vogel, Stefanie N. TI An essential role for Interferon-beta in the induction of interferon-stimulated gene expression by lipopolysaccharide in macrophages SO CYTOKINE LA English DT Meeting Abstract CT 2nd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 26-29, 2014 CL Melbourne, AUSTRALIA SP Int Cytokine & Interferon Soc C1 [Donnelly, Raymond P.; Sheikh, Faruk; Dickensheets, Harold] US FDA, Div Therapeut Prot, Bethesda, MD 20014 USA. [Gamero, Ana M.] Temple Univ, Dept Biochem, Sch Med, Philadelphia, PA 19122 USA. [Vogel, Stefanie N.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 2014 VL 70 IS 1 MA 38 BP 37 EP 37 DI 10.1016/j.cyto.2014.07.045 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA AQ7TI UT WOS:000343021700068 ER PT J AU Sahu, SC Zheng, JW Graham, L Chen, L Ihrie, J Yourick, JJ Sprando, RL AF Sahu, Saura C. Zheng, Jiwen Graham, Lesley Chen, Lynn Ihrie, John Yourick, Jeffrey J. Sprando, Robert L. TI Comparative cytotoxicity of nanosilver in human liver HepG2 and colon Caco2 cells in culture SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE nanoparticles; nanosilver; silver nanoparticles; cytotoxicity; HepG2 cells; Caco2 cells; oxidative stress; mitochondrial injury ID HUMAN HEPATOMA-CELL; SILVER NANOPARTICLES; IN-VITRO; OXIDATIVE STRESS; RAT HEPATOCYTES; GENE-EXPRESSION; ALAMAR BLUE; MECHANISTIC ASSAYS; INDUCED APOPTOSIS; DRUG-METABOLISM AB The use of silver nanoparticles in food, food contact materials, dietary supplements and cosmetics has increased significantly owing to their antibacterial and antifungal properties. As a consequence, the need for validated rapid screening methods to assess their toxicity is necessary to ensure consumer safety. This study evaluated two widely used in vitro cell culture models, human liver HepG2 cells and human colon Caco2 cells, as tools for assessing the potential cytotoxicity of food- and cosmetic-related nanoparticles. The two cell culture models were utilized to compare the potential cytotoxicity of 20-nm silver. The average size of the silver nanoparticle determined by our transmission electron microscopy (TEM) analysis was 20.4nm. The dynamic light scattering (DLS) analysis showed no large agglomeration of the silver nanoparticles. The concentration of the 20-nm silver solution determined by our inductively coupled plasma-mass spectrometry (ICP-MS) analysis was 0.962mgml(-1). Our ICP-MS and TEM analysis demonstrated the uptake of 20-nm silver by both HepG2 and Caco2 cells. Cytotoxicity, determined by the Alamar Blue reduction assay, was evaluated in the nanosilver concentration range of 0.1 to 20 mu gml(-1). Significant concentration-dependent cytotoxicity of the nanosilver in HepG2 cells was observed in the concentration range of 1 to 20 mu gml(-1) and at a higher concentration range of 10 to 20 mu gml(-1) in Caco2 cells compared with the vehicle control. A concentration-dependent decrease in dsDNA content was observed in both cell types exposed to nanosilver but not controls, suggesting an increase in DNA damage. The DNA damage was observed in the concentration range of 1 to 20 mu gml(-1). Nanosilver-exposed HepG2 and Caco2 cells showed no cellular oxidative stress, determined by the dichlorofluorescein assay, compared with the vehicle control in the concentration range used in this study. A concentration-dependent decrease in mitochondria membrane potential in both nanosilver exposed cell types suggested increased mitochondria injury compared with the vehicle control. The mitochondrial injury in HepG2 cells was significant in the concentration range of 1 to 20 mu gml(-1), but in Caco2 cells it was significant at a higher concentration range of 10 to 20 mu gml(-1). These results indicated that HepG2 cells were more sensitive to nanosilver exposure than Caco2 cells. It is generally believed that cellular oxidative stress induces cytotoxicity of nanoparticles. However, in this study we did not detect any nanosilver-induced oxidative stress in either cell type at the concentration range used in this study. Our results suggest that cellular oxidative stress did not play a major role in the observed cytotoxicity of nanosilver in HepG2 and Caco2 cells and that a different mechanism of nanosilver-induced mitochondrial injury leads to the cytotoxicity. The HepG2 and Caco2 cells used this study appear to be targets for silver nanoparticles. The results of this study suggest that the differences in the mechanisms of toxicity induced by nanosilver may be largely as a consequence of the type of cells used. This differential rather than universal response of different cell types exposed to nanoparticles may play an important role in the mechanism of their toxicity. In summary, the results of this study indicate that the widely used in vitro models, HepG2 and Caco2 cells in culture, are excellent systems for screening cytotoxicity of silver nanoparticles. These long established cell culture models and simple assays used in this study can provide useful toxicity and mechanistic information that can help to better inform safety assessments of food- and cosmetic-related silver nanoparticles. Published 2014. 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.] US FDA, Div Toxicol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Zheng, Jiwen; Graham, Lesley] US FDA, Div Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Chen, Lynn] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [Ihrie, John] US FDA, Div Publ Hlth Informat & Analyt, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Sahu, SC (reprint author), US FDA, Div Toxicol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. EM saura.sahu@fda.hhs.gov NR 86 TC 33 Z9 35 U1 7 U2 75 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 NOV PY 2014 VL 34 IS 11 BP 1155 EP 1166 DI 10.1002/jat.2994 PG 12 WC Toxicology SC Toxicology GA AQ4GF UT WOS:000342750800005 PM 24522958 ER PT J AU Sahu, SC Roy, S Zheng, J Yourick, JJ Sprando, RL AF Sahu, Saura C. Roy, Shambhu Zheng, Jiwen Yourick, Jeffrey J. Sprando, Robert L. TI Comparative genotoxicity of nanosilver in human liver HepG2 and colon Caco2 cells evaluated by fluorescent microscopy of cytochalasin B-blocked micronucleus formation SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE nanoparticles; nanosilver; silver nanoparticles; genotoxicity; HepG2 cells; Caco2 cells; cytochalasin B-blocked micronucleus assay; in vitro micronucleus assay ID HUMAN HEPATOMA HEPG2; IN-VITRO; SILVER NANOPARTICLES; GENE-EXPRESSION; HUMAN HEPATOCYTES; DNA-DAMAGE; COBALT NANOPARTICLES; MECHANISTIC ASSAYS; OXIDATIVE STRESS; DRUG-METABOLISM AB As a consequence of the increased use of silver nanoparticles in food, food contact materials, dietary supplements and cosmetics to prevent fungal and bacterial growth, there is a need for validated rapid screening methods to assess the safety of nanoparticle exposure. This study evaluated two widely used in vitro cell culture models, human liver HepG2 cells and human colon Caco2 cells, as tools for assessing the potential genotoxicity of 20-nm nanosilver. The average silver nanoparticle size as determined by transmission electron microscopy (TEM) was 20.4 nm. Dynamic light scattering (DLS) analysis showed no large agglomeration of the silver nanoparticles. The silver concentration in a 20-nm nanosilver solution determined by the inductively coupled plasma-mass spectrometry (ICP-MS) analysis was 0.962 mg ml(-1). Analysis by ICP-MS and TEM demonstrated the uptake of 20-nm silver by both HepG2 and Caco2 cells. Genotoxicity was determined by the cytochalasin B-blocked micronucleus assay with acridine orange staining and fluorescence microscopy. Concentration- and time-dependent increases in the frequency of binucleated cells with micronuclei induced by the nanosilver was observed in the concentration range of 0.5 to 15 mu g ml(-1) in both HepG2 and Caco2 cells compared with the control. Our results indicated that HepG2 cells were more sensitive than Caco2 cells in terms of micronuclei formation induced by nanosilver exposure. In summary, the results of this study indicate that the widely used in vitro models, HepG2 and Caco2 cells in culture, represent potential screening models for prediction of genotoxicity of silver nanoparticles by in vitro micronucleus assay. Published 2014. 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.] US FDA, Div Toxicol, Off Appl Res & Safety Assessment Food Safety & Ap, Laurel, MD 20708 USA. [Zheng, Jiwen] US FDA, Ctr Devices & Radiol Hlth, Div Chem & Mat Sci, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Roy, Shambhu] Bioreliance Corp, Rockville, MD 20850 USA. RP Sahu, SC (reprint author), US FDA, Div Toxicol, Off Appl Res & Safety Assessment Food Safety & Ap, Laurel, MD 20708 USA. EM saura.sahu@fda.hhs.gov NR 82 TC 7 Z9 7 U1 2 U2 25 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 NOV PY 2014 VL 34 IS 11 BP 1200 EP 1208 DI 10.1002/jat.3028 PG 9 WC Toxicology SC Toxicology GA AQ4GF UT WOS:000342750800009 PM 24909674 ER PT J AU Sahu, SC Njoroge, J Bryce, SM Yourick, JJ Sprando, RL AF Sahu, Saura C. Njoroge, Joyce Bryce, Steven M. Yourick, Jeffrey J. Sprando, Robert L. TI Comparative genotoxicity of nanosilver in human liver HepG2 and colon Caco2 cells evaluated by a flow cytometric in vitro micronucleus assay SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE Nanoparticles; nanosilver; silver nanoparticles; genotoxicity; HepG2 cells; Caco2 cells; micronucleus; flow cytometry ID HUMAN HEPATOMA HEPG2; SILVER NANOPARTICLES; HUMAN HEPATOCYTES; GENE-EXPRESSION; DNA-DAMAGE; COBALT NANOPARTICLES; MECHANISTIC ASSAYS; OXIDATIVE STRESS; MAMMALIAN-CELLS; DRUG-METABOLISM AB Two widely used in vitro cell culture models, human liver HepG2 cells and human colon Caco2 cells, and flow cytometry techniques were evaluated as tools for rapid screening of potential genotoxicity of food-related nanosilver. Comparative genotoxic potential of 20nm silver was evaluated in HepG2 and Caco2 cell cultures by a flow cytometric-based in vitro micronucleus assay. The nanosilver, characterized by the dynamic light scattering, transmission electron microscopy and inductively coupled plasma-mass spectrometry analysis, showed no agglomeration of the silver nanoparticles. The inductively coupled plasma-mass spectrometry and transmission electron microscopy analysis demonstrated the uptake of 20nm silver by both cell types. The 20nm silver exposure of HepG2 cells increased the concentration-dependent micronucleus formation sevenfold at 10 mu gml(-1) concentration in attached cell conditions and 1.3-fold in cell suspension conditions compared to the vehicle controls. However, compared to the vehicle controls, the 20nm silver exposure of Caco2 cells increased the micronucleus formation 1.2-fold at a concentration of 10 mu gml(-1) both in the attached cell conditions as well as in the cell suspension conditions. Our results of flow cytometric in vitro micronucleus assay appear to suggest that the HepG2 cells are more susceptible to the nanosilver-induced micronucleus formation than the Caco2 cells compared to the vehicle controls. However, our results also suggest that the widely used in vitro models, HepG2 and Caco2 cells and the flow cytometric in vitro micronucleus assay are valuable tools for the rapid screening of genotoxic potential of nanosilver and deserve more careful evaluation. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Sahu, Saura C.; Njoroge, Joyce; Yourick, Jeffrey J.; Sprando, Robert L.] US FDA, Ctr Food Safety & Appl Nutr, Div Toxicol, Off Appl Res Safety Assessment, Laurel, MD 20708 USA. [Bryce, Steven M.] Litron Labs, Rochester, NY 14623 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 69 TC 12 Z9 12 U1 1 U2 21 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 NOV PY 2014 VL 34 IS 11 BP 1226 EP 1234 DI 10.1002/jat.3065 PG 9 WC Toxicology SC Toxicology GA AQ4GF UT WOS:000342750800012 PM 25224830 ER PT J AU Dobhal, S Zhang, GD Royer, T Damicone, J Ma, L AF Dobhal, Shefali Zhang, Guodong Royer, Tom Damicone, John Ma, Li Maria TI Survival and growth of foodborne pathogens in pesticide solutions routinely used in leafy green vegetables and tomato production SO JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE LA English DT Article DE Salmonella; Escherichia coli O157:H7; pesticide; foodborne pathogen; survival; growth ID ESCHERICHIA-COLI O157-H7; WATER; BACTERIA; PLANT AB BACKGROUND: The consumption of fresh produce has increased tremendously in the past few years as have outbreaks of foodborne illnesses associated with these commodities. Pesticides routinely used in crop production could influence the outcomes of foodborne pathogen contamination of fresh produce. Experiments were performed to determine the effects of pesticides on the survival and growth characteristics of Escherichia coli O157:H7 and Salmonella spp. Eight commercial fungicides and insecticides commonly used for disease and insect pest control on leafy green vegetables and tomatoes were evaluated. RESULTS: Among the pesticides tested, copper hydroxide, acetamiprid, cypermethrin and permethrin were found to be significantly (P < 0.05) inhibitory to pathogens while no effect was observed for chlorothalonil, flonicamid and methoxyfenozide. At the highest concentration tested (2.66%), azoxystrobin had a significant (P < 0.05) stimulatory effect on the growth of E. coli O157: H7 after 24 h incubation. The results indicated that some pesticides can stimulate the growth of human pathogens if contaminated water is used in their preparation, whereas others were likely to inhibit or reduce pathogen populations. CONCLUSION: This information is helpful in mitigating the risk of microbial contamination in fresh produce, which is critical to public health and safety. (C) 2014 Society of Chemical Industry C1 [Dobhal, Shefali; Ma, Li Maria] Oklahoma State Univ, Natl Inst Microbial Forens & Food & Agr Biosecur, Dept Entomol & Plant Pathol, Stillwater, OK 74078 USA. [Zhang, Guodong] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Royer, Tom; Damicone, John] Oklahoma State Univ, Dept Entomol & Plant Pathol, Stillwater, OK 74078 USA. RP Ma, L (reprint author), Oklahoma State Univ, Noble Res Ctr 127, Stillwater, OK 74078 USA. EM li.ma@okstate.edu OI Royer, Tom/0000-0003-0912-7115 FU Oklahoma Agricultural Experiment Station, Oklahoma State University FX This work was partially supported by the Oklahoma Agricultural Experiment Station, Oklahoma State University. The mention of trade names or commercial products in this publication does not imply recommendation or endorsement by Oklahoma State University. We thank Dr Astri Wayadande and Dr Trenna Blagden for reviewing the manuscript. We also thank the scientific writer Aaron Heifetz for editing the paper. NR 21 TC 0 Z9 0 U1 1 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-5142 EI 1097-0010 J9 J SCI FOOD AGR JI J. Sci. Food Agric. PD NOV PY 2014 VL 94 IS 14 BP 2958 EP 2964 DI 10.1002/jsfa.6640 PG 7 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA AQ5ET UT WOS:000342829800017 PM 24615509 ER PT J AU Franz, MR Gray, RA Karasik, P Moore, HJ Singh, SN AF Franz, Michael R. Gray, Richard A. Karasik, Pamela Moore, Hans J. Singh, Steven N. TI Drug-induced post-repolarization refractoriness as an antiarrhythmic principle and its underlying mechanism SO EUROPACE LA English DT Article DE Amiodarone; D-Sotalol; Action potential duration; Effective refractory period; Post-repolarization refractoriness; Monophasic action potential; Computer model of human action potential AB Aims We hypothesized that amiodarone (AM), unlike D-sotalol (DS) (a 'pure' Class III agent), not only prolongs the action potential duration (APD) but also causes post-repolarization refractoriness (PRR), thereby preventing premature excitation and providing superior antiarrhythmic efficacy. Methods and results We tested this hypothesis in 31 patients with inducible ventricular tachycardia (VT) during programmed stimulation with the use of the 'Franz' monophasic action potential (MAP) catheter with simultaneous pacing capability. We determined the effective refractory period (ERP) for each of three extrastimuli (S2-S4) and the corresponding MAP duration at 90% repolarization (APD90), both during baseline and on randomized therapy with either DS (n = 15) or AM (n = 16). We defined ERP > APD90 as PRR and ERP < APD90 as 'encroachment' on repolarization. A revised computer action potential model was developed to help explain the mechanisms of these in-vivo human-heart phenomena. Encroachment but not PRR was present in all patients at baseline and during DS treatment (NS vs. baseline), and VT was non-inducible in only 2 of 15 DS patients. In contrast, in 12 of 16 AM patients PRR was present (P < 0.001 vs. baseline), and VT was no longer inducible. Our model (with revised sodium channel kinetics) reproduced encroachment and drug-induced PRR. Conclusion Both, AM and DS, prolonged APD90 but only AM produced PRR and prevented encroachment of premature extrastimuli. Our computer simulations suggest that PRR is due to altered kinetics of the slow inactivation of the rapid sodium current. This may contribute to the high antiarrhythmic efficacy of AM. C1 [Franz, Michael R.; Karasik, Pamela; Moore, Hans J.; Singh, Steven N.] Vet Affairs Med Ctr, Div Cardiol, 50 Irving St NW, Washington, DC 20422 USA. [Franz, Michael R.; Singh, Steven N.] Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA. [Gray, Richard A.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Franz, MR (reprint author), Vet Affairs Med Ctr, Div Cardiol, 50 Irving St NW, Washington, DC 20422 USA.; Franz, MR (reprint author), Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA. EM michael.r.franz@verizon.net NR 36 TC 4 Z9 4 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1099-5129 EI 1532-2092 J9 EUROPACE JI Europace PD NOV PY 2014 VL 16 SU 4 BP 39 EP 45 DI 10.1093/europace/euu274 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V45PC UT WOS:000209827500006 PM 25362169 ER PT J AU Ko, HK Guo, LW Su, B Gao, LQ Gelman, IH AF Ko, Hyun-Kyung Guo, Li-wu Su, Bing Gao, Lingqiu Gelman, Irwin H. TI Suppression of Chemotaxis by SSeCKS via Scaffolding of Phosphoinositol Phosphates and the Recruitment of the Cdc42 GEF, Frabin, to the Leading Edge SO PLOS ONE LA English DT Article ID C-KINASE SUBSTRATE; PROTEIN-KINASE; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; CYTOSKELETAL ARCHITECTURE; ONCOGENIC TRANSFORMATION; MEMBRANE INTERACTIONS; ACTIN-CYTOSKELETON; PROSTATE-CANCER; PLASMA-MEMBRANE; CELL INVASION AB Chemotaxis is controlled by interactions between receptors, Rho-family GTPases, phosphatidylinositol 3-kinases, and cytoskeleton remodeling proteins. We investigated how the metastasis suppressor, SSeCKS, attenuates chemotaxis. Chemotaxis activity inversely correlated with SSeCKS levels in mouse embryo fibroblasts (MEF), DU145 and MDA-MB-231 cancer cells. SSeCKS loss induced chemotactic velocity and linear directionality, correlating with replacement of leading edge lamellipodia with fascin-enriched filopodia-like extensions, the formation of thickened longitudinal F-actin stress fibers reaching to filopodial tips, relative enrichments at the leading edge of phosphatidylinositol (3,4,5)P3 (PIP3), Akt, PKC-zeta, Cdc42-GTP and active Src (Src(poY416)), and a loss of Rac1. Leading edge lamellipodia and chemotaxis inhibition in SSeCKS-null MEF could be restored by full-length SSeCKS or SSeCKS deleted of its Src-binding domain (Delta Src), but not by SSeCKS deleted of its three MARCKS (myristylated alanine-rich C kinase substrate) polybasic domains (Delta PBD), which bind PIP2 and PIP3. The enrichment of activated Cdc42 in SSeCKS-null leading edge filopodia correlated with recruitment of the Cdc42-specific guanine nucleotide exchange factor, Frabin, likely recruited via multiple PIP2/3-binding domains. Frabin knockdown in SSeCKS-null MEF restores leading edge lamellipodia and chemotaxis inhibition. However, SSeCKS failed to co-immunoprecipitate with Rac1, Cdc42 or Frabin. Consistent with the notion that chemotaxis is controlled by SSeCKS-PIP (vs. -Src) scaffolding activity, constitutively-active phosphatidylinositol 3-kinase could override the ability of the Src inhibitor, SKI-606, to suppress chemotaxis and filopodial enrichment of Frabin in SSeCKS-null MEF. Our data suggest a role for SSeCKS in controlling Rac1 vs. Cdc42-induced cellular dynamics at the leading chemotactic edge through the scaffolding of phospholipids and signal mediators, and through the reorganization of the actin cytoskeleton controlling directional movement. C1 [Ko, Hyun-Kyung; Su, Bing; Gao, Lingqiu; Gelman, Irwin H.] Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. [Guo, Li-wu] Natl Ctr Toxicol Res, Div Genet & Reprod Toxicol, Jefferson, AR 72079 USA. RP Gelman, IH (reprint author), Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. EM Irwin.gelman@roswellpark.org FU National Cancer Institute [CA94108, CA116430]; Department of Defense grants [PC074228, PC101210]; National Cancer Institute Comprehensive Cancer Center [P30-CA016056] FX This work was funded by National Cancer Institute grants CA94108, CA116430, and Department of Defense grants PC074228, PC101210 to IHG, and in part, through National Cancer Institute Comprehensive Cancer Center funds (P30-CA016056). The funders had no direct role in study design, data collection and analysis, decision to publish, or preparation of of the manuscript. NR 65 TC 2 Z9 2 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 OCT 30 PY 2014 VL 9 IS 10 AR e111534 DI 10.1371/journal.pone.0111534 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AX2HU UT WOS:000346765000067 PM 25356636 ER PT J AU Fitzsimmons, SP Aydanian, AG Clark, KJ Shapiro, MA AF Fitzsimmons, Sean P. Aydanian, Antonina G. Clark, Kathleen J. Shapiro, Marjorie A. TI Multiple factors influence the contribution of individual immunoglobulin light chain genes to the naive antibody repertoire SO BMC IMMUNOLOGY LA English DT Article DE B lymphocytes; Antibodies; Generation of diversity; Receptor editing; Rodent; Tonic signaling ID B-CELL RECEPTOR; RECOMBINATION SIGNAL SEQUENCE; MOUSE BONE-MARROW; V-KAPPA EXONS; HISTONE ACETYLATION; V(D)J RECOMBINATION; PRE-B; VARIABLE-REGION; IGK LOCUS; TRANSCRIPTION AB Background: The naive antibody repertoire is initially dependent upon the number of germline V(D)J genes and the ability of recombined heavy and light chains to pair. Individual VH and VL genes are not equally represented in naive mature B cells, suggesting that positive and negative selection also shape the antibody repertoire. Among the three member murine V kappa 10 L chain family, the V kappa 10C. gene is under-represented in the antibody repertoire. Although it is structurally functional and accessible to both transcriptional and recombination machinery, the V kappa 10P promoter is inefficient in pre-B cell lines and productive V kappa 10C rearrangements are lost as development progresses from pre-B cells through mature B cells. This study examined VH/V kappa 10 pairing, promoter mutations, V kappa 10 transcript levels and receptor editing as possible factors that are responsible for loss of productive V kappa 10C rearrangements in developing B cells. Results: We demonstrate that the loss of V kappa 10C expression is not due to an inability to pair with H chains, but is likely due to a combination of other factors. Levels of mRNA are low in sorted pre-B cells and undetectable in B cells. Mutation of a single base in the three prime region of the V kappa 10C. promoter increases V kappa 10C promoter function in pre-B cell lines. Pre-B and B cells harbor disproportionate levels of receptor edited productive V kappa 10C rearrangements. Conclusions: Our findings suggest that the weak V kappa 10C promoter initially limits the amount of available V kappa 10C L chain for pairing with H chains, resulting in sub threshold levels of cell surface B cell receptors, insufficient tonic signaling and subsequent receptor editing to limit the numbers of V kappa 10P expressing B cells emigrating from the bone marrow to the periphery. C1 [Fitzsimmons, Sean P.; Aydanian, Antonina G.; Clark, Kathleen J.; Shapiro, Marjorie A.] FDA, CDER, OBP, Div Monoclonal Antibodies,Lab Mol & Dev Immunol, Silver Spring, MD 20993 USA. RP Shapiro, MA (reprint author), FDA, CDER, OBP, Div Monoclonal Antibodies,Lab Mol & Dev Immunol, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM marjorie.shapiro@fda.hhs.gov FU Center for Drug Research and Review, Food and Drug Administration FX The authors thank Howard Mostowski for pre-B cell sorting and Dr. Mate Tolnay and Frederick Is for cirtical review of this manuscript. This work was supported by the intramural Research Program of the Center for Drug Research and Review, Food and Drug Administration NR 62 TC 2 Z9 2 U1 2 U2 6 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 30 PY 2014 VL 15 AR 51 DI 10.1186/s12865-014-0051-2 PG 12 WC Immunology SC Immunology GA AX0XY UT WOS:000346674400001 PM 25359572 ER PT J AU Stone, MB AF Stone, Marc B. TI The FDA Warning on Antidepressants and Suicidality - Why the Controversy? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID DEPRESSION C1 US FDA, Silver Spring, MD 20993 USA. RP Stone, MB (reprint author), US FDA, Silver Spring, MD 20993 USA. NR 5 TC 8 Z9 10 U1 0 U2 6 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 30 PY 2014 VL 371 IS 18 BP 1668 EP 1671 DI 10.1056/NEJMp1411138 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA AR7OG UT WOS:000343768500004 PM 25354102 ER PT J AU Mosholder, AD Taylor, LG Crentsil, V AF Mosholder, Andrew D. Taylor, Lockwood G. Crentsil, Victor TI ANTIDEPRESSANT USE AND FDA WARNINGS Reservations about study on antidepressant use by young people and suicidal behaviour after FDA warnings SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Letter C1 [Mosholder, Andrew D.; Taylor, Lockwood G.] US FDA, Ctr Drug Evaluat & Res, Div Epidemiol, Silver Spring, MD 20993 USA. [Crentsil, Victor] US FDA, Ctr Drug Evaluat & Res, Div Psychiat Prod, Silver Spring, MD 20993 USA. RP Mosholder, AD (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Epidemiol, Silver Spring, MD 20993 USA. EM andrew.mosholder@fda.hhs.gov NR 9 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD OCT 29 PY 2014 VL 349 AR g6503 DI 10.1136/bmj.g6503 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AS3DG UT WOS:000344155800008 PM 25355684 ER PT J AU Georgakilas, AG Redon, CE Ferguson, NF Kryston, TB Parekh, P Dickey, JS Nakamura, AJ Mitchell, JB Bonner, WM Martin, OA AF Georgakilas, Alexandros G. Redon, Christophe E. Ferguson, Nicholas F. Kryston, Thomas B. Parekh, Palak Dickey, Jennifer S. Nakamura, Asako J. Mitchell, James B. Bonner, William M. Martin, Olga A. TI Systemic DNA damage accumulation under in vivo tumor growth can be inhibited by the antioxidant Tempol SO CANCER LETTERS LA English DT Article DE Tumor-bearing mice; DNA damage; Antioxidants; Tempol; Non-targeted effects ID DOUBLE-STRAND BREAKS; OXIDATIVE STRESS; CANCER-CELLS; GENOMIC INSTABILITY; HYDROGEN-PEROXIDE; BYSTANDER CELLS; INTERCELLULAR COMMUNICATION; IONIZING-RADIATION; IRRADIATION; LESIONS AB Recently we found that mice bearing subcutaneous non-metastatic tumors exhibited elevated levels of two types of complex DNA damage, i.e., double-strand breaks and oxidatively-induced clustered DNA lesions in various tissues throughout the body, both adjacent to and distant from the tumor site. This DNA damage was dependent on CCL2, a cytokine involved in the recruitment and activation of macrophages, suggesting that this systemic DNA damage was mediated via tumor-induced chronic inflammatory responses involving cytokines, activation of macrophages, and consequent free radical production. If free radicals are involved, then a diet containing an antioxidant may decrease the distant DNA damage. Here we repeated our standard protocol in cohorts of two syngeneic tumor-bearing C57BL/6NCr mice that were on a Tempol-supplemented diet. We show that double-strand break and oxidatively-induced clustered DNA lesion levels were considerably decreased, about two- to three fold, in the majority of tissues studied from the tumor-bearing mice fed the antioxidant Tempol compared to the control tumor-bearing mice. Similar results were also observed in nude mice suggesting that the Tempol effects are independent of functioning adaptive immunity. This is the first in vivo study demonstrating the effect of a dietary antioxidant on abscopal DNA damage in tissues distant from a localized source of genotoxic stress. These findings may be important for understanding the mechanisms of genomic instability and carcinogenesis caused by chronic stress-induced systemic DNA damage and for developing preventative strategies. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Georgakilas, Alexandros G.; Ferguson, Nicholas F.; Kryston, Thomas B.] E Carolina Univ, Thomas Harriot Coll Arts & Sci, Dept Biol, Greenville, NC 27858 USA. [Georgakilas, Alexandros G.] Natl Tech Univ Athens, Dept Phys, GR-15773 Athens, Greece. [Redon, Christophe E.; Parekh, Palak; Dickey, Jennifer S.; Nakamura, Asako J.; Bonner, William M.; Martin, Olga A.] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Dickey, Jennifer S.] US FDA, Off In Vitro Diagnost, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Nakamura, Asako J.] Ibaraki Univ, Dept Biol Sci, Fac Sci, Ibaraki 3108512, Japan. [Mitchell, James B.] NCI, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Martin, Olga A.] Peter MacCallum Canc Ctr, Div Radiat Oncol & Canc Imaging, Melbourne, Vic 3002, Australia. [Martin, Olga A.] Peter MacCallum Canc Ctr, Lab Mol Radiat Biol, Melbourne, Vic 3002, Australia. [Martin, Olga A.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3002, Australia. RP Martin, OA (reprint author), Peter MacCallum Canc Ctr, Dept Radiat Oncol & Canc Imaging, Melbourne, Vic 3002, Australia. EM olga.martin@petermac.org RI Parekh, Palak/B-7042-2015 OI Parekh, Palak/0000-0001-9201-5194 FU NIH Intramural Program; East Carolina University; EU [MC-CIG-303514]; COST Action [CM1201]; Hellenic National Strategic Reference Framework (NSRF) - Research Funding Program: THALES [MIS 37946]; O.M.'s Australian National Health and Medical Research Council (NHMRC) [1027558] FX We are grateful to the Laboratory Animal Sciences Program and Pathology Histotechnology Laboratory staff (National Cancer Institute Frederick) for the help with animal maintenance and histological analysis. We thank Roger Martin, Peter MacCallum Cancer Centre, for his advice and comments on the manuscript. This study was partly supported by the NIH Intramural Program, by A.G.'s funding from East Carolina University, EU grant MC-CIG-303514, COST Action CM1201 'Biomimetic Radical Chemistry', Hellenic National Strategic Reference Framework (NSRF) - Research Funding Program: THALES (Grant number MIS 37946), and by O.M.'s Australian National Health and Medical Research Council (NHMRC) grant number 1027558. NR 91 TC 6 Z9 6 U1 1 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD OCT 28 PY 2014 VL 353 IS 2 BP 248 EP 257 DI 10.1016/j.canlet.2014.07.030 PG 10 WC Oncology SC Oncology GA AQ5UT UT WOS:000342874800014 PM 25069035 ER PT J AU Schaer, DJ Vinchi, F Ingoglia, G Tolosano, E Buehler, PW AF Schaer, Dominik J. Vinchi, Francesca Ingoglia, Giada Tolosano, Emanuela Buehler, Paul W. TI Haptoglobin, hemopexin, and related defense pathways-basic science, clinical perspectives, and drug development SO FRONTIERS IN PHYSIOLOGY LA English DT Review DE hemolysis; haptoglobin; hemopexin; CD163; vascular diseases; transfusion; sickle cell disease ID SCAVENGER RECEPTOR CD163; CELL-FREE HEMOGLOBIN; LOW-DENSITY-LIPOPROTEIN; CARRIERS CURRENT STATUS; CYSTEINE-RICH FAMILY; BLOOD SUBSTITUTES; OXYGEN CARRIERS; GUINEA-PIGS; MACROPHAGE DIFFERENTIATION; EXTRACELLULAR HEMOGLOBIN AB Hemolysis, which occurs in many disease states, can trigger a diverse pathophysiologic cascade that is related to the specific biochemical activities of free Hb and its porphyrin component heme. Normal erythropoiesis and concomitant removal of senescent red blood cells (RBC) from the circulation occurs at rates of approximately 2 x 10(6) RBCs/second. Within this physiologic range of RBC turnover, a small fraction of hemoglobin (Hb) is released into plasma as free extracellular Hb. In humans, there is an efficient multicomponent system of Hb sequestration, oxidative neutralization and clearance. Haptoglobin (Hp) is the primary Hb-binding protein in human plasma, which attenuates the adverse biochemical and physiologic effects of extracellular Hb. The cellular receptor target of Hp is the monocyte/macrophage scavenger receptor, CD 163. Following Hb-Hp binding to CD163, cellular internalization of the complex leads to globin and heme metabolism, which is followed by adaptive changes in antioxidant and iron metabolism pathways and macrophage phenotype polarization. When Hb is released from RBCs within the physiologic range of Hp, the potential deleterious effects of Hb are prevented. However, during hyper-hemolytic conditions or with chronic hemolysis, Hp is depleted and Hb readily distributes to tissues where it might be exposed to oxidative conditions. In such conditions, heme can be released from ferric Hb. The free heme can then accelerate tissue damage by promoting peroxidative reactions and activation of inflammatory cascades. Hemopexin (Hx) is another plasma glycoprotein able to bind heme with high affinity. Hx sequesters heme in an inert, non-toxic form and transports it to the liver for catabolism and excretion. In the present review we discuss the components of physiologic Hb/heme detoxification and their potential therapeutic application in a wide range of hemolytic conditions. C1 [Schaer, Dominik J.] Univ Zurich, Div Internal Med, Zurich, Switzerland. [Vinchi, Francesca; Ingoglia, Giada; Tolosano, Emanuela] Univ Turin, Dept Mol Biotechnol & Hlth Sci, Turin, Italy. [Buehler, Paul W.] US FDA, Div Hematol, Lab Biochem & Vasc Biol, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Schaer, DJ (reprint author), Univ Zurich Hosp, Dept Internal Med, Ramistr 100, CH-8091 Zurich, Switzerland. EM dominik.schaer@usz.ch RI Tolosano, Emanuela/A-4684-2015; Vinchi, Francesca/K-4549-2016 OI Tolosano, Emanuela/0000-0002-1622-2340; Vinchi, Francesca/0000-0003-1631-8286 FU Swiss National Science Foundation [310030/120658, 31003A/138500]; University of Zurich Research Priority Program "Integrative Human Physiology"; Swiss Federal Commission for Technology and Innovation (CTI); FDA; Telethon Grant [GGP12082] FX This work was supported by the Swiss National Science Foundation (grants 310030/120658 and 31003A/138500), University of Zurich Research Priority Program "Integrative Human Physiology," Swiss Federal Commission for Technology and Innovation (CTI), FDA Internal Funding and the Telethon Grant GGP12082. NR 119 TC 31 Z9 32 U1 2 U2 8 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD OCT 28 PY 2014 VL 5 AR 415 DI 10.3389/fphys.2014.00415 PG 13 WC Physiology SC Physiology GA AX8TN UT WOS:000347181400002 PM 25389409 ER PT J AU Chen, HC Zou, W Lu, TP Chen, JJ AF Chen, Hung-Chia Zou, Wen Lu, Tzu-Pin Chen, James J. TI A Composite Model for Subgroup Identification and Prediction via Bicluster Analysis SO PLOS ONE LA English DT Article ID FIELD GEL-ELECTROPHORESIS; HIGH-DIMENSIONAL DATA; SINGULAR-VALUE DECOMPOSITION; GENE-EXPRESSION DATA; ACUTE LYMPHOBLASTIC-LEUKEMIA; SALMONELLA-SEROTYPES; CLUSTER-ANALYSIS; MICROARRAY DATA; CLASSIFICATION; PATTERNS AB Background: A major challenges in the analysis of large and complex biomedical data is to develop an approach for 1) identifying distinct subgroups in the sampled populations, 2) characterizing their relationships among subgroups, and 3) developing a prediction model to classify subgroup memberships of new samples by finding a set of predictors. Each subgroup can represent different pathogen serotypes of microorganisms, different tumor subtypes in cancer patients, or different genetic makeups of patients related to treatment response. Methods: This paper proposes a composite model for subgroup identification and prediction using biclusters. A biclustering technique is first used to identify a set of biclusters from the sampled data. For each bicluster, a subgroup-specific binary classifier is built to determine if a particular sample is either inside or outside the bicluster. A composite model, which consists of all binary classifiers, is constructed to classify samples into several disjoint subgroups. The proposed composite model neither depends on any specific biclustering algorithm or patterns of biclusters, nor on any classification algorithms. Results: The composite model was shown to have an overall accuracy of 97.4% for a synthetic dataset consisting of four subgroups. The model was applied to two datasets where the sample's subgroup memberships were known. The procedure showed 83.7% accuracy in discriminating lung cancer adenocarcinoma and squamous carcinoma subtypes, and was able to identify 5 serotypes and several subtypes with about 94% accuracy in a pathogen dataset. Conclusion: The composite model presents a novel approach to developing a biclustering-based classification model from unlabeled sampled data. The proposed approach combines unsupervised biclustering and supervised classification techniques to classify samples into disjoint subgroups based on their associated attributes, such as genotypic factors, phenotypic outcomes, efficacy/safety measures, or responses to treatments. The procedure is useful for identification of unknown species or new biomarkers for targeted therapy. C1 [Chen, Hung-Chia; Zou, Wen; Lu, Tzu-Pin; Chen, James J.] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Chen, Hung-Chia; Chen, James J.] China Med Univ, Grad Inst Biostat, Taichung, Taiwan. [Chen, Hung-Chia; Chen, James J.] China Med Univ, Ctr Biostat, Taichung, Taiwan. [Lu, Tzu-Pin] Natl Taiwan Univ, Grad Inst Epidemiol & Prevent Med, Dept Publ Hlth, Taipei 10764, Taiwan. RP Chen, JJ (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. EM jamesj.chen@fda.hhs.gov OI LU, TZU-PIN/0000-0003-3697-0386 FU USDOE; USFDA FX The research by Hung-Chia and Tzu-Pin was supported by the Post-doctoral Fellowship Program at the NCTR administered by the Oak Ridge Institute for Science and Education through an interagency agreement between USDOE and USFDA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 0 Z9 0 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 OCT 27 PY 2014 VL 9 IS 10 AR e111318 DI 10.1371/journal.pone.0111318 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AZ1JF UT WOS:000347994900060 PM 25347824 ER PT J AU Wang, J Chow, W Chang, J Wong, JW AF Wang, Jian Chow, Willis Chang, James Wong, Jon W. TI Ultrahigh-Performance Liquid Chromatography Electrospray Ionization Q-Orbitrap Mass Spectrometry for the Analysis of 451 Pesticide Residues in Fruits and Vegetables: Method Development and Validation SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE UHPLC/ESI Q-Orbitrap; high-resolution mass spectrometer; pesticides; fruits and vegetables; quantification; identification; measurement uncertainty ID EXTRACTION; DRUGS; MS/MS; MS AB This paper presents an application of ultrahigh-performance liquid chromatography electrospray ionization quadrupole Orbitrap high-resolution mass spectrometry (UHPLC/ESI Q-Orbitrap MS) for the determination of 451 pesticide residues in fruits and vegetables. Pesticides were extracted from samples using the QuEChERS (quick, easy, cheap, effective, rugged, and safe) procedure. UHPLC/ESI Q-Orbitrap MS in full MS scan mode acquired full MS data for quantification, and UHPLC/ESI Q-Orbitrap Full MS/dd-MS2 (i.e., data-dependent scan mode) obtained product ion spectra for identification. UHPLC/ESI Q-Orbitrap MS quantification was achieved using matrix-matched standard calibration curves along with the use of isotopically labeled standards or a chemical analogue as internal standards to achieve optimal method accuracy. The method performance characteristics include overall recovery, intermediate precision, and measurement uncertainty evaluated according to a nested experimental design. For the 10 matrices studied, 94.5% of the pesticides in fruits and 90.7% in vegetables had recoveries between 81 and 110%; 99.3% of the pesticides in fruits and 99.1% of the pesticides in vegetables had an intermediate precision of <= 20%; and 97.8% of the pesticides in fruits and 96.4% of the pesticides in vegetables showed measurement uncertainty of <= 50%. Overall, the UHPLC/ESI Q-Orbitrap MS demonstrated acceptable performance for the quantification of pesticide residues in fruits and vegetables. The UHPLC/ESI Q-Orbitrap Full MS/dd-MS2 along with library matching showed great potential for identification and is being investigated further for routine practice. C1 [Wang, Jian; Chow, Willis] Canadian Food Inspect Agcy, Calgary Lab, Calgary, AB T2L 2L1, Canada. [Chang, James] ThermoFisher Sci, San Jose, CA 95134 USA. [Wong, Jon W.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Wang, J (reprint author), Canadian Food Inspect Agcy, Calgary Lab, 3650-36th St NW, Calgary, AB T2L 2L1, Canada. EM jian.wang@inspection.gc.ca NR 17 TC 20 Z9 20 U1 1 U2 28 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 OCT 22 PY 2014 VL 62 IS 42 BP 10375 EP 10391 DI 10.1021/jf503778c PG 17 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA AR6HU UT WOS:000343685700020 PM 25265038 ER PT J AU Ng, HW Zhang, WQ Shu, M Luo, H Ge, WG Perkins, R Tong, WD Hong, HX AF Ng, Hui Wen Zhang, Wenqian Shu, Mao Luo, Heng Ge, Weigong Perkins, Roger Tong, Weida Hong, Huixiao TI Competitive molecular docking approach for predicting estrogen receptor subtype alpha agonists and antagonists SO BMC BIOINFORMATICS LA English DT Article; Proceedings Paper CT 11th Annual Conference of the MidSouth-Computational-Biology-and-Bioinformatics-Society (MCBIOS) CY MAR 06-08, 2014 CL Oklahoma State Univ, Stillwater, OH SP MidSouth Computat Biol & Bioinformat Soc HO Oklahoma State Univ ID ENDOCRINE-DISRUPTING CHEMICALS; LIGAND-BINDING DOMAIN; ANDROGEN RECEPTOR; ENVIRONMENTAL CHEMICALS; DIETHYLSTILBESTROL DES; STRUCTURAL BASIS; BREAST-CANCER; BISPHENOL-A; PROTEIN; SYSTEM AB Background: Endocrine disrupting chemicals (EDCs) are exogenous compounds that interfere with the endocrine system of vertebrates, often through direct or indirect interactions with nuclear receptor proteins. Estrogen receptors (ERs) are particularly important protein targets and many EDCs are ER binders, capable of altering normal homeostatic transcription and signaling pathways. An estrogenic xenobiotic can bind ER as either an agonist or antagonist to increase or inhibit transcription, respectively. The receptor conformations in the complexes of ER bound with agonists and antagonists are different and dependent on interactions with co-regulator proteins that vary across tissue type. Assessment of chemical endocrine disruption potential depends not only on binding affinity to ERs, but also on changes that may alter the receptor conformation and its ability to subsequently bind DNA response elements and initiate transcription. Using both agonist and antagonist conformations of the ER alpha, we developed an in silico approach that can be used to differentiate agonist versus antagonist status of potential binders. Methods: The approach combined separate molecular docking models for ER agonist and antagonist conformations. The ability of this approach to differentiate agonists and antagonists was first evaluated using true agonists and antagonists extracted from the crystal structures available in the protein data bank (PDB), and then further validated using a larger set of ligands from the literature. The usefulness of the approach was demonstrated with enrichment analysis in data sets with a large number of decoy ligands. Results: The performance of individual agonist and antagonist docking models was found comparable to similar models in the literature. When combined in a competitive docking approach, they provided the ability to discriminate agonists from antagonists with good accuracy, as well as the ability to efficiently select true agonists and antagonists from decoys during enrichment analysis. Conclusion: This approach enables evaluation of potential ER biological function changes caused by chemicals bound to the receptor which, in turn, allows the assessment of a chemical's endocrine disrupting potential. The approach can be used not only by regulatory authorities to perform risk assessments on potential EDCs but also by the industry in drug discovery projects to screen for potential agonists and antagonists. C1 [Ng, Hui Wen; Zhang, Wenqian; Shu, Mao; Ge, Weigong; Perkins, Roger; Tong, Weida; Hong, Huixiao] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Luo, Heng] Univ Arkansas, Little Rock Univ Arkansas, Med Sci Bioinformat Grad Program, Little Rock, AR 72204 USA. RP Hong, HX (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. EM 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 [P20GM103429] NR 69 TC 14 Z9 14 U1 3 U2 10 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 OCT 21 PY 2014 VL 15 SU 11 AR S4 DI 10.1186/1471-2105-15-S11-S4 PG 15 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA AU6AN UT WOS:000345684600005 PM 25349983 ER PT J AU Zhang, WQ Meehan, J Su, ZQ Ng, HW Shu, M Luo, H Ge, WG Perkins, R Tong, WD Hong, HX AF Zhang, Wenqian Meehan, Joe Su, Zhenqiang Ng, Hui Wen Shu, Mao Luo, Heng Ge, Weigong Perkins, Roger Tong, Weida Hong, Huixiao TI Whole genome sequencing of 35 individuals provides insights into the genetic architecture of Korean population SO BMC BIOINFORMATICS LA English DT Article; Proceedings Paper CT 11th Annual Conference of the MidSouth-Computational-Biology-and-Bioinformatics-Society (MCBIOS) CY MAR 06-08, 2014 CL Oklahoma State Univ, Stillwater, OH SP MidSouth Computat Biol & Bioinformat Soc HO Oklahoma State Univ ID SHORT READ ALIGNMENT; MUTATION SPECTRUM; RARE VARIANTS; COMMON; MAP; CONSEQUENCES; WEBGESTALT; PROJECT; IMPACT; DNA AB Background: Due to a significant decline in the costs associated with next-generation sequencing, it has become possible to decipher the genetic architecture of a population by sequencing a large number of individuals to a deep coverage. The Korean Personal Genomes Project (KPGP) recently sequenced 35 Korean genomes at high coverage using the Illumina Hiseq platform and made the deep sequencing data publicly available, providing the scientific community opportunities to decipher the genetic architecture of the Korean population. Methods: In this study, we used two single nucleotide variant (SNV) calling pipelines: mapping the raw reads obtained from whole genome sequencing of 35 Korean individuals in KPGP using BWA and SOAP2 followed by SNV calling using SAMtools and SOAPsnp, respectively. The consensus SNVs obtained from the two SNV pipelines were used to represent the SNVs of the Korean population. We compared these SNVs to those from 17 other populations provided by the HapMap consortium and the 1000 Genomes Project (1KGP) and identified SNVs that were only present in the Korean population. We studied the mutation spectrum and analyzed the genes of nonsynonymous SNVs only detected in the Korean population. Results: We detected a total of 8,555,726 SNVs in the 35 Korean individuals and identified 1,213,613 SNVs detected in at least one Korean individual (SNV-1) and 12,640 in all of 35 Korean individuals (SNV-35) but not in 17 other populations. In contrast with the SNVs common to other populations in HapMap and 1KGP, the Korean only SNVs had high percentages of non-silent variants, emphasizing the unique roles of these Korean only SNVs in the Korean population. Specifically, we identified 8,361 non-synonymous Korean only SNVs, of which 58 SNVs existed in all 35 Korean individuals. The 5,754 genes of non-synonymous Korean only SNVs were highly enriched in some metabolic pathways. We found adhesion is the top disease term associated with SNV-1 and Nelson syndrome is the only disease term associated with SNV-35. We found that a significant number of Korean only SNVs are in genes that are associated with the drug term of adenosine. Conclusion: We identified the SNVs that were found in the Korean population but not seen in other populations, and explored the corresponding genes and pathways as well as the associated disease terms and drug terms. The results expand our knowledge of the genetic architecture of the Korean population, which will benefit the implementation of personalized medicine for the Korean population. C1 [Zhang, Wenqian; Meehan, Joe; Su, Zhenqiang; Ng, Hui Wen; Shu, Mao; Ge, Weigong; Perkins, Roger; Tong, Weida; Hong, Huixiao] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Luo, Heng] Univ Arkansas, Med Sci Bioinformat Grad Program, Little Rock, AR 72204 USA. RP Hong, HX (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, 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 FU NCRR NIH HHS [P20RR016460]; NIGMS NIH HHS [P20GM103429] NR 42 TC 7 Z9 7 U1 2 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 OCT 21 PY 2014 VL 15 SU 11 AR S6 DI 10.1186/1471-2105-15-S11-S6 PG 13 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA AU6AN UT WOS:000345684600007 PM 25350283 ER PT J AU Zhao, WZ Zou, W Chen, JJ AF Zhao, Weizhong Zou, Wen Chen, James J. TI Topic modeling for cluster analysis of large biological and medical datasets SO BMC BIOINFORMATICS LA English DT Article; Proceedings Paper CT 11th Annual Conference of the MidSouth-Computational-Biology-and-Bioinformatics-Society (MCBIOS) CY MAR 06-08, 2014 CL Oklahoma State Univ, Stillwater, OH SP MidSouth Computat Biol & Bioinformat Soc HO Oklahoma State Univ ID GENE-EXPRESSION; PREDICTION; CANCER AB Background: The big data moniker is nowhere better deserved than to describe the ever-increasing prodigiousness and complexity of biological and medical datasets. New methods are needed to generate and test hypotheses, foster biological interpretation, and build validated predictors. Although multivariate techniques such as cluster analysis may allow researchers to identify groups, or clusters, of related variables, the accuracies and effectiveness of traditional clustering methods diminish for large and hyper dimensional datasets. Topic modeling is an active research field in machine learning and has been mainly used as an analytical tool to structure large textual corpora for data mining. Its ability to reduce high dimensionality to a small number of latent variables makes it suitable as a means for clustering or overcoming clustering difficulties in large biological and medical datasets. Results: In this study, three topic model-derived clustering methods, highest probable topic assignment, feature selection and feature extraction, are proposed and tested on the cluster analysis of three large datasets: Salmonella pulsed-field gel electrophoresis (PFGE) dataset, lung cancer dataset, and breast cancer dataset, which represent various types of large biological or medical datasets. All three various methods are shown to improve the efficacy/effectiveness of clustering results on the three datasets in comparison to traditional methods. A preferable cluster analysis method emerged for each of the three datasets on the basis of replicating known biological truths. Conclusion: Topic modeling could be advantageously applied to the large datasets of biological or medical research. The three proposed topic model-derived clustering methods, highest probable topic assignment, feature selection and feature extraction, yield clustering improvements for the three different data types. Clusters more efficaciously represent truthful groupings and subgroupings in the data than traditional methods, suggesting that topic model-based methods could provide an analytic advancement in the analysis of large biological or medical datasets. C1 [Zhao, Weizhong; Zou, Wen; Chen, James J.] 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; jamesj.chen@fda.hhs.gov NR 34 TC 4 Z9 4 U1 6 U2 22 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 OCT 21 PY 2014 VL 15 SU 11 AR S11 DI 10.1186/1471-2105-15-S11-S11 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA AU6AN UT WOS:000345684600012 PM 25350106 ER PT J AU Shamsaddini, A Pan, Y Johnson, WE Krampis, K Shcheglovitova, M Simonyan, V Zanne, A Mazumder, R AF Shamsaddini, Amirhossein Pan, Yang Johnson, W. Evan Krampis, Konstantinos Shcheglovitova, Mariya Simonyan, Vahan Zanne, Amy Mazumder, Raja TI Census-based rapid and accurate metagenome taxonomic profiling SO BMC GENOMICS LA English DT Article DE Metagenome; Census-based; Next-gen sequence analysis; Taxonomic profiling; Diagnostics ID INFLAMMATORY-BOWEL-DISEASE; MICROBIAL COMMUNITY; GUT MICROBIOME; READ ALIGNMENT; GENOMES; CHALLENGES; DIVERSITY; SEQUENCES; BACTERIAL; CLASSIFICATION AB Background: Understanding the taxonomic composition of a sample, whether from patient, food or environment, is important to several types of studies including pathogen diagnostics, epidemiological studies, biodiversity analysis and food quality regulation. With the decreasing costs of sequencing, metagenomic data is quickly becoming the preferred typed of data for such analysis. Results: Rapidly defining the taxonomic composition (both taxonomic profile and relative frequency) in a metagenomic sequence dataset is challenging because the task of mapping millions of sequence reads from a metagenomic study to a non-redundant nucleotide database such as the NCBI non-redundant nucleotide database (nt) is a computationally intensive task. We have developed a robust subsampling-based algorithm implemented in a tool called CensuScope meant to take a 'sneak peak' into the population distribution and estimate taxonomic composition as if a census was taken of the metagenomic landscape. CensuScope is a rapid and accurate metagenome taxonomic profiling tool that randomly extracts a small number of reads (based on user input) and maps them to NCBI's nt database. This process is repeated multiple times to ascertain the taxonomic composition that is found in majority of the iterations, thereby providing a robust estimate of the population and measures of the accuracy for the results. Conclusion: CensuScope can be run on a laptop or on a high-performance computer. Based on our analysis we are able to provide some recommendations in terms of the number of sequence reads to analyze and the number of iterations to use. For example, to quantify taxonomic groups present in the sample at a level of 1% or higher a subsampling size of 250 random reads with 50 iterations yields a statistical power of >99%. Windows and UNIX versions of CensuScope are available for download at https://hive.biochemistry.gwu.edu/dna.cgi?cmd=censuscope. CensuScope is also available through the High-performance Integrated Virtual Environment (HIVE) and can be used in conjunction with other HIVE analysis and visualization tools. C1 [Shamsaddini, Amirhossein; Pan, Yang; Mazumder, Raja] George Washington Univ, Dept Biochem & Mol Med, Washington, DC 20037 USA. [Johnson, W. Evan] Boston Univ, Sch Med, Dept Med, Div Computat Biomed, Boston, MA 02118 USA. [Krampis, Konstantinos] J Craig Venter Inst, Bioinformat Dept, Rockville, MD 20850 USA. [Shcheglovitova, Mariya; Zanne, Amy] George Washington Univ, Dept Biol Sci, Washington, DC 20052 USA. [Simonyan, Vahan] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Zanne, Amy] Missouri Bot Garden, Ctr Conservat & Sustainable Dev, St Louis, MO 63166 USA. [Mazumder, Raja] George Washington Univ, McCormick Genom & Prote Ctr, Washington, DC 20037 USA. RP Mazumder, R (reprint author), George Washington Univ, Dept Biochem & Mol Med, Washington, DC 20037 USA. EM mazumder@gwu.edu OI Pan, Yang/0000-0003-3487-7233 NR 62 TC 5 Z9 5 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 21 PY 2014 VL 15 AR 918 DI 10.1186/1471-2164-15-918 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AT4CJ UT WOS:000344886500001 PM 25336203 ER PT J AU Saa, P Yakovleva, O de Castro, J Vasilyeva, I De Paoli, SH Simak, J Cervenakova, L AF Saa, Paula Yakovleva, Oksana de Castro, Jorge Vasilyeva, Irina De Paoli, Silvia H. Simak, Jan Cervenakova, Larisa TI First Demonstration of Transmissible Spongiform Encephalopathy-associated Prion Protein (PrPTSE) in Extracellular Vesicles from Plasma of Mice Infected with Mouse-adapted Variant Creutzfeldt-Jakob Disease by in Vitro Amplification SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MISFOLDING CYCLIC AMPLIFICATION; CHRONIC WASTING DISEASE; MESENCHYMAL STEM-CELLS; NEURODEGENERATIVE DISEASES; SELECTIVE EXTERNALIZATION; TRANSFERRIN RECEPTOR; NEUROBLASTOMA-CELLS; CEREBROSPINAL-FLUID; PROTEOMIC ANALYSIS; ENDOTHELIAL-CELLS AB The development of variant Creutzfeldt-Jakob disease (vCJD) in three recipients of non-leukoreduced red blood cells from asymptomatic donors who subsequently developed the disease has confirmed existing concerns about the possible spread of transmissible spongiform encephalopathies (TSEs) via blood products. In addition, the presence of disease-associated misfolded prion protein (PrPTSE), generally associated with infectivity, has been demonstrated in the blood of vCJD patients. However, its origin and distribution in this biological fluid are still unknown. Various studies have identified cellular prion protein (PrPC) among the protein cargo in human blood-circulating extracellular vesicles released from endothelial cells and platelets, and exosomes isolated from the conditioned media of TSE-infected cells have caused the disease when injected into experimental mice. In this study, we demonstrate the detection of PrPTSE in extracellular vesicles isolated from plasma samples collected during the preclinical and clinical phases of the disease from mice infected with mouse-adapted vCJD and confirm the presence of the exosomal marker Hsp70 in these preparations. C1 [Saa, Paula; Yakovleva, Oksana; de Castro, Jorge; Vasilyeva, Irina; Cervenakova, Larisa] Amer Natl Red Cross, Holland Lab, Biomed Serv, Transmissible Dis Dept, Rockville, MD 20855 USA. [De Paoli, Silvia H.; Simak, Jan] US FDA, Lab Cellular Hematol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Saa, P (reprint author), Amer Natl Red Cross, Holland Lab, Biomed Serv, Transmissible Dis Dept, 15601 Crabbs Branch Way, Rockville, MD 20855 USA. EM Paula.Saa@redcross.org OI Saa, Paula/0000-0001-6077-4532 FU American National Red Cross; Fondation Alliance BioSecure FX This study was supported by research funding from the American National Red Cross (to L. C.) and the Fondation Alliance BioSecure (to P. S.). NR 95 TC 11 Z9 11 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 17 PY 2014 VL 289 IS 42 BP 29247 EP 29260 DI 10.1074/jbc.M114.589564 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AS2XZ UT WOS:000344141000039 PM 25157106 ER PT J AU Viswanathan, P Iarikov, D Wassel, R Davidson, A Nambiar, S AF Viswanathan, Prabha Iarikov, Dmitri Wassel, Ronald Davidson, Alma Nambiar, Sumathi TI Hypoglycemia in Patients Treated With Linezolid SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE adverse reactions; hypoglycemia; linezolid AB Hypoglycemia was not previously known to be a linezolid-associated adverse reaction. A case report describing symptomatic hypoglycemia in a linezolid recipient prompted a review of the US Food and Drug Administration Adverse Event Reporting System, which demonstrated a relationship between linezolid and hypoglycemia. A warning with this information was added to the linezolid package insert. C1 [Viswanathan, Prabha; Iarikov, Dmitri; Wassel, Ronald; Davidson, Alma; Nambiar, Sumathi] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Viswanathan, P (reprint author), US FDA, Off Antimicrobial Prod, Ctr Drug Evaluat & Res, WO 22 Rm 6237,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM prabha.viswanathan@fda.hhs.gov FU International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) FX The Medical Dictionary for Regulatory Activities (MedDRA) terminology is the international medical terminology developed under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). MedDRA is owned by the International Federation of Pharmaceutical Manufacturers & Associations on behalf of ICH. NR 3 TC 1 Z9 1 U1 3 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 OCT 15 PY 2014 VL 59 IS 8 BP E93 EP E95 DI 10.1093/cid/ciu487 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AR2KG UT WOS:000343413200001 PM 24965346 ER PT J AU Pettengill, JB Luo, Y Davis, S Chen, Y Gonzalez-Escalona, N Ottesen, A Rand, H Allard, M Strain, E AF Pettengill, James B. Luo, Yan Davis, Steven Chen, Yi Gonzalez-Escalona, Narjol Ottesen, Andrea Rand, Hugh Allard, Marcw. Strain, Errol TI An evaluation of alternative methods for constructing phylogenies from whole genome sequence data: a case study with Salmonella SO PEERJ LA English DT Article DE Salmonella; Outbreak; Congruence; Phylogenetics; Next generation sequencing; Single nucleotide polymorphism ID READ ALIGNMENT; COPY NUMBER; OUTBREAK; ALGORITHMS; STRAIN; GAUGE; TREES AB Comparative genomics based on whole genome sequencing (WGS) is increasingly being applied to investigate questions within evolutionary and molecular biology, as well as questions concerning public health (e.g., pathogen outbreaks). Given the impact that conclusions derived from such analyses may have, we have evaluated the robustness of clustering individuals based on WGS data to three key factors: (1) next-generation sequencing (NGS) platform (HiSeq, MiSeq, IonTorrent, 454, and SOLiD), (2) algorithms used to construct a SNP (single nucleotide polymorphism) matrix (reference-based and reference-free), and (3) phylogenetic inference method (FastTreeMP, GARLI, and RAxML). We carried out these analyses on 194 whole genome sequences representing 107 unique Salmonella enterica subsp. enterica ser. Montevideo strains. Reference-based approaches for identifying SNPs produced trees that were significantly more similar to one another than those produced under the reference-free approach. Topologies inferred using a core matrix (i.e., no missing data) were significantly more discordant than those inferred using a non-core matrix that allows for some missing data. However, allowing for too much missing data likely results in a high false discovery rate of SNPs. When analyzing the same SNP matrix, we observed that the more thorough inference methods implemented in GARLI and RAxML produced more similar topologies than FastTreeMP. Our results also confirm that reproducibility varies among NGS platforms where the MiSeq had the lowest number of pairwise differences among replicate runs. Our investigation into the robustness of clustering patterns illustrates the importance of carefully considering how data from different platforms are combined and analyzed. We found clear differences in the topologies inferred, and certain methods performed significantly better than others for discriminating between the highly clonal organisms investigated here. The methods supported by our results represent a preliminary set of guidelines and a step towards developing validated standards for clustering based on whole genome sequence data. C1 [Pettengill, James B.; Luo, Yan; Davis, Steven; Chen, Yi; Gonzalez-Escalona, Narjol; Ottesen, Andrea; Rand, Hugh; Allard, Marcw.; Strain, Errol] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Strain, E (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM Errol.Strain@fda.hhs.gov OI Gonzalez-Escalona, Narjol/0000-0003-4568-0022 FU Center for Food Safety and Applied Nutrition at the US Food and Drug Administration FX This work was supported by the Center for Food Safety and Applied Nutrition at the US 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 52 TC 16 Z9 16 U1 1 U2 11 PU PEERJ INC PI LONDON PA 341-345 OLD ST, THIRD FLR, LONDON, EC1V 9LL, ENGLAND SN 2167-8359 J9 PEERJ JI PeerJ PD OCT 14 PY 2014 VL 2 AR e620 DI 10.7717/peerj.620 PG 26 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AY5PD UT WOS:000347623500003 PM 25332847 ER PT J AU Pan, Y Karagiannis, K Zhang, HC Dingerdissen, H Shamsaddini, A Wan, Q Simonyan, V Mazumder, R AF Pan, Yang Karagiannis, Konstantinos Zhang, Haichen Dingerdissen, Hayley Shamsaddini, Amirhossein Wan, Quan Simonyan, Vahan Mazumder, Raja TI Human germline and pan-cancer variomes and their distinct functional profiles SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PROTEIN POSTTRANSLATIONAL MODIFICATIONS; N-TERMINAL ACETYLATION; SINGLE-NUCLEOTIDE POLYMORPHISM; DNA-DAMAGE RESPONSE; S-NITROSYLATION; PHOSPHORYLATION SITES; SIGNAL-TRANSDUCTION; TUMOR TYPES; MUTATIONAL LANDSCAPE; HISTONE METHYLATION AB Identification of non-synonymous single nucleotide variations (nsSNVs) has exponentially increased due to advances in Next-Generation Sequencing technologies. The functional impacts of these variations have been difficult to ascertain because the corresponding knowledge about sequence functional sites is quite fragmented. It is clear that mapping of variations to sequence functional features can help us better understand the pathophysiological role of variations. In this study, we investigated the effect of nsSNVs on more than 17 common types of post-translational modification (PTM) sites, active sites and binding sites. Out of 1 705 285 distinct nsSNVs on 259 216 functional sites we identified 38 549 variations that significantly affect 10 major functional sites. Furthermore, we found distinct patterns of site disruptions due to germline and somatic nsSNVs. Pan-cancer analysis across 12 different cancer types led to the identification of 51 genes with 106 nsSNV affected functional sites found in 3 or more cancer types. 13 of the 51 genes overlap with previously identified Significantly Mutated Genes (Nature. 2013 Oct 17;502(7471)). 62 mutations in these 13 genes affecting functional sites such as DNA, ATP binding and various PTM sites occur across several cancers and can be prioritized for additional validation and investigations. C1 [Pan, Yang; Karagiannis, Konstantinos; Zhang, Haichen; Dingerdissen, Hayley; Shamsaddini, Amirhossein; Wan, Quan; Mazumder, Raja] George Washington Univ, Med Ctr, Dept Biochem & Mol Med, Washington, DC 20037 USA. [Simonyan, Vahan] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Mazumder, Raja] George Washington Univ, McCormick Genom & Prote Ctr, Washington, DC 20037 USA. RP Mazumder, R (reprint author), George Washington Univ, Med Ctr, Dept Biochem & Mol Med, Washington, DC 20037 USA. EM mazumder@gwu.edu OI Pan, Yang/0000-0003-3487-7233 FU National Cancer Institute/NIH; [156620] FX EDRN Associate Member, agreement #156620. National Cancer Institute/NIH. NR 141 TC 5 Z9 5 U1 0 U2 7 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 OCT 13 PY 2014 VL 42 IS 18 BP 11570 EP 11588 DI 10.1093/nar/gku772 PG 19 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AY6PC UT WOS:000347687100032 PM 25232094 ER PT J AU Sheng-Fowler, L Tu, W Fu, HQ Murata, H Lanning, L Foseh, G Macauley, J Blair, D Hughes, SH Coffin, JM Lewis, AM Peden, K AF Sheng-Fowler, Li Tu, Wei Fu, Haiqing Murata, Haruhiko Lanning, Lynda Foseh, Gideon Macauley, Juliete Blair, Donald Hughes, Stephen H. Coffin, John M. Lewis, Andrew M., Jr. Peden, Keith TI A Mouse Strain Defective in Both T Cells and NK Cells Has Enhanced Sensitivity to Tumor Induction by Plasmid DNA Expressing Both Activated H-Ras and c-Myc SO PLOS ONE LA English DT Article ID BLADDER-CARCINOMA CELLS; TRANSFORMING GENE; IN-VIVO; TUMORIGENIC CONVERSION; PAPILLOMAVIRUS DNA; POLYOMA-VIRUS; LINES; CANCER; MICE; ONCOGENES AB As part of safety studies to evaluate the risk of residual cellular DNA in vaccines manufactured in tumorigenic cells, we have been developing in vivo assays to detect and quantify the oncogenic activity of DNA. We generated a plasmid expressing both an activated human H-ras gene and murine c-myc gene and showed that 1 mu g of this plasmid, pMSV-T24-H-ras/MSV-c-myc, was capable of inducing tumors in newborn NIH Swiss mice. However, to be able to detect the oncogenicity of dominant activated oncogenes in cellular DNA, a more sensitive system was needed. In this paper, we demonstrate that the newborn CD3 epsilon transgenic mouse, which is defective in both T-cell and NK-cell functions, can detect the oncogenic activity of 25 ng of the circular form of pMSV-T24-H-ras/MSV-c-myc. When this plasmid was inoculated as linear DNA, amounts of DNA as low as 800 pg were capable of inducing tumors. Animals were found that had multiple tumors, and these tumors were independent and likely clonal. These results demonstrate that the newborn CD3 epsilon mouse is highly sensitive for the detection of oncogenic activity of DNA. To determine whether it can detect the oncogenic activity of cellular DNA derived from four human tumor-cell lines (HeLa, A549, HT-1080, and CEM), DNA (100 mu g) was inoculated into newborn CD3 epsilon mice both in the presence of 1 mu g of linear pMSV-T24-H-ras/MSV-c-myc as positive control and in its absence. While tumors were induced in 100% of mice with the positive-control plasmid, no tumors were induced in mice receiving any of the tumor DNAs alone. These results demonstrate that detection of oncogenes in cellular DNA derived from four human tumor-derived cell lines in this mouse system was not possible; the results also show the importance of including a positive-control plasmid to detect inhibitory effects of the cellular DNA. C1 [Sheng-Fowler, Li; Tu, Wei; Fu, Haiqing; Murata, Haruhiko; Foseh, Gideon; Macauley, Juliete; Lewis, Andrew M., Jr.; Peden, Keith] US FDA, Off Vaccines Res & Review, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Lanning, Lynda] Natl Inst Allergy & Infect Dis, Rockville, MD USA. [Blair, Donald] Natl Canc Inst, Rockville, MD USA. [Hughes, Stephen H.; Coffin, John M.] Natl Canc Inst, Frederick Canc Res Facil, Frederick, MD USA. [Coffin, John M.] Tufts Univ, Boston, MA 02111 USA. RP Peden, K (reprint author), US FDA, Off Vaccines Res & Review, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM keith.peden@fda.hhs.gov FU Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases; CBER/FDA [YI-AI-4893-02NIAID]; National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research; NCI, NIH [HHSN26120080001E] FX This work was supported by a contract from the Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases through an Interagency Agreement with CBER/FDA (contract number YI-AI-4893-02NIAID), program officer Sonnie Kim-Grossman. SHH is supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research, and in part with funds from the NCI, NIH, under contract HHSN26120080001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 0 Z9 0 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 10 PY 2014 VL 9 IS 10 AR e108926 DI 10.1371/journal.pone.0108926 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR6ZS UT WOS:000343730400036 PM 25302710 ER PT J AU Jones, CM Paulozzi, LJ Mack, KA AF Jones, Christopher M. Paulozzi, Leonard J. Mack, Karin A. TI Alcohol Involvement in Opioid Pain Reliever and Benzodiazepine Drug Abuse-Related Emergency Department Visits and Drug-Related Deaths - United States, 2010 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Jones, Christopher M.] US FDA, Off Publ Hlth Strategy & Anal, Off Commissioner, Rockville, MD 20857 USA. [Paulozzi, Leonard J.] 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. RP Jones, CM (reprint author), US FDA, Off Publ Hlth Strategy & Anal, Off Commissioner, Rockville, MD 20857 USA. EM christopher.m.jones@fda.hhs.gov NR 9 TC 23 Z9 23 U1 0 U2 5 PU CENTER DISEASE CONTROL & PREVENTION PI ATLANTA PA MAILSTOP E-90, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD OCT 10 PY 2014 VL 63 IS 40 BP 881 EP 885 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AQ6WX UT WOS:000342955700001 PM 25299603 ER PT J AU Boretti, FS Baek, JH Palmer, AF Schaer, DJ Buehler, PW AF Boretti, Felicitas S. Baek, Jin Hyen Palmer, Andre F. Schaer, Dominik J. Buehler, Paul W. TI Modeling hemoglobin and hennoglobin:haptoglobin complex clearance in a non-rodent species- pharrnacokinetic and therapeutic implications SO FRONTIERS IN PHYSIOLOGY LA English DT Article DE macrophage uptake; hemoglobin; haptoglobin; non-rodent; pharmacokinetic modeling ID SCAVENGER RECEPTOR; GUINEA-PIGS; EXTRACELLULAR HEMOGLOBIN; ANTIOXIDANT CAPACITY; HAPTOGLOBIN; MACROPHAGES; CD163; DIFFERENTIATION; PHENOTYPE; PROTEINS AB Background: Haptoglobin (Hp) prevents hemoglobin (Hb) extravasation and attenuates Hb induced tissue oxidation and vasoconstriction. Small animal models such as mouse, rat and guinea pig appear to demonstrate proof-of-concept for Hb neutralization by Hp in diverse pre-clinical conditions. However, these species differ significantly from humans in the clearance of Hb:Hp and demonstrate long persistence of circulating Hb:Hp complexes. Objective: The focus of this study is to understand Hb:Hp clearance in a non-rodent species. In contrast to rodents, dogs maintain high plasma Hp concentrations comparable to humans and demonstrate more rapid clearance of Hb:Hp when compared to rodent species, therefore dogs may represent a relevant species to evaluate Hb:Hp pharmacokinetics and cellular clearance. Results: In this study we show, that like human macrophages, dog peripheral blood monocyte derived macrophages express a glucocorticoid inducible endocytic clearance pathways with a high specificity for the Hb:Hp complex. Evaluating the Beagle dog as a non-rodent model species we provide the first pharmacokinetic parameter estimates of free Hb and Hb:Hp complexes. The data demonstrate a significantly reduced volume of distribution (Vc) for Hb:Hp compared to free Hb, increased maximum plasma concentrations and areas under plasma concentration time curves (Cmax and AUC). Significantly reduced total body clearance (CL) and a longer terminal half-life (t112) of approximately 12 h were also observed for the Hb:Hp complex. Distribution and clearance were identical for dimeric and multimeric Hb:Hp complexes. We found no significant effect of a high-dose glucocorticoid treatment protocol on Hb:Hp pharmacokinetic parameter estimates. Conclusion: Collectively, our study supports the dog as a non-rodent animal model to study pharmacological and pharmacokinetic aspects of Hb clearance systems and apply the model to studying Hp as a therapeutic in diseases of hemolysis. C1 [Boretti, Felicitas S.] Univ Zurich, Sch Vet Med, Div Vet Internal Med, Zurich, Switzerland. [Baek, Jin Hyen; Buehler, Paul W.] US FDA, Lab Biochem & Vasc Biol, Ctr Biol Evaluat & Res, Bethesda, MD 20850 USA. [Palmer, Andre F.] Ohio State Univ, Columbus, OH 43210 USA. [Schaer, Dominik J.] Univ Zurich, Univ Zurich Hosp, Div Internal Med, Zurich, Switzerland. RP Buehler, PW (reprint author), US FDA, Lab Biochem & Vasc Biol, Dept Hematol Res & Review, Ctr Biol Evaluat & Res, 29 Lincoln Dr, Bethesda, MD 20850 USA. EM paul.buehler@fda.hhs.gov FU FDA; Swiss National Science Foundation [310030/120658, 31003A/138500]; University of Zurich Research Priority Program "Integrative Human Physiology"; Swiss Federal Commission for Technology and Innovation (CTI) FX We would like to thank Joan Dalton and her research group, Bio Products Laboratory as well as Nathan Brinkman and his research group, CSL Behring for their efforts in the preparation of human plasma purified haptoglobins. This study was funded by FDA internal funding to Paul W. Buehler and by the Swiss National Science Foundation (grants 310030/120658 and 31003A/138500 to Dominik J. Schaer), the University of Zurich Research Priority Program "Integrative Human Physiology" and the Swiss Federal Commission for Technology and Innovation (CTI). NR 31 TC 8 Z9 8 U1 0 U2 1 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD OCT 9 PY 2014 VL 5 AR 385 DI 10.3389/fphys.2014.00385 PG 11 WC Physiology SC Physiology GA AX7UB UT WOS:000347119000001 PM 25346694 ER PT J AU Kurtz, SL Chou, AY Kubelkova, K Cua, DJ Elkins, KL AF Kurtz, Sherry L. Chou, Alicia Y. Kubelkova, Klara Cua, Daniel J. Elkins, Karen L. TI IL-23 p19 Knockout Mice Exhibit Minimal Defects in Responses to Primary and Secondary Infection with Francisella tularensis LVS SO PLOS ONE LA English DT Article ID LIVE VACCINE STRAIN; T-CELL RESPONSES; MYCOBACTERIUM-TUBERCULOSIS INFECTION; ADAPTIVE IMMUNITY; IL-12 P70; AUTOIMMUNE INFLAMMATION; INTRACELLULAR BACTERIUM; GAMMA-INTERFERON; P40 HOMODIMER; HOST-DEFENSE AB Our laboratory's investigations into mechanisms of protective immunity against Francisella tularensis Live Vaccine Strain (LVS) have uncovered mediators important in host defense against primary infection, as well as those correlated with successful vaccination. One such potential correlate was IL-12p40, a pleiotropic cytokine that promotes Th1 T cell function as part of IL-12p70. LVS-infected IL-12p40 deficient knockout (KO) mice maintain a chronic infection, but IL-12p35 KO mice clear LVS infection; thus the role that IL-12p40 plays in immunity to LVS is independent of the IL-12p70 heterodimer. IL-12p40 can also partner with IL-23p19 to create the heterodimeric cytokine IL-23. Here, we directly tested the role of IL-23 in LVS resistance, and found IL-23 to be largely dispensable for immunity to LVS following intradermal or intranasal infection. IL-23p19 KO splenocytes were fully competent in controlling intramacrophage LVS replication in an in vitro overlay assay. Further, antibody responses in IL-23p19 KO mice were similar to those of normal wild type mice after LVS infection. IL-23p19 KO mice or normal wild type mice that survived primary LVS infection survived maximal doses of LVS secondary challenge. Thus p40 has a novel role in clearance of LVS infection that is unrelated to either IL-12 or IL-23. C1 [Kurtz, Sherry L.; Chou, Alicia Y.; Kubelkova, Klara; Elkins, Karen L.] US FDA, Ctr Biol Evaluat & Res, Div Bacterial Parasit & Allergen Prod, Lab Mycobacterial Dis & Cellular Immunol, Rockville, MD 20857 USA. [Cua, Daniel J.] Merck Res Labs, Palo Alto, CA USA. RP Elkins, KL (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Bacterial Parasit & Allergen Prod, Lab Mycobacterial Dis & Cellular Immunol, Rockville, MD 20857 USA. EM Karen.elkins@fda.hhs.gov FU CBER/U.S. FDA; Ministry of Defence of the Czech Republic via Health Problems of Weapons of Mass Destruction [1011] FX This study was funded by CBER/U.S. FDA; Klara Kubelkova was supported by the Ministry of Defence of the Czech Republic via a grant entitled Health Problems of Weapons of Mass Destruction (long-term organization development plan 1011). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 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 8 PY 2014 VL 9 IS 10 AR e109898 DI 10.1371/journal.pone.0109898 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT8TE UT WOS:000345204000101 PM 25296161 ER PT J AU Parsons, LM Mizanur, RM Jankowska, E Hodgkin, J O'Rourke, D Stroud, D Ghosh, S Cipollo, JF AF Parsons, Lisa M. Mizanur, Rahman M. Jankowska, Ewa Hodgkin, Jonathan O'Rourke, Delia Stroud, Dave Ghosh, Salil Cipollo, John F. TI Caenorhabditis elegans Bacterial Pathogen Resistant bus-4 Mutants Produce Altered Mucins SO PLOS ONE LA English DT Article ID CHROMATOGRAPHY MASS-SPECTROMETRY; MICROBACTERIUM-NEMATOPHILUM; O-GLYCANS; C-ELEGANS; GENES; BINDING; IDENTIFICATION; GLYCOPROTEINS; ATTACHMENT; DIVERSITY AB Caenorabditis elegans bus-4 glycosyltransferase mutants are resistant to infection by Microbacterium nematophilum, Yersinia pestis and Yersinia pseudotuberculosis and have altered susceptibility to two Leucobacter species Verde1 and Verde2. Our objective in this study was to define the glycosylation changes leading to this phenotype to better understand how these changes lead to pathogen resistance. We performed MALDI-TOF MS, tandem MS and GC/MS experiments to reveal fine structural detail for the bus-4 N- and O-glycan pools. We observed dramatic changes in O-glycans and moderate ones in N-glycan pools compared to the parent strain. Ce core-I glycans, the nematode's mucin glycan equivalent, were doubled in abundance, halved in charge and bore shifts in terminal substitutions. The fucosyl O-glycans, Ce core-II and neutral fucosyl forms, were also increased in abundance as were fucosyl N-glycans. Quantitative expression analysis revealed that two mucins, let-653 and osm-8, were upregulated nearly 40 fold and also revealed was a dramatic increase in GDP-Man 4,6 dehydratease expression. We performed detailed lectin binding studies that showed changes in glycoconjugates in the surface coat, cuticle surface and intestine. The combined changes in cell surface glycoconjugate distribution, increased abundance and altered properties of mucin provide an environment where likely the above pathogens are not exposed to normal glycoconjugate dependent cues leading to barriers to these bacterial infections. C1 [Parsons, Lisa M.; Mizanur, Rahman M.; Jankowska, Ewa; Ghosh, Salil; Cipollo, John F.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Hodgkin, Jonathan; O'Rourke, Delia; Stroud, Dave] Univ Oxford, Dept Biochem, Genet Unit, Oxford OX1 3QU, England. RP Cipollo, JF (reprint author), US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM John.Cipollo@fda.hhs.gov FU Oak Ridge Institute for Scientific Education (ORISE); Center for Biologics Evaluation and Research (CBER) of the Food and Drug Administration (FDA); Medical Research Council UK [G0600238] FX This work has been supported in part by Oak Ridge Institute for Scientific Education (ORISE), and the Center for Biologics Evaluation and Research (CBER) of the Food and Drug Administration (FDA). The work from JH is supported by Medical Research Council UK, Grant G0600238. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 3 Z9 3 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 OCT 8 PY 2014 VL 9 IS 10 AR e107250 DI 10.1371/journal.pone.0107250 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT8TE UT WOS:000345204000004 PM 25296196 ER PT J AU Safo, MK Musayev, FN Mosier, PD Zhou, QB Xie, H Desai, UR AF Safo, Martin K. Musayev, Faik N. Mosier, Philip D. Zhou, Qibing Xie, Hang Desai, Umesh R. TI Crystal Structures of Influenza A Virus Matrix Protein M1: Variations on a Theme SO PLOS ONE LA English DT Article ID NUCLEAR-LOCALIZATION SIGNAL; LOW PH; ELECTRON-MICROSCOPY; NS2 PROTEIN; MEMBRANE; RIBONUCLEOPROTEINS; BINDING; EXPORT; TRANSPORT; DOMAIN AB Matrix protein 1 (M1) of the influenza A virus plays multiple roles in virion assembly and infection. Interest in the pH dependence of M1's multiple functions led us to study the effect of subtle pH changes on M1 structure, resulting in the elucidation of a unique low-pH crystal structure of the N1-165-domain of A/WSN/33 (H1N1) M1 that has never been reported. Although the 2.2 angstrom crystal structure of M1 N-terminus shows a dimer with the two monomers interacting in a face-to-face fashion at low pH as observed earlier, a 44 degrees rotation of the second monomer has led to a significantly different dimer interface that possibly affects dimer stability. More importantly, while one of the monomers is fully defined, the N-terminal half of the second monomer shows considerable disorder that appears inherent in the protein and is potentially physiologically relevant. Such disorder has not been observed in any other previously reported structure at either low or high pH conditions, despite similar crystallization pH conditions. By comparing our novel N1-165-domain structure with other low-pH or neutral-pH M1 structures, it appears that M1 can energetically access different monomer and dimer conformations, as well as oligomeric states, with varying degree of similarities. The study reported here provides further insights into M1 oligomerization that may be essential for viral propagation and infectivity. C1 [Safo, Martin K.; Musayev, Faik N.; Mosier, Philip D.; Desai, Umesh R.] Virginia Commonwealth Univ, Dept Med Chem, Sch Pharm, Richmond, VA 23298 USA. [Safo, Martin K.; Musayev, Faik N.; Mosier, Philip D.; Desai, Umesh R.] Virginia Commonwealth Univ, Inst Struct Biol & Drug Discovery, Richmond, VA 23298 USA. [Zhou, Qibing] Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Inst Mat Med, Wuhan, Hubei, Peoples R China. [Xie, Hang] US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Safo, MK (reprint author), Virginia Commonwealth Univ, Dept Med Chem, Sch Pharm, Richmond, VA 23298 USA. EM msafo@vcu.edu; Hang.Xie@fda.hhs.gov FU National Institutes of Health [P01 HL107152, CA16059] FX URD acknowledges the research support provided by grant P01 HL107152 from the National Institutes of Health. Structural biology resources were provided in part by National Institutes of Health grant CA16059 to the VCU Massey Cancer Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 8 Z9 9 U1 1 U2 19 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 8 PY 2014 VL 9 IS 10 AR e109510 DI 10.1371/journal.pone.0109510 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT8TE UT WOS:000345204000075 PM 25295515 ER PT J AU Rouse, R Zhang, LS Shea, K Zhou, HF Xu, L Stewart, S Rosenzweig, B Zhang, J AF Rouse, Rodney Zhang, Leshuai Shea, Katherine Zhou, Hongfei Xu, Lin Stewart, Sharron Rosenzweig, Barry Zhang, Jun TI Extended Exenatide Administration Enhances Lipid Metabolism and Exacerbates Pancreatic Injury in Mice on a High Fat, High Carbohydrate Diet SO PLOS ONE LA English DT Article ID CELL-SPECIFIC TRANSCRIPTION; PEPTIDE-1 RECEPTOR AGONIST; NUCLEAR FACTOR 3-BETA; ACINAR-CELLS; OXIDATIVE STRESS; PDX-1 GENE; BETA; RATS; ACTIVATION; EXENDIN-4 AB This study expanded upon a previous study in mice reporting a link between exenatide treatment and exocrine pancreatic injury by demonstrating temporal and dose responses and providing an initial mechanistic hypothesis. The design of the present study included varying lengths of exenatide exposure (3, 6 weeks to 12 weeks) at multiple concentrations (3, 10, or 30 mu g/kg) with multiple endpoints (histopathology evaluations, immunoassay for cytokines, immunostaining of the pancreas, serum chemistries and measurement of trypsin, amylase, and, lipase, and gene expression profiles). Time- and dose-dependent exocrine pancreatic injury was observed in mice on a high fat diet treated with exenatide. The morphological changes identified in the pancreas involved acinar cell injury and death (autophagy, apoptosis, necrosis, and atrophy), cell adaptations (hypertrophy and hyperplasia), and cell survival (proliferation/regeneration) accompanied by varying degrees of inflammatory response leading to secondary injury in pancreatic blood vessels, ducts, and adipose tissues. Gene expression profiles indicated increased signaling for cell survival and altered lipid metabolism in exenatide treated mice. Immunohistochemistry supported gene expression findings that exenatide caused and/or exacerbated pancreatic injury in a high fat diet environment potentially by further increasing high fat diet exacerbated lipid metabolism and resulting oxidative stress. Further investigation is required to confirm these findings and determine their relevance to human disease. C1 [Rouse, Rodney; Zhang, Leshuai; Shea, Katherine; Zhou, Hongfei; Xu, Lin; Stewart, Sharron; Rosenzweig, Barry; Zhang, Jun] US FDA, Div Appl Regulatory Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Rouse, R (reprint author), US FDA, Div Appl Regulatory Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM rodney.rouse@fda.hhs.gov RI Zhang, Leshuai/C-8077-2012 FU U.S. Food and Drug Administration FX All funding originated from U.S. congressional appropriation to fund the U.S. 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 44 TC 2 Z9 2 U1 1 U2 7 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 2014 VL 9 IS 10 AR e109477 DI 10.1371/journal.pone.0109477 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ4VK UT WOS:000342798000064 PM 25291183 ER PT J AU Wang, CC Xia, QS Li, M Wang, SG Zhao, YW Tolleson, WH Yin, JJ Fu, PP AF Wang, Chia-Chi Xia, Qingsu Li, Meng Wang, Shuguang Zhao, Yuewei Tolleson, William H. Yin, Jun-Jie Fu, Peter P. TI Metabolic Activation of Pyrrolizidine Alkaloids Leading to Phototoxicity and Photogenotoxicity in Human HaCaT Keratinocytes SO JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH PART C-ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS LA English DT Review DE human HaCaT keratinocytes; lipid peroxidation; reactive oxygen species; photoirradiation; UVA light; dehydropyrrolizidine alkaloids ID DNA ADDUCT FORMATION; DIETARY-SUPPLEMENTS; LIPID-PEROXIDATION; HUMAN LIVER; IN-VIVO; MEDICINAL-PLANTS; SINGLET OXYGEN; FREE-RADICALS; UVA; LASIOCARPINE AB Pyrrolizidine alkaloids, produced by a large number of poisonous plants with wide global distribution, are associated with genotoxicity, tumorigenicity, and hepatotoxicity in animals and humans. Mammalian metabolism converts pyrrolizidine alkaloids to reactive pyrrolic metabolites (dehydropyrrolizidine alkaloids) that form covalent protein and DNA adducts. Although a mechanistic understanding is currently unclear, pyrrolizidine alkaloids can cause secondary (hepatogenous) photosensitization and induce skin cancer. In this study, the phototoxicity of monocrotaline, riddelliine, dehydromonocrotaline, dehydroriddelliine, and dehydroretronecine (DHR) in human HaCaT keratinocytes under ultraviolet A (UVA) irradiation was determined. UVA irradiation of HaCaT cells treated with dehydromonocrotaline, dehydroriddelline, and DHR resulted in increased release of lactate dehydrogenase and enhanced photocytotoxicity proportional to the UVA doses. UVA-induced photochemical DNA damage also increased proportionally with dehydromonocrotaline and dehydroriddelline. UVA treatment potentiated the formation of 8-hydroxy-2 '-deoxyguanosine DNA adducts induced by dehydromonocrotaline in HaCaT skin keratinocytes. Using electron spin resistance trapping, we found that UVA irradiation of dehydromonocrotaline and dehydroriddelliine generates reactive oxygen species (ROS), including hydroxyl radical, singlet oxygen, and superoxide, and electron transfer reactions, indicating that cytotoxicity and genotoxicity of these compounds could be mediated by ROS. Our results suggest that dehydropyrrolizidine alkaloids formed or delivered to the skin cause pyrrolizidine alkaloid-induced secondary photosensitization and possible skin cancer. C1 [Wang, Chia-Chi; Xia, Qingsu; Wang, Shuguang; Zhao, Yuewei; Tolleson, William H.; Fu, Peter P.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Wang, Chia-Chi] Kaohsiung Med Univ, Sch Pharm, Kaohsiung, Taiwan. [Li, Meng; Yin, Jun-Jie] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 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 FU Postgraduate Research Program at the NCTR FX This research was supported in part by appointment (Y. Zhao; S. Wang) to the Postgraduate Research Program at the NCTR administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA. This article is not an official US Food and Drug Administration (FDA) guidance or policy statement. No official support or endorsement by the US FDA is intended or should be inferred. NR 52 TC 5 Z9 5 U1 3 U2 13 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 2014 VL 32 IS 4 BP 362 EP 384 DI 10.1080/10590501.2014.969980 PG 23 WC Oncology; Environmental Sciences; Toxicology SC Oncology; Environmental Sciences & Ecology; Toxicology GA AU3GY UT WOS:000345501600003 PM 25436474 ER PT J AU Zhao, YQ Zalkikar, J Tiwari, RC LaVange, LM AF Zhao, Yueqin Zalkikar, Jyoti Tiwari, Ram C. LaVange, Lisa M. TI A Bayesian Approach for Benefit-Risk Assessment SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Global measures; MCMC technique; Power prior; Dirichlet distribution ID CLINICAL-TRIALS; MODEL AB An important aspect of the drug evaluation process is to have an integrated benefit-risk assessment to determine, using some quantitative measures, whether the benefit outweighs the risk for the target population. Chuang-Stein etal. proposed a five-category random variable along with three global measures of benefit-risk assessment. Assuming the cell probabilities follow a multinomial distribution, we propose a Bayesian approach for the longitudinal assessment of benefit-risk using these three global measures and a new measure. A Dirichlet distribution is used as the natural conjugate prior for multinomial cell probabilities, and the posterior distributions of cell-probabilities are recursively derived as the data from multiple visits become available. In a more generalized approach, a power prior is used through the likelihood function to discount the information from previous visits, and, again, the posterior distributions of the cell-probabilities at multiple visits are derived. The estimates of the posterior means and credible intervals for the four global measures are derived, and the decision rules based on the credible intervals are applied for the assessment of the four global measures. Using two simulated datasets generated under two different scenarios-one where benefit outweighs risk and the other where benefit does not outweigh risk-the performances of the four measures are evaluated using a Markov chain Monte Carlo (MCMC) technique. We illustrate of the methodology using clinical trial data. C1 [Zhao, Yueqin] US FDA, Off Commissioner, Silver Spring, MD 20993 USA. [Zalkikar, Jyoti] US FDA, Div Biometr 5, Off Biostat, OTS,CDER, Silver Spring, MD 20993 USA. [Tiwari, Ram C.; LaVange, Lisa M.] US FDA, Off Biostat, OTS, CDER, Silver Spring, MD 20993 USA. RP Zhao, YQ (reprint author), US FDA, Off Commissioner, Silver Spring, MD 20993 USA. EM Yue-qin.Zhao@fda.hhs.gov; Jyoti.Zalkikar@fda.hhs.gov; Ram.Tiwari@fda.hhs.gov; Lisa.LaVange@fda.hhs.gov NR 22 TC 3 Z9 3 U1 0 U2 1 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PD OCT 2 PY 2014 VL 6 IS 4 BP 326 EP 337 DI 10.1080/19466315.2014.965845 PG 12 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA AU3IB UT WOS:000345504700004 ER PT J AU De Feo, CJ Wang, W Hsieh, ML Zhuang, M Vassell, R Weiss, CD AF De Feo, Christopher J. Wang, Wei Hsieh, Meng-Lun Zhuang, Min Vassell, Russell Weiss, Carol D. TI Resistance to N-peptide fusion inhibitors correlates with thermodynamic stability of the gp41 six-helix bundle but not HIV entry kinetics SO RETROVIROLOGY LA English DT Article DE gp41; Fusion; Entry kinetics; Peptide fusion inhibitor; HIV entry; Resistance ID IMMUNODEFICIENCY-VIRUS TYPE-1; TERMINAL HEPTAD REPEAT; ENFUVIRTIDE RESISTANCE; ENVELOPE GLYCOPROTEIN; COILED-COIL; POTENT INHIBITORS; CROSS-RESISTANCE; MEMBRANE-FUSION; HELICAL DOMAIN; BASE-LINE AB Background: The HIV-1 envelope glycoprotein (Env) undergoes conformational changes that mediate fusion between virus and host cell membranes. These changes involve transient exposure of two heptad-repeat domains (HR1 and HR2) in the gp41 subunit and their subsequent self-assembly into a six-helix bundle (6HB) that drives fusion. Env residues and features that influence conformational changes and the rate of virus entry, however, are poorly understood. Peptides corresponding to HR1 and HR2 (N and C peptides, respectively) interrupt formation of the 6HB by binding to the heptad repeats of a fusion-intermediate conformation of Env, making the peptides valuable probes for studying Env conformational changes. Results: Using a panel of Envs that are resistant to N-peptide fusion inhibitors, we investigated relationships between virus entry kinetics, 6HB stability, and resistance to peptide fusion inhibitors to elucidate how HR1 and HR2 mutations affect Env conformational changes and virus entry. We found that gp41 resistance mutations increased 6HB stability without increasing entry kinetics. Similarly, we show that increased 6HB thermodynamic stability does not correlate with increased entry kinetics. Thus, N-peptide fusion inhibitors do not necessarily select for Envs with faster entry kinetics, nor does faster entry kinetics predict decreased potency of peptide fusion inhibitors. Conclusions: These findings provide new insights into the relationship between 6HB stability and viral entry kinetics and mechanisms of resistance to inhibitors targeting fusion-intermediate conformations of Env. These studies further highlight how residues in HR1 and HR2 can influence virus entry by altering stability of the 6HB and possibly other conformations of Env that affect rate-limiting steps in HIV entry. C1 [De Feo, Christopher J.; Wang, Wei; Hsieh, Meng-Lun; Zhuang, Min; Vassell, Russell; Weiss, Carol D.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Weiss, CD (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM carol.weiss@fda.hhs.gov FU U.S. Food and Drug Administration; Intramural AIDS Targeted Antiviral Program from the National Institutes of Health FX We thank Drs. Tzanko Stantchev, Hana Golding, and Ira Berkower (U.S. Food and Drug Administration, Bethesda, MD) for critical reading of the manuscript. This work was supported in part by institutional funds from the U.S. Food and Drug Administration and the Intramural AIDS Targeted Antiviral Program from the National Institutes of Health. NR 65 TC 3 Z9 3 U1 1 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD OCT 2 PY 2014 VL 11 AR 86 DI 10.1186/s12977-014-0086-8 PG 12 WC Virology SC Virology GA AS9NJ UT WOS:000344569000001 PM 25274545 ER PT J AU Banda, M Myers, MB McKim, KL Wang, YY Parsons, BL AF Banda, Malathi Myers, Meagan B. McKim, Karen L. Wang, Yiying Parsons, Barbara L. TI Quantification of somatic hotspot mutations in KRAS, HRAS, BRAF, and PIK3CA: Comparing normal human breast and ductal carcinoma SO CANCER RESEARCH LA English DT Meeting Abstract CT 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 05-09, 2014 CL San Diego, CA SP Amer Assoc Canc Res C1 [Banda, Malathi; Myers, Meagan B.; McKim, Karen L.; Wang, Yiying; Parsons, Barbara L.] US FDA, Jefferson, AR 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 OCT 1 PY 2014 VL 74 IS 19 SU S MA 4267 DI 10.1158/1538-7445.AM2014-4267 PG 1 WC Oncology SC Oncology GA CB8VR UT WOS:000349910202243 ER PT J AU Comertpay, S Mezzapelle, R Tanji, M Strianese, O Pass, HI Weigel, T Friedberg, J Sugarbaker, P Krausz, T Wang, E Gaudino, G Yang, HN Powers, A Parsons, B Pastorino, S Carbone, M AF Comertpay, Sabahattin Mezzapelle, Rosanna Tanji, Mika Strianese, Oriana Pass, Harvey I. Weigel, Tracey Friedberg, Joseph Sugarbaker, Paul Krausz, Thomas Wang, Ena Gaudino, Giovanni Yang, Haining Powers, Amy Parsons, Barbara Pastorino, Sandra Carbone, Michele TI Evaluation of clonal origin of malignant mesothelioma/polyclonal origin of malignant mesothelioma SO CANCER RESEARCH LA English DT Meeting Abstract CT 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 05-09, 2014 CL San Diego, CA SP Amer Assoc Canc Res C1 [Comertpay, Sabahattin; Tanji, Mika; Strianese, Oriana; Gaudino, Giovanni; Yang, Haining; Powers, Amy; Pastorino, Sandra; Carbone, Michele] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Mezzapelle, Rosanna] Univ Piemonte Orientale Amedeo Avogadro, Novara, Italy. [Pass, Harvey I.] NYU, NYU Langone Med Ctr, New York, NY USA. [Weigel, Tracey] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Madison, WI USA. [Friedberg, Joseph] Penn Presbyterian Med Ctr, Philadelphia, PA USA. [Sugarbaker, Paul] MedStar Washington Hosp Ctr, Washington, DC USA. [Krausz, Thomas] Univ Chicago, Chicago, IL 60637 USA. [Wang, Ena] NIH, Bethesda, MD 20892 USA. [Parsons, Barbara] 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 OCT 1 PY 2014 VL 74 IS 19 SU S MA 3188 DI 10.1158/1538-7445.AM2014-3188 PG 1 WC Oncology SC Oncology GA CB8VR UT WOS:000349910200192 ER PT J AU Jochems, C Boyerinas, B Madan, RA Poole, DJ Ning, YM Figg, WD Liewehr, DJ Steinberg, SM Gulley, JL Tsang, KY Schlom, J AF Jochems, Caroline Boyerinas, Benjamin Madan, Ravi A. Poole, Diane J. Ning, Yang-Min Figg, William D. Liewehr, David J. Steinberg, Seth M. Gulley, James L. Tsang, Kwong-Yok Schlom, Jeffrey TI Analysis of immune cell subsets in a multidrug therapeutic regimen for patients with metastatic castration-resistant prostate cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 05-09, 2014 CL San Diego, CA SP Amer Assoc Canc Res C1 [Jochems, Caroline; Boyerinas, Benjamin; Madan, Ravi A.; Poole, Diane J.; Figg, William D.; Liewehr, David J.; Steinberg, Seth M.; Gulley, James L.; Tsang, Kwong-Yok; Schlom, Jeffrey] NCI, Bethesda, MD 20892 USA. [Ning, Yang-Min] US FDA, Bethesda, MD 20014 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 U1 0 U2 2 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 OCT 1 PY 2014 VL 74 IS 19 SU S MA 2546 DI 10.1158/1538-7445.AM2014-2546 PG 1 WC Oncology SC Oncology GA CB8UN UT WOS:000349906903284 ER PT J AU Joseph, SJ Nicolson, T Wang, HG Word, BR Hammons, G Lyn-Cook, B AF Joseph, Stancy J. Nicolson, Tamara Wang, Honggang Word, Beverly R. Hammons, George Lyn-Cook, Beverly TI Gender differences in the expression of drug metabolizing enzymes in human liver tissues SO CANCER RESEARCH LA English DT Meeting Abstract CT 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 05-09, 2014 CL San Diego, CA SP Amer Assoc Canc Res C1 [Joseph, Stancy J.; Word, Beverly R.; Hammons, George; Lyn-Cook, Beverly] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Nicolson, Tamara] Drug Discovery & Dev, Brisbane, Qld, Australia. [Wang, Honggang] FDA, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 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 OCT 1 PY 2014 VL 74 IS 19 SU S MA 770 DI 10.1158/1538-7445.AM2014-770 PG 1 WC Oncology SC Oncology GA CB8UN UT WOS:000349906905230 ER PT J AU Lee, EJ Rath, P Liu, J Ryu, D Free, A Pei, L Anthony, DC Sharma, S Kirk, MD Laterra, JJ Ryu, DH Choi, JH Shi, HD Miller, DC Litofsky, NS Feng, Q AF Lee, Eun Joon Rath, Prakash Liu, Jimei Ryu, Dungsheng Free, Alan Pei, Lirong Anthony, Douglas C. Sharma, Suash Kirk, Mark D. Laterra, John J. Ryu, Duck Hwan Choi, Jeong-Hyeon Shi, Huidong Miller, Douglas C. Litofsky, N. Scott Feng, Qi TI Identification of global DNA methylation signatures in glioblastoma-derived cancer stem cells SO CANCER RESEARCH LA English DT Meeting Abstract CT 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 05-09, 2014 CL San Diego, CA SP Amer Assoc Canc Res C1 [Lee, Eun Joon; Liu, Jimei; Ryu, Dungsheng; Free, Alan; Pei, Lirong; Sharma, Suash; Ryu, Duck Hwan; Choi, Jeong-Hyeon; Shi, Huidong] Georgia Regents Univ, Augusta, GA USA. [Rath, Prakash] US FDA, Silver Spring, MD USA. [Anthony, Douglas C.] Brown Univ, Providence, RI 02912 USA. [Kirk, Mark D.; Miller, Douglas C.; Feng, Qi] Univ Missouri, Columbia, MO USA. [Laterra, John J.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Litofsky, N. Scott] Univ Missouri, Columbia, MO 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 OCT 1 PY 2014 VL 74 IS 19 SU S MA 1379 DI 10.1158/1538-7445.AM2014-1379 PG 1 WC Oncology SC Oncology GA CB8UN UT WOS:000349906901111 ER PT J AU Lyn-Cook, LE Word, B Hammons, G AF Lyn-Cook, Lascelles E. Word, Beverly Hammons, George TI Array analysis of cigarette smoke condensate (CSC) on gene promoter methylation in human lung cells SO CANCER RESEARCH LA English DT Meeting Abstract CT 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 05-09, 2014 CL San Diego, CA SP Amer Assoc Canc Res C1 [Lyn-Cook, Lascelles E.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Word, Beverly; Hammons, George] NCTR, Jefferson, AR 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 OCT 1 PY 2014 VL 74 IS 19 SU S MA 401 DI 10.1158/1538-7445.AM2014-401 PG 2 WC Oncology SC Oncology GA CB8UN UT WOS:000349906904367 ER PT J AU Marrone, AK Tryndyak, V Chappell, G Beland, FA Rusyn, I Pogribny, IP AF Marrone, April K. Tryndyak, Volodymyr Chappell, Grace Beland, Frederick A. Rusyn, Ivan Pogribny, Igor P. TI The microRNA profile is altered in fibrosis-associated hepatocarcinogenesis in mice SO CANCER RESEARCH LA English DT Meeting Abstract CT 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 05-09, 2014 CL San Diego, CA SP Amer Assoc Canc Res C1 [Marrone, April K.; Tryndyak, Volodymyr; Beland, Frederick A.; Pogribny, Igor P.] FDA NCTR, Jefferson, AR USA. [Chappell, Grace; Rusyn, Ivan] Univ N Carolina, Chapel Hill, NC 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 OCT 1 PY 2014 VL 74 IS 19 SU S MA 5227 DI 10.1158/1538-7445.AM2014-5227 PG 1 WC Oncology SC Oncology GA CB8VR UT WOS:000349910204178 ER PT J AU Pang, L Word, B Xu, J Hammons, G Huang, SM Lyn-Cook, B AF Pang, Li Word, Beverly Xu, Joshua Hammons, George Huang, Shiew-Mei Lyn-Cook, Beverly TI ATP-binding cassette (ABC) genes genotype and expression: A potential association with pancreatic cancer development and chemoresistance SO CANCER RESEARCH LA English DT Meeting Abstract CT 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 05-09, 2014 CL San Diego, CA SP Amer Assoc Canc Res C1 [Pang, Li; Word, Beverly; Xu, Joshua; Hammons, George; Lyn-Cook, Beverly] FDA NCTR, Jefferson, AR USA. [Huang, Shiew-Mei] FDA CDER, White Oak, MD 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 OCT 1 PY 2014 VL 74 IS 19 SU S MA 759 DI 10.1158/1538-7445.AM2014-759 PG 1 WC Oncology SC Oncology GA CB8UN UT WOS:000349906905219 ER PT J AU Underbayev, C Kasar, S Degheidy, H Marti, G Lightfoote, M Raveche, E AF Underbayev, Chingiz Kasar, Siddha Degheidy, Heba Marti, Gerald Lightfoote, Marilyn Raveche, Elizabeth TI The role of microRNA-15a/16 in early B1 cell development in a mouse model of chronic lymphocytic leukemia SO CANCER RESEARCH LA English DT Meeting Abstract CT 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 05-09, 2014 CL San Diego, CA SP Amer Assoc Canc Res C1 [Underbayev, Chingiz; Kasar, Siddha; Raveche, Elizabeth] Rutgers State Univ, Newark, NJ 07102 USA. [Degheidy, Heba; Marti, Gerald] CBER FDA, Bethesda, MD USA. [Lightfoote, Marilyn] CBER FDA, Silver Spring, MD 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 OCT 1 PY 2014 VL 74 IS 19 SU S MA 4791 DI 10.1158/1538-7445.AM2014-4791 PG 2 WC Oncology SC Oncology GA CB8VR UT WOS:000349910203261 ER PT J AU Rosenfeld, LS Mihalov, JJ Carlson, SJ Mattia, A AF Rosenfeld, Leah S. Mihalov, Jeremy J. Carlson, Susan J. Mattia, Antonia TI Regulatory status of caffeine in the United States SO NUTRITION REVIEWS LA English DT Review DE caffeine; energy drinks; energy products; FDA regulations ID COFFEE AB This article summarizes the history of the regulation of caffeine, a key component of caffeine-containing energy drinks and other caffeine-containing energy products, in the United States. Caffeine as an ingredient in food has been regulated by the US Food and Drug Administration (FDA) since 1958, when the Food Additives Amendment to the Federal Food, Drug and Cosmetic Act was enacted. It is listed as a substance that is generally recognized as safe by experts for its intended use in cola-type beverages at levels not to exceed 200 parts per million. Here, the history of FDA evaluations of the safe use of, as well as consumer exposure to, caffeine in food in the United States is outlined. Finally, the FDA's current concerns about caffeine and caffeine-containing energy products are reported, along with the current activities to address those concerns. Published 2014. This article is a U.S. government work and is in the public domain in the USA. C1 [Rosenfeld, Leah S.; Mihalov, Jeremy J.; Carlson, Susan J.; Mattia, Antonia] US FDA, Ctr Food Safety & Appl Nutr, Off Food Addit Safety, Div Biotechnol, College Pk, MD 20740 USA. [Rosenfeld, Leah S.; Mihalov, Jeremy J.; Carlson, Susan J.; Mattia, Antonia] US FDA, GRAS Notice Review, College Pk, MD 20740 USA. RP Rosenfeld, LS (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Food Addit Safety, Div Biotechnol, College Pk, MD 20740 USA. EM Leah.Rosenfeld@fda.hhs.gov NR 39 TC 3 Z9 3 U1 4 U2 22 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0029-6643 EI 1753-4887 J9 NUTR REV JI Nutr. Rev. PD OCT PY 2014 VL 72 SU 1 SI SI BP 23 EP 33 DI 10.1111/nure.12136 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CB9PR UT WOS:000349964500004 PM 25293541 ER PT J AU Uzel, G Kuehn, HS Weiming, Q Lo, B Deenick, EK Niemela, JE Avery, DT Schickel, JN Tran, DQ Stoddard, J Zhang, Y Frucht, DM Rao, KV Su, HC Notarangelo, LD Olivier, KN McElwee, J Pittaluga, S Oliveira, JB Meffre, E Fleisher, TA Holland, SM Tangye, SG Lenardo, MJ AF Uzel, G. Kuehn, H. S. Weiming, Q. Lo, B. Deenick, E. K. Niemela, J. E. Avery, D. T. Schickel, J. N. Tran, D. Q. Stoddard, J. Zhang, Y. Frucht, D. M. Rao, K. V. Su, H. C. Notarangelo, L. D. Olivier, K. N. McElwee, J. Pittaluga, S. Oliveira, J. B. Meffre, E. Fleisher, T. A. Holland, S. M. Tangye, S. G. Lenardo, M. J. TI Human CTLA4 Haploinsufficiency Causes Severe Immune Dysregulation SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 16th Biennial Meeting of the European-Society-for-Immunodeficiencies CY OCT 29-NOV 01, 2014 CL Prague, CZECH REPUBLIC SP European Soc Immunodeficiencies C1 [Uzel, G.; Lo, B.; Zhang, Y.; Rao, K. V.; Su, H. C.; Olivier, K. N.; Holland, S. M.; Lenardo, M. J.] NIAID, NIH, Bethesda, MD 20892 USA. [Kuehn, H. S.; Niemela, J. E.; Stoddard, J.; Fleisher, T. A.] NIH, CC, Bethesda, MD 20892 USA. [Weiming, Q.; Frucht, D. M.] US FDA, CDER, Bethesda, MD 20014 USA. [Deenick, E. K.; Avery, D. T.; Tangye, S. G.] Garvan Inst Med Res, Immunol Dept, Sydney, NSW, Australia. [Schickel, J. N.; Meffre, E.] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. [Tran, D. Q.] Univ Texas Houston, Sch Med, Dept Pediat, Houston, TX USA. [Notarangelo, L. D.] Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. [McElwee, J.] Merck & Co Inc, Merck Res Labs, Boston, MA USA. [Pittaluga, S.] NCI, NIH, Boston, MA USA. [Oliveira, J. B.] Inst Med Integral Prof Fernando Figueira, IMIP, Recife, PE, Brazil. RI Notarangelo, Luigi/F-9718-2016 OI Notarangelo, Luigi/0000-0002-8335-0262 NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD OCT PY 2014 VL 34 SU 2 MA ESID-0767 BP S144 EP S145 PG 2 WC Immunology SC Immunology GA AY1ZS UT WOS:000347389100011 ER PT J AU Williams, GL Steck, GJ AF Williams, Gaye L. Steck, Gary J. TI OPHIOMYIA KWANSONIS SASAKAWA (DIPTERA: AGROMYZIDAE), THE DAYLILY LEAFMINER, AN ASIAN SPECIES RECENTLY IDENTIFIED IN THE CONTINENTAL UNITED STATES SO PROCEEDINGS OF THE ENTOMOLOGICAL SOCIETY OF WASHINGTON LA English DT Article DE Hemerocallis; biology; Liliaceae; Hemerocallidaceae; Slovenia AB Ophiomyia kwansonis Sasakawa, the daylily leafminer (DLM), previously known only from Japan and Taiwan, and present but unidentified in the continental United States since at least 2008, is here documented from detections made in 2011. Known distribution, including U.S. and European records, is given, with a number of new state records documented by photographic images of the characteristic, unique larval feeding damage found in Hemerocallis spp. Some biological observations are also included. C1 [Williams, Gaye L.] MDA, Plant Protect & Weed Management Sect, Annapolis, MD 21401 USA. [Steck, Gary J.] FDACS, Div Plant Ind, Gainesville, FL 32608 USA. RP Williams, GL (reprint author), MDA, Plant Protect & Weed Management Sect, 50 Harry S Truman Pkwy, Annapolis, MD 21401 USA. EM gaye.williams@maryland.gov; gary.steck@freshfromflorida.com FU Bowie Crofton Garden Club, Bowie, MD; National Capital Day lily Club, Edgewater, MD FX GLW thanks Maryland garden owners for allowing unlimited access to their properties, permitting seasonal biological observations of O. kwansonis. Thanks to Owen Lonsdale (CNC) for verifying the MD specimens and for his encouragement. Thanks to the AHS Scientific Studies Committee for posting early, short DLM articles on their AHS website. The rapid, wide dissemination of this updated information to a large segment of the daylily growing community resulted in many new detections. Thanks to the many growers who sent documenting images. Many, many thanks to Vada Ritchie, MDA, PPWM, for deciphering, typing, and retyping this manuscript. Many thanks to Dr. Ramesh Pokharel, MDA, for hours of patient computer help at each step in this process. Lastly, GLW thanks coauthor GJS for his constant, tactful prodding to (finally) make this paper happen. GJS thanks Lance Brown, Leslie Wilber, Charles Whitehill, Lindley Clark, and Cheryl Jones for their assistance in making the first collections of this pest in Florida. Thanks to anonymous reviewers who commented on earlier drafts. This publication was funded by grants from the Bowie Crofton Garden Club, Bowie, MD and the National Capital Day lily Club, Edgewater, MD. NR 14 TC 0 Z9 1 U1 1 U2 6 PU ENTOMOL SOC WASHINGTON PI WASHINGTON PA SMITHSONIAN INSTITUTION DEPT ENTOMOLOGY, WASHINGTON, DC 20560 USA SN 0013-8797 J9 P ENTOMOL SOC WASH JI Proc. Entomol. Soc. Wash. PD OCT PY 2014 VL 116 IS 4 BP 421 EP 428 DI 10.4289/0013-8797.116.4.421 PG 8 WC Entomology SC Entomology GA AX4HM UT WOS:000346894100006 ER PT J AU Suo, B Wang, XJ Pan, ZL Wang, N Ai, ZL Yu, SJ Salazar, JK AF Suo, Biao Wang, Xiaojie Pan, Zhili Wang, Na Ai, Zhilu Yu, Shuijing Salazar, Joelle K. TI Inactivation and Sublethal Injury Kinetics of Staphylococcus aureus in Broth at Low Temperature Storage SO JOURNAL OF FOOD PROTECTION LA English DT Article ID SALMONELLA-TYPHIMURIUM DT104; LISTERIA-MONOCYTOGENES; THERMAL INACTIVATION; ESCHERICHIA-COLI; HEAT INACTIVATION; PREDICTIVE MODEL; SURVIVAL CURVES; FROZEN STORAGE; CHICKEN SKIN; FOOD SAFETY AB Low temperatures are widely used to ensure food quality and safety. However, sublethally injured Staphylococcus aureus is an important microbiological safety concern in low temperature food. The objective of this study was to develop predictive inactivation kinetic models for the inactivation and sublethal injury of S. aureus in broth at different temperatures (4 to -18 degrees C) and time points. S. aureus was diluted in tryptic soy broth plus 0.6% (wt/vol) yeast extract (TSBYE) to obtain approximately 10(8) CFU/ml and was stored separately at 4, -3, -11, and -18 degrees C. After specific time points within 96 days, survival of S. aureus was determined on TSBYE and TSBYE agar plus 10% NaCl for enumeration of the total viable and noninjured cell numbers, respectively. Linear, Weibull, and modified Gompertz models were applied to determine survival curve regression. The combination of low temperature and time resulted in S. aureus inactivation, although the cells were able to survive in this sublethal state. Storage temperature was the critical parameter in survival of S. aureus. The modified Weibull model successfully described a second model of noninjured S. aureus cell survival at different low temperatures, whereas only the linear model was able to fit the total viable cells. The predictive model may be used to estimate the level of S. aureus contamination in food at low storage temperatures and times, and it provides new insight into the sublethally injured survival state of S. aureus in low temperature food. C1 [Suo, Biao; Wang, Xiaojie; Pan, Zhili; Ai, Zhilu] Henan Agr Univ, Coll Food Sci & Technol, Zhengzhou 450002, Peoples R China. [Suo, Biao; Wang, Na; Ai, Zhilu] Henan Agr Univ, Henan Key Lab Cultivat Base Quick Frozen Flour Ri, Zhengzhou 450002, Peoples R China. [Yu, Shuijing] Jiangxi Univ Sci & Technol, Fac Resource & Environm Engn, Ganzhou 341000, Jiangxi, Peoples R China. [Salazar, Joelle K.] US FDA, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. RP Ai, ZL (reprint author), Henan Agr Univ, Coll Food Sci & Technol, 63 Nongye Rd, Zhengzhou 450002, Peoples R China. EM zhila@163.com OI 艾, 志录/0000-0001-8102-0676 FU National Natural Science Foundation of China [U1204331]; National 12th Five-Year Science and Technology supporting grant in China [2012BAD37B07]; Science and Technology Department of Henan Province [122102310310]; Education Department of Henan Province [13A550486]; Science and Technology Bureau of Zhengzhou City [131PZDZX075] FX This study was financially supported by the National Natural Science Foundation of China (grant no. U1204331), the National 12th Five-Year Science and Technology supporting grant in China (grant no. 2012BAD37B07), the Science and Technology Department of Henan Province (grant no. 122102310310), the Education Department of Henan Province (grant no. 13A550486), and the Science and Technology Bureau of Zhengzhou City (grant no. 131PZDZX075). NR 39 TC 2 Z9 3 U1 1 U2 12 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 OCT PY 2014 VL 77 IS 10 BP 1689 EP 1695 DI 10.4315/0362-028X.JFP-13-540 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA AQ6AB UT WOS:000342888600005 PM 25285485 ER PT J AU Stephan, R Grim, CJ Gopinath, GR Mammel, MK Sathyamoorthy, V Trach, LH Chase, HR Fanning, S Tall, BD AF Stephan, Roger Grim, Christopher J. Gopinath, Gopal R. Mammel, Mark K. Sathyamoorthy, Venugopal Trach, Larisa H. Chase, Hannah R. Fanning, Seamus Tall, Ben D. TI Re-examination of the taxonomic status of Enterobacter helveticus, Enterobacter pulveris and Enterobacter turicensis as members of the genus Cronobacter and their reclassification in the genera Franconibacter gen. nov and Siccibacter gen. nov as Franconibacter helveticus comb. nov., Franconibacter pulveris comb. nov and Siccibacter turicensis comb. nov., respectively SO INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY LA English DT Article ID DUBLINENSIS SP-NOV; FRUIT POWDER; SAKAZAKII; PROPOSAL; CONDIMENTI AB Recently, a taxonomical re-evaluation of the genus Enterobacter, based on multi-locus sequence typing (MLST) analysis, has led to the proposal that the species Enterobacter pulveris, Enterobacter helveticus and Enterobacter turicensis should be reclassified as novel species of the genus Cronobacter. In the present work, new genome-scale analyses, including average nucleotide identity, genome-scale phylogeny and k-mer analysis, coupled with previously reported DNA DNA hybridization values and biochemical characterization strongly indicate that these three species of the genus Enterobacter are not members of the genus Cronobacter, nor do they belong to the re-evaluated genus Enterobacter. Furthermore, data from this polyphasic study indicated that all three species constitute two new genera. We propose reclassifying Enterobacter pulveris and Enterobacter helveticus in the genus Franconibacter gen. nov. as Franconibacter pulveris comb. nov. (type strain 601105(T)=LMG 24057(T)=DSM 19144(T)) and Franconibacter helveticus comb. nov. (type strain 513/05(T)=LMG 23732(T)=DSM 18396(T)), respectively, and Enterobacter turicensis in the genus Siccibacter gen. nov. as Siccibacter turicensis comb. nov. (type strain 508/05(T)=LMG 23730(T)=DSM 18397(T)). C1 [Stephan, Roger] Univ Zurich, Inst Food Safety & Hyg, Zurich, Switzerland. [Grim, Christopher J.; Gopinath, Gopal R.; Mammel, Mark K.; Sathyamoorthy, Venugopal; Trach, Larisa H.; Chase, Hannah R.; Tall, Ben D.] US FDA, CFSAN, Laurel, MD USA. [Fanning, Seamus] Univ Coll Dublin, UCD Ctr Food Safety, Sch Publ Hlth Physiotherapy & Populat Sci, Dublin 2, Ireland. [Fanning, Seamus] WHO Collaborating Ctr Cronobacter, Dublin, Ireland. RP Stephan, R (reprint author), Univ Zurich, Inst Food Safety & Hyg, Zurich, Switzerland. EM stephanr@fsafety.uzh.Ch NR 23 TC 32 Z9 33 U1 2 U2 14 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1466-5026 EI 1466-5034 J9 INT J SYST EVOL MICR JI Int. J. Syst. Evol. Microbiol. PD OCT PY 2014 VL 64 BP 3402 EP 3410 DI 10.1099/ijs.0.059832-0 PN 10 PG 9 WC Microbiology SC Microbiology GA AU8BN UT WOS:000345821800011 PM 25028159 ER PT J AU Wear, K Nagatani, Y Mizuno, K Matsukawa, M AF Wear, Keith Nagatani, Yoshiki Mizuno, Katsunori Matsukawa, Mami TI Fast and slow wave detection in bovine cancellous bone in vitro using bandlimited deconvolution and Prony's method SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID BAYESIAN PROBABILITY-THEORY; 2 LONGITUDINAL-WAVES; TRABECULAR BONE; ULTRASOUND ATTENUATION; PHASE CANCELLATION; STRUCTURAL ANISOTROPY; NEGATIVE DISPERSION; ACOUSTIC PARAMETERS; GROUP-VELOCITY; BIOT THEORY AB Fast and slow waves were detected in a bovine cancellous bone sample for thicknesses ranging from 7 to 12 mm using bandlimited deconvolution and the modified least-squares Prony's method with curve fitting (MLSP+CF). Bandlimited deconvolution consistently isolated two waves with linear-with-frequency attenuation coefficients as evidenced by high correlation coefficients between attenuation coefficient and frequency: 0.997 +/- 0.002 (fast wave) and 0.986 +/- 0.013 (slow wave) (mean +/- standard deviation). Average root-mean-squared (RMS) differences between the two algorithms for phase velocities were 5m/s (fast wave, 350 kHz) and 13 m/s (slow wave, 750 kHz). Average RMS differences for signal loss were 1.6 dB (fast wave, 350 kHz) and 0.4 dB (slow wave, 750 kHz). Phase velocities for thickness = 10 mm were 1726 m/s (fast wave, 350 kHz) and 1455 m/s (slow wave, 750 kHz). Results show support for the model of two waves with linear-with frequency attenuation, successful isolation of fast and slow waves, good agreement between bandlimited deconvolution and MLSP+CF as well as with a Bayesian algorithm, and potential variations of fast and/or slow wave properties with bone sample thickness. C1 [Wear, Keith] US FDA, Silver Spring, MD 20993 USA. [Nagatani, Yoshiki] Kobe City Coll Technol, Dept Elect, Nishi Ku, Kobe, Hyogo 6512194, Japan. [Mizuno, Katsunori] Univ Tokyo, Inst Ind Sci, Underwater Technol Collaborat Res Ctr, Meguro Ku, Tokyo 1538505, Japan. [Matsukawa, Mami] Doshisha Univ, Lab Ultrason Elect, Fac Sci & Engn, Kyoto 6100321, Japan. RP Wear, K (reprint author), US FDA, Silver Spring, MD 20993 USA. EM keith.wear@fda.hhs.gov FU Ministry of Education, Culture, Sports, Science; JSPS KAKENHI [24360161, 25871038] FX Part of this work was supported by the Regional Innovation Strategy Support Program of Ministry of Education, Culture, Sports, Science and JSPS KAKENHI Grant No. 24360161 and 25871038. NR 48 TC 5 Z9 5 U1 2 U2 6 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 OCT PY 2014 VL 136 IS 4 BP 2015 EP 2024 DI 10.1121/1.4895668 PG 10 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA AW0JF UT WOS:000345977400065 PM 25324100 ER PT J AU Balakumar, P Jagadeesh, G AF Balakumar, Pitchai Jagadeesh, Gowraganahalli TI Structural determinants for binding, activation, and functional selectivity of the angiotensin AT(1) receptor SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Review DE angiotensin II; AT1 receptor; beta-arrestin; renin-angiotensin system ID II TYPE-1 RECEPTOR; PROTEIN-COUPLED RECEPTORS; SITE-DIRECTED MUTAGENESIS; AGONIST-INDUCED INTERNALIZATION; SIGNAL-REGULATED KINASE-1; 7TH TRANSMEMBRANE DOMAIN; CARBOXYL-TERMINAL TAIL; 3RD CYTOPLASMIC LOOP; CONSERVED DRY MOTIF; AMINO-ACID-RESIDUES AB The renin-angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular disorders. Pharmacologic interventions targeting the RAS cascade have led to the discovery of renin inhibitors, angiotensin-converting enzyme inhibitors, and AT1 receptor blockers (ARBs) to treat hypertension and some cardiovascular and renal disorders. Mutagenesis and modeling studies have revealed that differential functional outcomes are the results of multiple active states conformed by the AT1 receptor upon interaction with angiotensin II (Ang II). The binding of agonist is dependent on both extracellular and intramembrane regions of the receptor molecule, and as a consequence occupies more extensive area of the receptor than a non-peptide antagonist. Both agonist and antagonist bind to the same intramembrane regions to interfere with each other's binding to exhibit competitive, surmountable interaction. The nature of interactions with the amino acids in the receptor is different for each of the ARBs given the small differences in the molecular structure between drugs. AT1 receptors attain different conformation states after binding various Ang II analogues, resulting in variable responses through activation of multiple signaling pathways. These include both classical and non-classical pathways mediated through growth factor receptor transactivations, and provide cross-communication between downstream signaling molecules. The structural requirements for AT1 receptors to activate extracellular signal-regulated kinases 1 and 2 through G proteins, or G protein-independently through beta-arrestin, are different. We review the structural and functional characteristics of Ang II and its analogs and antagonists, and their interaction with amino acid residues in the AT1 receptor. C1 [Balakumar, Pitchai] AIMST Univ, Fac Pharm, Pharmacol Unit, Bedong 08100, Kedah Darul Ama, Malaysia. [Jagadeesh, Gowraganahalli] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Balakumar, P (reprint author), AIMST Univ, Fac Pharm, Pharmacol Unit, Bedong 08100, Kedah Darul Ama, Malaysia. EM pbala2006@gmail.com NR 124 TC 9 Z9 9 U1 1 U2 24 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD OCT PY 2014 VL 53 IS 2 BP R71 EP R92 DI 10.1530/JME-14-0125 PG 22 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AU5AU UT WOS:000345620300004 PM 25013233 ER PT J AU Zhang, ZW AF Zhang, Zhiwei TI REVERSE REGRESSION: A METHOD FOR JOINT ANALYSIS OF MULTIPLE ENDPOINTS IN RANDOMIZED CLINICAL TRIALS SO STATISTICA SINICA LA English DT Article DE Density ratio; discriminant analysis; efficiency; logistic regression; multiplicity; semiparametric likelihood ID BONFERRONI PROCEDURE; MODELS; TESTS AB In clinical trials, treatment comparisons are often cast in a regression framework that evaluates the dependence of the relevant clinical outcomes on treatment assignment and possibly other baseline characteristics. This article introduces a reverse regression approach to randomized clinical trials, with focus on the dependence of treatment assignment on the clinical outcomes of interest. A reverse regression model is essentially a semiparametric density ratio model for the outcome distributions in the two treatment groups. The resulting inferences can be expected to be more robust than those based on fully parametric models for the outcome distributions and more efficient than nonparametric inferences. In the presence of multiple endpoints, the reverse regression approach leads to a novel procedure for multiplicity adjustment that is readily available in standard logistic regression routines. The proposed approach is evaluated in simulation experiments and illustrated with an example. C1 US FDA, Div Biostat, Off Surveillance & Biomet, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Zhang, ZW (reprint author), US FDA, Div Biostat, Off Surveillance & Biomet, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM zhiwei.zhang@fda.hhs.gov FU Intramural Research Program of the National Institutes of Health (NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The author would like to thank Dr. Peter Reitmeir for providing the clinical data and two anonymous reviewers for insightful comments that have greatly improved the manuscript. This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development. The computation was facilitated by the Biowulf cluster computer system made available by the Center for Information Technology at the NIH. The views expressed in this article do not represent the official position of the U.S. Food and Drug Administration. NR 24 TC 0 Z9 0 U1 5 U2 7 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 EI 1996-8507 J9 STAT SINICA JI Stat. Sin. PD OCT PY 2014 VL 24 IS 4 BP 1753 EP 1769 DI 10.5705/ss.2010.111 PG 17 WC Statistics & Probability SC Mathematics GA AT8SB UT WOS:000345201200014 ER PT J AU Liu, ZG Liu, MH Mercado, T Illoh, O Davey, R AF Liu, Zhugong Liu, Meihong Mercado, Teresita Illoh, Orieji Davey, Richard TI Extended Blood Group Molecular Typing and Next-Generation Sequencing SO TRANSFUSION MEDICINE REVIEWS LA English DT Review DE Blood group genotyping; Molecular assay; Target enrichment; Next generation sequencing; Blood group phenotype ID SICKLE-CELL-DISEASE; DE-NOVO MUTATIONS; AUTISM SPECTRUM DISORDERS; LONG-RANGE PCR; HIGH-THROUGHPUT; INTERNATIONAL WORKSHOP; HIGH-RESOLUTION; GROUP SYSTEM; LARGE-SCALE; MICROARRAY HYBRIDIZATION AB Several high-throughput multiplex blood group molecular typing platforms have been developed to predict blood group antigen phenotypes. These molecular systems support extended donor/patient matching by detecting commonly encountered blood group polymorphisms as well as rare alleles that determine the expression of blood group antigens. Extended molecular typing of a large number of blood donors by high-throughput platforms can increase the likelihood of identifying donor red blood cells that match those of recipients. This is especially important in the management of multiply-transfused patients who may have developed several alloantibodies. Nevertheless, current molecular techniques have limitations. For example, they detect only predefined genetic variants. In contrast, target enrichment next-generation sequencing (NGS) is an emerging technology that provides comprehensive sequence information, focusing on specified genomic regions. Target enrichment NGS is able to assess genetic variations that cannot be achieved by traditional Sanger sequencing or other genotyping platforms. Target enrichment NGS has been used to detect both known and de novo genetic polymorphisms, including single-nucleotide polymorphisms, indels (insertions/deletions), and structural variations. This review discusses the methodology, advantages, and limitations of the current blood group genotyping techniques and describes various target enrichment NGS approaches that can be used to develop an extended blood group genotyping assay system. Published by Elsevier Inc. C1 [Liu, Zhugong; Liu, Meihong; Mercado, Teresita; Illoh, Orieji; Davey, Richard] US FDA, Ctr Biol Evaluat & Res, Off Blood Res & Review, Div Blood Components & Devices, Silver Spring, MD USA. RP Liu, ZG (reprint author), 10903 New Hampshire Ave,WO71-4222, Silver Spring, MD 20993 USA. EM zhugong.liu@fda.hhs.gov NR 118 TC 7 Z9 7 U1 0 U2 5 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 2014 VL 28 IS 4 BP 177 EP 186 DI 10.1016/j.tmrv.2014.08.003 PG 10 WC Hematology SC Hematology GA AT6OS UT WOS:000345059300001 PM 25280589 ER PT J AU Derrick, SC Kolibab, K Yang, A Morris, SL AF Derrick, Steven C. Kolibab, Kristopher Yang, Amy Morris, Sheldon L. TI Intranasal Administration of Mycobacterium bovis BCG Induces Superior Protection against Aerosol Infection with Mycobacterium tuberculosis in Mice SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID BACILLUS-CALMETTE-GUERIN; SUBCUTANEOUS VACCINATION; PUBLISHED LITERATURE; IMMUNE-RESPONSE; T-CELLS; PHASE-I; EFFICACY; LUNG; IMMUNIZATION; PREVENTION AB Despite the widespread use of Mycobacterium bovis BCG, the only licensed vaccine against tuberculosis (TB), TB remains a global epidemic. To assess whether more direct targeting of the lung mucosa by respiratory immunization would enhance the potency and longevity of BCG-induced anti-TB protective immunity, the long-term impact of intranasal (i.n.) BCG vaccination was compared to conventional subcutaneous (s.c.) immunization by using a mouse model of pulmonary tuberculosis. Although significantly improved protection in the lung was seen at early time points (2 and 4 months postvaccination) in i.n. BCG-immunized mice, no differences in pulmonary protection were seen 8 and 10 months postvaccination. In contrast, in all of the study periods, i.n. BCG vaccination induced significantly elevated protective splenic responses relative to s.c. immunization. At five of nine time points, we observed a splenic protective response exceeding 1.9 log(10) protection relative to the s.c. route. Furthermore, higher frequencies of CD4 T cells expressing gamma interferon (IFN-gamma) and IFN-gamma/tumor necrosis factor alpha, as well as CD8 T cells expressing IFN-gamma, were detected in the spleens of i.n. vaccinated mice. Using PCR arrays, significantly elevated levels of IFN-gamma, interleukin-9 (IL-9), IL-11, and IL-21 expression were also seen in the spleen at 8 months after respiratory BCG immunization. Overall, while i.n. BCG vaccination provided short-term enhancement of protection in the lung relative to s.c. immunization, potent and extremely persistent splenic protective responses were seen for at least 10 months following respiratory immunization. C1 [Derrick, Steven C.; Kolibab, Kristopher; Yang, Amy; Morris, Sheldon L.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Derrick, SC (reprint author), US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM steven.derrick@fda.hhs.gov NR 35 TC 5 Z9 5 U1 2 U2 7 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 2014 VL 21 IS 10 BP 1443 EP 1451 DI 10.1128/CVI.00394-14 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0TN UT WOS:000344647800009 PM 25143340 ER PT J AU Beckmann, J Hagemann, U Bahri, P Bate, A Boyd, IW Dal Pan, GJ Edwards, BD Edwards, IR Hartigan-Go, K Lindquist, M McEwen, J Moride, Y Olsson, S Pal, SN Soulaymani-Bencheikh, R Tuccori, M Vaca, CP Wong, ICK AF Beckmann, Juergen Hagemann, Ulrich Bahri, Priya Bate, Andrew Boyd, Ian W. Dal Pan, Gerald J. Edwards, Brian D. Edwards, I. Ralph Hartigan-Go, Kenneth Lindquist, Marie McEwen, John Moride, Yola Olsson, Sten Pal, Shanthi N. Soulaymani-Bencheikh, Rachida Tuccori, Marco Vaca, Claudia P. Wong, Ian C. K. TI Teaching Pharmacovigilance: the WHO-ISoP Core Elements of a Comprehensive Modular Curriculum SO DRUG SAFETY LA English DT Article C1 [Bahri, Priya] European Med Agcy, London, England. [Bate, Andrew] Pfizer Ltd, Tadworth, Surrey, England. [Boyd, Ian W.] Ian Boyd Consulting, Canberra, ACT, Australia. [Dal Pan, Gerald J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Edwards, Brian D.] NDA Regulatory Sci Ltd, Leatherhead, Surrey, England. [Edwards, I. Ralph; Lindquist, Marie; Olsson, Sten] Uppsala Monitoring Ctr, Uppsala, Sweden. [Hartigan-Go, Kenneth] Food & Drugs Adm, Dept Hlth, Muntinlupa, Philippines. [McEwen, John] Univ Canberra, Discipline Pharm, Canberra, ACT 2601, Australia. [Moride, Yola] Univ Montreal, Fac Pharm, Montreal, PQ H3C 3J7, Canada. [Pal, Shanthi N.] WHO, CH-1211 Geneva, Switzerland. [Soulaymani-Bencheikh, Rachida] Ctr Anti Poison & Pharmacovigilance Maroc, Rabat, Morocco. [Tuccori, Marco] Hosp Pisa, Tuscan Reg Ctr Pharmacovigilance, Pisa, Italy. [Vaca, Claudia P.] Univ Nacl Colombia, Sch Pharm, Bogota, Colombia. [Wong, Ian C. K.] Univ Hong Kong, Li Ka Shing Fac Med, Dept Pharmacol & Pharm, Hong Kong, Hong Kong, Peoples R China. RP Beckmann, J (reprint author), Kaunstr 31, D-14163 Berlin, Germany. EM j.beckmann.berlin@web.de; Vigimax@gmx.de; Priya.Bahri@ema.europa.eu; andrew.bate@pfizer.com; ian@ianboydconsulting.com.au; Gerald.DalPan@fda.hhs.gov; Brian.Edwards@ndareg.com; ralph.edwards@who-umc.org; khgo@aim.edu; marie.lindquist@who-umc.org; mcewenj@webone.com.au; yola.moride@umontreal.ca; sten.olsson@who-umc.org; pals@who.int; rsoulaymani@gmail.com; marco.tuccori@gmail.com; cpvacag@unal.edu.co; wongick@hku.hk OI Wong, Ian Chi Kei/0000-0001-8242-0014 NR 21 TC 5 Z9 5 U1 0 U2 0 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 OCT PY 2014 VL 37 IS 10 BP 743 EP 759 DI 10.1007/s40264-014-0216-1 PG 17 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA AT0GO UT WOS:000344615300001 PM 25171836 ER PT J AU Hassan, M Ilev, I AF Hassan, Moinuddin Ilev, Ilko TI Grazing incidence angle based sensing approach integrated with fiber-optic Fourier transform infrared (FO-FTIR) spectroscopy for remote and label-free detection of medical device contaminations SO REVIEW OF SCIENTIFIC INSTRUMENTS LA English DT Article ID REFLECTION-ABSORPTION SPECTROSCOPY; VARYING ROUGHNESS; STAINLESS-STEEL; TRACE ANALYSIS; SURFACES; SPECTRA AB Contamination of medical devices has become a critical and prevalent public health safety concern since medical devices are being increasingly used in clinical practices for diagnostics, therapeutics and medical implants. The development of effective sensing methods for real-time detection of pathogenic contamination is needed to prevent and reduce the spread of infections to patients and the healthcare community. In this study, a hollow-core fiber-optic Fourier transform infrared spectroscopy methodology employing a grazing incidence angle based sensing approach (FO-FTIR-GIA) was developed for detection of various biochemical contaminants on medical device surfaces. We demonstrated the sensitivity of FO-FTIR-GIA sensing approach for non-contact and label-free detection of contaminants such as lipopolysaccharide from various surface materials relevant to medical device. The proposed sensing system can detect at a minimum loading concentration of approximately 0.7 mu g/cm(2). The FO-FTIR-GIA has the potential for the detection of unwanted pathogen in real time. C1 [Hassan, Moinuddin; Ilev, Ilko] US FDA, Opt Therapeut & Med Nanophoton Lab, Div Biomed Phys, Off Sci & Engn Labs,Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Hassan, M (reprint author), US FDA, Opt Therapeut & Med Nanophoton Lab, Div Biomed Phys, Off Sci & Engn Labs,Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM moinuddin.hassan@fda.hhs.gov FU Medical Counter Measure initiative (MCMi) of Center for Devices and Radiological Health (CDRH), U.S. Food and Drug Administration (FDA) FX This study is supported by the intramural research program of Medical Counter Measure initiative (MCMi) of Center for Devices and Radiological Health (CDRH), U.S. Food and Drug Administration (FDA). We like to thank Dr. Darrell Tata for his useful discussions. NR 20 TC 2 Z9 2 U1 0 U2 9 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0034-6748 EI 1089-7623 J9 REV SCI INSTRUM JI Rev. Sci. Instrum. PD OCT PY 2014 VL 85 IS 10 AR 103108 DI 10.1063/1.4897247 PG 5 WC Instruments & Instrumentation; Physics, Applied SC Instruments & Instrumentation; Physics GA AS9YL UT WOS:000344594200008 PM 25362372 ER PT J AU James, SJ Shpyleva, S Melnyk, S Pavliv, O Pogribny, IP AF James, S. J. Shpyleva, S. Melnyk, S. Pavliv, O. Pogribny, I. P. TI Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID EMBRYONIC STEM-CELLS; OXIDATIVE STRESS; DNA METHYLATION; RETT-SYNDROME; SPECTRUM DISORDER; NERVOUS-SYSTEM; PURKINJE-CELLS; HOMEOBOX GENE; BRAIN; 5-METHYLCYTOSINE AB Epigenetic mechanisms regulate programmed gene expression during prenatal neurogenesis and serve as a mediator between genetics and environment in postnatal life. The recent discovery of 5-hydroxymethylcytosine (5-hmC), with highest concentration in the brain, has added a new dimension to epigenetic regulation of neurogenesis and the development of complex behavior disorders. Here, we take a candidate gene approach to define the role 5-hmC in Engrailed-2 (EN-2) gene expression in the autism cerebellum. The EN-2 homeobox transcription factor, previously implicated in autism, is essential for normal cerebellar patterning and development. We previously reported EN-2 overexpression associated with promoter DNA hypermethylation in the autism cerebellum but because traditional DNA methylation methodology cannot distinguish 5-methylcytosine (5-mC) from 5-hmC, we now extend our investigation by quantifying global and gene-specific 5-mC and 5-hmC. Globally, 5-hmC was significantly increased in the autism cerebellum and accompanied by increases in the expression of de novo methyltransferases DNMT3A and DNMT3B, ten-eleven translocase genes TET1 and TET3, and in 8-oxo-deoxyguanosine (8-oxo-dG) content, a marker of oxidative DNA damage. Within the EN-2 promoter, there was a significant positive correlation between 5-hmC content and EN-2 gene expression. Based on reports of reduced MeCP2 affinity for 5-hmC, MeCP2 binding studies in the EN-2 promoter revealed a significant decrease in repressive MeCP2 binding that may contribute to the aberrant overexpression of EN-2. Because normal cerebellar development depends on perinatal EN-2 downregulation, the sustained postnatal overexpression suggests that a critical window of cerebellar development may have been missed in some individuals with autism with downstream developmental consequences. Epigenetic regulation of the programmed on-off switches in gene expression that occur at birth and during early brain development warrants further investigation C1 [James, S. J.; Shpyleva, S.; Melnyk, S.; Pavliv, O.] Univ Arkansas Med Sci, Arkansas Childrens Hosp, Res Inst, Dept Pediat, Little Rock, AR 72202 USA. [Pogribny, I. P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP James, SJ (reprint author), Univ Arkansas Med Sci, Arkansas Childrens Hosp, Res Inst, Dept Pediat, 13 Childrens Way,Slot 512-41B, Little Rock, AR 72202 USA. EM jamesjill@uams.edu FU National Institute of Child Health and Development [1RO1HD051873]; Jane Botsford Johnson Foundation; Arkansas Biosciences Institute FX We thank the families of individuals with autism for the thoughtful donation of postmortem tissues to the Autism Tissue Program at the Harvard Brain Tissue Resource Center and the National Institute of Child Health and Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland. This study was funded by the National Institute of Child Health and Development (1RO1HD051873 to SJJ) and the Jane Botsford Johnson Foundation and Arkansas Biosciences Institute. NR 54 TC 19 Z9 19 U1 3 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD OCT PY 2014 VL 4 AR e460 DI 10.1038/tp.2014.87 PG 9 WC Psychiatry SC Psychiatry GA AT3HT UT WOS:000344827100005 PM 25290267 ER PT J AU Williams, D Basavarajappay, MS Rasmussen, SA Morris, S Mattison, D AF Williams, Denita Basavarajappay, Mallikarjuna S. Rasmussen, Sonja A. Morris, Suzanne Mattison, Donald CA Anim Models Pregnancy Working Grp TI Highlights from the United States Food and Drug Administration's Public Workshop on the Development of Animal Models of Pregnancy to Address Medical Countermeasures in an "At-Risk" Population of Pregnant Women: Influenza as a Case Study SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article DE animal models; influenza; oseltamivir phosphate; oseltamivir carboxylate; medical countermeasures; pregnancy ID PHARMACOKINETICS; OSELTAMIVIR AB The U.S. Food and Drug Administration (FDA) and other federal agencies partner to ensure that medical countermeasures (e. g., drug therapies and vaccines) are available for public health emergencies (FDA, 2014). Despite continuing progress, providing medical countermeasures and treatment guidelines for certain populations (e. g., pregnant women) is challenging due to the lack of clinical and/or animal data. Thus, a workshop was convened to discuss animal models of pregnancy for the evaluation of disease progression and medical countermeasures. (C) 2014 Wiley Periodicals, Inc. C1 [Williams, Denita; Basavarajappay, Mallikarjuna S.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Williams, Denita] Huntingdon Life Sci Inc, Somerset, NJ USA. [Rasmussen, Sonja A.] US Ctr Dis Control & Prevent, Atlanta, GA USA. [Morris, Suzanne] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Mattison, Donald] Risk Sci Int, Ottawa, ON, Canada. [Mattison, Donald] Univ Ottawa, Ottawa, ON, Canada. RP Williams, D (reprint author), 100 Mettlers Rd, Somerset, NJ 08873 USA. EM williamsd@princeton.huntingdon.com FU NCTR; FDA; U.S. Department of Energy FX Authors Williams and Basavarajappa were supported by appointments to the Postgraduate Research Program at the NCTR administered by the Oak Ridge Institute for Science Education through an interagency agreement between FDA and the U.S. Department of Energy. The views in this study do not represent those of the U.S. Food and Drug Administration or the U.S. Centers for Disease Control and Prevention. NR 16 TC 1 Z9 1 U1 2 U2 5 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 OCT PY 2014 VL 100 IS 10 BP 806 EP 810 DI 10.1002/bdra.23319 PG 5 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA AS5YT UT WOS:000344343100011 PM 25296888 ER PT J AU Chen, SA Yang, FP Xuan, JK Chen, JY Zhong, HL Luo, H Zhou, P Sun, XH He, L Cao, ZH Luo, XQ Xing, QH AF Chen, Sheng'an Yang, Fanping Xuan, Jiekun Chen, Junyi Zhong, Hailei Luo, Heng Zhou, Peng Sun, Xinghuai He, Lin Cao, Zhihao Luo, Xiaoqun Xing, Qinghe TI HLA-B*5901: A MARKER FOR STEVENS-JOHNSON SYNDROME/TOXIC EPIDERMAL NECROLYSIS CAUSED BY METHAZOLAMIDE IN HAN CHINESE SO JOURNAL OF DERMATOLOGY LA English DT Meeting Abstract DE methazolamide; Stevens-Johnson syndrome; toxic epidermal necrolysis; HLA-B*5901 C1 [Chen, Sheng'an; Yang, Fanping; Cao, Zhihao; Luo, Xiaoqun] Fudan Univ, Huashan Hosp, Dept Dermatol, Shanghai, Peoples R China. [Xuan, Jiekun; Zhong, Hailei; He, Lin; Xing, Qinghe] Fudan Univ, Childrens Hosp, Dept Dermatol, Shanghai, Peoples R China. [Xuan, Jiekun; Zhong, Hailei; He, Lin; Xing, Qinghe] Fudan Univ, Inst Biomed Sci, Shanghai, Peoples R China. [Xuan, Jiekun] US FDA, Dept Natl Ctr Toxicol Res, Rockville, MD 20857 USA. [Chen, Junyi; Sun, Xinghuai] Fudan Univ, Eye & Ent Hosp, Dept Ophthalmol & Vis Sci, Shanghai, Peoples R China. [Luo, Heng] Univ Arkansas, Dept Biomed Sci, Joint Bioinformat Program, Little Rock, AR 72204 USA. [Zhou, Peng] Univ Elect Sci & Technol China, Minist Educ, Dept Ctr Bioinformat Cobi, Hefei, Peoples R China. [Zhou, Peng] Univ Elect Sci & Technol China, Minist Educ, Key Lab Neuroinformat, Hefei, Peoples R China. 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 0385-2407 EI 1346-8138 J9 J DERMATOL JI J. Dermatol. PD OCT PY 2014 VL 41 SU 1 SI SI MA P-421 BP 71 EP 71 PG 1 WC Dermatology SC Dermatology GA AS5TO UT WOS:000344332600422 ER PT J AU Yang, FP Gu, B Zhang, LR Xuan, JK Luo, H Zhou, P Zhu, QY Yan, SJ Chen, SA Cao, ZH Xu, JH Xing, QH Luo, XQ AF Yang, Fanping Gu, Bo Zhang, Lirong Xuan, Jiekun Luo, Heng Zhou, Peng Zhu, Qinyuan Yan, Sijia Chen, Sheng-An Cao, Zhihao Xu, Jinhua Xing, Qinghe Luo, Xiaoqun TI HLA-B*13:01 IS ASSOCIATED WITH SALAZOSULFAPYRIDINE-INDUCED DRUG RASH WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS IN CHINESE HAN POPULATION SO JOURNAL OF DERMATOLOGY LA English DT Meeting Abstract DE Salazosulfapyridine (SASP); Cutaneous adverse drug reactions; Han Chinese; HLA-B*13:01 C1 [Yang, Fanping; Zhu, Qinyuan; Chen, Sheng-An; Cao, Zhihao; Xu, Jinhua; Luo, Xiaoqun] Huashan Hosp, Dept Dermatol, Huashan, Peoples R China. [Gu, Bo; Xuan, Jiekun; Yan, Sijia; Xing, Qinghe] Fudan Univ, Dept Childrens Hosp, Shanghai, Peoples R China. [Gu, Bo; Xuan, Jiekun; Yan, Sijia; Xing, Qinghe] Fudan Univ, Inst Biomed Sci, Shanghai, Peoples R China. [Zhang, Lirong] Zhengzhou Univ, Dept Pharmacol, Zhengzhou 450052, Peoples R China. [Luo, Heng] Univ Arkansas, Dept Biomed Sci, Joint Bioinformat Program, Little Rock, AR 72204 USA. [Zhou, Peng] Univ Elect Sci & Technol China, Minist Educ, Dept Ctr Bioinformat Cobi, Hefei, Peoples R China. [Zhou, Peng] Univ Elect Sci & Technol China, Minist Educ, Key Lab Neuroinformat, Hefei, Peoples R China. [Xuan, Jiekun] US FDA, Dept Natl Ctr Toxicol Res, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0385-2407 EI 1346-8138 J9 J DERMATOL JI J. Dermatol. PD OCT PY 2014 VL 41 SU 1 SI SI MA P-420 BP 71 EP 71 PG 1 WC Dermatology SC Dermatology GA AS5TO UT WOS:000344332600419 ER PT J AU Ma, L Zhao, L Xu, Y Yim, S Doddapaneni, S Sahajwalla, CG Wang, YN Ji, P AF Ma, Lian Zhao, Liang Xu, Yun Yim, Sarah Doddapaneni, Suresh Sahajwalla, Chandrahas G. Wang, Yaning Ji, Ping TI Clinical endpoint sensitivity in rheumatoid arthritis: modeling and simulation SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Article DE Exposure-response; Modeling and simulation; Rheumatoid arthritis; ACR20; ACR50; ACR70; DAS28; Sensitivity analysis ID COLLEGE-OF-RHEUMATOLOGY; IMPROVEMENT; VALIDATION; CRITERIA AB The commonly used efficacy endpoints in Rheumatoid Arthritis (RA) clinical trials are American College of Rheumatology 20 % improvement criteria (ACR20), ACR50, and ACR70 response rates, and the 28-joint disease activity score (DAS28). Longitudinal models to quantitate the exposure-response relationships for ACRs and DAS28 score were developed for four biologics used for the management of RA. The models were then used to simulate the clinical outcome at various time points following different treatment regimens. Discriminative sensitivity of these endpoints was assessed using a power analysis. The trial simulation and subsequent power analysis showed that both ACR20 and DAS28 exhibit much lower power in distinguishing between two doses investigated compared with distinguishing treatment effect over placebo/Methotrexate (MTX) control. ACR20 response rate is generally more powerful in detecting treatment effect over placebo/MTX control as compared to DAS28. The findings of current study provide useful information which will help future clinical trial design for the treatment of patients with RA. C1 [Ma, Lian; Zhao, Liang; Wang, Yaning] US FDA, Div Pharmacometr, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Xu, Yun; Doddapaneni, Suresh; Sahajwalla, Chandrahas G.; Ji, Ping] US FDA, Div Clin Pharmacol 2, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Yim, Sarah] US FDA, Div Pulm Allergy & Rheumatol Prod, Off Drug Evaluat 2, Off New Drug,Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Wang, YN (reprint author), US FDA, Div Pharmacometr, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM yaning.wang@fda.hhs.gov; ping.ji@fda.hhs.gov FU Research Science Review (RSR) Funds at FDA FX This research was supported by the Research Science Review (RSR) Funds at FDA. NR 6 TC 1 Z9 1 U1 0 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 2014 VL 41 IS 5 SI SI BP 537 EP 543 DI 10.1007/s10928-014-9385-x PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AS5TE UT WOS:000344331600011 PM 25283268 ER PT J AU Malik, SM Pazdur, R Abrams, JS Socinski, MA Sause, WT Harpole, DH Welch, JJ Korn, EL Ullmann, CD Hirsch, FR AF Malik, Shakun M. Pazdur, Richard Abrams, Jeffrey S. Socinski, Mark A. Sause, William T. Harpole, David H., Jr. Welch, John J. Korn, Edward L. Ullmann, Claudio Dansky Hirsch, Fred R. TI Consensus Report of a Joint NCI Thoracic Malignancies Steering Committee: FDA Workshop on Strategies for Integrating Biomarkers into Clinical Development of New Therapies for Lung Cancer Leading to the Inception of "Master Protocols" in Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE NCI/FDA workshop leading to the Inception of "Master; Protocols" in Lung Cancer ID GROWTH-FACTOR RECEPTOR; PHASE-III TRIAL; PREDICTIVE BIOMARKERS; GEFITINIB; ERLOTINIB; DESIGN; CHEMOTHERAPY; MUTATIONS; SURVIVAL; MULTICENTER AB On February 2, 2012, the National Cancer Institute (NCI) sponsored a 2-day workshop with the NCI Thoracic Malignancies Steering Committee and the Food and Drug Administration to bring together leading academicians, clinicians, industry and government representatives to identify challenges and potential solutions in the clinical development of novel targeted therapies for lung cancer. Measures of success are rapidly evolving from a scientific and regulatory perspective and the objectives of this workshop were to achieve initial consensus on a high priority biomarker-driven clinical trial designed to rapidly assess the activity of targeted agents in molecularly defined lung cancer subsets and to facilitate generation of data leading to approval of these new therapies. Additionally, the meeting focused on identification of the barriers to conduct such a trial and the development of strategies to overcome those barriers. The "Lung Master Protocols" recently launched by NCI were the direct outcome of this workshop. C1 [Malik, Shakun M.; Abrams, Jeffrey S.; Welch, John J.; Ullmann, Claudio Dansky] NCI, Clin Invest Branch, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20850 USA. [Pazdur, Richard] US FDA, Off Hematol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Pazdur, Richard] US FDA, Off Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Socinski, Mark A.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Sause, William T.] Univ Utah, Salt Lake City, UT USA. [Harpole, David H., Jr.] Duke Univ, Med Ctr, Durham, NC USA. [Korn, Edward L.] NCI, Biometr Res Branch, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20850 USA. [Hirsch, Fred R.] Univ Colorado, Sch Med, Denver, CO USA. RP Malik, SM (reprint author), NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20850 USA. EM shakun.malik@nih.gov NR 32 TC 5 Z9 5 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD OCT PY 2014 VL 9 IS 10 BP 1443 EP 1448 DI 10.1097/JTO.0000000000000314 PG 6 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AS6IS UT WOS:000344368000008 PM 25521397 ER PT J AU Zhao, C Hoppe, T Setty, MKHG Murray, D Chun, TW Hewlett, I Appella, DH AF Zhao, Chao Hoppe, Travis Setty, Mohan Kumar Haleyur Giri Murray, Danielle Chun, Tae-Wook Hewlett, Indira Appella, Daniel H. TI Quantification of plasma HIV RNA using chemically engineered peptide nucleic acids SO NATURE COMMUNICATIONS LA English DT Article ID RESOURCE-LIMITED SETTINGS; SANDWICH-HYBRIDIZATION; DNA DETECTION; POINT; ASSAY; CARE; NANOPARTICLES; ACCURACY; COMPLEX; BLOOD AB The remarkable stability of peptide nucleic acids (PNAs) towards enzymatic degradation makes this class of molecules ideal to develop as part of a diagnostic device. Here we report the development of chemically engineered PNAs for the quantitative detection of HIV RNA at clinically relevant levels that are competitive with current PCR-based assays. Using a sandwich hybridization approach, chemical groups were systematically introduced into a surface PNA probe and a reporter PNA probe to achieve quantitative detection for HIV RNA as low as 20 copies per millilitre of plasma. For the surface PNA probe, four cyclopentane groups were incorporated to promote stronger binding to the target HIV RNA compared with PNA without the cyclopentanes. For the reporter PNA probe, 25 biotin groups were attached to promote strong signal amplification after binding to the target HIV RNA. These general approaches to engineer PNA probes may be used to detect other RNA target sequences. C1 [Zhao, Chao; Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. [Hoppe, Travis] NIDDK, Lab Biochem & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Setty, Mohan Kumar Haleyur Giri; Hewlett, Indira] FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Murray, Danielle; Chun, Tae-Wook] NIDDK, Immunoregulat Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Appella, DH (reprint author), NIDDK, Bioorgan Chem Lab, NIH, DHHS, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM appellad@niddk.nih.gov OI Hoppe, Travis/0000-0002-4694-3050 FU Intramural AIDS Targeted Antiviral Programme of NIH; Intramural Research Programme of NIDDK, NIH FX This research was supported by the Intramural Research Programme of NIDDK, NIH and the Intramural AIDS Targeted Antiviral Programme of NIH. We would like to thank Dr Frank Maldarelli for assistance in processing the patient samples. NR 44 TC 2 Z9 2 U1 3 U2 26 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 2014 VL 5 AR 5079 DI 10.1038/ncomms6079 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS0OR UT WOS:000343977900003 PM 25283173 ER PT J AU Orleans, RJ Li, L Kim, MJ Guo, J Sobhan, M Soule, L Joffe, HV AF Orleans, Ronald J. Li, Li Kim, Myong-Jin Guo, Jia Sobhan, Mahboob Soule, Lisa Joffe, Hylton V. TI FDA Approval of Paroxetine for Menopausal Hot Flushes EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB In June 2013, the Food and Drug Administration (FDA) approved paroxetine (Brisdelle, Noven) for the treatment of moderate to severe hot flushes (vasomotor symptoms) associated with menopause. Brisdelle is the only nonhormonal treatment approved by the FDA for this indication. Prior to approval of Brisdelle, FDA-approved treatments for hot flashes were hormones containing either estrogen alone or estrogen plus a progestin. Hormonal therapy is highly effective for treating vasomotor symptoms. However, the use of hormonal therapy dropped substantially after initial findings of the Women's Health Initiative randomized controlled trial suggested that the combined use of estrogens and progestin increased the risk of invasive breast cancer, coronary artery disease, stroke, and venous thromboembolism. Brisdelle contains a low dose of paroxetine (7.5 mg) and is given once daily. The drug provides modest relief of vasomotor symptoms in comparison to placebo. The safety and effectiveness of Brisdelle were established in 2 randomized, double-blind, placebo-controlled studies involving 1184 postmenopausal women who had a median of 10 moderate to severe hot flushes per day. In 1 study, after 12 weeks of treatment, Brisdelle-treated women had 5.9 fewer moderate-severe hot flushes per day, and placebo-treated women had 5.0 fewer moderate-severe hot flushes per day. The small difference between the 2 groups (0.9 hot flushes per day) was statistically significant (P < 0.01). Another study showed a larger difference (1.7 hot flushes per day), which was also statistically significant (P < 0.001). The efficacy of the drug was maintained at 6 months in both studies. Paroxetine is also the active moiety of 2 antidepressant drugs, Paxil (GlaxoSmithKline) and Pexeva (Noven). Both contain higher doses of paroxetine and are approved for treatment of major depressive disorders, obsessive-compulsive disorders, and generalized anxiety disorders. Recommended doses of these drugs start at 10 to 20 mg, with gradual increases, as needed, to a maximum recommended dose of 40 to 60 mg. Like other preparations of paroxetine, the most common adverse effects of Brisdelle are headache, fatigue, and nausea/vomiting. There is also a risk of bleeding events, hyponatremia, and akathisia. All antidepressant medications containing paroxetine including Brisdelle have a boxed warning about increased risk of suicide in children and young adults. The FDA Reproductive Health Drug Advisory Committee voted 10-to-4 against approval of Brisdelle. This negative vote reflected concerns of the Committee about Brisdelle's modest efficacy and the risk of suicidal ideation. Approval by the FDA in face of the negative vote by its Advisory Committee was mostly the due to the absence of any approved hormone-free drug to treat vasomotor symptoms and the FDA conclusion that Brisdelle would provide a clinically meaningful benefit for some menopausal women. C1 [Orleans, Ronald J.; Li, Li; Kim, Myong-Jin; Guo, Jia; Sobhan, Mahboob; Soule, Lisa; Joffe, Hylton V.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Orleans, RJ (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. NR 2 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD OCT PY 2014 VL 69 IS 10 BP 590 EP 591 DI 10.1097/OGX.0000000000000109 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AS7RS UT WOS:000344453200011 ER PT J AU Johnson, GE Soeteman-Hernandez, LG Gollapudi, BB Bodger, OG Dearfield, KL Heflich, RH Hixon, JG Lovell, DP MacGregor, JT Pottenger, LH Thompson, CM Abraham, L Thybaud, V Tanir, JY Zeiger, E van Benthem, J White, PA AF Johnson, G. E. Soeteman-Hernandez, L. G. Gollapudi, B. B. Bodger, O. G. Dearfield, K. L. Heflich, R. H. Hixon, J. G. Lovell, D. P. MacGregor, J. T. Pottenger, L. H. Thompson, C. M. Abraham, L. Thybaud, V. Tanir, J. Y. Zeiger, E. van Benthem, J. White, P. A. TI Derivation of Point of Departure (PoD) Estimates in Genetic Toxicology Studies and Their Potential Applications in Risk Assessment SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE benchmark dose; ENU; MNU; alkylating agents; margin of exposure ID DOSE-RESPONSE RELATIONSHIPS; CARCINOGENIC POTENCY; ALKYLATING-AGENTS; MUTATION ASSAYS; BISPHENOL-A; DNA-REPAIR; MICRONUCLEUS; THRESHOLDS; MICE AB Genetic toxicology data have traditionally been employed for qualitative, rather than quantitative evaluations of hazard. As a continuation of our earlier report that analyzed ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS) dose-response data (Gollapudi et al., 2013), here we present analyses of 1-ethyl-1-nitrosourea (ENU) and 1-methyl-1-nitrosourea (MNU) dose-response data and additional approaches for the determination of genetic toxicity point-of-departure (PoD) metrics. We previously described methods to determine the noobserved- genotoxic-effect-level (NOGEL), the breakpoint-dose (BPD; previously named Td), and the benchmark dose (BMD10) for genetic toxicity endpoints. In this study we employed those methods, along with a new approach, to determine the non-linear slope-transition-dose (STD), and alternative methods to determine the BPD and BMD, for the analyses of nine ENU and 22 MNU datasets across a range of in vitro and in vivo endpoints. The NOGEL, BMDL10 and BMDL1SD PoD metrics could be readily calculated for most gene mutation and chromosomal damage studies; however, BPDs and STDs could not always be derived due to data limitations and constraints of the underlying statistical methods. The BMDL10 values were often lower than the other PoDs, and the distribution of BMDL10 values produced the lowest median PoD. Our observations indicate that, among the methods investigated in this study, the BMD approach is the preferred PoD for quantitatively describing genetic toxicology data. Once genetic toxicology PoDs are calculated via this approach, they can be used to derive reference doses and margin of exposure values that may be useful for evaluating human risk and regulatory decision making. (C) 2014 Wiley Periodicals, Inc. C1 [Johnson, G. E.; Bodger, O. G.] Swansea Univ, Coll Med, Inst Life Sci, Swansea, W Glam, Wales. [Soeteman-Hernandez, L. G.; van Benthem, J.] Natl Inst Publ Hlth & Environm RIVM, Ctr Hlth Protect, Bilthoven, Netherlands. [Gollapudi, B. B.] Exponent, Ctr Toxicol & Mechanist Biol, Midland, MI USA. [Dearfield, K. L.] Food Safety & Inspect Serv, USDA, Off Publ Hlth Sci, Washington, DC USA. [Heflich, R. H.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Hixon, J. G.] ToxStrategies, Austin, TX USA. [Lovell, D. P.] St Georges Univ London, Div Biomed Sci, London, England. [MacGregor, J. T.] Toxicol Consulting Serv, Bonita Springs, FL USA. [Pottenger, L. H.] Dow Chem Co USA, Midland, MI 48674 USA. [Thompson, C. M.; Abraham, L.] ToxStrategies, Katy, TX USA. [Thybaud, V.] Sanofi, Vitry Alfortville Res Ctr, Drug Disposit, Preclin Safety & Anim Res, Vitry Sur Seine, France. [Tanir, J. Y.] ILSI Hlth & Environm Sci Inst, Washington, DC USA. [Zeiger, E.] Errol Zeiger Consulting, Chapel Hill, NC USA. [White, P. A.] Hlth Canada, Environm Hlth Sci & Res Bur, Hlth Environm & Consumer Safety Branch, Ottawa, ON K1A 0L2, Canada. RP Johnson, GE (reprint author), Swansea Univ, Coll Med, Inst Life Sci, Swansea, W Glam, Wales. EM g.johnson@swansea.ac.uk; paul.white@hc-sc.gc.ca OI white, paul/0000-0001-5853-4759; Johnson, George/0000-0001-5643-9942 NR 43 TC 35 Z9 35 U1 5 U2 13 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 2014 VL 55 IS 8 BP 609 EP 623 DI 10.1002/em.21870 PG 15 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AR8KK UT WOS:000343823800002 PM 24801602 ER PT J AU Kazandjian, D Blumenthal, GM Chen, HY He, K Patel, M Justice, R Keegan, P Pazdur, R AF Kazandjian, Dickran Blumenthal, Gideon M. Chen, Huan-Yu He, Kun Patel, Mona Justice, Robert Keegan, Patricia Pazdur, Richard TI FDA Approval Summary: Crizotinib for the Treatment of Metastatic Non-Small Cell Lung Cancer With Anaplastic Lymphoma Kinase Rearrangements SO ONCOLOGIST LA English DT Article DE EML4-ALK fusion protein; Crizotinib; Non-small cell lung carcinoma; Molecular targeted therapy; Neoplasm metastasis ID CHEMOTHERAPY; MUTATIONS; GENE; ALK; STATISTICS; ERLOTINIB; FUSION AB On August 26, 2011, crizotinib received accelerated approval for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is ALK-positive as detected by a test approved by the U. S. Food and Drug Administration (FDA). Approval was based on two single-arm trials demonstrating objective response rates (ORRs) of 50% and 61% and median response durations of 42 and 48 weeks. On November 20, 2013, crizotinib received regular approval based on confirmation of clinical benefit in study A8081007, a randomized trial in 347 patients with ALK-positive advanced NSCLC who had previously received one platinum-containing regimen. Patients were assigned (1:1) to receive crizotinib 250 mg orally twice daily or standard of care (docetaxel or pemetrexed). The primary endpoint was progression-free survival (PFS) determined by independent radiology review; secondary endpoints were ORR and overall survival (OS). PFS was significantly longer in the crizotinib arm, with median PFS of 7.7 and 3.0 months in the crizotinib and chemotherapy arms, respectively, and a 46% absolute increase in ORR but no difference in OS between treatment arms at the interim analysis. The most common adverse drug reactions (>25%) in crizotinib-treated patients were vision disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue. The most serious toxicities of crizotinib were hepatotoxicity, interstitial lung disease or pneumonitis, and QT-interval prolongation. Crizotinib's rapid clinical development program (6 years from identification of ALK rearrangements in a subset of NSCLC to full FDA approval) is a model of efficient drug development in this new era of molecularly targeted oncology therapy. C1 US FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, Silver Spring, MD 20993 USA. US FDA, Ctr Drug Evaluat & Res, Off Biostat, Silver Spring, MD 20993 USA. RP Kazandjian, D (reprint author), US FDA, White Oak Campus,10903 New Hampshire Ave,Bldg 22, Silver Spring, MD 20993 USA. EM Dickran.kazandjian@fda.hhs.gov NR 22 TC 30 Z9 33 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 OCT PY 2014 VL 19 IS 10 BP E5 EP E11 DI 10.1634/theoncologist.2014-0241 PG 7 WC Oncology SC Oncology GA AR9QS UT WOS:000343910500001 PM 25170012 ER PT J AU Sridhar, G Ekezue, BF Izurieta, HS Selvam, N Ovanesov, MV Divan, HA Liang, YD Golding, B Forshee, RA Anderson, SA Menis, M AF Sridhar, Gayathri Ekezue, Bola F. Izurieta, Hector S. Selvam, Nandini Ovanesov, Mikhail V. Divan, Hozefa A. Liang, Yideng Golding, Basil Forshee, Richard A. Anderson, Steven A. Menis, Mikhail TI Immune globulins and same-day thrombotic events as recorded in a large health care database during 2008 to 2012 SO TRANSFUSION LA English DT Article ID INTRAVENOUS IMMUNOGLOBULIN THERAPY; ADVERSE EVENTS; THROMBOEMBOLIC EVENTS; VENOUS THROMBOEMBOLISM; FACTOR XIA; RISK; COMPLICATIONS; IVIG; IMMUNOLOGY; GENERATION AB BackgroundThrombotic events (TEs) are rare and serious adverse events after administration of immune globulin (IG) products. Our study evaluated the occurrence of same-day TEs for different IG products and ascertained potential risk factors. Study Design and MethodsThis retrospective cohort study utilized HealthCore's Integrated Research Database (HIRD) to assess individuals exposed to IGs during 2008 to 2012. IG products were identified using recorded procedure codes and TEs were ascertained using ICD-9-CM diagnosis codes. The unadjusted same-day TE rates (per 1000 persons exposed) were estimated overall and by IG products, age, and sex. Multivariable logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for same-day TEs by IG products. ResultsOf 14,944 individuals exposed to IG products, 233 (15.6 per 1000 persons) had TE diagnosis code(s) recorded on the same-day as the IG exposure. Compared to Gammagard Liquid, Gammaplex (OR, 20.96; 95% CI, 2.45-179.33) and Vivaglobin (OR, 2.74; 95% CI, 1.19-6.32) users had a significantly increased same-day TE risk. Elevated, but nonsignificant TE risks were identified for Octagam, Gamunex, Privigen, and Lyophilized IG(s). An increased TE risk was also found with older age (45 years), prior TEs, and other health conditions. ConclusionOur claims-based cohort study suggests a potentially elevated TE risk with different IG products and shows importance of recipient factors such as older age, previous TE, hypercoagulable state(s), and other health conditions. The results of this study suggest the need for continuous evaluation of procoagulant activity and manufacturing processes for IG products to further assure their safety. C1 [Sridhar, Gayathri; Ekezue, Bola F.; Selvam, Nandini; Divan, Hozefa A.] HealthCore Inc, Alexandria, VA 22311 USA. [Izurieta, Hector S.; Ovanesov, Mikhail V.; Liang, Yideng; Golding, Basil; Forshee, Richard A.; Anderson, Steven A.; Menis, Mikhail] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Sridhar, G (reprint author), HealthCore Inc, 2001 N Beauregard St,Suite 500, Alexandria, VA 22311 USA. EM gsridhar@healthcore.com FU US Food and Drug Administration, Center for Biologics Evaluation and Research FX This study was funded by the US Food and Drug Administration, Center for Biologics Evaluation and Research. NR 51 TC 9 Z9 9 U1 0 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 OCT PY 2014 VL 54 IS 10 BP 2553 EP 2565 DI 10.1111/trf.12663 PG 13 WC Hematology SC Hematology GA AR8GN UT WOS:000343813900025 PM 24804899 ER PT J AU Zhao, YW Wang, SG Xia, QS da Costa, GG Doerge, DR Cai, LN Fu, PP AF Zhao, Yuewei Wang, Shuguang Xia, Qingsu da Costa, Goncalo Gamboa Doerge, Daniel R. Cai, Lining Fu, Peter P. TI Reaction of Dehydropyrrolizidine Alkaloids with Valine and Hemoglobin SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID DNA ADDUCT FORMATION; PYRROLIZIDINE ALKALOIDS; METABOLIC-ACTIVATION; MEDICINAL-PLANTS; DIETARY-SUPPLEMENTS; CROSS-LINKING; IN-VIVO; RIDDELLIINE; TUMORIGENICITY; RATS AB Pyrrolizidine alkaloid-containing plants are probably the most common poisonous Plants affecting livestock, wildlife, and humans. Pyrrolizidi e alkaloids exert toxicity through metabolism to dehydropyrrolizidine alkaloids that bind to cellular protein and DNA, leading to hepatotoxicity, genotoxicity, and tumorigenicity. To date, it is not clear how dehyclropyrrolizidine alkaloids bind to cellular constituents, including amino acids and proteins, resulting in. toxicity. Metabolism of carcinogenic monncrotaline; riddel-DHP-valinea lime, and heliotrine produces dehydromonocroline dehyroriddelliine, and dehydroheliotrine, respectively, as primary reactive metabolites. In this study, we report that reaction of dehydromonocrotaline with valine generated four highly unstabl e 6,7-dihyclro-7-hydroxy-l-hydroxymethyl-H-5-pyrrolizine (DHP)-denved valine (DHP valine) adducts. For structural elucidation, DI-IP valine adducts were derivatized with phenyl isothiocyanate (PITC) to DHP valine PIT'C' product's. After HPLC separation, their structures were characterized by mass spectrometry, UV visible spectrophotometry, NMR, and H-1-H-1 COSY NMR spectral analysis. Two DHP valine PITC adducts, designated as DHP valine PITC-1 and DHP valine PITC3, had the amino group of valine linked to the C7 position of the necine base, and the other two DHP--valine PITC P roducts, DHP valine-PITC-2 and DP valine PITC-4, linked to the C9 position of the necine base. DI-IP valine PITC I was interconvertible with DHP valine p ITC-3, and DHP valine--PITC 2 was interconvertible with DHP valine PI-TC 4 Reaction of dehydroriddelliine and dehyclroheliotrine with valine provided similar results. However, reaction of valine and dehydroretronecine (DHR) under similar experimental conditions did not produce DHP-valine adducts. Reaction of dehydromonocrotaline with rat hemoglobin followed by derivatization with PITC also generated the same four DHP valine PITC adducts. This represents the first full structural elucidation of protein conjugated pyrrolic adducts formed from reaction of dehydropyrrolizidine alkaloids with an amino acid (valine). In addition, it was found- that DHP-valine-2 and DHP-valine-4, with the valine amino group linked at the C7 position of the necine base, can lose the valine moiety to form DHP. C1 [Zhao, Yuewei; Wang, Shuguang; Xia, Qingsu; da Costa, Goncalo Gamboa; Doerge, Daniel R.; Fu, Peter P.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Cai, Lining] Biotranex LLC, Monmouth Jct, NJ 08852 USA. RP Fu, PP (reprint author), Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM peter.fu@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration (FDA) FX This research was supported in part by appointments (Y.Z. and S.W.) to the Postgraduate Research Program at the NCTR 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). NR 48 TC 7 Z9 7 U1 4 U2 19 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 OCT PY 2014 VL 27 IS 10 BP 1720 EP 1731 DI 10.1021/tx50021391 PG 12 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA AR3ZB UT WOS:000343526700008 PM 25211425 ER PT J AU Biddison, LD Berkowitz, KA Courtney, B De Jong, MJ Devereaux, AV Kissoon, N Roxland, BE Sprung, CL Dichter, JR Christian, MD Powell, T AF Biddison, Lee Daugherty Berkowitz, Kenneth A. Courtney, Brooke De Jong, Marla J. Devereaux, Asha V. Kissoon, Niranjan Roxland, Beth E. Sprung, Charles L. Dichter, Jeffrey R. Christian, Michael D. Powell, Tia CA Task Force Mass Critical Care TI Ethical Considerations Care of the Critically Ill and Injured During Pandemics and Disasters: CHEST Consensus Statement SO CHEST LA English DT Article ID MASS CRITICAL-CARE; TASK-FORCE; JANUARY 26-27; CONDUCTING RESEARCH; NATURAL DISASTERS; DEFINITIVE CARE; INFLUENZA; HEALTH; TRIAGE; ALLOCATION AB BACKGROUND: Mass critical care entails time-sensitive decisions and changes in the standard of care that it is possible to deliver. These circumstances increase provider uncertainty as well as patients' vulnerability and may, therefore, jeopardize disciplined, ethical decision-making. Planning for pandemics and disasters should incorporate ethics guidance to support providers who may otherwise make ad hoc patient care decisions that overstep ethical boundaries. This article provides consensus-developed suggestions about ethical challenges in caring for the critically ill or injured during pandemics or disasters. The suggestions in this article are important for all of those involved in any pandemic or disaster with multiple critically ill or injured patients, including front-line clinicians, hospital administrators, and public health or government officials. METHODS: We adapted the American College of Chest Physicians (CHEST) Guidelines Oversight Committee's methodology to develop suggestions. Twenty-four key questions were developed, and literature searches were conducted to identify evidence for suggestions. The detailed literature reviews produced 144 articles. Based on their expertise within this domain, panel members also supplemented the literature search with governmental publications, interdisciplinary workgroup consensus documents, and other information not retrieved through PubMed. The literature in this field is not suitable to support evidence-based recommendations. Therefore, the panel developed expert opinion-based suggestions using a modified Delphi process. RESULTS: We report the suggestions that focus on five essential domains: triage and allocation, ethical concerns of patients and families, ethical responsibilities to providers, conduct of research, and international concerns. CONCLUSIONS: Ethics issues permeate virtually all aspects of pandemic and disaster response. We have addressed some of the most pressing issues, focusing on five essential domains: triage and allocation, ethical concerns of patients and families, ethical responsibilities to providers, conduct of research, and international concerns. Our suggestions reflect the consensus of the Task Force. We recognize, however, that some suggestions, including those related to end-of-life care, may be controversial. We highlight the need for additional research and dialogue in articulating values to guide health-care decisions during disasters. CHEST 2014; 146 (4_Suppl): e145S-e155S C1 [Biddison, Lee Daugherty] Johns Hopkins Sch Med, Baltimore, MD 21287 USA. [Berkowitz, Kenneth A.] NYU, Sch Med, Vet Hlth Adm, New York, NY USA. [Courtney, Brooke] US FDA, Off Counterterrorism & Emerging Threats, Off Commissioner, Silver Spring, MD USA. [De Jong, Marla J.] US Air Force Sch Aerosp Med, Wright Patterson AFB, OH USA. [Devereaux, Asha V.] Sharp Hosp, Coronado, CA USA. [Kissoon, Niranjan] Univ British Columbia, BC Childrens Hosp, Vancouver, BC V5Z 1M9, Canada. [Kissoon, Niranjan] Univ British Columbia, Sunny Hill Hlth Ctr, Vancouver, BC V5Z 1M9, Canada. [Roxland, Beth E.] NYU, Sch Law, Langone Med Ctr, New York, NY 10003 USA. [Sprung, Charles L.] Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel. [Dichter, Jeffrey R.] Allina Hlth, Minneapolis, MN USA. [Dichter, Jeffrey R.] Aurora Hlth, Milwaukee, WI USA. [Christian, Michael D.] Canadian Armed Forces, Royal Canadian Med Serv, Toronto, ON, Canada. [Christian, Michael D.] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Powell, Tia] Albert Einstein Coll Med, Montefiore Med Ctr, New York, NY USA. RP Biddison, LD (reprint author), Johns Hopkins Sch Med, 1830 E Monument St,Room 549, Baltimore, MD 21287 USA. EM edaughe2@jhmi.edu OI West, T Eoin/0000-0001-5503-7204 FU Centers of Disease Control and Prevention [1U90TP00591-01]; Department of Health and Human Services from the Office of Preparedness of Emergency Operations [1 - HFPEP070013-01-00]; University of California-Davis FX This publication was supported by the Cooperative Agreement Number 1U90TP00591-01 from the Centers of Disease Control and Prevention, and through a research sub award agreement through the Department of Health and Human Services [Grant 1 - HFPEP070013-01-00] from the Office of Preparedness of Emergency Operations. In addition, this publication was supported by a grant from the University of California-Davis. NR 60 TC 3 Z9 3 U1 1 U2 8 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD OCT PY 2014 VL 146 IS 4 SU S BP E145S EP E155S DI 10.1378/chest.14-0742 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AR4RN UT WOS:000343574100010 PM 25144262 ER PT J AU Courtney, B Hodge, JG Toner, ES Roxland, BE Penn, MS Devereaux, AV Dichter, JR Kissoon, N Christian, MD Powell, T AF Courtney, Brooke Hodge, James G., Jr. Toner, Eric S. Roxland, Beth E. Penn, Matthew S. Devereaux, Asha V. Dichter, Jeffrey R. Kissoon, Niranjan Christian, Michael D. Powell, Tia CA Task Force Mass Critical Care TI Legal Preparedness Care of the Critically Ill and Injured During Pandemics and Disasters: CHEST Consensus Statement SO CHEST LA English DT Article ID PUBLIC-HEALTH EMERGENCIES; MASS CRITICAL-CARE; LIABILITY; CHALLENGES; STANDARDS; LESSONS; CRISIS; SANDY; LAWS AB BACKGROUND: Significant legal challenges arise when health-care resources become scarce and population-based approaches to care are implemented during severe disasters and pandemics. Recent emergencies highlight the serious legal, economic, and health impacts that can be associated with responding in austere conditions and the critical importance of comprehensive, collaborative health response system planning. This article discusses legal suggestions developed by the American College of Chest Physicians (CHEST) Task Force for Mass Critical Care to support planning and response efforts for mass casualty incidents involving critically ill or injured patients. The suggestions in this chapter are important for all of those involved in a pandemic or disaster with multiple critically ill or injured patients, including front-line clinicians, hospital administrators, and public health or government officials. METHODS: Following the CHEST Guidelines Oversight Committee's methodology, the Legal Panel developed 35 key questions for which specific literature searches were then conducted. The literature in this field is not suitable to provide support for evidence-based recommendations. Therefore, the panel developed expert opinion-based suggestions using a modified Delphi process resulting in seven final suggestions. RESULTS: Acceptance is widespread for the health-care community's duty to appropriately plan for and respond to severe disasters and pandemics. Hospitals, public health entities, and clinicians have an obligation to develop comprehensive, vetted plans for mass casualty incidents involving critically ill or injured patients. Such plans should address processes for evacuation and limited appeals and reviews of care decisions. To legitimize responses, deter independent actions, and trigger liability protections, mass critical care (MCC) plans should be formally activated when facilities and practitioners shift to providing MCC. Adherence to official MCC plans should contribute to protecting hospitals and practitioners who act in good faith from liability. Finally, to address anticipated staffing shortages during severe and prolonged disasters and pandemics, governments should develop approaches to formally expand the availability of qualified health-care workers, such as through using official foreign medical teams. CONCLUSIONS: As a fundamental element of health-care and public health emergency planning and preparedness, the law underlies critical aspects of disaster and pandemic responses. Effective responses require comprehensive advance planning efforts that include assessments of complex legal issues and authorities. Recent disasters have shown that although law is a critical response tool, it can also be used to hold health-care stakeholders who fail to appropriately plan for or respond to disasters and pandemics accountable for resulting patient or staff harm. Claims of liability from harms allegedly suffered during disasters and pandemics cannot be avoided altogether. However, appropriate planning and legal protections can help facilitate sound, consistent decision-making and support response participation among health-care entities and practitioners. CHEST 2014; 146 (4_Suppl): e134S-e144S C1 [Courtney, Brooke] US FDA, Off Counterterrorism & Emerging Threats, Off Commissioner, Silver Spring, MD USA. [Hodge, James G., Jr.] Arizona State Univ, Sandra Day OConnor Coll Law, Tempe, AZ USA. [Toner, Eric S.] Univ Pittsburgh, Med Ctr, UPMC Ctr Hlth Secur, Baltimore, MD USA. [Roxland, Beth E.] NYU, Sch Law, Langone Med Ctr, New York, NY 10003 USA. [Penn, Matthew S.] Ctr Dis Control & Prevent, Publ Hlth Law Program, Off State Tribal Local & Terr Support, Atlanta, GA USA. [Devereaux, Asha V.] Sharp Hosp, Coronado, CA USA. [Dichter, Jeffrey R.] Allina Hlth, Minneapolis, MN USA. [Dichter, Jeffrey R.] Aurora Healthcare, Milwaukee, WI USA. [Kissoon, Niranjan] Univ British Columbia, BC Childrens Hosp, Vancouver, BC V5Z 1M9, Canada. [Kissoon, Niranjan] Univ British Columbia, Sunny Hill Hlth Ctr, Vancouver, BC V5Z 1M9, Canada. [Christian, Michael D.] Canadian Armed Forces, Royal Canadian Med Serv, Toronto, ON, Canada. [Christian, Michael D.] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Powell, Tia] Albert Einstein Coll Med, Montefiore Med Ctr, New York, NY USA. RP Christian, MD (reprint author), Univ Toronto, Mt Sinai Hosp, Royal Canadian Air Force, 600 Univ Ave,Rm 18-232-1, Toronto, ON M4X 1P4, Canada. EM michael.christian@utoronto.ca OI West, T Eoin/0000-0001-5503-7204 FU Centers of Disease Control and Prevention [1U90TP00591-01]; Department of Health and Human Services from the Office of Preparedness of Emergency Operations [1 - HFPEP070013-01-00]; University of California-Davis FX This publication was supported by the Cooperative Agreement Number 1U90TP00591-01 from the Centers of Disease Control and Prevention, and through a research sub award agreement through the Department of Health and Human Services [Grant 1 - HFPEP070013-01-00] from the Office of Preparedness of Emergency Operations. In addition, this publication was supported by a grant from the University of California-Davis. NR 72 TC 0 Z9 0 U1 1 U2 4 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD OCT PY 2014 VL 146 IS 4 SU S BP E134S EP E144S DI 10.1378/chest.14-0741 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AR4RN UT WOS:000343574100009 PM 25144203 ER PT J AU Livio, S Strockbine, NA Panchalingam, S Tennant, SM Barry, EM Marohn, ME Antonio, M Hossain, A Mandomando, I Ochieng, JB Oundo, JO Qureshi, S Ramamurthy, T Tamboura, B Adegbola, RA Hossain, MJ Saha, D Sen, S Faruque, AS Alonso, PL Breiman, RF Zaidi, AKM Sur, D Sow, SO Berkeley, LY O'Reilly, CE Mintz, ED Biswas, K Cohen, D Farag, TH Nasrin, D Wu, YK Blackwelder, WC Kotloff, KL Nataro, JP Levine, MM AF Livio, Sofie Strockbine, Nancy A. Panchalingam, Sandra Tennant, Sharon M. Barry, Eileen M. Marohn, Mark E. Antonio, Martin Hossain, Anowar Mandomando, Inacio Ochieng, John B. Oundo, Joseph O. Qureshi, Shahida Ramamurthy, Thandavarayan Tamboura, Boubou Adegbola, Richard A. Hossain, Mohammed Jahangir Saha, Debasish Sen, Sunil Faruque, Abu Syed Golam Alonso, Pedro L. Breiman, Robert F. Zaidi, Anita K. M. Sur, Dipika Sow, Samba O. Berkeley, Lynette Y. O'Reilly, Ciara E. Mintz, Eric D. Biswas, Kousick Cohen, Dani Farag, Tamer H. Nasrin, Dilruba Wu, Yukun Blackwelder, William C. Kotloff, Karen L. Nataro, James P. Levine, Myron M. TI Shigella Isolates From the Global Enteric Multicenter Study Inform Vaccine Development SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE serotyping; Shigella; shigellosis; vaccines ID SHIGA BACILLUS DYSENTERY; FLEXNERI 2A; DIARRHEAL DISEASE; ORAL IMMUNIZATION; DEVELOPING-COUNTRIES; ENTEROTOXIN GENES; SERUM ANTIBODIES; YOUNG-CHILDREN; O-ANTIGEN; IN-VITRO AB Background. Shigella, a major diarrheal disease pathogen worldwide, is the target of vaccine development. The Global Enteric Multicenter Study (GEMS) investigated burden and etiology of moderate-to-severe diarrheal disease in children aged <60 months and matched controls without diarrhea during 3 years at 4 sites in Africa and 3 in Asia. Shigella was 1 of the 4 most common pathogens across sites and age strata. GEMS Shigella serotypes are reviewed to guide vaccine development. Methods. Subjects' stool specimens/rectal swabs were transported to site laboratories in transport media and plated onto xylose lysine desoxycholate and MacConkey agar. Suspect Shigella colonies were identified by biochemical tests and agglutination with antisera. Shigella isolates were shipped to the GEMS Reference Laboratory (Baltimore, MD) for confirmation and serotyping of S. flexneri; one-third of isolates were sent to the Centers for Disease Control and Prevention for quality control. Results. Shigella dysenteriae and S. boydii accounted for 5.0% and 5.4%, respectively, of 1130 Shigella case isolates; S. flexneri comprised 65.9% and S. sonnei 23.7%. Five serotypes/subserotypes comprised 89.4% of S. flexneri, including S. flexneri 2a, S. flexneri 6, S. flexneri 3a, S. flexneri 2b, and S. flexneri 1b. Conclusions. A broad-spectrum Shigella vaccine must protect against S. sonnei and 15 S. flexneri serotypes/subserotypes. A quadrivalent vaccine with O antigens from S. sonnei, S. flexneri 2a, S. flexneri 3a, and S. flexneri 6 can provide broad direct coverage against these most common serotypes and indirect coverage against all but 1 (rare) remaining subserotype through shared S. flexneri group antigens. C1 [Livio, Sofie; Panchalingam, Sandra; Tennant, Sharon M.; Barry, Eileen M.; Marohn, Mark E.; Sen, Sunil; Berkeley, Lynette Y.; Farag, Tamer H.; Nasrin, Dilruba; Wu, Yukun; Blackwelder, William C.; Kotloff, Karen L.; Nataro, James P.; Levine, Myron M.] Univ Maryland Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Strockbine, Nancy A.] Ctr Dis Control & Prevent, Escherichia & Shigella Reference Unit, Enter Dis Lab Branch, Atlanta, GA USA. [Strockbine, Nancy A.; O'Reilly, Ciara E.; Mintz, Eric D.] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Atlanta, GA USA. [Antonio, Martin; Adegbola, Richard A.; Hossain, Mohammed Jahangir; Saha, Debasish] Med Res Council Unit United Kingdom, Fajara, Gambia. [Hossain, Anowar; Faruque, Abu Syed Golam] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. [Mandomando, Inacio; Alonso, Pedro L.] Ctr Invest Saude Manhica, Manhica, Mozambique. [Mandomando, Inacio; Breiman, Robert F.] Univ Barcelona, Hosp Clinic, Ctr Recerca Salut Int Barcelona, E-08007 Barcelona, Spain. [Ochieng, John B.; Oundo, Joseph O.; Breiman, Robert F.] Ctr Dis Control & Prevent, Kenya Med Res Inst, Kisumu, Kenya. [Qureshi, Shahida; Zaidi, Anita K. M.] Aga Khan Univ, Dept Paediat & Child Hlth, Karachi, Pakistan. [Ramamurthy, Thandavarayan; Sur, Dipika] Natl Inst Cholera & Enter Dis, Kolkata, India. [Tamboura, Boubou; Sow, Samba O.] Ctr Dev Vaccins Mali, Bamako, Mali. [Breiman, Robert F.] US Ctr Dis Control & Prevent, Global Dis Detect Div, Kenya Off, Nairobi, Kenya. [Sur, Dipika] PATH, New Delhi, India. [Berkeley, Lynette Y.] US FDA, Rockville, MD 20857 USA. [Biswas, Kousick] US Dept Vet Affairs, Cooperat Studies Program Coordinating Ctr, Perry Point, MD USA. [Cohen, Dani] Tel Aviv Univ, Sackler Fac Med, Sch Publ Hlth, Dept Epidemiol & Prevent Med, Ramat Aviv, Israel. RP Levine, MM (reprint author), Univ Maryland Sch Med, Ctr Vaccine Dev, 685 West Baltimore St, Baltimore, MD 21201 USA. EM mlevine@medicine.umaryland.edu FU Bill & Melinda Gates Foundation [38774] FX This work was supported by grant 38774 from the Bill & Melinda Gates Foundation to M. M. L. NR 46 TC 51 Z9 52 U1 2 U2 16 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 OCT 1 PY 2014 VL 59 IS 7 BP 933 EP 941 DI 10.1093/cid/ciu468 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AR2JY UT WOS:000343411900005 PM 24958238 ER PT J AU Bae, D Mezal, EH Smiley, RD Cheng, CM Khan, AA AF Bae, Dongryeoul Mezal, Ezat H. Smiley, Ronald D. Cheng, Chorng-Ming Khan, Ashraf A. TI The sub-species characterization and antimicrobial resistance of Listeria monocytogenes isolated from domestic and imported food products from 2004 to 2011 SO FOOD RESEARCH INTERNATIONAL LA English DT Article DE Listeria monocytogenes; PFGE; Food; Antimicrobial resistance; Food safety ID EFFLUX PUMP MDRT; MULTIDRUG-RESISTANCE; UNITED-STATES; BENZALKONIUM CHLORIDE; RETAIL FOODS; SP NOV.; SUSCEPTIBILITY; EXPRESSION; STRAINS; OUTBREAKS AB Thirty-five Listeria monocytogenes strains isolated from domestic and imported food products including seafood, vegetables, and dairy foods were characterized by serotyping, molecular sub-typing, and antimicrobial susceptibility. L monocytogenes serovars 1/2a and 1/2b strains were dominant as cOmpared to other two serovars 4b and 1/2c strains. The dendrogram of Ascl or ApaI-digested PFGE profiles of L. monocytogenes strains was classified into 23 (with 8 groups) or 3 (with 2 groups) different PFGE types, respectively. The AscI-digested groups consisted of the same serovar or food-source. Antimicrobials such as ampicillin, gentamicin, and trimethoprim-sulfamethoxazole are widely used in the treatment of listeriosis. Of the isolates used in this study, NCTIUM14 and NCTR_LM57 were resistant to several classes of antimicrobials including aminoglycosides, penicillin, tetracycline, glycopeptide and fluoroquinolones. The multi-antimicrobial resistant isolates also showed higher efflux pump activity as compared to the antimicrobial sensitive strains NCTR_LM06 and L monocytogenes EGD-e. This study demonstrates that L monocytogenes isolates from various food products are genetically diverse with some isolates being resistant to more than 3 different antibiotic classes. This study also indicates that the efflux pump activity of the antibiotic resistant strains was higher than antimicrobial susceptible strains. Therefore, we propose that the antibiotic resistance observed in these strains may be conferred by the results of a highly active efflux pump system. Published by Elsevier Ltd. C1 [Bae, Dongryeoul; Mezal, Ezat H.; Khan, Ashraf A.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Mezal, Ezat H.] Univ Thi Qar, Dept Biol, Thi Qar, Iraq. [Smiley, Ronald D.] US FDA, Arkansas Reg Lab, Off Regulatory Affairs, Jefferson, AR 72079 USA. [Cheng, Chorng-Ming] US FDA, Pacific Reg Lab Southwest, Off Regulatory Affairs, Irvine, CA 92612 USA. RP Khan, AA (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Ashraf.Khan@fda.hhs.gov NR 51 TC 3 Z9 3 U1 1 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0963-9969 EI 1873-7145 J9 FOOD RES INT JI Food Res. Int. PD OCT PY 2014 VL 64 BP 656 EP 663 DI 10.1016/j.foodres.2014.07.049 PG 8 WC Food Science & Technology SC Food Science & Technology GA AR8QX UT WOS:000343840700079 ER PT J AU Nadler, Z Wang, B Schuman, JS Ferguson, RD Patel, A Hammer, DX Bilonick, RA Ishikawa, H Kagemann, L Sigal, IA Wollstein, G AF Nadler, Zach Wang, Bo Schuman, Joel S. Ferguson, R. Daniel Patel, Ankit Hammer, Daniel X. Bilonick, Richard A. Ishikawa, Hiroshi Kagemann, Larry Sigal, Ian A. Wollstein, Gadi TI In Vivo Three-Dimensional Characterization of the Healthy Human Lamina Cribrosa With Adaptive Optics Spectral-Domain Optical Coherence Tomography SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE in vivo; OCT; structure ID SCANNING LASER OPHTHALMOSCOPY; GLAUCOMATOUS EYES; NERVE DAMAGE; REGIONAL DIFFERENCES; DEFECTS; IMAGES; HEAD; MICROARCHITECTURE; REPRODUCIBILITY; MORPHOMETRY AB PURPOSE. To characterize the in vivo three-dimensional (3D) lamina cribrosa (LC) micro-architecture of healthy eyes using adaptive optics spectral-domain optical coherence tomography (AO-SDOCT). METHODS. A multimodal retinal imaging system with a light source centered at 1050 nm and AO confocal scanning laser ophthalmoscopy was used in this study. One randomly selected eye from 18 healthy subjects was scanned in a 6 degrees x 6 degrees window centered on the LC. Subjects also underwent scanning with Cirrus HD-OCT. Lamina cribrosa microarchitecture was semiautomatically segmented and quantified for connective tissue volume fraction (CTVF), beam thickness, pore diameter, pore area, and pore aspect ratio. The LC was assessed in central and peripheral regions of equal areas and quadrants and with depth. A linear mixed effects model weighted by the fraction of visible LC was used to compare LC structure between regions. RESULTS. The nasal quadrant was excluded due to poor visualization. The central sector showed greater CTVF and thicker beams as compared to the periphery (P < 0.01). Both superior and inferior quadrants showed greater CTVF, pore diameter, and pore mean area than the temporal quadrant (P < 0.05). Depth analysis showed that the anterior and posterior aspects of the LC contained smaller pores with greater density and thinner beams as compared to the middle third (P < 0.05). The anterior third also showed a greater CTVF than the middle third (P < 0.05). CONCLUSIONS. In vivo analysis of healthy eyes using AO-SDOCT showed significant, albeit small, regional variation in LC microarchitecture by quadrant, radially, and with depth, which should be considered in further studies of the LC. C1 [Nadler, Zach; Wang, Bo; Schuman, Joel S.; Bilonick, Richard A.; Ishikawa, Hiroshi; Kagemann, Larry; Sigal, Ian A.; Wollstein, Gadi] Univ Pittsburgh, Med Ctr, Ctr Eye,Dept Ophthalmol, Ophthalmol & Visual Sci Res Ctr,Sch Med,Eye & Ear, Pittsburgh, PA USA. [Wang, Bo; Schuman, Joel S.; Ishikawa, Hiroshi; Kagemann, Larry; Sigal, Ian A.] Univ Pittsburgh, Swanson Sch Engn, Dept Bioengn, Pittsburgh, PA USA. [Ferguson, R. Daniel; Patel, Ankit] Phys Sci Inc, Andover, MA USA. [Hammer, Daniel X.] Food & Drug Adm, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Bilonick, Richard A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. RP Schuman, JS (reprint author), UPMC, Ctr Eye, 203 Lothrop St,Suite 816, Pittsburgh, PA 15213 USA. EM schumanjs@upmc.edu OI Kagemann, Larry/0000-0001-8961-0187; Ishikawa, Hiroshi/0000-0001-6310-5748 FU National Institutes of Health (Bethesda, MD, USA) [R01-EY013178, R01-EY023966, R44-EY018986, P30-EY008098, T32-EY017271]; Eye and Ear Foundation (Pittsburgh, PA, USA); Research to Prevent Blindness (New York, NY, USA) FX Supported in part by National Institutes of Health Contracts R01-EY013178, R01-EY023966, R44-EY018986, P30-EY008098, and T32-EY017271 (Bethesda, MD, USA); Eye and Ear Foundation (Pittsburgh, PA, USA); and Research to Prevent Blindness (New York, NY, USA). NR 36 TC 14 Z9 15 U1 5 U2 15 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD OCT PY 2014 VL 55 IS 10 BP 6459 EP 6466 DI 10.1167/iovs.14-15177 PG 8 WC Ophthalmology SC Ophthalmology GA AQ9DY UT WOS:000343147100046 PM 25228539 ER PT J AU Zou, LK Meng, JH McDermott, PF Wang, F Yang, QR Cao, GJ Hoffmann, M Zhao, SH AF Zou, Likou Meng, Jianghong McDermott, Patrick F. Wang, Fei Yang, Qianru Cao, Guojie Hoffmann, Maria Zhao, Shaohua TI Presence of disinfectant resistance genes in Escherichia coli isolated from retail meats in the USA SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article DE quaternary ammonium compounds; qac genes; antimicrobial resistance; MICs ID QUATERNARY AMMONIUM-COMPOUNDS; ANTIMICROBIAL RESISTANCE; MULTIDRUG TRANSPORTER; SALMONELLA-ENTERICA; INTEGRONS; PROTEINS; FAMILY; SUGE; IDENTIFICATION; PSEUDOMONAS AB Objectives: To examine the distribution of all genes known to be responsible for resistance to quaternary ammonium compounds (QACs), and their association with resistance to QACs and other antimicrobials, in Escherichia coli recovered from retail meats. Methods: A total of 570 strains of E. coli isolated from US retailmeats in 2006were screened for the presence of 10 QAC resistance genes [qacE, qacED1, qacF, qacG, emrE, sugE(c), sugE(p), mdfA and ydgE/ydgF]. The MICs of six common disinfectants were determined using an agar dilutionmethod. Possible associations between the presence of the gene and bacterial resistance to QACs and antimicrobials were investigated. Results: emrE, sugE(c), mdfA and ydgE/ydgF were commonly present (77.2%- 100%) in the E. coli isolates, but qac and sugE(p) were less prevalent (0.4%- 22.3%). emrE- mdfA- sugE(c)- ydgE/F was the most common QAC resistance gene profile. A significant association was found between antimicrobial resistance and the presence of sugE(p) and qacED1 (P < 0.05). Antimicrobial- resistant E. coli isolates tended to containmore diverse combinations of disinfectant resistance genes than susceptible ones. All isolates showed reduced susceptibility to five of six disinfectants compared with the control strains. Higher MICs were generally associated with the presence of qac and sugE(p) genes. Conclusions: The QAC resistance genes were commonly present among E. coli isolated from retail meats, and the qac and sugE(p) geneswere highly associatedwithmultidrug resistance phenotypes. UsingQACs in the food industry may not be as effective as expected and could provide selection pressure for strains with acquired resistance to other antimicrobials. C1 [Zou, Likou; Meng, Jianghong; Wang, Fei; Cao, Guojie; Hoffmann, Maria] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Zou, Likou] Sichuan Agr Univ, Microbiol Lab, Dujiangyan, Sichuan, Peoples R China. [McDermott, Patrick F.; Hoffmann, Maria; Zhao, Shaohua] US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, Laurel, MD 20708 USA. [Yang, Qianru] Louisiana State Univ, Ctr Agr, Dept Food Sci, Baton Rouge, LA 70803 USA. RP Zhao, SH (reprint author), US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, Laurel, MD 20708 USA. EM shaohua.zhao@fda.hhs.gov NR 36 TC 13 Z9 15 U1 9 U2 24 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 2014 VL 69 IS 10 BP 2644 EP 2649 DI 10.1093/jac/dku197 PG 6 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA AR1DP UT WOS:000343322700008 PM 24908046 ER PT J AU Kaufman, AR Mays, D Koblitz, AR Portnoy, DB AF Kaufman, Annette R. Mays, Darren Koblitz, Amber R. Portnoy, David B. TI Judgments, Awareness, and the Use of Snus Among Adults in the United States SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID TOBACCO PRODUCT USE; SMOKING-CESSATION; SMOKELESS TOBACCO; HARM REDUCTION; RELATIVE RISK; CIGARETTES; PERCEPTIONS AB Introduction: Alternative tobacco products, such as snus, are emerging in the U. S. market. Understanding correlates of awareness and use, particularly judgments about harm and addictiveness, can inform public health communications about these products. Methods: Data were collected from a web panel representative of the U. S. population in March 2013 (N = 2,067). The survey assessed awareness and use of snus among adults. Absolute and comparative snus judgments, intentions, smoking status, and sociodemographic variables were measured. Bivariate and multivariable logistic regression analyses were conducted to examine associations between these variables and snus awareness and use. Results: Nearly 36% of the population was aware of snus, and 5.2% reported ever using snus. Current cigarette smokers were about 4 times more likely as nonsmokers to report snus awareness and use. Sociodemographic correlates of snus awareness and use included being male, employed full time, and younger. Compared with respondents who perceived snus to be as harmful and as addictive as cigarettes, those who perceived snus to be less harmful and less addictive than cigarettes were more likely to have used snus. Conclusions: Current smokers are more likely to be aware of and have used snus. Multiple tobacco product use poses a significant challenge for public health efforts to reduce tobacco-associated morbidity and mortality. Perceptions that snus is less harmful and less addictive compared with cigarettes are associated with snus use. These judgments can inform public health communications about emerging tobacco products and multiple product use. C1 [Kaufman, Annette R.] NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci,NIH, Rockville, MD 20850 USA. [Mays, Darren] US FDA, Tobacco Regulatory Sci Fellowship Program, Silver Spring, MD USA. [Mays, Darren] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Koblitz, Amber R.; Portnoy, David B.] US FDA, Ctr Tobacco Prod, Silver Spring, MD USA. RP Kaufman, AR (reprint author), NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci,NIH, 9609 Med Ctr Dr,3-E-546, Rockville, MD 20850 USA. EM kaufmana@mail.nih.gov OI Portnoy, David/0000-0003-2175-9457 FU National Cancer Institute; Center for Tobacco Products, U.S. Food and Drug Administration; RTI International FX This work was supported by the National Cancer Institute and the Center for Tobacco Products, U.S. Food and Drug Administration. Data collection was funded by RTI International. NR 12 TC 10 Z9 10 U1 2 U2 4 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 2014 VL 16 IS 10 BP 1404 EP 1408 DI 10.1093/ntr/ntu116 PG 5 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA AR6CS UT WOS:000343671300016 PM 25098672 ER PT J AU Tcheng, JE Crowley, J Tomes, M Reed, TL Dudas, JM Thompson, KP Garratt, KN Drozda, JP AF Tcheng, James E. Crowley, Jay Tomes, Madris Reed, Terrie L. Dudas, Joseph M. Thompson, Kweli P. Garratt, Kirk N. Drozda, Joseph P., Jr. CA MDEpiNet UDI Demonstration Expert TI Unique device identifiers for coronary stent postmarket surveillance and research: A report from the Food and Drug Administration Medical Device Epidemiology Network Unique Device Identifier Demonstration SO AMERICAN HEART JOURNAL LA English DT Article ID HEALTH AB Background Although electronic product identification in the consumer sector is ubiquitous, unique identification of medical devices is just being implemented in 2014. To evaluate unique device identifiers (UDIs) in health care, the US Food and Drug Administration (FDA) funded the Medical Device Epidemiology Network initiative, including a demonstration of the implementation of coronary stent UDI data in the information systems of a multihospital system (Mercy Health). This report describes the first phase of the demonstration. Methods An expert panel of interventional cardiologists nominated by the American College of Cardiology and the Society for Cardiovascular Angiography and Interventions was convened with representatives of industry, health system members of the Healthcare Transformation Group, the American College of Cardiology National Cardiovascular Data Registry, and FDA to articulate concepts needed to best use UDI-associated data. The expert panel identified 3: (1) use cases for UDI-associated data (eg, research), (2) a supplemental data set of clinically relevant attributes (eg, stent dimensions), and (3) governance and administrative principles for the authoritative management of these data. Results Eighteen use cases were identified, encompassing clinical care, supply chain management, consumer information, research, regulatory, and surveillance domains. In addition to the attributes of the FDA Global Unique Device Identification Database, 9 additional coronary stent-specific attributes were required to address use case requirements. Recommendations regarding governance were elucidated as foundational principles for UDI-associated data management. Conclusions This process for identifying requisite extensions to support the effective use of UDI-associated data should be generalizable. Implementation of a UDI system for medical devices must anticipate both global and device-specific information. C1 [Tcheng, James E.] Duke Univ, Med Ctr, Durham, NC USA. [Crowley, Jay] USDM Life Sci, Santa Barbara, CA USA. [Tomes, Madris] Avalere Hlth, Washington, DC USA. [Reed, Terrie L.] Duke Clin Res Inst, Durham, NC USA. [Dudas, Joseph M.] Mayo Clin, Rochester, MN USA. [Thompson, Kweli P.] Medtronic Corp, Minneapolis, MN USA. [Garratt, Kirk N.] Lenox Hill Hosp, North Shore Long Isl Jewish, New York, NY 10021 USA. [Drozda, Joseph P., Jr.] Mercy Hlth, Chesterfield, MO USA. [Crowley, Jay; Tomes, Madris; Reed, Terrie L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Drozda, JP (reprint author), Ctr Innovat Care Mercy, 14528 South Outer Forty, Chesterfield, MO 63017 USA. EM Joseph.Drozda@Mercy.net FU Center for Devices and Radiological Health, US Food and Drug Administration [DHHS/FDA-22320172C] FX This work is supported by contract DHHS/FDA-22320172C from the Center for Devices and Radiological Health, US Food and Drug Administration. NR 8 TC 2 Z9 2 U1 1 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD OCT PY 2014 VL 168 IS 4 BP 405 EP + AR 413e2 DI 10.1016/j.ahj.2014.07.001 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AQ8QZ UT WOS:000343096900004 PM 25262248 ER PT J AU Levy, MJ Gucinski, AC Sommers, CD Ghasriani, H Wang, B Keire, DA Boyne, MT AF Levy, Michaella J. Gucinski, Ashley C. Sommers, Cynthia D. Ghasriani, Houman Wang, Bo Keire, David A. Boyne, Michael T., II TI Analytical techniques and bioactivity assays to compare the structure and function of filgrastim (granulocyte-colony stimulating factor) therapeutics from different manufacturers SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Top-down mass spectrometry; Granulocyte-colony stimulating factor; Bioassay; Cell proliferation; Circular dichroism; NMR ID SECONDARY STRUCTURE; NMR-SPECTROSCOPY; PROTEIN; ASSIGNMENT; PRODUCTS; DYNAMICS AB The FDA has approved more than 100 protein and peptide drugs with hundreds more in the pipeline (Lanthier et al. in Nat Rev Drug Discov 7(9):733-737, 2008). Many of these originator biologic products are now coming off patent and are being manufactured by alternate methods than the innovator as follow-on drugs. Because changes to the production method often lead to subtle differences (e.g., degradation products, different posttranslational modifications or impurities) in the therapeutic (Schiestl et al. in Nat Biotechnol 29(4):310-312, 2011), there is a critical need to define techniques to test and insure the quality of these drugs. In addition, the emergence of protein therapeutics manufactured by unapproved methodologies presents an ongoing and growing regulatory challenge. In this work, high-resolution mass spectrometry was used to determine the presence or absence of posttranslational modifications for one FDA-approved and three foreign-sourced, unapproved filgrastim products. Circular dichroism (CD) was used to compare the secondary structure and probe the temperature stability of these products. Native 2D H-1,N-15-heteronuclear singular quantum coherence (HSQC) NMR test was applied to these samples to compare the higher-order structure of the four products. Finally, a cell proliferation assay was performed on the filgrastims to compare their bioactivity, and stressed filgrastim was tested in the bioassay to better understand the effects of changes in protein structure on activity. The results showed that orthogonal approaches are capable of characterizing the physiochemical properties of this protein drug and assessing the impact of structural changes on filgrastim purity and potency. C1 [Boyne, Michael T., II] US FDA, Div Pharmaceut Anal, Off Testing & Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Levy, Michaella J.; Gucinski, Ashley C.; Sommers, Cynthia D.; Ghasriani, Houman; Wang, Bo; Keire, David A.] US FDA, Div Pharmaceut Anal, Off Testing & Res, Ctr Drug Evaluat & Res, St Louis, MO 63110 USA. RP Boyne, MT (reprint author), US FDA, Div Pharmaceut Anal, Off Testing & Res, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM michael.boyne@fda.hhs.gov NR 21 TC 6 Z9 6 U1 0 U2 10 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 OCT PY 2014 VL 406 IS 26 BP 6559 EP 6567 DI 10.1007/s00216-013-7469-x PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AQ9BJ UT WOS:000343135400010 PM 24264620 ER PT J AU Le, HND Kim, MS Hwang, J Yang, Y U-Thainual, P Kang, JU Kim, DH AF Le, Hanh N. D. Kim, Moon S. Hwang, Jeeseong Yang, Yi U-Thainual, Paweena Kang, Jin U. Kim, Do-Hyun TI An average enumeration method of hyperspectral imaging data for quantitative evaluation of medical device surface contamination SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; CATHETER-RELATED INFECTIONS; SPECTRAL ANGLE MAPPER; BIOFILM RESISTANCE; ALGORITHM; GROWTH; AGENTS AB We propose a quantification method called Mapped Average Principal component analysis Score (MAPS) to enumerate the contamination coverage on common medical device surfaces. The method was adapted from conventional Principal Component Analysis (PCA) on non-overlapped regions of a full frame hyperspectral image to resolve the percentage of contamination from the substrate. The concept was proven by using a controlled contamination sample with artificial test soil and color simulating organic mixture, and was further validated using a bacterial system including biofilm on stainless steel surface. We also validate the results of MAPS with other statistical spectral analysis including Spectral Angle Mapper (SAM). The proposed method provides an alternative quantification method for hyperspectral imaging data, which can be easily implemented by basic PCA analysis. (C) 2014 Optical Society of America C1 [Le, Hanh N. D.; Yang, Yi; U-Thainual, Paweena; Kim, Do-Hyun] US FDA, Silver Spring, MD 20993 USA. [Le, Hanh N. D.; Kang, Jin U.] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [Kim, Moon S.] USDA, Washington, DC 20250 USA. [Hwang, Jeeseong] NIST, Boulder, CO 80305 USA. RP Le, HND (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM do-hyun.kim@fda.hhs.gov FU U.S. Food and Drug Administration Critical Path Initiative FX The authors thank Victoria M. Hitchins for the help in preparing biofilm samples. This work was supported by the U.S. Food and Drug Administration Critical Path Initiative. Disclaimer: The mention of commercial products, their sources, or their use in connection with material reported here is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services and National Institute of Standards and Technology (NIST). NR 35 TC 2 Z9 2 U1 1 U2 17 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD OCT 1 PY 2014 VL 5 IS 10 BP 3613 EP 3627 DI 10.1364/BOE.5.003613 PG 15 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA AQ9BI UT WOS:000343135200029 PM 25360377 ER PT J AU Chang, CM Stapleton, JT Klinzman, D McLinden, JH Purdue, MP Katki, HA Engels, EA AF Chang, Cindy M. Stapleton, Jack T. Klinzman, Donna McLinden, James H. Purdue, Mark P. Katki, Hormuzd A. Engels, Eric A. TI GBV-C Infection and Risk of NHL among US Adults SO CANCER RESEARCH LA English DT Article ID HEPATITIS-G VIRUS; C/HEPATITIS-G VIRUS; NON-HODGKINS-LYMPHOMA; B-CELL; ENVELOPE PROTEIN; BLOOD-DONORS; HIGH PREVALENCE; ASSOCIATION; ACTIVATION; HIV AB Some retrospective studies suggest an association between infection with GB virus-C (GBV-C) and non-Hodgkin lymphoma (NHL). We evaluated this association prospectively in a nested case-control study within the U.S. Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Cases (N = 658) and controls (N = 1,316) were individually matched by age, sex, race/ethnicity, timing of study entry, and sample selection. Prediagnostic PLCO serum samples were tested for GBV-C RNA (as a measure of active infection) and E2 antibody (active or resolved infection). Logistic regression was used to estimate odds ratios (OR) for the association between GBV-C and NHL overall and NHL subtypes. Twelve cases (1.8%) and seven controls (0.5%) were GBV-C RNA-positive. GBV-C RNA positivity was associated with NHL overall [OR, 3.43; 95% confidence interval (CI), 1.35-8.71] and, based on small numbers, diffuse large B-cell lymphoma (OR, 5.31; 95% CI, 1.54-18.36). The association with NHL persisted when the interval between testing and selection was greater than 4 years (OR, 6.00; 95% CI, 1.21-29.73). In contrast, E2 antibody positivity was not associated with NHL risk (OR, 1.08; 95% CI, 0.74-1.58). Our study demonstrates that GBV-C infection precedes development of NHL. GBV-C infection may play an etiologic role in a small proportion of NHL cases, perhaps by causing chronic immune stimulation or impaired immunosurveillance. (C) 2014 AACR. C1 [Chang, Cindy M.; Purdue, Mark P.; Katki, Hormuzd A.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Stapleton, Jack T.; Klinzman, Donna; McLinden, James H.] Univ Iowa, Dept Internal Med, Iowa City Vet Affairs Med Ctr, Iowa City, IA 52242 USA. RP Chang, CM (reprint author), Food & Drug Adm, Ctr Tobacco Prod, Dept Hlth & Human Serv, Off Sci, Bldg 71,Room G335,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM cindy.chang@fda.hhs.gov RI Katki, Hormuzd/B-4003-2015; Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU Intramural Research Program of the National Cancer Institute at the NIH; Department of Veterans Affairs Merit Review Grant [CX000821] FX This work was supported by the Intramural Research Program of the National Cancer Institute at the NIH and by the Department of Veterans Affairs Merit Review Grant (CX000821; J.T. Stapleton). NR 47 TC 5 Z9 5 U1 0 U2 4 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 OCT 1 PY 2014 VL 74 IS 19 BP 5553 EP 5560 DI 10.1158/0008-5472.CAN-14-0209 PG 8 WC Oncology SC Oncology GA AQ8WP UT WOS:000343118900020 PM 25115299 ER PT J AU Kim, G Mckee, AE Ning, YM Hazarika, M Theoret, M Johnson, JR Xu, QC Tang, S Sridhara, R Jiang, XP He, K Roscoe, D McGuinn, WD Helms, WS Russell, AM Miksinski, SP Zirkelbach, JF Earp, J Liu, Q Ibrahim, A Justice, R Pazdur, R AF Kim, Geoffrey Mckee, Amy E. Ning, Yang-Min Hazarika, Maitreyee Theoret, Marc Johnson, John R. Xu, Qiang Casey Tang, Shenghui Sridhara, Rajeshwari Jiang, Xiaoping He, Kun Roscoe, Donna McGuinn, W. David Helms, Whitney S. Russell, Anne Marie Miksinski, Sarah Pope Zirkelbach, Jeanne Fourie Earp, Justin Liu, Qi Ibrahim, Amna Justice, Robert Pazdur, Richard TI FDA Approval Summary: Vemurafenib for Treatment of Unresectable or Metastatic Melanoma with the BRAF(V600E) Mutation SO CLINICAL CANCER RESEARCH LA English DT Article ID BRAF; RAF; SURVIVAL; INHIBITION; RESISTANCE; IPILIMUMAB; PATHWAY; FUTURE; V600E AB On August 17, 2011, the U. S. Food and Drug Administration (FDA) approved vemurafenib tablets (Zelboraf, Hoffmann-LaRoche Inc.) for the treatment of patients with unresectable or metastatic melanoma with the BRAF(V600E) mutation as detected by an FDA-approved test. The cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems, Inc.) was approved concurrently. An international, multicenter, randomized, open-label trial in 675 previously untreated patients with BRAF(V600E) mutation-positive unresectable or metastatic melanoma allocated 337 patients to receive vemurafenib, 960 mg orally twice daily, and 338 patients to receive dacarbazine, 1,000 mg/m(2) intravenously every 3 weeks. Overall survival was significantly improved in patients receiving vemurafenib [HR, 0.44; 95% confidence interval (CI), 0.33-0.59; P <0.0001]. Progression-free survival was also significantly improved in patients receiving vemurafenib (HR, 0.26; 95% CI, 0.20-0.33; P <0.0001). Overall response rates were 48.4% and 5.5% in the vemurafenib and dacarbazine arms, respectively. The most common adverse reactions (>= 30%) in patients treated with vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea. Cutaneous squamous cell carcinomas or keratoacanthomas were detected in approximately 24% of patients treated with vemurafenib. Other adverse reactions included hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, uveitis, QT prolongation, and liver enzyme laboratory abnormalities. Clin Cancer Res; 20(19); 4994-5000. (C) 2014 AACR. C1 [Kim, Geoffrey; Mckee, Amy E.; Ning, Yang-Min; Hazarika, Maitreyee; Theoret, Marc; Johnson, John R.; McGuinn, W. David; Helms, Whitney S.; Ibrahim, Amna; Justice, Robert; Pazdur, Richard] US FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, Silver Spring, MD USA. [Xu, Qiang Casey; Tang, Shenghui; Sridhara, Rajeshwari; Jiang, Xiaoping; He, Kun] US FDA, Ctr Drug Evaluat & Res, Off Biostat, Silver Spring, MD USA. [Roscoe, Donna] US FDA, Ctr Devices & Radiol Hlth, Off In Vitro Diagnost & Radiol Hlth, Silver Spring, MD USA. [Russell, Anne Marie; Miksinski, Sarah Pope] US FDA, Ctr Drug Evaluat & Res, Off New Drug Qual Assessment, Silver Spring, MD USA. [Zirkelbach, Jeanne Fourie; Earp, Justin; Liu, Qi] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Silver Spring, MD USA. RP Kim, G (reprint author), Food & Drug Adm, 10903 New Hampshire Ave,Bldg 22,Room 2137, Silver Spring, MD 20993 USA. EM Geoffrey.Kim@fda.hhs.gov NR 23 TC 28 Z9 28 U1 1 U2 11 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 2014 VL 20 IS 19 BP 4994 EP 5000 DI 10.1158/1078-0432.CCR-14-0776 PG 7 WC Oncology SC Oncology GA AQ8XU UT WOS:000343123800005 PM 25096067 ER PT J AU Karres, J Pratt, V Guettier, JM Temeck, J Tamborlane, WV Dunger, D Bejnariu, C De Beaufort, C Tomasi, P AF Karres, Janina Pratt, Valerie Guettier, Jean-Marc Temeck, Jean Tamborlane, William V. Dunger, David Bejnariu, Cristina De Beaufort, Carine Tomasi, Paolo TI Joining Forces: A Call for Greater Collaboration to Study New Medicines in Children and Adolescents With Type 2 Diabetes SO DIABETES CARE LA English DT Editorial Material ID TODAY CLINICAL-TRIAL; YOUTH; PREVALENCE; COHORT; CARE C1 [Karres, Janina; Bejnariu, Cristina; Tomasi, Paolo] European Med Agcy, London, England. [Pratt, Valerie; Guettier, Jean-Marc] US FDA, Div Metab & Endocrinol Prod, Silver Spring, MD USA. [Temeck, Jean] US FDA, Off Pediat Therapeut, Silver Spring, MD USA. [Tamborlane, William V.] Yale Univ, Sch Med, Ctr Clin Invest, New Haven, CT USA. [Dunger, David] Univ Cambridge, Dept Paediat, Cambridge, England. [De Beaufort, Carine] Univ Luxembourg, Ctr Syst Biomed, Esch Sur Alzette, Luxembourg. RP Karres, J (reprint author), European Med Agcy, London, England. EM janina.karres@ema.europa.eu NR 25 TC 11 Z9 11 U1 0 U2 2 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 OCT PY 2014 VL 37 IS 10 BP 2665 EP 2667 DI 10.2337/dc14-0494 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AR4UM UT WOS:000343582400017 PM 25249667 ER PT J AU Dey, R Natarajan, G Bhattacharya, P Cummings, H Dagur, PK Terrazas, C Selvapandiyan, A Mccoy, JP Duncan, R Satoskar, AR Nakhasi, HL AF Dey, Ranadhir Natarajan, Gayathri Bhattacharya, Parna Cummings, Hannah Dagur, Pradeep K. Terrazas, Cesar Selvapandiyan, Angamuthu Mccoy, John P., Jr. Duncan, Robert Satoskar, Abhay R. Nakhasi, Hira L. TI Characterization of Cross-Protection by Genetically Modified Live-Attenuated Leishmania donovani Parasites against Leishmania mexicana SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROTEINASE-DEFICIENT MUTANTS; AZAR DERMAL LEISHMANIASIS; CD8(+) T-CELLS; DENDRITIC CELLS; CUTANEOUS LEISHMANIASIS; MURINE LEISHMANIASIS; BALB/C MICE; L. MAJOR; VISCERAL LEISHMANIASIS; AMAZONENSIS INFECTION AB Previously, we showed that genetically modified live-attenuated Leishmania donovani parasite cell lines (LdCen(-/-) and Ldp27(-/-)) induce a strong cellular immunity and provide protection against visceral leishmaniasis in mice. In this study, we explored the mechanism of cross-protection against cutaneous lesion-causing Leishmania mexicana. Upon challenge with wild-type L. mexicana, mice immunized either for short or long periods showed significant protection. Immunohistochemical analysis of ears from immunized/challenged mice exhibited significant influx of macrophages, as well as cells expressing MHC class II and inducible NO synthase, suggesting an induction of potent host-protective proinflammatory responses. In contrast, substantial inhibition of IL-10, IL-4, and IL-13 expression and the absence of degranulated mast cells and less influx of eosinophils within the ears of immunized/challenged mice suggested a controlled anti-inflammatory response. L. mexicana Ag-stimulated lymph node cell culture from the immunized/challenged mice revealed induction of IFN-gamma secretion by the CD4 and CD8 T cells compared with non-immunized/challenged mice. We also observed suppression of Th2 cytokines in the culture supernatants of immunized/challenged lymph nodes compared with non-immunized/challenged mice. Adoptively transferred total T cells from immunized mice conferred strong protection in recipient mice against L. mexicana infection, suggesting that attenuated L. donovani can provide protection against heterologous L. mexicana parasites by induction of a strong T cell response. Furthermore, bone marrow-derived dendritic cells infected with LdCen(-/-) and Ldp27(-/-) parasites were capable of inducing a strong proinflammatory response leading to the proliferation of Th1 cells. These studies demonstrate the potential of live-attenuated L. donovani parasites as pan-Leishmania species vaccines. C1 [Dey, Ranadhir; Bhattacharya, Parna; Duncan, Robert; Nakhasi, Hira L.] US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Natarajan, Gayathri; Cummings, Hannah; Terrazas, Cesar; Satoskar, Abhay R.] Ohio State Univ, Wexner Med Ctr, Dept Pathol, Columbus, OH 43210 USA. [Dagur, Pradeep K.; Mccoy, John P., Jr.] NHLBI, NIH, Bethesda, MD 20892 USA. [Selvapandiyan, Angamuthu] Inst Mol Med, New Delhi 110020, India. RP Nakhasi, HL (reprint author), US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Bldg 71,Room 4266,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Abhay.Satoskar@osumc.edu; Hira.Nakhasi@fda.hhs.gov FU Center for Biologics Evaluation and Research, U.S. Food and Drug Administration FX This work was supported by intramural funds and a critical path initiative of the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. Findings of this study are an informal communication and represent the best judgment of the authors. These comments do not bind or obligate the U.S. Food and Drug Administration. NR 73 TC 8 Z9 8 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2014 VL 193 IS 7 BP 3513 EP 3527 DI 10.4049/jimmunol.1303145 PG 15 WC Immunology SC Immunology GA AR0XQ UT WOS:000343298700032 PM 25156362 ER PT J AU Afonin, KA Viard, M Koyfman, AY Martins, AN Kasprzak, WK Panigaj, M Desai, R Santhanam, A Grabow, WW Jaeger, L Heldman, E Reiser, J Chiu, W Freed, EO Shapiro, BA AF Afonin, Kirill A. Viard, Mathias Koyfman, Alexey Y. Martins, Angelica N. Kasprzak, Wojciech K. Panigaj, Martin Desai, Ravi Santhanam, Arti Grabow, Wade W. Jaeger, Luc Heldman, Eliahu Reiser, Jakob Chiu, Wah Freed, Eric O. Shapiro, Bruce A. TI Multifunctional RNA Nanoparticles SO NANO LETTERS LA English DT Article DE RNA nanotechnology; RNA nanoparticles; RNA interference; aptamers; RNA-DNA hybrid reassociation ID MALACHITE GREEN APTAMER; IN-SILICO; THERAPEUTIC APPLICATIONS; SPLIT FUNCTIONALITIES; EMERGING FIELD; DNA HYBRIDS; DESIGN; NANOTECHNOLOGY; DELIVERY; INTERFERENCE AB Our recent advancements in RNA nanotechnology introduced novel nanoscaffolds (nanorings); however, the potential of their use for biomedical applications was never fully revealed. As presented here, besides functionalization with multiple different short interfering RNAs for combinatorial RNA interference (e.g., against multiple HIV-1 genes), nanorings also allow simultaneous embedment of assorted RNA aptamers, fluorescent dyes, proteins, as well as recently developed RNADNA hybrids aimed to conditionally activate multiple split functionalities inside cells. C1 [Afonin, Kirill A.; Viard, Mathias; Desai, Ravi; Santhanam, Arti; Shapiro, Bruce A.] NCI, Basic Res Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Viard, Mathias; Kasprzak, Wojciech K.; Heldman, Eliahu] NCI, Basic Sci Program, Leidos Biomed Res Inc, Ctr Canc Res,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Koyfman, Alexey Y.; Chiu, Wah] Baylor Coll Med, Natl Ctr Macromol Imaging, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Martins, Angelica N.; Freed, Eric O.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Panigaj, Martin; Reiser, Jakob] US FDA, Ctr Biol Evaluat & Res, Off Cellular Tissue & Gene Therapies, Silver Spring, MD 20993 USA. [Grabow, Wade W.] Seattle Pacific Univ, Dept Chem, Seattle, WA 98119 USA. [Jaeger, Luc] Univ Calif Santa Barbara, Dept Chem & Biochem, Biomol Sci & Engn Program, Santa Barbara, CA 93106 USA. RP Shapiro, BA (reprint author), NCI, Basic Res Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM shapirbr@mail.nih.gov RI Panigaj, Martin/G-6492-2013 FU NIH, Center for Cancer Research, NCI-Frederick; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; National Institutes of Health [P41GM103832, P50 GM1003297]; Postdoctoral Training Fellowship from the Keck Center Computational Cancer Biology Training Program of the Gulf Coast Consortia (CPRIT) [RP101489]; NIH [R01GM-079604]; U.S. Department of Energy; U.S. Food and Drug Administration FX We thank Faye M. Walker for her assistance at early stages of this project. We thank the Pathology Histology Lab of Leidos Biomedical Research, Inc. at the Frederick National Laboratory for Cancer Research for help with ex vivo imaging. We thank Patricia S. Steeg at the National Cancer Institute for providing GFP expressing cells for the in vivo experiments. We thank Andrew Anderson for technical assistance during electron microscopy reconstruction. This research was supported [in part] by the Intramural Research Program of the NIH, Center for Cancer Research, NCI-Frederick. This work has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the National Institutes of Health P41GM103832 and P50 GM1003297 (to W.C.) and the Postdoctoral Training Fellowship from the Keck Center Computational Cancer Biology Training Program of the Gulf Coast Consortia to A.Y.K. (CPRIT grant no. RP101489). This research was also supported by NIH grant no. R01GM-079604 (to L.J.). M.P. is supported in part by an appointment to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an inter agency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 64 TC 31 Z9 31 U1 5 U2 51 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 EI 1530-6992 J9 NANO LETT JI Nano Lett. PD OCT PY 2014 VL 14 IS 10 BP 5662 EP 5671 DI 10.1021/nl502385k PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA AQ7RH UT WOS:000343016400029 PM 25267559 ER PT J AU Lovegrove, MC Mathew, J Hampp, C Governale, L Wysowski, DK Budnitz, DS AF Lovegrove, Maribeth C. Mathew, Justin Hampp, Christian Governale, Laura Wysowski, Diane K. Budnitz, Daniel S. TI Emergency Hospitalizations for Unsupervised Prescription Medication Ingestions by Young Children SO PEDIATRICS LA English DT Article DE poisoning; unintentional overdose; pediatric hospitalization; buprenorphine; opioids; sulfonylureas; prescription drugs; drug packaging ID POISON DATA SYSTEM; AMERICAN ASSOCIATION; DEPARTMENT VISITS; EXPOSURES; SURVEILLANCE; OVERDOSES; DRUGS AB BACKGROUND: Emergency department visits and subsequent hospitalizations of young children after unsupervised ingestions of prescription medications are increasing despite widespread use of child-resistant packaging and caregiver education efforts. Data on the medications implicated in ingestions are limited but could help identify prevention priorities and intervention strategies. METHODS: We used nationally representative adverse drug event data from the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project and national retail pharmacy prescription data from IMS Health to estimate the frequency and rates of emergency hospitalizations for unsupervised prescription medication ingestions by young children (2007-2011). RESULTS: On the basis of 1513 surveillance cases, 9490 estimated emergency hospitalizations (95% confidence interval: 6420-12 560) occurred annually in the United States for unsupervised prescription medication ingestions among children aged <6 years from 2007 through 2011; 75.4% involved 1- or 2-year old children. Opioids (17.6%) and benzodiazepines (10.1%) were the most commonly implicated medication classes. The most commonly implicated active ingredients were buprenorphine (7.7%) and clonidine (7.4%). The top 12 active ingredients, alone or in combination with others, were implicated in nearly half (45.0%) of hospitalizations. Accounting for the number of unique patients who received dispensed prescriptions, the hospitalization rate for unsupervised ingestion of buprenorphine products was significantly higher than rates for all other commonly implicated medications and 97-fold higher than the rate for oxycodone products (200.1 vs 2.1 hospitalizations per 100 000 unique patients). CONCLUSIONS: Focusing unsupervised ingestion prevention efforts on medications with the highest hospitalization rates may efficiently achieve large public health impact. C1 [Lovegrove, Maribeth C.; Budnitz, Daniel S.] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA 30333 USA. [Mathew, Justin; Hampp, Christian; Governale, Laura; Wysowski, Diane K.] US FDA, Ctr Drug Evaluat & Res, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Governale, Laura] AstraZeneca, Patient Safety, Gaithersburg, MD USA. RP Lovegrove, MC (reprint author), Ctr Dis Control & Prevent, Div Healthcare Qual Promot, 1600 Clifton Rd NE,Mailstop A-24, Atlanta, GA 30333 USA. EM mlovegrove@cdc.gov FU Intramural CDC HHS [CC999999] NR 31 TC 13 Z9 13 U1 0 U2 2 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 2014 VL 134 IS 4 BP E1009 EP E1016 DI 10.1542/peds.2014-0840 PG 8 WC Pediatrics SC Pediatrics GA AQ9CV UT WOS:000343140500010 PM 25225137 ER PT J AU Jackson, KL Whitcraft, CR Dillon, JG AF Jackson, Karen L. Whitcraft, Christine R. Dillon, Jesse G. TI Diversity of Desulfobacteriaceae and Overall Activity of Sulfate-Reducing Microorganisms in and Around a Salt pan in a Southern California Coastal Wetland SO WETLANDS LA English DT Article DE Coastal salt pan; Desulfobacteriaceae; Sulfate-reducing bacteria; Sulfate reduction; Salt marshes ID MICROBIAL COMMUNITIES; SPARTINA-ALTERNIFLORA; MARINE SEDIMENT; MARSH SEDIMENTS; SULFUR CYCLE; GEN. NOV.; BACTERIA; REDUCTION; RHIZOSPHERE; GRADIENT AB Sulfate-reducing bacteria (SRB) are key mediators of anaerobic carbon cycling in coastal salt marsh sediments and have been shown to be important decomposer communities even in hypersaline habitats. Understanding how SRB function in various salt marsh habitats (vegetated, salt pans) is crucial to advancing our knowledge of salt marsh function. We compare overall sulfate reducing activity and the diversity of a subset of SRB (Desulfobacteriaceae) in two hypersaline sediments (salt pan and nearby area with desiccated vegetation) with a regularly inundated control site within the Huntington Beach Wetlands (HBW). Biological activity was quantified using radiotracer studies to measure sulfate reduction rates (SRR) with and without carbon amendment. All sites showed enhanced SRR under carbon amendment, suggesting short-term carbon limitation. Unique communities of Desulfobacteriaceae were found in all three sites with increased incidence of halotolerant genotypes in the salt pan. These findings indicate that, despite reduced anaerobic respiratory activity, highly diverse and functional deltaproteobacterial communities exist in salt pan and surrounding hypersaline habitats in coastal salt marshes in southern California. C1 [Jackson, Karen L.; Whitcraft, Christine R.; Dillon, Jesse G.] Calif State Univ Long Beach, Dept Biol Sci, Long Beach, CA 90840 USA. [Jackson, Karen L.] US FDA, Irvine, CA 92603 USA. RP Dillon, JG (reprint author), Calif State Univ Long Beach, Dept Biol Sci, 1250 Bellflower Blvd, Long Beach, CA 90840 USA. EM jesse.dillon@csulb.edu FU National Institutes of General Medical Sciences [5R25GM050089-12] FX The authors would like to thank the Huntington Beach Wetland Conservancy and Kristen Bender for allowing us to access the field site and for facilitating our research. We thank Nathan McLain for assistance in depositing sequences in Genbank and Salvador Deniz for his assistance in the laboratory. This research was funded in part by the National Institutes of General Medical Sciences Grant # 5R25GM050089-12. NR 48 TC 0 Z9 0 U1 8 U2 31 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0277-5212 EI 1943-6246 J9 WETLANDS JI Wetlands PD OCT PY 2014 VL 34 IS 5 BP 969 EP 977 DI 10.1007/s13157-014-0560-z PG 9 WC Ecology; Environmental Sciences SC Environmental Sciences & Ecology GA AQ8EW UT WOS:000343057700011 ER PT J AU Kim, MJ AF Kim, Myong Jin TI Member of the Month SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT News Item C1 US FDA, Silver Spring, MD 20993 USA. RP Kim, MJ (reprint author), US FDA, Silver Spring, MD 20993 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD OCT PY 2014 VL 96 IS 4 BP 410 EP 410 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AQ3FN UT WOS:000342675400013 ER PT J AU Yin, LL Coelho, SG Ebsen, D Smuda, C Mahns, A Miller, SA Beer, JZ Kolbe, L Hearing, VJ AF Yin, Lanlan Coelho, Sergio G. Ebsen, Dominik Smuda, Christoph Mahns, Andre Miller, Sharon A. Beer, Janusz Z. Kolbe, Ludger Hearing, Vincent J. TI Epidermal gene expression and ethnic pigmentation variations among individuals of Asian, European and African ancestry SO EXPERIMENTAL DERMATOLOGY LA English DT Article DE microarray; pigmentation; racial; ethnic; skin ID HUMAN SKIN PIGMENTATION; ULTRAVIOLET-RADIATION; MELANOCYTE DEVELOPMENT; MELANIN CONTENT; UV-RADIATION; DNA-DAMAGE; RESPONSES; COLOR; PROTEIN; PHOTOPROTECTION AB Differences in visible skin pigmentation give rise to the wide variation of skin colours seen in racial/ethnic populations. Skin pigmentation is important not only from cosmetic and psychological points of view, but more importantly because of its implications for the risk of all types of skin cancers, on photoaging, etc. Despite differences in those parameters in Caucasian and Asian skin types, they are remarkably similar in their production and distribution of melanins, and the mechanism(s) underlying their different characteristics have remained obscure. In this study, we used microarray analysis of skin suction blisters to investigate molecular differences underlying the determination of pigmentation in various skin types, and we used immunohistochemistry to validate the expression patterns of several interesting targets that were identified. Intriguingly, Caucasian and Asian skins had highly similar gene expression patterns that differed significantly from the pattern of African skin. The results of this study suggest the dynamic interactions of different types of cells in human skin that regulate its pigmentation, reveal that the known pigmentation genes have a limited contribution and uncover a new array of genes, including NINL and S100A4, that might be involved in that regulation. C1 [Yin, Lanlan; Coelho, Sergio G.; Ebsen, Dominik; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Smuda, Christoph; Mahns, Andre; Kolbe, Ludger] Beiersdorf AG, R&D Skin Res, Hamburg, Germany. [Miller, Sharon A.; Beer, Janusz Z.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Room 2132,MSC 4256, Bethesda, MD 20892 USA. EM hearingv@nih.gov FU Intramural Research Program of the National Cancer Institute; Office of Science; Center for Devices and Radiological Health, Food and Drug Administration FX This work was supported in part by the Intramural Research Program of the National Cancer Institute and in part by the Office of Science and the Center for Devices and Radiological Health, Food and Drug Administration. NR 41 TC 4 Z9 4 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0906-6705 EI 1600-0625 J9 EXP DERMATOL JI Exp. Dermatol. PD OCT PY 2014 VL 23 IS 10 BP 731 EP 735 DI 10.1111/exd.12518 PG 5 WC Dermatology SC Dermatology GA AQ4FY UT WOS:000342749900012 PM 25055985 ER PT J AU Siddiqui, A Rahman, Z Khan, SR Awotwe-Otoo, D Khan, MA AF Siddiqui, Akhtar Rahman, Ziyaur Khan, Saeed R. Awotwe-Otoo, David Khan, Mansoor A. TI Root cause evaluation of particulates in the lyophilized indomethacin sodium trihydrate plug for parenteral administration SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Indomethacin; Lyophilization; Stability; Spectrostopy; NIR ID AMORPHOUS INDOMETHACIN; PHYSICAL STABILITY; STATE; SPECTROSCOPY; TEMPERATURE; COUNTERIONS; DISPERSIONS; RELAXATION; SOLUBILITY; BEHAVIOR AB Particulate growth in parenteral product frequently results in product recalls causing drug shortages. While this is mostly attributed to quality issues in a firm, particulates growth could also be due to inadequate product, process, or environmental understanding. Therefore, the objective of this study was to use indomethacin sodium trihydrate (drug) as a model drug for lyophilization and evaluates short-term stability with respect to particulate growth at different storage temperatures. Under aseptic condition, each vial filled with filtered drug solution was lyophilized, and stoppered in LyoStar3. Crimped vials were kept at 5 degrees C, 15 degrees C, 25 degrees C, 25 degrees C/60%RH, and 40 degrees C/75%RH. At predefined time interval, samples were characterized using X-ray powder diffraction (XRPD), thermal, and spectroscopic method. Lyophilized formulation showed four thermal events: 60-90 degrees C demonstrating glass transition, 110-160 degrees C showing recrystallization exotherm,170-220 degrees C exhibiting endotherm of potential polymorph, and 250 degrees C showing melting endotherm. XRPD of the lyophilized powder demonstrated peak at 2 theta 11.10. Spectroscopic studies of lyophilized powder indicated alteration in symmetric and asymmetric carboxylate peaks over time indicating initiation of crystallization and crystal growth. Reconstitution studies indicated higher reconstitution time after six weeks for sample stored at 40 degrees C/75%RH. Furthermore, reconstituted solution showed presence of particulates after 8 weeks storage. These studies suggest that particulate growth can stem from poorly developed formulation and not necessarily due to frequently ascribed filtration issues. Published by Elsevier B.V. C1 [Siddiqui, Akhtar; Rahman, Ziyaur; Khan, Saeed R.; Awotwe-Otoo, David; Khan, Mansoor A.] US FDA, Div Product Qual Res, Off Testing & Res, OPS,CDER, Rockville, MD 20857 USA. RP Khan, MA (reprint author), FDA CDER DPQR, 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 23 TC 6 Z9 6 U1 1 U2 5 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 1 PY 2014 VL 473 IS 1-2 BP 545 EP 551 DI 10.1016/j.ijpharm.2014.07.035 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AQ2YV UT WOS:000342656800060 PM 25089509 ER PT J AU Dubey, JP Verma, SK Ferreira, LR Oliveira, S Cassinelli, AB Ying, Y Kwok, OCH Tuo, W Chiesa, OA Jones, JL AF Dubey, J. P. Verma, S. K. Ferreira, L. R. Oliveira, S. Cassinelli, A. B. Ying, Y. Kwok, O. C. H. Tuo, W. Chiesa, O. A. Jones, J. L. TI Detection and Survival of Toxoplasma gondii in Milk and Cheese from Experimentally Infected Goats SO JOURNAL OF FOOD PROTECTION LA English DT Article ID UNITED-STATES; CELL CULTIVATION; PREGNANT COWS; CAPTURE ELISA; CAT BIOASSAY; RAW CAPRINE; DAIRY GOATS; PCR METHODS; OOCYSTS; MICE AB The consumption of unpasteurized goat cheese and goat's milk has been suggested as a risk factor for toxoplasmosis in humans. In the present study, detection and survival of Toxoplasma gondii in milk and cheese was studied by bioassay in mice (milk) and in cats (cheese). Eight goats were inoculated orally with 300 to 10,000 oocysts of T. gondii strain TgGoatUS26. Milk samples were collected daily up to 30 days postinoculation and bioassayed in mice and cats. For mouse bioassay, 50 ml of milk samples were centrifuged, and the sediment was inoculated subcutaneously into mice. Mice were tested for T. gondii infection by seroconversion and by the demonstration of parasites. By mouse bioassay, T. gondii was detected in milk from all eight goats. The T. gondii excretion in milk was intermittent. For cat bioassay, 400 ml (100 ml or more from each goat) of milk from four goats from 6 to 27 days postinoculation were pooled daily, and cheese was made using rennin. Ten grams of cheese was fed daily to four cats, and cat feces were examined for oocyst shedding. One cat fed cheese shed oocysts 7 to 11 days after consuming cheese. Attempts were made to detect T. gondii DNA in milk of four goats; T. gondii was detected by PCR more consistently, but there was no correlation between detection of viable T. gondii by bioassay in mice and T. gondii DNA by PCR. Results indicate that T. gondii can be excreted in goat's milk and can survive in fresh cheese made by cold-enzyme treatment. To prevent transmission to humans or animals, milk should not be consumed raw. Raw fresh goat cheese made by cold-enzyme treatment of unpasteurized milk also should not be consumed. C1 [Dubey, J. P.; Verma, S. K.; Ferreira, L. R.; Oliveira, S.; Cassinelli, A. B.; Ying, Y.; Kwok, O. C. H.; Tuo, W.] ARS, USDA, Beltsville Agr Res Ctr, Anim Parasit Dis Lab, Beltsville, MD 20705 USA. [Chiesa, O. A.] US FDA, Div Appl Vet Res, Res Off, Ctr Vet Med, Laurel, MD 20708 USA. [Jones, J. L.] Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Ctr Global Hlth, Atlanta, GA 30333 USA. RP Dubey, JP (reprint author), ARS, USDA, Beltsville Agr Res Ctr, Anim Parasit Dis Lab, Bldg 1001, Beltsville, MD 20705 USA. EM jitender.dubey@ars.usda.gov NR 44 TC 4 Z9 5 U1 0 U2 19 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 OCT PY 2014 VL 77 IS 10 BP 1747 EP 1753 DI 10.4315/0362-028X.JFP-14-167 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA AQ6AB UT WOS:000342888600012 PM 25285492 ER PT J AU Hallas, J Rothman, KJ Kubota, K Blackburn, S Navarro, AA Dal Pan, G AF Hallas, Jesper Rothman, Kenneth J. Kubota, Kiyoshi Blackburn, Stella Navarro, Alejandro A. Dal Pan, Gerald TI A Guide to Guidelines. A Symposium Sponsored by the Public Policy Committee SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Hallas, Jesper] Univ Southern Denmark, Odense C, Denmark. [Rothman, Kenneth J.] RTI Hlth Solut, Res Triangle Pk, NC USA. [Kubota, Kiyoshi] Grad Sch Med, Dept Pharmacoepidemiol, Tokyo, Japan. [Blackburn, Stella] Quintiles, London, England. [Navarro, Alejandro A.] RTI Hlth Solut, Barcelona, Spain. [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 OCT PY 2014 VL 23 SU 1 SI SI MA 73 BP 40 EP 40 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600074 ER PT J AU Torosyan, Y Luo, QL Hoffman, S Marinac-Dabic, D AF Torosyan, Yelizaveta Luo, Qianlai Hoffman, Sarah Marinac-Dabic, Danica TI AHRQ/HCUPNet-Derived Pharmacoepidemiologic Evidence on Ventilation-Associated Iatrogenic Pneumothorax SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Torosyan, Yelizaveta; Luo, Qianlai; Hoffman, Sarah; Marinac-Dabic, Danica] US FDA, Div Epidemiol, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Luo, Qianlai; Hoffman, Sarah] Univ N Carolina, Chapel Hill, NC 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 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2014 VL 23 SU 1 SI SI MA 115 BP 63 EP 63 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600116 ER PT J AU Sedrakyan, A Paxton, EW Graves, SE Cafri, G Banerjee, S Allepuz, A Havelin, LI Mehle, S Stea, S Marinac-Dabic, D AF Sedrakyan, Art Paxton, Elizabeth W. Graves, Steven E. Cafri, Guy Banerjee, Samprit Allepuz, Alejandro Havelin, Leif I. Mehle, Susan Stea, Susanna Marinac-Dabic, Denica TI Distributed Analysis of Total Hip Arthroplasties Using Six International Registries: Comparing the Effects of Implant Bearing Surface and Size SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Sedrakyan, Art; Banerjee, Samprit] Weill Cornell Med Coll, New York, NY USA. [Paxton, Elizabeth W.; Cafri, Guy] Kaiser Permanente, Surg Outcomes & Anal, San Diego, CA USA. [Graves, Steven E.] Univ Adelaide, Australian Orthopaed Assoc Natl Joint Replacement, Adelaide, SA, Australia. [Stea, Susanna] Ist Ortoped Rizzoli, Emilia Romagna Joint Registry, Bologna, Italy. [Havelin, Leif I.] Haukeland Hosp, Dept Orthopaed Surg, N-5021 Bergen, Norway. [Mehle, Susan] HealthEast Care Syst, Res Dept, St Paul, MN USA. [Allepuz, Alejandro] Registre Artroplasties Catalunya RACat, Barcelona, Spain. [Marinac-Dabic, Denica] US FDA, Ctr Device & 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 OCT PY 2014 VL 23 SU 1 SI SI MA 339 BP 179 EP 179 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600338 ER PT J AU Kurz, X Martin, D Hoekman, J Bouvy, JC Roddam, A Ebbers, H Leufkens, HGM Chan, KA Dal Pan, G Reynolds, R De Bruin, ML AF Kurz, Xavier Martin, David Hoekman, Jarno Bouvy, Jacoline C. Roddam, Andrew Ebbers, Hans Leufkens, Hubert G. M. Chan, K. Arnold Dal Pan, Gerald Reynolds, Robert De Bruin, Marie L. TI Challenges in Implementing Findings of Regulatory Science to Evaluate and Improve the Drug Regulatory System SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Kurz, Xavier] EMA, Pharmacovigilance, London, England. [Martin, David] US FDA, CBER, Rockville, MD 20857 USA. [Hoekman, Jarno; Bouvy, Jacoline C.; Ebbers, Hans; Leufkens, Hubert G. M.; De Bruin, Marie L.] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Utrecht, Netherlands. [Roddam, Andrew] Natl Taiwan Univ Hosp, Taipei, Taiwan. [Leufkens, Hubert G. M.; De Bruin, Marie L.] Med Evaluat Board, Utrecht, Netherlands. [Chan, K. Arnold] GSK, Worldwide Epidemiol, Uxbridge, Middx, England. [Dal Pan, Gerald] US FDA, CDER, Silver Spring, MD USA. [Reynolds, Robert] Pfizer, New York, NY USA. RI Hoekman, Jarno/C-3287-2017 OI Hoekman, Jarno/0000-0002-2817-1229 NR 0 TC 0 Z9 0 U1 1 U2 9 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 OCT PY 2014 VL 23 SU 1 SI SI MA 388 BP 204 EP 205 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600385 ER PT J AU Liu, CF Polakowski, L Divan, HA Lu, Y Izurieta, H Selvam, N AF Liu, Chunfu Polakowski, Laura Divan, Hozefa A. Lu, Yun Izurieta, Hector Selvam, Nandini TI Idiopathic Thrombocytopenic Purpura After Seasonal Influenza Vaccination SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Liu, Chunfu; Divan, Hozefa A.; Selvam, Nandini] HealthCore Inc, Wilmington, DE USA. [Polakowski, Laura; Lu, Yun; Izurieta, Hector] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 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 OCT PY 2014 VL 23 SU 1 SI SI MA 396 BP 208 EP 209 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600393 ER PT J AU Andrade, S Toh, S Pitts, M Houstoun, M Mott, K Haffenreffer, K Reichman, M AF Andrade, Susan Toh, Sengwee Pitts, Marilyn Houstoun, Monika Mott, Katrina Haffenreffer, Katie Reichman, Marsha TI Evaluation of Medication Use During Pregnancy in the Mini-Sentinel Distributed Database SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Andrade, Susan] Meyers Primary Care Inst, Worcester, MA USA. [Toh, Sengwee; Haffenreffer, Katie] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Pitts, Marilyn; Houstoun, Monika; Mott, Katrina; Reichman, Marsha] 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 OCT PY 2014 VL 23 SU 1 SI SI MA 593 BP 314 EP 315 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600589 ER PT J AU Broussard, CS Frey, MT Hernandez-Diaz, S Greene, MF Chambers, CD Sahin, L Sharp, BAC Honein, MA AF Broussard, Cheryl S. Frey, Meghan T. Hernandez-Diaz, Sonia Greene, Michael F. Chambers, Christina D. Sahin, Leyla Sharp, Beth A. Collins Honein, Margaret A. TI Developing a Systematic Approach to Safer Medication Use during Pregnancy: Summary of a Centers for Disease Control and Prevention-Convened Meeting SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Broussard, Cheryl S.; Frey, Meghan T.; Honein, Margaret A.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. [Frey, Meghan T.] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. [Hernandez-Diaz, Sonia] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Greene, Michael F.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Greene, Michael F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chambers, Christina D.] Univ Calif San Francisco, Dept Pediat, La Jolla, CA USA. [Chambers, Christina D.] Univ Calif San Francisco, Dept Family & Prevent Med, La Jolla, CA USA. [Sahin, Leyla] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Sharp, Beth A. Collins] Agcy Healthcare Res & Qual, Rockville, 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 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2014 VL 23 SU 1 SI SI MA 594 BP 315 EP 315 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600590 ER PT J AU Dal Pan, G Ehrenstein, V John, S Thyagarajan, V Wright, NC Xu, HR Xue, F AF Dal Pan, Gerald Ehrenstein, Vera John, Seeger Thyagarajan, Veena Wright, Nicole C. Xu, Hairong Xue, Fei TI Confirmation of Medical Events (ME) Identified from Existing Electronic Databases in Pharmacoepidemiology (PE) Studies SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Dal Pan, Gerald] US Food & Drug Adm FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Ehrenstein, Vera] Aarhus Univ Hosp, Dept Clin Epidemiol, DK-8000 Aarhus, Denmark. [John, Seeger] Harvard Univ, Sch Publ Hlth, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Thyagarajan, Veena] Optum Epidemiol, Ann Arbor, MI USA. [Wright, Nicole C.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Xu, Hairong; Xue, Fei] Amgen Inc, CfOR, Thousand Oaks, CA 91320 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 OCT PY 2014 VL 23 SU 1 SI SI MA 633 BP 337 EP 338 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600629 ER PT J AU Matheny, ME Murimi, IB Ritchey, ME Lystig, T Kim, M Marinac-Dabic, D Steinbuch, M AF Matheny, Michael E. Murimi, Irene B. Ritchey, Mary E. Lystig, Ted Kim, Myoung Marinac-Dabic, Danica Steinbuch, Michael TI Drugs and Devices: Challenges and Opportunities for the Evaluation of Combination Medical Products SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Matheny, Michael E.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Murimi, Irene B.; Marinac-Dabic, Danica] Ctr Devices & Radiol Hlth, Div Epidemiol, Silver Spring, MD USA. [Murimi, Irene B.] Univ Florida, Coll Pharm, Dept Pharmaceut Outcomes & Policy, Gainesville, FL USA. [Ritchey, Mary E.] Merck & Co Inc, Comparat & Outcomes Evidence, N Wales, PA USA. [Lystig, Ted] Medtronic Inc, Strateg Sci Operat, Minneapolis, MN USA. [Kim, Myoung] Johnson & Johnson, Med Devices & Diagnost, New Brunswick, NJ USA. [Steinbuch, Michael] Procter & Gamble, Global Safety Surveillance & Anal, Cincinnati, OH 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 OCT PY 2014 VL 23 SU 1 SI SI MA 634 BP 338 EP 338 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600630 ER PT J AU Edlavitch, SA Dal Pan, GJ Raine, JM Leufkens, HG Park, BJ Avorn, J AF Edlavitch, Stanley A. Dal Pan, Gerald J. Raine, June M. Leufkens, Hubert G. Park, Byung-Joo Avorn, Jerry TI Improving the Science of Regulatory Decision-Making - Advances in 2013/2014 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 UMKC, Sch Med, Kansas City, MO USA. [Edlavitch, Stanley A.; Dal Pan, Gerald J.] US FDA, OSE, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Raine, June M.] Med & Healthcare Prod Regulatory Agcy, Vigilance Risk Management Med, London, England. [Leufkens, Hubert G.] Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands. [Park, Byung-Joo] Korea Inst Drug Safety & Risk Management, Seoul, South Korea. [Avorn, Jerry] Harvard Univ, Sch Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 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 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2014 VL 23 SU 1 SI SI MA 637 BP 340 EP 340 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600633 ER PT J AU Zhou, W Zineh, I Carleton, B Nyberg, F Chung, WH AF Zhou, Wei Zineh, Issam Carleton, Bruce Nyberg, Fredrik Chung, Wen-Hung TI International Collaboration on Pharmacogenomics in Epidemiology Research SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Zineh, Issam] US FDA, Off Clin Pharmacol, Rockville, MD 20857 USA. [Carleton, Bruce] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Nyberg, Fredrik] AstraZeneca, Epidemiol, Molndal, Sweden. [Chung, Wen-Hung] Chang Gung Mem Hosp, Taipei, Taiwan. 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 OCT PY 2014 VL 23 SU 1 SI SI MA 638 BP 340 EP 341 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600634 ER PT J AU Smith, M Bahri, P Dal Pan, G Banerjee, S Mol, P Dey, D AF Smith, Meredith Bahri, Priya Dal Pan, Gerald Banerjee, Swapu Mol, Peter Dey, Debashish TI The Patient's Voice in the Heart of BRACE (Benefit-Risk Assessment, Communication and Evaluation) SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Smith, Meredith] EMD Serono Inc, Drug Safety Strategy & Sci, Rockalnd, MA USA. [Bahri, Priya] European Med Agcy, Best Evidence Dev, London, England. [Dal Pan, Gerald] US FDA, Off Surveillance & Epidemiol CDER, Silver Spring, MD USA. [Banerjee, Swapu] Pope Woodhead & Associates Ltd, Regulatory Risk & Cin Dev, St Ives, Cambs, England. [Mol, Peter] Univ Groningen, Groningen, Netherlands. [Dey, Debashish] Eli Lilly & Co, Global Patient Safety, Indianapolis, IN 46285 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 OCT PY 2014 VL 23 SU 1 SI SI MA 680 BP 364 EP 365 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600675 ER PT J AU Lee, WJ Lee, TA Pickard, S Shoaibi, A Schumock, GT AF Lee, Wan-Ju Lee, Todd A. Pickard, Simon Shoaibi, Azadeh Schumock, Glen T. TI Feasibility of Alternative Methods for Health Outcomes of Interest Algorithm Validation SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Lee, Wan-Ju; Lee, Todd A.; Pickard, Simon; Schumock, Glen T.] Univ Illinois, Dept Pharm Syst Outcomes & Policy, Chicago, IL USA. [Lee, Todd A.; Pickard, Simon; Schumock, Glen T.] Univ Illinois, Ctr Pharmacoepidemiol & Pharmacoecon Res, Chicago, IL USA. [Shoaibi, Azadeh] US FDA, Ctr Drug Evaluat & Res, Off Med Policy, 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 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2014 VL 23 SU 1 SI SI MA 792 BP 425 EP 426 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600786 ER PT J AU Chien, HC Yang, YHK Bai, JPF AF Chien, Hsu-Chih Yang, Yea-Huei Kao Bai, Jane P. F. TI Trastuzumab-Related Cardiotoxicity Among Breast Cancer Patients in Taiwan 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 & Pharmaceut Sci, Tainan 70101, Taiwan. [Yang, Yea-Huei Kao] Natl Cheng Kung Univ, Hlth Outcome Res Ctr, Tainan 70101, Taiwan. [Bai, Jane P. F.] US FDA, Predict Drug Safety Grp, Off Clin Pharmacol, 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 OCT PY 2014 VL 23 SU 1 SI SI MA 821 BP 440 EP 441 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600814 ER PT J AU Torosyan, Y Marinac-Dabic, D AF Torosyan, Yelizaveta Marinac-Dabic, Danica TI A Novel Approach to Pharmacogenomic and Pharmacoepidemiologic Evidence Synthesis for Predictive Analysis and Regulatory Decision-Making on Medical Device Performance SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Torosyan, Yelizaveta; Marinac-Dabic, Danica] 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 OCT PY 2014 VL 23 SU 1 SI SI MA 893 BP 480 EP 480 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600885 ER PT J AU Sedrakyan, A Moon, JE Kuntz, L Normand, SLT Isaacs, AJ Roell, B Marinac-Dabic, D AF Sedrakyan, Art Moon, Jennifer E. Kuntz, Lauren Normand, Sharon-Lise T. Isaacs, Abby J. Roell, Bethany Marinac-Dabic, Denica TI Cardiac Resynchronization Devices with and Without Defibrillation: A Quantitative Systematic Review and Assessment of National Use SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Sedrakyan, Art; Moon, Jennifer E.; Isaacs, Abby J.] Weill Cornell Med Coll, New York, NY USA. [Kuntz, Lauren; Normand, Sharon-Lise T.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Med, Boston, MA USA. [Roell, Bethany] Univ Toledo, Coll Med, Toledo, OH 43606 USA. [Marinac-Dabic, Denica] US Food & Drug Adm FDA, Ctr Devices & Radiol Hlth, 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 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2014 VL 23 SU 1 SI SI MA 896 BP 481 EP 482 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600888 ER PT J AU Du, DY McKean, S Kelman, J Laschinger, J Johnson, C Warnock, R Worrall, C MaCurdy, TE Izurieta, H AF Du, Dongyi (Tony) McKean, Stephen Kelman, Jeffrey Laschinger, John Johnson, Chris Warnock, Rob Worrall, Chris MaCurdy, Thomas E. Izurieta, Hector TI The Selection of Prosthetics Aortic Valves for Elderly Medicare Patients from 2006 to 2011-A Population Based Cross-Sectional Study SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Du, Dongyi (Tony); Laschinger, John] US FDA, Ctr Devices & Radiol Healh, Silver Spring, MD USA. [McKean, Stephen; Johnson, Chris; Warnock, Rob; MaCurdy, Thomas E.] Acumen LLC, Burlingame, CA USA. [Kelman, Jeffrey; Worrall, Chris] Ctr Medicare & Medicaid, Washington, DC USA. [Izurieta, Hector] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 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 OCT PY 2014 VL 23 SU 1 SI SI MA 898 BP 483 EP 483 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600890 ER PT J AU Chen, C Eworuke, E Schelfhout, J Hartzema, A AF Chen, Chao Eworuke, Efe Schelfhout, Jonathan Hartzema, Abraham TI Hospital Volume and Outcomes for Total Hip Arthroplasty SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Chen, Chao; Eworuke, Efe; Schelfhout, Jonathan; Hartzema, Abraham] Univ Florida, Gainesville, FL USA. [Eworuke, Efe] US FDA, Off Surveillance & Epidemiol, Washington, DC 20204 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 OCT PY 2014 VL 23 SU 1 SI SI MA 908 BP 488 EP 489 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600900 ER PT J AU Hoffman, SR Loyo-Berrios, N Gatski, M Bayona, M Price, V AF Hoffman, Sarah R. Loyo-Berrios, Nilsa Gatski, Megan Bayona, Manuel Price, Veronica TI Creation and Use of a "Lag Time" Variable for Comparative Effectiveness Research Using Claims Data SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Hoffman, Sarah R.] US FDA, ORISE, Silver Spring, MD USA. [Loyo-Berrios, Nilsa; Gatski, Megan; Bayona, Manuel] US FDA, Div Epidemiol, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Price, Veronica] US FDA, Div Reprod Gastrorenal & Urol Devices, Off Device Evaluat, 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 OCT PY 2014 VL 23 SU 1 SI SI MA 910 BP 489 EP 490 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600902 ER PT J AU Sedrakyan, A Paxton, EW Graves, SE Cafri, G Isaacs, AJ Bordini, B Robertsson, O Allepuz, A Furnace, O Marinac-Dabic, D AF Sedrakyan, Art Paxton, Elixabeth W. Graves, Steven E. Cafri, Guy Isaacs, Abby J. Bordini, Barbara Robertsson, Otto Allepuz, Alejandro Furnace, Ove Marinac-Dabic, Denica TI Evaluation of Implant Stabilization and Mobility in Total Knee Arthroplasty SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Sedrakyan, Art; Isaacs, Abby J.] Weill Cornell Med Coll, New York, NY USA. [Paxton, Elixabeth W.; Cafri, Guy] Kaiser Permanente, Surg Outcomes & Anal, San Diego, CA USA. [Graves, Steven E.] Australian Orthopaed Assoc, Natl Joint Replacement Registry, Adelaide, SA, Australia. [Bordini, Barbara] Ist Ortoped Rizzoli, Emilia Romagna Joint Registry, Bologna, Italy. [Robertsson, Otto] Swedish Knee Arthroplasty Register, Gothenburg, Sweden. [Allepuz, Alejandro] Catalan Arthroplasty Register, Barcelona, Spain. [Furnace, Ove] Haukeland Hosp, Dept Orthopaed Surg, Norwegian Arthroplasty Register, N-5021 Bergen, Norway. [Marinac-Dabic, Denica] US FDA, Off Surveillance & Biometr, Ctr Device & 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 OCT PY 2014 VL 23 SU 1 SI SI MA 909 BP 489 EP 489 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600901 ER PT J AU Girman, CJ Faries, D Ryan, P Rotelli, M Belger, M Binkowitz, B O'Neill, R AF Girman, Cynthia J. Faries, Douglas Ryan, Patrick Rotelli, Matt Belger, Mark Binkowitz, Bruce O'Neill, Robert TI Identifying Important Sensitivity Analyses Empirically for Pre-Specification in CER Protocols SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Girman, Cynthia J.] Merck Sharp & Dohme Ltd, Ctr Observat & Real World Evidence, N Wales, PA USA. [Faries, Douglas; Belger, Mark] Eli Lilly & Co, Global Stat Sci, Indianapolis, IN 46285 USA. [Ryan, Patrick] Janssen Res & Dev, Epidemiol Analyt, Titusville, NJ USA. [Rotelli, Matt] Eli Lilly & Co, Global PK PD & Pharmacometr, Indianapolis, IN 46285 USA. [Binkowitz, Bruce] Merck Sharp & Dohme Ltd, Late Dev Stat, Rahay, NJ USA. [O'Neill, Robert] US FDA, Off Translat Sci, CDER, Rockville, MD 20857 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 OCT PY 2014 VL 23 SU 1 SI SI MA 911 BP 490 EP 491 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AQ4JZ UT WOS:000342763600903 ER PT J AU Kammerman, LA Grosser, S AF Kammerman, Lisa A. Grosser, Stella TI Statistical considerations in the design, analysis and interpretation of clinical studies that use patient-reported outcomes SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Editorial Material C1 [Kammerman, Lisa A.; Grosser, Stella] US FDA, Ctr Drug Evaluat & Res, Gaithersburg, MD 20877 USA. RP Kammerman, LA (reprint author), US FDA, Ctr Drug Evaluat & Res, One Medimmune Way, Gaithersburg, MD 20877 USA. EM Lisa.Kammerman@AstraZeneca.com NR 16 TC 0 Z9 0 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD OCT PY 2014 VL 23 IS 5 BP 393 EP 397 DI 10.1177/0962280213498013 PG 5 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA AQ5KW UT WOS:000342848700001 PM 25258383 ER PT J AU Izem, R Kammerman, LA Komo, S AF Izem, Rima Kammerman, Lisa A. Komo, Scott TI Statistical challenges in drug approval trials that use patient-reported outcomes SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE Patient-reported outcome; statistical review ID CYSTIC-FIBROSIS; CLINICAL-TRIALS AB This article describes challenging aspects of the use of patient-reported outcome instruments in clinical trials for drug approval, in our perspective as statistical reviewers at the US Food and Drug Administration. We discuss aspects of planning and interpreting results in clinical trials (1) adapting an existing patient-reported outcome instrument for use in clinical trials, (2) using multi-item patient-reported outcomes and (3) missing patient-reported outcome values from many subjects over time. These challenges are illustrated with multiple examples from different clinical trials for different indications. We finally discuss important considerations in labeling. C1 [Izem, Rima; Kammerman, Lisa A.; Komo, Scott] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Izem, R (reprint author), Bldg 21,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM rima.izem@fda.hhs.gov NR 18 TC 4 Z9 4 U1 1 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD OCT PY 2014 VL 23 IS 5 BP 398 EP 408 DI 10.1177/0962280213476376 PG 11 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA AQ5KW UT WOS:000342848700002 PM 23435284 ER PT J AU Pellegrini, KL Han, T Bijol, V Saikumar, J Craciun, FL Chen, WW Fuscoe, JC Vaidya, VS AF Pellegrini, Kathryn L. Han, Tao Bijol, Vanesa Saikumar, Janani Craciun, Florin L. Chen, William W. Fuscoe, James C. Vaidya, Vishal S. TI MicroRNA-155 Deficient Mice Experience Heightened Kidney Toxicity When Dosed with Cisplatin SO TOXICOLOGICAL SCIENCES LA English DT Article DE Kidney toxicity; cisplatin; miRNAs; microRNA-155 ID C-FOS; CANCER CELLS; INDUCED APOPTOSIS; EXPRESSION; INJURY; MIR-155; TARGETS; ARRAYTRACK; INDUCTION; EXCRETION AB The development of nephrotoxicity limits the maximum achievable dosage and treatment intervals for cisplatin chemotherapy. Therefore, identifying mechanisms that regulate this toxicity could offer novel methods to optimize cisplatin delivery. MicroRNAs are capable of regulating many different genes, and can influence diverse cellular processes, including cell death and apoptosis. We previously observed miR-155 to be highly increased following ischemic or toxic injury to the kidneys and, therefore, sought to determine whether mice deficient in miR-155 would respond differently to kidney injury. We treated C57BL/6 and miR-155(-/-) mice with 20 mg/kg of cisplatin and found a significantly higher level of kidney injury in the miR-155(-/-) mice. Genome-wide expression profiling and bioinformatic analysis indicated the activation of a number of canonical signaling pathways relating to apoptosis and oxidative stress over the course of the injury, and identified potential upstream regulators of these effects. One predicted upstream regulator was c-Fos, which has two confirmed miR-155 binding sites in its 3' UTR and, therefore, can be directly regulated by miR-155. We established that the miR-155(-/-) mice had significantly higher levels of c-Fos mRNA and protein than the C57BL/6 mice at 72 h after cisplatin exposure. These data indicate a role for miR-155 in the cisplatin response and suggest that targeting of c-Fos could be investigated to reduce cisplatin-induced nephrotoxicity. C1 [Pellegrini, Kathryn L.; Saikumar, Janani; Craciun, Florin L.; Vaidya, Vishal S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Renal Div,Dept Med, Boston, MA 02115 USA. [Han, Tao; Fuscoe, James C.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Bijol, Vanesa] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Chen, William W.; Vaidya, Vishal S.] Harvard Univ, Sch Med, Harvard Program Therapeut Sci, Lab Syst Pharmacol, Boston, MA USA. [Vaidya, Vishal S.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. RP Vaidya, VS (reprint author), Harvard Inst Med, Room 562,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM vvaidya@partners.org OI Pellegrini, Kathryn/0000-0002-5089-5477 FU National Institute of Environmental Health Sciences [ES017543] FX National Institute of Environmental Health Sciences (Outstanding New Environmental Scientist Award [ES017543] to V.S.V.). NR 34 TC 10 Z9 11 U1 0 U2 4 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 2014 VL 141 IS 2 BP 484 EP 492 DI 10.1093/toxsci/kfu143 PG 9 WC Toxicology SC Toxicology GA AQ8BD UT WOS:000343045100018 PM 25015656 ER PT J AU Rambod, M Heine, GH Seiler, S Dominic, EA Rogacev, KS Dwivedi, R Ramezani, A Wing, MR Amdur, RL Fliser, D Raj, DS AF Rambod, Mehdi Heine, Gunnar H. Seiler, Sarah Dominic, Elizabeth A. Rogacev, Kyrill S. Dwivedi, Rama Ramezani, Ali Wing, Maria R. Amdur, Richard L. Fliser, Danilo Raj, Dominic S. TI Association of vascular endothelial factors with cardiovascular outcome and mortality in chronic kidney disease patients: A 4-year cohort study SO ATHEROSCLEROSIS LA English DT Article DE sFlt; Placental growth factor; Vascular endothelial growth factors; Survival ID PLACENTAL GROWTH-FACTOR; ACUTE CORONARY SYNDROME; TYROSINE KINASE-1; MYOCARDIAL-INFARCTION; ADVERSE OUTCOMES; RISK; VEGF; CKD; ANGIOGENESIS; HYPERTENSION AB Background: Angiogenic cytokines fms-like tyrosine kinase-1(sFlt-1) and placental growth factor (PlGF) are associated with increased risk for cardiovascular disease (CVD) in the general population. In this study we examine the association between these vascular endothelial factors and atherosclerosis, cardiovascular outcome, and mortality in chronic kidney disease (CKD) patients. Methods: Serum level of PlGF and sFlt-1 were measured in 301 patients with CKD, who were followed for up to 4 years. Primary outcomes were CV events and all-cause mortality. Carotid-intima media thickness (CIMT) was used as marker of atherosclerosis. Kaplan-Meier survival curves and the Cox proportional hazard model were used to assess the association of biomarkers and clinical outcomes. Results: Mean (SD) PlGF and sFlt-1 were 5.45 ng/ml (3.76) and 68.6 (28.0) pg/ml, respectively. During the follow up time, 60 patients (19.9%) experienced CV events and 22 patients (7.3%) died. Compared with low PlGF, patients with PlGF above median level had higher CV events (12.7% vs. 27.2%, p = 0.002) and mortality (2.0% vs. 12.6%, p < 0.001). The associations of PlGF and sFlt-1 with CV events were not statistically significant in the fully adjusted model. Higher PlGF was associated with greater death risk (HR = 5.22, 95% CI: 1.49-18.33, p = 0.01), which was robust to adjustment for sFlt-1 and other risk factors. Elevated sFlt-1 level was also an independent predictor of mortality (HR 3.41, 95% CI: 1.49-9.51, p = 0.019). Conclusion: In CKD patients not yet on dialysis, higher serum level of PlGF and sFlt-1 are associated with increased mortality, but not CV events. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Rambod, Mehdi] Texas Tech Univ, Hlth Sci Ctr, Paul L Foster Sch Med, Dept Internal Med, El Paso, TX USA. [Heine, Gunnar H.; Seiler, Sarah; Rogacev, Kyrill S.; Fliser, Danilo] Univ Saarland, Med Ctr, Homburg, Germany. [Heine, Gunnar H.; Seiler, Sarah; Rogacev, Kyrill S.; Fliser, Danilo] Univ Saarland, Fac Med, Homburg, Germany. [Dwivedi, Rama; Ramezani, Ali; Wing, Maria R.; Raj, Dominic S.] George Washington Univ, Sch Med, Div Renal Dis & Hypertens, Washington, DC 20037 USA. [Dominic, Elizabeth A.] George Washington Univ, Washington, DC USA. [Dwivedi, Rama] US FDA, Off New Drugs, Div Cardiovasc & Renal Prod, Silver Spring, MD USA. [Amdur, Richard L.] George Washington Univ, Washington, DC 20037 USA. RP Raj, DS (reprint author), George Washington Univ, Sch Med, MFA, Div Nephrol & Hypertens, 2150 Penn Ave NW, Washington, DC 20037 USA. EM draj@mfa.gwu.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK073665-01A1, 1U01DK099924-01, 1U01DK099914-01]; NIH National Center for Advancing Translational Sciences [UL1TR000075] FX This work is supported in part by grants R01 DK073665-01A1, 1U01DK099924-01 and 1U01DK099914-01 from the National Institute of Diabetes and Digestive and Kidney Diseases, and grant UL1TR000075 from the NIH National Center for Advancing Translational Sciences, awarded to Dominic Raj. NR 36 TC 7 Z9 8 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD OCT PY 2014 VL 236 IS 2 BP 360 EP 365 DI 10.1016/j.atherosclerosis.2014.07.026 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AP9QP UT WOS:000342414700039 PM 25128974 ER PT J AU Wissing, MD Kluetz, PG Ning, YM Bull, J Merenda, C Murgo, AJ Pazdur, R AF Wissing, Michel D. Kluetz, Paul G. Ning, Yang-Min Bull, Jonca Merenda, Christine Murgo, Anthony J. Pazdur, Richard TI Under-Representation of Racial Minorities in Prostate Cancer Studies Submitted to the US Food and Drug Administration to Support Potential Marketing Approval, 1993-2013 SO CANCER LA English DT Article DE prostate cancer; race relations; clinical trial; phase 3; US Food and Drug Administration ID AFRICAN-AMERICAN MEN; CLINICAL-TRIALS; HEALTH DISPARITIES; IMPROVE SURVIVAL; ENROLLMENT; PARTICIPATION; RECRUITMENT; POPULATIONS; ETHNICITY; RACE AB BACKGROUND: US Food and Drug Administration (FDA) approval of newdrugs depends on results from clinical trials that must be generalized to the US population. However, racial minorities are frequently under-represented in clinical studies. The enrollment of racial minorities was compared in key clinical studies submitted to the FDA in the last 10 years in support of potential marketing approval for prostate cancer (PCa) prevention or treatment. METHODS: Patient demographic data were obtained from archival data sets of large registration trials submitted to the FDA to support proposed PCa indications. Six countries/regions were analyzed: the United States, Canada, Australia, Europe, the United Kingdom, and Eastern Europe. Background racial demographics were collected from national census data. RESULTS: Seventeen key PCa clinical trials were analyzed. These trials were conducted in the past 20 years, comprising 39,574 patients with known racial information. Most patients were enrolled in the United States, but there appeared to be a trend toward increased non-US enrollment over time. In all countries, racial minorities were generally under-represented. There was no significant improvement in racial minority enrollment over time. The United States enrolled the largest nonwhite population (7.1%). CONCLUSIONS: Over the past 20 years, racial minorities were consistently under-represented in key PCa trials. There is a need for effective measures that will improve enrollment of racial minorities. With increased global enrollment, drug developers should aim to recruit a patient population that resembles the racial demographics of the patient population to which drug use will be generalized upon approval. (C) 2014 American Cancer Society. C1 [Wissing, Michel D.; Kluetz, Paul G.; Ning, Yang-Min; Murgo, Anthony J.; Pazdur, Richard] US FDA, Off Hematol & Oncol Prod, Off New Drugs, Ctr Drug Evaluat Res, Silver Spring, MD 20993 USA. [Bull, Jonca; Merenda, Christine] US FDA, Off Minor Hlth, Silver Spring, MD 20993 USA. RP Kluetz, PG (reprint author), US FDA, Off Hematol & Oncol Prod, Off New Drugs, Ctr Drug Evaluat Res, 10903 New Hampshire Ave,Bldg 22,Room 2356, Silver Spring, MD 20993 USA. EM paul.kluetz@fda.hhs.gov FU Dutch Association of Medical Oncologists (Nederlandse Vereniging voor Medische Oncologie) FX Michel Wissing was supported by a grant from the Dutch Association of Medical Oncologists (Nederlandse Vereniging voor Medische Oncologie) and by an appointment to the Research Participation Program at the Center for Drug 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. NR 22 TC 7 Z9 7 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD OCT 1 PY 2014 VL 120 IS 19 BP 3025 EP 3032 DI 10.1002/cncr.28809 PG 8 WC Oncology SC Oncology GA AQ2PP UT WOS:000342630000015 PM 24965506 ER PT J AU Gray, MD Lampel, KA Strockbine, NA Fernandez, RE Melton-Celsa, AR Maurelli, AT AF Gray, Miranda D. Lampel, Keith A. Strockbine, Nancy A. Fernandez, Reinaldo E. Melton-Celsa, Angela R. Maurelli, Anthony T. TI Clinical Isolates of Shiga Toxin 1a-Producing Shigella flexneri with an Epidemiological Link to Recent Travel to Hispaniola SO EMERGING INFECTIOUS DISEASES LA English DT Article ID ESCHERICHIA-COLI STRAINS; III SECRETION SYSTEM; BACTERIOPHAGE; PATHOGENS; VIRULENCE; RELEASE; PHAGES AB Shiga toxins (Stx) are cytotoxins involved in severe human intestinal disease. These toxins are commonly found in Shigella dysenteriae serotype 1 and Shiga-toxin producing Escherichia colt; however, the toxin genes have been found in other Shigella species. We identified 26 Shigella flexneri serotype 2 strains isolated by public health laboratories in the United States during 2001-2013, which encode the Shiga toxin 1a gene (stx(1a)). These strains produced and released Stx1 a as measured by cytotoxicity and neutralization assays using anti-Stx/Stx1a antiserum. The release of Stx1a into culture supernatants increased approximate to 100-fold after treatment with mitomycin C, suggesting that stx(1a) is carried by a bacteriophage. Infectious phage were found in culture supernatants and increased approximate to 1,000-fold with mitonnycin C. Whole-genome sequencing of several isolates and PCR analyses of. all strains confirmed that stx(1a) was carried by a lambdoid bacteriophage. Furthermore, all patients who reported foreign travel had recently been to Hispaniola, suggesting that emergence of these novel strains is associated with that region. C1 [Gray, Miranda D.; Fernandez, Reinaldo E.; Melton-Celsa, Angela R.; Maurelli, Anthony T.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Lampel, Keith A.] US FDA, College Pk, MD USA. [Strockbine, Nancy A.] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Maurelli, AT (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, F Edward Hebert Sch Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM anthony.maurelli@usuhs.edu FU National Institute of Allergy and Infectious Diseases [R01AI24656, AI020148] FX This work was supported by grants R01AI24656 and AI020148 from the National Institute of Allergy and Infectious Diseases. NR 16 TC 11 Z9 11 U1 0 U2 6 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD OCT PY 2014 VL 20 IS 10 BP 1669 EP 1677 DI 10.3201/eid2010.140292 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AQ1ER UT WOS:000342525200008 PM 25271406 ER PT J AU Mehrotra, A Calvo, MS Beelman, RB Levy, E Siuty, J Kalaras, MD Uribarri, J AF Mehrotra, A. Calvo, M. S. Beelman, R. B. Levy, E. Siuty, J. Kalaras, M. D. Uribarri, J. TI Bioavailability of vitamin D-2 from enriched mushrooms in prediabetic adults: a randomized controlled trial SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID SERUM 25-HYDROXYVITAMIN D; AGARICUS-BISPORUS; UV-B; BUTTON MUSHROOMS; HEALTHY-ADULTS; D DEFICIENCY; SUPPLEMENTATION; ERGOCALCIFEROL; METAANALYSIS; CHOLECALCIFEROL AB BACKGROUND/OBJECTIVES: Based on the growing evidence of risk reduction from fresh fruit and vegetable consumption and an inverse relationship between serum 25-hydroxyvitamin D (25OHD) and the risk of type 2 diabetes (T2D), we determined the benefits of regularly consuming vitamin D-enriched mushrooms in a prediabetic cohort. Exposing edible mushrooms to ultraviolet B (UVB) light increases vitamin D-2 (D-2) and raises serum 25OHD(2) in healthy young adults; however, their benefit to deficient prediabetics and glucose metabolism remains untested. SUBJECTS/METHODS: Forty-three prediabetic, D-deficient adults (25OHD <= 20 ng/ml), BMI > 25 were randomized to four groups consuming daily entrees containing 100 g fresh sliced cooked mushrooms prepared by a chef for 16 weeks. Two groups were fed UVB-treated mushrooms initially containing: 600 IU D-2 or 4000 IU D-2; each one also received one capsule of placebo daily. Two control groups Were fed untreated mushrooms and D-3 dietary supplements at two label doses: 600 IU D-3 and 4000 IU D-3.D-2 and D-3 content were analyzed in mushrooms, before and after cooking and in over-the-counter supplements. RESULTS: After 16 weeks, both D-2 UVB-mushroom entre doses, which were significantly lower after cooking, produced modest or no increases in 25OHD(2) or total 25OHD relative to the positive control subjects who actually consumed about 1242 and 7320 IU per day of D3 (higher than stated on the label). CONCLUSIONS: Unanticipated D2 cooking loss from fresh UVB mushrooms and probable low absorption and/or hydroxylation may explain the smaller increase in 25OHD(2) in our prediabetic overweight/obese cohort compared with past findings in younger, healthy subjects. Moreover, no dose or vitamin D source was associated with modifying T2D risk factors. C1 [Mehrotra, A.; Levy, E.; Siuty, J.; Uribarri, J.] Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. [Calvo, M. S.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD USA. [Beelman, R. B.; Kalaras, M. D.] Penn State Univ, Dept Food Sci, University Pk, PA 16802 USA. RP Uribarri, J (reprint author), Mt Sinai Sch Med, One Gustave Levy Pl Box 1147, New York, NY 10029 USA. EM Jaime.uribarri@mssm.edu FU National Institutes of Health, National Institute of Research Resources [M01-RR-00071] FX The Mushroom Council, the US FDA Center for Food Safety and Applied Nutrition, the Center for Plant and Mushroom Products for Health at the Penn State University, and the National Institutes of Health, National Institute of Research Resources (Grant M01-RR-00071) to the General Clinical Research Center at The Mount Sinai School of Medicine. NR 39 TC 8 Z9 8 U1 0 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 EI 1476-5640 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD OCT PY 2014 VL 68 IS 10 BP 1154 EP 1160 DI 10.1038/ejcn.2014.157 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AQ4BC UT WOS:000342736200013 PM 25117997 ER PT J AU Encinosa, W Meyerhoefer, C Zuvekas, S Du, DY AF Encinosa, William Meyerhoefer, Chad Zuvekas, Samuel Du, Dongyi TI The Impact of Direct-to-Consumer Advertising on Health Insurance Markets SO GENEVA PAPERS ON RISK AND INSURANCE-ISSUES AND PRACTICE LA English DT Article DE health insurance; direct-to-consumer advertising; pharmaceuticals; prices ID PRESCRIPTION DRUGS; PRICE; INFORMATION; ANTIDEPRESSANTS; PERFORMANCE; ECONOMICS; QUANTITY AB Direct-to-consumer advertising (DTCA) for drugs has increased from US$200 million in 1997 to US$4 billion in 2011. While studies show that DTCA impacts the patient-physician relationship, little is known of the effect of DTCA on health insurance markets. We test whether DTCA raises the costs in these markets or makes the markets more efficient in drug pricing. Across 212 markets, we examine the impact of DTCA on insurers' negotiated prices for 166 drugs. Controlling for unobserved pharmacy and pharmacy benefit manager attributes, as well as manufacturer advertising market selection effects, we find that an increase in a manufacturer's DTCA spending lowers insurer prices and reduces insurance market price dispersion. These competitive effects intensify as DTCA competition increases between drug manufacturers. C1 [Encinosa, William] Georgetown Univ, McCourt Sch Publ Policy, Washington, DC 20057 USA. [Meyerhoefer, Chad] Lehigh Univ, Bethlehem, PA 18015 USA. [Meyerhoefer, Chad] NBER, Cambridge, MA 02138 USA. [Encinosa, William; Zuvekas, Samuel] Agcy Healthcare Res & Qual, Rockville, MD 20850 USA. [Du, Dongyi] Food & Drug Adm, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Encinosa, W (reprint author), Georgetown Univ, McCourt Sch Publ Policy, 37th St NW & O St NW,Old North 100, Washington, DC 20057 USA. EM william.encinosa@ahrq.hhs.gov; chm308@lehigh.edu; samuel.zuvekas@ahrq.hhs.gov; dongyi.du@fda.hhs.gov NR 51 TC 0 Z9 0 U1 3 U2 14 PU PALGRAVE MACMILLAN LTD PI BASINGSTOKE PA BRUNEL RD BLDG, HOUNDMILLS, BASINGSTOKE RG21 6XS, HANTS, ENGLAND SN 1018-5895 EI 1468-0440 J9 GENEVA PAP R I-ISS P JI Geneva Pap. Risk Insur.-Issues Pract. PD OCT PY 2014 VL 39 IS 4 BP 749 EP 767 DI 10.1057/gpp.2014.33 PG 19 WC Business, Finance SC Business & Economics GA AQ3ZI UT WOS:000342731600009 ER PT J AU Williams, DK Galvin, TA Choudhary, A Springman, R Khan, AS AF Williams, Dhanya K. Galvin, Teresa A. Choudhary, Anil Springman, Rachael Khan, Arifa S. TI SFV INFLUENCE ON SIV INFECTION IN A RHESUS MACAQUE MODEL SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Williams, Dhanya K.; Galvin, Teresa A.; Choudhary, Anil; Springman, Rachael; Khan, Arifa S.] US FDA, Lab Retroviruses, Div Viral Prod, Off Vaccines Res & Review,Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Choudhary, Anil] US FDA, Off Compliance & Biol Qual, DBSQC, CBER, Kensington, 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2014 VL 43 IS 5 MA 129 BP 431 EP 431 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA AQ3EZ UT WOS:000342673700142 ER PT J AU Fan, Y Ma, L Pippins, J Limb, S Xu, Y Sahajwalla, CG AF Fan, Ying Ma, Lian Pippins, Jennifer Limb, Susan Xu, Yun Sahajwalla, Chandrahas G. TI Impact of Study Design on the Evaluation of Inhaled and Intranasal Corticosteroids' Effect on Hypothalamic-Pituitary-Adrenal Axis Function SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Review DE study design; inhaled corticosteroids; intranasal corticosteroids; hypothalamic-pituitary-adrenal (HPA) axis; pulmonary; regulatory science; pharmacodynamics; toxicity; pediatrics ID AQUEOUS NASAL SPRAY; DRY-POWDER INHALER; PERENNIAL ALLERGIC RHINITIS; METERED-DOSE INHALER; LONG-TERM SAFETY; FLUTICASONE PROPIONATE; BECLOMETHASONE DIPROPIONATE; MOMETASONE FUROATE; TRIAMCINOLONE ACETONIDE; HPA-AXIS AB In part I of this review, an overview of the designs of hypothalamic-pituitary-adrenal (HPA) axis studies in the setting of inhaled corticosteroids (ICS) or intranasal corticosteroids (INS) use was discussed. Part II provides detailed discussion on the HPA axis evaluation results for each common ICS and INS, and how these results are possibly affected by the factors of study design. Significant adrenal suppression at conventional ICS/INS doses appears to be rare in clinical settings. The magnitude of cortisol suppression varies widely among different study designs. Factors potentially impacting this variability include: the choice of dose, dosing duration, assay sensitivity, statistical methodology, study population, and compliance. All of these factors have the potential to affect the extent of HPA axis effects detected and should be considered when designing or interpreting the results of a HPA axis study. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2963-2979, 2014 C1 [Fan, Ying; Xu, Yun; Sahajwalla, Chandrahas G.] US FDA, Div Clin Pharmacol 2, Off Clin Pharmacol, Silver Spring, MD 20993 USA. [Ma, Lian] US FDA, Div Pharmacometr, Off Clin Pharmacol, Silver Spring, MD USA. [Pippins, Jennifer; Limb, Susan] US FDA, Div Pulm Allergy & Rheumatol Prod, Off Drug Evaluat 2, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Sahajwalla, CG (reprint author), US FDA, Div Clin Pharmacol 2, Off Clin Pharmacol, Silver Spring, MD 20993 USA. EM chandrahas.sahajwalla@fda.hhs.gov NR 71 TC 2 Z9 2 U1 0 U2 6 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 2014 VL 103 IS 10 BP 2963 EP 2979 DI 10.1002/jps.24089 PG 17 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA AQ3AO UT WOS:000342661300002 PM 25103275 ER PT J AU Dwyer, JT Saldanha, LG Bailen, RA Bailey, RL Costello, RB Betz, JM Chang, FF Goshorn, J Andrews, KW Pehrsson, PR Milner, JA Burt, VL Gahche, JJ Hardy, CJ Emenaker, NJ AF Dwyer, Johanna T. Saldanha, Leila G. Bailen, Richard A. Bailey, Regan L. Costello, Rebecca B. Betz, Joseph M. Chang, Florence F. Goshorn, Jeanne Andrews, Karen W. Pehrsson, Pamela R. Milner, John A. Burt, Vicki L. Gahche, Jaime J. Hardy, Constance J. Emenaker, Nancy J. TI A Free New Dietary Supplement Label Database for Registered Dietitian Nutritionists SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Editorial Material ID UNITED-STATES; NATIONAL-HEALTH; AMERICA-NHANES; US ADULTS; ADOLESCENTS; MINERALS; CHILDREN; FOOD; EAT C1 [Dwyer, Johanna T.; Saldanha, Leila G.; Bailen, Richard A.; Bailey, Regan L.; Costello, Rebecca B.; Betz, Joseph M.] NIH, Dietary Supplement Analyt Methods & Reference Mat, Off Dietary Supplements, Bethesda, MD 20892 USA. [Chang, Florence F.; Goshorn, Jeanne] NIH, Biomed Informat Serv Branch, Specialized Informat Serv Div, Natl Lib Med, Bethesda, MD USA. [Andrews, Karen W.; Pehrsson, Pamela R.; Milner, John A.] ARS, US Dept Agr Human, Nutr Res Ctr, Beltsville, MD USA. [Burt, Vicki L.; Gahche, Jaime J.] Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Hardy, Constance J.] US FDA, Ctr Food Sci & Nutr, College Pk, MD USA. [Emenaker, Nancy J.] NCI, Canc Prevent Div, Nutr Sci Grp, Bethesda, MD USA. RP Dwyer, JT (reprint author), NIH, Dietary Supplement Analyt Methods & Reference Mat, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. OI Dwyer, Johanna/0000-0002-0783-1769 FU Intramural CDC HHS [CC999999] NR 21 TC 1 Z9 1 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 EI 2212-2680 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD OCT PY 2014 VL 114 IS 10 BP 1512 EP + DI 10.1016/j.jand.2014.04.015 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AQ2JD UT WOS:000342610700002 PM 24928780 ER PT J AU Tropea, MM Harper, BJA Graninger, GM Phillips, TM Ferreyra, G Mostowski, HS Danner, RL Suffredini, AF Solomon, MA AF Tropea, Margaret M. Harper, Bonnie J. A. Graninger, Grace M. Phillips, Terry M. Ferreyra, Gabriela Mostowski, Howard S. Danner, Robert L. Suffredini, Anthony F. Solomon, Michael A. TI Isolation of a circulating CD45(-), CD34(dim) cell population and validation of their endothelial phenotype SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Vascular cell markers; gene expression; flow cytometry; viability; circulating endothelial cells ID PERIPHERAL-BLOOD; PROGENITOR CELLS; MONOCLONAL-ANTIBODY; FLOW-CYTOMETRY; APOPTOSIS; CANCER; CD146; ENUMERATION; BIOMARKERS; DAMAGE AB Accurately detecting circulating endothelial cells (CECs) is important since their enumeration has been proposed as a biomarker to measure injury to the vascular endothelium. However, there is no single methodology for determining CECs in blood, making comparison across studies difficult. Many methods for detecting CECs rely on characteristic cell surface markers and cell viability indicators, but lack secondary validation. Here, a CEC population in healthy adult human subjects was identified by flow cytometry as CD45(-), CD34(dim) that is comparable to a previously described CD45-, CD31(bright) population. In addition, nuclear staining with 7-aminoactinomycin D (7-AAD) was employed as a standard technique to exclude dead cells. Unexpectedly, the CD45-, CD34(dim), 7-MD- CECs lacked surface detectable CD146, a commonly used marker of CECs. Furthermore, light microscopy revealed this cell population to be composed primarily of large cells without a clearly defined nucleus. Nevertheless, immunostains still demonstrated the presence of the lectin Ulex europaeus and von Willebrand factor. Ultramicro analytical immunochemistry assays for the endothelial cell proteins CD31, CD34, CD62E, CD105, CD141, CD144 and vWF indicated these cells possess an endothelial phenotype. However, only a small amount of RNA, which was mostly degraded, could be isolated from these cells. Thus the majority of CECs in healthy individuals as defined by CD45-, CD34(dim), and 7-AAD(-) have shed their CD146 surface marker and are senescent cells without an identifiable nucleus and lacking RNA of sufficient quantity and quality for transcriptomal analysis. This study highlights the importance of secondary validation of CEC identification. C1 [Tropea, Margaret M.; Harper, Bonnie J. A.; Graninger, Grace M.; Ferreyra, Gabriela; Danner, Robert L.; Suffredini, Anthony F.; Solomon, Michael A.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Phillips, Terry M.] Natl Inst Biomed Imaging & Bioengn, Ultramicro Analyt Immunochem Unit, NIH, Bethesda, MD USA. [Solomon, Michael A.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Mostowski, Howard S.] US FDA, Div Cell & Gene Therapy, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Solomon, MA (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Room 2C145, Bethesda, MD 20892 USA. EM msolomon@cc.nih.gov FU Critical Care Medicine Department, Clinical Center Intramural Research-Program FX This work was funded by Critical Care Medicine Department, Clinical Center Intramural Research-Program. NR 43 TC 2 Z9 2 U1 0 U2 1 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD OCT PY 2014 VL 112 IS 4 BP 770 EP 780 DI 10.1160/TH14-01-0043 PG 11 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AQ2YE UT WOS:000342655100017 PM 25057108 ER PT J AU Thompson, P Wheeler, HE Delaney, SM Lorier, R Broeckel, U Devidas, M Reaman, GH Scorsone, K Sung, L Dolan, ME Berg, SL AF Thompson, Patrick Wheeler, Heather E. Delaney, Shannon M. Lorier, Rachel Broeckel, Ulrich Devidas, Meenakshi Reaman, Gregory H. Scorsone, Kathleen Sung, Lillian Dolan, M. Eileen Berg, Stacey L. TI Pharmacokinetics and pharmacogenomics of daunorubicin in children: a report from the Children's Oncology Group SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Daunorubicin; Daunorubicinol; Pharmacokinetics; Pharmacogenetics; Pediatrics; Body composition; Obesity ID BREAST-CANCER PATIENTS; ACUTE LYMPHOBLASTIC-LEUKEMIA; S-TRANSFERASE P1; DOXORUBICIN DISPOSITION; DRUG-RESISTANCE; GLUTATHIONE; ASSOCIATION; POLYMORPHISMS; EXPRESSION; CARDIOTOXICITY AB We explored the impact of obesity, body composition, and genetic polymorphisms on the pharmacokinetics (PK) of daunorubicin in children with cancer. Patients a parts per thousand currency sign21 years receiving daunorubicin as an infusion of any duration < 24 h for any type of cancer were eligible. Plasma drug concentrations were measured by high-performance liquid chromatography. Body composition was measured by dual-energy X-ray absorptiometry. Obesity was defined as a BMI > 95 % for age or as body fat > 30 %. NONMEM was used to perform PK model fitting. The Affymetrix DMET chip was used for genotyping. The impact of genetic polymorphisms was investigated using SNP/haplotype association analysis with estimated individual PK parameters. A total of 107 subjects were enrolled, 98 patients had PK sampling, and 50 patients underwent DNA analysis. Population estimates for daunorubicin clearance and volume of distribution were 116 L/m(2)/h +/- A 14 % and 68.1 L/m(2) +/- A 24 %, respectively. Apparent daunorubicinol clearance and volume of distribution were 26.8 L/m(2)/h +/- A 5.6 % and 232 L/m(2) +/- A 10 %, respectively. No effect of body composition or obesity was observed on PK. Forty-four genes with variant haplotypes were tested for association with PK. FMO3-H1/H3 genotype was associated with lower daunorubicin clearance than FMO3-H1/H1, p = 0.00829. GSTP1*B/*B genotype was also associated with lower daunorubicin clearance compared to GSTP1*A/*A, p = 0.0347. However, neither of these associations was significant after adjusting for multiple testing by either Bonferroni or false discovery rate correction. We did not detect an effect of body composition or obesity on daunorubicin PK. We found suggestive associations between FMO3 and GSTP1 haplotypes with daunorubicin PK that could potentially affect efficacy and toxicity. C1 [Thompson, Patrick; Devidas, Meenakshi; Scorsone, Kathleen; Berg, Stacey L.] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Wheeler, Heather E.; Delaney, Shannon M.; Dolan, M. Eileen] Univ Chicago, Hematol Oncol Sect, Dept Med, Chicago, IL 60637 USA. [Lorier, Rachel; Broeckel, Ulrich] Med Coll Wisconsin, Dept Pediat, Childrens Res Inst, Sect Genom Pediat, Milwaukee, WI 53226 USA. [Lorier, Rachel; Broeckel, Ulrich] Med Coll Wisconsin, Human & Mol Genet Ctr, Milwaukee, WI 53226 USA. [Reaman, Gregory H.] US FDA, Silver Spring, MD USA. [Sung, Lillian] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. RP Berg, SL (reprint author), Baylor Coll Med, Texas Childrens Canc Ctr, 1102 Bates Ave,Suite 1570, Houston, TX 77030 USA. EM edolan@medicine.bsd.uchicago.edu; sberg@txch.org OI Wheeler, Heather/0000-0003-1365-9667 FU Better Pharmaceuticals for Children Act [U10 CA098543]; Pharmacogenomics of Anticancer Agent Research Grant NIH/NIGMS [GM61393]; Leukemia Lymphoma SCOR grant; University of Chicago Comprehensive Cancer Center; NIH/NCI National Research Service Award [F32CA165823] FX We would like to acknowledge the contributions of Dolly Yang. This study was supported in part by the Better Pharmaceuticals for Children Act through a supplement to National Cancer Institute grant U10 CA098543 (COG), the Pharmacogenomics of Anticancer Agent Research Grant NIH/NIGMS GM61393 (MED), a Leukemia Lymphoma SCOR grant (MED), University of Chicago Comprehensive Cancer Center (MED), and the NIH/NCI National Research Service Award F32CA165823 (HEW). NR 43 TC 8 Z9 8 U1 1 U2 7 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 OCT PY 2014 VL 74 IS 4 BP 831 EP 838 DI 10.1007/s00280-014-2535-4 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA AP9SG UT WOS:000342419600019 PM 25119182 ER PT J AU Cao, GJ Allard, M Strain, E Stones, R Zhao, SH Brown, E Meng, JH AF Cao, Guojie Allard, Marc Strain, Errol Stones, Robert Zhao, Shaohua Brown, Eric Meng, Jianghong TI Genetic Diversity of Salmonella Pathogenicity Islands SPI-5 and SPI-6 in Salmonella Newport SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article ID MULTISTATE OUTBREAK; SEQUENCE ALIGNMENT; SECRETION SYSTEMS; GENOMIC SEQUENCE; FIMBRIAL OPERONS; VI SECRETION; ENTERICA; BACTERIA; EVOLUTION; TYPHIMURIUM AB Salmonella enterica subspecies enterica serotype Newport is one of the common serotypes causing foodborne salmonellosis outbreaks in the United States. Salmonella Newport consists of three lineages exhibiting extensive genetic diversity. Due to the importance of Salmonella pathogenicity islands 5 and 6 (SPI-5 and SPI-6) in virulence of pathogenic Salmonella, the genetic diversity of these two SPIs may relate to different potentials of Salmonella Newport pathogenicity. Most Salmonella Newport strains from North America belong to Salmonella Newport lineages II and III. A total 28 Salmonella Newport strains of lineages II and III from diverse sources and geographic locations were analyzed, and 11 additional Salmonella genomes were used as outgroup in phylogenetic analyses. SPI-5 was identified in all Salmonella Newport strains and 146 single nucleotide polymorphisms (SNPs) were detected. Thirty-nine lineage-defining SNPs were identified, including 18 nonsynonymous SNPs. Two 40-kb genomic islands (SPI5-GI1 and SPI5-GI2) encoding bacteriophage genes were found between tRNA-ser and pipA. SPI5-GI1 was only present in Salmonella Newport multidrug-resistant strains of lineage II. SPI-6 was found in all strains but three Asian strains in Salmonella Newport lineage II, whereas the three Asian strains carried genomic island SPI6-GI1 at the same locus as SPI-6 in other Salmonella. SPI-6 exhibited 937 SNPs, and phylogenetic analysis demonstrated that clustering of Salmonella Newport isolates was a reflection of their geographic origins. The sequence diversity within SPI-5 and SPI-6 suggests possible recombination events and different virulence potentials of Salmonella Newport. The SNPs could be used as biomarkers during epidemiological investigations. C1 [Cao, Guojie; Meng, Jianghong] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Cao, Guojie; Meng, Jianghong] Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 USA. [Allard, Marc; Brown, Eric] US FDA, Div Microbiol, Off Regular Sci, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Strain, Errol] US FDA, Biostat Branch, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Stones, Robert] Food & Environm Res Agcy, York, N Yorkshire, England. [Zhao, Shaohua] US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, Laurel, MD USA. RP Meng, JH (reprint author), Univ Maryland, Dept Nutr & Food Sci, 0112 Skinner Bldg, College Pk, MD 20742 USA. EM jmeng@umd.edu FU Joint Institute for Food Safety and Applied Nutrition, University of Maryland FX This work was supported in part by the Joint Institute for Food Safety and Applied Nutrition, University of Maryland. NR 43 TC 0 Z9 0 U1 0 U2 18 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1535-3141 EI 1556-7125 J9 FOODBORNE PATHOG DIS JI Foodborne Pathog. Dis. PD OCT 1 PY 2014 VL 11 IS 10 BP 798 EP 807 DI 10.1089/fpd.2014.1784 PG 10 WC Food Science & Technology SC Food Science & Technology GA AP9WL UT WOS:000342431900008 PM 25188010 ER PT J AU Luo, S Uehara, H Shacter, E AF Luo, Shen Uehara, Hiroshi Shacter, Emily TI Taurine chloramine-induced inactivation of cofilin protein through methionine oxidation SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Cofilin; Actin; Oxidative stress; Methionine oxidation; Methionine sulfoxide reductases; Mass spectrometry; Taurine chloramine; G-actin-binding site; Phosphorylation ID ACTIN-BINDING; HYPOCHLOROUS ACID; SKELETAL-MUSCLE; SULFOXIDE; FRAGMENTATION; NEUTROPHILS; ADF/COFILIN; APOPTOSIS; PEPTIDES; DESTRIN AB Cofilin regulates reorganization of actin filaments (F-actin) in eukaryotes. A recent finding has demonstrated that oxidation of cofilin by taurine chloramine (TnCl), a physiological oxidant derived from neutrophils, causes cofilin to translocate to the mitochondria inducing apoptosis (F. Klamt et al. Nat. Cell Biol. 11:1241-1246; 2009). Here we investigated the effect of TnCl on biological activities of cofilin in vitro. Our data show that TnCl-induced oxidation of recombinant human cofilin-1 inhibits its F-actin-binding and depolymerization activities. Native cofilin contains four free Cys and three Met residues. Incubation of oxidized cofilin with DTT does not lead to its reactivation. A double Cys to Ala mutation on the two C-terminal Cys shows similar biological activities as the wild type, but does not prevent the TnCl-induced inactivation. In contrast, incubation of oxidized cofilin with methionine sulfoxide reductases results in its reactivation. Phosphorylation is known to inhibit cofilin activities. We found that Met oxidation also prevents phosphorylation of cofilin, which is reversed by incubating oxidized cofilin with methionine sulfoxide reductases. Interestingly, intact protein mass spectrometry of the oxidized mutant indicated one major oxidation product with an additional mass of 16 Da, consistent with oxidation of one specific Met residue. This residue was identified as Met-115 by peptide mapping and tandem mass spectrometry. It is adjacent to Lys-114, a known residue on globular-actin-binding site, implying that oxidation of Met-115 disrupts the globular-actin-binding site of cofilin, which causes TnCl-induced inactivation. The findings identify Met-115 as a redox switch on cofilin that regulates its biological activity. Published by Elsevier Inc. C1 [Luo, Shen; Uehara, Hiroshi; Shacter, Emily] US FDA, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Luo, S (reprint author), 10903 New Hampshire Ave,WO71 RM2260, Silver Spring, MD 20993 USA. EM shen.luo@fda.hhs.gov; hiroshi.uehara@fda.hhs.gov; emily.shacter@thinkfda.com FU FDA intramural research program FX This work was supported by the FDA intramural research program. We thank Rodney L. Levine and Geumsoo Kim (NHLBI) for helpful discussions and kindly providing the recombinant MsrA and MsrB proteins. We thank Edward E. Max (FDA) and Nancy Wehr (NHLBI) for critical reading and editorial advice on the manuscript. The authors declare no competing financial interests. NR 36 TC 3 Z9 3 U1 0 U2 5 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 OCT PY 2014 VL 75 BP 84 EP 94 DI 10.1016/j.freeradbiomed.2014.07.018 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA AP9II UT WOS:000342393100008 PM 25058340 ER PT J AU Dobhal, S Zhang, G Rohla, C Smith, MW Ma, LM AF Dobhal, S. Zhang, G. Rohla, C. Smith, M. W. Ma, L. M. TI A simple, rapid, cost-effective and sensitive method for detection of Salmonella in environmental and pecan samples SO JOURNAL OF APPLIED MICROBIOLOGY LA English DT Article DE detection; feces; inhibitors; PCR; pecan; Salmonella; soil ID POLYMERASE-CHAIN-REACTION; REAL-TIME PCR; BOVINE SERUM-ALBUMIN; DNA EXTRACTION; MULTIPLEX PCR; IMMUNOMAGNETIC SEPARATION; QUANTITATIVE PCR; STOOL SPECIMENS; GROUND-BEEF; INHIBITORS AB Aims: PCR is widely used in the routine detection of foodborne human pathogens; however, challenges remain in overcoming PCR inhibitors present in some sample matrices. The objective of this study was to develop a simple, sensitive, cost-effective and rapid method for processing large numbers of environmental and pecan samples for Salmonella detection. This study was also aimed at validation of a new protocol for the detection of Salmonella from in-shell pecans. Methods and Results: Different DNA template preparation methods, including direct boiling, prespin, multiple washing and commercial DNA extraction kits, were evaluated with pure cultures of Salmonella Typhimurium and with enriched soil, cattle feces and in-shell pecan each spiked individually with Salmonella Typhimurium. PCR detection of Salmonella was conducted using invA and 16S rRNA gene (internal amplification control) specific primers. The effect of amplification facilitators, including bovine serum albumin (BSA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) and gelatin on PCR sensitivity, was also evaluated. Conducting a prespin of sample matrices in combination with the addition of 0.4% (w/v) BSA and 1% (w/v) PVP in PCR mix was the simplest, most rapid, cost-effective and sensitive method for PCR detection of Salmonella, with up to 40 CFU Salmonella per reaction detectable in the presence of over 10(9) CFU ml(-1) of background micro-organisms from enriched feces soil or pecan samples. Conclusions: The developed method is rapid, cost-effective and sensitive for detection of Salmonella from different matrices. Significance and Impact of the study: This study provides a method with broad applicability for PCR detection of Salmonella in complex sample matrices. This method has a potential for its application in different research arenas and diagnostic laboratories. C1 [Dobhal, S.; Ma, L. M.] Oklahoma State Univ, Dept Entomol & Plant Pathol, Natl Inst Microbial Forens & Food & Agr Biosecur, Stillwater, OK 74078 USA. [Zhang, G.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Rohla, C.] Samuel Roberts Noble Fdn Inc, Ardmore, OK USA. [Smith, M. W.] Oklahoma State Univ, Dept Hort & Landscape Architecture, Stillwater, OK 74078 USA. RP Ma, LM (reprint author), Oklahoma State Univ, Dept Entomol & Plant Pathol, Natl Inst Microbial Forens & Food & Agr Biosecur, Stillwater, OK 74078 USA. EM li.ma@okstate.edu FU Oklahoma Agricultural Experiment Station; Samuel Roberts Noble Foundation, Ardmore FX This work was supported by the Oklahoma Agricultural Experiment Station and the Samuel Roberts Noble Foundation, Ardmore. We thank Dr. Jacqueline Fletcher and Dr. Astri Wayadande for reviewing this manuscript. We also thank Ms. Becky Cheary for providing the soil, fecal and pecan samples for the experiment. NR 44 TC 3 Z9 4 U1 1 U2 32 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1364-5072 EI 1365-2672 J9 J APPL MICROBIOL JI J. Appl. Microbiol. PD OCT PY 2014 VL 117 IS 4 BP 1181 EP 1190 DI 10.1111/jam.12583 PG 10 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA AP6VK UT WOS:000342216000024 PM 24947913 ER PT J AU Miller, DL Bhargavan-Chatfield, M Armstrong, MR Butler, PF AF Miller, Donald L. Bhargavan-Chatfield, Mythreyi Armstrong, Mark R. Butler, Priscilla F. TI Clinical Implementation of the National Electrical Manufacturers Association CT Dose Check Standard at ACR Dose Index Registry Sites SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE CT; radiation management; optimization; radiation protection AB Purpose: The goal of the study was to determine if and how the National Electrical Manufacturers Association CT Dose Check standard has been implemented in clinical practice. Methods: A survey was conducted of all sites participating in the ACR Dose Index Registry, using a web-based survey instrument, to determine whether respondents were aware of the CT Dose Check standard and the American Association of Physicists in Medicine (AAPM) recommendations for Dose Alert values, and if clinical sites had implemented it. Results: A total of 170 responses were received, representing 37% (170/460) of surveys sent and 23% (170/734) of facilities participating in the ACR Dose Index Registry. Of responding facilities, 57.1% (96/168) were aware of the CT Dose Check standard, and 51.2% (86/168) were aware of the AAPM recommendations. At 44% (73/165) of responding facilities, at least 1 CT scanner with Dose Check capability was present. Of sites responding that they had at least 1 CT scanner with this capability, 57% (42/74) had implemented Dose Alerts, and 71% (30/42) had implemented Dose Notifications on CT scanners with the capability. Most responding sites were located in community hospitals (55.8%; 86/154). Conclusions: Although the National Electrical Manufacturers Association CT Dose Check standard and the AAPM recommendations for its use had been available for at least 2 years at the time of the survey, nearly half of the participating sites were not familiar with them. Education and outreach are needed if this tool is to be used effectively. C1 [Miller, Donald L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Bhargavan-Chatfield, Mythreyi; Butler, Priscilla F.] ACR, Reston, VA USA. [Armstrong, Mark R.] Doshi Diagnost Imaging, New York, NY USA. RP Miller, DL (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM donald.miller@fda.hhs.gov OI Bhargavan-Chatfield, Mythreyi/0000-0001-7734-925X NR 14 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD OCT PY 2014 VL 11 IS 10 BP 989 EP 994 DI 10.1016/j.jacr.2014.04.010 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AQ1FY UT WOS:000342528500016 PM 24996294 ER PT J AU Mossoba, MM Srigley, CT Farris, S Kramer, JKG Chirtel, S Rader, J AF Mossoba, Magdi M. Srigley, Cynthia Tyburczy Farris, Samantha Kramer, John K. G. Chirtel, Stuart Rader, Jeanne TI Evaluation of the Performance of a Portable Mid-Infrared Analyzer for the Rapid Determination of Total Trans Fat in Fast Food SO JOURNAL OF THE AMERICAN OIL CHEMISTS SOCIETY LA English DT Article DE Trans fat; Fast food; Infrared; Portable IR analyzer; ATR-FTIR; Gas chromatography ID GAS CHROMATOGRAPHIC COLUMN; INFRARED-SPECTROSCOPY; REGULATORY COMPLIANCE; MILK-FAT; ACIDS; SEPARATION; ISOMERS; IDENTIFICATION; OIL; CIS AB The performance of a novel, transmission-mode, portable, Fourier transform infrared (FTIR) analyzer was evaluated and compared to that of a benchtop attenuated total reflection (ATR)-FTIR spectrometer. The total concentration of trans fatty acids in the fat extracted from 19 representative fast foods was rapidly (< 5 min) quantified in a single measurement after conversion to fatty acid methyl esters (FAME). While the FTIR determination is rapid, the time required for extraction and derivatization is not. For all extracts, the total trans FAME concentration varied from approximately 0.5 to 11 % (of total FAME) as determined using the portable FTIR analyzer. The trans fat contents (mean +/- A SD), expressed in grams per serving and calculated on the basis of total fat content and FTIR determination of trans fat content, were found to be 1.00 +/- A 0.42 for hamburgers, 0.67 +/- A 0.78 for chicken tenders, 1.00 +/- A 1.24 for French fries, and 0.27 +/- A 0.23 for apple pies. Determinations of total trans-unsaturated FAME were consistent with those obtained by use of ATR-FTIR and GC official methods (AOCS Cd 14e-09 and AOCS Ce 1j-07, respectively). These results indicate that the portable FTIR analyzer is suitable for the rapid and routine quantification of total trans fat measured as FAME prepared from fats extracted from fast foods. C1 [Mossoba, Magdi M.; Srigley, Cynthia Tyburczy; Farris, Samantha; Rader, Jeanne] US FDA, Off Regulatory Sci, CFSAN, College Pk, MD 20740 USA. [Kramer, John K. G.] Agr & Agri Food Canada, Guelph Food Res Ctr, Guelph, ON, Canada. [Chirtel, Stuart] US FDA, Off Analyt & Outreach, CFSAN, College Pk, MD 20740 USA. RP Mossoba, MM (reprint author), US FDA, Off Regulatory Sci, CFSAN, College Pk, MD 20740 USA. EM magdi.mossoba@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration FX This project was supported in part by appointment (CS) to the Research Participation Program at the Center for Food Safety and Applied Nutrition 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 authors would like to acknowledge Milan Milosevic, Joseph Lucania and Jeffrey Christenson (Harrick Scientific Products, Inc.) for kindly providing the seven-reflection ConcentratIR (R) ATR accessory and scientific support. NR 35 TC 3 Z9 3 U1 2 U2 40 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0003-021X EI 1558-9331 J9 J AM OIL CHEM SOC JI J. Am. Oil Chem. Soc. PD OCT PY 2014 VL 91 IS 10 BP 1651 EP 1663 DI 10.1007/s11746-014-2521-3 PG 13 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA AP9RN UT WOS:000342417600001 ER PT J AU Collier, MG Khudyakov, YE Selvage, D Adams-Cameron, M Epson, E Cronquist, A Jervis, RH Lamba, K Kimura, AC Sowadsky, R Hassan, R Park, SY Garza, E Elliott, AJ Rotstein, DS Beal, J Kuntz, T Lance, SE Dreisch, R Wise, ME Nelson, NP Suryaprasad, A Drobeniuc, J Holmberg, SD Xu, FJ AF Collier, Melissa G. Khudyakov, Yury E. Selvage, David Adams-Cameron, Meg Epson, Erin Cronquist, Alicia Jervis, Rachel H. Lamba, Katherine Kimura, Akiko C. Sowadsky, Rick Hassan, Rashida Park, Sarah Y. Garza, Eric Elliott, Aleisha J. Rotstein, David S. Beal, Jennifer Kuntz, Thomas Lance, Susan E. Dreisch, Rebecca Wise, Matthew E. Nelson, Noele P. Suryaprasad, Anil Drobeniuc, Jan Holmberg, Scott D. Xu, Fujie CA Hepatitis A Outbreak Invest Team TI Outbreak of hepatitis A in the USA associated with frozen pomegranate arils imported from Turkey: an epidemiological case study SO LANCET INFECTIOUS DISEASES LA English DT Article ID IMMUNIZATION PRACTICES ACIP; MULTISTATE OUTBREAK; SEMIDRIED TOMATOES; MOLECULAR EPIDEMIOLOGY; ADVISORY-COMMITTEE; VIRUS-INFECTION; UNITED-STATES; RECOMMENDATIONS; PREVENTION; SURVIVAL AB Background In May, 2013, an outbreak of symptomatic hepatitis A virus infections occurred in the USA. Federal, state, and local public health officials investigated the cause of the outbreak and instituted actions to control its spread. We investigated the source of the outbreak and assessed the public health measures used. Methods We interviewed patients, obtained their shopping information, and did genetic analysis of hepatitis A virus recovered from patients' serum and stool samples. We tested products for the virus and traced supply chains. Findings Of 165 patients identified from ten states, 69 (42%) were admitted to hospital, two developed fulminant hepatitis, and one needed a liver transplant; none died. Illness onset occurred from March 31 to Aug 12, 2013. The median age of patients was 47 years (IQR 35-58) and 91 (55%) were women. 153 patients (93%) reported consuming product B from retailer A. 40 patients (24%) had product B in their freezers, and 113 (68%) bought it according to data from retailer A. Hepatitis A virus genotype IB, uncommon in the Americas, was recovered from specimens from 117 people with hepatitis A virus illness. Pomegranate arils that were imported from Turkey-where genotype IB is common-were identified in product B. No hepatitis A virus was detected in product B. Interpretation Imported frozen pomegranate arils were identified as the vehicle early in the investigation by combining epidemiology-with data from several sources-genetic analysis of patient samples, and product tracing. Product B was removed from store shelves, the public were warned not to eat product B, product recalls took place, and postexposure prophylaxis with both hepatitis A virus vaccine and immunoglobulin was provided. Our findings show that modern public health actions can help rapidly detect and control hepatitis A virus illness caused by imported food. Our findings show that postexposure prophylaxis can successfully prevent hepatitis A illness when a specific product is identified. Imported food products combined with waning immunity in some adult populations might make this type of intervention necessary in the future. Funding US Centers for Disease Control and Prevention, US Food and Drug Administration, and US state and local public health departments. C1 [Collier, Melissa G.; Khudyakov, Yury E.; Nelson, Noele P.; Suryaprasad, Anil; Drobeniuc, Jan; Holmberg, Scott D.; Xu, Fujie] Ctr Dis Control & Prevent, Div Viral Hepatitis, Natl Ctr HIV Hepatitis STD & TB Prevent, Atlanta, GA USA. [Epson, Erin] Ctr Dis Control & Prevent, Epidem Intelligence Serv, Atlanta, GA USA. [Lance, Susan E.; Wise, Matthew E.] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA USA. [Selvage, David; Adams-Cameron, Meg] New Mexico Dept Hlth, Santa Fe, NM USA. [Epson, Erin; Cronquist, Alicia; Jervis, Rachel H.] Colorado Dept Publ Hlth & Environm, Denver, CO USA. [Lamba, Katherine; Kimura, Akiko C.] Calif Dept Publ Hlth, Sacramento, CA USA. [Sowadsky, Rick] Nevada Div Publ & Behav Hlth, Carson City, NV USA. [Hassan, Rashida] Arizona Dept Hlth Serv, Phoenix, AZ 85007 USA. [Park, Sarah Y.] Hawaii State Dept Hlth, Honolulu, HI USA. [Garza, Eric] Texas Dept State Hlth Serv, Austin, TX USA. [Elliott, Aleisha J.; Rotstein, David S.; Beal, Jennifer; Kuntz, Thomas; Lance, Susan E.; Dreisch, Rebecca] US FDA, Silver Spring, MD USA. [Elliott, Aleisha J.] Oakridge Inst Sci & Educ, Oakridge, TN USA. RP Collier, MG (reprint author), Div Viral Hepatitis, CDC Mailstop G-37, Atlanta, GA 30329 USA. EM mgcollier@cdc.gov FU US Centers for Disease Control and Prevention; US Food and Drug Administration; US state public health department; US local public health department FX US Centers for Disease Control and Prevention, US Food and Drug Administration, and US state and local public health departments. NR 26 TC 31 Z9 31 U1 2 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD OCT PY 2014 VL 14 IS 10 BP 976 EP 981 DI 10.1016/S1473-3099(14)70883-7 PG 6 WC Infectious Diseases SC Infectious Diseases GA AP7HY UT WOS:000342249600038 PM 25195178 ER PT J AU Gough, B Pereira, FC Ribeiro, CAF Ali, SF Binienda, ZK AF Gough, B. Pereira, F. C. Fontes Ribeiro, C. A. Ali, S. F. Binienda, Z. K. TI Propentophylline increases striatal dopamine release but dampens methamphetamine-induced dopamine dynamics: A microdialysis study SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE In vivo microdialysis; Dopamine; Methamphetamine; Propentofylline; Caudate nucleus ID RAT CAUDATE-NUCLEUS; CAFFEINE; MECHANISMS; ADENOSINE; MODULATION; MDMA; MICE AB While there are currently no medications approved for methamphetamine (METH) addiction, it has been shown that propentofylline (PPF), an atypical methylxanthine, can suppress the rewarding effects of methamphetamine (METH) in mice. This experiment studied the interactions of PPF with METH in striatal dopaminergic transmission. Herein, the impact of PPF (10-40 mM, intrastriatally perfused (80 min) on the effect of METH (5 mg/kg, i.p.) on striatal dopamine (DA) release was evaluated using brain microdialysis in Sprague-Dawley adult rats. METH was injected at the 60 min time point of the 80 min PPF perfusion. The extracellular levels of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined using high performance liquid chromatography with electrochemical detection (HPLC-ED). PPF induced a concentration-dependent increase in DA release beginning 30 min after the onset of PPF perfusion. DA peak levels evoked by 40 mM PPF were similar to those induced by 5 mg/kg METH i.p. Only the highest concentration of PPF decreased the METH-induced DA peak (circa 70%). The significant decreases in extracellular levels of DOPAC and HVA evoked by METH were partially blocked by 10 and 20 mM PPF. Although 40 mM of PPF also partially blocked the METH-induced DOPAC decrease, it completely blocked HVA depletion after a transient increase in HVA levels in METH-treated rats. Data indicates for the first time that while PPF increases presynaptic striatal DA dynamics it attenuates METH-induced striatal DA release and metabolism. Published by Elsevier Ltd. C1 [Gough, B.; Ali, S. F.; Binienda, Z. K.] NCTR FDA, Div Neurotoxicol, Jefferson, AR USA. [Pereira, F. C.; Fontes Ribeiro, C. A.] Univ Coimbra, Fac Med, Farmacol Terapeut Expt IBILL, Coimbra, Portugal. RP Pereira, FC (reprint author), Univ Coimbra, Fac Med, Lab Pharmacol & Expt Therapeut IBILI, Subunit 1 Polo 3, P-3000354 Azinhaga De Santa Comba, Celas Coimbra, Portugal. EM fredcp@ci.uc.pt; zbigniew.binienda@fda.hhs.gov OI Pereira, Frederico/0000-0002-9381-3320 FU NCTR/FDA protocol [E-7433.01] FX This work was Supported by the NCTR/FDA protocol E-7433.01. NR 19 TC 4 Z9 4 U1 0 U2 7 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 2014 VL 76 BP 109 EP 113 DI 10.1016/j.neuint.2014.07.003 PG 5 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AQ0MO UT WOS:000342477600012 PM 25049173 ER PT J AU Hartman, NR Mao, JJ Zhou, HF Boyne, MT Wasserman, AM Taylor, K Racoosin, JA Patel, V Colatsky, T AF Hartman, Neil R. Mao, Jinzhe J. Zhou, Hongfei Boyne, Michael T., II Wasserman, Adam M. Taylor, Kellie Racoosin, Judith A. Patel, Vikram Colatsky, Thomas TI More methemoglobin is produced by benzocaine treatment than lidocaine treatment in human in vitro systems SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Methemoglobin; Methemoglobinemia; Benzocaine; Lidocaine; Xylidine; Benzocaine hydroxylamine ID HAIRLESS GUINEA-PIG; METABOLISM; MICROSOMES; DAPSONE; LIVER; SULFAMETHOXAZOLE; ABSORPTION; EXPOSURE; RISK; SKIN AB The clinical use of local anesthetic products to anesthetize mucous membranes has been associated with methemoglobinemia (MetHba), a serious condition in which the blood has reduced capacity to carry oxygen. An evaluation of spontaneous adverse event reporting of MetHba submitted to FDA through 2013 identified 375 reports associated with benzocaine and 16 reports associated with lidocaine. The current study was performed to determine the relative ability of benzocaine and lidocaine to produce methemoglobin (MetHb) in vitro. Incubation of 500 mu M benzocaine with whole human blood and pooled human liver S9 over 5 h resulted in MetHb levels equaling 39.8 +/- 1.2% of the total hemoglobin. No MetHb formation was detected for 500 mu M lidocaine under the same conditions. Because liver S9 does not readily form lidocaine hydrolytic metabolites based on xylidine, a primary metabolic pathway, 500 mu M xylidine was directly incubated with whole blood and S9. Under these conditions MetHb levels of 4.4 +/- 0.4% were reached by 5 h. Studies with recombinant cytochrome P450 revealed benzocaine to be extensively metabolized by CYP 1A2, with 2B6, 2C19, 2D6, and 2E1 also having activity. We conclude that benzocaine produces much more MetHb in in vitro systems than lidocaine or xylidine and that benzocaine should be more likely to cause MetHba in vivo as well. Published by Elsevier Inc. C1 [Hartman, Neil R.; Mao, Jinzhe J.; Zhou, Hongfei; Patel, Vikram; Colatsky, Thomas] US FDA, Ctr Drug Evaluat & Res, Div Appl Regulatory Sci, Silver Spring, MD 20993 USA. [Boyne, Michael T., II] US FDA, Ctr Drug Evaluat & Res, Div Pharmaceut Anal, Silver Spring, MD 20993 USA. [Taylor, Kellie] US FDA, Ctr Drug Evaluat & Res, Div Medicat Error Prevent & Anal, Silver Spring, MD 20993 USA. RP Hartman, NR (reprint author), US FDA, Bldg 64,Rm 2020,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM neil.hartman@fda.hhs.goy FU FDA CDER Director Fund FX The authors would like to thank Dr. Paul Buehler for helpful discussions on the design of the investigation, Dr. Daniel Mans for insights as to the synthesis of benzocaine hydroxylamine, Dr. Patrick Faustino for NMR analysis of the same compound, and Tracy Pham and Laura Governale for researching the drug use trends. This work was funded through an FDA CDER Director Fund. NR 37 TC 1 Z9 1 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 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD OCT 1 PY 2014 VL 70 IS 1 BP 182 EP 188 DI 10.1016/j.yrtph.2014.07.002 PG 7 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA AQ0OI UT WOS:000342482200019 PM 25010377 ER PT J AU Sewell, F Chapman, K Baldrick, P Brewster, D Broadmeadow, A Brown, P Burns-Naas, LA Clarke, J Constan, A Couch, J Czupalla, O Danks, A DeGeorge, J de Haanm, L Hettinger, K Hill, M Festag, M Jacobs, A Jacobson-Kram, D Kopytek, S Lorenz, H Moesgaard, SG Moore, E Pasanen, M Perry, R Ragan, I Robinson, S Schmitt, PM Short, B Lima, BS Smith, D Sparrow, S van Bekkum, Y Jones, D AF Sewell, Fiona Chapman, Kathryn Baldrick, Paul Brewster, David Broadmeadow, Alan Brown, Paul Burns-Naas, Leigh Ann Clarke, Janet Constan, Alex Couch, Jessica Czupalla, Oliver Danks, Andy DeGeorge, Joseph de Haanm, Lolke Hettinger, Klaudia Hill, Marilyn Festag, Matthias Jacobs, Abby Jacobson-Kram, David Kopytek, Stephan Lorenz, Helga Moesgaard, Sophia Gry Moore, Emma Pasanen, Markku Perry, Rick Ragan, Ian Robinson, Sally Schmitt, Petra M. Short, Brian Lima, Beatriz Silva Smith, Diane Sparrow, Sue van Bekkum, Yvette Jones, David TI Recommendations from a global cross-company data sharing initiative on the incorporation of recovery phase animals in safety assessment studies to support first-in-human clinical trials SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Recovery; Reversibility; 3Rs; Reduction; Non-clinical; Repeat-dose studies; Regulatory toxicology; Rodent; Primate; Dog ID MONOCLONAL-ANTIBODIES; NONHUMAN-PRIMATES; TOXICOLOGY; TOXICITY; APPROPRIATE; REDUCTION; DESIGN; DOG AB An international expert group which includes 30 organisations (pharmaceutical companies, contract research organisations, academic institutions and regulatory bodies) has shared data on the use of recovery animals in the assessment of pharmaceutical safety for early development. These data have been used as an evidence-base to make recommendations on the inclusion of recovery animals in toxicology studies to achieve scientific objectives, while reducing animal use. Recovery animals are used in pharmaceutical development to provide information on the potential for a toxic effect to translate into long-term human risk. They are included on toxicology studies to assess whether effects observed during dosing persist or reverse once treatment ends. The group devised a questionnaire to collect information on the use of recovery animals in general regulatory toxicology studies to support first-in-human studies. Questions focused on study design, the rationale behind inclusion or exclusion and the impact this had on internal and regulatory decisions. Data on 137 compounds (including 53 biologicals and 78 small molecules) from 259 studies showed wide variation in where, when and why recovery animals were included. An analysis of individual study and programme design shows that there are opportunities to reduce the use of recovery animals without impacting drug development. (C) 2014 The Authors. Published by Elsevier Inc. C1 [Sewell, Fiona; Chapman, Kathryn] UK Natl Ctr Replacement Refinement & Reduct Anim, London NW1 2BE, England. [Baldrick, Paul] Covance Labs Ltd, Harrogate HG3 1PY, England. [Brewster, David] Vertex Pharmaceut Inc, Boston, MA 02139 USA. [Broadmeadow, Alan] Huntingdon Life Sci Ltd, Eye IP23 7PX, Suffolk, England. [Brown, Paul; Jacobs, Abby; Jacobson-Kram, David] FDA, Silver Spring, MD 20993 USA. [Burns-Naas, Leigh Ann] Gilead Sci Inc, Foster City, CA 94404 USA. [Clarke, Janet] Biogen Idec Inc, Cambridge, MA 02142 USA. [Constan, Alex] Infin Pharmaceut, Cambridge, MA 02139 USA. [Couch, Jessica] Genentech Inc, San Francisco, CA 94080 USA. [Czupalla, Oliver] Bayer Pharrna AG, D-13353 Berlin, Germany. [Danks, Andy] Charles River Labs, Preclin Serv, Edinburgh EH33 2NE, Midlothian, Scotland. [DeGeorge, Joseph] Merck, West Point, PA 19486 USA. [de Haanm, Lolke] Medlmmune, Cambridge CB21 6GH, England. [Hettinger, Klaudia] Austrian Agcy Hlth & Food Safety, A-1200 Vienna, Austria. [Hill, Marilyn] NIBR, Basel, Switzerland. [Festag, Matthias] Roche Innovat Ctr Basel, Roche Pharmaceut Res & Early Dev, CH-4070 Basel, Switzerland. [Kopytek, Stephan] Celgene, Summit, NJ 07901 USA. [Lorenz, Helga] AbbVie Deutschland GmbH & Co KG, D-67061 Ludwigshafen, Germany. [Moesgaard, Sophia Gry] Novo Nordisk AS, Malov, Denmark. [Moore, Emma] Huntingdon Life Sci Ltd, Huntingdon PE28 4HS, Cambs, England. [Pasanen, Markku] Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio, Finland. [Perry, Rick] Pfizer Drug Safety Res & Dev, Groton, CT 06340 USA. [Ragan, Ian] NC3Rs, Board Member, London NW1 2BE, England. [Robinson, Sally] AstraZeneca, Macclesfield SK10 4TG, Cheshire, England. [Schmitt, Petra M.] Paul Ehrlich Inst, Fed Agcy Vaccines & Biomed, Langen, Germany. [Short, Brian] Allergan, Drug Safety Evaluat, Irvine, CA 92612 USA. [Lima, Beatriz Silva] Univ Lisbon, IMED, UL, P-1699 Lisbon, Portugal. [Smith, Diane] Takeda Oncol Co, Millenium, Cambridge, MA USA. [Sparrow, Sue] GlaxoSmithKline, Ware SG12 0DP, Herts, England. [van Bekkum, Yvette] Janssen Res & Dev, B-2340 Beerse, Belgium. [Jones, David] Med Healthcare Prod Regulatory Agcy MHRA, London, England. RP Sewell, F (reprint author), UK Natl Ctr Replacement Refinement & Reduct Anim, Gibbs Bldg,215 Euston Rd, London NW1 2BE, England. EM fiona.sewell@nc3rs.org.uk RI iMed.ULisboa, iMed.ULisboa/C-6292-2014; iMed.ULisboa, PharmRegSci /B-5723-2014 OI iMed.ULisboa, PharmRegSci /0000-0003-0910-7245 NR 17 TC 5 Z9 5 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD OCT 1 PY 2014 VL 70 IS 1 BP 413 EP 429 DI 10.1016/j.yrtph.2014.07.018 PG 17 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA AQ0OI UT WOS:000342482200044 PM 25078890 ER PT J AU Marrone, AK Beland, FA Pogribny, IP AF Marrone, April K. Beland, Frederick A. Pogribny, Igor P. TI Noncoding RNA response to xenobiotic exposure: an indicator of toxicity and carcinogenicity SO EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY LA English DT Review DE long noncoding RNAs; microRNAs; noncoding RNAs; xenobiotics ID BREAST-CANCER CELLS; INDUCED LIVER-INJURY; BRONCHIAL EPITHELIAL-CELLS; X-CHROMOSOME INACTIVATION; ESTROGEN-RECEPTOR-ALPHA; MICRORNA EXPRESSION; GENE-EXPRESSION; MALIGNANT-TRANSFORMATION; BISPHENOL-A; HEPATOCELLULAR-CARCINOMA AB Introduction: Human exposure to certain environmental and occupational chemicals is one of the major risk factors for noncommunicable diseases, including cancer. Therefore, it is desirable to take advantage of subtle exposure-related adverse cellular events for early disease detection and to identify potential dangers caused by new and currently under-evaluated drugs and chemicals. Nongenotoxic events due to carcinogen/toxicant exposure are a general hallmark of sustained cellular stress leading to tumorigenesis. These processes are globally regulated via noncoding RNAs (ncRNAs). Tumorigenesis-associated genotoxic and nongenotoxic events lead to the altered expression of ncRNAs and may provide a mechanistic link between chemical exposure and tumorigenesis. Current advances in toxicogenomics are beginning to provide valuable insight into gene-chemical interactions at the transcriptome level. Areas covered: In this review, we summarize recent information about the impact of xenobiotics on ncRNAs. Evidence highlighted in this review suggests a critical role of ncRNAs in response to carcinogen/toxicant exposure. Expert opinion: Benefits for the use of ncRNAs in carcinogenicity assessment include remarkable tissue specificity, early appearance, low baseline variability, and their presence and stability in biological fluids, which suggests that the incorporation of ncRNAs in the evaluation of cancer risk assessment may enhance substantially the efficiency of toxicity and carcinogenicity testing. C1 [Marrone, April K.; Beland, Frederick A.; Pogribny, Igor P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov NR 151 TC 7 Z9 7 U1 0 U2 14 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1742-5255 EI 1744-7607 J9 EXPERT OPIN DRUG MET JI Expert Opin. Drug Metab. Toxicol. PD OCT PY 2014 VL 10 IS 10 BP 1409 EP 1422 DI 10.1517/17425255.2014.954312 PG 14 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA AP6QO UT WOS:000342202600008 PM 25171492 ER PT J AU Warfel, JM Merkel, TJ AF Warfel, Jason M. Merkel, Tod J. TI The baboon model of pertussis: effective use and lessons for pertussis vaccines SO EXPERT REVIEW OF VACCINES LA English DT Review DE baboons; pertussis; T-cell memory; Th17; vaccines; whooping cough ID NONHUMAN PRIMATE MODEL; DEFICIENT BORDETELLA-PERTUSSIS; EXPERIMENTAL WHOOPING-COUGH; WHOLE-CELL VACCINE; UNITED-STATES; INFANT PERTUSSIS; CONTROLLED TRIAL; VIRUS-INFECTION; INTENSIVE-CARE; ANIMAL-MODELS AB The USA is experiencing a pertussis resurgence that resulted in a 60-year high of 48,000 cases in 2012. Our ability to counteract this resurgence is hampered by the fact that pertussis pathogenesis and immunity to pertussis infection are not well studied. Studies in humans are difficult due to the low frequency of pertussis in the population, the cyclical nature of incidence and the sporadic geographic distribution of cases. While existing animal models reproduce many aspects of pertussis, none of them adequately reproduces the full spectrum of disease. We describe the baboon model of pertussis. The baboon model is the first animal model that recapitulates the full spectrum of human pertussis including coughing and transmission. This model is being utilized to examine pertussis pathogenesis and host responses to infection and vaccination. It is likely the baboon model will provide an important tool in the development of improved pertussis vaccines. C1 [Warfel, Jason M.; Merkel, Tod J.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Merkel, TJ (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 72,Room 3308, Silver Spring, MD 20993 USA. EM tod.merkel@fda.hhs.gov FU US FDA FX The authors' salaries are supported in full by the US FDA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 101 TC 10 Z9 10 U1 1 U2 9 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 EI 1744-8395 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD OCT PY 2014 VL 13 IS 10 BP 1241 EP 1252 DI 10.1586/14760584.2014.946016 PG 12 WC Immunology SC Immunology GA AP4UC UT WOS:000342073300010 PM 25182980 ER PT J AU Ibberson, CB Jones, CL Singh, S Wise, MC Hart, ME Zurawski, DV Horswill, AR AF Ibberson, Carolyn B. Jones, Crystal L. Singh, Shweta Wise, Matthew C. Hart, Mark E. Zurawski, Daniel V. Horswill, Alexander R. TI Staphylococcus aureus Hyaluronidase Is a CodY-Regulated Virulence Factor SO INFECTION AND IMMUNITY LA English DT Article ID SPREADING FACTOR; STREPTOCOCCUS-PNEUMONIAE; TISSUE PERMEABILITY; GENE-EXPRESSION; IN-VIVO; LYASE; INFECTION; ACID; DEGRADATION; EPIDEMIC AB Staphylococcus aureus is a Gram-positive pathogen that causes a diverse range of bacterial infections. Invasive S. aureus strains secrete an extensive arsenal of hemolysins, immunomodulators, and exoenzymes to cause disease. Our studies have focused on the secreted enzyme hyaluronidase (HysA), which cleaves the hyaluronic acid polymer at the beta-1,4 glycosidic bond. In the study described in this report, we have investigated the regulation and contribution of this enzyme to S. aureus pathogenesis. Using the Nebraska Transposon Mutant Library (NTML), we identified eight insertions that modulate extracellular levels of HysA activity. Insertions in the sigB operon, as well as in genes encoding the global regulators SarA and CodY, significantly increased HysA protein levels and activity. By altering the availability of branched-chain amino acids, we further demonstrated CodY-dependent repression of HysA activity. Additionally, through mutation of the CodY binding box upstream of hysA, the repression of HysA production was lost, suggesting that CodY is a direct repressor of hysA expression. To determine whether HysA is a virulence factor, a Delta hysA mutant of a community-associated methicillin-resistant S. aureus (CA-MRSA) USA300 strain was constructed and found to be attenuated in a neutropenic, murine model of pulmonary infection. Mice infected with this mutant strain exhibited a 4-log-unit reduction in bacterial burden in their lungs, as well as reduced lung pathology and increased levels of pulmonary hyaluronic acid, compared to mice infected with the wild-type, parent strain. Taken together, these results indicate that S. aureus hyaluronidase is a CodY-regulated virulence factor. C1 [Ibberson, Carolyn B.; Horswill, Alexander R.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Microbiol, Iowa City, IA 52242 USA. [Jones, Crystal L.; Singh, Shweta; Wise, Matthew C.; Zurawski, Daniel V.] WRAIR, Dept Wound Infect, Silver Spring, MD USA. [Hart, Mark E.] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. RP Horswill, AR (reprint author), Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Microbiol, Iowa City, IA 52242 USA. EM alex-horswill@uiowa.edu OI Zurawski, Daniel/0000-0002-7920-5601 FU National Institutes of Health [5T32GM008365-22]; NIH/NIDCR [T90 DE023520]; Military Infectious Diseases Research Program (MIDRP); Defense Medical Research and Development Program (DMRDP) FX We acknowledge National Institutes of Health training grant 5T32GM008365-22 and NIH/NIDCR award T90 DE023520 for supporting C.B.I. during this work. The D.V. Zurawski lab is supported by multiple grants from the Military Infectious Diseases Research Program (MIDRP) and the Defense Medical Research and Development Program (DMRDP). NR 64 TC 10 Z9 10 U1 0 U2 10 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 2014 VL 82 IS 10 BP 4253 EP 4264 DI 10.1128/IAI.01710-14 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AP2VY UT WOS:000341935100025 PM 25069977 ER PT J AU Sheikh, F Dickensheets, H Gamero, AM Vogel, SN Donnelly, RP AF Sheikh, Faruk Dickensheets, Harold Gamero, Ana M. Vogel, Stefanie N. Donnelly, Raymond P. TI An essential role for IFN-beta in the induction of IFN-stimulated gene expression by LPS in macrophages SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE endotoxin; TLR4; ISGF3; NF-B; STAT ID LIPOPOLYSACCHARIDE-INDUCIBLE GENES; INTERFERON-BETA; BACTERIAL LIPOPOLYSACCHARIDE; CYTOKINE SIGNALING-1; TARGETED DISRUPTION; RECEPTOR COMPLEX; ENDOTOXIN-SHOCK; INNATE IMMUNITY; I INTERFERONS; CUTTING EDGE AB TLR agonists such as LPS and poly(I:C) induce expression of type I IFNs, such as IFN- and -, by macrophages. To examine the role of IFN- in the induction of ISGs by LPS, we compared the ability of LPS to induce ISGF3 activity and ISG expression in bone marrow-derived macrophages from WT and Ifnb1(-/-) mice. We found that LPS treatment activated ISGF3 and induced expression of ISGs such as Oas1, Mx1, Ddx58 (RIG-I), and Ifih1 (MDA5) in WT macrophages, but not in macrophages derived from Ifnb1(-/-) mice or Ifnar1(-/-) mice. The inability of LPS to induce activation of ISGF3 and ISG expression in Ifnb1(-/-) macrophages correlated with the failure of LPS to induce activation of STAT1 and -2 in these cells. Consistent with these findings, LPS treatment also failed to induce ISG expression in bone marrow-derived macrophages from Stat2 KO mice. Although activation of ISGF3 and induction of ISG expression by LPS was abrogated in Ifnb1(-/-) and Ifnar1(-/-) macrophages, activation of NF-B and induction of NF-B-responsive genes, such as Tnf (TNF-) and Il1b (IL-1), were not affected by deletion of either the IFN- or IFN-R1 genes. These findings demonstrate that induction of ISGF3 activity and ISG expression by LPS is critically dependent on intermediate production of IFN- and autocrine signaling through type I IFN receptors. C1 [Sheikh, Faruk; Dickensheets, Harold; Donnelly, Raymond P.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [Gamero, Ana M.] Temple Univ, Dept Biochem, Sch Med, Philadelphia, PA 19122 USA. [Vogel, Stefanie N.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. RP Donnelly, RP (reprint author), FDA CDER, HFD-122,29 Lincoln Dr, Bethesda, MD 20892 USA. EM raymond.donnelly@fda.hhs.gov FU Intramural Research Program of the U.S. Food and Drug Administration; U.S. National Institutes of Health (NIH) [R01 CA140499]; NIH [R01 AI18797] FX This study was supported in part by the Intramural Research Program of the U.S. Food and Drug Administration, and in part by U.S. National Institutes of Health (NIH) grant R01 CA140499 to A. M. G. and NIH grant R01 AI18797 to S.N.V. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. NR 47 TC 13 Z9 14 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD OCT PY 2014 VL 96 IS 4 BP 591 EP 600 DI 10.1189/jlb.2A0414-191R PG 10 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA AP6YD UT WOS:000342223600010 PM 25024400 ER PT J AU Li, BG Vellidis, G Liu, HL Jay-Russell, M Zhao, SH Hu, ZL Wright, A Elkins, CA AF Li, Baoguang Vellidis, George Liu, Huanli Jay-Russell, Michele Zhao, Shaohua Hu, Zonglin Wright, Anita Elkins, Christopher A. TI Diversity and Antimicrobial Resistance of Salmonella enterica Isolates from Surface Water in Southeastern United States SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID PROPIDIUM MONOAZIDE; ESCHERICHIA-COLI; HUMAN PATHOGENS; FRESH PRODUCE; FOOD ANIMALS; NEWPORT; TYPHIMURIUM; SEDIMENT; SURVIVAL; FARMS AB A study of prevalence, diversity, and antimicrobial resistance of Salmonella enterica in surface water in the southeastern United States was conducted. A new scheme was developed for recovery of Salmonella from irrigation pond water and compared with the FDA's Bacteriological Analytical Manual (8th ed., 2014) (BAM) method. Fifty-one isolates were recovered from 10 irrigation ponds in produce farms over a 2-year period; nine Salmonella serovars were identified by pulsed-field gel electrophoresis analysis, and the major serovar was Salmonella enterica serovar Newport (S. Newport, n = 29), followed by S. enterica serovar Enteritidis (n = 6), S. enterica serovar Muenchen (n = 4), S. enterica serovar Javiana (n = 3), S. enterica serovar Thompson (n = 2), and other serovars. It is noteworthy that the PulseNet patterns of some of the isolates were identical to those of the strains that were associated with the S. Thompson outbreaks in 2010, 2012, and 2013, S. Enteritidis outbreaks in 2011 and 2013, and an S. Javiana outbreak in 2012. Antimicrobial susceptibility testing confirmed 16 S. Newport isolates of the multidrug resistant-AmpC (MDR-AmpC) phenotype, which exhibited resistance to ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline (ACSSuT), and to the 1st, 2nd, and 3rd generations of cephalosporins (cephalothin, amoxicillin-clavulanic acid, and ceftriaxone). Moreover, the S. Newport MDR-AmpC isolates had a PFGE pattern indistinguishable from the patterns of the isolates from clinical settings. These findings suggest that the irrigation water may be a potential source of contamination of Salmonella in fresh produce. The new Salmonella isolation scheme significantly increased recovery efficiency from 21.2 (36/170) to 29.4% (50/170) (P = 0.0002) and streamlined the turnaround time from 5 to 9 days with the BAM method to 4 days and thus may facilitate microbiological analysis of environmental water. C1 [Li, Baoguang; Liu, Huanli; Hu, Zonglin; Elkins, Christopher A.] 20708A, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Vellidis, George] Univ Georgia, Tifton, GA USA. [Jay-Russell, Michele] Univ Calif Davis, Western Ctr Food Safety, Davis, CA 95616 USA. [Zhao, Shaohua] US FDA, Ctr Vet Med, Laurel, MD USA. [Wright, Anita] Univ Florida, Gainesville, FL USA. RP Li, BG (reprint author), 20708A, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. EM baoguang.li@fda.hhs.gov NR 48 TC 11 Z9 11 U1 1 U2 32 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD OCT PY 2014 VL 80 IS 20 BP 6355 EP 6365 DI 10.1128/AEM.02063-14 PG 11 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA AP2IJ UT WOS:000341895600010 PM 25107969 ER PT J AU Siltz, LAF Viktorova, EG Zhang, B Kouiavskaia, D Dragunsky, E Chumakov, K Isaacs, L Belov, GA AF Siltz, Lauren A. Ford Viktorova, Ekaterina G. Zhang, Ben Kouiavskaia, Diana Dragunsky, Eugenia Chumakov, Konstantin Isaacs, Lyle Belov, George A. TI New Small-Molecule Inhibitors Effectively Blocking Picornavirus Replication SO JOURNAL OF VIROLOGY LA English DT Article ID STRAND RNA-SYNTHESIS; EXCHANGE FACTOR GBF1; POLIOVIRUS RNA; PROTEIN 3A; ENTEROVIRUS REPLICATION; BREFELDIN-A; SECRETORY PATHWAY; VIRAL PROTEIN; CANCER-CELLS; IN-VITRO AB Few drugs targeting picornaviruses are available, making the discovery of antivirals a high priority. Here, we identified and characterized three compounds from a library of kinase inhibitors that block replication of poliovirus, coxsackievirus B3, and encephalomyocarditis virus. Using an in vitro translation-replication system, we showed that these drugs inhibit different stages of the poliovirus life cycle. A4(1) inhibited both the formation and functioning of the replication complexes, while E5(1) and E7(2) were most effective during the formation but not the functioning step. Neither of the compounds significantly inhibited VPg uridylylation. Poliovirus resistant to E7(2) had a G5318A mutation in the 3A protein. This mutation was previously found to confer resistance to enviroxime-like compounds, which target a phosphatidylinositol 4-kinase III beta (PI4KIII beta)-dependent step in viral replication. Analysis of host protein recruitment showed that E7(2) reduced the amount of GBF1 on the replication complexes; however, the level of PI4KIII beta remained intact. E7(2) as well as another enviroxime-like compound, GW5074, interfered with viral polyprotein processing affecting both 3C- and 2A-dependent cleavages, and the resistant G5318A mutation partially rescued this defect. Moreover, E7(2) induced abnormal recruitment to membranes of the viral proteins; thus, enviroxime-like compounds likely severely compromise the interaction of the viral polyprotein with membranes. A4(1) demonstrated partial protection from paralysis in a murine model of poliomyelitis. Multiple attempts to isolate resistant mutants in the presence of A4(1) or E5(1) were unsuccessful, showing that effective broad-spectrum antivirals could be developed on the basis of these compounds. IMPORTANCE Diverse picornaviruses can trigger multiple human maladies, yet currently, only hepatitis A virus and poliovirus can be controlled with vaccination. The development of antipicornavirus therapeutics is also facing significant difficulties because these viruses readily generate resistance to compounds targeting either viral or cellular factors. Here, we describe three novel compounds that effectively block replication of distantly related picornaviruses with minimal toxicity to cells. The compounds prevent viral RNA replication after the synthesis of the uridylylated VPg primer. Importantly, two of the inhibitors are strongly refractory to the emergence of resistant mutants, making them promising candidates for further broad-spectrum therapeutic development. Evaluation of one of the compounds in an in vivo model of poliomyelitis demonstrated partial protection from the onset of paralysis. C1 [Siltz, Lauren A. Ford; Viktorova, Ekaterina G.; Belov, George A.] Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. [Siltz, Lauren A. Ford; Viktorova, Ekaterina G.; Belov, George A.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Zhang, Ben; Isaacs, Lyle] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Kouiavskaia, Diana; Dragunsky, Eugenia; Chumakov, Konstantin] US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Belov, GA (reprint author), Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. EM gbelov@umd.edu RI Isaacs, Lyle/B-4472-2009; Belov, George/B-4625-2008; Zhang, Ben/F-6580-2014 OI Isaacs, Lyle/0000-0002-4079-332X; Belov, George/0000-0002-0892-1731; FU University of Maryland start-up funds; National Institutes of Health [CA-168365] FX This work was supported by University of Maryland start-up funds (G.A.B.) and the National Institutes of Health (CA-168365) (L.I.). NR 53 TC 12 Z9 12 U1 0 U2 15 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 2014 VL 88 IS 19 BP 11091 EP 11107 DI 10.1128/JVI.01877-14 PG 17 WC Virology SC Virology GA AP1ZX UT WOS:000341872700009 ER PT J AU Earp, JC Fang, L Ma, L Wang, YM Rosario, M Dirks, NL Mehrotra, N AF Earp, Justin C. Fang, Lucy Ma, Lian Wang, Yow-Ming Rosario, Maria Dirks, Nathanael L. Mehrotra, Nitin TI Assessing Labeling Claims for Drug Interactions Using a Population PK Approach: Vedolizumab SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Earp, Justin C.; Fang, Lucy; Ma, Lian; Wang, Yow-Ming; Mehrotra, Nitin] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. [Rosario, Maria] Takeda, Cambridge, MA USA. [Dirks, Nathanael L.] Metrum Res Grp, Tariffville, CT USA. NR 1 TC 2 Z9 2 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 2014 VL 41 SU 1 MA M-073 BP S39 EP S39 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V45QB UT WOS:000209830000074 ER PT J AU Lee, JE Krudys, K AF Lee, Jee Eun Krudys, Kevin TI Surface Area-Based Dosing Versus Fixed Dosing of Omacetaxine in Chronic Myeloid Leukemia SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Lee, Jee Eun; Krudys, Kevin] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 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 2014 VL 41 SU 1 MA W-070 BP S100 EP S100 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V45QB UT WOS:000209830000216 ER PT J AU Ma, L Wang, XF Mehrotra, N Bhattaram, A Earp, J Florian, J Krudys, K Lee, JE Li, F Li, HS Liu, J Marathe, A Marathe, D Tworzyanski, J Wang, YN Yu, JY Zhang, L Zhao, L Zhao, P Sinha, V AF Ma, Lian Wang, Xiaofeng Mehrotra, Nitin Bhattaram, Atul Earp, Justin Florian, Jeffry Krudys, Kevin Lee, Jee Eun Li, Fang Li, Hongshan Liu, Jiang Marathe, Anshu Marathe, Dhananjay Tworzyanski, Jeffrey Wang, Yaning Yu, Jingyu Zhang, Li Zhao, Liang Zhao, Ping Sinha, Vikram TI Application of Pharmacometrics to Guide Regulatory Decisions for Drugs to Treat Rare Diseases SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Ma, Lian; Wang, Xiaofeng; Mehrotra, Nitin; Bhattaram, Atul; Earp, Justin; Florian, Jeffry; Krudys, Kevin; Lee, Jee Eun; Li, Fang; Li, Hongshan; Liu, Jiang; Marathe, Anshu; Marathe, Dhananjay; Tworzyanski, Jeffrey; Wang, Yaning; Yu, Jingyu; Zhang, Li; Zhao, Liang; Zhao, Ping; Sinha, Vikram] OCP OTS CDER FDA, Div Pharmacometr, Authorship Equal Contribut 1, Silver Spring, MD 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 2014 VL 41 SU 1 MA M-074 BP S40 EP S40 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V45QB UT WOS:000209830000075 ER PT J AU Marathe, D Menon-Andersen, D Madabushi, R Dunnmon, P Wang, YN AF Marathe, Dhananjay Menon-Andersen, Divya Madabushi, Rajanikanth Dunnmon, Preston Wang, Yaning TI Riociguat Dosing Recommendations in Pulmonary Arterial Hypertension (Pah)/Chronic Thromboembolic Pulmonary Hypertension (Cteph), Based on Pharmacometric Analyses SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Marathe, Dhananjay; Menon-Andersen, Divya; Madabushi, Rajanikanth; Dunnmon, Preston; Wang, Yaning] US FDA, Philadelphia, PA 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 2014 VL 41 SU 1 MA M-069 BP S38 EP S38 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V45QB UT WOS:000209830000070 ER PT J AU Rekic, D Florian, J Johannesen, L Zhao, L Brar, S AF Rekic, Dinko Florian, Jeffry Johannesen, Lars Zhao, Liang Brar, Satjit TI Dose Finding Based on the Model Averaging Approach SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Rekic, Dinko; Florian, Jeffry; Johannesen, Lars; Zhao, Liang; Brar, Satjit] US FDA, Silver Spring, MD USA. [Johannesen, Lars] Karolinska Inst, Stockholm, Sweden. 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 2014 VL 41 SU 1 MA W-002 BP S71 EP S71 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V45QB UT WOS:000209830000149 ER PT J AU Zhang, Y Ma, L Ji, P Yim, S Doddapaneni, S Liu, J Dinko, R Brar, S Wang, YN Sahajwalla, C AF Zhang, Yi Ma, Lian Ji, Ping Yim, Sarah Doddapaneni, Suresh Liu, Jiang Dinko, Rekic Brar, Satjit Wang, Yaning Sahajwalla, Chandrahas TI Exposure-Response Modeling and Power Analysis of ACR Core Components in Rheumatoid Arthritis SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Zhang, Yi; Ma, Lian; Ji, Ping; Yim, Sarah; Doddapaneni, Suresh; Liu, Jiang; Dinko, Rekic; Brar, Satjit; Wang, Yaning; Sahajwalla, Chandrahas] US FDA, Silver Spring, MD 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 2014 VL 41 SU 1 MA T-066 BP S68 EP S68 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V45QB UT WOS:000209830000141 ER PT J AU Markatou, M Ball, R AF Markatou, Marianthi Ball, Robert TI A Pattern Discovery Framework for Adverse Event Evaluation and Inference in Spontaneous Reporting Systems SO STATISTICAL ANALYSIS AND DATA MINING LA English DT Review DE pattern discovery; inference; probability models; pharmacovigilance; anaphylaxis; copulas; similarity/distance functions ID SIGNAL-DETECTION; DRUG EVENTS; SAFETY DATA; STATISTICAL METHODOLOGY; HOSPITALIZED-PATIENTS; SAMPLE SELECTION; PROPENSITY-SCORE; NETWORK ANALYSIS; VACCINE ALLERGY; DATA-COLLECTION AB Safety of medical products is a major public health concern. We present a critical discussion of the currently used analytical tools for mining spontaneous reporting systems (SRS) to identify safety signals after use of medical products. We introduce a pattern discovery framework for the analysis of SRS. The terminology 'pattern discovery' is borrowed from the engineering and artificial intelligence literature and signifies that the basis of the proposed framework is the medical case, formalizing the cognitive paradigm known to clinicians who evaluate individual patients and individual case safety reports submitted to SRS. The fundamental contribution of this approach is a strong probabilistic component that may account for selection and other biases and facilitates rigorous modeling and inference. We discuss somewhat in depth the concept of signal in pharmacovigilance and connect it with the concept of a pattern; we illustrate this conceptual framework using the example of anaphylaxis. Finally, we propose a research agenda in statistics, informatics, and pharmacovigilance practices needed to advance the pattern discovery framework in both the short and long terms. (C) 2014 Wiley Periodicals, Inc. C1 [Markatou, Marianthi] IBM Corp, Thomas J Watson Res Ctr, Yorktown Hts, NY 10598 USA. [Markatou, Marianthi] SUNY Buffalo, Sch Publ Hlth & Hlth Profess, Dept Biostat, Buffalo, NY 14216 USA. [Ball, Robert] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Ball, R (reprint author), US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Robert.Ball@fda.hhs.gov NR 71 TC 0 Z9 0 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-1864 EI 1932-1872 J9 STAT ANAL DATA MIN JI Stat. Anal. Data Min. PD OCT PY 2014 VL 7 IS 5 SI SI BP 352 EP 367 DI 10.1002/sam.11233 PG 16 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA CV3US UT WOS:000364192400003 ER PT J AU Franks, R Sandhu, S Avagyan, A Lu, Y Hong, H Garcia, B Worrall, C Kelman, J Ball, R MaCurdy, T AF Franks, Riley Sandhu, Sukhminder Avagyan, Armen Lu, Yun Hong, Han Garcia, Bruno Worrall, Christopher Kelman, Jeffrey Ball, Robert MaCurdy, Thomas TI Robustness Properties of a Sequential Test for Vaccine Safety in the Presence of Misspecification SO STATISTICAL ANALYSIS AND DATA MINING LA English DT Article DE sequential surveillance; active surveillance; claims delay; pharmacovigilance; vaccine safety; uncertainty; administrative data ID SURVEILLANCE; PROGRAM AB The Updating Sequential Probability Ratio Test (USPRT) developed by MaCurdy et al. (2009, Updating sequential probability ratio test for real-time surveillance of vaccine safety, unpublished working paper) has been used by the U.S. Food and Drug Administration for near real-time surveillance of the safety of the flu vaccine since 2008. This procedure was the first method developed to account for data delay in pharmacovigilance studies. However, the current implementation is based on the strong assumption that the clinical and reporting delays do not vary from previous years. When this assumption does not hold, size distortion of the USPRT procedure might result. The goal of this article is to numerically investigate the robustness of the detection probabilities of the USPRT method with respect to possible misspecification of the clinical and reporting delay distributions through extensive simulations. We find that if the delay distribution used in calibrating the critical bound is lengthier than the delay distribution in the data generating process, then there is a higher rate of false signaling and vice versa. This is an inherent property of a real-time testing procedure. However, the distortion created by misspecifying the reporting delay distribution appears to be insignificant when compared to the overall power generated by an elevation of the adverse event rate. The size distortion is unevenly distributed across the interim tests, so the effect of misspecification of the delay distributions is more prominent in the median time-to-signal. In summary, although a misspecified delay distribution induces size distortion, we find that it does not erode the overall power. (C) 2014 Wiley Periodicals, Inc. C1 [Franks, Riley; Avagyan, Armen; Hong, Han; Garcia, Bruno; MaCurdy, Thomas] Acumen LLC, Burlingame, CA 94010 USA. [Sandhu, Sukhminder; Lu, Yun; Ball, Robert] US FDA, Silver Spring, MD USA. [Hong, Han; MaCurdy, Thomas] Stanford Univ, Dept Econ, Palo Alto, CA 94304 USA. [Worrall, Christopher; Kelman, Jeffrey] Ctr Medicare & Medicaid Serv CMS, Baltimore, MD USA. RP Franks, R (reprint author), Acumen LLC, Burlingame, CA 94010 USA. EM rfranks@acumenllc.com NR 12 TC 2 Z9 2 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-1864 EI 1932-1872 J9 STAT ANAL DATA MIN JI Stat. Anal. Data Min. PD OCT PY 2014 VL 7 IS 5 SI SI BP 368 EP 375 DI 10.1002/sam.11234 PG 8 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA CV3US UT WOS:000364192400004 ER PT J AU Balakumar, P Jagadeesh, G AF Balakumar, Pitchai Jagadeesh, Gowraganahalli TI A century old renin-angiotensin system still grows with endless possibilities: AT(1) receptor signaling cascades in cardiovascular physiopathology SO CELLULAR SIGNALLING LA English DT Review DE RAS components; Alamandine; AT(1) receptor signal transduction; Transactivation cascades; G protein-dependent and-independent signals ID SMOOTH-MUSCLE-CELLS; II TYPE-1 RECEPTOR; ACTIVATED PROTEIN-KINASE; CARDIAC-SPECIFIC OVEREXPRESSION; POLYCYSTIC KIDNEY-DISEASE; ARRESTIN-BIASED LIGAND; BETA-ARRESTINS; DIACYLGLYCEROL-KINASE; CONVERTING-ENZYME; BLOOD-PRESSURE AB Ang II, the primary effector pleiotropic hormone of the renin-angiotensin system (RAS) cascade, mediates physiological control of blood pressure and electrolyte balance through its action on vascular tone, aldosterone secretion, renal sodium absorption, water intake, sympathetic activity and vasopressin release. It affects the function of most of the organs far beyond blood pressure control including heart, blood vessels, kidney and brain, thus, causing both beneficial and deleterious effects. However, the protective axis of the RAS composed of ACE2, Ang (1-7), alamandine, and Mas and MargD receptors might oppose some harmful effects of Ang II and might promote beneficial cardiovascular effects. Newly identified RAS family peptides, Ang A and angioprotectin, further extend the complexities in understanding the cardiovascular physiopathology of RAS. Most of the diverse actions of Ang II are mediated by AT, receptors, which couple to classical Gq/11 protein and activate multiple downstream signals, including PKC, ERK1/2, Raf, tyrosine kinases, receptor tyrosine kinases (EGFR, PDGF, insulin receptor), nuclear factor kappa B and reactive oxygen species (ROS). Receptor activation via G12/13 stimulates Rho-kinase, which causes vascular contraction and hypertrophy. The AT(1) receptor activation also stimulates G protein-independent signaling pathways such as beta-arrestin-mediated MAPK activation and Src-JAK/STAT. AT(1) receptor-mediated activation of NADPH oxidase releases ROS, resulting in the activation of pro-inflammatory transcription factors and stimulation of small G proteins such as Ras, Rac and RhoA. The components of the RAS and the major Ang II-induced signaling cascades of AT(1) receptors are reviewed. (C) 2014 Elsevier Inc. All rights reserved. C1 [Balakumar, Pitchai] AIMST Univ, Fac Pharm, Pharmacol Unit, Bedong 08100, Kedah Darul Ama, Malaysia. [Jagadeesh, Gowraganahalli] US FDA, Ctr Drug Evaluat & Res, Div Cardiovasc & Renal Prod, Silver Spring, MD 20993 USA. RP Balakumar, P (reprint author), AIMST Univ, Fac Pharm, Pharmacol Unit, Bedong 08100, Kedah Darul Ama, Malaysia. EM pbala2006@gmail.com; Gowra.Jagadeesh@fda.hhs.gov NR 192 TC 36 Z9 38 U1 1 U2 38 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 EI 1873-3913 J9 CELL SIGNAL JI Cell. Signal. PD OCT PY 2014 VL 26 IS 10 BP 2147 EP 2160 DI 10.1016/j.cellsig.2014.06.011 PG 14 WC Cell Biology SC Cell Biology GA AO0EZ UT WOS:000340983200009 PM 25007996 ER PT J AU Kweon, O Kim, SJ Kim, DW Kim, JM Kim, HL Ahn, Y Sutherland, JB Cerniglia, CE AF Kweon, Ohgew Kim, Seong-Jae Kim, Dae-Wi Kim, Jeong Myeong Kim, Hyun-lee Ahn, Youngbeom Sutherland, John B. Cerniglia, Carl E. TI Pleiotropic and Epistatic Behavior of a Ring-Hydroxylating Oxygenase System in the Polycyclic Aromatic Hydrocarbon Metabolic Network from Mycobacterium vanbaalenii PYR-1 SO JOURNAL OF BACTERIOLOGY LA English DT Article ID SP STRAIN PYR-1; MOLECULAR-WEIGHT; CARBAZOLE 1,9A-DIOXYGENASE; NAPHTHALENE DIOXYGENASE; MICROBIAL-METABOLISM; CRYSTAL-STRUCTURE; DEGRADATION; IDENTIFICATION; BIODEGRADATION; PYRENE AB Despite the considerable knowledge of bacterial high-molecular-weight (HMW) polycyclic aromatic hydrocarbon (PAH) metabolism, the key enzyme(s) and its pleiotropic and epistatic behavior(s) responsible for low-molecular-weight (LMW) PAHs in HMW PAH-metabolic networks remain poorly understood. In this study, a phenotype-based strategy, coupled with a spray plate method, selected a Mycobacterium vanbaalenii PYR-1 mutant (6G11) that degrades HMW PAHs but not LMW PAHs. Sequence analysis determined that the mutant was defective in pdoA2, encoding an aromatic ring-hydroxylating oxygenase (RHO). A series of metabolic comparisons using high-performance liquid chromatography (HPLC) analysis revealed that the mutant had a lower rate of degradation of fluorene, anthracene, and pyrene. Unlike the wild type, the mutant did not produce a color change in culture media containing fluorene, phenanthrene, and fluoranthene. An Escherichia coli expression experiment confirmed the ability of the Pdo system to oxidize biphenyl, the LMW PAHs naphthalene, phenanthrene, anthracene, and fluorene, and the HMW PAHs pyrene, fluoranthene, and benzo[a] pyrene, with the highest enzymatic activity directed toward three-ring PAHs. Structure analysis and PAH substrate docking simulations of the Pdo substrate-binding pocket rationalized the experimentally observed metabolic versatility on a molecular scale. Using information obtained in this study and from previous work, we constructed an RHO-centric functional map, allowing pleiotropic and epistatic enzymatic explanation of PAH metabolism. Taking the findings together, the Pdo system is an RHO system with the pleiotropic responsibility of LMW PAH-centric hydroxylation, and its epistatic functional contribution is also crucial for the metabolic quality and quantity of the PAH-MN. C1 [Kweon, Ohgew; Kim, Seong-Jae; Kim, Jeong Myeong; Kim, Hyun-lee; Ahn, Youngbeom; Sutherland, John B.; Cerniglia, Carl E.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Kim, Dae-Wi] Chung Ang Univ, Dept Biotechnol, Program BK21, Anseong, South Korea. [Kim, Dae-Wi] Chung Ang Univ, Inst Microbi, Anseong, South Korea. RP Cerniglia, CE (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM carl.cerniglia@fda.hhs.gov FU National Center for Toxicological Research FX This work was supported in part by an appointment to the Postgraduate Research Fellowship Program (D.-W. Kim, J.M. Kim, and H.-L. Kim) at the National Center for Toxicological 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. NR 55 TC 7 Z9 7 U1 2 U2 32 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD OCT PY 2014 VL 196 IS 19 BP 3503 EP 3515 DI 10.1128/JB.01945-14 PG 13 WC Microbiology SC Microbiology GA AO3NH UT WOS:000341237500015 PM 25070740 ER PT J AU Ardeshirpour, Y Hassan, M Zielinski, R Horton, JA Capala, J Gandjbakhche, AH Chernomordik, V AF Ardeshirpour, Yasaman Hassan, Moinuddin Zielinski, Rafal Horton, Jason A. Capala, Jacek Gandjbakhche, Amir H. Chernomordik, Victor TI In Vivo Assessment of HER2 Receptor Density in HER2-positive Tumors by Near-infrared Imaging, Using Repeated Injections of the Fluorescent Probe SO TECHNOLOGY IN CANCER RESEARCH & TREATMENT LA English DT Article DE Fluorescence imaging; Near-infrared optical imaging; Targeted fluorescent probe; Affibody; Cancer treatment; Cancer diagnostics; Human epidermal growth factor receptor ID BREAST-CANCER; EXPRESSION; QUANTIFICATION; THERAPY; PET AB HER2 overexpression and amplification of the HER2/neu gene have been found in approximately 25% of invasive breast carcinomas. They are associated with a poor prognosis and resistance to therapy in breast cancer patients. Up to now, clinical evaluation of human epidermal growth factor receptor 2 (HER2) expression is based on ex vivo methods (immuno histochemistry (I H C) or fluorescence in situ hybridization (FISH) staining of biopsied tissue). Our goal is to realize "image and treat" paradigm using targeted fluorescent probes to evaluate expression levels of cell biomarkers responsible for cancer progression and to monitor the efficacy of corresponding monoclonal antibody treatments. We used fluorescent Affibody-based probes for in vivo analysis of HER2 receptors using near-infrared optical imaging that do not interfere with binding of the therapeutic agents to these receptors. We have analyzed two types of breast carcinoma xenografts with significant differences in HER2 expression (3+ and 2+ according to classification) in the mouse model. Using our kinetic model to analyze the temporal variations of the fluorescence intensity in the tumor area after two subsequent injections allowed us to assess quantitatively the difference in HER2 expression levels for two tumor types (BT-474 and MD-MBA-361). This result was substantiated by ELISA ex vivo assays of HER2 expression in the same tumors. C1 [Ardeshirpour, Yasaman; Hassan, Moinuddin; Gandjbakhche, Amir H.; Chernomordik, Victor] NICHHD, NIH, Bethesda, MD 20892 USA. [Hassan, Moinuddin; Horton, Jason A.] US FDA, Div Phys, Off Sci & Engn Labs, CDRH, Silver Spring, MD 20993 USA. [Zielinski, Rafal; Capala, Jacek] NCI, NIH, Bethesda, MD 20892 USA. [Zielinski, Rafal] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Gandjbakhche, AH (reprint author), NICHHD, NIH, Bldg 9,9 Mem Dr, Bethesda, MD 20892 USA. EM gandjbaa@mail.nih.gov FU Intramural Research Program of National Cancer Institute, NIH; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX This research is supported by the Intramural Research Program of National Cancer Institute, NIH, and Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 19 TC 4 Z9 4 U1 0 U2 33 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-0346 EI 1533-0338 J9 TECHNOL CANCER RES T JI Technol. Cancer Res. Treat. PD OCT PY 2014 VL 13 IS 5 BP 427 EP 434 DI 10.7785/tcrt.2013.600265 PG 8 WC Oncology SC Oncology GA AL0IB UT WOS:000338809500007 PM 24000992 ER PT J AU Pouillot, R Hoelzer, K Ramirez, GA DeGraft-Hanson, J Dennis, SB AF Pouillot, R. Hoelzer, K. Ramirez, G. A. deGraft-Hanson, J. Dennis, S. B. TI Assessment of the risk of salmonellosis from internally contaminated shell eggs following initial storage at 18 degrees C (65 degrees F), compared with 7 degrees C (45 degrees F) SO FOOD MICROBIOLOGY LA English DT Article DE Salmonella Enteritidis; Eggs; Risk assessment ID UNITED-STATES; ENTERITIDIS; GROWTH; MODEL AB In the U.S., chicken-breeder farms that supply hatcheries typically store and transport eggs intended for broiler production at a temperature of 18.3 degrees C (65 degrees F). However, in case of surplus, some of these eggs may be diverted to human consumption. According to the U.S. Food and Drug Administration's 'Egg Safety Final Rule,' shell eggs intended for human consumption are required to be held or transported at or below 7.2 degrees C (45 degrees F) ambient temperature beginning 36 h after time of lay. We adapted a risk assessment model developed by the U.S. Department of Agriculture's Food Safety Inspection Service, to quantify human exposure to Salmonella Enteritidis and the risk of human salmonellosis if eggs are held and transported at 18.3 degrees C for up to 5.5 days after time of lay, as has been observed when hatchery eggs are diverted to human consumption, rather than held and transported at 7.2 degrees C within 36 h after time of lay. Storage at 18.3 degrees C leads to considerable bacterial growth in internally contaminated eggs. The model predicted that more than 10% of internally contaminated eggs would remain contaminated after in-shell pasteurization resulting in a 5-logio reduction, and that some bacteria would survive after home-cooking. The model predicted that, alternatively, eggs stored at 7.2 degrees C after lay would have limited bacterial growth prior to pasteurization, and Salmonella would be very unlikely to be present after pasteurization. The predicted risk of salmonellosis from the consumption of eggs held and transported at 183 degrees C and subsequently diverted to human consumption is 25 times higher than the risk when eggs are held and transported at 7.2 degrees C. Published by Elsevier Ltd. C1 [Pouillot, R.; Hoelzer, K.; Ramirez, G. A.; deGraft-Hanson, J.; Dennis, S. B.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Pouillot, R (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy,HFS 005, College Pk, MD 20740 USA. EM Regis.Pouillot@fda.hhs.gov; Karin.Hoelzer@fda.hhs.gov; Gerardo.Ramirez@fda.hhs.gov; June.deGraft-Hanson@fda.hhs.gov; Sherri.Dennis@fda.hhs.gov RI Pouillot, Regis/E-8103-2010 OI Pouillot, Regis/0000-0002-6107-5212 FU U.S. Food and Drug Administration FX The authors acknowledge John Sheehan, Monica Metz, and Nancy Bufano (U.S. FDA), as well as Janell Kause and Carl Schroeder (USDA - FSIS), for their insight and advice. This work was supported by the U.S. Food and Drug Administration and, in part, by appointments to the Research Participation Program at the Center for Food Safety and Applied Nutrition 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 16 TC 2 Z9 2 U1 2 U2 21 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 OCT PY 2014 VL 43 BP 16 EP 19 DI 10.1016/j.fm.2014.04.012 PG 4 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA AK4MW UT WOS:000338399800003 PM 24929877 ER PT J AU Kim, SHJ Jackson, AJ Hunt, CA AF Kim, Sean H. J. Jackson, Andre J. Hunt, C. Anthony TI In Silico, Experimental, Mechanistic Model for Extended-Release Felodipine Disposition Exhibiting Complex Absorption and a Highly Variable Food Interaction SO PLOS ONE LA English DT Article ID VIVO DRUG-RELEASE; GASTROINTESTINAL TRANSIT; PHARMACOKINETICS; SIMULATION; DELIVERY; TABLETS; SYSTEMS; IMPACT; VITRO AB The objective of this study was to develop and explore new, in silico experimental methods for deciphering complex, highly variable absorption and food interaction pharmacokinetics observed for a modified-release drug product. Toward that aim, we constructed an executable software analog of study participants to whom product was administered orally. The analog is an object- and agent-oriented, discrete event system, which consists of grid spaces and event mechanisms that map abstractly to different physiological features and processes. Analog mechanisms were made sufficiently complicated to achieve prespecified similarity criteria. An equation-based gastrointestinal transit model with nonlinear mixed effects analysis provided a standard for comparison. Subject-specific parameterizations enabled each executed analog's plasma profile to mimic features of the corresponding six individual pairs of subject plasma profiles. All achieved prespecified, quantitative similarity criteria, and outperformed the gastrointestinal transit model estimations. We observed important subject-specific interactions within the simulation and mechanistic differences between the two models. We hypothesize that mechanisms, events, and their causes occurring during simulations had counterparts within the food interaction study: they are working, evolvable, concrete theories of dynamic interactions occurring within individual subjects. The approach presented provides new, experimental strategies for unraveling the mechanistic basis of complex pharmacological interactions and observed variability. C1 [Kim, Sean H. J.] Univ Pittsburgh, Dept Pharm & Therapeut, Pittsburgh, PA 15261 USA. [Jackson, Andre J.] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. [Hunt, C. Anthony] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. RP Kim, SHJ (reprint author), Univ Pittsburgh, Dept Pharm & Therapeut, Pittsburgh, PA 15261 USA. EM skim@pitt.edu FU CDH Research Foundation; Alternatives Research and Development Foundation; American Association of Colleges of Pharmacy New Investigator Award FX This research was supported in part by the CDH Research Foundation (CAH, SHJK), the Alternatives Research and Development Foundation (CAH), and the American Association of Colleges of Pharmacy New Investigator Award (SHJK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 1 Z9 1 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 30 PY 2014 VL 9 IS 9 AR e108392 DI 10.1371/journal.pone.0108392 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR6CW UT WOS:000343671700089 PM 25268237 ER PT J AU Sorouri, M Fitzsimmons, SP Aydanian, AG Bennett, S Shapiro, MA AF Sorouri, Mahsa Fitzsimmons, Sean P. Aydanian, Antonina G. Bennett, Sonita Shapiro, Marjorie A. TI Diversity of the Antibody Response to Tetanus Toxoid: Comparison of Hybridoma Library to Phage Display Library SO PLOS ONE LA English DT Article ID IMMUNE-RESPONSE; GENE FAMILIES; AFFINITY; REPERTOIRE; GENERATION; SELECTION; EXPRESSION; STRATEGIES; ANTIGENS; SEQUENCE AB Monoclonal antibodies are important tools in research and since the 1990s have been an important therapeutic class targeting a wide variety of diseases. Earlier methods of mAb production relied exclusively on the lengthy process of making hybridomas. The advent of phage display technology introduced an alternative approach for mAb production. A potential concern with this approach is its complete dependence on an in vitro selection process, which may result in selection of V-H-V-L pairs normally eliminated during the in vivo selection process. The diversity of V-H-V-L pairs selected from phage display libraries relative to an endogenous response is unknown. To address these questions, we constructed a panel of hybridomas and a phage display library using the spleen of a single tetanus toxoid-immunized mouse and compared the diversity of the immune response generated using each technique. Surprisingly, the tetanus toxoid-specific antibodies produced by the hybridoma library exhibited a higher degree of V-H-V-L genetic diversity than their phage display-derived counterparts. Furthermore, the overlap among the V-genes from each library was very limited. Consistent with the notion that accumulation of many small DNA changes lead to increased antigen specificity and affinity, the phage clones displayed substantial micro-heterogeneity. Contrary to previous reports, we found that antigen specificity against tetanus toxoid is encoded by both V kappa and V-H genes. Finally, the phage-derived tetanus-specific clones had a lower binding affinity than the hybridomas, a phenomenon thought to be the result of random pairing of the V-genes. C1 [Sorouri, Mahsa; Fitzsimmons, Sean P.; Aydanian, Antonina G.; Bennett, Sonita; Shapiro, Marjorie A.] US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. RP Shapiro, MA (reprint author), US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. EM marjorie.shapiro@fda.hhs.gov FU FDA funds FX The source of support is internal FDA funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 1 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 SEP 30 PY 2014 VL 9 IS 9 AR e106699 DI 10.1371/journal.pone.0106699 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR6CW UT WOS:000343671700014 PM 25268771 ER PT J AU McCrindle, BW Li, JS Manlhiot, C Tweddell, JS Giglia, TM Massicotte, MP Monagle, P Krishnamurthy, R Mahaffey, KW Michelson, AD Verdun, N Almond, CS Newburger, JW Brandao, LR Esmon, CT Manco-Johnson, MJ Ichord, R Ortel, TL Chan, AK Portman, R Rose, M Strony, J Kaltman, JR AF McCrindle, Brian W. Li, Jennifer S. Manlhiot, Cedric Tweddell, James S. Giglia, Therese M. Massicotte, M. Patricia Monagle, Paul Krishnamurthy, Rajesh Mahaffey, Kenneth W. Michelson, Alan D. Verdun, Nicole Almond, Christopher S. Newburger, Jane W. Brandao, Leonardo R. Esmon, Charles T. Manco-Johnson, Marilyn J. Ichord, Rebecca Ortel, Thomas L. Chan, Anthony K. Portman, Ron Rose, Martin Strony, John Kaltman, Jonathan R. TI Challenges and Priorities for Research A Report From the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) Working Group on Thrombosis in Pediatric Cardiology and Congenital Heart Disease SO CIRCULATION LA English DT Article DE antithrombotic agents; cardiology; pediatrics; thrombosis ID MAGNETIC-RESONANCE ANGIOGRAPHY; CARDIOPULMONARY BYPASS; CLINICAL-TRIALS; KAWASAKI-DISEASE; PRIMARY THROMBOPROPHYLAXIS; DEVELOPMENTAL HEMOSTASIS; VENOUS THROMBOEMBOLISM; CARDIOVASCULAR-DISEASE; CIRCULATORY SUPPORT; ORAL ANTICOAGULANTS C1 [McCrindle, Brian W.; Manlhiot, Cedric; Brandao, Leonardo R.] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Li, Jennifer S.; Ortel, Thomas L.] Duke Univ, Med Ctr, Durham, NC USA. [Tweddell, James S.] Med Coll Wisconsin, Childrens Hosp Wisconsin, Milwaukee, WI 53226 USA. [Giglia, Therese M.; Ichord, Rebecca] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Philadelphia, PA 19104 USA. [Massicotte, M. Patricia] Univ Alberta, Stollery Childrens Hosp, Edmonton, AB, Canada. [Monagle, Paul] Univ Melbourne, Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Krishnamurthy, Rajesh] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Mahaffey, Kenneth W.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Michelson, Alan D.; Almond, Christopher S.; Newburger, Jane W.] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA USA. [Verdun, Nicole] George Washington Univ, Childrens Natl Med Ctr, Washington, DC USA. [Esmon, Charles T.] Oklahoma Med Res Fdn, Coagulat Biol Lab, Oklahoma City, OK 73104 USA. [Manco-Johnson, Marilyn J.] Univ Colorado, Childrens Hosp Colorado, Aurora, CO USA. [Chan, Anthony K.] McMaster Univ, McMaster Childrens Hosp, Hamilton, ON, Canada. [Portman, Ron] Bristol Myers Squibb Co, Princeton, NJ USA. [Rose, Martin] US FDA, Div Cardiovasc & Renal Protocol, Silver Spring, MD USA. [Strony, John] Merck, Whitehouse Stn, NJ USA. [Kaltman, Jonathan R.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. RP McCrindle, BW (reprint author), Univ Toronto, Labatt Family Heart Ctr, Dept Pediat, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM brian.mccrindle@sickkids.ca FU NIH/NHLBI, Bethesda MD FX Funding for the Working Group meeting was provided by the NIH/NHLBI, Bethesda MD. NR 75 TC 11 Z9 11 U1 0 U2 4 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 SEP 30 PY 2014 VL 130 IS 14 BP 1192 EP 1203 DI 10.1161/CIRCULATIONAHA.113.008428 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AQ8CA UT WOS:000343048800012 PM 25266860 ER PT J AU Choi, YS Eom, SY Park, H Ali, SF Lantz-McPeak, SM Kleinman, MT Kim, YD Kim, H AF Choi, Young-Sook Eom, Sang-Yong Park, Heejin Ali, Syed F. Lantz-McPeak, Susan M. Kleinman, Michael T. Kim, Yong-Dae Kim, Heon TI Toxicity of low doses of ultrafine diesel exhaust particles on bovine brain microvessel endothelial cells SO MOLECULAR & CELLULAR TOXICOLOGY LA English DT Article DE DEPs; BBB; BMECs; Oxidative stress; Permeability ID OXIDATIVE STRESS; PARTICULATE MATTER; ENGINE EXHAUST; AIR-POLLUTION; BARRIER; PERMEABILITY; TRANSLOCATION; EXPOSURE; PATHWAY; MODEL AB Diesel exhaust particles (DEPs) are an important risk factor for various health conditions including neurodegenerative diseases. However, information regarding the toxicity of low doses of ultrafine DEPs in relation to the brain is limited. This study was performed to evaluate the neurotoxicity of low doses of ultrafine DEPs (ng/mL level) using bovine brain microvessel endothelial cells (BMECs) as a model of the blood-brain bather (BBB). The cells were exposed to various concentrations of DEPs (from 1.28 ng/mL to 20 mu g/mL) for 24 h, and cytotoxicity was evaluated by assaying lactate dehydrogenase activity, the generation of reactive oxygen species (ROS) by the dichlorofluorescein diacetate method, total antioxidant capacity (TAC) using bathocuproinedisulfonic acid disodium salt, and cell permeability by measuring the flux of fluorescein. The results showed that low doses of DEPs decreased cell viability and induced oxidative stress by increasing ROS generation and decreasing TAC in a dose-dependent manner. Furthermore, DEPs exposure increased BMECs permeability. This study shows that exposure to low doses of ultrafine DEPs might disrupt the function of BMECs and generate oxidative stress, suggesting that exposure to DEPs even at extremely low doses may compromise the integrity of the BBB and induce adverse effects in the central nervous system. C1 [Choi, Young-Sook; Eom, Sang-Yong; Park, Heejin; Kim, Yong-Dae; Kim, Heon] Chungbuk Natl Univ, Coll Med, Dept Prevent Med, Cheongju 361763, Chungbuk, South Korea. [Ali, Syed F.; Lantz-McPeak, Susan M.] US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Kleinman, Michael T.] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. RP Kim, YD (reprint author), Chungbuk Natl Univ, Coll Med, Dept Prevent Med, Cheongju 361763, Chungbuk, South Korea. EM ydkim@cbu.ac.kr RI Eom, Sang-Yong/B-5705-2016; OI Eom, Sang-Yong/0000-0002-4559-8152; Kim, Heon/0000-0003-0329-5249 FU Chungbuk National University FX This work was supported in part by Chungbuk National University Grant in 2012. All authors report no potential conflict of interest relevant to this manuscript. NR 26 TC 1 Z9 1 U1 3 U2 17 PU KOREAN SOCIETY TOXICOGENOMICS & TOXICOPROTEOMICS-KSTT PI GYEONGGI-DO PA HANYANG UNIV, SCI & TECHNOL BLDG 1, RM 423, SA-DONG, SANGROK-GU, ANSAN, GYEONGGI-DO, 426 791, SOUTH KOREA SN 1738-642X EI 2092-8467 J9 MOL CELL TOXICOL JI Mol. Cell. Toxicol. PD SEP 30 PY 2014 VL 10 IS 3 BP 245 EP 250 DI 10.1007/s13273-014-0027-6 PG 6 WC Biochemistry & Molecular Biology; Toxicology SC Biochemistry & Molecular Biology; Toxicology GA AP9MQ UT WOS:000342404300003 ER PT J AU Elsheikha, HM Holmes, SA Wright, I Morgan, ER Lacher, DW AF Elsheikha, Hany M. Holmes, Sarah A. Wright, Ian Morgan, Eric R. Lacher, David W. TI Recent advances in the epidemiology, clinical and diagnostic features, and control of canine cardio-pulmonary angiostrongylosis SO VETERINARY RESEARCH LA English DT Review ID FOXES VULPES-VULPES; VASORUM 1ST-STAGE LARVAE; PANDA AILURUS-FULGENS; MELES-MELES L.; RED FOXES; PULMONARY-HYPERTENSION; HELMINTH-PARASITES; MILBEMYCIN OXIME; CRENOSOMA-VULPIS; DOGS AB The aim of this review is to provide a comprehensive update on the biology, epidemiology, clinical features, diagnosis, treatment, and prevention of canine cardio-pulmonary angiostrongylosis. This cardiopulmonary disease is caused by infection by the metastrongyloid nematode Angiostrongylus vasorum. The parasite has an indirect life cycle that involves at least two different hosts, gastropod molluscs (intermediate host) and canids (definitive host). A. vasorum represents a common and serious problem for dogs in areas of endemicity, and because of the expansion of its geographical boundaries to many areas where it was absent or uncommon; its global burden is escalating. A. vasorum infection in dogs can result in serious disorders with potentially fatal consequences. Diagnosis in the live patient depends on faecal analysis, PCR or blood testing for parasite antigens or anti-parasite antibodies. Identification of parasites in fluids and tissues is rarely possible except post mortem, while diagnostic imaging and clinical examinations do not lead to a definitive diagnosis. Treatment normally requires the administration of anthelmintic drugs, and sometimes supportive therapy for complications resulting from infection. C1 [Elsheikha, Hany M.; Holmes, Sarah A.] Univ Nottingham, Sch Vet Med & Sci, Loughborough LE12 5RD, Leics, England. [Wright, Ian] Withy Grove Vet Surg, Preston PR5 6QR, Lancs, England. [Morgan, Eric R.] Univ Bristol, Sch Vet Sci, Langford BS40 5DU, North Somerset, England. [Lacher, David W.] US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD USA. RP Elsheikha, HM (reprint author), Univ Nottingham, Sch Vet Med & Sci, Sutton Bonington Campus, Loughborough LE12 5RD, Leics, England. EM hany.elsheikha@nottingham.ac.uk FU Biotechnology and Biological Sciences Research Council NR 94 TC 12 Z9 12 U1 3 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 0928-4249 EI 1297-9716 J9 VET RES JI Vet. Res. PD SEP 27 PY 2014 VL 45 AR 92 DI 10.1186/s13567-014-0092-9 PG 12 WC Veterinary Sciences SC Veterinary Sciences GA AS9LK UT WOS:000344564000001 PM 25283220 ER PT J AU Kuehn, HS Ouyang, WM Lo, B Deenick, EK Niemela, JE Avery, DT Schickel, JN Tran, DQ Stoddard, J Zhang, Y Frucht, DM Dumitriu, B Scheinberg, P Folio, LR Frein, CA Price, S Koh, C Heller, T Seroogy, CM Huttenlocher, A Rao, VK Su, HC Kleiner, D Notarangelo, LD Rampertaap, Y Olivier, KN McElwee, J Hughes, J Pittaluga, S Oliveira, JB Meffre, E Fleisher, TA Holland, SM Lenardo, MJ Tangye, SG Uzel, G AF Kuehn, Hye Sun Ouyang, Weiming Lo, Bernice Deenick, Elissa K. Niemela, Julie E. Avery, Danielle T. Schickel, Jean-Nicolas Tran, Dat Q. Stoddard, Jennifer Zhang, Yu Frucht, David M. Dumitriu, Bogdan Scheinberg, Phillip Folio, Les R. Frein, Cathleen A. Price, Susan Koh, Christopher Heller, Theo Seroogy, Christine M. Huttenlocher, Anna Rao, V. Koneti Su, Helen C. Kleiner, David Notarangelo, Luigi D. Rampertaap, Yajesh Olivier, Kenneth N. McElwee, Joshua Hughes, Jason Pittaluga, Stefania Oliveira, Joao B. Meffre, Eric Fleisher, Thomas A. Holland, Steven M. Lenardo, Michael J. Tangye, Stuart G. Uzel, Gulbu TI Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4 SO SCIENCE LA English DT Article ID REGULATORY T-CELLS; COMMON VARIABLE IMMUNODEFICIENCY; B-CELLS; METASTATIC MELANOMA; AUTOIMMUNE-DISEASE; TOLERANCE; LYMPHOPROLIFERATION; ACCUMULATION; ACTIVATION; MECHANISMS AB Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3(+) regulatory T (T-reg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21(lo) B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis. C1 [Kuehn, Hye Sun; Niemela, Julie E.; Stoddard, Jennifer; Fleisher, Thomas A.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Ouyang, Weiming; Frucht, David M.] US FDA, Lab Cell Biol, Div Monoclonal Antibodies, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Lo, Bernice; Price, Susan; Rao, V. Koneti; Lenardo, Michael J.] NIAID, Mol Dev Immune Syst Sect, Immunol Lab, Bethesda, MD 20892 USA. [Lo, Bernice; Zhang, Yu; Price, Susan; Rao, V. Koneti; Su, Helen C.; Holland, Steven M.; Lenardo, Michael J.] NIAID, Clin Genom Program, Bethesda, MD 20892 USA. [Deenick, Elissa K.; Avery, Danielle T.; Tangye, Stuart G.] Garvan Inst Med Res, Immunol & Immunodeficiency Grp, Div Immunol, Sydney, NSW 2010, Australia. [Deenick, Elissa K.; Tangye, Stuart G.] Univ New S Wales, Fac Med, St Vincents Clin Sch, Sydney, NSW 2010, Australia. [Schickel, Jean-Nicolas; Meffre, Eric] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06511 USA. [Tran, Dat Q.] Univ Texas Med Sch, Dept Pediat, Houston, TX 77030 USA. [Zhang, Yu; Su, Helen C.] NIAID, Immunol Dis Unit, Lab Host Defenses, Bethesda, MD 20892 USA. [Dumitriu, Bogdan; Scheinberg, Phillip] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Folio, Les R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Frein, Cathleen A.] Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Leidos Biomed Res Inc, Frederick, MD 21702 USA. [Koh, Christopher; Heller, Theo] NIDDK, Liver Dis Branch, Bethesda, MD 20892 USA. [Seroogy, Christine M.; Huttenlocher, Anna] Univ Wisconsin, Dept Pediat, Madison, WI 53706 USA. [Huttenlocher, Anna] Univ Wisconsin, Dept Med Microbiol & Immunol, Madison, WI 53706 USA. [Kleiner, David; Pittaluga, Stefania] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Notarangelo, Luigi D.] Harvard Univ, Sch Med, Childrens Hosp, Div Immunol, Boston, MA 02117 USA. [Notarangelo, Luigi D.] Harvard Univ, Sch Med, Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA USA. [Rampertaap, Yajesh; Olivier, Kenneth N.; Holland, Steven M.; Uzel, Gulbu] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [McElwee, Joshua; Hughes, Jason] Merck & Co Inc, Merck Res Labs, Boston, MA 02130 USA. [Oliveira, Joao B.] Inst Med Integral Prof Fernando Figueira IMIP, BR-50070 Recife, PE, Brazil. RP Fleisher, TA (reprint author), NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. EM tfleishe@cc.nih.gov; lenardo@nih.gov; guzel@niaid.nih.gov RI Su, Helen/H-9541-2015; Notarangelo, Luigi/F-9718-2016; OI Su, Helen/0000-0002-5582-9110; Notarangelo, Luigi/0000-0002-8335-0262; Oliveira, Joao/0000-0001-9388-8173; Niemela, Julie/0000-0003-4197-3792; Lo, Bernice/0000-0002-1087-6845; Deenick, Elissa/0000-0002-9271-0004 FU Intramural Research Program, NIH Clinical Center; Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Cancer Institute [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases [5R01HL113304-01, AI071087, AI095848, AI061093]; National Health and Medical Research Council of Australia; Cancer Council NSW FX We thank the referring physicians, as well as the patients and families. The data are tabulated in the main paper and in the supplementary materials. Supported by the Intramural Research Program, NIH Clinical Center (H. S. K., T. A. F., J.S., J.E.N., L. R. F.); the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (B. L., Y.Z., V. K. R., H. C. S., Y.R., K.N.O., S.Pr., S. M. H., M.J.L., G. U.); the National Cancer Institute under contract HHSN261200800001E (C. A. F.); National Institute of Allergy and Infectious Diseases grant 5R01HL113304-01 (D. Q. T.); the National Health and Medical Research Council of Australia (E. K. D., S. G. T.); Cancer Council NSW (S. G. T.); and National Institute of Allergy and Infectious Diseases grants AI071087, AI095848, and AI061093 (E. M.). The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The sequencing data are deposited in dbGaP under accession no. phs000797.v1.p1. NR 28 TC 124 Z9 126 U1 5 U2 26 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD SEP 26 PY 2014 VL 345 IS 6204 BP 1623 EP 1627 DI 10.1126/science.1255904 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP6CG UT WOS:000342164500049 PM 25213377 ER PT J AU Berkhout, B Bodem, J Erlwein, O Herchenroder, O Khan, AS Lever, AM Lindemann, D Linial, ML Lochelt, M McClure, MO Scheller, C Weiss, RA AF Berkhout, Ben Bodem, Jochen Erlwein, Otto Herchenroeder, Ottmar Khan, Arifa S. Lever, Andrew M. L. Lindemann, Dirk Linial, Maxine L. Loechelt, Martin McClure, Myra O. Scheller, Carsten Weiss, Robin A. TI Obituary: Axel Rethwilm (1959-2014) SO RETROVIROLOGY LA English DT Biographical-Item ID FOAMY VIRUS C1 [Berkhout, Ben] Univ Amsterdam, Acad Med Ctr, Ctr Infect & Immun Amsterdam CINIMA, Dept Med Microbiol, NL-1105 AZ Amsterdam, Netherlands. [Bodem, Jochen; Scheller, Carsten] Univ Wurzburg, Inst Virol & Immunbiol, D-97070 Wurzburg, Germany. [Erlwein, Otto; McClure, Myra O.] Univ London Imperial Coll Sci Technol & Med, Wright Fleming Inst, Jefferiss Trust Labs, London, England. [Herchenroeder, Ottmar] Univ Rostock, Med Ctr, Inst Expt Gene Therapy & Canc Res, D-18055 Rostock, Germany. [Khan, Arifa S.] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Retrovirus Lab, Bethesda, MD 20014 USA. [Lever, Andrew M. L.] Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 2QQ, England. [Lindemann, Dirk] Tech Univ Dresden, Med Fac Carl Gustav Carus, Inst Virol, D-01062 Dresden, Germany. [Linial, Maxine L.] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98104 USA. [Loechelt, Martin] German Canc Res Ctr, Res Program Infect & Canc, Heidelberg, Germany. [Weiss, Robin A.] UCL, Div Infect & Immun, London, England. RP Lindemann, D (reprint author), Tech Univ Dresden, Med Fac Carl Gustav Carus, Inst Virol, D-01062 Dresden, Germany. EM dirk.lindemann@tu-dresden.de RI Lindemann, Dirk/H-5857-2013; OI Lindemann, Dirk/0000-0002-0320-4223; Bodem, Jochen/0000-0003-1908-4091 NR 8 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 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 25 PY 2014 VL 11 AR 85 DI 10.1186/s12977-014-0085-9 PG 4 WC Virology SC Virology GA AS8PC UT WOS:000344509400001 PM 25270643 ER PT J AU Gao, XG Yourick, JJ Sprando, RL AF Gao, Xiugong Yourick, Jeffrey J. Sprando, Robert L. TI Transcriptomic Characterization of C57BL/6 Mouse Embryonic Stem Cell Differentiation and Its Modulation by Developmental Toxicants SO PLOS ONE LA English DT Article ID IN-VITRO; TEST EST; TOXICITY; EMBRYOTOXICITY; CULTURES; TOXICOGENOMICS; REQUIREMENTS; DERIVATION; HISTORY; INVITRO AB The Tox21 program calls for transforming toxicology testing from traditional in vivo tests to less expensive and higher throughput in vitro methods. In developmental toxicology, a spectrum of alternative methods including cell line based tests has been developed. In particular, embryonic stem cells (ESCs) have received widespread attention as a promising alternative model for developmental toxicity assessment. Here, we characterized gene expression changes during mouse ESC differentiation and their modulation by developmental toxicants. C57BL/6 ESCs were allowed to differentiate spontaneously and RNA of vehicle controls was collected at 0, 24, 48, 72, 96, 120 and 168 h after embryoid body (EB) formation; RNA of compound-exposed EBs were collected at 24 h. Samples were hybridized to Affymetrix Mouse Gene 2.0 ST Array; using stringent cut-off criteria of Bonferroni-adjusted p<0.05 and fold change >2.0, a total of 1996 genes were found differentially expressed among the vehicle controls at different time points. Gene ontology (GO) analysis showed these regulated genes were mostly involved in differentiation-related processes such as development, morphogenesis, metabolism, cell differentiation, cell organization and biogenesis, embryonic development, and reproduction. Biomarkers of all three germ layers or of their derivative early cell types were identified in the gene list. Principal component analysis (PCA) based on these genes showed that the unexposed vehicle controls appeared in chronological order in the PCA plot, and formed a differentiation track when connected. Cultures exposed to thalidomide, monobutyl phthalate, or valproic acid deviated significantly from the differentiation track, manifesting the capacity of the differentiation track to identify the modulating effects of diverse developmental toxicants. The differentiation track defined in this study may be further exploited as a baseline for developmental toxicity testing, with compounds causing significant deviation from the differentiation track being predicted as potential developmental toxicants. C1 [Gao, Xiugong; Yourick, Jeffrey J.; Sprando, Robert L.] US FDA, Ctr Food Safety & Appl Nutr, Div Toxicol, Off Appl Res & Safety Assessment, Laurel, MD 20705 USA. RP Gao, XG (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Toxicol, Off Appl Res & Safety Assessment, Laurel, MD 20705 USA. EM xiugong.gao@fda.hhs.gov NR 48 TC 6 Z9 6 U1 2 U2 9 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 23 PY 2014 VL 9 IS 9 AR e108510 DI 10.1371/journal.pone.0108510 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP8TL UT WOS:000342351800095 PM 25247782 ER PT J AU Zafar, F Yesha, Y Badano, A AF Zafar, Fahad Yesha, Yaacov Badano, Aldo TI Computational observers and visualization methods for stereoscopic medical imaging SO OPTICS EXPRESS LA English DT Article ID QUANTITATIVE-EVALUATION; PERFORMANCE; DIAGNOSIS; PHANTOM; MRI AB As stereoscopic display devices become common, their image quality assessment evaluation becomes increasingly important. Most studies conducted on 3D displays are based on psychophysics experiments with humans rating their experience based on detection tasks. The physical measurements do not map to effects on signal detection performance. Additionally, human observer study results are often subjective and difficult to generalize. We designed a computational stereoscopic observer approach inspired by the mechanisms of stereopsis in human vision for task-based image assessment that makes binary decisions based on a set of image pairs. The stereo-observer is constrained to a left and a right image generated using a visualization operator to render voxel datasets. We analyze white noise and lumpy backgrounds using volume rendering techniques. Our simulation framework generalizes many different types of model observers including existing 2D and 3D observers as well as providing flexibility to formulate a stereo model observer approach following the principles of stereoscopic viewing. This methodology has the potential to replace human observer studies when exploring issues with stereo display devices to be used in medical imaging. We show results quantifying the changes in performance when varying stereo angle as measured by an ideal linear stereoscopic observer. Our findings indicate that there is an increase in performance of about 13-18% for white noise and 20-46% for lumpy backgrounds, where the stereo angle is varied from 0 to 30. The applicability of this observer extends to stereoscopic displays used for in the areas of medical and entertainment imaging applications. (C) 2014 Optical Society of America C1 [Zafar, Fahad; Yesha, Yaacov] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. [Zafar, Fahad; Badano, Aldo] OSEL CDRH FDA, Div Imaging & Appl Math, Washington, DC USA. RP Zafar, F (reprint author), Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. EM fahad.zafar@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 FU DOE; FDA FX The authors acknowledge support from the Research Participation Program administered by ORISE through an interagency agreement between DOE and FDA. We would also like to thank Dr. Adam Wunderlich and Dr. Berkman Sahiner (DIAM/CDRH/FDA) for their valuable input to this work. 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 Food and Drug Administration and is not subject to copyright. The authors acknowledge support from the Research Participation Program administered by ORISE through an interagency agreement between DOE and FDA. NR 34 TC 1 Z9 1 U1 0 U2 5 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD SEP 22 PY 2014 VL 22 IS 19 BP 22246 EP 22267 DI 10.1364/OE.22.022246 PG 22 WC Optics SC Optics GA AQ4IB UT WOS:000342756500001 PM 25321697 ER PT J AU Gosselin, MC Neufeld, E Moser, H Huber, E Farcito, S Gerber, L Jedensjo, M Hilber, I Di Gennaro, F Lloyd, B Cherubini, E Szczerba, D Kainz, W Kuster, N AF Gosselin, Marie-Christine Neufeld, Esra Moser, Heidi Huber, Eveline Farcito, Silvia Gerber, Livia Jedensjoe, Maria Hilber, Isabel Di Gennaro, Fabienne Lloyd, Bryn Cherubini, Emilio Szczerba, Dominik Kainz, Wolfgang Kuster, Niels TI Development of a new generation of high-resolution anatomical models for medical device evaluation: the Virtual Population 3.0 SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article; Proceedings Paper CT 4th International Workshop on Computational Phantoms for Radiation Protection, Imaging, and Radiotherapy CY MAY 20-22, 2013 CL Zurich, SWITZERLAND DE anatomical models; segmentation; human tissue parameters; high resolution ID HYBRID COMPUTATIONAL PHANTOMS; FEMALE VOXEL PHANTOM; COLOR PHOTOGRAPHS; BODY; SIMULATIONS; IMAGES; SEGMENTATION; DOSIMETRY; FREQUENCY; EXPOSURE AB The Virtual Family computational whole-body anatomical human models were originally developed for electromagnetic (EM) exposure evaluations, in particular to study how absorption of radiofrequency radiation from external sources depends on anatomy. However, the models immediately garnered much broader interest and are now applied by over 300 research groups, many from medical applications research fields. In a first step, the Virtual Family was expanded to the Virtual Population to provide considerably broader population coverage with the inclusion of models of both sexes ranging in age from 5 to 84 years old. Although these models have proven to be invaluable for EM dosimetry, it became evident that significantly enhanced models are needed for reliable effectiveness and safety evaluations of diagnostic and therapeutic applications, including medical implants safety. This paper describes the research and development performed to obtain anatomical models that meet the requirements necessary for medical implant safety assessment applications. These include implementation of quality control procedures, re-segmentation at higher resolution, more-consistent tissue assignments, enhanced surface processing and numerous anatomical refinements. Several tools were developed to enhance the functionality of the models, including discretization tools, posing tools to expand the posture space covered, and multiple morphing tools, e.g., to develop pathological models or variations of existing ones. A comprehensive tissue properties database was compiled to complement the library of models. The results are a set of anatomically independent, accurate, and detailed models with smooth, yet feature-rich and topologically conforming surfaces. The models are therefore suited for the creation of unstructured meshes, and the possible applications of the models are extended to a wider range of solvers and physics. The impact of these improvements is shown for the MRI exposure of an adult woman with an orthopedic spinal implant. Future developments include the functionalization of the models for specific physical and physiological modeling tasks. C1 [Gosselin, Marie-Christine; Neufeld, Esra; Moser, Heidi; Huber, Eveline; Farcito, Silvia; Gerber, Livia; Jedensjoe, Maria; Hilber, Isabel; Di Gennaro, Fabienne; Lloyd, Bryn; Szczerba, Dominik; Kuster, Niels] Fdn Res Informat Technol Soc ITIS, CH-8004 Zurich, Switzerland. [Gosselin, Marie-Christine; Kuster, Niels] ETH, Zurich, Switzerland. [Cherubini, Emilio] SPEAG, Zurich, Switzerland. [Kainz, Wolfgang] US FDA, Silver Spring, MD USA. RP Gosselin, MC (reprint author), Fdn Res Informat Technol Soc ITIS, Zeughausstr 43, CH-8004 Zurich, Switzerland. EM gosselin@itis.ethz.ch FU European Union's Seventh Framework Programm ([FP7]) [282891] FX The authors would like to thank the research group of Professor Klaas Prussmann (ETH Zurich, Switzerland) for performing the MR imaging of the volunteer for the generation of the model Glenn, and Siemens Healthcare (Erlangen, Germany) for the imaging of the obese male volunteer corresponding to Fats. The development of the 3 year old girl model has received funding from the European Union's Seventh Framework Programm ([FP7/2007-2013]) under grant agreement no. 282891. The authors would like to thank the team of biologists at THESS (Thessaloniki, Greece) for their valuable segmentation work and the independent review of the models. The authors would also like to thank Ludwig Tay for the realization of the generic implant model. Marie-Christine Gosselin is a NSERC (Natural Sciences and Engineering Research Council of Canada) grant holder. NR 53 TC 23 Z9 23 U1 0 U2 16 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD SEP 21 PY 2014 VL 59 IS 18 SI SI BP 5287 EP 5303 DI 10.1088/0031-9155/59/18/5287 PG 17 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AO5JW UT WOS:000341381900008 PM 25144615 ER PT J AU Jia, HM He, WW Wamer, WG Han, XN Zhang, BB Zhang, S Zheng, Z Xiang, Y Yin, JJ AF Jia, Huimin He, Weiwei Wamer, Wayne G. Han, Xiangna Zhang, Beibei Zhang, Shu Zheng, Zhi Xiang, Yong Yin, Jun-Jie TI Generation of Reactive Oxygen Species, Electrons/Holes, and Photocatalytic Degradation of Rhodamine B by Photoexcited CdS and Ag2S Micro-Nano Structures SO JOURNAL OF PHYSICAL CHEMISTRY C LA English DT Article ID VISIBLE-LIGHT IRRADIATION; CHARGE-CARRIER DYNAMICS; HYDROGEN-PEROXIDE; OXIDE NANOPARTICLES; SPIN-RESONANCE; TIO2; RADICALS; NANOSTRUCTURES; MECHANISM; NANOCRYSTALS AB Identifying the dominantly active species and their reactive behaviors in semiconductor photocatalysis is important for developing a full understanding of their photochemical and photophysical properties. Here we report an effective method for studying the reactive oxygen species (ROS) and charge carriers generated by irradiating single crystalline CdS and Ag2S micro-nano structures (MNS). Our method, based on electron spin resonance spectroscopy (ESR) combined with spin trapping and spin labeling techniques, confirmed the generation of superoxide and charge carriers and their contribution to photocatalytic degradation of rhodamine B elicited by CdS and Ag2S MNS. The electronic band structures determined the reactivity of photogenerated holes/electrons and the generation of reactive oxygen species. Our comparison of CdS and Ag2S MNS showed that, because of the large difference between their band edge positions, these two sulfides differ greatly in ROS production and in the reactivity of photoinduced electrons and holes. Our ESR method not only provides specific mechanistic information, but also can predict the photocatalytic activity for metal sulfide and possible metal oxide micro-nano structures. C1 [Jia, Huimin; He, Weiwei; Han, Xiangna; Zhang, Beibei; Zheng, Zhi] Xuchang Univ, Key Lab Micronano Energy Storage & Convers Mat He, Inst Surface Micro & Nano Mat, Xuchang 461000, Henan, Peoples R China. [He, Weiwei; Wamer, Wayne G.; Yin, Jun-Jie] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Zhang, Shu; Xiang, Yong] Univ Elect Sci & Technol China, State Key Lab Elect Thin Film & Integrated Device, Sch Energy Sci & Engn, Chengdu 611731, Sichuan, Peoples R China. RP He, WW (reprint author), Xuchang Univ, Key Lab Micronano Energy Storage & Convers Mat He, Inst Surface Micro & Nano Mat, 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, 21273192]; Program for Science & Technology Innovation Talents in Universities of Henan Province [14HASTIT008]; Innovation Scientists and Technicians Troop Construction Projects of Henan Province [144200510014]; Program for Science and Technology of Henan Province [124300510055, 12A150022] FX This work was supported by National Natural Science Foundation of China (Grant Nos. 21303153, 61204009, and 21273192), Program for Science & Technology Innovation Talents in Universities of Henan Province (Grant No. 14HASTIT008), Innovation Scientists and Technicians Troop Construction Projects of Henan Province (Grant No. 144200510014), and Program for Science and Technology of Henan Province (Grant Nos. 124300510055 and 12A150022). We would like to thank Dr. Philippa J. Benson for editorial assistance. This article is not an official US Food and Drug Administration (FDA) guidance or policy statement. No official support or endorsement by the US FDA is intended or should be inferred. NR 45 TC 19 Z9 20 U1 8 U2 118 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 SEP 18 PY 2014 VL 118 IS 37 BP 21447 EP 21456 DI 10.1021/jp505783y PG 10 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA AP5KQ UT WOS:000342118500016 ER PT J AU Yakes, BJ Kanyuck, KM DeGrasse, SL AF Yakes, Betsy Jean Kanyuck, Kelsey M. DeGrasse, Stacey L. TI First Report of a Direct Surface Plasmon Resonance Immunosensor for a Small Molecule Seafood Toxin SO ANALYTICAL CHEMISTRY LA English DT Article ID TETRODOTOXIN DETECTION; ORGANISMS; BIOSENSOR; TOXICITY; WATERS; ASSAY AB Tetrodotoxin (TTX), a small molecular weight neurotoxin, is responsible for poisoning events that traditionally occur from consumption of contaminated puffer fish. Recent studies have shown a growing number of foods contaminated with TTX and a larger number of waters and associated countries where the toxin may occur. The apparent expanding prevalence of TTX supports a growing need for screening assays that can be used to detect potentially harmful food. In the past few years, surface plasmon resonance (SPR) biosensors have been developed for rapid, robust detection of TTX; however, these assays focus on detection of unbound antibody from an inhibition reaction with the toxin. This manuscript introduces the first direct immunoassay for a seafood toxin, specifically TTX. Major advantages of this assay compared to indirect assays include increased speed of analysis, decreased use of biological reagents, and improved confidence in the detection of the toxin, along with the ability to characterize the antibody/toxin interaction. The analytical method introduced in this paper could be applied to other seafood toxins, as well as to a wide range of low molecular weight targets. C1 [Yakes, Betsy Jean; DeGrasse, Stacey L.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Kanyuck, Kelsey M.] Univ Maryland, JIFSAN, College Pk, MD 20742 USA. RP Yakes, BJ (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM betsy.yakes@fda.hhs.gov NR 28 TC 9 Z9 9 U1 2 U2 40 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 SEP 16 PY 2014 VL 86 IS 18 BP 9251 EP 9255 DI 10.1021/ac502271y PG 5 WC Chemistry, Analytical SC Chemistry GA AP1BK UT WOS:000341801200049 PM 25117539 ER PT J AU Khiati, S Rosa, ID Sourbier, C Ma, XF Rao, VA Neckers, LM Zhang, HL Pommier, Y AF Khiati, Salim Rosa, Ilaria Dalla Sourbier, Carole Ma, Xuefei Rao, V. Ashutosh Neckers, Leonard M. Zhang, Hongliang Pommier, Yves TI Mitochondrial Topoisomerase I (Top1mt) Is a Novel Limiting Factor of Doxorubicin Cardiotoxicity SO CLINICAL CANCER RESEARCH LA English DT Article ID CYTOCHROME-C-OXIDASE; ANTHRACYCLINE CARDIOTOXICITY; MOLECULAR-BASIS; HEART-FAILURE; MTDNA LESIONS; DNA DAMAGE; ADRIAMYCIN; CARDIOMYOPATHY; CHEMOTHERAPY; CANCER AB Purpose: Doxorubicin is one of the most effective chemotherapeutic agents. However, up to 30% of the patients treated with doxorubicin suffer from congestive heart failure. The mechanism of doxorubicin cardiotoxicity is likely multifactorial and most importantly, the genetic factors predisposing to doxorubicin cardiotoxicity are unknown. On the basis of the fact that mtDNA lesions and mitochondrial dysfunctions have been found in human hearts exposed to doxorubicin and that mitochondrial topoisomerase 1 (Top1mt) specifically controls mtDNA homeostasis, we hypothesized that Top1mt knockout (KO) mice might exhibit hypersensitivity to doxorubicin. Experimental Design: Wild-type (WT) and KO Top1mt mice were treated once a week with 4 mg/kg doxorubicin for 8 weeks. Heart tissues were analyzed one week after the last treatment. Results: Genetic inactivation of Top1mt in mice accentuates mtDNA copy number loss and mtDNA damage in heart tissue following doxorubicin treatment. Top1mt KO mice also fail to maintain respiratory chain protein production and mitochondrial cristae ultrastructure organization. These mitochondrial defects result in decreased O-2 consumption, increased reactive oxygen species production, and enhanced heart muscle damage in animals treated with doxorubicin. Accordingly, Top1mt KO mice die within 45 days after the last doxorubicin injection, whereas the WT mice survive. Conclusions: Our results provide evidence that Top1mt, which is conserved across vertebrates, is critical for cardiac tolerance to doxorubicin and adaptive response to doxorubicin cardiotoxicity. They also suggest the potential of Top1mt single-nucleotide polymorphisms testing to investigate patient susceptibility to doxorubicin-induced cardiotoxicity. (C) 2014 AACR. C1 [Khiati, Salim; Rosa, Ilaria Dalla; Zhang, Hongliang; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Khiati, Salim; Rosa, Ilaria Dalla; Zhang, Hongliang; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Sourbier, Carole; Neckers, Leonard M.] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Ma, Xuefei] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Rao, V. Ashutosh] US FDA, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. RP Pommier, Y (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov FU NIH through the Intramural Program of the NCI, Center for Cancer Research [Z01 BC 006161] FX This work was supported by the NIH through the Intramural Program of the NCI, Center for Cancer Research (Z01 BC 006161). NR 50 TC 19 Z9 19 U1 0 U2 15 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 2014 VL 20 IS 18 BP 4873 EP 4881 DI 10.1158/1078-0432.CCR-13-3373 PG 9 WC Oncology SC Oncology GA AP8VX UT WOS:000342358500016 PM 24714774 ER PT J AU Screven, R Kenyon, E Myers, MJ Yancy, HF Skasko, M Boxer, L Bigley, EC Borjesson, DL Zhu, M AF Screven, Rudell Kenyon, Elizabeth Myers, Michael J. Yancy, Haile F. Skasko, Mark Boxer, Lynne Bigley, Elmer C., III Borjesson, Dori L. Zhu, Min TI Immunophenotype and gene expression profile of mesenchymal stem cells derived from canine adipose tissue and bone marrow SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article DE Canine; Mesenchymal stem cells; Immunophenotype; Gene expression; PCR array ID UMBILICAL-CORD BLOOD; STROMAL CELLS; DIFFERENTIATION; THERAPY; DEFECTS AB Veterinary adult stem cell therapy is an emerging area of basic and clinical research. Like their human counterparts, veterinary mesenchymal stem cells (MSCs) offer many potential therapeutic benefits. The characterization of canine-derived MSCs, however, is poorly defined compared to human MSCs. Furthermore, little consensus exists regarding the expression of canine MSC cell surface markers. To address this issue, this study investigated characteristics of cultured canine MSCs derived from both adipose tissue and bone marrow. The canine MSCs were obtained from donors of various breeds and ages. A panel of cell surface markers for canine MSCs was selected based on current human and canine literature and the availability of canine-reactive antibodies. Using flow cytometry, canine MSCs were defined to be CD90(+)CD44(+)MHCI(+)CD14(-)CD29(-)CD34(-)MHC II-. Canine MSCs were further characterized using real-time RT-PCR as CD105(+)CD73(+)CD14(+)CD29(+)MHC II(+)CD45(-) at the mRNA level. Among these markers, canine MSCs differed from canine peripheral blood mononuclear cells (PBMCs) by the absence of CD45 expression at the mRNA level. A novel high-throughput canine-specific PCR array was developed and used to identify changes in the gene expression profiles of canine MSCs. Genes including PTPRC, TNF, beta M-2, TGF beta 1, and PDGFR beta, were identified as unique to canine MSCs as compared to canine PBMCs. Our findings will facilitate characterization of canine MSCs for use in research and clinical trials. Moreover, the high-throughput PCR array is a novel tool for characterizing canine MSCs isolated from different tissues and potentially from different laboratories. Published by Elsevier B.V. C1 [Screven, Rudell; Kenyon, Elizabeth; Myers, Michael J.; Yancy, Haile F.; Zhu, Min] US FDA, Res Off, Ctr Vet Med, Laurel, MD 20708 USA. [Skasko, Mark; Boxer, Lynne] US FDA, Off New Anim Drug Evaluat, Ctr Vet Med, Rockville, MD 20855 USA. [Bigley, Elmer C., III] US FDA, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Borjesson, Dori L.] Univ Calif Davis, Sch Vet Med, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA. RP Zhu, M (reprint author), US FDA, Res Off, Ctr Vet Med, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM min.zhu@fda.hhs.gov OI myers, michael/0000-0002-7729-6028 NR 28 TC 16 Z9 16 U1 3 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 EI 1873-2534 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD SEP 15 PY 2014 VL 161 IS 1-2 BP 21 EP 31 DI 10.1016/j.vetimm.2014.06.002 PG 11 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA AP7KY UT WOS:000342257400003 PM 25026887 ER PT J AU Wittenberg, JB Zhou, WL Wang, PG Krynitsky, AJ AF Wittenberg, James B. Zhou, Wanlong Wang, Perry G. Krynitsky, Alexander J. TI Determination of prostaglandin analogs in cosmetic products by high performance liquid chromatography with tandem mass spectrometry SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Prostaglandins; Cosmetics; QuEChERS; LC-MS/MS ID SOLID-PHASE EXTRACTION; LC-MS/MS; OCULAR HYPERTENSION; PESTICIDE-RESIDUES; HUMAN PLASMA; QUANTIFICATION; METABOLITES; DERIVATIZATION; BIMATOPROST; GLAUCOMA AB A method was developed and validated for the determination of 16 prostaglandin analogs in cosmetic products. The QuEChERS (Quick, Easy, Cheap, Efficient, Rugged, Safe) liquid liquid extraction method, typically used for pesticide residue analysis, was utilized as the sample preparation technique. The prostaglandin analogs were chromatographically separated and quantified using high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Thirty-one cosmetic products were surveyed, and 13 products were determined to contain a prostaglandin analog with amounts ranging from 27.4 to 297 mu g/g. The calculated concentrations for the cosmetic products were in a similar range when compared to the concentrations of three different prostaglandin analog-containing prescription products. (C) 2014 Elsevier B.V. All rights reserved. C1 [Wittenberg, James B.; Zhou, Wanlong; Wang, Perry G.; 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 39 TC 1 Z9 1 U1 2 U2 25 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD SEP 12 PY 2014 VL 1359 BP 140 EP 146 DI 10.1016/j.chroma.2014.07.032 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AO0FL UT WOS:000340984400018 PM 25085824 ER PT J AU Mamounas, EP Cortazar, P Zhang, LJ Von Minckwitz, G Mehta, K Cameron, DA Bonnefoi, HR Gianni, L Valagussa, P Wolmark, N Loibl, S Bogaerts, J Swain, SM Sridhara, R Costantino, JP Rastogi, P Geyer, CE Eidtmann, H Gerber, B Untch, M AF Mamounas, Eleftherios P. Cortazar, Patricia Zhang, Lijun Von Minckwitz, Gunter Mehta, Keyur Cameron, David A. Bonnefoi, Herve R. Gianni, Luca Valagussa, Pinuccia Wolmark, Norman Loibl, Sibylle Bogaerts, Jan Swain, Sandra M. Sridhara, Rajeshwari Costantino, Joseph P. Rastogi, Priya Geyer, Charles E. Eidtmann, Holger Gerber, Bernd Untch, Michael TI Locoregional recurrence (LRR) after neoadjuvant chemotherapy (NAC): Pooled-analysis results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Breast Cancer Symposium CY SEP 04-06, 2014 CL San Francisco, CA SP Amer Soc Clin Oncol C1 Orlando Hlth, Natl Surg Adjuvant Breast & Bowel Project, Orlando, FL USA. Orlando Hlth, UF Hlth Canc Ctr, Orlando, FL USA. US FDA, Silver Spring, MD USA. Goethe Univ Frankfurt, German Breast Grp, Neu Isenburg, Germany. German Breast Grp, Neu Isenburg, Germany. Univ Edinburgh, Edinburgh, Midlothian, Scotland. Inst Bergonie, Ctr Canc, Bordeaux, France. Ist Sci San Raffaele, I-20132 Milan, Italy. Fdn Michelangelo, Milan, Italy. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. Sana Klinikum Offenbach, German Breast Grp, Neu Isenburg, Germany. European Org Res Treatment Canc, Brussels, Belgium. MedStar Washington Hosp Ctr, Washington, DC USA. Univ Pittsburgh, Grad Sch Publ Hlth, Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Virginia Commonwealth Univ, Sch Med, Massey Canc Ctr, Richmond, VA USA. NRG Oncol, Richmond, VA USA. Univ Kiel, Kiel, Germany. Univ Rostock, D-18055 Rostock, Germany. Helios Klinikum Berlin Buch, Berlin, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 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 SEP 10 PY 2014 VL 32 IS 26 SU S MA 61 PG 2 WC Oncology SC Oncology GA CN2JK UT WOS:000358246700060 ER PT J AU He, WW Wu, HH Wamer, WG Kim, HK Zheng, JW Jia, HM Zheng, Z Yin, JJ AF He, Weiwei Wu, Haohao Wamer, Wayne G. Kim, Hyun-Kyung Zheng, Jiwen Jia, Huimin Zheng, Zhi Yin, Jun-Jie TI Unraveling the Enhanced Photocatalytic Activity and Phototoxicity of ZnO/Metal Hybrid Nanostructures from Generation of Reactive Oxygen Species and Charge Carriers SO ACS APPLIED MATERIALS & INTERFACES LA English DT Article ID HACAT KERATINOCYTES-GENERATION; OXIDE NANOPARTICLES; ZNO NANOPARTICLES; VISIBLE-LIGHT; SEMICONDUCTOR; IRRADIATION; MECHANISMS; RADICALS; DAMAGE; CELLS AB An effective way for promoting photocatalytic activity of a semiconductor is deposition of noble metal nanoparticles (NPs) onto it. In this paper, we deposited Ag and Pd onto ZnO NPs to form ZnO/Ag and ZnO/Pd hybrid nanostructures. It was found that both Ag and Pd nanocomponents can greatly enhance the photocatalytic activity and phototoxicity of ZnO toward human skin cells. Using electron spin resonance spectroscopy with spin trapping and spin labeling techniques, we observed that either deposition of Ag or Pd resulted in a significant increase in photogenerated electrons and holes and production of reactive oxygen species including hydroxyl radicals, superoxide, and singlet oxygen. We compared the enhancing effects of Ag and Pd and found that Pd is more effective than Ag in promoting the generation of hydroxyl radicals and holes and the photocatalytic activity of ZnO. Conversely, Ag is more effective than Pd in enhancing electron transfer and the generation of superoxide and singlet oxygen. The mechanism underlying the differences in the effects of Ag and Pd may be related to differences in Fermi levels for Ag and Pd and band bending accompanied by effects on Schottky barriers. The results of these studies provide information valuable for designing hybrid nanomaterials having photocatalytic and photobiological activities useful for applications such as water purification and formulation of antibacterial products. C1 [He, Weiwei; Jia, Huimin; 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; Wu, Haohao; Wamer, Wayne G.; Yin, Jun-Jie] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Kim, Hyun-Kyung] Minist Food & Drug Safety, Osong Hlth Technol Adm Complex, Cheongju 363700, Chungcheongbuk, South Korea. [Zheng, Jiwen] US FDA, Div Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Yin, JJ (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM junjie.yin@fda.hhs.gov RI Yin, Jun Jie /E-5619-2014; OI Wu, Haohao/0000-0003-3852-2608 FU National Natural Science Foundation of China [21303153, 21273192, 61204009]; Program for Science & Technology Innovation Talents in Universities of Henan Province [14HASTIT008]; Research Project of Basic and Advanced Technology of Henan Province [112300410106]; Innovation Scientists and Technicians Troop Construction Projects of Henan Province [144200510014]; Korean Government Scholarship Program; FDA Nanotechnology CORES Program; Office of Cosmetics and Colors, CFSAN/FDA FX W. He thanks the National Natural Science Foundation of China (Grant Nos. 21303153, 21273192, and 61204009), Program for Science & Technology Innovation Talents in Universities of Henan Province (14HASTIT008), and the Research Project of Basic and Advanced Technology of Henan Province (Grant No. 112300410106) for support. Z. Zheng is thankful for the support from Innovation Scientists and Technicians Troop Construction Projects of Henan Province (Grant No. 144200510014). H.-K. Kim is thankful for support from the Korean Government Scholarship Program. This work was supported by a regulatory science grant under the FDA Nanotechnology CORES Program and by the Office of Cosmetics and Colors, CFSAN/FDA (W.H., W.G.W., and J.-J.Y.). 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 30 TC 19 Z9 19 U1 5 U2 67 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 10 PY 2014 VL 6 IS 17 BP 15527 EP 15535 DI 10.1021/am5043005 PG 9 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA AO7PD UT WOS:000341544200093 PM 25116236 ER PT J AU Wang, QS Chu, CH Qian, L Chen, SH Wilson, B Oyarzabal, E Jiang, LL Ali, S Robinson, B Kim, HC Hong, JS AF Wang, Qingshan Chu, Chun-Hsien Qian, Li Chen, Shih-Heng Wilson, Belinda Oyarzabal, Esteban Jiang, Lulu Ali, Syed Robinson, Bonnie Kim, Hyoung-Chun Hong, Jau-Shyong TI Substance P Exacerbates Dopaminergic Neurodegeneration through Neurokinin-1 Receptor-Independent Activation of Microglial NADPH Oxidase SO JOURNAL OF NEUROSCIENCE LA English DT Article DE GPCR independence; NADPH oxidase; neuroinflammation; Parkinson's disease; substance P ID LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; CENTRAL-NERVOUS-SYSTEM; PARKINSONS-DISEASE; OXIDATIVE STRESS; PROGRESSIVE NEURODEGENERATION; CHRONIC NEUROINFLAMMATION; REACTIVE MICROGLIOSIS; BORRELIA-BURGDORFERI; NOX ENZYMES; INHIBITION AB Although dysregulated substance P (SP) has been implicated in the pathophysiology of Parkinson's disease (PD), how SP affects the survival of dopaminergic neurons remains unclear. Here, we found that mice lacking endogenous SP (TAC1(-/-)), but not those deficient in the SP receptor (neurokinin-1 receptor, NK1R), were more resistant to lipopolysaccharide (LPS)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic neurodegeneration than wild-type controls, suggesting a NK1R-independent toxic action of SP. In vitro dose-response studies revealed that exogenous SP enhanced LPS- and 1-methyl-4-phenylpyridinium (MPP+)-induced dopaminergic neurodegeneration in a bimodal manner, peaking at submicromolar and subpicomolar concentrations, but was substantially less effective at intermediate concentrations. Mechanistically, the actions of submicromolar levels of SP were NK1R-dependent, whereas subpicomolar SP-elicited actions required microglial NADPH oxidase (NOX2), the key superoxide-producing enzyme, but not NK1R. Subpicomolar concentrations of SP activated NOX2 by binding to the catalytic subunit gp91(phox) and inducing membrane translocation of the cytosolic subunits p47(phox) and p67(phox). The importance of NOX2 was further corroborated by showing that inhibition or disruption of NOX2 blocked subpicomolar SP-exacerbated neurotoxicity. Together, our findings revealed a critical role of microglial NOX2 in mediating the neuroinflammatory and dopaminergic neurodegenerative effects of SP, which may provide new insights into the pathogenesis of PD. C1 [Wang, Qingshan; Chu, Chun-Hsien; Qian, Li; Chen, Shih-Heng; Wilson, Belinda; Oyarzabal, Esteban; Jiang, Lulu; Hong, Jau-Shyong] Natl Inst Environm Hlth Sci, Lab Toxicol & Pharmacol, Neuropharmacol Sect, Res Triangle Pk, NC 27709 USA. [Ali, Syed; Robinson, Bonnie] US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Neurochem Lab, Jefferson, AR 72079 USA. [Kim, Hyoung-Chun] Kangwon Natl Univ, Coll Pharm, Neuropsychopharmacol & Toxicol Program, Chunchon 200701, South Korea. RP Wang, QS (reprint author), Natl Inst Environm Hlth Sci, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM wangq4@niehs.nih.gov; hong3@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. We thank Anthony Lockhart for assistance with animal colony management and maintenance of the timed pregnant mice. NR 49 TC 12 Z9 12 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 10 PY 2014 VL 34 IS 37 BP 12490 EP 12503 DI 10.1523/JNEUROSCI.2238-14.2014 PG 14 WC Neurosciences SC Neurosciences & Neurology GA AP0QH UT WOS:000341766900022 PM 25209287 ER PT J AU Zhang, K Wong, JW Krynitsky, AJ Trucksess, MW AF Zhang, Kai Wong, Jon W. Krynitsky, Alexander J. Trucksess, Mary W. TI Determining Mycotoxins in Baby Foods and Animal Feeds Using Stable Isotope Dilution and Liquid Chromatography Tandem Mass Spectrometry SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE stable isotope dilution; mycotoxins; baby foods; animal freeds; LC-MS/MS ID EXTRACTION; AFLATOXINS; CLEANUP; INGREDIENTS; OCHRATOXIN; FUMONISINS; PRODUCTS; FUSARIUM; TOXINS; MARKET AB We developed a stable isotope dilution assay with liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine multiple mycotoxins in baby foods and animal feeds. Samples were fortified with [C-13]-uniformly labeled mycotoxins as internal standards ([C-13]-IS) and prepared by solvent extraction (50% acetonitrile in water) and filtration, followed by LC-MS/MS analysis. Mycotoxins in each sample were quantitated with the corresponding [C-13]-IS. In general, recoveries of aflatoxins (2-100 ng/g), deoxynivalenol, fumonisins (50-2000 ng/g), ochratoxin A (20-1000 ng/kg), T-2 toxin, and zearalenone (40-2000 ng/g) in tested matrices (grain/rice/oatmeal-based formula, animal feed, dry cat/dog food) ranged from 70 to 120% with relative standard deviations (RSDs) <20%. The method provides sufficient selectivity, sensitivity, accuracy, and reproducibility to screen for aflatoxins at ng/g concentrations and deoxynivalenol and fumonisins at low mu g/g concentrations in baby foods and animal feeds, without using conventional standard addition or matrix-matched calibration standards to correct for matrix effects. C1 [Zhang, Kai; Wong, Jon W.; Krynitsky, Alexander J.; Trucksess, Mary W.] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Zhang, K (reprint author), US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, HFS 706,5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM kai.zhang@fda.hhs.gov NR 38 TC 11 Z9 11 U1 4 U2 46 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 10 PY 2014 VL 62 IS 36 BP 8935 EP 8943 DI 10.1021/jf503943r PG 9 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA AO7PF UT WOS:000341544400003 PM 25153173 ER PT J AU Beger, R Yang, X Pence, L Sun, JC Schnackenberg, L Salminen, W Shi, Q Greenhaw, J Gill, P Bhattacharyya, S Simpson, P Ye, K Mendrick, D James, L AF Beger, Richard Yang, Xi Pence, Lisa Sun, Jinchun Schnackenberg, Laura Salminen, William Shi, Qiang Greenhaw, James Gill, Prit Bhattacharyya, Sudeepa Simpson, Pippa Ye, Kan Mendrick, Donna James, Laura TI Metabolomics and miRNA biomarkers of paracetamol overdose in rodents and children SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 50th Congress of the European-Societies-of-Toxicology CY SEP 07-10, 2014 CL Edinburgh, SCOTLAND SP European Soc Toxicol, British Toxicol Soc, Soc Toxicol C1 [Beger, Richard; Yang, Xi; Pence, Lisa; Sun, Jinchun; Schnackenberg, Laura; Shi, Qiang; Greenhaw, James; Mendrick, Donna] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Salminen, William] PAREXEL Int, Sarasota, FL USA. [Gill, Prit; Bhattacharyya, Sudeepa; James, Laura] Arkansas Childrens Hosp, Res Inst, Little Rock, AR 72202 USA. [Simpson, Pippa; Ye, Kan] Med Coll Wisconsin, Milwaukee, WI 53226 USA. NR 0 TC 1 Z9 1 U1 0 U2 3 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 10 PY 2014 VL 229 SU S MA P-2.22 BP S99 EP S100 DI 10.1016/j.toxlet.2014.06.367 PG 2 WC Toxicology SC Toxicology GA AO2FY UT WOS:000341134000313 ER PT J AU Cayley, A Drewe, W Kruhlak, N Surfraz, MB AF Cayley, Alex Drewe, William Kruhlak, Naomi Surfraz, M. Bashir TI Utilising knowledge relating to 5 alpha-reductase inhibition in the prediction of teratogenicity SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 50th Congress of the European-Societies-of-Toxicology CY SEP 07-10, 2014 CL Edinburgh, SCOTLAND SP European Soc Toxicol, British Toxicol Soc, Soc Toxicol C1 [Cayley, Alex; Drewe, William; Surfraz, M. Bashir] Lhasa Ltd, Leeds, W Yorkshire, England. [Kruhlak, Naomi] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 10 PY 2014 VL 229 SU S MA P-3.37 BP S159 EP S159 DI 10.1016/j.toxlet.2014.06.547 PG 1 WC Toxicology SC Toxicology GA AO2FY UT WOS:000341134000499 ER PT J AU Chen, T Meng, FX Yan, J AF Chen, Tao Meng, Fanxue Yan, Jian TI 2-Bromo-3 '-chloropropiophenone is a genotoxic impurity SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 50th Congress of the European-Societies-of-Toxicology CY SEP 07-10, 2014 CL Edinburgh, SCOTLAND SP European Soc Toxicol, British Toxicol Soc, Soc Toxicol C1 [Chen, Tao; Meng, Fanxue; Yan, Jian] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 10 PY 2014 VL 229 SU S MA P-3.168 BP S203 EP S203 DI 10.1016/j.toxlet.2014.06.682 PG 1 WC Toxicology SC Toxicology GA AO2FY UT WOS:000341134000637 ER PT J AU Doerge, DR Camacho, L Delclos, KB AF Doerge, Daniel R. Camacho, Luisa Delclos, K. Barry TI Lifestage-dependent dosimetry and toxicology of BPA in a 90-D rat study and implications for human risk assessment SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 50th Congress of the European-Societies-of-Toxicology CY SEP 07-10, 2014 CL Edinburgh, SCOTLAND SP European Soc Toxicol, British Toxicol Soc, Soc Toxicol C1 [Doerge, Daniel R.; Camacho, Luisa; Delclos, K. Barry] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 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 10 PY 2014 VL 229 SU S MA PS7.3-O3 BP S36 EP S37 DI 10.1016/j.toxlet.2014.06.170 PG 2 WC Toxicology SC Toxicology GA AO2FY UT WOS:000341134000118 ER PT J AU Krais, AM Melis, JPM Speksnijder, EN Stiborova, M Singh, R da Costa, GG Luijten, M Phillips, DH Arlt, VM AF Krais, Annette M. Melis, Joost P. M. Speksnijder, Ewoud N. Stiborova, Marie Singh, Rajinder da Costa, Goncalo Gamboa Luijten, Mirjam Phillips, David H. Arlt, Volker M. TI Impact of P53 on DNA damage and metabolic activation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PHIP) in TRP53(+/+), TRP53(+/-) and TRP53(-/-) mice SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 50th Congress of the European-Societies-of-Toxicology CY SEP 07-10, 2014 CL Edinburgh, SCOTLAND SP European Soc Toxicol, British Toxicol Soc, Soc Toxicol C1 [Krais, Annette M.; Phillips, David H.; Arlt, Volker M.] Kings Coll London, London WC2R 2LS, England. [Melis, Joost P. M.; Luijten, Mirjam] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Melis, Joost P. M.; Speksnijder, Ewoud N.] Leiden Univ Med Ctr, Leiden, Netherlands. [Stiborova, Marie] Charles Univ Prague, Prague, Czech Republic. [Singh, Rajinder] Univ Leicester, Leicester, Leics, England. [da Costa, Goncalo Gamboa] NCTR, Jefferson, AR USA. NR 0 TC 0 Z9 0 U1 1 U2 3 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 10 PY 2014 VL 229 SU S MA P-3.2 BP S145 EP S145 DI 10.1016/j.toxlet.2014.06.511 PG 1 WC Toxicology SC Toxicology GA AO2FY UT WOS:000341134000459 ER PT J AU Thompson, K AF Thompson, Karol TI Best practice for measurement of injury-associated microRNAs in biofluids SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 50th Congress of the European-Societies-of-Toxicology CY SEP 07-10, 2014 CL Edinburgh, SCOTLAND SP European Soc Toxicol, British Toxicol Soc, Soc Toxicol C1 [Thompson, Karol] FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 10 PY 2014 VL 229 SU S MA PS2.3-O2 BP S22 EP S22 DI 10.1016/j.toxlet.2014.06.111 PG 1 WC Toxicology SC Toxicology GA AO2FY UT WOS:000341134000069 ER PT J AU Nieuwenhuijse, MJ Nelissen, RGHH Schoones, JW Sedrakyan, A AF Nieuwenhuijse, Marc J. Nelissen, R. G. H. H. Schoones, J. W. Sedrakyan, A. TI Appraisal of evidence base for introduction of new implants in hip and knee replacement: a systematic review of five widely used device technologies SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID METAL-ON-METAL; RANDOMIZED CONTROLLED-TRIALS; DIFFERENT BEARING SURFACES; NATIONAL JOINT REGISTRY; IDEAL FRAMEWORK; MEDICAL DEVICES; ARTHROPLASTY; METAANALYSES; GUIDELINES; STATEMENT AB Objective To determine the evidence of effectiveness and safety for introduction of five recent and ostensibly high value implantable devices in major joint replacement to illustrate the need for change and inform guidance on evidence based introduction of new implants into healthcare. Design Systematic review of clinical trials, comparative observational studies, and registries for comparative effectiveness and safety of five implantable device innovations. Data sources PubMed (Medline), Embase, Web of Science, Cochrane, CINAHL, reference lists of articles, annual reports of major registries, summaries of safety and effectiveness for pre-market application and mandated post-market studies at the US Food and Drug Administration. Study selection The five selected innovations comprised three in total hip replacement (ceramic-on-ceramic bearings, modular femoral necks, and uncemented monoblock cups) and two in total knee replacement (high flexion knee replacement and gender specific knee replacement). All clinical studies of primary total hip or knee replacement for symptomatic osteoarthritis in adults that compared at least one of the clinical outcomes of interest (patient centred outcomes or complications, or both) in the new implant group and control implant group were considered. Data searching, abstraction, and analysis were independently performed and confirmed by at least two authors. Quantitative data syntheses were performed when feasible. Results After assessment of 10 557 search hits, 118 studies (94 unique study cohorts) met the inclusion criteria and reported data related to 15 384 implants in 13 164 patients. Comparative evidence per device innovation varied from four low to moderate quality retrospective studies (modular femoral necks) to 56 studies of varying quality including seven high quality (randomised) studies (high flexion knee replacement). None of the five device innovations was found to improve functional or patient reported outcomes. National registries reported two to 12 year follow-up for revision occurrence related to more than 200 000 of these implants. Reported comparative data with well established alternative devices (over 1 200 000 implants) did not show improved device survival. Moreover, we found higher revision occurrence associated with modular femoral necks (hazard ratio 1.9) and ceramic-on-ceramic bearings (hazard ratio 1.0-1.6) in hip replacement and with high flexion knee implants (hazard ratio 1.0-1.8). Conclusion We did not find convincing high quality evidence supporting the use of five substantial, well known, and already implemented device innovations in orthopaedics. Moreover, existing devices may be safer to use in total hip or knee replacement. Improved regulation and professional society oversight are necessary to prevent patients from being further exposed to these and future innovations introduced without proper evidence of improved clinical efficacy and safety. C1 [Nieuwenhuijse, Marc J.; Sedrakyan, A.] Weill Cornell Med Coll, Patient Ctr Comparat Effectiveness Program, New York, NY 10065 USA. [Nieuwenhuijse, Marc J.; Sedrakyan, A.] Weill Cornell Med Coll, US FDA, Med Device Epidemiol Sci & Infrastructure Ctr, Dept Publ Hlth, New York, NY 10065 USA. [Nieuwenhuijse, Marc J.; Nelissen, R. G. H. H.] Leiden Univ, Med Ctr, Dept Orthopaed, NL-2300 RC Leiden, Netherlands. [Nieuwenhuijse, Marc J.; Sedrakyan, A.] US FDA, Ctr Devices & Radiol Hlth, Off Surveillance & Biometr, Silver Spring, MD 20993 USA. [Schoones, J. W.] Leiden Univ, Walaeus Lib, Med Ctr, NL-2300 RC Leiden, Netherlands. RP Sedrakyan, A (reprint author), Weill Cornell Med Coll, Patient Ctr Comparat Effectiveness Program, New York, NY 10065 USA. EM ars2013@med.cornell.edu RI Schoones, Johannes Wilhelmus/B-2837-2008 OI Schoones, Johannes Wilhelmus/0000-0003-1120-4781 FU US FDA Medical Device Epidemiology Network's (MDEpiNet) Science and Infrastructure Center under the International Consortium of Orthopaedic Registries initiative (ICOR); US FDA FX MJN received a fellowship from the US FDA Medical Device Epidemiology Network's (MDEpiNet) Science and Infrastructure Center (director AS) under the International Consortium of Orthopaedic Registries initiative (ICOR, www.icor-initiative.org). AS received funding from the US FDA for establishing the MDEpiNet Science and Infrastructure Center and is the principal investigator of ICOR contract. Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. NR 40 TC 15 Z9 16 U1 8 U2 18 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD SEP 9 PY 2014 VL 349 AR g5133 DI 10.1136/bmj.g5133 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA AO9QM UT WOS:000341691000001 PM 25208953 ER PT J AU Balsam, J Bruck, HA Rasooly, A AF Balsam, Joshua Bruck, Hugh Alan Rasooly, Avraham TI Webcam-based flow cytometer using wide-field imaging for low cell number detection at high throughput SO ANALYST LA English DT Article ID ARRAY BIOSENSOR; SMART-PHONE; MHEALTH AB Here we describe a novel low-cost flow cytometer based on a webcam capable of tow cell number detection in a large volume which may overcome the limitations of current flow cytometry. Several key elements have been combined to yield both high throughput and high sensitivity. The first element is a commercially available webcam capable of 187 frames per second video capture at a resolution of 320 x 240 pixels. The second element in this design is a 1 W 450 nm laser module for area-excitation, which combined with the webcam allows for rapid interrogation of a flow field. The final element is a 2D flow-cell which overcomes the flow limitation of hydrodynamic focusing and allows for higher sample throughput in a wider flow field. This cell allows for the linear velocity of target cells to be lower than in a conventional "1D" hydrodynamic focusing flow-cells typically used in cytometry at similar volumetric flow rates. It also allows cells to be imaged at the full frame rate of the webcam. Using this webcam-based flow cytometer with wide-field imaging, it was confirmed that the detection of fluorescently tagged 5 gm polystyrene beads in "1D" hydrodynamic focusing flow-cells was not practical for low cell number detection due to streaking from the motion of the beads, which did not occur with the 2D flow-cell design. The sensitivity and throughput of this webcam-based flow cytometer was then investigated using THP-1 human monocytes stained with SYTO-9 florescent dye in the 2D flow-cell The flow cytometer was found to be capable of detecting fluorescently tagged cells at concentrations as low as 1 cell per mL at flow rates of 500 mu L min(-1) in buffer and in blood. The effectiveness of detection was concentration dependent: at 100 cells per mL 84% of the cells were detected compared to microscopy, 10 cells per mL 79% detected and 1 cell per mL 59% of the cells were detected. With the blood samples spiked to 100 cells per mL, the average concentration for all samples was 91.4 cells per mL, with a 95% confidence interval of 86-97 cells per mL. These low cell concentrations and the large volume capabilities of the system may overcome the limitations of current cytometry, and are applicable to rare cell (such as circulating tumor cell) detection The simplicity and low cost of this device suggests that it may have a potential use in developing point-of-care clinical flow cytometry for resource-poor settings associated with global health. C1 [Balsam, Joshua; Rasooly, Avraham] US FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. [Balsam, Joshua; Bruck, Hugh Alan] Univ Maryland, College Pk, MD 20742 USA. [Rasooly, Avraham] Natl Canc Inst, Div Canc Biol, NIH NCI, Rockville, MD 20850 USA. RP Rasooly, A (reprint author), US FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. EM rasoolya@mail.nih.gov FU FDA's Center for Devices and Radiological Health; Division of Biology; National Cancer Institute FX This work was supported by the FDA's Center for Devices and Radiological Health, Division of Biology and the National Cancer Institute. The views expressed are those of the authors and do not necessarily reflect the views of the U.S. Government. NR 35 TC 4 Z9 4 U1 3 U2 20 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 0003-2654 EI 1364-5528 J9 ANALYST JI Analyst PD SEP 7 PY 2014 VL 139 IS 17 BP 4322 EP 4329 DI 10.1039/c4an00669k PG 8 WC Chemistry, Analytical SC Chemistry GA AN6KJ UT WOS:000340703100026 PM 24995370 ER PT J AU Lyn-Cook, L Word, B George, N Lyn-Cook, B Hammons, G AF Lyn-Cook, Lascelles Word, Beverly George, Nysia Lyn-Cook, Beverly Hammons, George TI Effect of cigarette smoke condensate on gene promoter methylation in human lung cells SO TOBACCO INDUCED DISEASES LA English DT Article DE DNA methylation; Cigarette smoke condensate; Lung cancer cells ID EPITHELIAL-CELLS; DNA METHYLATION; DOWN-REGULATION; CANCER; EXPRESSION; HYPERMETHYLATION; LET-7A-3 AB Background: In lung cancer, an association between tobacco smoking and promoter DNA hypermethylation has been demonstrated for several genes. However, underlying mechanisms for promoter hypermethylation in tobacco-induced cancer are yet to be fully established. Methods: Promoter methylation was evaluated in control and cigarette smoke condensate (CSC) exposed human lung cells using the Methyl-Profiler DNA Methylation PCR System. PSAE cells were exposed to 0.3 or 1.0 mu g/ml CSC for 72 hours and longer term for 14 and 30 days. NL-20 cells were exposed for 30 days to 10 or 100 mu g/ml CSC. Results: Promoters of several genes, including hsa-let-7a-3, CHD1, CXCL12, PAX5, RASSF2, and TCF21, were highly methylated (>90%); hsa-let-7a-3 was affected in both cell lines and under all exposure conditions. Level of methylation tended to increase with CSC concentration and exposure duration (statistical differences were not determined). Percentage methylation of TCF21, which was >98% at exposures of 10 or 100 mu g/ml CSC, was found to be reduced to 28% and 42%, respectively, in the presence of the dietary agent genistein. Conclusions: Using array techniques, several tumor suppressor genes in human lung cells were identified that undergo promoter hypermethylation, providing further evidence of their potential involvement in tobacco smoke-induced lung carcinogenesis and their use as potential biomarkers of harm in tobacco smoke exposure. Results from the study also demonstrated the potential of a dietary agent to exert chemopreventive activity in human tissue against tobacco smoke related diseases through modulation of DNA methylation. Additional studies are needed to confirm these findings. C1 [Lyn-Cook, Lascelles; Word, Beverly; George, Nysia; Lyn-Cook, Beverly; Hammons, George] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Hammons, G (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, HFT 100, Jefferson, AR 72079 USA. EM ghammons@nctr.fda.gov NR 28 TC 9 Z9 12 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1617-9625 J9 TOB INDUC DIS JI Tob. Induc. Dis. PD SEP 5 PY 2014 VL 12 AR 15 DI 10.1186/1617-9625-12-15 PG 6 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA AP3AS UT WOS:000341947900001 PM 25214829 ER PT J AU Bozza, WP Di, X Takeda, K Rosado, LAR Pariser, S Zhang, BL AF Bozza, William P. Di, Xu Takeda, Kazuyo Rosado, Leslie A. Rivera Pariser, Sarah Zhang, Baolin TI The Use of a Stably Expressed FRET Biosensor for Determining the Potency of Cancer Drugs SO PLOS ONE LA English DT Article ID INDUCED APOPTOSIS; CASPASE ACTIVATION; LIVING CELLS; ASSAY; PATHWAYS; DYNAMICS; SCREEN; LINES AB Many cancer drugs are intended to kill cancer cells by inducing apoptosis. However, the potency assays used for measuring the bioactivity of these products are generally cell viability assays which do not distinguish between cell death and growth inhibition. Here we describe a cell-based fluorescence resonance energy transfer (FRET) biosensor designed to measure the bioactivity of apoptosis inducing cancer drugs. The biosensor contains cyan fluorescent protein (CFP) linked via caspase 3 and caspase 8 specific cleavage recognition sequences to yellow fluorescent protein (YFP). Upon caspase activation, as in the case of apoptosis induction, the linker is cleaved abolishing the cellular FRET signal. This assay closely reflects the mechanism of action of cancer drugs, in killing cancer cells and therefore can function as a potency test for different cancer drugs. We rigorously demonstrate this through characterization of a class of proteins targeting the death receptors. The one-step assay appears to be superior to other apoptosis-based assays because of its simplicity, convenience, and robustness. C1 [Bozza, William P.; Di, Xu; Rosado, Leslie A. Rivera; Pariser, Sarah; Zhang, Baolin] US FDA, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. [Takeda, Kazuyo] US FDA, Microscopy & Imaging Core Facil, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Pariser, Sarah] Brown Univ, Providence, RI 02912 USA. RP Zhang, BL (reprint author), US FDA, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. EM Baolin.zhang@fda.hhs.gov FU Food and Drug Administration, Center for Drug Evaluation and Research, Critical Path Initiative fund; Food and Drug Administration, Center for Drug Evaluation and Research, Medical Countermeasure Initiative fund FX This work was supported by the Food and Drug Administration, Center for Drug Evaluation and Research, Critical Path Initiative fund; and the Food and Drug Administration, Center for Drug Evaluation and Research, Medical Countermeasure Initiative fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 5 Z9 5 U1 4 U2 18 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 4 PY 2014 VL 9 IS 9 AR e107010 DI 10.1371/journal.pone.0107010 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3XV UT WOS:000341271500107 PM 25188024 ER PT J AU Yang, XX Morris, SM Gearhart, JM Ruark, CD Paule, MG Slikker, W Mattison, DR Vitiello, B Twaddle, NC Doerge, DR Young, JF Fisher, JW AF Yang, Xiaoxia Morris, Suzanne M. Gearhart, Jeffery M. Ruark, Christopher D. Paule, Merle G. Slikker, William, Jr. Mattison, Donald R. Vitiello, Benedetto Twaddle, Nathan C. Doerge, Daniel R. Young, John F. Fisher, Jeffrey W. TI Development of a Physiologically Based Model to Describe the Pharmacokinetics of Methylphenidate in Juvenile and Adult Humans and Nonhuman Primates SO PLOS ONE LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; SINGLE-DOSE PHARMACOKINETICS; DL-THREO-METHYLPHENIDATE; DEFICIT HYPERACTIVITY DISORDER; MASS-SPECTROMETRIC ANALYSIS; ROUTE DEPENDENT DOSIMETRY; RELEASE METHYLPHENIDATE; HEALTHY-SUBJECTS; RITALINIC ACID; RHESUS-MONKEYS AB The widespread usage of methylphenidate (MPH) in the pediatric population has received considerable attention due to its potential effect on child development. For the first time a physiologically based pharmacokinetic (PBPK) model has been developed in juvenile and adult humans and nonhuman primates to quantitatively evaluate species-and age-dependent enantiomer specific pharmacokinetics of MPH and its primary metabolite ritalinic acid. The PBPK model was first calibrated in adult humans using in vitro enzyme kinetic data of MPH enantiomers, together with plasma and urine pharmacokinetic data with MPH in adult humans. Metabolism of MPH in the small intestine was assumed to account for the low oral bioavailability of MPH. Due to lack of information, model development for children and juvenile and adult nonhuman primates primarily relied on intra-and interspecies extrapolation using allometric scaling. The juvenile monkeys appear to metabolize MPH more rapidly than adult monkeys and humans, both adults and children. Model prediction performance is comparable between juvenile monkeys and children, with average root mean squared error values of 4.1 and 2.1, providing scientific basis for interspecies extrapolation of toxicity findings. Model estimated human equivalent doses in children that achieve similar internal dose metrics to those associated with pubertal delays in juvenile monkeys were found to be close to the therapeutic doses of MPH used in pediatric patients. This computational analysis suggests that continued pharmacovigilance assessment is prudent for the safe use of MPH. C1 [Yang, Xiaoxia; Morris, Suzanne M.; Paule, Merle G.; Slikker, William, Jr.; Twaddle, Nathan C.; Doerge, Daniel R.; Young, John F.; Fisher, Jeffrey W.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Gearhart, Jeffery M.; Ruark, Christopher D.] Henry M Jackson Fdn Adv Mil Med, Wright Patterson AFB, OH USA. [Mattison, Donald R.] Risk Sci Int, Ottawa, ON, Canada. [Mattison, Donald R.] Univ Ottawa, Ottawa, ON, Canada. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. RP Yang, XX (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM xiaoxia.yang@fda.hhs.gov OI Ruark, Christopher/0000-0003-1032-5696; Mattison, Donald/0000-0001-5623-0874 FU NCTR/FDA; FDA Commissioner's Program FX This work was supported by NCTR/FDA and the FDA Commissioner's Program. These sponsors had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views presented here do not necessarily reflect the position or opinions of the FDA/NIH nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the views of the FDA/NIH. NR 108 TC 5 Z9 5 U1 1 U2 11 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 3 PY 2014 VL 9 IS 9 AR e106101 DI 10.1371/journal.pone.0106101 PG 30 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3TB UT WOS:000341257700031 PM 25184666 ER PT J AU Marciniak, TA AF Marciniak, Thomas A. TI Cost-Effectiveness of Genotype-Guided and Dual Antiplatelet Therapies SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 US FDA, Silver Spring, MD 20993 USA. RP Marciniak, TA (reprint author), US FDA, Silver Spring, MD 20993 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 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 2 PY 2014 VL 161 IS 5 BP 378 EP 378 DI 10.7326/L14-5017-5 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AO7VT UT WOS:000341561400016 PM 25178576 ER PT J AU Zusterzeel, R Curtis, JP Canos, DA Sanders, WE Selzman, KA Pina, IL Spatz, ES Bao, HK Ponirakis, A Varosy, PD Masoudi, FA Strauss, DG AF Zusterzeel, Robbert Curtis, Jeptha P. Canos, Daniel A. Sanders, William E. Selzman, Kimberly A. Pina, Ileana L. Spatz, Erica S. Bao, Haikun Ponirakis, Angelo Varosy, Paul D. Masoudi, Frederick A. Strauss, David G. TI Sex-Specific Mortality Risk by QRS Morphology and Duration in Patients Receiving CRT Results From the NCDR SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiac resynchronization therapy; men; QRS duration; QRS morphology; women ID CARDIAC-RESYNCHRONIZATION THERAPY; BUNDLE-BRANCH-BLOCK; DEFIBRILLATOR IMPLANTATION TRIAL; RANDOMIZED-CONTROLLED-TRIALS; SYMPTOMATIC HEART-FAILURE; CLINICAL EVENT REDUCTION; MADIT-CRT; PREDICTORS; WOMEN; MEN AB BACKGROUND Prior studies have suggested that women have better outcomes than men after cardiac resynchronization therapy-defibrillator (CRT-D) implantation. OBJECTIVES The purpose of this study was to compare mortality after CRT-D implantation by sex, QRS morphology, and duration. METHODS Survival curves and covariate adjusted hazard ratios (HR) were used to assess mortality by sex in 31,892 CRT-D patients in the National Cardiovascular Data Registry (NCDR), implantable cardioverter defibrillator (ICD) registry between 2006 and 2009, with up to 5 years' follow-up (median 2.9 years, interquartile range: 2.0 to 3.9 years). Patients were grouped by QRS morphology and 10-ms increments in QRS duration. RESULTS Among patients with left bundle branch block (LBBB), women had a 21% lower mortality risk than men (HR: 0.79; 95% CI: 0.74 to 0.84; p < 0.001); however, there was no sex difference in non-LBBB (HR: 0.95; 95% CI: 0.85 to 1.06; p = 0.37). Longer QRS duration was associated with better survival in both sexes with LBBB, but not in patients without LBBB. Compared with women with LBBB and QRS of 120 to 129 ms, women with LBBB and QRS of 140 to 149 ms had a 27% lower mortality (HR: 0.73; 95% CI: 0.60 to 0.88; p = 0.001); this difference was 18% in men (HR: 0.82; 95% CI: 0.71 to 0.93; p = 0.003). Mortality in LBBB and QRS of 150 ms or longer compared with those with LBBB and QRS of 120 to 129 ms was similar between sexes (HR: 0.61 to 0.68; p < 0.001 for women and HR: 0.58 to 0.66; p < 0.001 for men). Sex interactions within 10-ms groups were not significant. CONCLUSIONS Among patients with LBBB who received CRT-D, mortality is lower in women than men. Additionally, longer QRS duration in LBBB is associated with better survival in both sexes. In contrast, there is no sex difference in patients without LBBB, regardless of QRS duration. Further studies should include a non-CRT comparator group to confirm these findings. (C) 2014 by the American College of Cardiology Foundation. C1 [Zusterzeel, Robbert; Canos, Daniel A.; Sanders, William E.; Selzman, Kimberly A.; Pina, Ileana L.; Strauss, David G.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Curtis, Jeptha P.; Spatz, Erica S.; Bao, Haikun] Yale Univ, Sch Med, New Haven, CT USA. [Ponirakis, Angelo] Amer Coll Cardiol Fdn, Washington, DC USA. [Varosy, Paul D.] Univ Colorado, VA Eastern Colorado Hlth Care Syst, Denver, CO 80202 USA. [Varosy, Paul D.] Colorado Cardiovasc Outcomes Res Grp, Denver, CO USA. [Masoudi, Frederick A.] Univ Colorado, Aurora, CO USA. RP Strauss, DG (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave 62-1126, Silver Spring, MD 20993 USA. EM david.strauss@fda.hhs.gov FU FDA Office of Women's Health; Oak Ridge Institute for Science and Education; ACC NCDR; Novartis; GE Healthcare FX This project was conducted under contract between the American College of Cardiology (ACC) and the U. S. Food and Drug Administration (FDA) and was supported by the FDA Office of Women's Health and by a research fellowship from the Oak Ridge Institute for Science and Education through an interagency agreement between the U. S. Department of Energy and the FDA. The ICD Registry is an initiative of the American College of Cardiology Foundation with partnering support from the Heart Rhythm Society. Dr. Masoudi is the Senior Medical Officer and Chair of the Science and Quality Oversight Committee of the National Cardiovascular Data Registry (NCDR). Dr. Curtis has received research and salary support under contract with the ACC NCDR. Dr. Curtis holds equity interest in Medtronic, a maker of cardiac devices. Dr. Pi a has received consulting fees/honoraria from Novartis and GE Healthcare. 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 Department of Health and Human Services. The views expressed in this manuscript represent those of the authors, and do not necessarily represent the official views of the NCDR or its associated professional societies identified at www.ncdr.com. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 33 TC 28 Z9 28 U1 0 U2 4 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 SEP 2 PY 2014 VL 64 IS 9 BP 887 EP 894 DI 10.1016/j.jacc.2014.06.1162 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN8XH UT WOS:000340888600007 PM 25169173 ER PT J AU Luccioli, S Zhang, YT Verrill, L Ramos-Valle, M Kwegyir-Afful, E AF Luccioli, Stefano Zhang, Yuanting Verrill, Linda Ramos-Valle, Moraima Kwegyir-Afful, Ernest TI Infant Feeding Practices and Reported Food Allergies at 6 Years of Age SO PEDIATRICS LA English DT Article DE breastfeeding; children; complementary foods; food allergy; physician diagnosis; prevalence; risk factors ID PROSPECTIVE BIRTH COHORT; ATOPIC DISEASE; COMPLEMENTARY FOODS; UNITED-STATES; CHILDREN; SENSITIZATION; CHILDHOOD; ASTHMA; ECZEMA; RISK AB OBJECTIVE: The goal of this study was to identify the frequency of physician-diagnosed food allergies among 6-year-old US children and study the impact of exclusive breastfeeding and complementary food introduction on this frequency. METHODS: Data were analyzed from children who participated in the Infant Feeding Practices Study II Year 6 Follow-Up Study (Y6FU). Children with probable food allergy (pFA) were defined as children with report of physician-diagnosed food allergy at age 6 years. Subgroups of pFA included children who were not diagnosed before 1 year of age (new pFA) and those with atopic risk factors (high risk). RESULTS: Prevalence of total pFA in the Y6FU was 6.34%. The majority of these children had new pFA and high-risk factors. Higher maternal education, higher family income, family history of food allergy, and reported eczema before 1 year of age were significantly associated with higher odds of total or new pFA. Exclusive breastfeeding duration and timing of complementary food introduction were not significantly associated with total pFA. However, exclusive breastfeeding of >= 4 months compared with no breastfeeding was marginally associated with lower odds of new pFA (adjusted odds ratio: 0.51; P = .07); this effect was not observed with high-risk children. CONCLUSIONS: Analysis of infant and maternal variables in the Y6FU cohort of US children revealed that socioeconomic and atopic factors were the main predictors of pFA at age 6 years. Exclusive breastfeeding of >= 4 months may have a preventive effect on development of pFA after 1 year of age in non high-risk children. C1 [Luccioli, Stefano; Ramos-Valle, Moraima; Kwegyir-Afful, Ernest] Food & Drug Adm, Ctr Food Safety & Appl Nutr, Off Food Addit Safety, College Pk, MD 20740 USA. [Zhang, Yuanting; Verrill, Linda] Food & Drug Adm, Ctr Food Safety & Appl Nutr, Off Analyt & Outreach, College Pk, MD 20740 USA. RP Luccioli, S (reprint author), Food & Drug Adm, Ctr Food Safety & Appl Nutr, Off Food Addit Safety, 5100 Paint Branch Pkwy,HFS 200, College Pk, MD 20740 USA. EM stefano.luccioli@fda.hhs.gov FU US Food and Drug Administration; Centers for Disease Control and Prevention; Office on Women's Health; National Institutes of Health; Maternal and Child Health Bureau in the US Department of Health and Human Services FX This study was funded by the US Food and Drug Administration, Centers for Disease Control and Prevention, Office on Women's Health, National Institutes of Health, and Maternal and Child Health Bureau in the US Department of Health and Human Services. NR 36 TC 12 Z9 12 U1 1 U2 10 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 SEP PY 2014 VL 134 SU 1 BP S21 EP S28 DI 10.1542/peds.2014-0646E PG 8 WC Pediatrics SC Pediatrics GA CO2NF UT WOS:000358992600004 PM 25183751 ER PT J AU Custer, B Sheon, N Siedle-Khan, B Pollack, LM Spencer, BR Bialkowski, W D'Andrea, PA Sullivan, M Glynn, S Williams, A AF Custer, B. Sheon, N. Siedle-Khan, B. Pollack, L. M. Spencer, B. R. Bialkowski, W. D'Andrea, P. A. Sullivan, M. Glynn, S. Williams, A. CA F NHLBI Recipient Epidemiology Don TI Noncompliance with the Men Who Have Sex with Men (MSM) Deferral among Male US Blood Donors SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Custer, B.] Blood Syst Res Inst, San Francisco, CA USA. [Williams, A.] US FDA, Silver Spring, MD USA. [Glynn, S.] NHLBI, Bethesda, MD 20892 USA. [Sullivan, M.] RTI Int, Rockville, MD USA. [D'Andrea, P. A.] Inst Transfus Med, Pittsburgh, PA USA. [Bialkowski, W.] BloodCtr Wisconsin, Milwaukee, WI USA. [Sheon, N.; Siedle-Khan, B.; Pollack, L. M.] USCF, Ctr AIDS Prevent Studies, San Francisco, CA USA. [Spencer, B. R.] ARC, Boston, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 5 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 2014 VL 54 SU 2 SI SI MA S46-030H BP 35A EP 35A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300054 ER PT J AU Menis, M Forshee, R Anderson, SA McKean, S Johnson, C Warnock, R Gondalia, R Mintz, PD Kelman, JA Izurieta, HS AF Menis, M. Forshee, R. Anderson, S. A. McKean, S. Johnson, C. Warnock, R. Gondalia, R. Mintz, P. D. Kelman, J. A. Izurieta, H. S. TI Transfusion-Associated Circulatory Overload (TACO) Among Inpatient US Elderly as Recorded in Medicare Administrative Databases during 2011-2013 SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Menis, M.; Forshee, R.; Anderson, S. A.; Mintz, P. D.; Izurieta, H. S.] US FDA, CBER, Rockville, MD 20857 USA. [Kelman, J. A.] CMS, Baltimore, MD USA. [McKean, S.; Johnson, C.; Warnock, R.; Gondalia, R.] Acumen LLC, Burlingame, CA 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA SP203 BP 137A EP 138A PG 2 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300296 ER PT J AU Menis, M Forshee, R Anderson, SA McKean, S Johnson, C Warnock, R Gondalia, R Mintz, PD Kelman, JA Izurieta, HS AF Menis, M. Forshee, R. Anderson, S. A. McKean, S. Johnson, C. Warnock, R. Gondalia, R. Mintz, P. D. Kelman, J. A. Izurieta, H. S. TI Transfusion-Related Anaphylaxis (TRA) Among the US Elderly, as Recorded in Medicare Administrative Databases during 2012-2013 SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Menis, M.; Forshee, R.; Anderson, S. A.; Mintz, P. D.; Izurieta, H. S.] US FDA, CBER, Rockville, MD 20857 USA. [McKean, S.; Johnson, C.; Warnock, R.; Gondalia, R.] Acumen LLC, Burlingame, CA USA. [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 2014 VL 54 SU 2 SI SI MA SP204 BP 138A EP 138A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300297 ER PT J AU Menis, M Forshee, R Anderson, SA McKean, S Johnson, C Warnock, R Gondalia, R Mintz, PD Kelman, JA Izurieta, HS AF Menis, M. Forshee, R. Anderson, S. A. McKean, S. Johnson, C. Warnock, R. Gondalia, R. Mintz, P. D. Kelman, J. A. Izurieta, H. S. TI Transfusion-Related Serum Reaction (TRSR) Among US Elderly, as Recorded by Large Administrative Databases during 2012-2013 SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Menis, M.; Forshee, R.; Anderson, S. A.; Mintz, P. D.; Izurieta, H. S.] US FDA, CBER, Rockville, MD 20857 USA. [Kelman, J. A.] CMS, Baltimore, MD USA. [McKean, S.; Johnson, C.; Warnock, R.; Gondalia, R.] 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA SP207 BP 139A EP 139A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300300 ER PT J AU Menis, M Forshee, R Anderson, SA McKean, S Johnson, C Warnock, R Gondalia, R Mintz, PD Kelman, JA Izurieta, HS AF Menis, M. Forshee, R. Anderson, S. A. McKean, S. Johnson, C. Warnock, R. Gondalia, R. Mintz, P. D. Kelman, J. A. Izurieta, H. S. TI Acute Infection Following Transfusion (AIFT) among the US Elderly, as Recorded by Large Administrative Databases during 2012-2013 SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Menis, M.; Forshee, R.; Anderson, S. A.; Mintz, P. D.; Izurieta, H. S.] US FDA, CBER, Rockville, MD 20857 USA. [McKean, S.; Johnson, C.; Warnock, R.; Gondalia, R.] Acumen LLC, Burlingame, CA USA. [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 2014 VL 54 SU 2 SI SI MA SP395 BP 214A EP 215A PG 2 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300487 ER PT J AU Choi, SL Loghin, C Garhyan, P Knadler, MP Lam, E Sinha, V Porksen, N Linnebjerg, H AF Choi, S. L. Loghin, C. Garhyan, P. Knadler, M. P. Lam, E. Sinha, V. Porksen, N. Linnebjerg, H. TI A single dose pharmacokinetic study of basal insulin peglispro in subjects with hepatic impairment SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Choi, S. L.; Lam, E.] Eli Lilly NUS Ctr Clin Pharmacol, Singapore, Singapore. [Loghin, C.] Eli Lilly & Co, Clin Pharmacol, Indianapolis, IN 46285 USA. [Garhyan, P.; Knadler, M. P.; Porksen, N.; Linnebjerg, H.] Eli Lilly & Co, US Endocrinol Diabet Care, Indianapolis, IN 46285 USA. [Sinha, V.] Ctr Drug Evaluat & Res, Off Clin Pharmacol, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2014 VL 57 SU 1 MA 957 BP S392 EP S392 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386102220 ER PT J AU Schaubel, DE Zhang, H Kalbfleisch, JD Shu, X AF Schaubel, Douglas E. Zhang, Hui Kalbfleisch, John D. Shu, Xu TI Semiparametric methods for survival analysis of case-control data subject to dependent censoring SO CANADIAN JOURNAL OF STATISTICS-REVUE CANADIENNE DE STATISTIQUE LA English DT Article DE Case-control study; Cox regression; dependent censoring; estimating equation; inverse weighting ID PROPORTIONAL HAZARDS MODELS; CASE-CONTROL FAMILY; CASE-COHORT DESIGN; SAMPLING DESIGNS; LIVER-TRANSPLANTATION; MISSING DATA; MELD SCORE; LIKELIHOOD; TIME; REGRESSION AB Case-control sampling can be an efficient and cost-saving study design, wherein subjects are selected into the study based on the outcome of interest. It was established long ago that proportional hazards regression can be applied to case-control data. However, each of the various estimation techniques available assumes that failure times are independently censored. Since independent censoring is often violated in observational studies, we propose methods for Cox regression analysis of survival data obtained through case-control sampling, but subject to dependent censoring. The proposed methods are based on weighted estimating equations, with separate inverse weights used to account for the case-control sampling and to correct for dependent censoring. The proposed estimators are shown to be consistent and asymptotically normal, and consistent estimators of the asymptotic covariance matrices are derived. Finite-sample properties of the proposed estimators are examined through simulation studies. The methods are illustrated through an analysis of pre-transplant mortality among end-stage liver disease patients obtained from a national organ failure registry. (C) 2014 Statistical Society of Canada C1 [Schaubel, Douglas E.; Kalbfleisch, John D.; Shu, Xu] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Zhang, Hui] US FDA, Silver Spring, MD USA. RP Schaubel, DE (reprint author), Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. EM deschau@umich.edu FU National Institutes of Health [R01 DK070869]; Health Resource and Service Administration, U.S. Department of Health and Human Services FX The authors thank the Associate Editor and Referees for their constructive comments and suggestions, which resulted in a substantially improved manuscript. This work was supported in part by National Institutes of Health Grant R01 DK070869. The authors also thank the Scientific Registry of Transplant Recipients (SRTR) access to the end-stage liver disease data. The SRTR is funded by a contract from the Health Resource and Service Administration, U.S. Department of Health and Human Services. NR 40 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0319-5724 EI 1708-945X J9 CAN J STAT JI Can. J. Stat.-Rev. Can. Stat. PD SEP PY 2014 VL 42 IS 3 BP 365 EP 383 DI 10.1002/cjs.11218 PG 19 WC Statistics & Probability SC Mathematics GA AT2ZR UT WOS:000344804100001 ER PT J AU Meng, FX Li, ZG Yan, J Manjanatha, M Shelton, S Yarborough, S Chen, T AF Meng, Fanxue Li, Zhiguang Yan, Jian Manjanatha, Mugimane Shelton, Sharon Yarborough, Stephanie Chen, Tao TI Tissue-specific microRNA responses in rats treated with mutagenic and carcinogenic doses of aristolochic acid SO MUTAGENESIS LA English DT Article ID RENAL-CELL CARCINOMA; DNA ADDUCT FORMATION; DOWN-REGULATION; MIR-21; CANCER; EXPRESSION; LIVER; EXPOSURE; MIR-34A; KIDNEY AB Aristolochic acid (AA) is an active component in herbal drugs derived from the Aristolochia species. Although these drugs have been used since antiquity, AA is both genotoxic and carcinogenic in animals and humans, resulting in kidney tumours in rats and upper urinary tract tumours in humans. In the present study, we conducted microarray analysis of microRNA (miRNA) expression in tissues from transgenic Big Blue rats that were treated for 12 weeks with 0.1-10 mg/kg AA, using a protocol that previous studies indicate eventually results in kidney tumours and mutations in kidney and liver. Global analysis of miRNA expression of rats treated with 10 mg/kg AA indicated that 19 miRNAs were significantly dysregulated in the kidney, with most of the miRNAs related to carcinogenesis. Only one miRNA, miR-34a (a tumour suppressor), was differentially expressed in the liver. The expression of the two most responsive kidney miRNAs (miR-21, an oncomiR and miR-34a) was further examined in the kidney, liver and testis of rats exposed to 0, 0.1, 1.0 and 10 mg/kg AA. Expression of miR-21 was up-regulated in the kidney only, while miR-34a was dose-dependently up-regulated in both the kidney and liver; the expression of miR-21 and miR-34a was unaltered by the AA treatment in the testis. Analysis of cII mutations in the testis of treated rats also was negative. Our results indicate that AA treatment of rats produced dysregulation of a large number of miRNAs in the tumour target tissue and that the up-regulation of miR-21 correlated with the carcinogenicity of AA while the up-regulation of miR-34a correlated with its mutagenicity. C1 [Meng, Fanxue; Yan, Jian; Manjanatha, Mugimane; Shelton, Sharon; Chen, Tao] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Li, Zhiguang] Dalian Med Univ, Inst Canc Stem Cell, Ctr Canc, Dalian 116044, Liaoning, Peoples R China. [Yarborough, Stephanie] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. RP Chen, T (reprint author), US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM tao.chen@fda.hhs.gov FU Research Participation Program at the National Center for Toxicological Research FX We would like to thank Dr Robert H. Heflich for his editing this manuscript. Views presented in this paper are those of the authors and do not necessarily reflect official positions or policies of the US Food and Drug Administration. Z.L. and S.Y. 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 US Department of Energy and the US Food and Drug Administration. NR 44 TC 4 Z9 5 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 EI 1464-3804 J9 MUTAGENESIS JI Mutagenesis PD SEP PY 2014 VL 29 IS 5 BP 357 EP 365 DI 10.1093/mutage/geu027 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA AT0KC UT WOS:000344624100008 PM 25106556 ER PT J AU Panos, JJ O'Callaghan, JP Miller, DB Ferguson, SA AF Panos, John J. O'Callaghan, James P. Miller, Diane B. Ferguson, Sherry A. TI Effects of developmental methylphenidate (MPH) treatment on monoamine neurochemistry of male and female rats SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Methylphenidate; Rat; Monoamines; Development; Dopamine ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DOPAMINE TRANSPORTER; NEONATAL-RAT; YOUNG-RATS; IN-VIVO; BRAIN; EXPRESSION; STRIATUM; STIMULANTS; PREVALENCE AB Attention Deficit Hyperactivity Disorder (ADHD) is estimated to affect 4-5% of the adult human population (Kessler et al., 2006; Willcutt, 2012). Often prescribed to attenuate ADHD symptoms (Nair and Moss, 2009), methylphenidate hydrochloride (MPH) can have substantial positive effects. However, there is a paucity of literature regarding its use during pregnancy. Thus, adult women with ADHD face a difficult decision when contemplating pregnancy. In this study, pregnant Sprague-Dawley rats were orally treated a total of 0 (water), 6 (low), 18 (medium), or 42 (high) mg MPH/kg body weight/day (divided into three doses) on gestational days 6-21 (i.e., the low dose received 2 mg MPH/kg body weight 3 x/day). Offspring were orally treated with the same daily dose as their dam (divided into two doses) on postnatal days (PNDs) 1-21. One offspring/sex/litter was sacrificed at PND 22 or PND 104 (n = 6-7/age/sex/treatment group) and the striatum was quickly dissected and frozen. High Performance Liquid Chromatography (HPLC) coupled to a Photo Diode Array detector (PDA) was used to analyze monoamine content in the striatum of one side while a sandwich ELISA was used to analyze tyrosine hydroxylase (TH) from the other side. Age significantly affected monoamine and metabolite content as well as turnover ratios (i.e., DA, DOPAC, HVA, DOPAC/DA, HVA/DA, 5-HT and 5-HIAA); however, there were no significant effects of sex. Adult rats of the low MPH group had higher DA levels than control adults (p < 0.05). At both ages, subjects of the low MPH group had higher TH levels than controls (p < 0.05), although neither effect (i.e., higher DA or TH levels) exhibited an apparent dose-response. PND 22 subjects of the high MPH treatment group had higher ratios of HVA/DA and DOPAC/DA than same-age control subjects (p < 0.05). The increased TH levels of the low MPH group may be related to the increased DA levels of adult rats. While developmental MPH treatment appears to have some effects on monoamine system development, further studies are required to determine if these alterations manifest as functional changes in behavior. Published by Elsevier Inc. C1 [Panos, John J.; Ferguson, Sherry A.] US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. [O'Callaghan, James P.; Miller, Diane B.] CDC, NIOSH, Atlanta, GA 30333 USA. RP Ferguson, SA (reprint author), US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Sherry.Ferguson@fda.hhs.gov OI Panos, John/0000-0002-7607-7114; Ferguson, Sherry/0000-0002-5120-0219 FU National Center for Toxicological Research/U.S. Food and Drug Administration [E7318] FX This work was supported by the National Center for Toxicological Research/U.S. Food and Drug Administration [Protocol #E7318 to S.A.F.]. 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. NR 33 TC 0 Z9 0 U1 2 U2 5 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 2014 VL 45 BP 70 EP 74 DI 10.1016/j.ntt.2014.08.001 PG 5 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA AS7HP UT WOS:000344427900007 PM 25132048 ER PT J AU Zhang, LY Manirarora, JN Wei, CH AF Zhang, Linyi Manirarora, Jean N. Wei, Cheng-Hong TI Evaluation of immunosuppressive function of regulatory T cells using a novel in vitro cytotoxicity assay SO CELL AND BIOSCIENCE LA English DT Article DE Regulatory T cells; Immunoregulation; Antigen specific; CD8 T cells; NOD ID NONOBESE DIABETIC MICE; CUTTING EDGE; INTERLEUKIN-2 PRODUCTION; AUTOIMMUNE DESTRUCTION; SUPPRESSIVE CAPACITY; MEDIATED SUPPRESSION; ADOPTIVE TRANSFER; DENDRITIC CELLS; SELF-TOLERANCE; GRANZYME-B AB Naturally occurring regulatory T cells (Tregs) play a pivotal role in the maintenance of self-tolerance due to their intrinsic immunosuppressive activity. Currently, a number of human clinical trials are being conducted to investigate the roles of Tregs in treating various immune-mediated disorders. Traditionally, the suppressive activity of Tregs is measured using either a thymidine incorporation assay, which is a radioactive assay; or CFSE based flow cytometry assay, which requires a relatively large number of cells. Consequently, there is an increasing need to develop novel alternative bioassays that can characterize various aspects of the immunosuppressive function of Tregs in vitro. In this study, using murine clonal CD8(+) T cells specific for an islet antigen as responder T cells, we first established a novel, sensitive and quantitative in vitro luminescence based cell viability assay to measure cytotoxicity. Then we used this assay to measure if Tregs could inhibit the cytotoxicity of CD8 effector T cells. This assay does not involve the use of radioisotopes and only needs relatively low number of Tregs. Since normally Tregs only constitute 5-10% of peripheral CD4(+) T cells, this advantage is noteworthy compared with other methods. With the assay we developed, we demonstrated that regulatory T cells (Tregs) could inhibit the antigen-specific killing of an adherent target cell monolayer by the CD8(+) cytotoxic T cells. We observed more inhibition when Tregs and CD8 killer T cells were incubated during the in vitro activation (stimulation) stage of the cytotoxic T lymphocytes (CTL) than when they were added later at the start of the effector phase. Interestingly, Tregs from B6 mice demonstrated higher suppression of CD8(+) T cell killing than Tregs from NOD mice. Moreover, IL-2/anti-IL-2 mAb complexes induced expansion of Tregs in vivo, as well as enhancing the Treg's suppressive activity per cell. Therefore, this novel non-radioactive, luminescence based cytotoxicity assay mediated by clonal islet antigen-specific CD8 T cells can be used to measure, characterize, and quantitate the immunosuppressive activity of natural Tregs, representing a useful approach to characterize the functions of Tregs in the setting of autoimmune diseases and to elucidate the mechanisms for Treg cell-mediated immunoregulation. C1 [Zhang, Linyi; Manirarora, Jean N.; Wei, Cheng-Hong] US FDA, Ctr Biol Evaluat & Res, Gene Transfer & Immunogen Branch, Div Cellular & Gene Therapies,Off Cellular Tissue, Bethesda, MD 20892 USA. RP Wei, CH (reprint author), US FDA, Ctr Biol Evaluat & Res, Gene Transfer & Immunogen Branch, Div Cellular & Gene Therapies,Off Cellular Tissue, Bethesda, MD 20892 USA. EM chenghong.wei@fda.hhs.gov FU FDA Modernizing Science grant program; Division of Cellular and Gene Therapies FX This work was supported by the FDA Modernizing Science grant program, and the Division of Cellular and Gene Therapies. Jean Manirarora was supported through fellowship administered by the Oak Ridge Institute for Science and Education. The authors would like to thank Drs. Suzanne Epstein and Andrew Byrnes of CBER, FDA for critically reviewing this manuscript. NR 43 TC 1 Z9 1 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD SEP 1 PY 2014 VL 4 AR 51 DI 10.1186/2045-3701-4-51 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AR8HW UT WOS:000343817200001 PM 25908962 ER PT J AU Kasza, KA Hyland, AJ Bansal-Travers, M Vogl, LM Chen, JP Evans, SE Fong, GT Cummings, KM O'Connor, RJ AF Kasza, Karin A. Hyland, Andrew J. Bansal-Travers, Maansi Vogl, Lisa M. Chen, Jiping Evans, Sarah E. Fong, Geoffrey T. Cummings, Kenneth Michael O'Connor, Richard J. TI Switching Between Menthol and Nonmenthol Cigarettes: Findings From the US Cohort of the International Tobacco Control Four Country Survey SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID UNITED-STATES; AFRICAN-AMERICAN; SMOKING-CESSATION; 1ST CIGARETTE; SMOKERS; DEPENDENCE; BUPROPION; PATTERNS; FOCUS; TIME AB Introduction: This article examines trends in switching between menthol and nonmenthol cigarettes, smoker characteristics associated with switching, and associations among switching, indicators of nicotine dependence, and quitting activity. Methods: Participants were 5,932 U. S. adult smokers who were interviewed annually as part of the International Tobacco Control Four Country Survey between 2002 and 2011. Generalized estimating equations (GEEs) were used to examine the prevalence of menthol cigarette use and switching between menthol and nonmenthol cigarettes (among 3,118 smokers who participated in at least 2 consecutive surveys). We also evaluated characteristics associated with menthol cigarette use and associations among switching, indicators of nicotine dependence, and quitting activity using GEEs. Results: Across the entire study period, 27% of smokers smoked menthol cigarettes; prevalence was highest among Blacks (79%), young adults (36%), and females (30%). Prevalence of switching between menthol and nonmenthol cigarettes was low (3% switched to menthol and 8% switched to nonmenthol), and switchers tended to revert back to their previous type. Switching types was not associated with indicators of nicotine dependence or quit attempts. However, those who switched cigarette brands within cigarette types were more likely to attempt to quit smoking. Conclusions: While overall switching rates were low, the percentage who switched from menthol to nonmenthol was significantly higher than the percentage who switched from nonmenthol to menthol. An asymmetry was seen in patterns of switching such that reverting back to menthol was more common than reverting back to nonmenthol, particularly among Black smokers. C1 [Kasza, Karin A.] Roswell Pk Canc Inst, Div Canc Prevent & Populat Sci, Buffalo, NY 14263 USA. [Hyland, Andrew J.; Bansal-Travers, Maansi; Vogl, Lisa M.; O'Connor, Richard J.] Roswell Pk Canc Inst, Dept Hlth Behav, Buffalo, NY 14263 USA. [Chen, Jiping; Evans, Sarah E.] US FDA, Ctr Tobacco Prod, Silver Spring, MD USA. [Fong, Geoffrey T.] Univ Waterloo, Dept Psychol, Waterloo, ON N2L 3G1, Canada. [Fong, Geoffrey T.] Ontario Inst Canc Res, Toronto, ON, Canada. [Cummings, Kenneth Michael] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. RP Kasza, KA (reprint author), Roswell Pk Canc Inst, Div Canc Prevent & Populat Sci, Buffalo, NY 14263 USA. EM karin.kasza@roswellpark.org RI O'Connor, Richard/A-6961-2009 FU Federal funds from the National Institute on Drug Abuse, National Institutes of Health; U.S. Food and Drug Administration, Department of Health and Human Services [HHSN271201100027C]; US National Cancer Institute [P50 CA111326, P01 CA138389, R01 CA100362, R01 CA125116]; Canadian Institutes of Health Research [57897, 79551, 115016]; National Health and Medical Research Council of Australia [265903, 450110, 1005922]; Cancer Research UK [C312/A3726, C312/A6465, C312/A11039]; Robert Wood Johnson Foundation [045734]; Canadian Tobacco Control Research Initiative [014578]; Ontario Institute for Cancer Research; Canadian Cancer Society Research Institute FX The preparation of this article was supported by Federal funds from the National Institute on Drug Abuse, National Institutes of Health, and the U.S. Food and Drug Administration, Department of Health and Human Services, under Contract No. HHSN271201100027C. The ITC Four Country Survey was funded by the US National Cancer Institute (P50 CA111326, P01 CA138389, R01 CA100362, and R01 CA125116), Canadian Institutes of Health Research (57897, 79551, and 115016), National Health and Medical Research Council of Australia (265903, 450110, and 1005922), Cancer Research UK (C312/A3726, C312/A6465, and C312/A11039), Robert Wood Johnson Foundation (045734), and Canadian Tobacco Control Research Initiative (014578). GTF was supported by a Senior Investigator Award from the Ontario Institute for Cancer Research and a Prevention Scientist Award from the Canadian Cancer Society Research Institute. NR 38 TC 5 Z9 5 U1 1 U2 1 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 SEP PY 2014 VL 16 IS 9 BP 1255 EP 1265 DI 10.1093/ntr/ntu098 PG 11 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA AR6CQ UT WOS:000343671100013 PM 24984878 ER PT J AU Roudier, B Davit, BM Beyssac, E Cardot, JM AF Roudier, B. Davit, B. M. Beyssac, E. Cardot, J-M. TI In Vitro- In Vivo Correlation's Dissolution Limits Setting SO PHARMACEUTICAL RESEARCH LA English DT Article DE in vitro in vivo correlation (IVIVC); dissolution limits; biowaiver; prediction; predictability ID CORRELATION IVIVC; FORMULATION; SPECIFICATIONS; PRODUCT; LEVEL AB In vitro in vivo correlation (IVIVC) is a biopharmaceutical tool recommended for use in formulation development. When validated, IVIVC can be used to set dissolution limits and, based on the dissolution limits, as a surrogate for an in vivo study. The purpose of this paper is to study the various methods used to fix dissolution limits. Fixing dissolution limits is not a straightforward process; various approaches exist. The classical +/- 10% of dissolution limits was compared to the recommended +/- 10% of Cmax and AUC and to an innovative back calculation of the 90% CI. Based on simulated values the influence of the calculation method as well as of the variability of the results and pharmacokinetic processes was investigated. Depending upon the method, the results are different and their comparison leads to possible rules. It appears that the usage of a back calculation of a 90% CI is an accurate and advantageous method when intra-individual variability associated with the drug is low. Those findings are in accordance with the current practice of IVIVC, which is not recommended for highly variable drugs. The approach of using a 90% CI allows the intra-subject variability to be taken into account and fixes limits that ensure a greater chance to show acceptable BE, in case of reasonable intra-subject variability, leading to setting broader in vitro dissolution limits compared to classical solutions. C1 [Roudier, B.] ESIEE Cites Descartes, F-93162 Noisy Le Grand, France. [Davit, B. M.] US FDA, Off Gener Drugs, Rockville, MD 20855 USA. [Roudier, B.; Beyssac, E.; Cardot, J-M.] Auvergne Univ, UFR Pharm, Dept Biopharmaceut, EA4678, F-63001 Clermont Ferrand, France. RP Cardot, JM (reprint author), Auvergne Univ, UFR Pharm, Dept Biopharmaceut, EA4678, 28 Pl H Dunant,BP 38, F-63001 Clermont Ferrand, France. EM roudierb@esiee.fr; barbara.davit@merck.com; j-michel.cardot@udamail.fr NR 34 TC 4 Z9 4 U1 1 U2 7 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 SEP PY 2014 VL 31 IS 9 BP 2529 EP 2538 DI 10.1007/s11095-014-1349-8 PG 10 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA AQ9AY UT WOS:000343133900025 PM 24676770 ER PT J AU Southworth, MR Stockbridge, N AF Southworth, Mary Ross Stockbridge, Norman TI Just Say No? SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Editorial Material C1 [Southworth, Mary Ross; Stockbridge, Norman] FDA CDER, Div Cardiovasc & Renal Prod, Silver Spring, MD 20993 USA. RP Stockbridge, N (reprint author), FDA CDER, 10903 New Hampshire Ave,Bldg 22,Room 4166, Silver Spring, MD 20993 USA. EM norman.stockbridge@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD SEP PY 2014 VL 48 IS 5 BP 552 EP 553 DI 10.1177/2168479014528340 PG 2 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA AQ7JE UT WOS:000342988200006 ER PT J AU Woodcock, J Khan, MA AF Woodcock, Janet Khan, Mansoor A. TI FDA Analysis of Atorvastatin Products Refutes Report of Methyl Ester Impurities SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Editorial Material C1 [Woodcock, Janet; Khan, Mansoor A.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. RP Khan, MA (reprint author), US FDA, 10903 New Hampshire Ave,WO Campus,64-1070, Silver Spring, MD 20903 USA. EM mansoor.khan@fda.hhs.gov NR 3 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 2014 VL 48 IS 5 BP 554 EP 556 DI 10.1177/2168479014536567 PG 3 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA AQ7JE UT WOS:000342988200007 ER PT J AU Shen, MY Tsong, Y Dong, XY AF Shen, Meiyu Tsong, Yi Dong, Xiaoyu TI Statistical Properties of Large Sample Tests for Dose Content Uniformity SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE uniformity of dosage units; dose content uniformity; large sample sizes; tolerance interval; operating characteristic curve; acceptance probability ID QUALITY-ASSURANCE TEST AB The European Union (EU) test for uniformity of dosage units using large sample sizes was published in European Pharmacopoeia 7.7 in 2012. There are 2 alternative tests. Option 1 is a parametric two-sided tolerance interval-based method modified with an indifference zone and counting units outside of (0.75 M, 1.25 M) (here, M is defined by sample mean, (X) over bar, as M = 98.5% if (X) over bar < 98.5%, M = 101.5% if <(X)over bar> > 101.5%, and M = (X) over bar otherwise). Option 2 is a nonparametric counting method with an additional indifference-zone concept. The authors extended the parametric two one-sided tolerance interval-based method that was proposed for dose content uniformity testing based on 30 tablets to large sample sizes with the restriction that all operating characteristic curves of the two one-sided tolerance intervals for any given sample size intersect with the operating characteristic curve of the US Pharmacopoeia harmonized method for a sample size of 30 at the acceptance probability of 90% when the individual tablets with on-target mean are assumed to be normally distributed. This paper studies the acceptance probabilities in relation to the batch mean and batch standard deviation among the 2 EU options and the authors' proposed method. The acceptance probabilities of EU options 1 and 2 and the proposed method were compared using simulation; results revealed that both EU options 1 and 2 produce larger acceptance probabilities when the batch mean is off-target. Furthermore, for a given standard deviation, the acceptance probability of EU option 2 at a mean 102% of the label claim is larger than that at a mean of 100% of the label claim under the normality assumption. C1 [Shen, Meiyu; Tsong, Yi; Dong, Xiaoyu] US FDA, Div Biometr 4, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Shen, MY (reprint author), US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM meiyu.shen@fda.hhs.gov NR 7 TC 2 Z9 2 U1 0 U2 0 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 2014 VL 48 IS 5 BP 613 EP 622 DI 10.1177/2168479014524961 PG 10 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA AQ7JE UT WOS:000342988200014 ER PT J AU Pearsall, BM Araojo, R AF Pearsall, Bryon M. Araojo, Richardae TI FDA Studies New Strategies for Presentation of Patient Information SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Letter C1 [Pearsall, Bryon M.; Araojo, Richardae] US FDA, Silver Spring, MD 20993 USA. RP Pearsall, BM (reprint author), US FDA, 10903 New Hampshire Ave,WO51 RM6352 Silver Spring, Silver Spring, MD 20993 USA. EM Bryon.Pearsall@fda.hhs.gov NR 10 TC 0 Z9 0 U1 1 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 2014 VL 48 IS 5 BP NP3 EP NP4 DI 10.1177/2168479013488881 PG 2 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA AQ7JE UT WOS:000342988200001 ER PT J AU Delclos, KB Doerge, DR AF Delclos, K. Barry Doerge, Daniel R. TI Invalid Controls Undermine Conclusions of FDA Studies Response SO TOXICOLOGICAL SCIENCES LA English DT Letter C1 [Delclos, K. Barry; Doerge, Daniel R.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Delclos, KB (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM barry.delclos@fda.hhs.gov NR 3 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2014 VL 141 IS 1 BP 2 EP 3 DI 10.1093/toxsci/kfu102 PG 2 WC Toxicology SC Toxicology GA AQ7JP UT WOS:000342990200005 ER PT J AU Oakley, MS Sahu, BR Lotspeich-Cole, L Majam, V Pham, PT Banerjee, AS Kozakai, Y Morris, SL Kumar, S AF Oakley, Miranda S. Sahu, Bikash R. Lotspeich-Cole, Leda Majam, Victoria Phuong Thao Pham Banerjee, Aditi Sengupta Kozakai, Yukiko Morris, Sheldon L. Kumar, Sanjai TI T-bet modulates the antibody response and immune protection during murine malaria SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE IgG1; Immunity; Plasmodium yoelii; T-bet ID BLOOD-STAGE MALARIA; PLASMODIUM-CHABAUDI; B-CELLS; MICE; INFECTION; VACCINE; EXPRESSION; YOELII; MOUSE AB CD4(+) T-cell subtypes govern the synthesis of different Ab isotypes and other immune functions. The influence of CD4(+) T-cell differentiation programs on isotype switching and other aspects of host immunological networks during malaria infection are currently poorly understood. Here, we used Tbx21(-/-) mice deficient for T-bet, a regulator of Th1 CD4(+) T-cell differentiation, to examine the effect of Th1 CD4(+) T cells on the immune protection to nonlethal murine malaria Plasmodium yoelii 17XNL. We found that Tbx21(-/-) mice exhibited significantly lower parasite burden that correlated with elevated levels of IgG1, indicating that T-bet-dependent Ab isotype switching may be responsible for lower parasite burden. Absence of T-bet was also associated with a transient but significant loss of T cells during the infection, suggesting that T-bet may suppress malaria-induced apoptosis or induce proliferation of T cells. However, Tbx21(-/-) mice produced greater numbers of Foxp3(+)CD25(+) regulatory CD4(+) T cells, which may contribute to the early contraction of T cells. Lastly, Tbx21(-/-) mice exhibited unimpaired production of IFN-gamma by a diverse repertoire of immune cell subsets and a selective expansion of IFN-gamma-producing T cells. These observations may have implications in malaria vaccine design. C1 [Oakley, Miranda S.; Lotspeich-Cole, Leda; Banerjee, Aditi Sengupta; Morris, Sheldon L.] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Sahu, Bikash R.; Majam, Victoria; Phuong Thao Pham; Kozakai, Yukiko; Kumar, Sanjai] US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Oakley, MS (reprint author), US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, 29 Lincoln Dr, Bethesda, MD 20892 USA. EM miranda.oakley@fda.hhs.gov FU Food and Drug Administration FX These studies were supported by intramural research funds provided by the Food and Drug Administration. We thank the veterinary staff at the Center for Biologics Evaluation and Research for the care and maintenance of mice. NR 28 TC 4 Z9 4 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD SEP PY 2014 VL 44 IS 9 BP 2680 EP 2691 DI 10.1002/eji.201344437 PG 12 WC Immunology SC Immunology GA AQ5BV UT WOS:000342818900016 PM 25047384 ER PT J AU Slikker, W AF Slikker, William, Jr. TI Of human-on-a-chip and humans: Considerations for creating and using microphysiological systems SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Editorial Material C1 US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Slikker, W (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM wslikker@nctr.fda.gov NR 0 TC 3 Z9 3 U1 4 U2 11 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1535-3702 EI 1535-3699 J9 EXP BIOL MED JI Exp. Biol. Med. PD SEP PY 2014 VL 239 IS 9 BP 1078 EP 1079 DI 10.1177/1535370214537754 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AQ4MV UT WOS:000342773100003 PM 25005165 ER PT J AU Sharfstein, JM AF Sharfstein, Joshua M. TI Speaking With Doctors in Restaurants SO MILBANK QUARTERLY LA English DT Editorial Material C1 [Sharfstein, Joshua M.] Maryland Dept Hlth & Mental Hyg, Baltimore, MD 21201 USA. [Sharfstein, Joshua M.] US FDA, Baltimore, MD USA. RP Sharfstein, JM (reprint author), Maryland Dept Hlth & Mental Hyg, 201 West Preston St,Ste 500, Baltimore, MD 21201 USA. EM jsharfstein@dhmh.state.md.us NR 1 TC 0 Z9 0 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-378X EI 1468-0009 J9 MILBANK Q JI Milbank Q. PD SEP PY 2014 VL 92 IS 3 BP 422 EP 425 DI 10.1111/1468-0009.12067 PG 4 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AQ4HS UT WOS:000342755200004 PM 25199889 ER PT J AU Munro, SA Lund, SP Pine, PS Binder, H Clevert, DA Conesa, A Dopazo, J Fasold, M Hochreiter, S Hong, HX Jafari, N Kreil, DP Labaj, PP Li, S Liao, Y Lin, SM Meehan, J Mason, CE Santoyo-Lopez, J Setterquist, RA Shi, LM Shi, W Smyth, GK Stralis-Pavese, N Su, ZQ Tong, WD Wang, C Wang, J Xu, J Ye, Z Yang, Y Yu, Y Salit, M AF Munro, Sarah A. Lund, Steven P. Pine, P. Scott Binder, Hans Clevert, Djork-Arne Conesa, Ana Dopazo, Joaquin Fasold, Mario Hochreiter, Sepp Hong, Huixiao Jafari, Nadereh Kreil, David P. Labaj, Pawel P. Li, Sheng Liao, Yang Lin, Simon M. Meehan, Joseph Mason, Christopher E. Santoyo-Lopez, Javier Setterquist, Robert A. Shi, Leming Shi, Wei Smyth, Gordon K. Stralis-Pavese, Nancy Su, Zhenqiang Tong, Weida Wang, Charles Wang, Jian Xu, Joshua Ye, Zhan Yang, Yong Yu, Ying Salit, Marc TI Assessing technical performance in differential gene expression experiments with external spike-in RNA control ratio mixtures SO NATURE COMMUNICATIONS LA English DT Article ID MICROARRAY EXPERIMENTS; QUALITY-CONTROL; SEQ EXPERIMENTS; REPRODUCIBILITY; BIOCONDUCTOR; CONSORTIUM; STANDARDS; ACCURACY; SAMPLES AB There is a critical need for standard approaches to assess, report and compare the technical performance of genome-scale differential gene expression experiments. Here we assess technical performance with a proposed standard 'dashboard' of metrics derived from analysis of external spike-in RNA control ratio mixtures. These control ratio mixtures with defined abundance ratios enable assessment of diagnostic performance of differentially expressed transcript lists, limit of detection of ratio (LODR) estimates and expression ratio variability and measurement bias. The performance metrics suite is applicable to analysis of a typical experiment, and here we also apply these metrics to evaluate technical performance among laboratories. An interlaboratory study using identical samples shared among 12 laboratories with three different measurement processes demonstrates generally consistent diagnostic power across 11 laboratories. Ratio measurement variability and bias are also comparable among laboratories for the same measurement process. We observe different biases for measurement processes using different mRNA-enrichment protocols. C1 [Munro, Sarah A.; Lund, Steven P.; Pine, P. Scott; Salit, Marc] NIST, Gaithersburg, MD 20899 USA. [Munro, Sarah A.; Pine, P. Scott; Salit, Marc] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Binder, Hans] Univ Leipzig, Interdisciplinary Ctr Bioinformat, D-04107 Leipzig, Germany. [Clevert, Djork-Arne; Hochreiter, Sepp] Johannes Kepler Univ Linz, Inst Bioinformat, A-4040 Linz, Austria. [Conesa, Ana; Dopazo, Joaquin] Principe Felipe Res Ctr, Computat Genom Program, Valencia 46012, Spain. [Dopazo, Joaquin; Santoyo-Lopez, Javier] CIBERER, Valencia, Spain. [Dopazo, Joaquin; Santoyo-Lopez, Javier] INB, Funct Genom Node, Valencia, Spain. [Fasold, Mario] ecSeq Bioinformat, D-04275 Leipzig, Germany. [Hong, Huixiao; Meehan, Joseph; Su, Zhenqiang; Tong, Weida; Xu, Joshua] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Jafari, Nadereh] Northwestern Univ, Feinberg Sch Med, Genom Core Facil, Chicago, IL 60611 USA. [Kreil, David P.; Labaj, Pawel P.; Stralis-Pavese, Nancy] Boku Univ Vienna, Chair Bioinformat, A-1190 Vienna, Austria. [Kreil, David P.] Univ Warwick, Coventry CV4 7AL, W Midlands, England. [Li, Sheng; Mason, Christopher E.] Weill Cornell Med Coll, Inst Computat Biomed, Dept Physiol & Biophys, New York, NY 10021 USA. [Liao, Yang; Shi, Wei; Smyth, Gordon K.] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia. [Liao, Yang] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia. [Lin, Simon M.] Nationwide Childrens Hosp, Columbus, OH 43205 USA. [Santoyo-Lopez, Javier] Med Genome Project, Genom & Bioinformat Platform Andalusia, Seville 41092, Spain. [Setterquist, Robert A.] Thermo Fisher Sci Res & Dev, Austin, TX 78744 USA. [Shi, Leming; Yu, Ying] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 201203, Peoples R China. [Shi, Leming; Yu, Ying] Fudan Univ, Sch Life Sci, MOE Key Lab Contemporary Anthropol, Shanghai 201203, Peoples R China. [Shi, Leming; Yu, Ying] Fudan Univ, Sch Pharm, State Key Lab Genet Engn, Shanghai 201203, Peoples R China. [Shi, Leming; Yu, Ying] Fudan Univ, Sch Pharm, MOE Key Lab Contemporary Anthropol, Shanghai 201203, Peoples R China. [Shi, Wei] Univ Melbourne, Dept Comp & Informat Syst, Parkville, Vic 3010, Australia. [Smyth, Gordon K.] Univ Melbourne, Dept Math & Stat, Parkville, Vic 3010, Australia. [Wang, Charles] Loma Linda Univ, Sch Med, Ctr Genom, Div Microbiol & Mol Genet, Loma Linda, CA 92350 USA. [Wang, Jian; Yang, Yong] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA. [Ye, Zhan] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI 54449 USA. RP Munro, SA (reprint author), NIST, 100 Bur Dr, Gaithersburg, MD 20899 USA. EM smunro@nist.gov; salit@nist.gov RI Labaj, Pawel/N-5425-2014; Dopazo, Joaquin/A-9270-2014; Smyth, Gordon/B-5276-2008; Kreil, D/O-1783-2013 OI Dopazo, Joaquin/0000-0003-3318-120X; Smyth, Gordon/0000-0001-9221-2892; Hochreiter, Sepp/0000-0001-7449-2528; Kreil, D/0000-0001-7538-2056 FU Vienna Scientific Cluster (VSC); Vienna Science and Technology Fund (WWTF); Baxter AG; Austrian Research Centres (ARC) Seibersdorf; Austrian Centre of Biopharmaceutical Technology (ACBT); Spanish Ministry of Economy and Competitiveness (MINECO) [BIO2011-27069]; China's National Supercomputing Center in Guangzhou FX We thank David L. Duewer and Jerod Parsons for review of the manuscript, Cecelie Boysen for discussion of results and all other members of the SEQC consortium who supported this work. P.P.L., N.S.-P. and D.P.K. acknowledge the support from the Vienna Scientific Cluster (VSC),the Vienna Science and Technology Fund (WWTF), Baxter AG, Austrian Research Centres (ARC) Seibersdorf and the Austrian Centre of Biopharmaceutical Technology (ACBT). J.D. was supported by grant BIO2011-27069 from the Spanish Ministry of Economy and Competitiveness (MINECO). L.S. and Y.Yu acknowledge support from China's National Supercomputing Center in Guangzhou. NR 41 TC 20 Z9 21 U1 3 U2 29 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 SEP PY 2014 VL 5 AR 5125 DI 10.1038/ncomms6125 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ7WS UT WOS:000343030500001 PM 25254650 ER PT J AU Li, H Johnson, T AF Li, Heng Johnson, Terri TI Wilcoxon's signed-rank statistic: what null hypothesis and why it matters SO PHARMACEUTICAL STATISTICS LA English DT Article DE matched-pairs design; one-sample t-test; sign test; pedagogy ID T-TEST; TESTS; EFFICIENCY; SYMMETRY; POWER AB In statistical literature, the term 'signed-rank test' (or 'Wilcoxon signed-rank test') has been used to refer to two distinct tests: a test for symmetry of distribution and a test for the median of a symmetric distribution, sharing a common test statistic. To avoid potential ambiguity, we propose to refer to those two tests by different names, as 'test for symmetry based on signed-rank statistic' and 'test for median based on signed-rank statistic', respectively. The utility of such terminological differentiation should become evident through our discussion of how those tests connect and contrast with sign test and one-sample t-test. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Li, Heng; Johnson, Terri] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Johnson, T (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM terri.johnson@fda.hhs.gov NR 28 TC 0 Z9 1 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1539-1604 EI 1539-1612 J9 PHARM STAT JI Pharm. Stat. PD SEP-OCT PY 2014 VL 13 IS 5 BP 281 EP 285 DI 10.1002/pst.1628 PG 5 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA AQ4MW UT WOS:000342773200002 PM 24943680 ER PT J AU Hao, K Di Narzo, A Chen, J Dudley, J Horowitz, N Schadt, E Lambertini, L Landrigan, P Aagaard, K Hobbs, C Varner, M Dole, N Culhane, J Swanson, J Thiex, N Murray, J Moye, J Kasten, C Stodgell, C Miller, R AF Hao, Ke Di Narzo, Antonio Chen, Jia Dudley, Joel Horowitz, Nina Schadt, Eric Lambertini, Luca Landrigan, Philip Aagaard, Kjersti Hobbs, Charlotte Varner, Michael Dole, Nancy Culhane, Jennifer Swanson, James Thiex, Natalie Murray, Jeffrey Moye, John Kasten, Carol Stodgell, Christopher Miller, Richard TI EXPRESSION QUANTITATIVE TRAIT LOCI IN PLACENTA TISSUES FROM THE NATIONAL CHILDREN'S STUDY REVEAL DEVELOPMENTAL ORIGINS OF HUMAN COMPLEX DISEASES SO PLACENTA LA English DT Meeting Abstract CT International-Federation-of-Placenta-Associations (IFPA)/EPG Meeting CY SEP 09-12, 2014 CL Paris, FRANCE SP Int Federat Placenta Assoc, EPG C1 [Hao, Ke; Di Narzo, Antonio; Chen, Jia; Dudley, Joel; Horowitz, Nina; Schadt, Eric; Lambertini, Luca; Landrigan, Philip] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Aagaard, Kjersti] Baylor Coll Med, Houston, TX 77030 USA. [Hobbs, Charlotte] Univ Arkansas, Coll Med, Little Rock, AR 72205 USA. [Varner, Michael] Univ Utah, Salt Lake City, UT USA. [Dole, Nancy] Univ N Carolina, Chapel Hill, NC USA. [Culhane, Jennifer] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Swanson, James] Univ Calif Irvine, Irvine, CA USA. [Thiex, Natalie] S Dakota State Univ, Brookings, SD 57007 USA. [Murray, Jeffrey] Univ Iowa, Iowa City, IA USA. [Moye, John] NIH, Natl Childrens Study, Bethesda, MD 20892 USA. [Kasten, Carol] US FDA, Silver Spring, MD USA. [Stodgell, Christopher; Miller, Richard] Univ Rochester, Sch Med & Dent, Rochester, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD SEP PY 2014 VL 35 IS 9 MA P1.125 BP A49 EP A49 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA AQ6ZC UT WOS:000342961400174 ER PT J AU Miller, RK Stodgell, CJ Katzman, P Friedman, A Friedman, M Ruffolo, L Penmetsa, A Salamone, L Salafia, C Chen, J Schadt, EE Hao, K Littman, L Landrigan, P Walker, C Darrah, T Li, A Dassayake, PS Szabo, S Aagaard, K Hobbs, C Clark, EB Varner, M Dole, N Culhane, J Swanson, J Thiex, N Murray, J Busch, T Misra, D Durkin, M Moyle, J Kasten, C O'Brien, B AF Miller, Richard K. Stodgell, Christopher J. Katzman, Philip Friedman, Alan Friedman, Michelle Ruffolo, Louis Penmetsa, Amulya Salamone, Linda Salafia, Carolyn Chen, Jia Schadt, Eric E. Hao, Ke Littman, Lisa Landrigan, Philip Walker, Cheryl Darrah, Thomas Li, An Dassayake, Priyanthi S. Szabo, Sarah Aagaard, Kjersti Hobbs, Charlotte Clark, Edward B. Varner, Michael Dole, Nancy Culhane, Jennifer Swanson, James Thiex, Natalie Murray, Jeffrey Busch, Tamara Misra, Dawn Durkin, Maureen Moyle, John Kasten, Carol O'Brien, Barbara TI HUMAN PLACENTAL STUDY OF GENETICS/GENOMIC, ENVIRONMENTAL CONTAMINANT AND MORPHOLOGY ASSESSMENTS FROM 12 US COUNTIES - METHODS AND RESULTS FROM THE US NATIONAL CHILDREN'S STUDY (NCS) SO PLACENTA LA English DT Meeting Abstract CT International-Federation-of-Placenta-Associations (IFPA)/EPG Meeting CY SEP 09-12, 2014 CL Paris, FRANCE SP Int Federat Placenta Assoc, EPG C1 [Miller, Richard K.; Stodgell, Christopher J.; Katzman, Philip; Friedman, Alan; Friedman, Michelle; Ruffolo, Louis; Penmetsa, Amulya; Salamone, Linda] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Salafia, Carolyn] Placenta Analyt LLP, Larchmont, NY USA. [Chen, Jia; Schadt, Eric E.; Hao, Ke; Littman, Lisa; Landrigan, Philip] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Walker, Cheryl] Univ Calif Davis, Davis, CA 95616 USA. [Darrah, Thomas] Ohio State Univ, Columbus, OH 43210 USA. [Li, An; Dassayake, Priyanthi S.] Univ Illinois, Chicago, IL USA. [Szabo, Sarah] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Aagaard, Kjersti] Baylor Coll Med, Houston, TX 77030 USA. [Hobbs, Charlotte] Univ Arkansas, Little Rock, AR 72204 USA. [Clark, Edward B.; Varner, Michael] Univ Utah, Salt Lake City, UT USA. [Dole, Nancy] Univ N Carolina, Chapel Hill, NC USA. [Culhane, Jennifer] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Swanson, James] Univ Calif Irvine, Irvine, CA USA. [Thiex, Natalie; Murray, Jeffrey] S Dakota State Univ, Brookings, SD 57007 USA. [Busch, Tamara] Univ Iowa, Iowa City, IA USA. [Misra, Dawn] Wayne State Univ, Detroit, MI USA. [Durkin, Maureen] Maureen Durkin, Madison, WI USA. [Moyle, John] NIH, Natl Childrens Study, Bethesda, MD 20892 USA. [Kasten, Carol] US FDA, Silver Spring, MD USA. [O'Brien, Barbara] Westat Corp, Rockville, MD USA. RI Durkin, Maureen/B-7834-2015; Darrah, Tom/I-2253-2016 NR 0 TC 1 Z9 1 U1 0 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD SEP PY 2014 VL 35 IS 9 MA KEY1 BP A2 EP A2 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA AQ6ZC UT WOS:000342961400020 ER PT J AU Stodgell, CJ Miller, RK Salamone, L Murray, J Chen, J Lambertini, L Schadt, E Littman, L Landrigan, P Aagaard, K Hobbs, C Clark, EB Varner, M Dole, N Culhane, J Swanson, J Thiex, N Busch, T Kasten, C Moye, J AF Stodgell, Christopher J. Miller, Richard K. Salamone, Linda Murray, Jeffrey Chen, Jia Lambertini, Luca Schadt, Eric Littman, Lisa Landrigan, Philip Aagaard, Kjersti Hobbs, Charlotte Clark, Edward B. Varner, Michael Dole, Nancy Culhane, Jennifer Swanson, James Thiex, Natalie Busch, Tamara Kasten, Carol Moye, John TI LACK OF CORRELATION BETWEEN PLACENTAL GENE EXPRESSION AND RNA INTEGRITY NUMBER (RIN) OR TIME TO COLLECTION SO PLACENTA LA English DT Meeting Abstract CT International-Federation-of-Placenta-Associations (IFPA)/EPG Meeting CY SEP 09-12, 2014 CL Paris, FRANCE SP Int Federat Placenta Assoc, EPG C1 [Stodgell, Christopher J.; Miller, Richard K.; Salamone, Linda] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Murray, Jeffrey; Busch, Tamara] Univ Iowa, Sch Med, Iowa City, IA 52242 USA. [Chen, Jia; Lambertini, Luca; Schadt, Eric; Littman, Lisa; Landrigan, Philip] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Aagaard, Kjersti] Baylor Coll Med, Houston, TX 77030 USA. [Hobbs, Charlotte] Univ Arkansas, Coll Med, Little Rock, AR 72205 USA. [Clark, Edward B.; Varner, Michael] Univ Utah, Sch Med, Salt Lake City, UT USA. [Dole, Nancy] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Culhane, Jennifer] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Swanson, James] Univ Calif Irvine, Sch Med, Irvine, CA 92717 USA. [Thiex, Natalie] S Dakota State Univ, Brookings, SD 57007 USA. [Kasten, Carol] US FDA, Silver Spring, MD USA. [Moye, John] NIH, Natl Childrens Study, Bethesda, MD 20892 USA. OI Stodgell, Christopher/0000-0002-1666-5299 NR 0 TC 1 Z9 1 U1 0 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD SEP PY 2014 VL 35 IS 9 MA P1.116 BP A46 EP A47 PG 2 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA AQ6ZC UT WOS:000342961400165 ER PT J AU Hunasikatti, M AF Hunasikatti, Mahadevappa TI Usefulness of Elbow Sign for Screening OSA Only SO CHEST LA English DT Letter C1 Inova Fairfax Hosp, Dept Pulm Med Crit Care Med & Sleep Med, Div Internal Med, Fairfax, VA 22031 USA. US FDA, Fairfax, VA USA. RP Hunasikatti, M (reprint author), Inova Fairfax Hosp, 2826 Old Lee Hwy 250, Fairfax, VA 22031 USA. EM drhunasikatti@gmail.com NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD SEP PY 2014 VL 146 IS 3 BP E113 EP E113 DI 10.1378/chest.14-0641 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AP9UM UT WOS:000342425800019 PM 25180740 ER PT J AU Su, ZQ Labaj, PP Li, S Thierry-Mieg, J Thierry-Mieg, D Shi, W Wang, C Schroth, GP Setterquist, RA Thompson, JF Jones, WD Xiao, WH Xu, WH Jensen, RV Kelly, R Xu, J Conesa, A Furlanello, C Gao, HL Hong, HX Jafari, N Letovsky, S Liao, Y Lu, F Oakeley, EJ Peng, ZY Praul, CA Santoyo-Lopez, J Scherer, A Shi, T Smyth, GK Staedtler, F Sykacek, P Tan, XX Thompson, EA Vandesompele, J Wang, MD Wang, J Wolfinger, RD Zavadil, J Auerbach, SS Bao, WJ Binder, H Blomquist, T Brilliant, MH Bushel, PR Cain, WM Catalano, JG Chang, CW Chen, T Chen, G Chen, R Chierici, M Chu, TM Clevert, DA Deng, YP Derti, A Devanarayan, V Dong, ZR Dopazo, J Du, TT Fang, H Fang, YX Fasold, M Fernandez, A Fischer, M Furio-Tari, P Fuscoe, JC Caiment, F Gaj, S Gandara, J Gao, H Ge, WG Gondo, Y Gong, BS Gong, MH Gong, ZL Green, B Guo, C Guo, L Guo, LW Hadfield, J Hellemans, J Hochreiter, S Jia, MW Jian, M Johnson, CD Kay, S Kleinjans, J Lababidi, S Levy, S Li, QZ Li, L Li, L Li, P Li, Y Li, HQ Li, JY Li, SY Lin, SM Lopez, FJ Lu, X Luo, H Ma, XW Meehan, J Megherbi, DB Mei, N Mu, B Ning, BT Pandey, A Perez-Florido, J Perkins, RG Peters, R Phan, JH Pirooznia, M Qian, F Qing, T Rainbow, L Rocca-Serra, P Sambourg, L Sansone, SA Schwartz, S Shah, R Shen, J Smith, TM Stegle, O Stralis-Pavese, N Stupka, E Suzuki, Y Szkotnicki, LT Tinning, M Tu, BM van Deft, J Vela-Boza, A Venturini, E Walker, SJ Wan, LQ Wang, W Wang, JH Wang, J Wieben, ED Willey, JC Wu, PY Xuan, J Yang, Y Ye, Z Yin, Y Yu, Y Yuan, YC Zhang, J Zhang, KK Zhang, WQ Zhang, WW Zhang, YY Zhao, C Zheng, YT Zhou, YM Zumbo, P Tong, WD Kreil, DP Mason, CE Shi, LM AF Su, Zhenqiang Labaj, Pawel P. Li, Sheng Thierry-Mieg, Jean Thierry-Mieg, Danielle Shi, Wei Wang, Charles Schroth, Gary P. Setterquist, Robert A. Thompson, John F. Jones, Wendell D. Xiao, Wenzhong Xu, Weihong Jensen, Roderick V. Kelly, Reagan Xu, Joshua Conesa, Ana Furlanello, Cesare Gao, Hanlin Hong, Huixiao Jafari, Nadereh Letovsky, Stan Liao, Yang Lu, Fei Oakeley, Edward J. Peng, Zhiyu Praul, Craig A. Santoyo-Lopez, Javier Scherer, Andreas Shi, Tieliu Smyth, Gordon K. Staedtler, Frank Sykacek, Peter Tan, Xin-Xing Thompson, E. Aubrey Vandesompele, Jo Wang, May D. Wang, Jian Wolfinger, Russell D. Zavadil, Jiri Auerbach, Scott S. Bao, Wenjun Binder, Hans Blomquist, Thomas Brilliant, Murray H. Bushel, Pierre R. Cain, Weimin Catalano, Jennifer G. Chang, Ching-Wei Chen, Tao Chen, Geng Chen, Rong Chierici, Marco Chu, Tzu-Ming Clevert, Djork-Arne Deng, Youping Derti, Adnan Devanarayan, Viswanath Dong, Zirui Dopazo, Joaquin Du, Tingting Fang, Hong Fang, Yongxiang Fasold, Mario Fernandez, Anita Fischer, Matthias Furio-Tari, Pedro Fuscoe, James C. Caiment, Florian Gaj, Stan Gandara, Jorge Gao, Huan Ge, Weigong Gondo, Yoichi Gong, Binsheng Gong, Meihua Gong, Zhuolin Green, Bridgett Guo, Chao Guo, Lei Guo, Li-Wu Hadfield, James Hellemans, Jan Hochreiter, Sepp Jia, Meiwen Jian, Min Johnson, Charles D. Kay, Suzanne Kleinjans, Jos Lababidi, Samir Levy, Shawn Li, Quan-Zhen Li, Li Li, Li Li, Peng Li, Yan Li, Haiqing Li, Jianying Li, Shiyong Lin, Simon M. Lopez, Francisco J. Lu, Xin Luo, Heng Ma, Xiwen Meehan, Joseph Megherbi, Dalila B. Mei, Nan Mu, Bing Ning, Baitang Pandey, Akhilesh Perez-Florido, Javier Perkins, Roger G. Peters, Ryan Phan, John H. Pirooznia, Mehdi Qian, Feng Qing, Tao Rainbow, Lucille Rocca-Serra, Philippe Sambourg, Laure Sansone, Susanna-Assunta Schwartz, Scott Shah, Ruchir Shen, Jie Smith, Todd M. Stegle, Oliver Stralis-Pavese, Nancy Stupka, Elia Suzuki, Yutaka Szkotnicki, Lee T. Tinning, Matthew Tu, Bimeng van Deft, Joost Vela-Boza, Alicia Venturini, Elisa Walker, Stephen J. Wan, Liqing Wang, Wei Wang, Jinhui Wang, Jun Wieben, Eric D. Willey, James C. Wu, Po-Yen Xuan, Jiekun Yang, Yong Ye, Zhan Yin, Ye Yu, Ying Yuan, Yate-Ching Zhang, John Zhang, Ke K. Zhang, Wenqian Zhang, Wenwei Zhang, Yanyan Zhao, Chen Zheng, Yuanting Zhou, Yiming Zumbo, Paul Tong, Weida Kreil, David P. Mason, Christopher E. Shi, Leming TI A comprehensive assessment of RNA-seq accuracy, reproducibility and information content by the Sequencing Quality Control Consortium SO NATURE BIOTECHNOLOGY LA English DT Article ID GENE-EXPRESSION ANALYSIS; GENOME ANNOTATION; ARRAYS; TRANSCRIPTOME; CALIBRATION; ALIGNER; PROJECT; CELLS; BIAS; PCR AB We present primary results from the Sequencing Quality Control (SEQC) project, coordinated by the US Food and Drug Administration. Examining Illumina HiSeq, Life Technologies SOLiD and Roche 454 platforms at multiple laboratory sites using reference RNA samples with built-in controls, we assess RNA sequencing (RNA-seq) performance for junction discovery and differential expression profiling and compare it to microarray and quantitative PCR (qPCR) data using complementary metrics. At all sequencing depths, we discover unannotated exon-exon junctions, with >80% validated by qPCR. We find that measurements of relative expression are accurate and reproducible across sites and platforms if specific-filters are used. In contrast, RNA-seq and microarrays do not provide accurate absolute measurements, and gene-specific biases are observed for all examined platforms, including qPCR. Measurement performance depends on the platform and data analysis pipeline, and variation is large for transcript-level profiling. The complete SEQC data sets, comprising >100 billion reads (10Tb), provide unique resources for evaluating RNA-seq analyses for clinical and regulatory settings. C1 [Su, Zhenqiang; Kelly, Reagan; Xu, Joshua; Hong, Huixiao; Chang, Ching-Wei; Chen, Tao; Fang, Hong; Fuscoe, James C.; Ge, Weigong; Gong, Binsheng; Green, Bridgett; Guo, Lei; Guo, Li-Wu; Li, Yan; Meehan, Joseph; Mei, Nan; Ning, Baitang; Perkins, Roger G.; Qian, Feng; Shen, Jie; Wan, Liqing; Xuan, Jiekun; Zhang, Wenqian; Tong, Weida; Shi, Leming] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Labaj, Pawel P.; Sykacek, Peter; Stralis-Pavese, Nancy; Kreil, David P.] Boku Univ Vienna, Chair Bioinformat Res Grp, Vienna, Austria. [Li, Sheng; Gandara, Jorge; Zumbo, Paul; Mason, Christopher E.] Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY USA. [Li, Sheng; Zumbo, Paul; Mason, Christopher E.] Weill Cornell Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY USA. [Thierry-Mieg, Jean; Thierry-Mieg, Danielle] NCBI, NIH, Bethesda, MD USA. [Shi, Wei; Liao, Yang; Smyth, Gordon K.] Walter & Eliza Hall Inst Med Res, Bioinformat Div, Parkville, Vic, Australia. [Shi, Wei] Univ Melbourne, Dept Comp & Informat Syst, Parkville, Vic 3052, Australia. [Wang, Charles] Loma Linda Univ, Ctr Genom, Sch Med, Loma Linda, CA 92350 USA. [Wang, Charles] Loma Linda Univ, Div Microbiol & Mol Genet, Sch Med, Loma Linda, CA 92350 USA. [Schroth, Gary P.] Illumina Inc, Hayward, CA USA. [Setterquist, Robert A.] Life Technol Corp, Austin, TX USA. [Thompson, John F.] Claritas Genom, Cambridge, MA USA. [Jones, Wendell D.] Express Anal Inc, Durham, NC USA. [Xiao, Wenzhong] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Xiao, Wenzhong; Xu, Weihong] Stanford Genome Technol Ctr, Palo Alto, CA USA. [Jensen, Roderick V.] Virginia Tech, Dept Biol Sci, Blacksburg, VA USA. [Conesa, Ana; Dopazo, Joaquin; Furio-Tari, Pedro] Ctr Invest Principe Felipe, Computat Genom Program, Valencia, Spain. [Furlanello, Cesare; Chierici, Marco] Fdn Bruno Kessler, Trento, Trento, Italy. [Gao, Hanlin; Wang, Jinhui] City Hope Natl Med Ctr, DNA Sequencing Solexa Core, Beckman Res Inst, City Hope Comprehens Canc Ctr, Duarte, CA 91010 USA. [Jafari, Nadereh] Northwestern Univ, Ctr Genet Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Letovsky, Stan] SynapDx Corp, Lexington, MA USA. [Liao, Yang] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia. [Lu, Fei; Tan, Xin-Xing; Szkotnicki, Lee T.] GE Healthcare SeqWright Genom Serv, Houston, TX USA. [Oakeley, Edward J.; Staedtler, Frank; Fernandez, Anita] Novartis Inst Biomed Res, Basel, Switzerland. [Peng, Zhiyu; Dong, Zirui; Gao, Huan; Gong, Meihua; Gong, Zhuolin; Jian, Min; Li, Shiyong; Tu, Bimeng; Wang, Jun; Yin, Ye; Zhang, Wenqian; Zhang, Wenwei; Zhang, Yanyan] BGI Shenzhen, Bei Shan Ind Zone, Shenzhen, Guangdong, Peoples R China. [Praul, Craig A.] Penn State Univ, University Pk, PA 16802 USA. [Santoyo-Lopez, Javier; Lopez, Francisco J.; Perez-Florido, Javier; Vela-Boza, Alicia] Genom & Bioinformat Platform Andalusia, Med Genome Project, Seville, Spain. [Santoyo-Lopez, Javier] Univ Edinburgh, Edinburgh Genom, Edinburgh, Midlothian, Scotland. [Scherer, Andreas; Tinning, Matthew] Australian Genome Res Facil Ltd, Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia. [Scherer, Andreas] Spheromics, Kontiolahti, Finland. [Shi, Tieliu; Chen, Geng; Li, Peng; Zhao, Chen] E China Normal Univ, Inst Biomed Sci, Ctr Bioinformat & Computat Biol, Shanghai Key Lab Regulatory Biol, Shanghai 200062, Peoples R China. [Shi, Tieliu; Chen, Geng; Li, Peng; Zhao, Chen] E China Normal Univ, Sch Life Sci, Shanghai 200062, Peoples R China. [Smyth, Gordon K.] Univ Melbourne, Dept Math & Stat, Parkville, Vic 3052, Australia. [Thompson, E. Aubrey] Mayo Clin Jacksonville, Dept Canc Biol, Jacksonville, FL 32224 USA. [Vandesompele, Jo; Hellemans, Jan] Biogazelle, Zwijnaarde, Belgium. [Wang, May D.; Phan, John H.] GeorgiaTech, Dept Biomed Engn, Atlanta, GA USA. [Wang, May D.; Phan, John H.] Emory Univ, Atlanta, GA 30322 USA. [Wang, Jian; Yang, Yong] Eli Lilly & Co, Lilly Corp Ctr, Res Informat, Indianapolis, IN 46285 USA. [Wolfinger, Russell D.; Bao, Wenjun; Chu, Tzu-Ming; Li, Li] SAS Inst Inc, Cary, NC USA. [Zavadil, Jiri; Venturini, Elisa] NYU, Langone Med Ctr, NYU Genome Technol Ctr, New York, NY USA. [Zavadil, Jiri] NYU, Langone Med Ctr, NYU Ctr Hlth Informat & Bioinformat, Dept Pathol, New York, NY USA. [Zavadil, Jiri] Int Agcy Res Canc, Mol Mech & Biomarkers Grp, F-69372 Lyon, France. [Auerbach, Scott S.; Bushel, Pierre R.; Li, Jianying] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Binder, Hans] Univ Leipzig, Interdisciplinary Ctr Bioinformat, D-04109 Leipzig, Germany. [Blomquist, Thomas; Willey, James C.] Univ Toledo, Div Pulm & Crit Care Med, Dept Med, Med Coll Ohio, Toledo, OH 43606 USA. [Brilliant, Murray H.] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA. [Cain, Weimin; Du, Tingting; Jia, Meiwen; Qing, Tao; Yu, Ying; Zheng, Yuanting] Fudan Univ, Sch Pharm, Shanghai 200433, Peoples R China. [Catalano, Jennifer G.] US FDA, Off Cellular Tissue & Gene Therapies, CBER, Bethesda, MD 20014 USA. [Chen, Rong; Li, Li] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Clevert, Djork-Arne; Hochreiter, Sepp] Johannes Kepler Univ Linz, Inst Bioinformat, A-4040 Linz, Austria. [Deng, Youping] Rush Univ, Ctr Canc, Dept Internal Med, Chicago, IL 60612 USA. [Derti, Adnan] Novartis Inst Biomed Res, Cambridge, MA USA. [Devanarayan, Viswanath] AbbVie Inc, Global Pharmaceut R&D, Souderton, PA USA. [Dopazo, Joaquin] CIBER Enfermedades Raras CIBERER, Valencia, Spain. [Dopazo, Joaquin] CIPF, Funct Genom Node INB, Valencia, Spain. [Fang, Yongxiang; Kay, Suzanne; Rainbow, Lucille] Univ Liverpool, Ctr Genom Res, Liverpool L69 3BX, Merseyside, England. [Fasold, Mario] ecSeq Bioinformat, Leipzig, Germany. [Fischer, Matthias] Univ Cologne, Dept Pediat Oncol & Hematol, D-50931 Cologne, Germany. [Fischer, Matthias] Univ Cologne, Ctr Mol Med CMMC, D-50931 Cologne, Germany. [Caiment, Florian; Gaj, Stan; Kleinjans, Jos; van Deft, Joost] Maastricht Univ, Dept Toxicogenom, Maastricht, Netherlands. [Gondo, Yoichi] RIKEN BioResource Ctr, Tsukuba, Ibaraki, Japan. [Guo, Chao] City Hope Natl Med Ctr, Beckman Res Inst, Funct Genom Core, Duarte, CA 91010 USA. [Hadfield, James] Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge, England. [Johnson, Charles D.; Schwartz, Scott] Texas A&M AgriLife Res, College Stn, TX USA. [Lababidi, Samir] US FDA, CBER, Rockville, MD 20857 USA. [Levy, Shawn] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [Li, Quan-Zhen] Univ Texas SW Med Ctr Dallas, UTSW, Dallas, TX 75390 USA. [Li, Haiqing; Mu, Bing; Yuan, Yate-Ching] City Hope Natl Med Ctr, Beckman Res Inst, Bioinformat Core, Duarte, CA 91010 USA. [Lin, Simon M.] Nationwide Childrens Hosp, Res Inst, Columbus, OH USA. [Lu, Xin] AbbVie Inc, Global Pharmaceut R&D, N Chicago, IL USA. [Luo, Heng] Univ Arkansas, UALR UAMS Joint Bioinformat Grad Program, Little Rock, AR 72204 USA. [Ma, Xiwen] Eli Lilly & Co, Lilly Corp Ctr, Discovery Stat, Indianapolis, IN 46285 USA. [Megherbi, Dalila B.] Univ Massachusetts, Dept Elect & Comp Engn, CMINDS Res Ctr, Lowell, MA USA. [Pandey, Akhilesh] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Pandey, Akhilesh] Inst Bioinformat, Bangalore, Karnataka, India. [Peters, Ryan] Partek Inc, St Louis, MO USA. [Pirooznia, Mehdi] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Rocca-Serra, Philippe; Sansone, Susanna-Assunta] Univ Oxford, Oxford e Res Ctr, Oxford, England. [Sambourg, Laure] UJF Grenoble, CNRS TIMC IMAG 1, UMR 5525, Computat & Math Biol BCM, Grenoble, France. [Shah, Ruchir] SRA Int Inc, Durham, NC USA. [Smith, Todd M.] Geospiza Inc, Seattle, WA USA. [Stegle, Oliver] European Bioinformat Inst, European Mol Biol Lab, Cambridge, England. [Stupka, Elia] Ist Sci San Raffaele, Ctr Translat Genom & Bioinformat, I-20132 Milan, Italy. [Suzuki, Yutaka] Univ Tokyo, Dept Med Genome Sci, Chiba, Japan. [Walker, Stephen J.] Wake Forest Univ, Wake Forest Inst Regenerat Med, Winston Salem, NC 27109 USA. [Wang, Wei] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [Wang, Jun] Univ Copenhagen, Dept Biol, Copenhagen, Denmark. [Wang, Jun] King Abdulaziz Univ, Jeddah 21413, Saudi Arabia. [Wang, Jun] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark. [Wieben, Eric D.] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN USA. [Wu, Po-Yen] Georgia Inst Technol, Sch Elect & Comp Engn, Atlanta, GA 30332 USA. [Ye, Zhan] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI USA. [Zhang, John] Zhejiang Univ Technol, Zhijiang Coll, Ctr Big Data Res, Hangzhou, Zhejiang, Peoples R China. [Zhang, Ke K.] Univ N Dakota, Sch Med, Dept Pathol, Grand Forks, ND 58202 USA. [Zhou, Yiming] Digomics LLC, Brookline, MA USA. [Kreil, David P.] Univ Warwick, Coventry CV4 7AL, W Midlands, England. [Shi, Leming] Fudan Univ, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Shi, Leming] Fudan Univ, Sch Life Sci, MOE Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Shi, Leming] Fudan Univ, Sch Pharm, Shanghai 200433, Peoples R China. [Shi, Leming] Fudan Zhangjiang Ctr Clin Genom, Shanghai, Peoples R China. [Shi, Leming] Zhanjiang Ctr Translat Med, Shanghai, Peoples R China. RP Shi, LM (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM david.krell@boku.ac.at; chm2042@med.cornell.edu; leming.shi@gmail.com RI Kreil, D/O-1783-2013; Wang, Jun/B-9503-2016; Labaj, Pawel/N-5425-2014; Guo, Chao/B-2647-2010; Conesa Cegarra, Ana/A-9559-2014; Kleinjans, Jos/E-7241-2015; caiment, florian/N-7623-2015; Gondo, Yoichi/A-5375-2016; Wang, Jun/C-8434-2016; Luo, Heng/D-3616-2016; Gong, Binsheng/E-2306-2015; Smyth, Gordon/B-5276-2008; THIERRY-MIEG, Jean/F-1975-2017 OI Johnson, Charles/0000-0003-3892-7082; Hochreiter, Sepp/0000-0001-7449-2528; Kreil, D/0000-0001-7538-2056; Chierici, Marco/0000-0001-9791-9301; Wang, Jun/0000-0002-2113-5874; MEI, NAN/0000-0002-3501-9014; Stupka, Elia/0000-0003-3154-4011; Stegle, Oliver/0000-0002-8818-7193; Guo, Chao/0000-0002-6673-0933; Conesa Cegarra, Ana/0000-0001-9597-311X; Gondo, Yoichi/0000-0003-2184-6489; Wang, Jun/0000-0002-8540-8931; Luo, Heng/0000-0001-5192-8878; Gong, Binsheng/0000-0002-8724-5435; Smyth, Gordon/0000-0001-9221-2892; THIERRY-MIEG, Jean/0000-0002-0396-6789 FU China's Program of Global Experts; US National Institutes of Health (NIH) [R01CA163256, R01HG006798, R01NS076465, R44HG005297, U54CA119338, PO1HG00205, R24GM102656]; Intramural Research Program of the NIH, National Library of Medicine, National Institute of Environmental Health Sciences (NIEHS) [Z01 ES102345-04]; Shriners Research Grant [85500]; Australia National Health and Medical Research Council (NHMRC) [1023454]; Victorian State Government Operational Infrastructure Support (Australia); National 973 Key Basic Research Program of China [2010CB945401]; National Natural Science Foundation of China [31240038, 31071162]; Science and Technology Commission of Shanghai Municipality [11DZ2260300] FX All SEQC (MAQC-III) participants freely donated their time and reagents for the completion and analyses of the project. Many participants contributed to the sometimes-heated discussions on the topic of this paper during numerous e-mail exchanges, teleconferences and face-to-face project meetings. The common conclusions and recommendations reported in this paper evolved from this extended discourse. The authors gratefully acknowledge support by the National Center for Biotechnology Information (NCBI)'s Supercomputing Center, the FDA's Supercomputing Center, China's National Supercomputing Center of Tianjin, the Vienna Scientific Cluster High Performance Computing Facility (VSC), the Vienna Science and Technology Fund (WWTF), Baxter, the Austrian Institute of Technology, and the Austrian Centre of Biopharmaceutical Technology. This work was supported in part by China's Program of Global Experts. This work was supported in part by the US National Institutes of Health (NIH) grants R01CA163256, R01HG006798, R01NS076465, R44HG005297, U54CA119338, PO1HG00205, R24GM102656 and the Intramural Research Program of the NIH, National Library of Medicine, National Institute of Environmental Health Sciences (NIEHS) Z01 ES102345-04, Shriners Research Grant 85500, an Australia National Health and Medical Research Council (NH&MRC) Project grant (1023454) and Victorian State Government Operational Infrastructure Support (Australia), the National 973 Key Basic Research Program of China (2010CB945401), the National Natural Science Foundation of China (31240038 and 31071162), and the Science and Technology Commission of Shanghai Municipality (11DZ2260300). We greatly appreciate SAS Institute, Inc. for kindly hosting several face-to-face meetings of the SEQC (MAQC-III) project. NR 46 TC 118 Z9 119 U1 20 U2 126 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD SEP PY 2014 VL 32 IS 9 BP 903 EP 914 DI 10.1038/nbt.2957 PG 12 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AQ2FD UT WOS:000342600300030 ER PT J AU Wang, C Gong, BS Bushel, PR Thierry-Mieg, J Thierry-Mieg, D Xu, JS Fang, H Hong, HX Shen, J Su, ZQ Meehan, J Li, XJ Yang, L Li, HQ Labaj, PP Kreil, DP Megherbi, D Gaj, S Caiment, F van Delft, J Kleinjans, J Scherer, A Devanarayan, V Wang, J Yang, Y Qian, HR Lancashire, LJ Bessarabova, M Nikolsky, Y Furlanello, C Chierici, M Albanese, D Jurman, G Riccadonna, S Filosi, M Visintainer, R Zhang, KK Li, JY Hsieh, JH Svoboda, DL Fuscoe, JC Deng, YD Shi, LM Paules, RS Auerbach, SS Tong, WD AF Wang, Charles Gong, Binsheng Bushel, Pierre R. Thierry-Mieg, Jean Thierry-Mieg, Danielle Xu, Joshua Fang, Hong Hong, Huixiao Shen, Jie Su, Zhenqiang Meehan, Joe Li, Xiaojin Yang, Lu Li, Haiqing Labaj, Pawel P. Kreil, David P. Megherbi, Dalila Gaj, Stan Caiment, Florian van Delft, Joost Kleinjans, Jos Scherer, Andreas Devanarayan, Viswanath Wang, Jian Yang, Yong Qian, Hui-Rong Lancashire, Lee J. Bessarabova, Marina Nikolsky, Yuri Furlanello, Cesare Chierici, Marco Albanese, Davide Jurman, Giuseppe Riccadonna, Samantha Filosi, Michele Visintainer, Roberto Zhang, Ke K. Li, Jainying Hsieh, Jui-Hua Svoboda, Daniel L. Fuscoe, James C. Deng, Youping Shi, Leming Paules, Richard S. Auerbach, Scott S. Tong, Weida TI The concordance between RNA-seq and microarray data depends on chemical treatment and transcript abundance SO NATURE BIOTECHNOLOGY LA English DT Article ID DIFFERENTIAL EXPRESSION ANALYSIS; GENE-EXPRESSION; ARRAYS; REPRODUCIBILITY; CONSISTENCY; PLATFORMS; SCIENCE AB The concordance of RNA-sequencing (RNA-seq) with microarrays for genome-wide analysis of differential gene expression has not been rigorously assessed using a range of chemical treatment conditions. Here we use a comprehensive study design to generate Illumina RNA-seq and Affymetrix microarray data from the same liver samples of rats exposed in triplicate to varying degrees of perturbation by 27 chemicals representing multiple modes of action (MOAs). The cross-platform concordance in terms of differentially expressed genes (DEGs) or enriched pathways is linearly correlated with treatment effect size (R-2 approximate to 0.8). Furthermore, the concordance is also affected by transcript abundance and biological complexity of the MOA. RNA-seq outperforms microarray (93% versus 75%) in DEG verification as assessed by quantitative PCR, with the gain mainly due to its improved accuracy for low-abundance transcripts. Nonetheless, classifiers to predict MOAs perform similarly when developed using data from either platform. Therefore, the endpoint studied and its biological complexity, transcript abundance and the genomic application are important factors in transcriptomic research and for clinical and regulatory decision making. C1 [Wang, Charles] Loma Linda Univ, Sch Med, Ctr Genom, Loma Linda, CA USA. [Wang, Charles] Loma Linda Univ, Sch Med, Div Microbiol & Mol Genet, Loma Linda, CA USA. [Gong, Binsheng; Xu, Joshua; Hong, Huixiao; Shen, Jie; Su, Zhenqiang; Meehan, Joe; Shi, Leming; Tong, Weida] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Bushel, Pierre R.; Li, Jainying] NIEHS, Microarray & Genome Informat Grp, Res Triangle Pk, NC 27709 USA. [Bushel, Pierre R.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Thierry-Mieg, Jean; Thierry-Mieg, Danielle] Natl Lib Med, Nat Ctr Biotechnol Informat, NIH, Bethesda, MD USA. [Fang, Hong] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Li, Xiaojin; Yang, Lu; Li, Haiqing] City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol Med, Funct Genom Core, Duarte, CA USA. [Labaj, Pawel P.; Kreil, David P.] Boku Univ Vienna, Chair Bioinformat Res Grp, Vienna, Austria. [Kreil, David P.] Univ Warwick, Coventry CV4 7AL, W Midlands, England. [Megherbi, Dalila] Univ Massachusetts, Dept Elect & Comp Engn, Francis Coll Engn, CMINDS Res Ctr, Lowell, MA USA. [Gaj, Stan; Caiment, Florian; van Delft, Joost; Kleinjans, Jos] Maastricht Univ, Dept Toxicogen, Maastricht, Netherlands. [Scherer, Andreas] Australian Genome Res Facil Ltd, Walter & Eliza Hall Inst Med Res, Melbourne, Vic, Australia. [Devanarayan, Viswanath] AbbVie Inc, N Chicago, IL USA. [Wang, Jian; Yang, Yong; Qian, Hui-Rong] Eli Lilly & Co, Lilly Corp Ctr, Res Informat & Stat, Indianapolis, IN 46285 USA. [Lancashire, Lee J.; Bessarabova, Marina] Thomson Reuters, IP & Sci, Carlsbad, CA USA. [Nikolsky, Yuri] Russian Acad Sci, Vavilov Inst Gen Genet, Moscow, Russia. [Furlanello, Cesare; Chierici, Marco; Albanese, Davide; Jurman, Giuseppe; Riccadonna, Samantha; Filosi, Michele; Visintainer, Roberto] Fdn Bruno Kessler, Trento, Italy. [Albanese, Davide; Riccadonna, Samantha] Fdn Edmund Mach, Computat Biol Dept, Res & Innovat Ctr, San Michele All Adige, Italy. [Zhang, Ke K.] Univ N Dakota, Dept Pathol, Bioinformat CORE, Grand Forks, ND 58201 USA. [Li, Jainying] Kelly Govt Solut Inc, Durham, NC USA. [Hsieh, Jui-Hua; Auerbach, Scott S.] NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Svoboda, Daniel L.] SRA Int, Durham, NC USA. [Fuscoe, James C.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Deng, Youping] Rush Univ, Med Ctr, Dept Internal Med & Biochem, Chicago, IL 60612 USA. [Shi, Leming] Fudan Univ, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Shi, Leming] Fudan Univ, MOE Key Lab Contemporary Anthropol, Sch Life Sci, Shanghai 200433, Peoples R China. [Shi, Leming] Fudan Univ, MOE Key Lab Contemporary Anthropol, Sch Pharm, Shanghai 200433, Peoples R China. [Paules, Richard S.] NIEHS, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. RP Tong, WD (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM bushel@niehs.nih.gov; AuerbachS@niehs.nih.gov; weida.tong@fda.hhs.gov RI Labaj, Pawel/N-5425-2014; yang, lu/D-5099-2015; Kleinjans, Jos/E-7241-2015; caiment, florian/N-7623-2015; Gong, Binsheng/E-2306-2015; THIERRY-MIEG, Jean/F-1975-2017; Kreil, D/O-1783-2013 OI Visintainer, Roberto/0000-0003-1289-6871; Chierici, Marco/0000-0001-9791-9301; Jurman, Giuseppe/0000-0002-2705-5728; Filosi, Michele/0000-0002-3872-347X; Gong, Binsheng/0000-0002-8724-5435; THIERRY-MIEG, Jean/0000-0002-0396-6789; Caiment, Florian/0000-0002-3325-0466; Riccadonna, Samantha/0000-0002-9737-8274; Kreil, D/0000-0001-7538-2056 FU National Institutes of Health (NIH); National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) [ES102345-04, ES023026]; National Library of Medicine; Vienna Scientific Cluster (VSC); Vienna Science and Technology Fund (WWTF); Baxter AG; Austrian Research Centres (ARC) Seibersdorf; Austrian Centre of Biopharmaceutical Technology (ACBT) FX We thank M. Arana and D. Mendrick for their critical review of the manuscript. This research was supported, in part, by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) (ES102345-04 and ES023026) and National Library of Medicine. P.P.L. and D.P.K. acknowledge support by the Vienna Scientific Cluster (VSC), the Vienna Science and Technology Fund (WWTF), Baxter AG, Austrian Research Centres (ARC) Seibersdorf and the Austrian Centre of Biopharmaceutical Technology (ACBT). NR 37 TC 100 Z9 103 U1 2 U2 55 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD SEP PY 2014 VL 32 IS 9 BP 926 EP 932 DI 10.1038/nbt.3001 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AQ2FD UT WOS:000342600300032 PM 25150839 ER PT J AU Sarkar, S Chigurupati, S Raymick, J Mann, D Bowyer, JF Schmitt, T Beger, RD Hanig, JP Schmued, LC Paule, MG AF Sarkar, Sumit Chigurupati, Srinivasulu Raymick, James Mann, Dushyant Bowyer, John F. Schmitt, Tom Beger, Richard D. Hanig, Joseph P. Schmued, Larry C. Paule, Merle G. TI Neuroprotective effect of the chemical chaperone, trehalose in a chronic MPTP-induced Parkinson's disease mouse model SO NEUROTOXICOLOGY LA English DT Article DE Parkinson's disease; Endothelial cells; Trehalose; Tyrosine hydroxylase; FT-gel ID BLOOD-BRAIN-BARRIER; MICE; AUTOPHAGY; STRESS; NEUROTOXICITY; PATHOLOGY; CELLS; METHAMPHETAMINE; AGGREGATION; INHIBITION AB Parkinson's disease (PD) is a progressive motor disease of unknown etiology in the majority of cases. The clinical features of PD emerge due to selective degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc), which project to the caudate putamen (CPu) where they release DA. In the current in vivo mouse model study, we tested trehalose for its ability to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage to DA neurons. Trehalose is a naturally occurring disaccharide present in plants and animals and appears capable of protecting cells against various environmental stresses. The effect of trehalose is likely due to its action as a pharmacological chaperone which promotes protein stability. In the present study, there were four treatment groups: saline only (control); probenecid only; MPTP + probenecid; and trehalose + MPTP + probenecid. MPTP-induced losses in tyrosine hydroxylase and DA transporter immunoreactivity in the ventral midbrain SNc and CPu were significantly reduced by trehalose. Decreases in CPu dopamine levels produced by MPTP were also blocked by trehalose. Microglial activation and astrocytic hypertrophy induced by MPTP were greatly reduced by trehalose, indicating protection against neuroinflammation. These effects are commensurate with the observed trehalose sparing of motor deficits produced by MPTP in this mouse model. Two tight junctional proteins, ZO-1 and occludin, are downregulated following MPTP treatment and trehalose blocks this effect. Likewise, the glucose transporter-1 that is expressed in brain endothelial cells is also protected by trehalose from MPTP-induced down-regulation. This study is the first to demonstrate using fluoro-turoquoise FT gel perfusion techniques, the protection afforded by trehalose from MPTP-induced damage to microvessels and endothelial and suggests that trehalose therapy may have the potential to slow or ameliorate PD pathology. Published by Elsevier Inc. C1 [Sarkar, Sumit; Chigurupati, Srinivasulu; Bowyer, John F.; Schmued, Larry C.; Paule, Merle G.] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Raymick, James] Toxicol Pathol Associates, Jefferson, AR 72079 USA. [Mann, Dushyant] Wayne State Univ, Sch Med, Detroit, MI 48201 USA. [Schmitt, Tom; Beger, Richard D.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Hanig, Joseph P.] US FDA, Off Testing & Res, CDER, White Oak, MD 20993 USA. RP Sarkar, S (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Sumit.Sarkar@FDA.hhs.gov FU National Center for Toxicological Research/FDA [E0751201] FX This study was supported by the National Center for Toxicological Research/FDA (E0751201) NR 45 TC 17 Z9 18 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X EI 1872-9711 J9 NEUROTOXICOLOGY JI Neurotoxicology PD SEP PY 2014 VL 44 BP 250 EP 262 DI 10.1016/j.neuro.2014.07.006 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA AQ2XY UT WOS:000342654500027 PM 25064079 ER PT J AU Willy, ME Graham, DJ Racoosin, JA Gill, R Kropp, GF Young, J Yang, J Choi, J MaCurdy, TE Worrall, C Kelman, JA AF Willy, Mary E. Graham, David J. Racoosin, Judith A. Gill, Rajdeep Kropp, Garner F. Young, Jessica Yang, Jeff Choi, Joyce MaCurdy, Thomas E. Worrall, Chris Kelman, Jeffrey A. TI Candidate Metrics for Evaluating the Impact of Prescriber Education on the Safe Use of Extended-Release/Long-Acting (ER/LA) Opioid Analgesics SO PAIN MEDICINE LA English DT Article DE REMS; Opioids; Metrics; Evaluation ID CHRONIC PAIN; THERAPY; RISK AB ObjectiveThe objective of this study was to develop metrics to assess opioid prescribing behavior as part of the evaluation of the Extended-Release/Long-Acting (ER/LA) Opioid Analgesic Risk Evaluation and Mitigation Strategies (REMS). DesignCandidate metrics were selected using published guidelines, examined using sensitivity analyses, and applied to cross-sectional rolling cohorts of Medicare patients prescribed with extended-release oxycodone (ERO) between July 2, 2006 and July 1, 2011. Potential metrics included prescribing opioid-tolerant-only ER/LA opioid analgesics to non-opioid-tolerant patients, prescribing early fills to patients, and ordering drug screens. ResultsProposed definitions for opioid tolerance were seven continuous days of opioid usage of at least 30mg oxycodone equivalents, within the 7 days (primary) or 30 days (secondary) prior to first opioid-tolerant-only ERO prescription. Forty-four percent of opioid-tolerant-only ERO episodes met the primary opioid tolerance definition; 56% met the secondary definition. Fills were deemed early if a prescription was filled before 70% (primary) or 50% (secondary) of the prior prescription's days' supply was to be consumed. Five percent (primary) and 2% (secondary) of episodes had more than or equal to two early fills during treatment. At least one drug screen was billed in 14% of episodes. Stratified analyses indicated that older patients were less likely to be opioid tolerant at the time of the first opioid-tolerant-only ERO prescription. ConclusionsInvestigators propose three metrics to monitor changes in prescribing behaviors for opioid analgesics that might be used to evaluate the ER/LA Opioid Analgesics REMS. Low frequencies of patients, particularly those >85 years, were likely to be opioid tolerant prior to receiving prescriptions for opioid-tolerant-only ERO. C1 [Willy, Mary E.; Graham, David J.; Racoosin, Judith A.; Gill, Rajdeep] Food & Drug Adm, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Kropp, Garner F.; Young, Jessica; Yang, Jeff; Choi, Joyce; MaCurdy, Thomas E.] Acumen LLC, SafeRx, Burlingame, CA USA. [Worrall, Chris; Kelman, Jeffrey A.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. RP Willy, ME (reprint author), Food & Drug Adm, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 22,Room 2420, Silver Spring, MD 20993 USA. EM mary.willy@fda.hhs.gov FU Centers for Medicare & Medicaid Services (CMS); Food and Drug Administration (FDA) FX Funding: This study was funded by the Centers for Medicare & Medicaid Services (CMS) and the Food and Drug Administration (FDA) under an intra-agency agreement. NR 20 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-2375 EI 1526-4637 J9 PAIN MED JI Pain Med. PD SEP PY 2014 VL 15 IS 9 BP 1558 EP 1568 DI 10.1111/pme.12459 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AQ2QA UT WOS:000342631300014 PM 24828968 ER PT J AU Courtney, B Bond, KC Maher, C AF Courtney, Brooke Bond, Katherine C. Maher, Carmen TI REGULATORY UNDERPINNINGS OF GLOBAL HEALTH SECURITY: FDA'S ROLES IN PREVENTING, DETECTING, AND RESPONDING TO GLOBAL HEALTH THREATS SO BIOSECURITY AND BIOTERRORISM-BIODEFENSE STRATEGY PRACTICE AND SCIENCE LA English DT Article ID CHALLENGES AB In February 2014, health officials from around the world announced the Global Health Security Agenda, a critical effort to strengthen national and global systems to prevent, detect, and respond to infectious disease threats and to foster stronger collaboration across borders. With its increasing global roles and broad range of regulatory responsibilities in ensuring the availability, safety, and security of medical and food products, the US Food and Drug Administration (FDA) is engaged in a range of efforts in support of global health security. This article provides an overview of FDA's global health security roles, focusing on its responsibilities related to the development and use of medical countermeasures (MCMs) for preventing, detecting, and responding to global infectious disease and other public health emergency threats. The article also discusses several areas-antimicrobial resistance, food safety, and supply chain integrity-in which FDA's global health security roles continue to evolve and extend beyond MCMs and, in some cases, beyond traditional infectious disease threats. C1 [Courtney, Brooke; Maher, Carmen] US FDA, Off Counterterrorism & Emerging Threats, Off Chief Scientist, Off Commissioner, Silver Spring, MD 20993 USA. [Bond, Katherine C.] US FDA, Off Strategy Partnerships & Analyt, Off Int Programs, Silver Spring, MD 20993 USA. RP Courtney, B (reprint author), US FDA, Off Counterterrorism & Emerging Threats, Off Commissioner, 10903 New Hampshire Ave,Bldg 1,Rm 4330, Silver Spring, MD 20993 USA. EM brooke.courtney@fda.hhs.gov NR 22 TC 2 Z9 2 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1538-7135 EI 1557-850X J9 BIOSECUR BIOTERROR JI Biosecur. Bioterror. PD SEP-OCT PY 2014 VL 12 IS 5 BP 239 EP 246 DI 10.1089/bsp.2014.0046 PG 8 WC Public, Environmental & Occupational Health; International Relations SC Public, Environmental & Occupational Health; International Relations GA AP7ZO UT WOS:000342297600005 PM 25254912 ER PT J AU Ng, HW Perkins, R Tong, WS Hong, HX AF Ng, Hui Wen Perkins, Roger Tong, Weida Hong, Huixiao TI Versatility or Promiscuity: The Estrogen Receptors, Control of Ligand Selectivity and an Update on Subtype Selective Ligands SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Review DE estrogen receptors (ERs); estrogen receptor alpha (ER alpha); estrogen receptor beta (ER beta); promiscuity; ligand selectivity; subtype selective ligands ID BETA-AGONISTS SERBAS; HUMAN BREAST-CANCER; ENDOCRINE-DISRUPTING CHEMICALS; ER-ALPHA; BINDING DOMAIN; NUCLEAR RECEPTORS; CRYSTAL-STRUCTURE; TETRAHYDROISOQUINOLINE LIGANDS; STRUCTURAL BASIS; SIDE-CHAINS AB The estrogen receptors (ERs) are a group of versatile receptors. They regulate an enormity of processes starting in early life and continuing through sexual reproduction, development, and end of life. This review provides a background and structural perspective for the ERs as part of the nuclear receptor superfamily and discusses the ER versatility and promiscuity. The wide repertoire of ER actions is mediated mostly through ligand-activated transcription factors and many DNA response elements in most tissues and organs. Their versatility, however, comes with the drawback of promiscuous interactions with structurally diverse exogenous chemicals with potential for a wide range of adverse health outcomes. Even when interacting with endogenous hormones, ER actions can have adverse effects in disease progression. Finally, how nature controls ER specificity and how the subtle differences in receptor subtypes are exploited in pharmaceutical design to achieve binding specificity and subtype selectivity for desired biological response are discussed. The intent of this review is to complement the large body of literature with emphasis on most recent developments in selective ER ligands. C1 [Ng, Hui Wen; 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 Huiwen.Ng@fda.hhs.gov; Roger.Perkins@fda.hhs.gov; Weida.Tong@fda.hhs.gov; Huixiao.Hong@fda.hhs.gov NR 129 TC 17 Z9 18 U1 0 U2 14 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD SEP PY 2014 VL 11 IS 9 BP 8709 EP 8742 DI 10.3390/ijerph110908709 PG 34 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA AP4DN UT WOS:000342027500008 PM 25162709 ER PT J AU Hait, J Tallent, S Melka, D Keys, C Bennett, R AF Hait, J. Tallent, S. Melka, D. Keys, C. Bennett, R. TI Prevalence of enterotoxins and toxin gene profiles of Staphylococcus aureus isolates recovered from a bakery involved in a second staphylococcal food poisoning occurrence SO JOURNAL OF APPLIED MICROBIOLOGY LA English DT Article DE food safety; multiplex PCR; PFGE; Staphylococcus aureus; staphylococcal enterotoxins ID OUTBREAK; ILLNESS; IDENTIFICATION AB Aims: The study objective was to characterize and analyse the distribution of enterotoxins and genes encoding enterotoxins in Staphylococcus aureus strains recovered from the 601 environment and ingredient samples obtained during multiple inspections of a bakery implicated in two separate staphylococcal food poisoning incidents. Methods and Results: Staphylococcus aureus isolates were evaluated using serological assays for identification of classical staphylococcal enterotoxins (SEs) SEA-SEE and polymerase chain reaction for the detection of newly described SE and SE-like enterotoxin genes seg-seu. Pulsed field gel electrophoresis identified thirteen pattern types. During these investigations, a total of 585 environmental swabs and 16 raw ingredient samples were collected by investigators, 85 of which were confirmed to contain Staph. aureus; of those isolates, 95.3% (81/85) harboured enterotoxin genes and 4.7% (4/85) carried newly described SE and SE-like enterotoxin genes in the absence of classical enterotoxins. Conclusions: Our research demonstrates the prevalence and diversity of classical SEs and the probable underestimated impact of nonclassical SE and SE-like enterotoxins role in domestic staphylococcal food poisoning outbreaks. Significance and Impact of the Study: Given the abundance of SEs and SE-like toxins, these findings illustrate the utilization of PCR for enterotoxin gene identification and its significance in outbreak investigations. C1 [Hait, J.; Tallent, S.; Melka, D.; Keys, C.; Bennett, R.] US FDA, College Pk, MD 20740 USA. RP Hait, J (reprint author), US FDA, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM jennifer.hait@fda.hhs.gov FU Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA) Programme under NIAID/NIH [NRS106, NRS111, HHSN272200700055C] FX We would like to thank all local, state and federal officials who participated in these investigations, with considerable appreciation to the Denver, Atlanta and Irvine FDA Field Laboratories for their role. We would like to thank Lili Velez, Ph.D., for her review of this manuscript. The following isolates were obtained through the Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA) Programme: < NRS106, NRS111 > supported under NIAID/NIH Contract No. HHSN272200700055C. NR 27 TC 5 Z9 5 U1 4 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1364-5072 EI 1365-2672 J9 J APPL MICROBIOL JI J. Appl. Microbiol. PD SEP PY 2014 VL 117 IS 3 BP 866 EP 875 DI 10.1111/jam.12571 PG 10 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA AP6VE UT WOS:000342215300025 PM 24917203 ER PT J AU Rupert, DJ Moultrie, RR Read, JG Amoozegar, JB Bornkessel, AS Donoghue, AC Sullivan, HW AF Rupert, Douglas J. Moultrie, Rebecca R. Read, Jennifer Gard Amoozegar, Jacqueline B. Bornkessel, Alexandra S. Donoghue, Arnie C. Sullivan, Helen W. TI Perceived healthcare provider reactions to patient and caregiver use of online health communities SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Online communities; Social media; Patient-provider communication; Shared decision making ID SHARED DECISION-MAKING; SOCIAL NETWORKS; FOCUS GROUPS; DOCTOR RELATIONSHIP; NATIONAL-SURVEY; INTERNET USE; WEB AB Objective: Many Internet users seek health information through online health communities (OHCs) and other social media. Yet few studies assess how individuals use peer-generated health information, and many healthcare providers (HCPs) believe OHCs interfere with patient-provider relationships. This study explored how individuals use OHC content in clinical discussions and how HCPs react to it. Methods: We conducted in-person and virtual focus groups with patients/caregivers who visited OHCs (n = 89). A trained moderator asked about reasons for membership, sharing OHC content with providers, HCP reactions, and preferred roles for HCPs. Two researchers independently coded verbatim transcripts (NVivo 9.2) and conducted thematic response analysis. Results: Participants described OHCs as supplementing information from HCPs, whom they perceived as too busy for detailed discussions. Almost all participants shared OHC content with HCPs, although only half cited OHCs as the source. Most HCPs reacted negatively to OHC content, making participants feel disempowered. Despite these reactions, participants continued to use OHCs, and most desired HCP feedback on the accuracy of OHC content. Conclusions: Individuals do not use OHCs to circumvent HCPs but instead to gather more in-depth information. Practice implications: HCPs should discuss OHC content with patients to help them avoid misinformation and make more informed decisions. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Rupert, Douglas J.; Moultrie, Rebecca R.; Read, Jennifer Gard; Bornkessel, Alexandra S.] RTI Int, Ctr Commun Sci, Res Triangle Pk, NC 27709 USA. [Amoozegar, Jacqueline B.] RTI Int, Social & Hlth Org Res & Evaluat Program, Res Triangle Pk, NC 27709 USA. [Donoghue, Arnie C.; Sullivan, Helen W.] US FDA, Off Prescript Drug Promot, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Rupert, DJ (reprint author), RTI Int, Ctr Commun Sci, 3040 Cornwallis Rd, Res Triangle Pk, NC 27709 USA. EM drupert@rti.org FU U.S. Food and Drug Administration (FDA), Office of Prescription Drug Promotion [HHSF223200910199G] FX This research was funded by a contract from the U.S. Food and Drug Administration (FDA) (Contract No. HHSF223200910199G), Office of Prescription Drug Promotion. NR 40 TC 4 Z9 4 U1 2 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD SEP PY 2014 VL 96 IS 3 BP 320 EP 326 DI 10.1016/j.pec.2014.05.015 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA AP7QF UT WOS:000342271100009 PM 24923652 ER PT J AU Nonnemaker, J Rostron, B Hall, P MacMonegle, A Apelberg, B AF Nonnemaker, James Rostron, Brian Hall, Patricia MacMonegle, Anna Apelberg, Benjamin TI Mortality and Economic Costs From Regular Cigar Use in the United States, 2010 SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID HIGH-SCHOOL-STUDENTS; SMOKING; TOBACCO; MEN; DISEASE; CANCER; MIDDLE; DEATH; RISK; LIFE AB Objectives. We estimated annual mortality, years of potential life lost, and associated economic costs attributable to regular cigar smoking among US adults aged 35 years or older. Methods. We estimated cigar-attributable mortality for the United States in 2010 using the Centers for Disease Control and Prevention's Smoking-Attributable Mortality, Morbidity, and Economic Costs methodology for smoking-related causes of death. We obtained cigar prevalence from the National Adult Tobacco Survey, relative risks from the Cancer Prevention Studies I and II, and annual US deaths from the National Vital Statistics System. We also estimated the economic cost of this premature mortality using the value of a statistical life-year. Results. Regular cigar smoking was responsible for approximately 9000 premature deaths and more than 140 000 years of potential life lost among US adults aged 35 years or older in 2010. These years of life had an economic value of approximately $ 23 billion. Conclusions. The health and economic burden of cigar smoking in the United States is large and may increase over time because of the increasing consumption of cigars in the United States. C1 [Nonnemaker, James; MacMonegle, Anna] RTI Int, Publ Hlth Policy Res, Res Triangle Pk, NC 27709 USA. [Rostron, Brian; Hall, Patricia; Apelberg, Benjamin] US FDA, Ctr Tobacco Prod, Silver Spring, MD USA. RP Nonnemaker, J (reprint author), RTI Int, Publ Hlth Policy Res, 3040 Cornwallis Rd,POB 12194, Res Triangle Pk, NC 27709 USA. EM jnonnemaker@rti.org OI Hall, Patricia S./0000-0002-4239-4226 FU Food and Drugs Administration Center for Tobacco Products [HHSF223201110005B/HHSF22311006] FX This article was funded by the Food and Drugs Administration Center for Tobacco Products (contract HHSF223201110005B/HHSF22311006). NR 28 TC 3 Z9 3 U1 0 U2 11 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 SEP PY 2014 VL 104 IS 9 BP E86 EP E91 DI 10.2105/AJPH.2014.301991 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP1XB UT WOS:000341864400014 PM 25033140 ER PT J AU Godar, DE Tang, R Merrill, SJ AF Godar, Dianne E. Tang, Rong Merrill, Stephen J. TI Pharyngeal and Cervical Cancer Incidences Significantly Correlate with Personal UV Doses Among Whites in the United States SO ANTICANCER RESEARCH LA English DT Article DE Cervical cancer; cytokines; environment; human papilloma virus; oral cancer; oropharyngeal cancer; pharyngeal cancer; sunlight; ultraviolet ID SALIVARY-GLAND CANCER; VERSUS-HOST-DISEASE; HUMAN-PAPILLOMAVIRUS; ULTRAVIOLET-B; ORAL-CANCER; OROPHARYNGEAL CANCER; DNA-DAMAGE; SKIN; IRRADIATION; CELLS AB Because we found UV-exposed oral tissue cells have reduced DNA repair and apoptotic cell death compared with skin tissue cells, we asked if a correlation existed between personal UV dose and the incidences of oral and pharyngeal cancer in the United States. We analyzed the International Agency for Research on Cancer's incidence data for oral and pharyngeal cancers by race (white and black) and sex using each state's average annual personal UV dose. We refer to our data as 'white' rather than 'Caucasian,' which is a specific subgroup of whites, and 'black' rather than African-American because blacks from other countries around the world reside in the U. S. Most oropharyngeal carcinomas harboured human papilloma virus (HPV), so we included cervical cancer as a control for direct UV activation. We found significant correlations between increasing UV dose and pharyngeal cancer in white males (p=0.000808) and females (p=0.0031) but not in blacks. Shockingly, we also found cervical cancer in whites to significantly correlate with increasing UV dose (p=0.0154). Thus, because pharyngeal and cervical cancer correlate significantly with increasing personal UV dose in only the white population, both direct (DNA damage) and indirect (soluble factors) effects may increase the risk of HPV-associated cancer. C1 [Godar, Dianne E.; Tang, Rong] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Merrill, Stephen J.] Marquette Univ, Dept Math Stat & Comp Sci, Milwaukee, WI 53233 USA. RP Godar, DE (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave Bldg 64,Rm 4024, Silver Spring, MD 20993 USA. EM Dianne.Godar@FDA.HHS.GOV FU U.S. Department of Energy; Oak Ridge Institute for Science and Education FX The authors would like to thank Eli Shindell and Samira Ashrafi for some preliminary data analysis. Under an agreement with the U.S. Department of Energy, the Oak Ridge Institute for Science and Education supported S. J. 0Merrill's work at the Food and Drug Administration. NR 60 TC 5 Z9 5 U1 0 U2 6 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 EI 1791-7530 J9 ANTICANCER RES JI Anticancer Res. PD SEP PY 2014 VL 34 IS 9 BP 4993 EP 4999 PG 7 WC Oncology SC Oncology GA AP1VS UT WOS:000341860700044 PM 25202082 ER PT J AU Yu, K Gong, BS Lee, M Liu, ZC Xu, J Perkins, R Tong, WD AF Yu, Ke Gong, Binsheng Lee, Mikyung Liu, Zhichao Xu, Joshua Perkins, Roger Tong, Weida TI Discovering Functional Modules by Topic Modeling RNA-Seq Based Toxicogenomic Data SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID ESTROGEN-RECEPTOR-ALPHA; PPAR-GAMMA; HUMAN MONOCYTES; EXPRESSION; METABOLISM; INHIBITION; PATHWAY AB Toxicogenomics (TGx) endeavors to elucidate the underlying molecular mechanisms through exploring gene expression profiles in response to toxic substances. Recently, RNA-Seq is increasingly regarded as a more powerful alternative to microarrays in TGx studies. However, realizing RNA-Seqs full potential requires novel approaches to extracting information from the complex TGx data. Considering read counts as the number of times a word occurs in a document, gene expression profiles from RNA-Seq are analogous to a word by document matrix used in text mining. Topic modeling aiming at to discover the latent structures in text corpora would be helpful to explore RNA-Seq based TGx data. In this study, topic modeling was applied on a typical RNA-Seq based TGx data set to discover hidden functional modules. The RNA-Seq based gene expression profiles were transformed into documents, on which latent Dirichlet allocation (LDA) was used to build a topic model. We found samples treated by the compounds with the same modes of actions (MoAs) could be clustered based on topic similarities. The topic most relevant to each cluster was identified as a marker topic, which was interpreted by gene enrichment analysis with MoAs then confirmed by compound and pathways associations mined from literature. To further validate the marker topics, we tested topic transferability from RNA-Seq to microarrays. The RNA-Seq based gene expression profile of a topic specifically associated with peroxisome proliferator-activated receptors (PPAR) signaling pathway was used to query samples with similar expression profiles in two different microarray data sets, yielding accuracy of about 85%. This proof-of-concept study demonstrates the applicability of topic modeling to discover functional modules in RNA-Seq data and suggests a valuable computational tool for leveraging information within TGx data in RNA-Seq era. C1 [Yu, Ke; Gong, Binsheng; Lee, Mikyung; Liu, Zhichao; Xu, Joshua; Perkins, Roger; Tong, Weida] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Tong, WD (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM weida.tong@fda.hhs.gov RI Liu, Zhichao/C-4035-2011; Gong, Binsheng/E-2306-2015 OI Gong, Binsheng/0000-0002-8724-5435 FU U.S. Food and Drug Administration [E0721511] FX This study was fully financed by the U.S. Food and Drug Administration (E0721511). NR 35 TC 2 Z9 2 U1 1 U2 8 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 2014 VL 27 IS 9 BP 1528 EP 1536 DI 10.1021/tx500148n PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA AP0JM UT WOS:000341747600007 PM 25083553 ER PT J AU Schmeisser, F Vasudevan, A Soto, J Kumar, A Williams, O Weir, JP AF Schmeisser, Falko Vasudevan, Anupama Soto, Jackeline Kumar, Arunima Williams, Ollie Weir, Jerry P. TI A monoclonal antibody-based immunoassay for measuring the potency of 2009 pandemic influenza H1N1 vaccines SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article DE Influenza virus vaccine; monoclonal antibody; potency assay ID SINGLE-RADIAL-IMMUNODIFFUSION; VIRUS VACCINES; SIMULTANEOUS QUANTIFICATION; MASS-SPECTROMETRY; HEMAGGLUTININ; NEURAMINIDASE; ASSAY; REACTOGENICITY; COMPLEMENT; A/USSR/77 AB BackgroundThe potency of inactivated influenza vaccines is determined using a single radial immunodiffusion (SRID) assay. This assay is relatively easy to standardize, it is not technically demanding, and it is capable of measuring the potency of several vaccine strain subtypes in a multivalent vaccine. Nevertheless, alternative methods that retain the major advantages of the SRID, but with a greater dynamic range of measurement and with reduced reagent requirements, are needed. ObjectivesThe feasibility of an ELISA-based assay format was explored as an alternative potency assay for inactivated influenza vaccines. MethodsSeveral murine monoclonal antibodies (mAbs), specific for the 2009 pandemic H1N1 influenza virus hemagglutinin (HA), were evaluated for their potential to capture and quantify HA antigen. Vaccine samples, obtained from four licensed influenza vaccine manufacturers, included monovalent bulk vaccine, monovalent vaccine, and trivalent vaccine. Traditional SRID potency assays were run in parallel with the mAb-ELISA potency assay using the reference antigen standard appropriate for the vaccine samples being tested. ResultsThe results indicated that the ELISA potency assay can quantify HA over a wide range of concentrations, including vaccine at subpotent doses, and the ELISA and SRID potency values correlated well for most vaccine samples. Importantly, the assay was capable of quantifying A/California HA in a trivalent formulation. ConclusionsThis study demonstrates the general feasibility of the mAb approach and strongly suggests that such ELISAs have potential for continued development as an alternative method to assay the potency of inactivated influenza vaccines. C1 [Schmeisser, Falko; Vasudevan, Anupama; Soto, Jackeline; Kumar, Arunima; Williams, Ollie; Weir, Jerry P.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Weir, JP (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, 8800 Rockville Pike, Bethesda, MD 20892 USA. EM jerry.weir@fda.hhs.gov FU Biomedical Advanced Research and Development Authority, Department of Health and Human Services FX This work was supported in part by the Biomedical Advanced Research and Development Authority, Department of Health and Human Services. Vaccine samples were provided by CSL Ltd., ID Biomedical Corp. of Quebec d/b/a/ GSK Biologicals, Novartis Vaccines and Diagnostics Ltd. and Sanofi Pasteur Inc. Anupama Vasudevan was a participant of the Oak Ridge Institute for Science and Education program at CBER. We thank Carol Weiss and Maryna Eichelberger for thorough review of the manuscript. NR 28 TC 4 Z9 4 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 EI 1750-2659 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD SEP PY 2014 VL 8 IS 5 BP 587 EP 595 DI 10.1111/irv.12272 PG 9 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA AP4RX UT WOS:000342067200013 PM 25087462 ER PT J AU Menis, M Anderson, SA Forshee, RA McKean, S Johnson, C Warnock, R Gondalia, R Mintz, PD Holness, L Worrall, CM Kelman, JA Izurieta, HS AF Menis, Mikhail Anderson, Steven A. Forshee, Richard A. McKean, Stephen Johnson, Chris Warnock, Rob Gondalia, Rahul Mintz, Paul D. Holness, Leslie Worrall, Christopher M. Kelman, Jeffrey A. Izurieta, Hector S. TI Transfusion-related acute lung injury and potential risk factors among the inpatient US elderly as recorded in Medicare claims data, during 2007 through 2011 SO TRANSFUSION LA English DT Article ID CIRCULATORY OVERLOAD; BLOOD-TRANSFUSION; CRITICALLY-ILL; ADMINISTRATIVE DATABASES; PULMONARY-EDEMA; TRALI; REDUCTION; COMPLICATIONS; EPIDEMIOLOGY; PATHOGENESIS AB BackgroundTransfusion-related acute lung injury (TRALI) is a serious complication leading to pulmonary edema and respiratory failure. This study's objective was to assess TRALI occurrence and potential risk factors among inpatient US elderly Medicare beneficiaries, ages 65 and older, during 2007 through 2011. Study Design and MethodsThis retrospective claims-based study utilized large Medicare administrative databases. Transfusions were identified by recorded procedure and revenue center codes. TRALI was ascertained via ICD-9-CM diagnosis code. The study evaluated TRALI rates among the inpatient elderly overall and by calendar year, age, sex, race, blood components, and units transfused. Logistic regression analyses were used to assess potential risk factors. ResultsOf 11,378,264 inpatient transfusion stays for elderly Medicare beneficiaries, 2556 had a recorded TRALI diagnosis code, an overall rate of 22.46 per 100,000 stays. TRALI rates were higher for platelet (PLT)- and plasma-containing transfusions and increased by year and number of units transfused (p<0.0001). Significantly higher odds of TRALI were also found for persons ages 65 to 79 years versus more than 79 years (OR, 1.19; 95% confidence interval CI, 1.09-1.29), females versus males (OR, 1.26; 95% CI, 1.16-1.38), white versus nonwhite (OR, 1.43; 95% CI, 1.27-1.66), and with 6-month histories of postinflammatory pulmonary fibrosis (OR, 1.89; 95% CI, 1.52-2.20), tobacco use (OR, 1.16; 95% CI, 1.00-1.26), and other diseases. ConclusionOur study among the elderly suggests TRALI to be a severe event and identifies a substantially increased TRALI occurrence with greater number of units and with PLT- or plasma-containing transfusions. The study also suggests importance of underlying health conditions, prior recipient alloimmunization, and nonimmune mechanism in TRALI development among the elderly. C1 [Menis, Mikhail; Anderson, Steven A.; Forshee, Richard A.; Mintz, Paul D.; Holness, Leslie; Izurieta, Hector S.] US FDA, Rockville, MD 20852 USA. [McKean, Stephen; Johnson, Chris; Warnock, Rob; Gondalia, Rahul] Acumen LLC, Burlingame, CA USA. [Worrall, Christopher M.; Kelman, Jeffrey A.] Ctr Medicare Serv, Baltimore, MD USA. [Worrall, Christopher M.; Kelman, Jeffrey A.] Ctr Medicaid Serv, Baltimore, MD USA. RP Menis, M (reprint author), US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, 1401 Rockville Pike,HFM 225, Rockville, MD 20852 USA. EM Mikhail.Menis@fda.hhs.gov FU US Food and Drug Administration, Center for Biologics Evaluation and Research FX This study was funded by the US Food and Drug Administration, Center for Biologics Evaluation and Research. NR 68 TC 9 Z9 9 U1 0 U2 1 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 2014 VL 54 IS 9 BP 2182 EP 2193 DI 10.1111/trf.12626 PG 12 WC Hematology SC Hematology GA AP5TJ UT WOS:000342141300009 PM 24673344 ER PT J AU Yang, H Gregori, L Asher, DM Epstein, JS Anderson, SA AF Yang, Hong Gregori, Luisa Asher, David M. Epstein, Jay S. Anderson, Steven A. TI Risk assessment for transmission of variant Creutzfeldt-Jakob disease by transfusion of red blood cells in the United States SO TRANSFUSION LA English DT Article ID PRION PROTEIN; CODON 129; VCJD; PRODUCTS; REMOVAL; BSE; CJD; UK AB BackgroundVariant Creutzfeldt-Jakob disease (vCJD) is transmitted by blood transfusion. To mitigate the risk of transfusion-transmitted vCJD (TTvCJD), the US Food and Drug Administration has recommended deferral of potential at-risk blood donors, but some risk remains. We describe a quantitative risk assessment to estimate residual, postdeferral TTvCJD risk in the United States. Study Design and MethodsWe assumed that certain US donors may have acquired vCJD infection through dietary exposure to the agent of bovine spongiform encephalopathy during time spent in the United Kingdom, France, and other countries in Europe. Because of uncertainties regarding the prevalence of vCJD in the United Kingdom, we used both low and high UK prevalence estimates as model inputs. The model estimated the risk of infection from a transfusion in year 2011 and the cumulative risk from 1980 through 2011. The model was validated by comparing the model predictions with reported cases of vCJD. ResultsUsing the low UK prevalence estimate, the model predicted a mean risk of 1 in 134 million transfusions, zero TTvCJD infections acquired in the year 2011, and zero cumulative clinical TTvCJD cases for the period spanning 1980 to 2011. With the high UK prevalence estimate, the model predicted a mean risk of 1 in 480,000 transfusions, six infections for 2011, and nine cumulative clinical cases from 1980 to 2011. ConclusionsModel validation exercises indicated that predictions based on the low prevalence estimate are more consistent with clinical cases actually observed to date, implying that the risk, while highly uncertain, is likely very small. C1 [Yang, Hong; Gregori, Luisa; Asher, David M.; Epstein, Jay S.; Anderson, Steven A.] US FDA, Rockville, MD 20857 USA. RP Yang, H (reprint author), 1401 Rockville Pike,300N, Rockville, MD 20852 USA. EM hong.yang@fda.hhs.gov FU US Food and Drug Administration FX This work was funded by the US Food and Drug Administration. NR 30 TC 0 Z9 0 U1 1 U2 5 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 2014 VL 54 IS 9 BP 2194 EP 2201 DI 10.1111/trf.12637 PG 8 WC Hematology SC Hematology GA AP5TJ UT WOS:000342141300010 PM 24689837 ER PT J AU Bradford, BM Piccardo, P Ironside, JW Mabbott, NA AF Bradford, Barry M. Piccardo, Pedro Ironside, James W. Mabbott, Neil A. TI Human Prion Diseases and the Risk of Their Transmission During Anatomical Dissection SO CLINICAL ANATOMY LA English DT Review DE prion disease; transmissible spongiform encephalopathy; anatomical dissection; risk of disease transmission; tissue distribution of prion infectivity ID CREUTZFELDT-JAKOB-DISEASE; FATAL FAMILIAL INSOMNIA; CENTRAL-NERVOUS-SYSTEM; BOVINE SPONGIFORM ENCEPHALOPATHY; TYPICAL CLINICAL-FEATURES; CHRONIC WASTING DISEASE; TO-PERSON TRANSMISSION; LEWY BODY DISEASE; ALZHEIMERS-DISEASE; VARIANT CJD AB Prion diseases (or transmissible spongiform encephalopathies) are a unique group of fatal progressive neurodegenerative diseases of the central nervous system. The infectious agent is hypothesized to consist solely of a highly protease-resistant misfolded isoform of the host prion protein. Prions display a remarkable degree of resistance to chemical and physical decontamination. Many common forms of decontamination or neutralization used in infection control are ineffective against prions, except chaotropic agents that specifically disrupt proteins. Human cadaveric prosection or dissection for the purposes of teaching and demonstration of human anatomy has a distinguished history and remains one of the fundamentals of medical education. Iatrogenic transmission of human prion diseases has been demonstrated from the inoculation or implantation of human tissues. Therefore, although the incidence of human prion diseases is rare, restrictions exist upon the use of tissues from patients reported with dementia, specifically the brain and other central nervous system material. A current concern is the potential for asymptomatic variant Creutzfeldt-Jakob disease transmission within the UK population. Therefore, despite the preventative measures, the transmission of prion disease through human tissues remains a potential risk to those working with these materials. In this review, we aim to summarize the current knowledge on human prion disease relevant to those working with human tissues in the context of anatomical dissection. (C) 2014 Wiley Periodicals, Inc. C1 [Bradford, Barry M.; Piccardo, Pedro; Mabbott, Neil A.] Univ Edinburgh, Roslin Inst, Roslin EH25 9RG, Midlothian, Scotland. [Bradford, Barry M.; Piccardo, Pedro; Mabbott, Neil A.] Univ Edinburgh, R D SVS, Roslin EH25 9RG, Midlothian, Scotland. [Piccardo, Pedro] Food & Drug Adm, Rockville, MD USA. [Ironside, James W.] Univ Edinburgh, Ctr Clin Brain Sci, Natl CJD Res & Surveillance Unit, Edinburgh EH4 2XU, Midlothian, Scotland. RP Mabbott, NA (reprint author), Univ Edinburgh, Roslin Inst, Roslin Inst Bldg,Easter Bush Campus, Roslin EH25 9RG, Midlothian, Scotland. EM neil.mabbott@roslin.ed.ac.uk OI Mabbott, Neil/0000-0001-7395-1796; Ironside, James/0000-0001-5869-2108 FU Biotechnological and Biological Sciences Research Council FX Contract grant sponsor: Biotechnological and Biological Sciences Research Council. NR 95 TC 2 Z9 2 U1 1 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0897-3806 EI 1098-2353 J9 CLIN ANAT JI Clin. Anat. PD SEP PY 2014 VL 27 IS 6 BP 821 EP 832 DI 10.1002/ca.22403 PG 12 WC Anatomy & Morphology SC Anatomy & Morphology GA AP2NO UT WOS:000341909400004 PM 24740900 ER PT J AU Meseda, CA Kuhn, J Atukorale, V Campbell, J Weir, JP AF Meseda, Clement A. Kuhn, Jordan Atukorale, Vajini Campbell, Joseph Weir, Jerry P. TI Glycosylated and Nonglycosylated Complement Control Protein of the Lister Strain of Vaccinia Virus SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID SMALLPOX VACCINE; INHIBITOR; IMMUNOGENICITY; PROTECTION; VIRULENCE; COFACTOR; ACAM2000; VARIOLA; PATHWAY; HUMANS AB The vaccinia virus complement control protein (VCP) is a secreted viral protein that binds the C3b and C4b complement components and inhibits the classic and alternative complement pathways. Previously, we reported that an attenuated smallpox vaccine, LC16m8, which was derived from the Lister strain of vaccinia virus (VV-Lister), expressed a glycosylated form of VCP, whereas published sequence data at that time indicated that the VV-Lister VCP has no motif for N-linked glycosylation. We were interested in determining whether the glycosylation of VCP impairs its biological activity, possibly contributing to the attenuation of LC16m8, and the likely origin of the glycosylated VCP. Expression analysis indicated that VV-Lister contains substrains expressing glycosylated VCP and substrains expressing nonglycosylated VCP. Other strains of smallpox vaccine, as well as laboratory strains of vaccinia virus, all expressed nonglycosylated VCP. Individual Lister virus clones expressing either the glycosylated VCP or the nonglycosylated species were isolated, and partially purified VCP from the isolates were found to be functional equivalents in binding human C3b and C4b complement proteins and inhibiting hemolysis and in immunogenicity. Recombinant vaccinia viruses expressing FLAG-tagged glycosylated VCP (FLAG-VCPg) and nonglycosylated VCP (FLAG-VCP) were constructed based on the Western Reserve strain. Purified FLAG-VCP and FLAG-VCPg bind human C3b and C4b and blocked complement-mediated hemolysis. Our data suggest that glycosylation did not affect the biological activity of VCP and thus may not have contributed to the attenuation of LC16m8. In addition, the LC16m8 virus likely originated from a substrain of VV-Lister that expresses glycosylated VCP. C1 [Meseda, Clement A.; Kuhn, Jordan; Atukorale, Vajini; Campbell, Joseph; Weir, Jerry P.] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD 20892 USA. RP Meseda, CA (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD 20892 USA. EM clement.meseda@fda.hhs.gov FU U.S. FDA intramural research fund FX This work was supported by the U.S. FDA intramural research fund. NR 31 TC 0 Z9 0 U1 5 U2 16 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 SEP PY 2014 VL 21 IS 9 BP 1330 EP 1338 DI 10.1128/CVI.00347-14 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AO8SO UT WOS:000341624800019 PM 25030055 ER PT J AU Amiri-Kordestani, L Blumenthal, GM Xu, QC Zhang, LJ Tang, SWH Ha, LN Weinberg, WC Chi, B Candau-Chacon, R Hughes, P Russell, AM Miksinski, SP Chen, XH McGuinn, WD Palmby, T Schrieber, SJ Liu, Q Wang, J Song, PF Mehrotra, N Skarupa, L Clouse, K Al-Hakim, A Sridhara, R Ibrahim, A Justice, R Pazdur, R Cortazar, P AF Amiri-Kordestani, Laleh Blumenthal, Gideon M. Xu, Qiang Casey Zhang, Lijun Tang, Shenghui W. Ha, Linan Weinberg, Wendy C. Chi, Bo Candau-Chacon, Reyes Hughes, Patricia Russell, Anne M. Miksinski, Sarah Pope Chen, Xiao Hong McGuinn, W. David Palmby, Todd Schrieber, Sarah J. Liu, Qi Wang, Jian Song, Pengfei Mehrotra, Nitin Skarupa, Lisa Clouse, Kathleen Al-Hakim, Ali Sridhara, Rajeshwari Ibrahim, Amna Justice, Robert Pazdur, Richard Cortazar, Patricia TI FDA Approval: Ado-Trastuzumab Emtansine for the Treatment of Patients with HER2-Positive Metastatic Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID PHASE-II; ANTIBODY; RECEPTOR; MAYTANSINE; DOCETAXEL; SCHEDULE; SURVIVAL; PLUS AB On February 22, 2013, the FDA licensed ado-trastuzumab emtansine (Kadcyla; Genentech, Inc.) for use as a single agent for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. The clinical basis for licensure was a phase III trial in 991 patients with HER2-positive MBC that randomly allocated patients to receive ado-trastuzumab emtansine (n = 495) or lapatinib in combination with capecitabine (n 496). The coprimary endpoints were progression-free survival (PFS) based on tumor assessments by an independent review committee and overall survival (OS). Statistically significant improvements in PFS and OS were observed in patients receiving ado-trastuzumab emtansine compared with patients receiving lapatinib plus capecitabine [ difference in PFS medians of 3.2 months, HR, 0.65 (95% confidence interval, CI, 0.55-0.77), P < 0.0001 and difference in OS medians of 5.8 months, HR, 0.68 (95% CI, 0.55-0.85), P = 0.0006]. The most common adverse reactions in patients receiving adotrastuzumab emtansine were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased aminotransferase levels, and constipation. Other significant adverse reactions included hepatobiliary disorders and left ventricular dysfunction. Given the PFS and OS results, the benefit-risk profile was considered favorable. (C) 2014 AACR. C1 [Amiri-Kordestani, Laleh; Blumenthal, Gideon M.; Xu, Qiang Casey; Zhang, Lijun; Tang, Shenghui W.; Ha, Linan; Weinberg, Wendy C.; Chi, Bo; Candau-Chacon, Reyes; Hughes, Patricia; Russell, Anne M.; Miksinski, Sarah Pope; Chen, Xiao Hong; McGuinn, W. David; Palmby, Todd; Schrieber, Sarah J.; Liu, Qi; Wang, Jian; Song, Pengfei; Mehrotra, Nitin; Skarupa, Lisa; Clouse, Kathleen; Al-Hakim, Ali; Sridhara, Rajeshwari; Ibrahim, Amna; Justice, Robert; Pazdur, Richard; Cortazar, Patricia] US FDA, Ctr Drug Evaluat & Res, White Oak, MD USA. RP Amiri-Kordestani, L (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Laleh.AmiriKordestani@fda.hhs.gov NR 25 TC 40 Z9 43 U1 1 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 SEP 1 PY 2014 VL 20 IS 17 BP 4436 EP 4441 DI 10.1158/1078-0432.CCR-14-0012 PG 6 WC Oncology SC Oncology GA AP1MV UT WOS:000341835500004 PM 24879797 ER PT J AU Krishnaiah, YSR Yang, YS Bykadi, S Sayeed, VA Khan, MA AF Krishnaiah, Yellela S. R. Yang, Yongsheng Bykadi, Srikant Sayeed, Vilayat A. Khan, Mansoor A. TI Comparative evaluation of in vitro efficacy of colesevelam hydrochloride tablets SO DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY LA English DT Article DE Affinity constant; bile salts; binding; bioequivalence; capacity constant; colesevelam hydrochloride; equilibrium; in vitro; kinetic; langmuir ID TYPE-2 DIABETES-MELLITUS; BILE-ACID SEQUESTRANT; GLYCEMIC CONTROL; LDL CHOLESTEROL; LOWERING AGENT; THERAPY; BINDING; HCL; POTENT; DRUG AB Context: Colesevelam hydrochloride is used as an adjunct to diet and exercise to reduce elevated low-density lipoprotein (LDL) cholesterol in patients with primary hyperlipidemia as well as to improve glycemic control in patients with type 2 diabetes. This is likely to result in submission of abbreviated new drug applications (ANDA). Objective: This study was conducted to compare the efficacy of two tablet products of colesevelam hydrochloride based on the in vitro binding of bile acid sodium salts of glycocholic acid (GC), glycochenodeoxycholic acid (GCDA) and taurodeoxycholic acid (TDCA). Methods: Kinetic binding study was carried out with constant initial bile salt concentrations as a function of time. Equilibrium binding studies were conducted under conditions of constant incubation time and varying initial concentrations of bile acid sodium salts. The unbound concentration of bile salts was determined in the samples of these studies. Langmuir equation was utilized to calculate the binding constants k(1) and k(2). Results: The amount of the three bile salts bound to both the products reached equilibrium at 3 h. The similarity factor (f(2)) was 99.5 based on the binding profile of total bile salts to the test and reference colesevelam tablets as a function of time. The 90% confidence interval for the test to reference ratio of k(2) values were 96.06-112.07 which is within the acceptance criteria of 80-120%. Conclusion: It is concluded from the results that the test and reference tablets of colesevelam hydrochloride showed a similar in vitro binding profile and capacity to bile salts. C1 [Krishnaiah, Yellela S. R.; Yang, Yongsheng; Bykadi, Srikant; Khan, Mansoor A.] US FDA, Div Product Qual Res, Off Testing & Res, Off Pharmaceut Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Sayeed, Vilayat A.] US FDA, Div Chem 3, Off Gener Drugs, Off Pharmaceut Sci,Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Krishnaiah, YSR (reprint author), US FDA, CDER OPS OTR DPQR, New Hampshire Ave, Silver Spring, MD 20993 USA. EM krishnaiah.yellela@fda.hhs.gov NR 37 TC 0 Z9 0 U1 1 U2 9 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0363-9045 EI 1520-5762 J9 DRUG DEV IND PHARM JI Drug Dev. Ind. Pharm. PD SEP PY 2014 VL 40 IS 9 BP 1173 EP 1179 DI 10.3109/03639045.2013.809534 PG 7 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AP0MA UT WOS:000341754400004 PM 23805883 ER PT J AU Xu, F Vostal, JG AF Xu, Fei Vostal, Jaroslav G. TI Inactivation of bacteria via photosensitization of vitamin K3 by UV-A light SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE ultraviolet light; pathogen reduction; vitamin K3; reactive oxygen species ID PATHOGENIC BACTERIA; HUMAN-FIBROBLASTS; PHOTOCHEMOTHERAPY; RIBOFLAVIN; RESISTANCE; MECHANISM; NM; DISINFECTION; CYTOTOXICITY; COMBINATION AB This study investigated inactivation of bacteria with ultraviolet light A irradiation in combination with vitamin K3 as a photosensitizer. Six bacteria including Bacillus cereus, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumoniae, and Escherichia coli suspended in vitamin K3 aqueous solution were exposed to ultraviolet light A. Five of six bacteria, with the exception of Pseudomonas aeruginosa, were reduced by eight logs with 1600M of vitamin K3 and 5.8Jcm(-2) UV-A irradiation. Pseudomonas aeruginosa was reduced by four logs under these conditions. Reactive oxygen species including singlet oxygen, hydroxyl radical and superoxide anion radical were generated in vitamin K3 aqueous solution under UV-A irradiation. These results suggest that vitamin K3 and UV-A irradiation may be effective for bacterial inactivation in environmental and medical applications. C1 [Xu, Fei; Vostal, Jaroslav G.] US FDA, Lab Cellular Hematol, CBER, Rockville, MD 20852 USA. RP Vostal, JG (reprint author), US FDA, Lab Cellular Hematol, CBER, 1401 Rockville Pike, Rockville, MD 20852 USA. EM jaroslav.vostal@fda.hhs.gov NR 47 TC 1 Z9 1 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0378-1097 EI 1574-6968 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD SEP PY 2014 VL 358 IS 1 BP 98 EP 105 DI 10.1111/1574-6968.12544 PG 8 WC Microbiology SC Microbiology GA AP0VO UT WOS:000341784200013 PM 25053393 ER PT J AU Zhang, ZF Meng, XF Wang, Y Xia, XD Wang, X Xi, ML Meng, JH Shi, XM Wang, DP Yang, BW AF Zhang, Zengfeng Meng, Xiaofeng Wang, Yin Xia, Xiaodong Wang, Xin Xi, Meili Meng, Jianghong Shi, Xianming Wang, Dapeng Yang, Baowei TI Presence of qnr, aac(6 ')-Ib, qepA, oqxAB, and Mutations in Gyrase and Topoisomerase in Nalidixic Acid-Resistant Salmonella Isolates Recovered from Retail Chicken Carcasses SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article ID MEDIATED QUINOLONE RESISTANCE; ESCHERICHIA-COLI; UNITED-STATES; ANTIMICROBIAL RESISTANCE; REDUCED SUSCEPTIBILITY; ANTIBIOTIC-RESISTANCE; SEROVAR-TYPHI; PARATYPHI-A; ENTERICA; PREVALENCE AB Four hundred sixty-two nalidixic acid-and/or ciprofloxacin-resistant Salmonella isolates were examined for presence of quinolone-resistance mechanisms. A total of 339 amino acid substitutions were identified in GyrA (204) and ParC (135). Ser83Phe/Asp87Gly (29.4%) were most commonly detected in GyrA in 136 isolates, and to a lesser extent of Asp87Asn (22.8%), Asp87Gly (19.1%), Ser83Phe/Asp87Asn (19.1%), and Ser83Tyr (5.1%). Ser80Arg (97.0%) was detected in ParC in 132 isolates. Simultaneous mutations in GyrA and ParC (n = 109) were commonly detected to be Ser83Phe/Asp87Gly(GyrA)-Ser80Arg(ParC) (35.8%), Asp87Asn (GyrA)-Ser80Arg(ParC) (22.9%), and Ser83Phe/Asp87Asn(GyrA)-Ser80Arg(ParC) (21.1%). qnrA, qnrB, qnrS, aac(6)-Ib, qepA, and oqxAB were detected in 52 (11.3%), 64 (13.9%), 11(2.4%), 107 (23.2%), 6 (1.3%), and 194 (42.0%) of 462 isolates, respectively. Isolates carried more qnr, aac(6')-Ib, qepA, and oqxAB genes, and amino acid substitution in GyrA and ParC was more resistant to nalidixic acid and fluoroquinolones. C1 [Zhang, Zengfeng; Meng, Xiaofeng; Wang, Yin; Xia, Xiaodong; Wang, Xin; Xi, Meili; Meng, Jianghong; Yang, Baowei] Northwest A&F Univ, Coll Food Sci & Engn, Yangling 712100, Shaanxi, Peoples R China. [Meng, Jianghong] Univ Maryland, Dept Nutr & Food Sci, Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 USA. [Shi, Xianming; Wang, Dapeng] Shanghai Jiao Tong Univ, Shanghai 200030, Peoples R China. RP Yang, BW (reprint author), Northwest A&F Univ, Coll Food Sci & Engn, 28 Xinong Rd, Yangling 712100, Shaanxi, Peoples R China. EM ybwsheng@163.com FU National Natural Science Foundation of China [31171682]; Outstanding Doctoral Dissertation of Shaanxi Province, China FX This research was supported in part by the National Natural Science Foundation of China (No. 31171682) and Outstanding Doctoral Dissertation of Shaanxi Province, China. NR 31 TC 3 Z9 3 U1 1 U2 11 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1535-3141 EI 1556-7125 J9 FOODBORNE PATHOG DIS JI Foodborne Pathog. Dis. PD SEP PY 2014 VL 11 IS 9 BP 698 EP 705 DI 10.1089/fpd.2014.1736 PG 8 WC Food Science & Technology SC Food Science & Technology GA AP0RG UT WOS:000341770000005 PM 25188409 ER PT J AU Nemser, SM Doran, T Grabenstein, M McConnell, T McGrath, T Pamboukian, R Smith, AC Achen, M Danzeisen, G Kim, S Liu, Y Robeson, S Rosario, G Wilson, KM Reimschuessel, R AF Nemser, Sarah M. Doran, Tara Grabenstein, Michael McConnell, Terri McGrath, Timothy Pamboukian, Ruiqing Smith, Angele C. Achen, Maya Danzeisen, Gregory Kim, Sun Liu, Yong Robeson, Sharon Rosario, Grisel Wilson, Karen McWilliams Reimschuessel, Renate TI Investigation of Listeria, Salmonella, and Toxigenic Escherichia coli in Various Pet Foods SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article ID DRY DOG FOOD; UNITED-STATES; DIETS; INFECTIONS; CANADA; PREGNANCY; TREATS; HUMANS; SAFETY AB The Veterinary Laboratory Investigation and Response Network (Vet-LIRN), in collaboration with the Food Emergency Response Network (FERN) and its Microbiology Cooperative Agreement Program (MCAP) laboratories, conducted a study to evaluate the prevalence of selected microbial organisms in various types of pet foods. The goal of this blinded study was to help the Center for Veterinary Medicine prioritize potential future pet food-testing efforts. The study also increased the FERN laboratories' screening capabilities for foodborne pathogens in animal feed matrices, since such pathogens may also be a significant health risk to consumers who come into contact with pet foods. Six U. S. Food and Drug Administration FERN MCAP laboratories analyzed approximately 1056 samples over 2 years. Laboratories tested for Salmonella, Listeria, Escherichia coli O157:H7 enterohemorrhagic E. coli, and Shiga toxin-producing strains of E. coli (STEC). Dry and semimoist dog and cat foods purchased from local stores were tested during Phase 1. Raw dog and cat foods, exotic animal feed, and jerky-type treats purchased through the Internet were tested in Phase 2. Of the 480 dry and semimoist samples, only 2 tested positive: 1 for Salmonella and 1 for Listeria greyii. However, of the 576 samples analyzed during Phase 2, 66 samples were positive for Listeria (32 of those were Listeria monocytogenes) and 15 samples positive for Salmonella. These pathogens were isolated from raw foods and jerky-type treats, not the exotic animal dry feeds. This study showed that raw pet foods may harbor food safety pathogens, such as Listeria monocytogenes and Salmonella. Consumers should handle these products carefully, being mindful of the potential risks to human and animal health. C1 [Nemser, Sarah M.; Grabenstein, Michael; Reimschuessel, Renate] US FDA, Ctr Vet Med, Res Off, Laurel, MD 21046 USA. [Doran, Tara] US FDA, Ctr Food Safety & Appl Nutr, Off Analyt & Outreach, College Pk, MD USA. [McConnell, Terri] US FDA, Off Regulatory Affairs, Atlanta, GA USA. [McGrath, Timothy; Pamboukian, Ruiqing; Smith, Angele C.] US FDA, Off Regulatory Affairs, Off Regulatory Sci, Rockville, MD 20857 USA. [Achen, Maya] Abbott Nutr, Columbus, OH USA. [Danzeisen, Gregory] Eurofins Microbiol Labs Inc, Mounds View, MN USA. [Kim, Sun] Florida State Dept Agr, Div Food Safety, Tallahassee, FL USA. [Liu, Yong] Washington Dept Agr, Microbiol Lab, Olympia, WA USA. [Robeson, Sharon] Michigan Dept Community Hlth, Bur Labs, Lansing, MI USA. [Rosario, Grisel] North Carolina Dept Agr & Consumer Serv, Raleigh, NC USA. [Wilson, Karen McWilliams] Michigan Dept Agr & Rural Dev, Geagley Lab, E Lansing, MI USA. RP Nemser, SM (reprint author), US FDA, Ctr Vet Med, Res Off, 8401 Muirkirk Rd, Laurel, MD 21046 USA. EM sarah.nemser@fda.hhs.gov NR 26 TC 6 Z9 6 U1 6 U2 37 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1535-3141 EI 1556-7125 J9 FOODBORNE PATHOG DIS JI Foodborne Pathog. Dis. PD SEP PY 2014 VL 11 IS 9 BP 706 EP 709 DI 10.1089/fpd.2014.1748 PG 4 WC Food Science & Technology SC Food Science & Technology GA AP0RG UT WOS:000341770000006 PM 24824368 ER PT J AU Beer, K Rothschild, K AF Beer, Kenneth Rothschild, Karen TI Importing Injectables SO JOURNAL OF DRUGS IN DERMATOLOGY LA English DT Editorial Material C1 [Beer, Kenneth] Beer Gen Surg & Esthet Dermatol, W Palm Beach, FL 33401 USA. [Beer, Kenneth] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Rothschild, Karen] US FDA, Washington, DC 20204 USA. RP Beer, K (reprint author), Beer Gen Surg & Esthet Dermatol, W Palm Beach, FL 33401 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU JOURNAL OF DRUGS IN DERMATOLOGY PI NEW YORK PA 377 PARK AVE SOUTH, 6TH FLOOR, NEW YORK, NY 10016 USA SN 1545-9616 J9 J DRUGS DERMATOL JI J. Drugs Dermatol. PD SEP PY 2014 VL 13 IS 9 BP 1156 EP 1158 PG 3 WC Dermatology SC Dermatology GA AP1CI UT WOS:000341803600025 PM 25226018 ER PT J AU Nguyen, AV Cohen, NJ Gao, HJ Fishbein, DB Keir, J Ocana, JM Senini, L Flores, A Waterman, SH AF Nguyen, An V. Cohen, Nicole J. Gao, Hongjiang Fishbein, Daniel B. Keir, Jane Ocana, J. Miguel Senini, Lori Flores, Aleta Waterman, Stephen H. TI Knowledge, Attitudes, and Practices among Border Crossers during Temporary Enforcement of a Formal Entry Requirement for Mexican-Style Soft Cheeses, 2009 SO JOURNAL OF FOOD PROTECTION LA English DT Article ID SURVEILLANCE NETWORK FOODNET; LISTERIA-MONOCYTOGENES; UNITED-STATES; MYCOBACTERIUM-BOVIS; HUMAN BRUCELLOSIS; QUESO FRESCO; SALMONELLA; OUTBREAKS; CONSUMPTION; CALIFORNIA AB Mexican-style soft cheese known as queso fresco (QF), which is often unpasteurized, has been implicated in outbreaks of foodborne illness in the United States. The U.S. Food and Drug Administration (FDA) exercises discretion in enforcement of noncommercial importation of cheese. To test control measures aimed at decreasing unlawful QF importation, in 2009 the FDA temporarily enforced a requirement for formal commercial entry for all cheeses over 5 lb (2.3 kg) at the San Diego-Tijuana border. Enforcement was combined with educational outreach. Border crossers importing cheese and those not importing cheese were surveyed at the beginning and end of the temporary enforcement period. Data collected included participant demographic information, knowledge of QF-associated health risks, and attitudes and practices regarding QF consumption and importation. We surveyed 306 importers and 381 nonimporters. Compared with nonimporters, importers had a lower level of knowledge regarding QF-associated health risks (P < 0.0001). Border crossers carrying cheese were more likely to have less education, be U.S. or dual residents, consume QF more frequently, and cross the border less often. Importation and consumption of unpasteurized QF remained prevalent among border crossers during the temporary enforcement period, and the level of knowledge regarding QF-associated risks remained low among these crossers. More vigorous, sustained messaging targeted at high-risk groups is needed to change behaviors. Definition and consistent enforcement of limits will likely be needed to reduce QF importation and the risk of QF-associated diseases along the U.S.-Mexico border; however, public health benefits will need to be balanced against the cost of enforcement. C1 [Nguyen, An V.; Cohen, Nicole J.; Gao, Hongjiang; Fishbein, Daniel B.; Keir, Jane; Ocana, J. Miguel; Waterman, Stephen H.] US Ctr Dis Control & Prevent, Div Global Migrat & Quarantine, Atlanta, GA 30333 USA. [Nguyen, An V.] Council State & Terr Epidemiologists, Atlanta, GA 30341 USA. [Keir, Jane] SRA Int, Atlanta, GA 30329 USA. [Senini, Lori] Hlth & Human Serv Agcy, San Diego Cty Off Publ Hlth Serv, San Diego, CA 92101 USA. [Flores, Aleta] US FDA, Alameda, CA 94502 USA. RP Cohen, NJ (reprint author), US Ctr Dis Control & Prevent, Div Global Migrat & Quarantine, Atlanta, GA 30333 USA. EM ncohen@cdc.gov FU Intramural CDC HHS [CC999999] NR 32 TC 1 Z9 1 U1 2 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 SEP PY 2014 VL 77 IS 9 BP 1571 EP 1578 DI 10.4315/0362-028X.JFP-13-395 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA AP1UE UT WOS:000341856300015 PM 25198849 ER PT J AU Sullivan, HW O'Donoghue, AC Aikin, KJ AF Sullivan, Helen W. O'Donoghue, Amie C. Aikin, Kathryn J. TI Primary Care Physicians' Use of FDA-Approved Prescription Drug Labels SO JOURNAL OF THE AMERICAN BOARD OF FAMILY MEDICINE LA English DT Article DE Drug Labeling; Prescription Drugs ID INFORMATION; BENEFIT; RISK AB Background: In 2006, the US Food and Drug Administration reorganized the approved label format and content for prescription drugs -also known as the prescribing information (PI). This research examines primary care physicians' use of the new PI and how it may influence their perceptions about prescription drugs. Methods: A total of 500 physicians responded to an Internet survey that displayed an interactive PI for a fictitious combination pain relief/heart attack-reducing drug. The physicians answered questions about perceived risk, perceived benefit, and intention to prescribe that focused on either the treatment indication or the prevention indication. Results: Physicians viewed PI sections in order, most often viewing sections relevant to safe use, such as Warnings and Precautions and Dosage and Administration. When asked to think about the drug's efficacy, many viewed the Clinical Studies section. Viewing certain PI sections was associated with greater perceived risk and lower perceived benefits and intention to prescribe. Conclusions: These results suggest that the information in the PI could affect physician decision making and do not support further reorganization of the PI. C1 [Sullivan, Helen W.; O'Donoghue, Amie C.; Aikin, Kathryn J.] US FDA, Silver Spring, MD USA. RP Sullivan, HW (reprint author), 10903 New Hampshire Ave,Bldg 51,Rm 3238, Silver Spring, MD 20993 USA. EM helen.sullivan@fda.hhs.gov FU U.S. Food and Drug Administration FX The study was funded by the U.S. Food and Drug Administration. NR 13 TC 0 Z9 0 U1 2 U2 3 PU AMER BOARD FAMILY MEDICINE PI LEXINGTON PA 2228 YOUNG DR, LEXINGTON, KY 40505 USA SN 1557-2625 EI 1558-7118 J9 J AM BOARD FAM MED JI J. Am. Board Fam. Med. PD SEP-OCT PY 2014 VL 27 IS 5 BP 694 EP 698 DI 10.3122/jabfm.2014.05.140039 PG 5 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA AP2GU UT WOS:000341891500014 PM 25201939 ER PT J AU Margulis, AV Kang, EM Hammad, TA AF Margulis, Andrea V. Kang, Elizabeth M. Hammad, Tarek A. TI Patterns of Prescription of Antidepressants and Antipsychotics Across and Within Pregnancies in a Population-Based UK Cohort SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Antidepressants; Antipsychotics; Clinical Practice Research Datalink; Drug utilization; Longitudinal; Pregnancy ID PRACTICE RESEARCH DATABASE; DRUG-USE; OUTCOMES; RISK; MALFORMATIONS; MEDICATIONS; PREVALENCE; VALIDATION; WOMEN AB Although antidepressant and antipsychotic utilization by gestational trimester has been described, longitudinal prescription patterns within pregnancies have received less attention. All mothers in the Clinical Practice Research Datalink's Mother Baby Link enrolled from 6 months before pregnancy to 3 months after delivery, with delivery date between 01/1989 and 12/2010 were included (n = 421,645). Drug use prevalence was calculated as the number of women with prescriptions for antidepressants or antipsychotics in capsules/tablets in the 3 months before pregnancy (T0), the first (T1), second (T2), or third (T3) pregnancy trimesters, or the 3 months after delivery (T4). In each pregnancy, prescriptions in T0 and T3 were compared to identify treatment discontinuation, simplification (some drugs discontinued or dose lowered), no treatment change, intensification (drugs added to prior treatment or dose increased), and start. Antidepressant use in T0 through T4 was 4.69, 2.81, 1.31, 1.34, and 5.46 %, respectively. Of 19,774 T0 antidepressant users, 79.57 % discontinued, 5.13 % simplified, 9.06 % did not change, and 2.19 % intensified treatment. 0.40 % of non-users in T0 started antidepressants by T3. Antipsychotic use in T0 through T4 was 0.57, 1.34, 0.54, 0.28 and 0.38 %. Excluding prochlorperazine, it was 0.15, 0.13, 0.08, 0.07 and 0.15 %, respectively; of 639 T0 users, 72.30 % discontinued, 7.51 % simplified, 11.11 % did not change, and 4.07 % intensified treatment. 0.03 % of non-users in T0 started antipsychotics by T3. Cross-sectional and longitudinal analyses identified a post-conception decrease in antidepressant and antipsychotic prescribing. Longitudinal treatment assessment additionally captured several treatment patterns among those who do not discontinue treatment that usually stay unrecognized. C1 [Margulis, Andrea V.; Kang, Elizabeth M.; Hammad, Tarek A.] US FDA, Dept Epidemiol DEP 1 1, Off Surveillance & Epidemiol OSE, Ctr Drug Evaluat & Res CDER, Silver Spring, MD 20993 USA. RP Kang, EM (reprint author), US FDA, Dept Epidemiol DEP 1 1, Off Surveillance & Epidemiol OSE, Ctr Drug Evaluat & Res CDER, 10903 New Hampshire Ave,Bldg 22, Silver Spring, MD 20993 USA. EM Elizabeth.Kang@fda.hhs.gov RI CPRD, CPRD/B-9594-2017 NR 23 TC 11 Z9 11 U1 2 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD SEP PY 2014 VL 18 IS 7 BP 1742 EP 1752 DI 10.1007/s10995-013-1419-2 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AO9RM UT WOS:000341693900024 PM 24374729 ER PT J AU King, KE Reddi, DM Ponnamperuma, RM Gerdes, M Weinberg, WC AF King, Kathryn E. Reddi, Deepti Muraleedharan Ponnamperuma, Roshini M. Gerdes, Michael Weinberg, Wendy C. TI Dysregulated Delta Np63 alpha Negatively Regulates the Maspin Promoter in Keratinocytes Via Blocking Endogenous p73 Binding SO MOLECULAR CARCINOGENESIS LA English DT Article DE squamous cell cancer; p53 homologs; protease inhibitory proteins ID PLASMINOGEN-ACTIVATOR INHIBITOR-2; SQUAMOUS-CELL CARCINOMA; HEPATOCYTE GROWTH-FACTOR; SUPPRESSOR GENE MASPIN; INDUCED APOPTOSIS; TUMOR-SUPPRESSOR; TISSUE INHIBITOR; SERINE-PROTEASE; TNF-ALPHA; MATRIX METALLOPROTEINASES AB While overexpression of the p63 isoform, Delta Np63 alpha, has been reported in squamous cell cancers, the contribution of p63 to cancer pathogenesis remains unclear. We previously demonstrated that overexpressed Delta Np63 alpha aberrantly maintains proliferation of primary mouse keratinocytes under conditions that normally induce growth arrest and differentiation. To identify genes downstream of dysregulated Delta Np63 alpha that may contribute to squamous cancer development and progression, we performed microarray analyses using primary mouse keratinocytes. Herein we report that elevated Delta Np63 alpha differentially regulates genes involved in a variety of cellular functions. Of note, multiple protease inhibitor mRNAs were downregulated including: maspin (serpinB5); plasminogen activator inhibitor-2 (PAI-2; serpinB2); and tissue inhibitor of metalloproteinase-3 (TIMP-3). Correspondingly, secreted TIMP-3 and PAI-2 protein declined in the presence of dysregulated Delta Np63 alpha, however secreted maspin remained stable. Intracellular maspin protein expression decreased in response to overexpressed Delta Np63 alpha, as did PAI-2. In contrast, TIMP-3 protein was not detected intracellularly, supporting a solely extracellular function. Electrophoretic mobility shift assays (EMSAs) using a maspin promoter p53/p63 consensus sequence revealed endogenous transcription factor(s) binding to this sequence in keratinocytes that was disrupted by overexpressed Delta Np63 alpha. This was confirmed by ChIP assays. This binding was interrupted by the addition of antibodies recognizing p73, but not p53 or p63, and significantly diminished in EMSA reactions from p73(-/-) keratinocytes, confirming p73 as a constituent. Physical association between p73/Delta Np63 alpha was observed in control beta-gal overexpressing keratinocytes and was enhanced in the presence of overexpressed Delta Np63 alpha These findings underscore the importance of properly balanced p53 homologs for tissue homeostasis. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. C1 [King, Kathryn E.; Reddi, Deepti Muraleedharan; Ponnamperuma, Roshini M.; Weinberg, Wendy C.] US FDA, Off Biotechnol Prod, CDER, Bethesda, MD 20892 USA. [Gerdes, Michael] NCI, NIH, Bethesda, MD 20892 USA. RP Weinberg, WC (reprint author), US FDA, Mol Oncol Lab, Off Biotechnol Prod, Ctr Drug Evaluat & Res, 29 Lincoln Dr,HFD 123, Bethesda, MD 20892 USA. NR 121 TC 1 Z9 1 U1 0 U2 2 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 SEP PY 2014 VL 53 IS 9 BP 698 EP 710 DI 10.1002/mc.22022 PG 13 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA AP4QD UT WOS:000342062100003 PM 23475637 ER PT J AU Wang, J Wang, YMC Ahn, HY AF Wang, Jie Wang, Yow-Ming C. Ahn, Hae-Young TI Biological Products for the Treatment of Psoriasis: Therapeutic Targets, Pharmacodynamics and Disease-Drug-Drug Interaction Implications SO AAPS JOURNAL LA English DT Review DE disease-drug-drug interactions (Disease-DDI); inflammatory disease; IL-6; interleukin-6; proinflammatory cytokines; psoriasis ID PLACEBO-CONTROLLED TRIAL; INTERLEUKIN-12/23 MONOCLONAL-ANTIBODY; CHRONIC PLAQUE PSORIASIS; DOUBLE-BLIND; SERUM-LEVELS; TNF-ALPHA; CERTOLIZUMAB PEGOL; ACTIVE PSORIASIS; GROWTH-FACTOR; EXPRESSION AB Psoriasis is a chronic inflammatory skin disease condition that involves altered expression of a broad spectrum of proinflammatory cytokines which are associated with activation of T cells and proliferation of keratinocytes. Currently approved biological products for psoriasis treatment fall into two main classes: cytokine modulators and biologics targeting T cells. In psoriatic patients, elevated levels of proinflammatory cytokines are observed. Elevated proinflammatory cytokines can suppress some cytochrome P450 (CYP) enzymes, and the treatment of psoriasis with biological products can reduce proinflammatory cytokine levels. Therefore, the exposure of CYP substrate drugs is anticipated to be affected by the psoriasis disease resulting in a higher exposure than in healthy state (named disease-drug interaction) as well as by the biological treatments due to disease improvements resulting in a decrease in exposure (named disease-drug-drug interaction, disease-DDI). However, the quantitative impact on CYP substrate exposure due to disease or due to treatment with biological products remains to be evaluated. The objective of the current review is to provide an overview of the therapeutic targets and cytokine-related pharmacodynamic effects of biological products in psoriasis treatment with a particular focus on their implications for disease-DDI. The clinical study design considerations for psoriasis disease-DDI evaluation are also discussed. C1 [Wang, Jie; Wang, Yow-Ming C.; Ahn, Hae-Young] US FDA, Div Clin Pharmacol 3, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Wang, YMC (reprint author), US FDA, Div Clin Pharmacol 3, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM yowming.wang@fda.hhs.gov NR 82 TC 2 Z9 3 U1 2 U2 8 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 2014 VL 16 IS 5 BP 938 EP 947 DI 10.1208/s12248-014-9637-0 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AO6BT UT WOS:000341434100006 PM 24993574 ER PT J AU Zhang, HY Li, HT Song, W Shen, DD Skanchy, D Shen, K Lionberger, RA Rosencrance, SM Yu, LX AF Zhang, Huyi Li, Haitao Song, Wei Shen, Diandian Skanchy, David Shen, Kun Lionberger, Robert A. Rosencrance, Susan M. Yu, Lawrence X. TI Completeness Assessment of Type II Active Pharmaceutical Ingredient Drug Master Files under Generic Drug User Fee Amendment: Review Metrics and Common Incomplete Items SO AAPS JOURNAL LA English DT Article DE active pharmaceutical ingredient; completeness assessment; drug master file; drug substance; GDUFA AB Under the Generic Drug User Fee Amendments (GDUFA) of 2012, Type II active pharmaceutical ingredient (API) drug master files (DMFs) must pay a user fee and pass a Completeness Assessment (CA) before they can be referenced in an Abbreviated New Drug Application (ANDA), ANDA amendment, or ANDA prior approval supplement (PAS). During the first year of GDUFA implementation, from October 1, 2012 to September 30, 2013, approximately 1,500 Type II API DMFs received at least one cycle of CA review and more than 1,100 Type II DMFs were deemed complete and published on FDA's "Available for Reference List". The data from CA reviews were analyzed for factors that influenced the CA review process and metrics, as well as the areas of DMF submissions which most frequently led to an incomplete CA status. The metrics analysis revealed that electronic DMFs appear to improve the completeness of submission and shorten both the review and response times. Utilizing the CA checklist to compile and proactively update the DMFs improves the chance for the DMFs to pass the CA in the first cycle. However, given that the majority of DMFs require at least two cycles of CA before being deemed complete, it is recommended that DMF fees are paid 6 months in advance of the ANDA submissions in order to avoid negatively impacting the filling status of the ANDAs. C1 [Zhang, Huyi; Li, Haitao; Song, Wei; Shen, Diandian; Skanchy, David; Shen, Kun; Lionberger, Robert A.; Rosencrance, Susan M.; Yu, Lawrence X.] US FDA, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Skanchy, D (reprint author), US FDA, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM david.skanchy@fda.hhs.gov NR 8 TC 1 Z9 1 U1 3 U2 7 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 2014 VL 16 IS 5 BP 1132 EP 1141 DI 10.1208/s12248-014-9630-7 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AO6BT UT WOS:000341434100025 PM 25034968 ER PT J AU Darpo, B Garnett, C Benson, CT Keirns, J Leishman, D Malik, M Mehrotra, N Prasad, K Riley, S Rodriguez, I Sager, P Sarapa, N Wallis, R AF Darpo, Borje Garnett, Christine Benson, Charles T. Keirns, James Leishman, Derek Malik, Marek Mehrotra, Nitin Prasad, Krishna Riley, Steve Rodriguez, Ignacio Sager, Philip Sarapa, Nenad Wallis, Robert TI Cardiac Safety Research Consortium: Can the thorough QT/QTc study be replaced by early QT assessment in routine clinical pharmacology studies? Scientific update and a research proposal for a path forward SO AMERICAN HEART JOURNAL LA English DT Article ID STATISTICAL ISSUES; DRUG DEVELOPMENT; REPOLARIZATION; PROLONGATION; TRAFFICKING; INTERVAL; MOXIFLOXACIN; SIMULATION; VARDENAFIL; GUIDANCE AB The International Conference on Harmonization E14 guidance for the clinical evaluation of QT/QTc interval prolongation requires almost all new drugs to undergo a dedicated clinical study, primarily in healthy volunteers, the so-called TQT study. Since 2005, when the E14 guidance was implemented in United States and Europe, close to 400 TQT studies have been conducted. In February 2012, the Cardiac Safety Research Consortium held a think tank meeting at Food and Drug Administration's White Oak campus to discuss whether "QT assessment" can be performed as part of routine phase1 studies. Based on these discussions, a group of experts convened to discuss how to improve the confidence in QT data from early clinical studies, for example, the First-Time-in-Human trial, through collection of serial electrocardiograms and pharmacokinetic samples and the use of exposure response analysis. Recommendations are given on how to design such "early electrocardiogram assessment," and the limitation of not having a pharmacologic-positive control in these studies is discussed. A research path is identified toward collecting evidence to replace or provide an alternative to the dedicated TQT study. C1 [Darpo, Borje] Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden. [Darpo, Borje] iCardiac Technol, Rochester, NY USA. [Garnett, Christine] Certara, St Louis, MO USA. [Benson, Charles T.] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA. [Keirns, James] Astellas Pharma Global Dev Inc, Global Clin Pharmacol & Exploratory Dev, Northbrook, IL USA. [Leishman, Derek] Eli Lilly & Co, Lilly Res Labs, Global PK PD & Pharmacometr, Indianapolis, IN 46285 USA. [Malik, Marek] Univ London, St Pauls Cardiac Electrophysiol, London, England. [Mehrotra, Nitin] US FDA, Div Pharmacometr, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Prasad, Krishna] DoH, Med & Healthcare Prod Regulatory Agcy, London, England. [Riley, Steve] Pfizer Inc, Global Innovat Pharma Business, Clin Pharmacol, Groton, CT 06340 USA. [Rodriguez, Ignacio] Roche TCRC Inc, Pharma Dev Safety Risk Management, New York, NY USA. [Sager, Philip] Stanford Sch Med, Palo Alto, CA USA. [Sarapa, Nenad] Bayer Healthcare Inc, Clin Sci, Whippany, NJ USA. [Wallis, Robert] Safety Pharmacol Consultant, Sandwich, Kent, England. RP Darpo, B (reprint author), Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden. EM borje.darpo@telia.com FU British Heart Foundation [PG/12/77/29857, PG/13/54/30358]; Medical Research Council [MR/J008761/1] NR 47 TC 18 Z9 18 U1 0 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD SEP PY 2014 VL 168 IS 3 BP 262 EP 272 DI 10.1016/j.ahj.2014.06.003 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO4QY UT WOS:000341327200005 PM 25173536 ER PT J AU Williams, M Mayer, SV Johnson, WL Chen, RB Volkova, E Vilcarromero, S Widen, SG Wood, TG Suarez-Ognio, L Long, KC Hanley, KA Morrison, AC Vasilakis, N Halsey, ES AF Williams, Maya Mayer, Sandra V. Johnson, William L. Chen, Rubing Volkova, Evgeniya Vilcarromero, Stalin Widen, Steven G. Wood, Thomas G. Suarez-Ognio, Luis Long, Kanya C. Hanley, Kathryn A. Morrison, Amy C. Vasilakis, Nikos Halsey, Eric S. TI Lineage II of Southeast Asian/American DENV-2 Is Associated with a Severe Dengue Outbreak in the Peruvian Amazon SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID ADJUSTED LIFE YEARS; HEMORRHAGIC-FEVER; ECONOMIC-IMPACT; VIRUS TYPE-2; FEBRILE ILLNESSES; SHOCK SYNDROME; PUERTO-RICO; 3 DECADES; AMERICA; INFECTION AB During 2010 and 2011, the Loreto region of Peru experienced a dengue outbreak of unprecedented magnitude and severity for the region. This outbreak coincided with the reappearance of dengue virus-2 (DENV-2) in Loreto after almost 8 years. Whole-genome sequence indicated that DENV-2 from the outbreak belonged to lineage II of the southeast Asian/American genotype and was most closely related to viruses circulating in Brazil during 2007 and 2008, whereas DENV-2 previously circulating in Loreto grouped with lineage I (DENV-2 strains circulating in South America since 1990). One amino acid substitution (NS5 A811V) in the 2010 and 2011 isolates resulted from positive selection. However, the 2010 and 2011 DENV-2 did not replicate to higher titers in monocyte-derived dendritic cells and did not infect or disseminate in a higher proportion of Aedes aegypti than DENV-2 isolates previously circulating in Loreto. These results suggest that factors other than enhanced viral replication played a role in the severity of this outbreak. C1 US Naval Med Res Unit 6, Dept Virol, Lima, Peru. [Mayer, Sandra V.; Chen, Rubing] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Mayer, Sandra V.; Chen, Rubing] Univ Texas Med Branch, Ctr Biodef & Emerging Infect Dis, Galveston, TX 77555 USA. [Hanley, Kathryn A.] New Mexico State Univ, Dept Biol, Las Cruces, NM 88003 USA. [Vilcarromero, Stalin; Morrison, Amy C.] US Naval Med Res Unit 6, Dept Virol, Iquitos, Peru. [Widen, Steven G.; Wood, Thomas G.] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. Minist Salud Peru, Direcc Gen Epidemiol, Lima, Peru. [Morrison, Amy C.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Vasilakis, Nikos] Univ Texas Med Branch, Inst Human Infect & Immun, Galveston, TX 77555 USA. [Vasilakis, Nikos] Univ Texas Med Branch, Ctr Trop Dis, Galveston, TX 77555 USA. [Williams, Maya] Naval Med Res Ctr, Viral & Rickettsial Dis Dept, Silver Spring, MD 20910 USA. [Johnson, William L.] Colorado Sch Publ Hlth, Ft Collins, CO USA. [Volkova, Evgeniya] US FDA, Lab Emerging Pathogens, Ctr Biol Evaluat & Res, Div Emerging & Transfus Transmitted Dis, Bethesda, MD 20014 USA. [Suarez-Ognio, Luis] Univ Ciencias Aplicadas, Fac Hlth Sci, Lima, Peru. [Long, Kanya C.] Andrews Univ, Dept Biol, Berrien Springs, MI 49104 USA. [Vasilakis, Nikos] Univ Texas Med Branch, Dept Pathol, Ctr Biodef & Emerging Infect Dis, Galveston, TX 77555 USA. [Halsey, Eric S.] US Ctr Dis Control & Prevent, Malaria Branch, Atlanta, GA USA. RP Williams, M (reprint author), Naval Med Res Ctr, Viral & Rickettsial Dis Dept, 503 Robert Grant Ave,Room 3A14, Silver Spring, MD 20910 USA. EM maya.williams@med.navy.mil; samayer@utmb.edu; w.johnson@rams.colostate.edu; ruchen@utmb.edu; Evgeniya.volkova@fda.hhs.gov; stalinf@yahoo.com; sgwiden@utmb.edu; tgwood@utmb.edu; luis.suarez@upc.edu.pe; kanya@andrews.edu; khanley@nmsu.edu; amy.aegypti@gmail.com; nivasila@utmb.edu; ehalsey@cdc.gov OI Vilcarromero, Stalin/0000-0002-9097-0638 FU Global Emerging Infections Surveillance and Response System, a Division of the Armed Forces Health Surveillance Center [800000.82000.25GB.B0016]; Military Infectious Diseases Research Program [6000 RAD1.S.B0302]; National Center for Research Resources Grant [5P20RR016480-12]; National Institute of General Medical Sciences Grant [8 P20 GM103451-12]; Department of Pathology, University of Texas Medical Branch; NIH [HHSN272201000040I/HHSN27200004/D04] FX This work was supported by the Global Emerging Infections Surveillance and Response System, a Division of the Armed Forces Health Surveillance Center (Work Unit Number 800000.82000.25GB.B0016) and the Military Infectious Diseases Research Program (Work Unit Number 6000 RAD1.S.B0302). W.L.J. and K.A.H. were supported by National Center for Research Resources Grant 5P20RR016480-12 and National Institute of General Medical Sciences Grant 8 P20 GM103451-12. N.V. was supported by start-up funds provided by the Department of Pathology, University of Texas Medical Branch and NIH contract HHSN272201000040I/HHSN27200004/D04. NR 62 TC 10 Z9 11 U1 1 U2 5 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 2014 VL 91 IS 3 BP 611 EP 620 DI 10.4269/ajtmh.13-0600 PG 10 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA AO4WQ UT WOS:000341342500029 PM 25002298 ER PT J AU Warady, BA Silverstein, DM AF Warady, Bradley A. Silverstein, Douglas M. TI Management of anemia with erythropoietic-stimulating agents in children with chronic kidney disease SO PEDIATRIC NEPHROLOGY LA English DT Review DE Anemia; Erythropoietin; Hemoglobin; Biosimilar ID RECOMBINANT-HUMAN-ERYTHROPOIETIN; RED-CELL APLASIA; CHRONIC-RENAL-FAILURE; LEFT-VENTRICULAR HYPERTROPHY; QUALITY-OF-LIFE; PERITONEAL-DIALYSIS; HEMODIALYSIS-PATIENTS; DARBEPOETIN-ALPHA; PEDIATRIC-PATIENTS; ADVERSE OUTCOMES AB Anemia management is an important component of the care provided to children with chronic kidney disease (CKD) and influences both morbidity and mortality risk. The introduction of recombinant human erythropoietin to the treatment regimen three decades ago revolutionized the therapy and significantly decreased the need for repeated blood transfusions and exposure to associated risks. Recent data on the efficacy and complications associated with erythropoietic-stimulating agent (ESA) usage has, however, prompted a reassessment of treatment-related recommendations. This review will address these recommendations, in addition to describing pediatric outcomes associated with current ESAs and presenting information on alternative ESAs, many of which will likely soon be incorporated into clinical practice. C1 [Silverstein, Douglas M.] US FDA, Renal Devices Branch RNDB, Off Device Evaluat, Silver Spring, MD 20903 USA. [Warady, Bradley A.] Childrens Mercy Hosp & Clin, Kansas City, MO 64108 USA. RP Silverstein, DM (reprint author), US FDA, Renal Devices Branch RNDB, Off Device Evaluat, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM bwarady@cmh.edu; dsilverstein2001@yahoo.com NR 125 TC 1 Z9 2 U1 0 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X EI 1432-198X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD SEP PY 2014 VL 29 IS 9 BP 1493 EP 1505 DI 10.1007/s00467-013-2557-x PG 13 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA AO5IM UT WOS:000341377700003 PM 24005791 ER PT J AU Houstoun, M Reichman, ME Graham, DJ Nambiar, S Shamsuddin, H Jones, SC Cao, K Wernecke, M Lam, C Worrall, CM MaCurdy, TE Kelman, JA AF Houstoun, Monika Reichman, Marsha E. Graham, David J. Nambiar, Sumathi Shamsuddin, Hala Jones, S. Christopher Cao, Kelly Wernecke, Michael Lam, Chelsea Worrall, Chris M. MaCurdy, Thomas E. Kelman, Jeffrey A. TI Use of an active surveillance system by the FDA to observe patterns of quinine sulfate use and adverse hematologic outcomes in CMS Medicare data SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE quinine; hematologic; active surveillance; pharmacoepidemiology AB Purpose In 2005, the Food and Drug Administration approved Qualaquin (quinine) for treatment of malaria and later ordered unapproved quinine formulations off the market. In 2009, labeling for Qualaquin added a warning for use for leg cramps, as serious hematologic reactions could occur. We examined quinine use trends among Medicare beneficiaries focusing on indications for use and associations with adverse hematologic outcomes. Methods Medicare beneficiaries, aged 65years and older, in 2006-2012, were included in incident quinine or comparator, diltiazem, cohorts if 183days prior to dispensing, they were enrolled in Medicare, had no dispensing of quinine, diltiazem, ticlodipine, clopidogrel, and sulfonamide drugs, and had no diagnoses of thrombocytopenia, immune thrombocytopenic purpura (ITP), thrombotic microangiopathy (TMA), or hemolytic-uremic syndrome (HUS). Diagnoses of malaria or leg cramps were observed during 183days prior to index dispensing. Outcomes of ITP, TMA, or HUS in inpatient or emergency room settings were then observed during drug use. Results Prevalent use of quinine decreased by 99%, from 419675 to 6036 users during 2006-2012. Of 88066 quinine users, 9 had diagnoses of malaria and 36218 had leg cramps. Incidence rates (per 1000 person-years) for ITP were quinine 1.67 and diltiazem 0.40 [incidence rate ratio 4.2 (95% confidence interval 2.5, 6.5)], for TMA were quinine 0.23 and diltiazem 0.03 [incidence rate ratio 6.9 (95% confidence interval 1.3, 24.0)], and for HUS were quinine 0 and diltiazem 0.01. Conclusions Use of quinine decreased substantially, although diagnoses of leg cramps persist. To our knowledge, this is the first demonstration of an association for quinine and ITP and TMA in claims data. Copyright (c) 2014 John Wiley & Sons, Ltd.. C1 [Houstoun, Monika; Reichman, Marsha E.; Graham, David J.; Jones, S. Christopher; Cao, Kelly] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Nambiar, Sumathi; Shamsuddin, Hala] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Wernecke, Michael; Lam, Chelsea] Acumen LLC, Burlingame, CA USA. [Worrall, Chris M.; Kelman, Jeffrey A.] CMS CM, Washington, DC USA. [MaCurdy, Thomas E.] Stanford Univ, Stanford, CA 94305 USA. RP Houstoun, M (reprint author), US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, WO22 RM 4466 10993 New Hampshire Ave, Silver Spring, MD 20993 USA. EM monika.houstoun@fda.hhs.gov FU FDA Sentinel CMS Interagency Agreement FX This project was funded by the FDA Sentinel CMS Interagency Agreement. NR 13 TC 6 Z9 6 U1 0 U2 4 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 2014 VL 23 IS 9 BP 911 EP 917 DI 10.1002/pds.3644 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AO8DS UT WOS:000341584200003 PM 24872151 ER PT J AU Jarow, JP Thompson, IM AF Jarow, Jonathan P. Thompson, Ian M. TI Re: Jarow et al.: Drug and Device Development for Localized Prostate Cancer: Report of a Food and Drug Administration/American Urological Association Public Workshop (Urology 2014;83:975-979) Reply SO UROLOGY LA English DT Letter C1 [Jarow, Jonathan P.] US FDA, Off Hematol & Oncol Prod, Silver Spring, MD 20993 USA. [Thompson, Ian M.] Univ Texas San Antonio, Hlth Sci Ctr, San Antonio, TX USA. RP Jarow, JP (reprint author), US FDA, Off Hematol & Oncol Prod, Silver Spring, MD 20993 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD SEP PY 2014 VL 84 IS 3 BP 733 EP 733 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA AO5EL UT WOS:000341366000060 PM 25168561 ER PT J AU Broussard, CS Frey, MT Hernandez-Diaz, S Greene, MF Chambers, CD Sahin, L Sharp, BAC Honein, MA AF Broussard, Cheryl S. Frey, Meghan T. Hernandez-Diaz, Sonia Greene, Michael F. Chambers, Christina D. Sahin, Leyla Sharp, Beth A. Collins Honein, Margaret A. TI Developing a systematic approach to safer medication use during pregnancy: summary of a Centers for Disease Control and Prevention-convened meeting SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE Centers for Disease Control and Prevention; expert review; medications; pregnancy; teratogens ID RECOMMENDATIONS; WOMEN; LACTATION; INFECTION; FETAL; BIRTH; RISK; CDC AB To address information gaps that limit informed clinical decisions on medication use in pregnancy, the Centers for Disease Control and Prevention (CDC) solicited expert input on a draft prototype outlining a systematic approach to evaluating the quality and strength of existing evidence for associated risks. The draft prototype outlined a process for the systematic review of available evidence and deliberations by a panel of experts to inform clinical decision making for managing health conditions in pregnancy. At an expert meeting convened by the CDC in January 2013, participants divided into working groups discussed decision points within the prototype. This report summarizes their discussions of best practices for formulating an expert review process, developing evidence summaries and treatment guidance, and disseminating information. There is clear recognition of current knowledge gaps and a strong collaboration of federal partners, academic experts, and professional organizations willing to work together toward safer medication use during pregnancy. C1 [Broussard, Cheryl S.; Frey, Meghan T.; Honein, Margaret A.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. [Frey, Meghan T.] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. [Hernandez-Diaz, Sonia] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Greene, Michael F.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Greene, Michael F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chambers, Christina D.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Chambers, Christina D.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Sahin, Leyla] US FDA, Ctr Drug Evaluat & Res, Off New Drugs, Maternal Hlth Team,Pediat & Maternal Hlth Staff, Silver Spring, MD USA. [Sharp, Beth A. Collins] Agcy Healthcare Res & Qual, Rockville, MD USA. RP Broussard, CS (reprint author), Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. FU Centers for Disease Control and Prevention (CDC) FX This work was supported in part by an appointment to the Research Participation Program at the Centers for Disease Control and Prevention (CDC) administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the CDC (M.T.F.). NR 35 TC 11 Z9 11 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2014 VL 211 IS 3 BP 208 EP U667 DI 10.1016/j.ajog.2014.05.040 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AO4HO UT WOS:000341297900007 PM 24881821 ER PT J AU Goodwin, D Rosenzweig, B Zhang, J Xu, L Stewart, S Thompson, K Rouse, R AF Goodwin, David Rosenzweig, Barry Zhang, Jun Xu, Lin Stewart, Sharron Thompson, Karol Rouse, Rodney TI Evaluation of miR-216a and miR-217 as potential biomarkers of acute pancreatic injury in rats and mice SO BIOMARKERS LA English DT Article DE Caerulein; microRNA; pancreas; pancreatitis ID INDUCED LIVER-INJURY; CIRCULATING MICRORNAS; SERUM AMYLASE; ACINAR-CELL; LIPASE; MARKERS; HYPERAMYLASEMIA; ULTRASTRUCTURE; ISOAMYLASE; ARGININE AB Mild injury of the exocrine pancreas is often asymptomatic and can be under-or mis-diagnosed. The pancreas-enriched microRNAs miR-216a and miR-217 were evaluated as potential serum biomarkers of exocrine pancreas injury in rodent models of acute pancreatitis induced by caerulein, L-arginine, and pancreatic duct ligation. Both microRNAs showed time-and dose-relevant responses to pancreatic injury and wider dynamic ranges of response than serum amylase or lipase. Pancreas-selective microRNAs were found to be relatively sensitive serum biomarkers of pancreatic injury in rodents with potentially greater specificity than the current standard assays. C1 [Goodwin, David; Rosenzweig, Barry; Zhang, Jun; Xu, Lin; Stewart, Sharron; Thompson, Karol; Rouse, Rodney] US FDA, Div Appl Regulatory Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Rouse, R (reprint author), US FDA, Div Appl Regulatory Sci, Ctr Drug Evaluat & Res, Bldg 64,Room 2088,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM rodney.rouse@fda.hhs.gov FU US FDA Center for Drug Evaluation and Regulatory Science Research program FX This article reflects the views of the authors and should not be construed to represent FDA's views or policies. The authors declare no conflicting interests. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article; this project received funding from the US FDA Center for Drug Evaluation and Regulatory Science Research program. NR 44 TC 15 Z9 16 U1 0 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1354-750X EI 1366-5804 J9 BIOMARKERS JI Biomarkers PD SEP PY 2014 VL 19 IS 6 BP 517 EP 529 DI 10.3109/1354750X.2014.944217 PG 13 WC Biotechnology & Applied Microbiology; Toxicology SC Biotechnology & Applied Microbiology; Toxicology GA AN7GZ UT WOS:000340768500013 PM 25059555 ER PT J AU Banda, M Myers, MB McKim, KL Parsons, BL AF Banda, M. Myers, M. B. McKim, K. L. Parsons, B. L. TI Mammary Ductal Carcinomas Contain HRAS G12D Mutant Subpopulations SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Banda, M.; Myers, M. B.; McKim, K. L.; Parsons, B. L.] 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 SEP PY 2014 VL 55 SU 1 MA P94 BP S62 EP S62 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900185 ER PT J AU Bushel, PR Wang, C Gong, B Thierry-Mieg, J Thierry-Mieg, D Xu, J Fang, H Kreil, DP Megherbi, D Li, J Paules, RS Shi, L Auerbach, SS Tong, W AF Bushel, P. R. Wang, C. Gong, B. Thierry-Mieg, J. Thierry-Mieg, D. Xu, J. Fang, H. Kreil, D. P. Megherbi, D. Li, J. Paules, R. S. Shi, L. Auerbach, S. S. Tong, W. TI Bioinformatics Applications Reveal Gene Regulation Complexities in Response to Toxicant Exposures. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Bushel, P. R.; Paules, R. S.; Auerbach, S. S.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Gong, B.; Xu, J.; Fang, H.; Shi, L.; Tong, W.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Wang, C.] Loma Linda Univ, Loma Linda, CA 92350 USA. [Thierry-Mieg, J.; Thierry-Mieg, D.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Kreil, D. P.] Boku Univ, Vienna, Austria. [Kreil, D. P.] Univ Warwick, Coventry CV4 7AL, W Midlands, England. [Megherbi, D.] Univ Massachusetts, Lowell, MA USA. [Li, J.] Kelly Govt Solut, Durham, NC USA. RI Gong, Binsheng/E-2306-2015 OI Gong, Binsheng/0000-0002-8724-5435 NR 0 TC 0 Z9 0 U1 0 U2 4 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 SEP PY 2014 VL 55 SU 1 MA S51 BP S31 EP S31 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900060 ER PT J AU Chen, Y Shelton, SD Gollapudi, BB Albertini, RJ Fensterheim, RJ Budinsky, R Haber, LT Moore, MM Manjanatha, MG AF Chen, Y. Shelton, S. D. Gollapudi, B. B. Albertini, R. J. Fensterheim, R. J. Budinsky, R. Haber, L. T. Moore, M. M. Manjanatha, M. G. TI Evaluation of Vinyl Acetate- and Acetaldehyde-Induced gpt Mutations in Mouse Lung Fibroblast Cell Line, GDL-1 SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Chen, Y.; Shelton, S. D.; Manjanatha, M. G.] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Budinsky, R.] Dow Chem Co USA, Midland, MI 48674 USA. [Fensterheim, R. J.] RegNet Environm Serv, Washington, DC USA. [Gollapudi, B. B.] Exponent, Ctr Toxicol & Mech Biol, Midland, MI USA. [Albertini, R. J.] Univ Vermont, Burlington, VT USA. [Moore, M. M.] Environ Int Corp, Little Rock, AR USA. [Haber, L. T.] Toxicol Excellence Risk Assessment, Cincinnati, OH USA. NR 0 TC 1 Z9 1 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 SEP PY 2014 VL 55 SU 1 MA P96 BP S62 EP S62 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900187 ER PT J AU Chigurupati, S Raymick, J Paule, MG Sarkar, S AF Chigurupati, S. Raymick, J. Paule, M. G. Sarkar, S. TI Characterization of microRNAs in Serum: A New Class of Biomarkers for Diagnosis of Parkinson Disease in Mouse Model. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Chigurupati, S.; Raymick, J.; Paule, M. G.; Sarkar, S.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 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 SEP PY 2014 VL 55 SU 1 MA 19 BP S37 EP S37 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900084 ER PT J AU Dobrovolsky, VN Mittelstaedt, RA Pearce, MG Petibone, DM Revollo, J AF Dobrovolsky, V. N. Mittelstaedt, R. A. Pearce, M. G. Petibone, D. M. Revollo, J. TI CD48-Deficient T-lymphocytes from ENU-Treated Rats Have Mutations in the Pig-a Gene. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Dobrovolsky, V. N.; Mittelstaedt, R. A.; Pearce, M. G.; Petibone, D. M.; Revollo, J.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 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 SEP PY 2014 VL 55 SU 1 MA 7 BP S34 EP S34 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900072 ER PT J AU Fuscoe, JC Vijay, V Han, T Desai, VG AF Fuscoe, J. C. Vijay, V. Han, T. Desai, V. G. TI Whole Genome Gene Expression Profiling of Cardiac Tissue from Mice Exposed to Doxorubicin. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Fuscoe, J. C.; Vijay, V.; Han, T.; 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 SEP PY 2014 VL 55 SU 1 MA P43 BP S50 EP S50 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900135 ER PT J AU Manjanatha, MG Shelton, SD Gaddameedhi, S Sancar, A Boudreau, M AF Manjanatha, M. G. Shelton, S. D. Gaddameedhi, S. Sancar, A. Boudreau, M. TI Development of a Transgenic, Hairless Albino Mouse Model for Testing UV-induced Circadian Clock in the Skin. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Manjanatha, M. G.; Shelton, S. D.; Boudreau, M.] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Manjanatha, M. G.; Shelton, S. D.; Boudreau, M.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Gaddameedhi, S.; Sancar, A.] Univ N Carolina, Sch Med, Dept Biochem & Biophys, Chapel Hill, NC 27599 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 SEP PY 2014 VL 55 SU 1 MA S30 BP S26 EP S26 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900039 ER PT J AU McKinzie, PB Pearce, MG McKim, KL AF McKinzie, P. B. Pearce, M. G. McKim, K. L. TI Kras Codon 12 GAT Mutant Fractions in Mouse Lung over the Lifespan of the Animals SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [McKinzie, P. B.; Pearce, M. G.; McKim, K. L.] 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 SEP PY 2014 VL 55 SU 1 MA P93 BP S62 EP S62 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900184 ER PT J AU Mei, N Lin, H Guo, X Manjanatha, MG Moore, MM AF Mei, N. Lin, H. Guo, X. Manjanatha, M. G. Moore, M. M. TI In Vitro Assessment of Genotoxic Effects of Ginkgo Biloba Leaf Extract and Its Eight Constitutes. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Mei, N.; Lin, H.; Guo, X.; Manjanatha, M. G.; Moore, M. M.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Moore, M. M.] ENVIRON Int Corp, Little Rock, AR 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 SEP PY 2014 VL 55 SU 1 MA P2 BP S40 EP S40 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900094 ER PT J AU Myers, MB Banda, M McKim, KL Wang, Y Parsons, BL AF Myers, M. B. Banda, M. McKim, K. L. Wang, Y. Parsons, B. L. TI PIK3CA H1047R Mutant Subpopulations in Normal Breast and Breast Tumors SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Myers, M. B.; Banda, M.; McKim, K. L.; Wang, Y.; Parsons, B. L.] 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 SEP PY 2014 VL 55 SU 1 MA P95 BP S62 EP S62 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900186 ER PT J AU Petibone, DM Ding, W Mustafa, T Lafont, A Xu, Y Watanabe, F Casciano, D Dobrovolsky, V Biris, AS Morris, SM AF Petibone, D. M. Ding, W. Mustafa, T. Lafont, A. Xu, Y. Watanabe, F. Casciano, D. Dobrovolsky, V Biris, A. S. Morris, S. M. TI Assessment of Carboxyl Graphene Nanoplatelet Toxicity in Human B-Lymphoblasts SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Petibone, D. M.; Ding, W.; Dobrovolsky, V] Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Mustafa, T.; Lafont, A.; Xu, Y.; Watanabe, F.; Casciano, D.; Biris, A. S.] Univ Arkansas, Ctr Integrat Nanotechnol Sci, Little Rock, AR 72204 USA. [Mustafa, T.] Univ Baghdad, Dept Biol, Coll Sci Women, 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 SEP PY 2014 VL 55 SU 1 MA P16 BP S43 EP S43 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900108 ER PT J AU Revollo, J Petibone, D Morris, SM Ning, B Dobrovolsky, V AF Revollo, J. Petibone, D. Morris, S. M. Ning, B. Dobrovolsky, V TI Identification of Single Nucleotide Polymorphisms and Novel Genetic Anomalies in the Normalized Transcriptomes of TK6, WTK1, and NH32 Cells by Next Generation Sequencing. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 45th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 13-17, 2014 CL Orlando, FL SP Environm Mutagenesis & Genom Soc C1 [Revollo, J.; Petibone, D.; Morris, S. M.; Ning, B.; Dobrovolsky, V] Natl Ctr Toxicol Res, Jefferson, AR 72079 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 SEP PY 2014 VL 55 SU 1 MA 15 BP S36 EP S36 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AO2ST UT WOS:000341176900080 ER PT J AU O'Connell, K Pariser, AR AF O'Connell, Kathryn Pariser, Anne R. TI Clinical trial safety population size: analysis of drug approvals for rare and common indications by FDA Center for Drug Evaluation and Research SO EXPERT OPINION ON ORPHAN DRUGS LA English DT Article DE clinical trial; drug approval; patient safety; prevalence; rare diseases ID ORPHAN DRUGS; DISEASES AB Background: Limited prevalence diseases present challenges for drug development and for the amount of safety information available to prescribers and patients when a drug is approved for marketing. Objective: To inform the issue of safety populations for rare disease drug clinical development programs, we analyzed the relationship between pre-marketing trial safety population size and estimated US disease prevalence as compared to common disease drugs. Methods: We based the analysis on therapeutic new molecular entity drug and original biological product marketing applications approved by FDA's Center for Drug Evaluation and Research between 1 January 2010 and 19 June 2013. Results: While drugs for rare diseases have small trial safety population sizes relative to common disease drugs, a larger proportion of patients are studied relative to the number of US patients with the approved indication. We did not find an excess of safety labeling changes or other post-marketing safety actions for the rare disease drugs over the observation period of our study. Conclusions: The overall assessment of benefit-risk within the context of disease characteristics, patient population and drug effects determines whether a safety database is adequate to support marketing approval. We encourage frequent communication between rare disease drug developers and FDA to facilitate efficient clinical programs that meet marketing approval standards, and maximal utilization of all appropriate strategies to accrue post-market safety data and enhance safety of use. C1 [O'Connell, Kathryn; Pariser, Anne R.] US FDA, Ctr Drug Evaluat & Res, Off New Drugs, Silver Spring, MD 20993 USA. RP O'Connell, K (reprint author), US FDA, Ctr Drug Evaluat & Res, Off New Drugs, 10903 New Hampshire Ave,WO22-6480, Silver Spring, MD 20993 USA. EM Kathryn.oconnell@fda.hhs.gov NR 22 TC 1 Z9 1 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 2167-8707 J9 EXPERT OPIN ORPHAN D JI Exp. Opin. Orphan Drugs PD SEP PY 2014 VL 2 IS 9 BP 869 EP 875 DI 10.1517/21678707.2014.935763 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AO1RL UT WOS:000341091200002 ER PT J AU Chen, MJ Borlak, J Tong, WD AF Chen, Minjun Borlak, Juergen Tong, Weida TI Predicting idiosyncratic drug-induced liver injury - some recent advances SO EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY LA English DT Editorial Material DE data integration; drug safety; HLA; idiosyncratic drug-induced liver injury; predictive model ID HEPATOTOXICITY; DETERMINANT; TOXICITY; HUMANS; RISK AB Drug-induced liver injury (DILI) is a major challenge for the pharmaceutical industry, regulatory authorities, and clinicians. It is usually categorized into 'intrinsic' and 'idiosyncratic', but DILI caused by most drugs is of an idiosyncratic nature and usually cannot be predicted from the regulatory required animal toxicity studies. Unfortunately, some individuals exposed to therapeutic dose will develop idiosyncratic DILI that might involve severe clinical outcome, and no biomarker is available to identify the susceptible patients prior to drug treatment. In this editorial, we summarized the recent advances in predicting idiosyncratic DILI and provided the perspectives to improve the prediction. C1 [Chen, Minjun; Tong, Weida] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Borlak, Juergen] Hannover Med Sch, Ctr Pharmacol & Toxicol, Hannover, Germany. RP Tong, WD (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM weida.tong@fda.hhs.gov NR 21 TC 8 Z9 8 U1 0 U2 13 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-4124 EI 1747-4132 J9 EXPERT REV GASTROENT JI Expert Rev. Gastroenterol. Hepatol. PD SEP PY 2014 VL 8 IS 7 BP 721 EP 723 DI 10.1586/17474124.2014.922871 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AN8CM UT WOS:000340829500001 PM 24857265 ER PT J AU Hu, ZL Leppla, SH Li, BG Elkins, CA AF Hu, Zonglin Leppla, Stephen H. Li, Baoguang Elkins, Christopher A. TI Antibodies specific for nucleic acids and applications in genomic detection and clinical diagnostics SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE anti-nucleic acids antibodies; apoptotic cells detection; biosensor; cancer detection; hybrid capture; metakaryotic stem cells; microarray; miRNA; R-loop detection; sRNA ID DNA-RNA HYBRIDS; DOUBLE-STRANDED-RNA; POLYMERASE CHAIN-REACTION; PHOTONIC MICRORING RESONATORS; SYSTEMIC LUPUS-ERYTHEMATOSUS; SOLUTION HYBRIDIZATION ASSAY; HUMAN IMMUNODEFICIENCY VIRUS; SURFACE-PLASMON RESONANCE; CERVICAL LAVAGE SPECIMENS; HUMAN-PAPILLOMAVIRUS DNA AB Detection of nucleic acids using antibodies is uncommon. This is in part because nucleic acids are poor immunogens and it is difficult to elicit antibodies having high affinity to each type of nucleic acid while lacking cross-reactivity to others. We describe the origins and applications of a variety of anti-nucleic acid antibodies, including ones reacting with modified nucleosides and nucleotides, single-stranded DNA, double-stranded DNA, RNA, DNA: RNA hybrids, locked-nucleic acids or peptide nucleic acid: nucleic acid hybrids. Carefully selected antibodies can be excellent reagents for detecting bacteria, viruses, small RNAs, microRNAs, R-loops, cancer cells, stem cells, apoptotic cells and so on. The detection may be sensitive, simple, rapid, specific, reproducible, quantitative and cost-effective. Current microarray and diagnostic methods that depend on cDNA or cRNA can be replaced by using antibody detection of nucleic acids. Therefore, development should be encouraged to explore new utilities and create a robust arsenal of new anti-nucleic acid antibodies. C1 [Hu, Zonglin] US FDA, Winchester Engn & Analyt Ctr, Off Regulatory Affairs, Winchester, MA 01890 USA. [Hu, Zonglin; Li, Baoguang; Elkins, Christopher A.] US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Leppla, Stephen H.] NIAID, Parasit Dis Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Hu, ZL (reprint author), US FDA, Winchester Engn & Analyt Ctr, Off Regulatory Affairs, 109 Holton St, Winchester, MA 01890 USA. EM Zonglin.hu@fda.hhs.gov FU Oak Ridge Institute for Science and Education, USA; Intramural Research Program of the NIH FX Research described here was supported in part by Oak Ridge Institute for Science and Education, USA, and by the Intramural Research Program of the NIH. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. NR 173 TC 0 Z9 0 U1 5 U2 29 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7159 EI 1744-8352 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD SEP PY 2014 VL 14 IS 7 BP 895 EP 916 DI 10.1586/14737159.2014.931810 PG 22 WC Pathology SC Pathology GA AN8CJ UT WOS:000340829200011 PM 25014728 ER PT J AU Zhang, J Rouse, RL AF Zhang, Jun Rouse, Rodney L. TI Histopathology and pathogenesis of caerulein-, duct ligation-, and arginine-induced acute pancreatitis in Sprague-Dawley rats and C57BL6 Mice SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Article DE Acute pancreatitis; Arginine; Caerulein; Ductal ligation; Lexicon of histopathology ID EDEMA FORMATION; VASCULAR INJURY; ACINAR-CELLS; FAT NECROSIS; TRYPSINOGEN ACTIVATION; ADHESION MOLECULES; OXIDATIVE STRESS; MAST-CELLS; APOPTOSIS; AUTOPHAGY AB Three classical rodent models of acute pancreatitis were created in an effort to identify potential pre-clinical models of drug-induced pancreatitis (DIP) and candidate non-invasive biomarkers for improved detection of DIP. Study objectives included designing a lexicon to minimize bias by capturing normal variation and spontaneous and injury-induced changes while maintaining the ability to statistically differentiate degrees of change, defining morphologic anchors for novel pancreatic injury biomarkers, and improving understanding of mechanisms responsible for pancreatitis. Models were created in male Sprague-Dawley rats and C57BL6 mice through: 1) administration of the cholecystokinin analog, caerulein; 2) administration of arginine; 3) surgical ligation of the pancreatic duct. Nine morphologically detectable processes were used in the lexicon; acinar cell hypertrophy; acinar cell autophagy; acinar cell apoptosis; acinar cell necrosis; vascular injury; interstitial edema, inflammation and hemorrhage; fat necrosis; ductal changes; acinar cell atrophy. Criteria were defined for scoring levels (0= absent, 1= mild, 2= moderate, 3= severe) for each lexicon component. Consistent with previous studies, histopathology scores were significantly greater in rats compared to mice at baseline and after treatment. The histopathology scores in caerulein and ligation-treated rats and mice were significantly greater than those of arginine-treated rats and mice. The present study supports a multifaceted pathogenesis for acute pancreatitis in which intra-acinar trypsinogen activation, damage to acinar cells, fat cells, and vascular cells as well as activation/degranulation of mast cells and activated macrophages all contribute to the initiation and/or progression of acute inflammation of the exocrine pancreas. C1 [Zhang, Jun; Rouse, Rodney L.] US FDA, Div Appl Regulatory Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Rouse, RL (reprint author), US FDA, Div Appl Regulatory Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM jun.zhang@fda.hhs.gov NR 66 TC 10 Z9 10 U1 0 U2 5 PU F HERNANDEZ PI MURCIA PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN SN 0213-3911 EI 1699-5848 J9 HISTOL HISTOPATHOL JI Histol. Histopath. PD SEP PY 2014 VL 29 IS 9 BP 1135 EP 1152 PG 18 WC Cell Biology; Pathology SC Cell Biology; Pathology GA AN9BJ UT WOS:000340900300007 PM 24585404 ER PT J AU Bush, CA Yang, JH Yu, BW Cisar, JO AF Bush, C. Allen Yang, Jinghua Yu, Bingwu Cisar, John O. TI Chemical Structures of Streptococcus pneumoniae Capsular Polysaccharide Type 39 (CPS39), CPS47F, and CPS34 Characterized by Nuclear Magnetic Resonance Spectroscopy and Their Relation to CPS10A SO JOURNAL OF BACTERIOLOGY LA English DT Article ID COAGGREGATION RECEPTOR POLYSACCHARIDES; O-ACETYL GROUPS; US TYPE 41; MOLECULAR CHARACTERIZATION; BIOSYNTHETIC LOCI; FULL ASSIGNMENT; SEROTYPE; SUBSTANCE; ORALIS; ELUCIDATION AB Structural characterization of Streptococcus pneumoniae capsular polysaccharides (CPS) is a prerequisite for unraveling both antigenic and genetic relationships that exist between different serotypes. In the current study, comparative structural studies of S. pneumoniae CPS serogroup 10 (CPS10) were extended to include genetically related S. pneumoniae CPS34, CPS39, and CPS47F. High-resolution heteronuclear nuclear magnetic resonance (NMR) spectroscopy confirmed the published structure of CPS34 and, in conjunction with glycosyl composition analyses, revealed the following repeat unit structures of the other serotypes, which have not been previously characterized: [GRAPHICS] Common and unique structural features of these polysaccharides, including different positions of O-acetylation, were unambiguously associated with specific genes in each corresponding cps locus. The only exception involved the gene designated wcrC, which is associated with the alpha 1-2 transfer of Gal pyranoside (Galp) to ribitol-5-phosphate in the synthesis of CPS10A, CPS47F, and CPS34 but with alpha 1-1 transfer of Gal to ribitol-5-phosphate in the synthesis of CPS39. The corresponding gene in the cps39 locus, although related to wcrC, more closely resembled a previously identified gene (i.e., wefM) of Streptococcus oralis that is associated with alpha 1-1 transfer of Galp to ribitol-5-phosphate. These and other recent findings identify linkages from alpha-Galp to ribitol-5-phosphate and from this residue to adjacent Gal furanoside (Galf) as important sites of CPS structural and genetic diversity. C1 [Bush, C. Allen] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21228 USA. [Yang, Jinghua; Cisar, John O.] Natl Inst Dent & Craniofacial Res, Microbial Receptors Sect, NIH, Bethesda, MD USA. [Yu, Bingwu] CBER FDA, Lab Bacterial Polysaccharides, Bethesda, MD USA. RP Bush, CA (reprint author), Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21228 USA. EM bush@umbc.edu FU Intramural Research Program of the NIDCR; NIH [P01-HL-107153] FX This work was supported in part by the Intramural Research Program of the NIDCR, NIH, and by NIH P01-HL-107153. NR 24 TC 2 Z9 2 U1 0 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD SEP PY 2014 VL 196 IS 18 BP 3271 EP 3278 DI 10.1128/JB.01731-14 PG 8 WC Microbiology SC Microbiology GA AO3MG UT WOS:000341233500007 PM 25002537 ER PT J AU Trumbo, PR Rivers, CR AF Trumbo, Paula R. Rivers, Crystal R. TI Systematic review of the evidence for an association between sugar-sweetened beverage consumption and risk of obesity SO NUTRITION REVIEWS LA English DT Review DE body mass index; obesity; sugar-sweetened beverages ID BODY-MASS INDEX; SOFT DRINK CONSUMPTION; PREVENTING CHILDHOOD OBESITY; INCOME PRESCHOOL-CHILDREN; TYPE-2 DIABETES-MELLITUS; HIGH-SCHOOL-STUDENTS; FRUCTOSE CORN SYRUP; LIFE-STYLE FACTORS; PHYSICAL-ACTIVITY; WEIGHT-GAIN AB A systematic review of the evidence for an association between sugar-sweetened beverages and risk of obesity was conducted. This review focused specifically on the role of sugar-sweetened beverages in obesity risk, taking into account energy balance. For the purpose of this review, scientific conclusions could not be drawn from the intervention studies that evaluated the relationship between sugar-sweetened beverage intake and obesity risk. Results of observational studies that examined the relationship between sugar-sweetened beverage intake and obesity risk that were adjusted for energy intake and physical activity were inconsistent for each of the three age groups evaluated (children, adolescents, and adults). From this review, evidence for an association between sugar-sweetened beverage intake and obesity risk is inconsistent when adjustment for energy balance is made. (C) 2014 International Life Sciences Institute C1 [Trumbo, Paula R.; Rivers, Crystal R.] Ctr Food Safety & Appl Nutr, Nutr Programs, Off Nutr Labeling & Dietary Supplements, College Pk, MD USA. RP Trumbo, PR (reprint author), 5100 Paint Branch Pkwy HFS 830, College Pk, MD 20740 USA. EM Paula.Trumbo@FDA.HHS.gov NR 104 TC 15 Z9 15 U1 7 U2 66 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0029-6643 EI 1753-4887 J9 NUTR REV JI Nutr. Rev. PD SEP PY 2014 VL 72 IS 9 BP 566 EP 574 DI 10.1111/nure.12128 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AO3ML UT WOS:000341234300002 PM 25091794 ER PT J AU White, SC Scarfe, WC Schulze, RKW Lurie, AG Douglass, JM Farman, AG Law, CS Levin, MD Sauer, RA Valachovic, RW Zeller, GG Goske, MJ AF White, Stuart C. Scarfe, William C. Schulze, Ralf K. W. Lurie, Alan G. Douglass, Joanna M. Farman, Allan G. Law, Clarice S. Levin, Martin D. Sauer, Robert A. Valachovic, Richard W. Zeller, Gregory G. Goske, Marilyn J. TI The Image Gently in Dentistry campaign: promotion of responsible use of maxillofacial radiology in dentistry for children SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY LA English DT Editorial Material ID BEAM COMPUTED-TOMOGRAPHY; DENTAL X-RAYS; RADIATION-EXPOSURE; THYROID-CANCER; BRAIN-TUMORS; CT SCANS; RISK; RADIOGRAPHY; CHILDHOOD; DOSIMETRY C1 [White, Stuart C.] Univ Calif Los Angeles, Sch Dent, Los Angeles, CA 90024 USA. [Scarfe, William C.] Univ Louisville, Sch Dent, Louisville, KY 40292 USA. [Schulze, Ralf K. W.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, D-55122 Mainz, Germany. [Lurie, Alan G.] Univ Connecticut, Sch Dent Med, Farmington, CT 06032 USA. [Douglass, Joanna M.; Levin, Martin D.] Univ Penn, Sch Dent Med, Philadelphia, PA 19104 USA. [Sauer, Robert A.] US FDA, Div Radiol Hlth, Silver Spring, MD USA. [Valachovic, Richard W.] Amer Dent Educ Assoc, Washington, DC USA. [Zeller, Gregory G.] Univ Kentucky, Coll Dent, Lexington, KY USA. [Goske, Marilyn J.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. RP Scarfe, WC (reprint author), Univ Louisville, Sch Dent, Dept Surg & Hosp Dent, Louisville, KY 40292 USA. EM wcscar01@louisville.edu NR 38 TC 10 Z9 10 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-4403 EI 1528-395X J9 OR SURG OR MED OR PA JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. PD SEP PY 2014 VL 118 IS 3 BP 257 EP 261 DI 10.1016/j.0000.2014.06.001 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AO1LX UT WOS:000341074700001 PM 25066244 ER PT J AU Liu, Y Kainz, W Qian, SS Wu, W Chen, J AF Liu, Yan Kainz, Wolfgang Qian, Songsong Wu, Wen Chen, Ji TI Effect of insulating layer material on RF-induced heating for external fixation system in 1.5 T MRI system SO ELECTROMAGNETIC BIOLOGY AND MEDICINE LA English DT Article DE eMedical device; MRI; RF heating ID DEVICES; SAFETY AB The radio frequency (RF)-induced heating is a major concern when patients with medical devices are placed inside a magnetic resonance imaging (MRI) system. In this article, numerical studies are applied to investigate the potentials of using insulated materials to reduce the RF heating for external fixation devices. It is found that by changing the dielectric constant of the insulation material, the RF-induced heating at the tips of devices can be altered. This study indicates a potential technique of developing external fixation device with low MRI RF heating. C1 [Liu, Yan; Chen, Ji] Univ Houston, Dept Elect & Comp Engn, Houston, TX 77204 USA. [Kainz, Wolfgang] US FDA, Ctr Device & Radiol Hlth, Silver Spring, MD USA. [Qian, Songsong; Wu, Wen] Nanjing Univ Sci & Technol, Dept Elect & Opt Engn, Nanjing, Jiangsu, Peoples R China. RP Chen, J (reprint author), Univ Houston, Dept Elect & Comp Engn, Houston, TX 77204 USA. EM jchen18@u-h.edu NR 13 TC 1 Z9 1 U1 0 U2 7 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1536-8378 EI 1536-8386 J9 ELECTROMAGN BIOL MED JI Electromagn. Biol. Med. PD SEP PY 2014 VL 33 IS 3 BP 223 EP 227 DI 10.3109/15368378.2013.802244 PG 5 WC Biology; Biophysics SC Life Sciences & Biomedicine - Other Topics; Biophysics GA AN1UB UT WOS:000340368000007 PM 23781983 ER PT J AU Dibaji, SAR Wansapura, J Myers, MR Banerjee, RK AF Dibaji, Seyed Ahmad Reza Wansapura, Janaka Myers, Matthew R. Banerjee, Rupak K. TI In Vivo Monitoring of HIFU Induced Temperature Rise in Porcine Liver Using Magnetic Resonance Thermometry SO JOURNAL OF MEDICAL DEVICES-TRANSACTIONS OF THE ASME LA English DT Article; Proceedings Paper CT 13th Annual University-of-Minnesota Design of Medical Devices Conference CY APR 07-10, 2014 CL Minneapolis, MN C1 [Dibaji, Seyed Ahmad Reza; Banerjee, Rupak K.] Univ Cincinnati, Coll Engn & Appl Sci, Dept Mech & Mat Engn, Cincinnati, OH 45221 USA. [Wansapura, Janaka] Cincinnati Childrens Hosp Med Ctr, Imaging Res Ctr, Cincinnati, OH 45221 USA. [Myers, Matthew R.] US FDA, Ctr Devices & Radiol Hlth, Div Solid & Fluid Mech, Silver Spring, MD 20993 USA. RP Dibaji, SAR (reprint author), Univ Cincinnati, Coll Engn & Appl Sci, Dept Mech & Mat Engn, Cincinnati, OH 45221 USA. FU NSF [1041508, 1137166] FX This project was funded by NSF#1041508 and NSF#1137166. NR 6 TC 1 Z9 1 U1 0 U2 0 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 1932-6181 EI 1932-619X J9 J MED DEVICES JI J. Med. Devices PD SEP PY 2014 VL 8 IS 3 AR 030937 DI 10.1115/1.4027082 PG 2 WC Engineering, Biomedical SC Engineering GA AN2SC UT WOS:000340434600038 ER PT J AU Vesnovsky, O Topoleski, LDT Grossman, LW Casamento, JP Zhu, L AF Vesnovsky, Oleg Topoleski, L. D. Timmie Grossman, Lawrence W. Casamento, Jon P. Zhu, Liang TI Performance Testing of Fast Read Digital Thermometers SO JOURNAL OF MEDICAL DEVICES-TRANSACTIONS OF THE ASME LA English DT Article; Proceedings Paper CT 13th Annual University-of-Minnesota Design of Medical Devices Conference CY APR 07-10, 2014 CL Minneapolis, MN C1 [Vesnovsky, Oleg; Topoleski, L. D. Timmie; Grossman, Lawrence W.; Casamento, Jon P.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Topoleski, L. D. Timmie; Zhu, Liang] Univ Maryland Baltimore Cty, Dept Mech Engn, Baltimore, MD 21250 USA. RP Vesnovsky, O (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,WO66-5429, Silver Spring, MD 20993 USA. NR 1 TC 1 Z9 1 U1 0 U2 4 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 1932-6181 EI 1932-619X J9 J MED DEVICES JI J. Med. Devices PD SEP PY 2014 VL 8 IS 3 AR 030905 DI 10.1115/1.4027098 PG 3 WC Engineering, Biomedical SC Engineering GA AN2SC UT WOS:000340434600006 ER PT J AU Siddiqui, A Rahman, Z Bykadi, S Khan, MA AF Siddiqui, Akhtar Rahman, Ziyaur Bykadi, Srikant Khan, Mansoor A. TI Chemometric Methods for the Quantification of Crystalline Tacrolimus in Solid Dispersion by Powder X-Ray Diffractrometry SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE tacrolimus; solid dispersion; powder X-ray diffraction; chemometric; principal component analysis; partial least square; multivariate analysis ID ORAL BIOAVAILABILITY; SOLUBILITY; DRUG; RATS; FORMULATIONS; DIFFRACTION AB The objective of this study was to develop powder X-ray diffraction (XRPD) chemometric model for quantifying crystalline tacrolimus from solid dispersion (SD). Three SDs (amorphous tacrolimus component) with varying drug to excipient ratios (24.4%, 6.7%, and 4.3% drug) were prepared. Placebo SDs were mixed with crystalline tacrolimus to make their composition equivalent to three SD (crystalline tacrolimus component). These two components were mixed to cover 0%-100% of crystalline drug. Uniformity of the sample mixtures was confirmed by near-infrared chemical imaging. XRPD showed three distinct peaks of crystalline drug at 8.5 degrees, 10.3 degrees, and 11.2 degrees (2 theta), which were nonoverlapping with the excipients. Principal component regressions (PCR) and partial least square (PLS) regression used in model development showed high R-2 (>0.99) for all the mixtures. Overall, the model showed low root mean square of standard error, standard error, and bias, which was smaller in PLS than PCR-based model. Furthermore, the model performance was evaluated on the formulations with known percentage of crystalline drug. Model-calculated crystalline drug percentage values were close to actual value. Therefore, these studies strongly suggest the application of chemometric-XRPD models as a quality control tool to quantitatively predict the crystalline drug in the formulation. (C) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association C1 [Siddiqui, Akhtar; Rahman, Ziyaur; Bykadi, Srikant; Khan, Mansoor A.] US FDA, Div Prod Qual Res, Off Testing & Res, OPS,CDER, Rockville, MD 20857 USA. RP Khan, MA (reprint author), US FDA, Div Prod Qual Res, Off Testing & Res, OPS,CDER, Rockville, MD 20857 USA. EM Mansoor.Khan@fda.hhs.gov OI Rahman, Ziyaur/0000-0002-0402-825X FU NIH; Medical Counter Measure initiative; Oak Ridge Institute for Science and Education (ORISE) FX This work was supported by funding from the NIH and the Medical Counter Measure initiative. The authors would like to thank Oak Ridge Institute for Science and Education (ORISE) for supporting post-doctoral research program. NR 19 TC 5 Z9 5 U1 2 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 SEP PY 2014 VL 103 IS 9 SI SI BP 2819 EP 2828 DI 10.1002/jps.23912 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA AN4FB UT WOS:000340541900021 PM 24585357 ER PT J AU Woo, EJ AF Woo, Emily Jane TI Letter to the Editor: Safety in Surgery and Overall Health: What is the Responsibility of the Patient? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Letter C1 US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Woo, EJ (reprint author), US FDA, Ctr Biol Evaluat & Res, 1401 Rockville Pike, Rockville, MD 20852 USA. EM jane.woo@fda.hhs.gov NR 3 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD SEP PY 2014 VL 472 IS 9 BP 2893 EP 2894 DI 10.1007/s11999-014-3749-9 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AM7LR UT WOS:000340049200052 PM 24973086 ER PT J AU Hu, Y Arsov, I AF Hu, Yuan Arsov, Ivica TI A Rapid Single-Tube Protocol for HAV Detection by Nested Real-Time PCR SO FOOD AND ENVIRONMENTAL VIROLOGY LA English DT Article DE Hepatitis A virus; Nested-PCR; Nested real-time PCR and real-time PCR ID HEPATITIS-A-VIRUS; HUMAN ENTERIC VIRUSES; REVERSE TRANSCRIPTION-PCR; RT-PCR; GREEN ONIONS; EXTRACTION; NOROVIRUS; SHELLFISH; OUTBREAK; FOODS AB Infections by food-borne viruses such as hepatitis A virus (HAV) and norovirus are significant public health concerns worldwide. Since food-borne viruses are rarely confirmed through direct isolation from contaminated samples, highly sensitive molecular techniques remain the methods of choice for the detection of viral genetic material. Our group has previously developed a specific nested real-time PCR (NRT-PCR) assay for HAV detection that improved overall sensitivity. Furthermore in this study, we have developed a single-tube NRT-PCR approach for HAV detection in food samples that reduces the likelihood of cross contamination between tubes during sample manipulation. HAV RNA was isolated from HAV-spiked food samples and HAV-infected cell cultures. All reactions following HAV RNA isolation, including conventional reverse transcriptase PCR, nested-PCR, and RT-PCR were performed in a single tube. Our results demonstrated that all the samples tested positive by RT-PCR and nested-PCR were also positive by a single-tube NRT-PCR. The detection limits observed for HAV-infected cell cultures and HAV-spiked green onions were 0.1 and 1 PFU, respectively. This novel method retained the specificity and robustness of the original NRT-PCR method, while greatly reducing sample manipulation, turnaround time, and the risk of carry-over contamination. Single-tube NRT-PCR thus represents a promising new tool that can potentially facilitate the detection of HAV in foods thereby improving food safety and public health. C1 [Hu, Yuan] US FDA, Northeast Reg Lab, Jamaica, NY 11433 USA. [Arsov, Ivica] York Coll Penn, Dept Biol, Jamaica, NY USA. RP Hu, Y (reprint author), US FDA, Northeast Reg Lab, 158-15 Liberty Ave, Jamaica, NY 11433 USA. EM yuan.hu@fda.hhs.gov NR 35 TC 2 Z9 2 U1 3 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1867-0334 EI 1867-0342 J9 FOOD ENVIRON VIROL JI Food Environ. Virol. PD SEP PY 2014 VL 6 IS 3 BP 189 EP 195 DI 10.1007/s12560-014-9152-6 PG 7 WC Environmental Sciences; Microbiology; Virology SC Environmental Sciences & Ecology; Microbiology; Virology GA AM8AZ UT WOS:000340092700005 PM 24902810 ER PT J AU Toomer, OT Ferguson, M Pereira, M Do, A Bigley, E Gaines, D Williams, K AF Toomer, Ondulla T. Ferguson, Martine Pereira, Marion Do, Andrew Bigley, Elmer Gaines, Dennis Williams, Kristina TI Maternal and postnatal dietary probiotic supplementation enhances splenic regulatory T helper cell population and reduces peanut allergen-induced hypersensitivity responses in mice SO IMMUNOBIOLOGY LA English DT Article DE Food allergy; Mouse; Peanut; Probiotics ID PLACEBO-CONTROLLED TRIAL; BLOOD MONONUCLEAR-CELLS; IMMUNE-SYSTEM; FOOD ALLERGY; HUMAN-MILK; ENVIRONMENTAL ALLERGENS; CYTOKINE PROFILE; DOUBLE-BLIND; MOUSE MODEL; CORD BLOOD AB Neonatal to early childhood is the critical period for establishing a balance of T helper 1 (Th1) versus T helper 2 (Th2) cellular immunity within the gut, which is strongly influenced by the source and establishment of gut microflora. Probiotic administration has been shown to attenuate Th2-biased cellular immunity and predisposition to food allergies. To test this hypothesis we provided ad libitum a probiotic-supplemented (Primalac 454 Feed Grade Microbials) or control diet to lactating dams with suckling pups and weaned pups until 10 weeks of age. Weaned mice were sensitized/challenged with peanut extract, saline or adjuvant at 6, 8 and 10 weeks of age. At 3, 6, 8 and 10 weeks, fecal samples were collected for microbial analysis, while blood samples were analyzed for total plasma IgE levels. At termination (10 weeks of age), splenic T lymphocyte population subtypes were determined using FACS analysis and Th1/Th2/Th17 gene expression by PCR array. Mice given the probiotic-supplemented diet had significantly enhanced probiotic fecal counts compared to controls at 3, 6, 8 and 10 weeks. Moreover, mice fed the probiotic-supplemented diet-had enhanced splenic naturally occurring T regulatory cell populations, and reduced splenic gene expression of allergic mediator IL-13 compared to controls. These results provide evidence that early probiotic supplementation may provide host protection to hypersensitivity reactions to food allergens by attenuating food allergen inflammatory responses. Published by Elsevier GmbH. C1 [Toomer, Ondulla T.; Ferguson, Martine; Pereira, Marion; Do, Andrew; Bigley, Elmer; Gaines, Dennis; Williams, Kristina] US FDA, Laurel, MD 20708 USA. RP Toomer, OT (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Virulence Assessment, Immunobiol Branch,Off Appl Res & Safety Assessmen, 8301 Muirkirk Rd,MOD 1,Room 2007, Laurel, MD 20708 USA. EM ondulla.toomer@fda.hhs.gov NR 43 TC 1 Z9 1 U1 3 U2 28 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0171-2985 J9 IMMUNOBIOLOGY JI Immunobiology PD SEP PY 2014 VL 219 IS 9 BP 661 EP 670 DI 10.1016/j.imbio.2014.03.019 PG 10 WC Immunology SC Immunology GA AL9PC UT WOS:000339472200002 PM 24882556 ER PT J AU Petrochenko, PE Zhang, Q Bayati, R Skoog, SA Phillips, KS Kumar, G Narayan, RJ Goering, PL AF Petrochenko, Peter E. Zhang, Qin Bayati, Reza Skoog, Shelby A. Phillips, K. Scott Kumar, Girish Narayan, Roger J. Goering, Peter L. TI Cytotoxic evaluation of nanostructured zinc oxide (ZnO) thin films and leachates SO TOXICOLOGY IN VITRO LA English DT Article DE Zinc oxide (ZnO); Surface toxicity; Metal leaching; Nanoroughness; Pulsed laser deposition; Macrophage ID LASER INTERVAL DEPOSITION; BY-LAYER GROWTH; TOXICITY; CELLS; HYDROXYAPATITE; OSTEOBLAST; NANORODS AB Nanostructured ZnO films have potential use as coatings on medical devices and food packaging due to their antimicrobial and UV-protection properties. However, their influence on mammalian cells during clinical use is not fully understood. This study investigated the potential cytotoxicity of ZnO thin films in RAW 264.7 macrophages. ZnO thin films (similar to 96 nm thick with a 50 nm grain) were deposited onto silicon wafers using pulsed laser deposition. Cells grown directly on ZnO thin film coatings exhibited less toxicity than cells exposed to extracts of the coatings. Cells on ZnO thin films exhibited a 43% and 68% decrease in cell viability using the MTT and 7-AAD/Annexin V flow cytometry assays, respectively, after a 24-h exposure as compared to controls. Undiluted 100% 24- and 48-h extracts decreased viability by 89%, increased cell death by LDH release to 76% 24 h after treatment, and increased ROS after 5-24 h of exposure. In contrast, no cytotoxicity or ROS were observed for 25% and 50% extracts, indicating a tolerable concentration. Roughly 24 and 34 mu g/m(2) Zn leached off the surfaces after 24 and 48 h of incubation, respectively. ZnO coatings may produce gradual ion release which becomes toxic after a certain level and should be evaluated using both direct exposure and extraction methods. Published by Elsevier Ltd. C1 [Petrochenko, Peter E.; Zhang, Qin; Phillips, K. Scott; Kumar, Girish; Goering, Peter L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Petrochenko, Peter E.; Skoog, Shelby A.; Narayan, Roger J.] Univ North Carolina Chapel Hill, Joint Dept Biomed Engn, Raleigh, NC 27695 USA. [Petrochenko, Peter E.; Skoog, Shelby A.; Narayan, Roger J.] N Carolina State Univ, Raleigh, NC 27695 USA. [Bayati, Reza] Intel Corp, IMO SC, Santa Clara, CA 95052 USA. RP Goering, PL (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 64,Room 4064, Silver Spring, MD 20993 USA. EM Peter.Goering@fda.hhs.gov RI phillips, kenneth/F-7560-2014; Phillips, Kenneth/A-2156-2013 OI phillips, kenneth/0000-0002-6552-0694; Phillips, Kenneth/0000-0002-6552-0694 FU NSF/FDA Scholarin-Residence Award [1041375]; USFDA Medical Countermeasures Initiative (MCMi) FX Peter E. Petrochenko is supported in part by a NSF/FDA Scholarin-Residence Award #1041375 granted to Roger J. Narayan. This research was supported in part by the USFDA Medical Countermeasures Initiative (MCMi). The authors would also like to thank Sohrab Habibi for ICP-MS analyses at UNC-Chapel Hill Mass Spectrometry Facility. NR 46 TC 5 Z9 5 U1 2 U2 38 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD SEP PY 2014 VL 28 IS 6 BP 1144 EP 1152 DI 10.1016/j.tiv.2014.05.004 PG 9 WC Toxicology SC Toxicology GA AM1IJ UT WOS:000339599300007 PM 24878115 ER PT J AU Yang, BW Wang, QN Cui, SH Wang, Y Shi, C Xia, XD Xi, ML Wang, X Shi, XM Wang, DP Zhang, ZF Meng, JH AF Yang, Baowei Wang, Qianning Cui, Shenghui Wang, Yin Shi, Chao Xia, Xiaodong Xi, Meili Wang, Xin Shi, Xianming Wang, Dapeng Zhang, Zengfeng Meng, Jianghong TI Characterization of extended-spectrum beta-lactamases-producing Salmonella strains isolated from retail foods in Shaanxi and Henan Province, China SO FOOD MICROBIOLOGY LA English DT Article DE Extended-spectrum beta-lactamases; Foodborne Salmonella; Antimicrobial resistance ID RESISTANT SALMONELLA; ESCHERICHIA-COLI; UNITED-STATES; SOUTH-AFRICA; ENTERICA; PREVALENCE; INFECTIONS; TYPHIMURIUM; CEPHALOSPORINS; BACTERIA AB Extended-spectrum beta-lactamases (ESBL)-producing Salmonella enterica have been reported worldwide. However, research on foodborne ESBL-producing Salmonella has been rarely conducted. One hundred and thirty eight ceftriaxone or/and cefoperazone-resistant Salmonella strains recovered from retail foods in Shaanxi and Henan Province, China, were screened for ESBL. The ESBL-producing strains were further characterized for antimicrobial resistance, pulse field gel electrophoresis (PFGE) profiles, and the presence of bla(TEM), bla(SHV), bla(OXA), bla(CTX-M), and bla(PSE). The transferability of ESBL encoding genes to a susceptible Escherichia coli strain was also investigated. Thirty (21.7%) isolates were identified as ESBL positive and belonged to S. enterica serovars Indiana, Shubra, Typhimurium, and Enteritidis. S. Indiana and S. Shubra isolates were firstly identified in ESBL-producing strains. Great genetic diversity was seen among these ESBL-producing strains. Nucleotide sequence analysis revealed that bla(TEM-1B) was the only ESBL-encoding gene among the genes tested and was detected in 26 of 30 strains and was carried in the conjugative plasmids. The bla(TEM-1B) gene was transferable through conjugation at rates ranging from 4.71 x 10(-7) to 7.55 x 10(-6) transconjugant per recipient cell. This study provides the evidence of foodborne ESBL-producing Salmonella, and the transferability of plasmid harboring ESBL-encoding genes could possibly contribute to the dissemination of ESBL. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Yang, Baowei; Wang, Qianning; Wang, Yin; Shi, Chao; Xia, Xiaodong; Xi, Meili; Wang, Xin; Zhang, Zengfeng; Meng, Jianghong] Northwest A&F Univ, Yangling 712100, Shaanxi, Peoples R China. [Cui, Shenghui] Natl Inst Food & Drug Control, Beijing 100050, Peoples R China. [Shi, Xianming; Wang, Dapeng] Shanghai Jiao Tong Univ, Shanghai 200240, Peoples R China. [Meng, Jianghong] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Meng, Jianghong] Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 USA. RP Xia, XD (reprint author), Northwest A&F Univ, Coll Food Sci & Engn, 28 Xinong Rd, Yangling 712100, Shaanxi, Peoples R China. EM foodscixiaodong@yahoo.com FU Twelve-Five Science and Technology Support Program [2012BAK17B06]; Fundamental Research Funds for the Central Universities from Northwest AF University; Science and Technology Development Plan Program of Shaanxi Province [2013KJXX-16] FX This work was supported in part by the Twelve-Five Science and Technology Support Program (No. 2012BAK17B06), the Fundamental Research Funds for the Central Universities from Northwest A&F University, and Science and Technology Development Plan Program of Shaanxi Province (No. 2013KJXX-16). NR 37 TC 7 Z9 7 U1 0 U2 31 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 2014 VL 42 BP 14 EP 18 DI 10.1016/j.fm.2014.02.003 PG 5 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA AK7GQ UT WOS:000338597100003 PM 24929711 ER PT J AU Beaubrun, JJG Ewing, L Jarvis, K Dudley, K Grim, C Gopinath, G Flamer, ML Auguste, W Jayaram, A Elmore, J Lamont, M McGrath, T Hanes, DE AF Beaubrun, J. Jean-Gilles Ewing, L. Jarvis, K. Dudley, K. Grim, C. Gopinath, G. Flamer, M. -L. Auguste, W. Jayaram, A. Elmore, J. Lamont, M. McGrath, T. Hanes, D. E. TI Comparison of a PCR serotyping assay, Check&Trace assay for Salmonella, and Luminex Salmonella serotyping assay for the characterization of Salmonella enterica identified from fresh and naturally contaminated cilantro SO FOOD MICROBIOLOGY LA English DT Article DE Salmonella spp.; Molecular serotyping; Cilantro ID REAL-TIME PCR; MULTIPLEX PCR AB Salmonella enterica isolated from fresh cilantro samples collected through the USDA/AMS Microbiological Data Program (MDP) were used to compare a PCR serotyping assay against the Check&Trace assay and the Luminex (BioPlex) Salmonella serotyping assay. The study was conducted to evaluate the effectiveness of the three methods for serotyping Salmonella from both enrichment broth cultures and pure Salmonella cultures. In this investigation, Salmonella spp. serotyping was conducted using 24 h enrichment broth cultures and pure Salmonella cultures from cilantro samples, with the PCR serotyping assay. Conversely, the Check&Trace and Luminex for Salmonella assays required pure cultures for Salmonella serotyping. The cilantro samples contained S. enterica serovar Montevideo, Newport, Saintpaul, and Tennessee, identified by the PCR serotyping assay and Check&Trace for Salmonella, but the Luminex assay only identified two of the four serotypes of the cilantro samples. The anticipated impact from this study is that the PCR serotyping assay provides a time- and cost-effective means for screening, identifying and serotyping Salmonella using DNA extracted from 24 h enrichment cilantro samples. Published by Elsevier Ltd. C1 [Beaubrun, J. Jean-Gilles; Ewing, L.; Jarvis, K.; Dudley, K.; Grim, C.; Gopinath, G.; Flamer, M. -L.; Auguste, W.; Jayaram, A.; Elmore, J.; Hanes, D. E.] US FDA, Laurel, MD 20708 USA. [Grim, C.] Oak Ridge Inst Sci & Technol, Oak Ridge, TN USA. [Lamont, M.] USDA AMS Microbiol Data Program MDP, Manassas, VA 20110 USA. [McGrath, T.] ORA DFS FERN, Rockville, MD 20857 USA. [Flamer, M. -L.] Univ Maryland, UMCP JIFSAN Program, College Pk, MD 20742 USA. [Auguste, W.] Frostburg State Univ, Frostburg, MD 21532 USA. [Jayaram, A.] Richard Montgomery High Sch, Rockville, MD 20852 USA. [Elmore, J.] Howard Univ, Washington, DC 20059 USA. RP Beaubrun, JJG (reprint author), US FDA, MOD Facil 1, Virulence Mech Branch,Ctr Food Safety & Appl Nutr, Div Virulence Assessment,Off Appl Res & Safety As, HFS 025,8301 Muirkirk Rd, Laurel, MD 20708 USA. EM junia.jean-gillesbeaubrun@fda.hhs.gov NR 9 TC 2 Z9 2 U1 1 U2 13 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 2014 VL 42 BP 181 EP 187 DI 10.1016/j.fm.2014.02.008 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA AK7GQ UT WOS:000338597100027 ER PT J AU Lyn-Cook, BD Xie, C Oates, J Treadwell, E Word, B Hammons, G Wiley, K AF Lyn-Cook, Beverly D. Xie, Chenghui Oates, Jarren Treadwell, Edward Word, Beverly Hammons, George Wiley, Kenneth TI Increased expression of Toll-like receptors (TLRs) 7 and 9 and other cytokines in systemic lupus erythematosus (SLE) patients: Ethnic differences and potential new targets for therapeutic drugs SO MOLECULAR IMMUNOLOGY LA English DT Article DE Systemic lupus erythematous; Toll-like receptors; African American women; Interleukin-6; Tumor necrosis factor alpha; Interferon gamma ID AUTOANTIBODY PRODUCTION; RHEUMATOID-ARTHRITIS; REGULATORY FACTOR; INNATE IMMUNITY; DISEASE; IRF5; LINK; DNA AB Increased expression of pro-inflammatory cytokines such as interferon, tumor necrosis factors (TNFs) and specific interleukins (ILs) has been found in a number of autoimmune diseases, including systemic lupus erythematous (SLE). These cytokines are induced by toll-like receptors (TLRs). Toll-like receptors are activated in response to accumulation of apoptotic bodies. These receptors play critical roles in innate immune systems. Increased levels of interferon-alpha (INF-alpha) have also been found in many SLE patients and often correlate with disease severity. The objectives of this study were to examine the expression of selected TLRs and cytokines that have been identified in animal models and some limited human studies in a group of African Americans (AA) and European Americans (EA) women with lupus in comparison to age-matched non-lupus women. Blood samples were consecutively obtained by informed consent from 286 patients, 153 lupus and 136 non-lupus, seen in the rheumatology clinics at East Carolina University. Cytokines were analyzed from blood serum using enzyme linked immunoassay (ELISA) for IL-6 and INF-alpha. Total RNA was isolated, using a Paxgene kit, from peripheral blood mononuclear cells of African American and European American women blood samples. Quantitative real-time PCR using the CFX real-time system was conducted on all samples to determine TLRs 7 and 9, as well as INF-alpha expression. Toll-like receptor 7 (p < 0.01) and 9 (p = 0.001) expression levels were significantly increased in lupus patients compared to age-matched controls. African American women with lupus had a 2-fold increase in TLR-9 expression level when compared to their healthy controls or European American lupus patients. However, there was no ethnic difference in expression of TLR-7 in lupus patients. INF-alpha expression was significantly higher in lupus patients (p < 0.0001) and also showed ethnic difference in expression. Serum levels revealed significant increases in expression of IL-6, IFN-gamma and TNF-alpha in lupus patients compared to non-lupus patients. African American women with lupus had significantly higher serum levels of IL-6 and TNF-alpha. African American women with lupus demonstrated increased levels of specific pro-inflammatory cytokines and Toll-like receptors when compared to EA women. Increased expression in these lupus patients provides an opportunity for targeting with antagonist as a new therapy for systemic lupus erythematous. Published by Elsevier Ltd. C1 [Oates, Jarren] Univ Arkansas Pine Bluff, Pine Bluff, AR USA. [Treadwell, Edward; Hammons, George; Wiley, Kenneth] East Carolina Brody Sch Med, Greenville, NC USA. [Lyn-Cook, Beverly D.; Xie, Chenghui; Word, Beverly] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Lyn-Cook, BD (reprint author), Natl Ctr Toxicol, Off Associate Director Regulatory Activ, Bldg 50,Suite 630,3900 NCTR Rd, Jefferson, AR 72079 USA. EM Beverly.lyn-cook@fda.hhs.gov OI Oates, Jarren/0000-0002-4734-5597 FU FDA Office of Women's Health FX This study was supported by a FDA Office of Women's Health grant to Dr. Lyn-Cook. NR 30 TC 17 Z9 18 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2014 VL 61 IS 1 BP 38 EP 43 DI 10.1016/j.molimm.2014.05.001 PG 6 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA AJ7JJ UT WOS:000337872700006 PM 24865418 ER PT J AU Shults, J Guerra, MW AF Shults, Justine Guerra, Matthew W. TI A note on implementation of decaying product correlation structures for quasi-least squares SO STATISTICS IN MEDICINE LA English DT Article DE decaying product; feasible; generalized estimating equations; longitudinal binary data; quasi-least squares ID WORKING CORRELATION MATRIX; ESTIMATING EQUATIONS NOTES; GENERALIZED LINEAR-MODELS; LONGITUDINAL DATA; BINARY DATA; REGRESSION; CHOICE; EFFICIENCY; GEE AB This note implements an unstructured decaying product matrix via the quasi-least squares approach for estimation of the correlation parameters in the framework of generalized estimating equations. The structure we consider is fairly general without requiring the large number of parameters that are involved in a fully unstructured matrix. It is straightforward to show that the quasi-least squares estimators of the correlation parameters yield feasible values for the unstructured decaying product structure. Furthermore, subject to conditions that are easily checked, the quasi-least squares estimators are valid for longitudinal Bernoulli data. We demonstrate implementation of the structure in a longitudinal clinical trial with both a continuous and binary outcome variable. Copyright (C) 2014 John Wiley & Sons, Ltd. C1 [Shults, Justine] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Guerra, Matthew W.] US FDA, Div Biometr 3, Off Biostat, OTS,CDER, Silver Spring, MD USA. RP Shults, J (reprint author), Univ Penn, Sch Med, Dept Biostat & Epidemiol, 423 Guardian Dr,635 Blockley Hall, Philadelphia, PA 19104 USA. EM jshults@mail.med.upenn.edu NR 25 TC 1 Z9 1 U1 0 U2 2 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 2014 VL 33 IS 19 BP 3398 EP 3404 DI 10.1002/sim.6194 PG 7 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 AL9AE UT WOS:000339430800011 PM 24810946 ER PT J AU Erickson, BD Elkins, CA Mullis, LB Heinze, TM Wagner, RD Cerniglia, CE AF Erickson, Bruce D. Elkins, Christopher A. Mullis, Lisa B. Heinze, Thomas M. Wagner, R. Doug Cerniglia, Carl E. TI A metallo-beta-lactamase is responsible for the degradation of ceftiofur by the bovine intestinal bacterium Bacillus cereus P41 SO VETERINARY MICROBIOLOGY LA English DT Article DE Cephalosporins; Biodegradation; Drug residues; Veterinary drugs; Mass spectrometry ID STANDARD NUMBERING SCHEME; ESCHERICHIA-COLI; ANTIBIOTICS; CEPHALOSPORINS; RESISTANCE; RESOLUTION; RELATIVES; UPDATE; EFFLUX AB Ceftiofur is a highly effective veterinary cephalosporin, yet it is rapidly degraded by bacteria in the gut. The goal of this work was to directly determine the mechanism of ceftiofur degradation by the bovine intestinal isolate Bacillus cereus P41. B. cereus P41 was isolated from the feces of a cow that had not been treated with cephalosporins, and was found to rapidly degrade ceftiofur in culture. Analysis of spent culture media by HPLC/UV and HPLC/MS revealed one major metabolite of ceftiofur, with a negative ion m/z of 127. Comparison of ceftiofur, ceftriaxone, and cefpodoxime degradation suggested that the major stable ceftiofur metabolite was the thiofuroic acid group eliminated from the C-3 position of the drug after hydrolysis by beta-lactamase. Genomic DNA from B. cereus P41 was cloned into Escherichia colt, and the transformants were screened for growth in the presence of ceftiofur. DNA sequencing of the plasmid pHSG299-BC-3 insert revealed the presence of a gene encoding a metallo-beta-lactamase. Incubation of ceftiofur with either the E. coli transformant or a commercial B. cereus metallo-beta-lactamase showed degradation of the drug and formation of the same major metabolite produced by B. cereus P41. These data demonstrate that a metallo-beta-lactamase plays a major role in the degradation of ceftiofur by the bovine intestinal bacterium B. cereus P41. Published by Elsevier B.V. C1 [Erickson, Bruce D.; Elkins, Christopher A.; Mullis, Lisa B.; Wagner, R. Doug; Cerniglia, Carl E.] Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. [Heinze, Thomas M.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Erickson, BD (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM bruce.erickson@fda.hhs.gov FU cooperative research and development agreement between Zoetis (formerly Pfizer Animal Health) and U.S. Food and Drug Administration; National Center for Toxicological Research, U.S. Food and Drug Administration FX This work was supported by a cooperative research and development agreement between Zoetis (formerly Pfizer Animal Health) and the U.S. Food and Drug Administration, and by the National Center for Toxicological Research, U.S. Food and Drug Administration. We would like to thank Drs John B. Sutherland and Steven L Foley for critical reading of this manuscript. The opinions presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration or Zoetis. NR 24 TC 2 Z9 3 U1 4 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1135 EI 1873-2542 J9 VET MICROBIOL JI Vet. Microbiol. PD AUG 27 PY 2014 VL 172 IS 3-4 BP 499 EP 504 DI 10.1016/j.vetmic.2014.05.032 PG 6 WC Microbiology; Veterinary Sciences SC Microbiology; Veterinary Sciences GA AN6GL UT WOS:000340692900020 PM 24972871 ER PT J AU Pan, HM Zhang, YB He, GX Katagori, N Chen, HZ AF Pan, Hongmiao Zhang, Yongbin He, Gui-Xin Katagori, Namrata Chen, Huizhong TI A comparison of conventional methods for the quantification of bacterial cells after exposure to metal oxide nanoparticles SO BMC MICROBIOLOGY LA English DT Article DE Nanoparticles; Bacterial quantification; Flow cytometry (FCM); Colony-forming units (CFU); Optical density (OD) ID SUDAN AZO DYES; ESCHERICHIA-COLI; SILVER NANOPARTICLES; TIO2 NANOPARTICLES; ZNO NANOPARTICLES; FLOW-CYTOMETRY; TOXICITY; VIABILITY; CYTOTOXICITY; MEMBRANE AB Background: Due to potential interference of nanoparticles on bacterial quantification, there is a challenge to develop a fast, accurate and reproducible method for bacterial quantification. Currently various bacterial quantification methods are used by researchers performing nanoparticles study, but there has been no efficacy evaluation of these methods. Here we study interference of nanoparticles on three most commonly used conventional bacterial quantification methods, including colony counting to determine the colony-forming units (CFU), spectrophotometer method of optical density (OD) measurement, and flow cytometry (FCM). Results: Three oxide nanoparticles including ZnO, TiO2, and SiO2 and four bacterial species including Salmonella enterica serovar Newport, Staphylococcus epidermidis, Enterococcus faecalis, and Escherichia coli were included in the test. Results showed that there is no apparent interference of the oxide nanoparticles on quantifications of all four bacterial species by FCM measurement; CFU counting is time consuming, less accurate and not suitable for automation; and the spectrophotometer method using OD measurement was the most unreliable method to quantify and detect the bacteria in the presence of the nanoparticles. Conclusion: In summary, FCM measurement proved to be the best method, which is suitable for rapid, accurate and automatic detection of bacteria in the presence of the nanoparticles. C1 [Pan, Hongmiao; Chen, Huizhong] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Zhang, Yongbin] US FDA, Nanotechnol Core Facil, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [He, Gui-Xin; Katagori, Namrata] Univ Massachusetts Lowell, Dept Clin Lab & Nutr Sci, Lowell, MA 01854 USA. RP Chen, HZ (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM huizhong.chen@fda.hhs.gov FU National Center for Toxicological Research, United States Food and Drug Administration; Oak Ridge Institute for Science and Education FX We would like to thank Drs. Steven L. Foley and Jing Han for their critical review of this manuscript. This study was funded by National Center for Toxicological Research, United States Food and Drug Administration, and supported in part by appointment (H.P.) to the Postgraduate Research Fellowship Program 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 authors would like to thank M. Yvonne Jones for assistance with TEM images. The views presented in this article do not necessarily reflect those of the Food and Drug Administration. NR 45 TC 5 Z9 5 U1 1 U2 17 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 21 PY 2014 VL 14 AR 222 DI 10.1186/s12866-014-0222-6 PG 11 WC Microbiology SC Microbiology GA AO3EO UT WOS:000341211800001 PM 25138641 ER PT J AU Cox, E Laessig, K AF Cox, Edward Laessig, Katherine TI FDA Approval of Bedaquiline - The Benefit-Risk Balance for Drug-Resistant Tuberculosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Cox, Edward; Laessig, Katherine] US FDA, Off Antimicrobial Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Cox, E (reprint author), US FDA, Off Antimicrobial Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. NR 5 TC 40 Z9 41 U1 0 U2 9 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 21 PY 2014 VL 371 IS 8 BP 689 EP 691 DI 10.1056/NEJMp1314385 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AN3SV UT WOS:000340509900001 PM 25140952 ER PT J AU Barr, IG Russell, C Besselaar, TG Cox, NJ Daniels, RS Donis, R Engelhardt, OG Grohmann, G Itamura, S Kelso, A McCauley, J Odagiri, T Schultz-Cherry, S Shu, YL Smith, D Tashiro, M Wang, DY Webby, R Xu, XY Ye, ZP Zhang, WQ AF Barr, Ian G. Russell, Colin Besselaar, Terry G. Cox, Nancy J. Daniels, Rod S. Donis, Ruben Engelhardt, Othmar G. Grohmann, Gary Itamura, Shigeyuki Kelso, Anne McCauley, John Odagiri, Takato Schultz-Cherry, Stacey Shu, Yuelong Smith, Derek Tashiro, Masato Wang, Dayan Webby, Richard Xu, Xiyan Ye, Zhiping Zhang, Wenqing CA Writing Comm World Hlth Org Consul TI WHO recommendations for the viruses used in the 2013-2014 Northern Hemisphere influenza vaccine: Epidemiology, antigenic and genetic characteristics of influenza A(H1N1)pdm09, A(H3N2) and B influenza viruses collected from October 2012 to January 2013 SO VACCINE LA English DT Article DE Influenza; Vaccine; Human; Trivalent; Quadrivalent; Recommendation; Northern Hemisphere 2013-2014 ID SUBSTITUTION AB In February the World Health Organisation (WHO) recommends influenza viruses to be included in influenza vaccines for the forthcoming winter in the Northern Hemisphere. These recommendations are based on data collected by National Influenza Centres (NICs) through the WHO Global Influenza Surveillance and Response System (GISRS) and a more detailed analysis of representative and potential antigenically variant influenza viruses from the WHO Collaborating Centres for Influenza (WHO CCs) and Essential Regulatory Laboratories (ERLs). This article provides a detailed summary of the antigenic and genetic properties of viruses and additional background data used by WHO experts during development of the recommendations of the 2013-2014 Northern Hemisphere influenza vaccine composition. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). C1 [Barr, Ian G.; Kelso, Anne] WHO Collaborating Ctr Reference & Res Influenza, Victorian Infect Dis Reference Lab, Melbourne, Vic, Australia. [Russell, Colin] Univ Cambridge, Cambridge CB2 1TN, England. [Besselaar, Terry G.; Zhang, Wenqing] WHO Global Influenza Programme GIP, Geneva, Switzerland. [Cox, Nancy J.; Donis, Ruben; Xu, Xiyan] Ctr Dis Control & Prevent, WHO Collaborating Ctr Surveillance Epidemiol & Co, Atlanta, GA USA. [Daniels, Rod S.; McCauley, John] Natl Inst Med Res, MRC, WHO Collaborating Ctr Reference & Res Influenza, London NW7 1AA, England. [Grohmann, Gary] Hlth Protect Agcy, Natl Inst Biol Stand & Control, Potters Bar, Herts, England. [Grohmann, Gary] Therapeut Goods Adm, Canberra, ACT, Australia. [Itamura, Shigeyuki; Odagiri, Takato; Tashiro, Masato] Natl Inst Infect Dis, WHO Collaborating Ctr Reference & Res Influenza, Tokyo, Japan. [Schultz-Cherry, Stacey; Webby, Richard] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Shu, Yuelong; Wang, Dayan] Chinese Natl Influenza Ctr, WHO Collaborating Ctr Reference & Res Influenza, Beijing, Peoples R China. [Smith, Derek] Univ Cambridge, Ctr Pathogen Evolut, Cambridge CB2 1TN, England. [Smith, Derek] Univ Cambridge, WHOCC Modelling Evolut & Control Emerging Infect, Cambridge CB2 1TN, England. [Smith, Derek] NIH, Fogarty Int Ctr, Bethesda, MD USA. [Ye, Zhiping] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Barr, IG (reprint author), WHO Collaborating Ctr Reference & Res Influenza, Victorian Infect Dis Reference Lab, Melbourne, Vic, Australia. EM Ian.Barr@influenzacentre.org FU Australian Government Department of Health; WHO Collaborating Centre for Reference and Research on Influenza at the MRC National Institute for Medical Research; Medical Research Programme [U1175512723]; NIH [HHSN266200700010C] FX The writing committee would like to thank all of their colleagues in their institutes, the WHO NICs and other laboratories and organisations for their efforts in supplying, testing and analysing the influenza viruses characterised in the course of generating the data for this report. The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health and the WHO Collaborating Centre for Reference and Research on Influenza at the MRC National Institute for Medical Research, Mill Hill, is supported by Medical Research Programme U1175512723. DS is supported by NIH contract HHSN266200700010C. NR 9 TC 32 Z9 34 U1 0 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 20 PY 2014 VL 32 IS 37 BP 4713 EP 4725 DI 10.1016/j.vaccine.2014.02.014 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AO0DR UT WOS:000340979800004 PM 24582632 ER PT J AU McNeil, MM Cano, M Miller, ER Petersen, BW Engler, RJM Bryant-Genevier, MG AF McNeil, Michael M. Cano, Maria Miller, Elaine R. Petersen, Brett W. Engler, Renata J. M. Bryant-Genevier, Marthe G. TI Ischemic cardiac events and other adverse events following ACAM2000 (R) smallpox vaccine in the Vaccine Adverse Event Reporting System SO VACCINE LA English DT Article DE ACAM2000 (R); Ischemic cardiac events; Myocarditis; Pericarditis; Myo/pericarditis ID ACUTE MYOCARDIAL-INFARCTION; JANUARY-OCTOBER 2003; UNITED-STATES; MILITARY; PROGRAM; SAFETY; EXPERIENCE AB Background: The Vaccine Adverse Event Reporting System (VAERS) is a passive reporting system, used for monitoring the safety of all US licensed vaccines. In March 2008, ACAM2000 (R) replaced Dryvax (R) as the only licensed smallpox vaccine and is administered to all persons entering military service and certain civilian researchers. In 2011, routine data mining of VAERS identified a vaccine safety concern resulting in acute ischemic cardiac events (ICE) following ACAM2000 (R). Methods: During March 1, 2008 through June 30, 2013, we reviewed all serious reports received following ACAM2000 (R) and classified them by diagnostic category. We identified possible ICE cases by searching the Medical Dictionary for Regulatory Affairs (MedDRA (R)) terms for "myocardial ischaemia," "acute myocardial infarction," "myocardial infarction," and "ischaemia," and applied standardized surveillance case definitions. Results: VAERS received 1149 reports following ACAM2000 (R) administration; 169 (14.7%) were serious (resulting in permanent disability, hospitalization or prolongation of hospitalization, life-threatening illness or death), including one death. The two most frequent diagnostic categories for serious reports were cardiovascular and other infectious conditions. The MedDRA (R) search found 31 reports of possible ICE after receipt of ACAM2000 (R) vaccine. Of a total 30 possible ICE cases with demographic information, all but one was male; the age range was 20-45 years (median 32) and median interval to onset of symptoms was 12 days. On clinical review there were 16 cases of myocarditis/pericarditis and 15 ICE cases. Conclusions: Our review of the data mining signal did not substantiate the concerns about ICE after ACAM2000 (R). Our study also suggests that with current pre-vaccination screening, cardiac morbidity in generally healthy vaccinated populations remains uncommon. Published by Elsevier Ltd. C1 [McNeil, Michael M.; Cano, Maria; Miller, Elaine R.] Ctr Dis Control & Prevent, Immunizat Safety Off, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Petersen, Brett W.] Ctr Dis Control & Prevent, Poxvirus & Rabies Branch, Div High Consequence Pathogens & Pathol, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Engler, Renata J. M.] Mil Vaccine Agcy, Vaccine Healthcare Ctr Network, US Army Publ Hlth Command, Walter Reed Natl Mil Med Ctr, Bethesda, MD 20889 USA. [Bryant-Genevier, Marthe G.] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP McNeil, MM (reprint author), Ctr Dis Control & Prevent, MS D-126,1600 Clifton Rd NE, Atlanta, GA 30333 USA. EM mmm2@cdc.gov FU comprehensive VAERS investigations; CDC FX This work was supported by the comprehensive VAERS investigations submitted by the clinical staff of the Department of Defense Vaccine Healthcare Centers Network (Division of the Military Vaccine Agency, U.S. Army Public Health Command) Myocarditis/Pericarditis Clinical Case Management Consortium (including the DoD allergists-immunologists/cardiologists leaders - Dr. Limone C. Collins, Dr. Jay Montgomery, COL John E. Atwood, LTC Brian Hemann and LTC Barnett Gibbs). The authors thank Frank DeStefano, MD MPH, for his critical review of the manuscript. The funding for this study was provided solely by the CDC. NR 35 TC 1 Z9 1 U1 0 U2 5 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 20 PY 2014 VL 32 IS 37 BP 4758 EP 4765 DI 10.1016/j.vaccine.2014.06.034 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AO0DR UT WOS:000340979800010 PM 24951868 ER PT J AU Teferedegne, B Macauley, J Foseh, G Dragunsky, E Chumakov, K Murata, H Peden, K Lewis, AM AF Teferedegne, Belete Macauley, Juliete Foseh, Gideon Dragunsky, Eugenia Chumakov, Konstantin Murata, Haruhiko Peden, Keith Lewis, Andrew M., Jr. TI MicroRNAs as potential biomarkers for VERO cell tumorigenicity SO VACCINE LA English DT Article DE African green monkey kidney (VERO) cells; Neoplastic development; Transformation; Tumorigenicity; miRNA; Biomarkers ID EPITHELIAL-MESENCHYMAL TRANSITION; VACCINE PRODUCTION; INFLUENZA VACCINES; TARGETING ZEB1; PASSAGE NUMBER; HUMAN CANCERS; EXPRESSION; SIGNATURE; PROTECTION; PHENOTYPE AB MicroRNA expression appears to capture the process of neoplastic development in vitro in the VERO line of African green monkey kidney (AGMK) cells (Teferedegne et al. PLoS One 2010;5(12): e14416). In that study, specific miRNA signatures were correlated with the transition, during serial tissue-culture passage, of low-density passaged 10-87 VERO cells from a non-tumorigenic phenotype at passage (p) 148 to a tumorigenic phenotype at p256. In the present study, six miRNAs (miR-376a, miR-654-3p, miR-543, miR-299-3p, miR-134 and miR-369-3p) were chosen from the identified signature miRNAs for evaluation of their use as potential biomarkers to track the progression of neoplastic development in VERO cells. Cells from the 10-87 VERO cell line at passage levels from p148 to p256 were inoculated into newborn and adult athymic nude mice. No tumors were observed in animals inoculated with cells from p148 to p186. In contrast, tumor incidences of 20% developed only in newborn mice that received 10-87 VERO cells at p194, p234 and p256. By qPCR profiling of the signature miRNAs of 10-87 VERO cells from these cell banks, we identified p194 as the level at which signature miRNAs elevated concurrently with the acquisition of tumorigenic phenotype with similar levels expressed beyond this passage. In wound-healing assays at 10-passage intervals between p150 to p250, the cells displayed a progressive increase in migration from p165 to p186; beginning at p194 and higher passages thereafter, the cells exhibited the highest rates of migration. By qPCR analysis, the same signature miRNAs were overexpressed with concomitant acquisition of the tumorigenic phenotype in another lineage of 10-87 VERO cells passaged independently at high density. Correlation between the passages at which the cells expressed a tumorigenic phenotype and the passages representing peaks in expression levels of signature miRNAs indicates that these miRNAs are potential biomarkers for the expression of the VERO cell tumorigenic phenotype. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). C1 [Teferedegne, Belete; Macauley, Juliete; Foseh, Gideon; Murata, Haruhiko; Peden, Keith; Lewis, Andrew M., Jr.] US FDA, Lab DNA Viruses, Div Viral Prod, Off Vaccines Res & Review,Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Dragunsky, Eugenia; Chumakov, Konstantin] US FDA, Lab Method Dev, Div Viral Prod, Off Vaccines Res & Review,Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Teferedegne, B (reprint author), US FDA, Lab DNA Viruses, Div Viral Prod, Off Vaccines Res & Review,Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM belete.teferedegne@fda.hhs.gov; andrew.lewis@fda.hhs.gov FU Division of Microbiology and Infectious Diseases, NIAID, NIH; Medical Countermeasures Initiative (MCMi), (FDA); Division of Viral Products, Center for Biologics Evaluation and Research, FDA; Oak Ridge Institute for Science and Education FX We thank members of our laboratories for advice and discussions. We also extend our thanks to Drs. Steve Feinstone, Robin Levis, and Carol Weiss for helpful discussions and/or comments on the manuscript. This work was supported by Division of Microbiology and Infectious Diseases, NIAID, NIH; Medical Countermeasures Initiative (MCMi), (FDA); Division of Viral Products, Center for Biologics Evaluation and Research, FDA and the Oak Ridge Institute for Science and Education. NR 58 TC 2 Z9 2 U1 1 U2 6 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 20 PY 2014 VL 32 IS 37 BP 4799 EP 4805 DI 10.1016/j.vaccine.2014.05.065 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AO0DR UT WOS:000340979800016 PM 25024114 ER PT J AU Smith, MA Altekruse, SF Adamson, PC Reaman, GH Seibel, NL AF Smith, Malcolm A. Altekruse, Sean F. Adamson, Peter C. Reaman, Gregory H. Seibel, Nita L. TI Declining Childhood and Adolescent Cancer Mortality SO CANCER LA English DT Article DE childhood cancer; adolescents; childhood leukemia; mortality rates; childhood solid tumors ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHILDRENS ONCOLOGY GROUP; IMPROVES EVENT-FREE; ARSENIC TRIOXIDE; CLINICAL-TRIALS; HISTONE H3.3; YOUNG-ADULTS; SURVIVAL; GLIOBLASTOMA; MUTATIONS AB BACKGROUND: To evaluate whether progress continues in identifying more effective treatments for children and adolescents with cancer, the authors examined both overall and disease-specific childhood cancer mortality rates for the United States, focusing on data from 2000 to 2010. METHODS: Age-adjusted US mortality trends from 1975 to 2010 were estimated using joinpoint regression analysis. Analyses of annual percentage change (APC) were performed on the same diagnostic groupings for the period restricted to 2000 through 2010 for groupings ages < 20 years, < 15 years, and 15 to 19 years. RESULTS: After a plateau in mortality rates during 1998 to 2002 (APC, 0.3%), the annual decline in childhood cancer mortality from 2002 to 2010 (APC, -2.4%) was similar to that observed from 1975 to 1998 (APC, -2.7%). Statistically significant declines in mortality rates from 2000 to 2010 were noted for acute lymphoblastic leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, neuroblastoma, central nervous system cancers, and gonadal cancers. From 2000 to 2010, the rates of decline in mortality for the group ages 15 to 19 years generally were equal to or greater than the rates of decline for the group ages birth to 14 years. Improvements in treatment since 1975 resulted > 45,000 cancer deaths averted through 2010. CONCLUSIONS: Cancer mortality for both children and adolescents declined from 2000 to 2010, with significant declines observed for multiple cancer types. However, greater than 1900 cancer deaths still occur each year among children and adolescents in the United States, and many survivors experience long-term effects that limit their quality of life. Continued research directed toward identifying more effective treatments that produce fewer long-term sequelae is critical to address these remaining challenges. Published 2014. C1 [Smith, Malcolm A.; Seibel, Nita L.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Altekruse, Sean F.] NCI, Surveillance Res Program, Bethesda, MD 20892 USA. [Adamson, Peter C.] Childrens Hosp Philadelphia, Dept Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA. [Reaman, Gregory H.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Smith, MA (reprint author), NCI, Canc Therapy Evaluat Program, 9609 Med Ctr Dr,RM 5-W414,MSC 9737, Bethesda, MD 20892 USA. EM Malcolm.Smith@nih.gov FU National Cancer Institute [U10CA98543] FX This work was supported by a grant from the National Cancer Institute (U10CA98543) to Dr. Adamson. NR 33 TC 53 Z9 58 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2014 VL 120 IS 16 BP 2497 EP 2506 DI 10.1002/cncr.28748 PG 10 WC Oncology SC Oncology GA AN3DB UT WOS:000340464100017 PM 24853691 ER PT J AU Warfel, JM Papin, JF Wolf, RF Zimmerman, LI Merkel, TJ AF Warfel, Jason M. Papin, James F. Wolf, Roman F. Zimmerman, Lindsey I. Merkel, Tod J. TI Maternal and Neonatal Vaccination Protects Newborn Baboons From Pertussis Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE pertussis; maternal vaccination; neonatal vaccination; baboon; animal models ID NONHUMAN PRIMATE MODEL; BORDETELLA-PERTUSSIS; INFANT PERTUSSIS; INTENSIVE-CARE; IMMUNIZATION; DIPHTHERIA; TETANUS; TRANSMISSION; VACCINES; ANTIBODY AB Background. The United States is experiencing a pertussis resurgence that resulted in a 60-year high of 48 000 cases in 2012. The majority of hospitalizations and deaths occur in infants too young to be vaccinated. Neonatal and maternal vaccination have been proposed to protect newborns until the first vaccination, currently recommended at 2 months of age. These interventions result in elevated anti-Bordetella pertussis titers, but there have been no studies demonstrating that these measures confer protection. Methods. Baboons were vaccinated with acellular pertussis vaccine at 2 days of age or at 2 and 28 days of age. To model maternal vaccination, adult female baboons primed with acellular pertussis vaccine were boosted in the third trimester of pregnancy. Neonatally vaccinated infants, infants born to vaccinated mothers, and naive infants born to unvaccinated mothers were infected with B. pertussis at 5 weeks of age. Results. Naive infant baboons developed severe disease when challenged with B. pertussis at 5 weeks of age. Baboons receiving acellular pertussis vaccine and infants born to mothers vaccinated at the beginning of their third trimester were protected. Conclusions. Our results demonstrate that neonatal vaccination and maternal vaccination confer protection in the baboon model and support further study of these strategies for protection of newborns from pertussis. C1 [Warfel, Jason M.; Zimmerman, Lindsey I.; Merkel, Tod J.] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Papin, James F.; Wolf, Roman F.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma Baboon Res Resource, Oklahoma City, OK USA. RP Merkel, TJ (reprint author), US FDA, Lab Resp & Special Pathogens, DBPAP, CBER, Bldg 29,Rm 419,29 Lincoln Dr, Bethesda, MD 20892 USA. EM tod.merkel@fda.hhs.gov FU Food and Drug Administration; National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) [Y1-AI-1727-01]; National Center For Research Resources, NIH [P40RR012317, 5R24RR016556-10] FX This work was supported by the Food and Drug Administration and the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH; interagency agreement Y1-AI-1727-01); and the National Center For Research Resources, NIH (grants P40RR012317 and 5R24RR016556-10 to the Oklahoma Baboon Research Resource). NR 39 TC 14 Z9 15 U1 1 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2014 VL 210 IS 4 BP 604 EP 610 DI 10.1093/infdis/jiu090 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AN0AN UT WOS:000340243500014 PM 24526741 ER PT J AU Gucinski, AC Boyne, MT AF Gucinski, Ashley C. Boyne, Michael T., II TI Identification of site-specific heterogeneity in peptide drugs using intact mass spectrometry with electron transfer dissociation SO RAPID COMMUNICATIONS IN MASS SPECTROMETRY LA English DT Article ID AMINO-ACID SEQUENCE; LIQUID-CHROMATOGRAPHY; CLUPEINE-YII; PROTAMINES AB RATIONALE: Protamine sulfate is a peptide drug product consisting of multiple basic peptides. As traditional high-performance liquid chromatography (HPLC) separation methods may not resolve these peptides, as well as any possible peptide-related impurities, a method utilizing top-down mass spectrometry was developed for the characterization of complex peptide drug products, including any low-level impurities, which is described in this study. METHODS: Herring protamine sulfate was used as a model system to demonstrate the applicability of the method. Direct infusion mass spectrometry and tandem mass spectrometry (MS/MS) on a high-resolution, mass accurate instrument with electron transfer dissociation (ETD) were used to identify all the species present in the herring protamine sulfate sample. Identifications were made based on mass accuracy analysis as well as MS/MS fragmentation patterns. RESULTS: Complete sequence coverage of the three abundant herring protamine peptides was obtained using the top-down ETD-MS/MS method, which also identified a discrepancy with the published herring protamine peptide sequences. Additionally, three low-abundance related peptide species were also identified and fully characterized. These three peptides had not previously been reported as herring protamine peptides, but could be related to the published sequences through amino acid additions and/or substitutions. CONCLUSIONS: A method for the characterization of protamine, a complex peptide drug product, was developed that can be extended to other complex peptide or protein drug products. The selectivity and sensitivity of thismethod improves a regulator's ability to identify peptide impurities not previously observed using the established methods and presents an opportunity to better understand the composition of complex peptide drug products. Published in 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Gucinski, Ashley C.; Boyne, Michael T., II] US FDA, CDER OPS OTR Div Pharmaceut Anal, Silver Spring, MD 20993 USA. RP Boyne, MT (reprint author), US FDA, CDER OPS OTR Div Pharmaceut Anal, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM michael.boyne@fda.hhs.gov FU CDER Critical Path Program FX Funding and support for this work was provided by the CDER Critical Path Program (MTB) and is gratefully acknowledged. Helpful discussions with David Keire also are gratefully acknowledged. The findings and conclusions of 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 32 TC 5 Z9 5 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0951-4198 EI 1097-0231 J9 RAPID COMMUN MASS SP JI Rapid Commun. Mass Spectrom. PD AUG 15 PY 2014 VL 28 IS 15 BP 1757 EP 1763 DI 10.1002/rcm.6957 PG 7 WC Biochemical Research Methods; Chemistry, Analytical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA AK9SP UT WOS:000338767300014 PM 24975256 ER PT J AU Liu, CL Liu, AY Hu, J Yuan, VVA Halabi, S AF Liu, Chunling Liu, Aiyi Hu, Jiang Yuan, Vivian Halabi, Susan TI Adjusting for misclassification in a stratified biomarker clinical trial SO STATISTICS IN MEDICINE LA English DT Article DE biomarkers; classification error; correction for error; personalized medicine; power and sample size; prevalence; randomized controlled clinical trials; sensitivity and specificity ID RENAL-CELL CARCINOMA; THERAPEUTIC RESPONSE; INTERFERON-ALPHA; CANCER; DESIGNS; CHALLENGES; EFFICIENCY; ERROR AB Clinical trials utilizing predictive biomarkers have become a research focus in personalized medicine. We investigate the effects of biomarker misclassification on the design and analysis of stratified biomarker clinical trials. For a variety of inference problems including marker-treatment interaction in particular, we show that marker misclassification may have profound adverse effects on the coverage of confidence intervals, power of the tests, and required sample sizes. For each inferential problem, we propose methods to adjust for the classification errors. Copyright (C) 2014 JohnWiley & Sons, Ltd. C1 [Liu, Chunling] Hong Kong Polytech Univ, Dept Appl Math, Hong Kong, Hong Kong, Peoples R China. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Rockville, MD 20852 USA. [Hu, Jiang] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Yuan, Vivian] US FDA, Ctr Drug Dev & Res, Silver Spring, MD 20993 USA. [Halabi, Susan] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27708 USA. RP Liu, AY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Rockville, MD 20852 USA. EM liua@mail.nih.gov RI Liu, Chunling/A-4827-2015; OI Liu, Chunling/0000-0003-3410-445X; Liu, Aiyi/0000-0002-6618-5082 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health; [R01-CA155296]; [U01-CA157703] FX Research of A. Liu was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. Research of S. Halabi was supported by grants R01-CA155296 and U01-CA157703. NR 19 TC 1 Z9 1 U1 1 U2 5 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 15 PY 2014 VL 33 IS 18 BP 3100 EP 3113 DI 10.1002/sim.6164 PG 14 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 AL4OX UT WOS:000339113400004 PM 24733510 ER PT J AU Tulio, AZ Jablonski, JE Jackson, LS Chang, C Edirisinghe, I Burton-Freeman, B AF Tulio, Artemio Z., Jr. Jablonski, Joseph E. Jackson, Lauren S. Chang, Claire Edirisinghe, Indika Burton-Freeman, Britt TI Phenolic composition, antioxidant properties, and endothelial cell function of red and white cranberry fruits (Retracted article. See vol. 166, pg. 514, 2015) SO FOOD CHEMISTRY LA English DT Article; Retracted Publication DE Cranberry; Phenolic compounds; Antioxidants; Anthocyanins; Proanthocyanidins; Flavonols; Phenolic acids; Endothelial cell function; p-Akt; Cell migration; Tube formation ID FIMBRIATED ESCHERICHIA-COLI; DEPENDENT RELAXATION; VACCINIUM-MACROCARPON; INHIBIT ADHERENCE; CAPACITY; EXTRACT; PROANTHOCYANIDINS; ANTHOCYANINS; PROCYANIDINS; VALIDATION AB The effects of phenolic constituents in red cranberry extracts (RCE) and white cranberry extracts (WCE) on the endothelial cell function were investigated. Peonidin-3-O-galactoside, cyanidin-3-O-arabinoside, and cyanidin-3-O-galactoside were the predominant anthocyanins characterized, whereas a procyanidin tetramer was the predominant proanthocyanidin identified. The antioxidant properties of RCE and WCE were not significantly different regardless of antioxidant assays (DPPH, FRAP, and TEAC) used. Both RCE and WCE induced the phosphorylation of Akt in vitro in human umbilical endothelial cells (HUVEC), resulting in the phosphorylation of endothelial nitric oxide synthase, cell migration, and tube formation. The enhanced phosphorylation of PI3/Akt kinase in HUVEC, endothelial cell wound healing, and tube formation elicited by RCE and WCE suggest that overall phenolic constituents rather than individual phenolic compounds within the cranberry matrix may be responsible for these biological effects. Published by Elsevier Ltd. C1 [Tulio, Artemio Z., Jr.; Jablonski, Joseph E.; Jackson, Lauren S.; Chang, Claire] US FDA, Ctr Food Safety & Appl Nutr, Bedford Pk, IL 60501 USA. [Chang, Claire] Oak Ridge Inst Sci & Educ, Oak Ridge, TN 37830 USA. [Edirisinghe, Indika; Burton-Freeman, Britt] IIT, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. RP Tulio, AZ (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM artemio.tulio@fda.hhs.gov NR 29 TC 4 Z9 4 U1 3 U2 78 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0308-8146 EI 1873-7072 J9 FOOD CHEM JI Food Chem. PD AUG 15 PY 2014 VL 157 BP 540 EP 552 DI 10.1016/j.foodchem.2014.02.047 PG 13 WC Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics SC Chemistry; Food Science & Technology; Nutrition & Dietetics GA AF8NT UT WOS:000334973600073 PM 24679816 ER PT J AU Sarntivijai, S Lin, Y Xiang, ZS Meehan, TF Diehl, AD Vempati, UD Schurer, SC Pang, C Malone, J Parkinson, H Liu, Y Takatsuki, T Saijo, K Masuya, H Nakamura, Y Brush, MH Haendel, MA Zheng, J Stoeckert, CJ Peters, B Mungall, CJ Carey, TE States, DJ Athey, BD He, YQ AF Sarntivijai, Sirarat Lin, Yu Xiang, Zuoshuang Meehan, Terrence F. Diehl, Alexander D. Vempati, Uma D. Schuerer, Stephan C. Pang, Chao Malone, James Parkinson, Helen Liu, Yue Takatsuki, Terue Saijo, Kaoru Masuya, Hiroshi Nakamura, Yukio Brush, Matthew H. Haendel, Melissa A. Zheng, Jie Stoeckert, Christian J. Peters, Bjoern Mungall, Christopher J. Carey, Thomas E. States, David J. Athey, Brian D. He, Yongqun TI CLO: The cell line ontology SO JOURNAL OF BIOMEDICAL SEMANTICS LA English DT Article DE Cell line; Cell line cell; Immortal cell line cell; Mortal cell line cell; Cell line cell culturing; Anatomy AB Background: Cell lines have been widely used in biomedical research. The community-based Cell Line Ontology (CLO) is a member of the OBO Foundry library that covers the domain of cell lines. Since its publication two years ago, significant updates have been made, including new groups joining the CLO consortium, new cell line cells, upper level alignment with the Cell Ontology (CL) and the Ontology for Biomedical Investigation, and logical extensions. Construction and content: Collaboration among the CLO, CL, and OBI has established consensus definitions of cell line-specific terms such as 'cell line', 'cell line cell', 'cell line culturing', and 'mortal' vs. 'immortal cell line cell'. A cell line is a genetically stable cultured cell population that contains individual cell line cells. The hierarchical structure of the CLO is built based on the hierarchy of the in vivo cell types defined in CL and tissue types (from which cell line cells are derived) defined in the UBERON cross-species anatomy ontology. The new hierarchical structure makes it easier to browse, query, and perform automated classification. We have recently added classes representing more than 2,000 cell line cells from the RIKEN BRC Cell Bank to CLO. Overall, the CLO now contains similar to 38,000 classes of specific cell line cells derived from over 200 in vivo cell types from various organisms. Utility and discussion: The CLO has been applied to different biomedical research studies. Example case studies include annotation and analysis of EBI ArrayExpress data, bioassays, and host-vaccine/pathogen interaction. CLO's utility goes beyond a catalogue of cell line types. The alignment of the CLO with related ontologies combined with the use of ontological reasoners will support sophisticated inferencing to advance translational informatics development. C1 [Sarntivijai, Sirarat] US FDA, Silver Spring, MD 20993 USA. [Sarntivijai, Sirarat; Lin, Yu; Xiang, Zuoshuang; Liu, Yue; Carey, Thomas E.; Athey, Brian D.; He, Yongqun] Univ Michigan, Ann Arbor, MI 48109 USA. [Meehan, Terrence F.; Malone, James; Parkinson, Helen] EMBL EBI, European Mol Biol Lab, Hinxton, Oxon, England. [Diehl, Alexander D.] SUNY Buffalo, Buffalo, NY 14260 USA. [Vempati, Uma D.; Schuerer, Stephan C.] Univ Miami, Miami, FL USA. [Pang, Chao] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Takatsuki, Terue; Saijo, Kaoru; Masuya, Hiroshi; Nakamura, Yukio] RIKEN, BioResource Ctr, Tsukuba, Ibaraki, Japan. [Brush, Matthew H.; Haendel, Melissa A.] Oregon Hlth & Sci Univ, Portland, OR USA. [Zheng, Jie; Stoeckert, Christian J.] Univ Penn, Philadelphia, PA 19104 USA. [Peters, Bjoern] La Jolla Inst Allergy & Immunol, La Jolla, CA USA. [Mungall, Christopher J.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA. [States, David J.] OncProTech LLC, Ann Arbor, MI USA. RP Sarntivijai, S (reprint author), US FDA, Silver Spring, MD 20993 USA. EM siiraa@umich.edu; yongqunh@med.umich.edu RI Zheng, Jie/M-1191-2015; Nakamura, Yukio/A-5263-2016; Masuya, Hiroshi/A-6442-2016; Diehl, Alexander/G-9883-2016; OI Zheng, Jie/0000-0002-2999-0103; Masuya, Hiroshi/0000-0002-3392-466X; Diehl, Alexander/0000-0001-9990-8331; Athey, Brian/0000-0002-9793-535X; Parkinson, Helen/0000-0003-3035-4195; He, Yongqun/0000-0001-9189-9661; Sarntivijai, Sirarat/0000-0002-2548-641X; Meehan, Terrence/0000-0003-1980-3228; Carey, Thomas/0000-0002-5202-7518 FU National Institutes of Health (NIH) [1R01AI081062]; National Institute of Allergy and Infectious Diseases (NIAID) [U54 DA021519]; NIH Office of the Director [1R24OD011883]; NIH [1R01GM093132-01, HHSN272201200010C, U01HL111561]; National Human Genome Research Institute (NHGRI) [RC2HG005668]; European Molecular Biology Laboratory (EMBL-EBI) core funds; EC [200754]; National Bioscience Database Center (NBDC) of the Japan Science and Technology Agency (JST) FX The work described is funded in part by the National Institutes of Health (NIH) grants 1R01AI081062 (YH) from the National Institute of Allergy and Infectious Diseases (NIAID), U54 DA021519 for the National Center for Integrative Biomedical Informatics (BDA), 1R24OD011883 from the NIH Office of the Director (MAH and MHB), NIH grant 1R01GM093132-01 (JZ and CJS), NIH contract HHSN272201200010C (BP), U01HL111561 (SCS) as part of the Library of Integrated Network-based Cellular Signatures (LINCS) program, and RC2HG005668 (SCS) supported by the National Human Genome Research Institute (NHGRI), European Molecular Biology Laboratory (EMBL-EBI) core funds (HP, JM), EC FP7 Funds Grant number: 200754 Gen2Phen (CP), and funding from the National Bioscience Database Center (NBDC) of the Japan Science and Technology Agency (JST) for BRC [21]. The content of this paper is solely the responsibility of the author and does not necessarily represent the official views of the NIAID, NHGRI, the NIH or other funding organizations. The article-processing charge for this article was paid by a discretionary fund from Dr. Robert Dysko, the director of the Unit for Laboratory Animal Medicine (ULAM) in the University of Michigan. NR 22 TC 8 Z9 8 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2041-1480 J9 J BIOMED SEMANT JI J. Biomed. Semant. PD AUG 13 PY 2014 VL 5 AR 37 DI 10.1186/2041-1480-5-37 PG 10 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AR6SK UT WOS:000343713200001 PM 25852852 ER PT J AU Lee, M Liu, ZC Kelly, R Tong, WD AF Lee, Mikyung Liu, Zhichao Kelly, Reagan Tong, Weida TI Of text and gene - using text mining methods to uncover hidden knowledge in toxicogenomics SO BMC SYSTEMS BIOLOGY LA English DT Article DE Topic modeling; Toxicogenomics; Latent Dirichlet Allocation; Text-mining; Systems biology ID HUMAN BREAST-CANCER; FDA DRUG LABELS; EXPRESSION PROFILES; LIVER AB Background: Toxicogenomics studies often profile gene expression from assays involving multiple doses and time points. The dose-and time-dependent pattern is of great importance to assess toxicity but computational approaches are lacking to effectively utilize this characteristic in toxicity assessment. Topic modeling is a text mining approach, but may be used analogously in toxicogenomics due to the similar data structures between text and gene dysregulation. Results: Topic modeling was applied to a very large toxicogenomics dataset containing microarray gene expression data from > 15,000 samples associated with 131 drugs tested in three different assay platforms (i.e., in vitro assay, in vivo repeated dose study and in vivo single dose experiment) with a design including multiple doses and time points. A set of "topics" which each consist of a set of genes was determined, by which the varying sensitivity of three assay systems was observed. We found that the drug-dependent effect was more pronounced in the two in vivo systems than the in vitro system, while the time-dependent effect was most strongly reflected in the in vitro system followed by the single dose study and lastly the repeated dose experiment. The dose-dependent effect was similar across three assay systems. Although the results indicated a challenge to extrapolate the in vitro results to the in vivo situation, we did notice that, for some drugs but not for all the drugs, the similarity in gene expression patterns was observed across all three assay systems, indicating a possibility of using in vitro systems with careful designs (such as the choice of dose and time point), to replace the in vivo testing strategy. Nonetheless, a potential to replace the repeated dose study by the single-dose short-term methodology was strongly implied. Conclusions: The study demonstrated that text mining methodologies such as topic modeling provide an alternative method compared to traditional means for data reduction in toxicogenomics, enhancing researchers' capabilities to interpret biological information. C1 [Lee, Mikyung; Liu, Zhichao; Kelly, Reagan; Tong, Weida] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. RP Tong, WD (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM weida.tong@fda.hhs.gov RI Liu, Zhichao/C-4035-2011 FU National Center for Toxicological Research (NCTR) of U.S. Food and Drug Administration (FDA) through the Oak Ridge Institute for Science and Education (ORISE) FX ML is grateful to the National Center for Toxicological Research (NCTR) of U.S. Food and Drug Administration (FDA) for post-doctoral support through the Oak Ridge Institute for Science and Education (ORISE). NR 23 TC 3 Z9 3 U1 2 U2 25 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 AUG 13 PY 2014 VL 8 AR 3 DI 10.1186/s12918-014-0093-3 PG 11 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AN5SB UT WOS:000340650500001 PM 25115450 ER PT J AU Soler-Garcia, AA De Jesus, AJ Taylor, K Brown, EW AF Soler-Garcia, Angel A. De Jesus, Antonio J. Taylor, Kishana Brown, Eric W. TI Differentiation of Salmonella strains from the SARA, SARB and SARC reference collections by using three genes PCR-RFLP and the 2100 Agilent Bioanalyzer SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE Salmonella enterica; Bioanalyzer; PCR-RFLP; restriction type; reference collection ID FRAGMENT-LENGTH-POLYMORPHISM; REAL-TIME PCR; NEIGHBOR-JOINING METHOD; TYPING METHODS; MICROARRAY HYBRIDIZATION; CAMPYLOBACTER-JEJUNI; TYPHIMURIUM COMPLEX; FLAGELLIN GENES; DNA-POLYMERASE; SUBSPECIES-I AB Rapid molecular typing methods are important tools in surveillance and outbreak investigations of human Salmonella infections. Here we described the development of a three-genes PCR-RFLP typing method for the differentiation of Salmonella species, subspecies and serovars using the Agilent 2100 Bioanalyzer. The fliC, gnd, and mutS genes were PCR-amplified in 160 Salmonella strains representing the two Salmonella species, six subspecies, and 41 different serovars of S. enterica subspecies enterica. PCR products were individually cut with two different restriction enzymes and the resulting 930 restriction patterns were collected using the Agilent 2100 Bioanalyzer followed by cluster analysis. Both species of Salmonella were differentiated by conventional PCR. All of S. bongori tested were gnd PCR negative due to a mismatch at the 3'-end in one the PCR primers. Salmonella subspecies were differentiated into third-teen homogeneous groups representing each of the six subspecies by cluster analysis of restriction patterns generated from the mutS gene cut with Acil. S. enterica subspecies enterica serovars were further differentiated by the combination of the three target genes and five out the six sets of restriction patterns with a discriminatory power of 0.9725 by cluster analysis. The combined RFLP results of five sets of restriction patterns allowed us to assign each of the 160 strains to one of 128 restriction types. During inoculation studies we were able to identify S. Saintpaul and Typhimurium from 24h pre-enrichment samples using the described method. The use of fliC, gnd, and mutS PCR-RFLP with the Agilent 2100 Bioanalyzer can provide an accessible and automated alternative method for differentiation of Salmonella pathogens. C1 [Soler-Garcia, Angel A.; De Jesus, Antonio J.; Taylor, Kishana; Brown, Eric W.] US FDA, Mol Methods & Subtyping Branch, Div Microbiol, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Soler-Garcia, AA (reprint author), US FDA, Urol & Lithotripsy Devices Branch, Div Reprod Gastrorenal & Urol Devices, Ctr Devices & Radiol Hlth, WO66 RmG223,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM angel.soler-garcia@fda.hhs.gov FU Research Participation Program at the US FDA-Center for Food Safety and Applied Nutrition FX Angel A. Soler-Garcia was supported by an appointment with the Research Participation Program at the US FDA-Center for Food Safety and Applied Nutrition administered by the Oak Ridge Institute for Science and Education. We thank Lili Velez, Technical writer at US FDA-CFSAN for critical review of the manuscript. NR 78 TC 3 Z9 4 U1 1 U2 11 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD AUG 11 PY 2014 VL 5 AR 417 DI 10.3389/fmicb.2014.00417 PG 19 WC Microbiology SC Microbiology GA AO7FU UT WOS:000341518600002 PM 25157247 ER PT J AU Ackerman, LK Bentayeb, K Begley, TH AF Ackerman, Luke K. Bentayeb, Karim Begley, Timothy H. TI False or not: Direct mass spectrometric screening for food contaminants SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Ackerman, Luke K.; Begley, Timothy H.] FDA Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Bentayeb, Karim] Univ Zaragoza, Dept Analyt Chem, Zaragoza, Spain. EM Luke.Ackerman@fda.hhs.gov RI Ackerman, Luke/E-4597-2011 OI Ackerman, Luke/0000-0001-6626-3039 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 141-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100213 ER PT J AU Belai, N AF Belai, Nebebech TI Determination of organic impurities in D&C Red No. 6, D&C Red No. 7, and D&C Yellow No. 10 using solid phase extraction and ultra-performance liquid chromatography SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Belai, Nebebech] US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM Nebebech.Belai@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 235-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165101681 ER PT J AU Belai, N Bowes, B White, SR AF Belai, Nebebech Bowes, Bryan White, Samuel R. TI Determination of unsulfonated aromatic amines in the color additives FD&C Yellow No. 5, FD&C Yellow No. 6, and D&C Red No. 33 using liquid chromatography/mass spectrometry SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Belai, Nebebech; Bowes, Bryan; White, Samuel R.] US FDA, Ctr Food Safety & Appl Nutr, Off Cosmet & Colors, College Pk, MD 20740 USA. EM Nebebech.Belai@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 119-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165101570 ER PT J AU Bennett, EH Akbas, NP Burgos, J Schmitt, M Collins, D Dawson, J Lukat-Rodgers, G Rodgers, K Dixon, DW AF Bennett, Elizabeth H. Akbas, Neval P. Burgos, Jonathan Schmitt, Michael Collins, Daniel Dawson, John Lukat-Rodgers, Gudrun Rodgers, Kenton Dixon, Dabney W. TI Axial ligation of the HmuT heme binding protein in Corynebacterium diphtheriae SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Bennett, Elizabeth H.; Akbas, Neval P.; Dixon, Dabney W.] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA. [Burgos, Jonathan; Schmitt, Michael] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Collins, Daniel; Dawson, John] Univ S Carolina, Dept Chem & Biochem, Columbia, SC 29208 USA. [Lukat-Rodgers, Gudrun; Rodgers, Kenton] N Dakota State Univ, Dept Chem Biochem & Mol Biol, Fargo, ND 58105 USA. EM ebennett9@gsu.edu NR 0 TC 0 Z9 0 U1 4 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 6-AEI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100006 ER PT J AU Cassias, I Chang, E Wilson, S Lane, S Barrera, T Blount, J Limson, A Ajayi, O AF Cassias, Irene Chang, Eugene Wilson, Sarah Lane, Shannon Barrera, Trojan Blount, Janet Limson, Andrew Ajayi, Olusegun TI LC-MS/MS method for pyrithroids analysis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Cassias, Irene; Chang, Eugene; Wilson, Sarah; Lane, Shannon; Barrera, Trojan; Blount, Janet; Limson, Andrew; Ajayi, Olusegun] US FDA, Pacific Reg Lab, Irvine, CA 92612 USA. EM irene.cassias@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 548-ENVR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165106106 ER PT J AU Chang, E AF Chang, Eugene TI Cypermethrin isomers separation and quantitation with LC-MS/MS SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Chang, Eugene] US FDA, Pacific Reg Lab, Irvine, CA 92612 USA. EM eugene.chang@fda.hhs.gov NR 0 TC 0 Z9 0 U1 6 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 554-ENVR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165106112 ER PT J AU Doell, DL Folmer, DE Lee, HS Butts, KM Carberry, SE AF Doell, Diana L. Folmer, Daniel E. Lee, Hyoung S. Butts, Kyla M. Carberry, Susan E. TI Exposure estimate for FD&C colors for the US population SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Doell, Diana L.; Folmer, Daniel E.; Lee, Hyoung S.; Butts, Kyla M.; Carberry, Susan E.] US FDA, College Pk, MD 20740 USA. EM Diana.Doell@fda.hhs.gov NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 211-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100282 ER PT J AU Folmer, DE Doell, DL Lee, HS Noonan, GO Carberry, SE AF Folmer, Daniel E. Doell, Diana L. Lee, Hyoung S. Noonan, Gregory O. Carberry, Susan E. TI Refined exposure assessment for 4-methylimidazole (4-MEI) for the US population based on quantitative data from foods containing caramel color SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Folmer, Daniel E.; Doell, Diana L.; Lee, Hyoung S.; Noonan, Gregory O.; Carberry, Susan E.] US FDA, College Pk, MD 20740 USA. EM daniel.folmer@fda.hhs.gov NR 0 TC 0 Z9 0 U1 4 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 206-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100277 ER PT J AU Fu, TJ AF Fu, Tong-Jen TI Processing effects on food allergens: Implications for allergen control SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Fu, Tong-Jen] US FDA, Div Food Proc Sci & Technol, Bedford Pk, IL 60501 USA. EM tongjen.fu@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 88-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100160 ER PT J AU Harjivan, SG Charneira, C Pereira, SA Espadas, G Sabido, E Beland, FA Marques, MM Antunes, AMM AF Harjivan, Shrika G. Charneira, Catarina Pereira, Sofia A. Espadas, Guadalupe Sabido, Eduard Beland, Frederick A. Matilde Marques, M. Antunes, Alexandra M. M. TI Covalent histone modification by nevirapine: Potential association with non-AIDS defining cancers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Harjivan, Shrika G.; Charneira, Catarina; Matilde Marques, M.; Antunes, Alexandra M. M.] Univ Lisbon, Inst Super Tecn, Ctr Quim Estrutural, P-1699 Lisbon, Portugal. [Pereira, Sofia A.] NOVA Med Sch, Ctr Estudos Doencas Cron CEDOC, Lisbon, Portugal. [Espadas, Guadalupe; Sabido, Eduard] Univ Pompeu Fabra, CRG, Prote Unit, Barcelona, Spain. [Beland, Frederick A.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM matilde.marques@tecnico.ulisboa.pt RI Sabido, Eduard/F-7914-2015; Marques, M. Matilde/E-2535-2012; Antunes, Alexandra/B-7871-2009; Faculdade de Ciencias Medicas, Nova Medical School/K-6209-2013 OI Sabido, Eduard/0000-0001-6506-7714; Marques, M. Matilde/0000-0002-7526-4962; Antunes, Alexandra/0000-0003-1827-7369; NR 5 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 136-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167406286 ER PT J AU Jackson, LS AF Jackson, Lauren S. TI Importance of analytical methods for allergen control in food processing facilities SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Jackson, Lauren S.] US FDA, Div Food Proc Sci & Technol, Bedford Pk, IL 60501 USA. EM Lauren.Jackson@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 60-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100132 ER PT J AU Jacobs, RM Nausin, M Nausin, C Qiu, C Juarez, E Huang, L Ferguson, E Yee, S AF Jacobs, Richard M. Nausin, Michael Nausin, Consuelo Qiu, Christina Juarez, Elizabeth Huang, Lillian Ferguson, Eric Yee, Sally TI Application of portable, energy dispersive X-ray fluorescence (pXRF) analyzers to FDA regulated products SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Jacobs, Richard M.; Nausin, Michael; Nausin, Consuelo; Qiu, Christina; Juarez, Elizabeth; Huang, Lillian; Ferguson, Eric; Yee, Sally] US FDA, ORA ORS SAN Lab, Alameda, CA 94502 USA. EM richard.jacobs@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 300-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165101740 ER PT J AU Jayasuriya, H Reimschuessel, R Chattopadhaya, C AF Jayasuriya, Hiranthi Reimschuessel, Renate Chattopadhaya, Chaitali TI Rapid detection and identification of potential toxins in technical grade glycerin by differential analysis of high resolution mass spectrometric data SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Jayasuriya, Hiranthi; Reimschuessel, Renate; Chattopadhaya, Chaitali] US FDA, Ctr Vet Med, Laurel, MD 21045 USA. EM hiranthi.jayasuriya@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 210-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100281 ER PT J AU Kern, SE Lin, LA Fricke, FL AF Kern, Sara E. Lin, Lora A. Fricke, Frederick L. TI Accurate mass fragment library for rapid analysis of produce using ambient pressure desorption ionization with high-resolution mass spectrometry SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Kern, Sara E.; Lin, Lora A.; Fricke, Frederick L.] US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. EM sara.kern@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 136-AGRO PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100504 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 Gold nanoparticle-based colorimetric assay for detection of cholera toxin SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Khan, Sadia Afrin; Degrasse, Jeffrey A.; Yakes, Betsy Jean; Croley, Timothy R.] US FDA, Ctr Food Safety & Appl Nutr CFSAN, College Pk, MD 20740 USA. EM sadia.afrin.khan@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 245-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165103681 ER PT J AU Lim, JH Howard, PC Quevedo, I Linder, SW AF Lim, Jin-Hee Howard, Paul C. Quevedo, Ivan Linder, Sean W. TI Detection and characterization of nanoscale materials in dietary supplements SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Lim, Jin-Hee; Quevedo, Ivan; Linder, Sean W.] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, Jefferson, AR 72079 USA. [Howard, Paul C.] US FDA, Natl Ctr Toxicol Res, Off Sci Coordinat, Jefferson, AR 72079 USA. EM jin.lim@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 221-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100292 ER PT J AU Lunn, G AF Lunn, George TI PEPFAR - a US Government program that is helping to keep millions alive around the world SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Lunn, George] US FDA, Silver Spring, MD 20993 USA. EM george.lunn@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 17-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165103304 ER PT J AU Parker, CH Ross, MM Callahan, JH AF Parker, Christine H. Ross, Mark M. Callahan, John H. TI Multi-allergen detection in thermally-processed baked goods by mass spectrometry SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Parker, Christine H.; Ross, Mark M.; Callahan, John H.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM christine.parker@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 59-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100131 ER PT J AU Pawar, RS Vaclavik, L Ma, J Grundel, E Krynitsky, A AF Pawar, Rahul S. Vaclavik, Lukas Ma, Jun Grundel, Erich Krynitsky, Alexander TI Adulteration in botanical dietary supplements: Problems and approaches for their detection SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Pawar, Rahul S.; Vaclavik, Lukas; Ma, Jun; Grundel, Erich; Krynitsky, Alexander] US FDA, CFSAN, College Pk, MD 20740 USA. EM Rahul.Pawar@fda.hhs.gov NR 0 TC 0 Z9 0 U1 2 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 46-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100119 ER PT J AU Qu, H Mudalige, T Linder, S Quevedo, I AF Qu, Haiou Mudalige, Thilak Linder, Sean Quevedo, Ivan TI Online separation and characterization of metallic nanomaterials in consumer products with capillary electrophoresis/inductively-coupled plasma-mass spectrometry SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Qu, Haiou; Mudalige, Thilak; Linder, Sean; Quevedo, Ivan] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, Jefferson, AR 72079 USA. EM Haiou.Qu@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 547-ENVR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165106105 ER PT J AU Quevedo, IR Lim, JH Mudalige, TK Qu, HO Sanchez-Pomales, G Sisco, PN Howard, PC Linder, SW AF Quevedo, Ivan R. Lim, Jin-Hee Mudalige, Thilak K. Qu, Haiou Sanchez-Pomales, Germarie Sisco, Patrick N. Howard, Paul C. Linder, Sean W. TI Isolating and characterizing metal oxide nanoparticles in sunscreens: Multimethod determination of their physicochemical properties SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Quevedo, Ivan R.; Lim, Jin-Hee; Mudalige, Thilak K.; Qu, Haiou; Sanchez-Pomales, Germarie; Sisco, Patrick N.; Linder, Sean W.] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, Jefferson, AR 72079 USA. [Howard, Paul C.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Ivan.Quevedo@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 205-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165101654 ER PT J AU Rossiter, LM Taylor, KM AF Rossiter, Lana M. Taylor, Kenneth M. TI Survey of flavor ingredient use in tobacco products SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Rossiter, Lana M.; Taylor, Kenneth M.] US FDA, Ctr Tobacco Prod, Rockville, MD 20850 USA. EM Lana.Rossiter@fda.hhs.gov; Kenneth.Taylor@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 194-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100265 ER PT J AU Salvador, A Muldoon, MT Lin, A Clotilde, LM Carter, JM AF Salvador, Alexandra Muldoon, Mark T. Lin, Andrew Clotilde, Laurie M. Carter, John M. TI Multiplex microbead immunoassay for detection in food of the 10 most common Shiga toxin producing E. coli pathogen serotypes SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Salvador, Alexandra; Carter, John M.] USDA, Produce Safety & Microbiol Res Unit, Albany, CA 94710 USA. [Muldoon, Mark T.] Romer Labs Technol Inc, Res & Dev, Newark, DE 19713 USA. [Lin, Andrew] US FDA, San Francisco Dist Lab, Alameda, CA 94502 USA. [Clotilde, Laurie M.] MagArray Inc, Sunnyvale, CA 94089 USA. EM alexandra.salvador@ars.usda.gov RI Carter, John Mark/K-2485-2015 OI Carter, John Mark/0000-0001-8251-4168 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 201-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100272 ER PT J AU Scholl, PF Romero, R Harrington, PB Farris, SM Mossoba, MM Moore, JC Lutter, P AF Scholl, Peter F. Romero, Roman Harrington, Peter B. Farris, Samantha M. Mossoba, Magdi M. Moore, Jeffrey C. Lutter, Petra TI Development of screening assays to detect the economically motivated adulteration of skim milk powder with plant proteins SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Scholl, Peter F.; Farris, Samantha M.; Mossoba, Magdi M.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Romero, Roman] Nestle Res Ctr, Analyt Sci Pillar, CH-1000 Lausanne, Switzerland. [Harrington, Peter B.] Ohio Univ, Dept Chem & Biochem, Athens, OH 45701 USA. [Moore, Jeffrey C.] US Pharmacopeial Convent Inc, Rockville, MD 20852 USA. [Lutter, Petra] Nestle, Qual Assurance Ctr, Weiding, Germany. EM peter.scholl@fda.hhs.gov NR 0 TC 0 Z9 0 U1 2 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 74-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100146 ER PT J AU Shapiro, MA AF Shapiro, Marjorie A. TI Regulatory perspectives on the characterization of therapeutic monoclonal antibody quality attributes SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Shapiro, Marjorie A.] US FDA, Div Monoclonal Antibodies, Rockville, MD 20857 USA. EM marjorie.shapiro@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 77-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165101533 ER PT J AU Tulio, AZ AF Tulio, Artemio Z., Jr. TI Authentication and adulteration of lemon juice SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Tulio, Artemio Z., Jr.] US FDA, Bedford Pk, IL 60501 USA. EM artemio.tulio@fda.hhs.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 26-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100099 ER PT J AU Vann, WF Lee, RC Kovac, P Ryan, ET McCarthy, PC LaForce, M Alderson, M Maisonneuve, J Banoub, JH An, YM Cipollo, JF AF Vann, Willie F. Lee, Robert C. Kovac, Pavol Ryan, Edward T. McCarthy, Pumtiwitt C. LaForce, Marc Alderson, Mark Maisonneuve, Jeff Banoub, Joseph H. An, Yanming Cipollo, John F. TI Alternate technology for preparation of glycoconjugate vaccines SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Vann, Willie F.; Lee, Robert C.; An, Yanming; Cipollo, John F.] US FDA, Lab Bacterial Polysaccharides, CBER, Bethesda, MD 20892 USA. [Kovac, Pavol] NIDDK, NIH, Bethesda, MD 20892 USA. [Ryan, Edward T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [McCarthy, Pumtiwitt C.] Morgan State Univ, Dept Chem, Baltimore, MD 21239 USA. [LaForce, Marc; Alderson, Mark; Maisonneuve, Jeff] PATH, Seattle, WA USA. [Banoub, Joseph H.] Fisheries & Oceans Canada, St John, NF, Canada. EM wvann@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 9-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165102174 ER PT J AU Vrdoljak, GA Palmer, PT Jacobs, R Moezzi, B AF Vrdoljak, Gordon A. Palmer, Peter T. Jacobs, Richard Moezzi, Bahman TI Comparison of XRF, TXRF, and ICP-MS methods for determination of mercury in face cream SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Vrdoljak, Gordon A.; Moezzi, Bahman] State Calif Dept Publ Hlth, Food & Drug Lab Branch, Richmond, CA 94804 USA. [Palmer, Peter T.] San Francisco State Univ, Dept Chem & Biochem, San Francisco, CA 94132 USA. [Jacobs, Richard] US FDA, Div Field Sci, Alameda, CA 94502 USA. EM Gordon.Vrdoljak@cdph.ca.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 302-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165101742 ER PT J AU Bisgin, H Liu, ZC Fang, H Kelly, R Xu, XW Tong, WD AF Bisgin, Halil Liu, Zhichao Fang, Hong Kelly, Reagan Xu, Xiaowei Tong, Weida TI A phenome-guided drug repositioning through a latent variable model SO BMC BIOINFORMATICS LA English DT Article DE Drug repositioning; Bayesian methods; Latent dirichlet allocation; Data mining; Phenome; Side effects; Indications ID DISEASE; SEDATION; THALIDOMIDE; PHENOTYPES; MIGRAINE; LABELS; GENES; RATS AB Background: The phenome represents a distinct set of information in the human population. It has been explored particularly in its relationship with the genome to identify correlations for diseases. The phenome has been also explored for drug repositioning with efforts focusing on the search space for the most similar candidate drugs. For a comprehensive analysis of the phenome, we assumed that all phenotypes (indications and side effects) were inter-connected with a probabilistic distribution and this characteristic may offer an opportunity to identify new therapeutic indications for a given drug. Correspondingly, we employed Latent Dirichlet Allocation (LDA), which introduces latent variables (topics) to govern the phenome distribution. Results: We developed our model on the phenome information in Side Effect Resource (SIDER). We first developed a LDA model optimized based on its recovery potential through perturbing the drug-phenotype matrix for each of the drug-indication pairs where each drug-indication relationship was switched to "unknown" one at the time and then recovered based on the remaining drug-phenotype pairs. Of the probabilistically significant pairs, 70% was successfully recovered. Next, we applied the model on the whole phenome to narrow down repositioning candidates and suggest alternative indications. We were able to retrieve approved indications of 6 drugs whose indications were not listed in SIDER. For 908 drugs that were present with their indication information, our model suggested alternative treatment options for further investigations. Several of the suggested new uses can be supported with information from the scientific literature. Conclusions: The results demonstrated that the phenome can be further analyzed by a generative model, which can discover probabilistic associations between drugs and therapeutic uses. In this regard, LDA serves as an enrichment tool to explore new uses of existing drugs by narrowing down the search space. C1 [Bisgin, Halil; Liu, Zhichao; Kelly, Reagan; Xu, Xiaowei; Tong, Weida] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Fang, Hong] US FDA, Natl Ctr Toxicol Res, Off Sci Coordinat, Jefferson, AR 72079 USA. [Xu, Xiaowei] Univ Arkansas, Dept Informat Sci, Little Rock, AR 72204 USA. RP Xu, XW (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM xwxu@ualr.edu; weida.tong@fda.hhs.gov RI Liu, Zhichao/C-4035-2011 FU National Center for Toxicological Research (NCTR) of U.S. Food and Drug Administration (FDA) for postdoctoral support through the Oak Ridge Institute for Science and Education (ORISE) FX HB is grateful to the National Center for Toxicological Research (NCTR) of U.S. Food and Drug Administration (FDA) for postdoctoral support through the Oak Ridge Institute for Science and Education (ORISE). NR 44 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 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD AUG 8 PY 2014 VL 15 AR 267 DI 10.1186/1471-2105-15-267 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA AN7SC UT WOS:000340799800001 PM 25103881 ER PT J AU Strader, MB Hicks, WA Kassa, T Singleton, E Soman, J Olson, JS Weiss, MJ Mollan, TL Wilson, MT Alayash, AI AF Strader, Michael Brad Hicks, Wayne A. Kassa, Tigist Singleton, Eileen Soman, Jayashree Olson, John S. Weiss, Mitchell J. Mollan, Todd L. Wilson, Michael T. Alayash, Abdu I. TI Post-translational Transformation of Methionine to Aspartate Is Catalyzed by Heme Iron and Driven by Peroxide A NOVEL SUBUNIT-SPECIFIC MECHANISM IN HEMOGLOBIN SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HYDROGEN-PEROXIDE; HB-BRISTOL; PUMMERER REARRANGEMENT; INTRAMOLECULAR CAPTURE; ANGSTROM RESOLUTION; OXIDATION REACTIONS; PROTEIN OXIDATION; ESCHERICHIA-COLI; HEMOLYTIC-ANEMIA; MYOGLOBIN AB A pathogenic V67M mutation occurs at the E11 helical position within the heme pockets of variant human fetal and adult hemoglobins (Hb). Subsequent post-translational modification of Met to Asp was reported in gamma subunits of human fetal Hb Toms River (gamma 67(E11) Val -> Met) and beta subunits of adult Hb (HbA) Bristol-Alesha (beta 67(E11) Val -> Met) that were associated with hemolytic anemia. Using kinetic, proteomic, and crystal structural analysis, we were able to show that the Met -> Asp transformation involves heme cycling through its oxoferryl state in the recombinant versions of both proteins. The conversion to Met and Asp enhanced the spontaneous autoxidation of the mutants relative to wild-type HbA and human fetal Hb, and the levels of Asp were elevated with increasing levels of hydrogen peroxide (H2O2). Using H-2 O-18(2), we verified incorporation of (18)Ointo the Asp carboxyl side chain confirming the role ofH(2)O(2) in the oxidation of the Met side chain. Under similar experimental conditions, there was no conversion to Asp at the alpha Met(E11) position in the correspondingHbAEvans (alpha 62(E11) Val -> Met). The crystal structures of the three recombinant Met(E11) mutants revealed similar thioether side chain orientations. However, asinthesolutionexperiments, autoxidationof theHbmutantcrystals leads to electron density maps indicative of Asp(E11) formation in beta subunits but not in alpha subunits. This novel post-translational modification highlights the nonequivalence of human Hb alpha, beta, and gamma subunits with respect to redox reactivity and may have direct implications to alpha/beta hemoglobinopathies and design of oxidatively stable Hb-based oxygen therapeutics. C1 [Mollan, Todd L.; Alayash, Abdu I.] US FDA, Lab Biochem & Vasc Biol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Singleton, Eileen; Soman, Jayashree; Olson, John S.] Rice Univ, Dept Biochem & Cell Biol, Houston, TX 77251 USA. [Weiss, Mitchell J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Wilson, Michael T.] Univ Essex, Dept Biol Sci, Colchester CO4 3SQ, Essex, England. RP Alayash, AI (reprint author), US FDA, Lab Biochem & Vasc Biol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM abdu.alayash@fda.hhs.gov OI Olson, John/0000-0002-0760-5403 FU National Institutes of Health from NHLBI [P01-HL110900]; Welch Grant [C-0612]; United States Food and Drug Administration [MODSCI 2012, P30 DK090969, R01 DK61692] FX This work was supported, in whole or in part, by National Institutes of Health Grant P01-HL110900 from NHLBI (to A. I. A. and J. S. O.). This work was also supported by Welch Grant C-0612 (to J. S. O.) and United States Food and Drug Administration Grants MODSCI 2012 (to A. I. A.), P30 DK090969 (to M. J. W.), and R01 DK61692 (to M. J. W.). NR 48 TC 7 Z9 7 U1 1 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 8 PY 2014 VL 289 IS 32 BP 22342 EP 22357 DI 10.1074/jbc.M114.568980 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AN4XQ UT WOS:000340593500045 PM 24939847 ER PT J AU Seidman, SJ Bekdash, O Guag, J Mehryar, M Booth, P Frisch, P AF Seidman, Seth J. Bekdash, Omar Guag, Joshua Mehryar, Maryam Booth, Paul Frisch, Paul TI Feasibility results of an electromagnetic compatibility test protocol to evaluate medical devices to radio frequency identification exposure SO BIOMEDICAL ENGINEERING ONLINE LA English DT Article DE Electromagnetic compatibility; Electromagnetic interference; EMC; EMI; Radio-frequency identification; RFID; Medical device; Test methods; Simulator AB Background: The use of radio frequency identification (RFID) systems in healthcare is increasing, and concerns for electromagnetic compatibility (EMC) pose one of the biggest obstacles for widespread adoption. Numerous studies have demonstrated that RFID systems can interfere with medical devices; however, the majority of past studies relied on time-consuming and burdensome test schemes based on ad hoc test methods applied to individual RFID systems. Methods: This paper presents the results of using an RFID simulator that allows for faster evaluation of RFID-medical device EMC against a library of RFID test signals at various field strengths. Results: The results of these tests demonstrate the feasibility and adequacy of simulator testing and can be used to support its incorporation into applicable consensus standards. Conclusions: This work can aid the medical device community in better assessing the risks associated with medical device exposure to RFID. C1 [Seidman, Seth J.; Bekdash, Omar; Guag, Joshua] FDA CDRH OSEL, Silver Spring, MD 20993 USA. [Mehryar, Maryam; Booth, Paul; Frisch, Paul] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. RP Seidman, SJ (reprint author), FDA CDRH OSEL, 10903 New Hampshire Ave,WO Bldg 62 Room 1134, Silver Spring, MD 20993 USA. EM seth.seidman@fda.hhs.gov NR 10 TC 1 Z9 1 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-925X J9 BIOMED ENG ONLINE JI Biomed. Eng. Online PD AUG 3 PY 2014 VL 13 AR 110 DI 10.1186/1475-925X-13-110 PG 8 WC Engineering, Biomedical SC Engineering GA AN9FE UT WOS:000340910700002 PM 25086451 ER PT J AU Bailey, AM Mendicino, M Au, P AF Bailey, Alexander M. Mendicino, Michael Au, Patrick TI An FDA perspective on preclinical development of cell-based regenerative medicine products SO NATURE BIOTECHNOLOGY LA English DT Letter C1 [Bailey, Alexander M.; Mendicino, Michael; Au, Patrick] US FDA, Ctr Biol Evaluat & Res, Off Cellular Tissue & Gene Therapies, Silver Spring, MD 20993 USA. [Mendicino, Michael] US FDA, Off Commissioner, Off Chief Scientist, Off Regulatory Sci & Innovat, Silver Spring, MD USA. RP Bailey, AM (reprint author), US FDA, Ctr Biol Evaluat & Res, Off Cellular Tissue & Gene Therapies, Silver Spring, MD 20993 USA. EM alexander.bailey@fda.hhs.gov; m.mendicino.phd@gmail.com; pakwai.au@fda.hhs.gov NR 4 TC 15 Z9 16 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2014 VL 32 IS 8 BP 721 EP 723 DI 10.1038/nbt.2971 PG 3 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AW7PF UT WOS:000346455900008 PM 25093890 ER PT J AU Maro, JC Brown, JS Dal Pan, GJ Li, LL AF Maro, Judith C. Brown, Jeffrey S. Dal Pan, Gerald J. Li, Lingling TI Orphan Therapies: Making Best Use of Postmarket Data SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE pharmacoepidemiology; population health; comparative effectiveness; statistical modeling; applied informatics ID CARE UTILIZATION DATABASES; HEALTH DATA-NETWORKS; VACCINE SAFETY; IMMUNIZATION SAFETY; ADVERSE EVENTS; FAMILIAL HYPERCHOLESTEROLEMIA; INFLUENZA VACCINE; SURVEILLANCE; PROJECT; DESIGN AB BACKGROUND: Postmarket surveillance of the comparative safety and efficacy of orphan therapeutics is challenging, particularly when multiple therapeutics are licensed for the same orphan indication. To make best use of product-specific registry data collected to fulfill regulatory requirements, we propose the creation of a distributed electronic health data network among registries. Such a network could support sequential statistical analyses designed to detect early warnings of excess risks. We use a simulated example to explore the circumstances under which a distributed network may prove advantageous. METHODS: We perform sample size calculations for sequential and non-sequential statistical studies aimed at comparing the incidence of hepatotoxicity following initiation of two newly licensed therapies for homozygous familial hypercholesterolemia. We calculate the sample size savings ratio, or the proportion of sample size saved if one conducted a sequential study as compared to a non-sequential study. Then, using models to describe the adoption and utilization of these therapies, we simulate when these sample sizes are attainable in calendar years. We then calculate the analytic calendar time savings ratio, analogous to the sample size savings ratio. We repeat these analyses for numerous scenarios. KEY RESULTS: Sequential analyses detect effect sizes earlier or at the same time as non-sequential analyses. The most substantial potential savings occur when the market share is more imbalanced (i.e., 90 % for therapy A) and the effect size is closest to the null hypothesis. However, due to low exposure prevalence, these savings are difficult to realize within the 30-year time frame of this simulation for scenarios in which the outcome of interest occurs at or more frequently than one event/ 100 person-years. CONCLUSIONS: We illustrate a process to assess whether sequential statistical analyses of registry data performed via distributed networks may prove a worthwhile infrastructure investment for pharmacovigilance. C1 [Maro, Judith C.; Brown, Jeffrey S.; Li, Lingling] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA 02215 USA. [Maro, Judith C.; Brown, Jeffrey S.; Li, Lingling] Harvard Pilgrim Hlth Care Inst, Boston, MA 02215 USA. [Dal Pan, Gerald J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Maro, JC (reprint author), Harvard Univ, Sch Med, Dept Populat Med, 133 Brookline Ave,6th Floor, Boston, MA 02215 USA. EM jmaro@mit.edu NR 39 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2014 VL 29 SU 3 BP S745 EP S751 DI 10.1007/s11606-014-2882-1 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AU1XU UT WOS:000345411700006 PM 25029972 ER PT J AU Pariser, AR Gahl, WA AF Pariser, Anne R. Gahl, William A. TI Important Role of Translational Science in Rare Disease Innovation, Discovery, and Drug Development SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE rare disease; translational medical research; diagnosis; registries ID UNDIAGNOSED DISEASES; DISORDERS; MUTATION; MELANOMA; CANCER; BRAF AB Rare diseases play a leading role in innovation and the advancement of medical and pharmaceutical science. Most rare diseases are genetic disorders or atypical manifestations of infectious, immunologic, or oncologic diseases; they all provide opportunities to study extremes of human pathology and provide insight into both normal and aberrant physiology. Recently, drug development has become increasingly focused on classifying diseases largely on genetic grounds; this has allowed the identification of molecularly defined targets and the development of targeted therapies. Clinical trials are now focusing on progressively smaller subgroups within both common and rare disease populations, often based on genetic tests or biomarkers. Drug developers, researchers, and regulatory agencies face a variety of challenges throughout the life cycle of drug research and development for rare diseases. These include the small numbers of patients available for study, lack of knowledge of the disease's natural history, incomplete understanding of the basic mechanisms causing the disorder, and variability in disease severity, expression, and course. Traditional approaches to rare disease clinical research have not kept pace with advances in basic science, and increased attention to translational science is needed to address these challenges, especially diagnostic testing, registries, and novel trial designs. C1 [Pariser, Anne R.] US FDA, Off New Drugs, Rare Dis Program, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Gahl, William A.] NIH, Undiagnosed Dis Program, Off Director, Bethesda, MD 20892 USA. [Gahl, William A.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Pariser, AR (reprint author), US FDA, Off New Drugs, Rare Dis Program, Ctr Drug Evaluat & Res, WO22-6471,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Anne.pariser@fda.hhs.gov FU Intramural NIH HHS NR 20 TC 4 Z9 5 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2014 VL 29 SU 3 BP S804 EP S807 DI 10.1007/s11606-014-2881-2 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AU1XU UT WOS:000345411700014 PM 25029971 ER PT J AU Jaradat, ZW Al Mousa, W Elbetieha, A Al Nabulsi, A Tall, BD AF Jaradat, Ziad W. Al Mousa, Waseem Elbetieha, Ahmed Al Nabulsi, Anas Tall, Ben D. TI Cronobacter spp. - opportunistic food-borne pathogens. A review of their virulence and environmental-adaptive traits SO JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Review ID POWDERED INFANT FORMULA; MICROVASCULAR ENDOTHELIAL-CELLS; ENTEROBACTER-SAKAZAKII STRAINS; INTESTINAL EPITHELIAL-CELLS; MEMBRANE PROTEIN-A; INTENSIVE-CARE-UNIT; DUBLINENSIS SP-NOV; NEWBORN RAT MODEL; NECROTIZING ENTEROCOLITIS; BIOFILM FORMATION AB The genus Cronobacter consists of a diverse group of Gram-negative bacilli and comprises seven species: Cronobacter sakazakii, Cronobacter malonaticus, Cronobacter muytjensii, Cronobacter turicensis, Cronobacter dublinensis, Cronobacter universalis and Cronobacter condimenti. Cronobacter are regarded as opportunistic pathogens, and have been implicated in newborn and infant infections, causing meningitis, necrotizing enterocolitis and bacteraemia or sepsis. Cronobacter virulence is believed to be due to multiple factors. Some strains were found to produce diarrhoea or cause significant fluid accumulation in suckling mice. Two iron acquisition systems (eitCBAD and iucABCDliutA), Cronobacter plasminogen activator gene (cpa), a 17 kb type VI secretion system (T6SS), and a 27 kb filamentous haemagglutinin gene (fhaBC) and associated putative adhesins locus are harboured on a family of RepFIB-related plasmids (pESA3 and pCTU1), suggesting that these are common virulence plasmids; 98% of 229 tested Cronobacter strains possessed these plasmids. Even though pESA3 and pCTU1 share a common backbone composed of the repA gene and eitCBAD and iucABCD/iutA gene clusters, the presence of cpa, T6SS and FHA loci depended on species, demonstrating a strong correlation with the presence of virulence traits, plasmid type and species. Other factors were observed, in that Cronobacter form biofilms, and show unusual resistance to heat, dry and acid stress growth conditions. The outer-membrane protein A is probably one of the best-characterized virulence markers of Cronobacter. Furthermore, it was reported that Cronobacter employ phosphatidylinositide 3-kinase/Akt signalling, which activates protein kinase C-alpha and impairs the host cell's mitogen-activated protein kinase pathway, in order to invade cells. Cronobacter can also use immature dendritic cells and macrophages to escape the immune response. This review addresses the various virulence and environmental-adaptive characteristics possessed by members of the genus Cronobacter. C1 [Jaradat, Ziad W.; Al Mousa, Waseem; Elbetieha, Ahmed] Jordan Univ Sci & Technol, Dept Biotechnol & Genet Engn, Irbid 22110, Jordan. [Al Nabulsi, Anas] Jordan Univ Sci & Technol, Dept Nutr & Food Technol, Irbid 22110, Jordan. [Tall, Ben D.] US FDA, Ctr Food Safety & Appl Nutr, Div Virulence Assessment, Laurel, MD 20708 USA. RP Jaradat, ZW (reprint author), Jordan Univ Sci & Technol, Dept Biotechnol & Genet Engn, POB 3030, Irbid 22110, Jordan. EM jaradatz@just.edu.jo OI Tall, Ben/0000-0003-0399-3629 NR 127 TC 17 Z9 17 U1 7 U2 42 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-2615 EI 1473-5644 J9 J MED MICROBIOL JI J. Med. Microbiol. PD AUG PY 2014 VL 63 BP 1023 EP 1037 DI 10.1099/jmm.0.073742-0 PN 8 PG 15 WC Microbiology SC Microbiology GA AP6LQ UT WOS:000342189700001 PM 24878566 ER PT J AU Shibeko, AM Woodle, SA Mahmood, I Jain, N Ovanesov, MV AF Shibeko, A. M. Woodle, S. A. Mahmood, I. Jain, N. Ovanesov, M. V. TI Predicting dosing advantages of factor VIIa variants with altered tissue factor-dependent and lipid-dependent activities SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE factor VIIa; hemophilia; pharmacology; thrombin; thromboplastin ID RECOMBINANT FACTOR VIIA; ACTIVATED FACTOR-VII; HEMOPHILIA-A PATIENTS; THROMBIN GENERATION TEST; RANDOMIZED-TRIAL; DOUBLE-BLIND; BYPASSING AGENTS; HOME TREATMENT; JOINT BLEEDS; CROSS-OVER AB Background: Recombinant factor VIIa (rFVIIa) is an FX-cleaving coagulation enzyme licensed for the treatment of bleeding episodes in hemophiliacs with inhibitory antibodies. Even though the optimal dosing and comparative dose efficacy of rFVIIa remain poorly understood, genetic or chemical modifications of rFVIIa have been proposed, with the goal of achieving faster and longer hemostatic action. No ongoing trial is currently comparing rFVIIa variants with each other. Objectives and methods: We used mathematical modeling to compare the pharmacokinetics, dose-response (pharmacodynamics) and dose-effect duration (pharmacokinetics/pharmacodynamics) of rFVIIa variants to predict their optimal doses. The pharmacodynamic (PD) model of FXa generation by FVIIa in complexes with tissue factor (TF) and procoagulant lipids (PLs) was validated against published ex vivo and in vitro thrombin generation (TG) experiments. To compare variants' safety profiles, the highest non-thrombogenic doses were estimated from the clinical evidence reported for the licensed rFVIIa product. Results: The PD model correctly described the biphasic TF-dependent and PL-dependent dose response observed in TG experiments in vitro. The pharmacokinetic/PD simulations agreed with published ex vivo TG data for rFVIIa and the BAY 86-6150 variant, and explained the similar efficacies of a single dose of 270 mu g kg(-1) (as reported in the literature) and repeated doses of 90 mu g kg(-1) of unmodified rFVIIa. The duration of the simulated hemostatic effect after a single optimal dose was prolonged for rFVIIa variants with increased TF affinity or extended half-lives, but not for those with modulated PL activity. Conclusions: Some modifications of the rFVIIa molecule may not translate into a prolonged hemostatic effect. C1 [Shibeko, A. M.] RAS, Ctr Theoret Problems Physicochem Pharmacol, Moscow 117901, Russia. [Woodle, S. A.; Mahmood, I.; Jain, N.; Ovanesov, M. V.] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Ovanesov, MV (reprint author), US FDA, 29 Lincoln Dr,N29-309, Bethesda, MD 20892 USA. EM mikhail.ovanesov@fda.hhs.gov OI Shibeko, Alexey/0000-0003-1494-3125 FU Oak Ridge Institute for Science and Education (ORISE) FX This study was supported in part by a Postgraduate and Postbaccalaureate Research Fellowship Award to A. M. Shibeko and S. A. Woodle from the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. A. M. Shibeko, S. A. Woodle, I. Mahmood, N. Jain, and M. V. Ovanesov are employees of the US Food and Drug Administration. This paper is an informal communication and represents the authors' best judgement. These comments do not bind or obligate the US Food and Drug Administration. NR 50 TC 3 Z9 3 U1 0 U2 0 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 2014 VL 12 IS 8 BP 1302 EP 1312 DI 10.1111/jth.12628 PG 11 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AP5TX UT WOS:000342142700016 PM 24913469 ER PT J AU Hammer, DX Lozzi, A Abliz, E Greenbaum, N Agrawal, A Krauthamer, V Welle, CG AF Hammer, Daniel X. Lozzi, Andrea Abliz, Erkinay Greenbaum, Noah Agrawal, Anant Krauthamer, Victor Welle, Cristin G. TI Longitudinal vascular dynamics following cranial window and electrode implantation measured with speckle variance optical coherence angiography SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID BLOOD-FLOW; TOMOGRAPHY; TETRAPLEGIA; BRAIN; MICROSCOPY; RESOLUTION; CONTRAST; HUMANS; TISSUE AB Speckle variance optical coherence angiography (OCA) was used to characterize the vascular tissue response from craniotomy, window implantation, and electrode insertion in mouse motor cortex. We observed initial vasodilation similar to 40% greater than original diameter 2-3 days postsurgery (dps). After 4 weeks, dilation subsided in large vessels (>50 mu m diameter) but persisted in smaller vessels (25-50 mu m diameter). Neovascularization began 8-12 dps and vessel migration continued throughout the study. Vasodilation and neovascularization were primarily associated with craniotomy and window implantation rather than electrode insertion. Initial evidence of capillary re-mapping in the region surrounding the implanted electrode was manifest in OCA image dissimilarity. Further investigation, including higher resolution imaging, is required to validate the finding. Spontaneous lesions also occurred in many electrode animals, though the inception point appeared random and not directly associated with electrode insertion. OCA allows high resolution, label-free in vivo visualization of neurovascular tissue, which may help determine any biological contribution to chronic electrode signal degradation. Vascular and flow-based biomarkers can aid development of novel neural prostheses. (C)2014 Optical Society of America C1 [Hammer, Daniel X.; Lozzi, Andrea; Abliz, Erkinay; Greenbaum, Noah; Agrawal, Anant; Krauthamer, Victor; Welle, Cristin G.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Hammer, DX (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM daniel.hammer@fda.hhs.gov OI Welle, Cristin/0000-0001-8735-0983 FU DARPA (RE-NET Program, Microsystems Technology Office); FDA Medical Counter Measures Initiative FX This work was funded by an interagency agreement with DARPA (RE-NET Program, Microsystems Technology Office) and a grant from the FDA Medical Counter Measures Initiative. We thank Sina Farsui for helpful suggestions. 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 US Department of Health and Human Services. NR 32 TC 9 Z9 9 U1 0 U2 2 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD AUG 1 PY 2014 VL 5 IS 8 BP 2823 EP 2836 DI 10.1364/BOE.5.002823 PG 14 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA AO9BA UT WOS:000341649300030 PM 25136505 ER PT J AU Wu, F Lu, GH Zhao, P Jamei, M Huang, SM Bashaw, ED Lee, SC AF Wu, Fang Lu Gaohua Zhao, Ping Jamei, Masoud Huang, Shiew-Mei Bashaw, Edward D. Lee, Sue-Chih TI Predicting Nonlinear Pharmacokinetics of Omeprazole Enantiomers and Racemic Drug Using Physiologically Based Pharmacokinetic Modeling and Simulation: Application to Predict Drug/Genetic Interactions SO PHARMACEUTICAL RESEARCH LA English DT Article DE esomeprazole; nonlinear pharmacokinetics; omeprazole; physiologically based pharmacokinetic (PBPK) model; racemic drug ID HUMAN CYTOCHROME-P450 ENZYMES; STEREOSELECTIVE INTERACTION; HEALTHY-SUBJECTS; CYP2C19; METABOLISM; PHARMACODYNAMICS; ESOMEPRAZOLE; INHIBITOR; SINGLE; POLYMORPHISM AB The objective of this study is to develop a physiologically-based pharmacokinetic (PBPK) model for each omeprazole enantiomer that accounts for nonlinear PK of the two enantiomers as well as omeprazole racemic drug. By integrating in vitro, in silico and human PK data, we first developed PBPK models for each enantiomer. Simulation of racemic omeprazole PK was accomplished by combining enantiomer models that allow mutual drug interactions to occur. The established PBPK models for the first time satisfactorily predicted the nonlinear PK of esomeprazole, R-omeprazole and the racemic drug. The modeling exercises revealed that the strong time-dependent inhibition of CYP2C19 by esomeprazole greatly altered the R-omeprazole PK following administration of racemic omeprazole as in contrast to R-omeprazole given alone. When PBPK models incorporated both autoinhibition of each enantiomer and mutual interactions, the ratios between predicted and observed AUC following single and multiple dosing of omeprazole were 0.97 and 0.94, respectively. PBPK models of omeprazole enantiomers and racemic drug were developed. These models can be utilized to assess CYP2C19-mediated drug and genetic interaction potential for omeprazole and esomeprazole. C1 [Wu, Fang; Zhao, Ping; Huang, Shiew-Mei; Bashaw, Edward D.; Lee, Sue-Chih] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Lu Gaohua; Jamei, Masoud] SIMCYP Ltd, Blades Enterprise Ctr, Sheffield, S Yorkshire, England. RP Lee, SC (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM suechih.lee@fda.hhs.gov RI Jamei, Masoud/H-6281-2013 FU FDA's Critical Path Fellowship; Center for Drug Evaluation and Research FX The authors would like to thank Professor Amin Rostami-Hodjegan from the University of Manchester for his valuable scientific input. This project was supported by FDA's Critical Path Fellowship. This project was also supported in part by an appointment to the ORISE Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an agreement between the U.S. Department of Energy and CDER. The views presented in this manuscript are those of authors and do not necessarily reflect the official view of the FDA. NR 32 TC 3 Z9 4 U1 0 U2 8 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 AUG PY 2014 VL 31 IS 8 BP 1919 EP 1929 DI 10.1007/s11095-013-1293-z PG 11 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA AO9WZ UT WOS:000341712400005 PM 24590877 ER PT J AU Chen, CC Chen, JJ AF Chen, Chu-Chih Chen, James J. TI Benchmark Dose Calculation for Ordered Categorical Responses SO RISK ANALYSIS LA English DT Article DE Categorical regression; interval censoring; loss function; Markov chain Monte Carlo simulation; misspecification probability ID SEYCHELLES CHILD-DEVELOPMENT; NONCANCER RISK-ASSESSMENT; 9-YEAR FOLLOW-UP; EXPOSURE; MODEL; REGRESSION; TOXICITY AB The use of benchmark dose (BMD) calculations for dichotomous or continuous responses is well established in the risk assessment of cancer and noncancer endpoints. In some cases, responses to exposure are categorized in terms of ordinal severity effects such as none, mild, adverse, and severe. Such responses can be assessed using categorical regression (CATREG) analysis. However, while CATREG has been employed to compare the benchmark approach and the no-adverse-effect-level (NOAEL) approach in determining a reference dose, the utility of CATREG for risk assessment remains unclear. This study proposes a CATREG model to extend the BMD approach to ordered categorical responses by modeling severity levels as censored interval limits of a standard normal distribution. The BMD is calculated as a weighted average of the BMDs obtained at dichotomous cutoffs for each adverse severity level above the critical effect, with the weights being proportional to the reciprocal of the expected loss at the cutoff under the normal probability model. This approach provides a link between the current BMD procedures for dichotomous and continuous data. We estimate the CATREG parameters using a Markov chain Monte Carlo simulation procedure. The proposed method is demonstrated using examples of aldicarb and urethane, each with several categories of severity levels. Simulation studies comparing the BMD and BMDL (lower confidence bound on the BMD) using the proposed method to the correspondent estimates using the existing methods for dichotomous and continuous data are quite compatible; the difference is mainly dependent on the choice of cutoffs for the severity levels. C1 [Chen, Chu-Chih] Natl Hlth Res Inst, Div Biostat & Bioinformat, Inst Populat Hlth Sci, Zhunan 350, Taiwan. [Chen, James J.] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR USA. [Chen, James J.] China Med Univ, Grad Inst Biostat, Taichung, Taiwan. [Chen, James J.] China Med Univ, Biostat Ctr, Taichung, Taiwan. RP Chen, CC (reprint author), Natl Hlth Res Inst, Div Biostat & Bioinformat, Inst Populat Hlth Sci, 35 Keyan Rd, Zhunan 350, Taiwan. EM ccchen@nhri.org.tw RI Chen, Chu-Chih /E-3843-2010; Chen, Chu-Chih/B-8308-2015 OI Chen, Chu-Chih/0000-0002-4594-4991 FU National Science Council [NSC 101-2118-M-400-001]; National Health Research Institutes of Taiwan [PH-102-PP-09] FX This research was supported by the National Science Council (NSC 101-2118-M-400-001) and the National Health Research Institutes (PH-102-PP-09) of Taiwan. The authors wish to thank Dr. Jeffrey S. Gift of the U.S. EPA for providing the first author very helpful discussions and related literatures at the early stage of this work, and the associate editor and two anonymous reviewers for their insightful comments regarding an earlier draft of this article. The authors also thank Ms. Chia-Yen Yu and Mr. Jih-Shin Liu for their help in statistical computations and programming. The views presented in this article are those of the authors and do not necessarily represent those of the U.S. Food and Drug Administration. NR 29 TC 0 Z9 0 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0272-4332 EI 1539-6924 J9 RISK ANAL JI Risk Anal. PD AUG PY 2014 VL 34 IS 8 BP 1435 EP 1447 DI 10.1111/risa.12167 PG 13 WC Public, Environmental & Occupational Health; Mathematics, Interdisciplinary Applications; Social Sciences, Mathematical Methods SC Public, Environmental & Occupational Health; Mathematics; Mathematical Methods In Social Sciences GA AO8XT UT WOS:000341639800008 PM 24444309 ER PT J AU Luccioli, S Kwegyir-Afful, EK AF Luccioli, Stefano Kwegyir-Afful, Ernest K. TI Benefits of understanding allergen thresholds SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Editorial Material DE Food allergen; threshold; risk; challenge; dose ID PEANUT ALLERGY; FOOD CHALLENGES; IGE; CHILDREN; MANAGEMENT C1 [Luccioli, Stefano; Kwegyir-Afful, Ernest K.] Food & Drug Adm, Ctr Food Safety & Appl Nutr, Off Food Addit Safety, College Pk, MD 20740 USA. RP Luccioli, S (reprint author), Food & Drug Adm, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy,HFS 200, College Pk, MD 20740 USA. EM stefano.luccioli@fda.hhs.gov NR 16 TC 2 Z9 2 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2014 VL 134 IS 2 BP 399 EP 400 DI 10.1016/j.jaci.2014.05.007 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA AO5GB UT WOS:000341370800020 PM 24954274 ER PT J AU Bearden, DW Beger, RD Broadhurst, D Dunn, W Edison, A Guillou, C Trengove, R Viant, M Wilson, I AF Bearden, Daniel W. Beger, Richard D. Broadhurst, David Dunn, Warwick Edison, Arthur Guillou, Claude Trengove, Robert Viant, Mark Wilson, Ian TI The New Data Quality Task Group (DQTG): ensuring high quality data today and in the future SO METABOLOMICS LA English DT News Item C1 [Bearden, Daniel W.] NIST, Hollings Marine Lab, Charleston, SC 29412 USA. [Beger, Richard D.] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. [Broadhurst, David] Univ Alberta, Dept Med, Edmonton, AB, Canada. [Dunn, Warwick; Viant, Mark] Univ Birmingham, Sch Biosci, Birmingham, W Midlands, England. [Edison, Arthur] Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. [Guillou, Claude] Commiss European Communities, Joint Res Ctr, Inst Hlth & Consumer Protect, I-21020 Ispra, Italy. [Trengove, Robert] Murdoch Univ, Separat Sci & Metabol Lab, Murdoch, WA 6150, Australia. [Wilson, Ian] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London, England. RP Bearden, DW (reprint author), NIST, Hollings Marine Lab, Charleston, SC 29412 USA. EM dan.bearden@nist.gov; richard.beger@fda.hhs.gov NR 0 TC 1 Z9 1 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1573-3882 EI 1573-3890 J9 METABOLOMICS JI Metabolomics PD AUG PY 2014 VL 10 IS 4 BP 539 EP 540 DI 10.1007/s11306-014-0679-1 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AO5YE UT WOS:000341422300001 ER PT J AU Jarow, J Kluetz, PG Lerner, SP Liu, K Sridhara, R Bajorin, D Chang, S Dinney, CPN Groshen, S Morton, RA O'Donnell, M Quale, DZ Schoenberg, M Seigne, J Vikram, B AF Jarow, Jonathan Kluetz, Paul G. Lerner, Seth P. Liu, Ke Sridhara, Rajeshwari Bajorin, Dean Chang, Sam Dinney, Colin P. N. Groshen, Susan Morton, Ronald A. O'Donnell, Michael Quale, Diane Zipursky Schoenberg, Mark Seigne, John Vikram, Bhadrasain TI Re: Jarow JP et al.: Clinical Trial Design For the Development of New Therapies for Non-muscle-invasive Bladder Cancer: Report of a Food and Drug Administration and American Urological Association Public Workshop (Urology 2014;83:262-265) Reply SO UROLOGY LA English DT Letter C1 [Jarow, Jonathan; Kluetz, Paul G.] US FDA, Off Hematol & Oncol Prod, Silver Spring, MD 20993 USA. [Lerner, Seth P.] Baylor Coll Med, Med Ctr, Scott Dept Urol, Houston, TX 77030 USA. [Liu, Ke] Ctr Biol Evaluat & Res Food & Drug Adm, Off Cellular Tissue & Gene Therapies, Silver Spring, MD USA. [Sridhara, Rajeshwari] CDER Food & Drug Adm, Div Biometr 5, Off Biostat, Silver Spring, MD USA. [Bajorin, Dean] Mem Sloan Kettering Canc Ctr, Weill Cornell Med Coll, New York, NY 10021 USA. [Chang, Sam] Vanderbilt Univ, Med Ctr, Dept Urol Surg, Nashville, TN USA. [Dinney, Colin P. N.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Groshen, Susan] USC, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Morton, Ronald A.] Amer Med Syst, Minnetonka, MN USA. [O'Donnell, Michael] Univ Iowa, Iowa City, IA USA. [Quale, Diane Zipursky] Bladder Canc Advocacy Network, Bethesda, MD USA. [Schoenberg, Mark] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Seigne, John] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Seigne, John] Norris Cotton Canc Ctr, Lebanon, NH USA. [Vikram, Bhadrasain] NCI, Bethesda, MD 20892 USA. RP Jarow, J (reprint author), US FDA, Off Hematol & Oncol Prod, Silver Spring, MD 20993 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD AUG PY 2014 VL 84 IS 2 BP 495 EP 496 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA AO5EH UT WOS:000341365500079 PM 25065996 ER PT J AU Hatzis, C Bedard, PL Birkbak, NJ Beck, AH Aerts, HJWL Stern, DF Shi, LM Clarke, R Quackenbush, J Haibe-Kains, B AF Hatzis, Christos Bedard, Philippe L. Birkbak, Nicolai J. Beck, Andrew H. Aerts, Hugo J. W. L. Stern, David F. Shi, Leming Clarke, Robert Quackenbush, John Haibe-Kains, Benjamin TI Enhancing Reproducibility in Cancer Drug Screening: How Do We Move Forward? SO CANCER RESEARCH LA English DT Review ID MICROARRAY DATA; CYTOTOXICITY; INHIBITION; DISCOVERY; SENSITIVITY; STANDARDS; MELANOMA; STRATEGY; IMPACT; TARGET AB Large-scale pharmacogenomic high-throughput screening (HTS) studies hold great potential for generating robust genomic predictors of drug response. Two recent large-scale HTS studies have reported results of such screens, revealing several known and novel drug sensitivities and biomarkers. Subsequent evaluation, however, found only moderate interlaboratory concordance in the drug response phenotypes, possibly due to differences in the experimental protocols used in the two studies. This highlights the need for community-wide implementation of standardized assays for measuring drug response phenotypes so that the full potential of HTS is realized. We suggest that the path forward is to establish best practices and standardization of the critical steps in these assays through a collective effort to ensure that the data produced from large-scale screens would not only be of high intrastudy consistency, so that they could be replicated and compared successfully across multiple laboratories. (C)2014 AACR. C1 [Hatzis, Christos] Yale Univ, Sch Med, Sect Med Oncol, New Haven, CT USA. [Stern, David F.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Hatzis, Christos; Stern, David F.] Yale Univ, Yale Canc Ctr, New Haven, CT USA. [Beck, Andrew H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Aerts, Hugo J. W. L.; Quackenbush, John] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Biostat & Computat Bio, Boston, MA 02215 USA. [Aerts, Hugo J. W. L.; Quackenbush, John] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Ctr Canc Computat Biol, Boston, MA 02215 USA. [Quackenbush, John] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Canc Biol, Boston, MA 02215 USA. [Aerts, Hugo J. W. L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Radiat Oncol & Radiol, Boston, MA 02215 USA. [Shi, Leming] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Clarke, Robert] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Bedard, Philippe L.; Haibe-Kains, Benjamin] Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Bedard, Philippe L.] Univ Toronto, Fac Med, Toronto, ON, Canada. [Haibe-Kains, Benjamin] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Birkbak, Nicolai J.] Tech Univ Denmark, Ctr Biol Sequence Anal, Dept Syst Biol, DK-2800 Lyngby, Denmark. [Shi, Leming] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Shi, Leming] Fudan Univ, Sch Life Sci, MOE Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Shi, Leming] Fudan Univ, Sch Pharm, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Shi, Leming] Fudan Univ, Sch Pharm, MOE Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Shi, Leming] Zhanjiang Ctr Translat Med, Shanghai, Peoples R China. RP Haibe-Kains, B (reprint author), Univ Hlth Network, Princess Margaret Canc Ctr, 101 Coll St, Toronto, ON M5G 1L7, Canada. EM bhaibeka@uhnresearch.ca RI Clarke, Robert/A-6485-2008; Hatzis, Christos/M-3867-2015; Aerts, Hugo/P-6350-2015; Haibe-Kains, Benjamin/D-3702-2011 OI Clarke, Robert/0000-0002-9278-0854; Hatzis, Christos/0000-0002-8120-2290; Aerts, Hugo/0000-0002-2122-2003; Haibe-Kains, Benjamin/0000-0002-7684-0079 FU Yale University; United States National Institute of Health [UM1 CA186644]; Villum Kann Rasmussen Foundation; Klarman Family Foundation; US National Institutes of Health (NIH) [CA087969]; NIH National Cancer Institute (NCI) [R01CA80065]; NIH [U54 CA149147, R01 CA131465]; NCI GAME-ON Cancer Post-GWAS initiative [5U19 CA148065]; NHLBI [5R01HL111759]; Gattuso Slaight Personalized Cancer Medicine Fund at Princess Margaret Cancer Centre FX C. Hatzis was supported by Yale University. P.L. Bedard was supported by a grant from the United States National Institute of Health (UM1 CA186644). N. Juul Birkbak was funded by The Villum Kann Rasmussen Foundation. A.H. Beck was supported by an award from the Klarman Family Foundation and by support from US National Institutes of Health (NIH) grant CA087969. D.F. Stern was supported by the NIH National Cancer Institute (NCI) under award number R01CA80065. R. Clarke was supported by Public Health Service grants (U54 CA149147 and R01 CA131465) from the NIH. J. Quackenbush was supported by grants from the NCI GAME-ON Cancer Post-GWAS initiative (5U19 CA148065) and the NHLBI (5R01HL111759). B. Haibe-Kains was supported by the Gattuso Slaight Personalized Cancer Medicine Fund at Princess Margaret Cancer Centre. NR 41 TC 16 Z9 16 U1 1 U2 13 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 2014 VL 74 IS 15 BP 4016 EP 4023 DI 10.1158/0008-5472.CAN-14-0725 PG 8 WC Oncology SC Oncology GA AO2VM UT WOS:000341184400003 PM 25015668 ER PT J AU Zusterzeel, R Selzman, KA Sanders, WE Canos, DA O'Callaghan, KM Carpenter, JL Pina, IL Strauss, DG AF Zusterzeel, Robbert Selzman, Kimberly A. Sanders, William E. Canos, Daniel A. O'Callaghan, Kathryn M. Carpenter, Jamie L. Pina, Ileana L. Strauss, David G. TI Cardiac Resynchronization Therapy in Women US Food and Drug Administration Meta-analysis of Patient-Level Data SO JAMA INTERNAL MEDICINE LA English DT Article ID BUNDLE-BRANCH BLOCK; DEFIBRILLATOR IMPLANTATION TRIAL; RANDOMIZED-CONTROLLED-TRIALS; LEFT-VENTRICULAR DYSFUNCTION; SYMPTOMATIC HEART-FAILURE; CLINICAL EVENT REDUCTION; QRS DURATION; MADIT-CRT; MORPHOLOGY; OUTCOMES AB IMPORTANCE Women were underrepresented in cardiac resynchronization therapy (CRT) trials for heart failure (making up about 20% of enrollees). Combining individual patient data from multiple clinical trials would enable assessment of CRT benefit in women. OBJECTIVE To evaluate whether women with left bundle branch block (LBBB) benefit from CRT-defibrillators (CRT-D) at a shorter QRS duration than men with LBBB do. DESIGN, SETTING, AND PARTICIPANTS Individual patient data were pooled from 3 CRT-D vs implantable cardioverter defibrillator (ICD) trials (4076 patients) enrolling predominantly patients with New York Heart Association (NYHA) class II heart failure and follow-up to 3 years. The effect of CRT-D compared with ICD on outcomes was assessed using random effects Cox proportional hazards. MAIN OUTCOMES AND MEASURES Time to heart failure event or death (primary) and death alone (secondary). RESULTS Women benefited from CRT-D more than men. The main difference occurred in patients with LBBB and a QRS of 130 to 149 milliseconds. In this group, women had a 76% reduction in heart failure or death (absolute CRT-D to ICD difference, 23%; hazard ratio [HR], 0.24, [95% CI, 0.11-0.53]; P <.001) and a 76% reduction in death alone (absolute difference 9%; HR, 0.24, [95% CI, 0.06-0.89]; P = .03), while there was no significant benefit in men for heart failure or death (absolute difference 4%; HR, 0.85 [95% CI, 0.60-1.21]; P = .38) or death alone (absolute difference 2%; HR, 0.86 [95% CI, 0.49-1.52]; P = .60). Neither women nor men with LBBB benefited from CRT-D at QRS shorter than 130 milliseconds, while both sexes with LBBB benefited at QRS of 150 milliseconds or longer. CONCLUSIONS AND RELEVANCE In this population of patients with primarily mild heart failure, women with LBBB benefited from CRT-D at a shorter QRS duration than men with LBBB. This is important because recent guidelines limit the class I indication for CRT-D to patients with LBBB and QRS of 150 milliseconds or longer. While guidelines do give a class IIa indication to patients with LBBB and a QRS of 120 to 149 milliseconds, the present findings are important to communicate because women are less likely to receive CRT-D than men are. This study exemplifies the potential public health and regulatory science value of combining data from multiple clinical trials submitted to the FDA. C1 [Zusterzeel, Robbert; Selzman, Kimberly A.; Sanders, William E.; Canos, Daniel A.; O'Callaghan, Kathryn M.; Carpenter, Jamie L.; Pina, Ileana L.; Strauss, David G.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Strauss, DG (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,62-1126, Silver Spring, MD 20993 USA. EM david.strauss@fda.hhs.gov FU FDA Office of Women's Health; Oak Ridge Institute for Science and Education FX This project was supported in part by the FDA Office of Women's Health and by a research fellowship from the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA. NR 35 TC 33 Z9 34 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD AUG PY 2014 VL 174 IS 8 BP 1340 EP 1348 DI 10.1001/jamainternmed.2014.2717 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AN2WP UT WOS:000340447000029 PM 25090172 ER PT J AU Soneji, S Ambrose, BK Lee, W Sargent, J Tanski, S AF Soneji, Samir Ambrose, Bridget K. Lee, Won Sargent, James Tanski, Susanne TI Direct-To-Consumer Tobacco Marketing and Its Association With Tobacco Use Among Adolescents and Young Adults SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Adolescents; Direct-to-consumer marketing; Tobacco; Young Adults ID YOUTH SMOKING; UNITED-STATES; PRICES AB Objective: We assess exposure to direct-to-consumer tobacco marketing and its association with ever having tried smoking, smoking within past 30 days (current), and smoking >= 100 cigarettes in lifetime (established) among adolescents and young adults. Methods: We surveyed a U. S. telephone sample of 3,342 15- to 23-year-olds and 2,541 respondents subsequently completed a web-based survey. Among respondents completing both the telephone and web-based surveys (N=2,541 [75%]), we assessed their exposure to direct-to-consumer tobacco marketing (receiving direct mail from tobacco companies and seeing tobacco company websites) and their associations with ever having tried smoking, current smoking, and established smoking. Results: Overall, 12% of 15- to 17-year-olds and 26% of 18- to 23-year-olds were exposed to direct-to-consumer tobacco marketing. Racial/ethnic minority nonsmoking respondents were more likely to see tobacco websites than nonsmoking whites. Respondents exposed to either form of direct-to-consumer tobacco marketing were more likely to currently smoke (adjusted odds ratio 2.2, 95% confidence interval 1.3-3.8), while those exposed to both forms of marketing experienced even higher odds of currently smoking (adjusted odds ratio 2.7, 95% confidence interval 1.1-6.6). We observed similar relationships for ever having tried smoking and established smoking. Conclusions: Direct-to-consumer tobacco marketing reaches adolescent and young adult nonsmokers and is associated with smoking behavior. (C) 2014 Society for Adolescent Health and Medicine. All rights reserved. C1 [Soneji, Samir; Sargent, James; Tanski, Susanne] Geisel Sch Med Dartmouth, Norris Cotton Canc Ctr, Lebanon, NH USA. [Soneji, Samir; Sargent, James] Geisel Sch Med Dartmouth, Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH USA. [Ambrose, Bridget K.; Lee, Won] US FDA, Off Sci, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Soneji, S (reprint author), Norris Cotton Canc Ctr, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM samir.soneji@dartmouth.edu FU National Cancer Institute [CA077026]; National Center For Advancing Translational Sciences of the National Institutes of Health [KL2TR001088]; 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 by the National Cancer Institute (CA077026; PI Sargent), National Center For Advancing Translational Sciences of the National Institutes of Health under Award Number KL2TR001088, and 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. NR 30 TC 7 Z9 7 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X EI 1879-1972 J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD AUG PY 2014 VL 55 IS 2 BP 209 EP 215 DI 10.1016/j.jadohealth.2014.01.019 PG 7 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA AO2GU UT WOS:000341137000009 PM 24661738 ER PT J AU Liu, P Badano, A AF Liu, Peter Badano, Aldo TI Characterizing the reflectivity of handheld display devices SO MEDICAL PHYSICS LA English DT Article DE diffuse reflection; specular reflection; TG18; handheld displays ID IPAD AB Purpose: With increased use of handheld and tablet display devices for viewing medical images, methods for consistently measuring reflectivity of the devices are needed. In this note, the authors report on the characterization of diffuse reflections for handheld display devices including mobile phones and tablets using methods recommended by the American Association of Physicists in Medicine Task Group 18 (TG18). Methods: The authors modified the diffuse reflectance coefficient measurement method outlined in the TG18 report. The authors measured seven handheld display devices (two phones and five tablets) and three workstation displays. The device was attached to a black panel with Velcro. To study the effect of the back surface on the diffuse reflectance coefficient, the authors created Styrofoam masks with different size square openings and placed it in front of the device. Overall, for each display device, measurements of illuminance and reflected luminance on the display screen were taken. The authors measured with no mask, with masks of varying size, and with display-size masks, and calculated the corresponding diffuse reflectance coefficient. Results: For all handhelds, the diffuse reflectance coefficient measured with no back panel were lower than measurements performed with a mask. The authors found an overall increase in reflectivity as the size of the mask decreases. For workstations displays, diffuse reflectance coefficients were higher when no back panel was used, and higher than with masks. In all cases, as luminance increased, illuminance increased, but not at the same rate. Conclusions: Since the size of handheld displays is smaller than that of workstation devices, the TG18 method suffers from a dependency on illumination condition. The authors show that the diffuse reflection coefficients can vary depending on the nature of the back surface of the illuminating box. The variability in the diffuse coefficient can be as large as 20% depending on the size of the mask. For all measurements, both luminance and illuminance increased as the size of the display window decreased. The TG18 method does not account for this variability. The authors conclude that the method requires a definitive description of the back panel used in the light source setup. The methods described in the TG18 document may need to be improved to provide consistent comparisons of desktop monitors, phones, and tablets. (C) 2014 American Association of Physicists in Medicine. C1 [Liu, Peter; Badano, Aldo] US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Badano, A (reprint author), US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM aldo.badano@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 FU CDRH FX P.L. acknowledges funding by appointments to the Research Participation Program at the CDRH administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the (U.S.) DOE and the U.S. FDA. 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 FDA and is not subject to copyright. NR 5 TC 0 Z9 0 U1 1 U2 5 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 AUG PY 2014 VL 41 IS 8 BP 348 EP 352 DI 10.1118/1.4887813 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AO1JJ UT WOS:000341068100032 PM 25086540 ER PT J AU Shea, K Stewart, S Rouse, R AF Shea, Katherine Stewart, Sharron Rouse, Rodney TI Assessment Standards: Comparing Histopathology, Digital Image Analysis, and Stereology for Early Detection of Experimental Cisplatin-induced Kidney Injury in Rats SO TOXICOLOGIC PATHOLOGY LA English DT Article DE methods; kidney tissue injury; histopathology; digital image analysis; stereology ID BIOMARKER QUALIFICATION; MOLECULE-1 KIM-1; RENAL INJURY; NEPHROTOXICITY; TISSUE AB Histopathology generally represents the reference standard for performance evaluation of nonclinical biomarkers used to inform regulatory decision making. This study uses drug-induced nephrotoxicity in rats to evaluate histopathology methods utilized in biomarker performance assessments. Male Sprague-Dawley rats received a single dose of cisplatin (0.5-5.0 mg/kg, intraperitoneally) to produce mild renal injury. Animals were euthanized 72 hr postdose and perfusion fixed. Kidneys were processed for histology and stereology procedures. Kidney injury molecule-1 (Kim-1) was measured in urine and in kidney tissue. Digital slide images were generated and analyzed by pathologists after collaborating on a training set of glass slides and digital images. Image analysis identified immunohistochemistry (IHC)-defined tubular injury. Stereology methods yielded estimations of proximal tubular cell number and volume. Statistical relationships among data sets were determined using correlation coefficients. Receiver operator characteristic (ROC) analyses determined the effect of method on biomarker assessment. Urinary Kim-1 was strongly correlated with digital image analysis and secondarily to histopathology evaluations. Stereology demonstrated weak or no correlation to pathology and urinary Kim-1. In ROC analyses, semiquantitative evaluations determined higher values for urinary Kim-1 performance than did IHC-based qualitative digital analyses. Semiquantitative evaluation as used in this study was most predictive of urinary Kim-1 values. C1 [Shea, Katherine; Stewart, Sharron; Rouse, Rodney] US FDA, Div Drug Safety Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Rouse, R (reprint author), US FDA, Div Drug Safety Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM rodney.rouse@fda.hhs.gov NR 29 TC 2 Z9 2 U1 0 U2 3 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 2014 VL 42 IS 6 BP 1004 EP 1015 DI 10.1177/0192623313509905 PG 12 WC Pathology; Toxicology SC Pathology; Toxicology GA AN6SF UT WOS:000340726400007 PM 24201815 ER PT J AU Ferguson, SA Law, CD Kissling, GE AF Ferguson, Sherry A. Law, Charles Delbert Kissling, Grace E. TI Developmental Treatment with Ethinyl Estradiol, but Not Bisphenol A, Causes Alterations in Sexually Dimorphic Behaviors in Male and Female Sprague Dawley Rats SO TOXICOLOGICAL SCIENCES LA English DT Article DE bisphenol A; ethinyl estradiol; developmental; behavior; estrous cycle; puberty ID LORDOSIS REFLEX INTENSITY; ESTROGEN-RECEPTOR-ALPHA; SOCIAL PLAY-BEHAVIOR; LACTATIONAL EXPOSURE; IN-UTERO; CIRCADIAN-RHYTHMS; REPRODUCTIVE DEVELOPMENT; INDIVIDUAL-DIFFERENCES; ENDOCRINE DISRUPTION; OVARIECTOMIZED RATS AB The developing central nervous system may be particularly sensitive to bisphenol A (BPA)-induced alterations. Here, pregnant Sprague Dawley rats (n = 11-12/group) were gavaged daily with vehicle, 2.5 or 25.0 mu g/kg BPA, or 5.0 or 10.0 mu g/kg ethinyl estradiol (EE2) on gestational days 6-21. The BPA doses were selected to be below the no-observed-adverse-effect level (NOAEL) of 5 mg/kg/day. On postnatal days 1-21, all offspring/litter were orally treated with the same dose. A naive control group was not gavaged. Body weight, pubertal age, estrous cyclicity, and adult serum hormone levels were measured. Adolescent play, running wheel activity, flavored solution intake, female sex behavior, and manually elicited lordosis were assessed. No significant differences existed between the vehicle and naive control groups. Vehicle controls exhibited significant sexual dimorphism for most behaviors, indicating these evaluations were sensitive to sex differences. However, only EE2 treatment caused significant effects. Relative to female controls, EE2-treated females were heavier, exhibited delayed vaginal opening, aberrant estrous cyclicity, increased play behavior, decreased running wheel activity, and increased aggression toward the stimulus male during sexual behavior assessments. Relative to male controls, EE2-treatedmales were older at testes descent and preputial separation and had lower testosterone levels. These results suggest EE2-induced masculinization/defeminization of females and are consistent with increased volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) at weaning in female siblings of these subjects (He, Z., Paule, M. G. and Ferguson, S. A. (2012) Low oral doses of bisphenol A increase volume of the sexually dimorphic nucleus of the preoptic area in male, but not female, rats at postnatal day 21. Neurotoxicol. Teratol. 34, 331-337). Although EE2 treatment caused pubertal delays and decreased testosterone levels in males, their behaviors were within the range of controlmales. Conversely, BPA treatment did not alter anymeasured endpoint. Similar to our previous reports (Ferguson, S. A., Law, C. D. Jr and Abshire, J. S. (2011) Developmental treatment with bisphenolAor ethinyl estradiol causes few alterations on early preweaning measures. Toxicol. Sci. 124, 149-160; Ferguson, S. A., Law, C. D. and Abshire, J. S. (2012) Developmental treatment with bisphenol A causes few alterations on measures of postweaning activity and learning. Neurotoxicol. Teratol. 34, 598-606), the BPA doses and design used here produced few alterations. C1 [Ferguson, Sherry A.; Law, Charles Delbert] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Ferguson, SA (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, HFT 132,3900 NCTR Rd, Jefferson, AR 72079 USA. EM sherry.ferguson@fda.hhs.gov FU National Center for Toxicological Research/Food and Drug Administration [P00706]; National Institutes of Health [Z01ES45003] FX National Center for Toxicological Research/Food and Drug Administration (Protocol no. P00706 to S.A.F.); National Institutes of Health (Project no. Z01ES45003 to G.E.K., in part). NR 94 TC 13 Z9 14 U1 4 U2 21 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 AUG PY 2014 VL 140 IS 2 BP 374 EP 392 DI 10.1093/toxsci/kfu077 PG 19 WC Toxicology SC Toxicology GA AN6DL UT WOS:000340684100012 PM 24798382 ER PT J AU Petersen, LR Epstein, JS AF Petersen, Lyle R. Epstein, Jay S. TI Chikungunya virus: new risk to transfusion safety in the Americas SO TRANSFUSION LA English DT Editorial Material ID WEST-NILE-VIRUS; DENGUE HEMORRHAGIC-FEVER; TEXAS-MEXICO BORDER; INDIAN-OCEAN; BLOOD-TRANSFUSION; REUNION ISLAND; 2005-2006 OUTBREAK; AEDES-ALBOPICTUS; LA REUNION; INFECTION C1 [Petersen, Lyle R.] Ctr Dis Control & Prevent, Div Vector Borne Dis, Natl Ctr Emerging & Zoonot Infect Dis, Ft Collins, CO 80521 USA. [Epstein, Jay S.] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Petersen, LR (reprint author), Ctr Dis Control & Prevent, Div Vector Borne Dis, Natl Ctr Emerging & Zoonot Infect Dis, Ft Collins, CO 80521 USA. EM lxp2@cdc.gov NR 47 TC 12 Z9 12 U1 0 U2 7 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 AUG PY 2014 VL 54 IS 8 BP 1911 EP 1915 DI 10.1111/trf.12790 PG 5 WC Hematology SC Hematology GA AN5AI UT WOS:000340601000029 PM 25130331 ER PT J AU Puligedda, RD Kouiavskaia, D Adekar, SP Sharma, R Kattala, CD Rezapkin, G Bidzhieva, B Dessain, SK Chumakov, K AF Puligedda, Rama Devudu Kouiavskaia, Diana Adekar, Sharad P. Sharma, Rashmi Kattala, Chandana Devi Rezapkin, Gennady Bidzhieva, Bella Dessain, Scott K. Chumakov, Konstantin TI Human monoclonal antibodies that neutralize vaccine and wild-type poliovirus strains SO ANTIVIRAL RESEARCH LA English DT Article DE Poliovirus; Antiviral therapeutic; Neutralization; Epitope; Chronic viral infection; Eradication ID OUTBREAK; POLIOMYELITIS; ERADICATION; RESISTANCE; RECEPTOR; V-073; CHINA AB An essential requirement for eradication of poliomyelitis is the elimination of circulating vaccine derived polioviruses (cVDPV) and polioviruses excreted by chronically infected individuals with immunodeficiencies (iVDPV). As part of a post-eradication risk management strategy, a human monoclonal antibody (mAb) therapeutic could play a role in halting excretion in asymptomatic carriers and could be used, in combination with vaccines and antiviral drugs, to protect polio-exposed individuals. Cross-neutralizing mAbs may be particularly useful, as they would reduce the number of mAbs needed to create a comprehensive PV therapeutic. We cloned a panel of IgG mAbs from OPV-vaccinated, IPV-boosted healthy subjects. Many of the mAbs had potent neutralizing activities against PV wild-type (WT) and Sabin strains, and two of the mAbs, 12F8 and 1E4, were significantly cross-reactive against types 1 and 2 and types 1 and 3, respectively. Mapping the binding epitopes using strains resistant to neutralization (escape mutants) suggested that cross-specific PV binding epitopes may primarily reside within the canyon region, which interacts with the cellular receptor molecule CD155 and the cross-neutralizing chimpanzee/human mAb, A12. Despite their close proximity, the epitopes for the 12F8 and 1E4 mAbs on Sabin 1 were not functionally identical to the A12 epitope. When tested together, 12F8 and 1E4 neutralized a diverse panel of clinically relevant PV strains and did not exhibit interference. Virus mutants resistant to the anti-poliovirus drug V-073 were also neutralized by the mAbs. The 12F8 and 1E4 mAbs may suitable for use as anti-PV therapeutics. (C) 2014 Published by Elsevier B.V. C1 [Puligedda, Rama Devudu; Adekar, Sharad P.; Sharma, Rashmi; Kattala, Chandana Devi; Dessain, Scott K.] Lankenau Inst Med Res, Wynnewood, PA 19096 USA. [Kouiavskaia, Diana; Rezapkin, Gennady; Bidzhieva, Bella; Chumakov, Konstantin] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Adekar, Sharad P.; Dessain, Scott K.] Immunome Inc, Wynnewood, PA 19096 USA. RP Dessain, SK (reprint author), Lankenau Inst Med Res, 100 Lancaster Ave, Wynnewood, PA 19096 USA. EM dessain@limr.org; Konstantin.Chumakov@fda.hhs.gov FU World Health Organization; FDA FX Authors thank Drs. Olen Kew, Steve Oberste (CDC, Atlanta, GA) and Dr. Merja Roivainen (National Institute for Health and Welfare, Helsinki, Finland) for providing PV strains. This work was supported by a grant to S.D. from the World Health Organization and the intramural research program of the FDA. NR 28 TC 5 Z9 5 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD AUG PY 2014 VL 108 BP 36 EP 43 DI 10.1016/j.antiviral.2014.05.005 PG 8 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA AM9SD UT WOS:000340220400006 PM 24824031 ER PT J AU Dokmanovic, M Wu, Y Shen, Y Chen, JQ Hirsch, DS Wu, WJ AF Dokmanovic, Milos Wu, Yun Shen, Yi Chen, Jieqing Hirsch, Dianne S. Wu, Wen Jin TI Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition SO CANCER BIOLOGY & THERAPY LA English DT Article DE trastuzumab; ErbB2/HER2; ErbB2-Y1248; CHK/MATK; breast cancer ID BREAST-CANCER CELLS; MONOCLONAL-ANTIBODY; DOWN-REGULATION; RESISTANCE; ACTIVATION; HERCEPTIN; TRANSFORMATION; THERAPY; SITES; AUTOPHOSPHORYLATION AB The inhibitory effect of trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of ErbB2, is associated with its ability to induce ErbB2-Y1248 phosphorylation, and the status of phosphorylated ErbB2-Y1248 (ErbB2-pY1248) may correlate with the sensitivity of breast cancers to trastuzumab. The mechanisms of which remain unclear. Here, we show that binding of trastuzumab to ErbB2 activates ErbB2 kinase activity and enhances ErbB2-Y1248 phosphorylation in trastuzumab-sensitive breast cancer cells. This in turn increases the interaction between ErbB2 and non-receptor Csk-homologous kinase (CHK), leading to growth inhibition of breast cancer cells. Overexpression of CHK mimics trastuzumab treatment to mediate ErbB2-Y1248 phosphorylation, Akt downregulation, and growth inhibition of trastuzumab-sensitive breast cancer cells. CHK overexpression combined with trastuzumab exerts an additive effect on cell growth inhibition. We further demonstrate that positive ErbB2-pY1248 staining in ErbB2-positive breast cancer biopsies correlates with the increased trastuzumab response in trastuzumab neoadjuvant settings. Collectively, this study highlights an important role for ErbB2-pY1248 in mediating trastuzumab-induced growth inhibition and trastuzumab-induced interactions between CHK and ErbB2-pY1248 is identified as a novel mechanism of action that mediates the growth inhibition of breast cancer cells. The novel mechanistic insights into trastuzumab action revealed by this study may impact the design of next generation of therapeutic monoclonal antibodies targeting receptor tyrosine kinases, as well as open new avenues to identify novel targets for the treatment of ErbB2-positive cancers. C1 [Dokmanovic, Milos; Shen, Yi; Hirsch, Dianne S.; Wu, Wen Jin] US FDA, Div Monoclonal Antibodies, Off Biotechnol Prod, Off Pharmaceut Sci,Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [Wu, Yun; Chen, Jieqing] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. RP Wu, WJ (reprint author), US FDA, Div Monoclonal Antibodies, Off Biotechnol Prod, Off Pharmaceut Sci,Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. EM wen.wu@fda.hhs.gov FU US Food and Drug Administration FX We thank Drs Avin Lalmansingh and Ying-Xin Fan for the critical review of the manuscript. US Food and Drug Administration Critical Path Funding for FY2011. NR 42 TC 5 Z9 5 U1 1 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 EI 1555-8576 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG PY 2014 VL 15 IS 8 BP 1029 EP 1041 DI 10.4161/cbt.29171 PG 13 WC Oncology SC Oncology GA AN4IJ UT WOS:000340550800009 PM 24835103 ER PT J AU Lehmann, GM Verner, MA Luukinen, B Henning, C Assimon, SA LaKind, JS McLanahan, ED Phillips, LJ Davis, MH Powers, CM Hines, EP Haddad, S Longnecker, MP Poulsen, MT Farrer, DG Marchitti, SA Tan, YM Swartout, JC Sagiv, SK Welsh, C Campbell, JL Foster, WG Yang, RSH Fenton, SE Tornero-Velez, R Francis, BM Barnett, JB El-Masri, HA Simmons, JE AF Lehmann, Geniece M. Verner, Marc-Andre Luukinen, Bryan Henning, Cara Assimon, Sue Anne LaKind, Judy S. McLanahan, Eva D. Phillips, Linda J. Davis, Matthew H. Powers, Christina M. Hines, Erin P. Haddad, Sami Longnecker, Matthew P. Poulsen, Michael T. Farrer, David G. Marchitti, Satori A. Tan, Yu-Mei Swartout, Jeffrey C. Sagiv, Sharon K. Welsh, Clement Campbell, Jerry L., Jr. Foster, Warren G. Yang, Raymond S. H. Fenton, Suzanne E. Tornero-Velez, Rogelio Francis, Bettina M. Barnett, John B. El-Masri, Hisham A. Simmons, Jane Ellen TI Improving the risk assessment of lipophilic persistent environmental chemicals in breast milk SO CRITICAL REVIEWS IN TOXICOLOGY LA English DT Review DE children; exposure; PBT chemicals; persistent organic pollutants; POPs; research needs; risk assessment; uncertainty ID CHILDRENS HEALTH; POLYCHLORINATED-BIPHENYLS; PARTITION-COEFFICIENTS; LACTATIONAL TRANSFER; UNITED-STATES; PHARMACOKINETIC MODELS; TECHNICAL WORKSHOP; CRITICAL WINDOWS; INFANT EXPOSURE; EXPERT PANEL AB Lipophilic persistent environmental chemicals (LPECs) have the potential to accumulate within a woman's body lipids over the course of many years prior to pregnancy, to partition into human milk, and to transfer to infants upon breastfeeding. As a result of this accumulation and partitioning, a breastfeeding infant's intake of these LPECs may be much greater than his/her mother's average daily exposure. Because the developmental period sets the stage for lifelong health, it is important to be able to accurately assess chemical exposures in early life. In many cases, current human health risk assessment methods do not account for differences between maternal and infant exposures to LPECs or for lifestage-specific effects of exposure to these chemicals. Because of their persistence and accumulation in body lipids and partitioning into breast milk, LPECs present unique challenges for each component of the human health risk assessment process, including hazard identification, dose-response assessment, and exposure assessment. Specific biological modeling approaches are available to support both dose-response and exposure assessment for lactational exposures to LPECs. Yet, lack of data limits the application of these approaches. The goal of this review is to outline the available approaches and to identify key issues that, if addressed, could improve efforts to apply these approaches to risk assessment of lactational exposure to these chemicals. C1 [Lehmann, Geniece M.; McLanahan, Eva D.; Powers, Christina M.; Hines, Erin P.; Tan, Yu-Mei; Tornero-Velez, Rogelio; El-Masri, Hisham A.; Simmons, Jane Ellen] US EPA, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Verner, Marc-Andre] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Luukinen, Bryan; Henning, Cara] ICF Int, Res Triangle Pk, NC USA. [Assimon, Sue Anne] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [LaKind, Judy S.] LaKind Associates LLC, Catonsville, MD USA. [LaKind, Judy S.] Univ Maryland Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD USA. [LaKind, Judy S.] Penn State Univ Coll Med, Dept Pediat, Hershey, PA USA. [Phillips, Linda J.] US EPA, Off Res & Dev, Washington, DC 20460 USA. [Davis, Matthew H.] US EPA, Off Childrens Hlth Protect, Washington, DC 20460 USA. [Haddad, Sami] Univ Quebec, Dept Environm Hlth & Occupat Hlth, IRSPUM Univ Montreal Publ Hlth Res Inst, Montreal, PQ H3C 3P8, Canada. [Longnecker, Matthew P.; Fenton, Suzanne E.] NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Poulsen, Michael T.] Oregon Dept Environm Qual, Portland, OR USA. [Farrer, David G.] Oregon Hlth Author, Portland, OR USA. [Marchitti, Satori A.] US EPA, Off Res & Dev, Athens, GA USA. [Swartout, Jeffrey C.] US EPA, Off Res & Dev, Cincinnati, OH 45268 USA. [Sagiv, Sharon K.] Boston Univ Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Welsh, Clement] Agcy Tox Subst & Dis Registry, Div Toxicol & Human Hlth Sci, Atlanta, GA USA. [Campbell, Jerry L., Jr.] Hamner Inst Hlth Sci, Res Triangle Pk, NC USA. [Foster, Warren G.] McMaster Univ, Dept Obstet & Gynecol, Hamilton, ON, Canada. [Yang, Raymond S. H.] Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. [Francis, Bettina M.] Univ Illinois, Dept Entomol, Urbana, IL 61801 USA. [Barnett, John B.] West Virginia Univ Sch Med, Dept Microbiol Immunol & Cell Biol, Morgantown, WV USA. RP Lehmann, GM (reprint author), US EPA, MD B243-01,4930 Old Page Rd, Durham, NC 27703 USA. EM lehmann.geniece@epa.gov RI Haddad, Sami/F-4537-2012; OI Haddad, Sami/0000-0001-8906-9693; Hines, Erin Pias/0000-0002-2458-6267; Verner, Marc-Andre/0000-0002-1935-8913; Longnecker, Matthew/0000-0001-6073-5322 FU U.S. EPA [EP-C-09-009, 2-62, 3-62, 4-62]; Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS); NIH FX The employment affiliation of the authors is shown on the cover page. The following authors were participants in a multidisciplinary workshop that served as the basis for this review paper: MAV, SAA, JSL, MHD, SH, MPL, MTP, DGF, YMT, SKS, CW, JCS, JLC, WGF, BMF, RSHY, JBB, HAE, SEF, JES, and RT. Some workshop participants chose not to participate as authors in the development of this review. Those individuals are acknowledged in the preceding section. The workshop was co-chaired by GML and EDM. ICF International organized the workshop under contract from the U.S. EPA (Contract No. EP-C-09-009, Work Assignments 2-62, 3-62, and 4-62). Workshop organization functions performed by ICF International included the independent identification and selection of workshop participants. ICF International is a for-profit firm providing professional services and technology solutions to clients in the following markets: energy, environment, and infrastructure; health, social programs, and consumer/financial; and public safety and defense. ICF International provides these services to both government and private sector clients. This research was also supported [in part] by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS). The following workshop participants received support for travel and/or lodging: MAV, SAA, JSL, MHD, SH, MTP, DGF, SKS, WGF, BMF, RSHY, and JBB. MAV, SH, SKS, JLC, WGF, BMF, RSHY, JBB, and JSL received an honorarium for their participation in the workshop. LaKind Associates is a private consulting firm specializing in strategic risk management, assessment of human exposures and health risks, biomonitoring, state-of-the-science reviews, and environmental regulatory review; LaKind Associates consults to governmental and private sectors. The Hamner Institutes for Health Sciences is a nonprofit research institute with a primary focus on drug and chemical safety, including the development of methods to improve human health risk assessment. This paper has been reviewed in accordance with the peer and administrative review policies of the U. S. EPA, Food and Drug Administration (FDA), NIEHS, and Agency for Toxic Substances and Disease Registry (ATSDR) and approved for publication. The views expressed in this report are those of the authors and do not necessarily reflect the opinions and/or policies of the U. S. EPA, FDA, NIEHS or ATSDR. The remaining authors are all employees of either state governments or various academic institutions. Many of the academic scientists participating in the workshop and authoring this paper have received financial support for their research programs from the U.S. EPA and/or the NIH. All authors have sole responsibility as individual scientists for the writing and content of this review. The views, conclusions and recommendations are not necessarily those of their employers. NR 80 TC 7 Z9 7 U1 1 U2 24 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-8444 EI 1547-6898 J9 CRIT REV TOXICOL JI Crit. Rev. Toxicol. PD AUG PY 2014 VL 44 IS 7 BP 600 EP 617 DI 10.3109/10408444.2014.926306 PG 18 WC Toxicology SC Toxicology GA AN1QZ UT WOS:000340360000005 PM 25068490 ER PT J AU Imoisili, MA Mueller, C Needleman, KIM AF Imoisili, Menfo A. Mueller, Christine Needleman, Katherine I. Miller TI Fueling the development of products for rare diseases: the impact of the FDA's orphan products grants program SO EXPERT OPINION ON ORPHAN DRUGS LA English DT Review DE clinical trials; orphan product development; rare diseases ID INCENTIVES; INNOVATION AB Introduction: The US Congress enacted the Orphan Drug Act in 1983 to provide incentives to accelerate the development of products for the treatment, prevention or diagnosis of rare diseases and conditions. The support of clinical research continues to be an important incentive to assist in finding treatments for rare diseases. Our aim was to provide a descriptive analysis of the US FDA's Orphan Products Grants Program and its impact on bringing products for rare diseases to market. Areas covered: Data from the Program was analyzed from 1983 to the end of 2013. The main outcome measures included the yearly dollar amount invested in the Program in actual dollars and adjusted for inflation; the number of grant applications submitted and awards made overall and by year; the product types investigated and their therapeutic class; and grants awarded which have led to marketing approvals of products, by therapeutic class and indication. Expert opinion: Over $320 million have been awarded to fund clinical studies through the Program. The amount of funding appropriated was $500,000 in 1983 and has remained constant at $14 - $15 million since 2005; $6 - $8 million when adjusted for inflation. Funding received from the Program has served an unmet medical need and has contributed to approximately 10% of orphan product approvals in the US. This and many other programs are important to assist in finding treatments for rare diseases. C1 [Imoisili, Menfo A.; Mueller, Christine; Needleman, Katherine I. Miller] US FDA, Off Orphan Prod Dev, Off Special Med Programs, Silver Spring, MD 20993 USA. RP Needleman, KIM (reprint author), US FDA, Off Orphan Prod Dev, Off Special Med Programs, 10903 New Hampshire Ave,WO32 5271, Silver Spring, MD 20993 USA. EM katherine.needleman@fda.hhs.gov FU US FDA, Office of Orphan Products Development FX This research was supported by the US FDA, Office of Orphan Products Development. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. NR 13 TC 0 Z9 1 U1 1 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 2167-8707 J9 EXPERT OPIN ORPHAN D JI Exp. Opin. Orphan Drugs PD AUG PY 2014 VL 2 IS 8 BP 807 EP 815 DI 10.1517/21678707.2014.923305 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AN2TL UT WOS:000340438100006 ER PT J AU Dechet, AM Herman, KM Parker, CC Taormina, P Johanson, J Tauxe, RV Mahon, BE AF Dechet, Amy M. Herman, Karen M. Parker, Cary Chen Taormina, Peter Johanson, Joy Tauxe, Robert V. Mahon, Barbara E. TI Outbreaks Caused by Sprouts, United States, 1998-2010: Lessons Learned and Solutions Needed SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article ID ESCHERICHIA-COLI O157-H7; MUNG BEAN-SEEDS; HIGH HYDROSTATIC-PRESSURE; CONTAMINATED ALFALFA SEEDS; ACIDIFIED SODIUM-CHLORITE; CHEMICAL TREATMENTS; SALMONELLA-TYPHIMURIUM; LISTERIA-MONOCYTOGENES; ELIMINATING SALMONELLA; FOODBORNE PATHOGENS AB After a series of outbreaks associated with sprouts in the mid-1990s, the U. S. Food and Drug Administration (FDA) published guidelines in 1999 for sprouts producers to reduce the risk of contamination. The recommendations included treating seeds with an antimicrobial agent such as calcium hypochlorite solution and testing spent irrigation water for pathogens. From 1998 through 2010, 33 outbreaks from seed and bean sprouts were documented in the United States, affecting 1330 reported persons. Twenty-eight outbreaks were caused by Salmonella, four by Shiga toxin-producing Escherichia coli, and one by Listeria. In 15 of the 18 outbreaks with information available, growers had not followed key FDA guidelines. In three outbreaks, however, the implicated sprouts were produced by firms that appeared to have implemented key FDA guidelines. Although seed chlorination, if consistently applied, reduces pathogen burden on sprouts, it does not eliminate the risk of human infection. Further seed and sprouts disinfection technologies, some recently developed, will be needed to enhance sprouts safety and reduce human disease. Improved seed production practices could also decrease pathogen burden but, because seeds are a globally distributed commodity, will require international cooperation. C1 [Dechet, Amy M.] Portland Providence Med Ctr, Portland, OR 97213 USA. [Herman, Karen M.; Mahon, Barbara E.] Ctr Dis Control & Prevent, Enter Dis Epidemiol Branch, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA USA. [Parker, Cary Chen] US FDA, Off Analyt & Outreach, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Taormina, Peter] Univ Georgia, Ctr Food Safety, Dept Food Sci & Technol, Griffin, GA USA. [Johanson, Joy] US FDA, Off Food Safety, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Tauxe, Robert V.] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA USA. RP Dechet, AM (reprint author), Portland Providence Med Ctr, 5050 NE Hoyt St,Suite 540, Portland, OR 97213 USA. EM adechet@gmail.com NR 70 TC 12 Z9 12 U1 1 U2 27 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1535-3141 EI 1556-7125 J9 FOODBORNE PATHOG DIS JI Foodborne Pathog. Dis. PD AUG PY 2014 VL 11 IS 8 BP 635 EP 644 DI 10.1089/fpd.2013.1705 PG 10 WC Food Science & Technology SC Food Science & Technology GA AN4AX UT WOS:000340531100008 PM 25076040 ER PT J AU Williams, G Bickmann, D Schiewe, J Hauviller, C Blatchford, C Doub, W Mitchell, J Nichols, S Suman, J Weda, M AF Williams, G. Bickmann, D. Schiewe, J. Hauviller, C. Blatchford, C. Doub, W. Mitchell, J. Nichols, S. Suman, J. Weda, M. CA EPAG TI TOWARDS STANDARDIZING METHODOLOGY FOR QUANTIFYING THE FINE PARTICLE MASS (DOSE) OF ACTIVE PHARMACEUTICAL INGREDIENT (API) FROM NASAL PRODUCTS (NPS) SO JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY LA English DT Meeting Abstract C1 [Williams, G.] Aptar Pharma, F-27100 Le Vaudreuil, France. [Bickmann, D.; Schiewe, J.; Hauviller, C.] Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany. [Blatchford, C.] 3M Hlth Care, Loughborough, Leics, England. [Doub, W.] FDA CDER, St Louis, MO USA. [Mitchell, J.] OIP Consultant, London, ON, Canada. [Nichols, S.] OINDP Consultant, Rugby, England. [Suman, J.] Next Breath LLC, Baltimore, MD USA. [Weda, M.] RIVM, Bilthoven, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1941-2711 EI 1941-2703 J9 J AEROSOL MED PULM D JI J. Aerosol Med. Pulm. Drug Deliv. PD AUG PY 2014 VL 27 IS 4 MA 38 BP A14 EP A14 PG 1 WC Respiratory System SC Respiratory System GA AN3WW UT WOS:000340520400039 ER PT J AU Dearfield, KL Hoelzer, K Kause, JR AF Dearfield, Kerry L. Hoelzer, Karin Kause, Janell R. TI Review of Various Approaches for Assessing Public Health Risks in Regulatory Decision Making: Choosing the Right Approach for the Problem SO JOURNAL OF FOOD PROTECTION LA English DT Article ID UNITED-STATES; FOOD SAFETY; PRODUCTS; EXPOSURE; ILLNESS; TRADE AB Stakeholders in the public health risk analysis community can possess differing opinions about what is meant by "conduct a risk assessment." In reality, there is no one-size-fits-all risk assessment that can address all public health issues, problems, and regulatory needs. Although several international and national organizations (e.g., Codex Alimentarius Commission, Office International des Epizooties, Food and Agricultural Organization, World Health Organization, National Research Council, and European Food Safety Authority) have addressed this issue, confusion remains. The type and complexity of a risk assessment must reflect the risk management needs to appropriately inform a regulatory or nonregulatory decision, i.e., a risk assessment is ideally "fit for purpose" and directly applicable to risk management issues of concern. Frequently however, there is a lack of understanding by those not completely familiar with risk assessment regarding the specific utility of different approaches for assessing public health risks. This unfamiliarity can unduly hamper the acceptance of risk assessment results by risk managers and may reduce the usefulness of such results for guiding public health policies, practices, and operations. Differences in interpretation of risk assessment terminology further complicate effective communication among risk assessors, risk managers, and stakeholders. This article provides an overview of the types of risk assessments commonly conducted, with examples primarily from the food and agricultural sectors, and a discussion of the utility and limitations of these specific approaches for assessing public health risks. Clarification of the risk management issues and corresponding risk assessment design needs during the formative stages of the risk analysis process is a key step for ensuring that the most appropriate assessment of risk is developed and used to guide risk management decisions. C1 [Dearfield, Kerry L.; Kause, Janell R.] US Food Safety & Inspect Serv, USDA, Off Publ Hlth Sci, Washington, DC 20250 USA. [Hoelzer, Karin] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Dearfield, KL (reprint author), US Food Safety & Inspect Serv, USDA, Off Publ Hlth Sci, Washington, DC 20250 USA. EM kerry.dearfield@fsis.usda.gov FU Center for Food Safety and Applied Nutrition FX This work was supported in part by appointments to the Research Participation Program at the Center for Food Safety and Applied Nutrition administered by 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 79 TC 4 Z9 4 U1 1 U2 16 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 2014 VL 77 IS 8 BP 1428 EP 1440 DI 10.4315/0362-028X.JFP-14-046 PG 13 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA AM6YR UT WOS:000340012400025 PM 25198609 ER PT J AU Chen, Q Boulanger, A Hinton, DM Stibitz, S AF Chen, Qing Boulanger, Alice Hinton, Deborah M. Stibitz, Scott TI Strong inhibition of fimbrial 3 subunit gene transcription by a novel downstream repressive element in Bordetella pertussis SO MOLECULAR MICROBIOLOGY LA English DT Article ID RESPONSE REGULATOR BVGA; FILAMENTOUS HEMAGGLUTININ; VIRULENCE FACTORS; FHA PROMOTER; ACTIVATION; EXPRESSION; REGION; MUTAGENESIS; MECHANISM; SEQUENCES AB The Bvg-regulated promoters for the fimbrial subunit genes fim2 and fim3 of Bordetella pertussis behave differently from each other both in vivo and in vitro. In vivo P-fim2 is significantly stronger than P-fim3, even though predictions based on the DNA sequences of BvgA-binding motifs and core promoter elements would indicate the opposite. In vitro P-fim3 demonstrated robust BvgA similar to P-dependent transcriptional activation, while none was seen with P-fim2. This apparent contradiction was investigated further. By swapping sequence elements we created a number of hybrid promoters and assayed their strength in vivo. We found that, while P-fim3 promoter elements upstream of the +1 transcriptional start site do indeed direct Bvg-activated transcription more efficiently than those of P-fim2, the overall promoter strength of P-fim3 in vivo is reduced due to sequences downstream of +1 that inhibit transcription more than 250-fold. This element, the DRE (downstream repressive element), was mapped to the 15 bp immediately downstream of the P-fim3 +1. Placing the DRE in different promoter contexts indicated that its activity was not specific to fim promoters, or even to Bvg-regulated promoters. However it does appear to be specific to Bordetella species in that it did not function in Escherichia coli. C1 [Chen, Qing; Stibitz, Scott] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Boulanger, Alice; Hinton, Deborah M.] NIDDK, Gene Express & Regulat Sect, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. RP Chen, Q (reprint author), US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM qing.chen@fda.hhs.gov FU Intramural NIH HHS [ZIA DK057813-07] NR 33 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD AUG PY 2014 VL 93 IS 4 BP 748 EP 758 DI 10.1111/mmi.12690 PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA AN4LF UT WOS:000340558600013 PM 24963821 ER PT J AU Li, Y Bhalli, JA Ding, W Yan, J Pearce, MG Sadiq, R Cunningham, CK Jones, MY Monroe, WA Howard, PC Zhou, T Chen, T AF Li, Yan Bhalli, Javed A. Ding, Wei Yan, Jian Pearce, Mason G. Sadiq, Rakhshinda Cunningham, Candice K. Jones, M. Yvonne Monroe, William A. Howard, Paul C. Zhou, Tong Chen, Tao TI Cytotoxicity and genotoxicity assessment of silver nanoparticles in mouse SO NANOTOXICOLOGY LA English DT Article DE Clastogenicity; in vivo comet assay; in vivo micronucleus assay; in vivo pig-a gene mutation assay; mutagenicity; silver nanoparticles ID SPRAGUE-DAWLEY RATS; IN-VIVO; MICRONUCLEATED ERYTHROCYTES; OXIDATIVE STRESS; FLOW-CYTOMETRY; CELLS; TOXICITY; ASSAY; MICE; NANOMATERIALS AB Silver nanoparticles (AgNPs) are among the most commercially used nanomaterials and their toxicity and genotoxicity are controversial. Although many in vitro studies have been conducted to evaluate the genotoxicity of AgNPs, in vivo genotoxicity studies on the nanomaterials are limited. Given the unique physicochemical properties and complex pharmacokinetics behavior of nanoparticles (NPs), in vivo genotoxicity assessment of AgNPs is badly needed. In this study, the clastogenicity and mutagenicity of AgNPs with different sizes and coatings were evaluated using mouse micronucleus (MN) assay, Pig-a assay and Comet assay. Five 7-week-old male B6C3F1 mice per group were treated with 5 nm polyvinylpyrrolidone (PVP)-coated AgNPs at a single dose of 0.5, 1.0, 2.5, 5.0, 10.0 or 20.0 mg/kg body weight (bw) via intravenous injection for both the MN and Pig-a assays; or with 15-100 nm PVP- or 10-80 nm silicon-coated AgNPs at a single or 3-day repeated dose of 25.0 mg/kg bw for the MN assay and Comet assay in mouse liver. Inductively coupled plasma mass spectrometry (ICP-MS) and transmission electron microscopy (TEM) analyses indicated that AgNPs reached the testing tissues (bone marrow for the MN and Pig-a assays and liver for the Comet assay). Although there was a reduction of reticulocytes in the PVP-coated AgNPs-treated animals, indicating cytotoxicity of the AgNPs, none of the treatments resulted in a significant increase of either mutant frequencies in the Pig-a gene or the percent of micronucleated reticulocyte over the concurrent controls. However, both the PVP- and silicon-coated AgNPs induced oxidative DNA damage in mouse liver. These results demonstrate that the AgNPs can reach mouse bone marrow and liver, and generate cytotoxicity to the reticulocytes and oxidative DNA damage to the liver. C1 [Li, Yan; Bhalli, Javed A.; Ding, Wei; Yan, Jian; Pearce, Mason G.; Chen, Tao] US FDA, Div Genet & Mol Toxicol, NCTR, Jefferson, AR 72079 USA. [Sadiq, Rakhshinda] NIBGE, Faisalabad, Pakistan. [Cunningham, Candice K.; Jones, M. Yvonne; Monroe, William A.; Howard, Paul C.] US FDA, Nanotechnol Core Facil, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Zhou, Tong] US FDA, Ctr Vet Med, Rockville, MD 20857 USA. RP Chen, T (reprint author), US FDA, Div Genet & Mol Toxicol, NCTR, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM tao.chen@fda.hhs.gov RI Ding, Wei/L-1503-2014 FU U.S. Department of Energy; U.S. FDA FX The authors declare that they have no competing interests. YL was supported by the appointment to the Postgraduate Research Program 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. NR 44 TC 23 Z9 27 U1 1 U2 32 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1743-5390 EI 1743-5404 J9 NANOTOXICOLOGY JI Nanotoxicology PD AUG PY 2014 VL 8 SU 1 BP 36 EP 45 DI 10.3109/17435390.2013.855827 PG 10 WC Nanoscience & Nanotechnology; Toxicology SC Science & Technology - Other Topics; Toxicology GA AN3YH UT WOS:000340524300004 PM 24266757 ER PT J AU Wharton, GT Murphy, MD Avant, D Goldsmith, JV Chai, G Rodriguez, WJ Eisenstein, EL AF Wharton, Gerold T. Murphy, M. Dianne Avant, Debbie Goldsmith, John V. Chai, Grace Rodriguez, William J. Eisenstein, Eric L. TI Impact of Pediatric Exclusivity on Drug Labeling and Demonstrations of Efficacy SO PEDIATRICS LA English DT Article DE FDA; pediatric exclusivity; blockbuster drug; labeling changes; negative studies; clinical trials; moiety; drug safety; efficacy; cancer/oncology; gastrointestinal; drug sales ID CANCER AB BACKGROUND: Besides vaccines and otitis media medicines, most products prescribed for children have not been studied in the pediatric population. To remedy this, Congress enacted legislation in 1997, known as pediatric exclusivity (PE), which provides 6 months of additional market protection to drug sponsors in exchange for studying their products in children. METHODS: We reviewed requests for pediatric studies and subsequent labeling for drugs granted PE from 1998 through 2012. Regression analysis estimates the probability of demonstrating efficacy in PE trials. Variables include therapeutic group, year of exclusivity, product sales, initiation process, and small disease population. RESULTS: From 1998 through 2012, the US Food and Drug Administration issued 401 pediatric study requests. For 189 drugs, studies were completed and granted exclusivity. A total of 173 drugs (92%) received new pediatric labeling, with 108 (57%) receiving a new or expanded pediatric indication. Three drugs had non-efficacy trials. Efficacy was not established for 78 drugs. Oncology, cardiovascular, and endocrine drugs were less likely to demonstrate efficacy (P < .01) compared with gastrointestinal and pain/anesthesia drugs. Drugs studied later in the program were less likely to demonstrate efficacy (P < .05). Sales, initiation process, and small disease population were not significant predictors. CONCLUSIONS: Most drugs (173; 92%) granted exclusivity added pediatric information to their labeling as a result of PE, with 108 (57%) receiving a new or expanded pediatric indication. Therapeutic area and year of exclusivity influenced the likelihood of obtaining a pediatric indication. Positive and negative outcomes continue to inform the construct of future pediatric trials. C1 [Wharton, Gerold T.; Murphy, M. Dianne; Avant, Debbie; Rodriguez, William J.] US FDA, Off Pediat Therapeut, Off Commissioner, Silver Spring, MD USA. [Goldsmith, John V.] US FDA, Off Policy & Planning, Off Commissioner, Silver Spring, MD USA. [Chai, Grace] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Chai, Grace] US PHS, Durham, NC USA. [Eisenstein, Eric L.] Duke Univ, Duke Clin Res Inst, Durham, NC USA. RP Wharton, GT (reprint author), 10903 New Hampshire Ave,Bldg 32,Room 5159, Silver Spring, MD 20993 USA. EM gerold.wharton@fda.hhs.gov FU Medtronic Endovascular FX Dr Eisenstein reported receiving research funding from Medtronic Endovascular; the other authors have indicated they have no financial relationships relevant to this article to disclose. NR 13 TC 10 Z9 12 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 AUG PY 2014 VL 134 IS 2 BP E512 EP E518 DI 10.1542/peds.2013-2987 PG 7 WC Pediatrics SC Pediatrics GA AN0HS UT WOS:000340266000024 PM 25022732 ER PT J AU Maro, JC Brown, JS Dal Pan, GJ Kulldorff, M AF Maro, Judith C. Brown, Jeffrey S. Dal Pan, Gerald J. Kulldorff, Martin TI Minimizing signal detection time in postmarket sequential analysis: balancing positive predictive value and sensitivity SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE adverse drug event; bias (epidemiology); outcome measurement error; pharmacovigilance; postmarketing product surveillance; pharmacoepidemiology ID VACCINE SAFETY DATALINK; IMMUNE THROMBOCYTOPENIC PURPURA; MINI-SENTINEL PROGRAM; HEALTH-CARE DATA; ADVERSE EVENTS; NONDIFFERENTIAL MISCLASSIFICATION; DISEASE MISCLASSIFICATION; ACTIVE SURVEILLANCE; RELATIVE RISK; DRUG AB Purpose Outcome misclassification in retrospective epidemiologic analyses has been well-studied, but little is known about such misclassification with respect to sequential statistical analysis during surveillance of medical product-associated risks, a planned capability of the US Food and Drug Administration's Sentinel System. Methods Using a vaccine example, we model and simulate sequential database surveillance in an observational data network using a variety of outcome detection algorithms. We consider how these algorithms, as characterized by sensitivity and positive predictive value, impact the length of surveillance and timeliness of safety signal detection. We show investigators/users of these networks how they can perform preparatory study design calculations that consider outcome misclassification in sequential database surveillance. Results Non-differential outcome misclassification generates longer surveillance times and less timely safety signal detection as compared with the case of no misclassification. Inclusive algorithms characterized by high sensitivity but low positive predictive value outperform more narrow algorithms when detecting rare outcomes. This decision calculus may change considerably if medical chart validation procedures were required. Conclusions These findings raise important questions regarding the design of observational data networks used for pharmacovigilance. Specifically, there are tradeoffs involved when choosing to populate such networks with component databases that are large as compared with smaller integrated delivery system databases that can more easily access laboratory or clinical data and perform medical chart validation. Copyright (C) 2014 John Wiley & Sons, Ltd. C1 [Maro, Judith C.; Brown, Jeffrey S.; Kulldorff, Martin] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA 02215 USA. [Maro, Judith C.; Brown, Jeffrey S.; Kulldorff, Martin] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Dal Pan, Gerald J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Maro, JC (reprint author), Harvard Univ, Sch Med, Dept Populat Med, Harvard Pilgrim Hlth Care Inst, 133 Brookline Ave,6th Floor, Boston, MA 02215 USA. EM jmaro@mit.edu OI Kulldorff, Martin/0000-0002-5284-2993 FU US Department of Energy; US Food and Drug Administration; Mini-Sentinel Contract - USFDA through the Department of Health and Human Services [HHSF223200910006I] FX JCM was supported in part by an appointment to the Research Participation Program at the Center for Drug 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.; JSB and MK are supported in part by the Mini-Sentinel Contract, which is funded by the USFDA through the Department of Health and Human Services contract number HHSF223200910006I. NR 45 TC 2 Z9 2 U1 1 U2 3 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 2014 VL 23 IS 8 BP 839 EP 848 DI 10.1002/pds.3618 PG 10 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AN1PG UT WOS:000340355200008 PM 24700557 ER PT J AU Winterstein, AG Kubilis, P Bird, S Cooper-DeHoff, RM Nichols, GA Delaney, JA AF Winterstein, Almut G. Kubilis, Paul Bird, Steve Cooper-DeHoff, Rhonda M. Nichols, Greg A. Delaney, Joseph A. TI Misclassification in assessment of diabetogenic risk using electronic health records SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE measurement bias; diabetogenic risk; drug safety; electronic health records; antihypertensives; antipsychotics; statins; pharmacoepidemiology ID ATYPICAL ANTIPSYCHOTIC USE; ONSET DIABETES-MELLITUS; BIPOLAR DISORDER; CLINICAL-TRIALS; OLDER-ADULTS; SCHIZOPHRENIA; METAANALYSIS; ASSOCIATION; DRUGS; HYPERTENSION AB Purpose Suspected diabetogenic effects or drug indication may increase testing for diabetes mellitus (DM), resulting in measurement bias when evaluating diabetogenic drug effects. We sought to evaluate the validity of electronic health record data in determining DM risk. Methods We used time-dependent Cox proportional hazard models within a retrospective cohort design to assess associations between use of antihypertensives, statins, atypical antipsychotics, and antidepressants, and two endpoints: (i) DM onset defined as fasting blood glucose (BG) >= 126 mg/dl, random BG >= 200 mg/dl, HbA1c >= 7.0%, or antidiabetic drug initiation; and (ii) first negative DM test. We used Poisson regression to assess the influence of these drugs on DM testing rates. Patients aged 35-64 years enrolled in Kaiser Permanente Northwest between 1997 and 2010 entered the cohort at the first negative BG test after >= 6 months without manifest DM. Results All drug classes showed significant associations not only with DM onset but also with first negative BG test and with DM testing rates. Antipsychotics had the greatest diabetogenic risk (adjusted hazard ratio [HR] = 1.73 [1.44-2.08]), the greatest propensity for a first negative test (adjusted HR = 1.87 [1.74-2.01]), and the highest testing rate (adjusted rate ratio = 1.76 [1.72-1.81]. Although renin-angiotensin system blockers and calcium channel blockers have shown no diabetogenic risk in clinical trials, both were associated with DM (HR= 1.19 [1.12-1.26] and 1.27 [1.17-1.38]), a negative glucose test (1.38 [1.35-1.41] and 1.24 [1.20-1.28]), and increased testing rates (rate ratio = 1.26 [1.24-1.27] and 1.27 [1.25-1.28]). Conclusion Caution should be used when diabetogenic risk is evaluated using data that rely on DM testing in general practice. Copyright (C) 2014 John Wiley & Sons, Ltd. C1 [Winterstein, Almut G.; Kubilis, Paul] Univ Florida, Coll Pharm, Gainesville, FL 32610 USA. [Winterstein, Almut G.] Univ Florida, Coll Publ Hlth, Gainesville, FL 32610 USA. [Winterstein, Almut G.] Univ Florida, Coll Hlth Profess & Med, Gainesville, FL 32610 USA. [Bird, Steve] US FDA, Dept Hlth & Human Serv, Ctr Drug Evaluat & Res, Off Surveillance & Epidemiol,Dept Epidemiol, Silver Spring, MD USA. [Cooper-DeHoff, Rhonda M.] Univ Florida, Coll Pharm, Gainesville, FL 32610 USA. [Cooper-DeHoff, Rhonda M.] Univ Florida, Coll Med, Gainesville, FL 32610 USA. [Nichols, Greg A.] Kaiser Permanent Northwest, Ctr Hlth Res, Portland, OR USA. [Delaney, Joseph A.] Univ Washington, Seattle, WA 98195 USA. RP Winterstein, AG (reprint author), Univ Florida, Ctr Dr 1225, Gainesville, FL 32610 USA. EM Almut@ufl.edu FU Bristol Myers Squibb; Novartis; AstraZeneca; Centers for Medicaid and Medicaid Services; Agency for Healthcare Research and Quality FX Dr. Nichol reports that he has received funding from Bristol Myers Squibb, Novartis, and AstraZeneca. Dr. Winterstein was funded by the Centers for Medicaid and Medicaid Services and the Agency for Healthcare Research and Quality during the study period. None of the authors had any conflict of interest. The study represents the opinions of the authors and not those of the Food and Drug Administration. NR 38 TC 1 Z9 1 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 2014 VL 23 IS 8 BP 875 EP 881 DI 10.1002/pds.3656 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AN1PG UT WOS:000340355200012 PM 24923707 ER PT J AU Hess, CN Roe, MT Gibson, CM Temple, RJ Pencina, MJ Zarin, DA Anstrom, KJ Alexander, JH Sherman, RE Fiedorek, FT Mahaffey, KW Lee, KL Chow, SC Armstrong, PW Califf, RM AF Hess, Connie N. Roe, Matthew T. Gibson, C. Michael Temple, Robert J. Pencina, Michael J. Zarin, Deborah A. Anstrom, Kevin J. Alexander, John H. Sherman, Rachel E. Fiedorek, Fred T. Mahaffey, Kenneth W. Lee, Kerry L. Chow, Shein-Chung Armstrong, Paul W. Califf, Robert M. TI Independent data monitoring committees: Preparing a path for the future SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE CORONARY SYNDROME; CLINICALTRIALS.GOV; TRIALS AB Independent data monitoring committees (IDMCs) were introduced to monitor patient safety and study conduct in randomized clinical trials (RCTs), but certain challenges regarding the utilization of IDMCs have developed. First, the roles and responsibilities of IDMCs are expanding, perhaps due to increasing trial complexity and heterogeneity regarding medical, ethical, legal, regulatory, and financial issues. Second, no standard for IDMC operating procedures exists, and there is uncertainty about who should determine standards and whether standards should vary with trial size and design. Third, considerable variability in communication pathways exist across IDMC interfaces with regulatory agencies, academic coordinating centers, and sponsors. Finally, there has been a substantial increase in the number of RCTs using IDMCs, yet there is no set of qualifications to help guide the training and development of the next generation of IDMC members. Recently, an expert panel of representatives from government, industry, and academia assembled at the Duke Clinical Research Institute to address these challenges and to develop recommendations for the future utilization of IDMCs in RCTs. C1 [Hess, Connie N.; Roe, Matthew T.; Pencina, Michael J.; Alexander, John H.; Lee, Kerry L.] Duke Clin Res Inst, Durham, NC USA. [Gibson, C. Michael; Anstrom, Kevin J.] Beth Israel Deaconess Med Ctr, PERFUSE Study Grp, Boston, MA 02215 USA. [Gibson, C. Michael; Anstrom, Kevin J.] Harvard Univ, Sch Med, Boston, MA USA. [Temple, Robert J.; Sherman, Rachel E.] US FDA, Silver Spring, MD USA. [Zarin, Deborah A.] NIH, Bethesda, MD 20892 USA. [Fiedorek, Fred T.] Bristol Myers Squibb Co, New York, NY 10154 USA. [Mahaffey, Kenneth W.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Chow, Shein-Chung; Califf, Robert M.] Duke Univ, Sch Med, Durham, NC 27705 USA. [Armstrong, Paul W.] Univ Alberta, Edmonton, AB, Canada. RP Roe, MT (reprint author), Duke Univ, Med Ctr, 2400 Pratt St,Rm 7035, Durham, NC 27705 USA. EM matthew.roe@duke.edu FU National Institutes of Health (NIH) [5T32HL069749-09]; Bristol-Myers Squibb (New York, NY); AstraZeneca (Wilmington, DE); Pfizer (New York, NY) FX Connie N. Hess received support from the National Institutes of Health (NIH) (5T32HL069749-09). Funding sources had no role in the design, conduct, or reporting of the study. The independent data monitoring committee (IDMC) think tank meeting was supported by unrestricted grants to Duke University from Bristol-Myers Squibb (New York, NY), AstraZeneca (Wilmington, DE), and Pfizer (New York, NY). NR 16 TC 3 Z9 3 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD AUG PY 2014 VL 168 IS 2 BP 135 EP + DI 10.1016/j.ahj.2014.05.003 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM9NG UT WOS:000340207700006 PM 25066551 ER PT J AU Greene, SJ Shah, AN Butler, J Ambrosy, AP Anker, SD Chioncel, O Collins, SP Dinh, W Dunnmon, PM Fonarow, GC Lam, CSP Mentz, RJ Pieske, B Roessig, L Rosano, GMC Sato, N Vaduganathan, M Gheorghiade, M AF Greene, Stephen J. Shah, Ami N. Butler, Javed Ambrosy, Andrew P. Anker, Stefan D. Chioncel, Ovidiu Collins, Sean P. Dinh, Wilfried Dunnmon, Preston M. Fonarow, Gregg C. Lam, Carolyn S. P. Mentz, Robert J. Pieske, Burkert Roessig, Lothar Rosano, Giuseppe M. C. Sato, Naoki Vaduganathan, Muthiah Gheorghiade, Mihai TI Designing effective drug and device development programs for hospitalized heart failure: A proposal for pretrial registries SO AMERICAN HEART JOURNAL LA English DT Article ID PERCUTANEOUS CORONARY INTERVENTION; EUROBSERVATIONAL RESEARCH-PROGRAM; VENTRICULAR EJECTION FRACTION; ESC-HF PILOT; MYOCARDIAL-INFARCTION; CLINICAL-TRIALS; PATIENT CHARACTERISTICS; THROMBUS ASPIRATION; UNITED-STATES; RISK-FACTORS AB Recent international phase III clinical trials of novel therapies for hospitalized heart failure (HHF) have failed to improve the unacceptably high postdischarge event rate. These large studies have demonstrated notable geographic and site-specific variation in patient profiles and enrollment. Possible contributors to the lack of success in HHF outcome trials include challenges in selecting clinical sites capable of (1) providing adequate numbers of appropriately selected patients and (2) properly executing the study protocol. We propose a "pretrial registry" as a novel tool for improving the efficiency and quality of international HHF trials by focusing on the selection and cultivation of high-quality sites. A pretrial registry may help assess a site's ability to achieve adequate enrollment of the target patient population, integrate protocol requirements into clinical workflow, and accomplish appropriate follow-up. Although such a process would be associated with additional upfront resource investment, this appropriation may be modest in comparison with the downstream costs associated with maintenance of poorly performing sites, failed clinical trials, and the global health and economic burden of HHF. This review is based on discussions between scientists, clinical trialists, and regulatory representatives regarding methods for improving international HHF trials that took place at the United States Food and Drug Administration on January 12th, 2012. C1 [Greene, Stephen J.; Shah, Ami N.; Gheorghiade, Mihai] Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. [Butler, Javed] Emory Univ, Div Cardiol, Atlanta, GA 30322 USA. [Ambrosy, Andrew P.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Anker, Stefan D.] Univ Med Ctr Gottingen, Dept Innovat Clin Trials, Gottingen, Germany. [Chioncel, Ovidiu] Univ Med & Pharm Carol Davila, Inst Emergency Cardiovasc Dis Prof CC Iliescu, Bucharest, Romania. [Collins, Sean P.] Vanderbilt Univ, Dept Emergency Med, Nashville, TN 37235 USA. [Dinh, Wilfried] Witten Univ, Dept Cardiol, Witten, Germany. [Dinh, Wilfried] Bayer Pharma AG, Clin Sci, Global Drug Discovery, Berlin, Germany. [Dunnmon, Preston M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Fonarow, Gregg C.] Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. [Lam, Carolyn S. P.] Natl Univ Hlth Syst, Singapore, Singapore. [Mentz, Robert J.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Pieske, Burkert] Dept Cardiol, Graz, Austria. [Roessig, Lothar] Bayer Pharma AG, Global Clin Dev, Berlin, Germany. [Rosano, Giuseppe M. C.] IRCC San Raffaele, Div Cardiol, Rome, Italy. [Sato, Naoki] Nippon Med Sch, Musashi Kosugi Hosp, Tokyo, Kanagawa, Japan. [Vaduganathan, Muthiah] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Gheorghiade, M (reprint author), Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, 201 E Huron St,Galter 3-150, Chicago, IL 60611 USA. EM m-gheorghiade@northwestern.edu OI chioncel, ovidiu/0000-0002-3197-3628 FU Vifor Pharma; Bayer; Novartis; Abbott; Servier; Vifor; NIH/NHLBI; Medtronic; Radiometer; Cardiorentis; NHLBI; AHRQ; Gambro FX S.D.A. has received honoraria from Vifor Pharma, Bayer, CardioMems, ThermoFisher, St Jude Medical, Novartis, and Cardiorentis and received research support from Vifor Pharma, Bayer, and Novartis; O.C. has received research support from Abbott, Servier, and Vifor and served as a consultant for Philips, Novartis, and Janssen; S.P.C. has received research support from NIH/NHLBI, Medtronic, Radiometer, Cardiorentis, and Novartis and served as a consultant for Medtronic, Trevena, Novartis, Janssen, and Radiometer; W.D. and L.R. are employees of Bayer Pharma AG; G.C.F. has received research support from NHLBI, AHRQ, and Gambro and has served as a consultant for Novartis, Medtronic, Bayer, Johnson & Johnson, and Medicines Company; N.S. has received honoraria from Otsuka Pharmacueticals, Daiichi-Sankyo, Novartis Pharma, Eisai, Bayer, Boehringer-Ingelheim, Bristol-Myers, Philips Respironics, Ono Pharma, Kyowa-Hakko- Kirin, and Astellas and served as a consultant for Novartis and Bayer; B.P. has received modest speaker honoraria or served as a steering committee member for Bayer Healthcare, Novartis, Stealth Peptides, Boehringer Ingelheim, Bristol Myers-Squibb, Daiichio Sankyo Medtronic, and Biotronik; M.G. has served as a consultant or received honoraria from Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd, CorThera, Cytokinetics, CytoPherx, Inc, DebioPharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, INC, Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Parmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda Pharmaceuticals North America, Inc, and Trevena Therapeutics. All other authors have no relevant conflicts to declare. NR 55 TC 15 Z9 15 U1 3 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD AUG PY 2014 VL 168 IS 2 BP 142 EP 149 DI 10.1016/j.ahj.2014.05.009 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM9NG UT WOS:000340207700007 PM 25066552 ER PT J AU Lee, HZ Miller, BW Kwitkowski, VE Ricci, S DelValle, P Saber, H Grillo, J Bullock, J Florian, J Mehrotra, N Ko, CW Nie, L Shapiro, M Tolnay, M Kane, RC Kaminskas, E Justice, R Farrell, AT Pazdur, R AF Lee, Hyon-Zu Miller, Barry W. Kwitkowski, Virginia E. Ricci, Stacey DelValle, Pedro Saber, Haleh Grillo, Joseph Bullock, Julie Florian, Jeffry Mehrotra, Nitin Ko, Chia-Wen Nie, Lei Shapiro, Marjorie Tolnay, Mate Kane, Robert C. Kaminskas, Edvardas Justice, Robert Farrell, Ann T. Pazdur, Richard TI U.S. Food and Drug Administration Approval: Obinutuzumab in Combination with Chlorambucil for the Treatment of Previously Untreated Chronic Lymphocytic Leukemia SO CLINICAL CANCER RESEARCH LA English DT Article ID STATISTICS AB On November 1, 2013, the U. S. Food and Drug Administration (FDA) approved obinutuzumab (GAZYVA; Genentech, Inc.), a CD20-directed cytolytic antibody, for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In stage 1 of the trial supporting approval, patients with previously untreated CD20-positive CLL were randomly allocated (2: 2: 1) to obinutuzumab+chlorambucil (GClb, n = 238), rituximab+chlorambucil (RClb, n = 233), or chlorambucil alone (Clb, n = 118). The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR). Only the comparison of GClb to Clb was relevant to this approval and is described herein. A clinically meaningful and statistically significant improvement in PFS with medians of 23.0 and 11.1 months was observed in the GClb and Clb arms, respectively (HR, 0.16; 95% CI, 0.11-0.24; P < 0.0001, log-rank test). The ORRs were 75.9% and 32.1% in the GClb and Clb arms, respectively, and the complete response rates were 27.8% and 0.9% in the GClb and Clb arms, respectively. The most common adverse reactions (>= 10%) reported in the GClb arm were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Obinutuzumab was the first Breakthrough Therapy-designated drug to receive FDA approval. (C) 2014 AACR. C1 [Lee, Hyon-Zu; Miller, Barry W.; Kwitkowski, Virginia E.; Ricci, Stacey; DelValle, Pedro; Saber, Haleh; Kane, Robert C.; Kaminskas, Edvardas; Justice, Robert; Farrell, Ann T.; Pazdur, Richard] US FDA, Off Hematol & Oncol Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Grillo, Joseph; Bullock, Julie; Florian, Jeffry; Mehrotra, Nitin] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Ko, Chia-Wen; Nie, Lei] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Shapiro, Marjorie; Tolnay, Mate] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Lee, HZ (reprint author), US FDA, Div Hematol Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Hyon.Lee@fda.hhs.gov NR 11 TC 18 Z9 19 U1 2 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 1 PY 2014 VL 20 IS 15 BP 3902 EP 3907 DI 10.1158/1078-0432.CCR-14-0516 PG 6 WC Oncology SC Oncology GA AM9DF UT WOS:000340179500002 PM 24824310 ER PT J AU Anderson, K Joffe, M Kosorok, MR Troxel, A Kumm, E Whyte, J Lavori, PW Karnoub, M Russek-Cohen, E Ellenberg, S AF Anderson, Keaven Joffe, Marshall Kosorok, Michael R. Troxel, Andrea Kumm, Elizabeth Whyte, John Lavori, Philip W. Karnoub, Maha Russek-Cohen, Estelle Ellenberg, Susan TI University of Pennsylvania 6th annual conference on statistical issues in clinical trials: Dynamic treatment regimes (morning session) SO CLINICAL TRIALS LA English DT Editorial Material C1 [Joffe, Marshall; Troxel, Andrea; Ellenberg, Susan] Univ Penn, Philadelphia, PA 19104 USA. [Anderson, Keaven] Merck, Ludwigshafen, Germany. [Kosorok, Michael R.] Univ N Carolina, Chapel Hill, NC USA. [Kumm, Elizabeth] InVentiv Hlth Clin, Montreal, PQ, Canada. [Whyte, John] Moss Rehabil Res Inst, New York, NY USA. [Lavori, Philip W.] Stanford Sch Med, Stanford, CA USA. [Karnoub, Maha] Celgene, Summit, NJ USA. [Russek-Cohen, Estelle] Food & Drug Adm, Silver Spring, MD USA. RP Anderson, K (reprint author), Merck, Ludwigshafen, Germany. FU NCI NIH HHS [R13 CA132565] NR 4 TC 0 Z9 0 U1 0 U2 3 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 2014 VL 11 IS 4 BP 418 EP 425 DI 10.1177/1740774514538553 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AN0WX UT WOS:000340305800005 PM 25053776 ER PT J AU Chuang-Stein, C Follman, D Chappell, R French, B Russek-Cohen, E Chappell, RJ Collins, L Lynch, K Kidwell, KM Whyte, J Chakraborty, B Ellenberg, SS AF Chuang-Stein, Christy Follman, Dean Chappell, Rick French, Benjamin Russek-Cohen, Estelle Chappell, Richard J. Collins, Linda Lynch, Kevin Kidwell, Kelley M. Whyte, John Chakraborty, Bibhas Ellenberg, Susan S. TI University of Pennsylvania 6th annual conference on statistical issues in clinical trials: Dynamic treatment regimes (afternoon session) SO CLINICAL TRIALS LA English DT Editorial Material ID AGENTS; DESIGN C1 [French, Benjamin; Lynch, Kevin; Ellenberg, Susan S.] Univ Penn, Philadelphia, PA 19104 USA. [Chuang-Stein, Christy] Pfizer, New York, NY 10017 USA. [Follman, Dean] NIAID, Bethesda, MD USA. [Russek-Cohen, Estelle] FDA, Philadelphia, PA USA. [Chappell, Rick] Univ Wisconsin Madison, Madison, WI USA. [Collins, Linda] Penn State Univ, University Pk, PA 16802 USA. [Kidwell, Kelley M.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Whyte, John] Moss Rehabil Res Inst, Elkins Pk, PA USA. [Chakraborty, Bibhas] Columbia Univ, New York, NY 10027 USA. RP Chuang-Stein, C (reprint author), Pfizer, New York, NY 10017 USA. NR 8 TC 0 Z9 0 U1 0 U2 3 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 2014 VL 11 IS 4 BP 457 EP 466 DI 10.1177/1740774514538552 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AN0WX UT WOS:000340305800009 PM 25053777 ER PT J AU den Bakker, HC Allard, MW Bopp, D Brown, EW Fontana, J Iqbal, Z Kinney, A Limberger, R Musser, KA Shudt, M Strain, E Wiedmann, M Wolfgang, WJ AF den Bakker, Henk C. Allard, Marc W. Bopp, Dianna Brown, Eric W. Fontana, John Iqbal, Zamin Kinney, Aristea Limberger, Ronald Musser, Kimberlee A. Shudt, Matthew Strain, Errol Wiedmann, Martin Wolfgang, William J. TI Rapid Whole-Genome Sequencing for Surveillance of Salmonella enterica Serovar Enteritidis SO EMERGING INFECTIOUS DISEASES LA English DT Article ID FIELD GEL-ELECTROPHORESIS; TANDEM REPEAT ANALYSIS; OUTBREAK; STRAINS AB For Salmonella enterica serovar Enteritidis, 85% of isolates can be classified into 5 pulsed-field gel electrophoresis (PFGE) types. However, PFGE has limited discriminatory power for outbreak detection. Although whole-genome sequencing has been found to improve discrimination of outbreak clusters, whether this procedure can be used in real-time in a public health laboratory is not known. Therefore, we conducted a retrospective and prospective analysis. The retrospective study investigated isolates from 1 confirmed outbreak. Additional cases could be attributed to the outbreak strain on the basis of whole-genome data. The prospective study included 58 isolates obtained in 2012, including isolates from 1 epidemiologically defined outbreak. Whole-genome sequencing identified additional isolates that could be attributed to the outbreak, but which differed from the outbreak-associated PFGE type. Additional putative outbreak clusters were detected in the retrospective and prospective analyses. This study demonstrates the practicality of implementing this approach for outbreak surveillance in a state public health laboratory. C1 [den Bakker, Henk C.; Wiedmann, Martin] Cornell Univ, Ithaca, NY USA. [Allard, Marc W.; Brown, Eric W.; Strain, Errol] US FDA, College Pk, MD USA. [Bopp, Dianna; Limberger, Ronald; Musser, Kimberlee A.; Shudt, Matthew; Wolfgang, William J.] New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. [Fontana, John; Kinney, Aristea] Connecticut Dept Publ Hlth, Rocky Hill, CT USA. [Iqbal, Zamin] Wellcome Trust Ctr Human Genet, Oxford, England. RP Wolfgang, WJ (reprint author), New York State Dept Hlth, Bacteriol Lab, Wadsworth Ctr, Albany, NY 12208 USA. EM wwolfgan@wadsworth.org RI Wiedmann, Martin/A-9683-2008; den Bakker, Henk/A-8136-2010 OI Wiedmann, Martin/0000-0002-4168-5662; Wolfgang, William/0000-0003-1769-0215; den Bakker, Henk/0000-0002-4086-1580 FU Wadsworth Center Public Health Genomics Pilot Program; US Food and Drug Administration; US Department of Agriculture-Agriculture and Food Research Initiative [2010-34459-20756, 2009-34459-19750] FX The study was supported by the Wadsworth Center Public Health Genomics Pilot Program (W.J.W.), the US Food and Drug Administration (M.W.A.), and US Department of Agriculture-Agriculture and Food Research Initiative special research grants 2010-34459-20756 and 2009-34459-19750 (M.W.). NR 28 TC 41 Z9 43 U1 3 U2 19 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD AUG PY 2014 VL 20 IS 8 BP 1306 EP 1314 DI 10.3201/eid2008.131399 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AM4ZF UT WOS:000339864000005 PM 25062035 ER PT J AU Shi, Q Greenhaw, J Salminen, WF AF Shi, Qiang Greenhaw, James Salminen, William F. TI Inhibition of cytochrome P450s enhances (+)-usnic acid cytotoxicity in primary cultured rat hepatocytes SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE usnic acid; hepatotoxicity; rat; hepatocytes; cytochrome P450 ID INDUCED LIVER-INJURY; USNIC-ACID; INDUCED HEPATOTOXICITY; HEPG2 CELLS; WEIGHT-LOSS; METABOLISM; TOXICITY; MITOCHONDRIA; SUPPLEMENTS; MICROSOMES AB (+)-Usnic acid (UA) is consumed as a dietary supplement to promote weight loss; however, dietary supplements containing UA have been associated with clinical cases of severe liver injury. UA has been shown to be hepatotoxic in rats and is extensively metabolized by hepatic cytochrome P450s (CYPs); therefore, we examined if UA metabolism results in the formation of cytotoxic metabolites or if metabolism is a detoxification process in primary rat hepatocytes. When CYP activity was suppressed by the non-isoenzyme-selective inhibitor SKF-525A (20 mu M), or the CYP1A inhibitor alpha-naphthoflavone (10 mu M), or the CYP3A inhibitor ketoconazole (25 mu M), the cytotoxicity of UA at 3 similar to 6 mu M after 3 similar to 20 h of exposure was significantly increased as measured by lactate dehydrogenase (LDH) leakage. At 2 h after UA exposure, an earlier time point prior to LDH release, these CYP inhibitors potentiated UA-induced inhibition of cellular respiration as determined by the Clark type oxygen electrode. Cellular adenosine triphosphate (ATP) depletion by UA was also exacerbated by these CYP inhibitors. The CYP2B/2C inhibitor, ticlopidine at 20 mu M, showed no effects in parallel experiments. These data demonstrate that UA is bio-transformed to less toxic metabolites in rat primary hepatocytes, probably mainly by CYP1A and 3A, but not 2B/2C. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. C1 [Shi, Qiang; Greenhaw, James; Salminen, William F.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Salminen, William F.] PAREXEL Int, Sarasota, FL 34241 USA. RP Salminen, WF (reprint author), PAREXEL Int, 7321 Hemlock Lane, Sarasota, FL 34241 USA. EM Willie.Salminen@parexel.com NR 25 TC 6 Z9 6 U1 0 U2 11 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 AUG PY 2014 VL 34 IS 8 BP 835 EP 840 DI 10.1002/jat.2892 PG 6 WC Toxicology SC Toxicology GA AN0QQ UT WOS:000340289500003 PM 23686521 ER PT J AU Daiuto, ER Russo, VC Vietes, RL Fumes, JGF Vileigas, DF Smith, RE AF Daiuto, Erica R. Russo, Viviane Citadini Vietes, Rogerio L. Figeueiredo Fumes, Joana Giffoni Vileigas, Danielle Fernandes Smith, Robert E. TI STABILITY OF A PRODUCT PREPARED WITH "FUERTE" AVOCADOS EXPOSED TO GAMMA AND UV-C RADIATION SO JOURNAL OF FOOD PROCESSING AND PRESERVATION LA English DT Article ID HEAT-TREATMENT; FRESH FRUITS; STRAWBERRY; LIGHT; DECAY; LIFE; ROT AB Recently collected fruits were submitted to doses of 0.2, 0.4, 0.6 and 1.0 kGy of gamma irradiation and exposed to UV-C light for 5, 10, 15 and 20 min, made into guacamole and stored refrigerated (10 +/- 1C and 90 +/- 5% relative humidity). The ripened fruit was characterized by pH, titratable acidity and color. The product was also frozen in a domestic freezer at -18C and evaluated after 0, 30, 60 and 90 days. Guacamole prepared from fruits submitted to gamma radiation had lower values of polyphenol oxidase activity, titratable acidity and the more lipids when compared to other treatments. Gamma radiation did not change the sensorial quality of the product compared to the control. C1 [Daiuto, Erica R.; Russo, Viviane Citadini; Vietes, Rogerio L.; Figeueiredo Fumes, Joana Giffoni; Vileigas, Danielle Fernandes] UNESP Botucatu, Fac Agron Sci UNESP, Botucatu, SP, Brazil. [Smith, Robert E.] US FDA, Lenexa, KS 66224 USA. RP Smith, RE (reprint author), US FDA, 11510 W 80th St, Lenexa, KS 66224 USA. EM robert.smith@fda.hhs.gov FU CAPES (Federal Agency for the Support and Evaluation of Postgraduate Education) FX The authors gratefully acknowledge the CAPES (Federal Agency for the Support and Evaluation of Postgraduate Education) for their financial support. NR 36 TC 0 Z9 0 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-8892 EI 1745-4549 J9 J FOOD PROCESS PRES JI J. Food Process Preserv. PD AUG PY 2014 VL 38 IS 4 BP 1999 EP 2005 DI 10.1111/jfpp.12176 PG 7 WC Food Science & Technology SC Food Science & Technology GA AM8ZI UT WOS:000340168200067 ER PT J AU Russo, VC Daiuto, ER Vietes, RL Smith, RE AF Russo, Viviane C. Daiuto, Erica R. Vietes, Rogerio L. Smith, Robert E. TI POSTHARVEST PARAMETERS OF THE "FUERTE" AVOCADO WHEN REFRIGERATED IN DIFFERENT MODIFIED ATMOSPHERES SO JOURNAL OF FOOD PROCESSING AND PRESERVATION LA English DT Article ID PERSEA-AMERICANA; ANTIOXIDANT CAPACITY; FRUIT; POLYGALACTURONASE; PECTINMETHYLESTERASE; POLYSACCHARIDES; PECTINESTERASE; SOLUBILIZATION; PURIFICATION; CELLULASE AB The objective of this work was to evaluate the refrigerated "Fuerte" avocados stored in different modified active atmospheres. The fruits were wrapped in bags made of nylon plus polyethylene and submitted to the following atmospheres: (I) mixture of ambient gases (0.03% CO2 and 21.0% O-2); (II) 5.0% CO2 and 4.0% O-2; (III) 6.0% CO2 and 4.0% O-2; (IV) 7.0% CO2 and 4.0% O-2; and (V) 8.0% CO2 and 4.0% O-2. The bags containing the fruits were stored at 10C +/- 1 and 90 +/- 5% relative humidity for 25 days and were analyzed every 5 days for weight loss, respiratory activity, pH, firmness, titratable acidity, soluble solids, and activities of the enzymes pectin methylesterase and polygalacturonase. The atmosphere of 7.0% CO2 and 4.0% O-2 was the most effective in limiting the weight loss and the production of CO2. C1 [Russo, Viviane C.; Daiuto, Erica R.; Vietes, Rogerio L.] UNESP Botucatu, Fac Agron Sci UNESP, Botucatu, SP, Brazil. [Smith, Robert E.] US FDA, Lenexa, KS 66224 USA. RP Smith, RE (reprint author), US FDA, 11510 W 80th St, Lenexa, KS 66224 USA. EM robert.smith@fda.hhs.gov FU CAPES (Federal Agency for the Support and Evaluation of Postgraduate Education) FX The authors gratefully acknowledge the CAPES (Federal Agency for the Support and Evaluation of Postgraduate Education) for their financial support. NR 50 TC 0 Z9 0 U1 3 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-8892 EI 1745-4549 J9 J FOOD PROCESS PRES JI J. Food Process Preserv. PD AUG PY 2014 VL 38 IS 4 BP 2006 EP 2013 DI 10.1111/jfpp.12177 PG 8 WC Food Science & Technology SC Food Science & Technology GA AM8ZI UT WOS:000340168200068 ER PT J AU Rahman, Z Siddiqui, A Bykadi, S Khan, MA AF Rahman, Ziyaur Siddiqui, Akhtar Bykadi, Srikant Khan, Mansoor A. TI Near-Infrared and Fourier Transform Infrared Chemometric Methods for the Quantification of Crystalline Tacrolimus from Sustained-Release Amorphous Solid Dispersion SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE solid dispersion; crystallinity; amorphous; near-infrared spectroscopy; infrared spectroscopy; chemometrics; partial least squares; principal component analysis ID DRUG; FORMULATION; SPECTROSCOPY; MISCIBILITY; SOLUBILITY; PREDICTION; STATE AB The objective of the present research was to study the feasibility of using near-infrared (NIR) and Fourier transform infrared (FTIR)-based chemometric models in quantifying crystalline and amorphous tacrolimus from its sustained-release amorphous solid dispersion (ASD). ASD contained ethyl cellulose, hydroxypropyl methyl cellulose, and lactose monohydrate as carriers, and amorphous form of tacrolimus in it was confirmed by X-ray powder diffraction. Crystalline physical mixture was mixed with ASD in various proportions to prepare sample matrices containing 0%-100% amorphous/crystalline tacrolimus. NIR and FTIR of the samples were recorded, and data were mathematically pretreated using multiple scattering correction, standard normal variate, or Savitzky-Golay before multivariate analysis, partial-least-square regression (PLSR), and principle component regression (PCR). The PLSR models were more accurate than PCR for NIR and FTIR data as indicated by low value of root-mean-squared error of prediction, standard error of prediction and bias, and high value of R-2. Additionally, NIR data-based models were more accurate and precise than FTIR data models. In conclusion, NIR chemometric models provide simple and fast method to quantitate crystalline tacrolimus in the ASD formulation. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2376-2385, 2014 C1 [Rahman, Ziyaur; Siddiqui, Akhtar; Bykadi, Srikant; 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 31 TC 3 Z9 3 U1 2 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 2014 VL 103 IS 8 BP 2376 EP 2385 DI 10.1002/jps.24055 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA AN0MC UT WOS:000340277700018 PM 24931728 ER PT J AU Zhang, ZW Nie, L Soon, G Zhang, B AF Zhang, Zhiwei Nie, Lei Soon, Guoxing Zhang, Bo TI Sensitivity analysis in non-inferiority trials with residual inconstancy after covariate adjustment SO JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES C-APPLIED STATISTICS LA English DT Article DE Active control; Conditional effect; Constancy; Discounting; Effect retention; Putative placebo ID ACTIVE-CONTROL TRIALS; RESISTANT HIV-1 INFECTION; PLACEBO-CONTROLLED TRIALS; PUTATIVE PLACEBO; CLINICAL-TRIALS; ISSUES; NONINFERIORITY; RALTEGRAVIR; DESIGN; EQUIVALENCE AB A major issue in non-inferiority trials is the controversial assumption of constancy, namely that the active control has the same effect relative to placebo as in previous studies comparing the active control with placebo. The constancy assumption is often in doubt, which has motivated various methods that 'discount' the control effect estimate from historical data as well as methods that adjust for imbalances in observed covariates. We develop a new approach to deal with residual inconstancy, i.e. possible violations of the constancy assumption due to imbalances in unmeasured covariates after adjusting for the measured covariates. We characterize the extent of residual inconstancy under a generalized linear model framework and use the results to obtain fully adjusted estimates of the control effect in the current study based on plausible assumptions about an unmeasured covariate. Because such assumptions may be difficult to justify, we propose a sensitivity analysis approach that covers a range of situations. This approach is developed for indirect comparison with placebo and effect retention, and implemented through additive andmultiplicative adjustments. The approach proposed is applied to two examples concerning benign prostate hyperplasia and human immunodeficiency virus infection, and evaluated in simulation studies. C1 [Zhang, Zhiwei; Nie, Lei; Soon, Guoxing] US FDA, Silver Spring, MD 20993 USA. [Zhang, Bo] Oregon State Univ, Corvallis, OR 97331 USA. RP Zhang, ZW (reprint author), US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM zhiwei.zhang@fda.hhs.gov NR 36 TC 1 Z9 1 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0035-9254 EI 1467-9876 J9 J R STAT SOC C-APPL JI J. R. Stat. Soc. Ser. C-Appl. Stat. PD AUG PY 2014 VL 63 IS 4 BP 515 EP 538 DI 10.1111/rssc.12050 PG 24 WC Statistics & Probability SC Mathematics GA AM9CX UT WOS:000340178600001 ER PT J AU Corey, CG King, BA Coleman, BN Delnevo, CD Husten, CG Ambrose, BK Apelberg, BJ AF Corey, Catherine G. King, Brian A. Coleman, Blair N. Delnevo, Cristine D. Husten, Corinne G. Ambrose, Bridget K. Apelberg, Benjamin J. TI Little Filtered Cigar, Cigarillo, and Premium Cigar Smoking Among Adults - United States, 2012-2013 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID TOBACCO C1 [Corey, Catherine G.; Coleman, Blair N.; Husten, Corinne G.; Ambrose, Bridget K.; Apelberg, Benjamin J.] CDC, Ctr Tobacco Prod Food & Drug Adm, Atlanta, GA 30333 USA. [King, Brian A.] CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Delnevo, Cristine D.] Rutgers Sch Publ Hlth, Ctr Tobacco Studies, Piscataway Township, NJ USA. RP Corey, CG (reprint author), CDC, Ctr Tobacco Prod Food & Drug Adm, Atlanta, GA 30333 USA. EM catherine.corey@fda.hhs.gov RI Delnevo, Cristine/D-5002-2015 NR 11 TC 16 Z9 16 U1 0 U2 2 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 1 PY 2014 VL 63 IS 30 BP 650 EP 654 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AM7VC UT WOS:000340075800002 PM 25078654 ER PT J AU Gordonov, T Kim, E Cheng, Y Ben-Yoav, H Ghodssi, R Rubloff, G Yin, JJ Payne, GF Bentley, WE AF Gordonov, Tanya Kim, Eunkyoung Cheng, Yi Ben-Yoav, Hadar Ghodssi, Reza Rubloff, Gary Yin, Jun-Jie Payne, Gregory F. Bentley, William E. TI Electronic modulation of biochemical signal generation SO NATURE NANOTECHNOLOGY LA English DT Article ID ESCHERICHIA-COLI; PRO-TAG; CHIP; BIOFABRICATION; LUXS; BIOSYNTHESIS; TOXICITY; REVEALS; DEVICES; ENZYME AB Microelectronic devices that contain biological components are typically used to interrogate biology(1,2) rather than control biological function. Patterned assemblies of proteins and cells have, however, been used for in vitro metabolic engineering(3-7), where coordinated biochemical pathways allow cell metabolism to be characterized and potentially controlled(8) on a chip. Such devices form part of technologies that attempt to recreate animal and human physiological functions on a chip(9) and could be used to revolutionize drug development(10). These ambitious goals will, however, require new biofabrication methodologies that help connect microelectronics and biological systems(11,12) and yield new approaches to device assembly and communication. Here, we report the electrically mediated assembly, interrogation and control of a multi-domain fusion protein that produces a bacterial signalling molecule. The biological system can be electrically tuned using a natural redox molecule, and its biochemical response is shown to provide the signalling cues to drive bacterial population behaviour. We show that the biochemical output of the system correlates with the electrical input charge, which suggests that electrical inputs could be used to control complex on-chip biological processes. C1 [Gordonov, Tanya; Payne, Gregory F.; Bentley, William E.] Univ Maryland, Fischel Dept Bioengn, College Pk, MD 20742 USA. [Gordonov, Tanya; Kim, Eunkyoung; Payne, Gregory F.; Bentley, William E.] Univ Maryland, Inst Biosci & Biotechnol Res, College Pk, MD 20742 USA. [Cheng, Yi; Ben-Yoav, Hadar; Ghodssi, Reza; Rubloff, Gary] Univ Maryland, Syst Res Inst, College Pk, MD 20742 USA. [Cheng, Yi; Rubloff, Gary] Univ Maryland, Dept Mat Sci & Engn, College Pk, MD 20742 USA. [Ben-Yoav, Hadar; Ghodssi, Reza] Univ Maryland, Dept Elect & Comp Engn, College Pk, MD 20742 USA. [Yin, Jun-Jie] US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Gordonov, T (reprint author), Univ Maryland, Fischel Dept Bioengn, College Pk, MD 20742 USA. EM bentley@umd.edu RI Cheng, Yi/E-7670-2010; Yin, Jun Jie /E-5619-2014; Rubloff, Gary/D-4142-2009; OI Cheng, Yi/0000-0001-9776-395X; Rubloff, Gary/0000-0002-1901-3982; Ben-Yoav, Hadar/0000-0002-6237-0440 FU Defense Threat Reduction Agency [HDTRA1-13-0037]; National Science Foundation [1160005, 1264509]; RWD Foundation FX The authors thank the UMD Fischell Department of Bioengineering Core FACS Facility for assistance with FACS data collection and the UMD Nanocenter for providing workspace and tools for electrode fabrication and ICP-EOS measurements. The authors thank Y. Zhou of the UMD Department of Nutrition and Food Science for help with EPR measurements. Financial support for this work was provided by the Defense Threat Reduction Agency (HDTRA1-13-0037), the National Science Foundation (no. 1160005 to WEB, no. 1264509 to HO Sintim) and the RWD Foundation. NR 27 TC 18 Z9 18 U1 5 U2 60 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1748-3387 EI 1748-3395 J9 NAT NANOTECHNOL JI Nat. Nanotechnol. PD AUG PY 2014 VL 9 IS 8 BP 605 EP 610 DI 10.1038/NNANO.2014.151 PG 6 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA AM8PS UT WOS:000340140100013 PM 25064394 ER PT J AU Farrar, JT Troxel, AB Haynes, K Gilron, I Kerns, RD Katz, NP Rappaport, BA Rowbotham, MC Tierney, AM Turk, DC Dworkin, RH AF Farrar, John T. Troxel, Andrea B. Haynes, Kevin Gilron, Ian Kerns, Robert D. Katz, Nathaniel P. Rappaport, Bob A. Rowbotham, Michael C. Tierney, Ann M. Turk, Dennis C. Dworkin, Robert H. TI Effect of variability in the 7-day baseline pain diary on the assay sensitivity of neuropathic pain randomized clinical trials: An ACTTION study SO PAIN LA English DT Article DE Randomized controlled trials as topic; Assay sensitivity; Research design; Neuropathic pain; Reproducibility of results; Treatment efficacy; Pain measurement ID DIABETIC PERIPHERAL NEUROPATHY; PLACEBO-CONTROLLED TRIAL; ANTIDEPRESSANT EFFICACY TRIALS; POSTHERPETIC NEURALGIA; DOUBLE-BLIND; DRUG TRIALS; PREGABALIN; TOLERABILITY; SLEEP AB The degree of variability in the patient baseline 7-day diary of pain ratings has been hypothesized to have a potential effect on the assay sensitivity of randomized clinical trials of pain therapies. To address this issue, we obtained clinical trial data from the Food and Drug Administration (FDA) through the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership, and harmonized patient level data from 12 clinical trials (4 gabapentin and 8 pregabalin) in postherpetic neuralgia (PHN) and painful diabetic peripheral neuropathy (DPN). Models were developed using exploratory logistic regression to examine the interaction between available baseline factors and treatment (placebo vs active medication) in predicting patient response to therapy (ie, >30% improvement). Our analysis demonstrated an increased likelihood of response in the placebo-treated group for patients with a higher standard deviation in the baseline 7-day diary without affecting the likelihood of a response in the active medication-treated group, confirming our hypothesis. In addition, there was a small but significant age-by-treatment interaction in the PHN model, and small weight-by-treatment interaction in the DPN model. The patient's sex, baseline pain level, and the study protocol had an effect only on the likelihood of response overall. Our results suggest the possibility that, at least in some disease processes, excluding patients with a highly variable baseline 7-day diary has the potential to improve the assay sensitivity of these analgesic clinical trials, although reductions of external validity must be considered when increasing the homogeneity of the investigated sample. (C) 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 [Farrar, John T.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Troxel, Andrea B.; Haynes, Kevin; Tierney, Ann M.] Univ Penn, Philadelphia, PA 19104 USA. [Gilron, Ian] Queens Univ, Kingston, ON, Canada. [Kerns, Robert D.] VA Connecticut Healthcare, Pain Res Informat Multimorbid & Educ Ctr, New Haven, CT USA. [Kerns, Robert D.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Katz, Nathaniel P.] Analges Solut, Natick, MA USA. [Katz, Nathaniel P.] Tufts Univ, Boston, MA 02111 USA. [Rappaport, Bob A.] US FDA, Silver Spring, MD USA. [Rowbotham, Michael C.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Turk, Dennis C.] Univ Washington, Seattle, WA 98195 USA. [Dworkin, Robert H.] Univ Rochester, Rochester, NY USA. RP Farrar, JT (reprint author), Univ Penn, Ctr Clin Epidemiol & Biostat, 423 Guardian Dr,Room 816 Blockley, Philadelphia, PA 19104 USA. EM jfarrar@upenn.edu OI Troxel, Andrea/0000-0002-1393-3075 FU US Food and Drug Administration; FDA [HHSF 223201000078C]; ACTTION public private partnership FX No official endorsement by the US Food and Drug Administration or the pharmaceutical companies that provided unrestricted grants to support the activities of ACTTION should be inferred. Financial support for this project was provided by a research contract (HHSF 223201000078C) from the FDA to the University of Rochester and a subcontract to the University of Pennsylvania, and by the ACTTION public private partnership, which has received research grants or other revenue from the FDA, various pharmaceutical companies, and other sources. NR 28 TC 15 Z9 15 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD AUG PY 2014 VL 155 IS 8 BP 1622 EP 1631 DI 10.1016/j.pain.2014.05.009 PG 10 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA AN0YL UT WOS:000340309800026 PM 24831421 ER PT J AU Ambrose, BK Rostron, BL Johnson, SE Portnoy, DB Apelberg, BJ Kaufman, AR Choiniere, CJ AF Ambrose, Bridget K. Rostron, Brian L. Johnson, Sarah E. Portnoy, David B. Apelberg, Benjamin J. Kaufman, Annette R. Choiniere, Conrad J. TI Perceptions of the Relative Harm of Cigarettes and E-cigarettes Among U.S. Youth SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID NICOTINE DEPENDENCE SYMPTOMS; ADOLESCENT SMOKERS; UNREALISTIC OPTIMISM; SMOKING; RISKS AB Background: Despite progress in reducing youth smoking, adolescents remain highly susceptible to tobacco use. Of concern is whether youth perceive electronic cigarettes (e-cigarettes) as a preferable alternative to conventional cigarettes. Purpose: To describe cigarette harm perception patterns among youth based on the frequency and intensity of cigarette smoking, and examine the relative harm perceptions of conventional versus e-cigarettes, using data from a large, nationally representative sample of U.S. youth. Methods: Data from the 2012 National Youth Tobacco Survey (N=24,658) were analyzed in 2013 to identify patterns of cigarette harm perceptions. Multinomial logistic regression was conducted to identify associations between demographic and tobacco use characteristics and cigarette harm perception patterns. Logistic regression was conducted to examine the relationship between cigarette harm perceptions and the perception of e-cigarettes as less harmful than cigarettes for current, ever, and never cigarette smokers. Results: The majority of youth (64.2%) perceived the harmfulness of cigarettes as dose-dependent. Approximately one in three students perceived e-cigarettes as less harmful than conventional cigarettes. Regardless of cigarette smoking status, ever users of e-cigarettes and those with "dose-dependent" cigarette harm perceptions consistently were more likely to perceive e-cigarettes as less harmful than conventional cigarettes. Conclusions: Many youth perceive tobacco use on a continuum of harm. Youth who perceive gradations in harm-both by frequency and intensity of cigarette use and by type of product-may be particularly susceptible to e-cigarette use. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Ambrose, Bridget K.; Rostron, Brian L.; Johnson, Sarah E.; Portnoy, David B.; Apelberg, Benjamin J.; Choiniere, Conrad J.] US FDA, Ctr Tobacco Prod, Off Sci, Rockville, MD 20850 USA. [Kaufman, Annette R.] NCI, Tobacco Control Res Branch, NIH, Rockville, MD USA. RP Ambrose, BK (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, 9200 Corp Blvd, Rockville, MD 20850 USA. EM bridget.ambrose@fda.hhs.gov OI Portnoy, David/0000-0003-2175-9457 FU U.S. Food and Drug Administration, Center for Tobacco Products FX Publication of this article was supported by the U.S. Food and Drug Administration, Center for Tobacco Products. NR 21 TC 35 Z9 35 U1 3 U2 36 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 AUG PY 2014 VL 47 IS 2 SU 1 BP S53 EP S60 DI 10.1016/j.amepre.2014.04.016 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM2NF UT WOS:000339687400006 PM 25044196 ER PT J AU Apelberg, BJ Backinger, CL Curry, SJ AF Apelberg, Benjamin J. Backinger, Cathy L. Curry, Susan J. TI Enhancing Youth Tobacco Surveillance to Inform Tobacco Product Regulation Findings from the 2012 National Youth Tobacco Survey SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Editorial Material ID HIGH-SCHOOL-STUDENTS; UNITED-STATES; MIDDLE C1 [Apelberg, Benjamin J.; Backinger, Cathy L.] US FDA, Off Sci, Ctr Tobacco Prod, Rockville, MD 20850 USA. [Curry, Susan J.] Univ Iowa, Coll Publ Hlth, Iowa City, IA USA. RP Apelberg, BJ (reprint author), US FDA, Off Sci, Ctr Tobacco Prod, 9200 Corp Blvd, Rockville, MD 20850 USA. EM Benjamin.Apelberg@fda.hhs.gov NR 14 TC 0 Z9 0 U1 0 U2 2 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 AUG PY 2014 VL 47 IS 2 SU 1 BP S1 EP S3 DI 10.1016/j.amepre.2014.05.010 PG 3 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM2NF UT WOS:000339687400001 PM 25044191 ER PT J AU Apelberg, BJ Corey, CG Hoffman, AC Schroeder, MJ Husten, CG Caraballo, RS Backinger, CL AF Apelberg, Benjamin J. Corey, Catherine G. Hoffman, Allison C. Schroeder, Megan J. Husten, Corinne G. Caraballo, Ralph S. Backinger, Cathy L. TI Symptoms of Tobacco Dependence Among Middle and High School Tobacco Users Results from the 2012 National Youth Tobacco Survey SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID ONSET ADOLESCENT SMOKERS; NICOTINE-DEPENDENCE; DIMINISHED AUTONOMY; SMOKELESS TOBACCO; SMOKING; SCALE; WITHDRAWAL; FREQUENCY AB Background: A growing body of evidence suggests that tobacco dependence symptoms can occur soon after smoking onset and with low levels of use. However, limited data are available nationally and among non-cigarette tobacco users. Purpose: To examine the prevalence and determinants of tobacco dependence symptoms among adolescent tobacco users in the 2012 National Youth Tobacco Survey, a nationally representative, school-based survey of U.S. middle and high school students. Methods: Multivariate logistic regression was used to identify independent predictors of dependence symptoms among current users (i.e., past 30-day use) of cigarettes, cigars, or smokeless tobacco. Analyses were conducted in 2013 using SAS-callable SUDAAN, version 11 to account for the complex survey design. Results: Prevalence of tobacco dependence symptoms ranged from 20.8% (95% CI=18.6, 23.1) of current tobacco users reporting wanting to use tobacco within 30 minutes of waking to 41.9% (95% CI=39.3, 44.5) reporting recent strong cravings. Reporting of dependence symptoms was most consistently associated with polytobacco use, higher frequency of use, earlier initiation age, and female gender. A 2-4-fold increase in the odds of symptom reporting was found in adolescents using tobacco products on as few as 3-5 days compared to those who only used it for 1-2 of the past 30 days. Conclusions: A substantial proportion of U.S. adolescent tobacco users, including those with low levels of use, report symptoms of tobacco dependence. These findings demonstrate the need for full implementation of evidence-based strategies to prevent both experimentation and progression to regular tobacco use among youth. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Apelberg, Benjamin J.; Corey, Catherine G.; Hoffman, Allison C.; Schroeder, Megan J.; Backinger, Cathy L.] US FDA, Ctr Tobacco Prod, Off Sci, Rockville, MD 20850 USA. [Husten, Corinne G.] US FDA, Ctr Tobacco Prod, Off Ctr Director, Rockville, MD 20850 USA. [Caraballo, Ralph S.] CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. RP Apelberg, BJ (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, 9200 Corp Blvd, Rockville, MD 20850 USA. EM benjamin.apelberg@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Tobacco Products FX Publication of this article was supported by the U.S. Food and Drug Administration, Center for Tobacco Products. NR 22 TC 15 Z9 15 U1 0 U2 3 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 AUG PY 2014 VL 47 IS 2 SU 1 BP S4 EP S14 DI 10.1016/j.amepre.2014.04.013 PG 11 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM2NF UT WOS:000339687400002 PM 25044195 ER PT J AU Corey, CG Dube, SR Ambrose, BK King, BA Apelberg, BJ Husten, CG AF Corey, Catherine G. Dube, Shanta R. Ambrose, Bridget K. King, Brian A. Apelberg, Benjamin J. Husten, Corinne G. TI Cigar Smoking Among US Students Reported Use After Adding Brands to Survey Items SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID YOUNG-ADULTS; UNITED-STATES; YOUTH; ADOLESCENTS; RISK; MEN; FLAVORS; DISEASE; DEATH; FOCUS AB Background: Among U.S. youth overall, cigars are the most commonly used tobacco product after cigarettes. However, youth who identify their products by brand names, not general terms like "cigar," may underreport use. Purpose: To examine changes in reported cigar (cigar, cigarillo, or little cigar) smoking among students following inclusion of cigar brand examples on the National Youth Tobacco Survey (NYTS). Methods: Data from the 2011 and 2012 NYTS and National Survey on Drug Use and Health (NSDUH) were analyzed in 2013 to estimate ever and current cigar smoking, overall and by race/ ethnicity. The 2012 NYTS included cigar brand examples (Black and Mild, Swisher Sweets, Dutch Masters, White Owl, Phillies Blunt) in the survey instructions and ever use question, but the 2011 NYTS and 2011 and 2012 NSDUH did not. Results: NYTS ever cigar smoking was higher in 2012 (27.8%) than 2011 (19.5%) among black students overall. Current cigar smoking was 60%-70% higher among black females and students aged >= 17 years, in 2012 than 2011. For black females, current cigar smoking (11.5%) was two times greater than that of white females (4.3%) in 2012, whereas the prevalence among these subgroups was comparable in 2011. Similar changes were not observed among these subgroups in the 20112012 NSDUH. Conclusions: This study highlights the high burden of cigar use among U.S. youth and suggests that NYTS ascertainment of cigar smoking may have improved by including brands. Disparities in cigar smoking need to be addressed to prevent and reduce all youth tobacco use. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Corey, Catherine G.; Ambrose, Bridget K.; Apelberg, Benjamin J.] US FDA, Off Sci, Ctr Tobacco Prod, Rockville, MD 20850 USA. [Husten, Corinne G.] US FDA, Off Ctr Director, Ctr Tobacco Prod, Rockville, MD 20850 USA. [Dube, Shanta R.] Georgia State Univ, Div Epidemiol & Biostat, Sch Publ Hlth, Atlanta, GA 30303 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, Off Sci, Ctr Tobacco Prod, 9200 Corp Blvd, Rockville, MD 20850 USA. EM catherine.corey@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Tobacco Products FX Publication of this article was supported by the U.S. Food and Drug Administration, Center for Tobacco Products. NR 32 TC 11 Z9 11 U1 0 U2 4 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 AUG PY 2014 VL 47 IS 2 SU 1 BP S28 EP S35 DI 10.1016/j.amepre.2014.05.004 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM2NF UT WOS:000339687400004 PM 25044193 ER PT J AU Johnson, SE Wu, CC Coleman, BN Choiniere, CJ AF Johnson, Sarah E. Wu, Charles C. Coleman, Blair N. Choiniere, Conrad J. TI Self-Reported Exposure to Tobacco Warning Labels Among U.S. Middle and High School Students SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID HEALTH WARNINGS; CANADIAN SMOKERS; SMOKING; MESSAGES; ADOLESCENTS; PRODUCTS; BEHAVIOR; WEAROUT; IMPACT AB Background: Warning labels on tobacco products are a means to communicate information about the negative health effects of tobacco use to current and potential users. Most tobacco use begins in early adolescence, making it particularly important to understand the degree to which warning labels reach adolescents. Purpose: To examine the extent to which youth report (1) seeing the current warnings on cigarettes and smokeless tobacco (SLT) products in the U.S. and (2) that seeing warnings makes them think about the health risks associated with tobacco use. Methods: Exposure to warning labels on cigarettes and SLT, as well as the degree to which adolescents report thinking about health risks in response to warnings, was examined among U.S. middle and high school students using data from the 2012 National Youth Tobacco Survey (NYTS) and analyzed in 2013. Results: Current data suggest that less than half of adolescents who saw a cigarette pack (46.9%) or SLT product (40.3%) reported seeing the warning label "most of the time" or "always." Among adolescents who reported seeing a warning, less than one third reported that cigarette (30.4%) or SLT (25.2%) warning labels made them think about health risks "a lot." These rates were even lower among current tobacco users (<14%). Conclusions: Current warning labels for cigarettes and SLT could be improved by implementing warnings that incorporate features that make them salient and more likely to evoke thoughts about health risks. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Johnson, Sarah E.; Coleman, Blair N.; Choiniere, Conrad J.] US FDA, Ctr Tobacco Prod, Off Sci, Rockville, MD 20850 USA. [Wu, Charles C.] NIH, Off Extramural Res, Bethesda, MD 20892 USA. RP Johnson, SE (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, 9200 Corp Blvd, Rockville, MD 20850 USA. EM sarah.johnson@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Tobacco Products FX Publication of this article was supported by the U.S. Food and Drug Administration, Center for Tobacco Products. NR 29 TC 7 Z9 7 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2014 VL 47 IS 2 SU 1 BP S69 EP S75 DI 10.1016/j.amepre.2014.05.005 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM2NF UT WOS:000339687400008 PM 25044198 ER PT J AU Portnoy, DB Wu, CC Tworek, C Chen, JP Borek, N AF Portnoy, David B. Wu, Charles C. Tworek, Cindy Chen, Jiping Borek, Nicolette TI Youth Curiosity About Cigarettes, Smokeless Tobacco, and Cigars SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID HIGH-SCHOOL-STUDENTS; UNITED-STATES; ESTABLISHED SMOKING; ADOLESCENTS; INITIATION; SUSCEPTIBILITY; PREDICTOR; MIDDLE AB Background: Curiosity about cigarettes is a reliable predictor of susceptibility to smoking and established use among youth. Related research has been limited to cigarettes, and lacks national-level estimates. Factors associated with curiosity about tobacco products, such as advertising, have been postulated but rarely tested. Purpose: To describe the prevalence of curiosity about cigarettes, smokeless tobacco, and cigars among youth and explore the association between curiosity and self-reported tobacco advertising exposure. Methods: Data from the 2012 National Youth Tobacco Survey, a nationally representative survey of 24,658 students, were used. In 2013, estimates weighted to the national youth school population were calculated for curiosity about cigarettes, smokeless tobacco, and cigars among never users of any tobacco product. Associations between tobacco advertising and curiosity were explored using multivariable regressions. Results: Curiosity about cigarettes (28.8%); cigars (19.5%); and smokeless tobacco (9.7%) was found, and many youth were curious about more than one product. Exposure to point-of-sale advertising (e.g., OR=1.35, 95% CI=1.19, 1.54 for cigarette curiosity); tobacco company communications (e.g., OR=1.70, 95% CI=1.38, 2.09 for cigarette curiosity); and tobacco products, as well as viewing tobacco use in TV/movies (e.g., OR=1.37, 95% CI=1.20, 1.58 for cigarette curiosity) were associated with curiosity about each examined tobacco product. Conclusions: Despite decreasing use of tobacco products, youth remain curious about them. Curiosity is associated with various forms of tobacco advertising. These findings suggest the importance of measuring curiosity as an early warning signal for potential future tobacco use and evaluating continued efforts to limit exposure to tobacco marketing among youth. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Portnoy, David B.; Tworek, Cindy; Chen, Jiping; Borek, Nicolette] US FDA, Off Sci, Ctr Tobacco Prod, Rockville, MD 20850 USA. [Wu, Charles C.] NIH, Off Extramural Res, Bethesda, MD 20892 USA. RP Portnoy, DB (reprint author), US FDA, Off Sci, Ctr Tobacco Prod, 9200 Corp Blvd,CORP 300H, Rockville, MD 20850 USA. EM david.portnoy@fda.hhs.gov OI Portnoy, David/0000-0003-2175-9457 FU U.S. Food and Drug Administration, Center for Tobacco Products FX Publication of this article was supported by the U.S. Food and Drug Administration, Center for Tobacco Products. NR 29 TC 12 Z9 12 U1 1 U2 11 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 AUG PY 2014 VL 47 IS 2 SU 1 BP S76 EP S86 DI 10.1016/j.amepre.2014.04.012 PG 11 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM2NF UT WOS:000339687400009 PM 25044199 ER PT J AU Tessman, GK Caraballo, RS Corey, CG Xu, X Chang, CM AF Tessman, Greta K. Caraballo, Ralph S. Corey, Catherine G. Xu, Xin Chang, Cindy M. TI Exposure to Tobacco Coupons Among US Middle and High School Students SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID 4 COUNTRY SURVEY; CIGARETTE PURCHASE PATTERNS; UNITED-STATES; SMOKING; PRICE; BEHAVIORS; SMOKERS; STRATEGIES; INITIATION; CESSATION AB Background: Tobacco marketing contributes to increased tobacco use susceptibility and sustained use. There are limited data on youth exposure to tobacco coupons, a type of pro-tobacco promotion. Purpose: To explore channels through which youth report exposure to coupons and characteristics associated with this exposure. This may help inform efforts aimed at decreasing youth exposure to advertising and promotion. Methods: Data from the 2012 National Youth Tobacco Survey were analyzed in 2013 to estimate the self-reported prevalence of U.S. middle and high school student exposure to coupons through various channels. Associations among exposure to coupons and demographics, tobacco use, living with a tobacco user, and receptivity to tobacco marketing were examined using multivariate logistic regression models. Results: Approximately 13% of students reported exposure to tobacco coupons in the past 30 days through mail, digital communications, or tobacco packages. Prevalence was greatest among current tobacco users (34.0%) and those receptive to tobacco marketing (23.4%) compared to non-tobacco users (9.3%) and those not receptive to tobacco marketing (8.2%), respectively. Coupon exposure varied by sex, grade, and race/ethnicity. In adjusted models, current tobacco use (AOR=3.4, 95% CI=3.0, 3.9); living with a tobacco user (AOR=2.1, 95% CI=1.9, 2.4); and receptivity to tobacco marketing (AOR=2.3, 95% CI=2.0, 2.7) were independently associated with coupon exposure. Conclusions: Findings from this study indicate that despite restrictions on marketing to youth, youth are still being exposed to tobacco promotions such as coupons. Efforts to limit youth exposure may be valuable in reducing curiosity, susceptibility, and initiation. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Tessman, Greta K.; Corey, Catherine G.; Chang, Cindy M.] US FDA, Ctr Tobacco Prod, Off Sci, Rockville, MD 20850 USA. [Caraballo, Ralph S.; Xu, Xin] CDC, Off Smoking & Hlth, Epidemiol Branch, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. RP Tessman, GK (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, 9200 Corp Blvd, Rockville, MD 20850 USA. EM greta.tessman@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Tobacco Products FX Publication of this article was supported by the U.S. Food and Drug Administration, Center for Tobacco Products. NR 38 TC 9 Z9 9 U1 0 U2 7 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 AUG PY 2014 VL 47 IS 2 SU 1 BP S61 EP S68 DI 10.1016/j.amepre.2014.05.001 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM2NF UT WOS:000339687400007 PM 25044197 ER PT J AU Tworek, C Schauer, GL Wu, CC Malarcher, AM Jackson, KJ Hoffman, AC AF Tworek, Cindy Schauer, Gillian L. Wu, Charles C. Malarcher, Ann M. Jackson, Kia J. Hoffman, Allison C. TI Youth Tobacco Cessation Quitting Intentions and Past-Year Quit Attempts SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID HIGH-SCHOOL-STUDENTS; UNITED-STATES; SMOKING-CESSATION; COLLEGE-STUDENTS; USE PREVENTION; PRODUCT USE; ADOLESCENTS; SMOKERS; ADULTS; MIDDLE AB Background: Despite declining use of conventional tobacco products, youth use of non-cigarette tobacco has become prevalent; however, quitting behaviors remain largely unexplored. Purpose: To examine nationally representative data on quit intentions and past-year attempts to quit all tobacco use among current youth tobacco users. Methods: In 2013, data were analyzed from the 2012 National Youth Tobacco Survey (NYTS). Weighted prevalence estimates of quit intentions and past-year quit attempts for current youth tobacco users are presented. Results: Prevalence of quit intentions and past-year attempts to quit all tobacco use were 52.8% and 51.5%, respectively, among current youth tobacco users. Among non mutually exclusive, groups, current cigarette smokers had the highest prevalence of quit intentions (56.8%) and past-year quit attempts (52.5%), whereas current hookah users had the lowest prevalence of quit intentions (41.5%) and past-year quit attempts (43.7%). Quit intentions among black, non-Hispanics (65.0%) and Hispanics (60.4%) were significantly higher versus white, non-Hispanics (47.5%). Youth reporting parental advice against tobacco had significantly higher prevalence of quit intentions (56.7%) and past-year quit attempts (55.0%) than those not reporting parental advice. Youth who agreed all tobacco products are dangerous (58.5%) had significantly higher prevalence of quit intentions than those who disagreed (37.0%). Conclusions: Continued efforts are needed to better understand youth motivation for quitting all tobacco products. Public health messaging about the dangers of all tobacco and cessation efforts should be aimed at the full range of tobacco products, not just cigarettes, and tailored to meet the needs of youth polytobacco users. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Tworek, Cindy; Jackson, Kia J.; Hoffman, Allison C.] US FDA, Ctr Tobacco Prod, Off Sci, Rockville, MD 20850 USA. [Wu, Charles C.] NIH, Off Extramural Res, Bethesda, MD 20892 USA. [Schauer, Gillian L.; Malarcher, Ann M.] CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. RP Tworek, C (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, 9200 Corp Blvd, Rockville, MD 20850 USA. EM cindy.tworek@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Tobacco Products FX Publication of this article was supported by the U.S. Food and Drug Administration, Center for Tobacco Products. NR 38 TC 7 Z9 7 U1 2 U2 8 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 AUG PY 2014 VL 47 IS 2 SU 1 BP S15 EP S27 DI 10.1016/j.amepre.2014.05.009 PG 13 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM2NF UT WOS:000339687400003 PM 25044192 ER PT J AU Wang, BG King, BA Corey, CG Arrazola, RA Johnson, SE AF Wang, Baoguang King, Brian A. Corey, Catherine G. Arrazola, Rene A. Johnson, Sarah E. TI Awareness and Use of Non-conventional Tobacco Products Among US Students, 2012 SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID HIGH-SCHOOL-STUDENTS; ELECTRONIC CIGARETTE USE; SMOKELESS TOBACCO; UNITED-STATES; COLLEGE-STUDENTS; HOOKAH USE; UNIVERSITY-STUDENTS; CARCINOGEN EXPOSURE; WATERPIPE SMOKING; NATIONAL-SURVEY AB Background: Increasing diversity of the tobacco product landscape, including electronic cigarettes (e-cigarettes), hookah, snus, and dissolvable tobacco products (dissolvables), raises concerns about the public health impact of these non-conventional tobacco products among youth. Purpose: This study assessed awareness, ever use, and current use of non-conventional tobacco products among U.S. students in 2012, overall and by demographic and tobacco use characteristics. Methods: Data from the 2012 National Youth Tobacco Survey, a nationally representative survey of U.S. middle and high school students, were analyzed in 2013. Prevalence of awareness, ever use, and current use of e-cigarettes, hookah, snus, and dissolvables were calculated overall and by sex, school level, race/ethnicity, and conventional tobacco product use, including cigarettes, cigars, or smokeless tobacco (chewing tobacco, snuff, or dip). Results: Overall, 50.3% of students were aware of e-cigarettes; prevalence of ever and current use of e-cigarettes was 6.8% and 2.1%, respectively. Awareness of hookah was 41.2% among all students, and that of ever and current use were 8.9% and 3.6%, respectively. Overall awareness; ever; and current use of snus (32%, 5.3%, 1.7%, respectively) and dissolvables (19.3%, 2.0%, 0.7%, respectively) were generally lower than those of e-cigarettes or hookah. Conventional tobacco product users were more likely to be aware of and to use non-conventional tobacco products. Conclusions: Many U.S. students are aware of and use non-conventional tobacco products. Evidence-based interventions should be implemented to prevent and reduce all tobacco use among youth. Published by Elsevier Inc. on behalf of American journal of Preventive Medicine C1 [Wang, Baoguang; Corey, Catherine G.; Johnson, Sarah E.] US FDA, Ctr Tobacco Prod, Off Sci, Rockville, MD 20850 USA. [King, Brian A.; Arrazola, Rene A.] CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. RP Wang, BG (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, 9200 Corp Blvd, Rockville, MD 20850 USA. EM baoguang.wang@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Tobacco Products FX Publication of this article was supported by the U.S. Food and Drug Administration, Center for Tobacco Products. NR 60 TC 18 Z9 18 U1 3 U2 27 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 AUG PY 2014 VL 47 IS 2 SU 1 BP S36 EP S52 DI 10.1016/j.amepre.2014.05.003 PG 17 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AM2NF UT WOS:000339687400005 PM 25044194 ER PT J AU Mulloy, B Heath, A Shriver, Z Jameison, F Al Hakim, A Morris, TS Szajek, AY AF Mulloy, Barbara Heath, Alan Shriver, Zachary Jameison, Fabian Al Hakim, Ali Morris, Tina S. Szajek, Anita Y. TI USP compendial methods for analysis of heparin: chromatographic determination of molecular weight distributions for heparin sodium SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article ID SIZE-EXCLUSION CHROMATOGRAPHY; X-RAY-SCATTERING; UNFRACTIONATED HEPARIN; SULFATE; GLYCOSAMINOGLYCANS; SPECTROMETRY; CALIBRATION C1 [Mulloy, Barbara; Heath, Alan] Natl Inst Biol Stand & Controls, Potters Bar EN6 3QG, Herts, England. [Shriver, Zachary] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Jameison, Fabian; Morris, Tina S.; Szajek, Anita Y.] US Pharmacopeial Convent Inc, Biol & Biotechnol, Rockville, MD 20852 USA. [Al Hakim, Ali] US FDA, Off New Drug Qual Assessment, CDER, Silver Spring, MD 20993 USA. RP Mulloy, B (reprint author), Kings Coll London, Inst Pharmaceut Sci, Franklin Wilkins Bldg,100 Stamford St, London SE1 9NH, England. EM barbara.mulloy@kcl.ac.uk NR 28 TC 7 Z9 7 U1 1 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 AUG PY 2014 VL 406 IS 20 BP 4815 EP 4823 DI 10.1007/s00216-014-7940-3 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AM5FA UT WOS:000339880500002 PM 24958344 ER PT J AU Neal-Kluever, A Aungst, J Gu, Y Hatwell, K Muldoon-Jacobs, K Liem, A Ogungbesan, A Shackelford, M AF Neal-Kluever, April Aungst, Jason Gu, Yan Hatwell, Karen Muldoon-Jacobs, Kristi Liem, Ayesha Ogungbesan, Adejoke Shackelford, Mary TI Infant toxicology: State of the science and considerations in evaluation of safety SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Review DE Infants; Toxicology; Safety assessment; Developmental toxicology ID RESPIRATORY SYNCYTIAL VIRUS; AGE-RELATED DIFFERENCES; EXPERT WORKING GROUP; RISK-ASSESSMENT; DEVELOPMENTAL NEUROTOXICITY; LIFE STAGES; PHARMACOKINETIC DIFFERENCES; RETROSPECTIVE ANALYSIS; REPRODUCTIVE TOXICITY; NEWBORN-INFANTS AB Differences in the physiology and biological susceptibilities of adults and infants have led to growing interest in safety evaluation methods for exposures from infant formula packaging. In addition to potential physiological differences, infants aged 0-6 months may consume a sole source of food, infant formula or breast milk, and consume higher amounts of food relative to body weight compared to adults. While the duration of the exposure is short compared to the expected lifespan of the individual, it occurs during a period of important developmental processes. The purpose of this document is to (1) review key biological and exposure elements that may impact the evaluation of safety for food contact products intended for use by infants, (2) summarize the current reproductive and developmental toxicity testing protocols available, and (3) identify potential data gaps concerning this period of development. (C) 2014 Published by Elsevier Ltd. C1 [Neal-Kluever, April; Aungst, Jason; Gu, Yan; Hatwell, Karen; Muldoon-Jacobs, Kristi; Ogungbesan, Adejoke; Shackelford, Mary] US FDA, Ctr Food Safety & Appl Nutr, Off Food Addit Safety, Div Food Contact Notificat, College Pk, MD 20740 USA. [Liem, Ayesha] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. RP Neal-Kluever, A (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Food Addit Safety, Div Food Contact Notificat, 5100 Paint Branch Pkwy,HFS 275, College Pk, MD 20740 USA. EM april.kluever@fda.hhs.gov NR 171 TC 4 Z9 5 U1 1 U2 30 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 AUG PY 2014 VL 70 BP 68 EP 83 DI 10.1016/j.fct.2014.05.003 PG 16 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA AM1IO UT WOS:000339599800010 PM 24824476 ER PT J AU Suzuki, A Leland, P Kobayashi, H Choyke, PL Jagoda, EM Inoue, T Joshi, BH Puri, RK AF Suzuki, Akiko Leland, Pamela Kobayashi, Hisataka Choyke, Peter L. Jagoda, Elaine M. Inoue, Tomio Joshi, Bharat H. Puri, Raj K. TI Analysis of Biodistribution of Intracranially Infused Radio labeled Interleukin-13 Receptor-Targeted Immunotoxin IL-13PE by SPECT/CT in an Orthotopic Mouse Model of Human Glioma SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE SPECT; brain tumor; convection-enhanced delivery; biodistribution; IL-13PE; radioiodination ID CONVECTION-ENHANCED DELIVERY; RECURRENT MALIGNANT GLIOMA; GLIOBLASTOMA; THERAPY; CYTOTOXIN; PATIENT; TRIAL AB Interleukin-13 Pseudomonas exotoxin (IL-13PE), a targeted agent for interleukin-13 receptor alpha 2 (IL-13R alpha 2)-expressing tumors, has been administered intracranially by convection-enhanced delivery (CED) for glioma therapy in several clinical trials including a randomized phase 3 clinical trial. However, its intracranial distribution was not optimally evaluated. We investigated the intracranial distribution of radiolabeled IL-13PE after CED in a murine model of glioblastoma multiforme. Methods: IL-13PE was radiolabeled with (NaI)-I-125 and evaluated for its activity in vitro in receptor-positive U251 or -negative T98G human glioma cell lines. Gliomas were grown in nude mice after intracranial implantation with U251 cells, and I-125-IL-13PE was stereotactically administered by bolus or CED for 3 d, followed by micro-SPECT/CT imaging. SPECT images were evaluated quantitatively and compared with histology and autoradiography results. Results: The radioiodination technique resulted in a specific and biologically active I-125-IL-13PE, which bound and was cytotoxic to IL-13R alpha 2-positive but not to IL-13R alpha 2-negative tumor cells. Both the binding and the cytotoxic activities were blocked by a 100-fold excess of IL-13, which indicated the specificity of binding and cytotoxicity. SPECT/CT imaging revealed retention of I-125-IL-13PE administered by CED in U251 tumors and showed significantly higher volumes of distribution and maintained detectable drug levels for a longer period of time than the bolus route. These results were confirmed by autoradiography. Conclusion: IL-13PE can be radioiodinated without the loss of specificity, binding, or cytotoxic activity. Intracranial CEO administration produces a higher volume of distribution for a longer period of time than,the bolus route. Thus, CED of IL-13PE is superior to bolus injection in delivering the drug to the entire tumor. C1 [Suzuki, Akiko; Leland, Pamela; Joshi, Bharat H.; Puri, Raj K.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Kobayashi, Hisataka; Choyke, Peter L.; Jagoda, Elaine M.] NCI, NIH, Bethesda, MD 20892 USA. [Inoue, Tomio] Yokohama City Univ, Dept Radiol, Yokohama, Kanagawa 232, Japan. RP Puri, RK (reprint author), NIH, Div Cellular & Gene Therapy, Ctr Biol Evaluat & Res, Food & Drug Adm, Bldg 29B,Rm 2NN20,29 Lincoln Dr, Bethesda, MD 20892 USA. EM raj.puri@fda.hhs.gov FU Akiko Suzuki to the Research Participation Program at the Center for Biologics Evaluation and Research FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. This project was supported by an appointment of Akiko Suzuki to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education. No other potential conflict of interest relevant to this article was reported. NR 18 TC 7 Z9 8 U1 0 U2 8 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD AUG PY 2014 VL 55 IS 8 BP 1323 EP 1329 DI 10.2967/jnumed.114.138404 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AM7CM UT WOS:000340022300023 PM 24947060 ER PT J AU Kern, SE Lin, LA Fricke, FL AF Kern, Sara E. Lin, Lora A. Fricke, Frederick L. TI Accurate Mass Fragment Library for Rapid Analysis of Pesticides on Produce Using Ambient Pressure Desorption Ionization with High-Resolution Mass Spectrometry SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article DE DART ionization; Exactive Orbitrap; Q-Exactive Orbitrap; Pesticide analysis; Surface screening technique; Rapid analysis ID DART-MS; VALIDATION; FOOD AB U.S. food imports have been increasing steadily for decades, intensifying the need for a rapid and sensitive screening technique. A method has been developed that uses foam disks to sample the surface of incoming produce. This work provides complimentary information to the extensive amount of published pesticide fragmentation data collected using LCMS systems (Sack et al. Journal of Agricultural and Food Chemistry, 59, 6383-6411, 2011; Mol et al. Analytical and Bioanalytical Chemistry, 403, 2891-2908, 2012). The disks are directly analyzed using transmission-mode direct analysis in real time (DART) ambient pressure desorption ionization coupled to a high resolution accurate mass-mass spectrometer (HRAM-MS). In order to provide more certainty in the identification of the pesticides detected, a library of accurate mass fragments and isotopes of the protonated parent molecular ion (the [M+H](+)) has been developed. The HRAM-MS is equipped with a quadrupole mass filter, providing the capability of "data-dependent" fragmentation, as opposed to "all -ion" fragmentation (where all of the ions enter a collision chamber and are fragmented at once). A temperature gradient for the DART helium stream and multiple collision energies were employed to detect and fragment 164 pesticides of varying chemical classes, sizes, and polarities. The accurate mass information of precursor ([M+H](+) ion) and fragment ions is essential in correctly identifying chemical contaminants on the surface of imported produce. Additionally, the inclusion of isotopes of the [M+H](+) in the database adds another metric to the confirmation process. The fragmentation data were collected using a Q-Exactive mass spectrometer and were added to a database used to process data collected with an Exactive mass spectrometer, an instrument that is more readily available for this screening application. The commodities investigated range from smooth-skinned produce such as apples to rougher surfaces like broccoli. The minimal sample preparation and absence of chromatography has shortened the analysis time to about 15 min per sample, and the simplicity and robustness of the technique make it ideal for rapid screening. C1 [Kern, Sara E.; Lin, Lora A.; Fricke, Frederick L.] US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. RP Kern, SE (reprint author), US FDA, Forens Chem Ctr, 6751 Steger Dr, Cincinnati, OH 45237 USA. EM sara.kern@fda.hhs.gov NR 18 TC 8 Z9 9 U1 9 U2 73 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 AUG PY 2014 VL 25 IS 8 BP 1482 EP 1488 DI 10.1007/s13361-014-0912-1 PG 7 WC Biochemical Research Methods; Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA AM4FB UT WOS:000339807400018 PM 24845356 ER PT J AU Ashley, DL Backinger, CL van Bemmel, DM Neveleff, DJ AF Ashley, David L. Backinger, Cathy L. van Bemmel, Dana M. Neveleff, Deborah J. TI Tobacco Regulatory Science: Research to Inform Regulatory Action at the Food and Drug Administration's Center for Tobacco Products SO NICOTINE & TOBACCO RESEARCH LA English DT Editorial Material ID FAMILY SMOKING PREVENTION; RESEARCH OPPORTUNITIES; PUBLIC-HEALTH; PRIORITIES; POLICY; NEEDS; FDA AB The U. S. Food and Drug Administration (FDA) promotes the development of regulatory science to ensure that a strong evidence base informs all of its regulatory activities related to the manufacture, marketing, and distribution of tobacco products as well as public education about tobacco product constituents and effects. Toward that end, the FDA's Center for Tobacco Products (CTP) provides funding for research studies with scientific aims that fall within its defined regulatory authority. However, given their traditional biomedical focus on basic and applied research, some researchers may not understand the principles of regulatory science or the types of studies CTP funds. The purpose of this paper is (1) to clarify the definition of regulatory science as a distinct scientific discipline, (2) to explore the role of tobacco regulatory science in order to help researchers understand the parameters and types of research that can be funded by CTP, and (3) to describe the types of research efforts that will inform the FDA's public health framework for tobacco product regulation. C1 [Ashley, David L.; Backinger, Cathy L.; van Bemmel, Dana M.; Neveleff, Deborah J.] US FDA, Off Sci, Ctr Tobacco Prod, Rockville, MD 20850 USA. RP Backinger, CL (reprint author), US FDA, Off Sci, Ctr Tobacco Prod, 9200 Corp Blvd,Room 320A, Rockville, MD 20850 USA. EM cathy.backinger@fda.hhs.gov NR 19 TC 14 Z9 14 U1 1 U2 7 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 AUG PY 2014 VL 16 IS 8 BP 1045 EP 1049 DI 10.1093/ntr/ntu038 PG 5 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA AM6CQ UT WOS:000339949600002 PM 24638850 ER PT J AU Chen, W Samuelson, FW AF Chen, W. Samuelson, F. W. TI The average receiver operating characteristic curve in multireader multicase imaging studies SO BRITISH JOURNAL OF RADIOLOGY LA English DT Article ID MAXIMUM-LIKELIHOOD-ESTIMATION; ROC ANALYSIS; DIAGNOSIS; SYSTEMS; DEVICES AB Objective: In multireader, multicase (MRMC) receiver operating characteristic (ROC) studies for evaluating medical imaging systems, the area under the ROC curve (AUC) is often used as a summary metric. Owing to the limitations of AUC, plotting the average ROC curve to accompany the rigorous statistical inference on AUC is recommended. The objective of this article is to investigate methods for generating the average ROC curve from ROC curves of individual readers. Methods: We present both a non-parametric method and a parametric method for averaging ROC curves that produce a ROC curve, the area under which is equal to the average AUC of individual readers (a property we call area preserving). We use hypothetical examples, simulated data and a real-world imaging data set to illustrate these methods and their properties. Results: We show that our proposed methods are area preserving. We also show that the method of averaging the ROC parameters, either the conventional bi-normal parameters (a, b) or the proper bi-normal parameters (c, d(a)), is generally not area preserving and may produce a ROC curve that is intuitively not an average of multiple curves. Conclusion: Our proposed methods are useful for making plots of average ROC curves in MRMC studies as a companion to the rigorous statistical inference on the AUC end point. The software implementing these methods is freely available from the authors. Advances in knowledge: Methods for generating the average ROC curve in MRMC ROC studies are formally investigated. The area-preserving criterion we defined is useful to evaluate such methods. C1 [Chen, W.; Samuelson, F. W.] US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Chen, W (reprint author), US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM weijie.chen@fda.hhs.gov NR 18 TC 1 Z9 2 U1 0 U2 3 PU BRITISH INST RADIOLOGY PI LONDON PA 36 PORTLAND PLACE, LONDON W1N 4AT, ENGLAND SN 0007-1285 EI 1748-880X J9 BRIT J RADIOL JI Br. J. Radiol. PD AUG PY 2014 VL 87 IS 1040 AR 20140016 DI 10.1259/bjr.20140016 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AL8WF UT WOS:000339419800007 PM 24884728 ER PT J AU Reynolds, KS AF Reynolds, K. S. TI Combining Forces to Combat Infectious Diseases SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB Because the threat of infectious diseases can cause widespread fear in a community, these diseases receive much public attention. Collaborations that bring together industry, academia, regulators, and the public can lead to improved and accelerated drug development. The collaborations must be grounded in strong science and expertise in clinical trials. Development of drugs to treat infections caused by resistant bacteria, drugs to treat hepatitis C virus (HCV), and drugs to prevent HIV is taking advantage of these collaborations. C1 US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Reynolds, KS (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM kellie.reynolds@fda.hhs.gov NR 9 TC 1 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD AUG PY 2014 VL 96 IS 2 BP 123 EP 126 DI 10.1038/clpt.2014.119 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AM1JT UT WOS:000339602900001 PM 25056386 ER PT J AU Nambiar, S Laessig, K Toerner, J Farley, J Cox, E AF Nambiar, S. Laessig, K. Toerner, J. Farley, J. Cox, E. TI Antibacterial Drug Development: Challenges, Recent Developments, and Future Considerations SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID PNEUMONIA AB A decline in antibacterial drug development coupled with emerging bacterial resistance has resulted in limited treatment options. One of the challenges facing antibacterial drug development is appropriate clinical trial designs. Noninferiority trials are appropriate to study new antibacterial drugs for the treatment of serious diseases; superiority trials can be challenging and cannot be the only acceptable trial design to study antibacterial drugs. Our efforts must continue to make new therapies available to meet patient needs. C1 [Nambiar, S.; Laessig, K.] US FDA, Div Antiinfect Prod, Silver Spring, MD 20993 USA. [Toerner, J.; Farley, J.; Cox, E.] US FDA, Off Antimicrobial Prod, Silver Spring, MD USA. RP Nambiar, S (reprint author), US FDA, Div Antiinfect Prod, Silver Spring, MD 20993 USA. EM Sumathi.nambiar@fda.hhs.gov NR 7 TC 15 Z9 16 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD AUG PY 2014 VL 96 IS 2 BP 147 EP 149 DI 10.1038/mt.2014.116 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AM1JT UT WOS:000339602900019 PM 25056394 ER PT J AU Sarntivijai, S Abernethy, DR AF Sarntivijai, S. Abernethy, D. R. TI Use of Internet Search Logs to Evaluate Potential Drug Adverse Events SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID DIAGNOSES; RECORDS; SYSTEMS AB Internet search logs provide an abundant source of data that can be explored for purposes such as identifying drug exposure-adverse event relationships. The methodology to rigorously conduct such evaluations is not well characterized, and the utility of such analyses is not well defined. In this issue, White and colleagues propose an approach using Internet search logs for this purpose and compare it to parallel analyses conducted using the US Food and Drug Administration's spontaneous reporting database. C1 [Sarntivijai, S.; Abernethy, D. R.] US FDA, Silver Spring, MD 20993 USA. RP Sarntivijai, S (reprint author), US FDA, Silver Spring, MD 20993 USA. EM darrell.abernethy@fda.hhs.gov OI Sarntivijai, Sirarat/0000-0002-2548-641X NR 10 TC 4 Z9 4 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD AUG PY 2014 VL 96 IS 2 BP 149 EP 150 DI 10.1038/clpt.2014.115 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AM1JT UT WOS:000339602900020 PM 25056395 ER PT J AU Hutchison, C Kwong, A Ray, S Struble, K Swan, T Miller, V AF Hutchison, C. Kwong, A. Ray, S. Struble, K. Swan, T. Miller, V. TI Accelerating Drug Development Through Collaboration:The Hepatitis C Drug Development Advisory Group SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article AB Over the past decade, landmark collaboration between regulatory agencies, pharmaceutical companies, academia, and patient community representatives has enabled the development and approval of new hepatitis C virus (HCV) treatment regimens with unprecedented speed. By providing a neutral platform for cross-sector engagement, the Forum for Collaborative HIV Research's(1) HCV Drug Development Advisory Group played a critical role in fostering this collaboration and expediting drug development. The applicability of this model to other therapeutic areas should be explored. C1 [Hutchison, C.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Kwong, A.] InnovaTID, Cambridge, MA USA. [Ray, S.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Struble, K.] US FDA, Div Antiviral Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Swan, T.] Treatment Act Grp, New York, NY USA. [Miller, V.] Univ Calif Berkeley, Forum Collaborat HIV Res, Washington, DC USA. RP Miller, V (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. EM veronicam@berkeley.edu RI Ray, Stuart/B-7527-2008 OI Ray, Stuart/0000-0002-1051-7260 FU Abbvie; Abbott Molecular; Achillion; Boehringer Ingelheim; Bristol-Myers Squibb; Cenetron; DDL Diagnostics; Genentech; Gilead Sciences; GlaxoSmithKline; Idenix; Janssen; Merck Laboratories; Monogram; Novartis; PPD; Quest; Quintiles; Roche Molecular Diagnostics; Vertex FX The HCV DrAG is supported by unrestricted grants from Abbvie, Abbott Molecular, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb,Cenetron, DDL Diagnostics, Genentech, Gilead Sciences, GlaxoSmithKline, Idenix, Janssen, Merck Laboratories, Monogram, Novartis, PPD, Quest, Quintiles, Roche Molecular Diagnostics, and Vertex. NR 5 TC 8 Z9 8 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD AUG PY 2014 VL 96 IS 2 BP 162 EP 165 DI 10.1038/clpt.2014.113 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AM1JT UT WOS:000339602900026 PM 24853733 ER PT J AU Zhang, L Wu, F Lee, SC Zhao, H Zhang, L AF Zhang, L. Wu, F. Lee, S. C. Zhao, H. Zhang, L. TI pH-Dependent Drug-Drug Interactions for Weak Base Drugs: Potential Implications for New Drug Development SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID PROTON-PUMP INHIBITORS; ACID-REDUCING AGENTS; CONCOMITANT USE; ABSORPTION; PANTOPRAZOLE; ANTACIDS; LANSOPRAZOLE; OMEPRAZOLE; THERAPY; UPDATE AB Absorption of an orally administered drug with pH-dependent solubility may be altered when it is coadministered with a gastric acid-reducing agent (ARA). Assessing a drug's potential for pH-dependent drug-drug interactions (DDIs), considering study design elements for such DDI studies, and interpreting and communicating study results in the drug labeling to guide drug dosing are important for drug development. We collected pertinent information related to new molecular entities approved from January 2003 to May 2013 by the US Food and Drug Administration for which clinical DDI studies with ARAs were performed. On the basis of assessments of data on pH solubility and in vivo DDIs with ARAs, we proposed a conceptual framework for assessing the need for clinical pH-dependent DDI studies for weak base drugs (WBDs). Important study design considerations include selection of ARAs and timing of dosing of an ARA relative to the WBD in a DDI study. Labeling implications for drugs having DDIs with ARAs are also illustrated. C1 [Zhang, L.; Wu, F.; Lee, S. C.; Zhao, H.; Zhang, L.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Wu, F.] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. RP Zhang, L (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM leik.zhang@fda.hhs.gov FU Center for Drug Evaluation and Research FX The authors thank Issam Zineh and Shiew-Mei Huang for their valuable comments and critical review of the manuscript and Katie Pauley for her help with the initial data collection. This work was supported in part by an appointment to the Research Participation Program at the Center for Drug 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 (F.W.). The views presented are those of the authors and do not necessarily reflect the official policy of the US Food and Drug Administration. NR 31 TC 17 Z9 17 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD AUG PY 2014 VL 96 IS 2 BP 266 EP 277 DI 10.1038/clpt.2014.87 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AM1JT UT WOS:000339602900038 PM 24733008 ER PT J AU Hsieh, PH Xu, YM Keire, DA Liu, J AF Hsieh, Po-Hung Xu, Yongmei Keire, David A. Liu, Jian TI Chemoenzymatic synthesis and structural characterization of 2-O-sulfated glucuronic acid-containing heparan sulfate hexasaccharides SO GLYCOBIOLOGY LA English DT Article DE chemoenzymatic synthesis; heparan sulfate; heparin; oligosaccharides; sulfotransferase ID ANTITHROMBIN-BINDING OCTASACCHARIDES; ACTIVE PENTASACCHARIDE SEQUENCE; FIBROBLAST-GROWTH-FACTOR; MOLECULAR-WEIGHT; IDURONIC ACID; OLIGOSACCHARIDES; SULFOTRANSFERASES; BIOSYNTHESIS; CONFORMATION; ELUCIDATION AB Heparan sulfate and heparin are highly sulfated polysaccharides that consist of a repeating disaccharide unit of glucosamine and glucuronic or iduronic acid. The 2-O-sulfated iduronic acid (IdoA2S) residue is commonly found in heparan sulfate and heparin; however, 2-O-sulfated glucuronic acid (GlcA2S) is a less abundant monosaccharide (similar to < 5% of total saccharides). Here, we report the synthesis of three GlcA2S-containing hexasaccharides using a chemoenzymatic approach. For comparison purposes, additional IdoA2S-containing hexasaccharides were synthesized. Nuclear magnetic resonance analyses were performed to obtain full chemical shift assignments for the GlcA2S- and IdoA2S-hexasaccharides. These data show that GlcA2S is a more structurally rigid saccharide residue than IdoA2S. The antithrombin (AT) binding affinities of a GlcA2S- and an IdoA2S-hexasaccharide were determined by affinity co-electrophoresis. In contrast to IdoA2S-hexasaccharides, the GlcA2S-hexasaccharide does not bind to AT, confirming that the presence of IdoA2S is critically important for the anticoagulant activity. The availability of pure synthetic GlcA2S-containing oligosaccharides will allow the investigation of the structure and activity relationships of individual sites in heparin or heparan sulfate. C1 [Hsieh, Po-Hung; Xu, Yongmei; Liu, Jian] Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Keire, David A.] US FDA, CDER, Div Pharmaceut Anal, St Louis, MO 63110 USA. RP Liu, J (reprint author), Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Rm 303,Beard Hall, Chapel Hill, NC 27599 USA. EM jian_liu@unc.edu FU Food and Drug Administration [U19FD004994]; National Institutes of Health [HL094463, GM102137] FX This work is supported in part by Food and Drug Administration grant U19FD004994 and National Institutes of Health grants HL094463 and GM102137. NR 37 TC 7 Z9 8 U1 1 U2 27 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 AUG PY 2014 VL 24 IS 8 BP 681 EP 692 DI 10.1093/glycob/cwu032 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL8VO UT WOS:000339418000002 PM 24770491 ER PT J AU Sheffet, AJ Flaxman, L Tom, M Hughes, SE Longbottom, ME Howard, VJ Marler, JR Brott, TG AF Sheffet, Alice J. Flaxman, Linda Tom, MeeLee Hughes, Susan E. Longbottom, Mary E. Howard, Virginia J. Marler, John R. Brott, Thomas G. CA CREST Investigators TI Financial management of a large multisite randomized clinical trial SO INTERNATIONAL JOURNAL OF STROKE LA English DT Article DE carotid endarterectomy; carotid stenting; clinical trial; cost factors; economics; stroke ID CAROTID REVASCULARIZATION ENDARTERECTOMY; CREST AB Background The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) received five years' funding ($21 112 866) from the National Institutes of Health to compare carotid stenting to surgery for stroke prevention in 2500 randomized participants at 40 sites. Aims Herein we evaluate the change in the CREST budget from a fixed to variable-cost model and recommend strategies for the financial management of large-scale clinical trials. Methods Projections of the original grant's fixed-cost model were compared to the actual costs of the revised variable-cost model. The original grant's fixed-cost budget included salaries, fringe benefits, and other direct and indirect costs. For the variable-cost model, the costs were actual payments to the clinical sites and core centers based upon actual trial enrollment. We compared annual direct and indirect costs and per-patient cost for both the fixed and variable models. Differences between clinical site and core center expenditures were also calculated. Results Using a variable-cost budget for clinical sites, funding was extended by no-cost extension from five to eight years. Randomizing sites tripled from 34 to 109. Of the 2500 targeted sample size, 138 (5.5%) were randomized during the first five years and 1387 (55.5%) during the no-cost extension. The actual per-patient costs of the variable model were 9% ($13 845) of the projected per-patient costs ($152 992) of the fixed model. Conclusions Performance-based budgets conserve funding, promote compliance, and allow for additional sites at modest additional cost. Costs of large-scale clinical trials can thus be reduced through effective management without compromising scientific integrity. C1 [Sheffet, Alice J.; Flaxman, Linda; Tom, MeeLee; Hughes, Susan E.] Rutgers State Univ, New Jersey Med Sch, Dept Surg, Newark, NJ 07102 USA. [Longbottom, Mary E.; Brott, Thomas G.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Howard, Virginia J.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Marler, John R.] US FDA, Div Neurol Prod, CDER, Silver Spring, MD USA. RP Brott, TG (reprint author), Mayo Clin, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM brott.thomas@mayo.edu FU National Institute of Neurological Disorders and Stroke of the National Institutes of Health [NS038384]; Abbott Vascular FX The study was funded by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NS038384) with supplemental funding provided by Abbott Vascular (formerly Guidant). NR 8 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1747-4930 EI 1747-4949 J9 INT J STROKE JI Int. J. Stroke PD AUG PY 2014 VL 9 IS 6 BP 811 EP 813 DI 10.1111/ijs.12259 PG 3 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AL9RC UT WOS:000339477400026 PM 24661748 ER PT J AU Lacher, DW Gangiredla, J Jackson, SA Elkins, CA Feng, PCH AF Lacher, David W. Gangiredla, Jayanthi Jackson, Scott A. Elkins, Christopher A. Feng, Peter C. H. TI Novel Microarray Design for Molecular Serotyping of Shiga Toxin-Producing Escherichia coli Strains Isolated from Fresh Produce SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; O-ANTIGENS; IDENTIFICATION; GENE; RESTRICTION; DIVERSITY; SHIGELLA; O157-H7; CLUSTER AB Serotyping Escherichia coli is a cumbersome and complex procedure due to the existence of large numbers of O- and H-antigen types. It can also be unreliable, as many Shiga toxin-producing E. coli (STEC) strains isolated from fresh produce cannot be typed by serology or have only partial serotypes. The FDA E. coli identification (FDA-ECID) microarray, designed for characterizing pathogenic E. coli, contains a molecular serotyping component, which was evaluated here for its efficacy. Analysis of a panel of 75 reference E. coli strains showed that the array correctly identified the O and H types in 97% and 98% of the strains, respectively. Comparative analysis of 73 produce STEC strains showed that serology and the array identified 37% and 50% of the O types, respectively, and that the array was able to identify 16 strains that could not be O serotyped. Furthermore, the array identified the H types of 97% of the produce STEC strains compared to 65% by serology, including six strains that were mistyped by serology. These results show that the array is an effective alternative to serology in serotyping environmental E. coli isolates. C1 [Lacher, David W.; Gangiredla, Jayanthi; Jackson, Scott A.; Elkins, Christopher A.] US FDA, Div Mol Biol, Laurel, MD 20708 USA. [Feng, Peter C. H.] US FDA, Div Microbiol, College Pk, MD USA. RP Elkins, CA (reprint author), US FDA, Div Mol Biol, Laurel, MD 20708 USA. EM chris.elkins@fda.hhs.gov FU Center for Food Safety and Applied Nutrition FX This study was funded by the Center for Food Safety and Applied Nutrition. NR 24 TC 11 Z9 11 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD AUG PY 2014 VL 80 IS 15 BP 4677 EP 4682 DI 10.1128/AEM.01049-14 PG 6 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA AK8VX UT WOS:000338707800022 PM 24837388 ER PT J AU Feng, PCH Delannoy, S Lacher, DW dos Santos, LF Beutin, L Fach, P Rivas, M Hartland, EL Paton, AW Guth, BEC AF Feng, Peter C. H. Delannoy, Sabine Lacher, David W. dos Santos, Luis Fernando Beutin, Lothar Fach, Patrick Rivas, Marta Hartland, Elizabeth L. Paton, Adrienne W. Guth, Beatriz E. C. TI Genetic Diversity and Virulence Potential of Shiga Toxin-Producing Escherichia coli O113:H21 Strains Isolated from Clinical, Environmental, and Food Sources SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; ENTEROCYTE EFFACEMENT; SUBTILASE CYTOTOXIN; HUMANS; LOCUS; AUTOTRANSPORTER; O113-H21; MARKERS; CLUSTER; BRAZIL AB Shiga toxin-producing Escherichia coli strains of serotype O113:H21 have caused severe human diseases, but they are unusual in that they do not produce adherence factors coded by the locus of enterocyte effacement. Here, a PCR microarray was used to characterize 65 O113:H21 strains isolated from the environment, food, and clinical infections from various countries. In comparison to the pathogenic strains that were implicated in hemolytic-uremic syndrome in Australia, there were no clear differences between the pathogens and the environmental strains with respect to the 41 genetic markers tested. Furthermore, all of the strains carried only Shiga toxin subtypes associated with human infections, suggesting that the environmental strains have the potential to cause disease. Most of the O113:H21 strains were closely related and belonged in the same clonal group (ST-223), but CRISPR analysis showed a great degree of genetic diversity among the O113:H21 strains. C1 [Feng, Peter C. H.] Food & Drug Adm, Div Microbiol, College Pk, MD 20740 USA. [Delannoy, Sabine; Fach, Patrick] French Agcy Food Environm & Occupat Hlth & Safety, Lab Food Safety, Maisons Alfort, France. [Lacher, David W.] Food & Drug Adm, Div Mol Biol, Laurel, MD USA. [dos Santos, Luis Fernando; Guth, Beatriz E. C.] Univ Fed Sao Paulo, Dept Microbiol Immunol & Parasitol, Sao Paulo, Brazil. [Beutin, Lothar] Fed Inst Risk Assessment, Natl Reference Lab Escherichia coli, Berlin, Germany. [Rivas, Marta] Inst Nacl Enfermedades Infecciosas ANLIS Dr Carlo, Serv Fisiopatogenia, Buenos Aires, DF, Argentina. [Hartland, Elizabeth L.] Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Melbourne, Vic, Australia. [Paton, Adrienne W.] Univ Adelaide, Res Ctr Infect Dis, Sch Mol & Biomed Sci, Adelaide, SA, Australia. RP Feng, PCH (reprint author), Food & Drug Adm, Div Microbiol, College Pk, MD 20740 USA. EM peter.feng@fda.hhs.gov RI Hartland, Elizabeth/O-2569-2014 OI Hartland, Elizabeth/0000-0003-4254-2863 FU French Joint Ministerial Program of R&D against CBRNE Risks [C17609-2]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) of Brazil FX The microarray and CRISPR assays were developed with funding from the French Joint Ministerial Program of R&D against CBRNE Risks (grant C17609-2). The characterizations of the Brazilian strains were done with a past grant from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) of Brazil. NR 38 TC 8 Z9 8 U1 0 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD AUG PY 2014 VL 80 IS 15 BP 4757 EP 4763 DI 10.1128/AEM.01182-14 PG 7 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA AK8VX UT WOS:000338707800030 PM 24858089 ER PT J AU Pelc, RS McClure, JC Sears, KT Chung, A Rahman, MS Ceraul, SM AF Pelc, R. S. McClure, J. C. Sears, K. T. Chung, A. Rahman, M. S. Ceraul, S. M. TI Defending the fort: a role for defensin-2 in limiting Rickettsia montanensis infection of Dermacentor variabilis SO INSECT MOLECULAR BIOLOGY LA English DT Article DE tick; defensin; innate immunity; rickettsia ID HUMAN ALPHA-DEFENSINS; ANTIMICROBIAL PEPTIDES; INNATE IMMUNITY; PROTEASE INHIBITOR; ESCHERICHIA-COLI; TICK DEFENSIN; VECTOR; ESCULENTIN-1B(1-18); EXPRESSION; DROSOPHILA AB The importance of tick defensins is evidenced by their expression in a wide variety of tick tissues and prevalence across many tick genera. To date, the functional and biological significance of defensin-2 as a rickettsiastatic or rickettsiacidal antimicrobial peptide has not been addressed. In a previous study, defensin-2 transcription was shown to increase in Dermacentor variabilis ticks challenged with Rickettsia montanensis. In the present study, the hypothesis that defensin-2 is functional as a rickettsiastatic and/or rickettsiacidal antimicrobial peptide is tested. We show that defensin-2 plays a role in reducing burden after acquisition of Rickettsia montanensis through capillary feeding. Moreover, defensin-2 is shown to associate with R. montanensis in vitro and in vivo, causing cytoplasmic leakiness. C1 [Pelc, R. S.; McClure, J. C.; Sears, K. T.; Rahman, M. S.; Ceraul, S. M.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [McClure, J. C.] Irish Cattle Breeders Federat Soc Ltd, Bandon, Cork, Ireland. [Chung, A.] US FDA, Bethesda, MD 20014 USA. RP Ceraul, SM (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, HSFI Suite 380,685 West Baltimore St, Baltimore, MD 21201 USA. EM scera001@umaryland.edu OI Pelc, Rebecca/0000-0001-5080-4945 FU National Institutes of Health/National Institute of Allergy and Infectious Diseases [1K22AI08040-01A1, R01AI043006, R01AI017828] FX The authors would like to thank Dr Dan Sonenshine, Dr Kevin Macaluso, and Oklahoma State University's tick-rearing facility for the ticks used in this project. Work for this manuscript was supported by funds from the National Institutes of Health/National Institute of Allergy and Infectious Diseases 1K22AI08040-01A1 to SMC and R01AI043006 and R01AI017828 to Abdu F. Azad. The content is solely the responsibility of the authors and does not represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. NR 28 TC 3 Z9 3 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1075 EI 1365-2583 J9 INSECT MOL BIOL JI Insect Mol. Biol. PD AUG PY 2014 VL 23 IS 4 BP 457 EP 465 DI 10.1111/imb.12094 PG 9 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA AL6RL UT WOS:000339260300006 PM 24779891 ER PT J AU Horenstein, RB Madabushi, R Zineh, I Yerges-Armstrong, LM Peer, CJ Schuck, RN Figg, WD Shuldiner, AR Pacanowski, MA AF Horenstein, Richard B. Madabushi, Rajnikanth Zineh, Issam Yerges-Armstrong, Laura M. Peer, Cody J. Schuck, Robert N. Figg, William Douglas Shuldiner, Alan R. Pacanowski, Michael A. TI Effectiveness of Clopidogrel Dose Escalation to Normalize Active Metabolite Exposure and Antiplatelet Effects in CYP2C19 Poor Metabolizers SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE pharmacogenomics; clopidogrel; CYP2C19; pharmacokinetics ID PERCUTANEOUS CORONARY INTERVENTION; PLATELET REACTIVITY; TREATED PATIENTS; PRASUGREL; GENOTYPE; THERAPY; METAANALYSIS; RISK; PHARMACOGENETICS; POLYMORPHISMS AB Carriers of two copies of the loss-of-function CYP2C19*2 variant convert less clopidogrel into its active metabolite, resulting in diminished antiplatelet responses and higher cardiovascular event rates. To evaluate whether increasing the daily clopidogrel dose in poor metabolizers (PM) overcomes the effect of the CYP2C19*2 variant, we enrolled 18 healthy participants in a genotype-stratified, multi-dose, three-period, fixed-sequence crossover study. Six participants with the *1/*1 extensive (EM), *1/*2 intermediate (IM), and *2/*2 poor metabolizer genotypes each received 75 mg, 150 mg, and 300 mg each for 8 days. In each period, maximal platelet aggregation 4 hours post-dose (MPA4) and active metabolite area under the curve (AUC) differed among genotype groups (P<.05 for all). At day 8, PMs needed 300 mg daily and IMs needed 150 mg daily to attain a similar MPA4 as EMs on the 75 mg dose (32.6%, 33.2%, 31.3%, respectively). Similarly, PMs needed 300 mg daily to achieve active metabolite concentrations that were similar to EMs on 75 mg (AUC 37.7 and 33.5 ng h/mL, respectively). These results suggest that quadrupling the usual clopidogrel dose might be necessary to overcome the effect of poor CYP2C19 metabolism. C1 [Horenstein, Richard B.; Yerges-Armstrong, Laura M.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Madabushi, Rajnikanth; Zineh, Issam; Schuck, Robert N.; Pacanowski, Michael A.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Peer, Cody J.; Figg, William Douglas] NCI, Clin Pharmacol Program, Bethesda, MD 20892 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. RP Pacanowski, MA (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,White Oak Bldg 51, Silver Spring, MD 20993 USA. EM michael.pacanowski@fda.hhs.gov RI Figg Sr, William/M-2411-2016 FU National Institutes of Health [128475, U01GM074518, U01HL105198] FX This study was funded by the Bench to Bedside Program of the National Institutes of Health (128475) and the National Institutes of Health (U01GM074518 and U01HL105198). NR 32 TC 10 Z9 10 U1 0 U2 7 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 2014 VL 54 IS 8 BP 865 EP 873 DI 10.1002/jcph.293 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AL5HB UT WOS:000339163200005 PM 24710841 ER PT J AU Hariharan, S Southworth, MR Madabushi, R AF Hariharan, Sudharshan Southworth, Mary Ross Madabushi, Rajanikanth TI Clopidogrel, CYP2C19 and Proton Pump Inhibitors: What We Know and What it Means SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Editorial Material DE clinical pharmacology (CPH); drug interactions; pharmacokinetics and drug metabolism; cardiovascular (CAR); pharmacogenomics ID PERCUTANEOUS CORONARY INTERVENTION; ACTIVE METABOLITE; HEALTHY-SUBJECTS; PLATELET REACTIVITY; ANTIAGGREGATING ACTIVITY; CARDIOVASCULAR EVENTS; MAJOR DETERMINANT; CYTOCHROMES P450; OMEPRAZOLE; PHARMACODYNAMICS C1 [Hariharan, Sudharshan; Madabushi, Rajanikanth] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Southworth, Mary Ross] US FDA, Div Cardiovasc & Renal Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Madabushi, R (reprint author), 10903 New Hampshire Ave,White Oak Bldg 51,Rm 2173, Silver Spring, MD 20993 USA. EM Rajnikanth.Madabushi@fda.hhs.gov NR 41 TC 3 Z9 3 U1 0 U2 6 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 2014 VL 54 IS 8 BP 884 EP 888 DI 10.1002/jcph.337 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AL5HB UT WOS:000339163200008 PM 25044100 ER PT J AU De Paoli, SH Diduch, LL Tegegn, TZ Orecna, M Strader, MB Karnaukhova, E Bonevich, JE Holada, K Simak, J AF De Paoli, Silvia H. Diduch, Lukas L. Tegegn, Tseday Z. Orecna, Martina Strader, Michael B. Karnaukhova, Elena Bonevich, John E. Holada, Karel Simak, Jan TI The effect of protein corona composition on the interaction of carbon nanotubes with human blood platelets SO BIOMATERIALS LA English DT Article DE Carbon nanotubes; Nanoparticles; Platelets; Biocompatibility; Nanotoxicity; Protein corona ID CRYSTAL-STRUCTURE; CONFORMATIONAL-CHANGES; HUMAN FIBRINOGEN; DRUG-DELIVERY; CALCIUM-ENTRY; SURFACE; NANOPARTICLES; ADSORPTION; ALBUMIN; BINDING AB Carbon nanotubes (CNT) are one of the most promising nanomaterials for use in medicine. The blood biocompatibility of CNT is a critical safety issue. In the bloodstream, proteins bind to CNT through non-covalent interactions to form a protein corona, thereby largely defining the biological properties of the CNT. Here, we characterize the interactions of carboxylated-multiwalled carbon nanotubes (CNTCOOH) with common human proteins and investigate the effect of the different protein coronas on the interaction of CNTCOOH with human blood platelets (PLT). Molecular modeling and different photophysical techniques were employed to characterize the binding of albumin (HSA), fibrinogen (FBG), gamma-globulins (IgG) and histone H1 (H1) on CNTCOOH. We found that the identity of protein forming the corona greatly affects the outcome of CNTCOOH's interaction with blood PLT. Bare CNTCOOH-induced PLT aggregation and the release of platelet membrane microparticles (PMP). HSA corona attenuated the PLT aggregating activity of CNTCOOH, while FBG caused the agglomeration of CNTCOOH nanomaterial, thereby diminishing the effect of CNTCOOH on PLT. In contrast, the IgG corona caused PLT fragmentation, and the NI corona induced a strong PLT aggregation, thus potentiating the release of PMP. Published by Elsevier Ltd. C1 [De Paoli, Silvia H.; Tegegn, Tseday Z.; Orecna, Martina; Strader, Michael B.; Karnaukhova, Elena; Simak, Jan] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Holada, Karel] Charles Univ Prague, Fac Med 1, Inst Microbiol & Immunol, Prague, Czech Republic. [Diduch, Lukas L.; Bonevich, John E.] NIST, Gaithersburg, MD 20899 USA. RP Simak, J (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM jan.simak@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration; Ministry of Education, Youth and Sports of Czech Republic [LH12014]; Charles University in Prague [PRVOUK-P24/LF1/3]; FDA CORES FX This project was supported in part by an appointment to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through and interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. In addition, the study was supported in part by the grant LH12014 of the Ministry of Education, Youth and Sports of Czech Republic. KH was supported by project of Charles University in Prague: PRVOUK-P24/LF1/3. The study was supported by FDA CORES. NR 54 TC 24 Z9 24 U1 1 U2 66 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD AUG PY 2014 VL 35 IS 24 BP 6182 EP 6194 DI 10.1016/j.biomaterials.2014.04.067 PG 13 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA AL0GD UT WOS:000338804500005 PM 24831972 ER PT J AU Chen, S Xuan, JK Couch, L Iyer, A Wu, YF Li, QZ Guo, L AF Chen, Si Xuan, Jiekun Couch, Letha Iyer, Advait Wu, Yuanfeng Li, Quan-Zhen Guo, Lei TI Sertraline induces endoplasmic reticulum stress in hepatic cells SO TOXICOLOGY LA English DT Article DE Apoptosis; Endoplasmic reticulum stress; Drug-induced liver toxicity; Reporter gene assay; Sertraline; MAPK pathway ID METHAPYRILENE-INDUCED HEPATOTOXICITY; GENE-EXPRESSION CHANGES; INDUCED LIVER-INJURY; OF-THE-LITERATURE; MITOCHONDRIAL DYSFUNCTION; ER STRESS; PROTEIN-SYNTHESIS; CULTURED-CELLS; MOUSE-LIVER; IN-VITRO AB Sertraline is used for the treatment of depression, and is also used for the treatment of panic, obsessive-compulsive, and post-traumatic stress disorders. Previously, we have demonstrated that sertraline caused hepatic cytotoxicity, with mitochondrial dysfunction and apoptosis being underlying mechanisms. In this study, we used microarray and other biochemical and molecular analyses to identify endoplasmic reticulum (ER) stress as a novel molecular mechanism. HepG2 cells were exposed to sertraline and subjected to whole genome gene expression microarray analysis. Pathway analysis revealed that ER stress is among the significantly affected biological changes. We confirmed the increased expression of ER stress makers by real-time PCR and Western blots. The expression of typical ER stress markers such as PERK, IRE1 alpha, and CHOP was significantly increased. To study better ER stress-mediated drug-induced liver toxicity; we established in vitro systems for monitoring ER stress quantitatively and efficiently, using Gaussia luciferase (Gluc) and secreted alkaline phosphatase (SEAP) as ER stress reporters. These in vitro systems were validated using well-known ER stress inducers. In these two reporter assays, sertraline inhibited the secretion of Gluc and SEAP. Moreover, we demonstrated that sertraline-induced apoptosis was coupled to ER stress and that the apoptotic effect was attenuated by 4-phenylbutyrate, a potent ER stress inhibitor. In addition, we showed that the MAP4K4-JNK signaling pathway contributed to the process of sertraline-induced ER stress. In summary, we demonstrated that ER stress is a mechanism of sertraline-induced liver toxicity. Published by Elsevier Ireland Ltd. C1 [Chen, Si; Xuan, Jiekun; Couch, Letha; Iyer, Advait; Wu, Yuanfeng; Guo, Lei] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Iyer, Advait] Univ Maryland, Baltimore, MD 21250 USA. [Li, Quan-Zhen] Univ Texas SW Med Ctr Dallas, Microarray Core Facil, Dept Immunol & Internal Med, Dallas, TX 75390 USA. RP Guo, L (reprint author), 3900 NCTR Rd,HFT-110, Jefferson, AR 72079 USA. EM Lei.Guo@fda.hhs.gov RI Wu, Yuanfeng/O-2920-2014 OI Wu, Yuanfeng/0000-0001-6390-3635 FU NCTR Summer Science Research Program; Postgraduate Research Program at the National Center for Toxicological Research FX SC, JX, and YW were supported by appointments to the Postgraduate Research Program at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science Education through an interagency agreement between the U.S. Department of Energy and the U.S. FDA. AI was supported by NCTR Summer Science Research Program. We thank Drs. William Melchior and Vasily Dobrovolsky for their critical review of this manuscript. NR 48 TC 17 Z9 17 U1 3 U2 15 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 AUG 1 PY 2014 VL 322 BP 78 EP 88 DI 10.1016/j.tox.2014.05.007 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AL2TQ UT WOS:000338978800009 PM 24865413 ER PT J AU Silverstein, DM Fletcher, A Moylan, K AF Silverstein, Douglas M. Fletcher, Angela Moylan, Kathleen TI Barriers to medication adherence and its relationship with outcomes in pediatric dialysis patients SO PEDIATRIC NEPHROLOGY LA English DT Article DE Chronic disease; Peritoneal dialysis; Hemodialysis; Children ID ADOLESCENT TRANSPLANT RECIPIENTS; HEMODIALYSIS; ADJUSTMENT; MANAGEMENT; CHILDREN; DISEASE AB Medication adherence is a major factor determining outcome in children with chronic disease. Children with end-stage renal disease are challenged with requirements for renal replacement therapy in addition to complicated medication regimens. We assessed barriers to medication adherence in 22 pediatric patients receiving chronic dialysis [63.6 % hemodialysis (HD), 36.4 % peritoneal dialysis (PD); age 15.9 +/- 0.7 years, dialysis vintage 31.6 +/- 6.5 months]. Adherence was assessed by a 16-question survey with a maximum score (difficulty) of 64. The overall mean adherence score was 30.9 +/- 2.4 (range 16-49; median 27.5). There was a trend for lower adherence scores in patients on HD (27.5 +/- 2.9) compared to those on PD (36.8 +/- 3.7) (p = 0.06). Compared to HD patients, the mean score/question was significantly higher in PD patients (1.7 +/- 0.2 vs. 2.4 +/- 0.2, respectively; p = 0.006). Of the 16 questions, HD and PD patients gave a mean response of a parts per thousand currency sign1.2 for five and zero questions, respectively. Neither gender, age nor dialysis vintage was related to adherence scores. There was also a trend for adherence scores to be higher in females (35.6 +/- 3.7) than in males (27.5 +/- 2.9) (p = 0.1), but this difference did not reach statistical significance. Markers of mineral bone disease were similar in HD and PD patients. Among all targets in HD and PD patients combined, there was no relationship between adherence scores and number of targets reached (r = -0.09, p = 0.7). There are many barriers to medication adherence in pediatric patients receiving dialysis. In our patient group the difficulties were more evident in patients receiving PD than in those receiving HD. C1 [Silverstein, Douglas M.] US FDA, Off Device Evaluat, Renal Devices Branch RNDB, Silver Spring, MD 20903 USA. [Fletcher, Angela] Childrens Natl Med Ctr, Childrens Natl Sheikh Zayed Inst, Washington, DC 20010 USA. [Moylan, Kathleen] DaVita Hlth Care Partners, Denver, CO USA. RP Silverstein, DM (reprint author), US FDA, Off Device Evaluat, Renal Devices Branch RNDB, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM dsilverstein2001@yahoo.com NR 17 TC 2 Z9 2 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X EI 1432-198X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD AUG PY 2014 VL 29 IS 8 BP 1425 EP 1430 DI 10.1007/s00467-014-2780-0 PG 6 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA AK8TH UT WOS:000338700400018 PM 24566813 ER PT J AU Lerner, HP AF Lerner, Herbert P. TI SAGES guidelines for the introduction of new technology and techniques SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES LA English DT Editorial Material C1 US FDA, Silver Spring, MD 20993 USA. RP Lerner, HP (reprint author), US FDA, Silver Spring, MD 20993 USA. EM herbert.lerner@fda.hhs.gov NR 1 TC 0 Z9 0 U1 0 U2 1 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 AUG PY 2014 VL 28 IS 8 BP 2255 EP 2256 DI 10.1007/s00464-014-3641-4 PG 2 WC Surgery SC Surgery GA AK9RK UT WOS:000338764200001 PM 24969851 ER PT J AU Baker, BA Pine, PS Chatterjee, K Kumar, G Lin, NJ McDaniel, JH Salit, ML Simon, CG AF Baker, Bryan A. Pine, P. Scott Chatterjee, Kaushik Kumar, Girish Lin, Nancy J. McDaniel, Jennifer H. Salit, Marc L. Simon, Carl G., Jr. TI Ontology analysis of global gene expression differences of human bone marrow stromal cells cultured on 3D scaffolds or 2D films SO BIOMATERIALS LA English DT Article DE 3D scaffolds; Cell differentiation; Cell-material interactions; Human bone marrow stromal cells; mRNA microarrays; Pathway analysis ID MESENCHYMAL STEM-CELLS; GROWTH-FACTOR-BETA; TGF-BETA; OSTEOBLAST DIFFERENTIATION; CHONDROGENIC DIFFERENTIATION; OSTEOGENIC DIFFERENTIATION; MORPHOGENETIC PROTEIN; NANOFIBROUS SCAFFOLDS; COLLAGEN; LINEAGES AB Differences in gene expression of human bone marrow stromal cells (hBMSCs) during culture in three-dimensional (3D) nanofiber scaffolds or on two-dimensional (2D) films were investigated via pathway analysis of microarray mRNA expression profiles. Previous work has shown that hBMSC culture in nanofiber scaffolds can induce osteogenic differentiation in the absence of osteogenic supplements (OS). Analysis using ontology databases revealed that nanofibers and OS regulated similar pathways and that both were enriched for TGF-beta and cell-adhesion/ECM-receptor pathways. The most notable difference between the two was that nanofibers had stronger enrichment for cell-adhesion/ECM-receptor pathways. Comparison of nanofibers scaffolds with flat films yielded stronger differences in gene expression than comparison of nanofibers made from different polymers, suggesting that substrate structure had stronger effects on cell function than substrate polymer composition. These results demonstrate that physical (nanofibers) and biochemical (OS) signals regulate similar ontological pathways, suggesting that these cues use similar molecular mechanisms to control hBMSC differentiation. Published by Elsevier Ltd. C1 [Baker, Bryan A.; Pine, P. Scott; Chatterjee, Kaushik; Kumar, Girish; Lin, Nancy J.; McDaniel, Jennifer H.; Salit, Marc L.; Simon, Carl G., Jr.] NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. [Chatterjee, Kaushik] Indian Inst Sci, Dept Mat Engn, Bangalore 560012, Karnataka, India. [Kumar, Girish] US FDA, Div Biol, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Simon, CG (reprint author), NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. EM carl.simon@nist.gov FU NIST-ARRA NRC Research Associateship; NIH-NIBIB/NIST NRC Research Associateship; NCRR of the NIH [P40RR017447] FX B.A.B. was supported by NIST-ARRA NRC Research Associateship. G.K. and K.C. were supported by NIH-NIBIB/NIST NRC Research Associateship. hBMSCs employed in this work were provided by the Tulane Center for Gene Therapy through a grant from NCRR of the NIH P40RR017447. The authors would like to acknowledge Sumona Sarkar, Dongbo Wang, Swarnavo Sarkar, and Subhadip Bodhak for helpful discussions. This manuscript is a contribution of NIST, and therefore is not subject to copyright in the United States. Certain equipment, instruments or materials are identified in this paper in order to adequately specify the experimental details. Such identification does not imply recommendation by the NIST nor does it imply the materials are necessarily the best available for the purpose. NR 46 TC 7 Z9 7 U1 3 U2 28 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD AUG PY 2014 VL 35 IS 25 BP 6716 EP 6726 DI 10.1016/j.biomaterials.2014.04.075 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA AK4IB UT WOS:000338386800006 PM 24840613 ER PT J AU Schneiderman, N Llabre, M Cowie, C Barnhart, J Carnethon, M Gallo, L Giachello, A Heiss, G Kaplan, R LaVange, L Teng, Y Villa-Caballero, L Aviles-Santa, L AF Schneiderman, N. Llabre, M. Cowie, C. Barnhart, J. Carnethon, M. Gallo, L. Giachello, A. Heiss, G. Kaplan, R. LaVange, L. Teng, Y. Villa-Caballero, L. Aviles-Santa, L. TI DIABETES DISPARITIES AMONG US LATINOS/HISPANICS FROM DIVERSE BACKGROUNDS SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract CT INTERNATIONAL CONGRESS OF BEHAVIORAL MEDICINE (ICBM 2014) CY AUG 14-17, 2014 CL Brainerd, MN C1 [Schneiderman, N.; Llabre, M.] Univ Miami, Coral Gables, FL 33124 USA. [Cowie, C.] Natl Inst Diabet, Bethesda, MD USA. [Barnhart, J.; Kaplan, R.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Carnethon, M.; Giachello, A.] Northwestern, Chicago, IL USA. [Gallo, L.; Villa-Caballero, L.] San Diego State Univ, San Diego, CA 92182 USA. [Heiss, G.; Teng, Y.] Univ N Carolina, Chapel Hill, NC USA. [LaVange, L.] US FDA, US Dept HHS, Silver Spring, MD USA. [Aviles-Santa, L.] NHLBI, NIH, Bethesda, MD 20892 USA. EM nschneid@miami.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD AUG PY 2014 VL 21 SU 1 MA S440 BP S132 EP S132 PG 1 WC Psychology, Clinical SC Psychology GA V45KS UT WOS:000209816100456 ER PT J AU Wang, X Tan, JY Zhao, JQ Ragupathy, V Haleyurgirisetty, M Hewlett, I AF Wang, Xue Tan, Jiying Zhao, Jiangqin Ragupathy, Viswannath Haleyurgirisetty, Mohan Hewlett, Indira TI Some findings of FADD knockdown in inhibition of HIV-1 replication in Jurkat cells and PBMCs SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE Apoptosis; FADD; HIV-1; Replication; Lipid raft; NF-kappa B ID NF-KAPPA-B; LIPID RAFTS; APOPTOTIC PATHWAYS; ACTIVATION; INFECTION; CASPASE-8; RECEPTOR; PHOSPHORYLATION; ANTIGEN; ENTRY AB Fas-associated protein with death domain (FADD) is a key adaptor molecule transmitting the death signal mediated by death receptors, and it is also required for T cell proliferation. A recent study indicated that FADD is able to affect HIV-1 production, but the mechanism is not known. Using the susceptible Jurkat cell line and peripheral blood mononuclear cells, we studied the effects of FADD on HIV-1 production. TaqMan RT-PCR was used to quantify HIV-1 viral RNA copies, and Western blot analysis was used to detect protein expression. FADD knockdown decreased HIV-1 replication and inactivated caspase-3 activity in the cells and blocked CD4 translocation to the lipid rafts of the plasma membrane. Reduced expression of FADD suppressed TCR signaling through downregulation of TCR, CD3, and Zap-70 in response to HIV-1 infection and blocked the trafficking of TCR, CD3, CD28, and Zap-70 to lipid rafts, leading to reduced activation of NF-kappa B and NFAT, which are required for HIV-1 replication. FADD knockdown diminished caspase-8 migration to lipid rafts and its expression in response to HIV-1 infection. These results indicate that FADD, as a host pro-apoptotic protein, plays important roles in regulating HIV-1 replication and production in several ways, and apoptotic pathway inhibition is able to decrease HIV-1 replication and production. C1 [Wang, Xue; Tan, Jiying; Zhao, Jiangqin; Ragupathy, Viswannath; Haleyurgirisetty, Mohan; Hewlett, Indira] US FDA, Mol Virol Lab, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Wang, X (reprint author), US FDA, Mol Virol Lab, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Bldg 29B,Rm 4NN22 8800 Rockville Pike, Bethesda, MD 20892 USA. EM xue.wang@fda.hhs.gov; indira.hewlett@fda.hhs.gov RI Haleyur Giri Setty, Mohan Kumar/F-5841-2014 OI Haleyur Giri Setty, Mohan Kumar/0000-0001-6423-1420 NR 38 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-8177 EI 1573-4919 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD AUG PY 2014 VL 393 IS 1-2 BP 181 EP 190 DI 10.1007/s11010-014-2058-7 PG 10 WC Cell Biology SC Cell Biology GA AK3TX UT WOS:000338348700019 PM 24752353 ER PT J AU Wells, EM Navas-Acien, A Apelberg, BJ Herbstman, JB Jarrett, JM Lin, YH Verdon, CP Ward, C Caldwell, KL Hibbeln, JR Halden, RU Witter, FR Goldman, LR AF Wells, E. M. Navas-Acien, A. Apelberg, B. J. Herbstman, J. B. Jarrett, J. M. Lin, Y. H. Verdon, C. P. Ward, C. Caldwell, K. L. Hibbeln, J. R. Halden, R. U. Witter, F. R. Goldman, L. R. TI Association of selenium and copper with lipids in umbilical cord blood SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Article DE copper; infant; newborn; selenium; total cholesterol; triglyceride ID CARDIOVASCULAR RISK-FACTORS; SERUM SELENIUM; GLUTATHIONE-PEROXIDASE; RANDOMIZED-TRIAL; TRACE-ELEMENTS; HEART-DISEASE; YOUNG FINNS; ADULTS; ZINC; SUPPLEMENTATION AB Altered levels of selenium and copper have been linked with altered cardiovascular disease risk factors including changes in blood triglyceride and cholesterol levels. However, it is unclear whether this can be observed prenatally. This cross-sectional study includes 274 singleton births from 2004 to 2005 in Baltimore, Maryland. We measured umbilical cord serum selenium and copper using inductively coupled plasma mass spectrometry. We evaluated exposure levels vis-a-vis umbilical cord serum triglyceride and total cholesterol concentrations in multivariable regression models adjusted for gestational age, birth weight, maternal age, race, parity, smoking, prepregnancy body mass index, n-3 fatty acids and methyl mercury. The percent difference in triglycerides comparing those in the highest v. lowest quartile of selenium was 22.3% (95% confidence interval (CI): 7.1, 39.7). For copper this was 43.8% (95% CI: 25.9, 64.3). In multivariable models including both copper and selenium as covariates, copper, but not selenium, maintained a statistically significant association with increased triglycerides (percent difference: 40.7%, 95% CI: 22.1, 62.1). There was limited evidence of a relationship of increasing selenium with increasing total cholesterol. Our findings provide evidence that higher serum copper levels are associated with higher serum triglycerides in newborns, but should be confirmed in larger studies. C1 [Wells, E. M.] Purdue Univ, Sch Hlth Sci, W Lafayette, IN 47907 USA. [Navas-Acien, A.; Halden, R. U.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Navas-Acien, A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Apelberg, B. J.] US FDA, Off Policy, Ctr Tobacco Prod, Rockville, MD 20857 USA. [Herbstman, J. B.] Columbia Univ, Mailman Sch Publ Hlth, Columbia Ctr Childrens Environm Hlth, New York, NY USA. [Jarrett, J. M.; Verdon, C. P.; Ward, C.; Caldwell, K. L.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Div Sci Lab, Atlanta, GA USA. [Lin, Y. H.; Hibbeln, J. R.] NIAAA, NIH, Rockville, MD 20852 USA. [Halden, R. U.] Arizona State Univ, Biodesign Inst, Ctr Environm Secur, Tempe, AZ USA. [Witter, F. R.] Johns Hopkins Univ, Sch Med, Dept Obstet & Gynecol, Baltimore, MD 21205 USA. [Goldman, L. R.] George Washington Univ, Sch Publ Hlth & Hlth Serv, Washington, DC USA. RP Wells, EM (reprint author), Purdue Univ, Sch Hlth Sci, 550 Stadium Mall Dr,HAMP 1269, W Lafayette, IN 47907 USA. EM wells54@purdue.edu RI Halden, Rolf/F-9562-2010; OI Halden, Rolf/0000-0001-5232-7361; Wells, Ellen/0000-0002-7293-1395; Jarrett, Jeffery/0000-0001-5755-3552 FU Maryland Cigarette Restitution Program Research Grant; United States National Institute for Environmental Health Sciences [1R01ES015445]; United States STAR Fellowship Program FX This study received funding from the Maryland Cigarette Restitution Program Research Grant, the United States National Institute for Environmental Health Sciences (R.U.H., grant #: 1R01ES015445), and the United States STAR Fellowship Program (E.M.W.). NR 46 TC 2 Z9 2 U1 1 U2 9 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 EI 2040-1752 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD AUG PY 2014 VL 5 IS 4 BP 281 EP 287 DI 10.1017/S2040174414000233 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AJ5VN UT WOS:000337758200002 PM 24965134 ER PT J AU Marchiondo, AA Kornele, M O'Brien, A Phillippi-Taylor, A AF Marchiondo, Alan A. Kornele, Michelle O'Brien, Anna Phillippi-Taylor, Aimee TI Preface SO VETERINARY PARASITOLOGY LA English DT Editorial Material C1 [Marchiondo, Alan A.] Amer Assoc Vet Parasitologists, Kalamazoo, MI 49007 USA. [Marchiondo, Alan A.] Zoetis, Global Therapeut Res, Late Stage Antiparasit, Kalamazoo, MI 49007 USA. [Kornele, Michelle; O'Brien, Anna; Phillippi-Taylor, Aimee] FDA, Ctr Vet Med, Off New Anim Drug Evaluat, Rockville, MD 20855 USA. RP Marchiondo, AA (reprint author), Amer Assoc Vet Parasitologists, 333 Portage Rd, Kalamazoo, MI 49007 USA. EM alan.marchiondo@zoetis.com NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4017 EI 1873-2550 J9 VET PARASITOL JI Vet. Parasitol. PD JUL 30 PY 2014 VL 204 IS 1-2 SI SI BP 1 EP 2 DI 10.1016/j.vetpar.2014.04.010 PG 2 WC Parasitology; Veterinary Sciences SC Parasitology; Veterinary Sciences GA AN8JJ UT WOS:000340850100001 ER PT J AU Chen, YF Zhang, XM Tamura, RN Chen, CM AF Chen, Yeh-Fong Zhang, Xiangmin Tamura, Roy N. Chen, Chiung M. TI A sequential enriched design for target patient population in psychiatric clinical trials SO STATISTICS IN MEDICINE LA English DT Article DE sequential enriched design; sequential parallel design; two-way enriched design; enrichment design; placebo response ID MAJOR DEPRESSIVE DISORDER; PLACEBO RUN-IN; DOUBLE-BLIND; EXPLORATORY ANALYSES; DRUG APPLICATIONS; EFFICACY DATA; THERAPY; SUPPORT AB High placebo response is widely believed to be one major reason why many psychiatric clinical trials fail to demonstrate drug efficacy. In order to alleviate this problem, research has developed several enrichment designs, including the parallel design with a placebo lead-in phase, the sequential parallel design, and a recently proposed two-way enriched design. While these designs have been evaluated and discussed individually, their effectiveness against each other has not been rigorously compared. The current study examines the various enrichment designs simultaneously. Building on their strengths, we introduce a new improved design named 'sequential enriched design' (SED) aimed at removing not only patients with high placebo response but also patients who do not respond to any treatment from the study. The SED begins with a double-blind placebo lead-in phase followed by a traditional parallel design in the first stage. Only patients who respond to the drug in the first stage are re-randomized to the drug or placebo at the second stage. We simulate data for a mixed population composed of four subgroups of patients who are predetermined as to whether they respond to drug or not as well as to placebo or not. By focusing on the target patients whose responses reflect the drug's efficacy, we evaluate the bias, mean squared error, and power for different designs. We demonstrate that the SED produces a less biased estimate for the target treatment effect and yields reasonably high power in general compared with the other designs. Copyright (C) 2014 John Wiley & Sons, Ltd. C1 [Chen, Yeh-Fong] US FDA, Div Biometr 1, Off Biostat, Off Translat Sci,CDER, Silver Spring, MD USA. [Zhang, Xiangmin] Univ Iowa, Dept Stat & Actuarial Sci, Iowa City, IA 52242 USA. [Tamura, Roy N.] Univ S Florida, Pediat Epidemiol Ctr, Tampa, FL USA. [Chen, Chiung M.] CSR Inc, Arlington, VA USA. RP Chen, YF (reprint author), US FDA, Off Biostat, Off Translat Sci, CDER, 10903 New Hampshire Ave,Bldg 21,Room 4610, Silver Spring, MD 20993 USA. EM yehfong.chen@fda.hhs.gov NR 19 TC 0 Z9 0 U1 0 U2 4 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 JUL 30 PY 2014 VL 33 IS 17 BP 2953 EP 2967 DI 10.1002/sim.6116 PG 15 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 AL3ZO UT WOS:000339071900006 PM 25927082 ER PT J AU Breger, JC Sapsford, KE Ganek, J Susumu, K Stewart, MH Medintz, IL AF Breger, Joyce C. Sapsford, Kim E. Ganek, Jessica Susumu, Kimihiro Stewart, Michael H. Medintz, Igor L. TI Detecting Kallikrein Proteolytic Activity with Peptide-Quantum Dot Nanosensors SO ACS APPLIED MATERIALS & INTERFACES LA English DT Article DE fluorescence; nanoparticle; biosensor; quantum dot; FRET; enzyme; protease; kallikrein; substrate; K-m nanocrystal; blood clotting; adulterant; assay ID RESONANCE ENERGY-TRANSFER; OVERSULFATED CHONDROITIN SULFATE; ADVERSE CLINICAL EVENTS; ENZYME-ACTIVITY; HUMAN-PLASMA; PROTEASE; HEPARIN; CONTAMINATION; PRODUCTS; AUTOACTIVATION AB Contamination and adulterants in both naturally derived and synthetic drugs pose a serious threat to the worldwide medical community. Developing rapid and sensitive sensors/devices to detect these hazards is thus a continuing need. We describe a hydrophilic semiconductor quantum dot (QD)-peptide Forster resonance energy transfer (FRET) nanosensor for monitoring the activity of kallikrein, a key proteolytic enzyme functioning at the initiation of the blood clotting cascade. Kallikrein is also activated by the presence of an oversulfated contaminant recently found in preparations of the drug heparin. Quantitatively monitoring the activity of this enzyme within a nanosensor format has proven challenging because of inherent steric and kinetic considerations. Our sensor is designed around a central QD donor platform which displays controlled ratios of a modular peptidyl substrate. This peptide, in turn, sequentially expresses a terminal oligohistidine motif that mediates the rapid self-assembly of peptides to the QD surface, a linker-spacer sequence to extend the peptide away from the QD surface, a kallikrein recognized-cleavage site, and terminates in an acceptor dye-labeling site. Hydrophilic QDs prepared with compact, zwitterionic surface coatings were first evaluated for their ability to self-assemble the dye-labeled peptide substrates. An optimized two-step protocol was then utilized where high concentrations of peptide were initially digested with purified human kallikrein and samples collected at distinct time points were subsequently diluted into QD-containing solutions for assaying. This sensor provided a quantitative FRET-based readout for monitoring kallikrein activity and comparison to a calibration curve allowed estimation of the relevant Michaelis-Menten kinetic descriptors. The results further suggest that almost any protease should be amenable to a QD-based FRET assay format with appropriate design considerations. C1 [Breger, Joyce C.; Medintz, Igor L.] US Naval Res Lab, Ctr Bio Mol Sci & Engn, Washington, DC 20375 USA. [Susumu, Kimihiro; Stewart, Michael H.] US Naval Res Lab, Opt Sci Div, Washington, DC 20375 USA. [Breger, Joyce C.] Amer Soc Engn Educ, Washington, DC 20036 USA. [Sapsford, Kim E.; Ganek, Jessica] US FDA, OMPT CDRH OSEL DB, Silver Spring, MD 20993 USA. [Susumu, Kimihiro] Sotera Def Solut Inc, Columbia, MD 21046 USA. RP Medintz, IL (reprint author), US Naval Res Lab, Ctr Bio Mol Sci & Engn, Code 6900, Washington, DC 20375 USA. EM igor.medintz@nrl.navy.mil FU NRL-NSI; ONR; DTRA; Office of the Chief Scientist; Division of Biology FDA FX Financial support is gratefully acknowledged from the NRL-NSI, ONR, and DTRA. K.E.S would like to thank Office of the Chief Scientist and Division of Biology FDA for financial support. Postdoctoral fellowship for J.C.B. administered by the American Society for Engineering Education (ASEE). NR 44 TC 17 Z9 17 U1 4 U2 71 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 JUL 23 PY 2014 VL 6 IS 14 BP 11529 EP 11535 DI 10.1021/am502135h PG 7 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA AL9PB UT WOS:000339472100087 PM 25003700 ER PT J AU Srigley, CT Rader, JI AF Srigley, Cynthia Tyburczy Rader, Jeanne I. TI Content and Composition of Fatty Acids in Marine Oil Omega-3 Supplements SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE marine oil; SLB-IL111; EPA; DHA; trans PUFA; dietary supplement ID GAS CHROMATOGRAPHIC COLUMN; FISH-OIL; MASS-SPECTROMETRY; CARDIOVASCULAR-DISEASE; METHYL-ESTERS; OMEGA-3-FATTY-ACIDS; DEODORIZATION; SEPARATIONS; MICROALGAE; CAPSULES AB Marine oil omega-3 supplements are among the most frequently consumed dietary supplements in the United States. However, few studies have evaluated the overall fatty acid composition of these products. We investigated the content and composition of fatty acids in 46 commercially available marine oil omega-3 supplements by gas chromatography with flame ionization detection using the 200 m SLB-IL111 ionic liquid column. Seventy-three fatty acid isomers were quantified, including n-6, n-4, n-3, and n-1 polyunsaturated fatty acids and trans isomers of eicosapentaenoic acid (EPA; C20:5n-3) and docosahexaenoic acid (DHA; C22:6n-3), the chromatographic separations of which we report for the first time on the 200 m SLB-IL111 column. Contents of EPA and DHA met their respective label declarations in more than 80% of the products examined. Eleven of the products (2496) carried the Food and Drug Administration's qualified health claim for EPA and DHA omega-3 fatty acids. C1 [Srigley, Cynthia Tyburczy; Rader, Jeanne I.] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Srigley, CT (reprint author), US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM cynthia.srigley@fda.hhs.gov NR 37 TC 5 Z9 5 U1 0 U2 34 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 JUL 23 PY 2014 VL 62 IS 29 SI SI BP 7268 EP 7278 DI 10.1021/jf5016973 PG 11 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA AL9OY UT WOS:000339471800045 PM 25003526 ER PT J AU Deng, L Ma, L Virata-Theimer, ML Zhong, LL Yan, HL Zhao, Z Struble, E Feinstone, S Alter, H Zhang, P AF Deng, Lu Ma, Li Virata-Theimer, Maria Luisa Zhong, Lilin Yan, Hailing Zhao, Zhong Struble, Evi Feinstone, Stephen Alter, Harvey Zhang, Pei TI Discrete conformations of epitope II on the hepatitis C virus E2 protein for antibody-mediated neutralization and nonneutralization SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunoglobulins; prophylaxis; vaccine ID GP120 V3 LOOP; ALTERNATIVE CONFORMATIONS; CORECEPTOR SELECTIVITY; BETA-HAIRPINS; BINDING; CD81; COMPLEXES; INFECTION; REGIONS; MODE AB The X-ray crystal structure of epitope II on the E2 protein of hepatitis C virus, in complex with nonneutralizing antibody mAb#12, has been solved at 2.90-angstrom resolution. The spatial arrangement of the essential components of epitope II (ie, the C-terminal a-helix and the N-terminal loop) was found to deviate significantly from that observed in those corresponding complexes with neutralizing antibodies. The distinct conformations are mediated largely by the flexibility of a highly conserved glycine residue that connects these components. Thus, it is the particular tertiary structure of epitope II, which is presented in a spatial and temporal manner, that determines the specificity of antibody recognition and, consequently, the outcome of neutralization or nonneutralization. C1 [Deng, Lu; Ma, Li; Virata-Theimer, Maria Luisa; Zhong, Lilin; Yan, Hailing; Zhao, Zhong; Struble, Evi; Zhang, Pei] US FDA, Ctr Biol Evaluat & Res, Off Blood Res & Review, Div Hematol, Bethesda, MD 20892 USA. [Feinstone, Stephen] George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Med, Washington, DC 20037 USA. [Alter, Harvey] Warren Grant Magnuson Clin Ctr, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. RP Alter, H (reprint author), Warren Grant Magnuson Clin Ctr, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. EM halter@dtm.cc.nih.gov; pei.zhang@fda.hhs.gov FU US Department of Energy Offices of Biological and Environmental Research and Basic Energy Sciences; National Center for Research Resources of the National Institutes of Health; CBER; FDA; Research Participation Program at CBER FX We thank Dr. John Finlayson for his comments on the manuscript, Dr. Tsan Xiao and Dr. Tengchuan Jin (National Institute of Allergy and Infectious Diseases) for providing the instrument for crystallization screening, Dr. Hongying Duan (CBER/FDA) for providing the monoclonal antibody reagents, and the FDA CBER Core Laboratory for assisting in protein sequence analysis. We also thank Howard Robinson (Brookhaven National Synchrotron Light Source) for X-ray data collection. Beamline X29 is supported by the US Department of Energy Offices of Biological and Environmental Research and Basic Energy Sciences and by the National Center for Research Resources of the National Institutes of Health. This study was funded by a Modernizing Science grant from CBER, FDA. L. M. and Z.Z. were supported by the Research Participation Program at CBER administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA. NR 33 TC 14 Z9 14 U1 1 U2 3 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 22 PY 2014 VL 111 IS 29 BP 10690 EP 10695 DI 10.1073/pnas.1411317111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL7JS UT WOS:000339310700068 PM 25002515 ER PT J AU Chen, JJ Bozza, WP Di, X Zhang, YQ Hallett, W Zhang, BL AF Chen, Jun-Jie Bozza, William P. Di, Xu Zhang, Yaqin Hallett, William Zhang, Baolin TI H-Ras regulation of TRAIL death receptor mediated apoptosis SO ONCOTARGET LA English DT Article DE H-Ras; death receptors; TRAIL; apoptosis; cancer drug resistance ID TUMOR-NECROSIS-FACTOR; BREAST-CANCER CELLS; LIGAND-INDUCED APOPTOSIS; ONCOGENIC RAS; LIPID RAFTS; FACTOR-ALPHA; CARCINOMA-CELLS; SENSITIVITY; RESISTANCE; EXPRESSION AB TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis through the death receptors (DRs) 4 and/or 5 expressed on the cell surface. Multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL and agonistic antibodies to DR4 or DR5. However, their therapeutic potential is limited by the high frequency of cancer resistance. Here we provide evidence demonstrating the role of H-Ras in TRAIL receptor mediated apoptosis. By analyzing the genome wide mRNA expression data of the NCI60 cancer cell lines, we found that H-Ras expression was consistently upregulated in TRAIL-resistant cell lines. By contrast, no correlation was found between TRAIL sensitivity and K-Ras expression levels or their mutational profiles. Notably, H-Ras upregulation associated with a surface deficiency of TRAIL death receptors. Selective inhibition of H-Ras activity in TRAIL-resistant cells restored the surface expression of both DR4 and DR5 without changing their total protein levels. The resulting cells became highly susceptible to both TRAIL and agonistic DR5 antibody, whereas K-Ras inhibition had little or no effect on TRAIL-induced apoptosis, indicating H-Ras plays a distinct role in the regulation of TRAIL death receptors. Further studies are warranted to determine the therapeutic potential of H-Ras-specific inhibitors in combination with TRAIL receptor agonists. C1 [Chen, Jun-Jie; Bozza, William P.; Di, Xu; Zhang, Yaqin; Hallett, William; Zhang, Baolin] US FDA, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [Chen, Jun-Jie] I Shou Univ, E DA Hosp, Dept Med Res, Kaohsiung 824, Taiwan. RP Zhang, BL (reprint author), US FDA, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. EM Baolin.zhang@fda.hhs.gov FU FDA/CDER Critical Path Initiatives FX This work was partly supported by funding from the FDA/CDER Critical Path Initiatives. NR 54 TC 10 Z9 11 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 15 PY 2014 VL 5 IS 13 BP 5125 EP 5137 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ0EG UT WOS:000347918500043 PM 25026275 ER PT J AU Zannad, F Stough, WG Pina, IL Mehran, R Abraham, WT Anker, SD De Ferrari, GM Farb, A Geller, NL Kieval, RS Linde, C Redberg, RF Stein, K Vincent, A Woehrle, H Pocock, SJ AF Zannad, Faiez Stough, Wendy Gattis Pina, Ileana L. Mehran, Roxana Abraham, William T. Anker, Stefan D. De Ferrari, Gaetano M. Farb, Andrew Geller, Nancy L. Kieval, Robert S. Linde, Cecilia Redberg, Rita F. Stein, Kenneth Vincent, Alphons Woehrle, Holger Pocock, Stuart J. TI Current challenges for clinical trials of cardiovascular medical devices SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Review DE Cardiovascular devices; Device approval; Clinical trial; Research design ID CARDIAC RESYNCHRONIZATION THERAPY; LEFT-VENTRICULAR DYSFUNCTION; HEART-FAILURE; RANDOMIZED-TRIALS; EUROPEAN-SOCIETY; PREMARKET APPROVAL; CONTINUOUS-FLOW; ASSIST DEVICE; SURVEILLANCE; SAFETY AB Several features of cardiovascular devices raise considerations for clinical trial conduct. Prospective, randomized, controlled trials remain the highest quality evidence for safety and effectiveness assessments, but, for instance, blinding may be challenging. In order to avoid bias and not confound data interpretation, the use of objective endpoints and blinding patients, study staff, core labs, and clinical endpoint committees to treatment assignment are helpful approaches. Anticipation of potential bias should be considered and planned for prospectively in a cardiovascular device trial. Prospective, single-arm studies (often referred to as registry studies) can provide additional data in some cases. They are subject to selection bias even when carefully designed; thus, they are generally not acceptable as the sole basis for pre-market approval of high risk cardiovascular devices. However, they complement the evidence base and fill the gaps unanswered by randomized trials. Registry studies present device safety and effectiveness in day-to-day clinical practice settings and detect rare adverse events in the post-market period. No single research design will be appropriate for every cardiovascular device or target patient population. The type of trial, appropriate control group, and optimal length of follow-up will depend on the specific device, its potential clinical benefits, the target patient population and the existence (or lack) of effective therapies, and its anticipated risks. Continued efforts on the part of investigators, the device industry, and government regulators are needed to reach the optimal approach for evaluating the safety and performance of innovative devices for the treatment of cardiovascular disease. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Zannad, Faiez] Univ Lorraine, Dept Cardiol, Nancy, France. [Stough, Wendy Gattis] Campbell Univ, Coll Pharm & Hlth Sci, Buies Creek, NC 27506 USA. [Pina, Ileana L.] Montefiore Med Ctr, Dept Med, Div Cardiol, Bronx, NY 10467 USA. [Mehran, Roxana] Cardiovasc Res Fdn, New York, NY USA. [Mehran, Roxana] Mt Sinai Med Ctr, New York, NY 10029 USA. [Abraham, William T.] Ohio State Univ, Div Cardiovasc Med, Columbus, OH 43210 USA. [Anker, Stefan D.] Charite, Dept Cardiol, Berlin, Germany. [De Ferrari, Gaetano M.] IRCCS Policlin San Matteo, Dept Cardiol, Pavia, Italy. [Farb, Andrew] US FDA, Silver Spring, MD USA. [Geller, Nancy L.] Natl Heart Lung & Blood Inst, Bethesda, MD USA. [Kieval, Robert S.] CVRx Inc, Minneapolis, MN USA. [Linde, Cecilia] Karolinska Univ Hosp, Karolinska Inst, Dept Cardiol, Stockholm, Sweden. [Redberg, Rita F.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Stein, Kenneth] Boston Sci Corp, St Paul, MN USA. [Vincent, Alphons] Medtronic, Tolochenaz, Switzerland. [Woehrle, Holger] ResMed Sci Ctr, Martinsried, Germany. [Woehrle, Holger] Sleep & Ventilat Ctr Blaubeuren, Lung Ctr, Ulm, Germany. [Pocock, Stuart J.] London Sch Hyg & Trop Med, Dept Med Stat, London WC1, England. RP Zannad, F (reprint author), Univ Lorraine Coordinateur Sci, CHU, F-54500 Vandoeuvre Les Nancy, France. EM f.zannad@chu-nancy.fr RI De Ferrari, Gaetano/K-5188-2016; Stough, Wendy/R-4287-2016; OI De Ferrari, Gaetano/0000-0003-4940-0876; Stough, Wendy/0000-0001-8290-1205; LInde, Cecilia/0000-0002-9039-6023 NR 50 TC 9 Z9 9 U1 4 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUL 15 PY 2014 VL 175 IS 1 BP 30 EP 37 DI 10.1016/j.ijcard.2014.05.021 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM3ZG UT WOS:000339790700013 PM 24861254 ER PT J AU McFarland, MA Andrzejewski, D Musser, SM Callahan, JH AF McFarland, Melinda A. Andrzejewski, Denis Musser, Steven M. Callahan, John H. TI Platform for Identification of Salmonella Serovar Differentiating Bacterial Proteins by Top-Down Mass Spectrometry: S. Typhimurium vs S. Heidelberg SO ANALYTICAL CHEMISTRY LA English DT Article ID DESORPTION IONIZATION-TIME; ESCHERICHIA-COLI; POSTTRANSLATIONAL MODIFICATIONS; INTACT PROTEINS; MALDI; STRAINS; CELLS; CLASSIFICATION; STANDARDS; COMPLEX AB Intact protein expression profiling has proven to be a powerful tool for bacterial subspecies differentiation. To facilitate typing, epidemiology, and trace-back of Salmonella contamination in the food supply, a minimum of serovar level differentiation is required. Subsequent identification and validation of marker proteins is integral to rapid screening development and to determining which proteins are subject to environmental pressure. Bacterial sequencing efforts have expanded the number of sequenced genomes available for single-nucleotide polymorphism (SNP) analyses, but annotation is often missing, start site errors are not uncommon, and the likelihood of expression is not known. In this work we show that the combination of intact protein expression profiles and top-down liquid chromatography mass spectrometry (LC-MS/MS) facilitates the identification of proteins that result from expressed serovar specific nonsynonymous SNPs. Combinations of these marker proteins can be used in assays for rapid differentiation of bacteria. LC-MS generated intact protein expression profiles establish which bacterial protein masses differ across samples and can be determined without prior knowledge of the sample. Subsequent top-down LC-MS/MS is used to identify expressed proteins and their post-translational modifications (PTM), identify serovar specific markers, and validate genomic predicted orthologues as expressed biomarkers. C1 [McFarland, Melinda A.; Andrzejewski, Denis; Musser, Steven M.; Callahan, John H.] US FDA, Spect & Mass Spectrometry Branch, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP McFarland, MA (reprint author), US FDA, Spect & Mass Spectrometry Branch, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM melinda.mcfarland@fda.hhs.gov NR 33 TC 6 Z9 6 U1 2 U2 25 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 15 PY 2014 VL 86 IS 14 BP 6879 EP 6886 DI 10.1021/ac500786s PG 8 WC Chemistry, Analytical SC Chemistry GA AL6FG UT WOS:000339227400024 PM 24896398 ER PT J AU Wang, Y Harigaya, Y Coll, MC AF Wang, Y. Harigaya, Y. Coll, M. Cavaille TI A Pharmacometric Approach to Support a Treatment Effect of Everolimus in Liver Transplantation. SO TRANSPLANTATION LA English DT Meeting Abstract CT World Transplant Congress CY JUL 26-31, 2014 CL San Francisco, CA SP Amer Soc Transplant Surg, Transplantat Soc, Amer Soc Transplantat C1 [Wang, Y.; Harigaya, Y.; Coll, M. Cavaille] US FDA, CDER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2014 VL 98 SU 1 MA A442 BP 713 EP 713 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AL4LN UT WOS:000339104604345 ER PT J AU Schmeiser, HH Nortier, JL Singh, R da Costa, GG Sennesael, J Cassuto-Viguier, E Ambrosetti, D Rorive, S Pozdzik, A Phillips, DH Stiborova, M Arlt, VM AF Schmeiser, Heinz H. Nortier, Joelle L. Singh, Rajinder da Costa, Goncalo Gamboa Sennesael, Jacques Cassuto-Viguier, Elisabeth Ambrosetti, Damien Rorive, Sandrine Pozdzik, Agnieszka Phillips, David H. Stiborova, Marie Arlt, Volker M. TI Exceptionally long- term persistence of DNA adducts formed by carcinogenic aristolochic acid I in renal tissue from patients with aristolochic acid nephropathy SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE aristolochic acid; DNA adducts; persistence of adducts; aristolochic acid nephropathy; biomarker of exposure ID CHINESE HERBS NEPHROPATHY; UROTHELIAL CANCER; MASS-SPECTROMETRY; EXPOSURE; DISEASE; KIDNEY AB Aristolochic acid (AA) causes aristolochic acid nephropathy (AAN), first described in women in Belgium accidently prescribed Aristolochia fangchi in a slimming treatment, and also Balkan endemic nephropathy (BEN), through probable dietary contamination with Aristolochia clematitis seeds. Both nephropathies have a high risk of urothelial cancer, with AA being the causative agent. In tissues of AAN and BEN patients, a distinct DNA adduct, 7-(deoxyadenosin-N-6-yl)-aristolactam I (dA-AAI), has been detected. DNA adducts can be removed through DNA repair, they can result in mutations through erroneous DNA replication or they can cause cell death. The dA-AAI adduct induces AT to TA transversions in the tumor-suppressor TP53 gene in experimental systems, matching TP53 mutations observed in urothelial tumors from AAN cancer cases. Using thin-layer chromatography P-32-postlabeling and mass spectrometric analysis we report the detection of dA-AAI in renal DNA from 11 Belgian AAN patients over 20 years after exposure to AA had ceased. Our results showed that dA-AAI is an established biomarker of AA exposure, and that this biomarker can be demonstrated to be persistent decades after a distinct AA exposure. Further, the persistence of dA-AAI adducts appears to be a critical determinant for the AA mutational fingerprint frequently found in oncogenes and tumor suppressor genes recently identified by whole genome sequencing of AA-associated urothelial tumors. The potential for exposure to AA worldwide is high; the unprecedented long-term persistence of dA-AAI provides a useful long-term biomarker of exposure and attests to the role of AA in human urothelial malignancy. What's new? Aristolochic acid (AA), present in Aristolochia-derived herbal drugs frequently used in traditional Chinese medicine, can cause aristolochic acid nephropathy and urothelial cancer. The true extent of AA exposure is unknown as reliable biomarkers are missing. This study demonstrates that premutagenic AA-DNA adducts, specifically 7-(deoxyadenosin-N6-yl)-aristolactam I adducts, have an exceptionally long-term persistence in the renal DNA of aristolochic acid nephropathy patients and thus can serve as biomarkers to assess exposure to AA, even decades later. C1 [Schmeiser, Heinz H.] Res Grp Genet Alterat Carcinogenesis, German Canc Res Ctr DKFZ, Neuenheimer Feld, D-69120 Heidelberg, Germany. [Nortier, Joelle L.] Univ Libre Brussels, Fac Med, Lab Expt Nephrol, Brussels, Belgium. [Nortier, Joelle L.; Rorive, Sandrine; Pozdzik, Agnieszka] Univ Libre Brussels, Dept Pathol, Erasme Hosp, Brussels, Belgium. [Singh, Rajinder] Univ Leicester, Dept Canc Studies & Mol Med, Leicester, Leics, England. [da Costa, Goncalo Gamboa] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Sennesael, Jacques] Vrije Univ Brussel, Univ Ziekenhuis Brussel, Dept Hypertens & Nephrol, Brussels, Belgium. [Cassuto-Viguier, Elisabeth] Pasteur Hosp, Dept Nephrol, Nice, France. [Ambrosetti, Damien] Pasteur Hosp, Dept Pathol, Nice, France. [Phillips, David H.; Arlt, Volker M.] Kings Coll London, MRC PHE Ctr Environm & Hlth, Analyt & Environm Sci Div, London WC2R 2LS, England. [Stiborova, Marie] Charles Univ Prague, Fac Sci, Dept Biochem, Prague, Czech Republic. RP Schmeiser, HH (reprint author), German Canc Res Ctr, Res Grp Genet Alterat Carcinogenesis, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. EM h.schmeiser@dkfz.de RI Stiborova, Marie/A-5982-2015; AMBROSETTI, Damien/E-2131-2015; OI Stiborova, Marie/0000-0001-5430-4403; AMBROSETTI, Damien/0000-0001-8665-0546; Phillips, David/0000-0001-8509-3485; Arlt, Volker Manfred/0000-0003-4314-9318 FU Cancer Research UK; European Union Network of Excellence ECNIS2-"Environmental cancer risk, nutrition and individual susceptibility 2"; Grant Agency of the Czech Republic [303/09/0472] FX Grant sponsor: Work at King's College London was supported by Cancer Research UK and the European Union Network of Excellence ECNIS2-"Environmental cancer risk, nutrition and individual susceptibility 2"; Grant sponsor: Work at Charles University was supported by the Grant Agency of the Czech Republic; Grant number: 303/09/0472 NR 24 TC 30 Z9 31 U1 3 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUL 15 PY 2014 VL 135 IS 2 BP 502 EP 507 DI 10.1002/ijc.28681 PG 6 WC Oncology SC Oncology GA AG5LL UT WOS:000335460400027 PM 24921086 ER PT J AU Sen, SK Boelte, KC Barb, JJ Joehanes, R Zhao, XQ Cheng, Q Adams, L Teer, JK Accame, DS Chowdhury, S Singh, LN Kavousi, M Peyser, PA Quigley, L Priel, DL Lau, K Kuhns, DB Yoshimura, T Johnson, AD Hwang, SJ Chen, MY Arai, AE Green, ED Mullikin, JC Kolodgie, FD O'Donnell, CJ Virmani, R Munson, PJ McVicar, DW Biesecker, LG AF Sen, Shurjo K. Boelte, Kimberly C. Barb, Jennifer J. Joehanes, Roby Zhao, XiaoQing Cheng, Qi Adams, Lila Teer, Jamie K. Accame, David S. Chowdhury, Soma Singh, Larry N. Kavousi, Maryam Peyser, Patricia A. Quigley, Laura Priel, Debra Long Lau, Karen Kuhns, Douglas B. Yoshimura, Teizo Johnson, Andrew D. Hwang, Shih-Jen Chen, Marcus Y. Arai, Andrew E. Green, Eric D. Mullikin, James C. Kolodgie, Frank D. O'Donnell, Christopher J. Virmani, Renu Munson, Peter J. McVicar, Daniel W. Biesecker, Leslie G. CA NISC Comparative Sequencing Progra CHARGE Consortium TI Integrative DNA, RNA, and Protein Evidence Connects TREML4 to Coronary Artery Calcification SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; HEART-DISEASE; GENE-EXPRESSION; WHOLE-BLOOD; CELLS; INFLAMMATION; RISK; ATHEROSCLEROSIS; MYELOPEROXIDASE; MECHANISMS AB Coronary artery calcification (CAC) is a heritable and definitive morphologic marker of atherosclerosis that strongly predicts risk for future cardiovascular events. To search for genes involved in CAC, we used an integrative transcriptomic, genomic, and protein expression strategy by using next-generation DNA sequencing in the discovery phase with follow-up studies using traditional molecular biology and histopathology techniques. RNA sequencing of peripheral blood from a discovery set of CAC cases and controls was used to identify dysregulated genes, which were validated by ClinSeq and Framingham Heart Study data. Only a single gene, TREML4, was upregulated in CAC cases in both studies. Further examination showed that rs2803496 was a TREML4 cis-eQTL and that the minor allele at this locus conferred up to a 6.5-fold increased relative risk of CAC. We characterized human TREML4 and demonstrated by immunohistochemical techniques that it is localized in macrophages surrounding the necrotic core of coronary plaques complicated by calcification (but not in arteries with less advanced disease). Finally, we determined by von Kossa staining that TREML4 colocalizes with areas of microcalcification within coronary plaques. Overall, we present integrative RNA, DNA, and protein evidence implicating TREML4 in coronary artery calcification. Our findings connect mulfimodal genomics data with a commonly used clinical marker of cardiovascular disease. C1 [Sen, Shurjo K.; Accame, David S.; Singh, Larry N.; Green, Eric D.; Mullikin, James C.; Biesecker, Leslie G.; NISC Comparative Sequencing Progra] NHGRI, NIH, Bethesda, MD 20892 USA. [Boelte, Kimberly C.; Quigley, Laura; Yoshimura, Teizo; McVicar, Daniel W.] NCI, NTH, Frederick, MD 21702 USA. [Barb, Jennifer J.; Joehanes, Roby; Munson, Peter J.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Zhao, XiaoQing; Cheng, Qi; Adams, Lila; Kolodgie, Frank D.; Virmani, Renu] CVPath Inst, Gaithersburg, MD 20878 USA. [Teer, Jamie K.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Chowdhury, Soma] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Kavousi, Maryam] Erasmus Univ, Med Ctr, Netherlands Genom Initiat Sponsored Netherlands C, NL-3000 CA Rotterdam, Netherlands. [Kavousi, Maryam] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Peyser, Patricia A.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48104 USA. [Priel, Debra Long; Lau, Karen; Kuhns, Douglas B.] SAIC Frederick Inc, Appl Dev Res Directorate, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Johnson, Andrew D.; Hwang, Shih-Jen; O'Donnell, Christopher J.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Johnson, Andrew D.; Hwang, Shih-Jen; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Chen, Marcus Y.; Arai, Andrew E.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov RI McVicar, Daniel/G-1970-2015; Johnson, Andrew/G-6520-2013 FU NHGRI; NCI; NHLBI; NIH [NO1-HC-25195]; National Cancer Institute, NIH [HHSN261200800001E] FX The authors thank Marjorie Lindhurst, Jennifer Johnston, David Ng, Steve Gonsalves, and the ClinSeq support and nursing staff for their help with the clinical aspects of this study; Yusuf Demirkale for help with statistical analyses; and Danielle Fink, Laura Coffin, and Dara Riva for their help with the neutrophil studies. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was funded by the NHGRI, NCI, and NHLBI Intramural Research Programs. The National Heart, Lung, and Blood Institute's (NHLBI's) FHS is supported by NIH Grant NO1-HC-25195. This project has also been funded in part with federal funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E. L.G.B. is an uncompensated advisor to the Illumina Corporation and receives royalties from the Genentech Corporation. NR 50 TC 3 Z9 3 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 13 PY 2014 VL 95 IS 1 BP 66 EP 76 DI 10.1016/j.ajhg.2014.06.003 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA AL1RP UT WOS:000338904100005 PM 24975946 ER PT J AU Cortazar, P Zhang, LJ Untch, M Mehta, K Costantino, JP Wolmark, N Bonnefoi, H Cameron, D Gianni, L Valagussa, P Swain, SM Prowell, T Loibl, S Wickerham, DL Bogaerts, J Baselga, J Perou, C Blumenthal, G Blohmer, J Mamounas, EP Bergh, J Semiglazov, V Justice, R Eidtmann, H Paik, S Piccart, M Sridhara, R Fasching, PA Slaets, L Tang, SH Gerber, B Geyer, CE Pazdur, R Ditsch, N Rastogi, P Eiermann, W von Minckwitz, G AF Cortazar, Patricia Zhang, Lijun Untch, Michael Mehta, Keyur Costantino, Joseph P. Wolmark, Norman Bonnefoi, Herve Cameron, David Gianni, Luca Valagussa, Pinuccia Swain, Sandra M. Prowell, Tatiana Loibl, Sibylle Wickerham, D. Lawrence Bogaerts, Jan Baselga, Jose Perou, Charles Blumenthal, Gideon Blohmer, Jens Mamounas, Eleftherios P. Bergh, Jonas Semiglazov, Vladimir Justice, Robert Eidtmann, Holger Paik, Soonmyung Piccart, Martine Sridhara, Rajeshwari Fasching, Peter A. Slaets, Leen Tang, Shenghui Gerber, Bernd Geyer, Charles E., Jr. Pazdur, Richard Ditsch, Nina Rastogi, Priya Eiermann, Wolfgang von Minckwitz, Gunter TI Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis SO LANCET LA English DT Article ID DOSE-INTENSIFIED CHEMOTHERAPY; SURGICAL ADJUVANT BREAST; III RANDOMIZED GEPARTRIO; PRIMARY SYSTEMIC THERAPY; NEOADJUVANT CHEMOTHERAPY; PREOPERATIVE CHEMOTHERAPY; DARBEPOETIN ALPHA; PREPARE TRIAL; CYCLOPHOSPHAMIDE; DOXORUBICIN AB Background Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS. Methods We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response-ypT0 ypN0, ypT0/is ypN0, and ypT0/is-for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS. Findings We obtained data from 12 identified international trials and 11955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0.44, 95% CI 0.39-0.51; ypT0/is ypN0: 0.48, 0.43-0.54) and OS (0.36, 0.30-0.44; 0.36, 0.31-0.42) than was tumour eradication from the breast alone(ypT0/is; EFS: HR 0.60, 95% CI 0.55-0.66; OS 0.51, 0.45-0.58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0.24, 95% CI 0.18-0.33; OS: 0.16, 0.11-0.25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0.15, 0.09-0.27; OS: 0.08, 0.03, 0. 22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R-2=0.03, 95% CI 0.00-0.25) and OS (R-2=0.24,0.00-0.70). Interpretation Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS. Funding US Food and Drug Administration. C1 [Cortazar, Patricia; Zhang, Lijun; Prowell, Tatiana; Blumenthal, Gideon; Justice, Robert; Sridhara, Rajeshwari; Tang, Shenghui; Pazdur, Richard] US FDA, Silver Spring, MD USA. [Untch, Michael] HELIOS Klin, Berlin, Germany. [Mehta, Keyur; Loibl, Sibylle; von Minckwitz, Gunter] German Breast Grp, Neu Isenburg, Germany. [Costantino, Joseph P.; Wolmark, Norman; Wickerham, D. Lawrence; Paik, Soonmyung; Rastogi, Priya] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Bonnefoi, Herve] Inst Bergonie INSERM U916, Bordeaux, France. [Bonnefoi, Herve] Univ Bordeaux Segalen, Bordeaux, France. [Cameron, David] Univ Edinburgh, Edinburgh Canc Res Ctr, Edinburgh EH8 9YL, Midlothian, Scotland. [Cameron, David] NHS Lothian, Edinburgh, Midlothian, Scotland. [Gianni, Luca] Ist Sci San Raffaele, I-20132 Milan, Italy. [Valagussa, Pinuccia] Fdn Michelangelo, Milan, Italy. [Swain, Sandra M.] Medstar Washington Hosp Ctr, Washington, DC USA. [Bogaerts, Jan; Slaets, Leen] EORTC Headquarters, Brussels, Belgium. [Baselga, Jose] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Perou, Charles] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Blohmer, Jens] St Gertrauden Hosp, Berlin, Germany. [Mamounas, Eleftherios P.] MD Anderson Canc Ctr Orlando, Orlando, FL USA. [Bergh, Jonas] KarolinskaInst, Stockholm, Sweden. [Bergh, Jonas] Univ Hosp, Stockholm, Sweden. [Semiglazov, Vladimir] NN Petrov Oncol Res Inst, St Petersburg, Russia. [Eidtmann, Holger] Univ Womens Hosp, Kiel, Germany. [Piccart, Martine] Inst Jules Bordet, B-1000 Brussels, Belgium. [Fasching, Peter A.] Univ Klinikums, Frauenklin, Erlangen, Germany. [Gerber, Bernd] Univ Frauenklin, Rostock, Germany. [Geyer, Charles E., Jr.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. [Ditsch, Nina; Eiermann, Wolfgang] Hosp Ludwig Maximilian Univ Munich, Munich, Germany. RP Cortazar, P (reprint author), 10903 New Hampshire Ave,Bldg 22,Room 2333, Silver Spring, MD 20993 USA. EM patricia.cortazar@fda.hhs.gov OI Semiglazov, Vladimir/0000-0003-0077-9619; Perou, Charles/0000-0001-9827-2247; Swain, Sandra/0000-0002-1320-3830 FU US Food and Drug Administration; CTNeoBC pooled analysis FX This project was partly funded by the US Food and Drug Administration. We thank Janet Woodcock, who provided financial support for the CTNeoBC pooled analysis; all the patients, Breast Cancer Cooperative Groups, investigators, pathologists, and statisticians who participated in the neoadjuvant trials; and Jo Anne Zujewski for her help. NR 28 TC 426 Z9 451 U1 5 U2 56 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 JUL 12 PY 2014 VL 384 IS 9938 BP 164 EP 172 DI 10.1016/S0140-6736(13)62422-8 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AL1YC UT WOS:000338921500035 PM 24529560 ER PT J AU Huang, RL Sakamuru, S Martin, MT Reif, DM Judson, RS Houck, KA Casey, W Hsieh, JH Shockley, KR Ceger, P Fostel, J Witt, KL Tong, WD Rotroff, DM Zhao, TG Shinn, P Simeonov, A Dix, DJ Austin, CP Kavlock, RJ Tice, RR Xia, MH AF Huang, Ruili Sakamuru, Srilatha Martin, Matt T. Reif, David M. Judson, Richard S. Houck, Keith A. Casey, Warren Hsieh, Jui-Hua Shockley, Keith R. Ceger, Patricia Fostel, Jennifer Witt, Kristine L. Tong, Weida Rotroff, Daniel M. Zhao, Tongan Shinn, Paul Simeonov, Anton Dix, David J. Austin, Christopher P. Kavlock, Robert J. Tice, Raymond R. Xia, Menghang TI Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway SO SCIENTIFIC REPORTS LA English DT Article ID BREAST-CANCER CELLS; IN-VITRO ASSAYS; PYRETHROID INSECTICIDES; ANTIESTROGENIC ACTIVITY; ANDROGENIC ACTIVITY; IONIC LIQUIDS; HUMAN HEALTH; CHEMICALS; PHYTOESTROGENS; MECHANISMS AB The U.S. Tox21 program has screened a library of approximately 10,000 (10K) environmental chemicals and drugs in three independent runs for estrogen receptor alpha (ER alpha) agonist and antagonist activity using two types of ER reporter gene cell lines, one with an endogenous full length ER alpha (ER-luc; BG1 cell line) and the other with a transfected partial receptor consisting of the ligand binding domain (ER-bla; ER alpha beta-lactamase cell line), in a quantitative high-throughput screening (qHTS) format. The ability of the two assays to correctly identify ER alpha agonists and antagonists was evaluated using a set of 39 reference compounds with known ERa activity. Although both assays demonstrated adequate (i.e. 80%) predictivity, the ER-luc assay was more sensitive and the ER-bla assay more specific. The qHTS assay results were compared with results from previously published ER alpha binding assay data and showed >80% consistency. Actives identified from both the ER-bla and ER-luc assays were analyzed for structure-activity relationships (SARs) revealing known and potentially novel ERa active structure classes. The results demonstrate the feasibility of qHTS to identify environmental chemicals with the potential to interact with the ERa signaling pathway and the two different assay formats improve the confidence in correctly identifying these chemicals. C1 [Huang, Ruili; Sakamuru, Srilatha; Zhao, Tongan; Shinn, Paul; Simeonov, Anton; Austin, Christopher P.; Xia, Menghang] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Martin, Matt T.; Reif, David M.; Judson, Richard S.; Houck, Keith A.; Rotroff, Daniel M.; Dix, David J.; Kavlock, Robert J.] US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Casey, Warren; Hsieh, Jui-Hua; Shockley, Keith R.; Fostel, Jennifer; Witt, Kristine L.; Tice, Raymond R.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Ceger, Patricia] ILS Inc, Res Triangle Pk, NC 27709 USA. [Tong, Weida] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Huang, RL (reprint author), NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. EM huangru@mail.nih.gov OI Judson, Richard/0000-0002-2348-9633; Reif, David/0000-0001-7815-6767 FU Intramural Research Programs of the National Toxicology Program [Y2-ES-7020-01]; National Institute of Environmental Health Sciences; U.S. Environmental Protection Agency [Y3-HG-7026-03]; National Center for Advancing Translational Sciences, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Toxicology Program (Interagency agreement #Y2-ES-7020-01), the National Institute of Environmental Health Sciences, the U.S. Environmental Protection Agency (Interagency Agreement #Y3-HG-7026-03), and the National Center for Advancing Translational Sciences, National Institutes of Health. We would also like to thank Samuel Michael for assisting with the screens, Misha Itkin and Danielle VanLeer for compound management, William Leister for the Tox21 10K library quality control, and Drs. Kevin Crofton, Rusty Thomas and John Bucher for critical review of this manuscript. The views expressed in this article are those of the authors and do not necessarily reflect the statements, opinions, views, conclusions, or policies of the National Institute of Environmental Health Sciences, National Center for Advancing Translational Sciences, National Institutes of Health, U.S. Environmental Protection Agency, or the United States government. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. NR 56 TC 27 Z9 29 U1 4 U2 35 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 11 PY 2014 VL 4 AR 5664 DI 10.1038/srep05664 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL0PJ UT WOS:000338828500005 PM 25012808 ER PT J AU Ghammraoui, B Badal, A AF Ghammraoui, Bahaa Badal, Andreu TI Monte Carlo simulation of novel breast imaging modalities based on coherent x-ray scattering SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE Monte Carlo simulation; coherent scatter; x- ray scattering; breast cancer; EDXRD; coherent scatter CT ID COMPUTED-TOMOGRAPHY; FORM-FACTORS; TISSUES; DIFFRACTION; PERFORMANCE; CONTRAST; PLASTICS; PHANTOM AB We present upgraded versions of MC-GPU and penEasy_Imaging, two open source Monte Carlo codes for the simulation of radiographic projections and CT, that have been extended and validated to account for the effect of molecular interference in the coherent x-ray scatter. The codes were first validation by comparison between simulated and measured energy dispersive x-ray diffraction (EDXRD) spectra. A second validation was by evaluation of the rejection factor of a focused anti-scatter grid. To exemplify the capabilities of the new codes, the modified MC-GPU code was used to examine the possibility of characterizing breast tissue composition and microcalcifications in a volume of interest inside a whole breast phantom using EDXRD and to simulate a coherent scatter computed tomography (CSCT) system based on first generation CT acquisition geometry. It was confirmed that EDXRD and CSCT have the potential to characterize tissue composition inside a whole breast. The GPU-accelerated code was able to simulate, in just a few hours, a complete CSCT acquisition composed of 9758 independent pencil-beam projections. In summary, it has been shown that the presented software can be used for fast and accurate simulation of novel breast imaging modalities relying on scattering measurements and therefore can assist in the characterization and optimization of promising modalities currently under development. C1 [Ghammraoui, Bahaa; Badal, Andreu] US FDA, Div Imaging & Appl Math, OSEL, CDRH, Silver Spring, MD 20993 USA. RP Ghammraoui, B (reprint author), US FDA, Div Imaging & Appl Math, OSEL, CDRH, Silver Spring, MD 20993 USA. EM bahaa.ghammraoui@fda.hhs.gov NR 29 TC 5 Z9 5 U1 0 U2 15 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 7 PY 2014 VL 59 IS 13 BP 3501 EP 3516 DI 10.1088/0031-9155/59/13/3501 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AK4WK UT WOS:000338424800019 PM 24898114 ER PT J AU He, YQ Sarntivijai, S Lin, Y Xiang, ZS Guo, A Zhang, S Jagannathan, D Toldo, L Tao, C Smith, B AF He, Yongqun Sarntivijai, Sirarat Lin, Yu Xiang, Zuoshuang Guo, Abra Zhang, Shelley Jagannathan, Desikan Toldo, Luca Tao, Cui Smith, Barry TI OAE: The Ontology of Adverse Events SO JOURNAL OF BIOMEDICAL SEMANTICS LA English DT Article DE Ontology of Adverse Events; OAE; Adverse event; Ontology; Vaccine; Drug; Vaccine adverse event; VAERS; Drug adverse event; Design pattern ID REGULATORY ACTIVITIES MEDDRA; COORDINATED EVOLUTION; MEDICAL DICTIONARY; SIGNAL GENERATION; VACCINATION; INTEGRATION; ANATOMY; SUPPORT; REALISM AB Background: A medical intervention is a medical procedure or application intended to relieve or prevent illness or injury. Examples of medical interventions include vaccination and drug administration. After a medical intervention, adverse events (AEs) may occur which lie outside the intended consequences of the intervention. The representation and analysis of AEs are critical to the improvement of public health. Description: The Ontology of Adverse Events (OAE), previously named Adverse Event Ontology (AEO), is a community-driven ontology developed to standardize and integrate data relating to AEs arising subsequent to medical interventions, as well as to support computer-assisted reasoning. OAE has over 3,000 terms with unique identifiers, including terms imported from existing ontologies and more than 1,800 OAE-specific terms. In OAE, the term 'adverse event' denotes a pathological bodily process in a patient that occurs after a medical intervention. Causal adverse events are defined by OAE as those events that are causal consequences of a medical intervention. OAE represents various adverse events based on patient anatomic regions and clinical outcomes, including symptoms, signs, and abnormal processes. OAE has been used in the analysis of several different sorts of vaccine and drug adverse event data. For example, using the data extracted from the Vaccine Adverse Event Reporting System (VAERS), OAE was used to analyse vaccine adverse events associated with the administrations of different types of influenza vaccines. OAE has also been used to represent and classify the vaccine adverse events cited in package inserts of FDA-licensed human vaccines in the USA. Conclusion: OAE is a biomedical ontology that logically defines and classifies various adverse events occurring after medical interventions. OAE has successfully been applied in several adverse event studies. The OAE ontological framework provides a platform for systematic representation and analysis of adverse events and of the factors (e.g., vaccinee age) important for determining their clinical outcomes. C1 [He, Yongqun; Sarntivijai, Sirarat; Lin, Yu; Xiang, Zuoshuang; Guo, Abra; Zhang, Shelley; Jagannathan, Desikan] Univ Michigan, Ann Arbor, MI 48109 USA. [Sarntivijai, Sirarat] US FDA, Silver Spring, MD USA. [Toldo, Luca] Merck KGaA, Darmstadt, Germany. [Tao, Cui] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Smith, Barry] SUNY Buffalo, Buffalo, NY 14260 USA. RP He, YQ (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. EM yongqunh@med.umich.edu OI He, Yongqun/0000-0001-9189-9661; Sarntivijai, Sirarat/0000-0002-2548-641X FU NIH National Institute of Allergy and Infectious Diseases [1R01AI081062]; NIH [U54 DA021519]; NIAID grant [R01AI77706] FX The development of OAE is supported by the NIH National Institute of Allergy and Infectious Diseases grant 1R01AI081062, and the NIH grant U54 DA021519 for the National Center for Integrative Biomedical Informatics. Smith's work on this paper was supported by NIAID grant R01AI77706 on Immune System Biological Networks. The article-processing charge for this article was paid by a discretionary fund from Dr. Robert Dysko, the director of the Unit for Laboratory Animal Medicine (ULAM) in the University of Michigan. The significant contribution of Werner Ceusters in the early AEO development is acknowledged and appreciated. We appreciate discussions and comments from Melanie Courtot, Brink Ryan, and Alan Ruttenberg in the development of OAE. We appreciate Darrell Abernethy and Keith Burkhart for their consultation in the domain of clinical adverse event reporting. The critical comments and suggestions provided by three anonymous reviewers are also appreciated. NR 43 TC 15 Z9 15 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2041-1480 J9 J BIOMED SEMANT JI J. Biomed. Semant. PD JUL 5 PY 2014 VL 5 AR 29 DI 10.1186/2041-1480-5-29 PG 13 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AR6RU UT WOS:000343711400001 PM 25093068 ER PT J AU Mayer-Barber, KD Andrade, BB Oland, SD Amaral, EP Barber, DL Gonzales, J Derrick, SC Shi, RR Kumar, NP Wei, W Yuan, X Zhang, GL Cai, Y Babu, S Catalfamo, M Salazar, AM Via, LE Barry, CE Sher, A AF Mayer-Barber, Katrin D. Andrade, Bruno B. Oland, Sandra D. Amaral, Eduardo P. Barber, Daniel L. Gonzales, Jacqueline Derrick, Steven C. Shi, Ruiru Kumar, Nathella Pavan Wei, Wang Yuan, Xing Zhang, Guolong Cai, Ying Babu, Subash Catalfamo, Marta Salazar, Andres M. Via, Laura E. Barry, Clifton E., III Sher, Alan TI Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk SO NATURE LA English DT Article ID NECROSIS-FACTOR-ALPHA; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; LIPID MEDIATORS; INDUCTION; INFECTION; SUSCEPTIBILITY; INFLAMMATION; IMMUNITY; INNATE AB Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent(1). Despite chemotherapy, the global tuberculosis epidemic has intensified because of HIV co-infection, the lack of an effective vaccine and the emergence of multi-drug-resistant bacteria(2-5). Alternative host-directed strategies could be exploited to improve treatment efficacy and outcome, contain drug-resistant strains and reduce disease severity and mortality(6). The innate inflammatory response elicited by Mycobacterium tuberculosis (Mtb) represents a logical host target(7). Here we demonstrate that interleukin-1 (IL-1) confers host resistance through the induction of eicosanoids that limit excessive type I interferon (IFN) production and foster bacterial containment. We further show that, in infected mice and patients, reduced IL-1 responses and/or excessive type I IFN induction are linked to an eicosanoid imbalance associated with disease exacerbation. Host-directed immunotherapy with clinically approved drugs that augment prostaglandin E2 levels in these settings prevented acute mortality of Mtb-infected mice. Thus, IL-1 and type I IFNs represent two major counter-regulatory classes of inflammatory cytokines that control the outcome of Mtb infection and are functionally linked via eicosanoids. Our findings establish proof of concept for host-directed treatment strategies that manipulate the host eicosanoid network and represent feasible alternatives to conventional chemotherapy. C1 [Mayer-Barber, Katrin D.; Andrade, Bruno B.; Oland, Sandra D.; Amaral, Eduardo P.; Sher, Alan] NIAID, Immunobiol Sect, LPD, NIH, Bethesda, MD 20892 USA. [Amaral, Eduardo P.] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, BR-05508900 Sao Paulo, Brazil. [Barber, Daniel L.] NIAID, Lymphocyte Biol Unit T, LPD, NIH, Bethesda, MD 20892 USA. [Gonzales, Jacqueline; Via, Laura E.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Derrick, Steven C.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Shi, Ruiru; Wei, Wang; Yuan, Xing] Henan Chest Hosp, Zhengzhou 450003, Peoples R China. [Kumar, Nathella Pavan; Babu, Subash] Int Ctr Excellence Res, NIH, Madras 600031, Tamil Nadu, India. [Kumar, Nathella Pavan] NIRT, Madras 600031, Tamil Nadu, India. [Zhang, Guolong] SinoUS Int Res Ctr TB, Zhengzhou 450003, Peoples R China. [Zhang, Guolong] Henan Publ Hlth Ctr, Zhengzhou 450003, Peoples R China. [Babu, Subash] NIAID, Helminth Immunol Sect, LPD, NIH, Bethesda, MD 20892 USA. [Catalfamo, Marta] NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Salazar, Andres M.] Oncovir Inc, Washington, DC 20008 USA. RP Mayer-Barber, KD (reprint author), NIAID, Immunobiol Sect, LPD, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mayerk@niaid.nih.gov RI Andrade, Bruno/J-9111-2012; Amaral, Eduardo/M-2456-2014; Barry, III, Clifton/H-3839-2012; OI Andrade, Bruno/0000-0001-6833-3811; Amaral, Eduardo/0000-0001-5465-8113; Via, Laura/0000-0001-6074-9521 FU NIAID Intramural Research program; Concept Acceleration Program-Award from DMID, NIAID FX This work was supported by the NIAID Intramural Research program and a Concept Acceleration Program-Award (K.D.M.-B., B.B.A. and A.S.) from DMID, NIAID. We are grateful to K. Elkins, S. Morris, M. Belcher as well as the NIAID ABSL3 support staff for facilitating our animal studies. We thank R. Chen, L. Goldfeder and Q. Gao for sharing their clinical trial expertise and research facilities, respectively. We also thank K. Kauffman, R. Thompson, S. Hieny, P. Dayal, D. Surman, L. Meng, Z. Li, L. Lifa, Q. Shen and Z. Huang for technical assistance, H. Boshoff for help with direct anti-mycobacterial activity assays and M. S. Jawahar, V. V. Banurekha and R. Sridhar for recruitment and clinical evaluation of patients in Chennai, India. We are grateful to F. Andrade Neto, H. Remold, K. Arora, J. Aliberti, M. Moayeri, P. Murphy, A. O'Garra, R. Germain and C. Serhan for discussion or critical reading of the manuscript. Finally, we thank the patients, volunteer participants, and clinical staff of the Tuberculosis department of Henan Chest Hospital in Zhengzhou, China and the Department of Clinical Research (NIRT) and Department of Thoracic Medicine (Government Stanley Medical Hospital) in Chennai, India for their participation in our clinical studies. NR 32 TC 164 Z9 167 U1 9 U2 90 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUL 3 PY 2014 VL 511 IS 7507 BP 99 EP U491 DI 10.1038/nature13489 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK1TN UT WOS:000338199400044 PM 24990750 ER PT J AU Zhu, X Kruhlak, NL AF Zhu, Xiao Kruhlak, Naomi L. TI Construction and analysis of a human hepatotoxicity database suitable for QSAR modeling using post-market safety data SO TOXICOLOGY LA English DT Article DE Drug-induced liver injury; Predictive toxicology; QSAR; Post-market safety ID INDUCED LIVER-INJURY; URINARY-TRACT TOXICITIES; ADVERSE DRUG-REACTIONS; PHARMACOVIGILANCE; PHARMACEUTICALS; IDENTIFICATION; HEPATOBILIARY; TORCETRAPIB; DISEASE; SYSTEMS AB Drug-induced liver injury (DILI) is one of the most common drug-induced adverse events (AEs) leading to life-threatening conditions such as acute liver failure. It has also been recognized as the single most common cause of safety-related post-market withdrawals or warnings. Efforts to develop new predictive methods to assess the likelihood of a drug being a hepatotoxicant have been challenging due to the complexity and idiosyncrasy of clinical manifestations of DILI. The FDA adverse event reporting system (AERS) contains post-market data that depict the morbidity of AEs. Here, we developed a scalable approach to construct a hepatotoxicity database using post-market data for the purpose of quantitative structure-activity relationship (QSAR) modeling. A set of 2029 unique and modelable drug entities with 13,555 drug-AE combinations was extracted from the AERS database using 37 hepatotoxicity-related query preferred terms (PTs). In order to determine the optimal classification scheme to partition positive from negative drugs, a manually-curated DILI calibration set composed of 105 negatives and 177 positives was developed based on the published literature. The final classification scheme combines hepatotoxicity-related PT data with supporting information that optimize the predictive performance across the calibration set. Data for other toxicological endpoints related to liver injury such as liver enzyme abnormalities, cholestasis, and bile duct disorders, were also extracted and classified. Collectively, these datasets can be used to generate a battery of QSAR models that assess a drug's potential to cause DILI. Published by Elsevier Ireland Ltd. C1 [Zhu, Xiao; Kruhlak, Naomi L.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Kruhlak, NL (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Naomi.Kruhlak@fda.hhs.gov FU FDA Critical Path Initiative FX This study was supported by intramural funding from the FDA Critical Path Initiative. Xiao Zhu is appointed by the ORISE Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education. NR 56 TC 12 Z9 12 U1 2 U2 15 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 2014 VL 321 BP 62 EP 72 DI 10.1016/j.tox.2014.03.009 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AJ7IO UT WOS:000337870600007 PM 24721472 ER PT J AU Portnoy, DB Ferrer, RA Bergman, HE Klein, WMP AF Portnoy, David B. Ferrer, Rebecca A. Bergman, Hannah E. Klein, William M. P. TI Changing deliberative and affective responses to health risk: a meta-analysis SO HEALTH PSYCHOLOGY REVIEW LA English DT Article DE perceived risk; perceived susceptibility; affect; worry; meta-analysis ID BREAST-CANCER SUSCEPTIBILITY; BELIEF MODEL; PERCEIVED SUSCEPTIBILITY; INFLUENZA VACCINATION; OVARIAN-CANCER; COLON-CANCER; WORRY; PERCEPTIONS; BEHAVIOR; INTENTIONS AB Perceptions of risk for health outcomes are integral to many theories of health behaviour, and are often targeted in interventions. Evidence suggests that affective responses to risk, including worry, are empirically distinguishable from commonly used perceived risk measures such as perceived susceptibility. The aims of this meta-analysis were to (1) examine if perceived susceptibility and worry can be independently influenced, and what manipulation types are most effective at changing each construct and (2) examine the efficacy of interventions to change worry and perceived susceptibility. Thirty-eight studies using 43 separate samples provided 78 independent comparisons that were meta-analysed using the inverse variance method with random-effects modelling. The overall effect size (d) was 0.50, 95% CI [0.362, 0.632] for perceived susceptibility; and 0.25, 95% CI [0.148, 0.349] for worry. Effect sizes for perceived susceptibility were significantly related to those for worry, B=0.495, p < 0.001. Moderators of these effects are discussed. The present meta-analysis provides further evidence that perceived susceptibility and worry are distinguishable but related constructs, and that it is possible to perturb one and not the other. C1 [Portnoy, David B.] NCI, Canc Prevent Fellowship Program, Rockville, MD USA. [Portnoy, David B.; Ferrer, Rebecca A.; Bergman, Hannah E.; Klein, William M. P.] NCI, Behav Res Program, Rockville, MD USA. RP Portnoy, DB (reprint author), US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. EM david.portnoy@fda.hhs.gov OI Portnoy, David/0000-0003-2175-9457 NR 71 TC 7 Z9 7 U1 4 U2 15 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1743-7199 EI 1743-7202 J9 HEALTH PSYCHOL REV JI Health Psychol. Rev. PD JUL 3 PY 2014 VL 8 IS 3 BP 296 EP 318 DI 10.1080/17437199.2013.798829 PG 23 WC Psychology, Clinical SC Psychology GA AH2IH UT WOS:000335944200004 PM 25053216 ER PT J AU Freifeld, CC Brownstein, JS Menone, CM Bao, WJ Filice, R Kass-Hout, T Dasgupta, N AF Freifeld, Clark C. Brownstein, John S. Menone, Christopher M. Bao, Wenjie Filice, Ross Kass-Hout, Taha Dasgupta, Nabarun TI Digital Drug Safety Surveillance: Monitoring Pharmaceutical Products in Twitter (vol 37, pg 343, 2014) SO DRUG SAFETY LA English DT Correction C1 [Freifeld, Clark C.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Freifeld, Clark C.; Brownstein, John S.] Boston Childrens Hosp, Childrens Hosp Informat Program, Boston, MA USA. [Brownstein, John S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Brownstein, John S.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA USA. [Menone, Christopher M.; Bao, Wenjie; Dasgupta, Nabarun] Epidemico Inc, Boston, MA USA. [Filice, Ross] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Kass-Hout, Taha] US FDA, Silver Spring, MD USA. [Dasgupta, Nabarun] Univ N Carolina, Chapel Hill, NC 27599 USA. EM nabarund@gmail.com NR 1 TC 2 Z9 2 U1 0 U2 3 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 JUL PY 2014 VL 37 IS 7 BP 555 EP 555 DI 10.1007/s40264-014-0172-9 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA AT0GG UT WOS:000344614500009 ER EF