FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Lantz-McPeak, S Guo, XQ Cuevas, E Dumas, M Newport, GD Ali, SF Paule, MG Kanungo, J AF Lantz-McPeak, Susan Guo, Xiaoqing Cuevas, Elvis Dumas, Melanie Newport, Glenn D. Ali, Syed F. Paule, Merle G. Kanungo, Jyotshna TI Developmental toxicity assay using high content screening of zebrafish embryos SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Review DE zebrafish embryo; high content screening; automated imaging; integrated morphometric analysis; ethanol; nicotine; ketamine ID BASS DICENTRARCHUS-LABRAX; TAGGED TRIAZINE LIBRARY; DANIO-RERIO; ALCOHOL-CONSUMPTION; SEA BASS; LARVAL ZEBRAFISH; ETHANOL EXPOSURE; MOTOR-NEURONS; BIRTH-WEIGHT; MODEL SYSTEM AB Typically, time-consuming standard toxicological assays using the zebrafish (Danio rerio) embryo model evaluate mortality and teratogenicity after exposure during the first 2days post-fertilization. Here we describe an automated image-based high content screening (HCS) assay to identify the teratogenic/embryotoxic potential of compounds in zebrafish embryos in vivo. Automated image acquisition was performed using a high content microscope system. Further automated analysis of embryo length, as a statistically quantifiable endpoint of toxicity, was performed on images post-acquisition. The biological effects of ethanol, nicotine, ketamine, caffeine, dimethyl sulfoxide and temperature on zebrafish embryos were assessed. This automated developmental toxicity assay, based on a growth-retardation endpoint should be suitable for evaluating the effects of potential teratogens and developmental toxicants in a high throughput manner. This approach can significantly expedite the screening of potential teratogens and developmental toxicants, thereby improving the current risk assessment process by decreasing analysis time and required resources. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. High content assay quantifies developmental toxicity in zebrafish embryos. C1 [Lantz-McPeak, Susan; Guo, Xiaoqing; Cuevas, Elvis; Dumas, Melanie; Newport, Glenn D.; Ali, Syed F.; Paule, Merle G.; Kanungo, Jyotshna] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Kanungo, J (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Bldg 53D,Room 203O, Jefferson, AR 72079 USA. EM jyotshnabala.kanungo@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 103 TC 10 Z9 11 U1 4 U2 30 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 MAR PY 2015 VL 35 IS 3 BP 261 EP 272 DI 10.1002/jat.3029 PG 12 WC Toxicology SC Toxicology GA CB1EV UT WOS:000349370600005 PM 24871937 ER PT J AU Gelting, RJ Baloch, MA Zarate-Bermudez, M Hajmeer, MN Yee, JC Brown, T Yee, BJ AF Gelting, Richard J. Baloch, Mansoor A. Zarate-Bermudez, Max Hajmeer, Maha N. Yee, J. Christopher Brown, Teresa Yee, Benson J. TI A systems analysis of irrigation water quality in an environmental assessment of an E. coli 0157:H7 outbreak in the United States linked to iceberg lettuce SO AGRICULTURAL WATER MANAGEMENT LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; ESCHERICHIA-COLI; BOVINE MANURE; FRESH PRODUCE; LEAF LETTUCE; CONTAMINATED MANURE; ANIMAL WASTE; O157-H7; SURVIVAL; O157H7 AB A foodborne Escherichia coli 0157:H7 outbreak in December 2006 included 77 illnesses reported in Iowa and Minnesota. Epidemiologic investigations by health departments in those states and the U.S. Centers for Disease Control and Prevention (CDC) identified shredded iceberg lettuce (Lactuca sativa L) as the vehicle of transmission. The U.S. Food and Drug Administration (FDA) and Minnesota and California public health agencies traced the lettuce to several growing regions in California based on information from a lettuce processor in Minnesota. Samples from an environmental investigation initiated by the California Food Emergency Response Team (CalFERT) revealed a genetic match between the outbreak strain and environmental samples from a single farm, leading to an in-depth systems-based analysis of the irrigation water system on that farm. This paper presents findings from that systems-based analysis, which assessed conditions on the farm potentially contributing to contamination of the lettuce. The farm had three sources of irrigation water: groundwater from onsite wells, surface water delivered by a water management agency and effluent from wastewater lagoons on nearby dairy farms. Wastewater effluent was blended with the other sources and used only to irrigate animal feed crops. However, water management on the farm, including control of wastewater blending, appeared to create potential for cross-contamination. Pressure gradients and lack of backflow measures in the irrigation system might have created conditions for cross-contamination of water used to irrigate lettuce. The irrigation network on the farm had evolved over time to meet various needs, without an overall analysis of how that evolution potentially created vulnerabilities to contamination,of irrigation water. The type of systems analysis described here is one method for helping to ensure that such vulnerabilities are identified and addressed. A preventive, risk-based management approach, such as the Water Safety Plan process for drinking water, may also be useful in managing irrigation water quality. Published by Elsevier B.V. C1 [Gelting, Richard J.] Ctr Dis Control & Prevent, Ctr Global Hlth, Hlth Syst Reconstruct Team, Atlanta, GA 30341 USA. [Baloch, Mansoor A.; Zarate-Bermudez, Max] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Environm Hlth Serv Branch, Atlanta, GA 30341 USA. [Hajmeer, Maha N.; Yee, Benson J.] Calif Dept Publ Hlth, Food & Drug Branch, Sacramento, CA 95899 USA. [Yee, J. Christopher] US FDA, Oakland, CA 94612 USA. [Brown, Teresa] Univ Tennessee, Dept Earth & Planetary Sci, Knoxville, TN 37996 USA. RP Gelting, RJ (reprint author), Ctr Dis Control & Prevent, Ctr Global Hlth, Hlth Syst Reconstruct Team, MS F-57, Atlanta, GA 30341 USA. EM rgelting@cdc.gov; mzaratebermudez@cdc.gov NR 55 TC 2 Z9 2 U1 3 U2 46 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-3774 EI 1873-2283 J9 AGR WATER MANAGE JI Agric. Water Manage. PD MAR 1 PY 2015 VL 150 BP 111 EP 118 DI 10.1016/j.agwat.2014.12.002 PG 8 WC Agronomy; Water Resources SC Agriculture; Water Resources GA CA5NK UT WOS:000348954900011 ER PT J AU Saylor, DM Soneson, JE Kleinedler, JJ Homer, M Warren, JA AF Saylor, David M. Soneson, Joshua E. Kleinedler, James J. Homer, Marc Warren, James A. TI A structure-sensitive continuum model of arterial drug deposition SO INTERNATIONAL JOURNAL OF HEAT AND MASS TRANSFER LA English DT Article DE Diffusion; Model; Microstructure; Controlled release; Laminate; Stent ID ELUTING STENTS; PACLITAXEL; PHARMACOKINETICS; DIFFUSION; MICROSTRUCTURE; TRANSPORT; COATINGS; DELIVERY; BINDING; BALLOON AB The successful function of drug-eluting devices used in the treatment of atherosclerosis relies on the concentration and retention of the drug in the vessel wall. While drug deposition necessarily depends on the underlying tissue structure, conventional models do not account for the intrinsic structural complexity of arterial tissue and its impact on deposition. By employing only average bulk material properties, the capability to predict the potential for local toxicity or therapeutic failure is limited. To address these limitations, we have developed a model that accounts explicitly for variations in the tissue structure. The approach uses a laminate approximation of the underlying microscopic structure to specify an expression for the continuous spatial dependence of the effective macroscopic material properties. Based on this continuum description, we derive an analytic expression for drug uptake into arterial tissue under typical ex vivo experimental conditions. This expression is used to extract relevant material properties for paclitaxel in bovine arteries based on available literature data. The best fit parameters are then used as the basis for numerical simulations of long-term deposition behavior from a stent with a pure paclitaxel coating. The results of these simulations are quantitatively consistent with previously reported in vivo observations. We also demonstrate that significant errors can arise in both the interpretation of experimental data and the prediction of drug deposition when structural heterogeneities are ignored. Establishing a robust deposition model can ultimately reduce empiricism in the design of drug-eluting devices, providing a facile means to guide the development and refinement of these technologies. Published by Elsevier Ltd. C1 [Saylor, David M.; Soneson, Joshua E.; Kleinedler, James J.] Ctr Devices & Radiol Hlth, FDA, Silver Spring, MD 20993 USA. [Homer, Marc] ANSYS Inc, Evanston, IL 60201 USA. [Warren, James A.] Natl Inst Stand & Technol, Gaithersburg, MD 20899 USA. RP Saylor, DM (reprint author), Ctr Devices & Radiol Hlth, FDA, Silver Spring, MD 20993 USA. EM david.saylor@fda.hhs.gov NR 35 TC 3 Z9 3 U1 1 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0017-9310 EI 1879-2189 J9 INT J HEAT MASS TRAN JI Int. J. Heat Mass Transf. PD MAR PY 2015 VL 82 BP 468 EP 478 DI 10.1016/j.ijheatmasstransfer.2014.10.059 PG 11 WC Thermodynamics; Engineering, Mechanical; Mechanics SC Thermodynamics; Engineering; Mechanics GA CA5OI UT WOS:000348957300044 ER PT J AU Gitterman, S AF Gitterman, Steven TI Revised Device Labeling for the Cepheid Xpert MTB/RIF Assay for Detecting Mycobacterium tuberculosis SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID UNITED-STATES C1 US FDA, Div Microbiol Devices, Off In Vitro Diagnost & Radiol Hlth, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. RP Gitterman, S (reprint author), US FDA, Div Microbiol Devices, Off In Vitro Diagnost & Radiol Hlth, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. EM steven.gitterman@fda.hhs.gov NR 4 TC 7 Z9 7 U1 0 U2 0 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 FEB 27 PY 2015 VL 64 IS 7 BP 193 EP 193 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CC3BV UT WOS:000350220300008 ER PT J AU Rappaport, BA Suresh, S Hertz, S Evers, AS Orser, BA AF Rappaport, Bob A. Suresh, Santhanam Hertz, Sharon Evers, Alex S. Orser, Beverley A. TI Anesthetic Neurotoxicity - Clinical Implications of Animal Models SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID RHESUS MACAQUE BRAIN; FETAL C1 [Rappaport, Bob A.; Hertz, Sharon] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Suresh, Santhanam] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Evers, Alex S.] Washington Univ, Sch Med, St Louis, MO USA. [Orser, Beverley A.] Univ Toronto, Dept Anesthesia & Physiol, Toronto, ON, Canada. RP Rappaport, BA (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. NR 6 TC 80 Z9 81 U1 2 U2 14 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 FEB 26 PY 2015 VL 372 IS 9 BP 796 EP 797 DI 10.1056/NEJMp1414786 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CB8SQ UT WOS:000349901700002 PM 25714157 ER PT J AU Mecker-Pogue, LC Kauffman, JF AF Mecker-Pogue, Laura C. Kauffman, John F. TI Raman imaging of pharmaceutical materials: Refractive index effects on contrast at buried interfaces SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Raman; Chemical imaging; Pharmaceuticals; Microfabrication; Image Resolution ID SPATIAL-RESOLUTION; QUALITY-CONTROL; SPECTROSCOPY; MICROSCOPY; DEPTH; TRANSMISSION; FORMULATIONS; TABLETS; SAMPLES; SIZE AB Resolution targets composed of bilayer polydimethylsiloxane (PDMS) devices with buried polyethylene glycol (PEG) channels have been fabricated using traditional photolithographic and micromolding techniques to develop resolution targets that mimic pharmaceutical materials. Raman chemical images of the resulting PEG-in-PDMS devices composed of varying parallel line widths were investigated by imaging the PEG lines through a thin overlayer of PDMS. Additionally, a scattering agent, Al2O3, was introduced at varying concentrations to each layer of the device to explore the effects of scattering materials on Raman images. Features in the resulting chemical images of the PEG lines suggest that reflection at the PEG/PDMS interface contributes to the Raman signal. A model based on geometric optics was developed to simulate the observed image functions of the targets. The results emphasize the influence of refractive index discontinuities at the PEG/PDMS interface on the apparent size and shape of the PEG features. Such findings have an impact on interpretation of Raman images of nonabsorbing, opaque pharmaceutical samples. Published by Elsevier B.V. C1 [Mecker-Pogue, Laura C.; Kauffman, John F.] Ctr Drug Evaluat & Res, Div Pharmaceut Anal Food & Drug Adm, St Louis, MO 63110 USA. RP Kauffman, JF (reprint author), Ctr Drug Evaluat & Res, Div Pharmaceut Anal Food & Drug Adm, 645 S Newstead Ave, St Louis, MO 63110 USA. EM john.kauffman@fda.hhs.gov NR 27 TC 0 Z9 0 U1 3 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 EI 1873-264X J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD FEB 25 PY 2015 VL 105 BP 17 EP 23 DI 10.1016/j.jpba.2014.11.033 PG 7 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA CA6YU UT WOS:000349064600003 PM 25527977 ER PT J AU Yu, DK Green, B Marrone, A Guo, YL Kadlubar, S Lin, DX Fuscoe, J Pogribny, I Ning, BT AF Yu, Dianke Green, Bridgett Marrone, April Guo, Yongli Kadlubar, Susan Lin, Dongxin Fuscoe, James Pogribny, Igor Ning, Baitang TI Suppression of CYP2C9 by MicroRNA hsa-miR-128-3p in Human Liver Cells and Association with Hepatocellular Carcinoma SO SCIENTIFIC REPORTS LA English DT Article ID GENE-EXPRESSION; CANCER RISK; CYTOCHROME-P450 ENZYMES; PROSTATE-CANCER; CARCINOGENESIS; POLYMORPHISMS; PROGRESSION; MIR-128; BENZOPYRENE; SUSCEPTIBILITY AB Published studies have identified genetic variants, somatic mutations, and changes in gene expression profiles that are associated with hepatocellular carcinoma (HCC), particularly involving genes that encode drug metabolizing enzymes (DMEs). CYP2C9, one of the most abundant and important DMEs, is involved in the metabolism of many carcinogens and drugs and is down-regulated in HCC. To investigate the molecular mechanisms that control CYP2C9 expression, we applied integrative approaches including in silico, in vitro, and in vivo analyses to elucidate the role of microRNA hsa-miR-128-3p in the regulation of CYP2C9 expression and translation. RNA electrophoresis mobility shift assays demonstrated a direct interaction between hsa-miR-128-3p and its cognate target, the CYP2C9 transcript. Furthermore, the expression of a luciferase reporter gene containing the 3'-UTR of CYP2C9 and the endogenous expression of CYP2C9 were suppressed by transfection of hsa-miR-128-3p. Importantly, chemically-induced up- or down-regulation of hsa-miR-128-3p correlated inversely with the expression of CYP2C9. Finally, an association analysis revealed that the expression of hsa-miR-128-3p is inversely correlated with the expression of CYP2C9 in HCC tumor tissues. Altogether, the study helped to elucidate the mechanism of CYP2C9 regulation by hsa-miR-128-3p, and the inverse association in HCC. C1 [Yu, Dianke; Green, Bridgett; Marrone, April; Fuscoe, James; Pogribny, Igor; Ning, Baitang] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Yu, Dianke; Lin, Dongxin] Chinese Acad Med Sci, Canc Inst & Hosp, State Key Lab Mol Oncol, Beijing 100021, Peoples R China. [Yu, Dianke; Lin, Dongxin] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Etiol & Carcinogenesis, Beijing 100021, Peoples R China. [Yu, Dianke; Lin, Dongxin] Peking Union Med Coll, Beijing 100021, Peoples R China. [Guo, Yongli] Capital Med Univ, Beijing Childrens Hosp, Beijing 100045, Peoples R China. [Kadlubar, Susan] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. RP Ning, BT (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM baitang.ning@fda.hhs.gov NR 45 TC 13 Z9 13 U1 1 U2 11 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 FEB 23 PY 2015 VL 5 AR 8534 DI 10.1038/srep08534 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB6BW UT WOS:000349712900007 PM 25704921 ER PT J AU Cao, XF Lin, HX Muskhelishvili, L Latendresse, J Richter, P Heflich, RH AF Cao, Xuefei Lin, Haixia Muskhelishvili, Levan Latendresse, John Richter, Patricia Heflich, Robert H. TI Tight junction disruption by cadmium in an in vitro human airway tissue model SO RESPIRATORY RESEARCH LA English DT Article DE Cadmium; Airway air-liquid-interface (ALI) culture; Tight junction; Occludin phosphorylation; Intracellular junctional interacting proteins ID PROTEIN-KINASE-C; TYROSINE PHOSPHORYLATION; EPITHELIAL-CELLS; OCCLUDIN; ZO-1; CARCINOGENESIS; LOCALIZATION; POPULATION; EXPRESSION; EXPOSURE AB Background: The cadmium (Cd) present in air pollutants and cigarette smoke has the potential of causing multiple adverse health outcomes involving damage to pulmonary and cardiovascular tissue. Injury to pulmonary epithelium may include alterations in tight junction (TJ) integrity, resulting in impaired epithelial barrier function and enhanced penetration of chemicals and biomolecules. Herein, we investigated mechanisms involved in the disruption of TJ integrity by Cd exposure using an in vitro human air-liquid-interface (ALI) airway tissue model derived from normal primary human bronchial epithelial cells. Methods: ALI cultures were exposed to noncytotoxic doses of CdCl2 basolaterally and TJ integrity was measured by Trans-Epithelial Electrical Resistance (TEER) and immunofluorescence staining with TJ markers. PCR array analysis was used to identify genes involved with TJ collapse. To explore the involvement of kinase signaling pathways, cultures were treated with CdCl2 in the presence of kinase inhibitors specific for cellular Src or Protein Kinase C (PKC). Results: Noncytotoxic doses of CdCl2 resulted in the collapse of barrier function, as demonstrated by TEER measurements and Zonula occludens-1 (ZO-1) and occludin staining. CdCl2 exposure altered the expression of several groups of genes encoding proteins involved in TJ homeostasis. In particular, down-regulation of select junction- interacting proteins suggested that a possible mechanism for Cd toxicity involves disruption of the peripheral junctional complexes implicated in connecting membrane-bound TJ components to the actin cytoskeleton. Inhibition of kinase signaling using inhibitors specific for cellular Src or PKC preserved the integrity of TJs, possibly by preventing occludin tyrosine hyperphosphorylation, rather than reversing the down-regulation of the junction interacting proteins. Conclusions: Our findings indicate that acute doses of Cd likely disrupt TJ integrity in human ALI airway cultures both through occludin hyperphosphorylation via kinase activation and by direct disruption of the junction-interacting complex. C1 [Cao, Xuefei; Lin, Haixia] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72205 USA. [Muskhelishvili, Levan; Latendresse, John] Toxicol Pathol Associates, Jefferson, AR 72079 USA. [Richter, Patricia] US Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. [Heflich, Robert H.] Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. RP Heflich, RH (reprint author), Div Genet & Mol Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM robert.heflich@fda.hhs.gov FU U.S. Food and Drug Administration through Center for Tobacco Products; Oak Ridge Institute for Science and Education FX This work is supported by U.S. Food and Drug Administration funding through the Center for Tobacco Products (this study was conducted between March and August of 2013). H.L was supported by a post-doctoral fellowship through the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 34 TC 6 Z9 7 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-993X EI 1465-9921 J9 RESP RES JI Respir. Res. PD FEB 21 PY 2015 VL 16 AR 30 DI 10.1186/s12931-015-0191-9 PG 14 WC Respiratory System SC Respiratory System GA CD0VA UT WOS:000350790800001 PM 25851441 ER PT J AU Ratanasopa, K Strader, MB Alayash, AI Bulow, L AF Ratanasopa, Khuanpiroon Strader, Michael Brad Alayash, Abdu I. Bulow, Leif TI Dissection of the radical reactions linked to fetal hemoglobin reveals enhanced pseudoperoxidase activity SO FRONTIERS IN PHYSIOLOGY LA English DT Article DE hemoglobins; fetal blood; peroxidases; kinetics; spectrophotometry; quantitative mass spectrometry ID HYDROGEN-PEROXIDE; BLOOD SUBSTITUTES; ELECTRON-TRANSFER; HEME; ADULT; KINETICS; SUBUNIT; ALPHA(1)-MICROGLOBULIN; FERRYLHEMOGLOBIN; OXYHEMOGLOBIN AB In the presence of excess hydrogen peroxide (H2O2), ferrous (Fe+2) human hemoglobin (Hb) (alpha 2 beta 2) undergoes a rapid conversion to a higher oxidation ferryl state (Fe+4) which rapidly autoreduces back to the ferric form (Fe+3) as H2O2 is consumed in the reaction. In the presence of additional H2O2 the ferric state can form both ferryl Hb and an associated protein radical in a pseudoperoxidative cycle that results in the loss of radicals and heme degradation. We examined whether adult HbA (beta 2 alpha 2) exhibits a different pseudoenzymatic activity than fetal Hb (gamma 2 alpha 2) due to the switch of gamma to beta subunits. Rapid mixing of the ferric forms of both proteins with excess H2O2 resulted in biphasic kinetic time courses that can be assigned to gamma/beta and alpha, respectively. Although there was a 1.5 fold increase in the fast reacting gamma/beta subunits the slower reacting phases (attributed to alpha subunits of both proteins) were essentially the same. However, the rate constant for the auto-reduction of ferryl back to ferric for both proteins was found to be 76% higher for HbF than HbA and in the presence of the mild reducing agent, ascorbate there was a 3-fold higher reduction rate in ferryl HbF as opposed to ferryl HbA. Using quantitative mass spectrometry in the presence of H2O2 we found oxidized gamma/beta Cys93, to be more abundantly present in HbA than HbF, whereas higher levels of nitrated beta Tyr35 containing peptides were found in HbA samples treated with nitrite. The extraordinary stability of HbF reported here may explain the evolutionary advantage this protein may confer onto co-inherited hemoglobinopathies and can also be utilized in the engineering of oxidatively stable Hb-based oxygen carriers. C1 [Ratanasopa, Khuanpiroon; Bulow, Leif] Lund Univ, Pure & Appl Biochem, Dept Chem, S-22100 Lund, Sweden. [Strader, Michael Brad; Alayash, Abdu I.] US FDA, Lab Biochem & Vasc Biol, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Bulow, L (reprint author), Lund Univ, Pure & Appl Biochem, Dept Chem, Getingevagen 60,POB 124, S-22100 Lund, Sweden. EM leif.bulow@tbiokem.lth.se FU Swedish Science Foundation; Swedish Foundation for Strategic Research; Royal Thai Government Scholarship; National Institutes of Health from NHLBI [P01-HL110900]; United States Food and Drug Administration Grants MODSCI FX We wish to acknowledge the financial support from the Swedish Science Foundation and the Swedish Foundation for Strategic Research as well as a Royal Thai Government Scholarship (to KR). We also thank Cedric Dicko for constructive discussions on the kinetic evaluations. This work was also supported by National Institutes of Health Grant P01-HL110900 from NHLBI (AIA.) and by United States Food and Drug Administration Grants MODSCI (AIA). NR 44 TC 1 Z9 1 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 FEB 20 PY 2015 VL 6 AR 39 DI 10.3389/fphys.2015.00039 PG 11 WC Physiology SC Physiology GA CG0BX UT WOS:000352932700001 PM 25750627 ER PT J AU Angelo, KM Chu, A Anand, M Nguyen, TA Bottichio, L Wise, M Williams, I Seelman, S Bell, R Fatica, M Lance, S Baldwin, D Shannon, K Lee, H Trees, E Strain, E Gieraltowski, L AF Angelo, Kristina M. Chu, Alvina Anand, Madhu Thai-An Nguyen Bottichio, Lyndsay Wise, Matthew Williams, Ian Seelman, Sharon Bell, Rebecca Fatica, Marianne Lance, Susan Baldwin, Deanna Shannon, Kyle Lee, Hannah Trees, Eija Strain, Errol Gieraltowski, Laura TI Outbreak of Salmonella Newport Infections Linked to Cucumbers - United States, 2014 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Angelo, Kristina M.] CDC, Epidem Intelligence Serv, Atlanta, GA 30333 USA. [Angelo, Kristina M.; Thai-An Nguyen; Bottichio, Lyndsay; Wise, Matthew; Williams, Ian; Trees, Eija; Gieraltowski, Laura] CDC, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Chu, Alvina; Shannon, Kyle; Lee, Hannah] Maryland Dept Hlth & Mental Hyg, Baltimore, MD 21201 USA. [Anand, Madhu] New York State Dept Hlth, Albany, NY 12237 USA. [Seelman, Sharon; Bell, Rebecca; Fatica, Marianne; Lance, Susan; Strain, Errol] US FDA, Rockville, MD 20857 USA. [Baldwin, Deanna] Maryland Dept Agr, College Pk, MD USA. RP Angelo, KM (reprint author), CDC, Epidem Intelligence Serv, Atlanta, GA 30333 USA. EM kangelo@cdc.gov NR 3 TC 16 Z9 17 U1 1 U2 19 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD FEB 20 PY 2015 VL 64 IS 6 BP 144 EP 147 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CB7VT UT WOS:000349837300003 PM 25695319 ER PT J AU Kang, L Chen, WJ Petrick, NA Gallas, BD AF Kang, Le Chen, Weijie Petrick, Nicholas A. Gallas, Brandon D. TI Comparing two correlated C indices with right-censored survival outcome: a one-shot nonparametric approach SO STATISTICS IN MEDICINE LA English DT Article DE C index; bootstrap; concordance; hypothesis testing; jackknife; type I error; power ID CORONARY-HEART-DISEASE; OPERATING CHARACTERISTIC ANALYSIS; DIAGNOSTIC-TESTS; BLOOD-PRESSURE; CHARACTERISTIC CURVES; EXPLAINED VARIATION; ROC CURVES; FRAMINGHAM; DISCRIMINATION; AREA AB The area under the receiver operating characteristic curve is often used as a summary index of the diagnostic ability in evaluating biomarkers when the clinical outcome (truth) is binary. When the clinical outcome is right-censored survival time, the C index, motivated as an extension of area under the receiver operating characteristic curve, has been proposed by Harrell as a measure of concordance between a predictive biomarker and the right-censored survival outcome. In this work, we investigate methods for statistical comparison of two diagnostic or predictive systems, of which they could either be two biomarkers or two fixed algorithms, in terms of their C indices. We adopt a U-statistics-based C estimator that is asymptotically normal and develop a nonparametric analytical approach to estimate the variance of the C estimator and the covariance of two C estimators. A z-score test is then constructed to compare the two C indices. We validate our one-shot nonparametric method via simulation studies in terms of the type I error rate and power. We also compare our one-shot method with resampling methods including the jackknife and the bootstrap. Simulation results show that the proposed one-shot method provides almost unbiased variance estimations and has satisfactory type I error control and power. Finally, we illustrate the use of the proposed method with an example from the Framingham Heart Study. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Kang, Le] Virginia Commonwealth Univ, Sch Med, Dept Biostat, Richmond, VA USA. [Kang, Le; Chen, Weijie; Petrick, Nicholas A.; Gallas, Brandon D.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Imaging Diagnost & Software Reliabil, Silver Spring, MD 20993 USA. RP Kang, L (reprint author), VCU Med Ctr, Dept Biostat, 830 East Main St, Richmond, VA 23298 USA. EM LKang@vcu.edu; Weijie.Chen@fda.hhs.gov OI KANG, LE/0000-0002-4277-902X FU Center for Devices and Radiological Health; National Heart, Lung, and Blood Institute [R01HL113697]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD060913] FX This project was supported in part by an appointment to the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. Le Kang was partly supported by the National Heart, Lung, and Blood Institute grant R01HL113697 and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development grant R01HD060913. The authors are indebted to Dr. Frank Samuelson and Dr. Adam Wunderlich for helpful discussions. The opinions expressed are those of the authors and not necessarily those of the Editors. The authors thank the Associated Editor and three anonymous referees for constructive comments that greatly improved the article. NR 56 TC 12 Z9 12 U1 2 U2 11 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 FEB 20 PY 2015 VL 34 IS 4 BP 685 EP 703 DI 10.1002/sim.6370 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 AZ7TM UT WOS:000348420600010 PM 25399736 ER PT J AU Haendiges, J Timme, R Allard, MW Myers, RA Brown, EW Gonzalez-Escalona, N AF Haendiges, Julie Timme, Ruth Allard, Marc W. Myers, Robert A. Brown, Eric W. Gonzalez-Escalona, Narjol TI Characterization of Vibrio parahaemolyticus clinical strains from Maryland (2012-2013) and comparisons to a locally and globally diverse V-parahaemolyticus strains by whole-genome sequence analysis SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE NGS; WGS; Vibrio parahaemolyticus; clinical; phylogenetic analysis; phylogeny; SNPs ID THERMOSTABLE DIRECT HEMOLYSIN; UNITED-STATES; PACIFIC-NORTHWEST; WEST-COAST; TDH GENE; TRH; EPIDEMIOLOGY; OUTBREAKS; OYSTERS; CHILE AB Vibrio parahaemolyticus is the leading cause of foodborne illnesses in the US associated with the consumption of raw shellfish. Previous population studies of V parahaemolyticus have used Multi-Locus Sequence Typing (MLST) or Pulsed Field Gel Electrophoresis (PFGE). Whole genome sequencing (WGS) provides a much higher level of resolution, but has been used to characterize only a few United States (US) clinical isolates. Here we report the WGS characterization of 34 genomes of V parahaemolyticus strains that were isolated from clinical cases in the state of Maryland (MD) during 2 years (2012-2013). These 2 years saw an increase of V parahaemolyticus cases compared to previous years. Among these MD isolates, 28% were negative for tdh and trh, 8% were tdh positive only, 11% were trh positive only, and 53% contained both genes. We compared this set of V parahaemolyticus genomes to those of a collection of 17 archival strains from the US (10 previously sequenced strains and 7 from NCBI, collected between 1988 and 2004) and 15 international strains, isolated from geographically-diverse environmental and clinical sources (collected between 1980 and 2010). A WGS phylogenetic analysis of these strains revealed the regional outbreak strains from MD are highly diverse and yet genetically distinct from the international strains. Some MD strains caused outbreaks 2 years in a row, indicating a local source of contamination (e.g., 5T631). Advances in WGS will enable this type of analysis to become routine, providing an excellent tool for improved surveillance. Databases built with phylogenetic data will help pinpoint sources of contamination in future outbreaks and contribute to faster outbreak control. C1 [Haendiges, Julie; Myers, Robert A.] Dept Hlth & Mental Hyg, Baltimore, MD USA. [Timme, Ruth; Allard, Marc W.; Brown, Eric W.; Gonzalez-Escalona, Narjol] US FDA, Ctr Food & Appl Nutr, College Pk, MD 20740 USA. RP Gonzalez-Escalona, N (reprint author), US FDA, Ctr Food & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM narjol.gonzalez-escalona@fda.hhs.gov OI Gonzalez-Escalona, Narjol/0000-0003-4568-0022 FU FDA Foods Program Intramural Funds FX This project was supported by the FDA Foods Program Intramural Funds. The authors thank Dr. Lili Fox Velez for her editorial assistance on this manuscript. NR 66 TC 12 Z9 13 U1 2 U2 13 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD FEB 19 PY 2015 VL 6 AR 125 DI 10.3389/fmicb.2015.00125 PG 11 WC Microbiology SC Microbiology GA CC4GK UT WOS:000350309900001 PM 25745421 ER PT J AU Roberts, JN Gruber, MF AF Roberts, Jeffrey N. Gruber, Marion F. TI Regulatory considerations in the clinical development of vaccines indicated for use during pregnancy SO VACCINE LA English DT Review DE Pregnancy; Regulations; Clinical development ID MATERNAL IMMUNIZATION PROGRAM; INFLUENZA IMMUNIZATION; INFANTS; IMMUNOGENICITY; MOTHERS; SAFETY; WOMEN; PERSPECTIVE; VACCINATION; MORBIDITY AB Despite supportive public health policies (e.g., ACIP recommendations), the potential for providing clinical benefit through maternal immunization has yet to be fully realized. For vaccines already licensed and approved for use in adults, specific FDA approval for use during pregnancy to prevent disease in the mother and/or infant may have a significant impact on uptake and usage in pregnant women. In addition, for either a licensed vaccine or a novel vaccine, FDA approval for use during pregnancy would result in labeling that would serve as a resource for practitioners and would facilitate the safe and effective use of the vaccine during pregnancy. In the U.S., while many vaccines are approved for use in adults and most are not contraindicated for use in pregnant women, no vaccine is licensed for use specifically during pregnancy. Among the perceived obstacles hindering the clinical development of vaccines for use in pregnancy, regulatory issues are frequently cited. One aim of this article is to address the perceived regulatory obstacles. General concepts and regulatory considerations for clinical safety and effectiveness evaluations for vaccines indicated for use during pregnancy will be discussed. This discussion is not intended to establish data requirements or to articulate agency policy or guidance regarding specific vaccine products. Published by Elsevier Ltd. C1 [Roberts, Jeffrey N.; Gruber, Marion F.] US FDA, CBER, Off Vaccines Res & Review, Silver Spring, MD 20993 USA. RP Roberts, JN (reprint author), US FDA, CBER, Off Vaccines Res & Review, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jeff.roberts@fda.hhs.gov NR 38 TC 10 Z9 10 U1 1 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 FEB 18 PY 2015 VL 33 IS 8 BP 966 EP 972 DI 10.1016/j.vaccine.2014.12.068 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CC2PX UT WOS:000350188200004 PM 25573034 ER PT J AU Rallabhandi, P Sharma, GM Pereira, M Williams, KM AF Rallabhandi, Prasad Sharma, Girdhari M. Pereira, Marion Williams, Kristina M. TI Immunological Characterization of the Gluten Fractions and Their Hydrolysates from Wheat, Rye and Barley SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE gluten; ELISA; celiac disease; gluten free; wheat; allergens ID CELIAC-DISEASE; MONOCLONAL-ANTIBODIES; MASS-SPECTROMETRY; FREE FOOD; PROTEINS; GLIADIN; OATS; PEPTIDES; ELISA; QUANTIFICATION AB Gluten proteins in wheat, rye and barley cause celiac disease, an autoimmune disorder of the small intestine, which affects approximately 1% of the world population. Gluten is comprised of prolamin and glutelin. Since avoidance of dietary gluten is the only option for celiac patients, a sensitive gluten detection and quantitation method is warranted. Most regulatory agencies have set a threshold of 20 ppm gluten in foods labeled gluten-free, based on the currently available ELISA methods. However, these methods may exhibit differences in gluten quantitation from different gluten-containing grains. In this study, prolamin and glutelin fractions were isolated from wheat, rye, barley, oats and corn. Intact and pepsin-trypsin (PT)-digested prolamin and glutelin fractions were used to assess their immunoreactivity and gluten recovery by three sandwich and two competitive ELISA kits. The Western blots revealed varied affinity of ELISA antibodies to gluten-containing grain proteins and no reactivity to oat and corn proteins. ELISA results showed considerable variation in gluten recoveries from both intact and PT-digested gluten fractions among different kits. Prolamin fractions showed higher gluten recovery compared to their respective glutelin fractions. Among prolamins, barley exhibited higher recovery compared to wheat and rye with most of the ELISA kits used. Hydrolysis resulted in reduced gluten recovery of most gluten fractions. These results suggest that the suitability of ELISA for accurate gluten quantitation is dependent upon various factors, such as grain source, antibody specificity, gluten proteins and the level of their hydrolysis in foods. C1 [Rallabhandi, Prasad; Sharma, Girdhari M.; Pereira, Marion; Williams, Kristina M.] US FDA, Ctr Food Safety & Appl Nutr, Immunobiol Branch, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. RP Rallabhandi, P (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Immunobiol Branch, Off Appl Res & Safety Assessment, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM Prasad.Rallabhandi@fda.hhs.gov FU U.S. FDA Office of Women's Health (OWH) FX This work was supported by a U.S. FDA Office of Women's Health (OWH) grant (to Prasad Rallabhandi). NR 44 TC 9 Z9 9 U1 5 U2 43 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 FEB 18 PY 2015 VL 63 IS 6 BP 1825 EP 1832 DI 10.1021/jf505716p PG 8 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA CB7LB UT WOS:000349807400018 PM 25619974 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 CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR Precision Medicine Conference on Drug Sensitivity and Resistance - Improving Cancer Therapy CY JUN 18-21, 2014 CL Orlando, FL SP Amer Assoc Canc Res C1 [Dokmanovic, Milos; Shen, Yi; Hirsch, Dianne S.; Wu, Wen Jin] US FDA, Bethesda, MD 20014 USA. [Wu, Yun; Chen, Jieqing] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 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 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2015 VL 21 SU 4 MA B38 DI 10.1158/1557-3265.PMS14-B38 PG 1 WC Oncology SC Oncology GA CR5LZ UT WOS:000361385600065 ER PT J AU Soltysik, DA Thomasson, D Rajan, S Biassou, N AF Soltysik, David A. Thomasson, David Rajan, Sunder Biassou, Nadia TI Improving the use of principal component analysis to reduce physiological noise and motion artifacts to increase the sensitivity of task-based fMRI SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE BOLD fMRI; Physiological noise, Principal components analysis ID RESTING STATE NETWORKS; FUNCTIONAL MRI; BRAIN ACTIVATION; BOLD SIGNAL; FLUCTUATIONS; CONNECTIVITY; STRATEGIES; RESPONSES; CORTEX AB Background: Functional magnetic resonance imaging (fMRI) time series are subject to corruption by many noise sources, especially physiological noise and motion. Researchers have developed many methods to reduce physiological noise, including RETROICOR, which retroactively removes cardiac and respiratory waveforms collected during the scan, and CompCor, which applies principal components analysis (PCA) to remove physiological noise components without any physiological monitoring during the scan. New method: We developed four variants of the CompCor method. The optimized CompCor method applies PCA to time series in a noise mask, but orthogonalizes each component to the BOLD response waveform and uses an algorithm to determine a favorable number of components to use as "nuisance regressors." Whole brain component correction (WCompCor) is similar, except that it applies PCA to time-series throughout the whole brain. Low-pass component correction (LCompCor) identifies low-pass filtered components throughout the brain, while high-pass component correction (HCompCor) identifies high-pass filtered components. Comparison with existing method: We compared the new methods with the original CompCor method by examining the resulting functional contrast-to-noise ratio (CNR), sensitivity, and specificity. Results: (1) The optimized CompCor method increased the CNR and sensitivity compared to the original CompCor method and (2) the application of WCompCor yielded the best improvement in the CNR and sensitivity. Conclusions:The sensitivity of the optimized CompCor,WCompCor, and LCompCor methods exceeded that of the original CompCor method. However, regressing noise signals showed a paradoxical consequence of reducing specificity for all noise reduction methods attempted. Published by Elsevier B.V. C1 [Soltysik, David A.; Rajan, Sunder] US FDA, Ctr Devices & Radiol Hlth, Div Biomed Phys, Off Med Prod & Tobacco,Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Thomasson, David] NIAID, Integrated Res Facil, Ft Detrick, MD 21702 USA. [Biassou, Nadia] NIH, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Soltysik, DA (reprint author), US FDA, Ctr Devices & Radiol Hlth, Div Biomed Phys, Off Med Prod & Tobacco,Off Sci & Engn Labs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM davitl.soltysik@fda.hhs.gov OI SOLTYSIK, DAVID/0000-0002-6597-5226 FU Radiology and Imaging Sciences Department of the Warren G. Magnuson Clinical Center at the National Institutes of Health FX This project is supported by the Radiology and Imaging Sciences Department of the Warren G. Magnuson Clinical Center at the National Institutes of Health. NR 46 TC 2 Z9 3 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD FEB 15 PY 2015 VL 241 BP 18 EP 29 DI 10.1016/j.jneumeth.2014.11.015 PG 12 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CC2PW UT WOS:000350188100003 PM 25481542 ER PT J AU Balsam, J Bruck, HA Rasooly, A AF Balsam, Joshua Bruck, Hugh Alan Rasooly, Avraham TI Cell streak imaging cytometry for rare cell detection SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE Flow cytometry; Wide-field imaging; Rare cells; Resource-poor settings; Image enhancement; mHealth ID ARRAY BIOSENSOR AB Detection of rare cells, such as circulating tumor cells, have many clinical applications. To measure rare cells with increased sensitivity and improved data managements, we developed an imaging flow cytometer with a streak imaging mode capability. The new streak mode imaging mode utilizes low speed video to capture moving fluorescently labeled cells in a flow cell. Each moving cell is imaged on multiple pixels on each frame, where the cell path is marked as a streak line proportional to the length of the exposure. Finding rare cells (e.g., <1 cell/mL) requires measuring larger sample volumes to achieve higher sensitivity, therefore we combined streak mode imaging with a "wide" high throughput flow cell (e.g. flow rates set to 10 mL/min) in contrast to the conventional "narrow" hydrodynamic focusing cells typically used in cytometry that are inherently limited to low flow rates. The new flow cell is capable of analyzing 20 mL/min of fluorescently labeled cells. To further increase sensitivity, the signal to noise ratio of the images was also enhanced by combining three imaging methods: (1) background subtraction, (2) pixel binning, and (3) CMOS color channel selection. The streaking mode cytometer has been used for the analysis of SYTO-9 labeled THP-1 human monocytes in buffer and in blood. Samples of cells at 1 cell/mL and 0.1 cell/mL were analyzed in 30 mL with flow rates set to 10 mL/min and frame rates of 4 fps (frame per second). For the target of 1 cell/mL, an average concentration of 0.91 cell/mL was measured by cytometry, with a standard error of 0.03 (C-95 = 0.85-0.97). For the target of 0.1 cell/mL, an average concentration of 0.083 cell/mL was measured, with a standard error of 0.01 (C-95 = 0.065-0.102). Whole blood was also spiked with SYTO-9 labeled cells to a concentration of 10 cell/mL, and the average flow cytometry measurement was 8.7 cells/mL (i.e. 0.87 cells/mL in diluted blood) with a 95% CL of 8.1-9.2 cells/mL. This demonstrated the ability to detect rare cells in blood with high accuracy. Such detection approaches for rare cells have many potential clinical applications. Furthermore, the simplicity and low cost of this device may enable expansion of cell-based clinical diagnostics, especially in resource-poor settings. Published by Elsevier B.V. C1 [Balsam, Joshua; Rasooly, Avraham] 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] NCI, Off Canc Complementary & Alternat Med, Rockville, MD 20850 USA. RP Rasooly, A (reprint author), NIH NCI, 9609 Med Ctr Dr, Rockville, MD 20850 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 represent those of the U.S. Government. NR 11 TC 3 Z9 3 U1 4 U2 62 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 FEB 15 PY 2015 VL 64 BP 154 EP 160 DI 10.1016/j.bios.2014.08.065 PG 7 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA AT6OQ UT WOS:000345059100024 PM 25212069 ER PT J AU Sharma, GM Pereira, M Williams, KM AF Sharma, Girdhari M. Pereira, Marion Williams, Kristina M. TI Gluten detection in foods available in the United States - A market survey SO FOOD CHEMISTRY LA English DT Article DE Gluten; Gluten free foods; ELISA; Immunoassay ID EXERCISE-INDUCED ANAPHYLAXIS; REAL-TIME PCR; CELIAC-DISEASE; WHEAT GLUTEN; CONTAMINATION; BARLEY; IMMUNOASSAYS; ANTIBODIES; PEPTIDES; PRODUCTS AB Many gluten-free (GF) food choices are now available in supermarkets. However, the unintentional presence of gluten in these foods poses a serious health risk to wheat-allergic and celiac patients. Different GF labelled foods (275) and non-GF labelled foods, without wheat/rye/barley on the ingredient label (186), were analysed for gluten content by two different enzyme linked immunosorbent assay (ELISA) kits. Considering the gluten threshold of 20 ppm, GF labelled foods had 98.9% GF labelling compliance with 1.1% (3 out of 275) of foods being mislabelled/misbranded. Among the non-GF labelled foods, 19.4% (36 out of 186) of foods had >20 ppm of gluten, as measured by at least one ELISA kit, of which 19 foods had >100 ppm of gluten. The presence of oats in non-GF labelled foods was strongly correlated with a positive ELISA result. Gluten was also found in a significant number of foods with gluten/wheat-related advisory warnings. Published by Elsevier Ltd. C1 [Sharma, Girdhari M.; Pereira, Marion; Williams, Kristina M.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Sharma, GM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM Girdhari.Sharma@fda.hhs.gov NR 34 TC 6 Z9 7 U1 5 U2 121 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 FEB 15 PY 2015 VL 169 BP 120 EP 126 DI 10.1016/j.foodchem.2014.07.134 PG 7 WC Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics SC Chemistry; Food Science & Technology; Nutrition & Dietetics GA AR1IV UT WOS:000343339800017 PM 25236206 ER PT J AU Kweon, O Kim, SJ Blom, J Kim, SK Kim, BS Baek, DH Park, SI Sutherland, JB Cerniglia, CE AF Kweon, Ohgew Kim, Seong-Jae Blom, Jochen Kim, Sung-Kwan Kim, Bong-Soo Baek, Dong-Heon Park, Su Inn Sutherland, John B. Cerniglia, Carl E. TI Comparative functional pan-genome analyses to build connections between genomic dynamics and phenotypic evolution in polycyclic aromatic hydrocarbon metabolism in the genus Mycobacterium SO BMC EVOLUTIONARY BIOLOGY LA English DT Article DE Mycobacterium; PAH metabolism; Pan-genome; Functional genomics; Functional pan-genome; Phenotype network; Evolution; Epistasis; Pleiotropy ID RING-HYDROXYLATING OXYGENASES; SP STRAIN PYR-1; VANBAALENII PYR-1; TUBERCULOSIS COMPLEX; INTERACTION NETWORKS; PYRENE DEGRADATION; MOLECULAR-CLONING; SEQUENCE-ANALYSIS; IDENTIFICATION; EPISTASIS AB Background: The bacterial genus Mycobacterium is of great interest in the medical and biotechnological fields. Despite a flood of genome sequencing and functional genomics data, significant gaps in knowledge between genome and phenome seriously hinder efforts toward the treatment of mycobacterial diseases and practical biotechnological applications. In this study, we propose the use of systematic, comparative functional pan-genomic analysis to build connections between genomic dynamics and phenotypic evolution in polycyclic aromatic hydrocarbon (PAH) metabolism in the genus Mycobacterium. Results: Phylogenetic, phenotypic, and genomic information for 27 completely genome-sequenced mycobacteria was systematically integrated to reconstruct a mycobacterial phenotype network (MPN) with a pan-genomic concept at a network level. In the MPN, mycobacterial phenotypes show typical scale-free relationships. PAH degradation is an isolated phenotype with the lowest connection degree, consistent with phylogenetic and environmental isolation of PAH degraders. A series of functional pan-genomic analyses provide conserved and unique types of genomic evidence for strong epistatic and pleiotropic impacts on evolutionary trajectories of the PAH-degrading phenotype. Under strong natural selection, the detailed gene gain/loss patterns from horizontal gene transfer (HGT)/deletion events hypothesize a plausible evolutionary path, an epistasis-based birth and pleiotropy-dependent death, for PAH metabolism in the genus Mycobacterium. This study generated a practical mycobacterial compendium of phenotypic and genomic changes, focusing on the PAH-degrading phenotype, with a pan-genomic perspective of the evolutionary events and the environmental challenges. Conclusions: Our findings suggest that when selection acts on PAH metabolism, only a small fraction of possible trajectories is likely to be observed, owing mainly to a combination of the ambiguous phenotypic effects of PAHs and the corresponding pleiotropy-and epistasis-dependent evolutionary adaptation. Evolutionary constraints on the selection of trajectories, like those seen in PAH-degrading phenotypes, are likely to apply to the evolution of other phenotypes in the genus Mycobacterium. C1 [Kweon, Ohgew; Kim, Seong-Jae; Sutherland, John B.; Cerniglia, Carl E.] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. [Blom, Jochen] Univ Bielefeld, Ctr Biotechnol, D-33615 Bielefeld, Nordrhein Westf, Germany. [Kim, Sung-Kwan] Univ Arkansas, Dept Management, Little Rock, AR 72204 USA. [Kim, Bong-Soo] Hallym Univ, Dept Life Sci, Chunchon 200702, Gangwon Do, South Korea. [Baek, Dong-Heon] Dankook Univ, Sch Dent, Dept Oral Microbiol & Immunol, Cheonan, South Korea. [Park, Su Inn] Texas A&M Univ, Dept Comp Sci & Engn, College Stn, TX USA. RP Cerniglia, CE (reprint author), US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. EM carl.cerniglia@fda.hhs.gov FU Postgraduate Research Fellowship Program at the National Center for Toxicological Research FX We thank Kuppan Gokulan and Mark Hart for critical review of the manuscript. We also thank Dr. Joshua Xu for his statistical advice. This work was supported in part by an appointment to the Postgraduate Research Fellowship 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. The views presented in this article do not necessarily reflect those of the U.S. FDA. NR 85 TC 6 Z9 6 U1 3 U2 28 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD FEB 14 PY 2015 VL 15 AR 21 DI 10.1186/s12862-015-0302-8 PG 23 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA CC0XB UT WOS:000350061900003 PM 25880171 ER PT J AU Gonzalez-Escalona, N Gavilan, RG Brown, EW Martinez-Urtaza, J AF Gonzalez-Escalona, Narjol Gavilan, Ronnie G. Brown, Eric W. Martinez-Urtaza, Jaime TI Transoceanic Spreading of Pathogenic Strains of Vibrio parahaemolyticus with Distinctive Genetic Signatures in the recA Gene SO PLOS ONE LA English DT Article ID GENOME SEQUENCE DATA; O3-K6; EPIDEMIOLOGY; EMERGENCE; OUTBREAKS; CHOLERAE; CLUSTERS; DIARRHEA; SEROTYPE; OYSTERS AB Vibrio parahaemolyticus is an important human pathogen whose transmission is associated with the consumption of contaminated seafood. Consistent multilocus sequence typing for V. parahaemolyticus has shown difficulties in the amplification of the recA gene by PCR associated with a lack of amplification or a larger PCR product than expected. In one strain (090-96, Peru, 1996), the produced PCR product was determined to be composed of two recA fragments derived from different Vibrio species. To better understand this phenomenon, we sequenced the whole genome of this strain. The hybrid recA gene was found to be the result of a fragmentation of the original lineage-specific recA gene resulting from a DNA insertion of approximately 30 kb in length. This insert had a G+C content of 38.8%, lower than that of the average G+C content of V. parahaemolyticus (45.2%), and contained 19 ORFs, including a complete recA gene. This new acquired recA gene deviated 24% in sequence from the original recA and was distantly related to recA genes from bacteria of the Vibrionaceae family. The reconstruction of the original recA gene (recA3) identified the precursor as belonging to ST189, a sequence type reported previously only in Asian countries. The identification of this singular genetic feature in strains from Asia reveals new evidence for genetic connectivity between V. parahaemolyticus populations at both sides of the Pacific Ocean that, in addition to the previously described pandemic clone, supports the existence of a recurrent transoceanic spreading of pathogenic V. parahaemolyticus with the corresponding potential risk of pandemic expansion. C1 [Gonzalez-Escalona, Narjol; Brown, Eric W.] US FDA, Ctr Food & Appl Nutr, College Pk, MD 20740 USA. [Gavilan, Ronnie G.] Inst Nacl Salud, Ctr Nacl Salud Publ, Lima, Peru. [Martinez-Urtaza, Jaime] Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England. RP Gonzalez-Escalona, N (reprint author), US FDA, Ctr Food & Appl Nutr, College Pk, MD 20740 USA. EM narjol.gonzalez-escalona@fda.hhs.gov OI Gonzalez-Escalona, Narjol/0000-0003-4568-0022 FU FDA Foods Program Intramural Funds FX This project was supported by the FDA Foods Program Intramural Funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 7 Z9 8 U1 1 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 FEB 13 PY 2015 VL 10 IS 2 AR UNSP e0117485 DI 10.1371/journal.pone.0117485 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC9IO UT WOS:000350682600067 PM 25679989 ER PT J AU Ballesteros, A Mentink-Kane, MM Warren, J Kaplan, GG Dveksler, GS AF Ballesteros, Angela Mentink-Kane, Margaret M. Warren, James Kaplan, Gerardo G. Dveksler, Gabriela S. TI Induction and Activation of Latent Transforming Growth Factor-beta(1) Are Carried out by Two Distinct Domains of Pregnancy-specific Glycoprotein 1 (PSG1) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TGF-BETA; SWISS-MODEL; GROWTH-FACTOR-BETA-1; MONOCYTES; RECEPTOR; FAMILY; CELLS; MACROPHAGES; TGF-BETA-1; PLACENTA AB Pregnancy-specific glycoproteins (PSGs) are a family of Ig-like proteins secreted by specialized placental cells. The PSG1 structure is composed of a single Ig variable region-like N-terminal domain and three Ig constant region-like domains termed A1, A2, and B2. Members of the human and murine PSG family have been shown to induce anti-inflammatory cytokines from monocytes and macrophages and to stimulate angiogenesis. We recently showed that recombinant forms of PSG1 (PSG1-Fc and PSG1-His) and PSG1 purified from the serum of pregnant women are associated with the immunoregulatory cytokine TGF-beta(1) and activated latent TGF-beta(1). Here, we sought to examine the requirement of specific PSG1 domains in the activation of latent TGF-beta(1). Plasmon surface resonance studies showed that PSG1 directly bound to the small latent complex and to the latency-associated peptide of TGF-beta(1) and that this binding was mediated through the B2 domain. Furthermore, the B2 domain alone was sufficient for activating the small latent complex. In separate experiments, we found that the PSG1-mediated induction of TGF-beta(1) secretion in macrophages was dependent on the N-terminal domain. Mutagenesis analysis revealed that four amino acids (LYHY) of the CC' loop of the N-terminal domain were required for induction of latent TGF-beta(1) secretion. Together, our results show that two distinct domains of PSG1 are involved in the regulation of TGF-beta(1) and provide a mechanistic framework for how PSGs modulate the immunoregulatory environment at the maternal-fetal interface for successful pregnancy outcome. C1 [Ballesteros, Angela; Kaplan, Gerardo G.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Mentink-Kane, Margaret M.; Warren, James; Dveksler, Gabriela S.] Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. RP Dveksler, GS (reprint author), Uniformed Serv Hlth Sci, Dept Pathol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM gabriela.dveksler@usuhs.edu FU National Institutes of Health from NIAID [R21AI101979] FX This work was supported, in whole or in part, by National Institutes of Health Award R21AI101979 from NIAID. NR 39 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 13 PY 2015 VL 290 IS 7 BP 4422 EP 4431 DI 10.1074/jbc.M114.597518 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CB2LH UT WOS:000349458400049 PM 25548275 ER PT J AU Uhl, K Peters, JR Flanagan, K AF Uhl, Kathleen Peters, John R. Flanagan, Keith TI High-Cost Generic Drugs - Implications for Patients and Policymakers SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Uhl, Kathleen; Peters, John R.; Flanagan, Keith] US FDA, Silver Spring, MD 20993 USA. RP Uhl, K (reprint author), US FDA, Silver Spring, MD 20993 USA. EM kathleen.uhl@fda.hhs.gov NR 3 TC 1 Z9 1 U1 1 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 FEB 12 PY 2015 VL 372 IS 7 BP 685 EP 686 DI 10.1056/NEJMc1415471 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CA8CK UT WOS:000349143900023 PM 25671270 ER PT J AU Wang, LM Sun, Q Wang, X Wen, T Yin, JJ Wang, PY Bai, R Zhang, XQ Zhang, LH Lu, AH Chen, CY AF Wang, Liming Sun, Qiang Wang, Xin Wen, Tao Yin, Jun-Jie Wang, Pengyang Bai, Ru Zhang, Xiang-Qian Zhang, Lu-Hua Lu, An-Hui Chen, Chunying TI Using Hollow Carbon Nanospheres as a Light-Induced Free Radical Generator To Overcome Chemotherapy Resistance SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MESOPOROUS SILICA NANOPARTICLES; BREAST-CANCER CELLS; MULTIDRUG-RESISTANCE; GRAPHENE OXIDE; DRUG-RESISTANCE; GOLD NANORODS; CONFINED NANOSPACE; IN-VIVO; DOXORUBICIN; DELIVERY AB Under evolutionary pressure from chemotherapy, cancer cells develop resistance characteristics such as a low redox state, which eventually leads to treatment failures. An attractive option for combatting resistance is producing a high concentration of produced free radicals in situ. Here, we report the production and use of dispersible hollow carbon nanospheres (HCSs) as a novel platform for delivering the drug doxorubicine (DOX) and generating additional cellular reactive oxygen species using near-infrared laser irradiation. These irradiated HCSs catalyzed sufficiently persistent free radicals to produce a large number of heat shock factor-1 protein homotrimers, thereby suppressing the activation and function of resistance-related genes. Laser irradiation also promoted the release of DOX from lysosomal DOX@HCSs into the cytoplasm so that it could enter cell nuclei. As a result, DOX@HCSs reduced the resistance of human breast cancer cells (MCF-7/ADR) to DOX through the synergy among photothermal effects, increased generation of free radicals, and chemotherapy with the aid of laser irradiation. HCSs can provide a unique and versatile platform for combatting chemotherapy-resistant cancer cells. These findings provide new clinical strategies and insights for the treatment of resistant cancers. C1 [Wang, Liming; Wang, Xin; Wen, Tao; Wang, Pengyang; Bai, Ru; Chen, Chunying] Chinese Acad Sci, Natl Ctr Nanosci & Technol China, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing, Peoples R China. [Wang, Liming; Wang, Xin; Wen, Tao; Wang, Pengyang; Bai, Ru; Chen, Chunying] Chinese Acad Sci, Inst High Energy Phys, Beijing, Peoples R China. [Sun, Qiang; Zhang, Xiang-Qian; Zhang, Lu-Hua; Lu, An-Hui] Dalian Univ Technol, Sch Chem Engn, State Key Lab Fine Chem, Dalian 116024, Peoples R China. [Yin, Jun-Jie] US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Chen, CY (reprint author), Chinese Acad Sci, Natl Ctr Nanosci & Technol China, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing, Peoples R China. EM anhuilu@dlut.edu.cn; chenchy@nanoctr.cn RI Yin, Jun Jie /E-5619-2014; Wang, Liming/A-6924-2012 OI Wang, Liming/0000-0003-1382-9195 FU National Basic Research Program of China [2012CB934000, 2011CB933401]; National Natural Science Foundation of China [11205166, 21225312, 21320102003]; National Science Fund for Distinguished Young Scholars [11425520]; International Science & Technology Cooperation Program of China [2013DFG32340]; Ministry of Science Technology of China [2011YQ030134]; German Federal Ministry of Education and Research [BMBF 0315773A]; FDA Nanotechnology CORES Program FX We are grateful for financial support by the National Basic Research Program of China (2012CB934000 and 2011CB933401), the National Natural Science Foundation of China (11205166, 21225312, and 21320102003), the National Science Fund for Distinguished Young Scholars (No.11425520), the International Science & Technology Cooperation Program of China (2013DFG32340), the Major Equipment Program (2011YQ030134) from the Ministry of Science Technology of China, and the German Federal Ministry of Education and Research (BMBF 0315773A). The work was also partially supported by a regulatory science grant under the FDA Nanotechnology CORES Program (JY). We appreciate Prof. Meihua Sui of Zhejiang University for discussion on cell culture experiment, Miss Jing Liu at NCNST for 1O2 measurement, and Dr. Ru Liu at IHEP for assistance with confocal imaging. We are grateful to Dr. Ann Motten from NIEHS/NIH and Prof. Peter Thrower for their comments on the manuscript. We thank Dr. Lili Fox Velez for her scientific editing. NR 66 TC 35 Z9 36 U1 30 U2 268 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD FEB 11 PY 2015 VL 137 IS 5 BP 1947 EP 1955 DI 10.1021/ja511560b PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA CB4CM UT WOS:000349575800037 PM 25597855 ER PT J AU Boulanger, A Moon, K Decker, KB Chen, Q Knipling, L Stibitz, S Hinton, DM AF Boulanger, Alice Moon, Kyung Decker, Kimberly B. Chen, Qing Knipling, Leslie Stibitz, Scott Hinton, Deborah M. TI Bordetella pertussis fim3 gene regulation by BvgA: Phosphorylation controls the formation of inactive vs. active transcription complexes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE transcription; BvgA; RNA polymerase; Bordetella pertussis; fim3 ID POLYMERASE-PROMOTER INTERACTIONS; RNA-POLYMERASE; ESCHERICHIA-COLI; DNA-BINDING; ACTIVATION; PROTEIN; INITIATION; CLEARANCE; BACTERIAL; DOMAIN AB Two-component systems [sensor kinase/response regulator (RR)] are major tools used by microorganisms to adapt to environmental conditions. RR phosphorylation is typically required for gene activation, but few studies have addressed how and if phosphorylation affects specific steps during transcription initiation. We characterized transcription complexes made with RNA polymerase and the Bordetella pertussis RR, BvgA, in its nonphosphorylated or phosphorylated (BvgA similar to P) state at P-fim3, the promoter for the virulence gene fim3 (fimbrial subunit), using gel retardation, potassium permanganate and DNase I footprinting, cleavage reactions with protein conjugated with iron bromoacetamidobenzyl-EDTA, and in vitro transcription. Previous work has shown that the level of nonphosphorylated BvgA remains high in vivo under conditions in which BvgA is phosphorylated. Our results here indicate that surprisingly both BvgA and BvgA similar to P form open and initiating complexes with RNA polymerase at P-fim3. However, phosphorylation of BvgA is needed to generate the correct conformation that can transition to competent elongation. Footprints obtained with the complexes made with nonphosphorylated BvgA are atypical; while the initiating complex with BvgA synthesizes short RNA, it does not generate full-length transcripts. Extended incubation of the BvgA/RNA polymerase initiated complex in the presence of heparin generates a stable, but defective species that depends on the initial transcribed sequence of fim3. We suggest that the presence of nonphosphorylated BvgA down-regulates P-fim3 activity when phosphorylated BvgA is present and may allow the bacterium to quickly adapt to the loss of inducing conditions by rapidly eliminating P-fim3 activation once the signal for BvgA phosphorylation is removed. C1 [Boulanger, Alice; Moon, Kyung; Decker, Kimberly B.; Knipling, Leslie; Stibitz, Scott; Hinton, Deborah M.] Natl Inst Diabet & Digest & Kidney Dis, Gene Express & Regulat Sect, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Chen, Qing] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Hinton, DM (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Gene Express & Regulat Sect, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM dhinton@helix.nih.gov FU Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (A.B., K.B.D., K.M., L.K., and D.M.H.). NR 44 TC 2 Z9 2 U1 2 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 10 PY 2015 VL 112 IS 6 BP E526 EP E535 DI 10.1073/pnas.1421045112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA8XL UT WOS:000349204200006 PM 25624471 ER PT J AU Zusterzeel, R Canos, DA Sanders, WE Selzman, KA Ponirakis, A Varosy, PD Strauss, DG AF Zusterzeel, Robbert Canos, Daniel A. Sanders, William E. Selzman, Kimberly A. Ponirakis, Angelo Varosy, Paul D. Strauss, David G. TI REPLY: Some Caveats About QRS Duration in Patients Receiving Cardiac Resynchronization Therapy SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter C1 [Zusterzeel, Robbert; Canos, Daniel A.; Sanders, William E.; Selzman, Kimberly A.; Ponirakis, Angelo; Varosy, Paul D.; 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 NR 1 TC 0 Z9 0 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 FEB 10 PY 2015 VL 65 IS 5 BP 515 EP 515 DI 10.1016/j.jacc.2014.10.062 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CA1IS UT WOS:000348667000022 PM 25660935 ER PT J AU Zeng, RP Park, S Bakic, P Myers, KJ AF Zeng, Rongping Park, Subok Bakic, Predrag Myers, Kyle J. TI Evaluating the sensitivity of the optimization of acquisition geometry to the choice of reconstruction algorithm in digital breast tomosynthesis through a simulation study SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE digital breast tomosynthesis; image reconstruction; system optimization; image quality assessment; lesion detectability; channelized hotelling observer ID MODEL-OBSERVER PERFORMANCE; TRANSMISSION TOMOGRAPHY; IMAGE ACQUISITION; SOFTWARE PHANTOM; DETECTION TASKS; MAMMOGRAPHY; PROJECTION; SIGNAL; 3D; MICROCALCIFICATIONS AB Due to the limited number of views and limited angular span in digital breast tomosynthesis (DBT), the acquisition geometry design is an important factor that affects the image quality. Therefore, intensive studies have been conducted regarding the optimization of the acquisition geometry. However, different reconstruction algorithms were used in most of the reported studies. Because each type of reconstruction algorithm can provide images with its own image resolution, noise properties and artifact appearance, it is unclear whether the optimal geometries concluded for the DBT system in one study can be generalized to the DBT systems with a reconstruction algorithm different to the one applied in that study. Hence, we investigated the effect of the reconstruction algorithm on the optimization of acquisition geometry parameters through carefully designed simulation studies. Our results show that using various reconstruction algorithms, including the filtered back-projection, the simultaneous algebraic reconstruction technique, the maximum-likelihood method and the total-variation regularized least-square method, gave similar performance trends for the acquisition parameters for detecting lesions. The consistency of system ranking indicates that the choice of the reconstruction algorithm may not be critical for DBT system geometry optimization. C1 [Zeng, Rongping; Park, Subok; Myers, Kyle J.] US FDA, Div Imaging Diagonist & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Bakic, Predrag] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Zeng, RP (reprint author), US FDA, Div Imaging Diagonist & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM rongping.zeng@fda.hhs.gov; subok.park@fda.hhs.gov; Predrag.Bakic@uphs.upenn.edu; kyle.myers@fda.hhs.gov FU NIH [154444] FX The authors would like to acknowledge Dr Stefano Young's support for sharing the breast phantoms, used in the Young et al study, for this work. Our thanks also goes to Dr Robert Jennings for his advice and help on determining the proper incident photon fluence for the DBT system simulation. The digital breast phantom research at the University of Pennsylvania was supported by the NIH R01 grant (no. 154444). NR 56 TC 9 Z9 9 U1 1 U2 13 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 FEB 7 PY 2015 VL 60 IS 3 BP 1259 EP 1288 DI 10.1088/0031-9155/60/3/1259 PG 30 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CB2EB UT WOS:000349438400026 PM 25591807 ER PT J AU Weisz, A Ridge, CD Mazzola, EP Ito, Y AF Weisz, Adrian Ridge, Clark D. Mazzola, Eugene P. Ito, Yoichiro TI Preparative separation and identification of novel subsidiary colors of the color additive D&C Red No. 33 (Acid Red 33) using spiral high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE D&C Red No. 33; Spiral high-speed counter-current chromatography; NMR spectra of dye impurities; 5-Amino-3-biphenyl-3-ylazo-4-hydroxy-naphthalene-2,7-disulfonic acid; 5-Amino-4-hydroxy-6-phenyl-3-phenylazo-naphthalene-2,7-disulfonic acid; 5-Amino-4-hydroxy-3,6-bis-phenylazo-naphthalene-2,7-disulfonic acid ID PERFORMANCE LIQUID-CHROMATOGRAPHY; SOLID-PHASE MICROEXTRACTION; TUBING SUPPORT ROTOR; MASS-SPECTROMETRY; PHLOXINE-B; NOS. 27; QUINOLINE YELLOW; BASE EQUILIBRIA; AZO-HYDRAZONE; 5 TARTRAZINE AB Three low-level subsidiary color impurities (A, B, and C) often present in batches of the color additive D&C Red No. 33 (R33, Acid Red 33, Colour Index No. 17200) were separated from a portion of R33 by spiral high-speed counter-current chromatography (HSCCC). The separation involved use of a very polar solvent system, 1-BuOH/5 mM aq. (NH4)(2)SO4. Addition of ammonium sulfate to the lower phase forced partition of the components into the upper phase, thereby eliminating the need to add a hydrophobic counterion as was previously required for separations of components from sulfonated dyes. The very polar solvent system used would not have been retained in a conventional multi-layer coil HSCCC instrument, but the spiral configuration enabled retention of the stationary phase, and thus, the separation was possible. A 1 g portion of R33 enriched in A, B, and C was separated using the upper phase of the solvent system as the mobile phase. The retention of the stationary phase was 38.1%, and the separation resulted in 4.8 mg of A of >90% purity, 18.3 mg of B of >85% purity, and 91 mg of C of 65-72% purity. A second separation of a portion of the C mixture resulted in 7 mg of C of >94% purity. The separated impurities were identified by high-resolution mass spectrometry and NMR spectroscopic techniques as follows: 5-amino-3-bipheny1-3-ylazo-4-hydroxy-naphthalene2,7-disulfonic acid, A; 5-amino-4-hydroxy-6-pheny1-3-phenylazo-naphthalene-2,7-disulfonic acid, B; and 5-amino-4-hydroxy-3,6-bis-phenylazo-naphthalene-2,7-disulfonic acid, C. The isomers A and B are compounds reported for the first time. Application of the spiral HSCCC method resulted in the additional benefit of yielding 930 mg of the main component of R33, 5-amino-4-hydroxy-3-phenylazo-naphthalene2,7-disulfonic acid, of >97% purity. Published by Elsevier B.V. C1 [Weisz, Adrian] US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Ridge, Clark D.; Mazzola, Eugene P.] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Ito, Yoichiro] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Weisz, A (reprint author), US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM adrian.weisz@fda.hhs.gov FU Intramural NIH HHS [ZIA HL005107-07] NR 48 TC 3 Z9 3 U1 2 U2 23 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 FEB 6 PY 2015 VL 1380 BP 120 EP 129 DI 10.1016/j.chroma.2014.12.072 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CA4RW UT WOS:000348893100015 PM 25591404 ER PT J AU Levine, RA Richards, KM Tran, K Luo, RS Thomas, AL Smith, RE AF Levine, Robert A. Richards, Kristy M. Kevin Tran Luo, Rensheng Thomas, Andrew L. Smith, Robert E. TI Determination of Neurotoxic Acetogenins in Pawpaw (Asimina triloba) Fruit by LC-HRMS SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE pawpaw; Asimina Triloba; Parkinson's disease; LC-HRMS; annonacin; squamocin ID MITOCHONDRIAL COMPLEX-I; ATYPICAL PARKINSONISM; ANNONACIN; CONSUMPTION; GUADELOUPE; INHIBITOR; PRODUCTS AB The concentrations of the neurotoxins, annonacin and squamocin, were determined in a lyophilized sample of the fruit pulp of the North American pawpaw (Asimina triloba) by LC coupled to high resolution mass spectrometry or LC-HRMS. The sample was extracted using dry methanol at 100 degrees C and 10 MPa pressure in a sealed container. The extraction of annonacin and squamocin was optimal at 100 degrees C with 7.72 and 0.162 mg/g, respectively, being found. Also, several isomers of annonacin and squamocin were separated and detected but not quantified. C1 [Levine, Robert A.; Richards, Kristy M.; Kevin Tran; Smith, Robert E.] US FDA, Total Diet & Pesticide Res Ctr, Lenexa, KS 66214 USA. [Luo, Rensheng] Univ Missouri, St Louis, MO 63121 USA. [Thomas, Andrew L.] Univ Missouri, Southwest Res Ctr, Mt Vernon, MO 65712 USA. RP Smith, RE (reprint author), US FDA, Total Diet & Pesticide Res Ctr, 11510 West 80th St, Lenexa, KS 66214 USA. EM robert.smith@fda.hhs.gov NR 16 TC 5 Z9 5 U1 4 U2 24 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 FEB 4 PY 2015 VL 63 IS 4 BP 1053 EP 1056 DI 10.1021/jf504500g PG 4 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA CA8AG UT WOS:000349138300001 ER PT J AU Kaufman, RM Djulbegovic, B Gernsheimer, T Kleinman, S Tinmouth, AT Capocelli, KE Cipolle, MD Cohn, CS Fung, MK Grossman, BJ Mintz, PD O'Malley, BA Sesok-Pizzini, DA Shander, A Stack, GE Webert, KE Weinstein, R Welch, BG Whitman, GJ Wong, EC Tobian, AAR AF Kaufman, Richard M. Djulbegovic, Benjamin Gernsheimer, Terry Kleinman, Steven Tinmouth, Alan T. Capocelli, Kelley E. Cipolle, Mark D. Cohn, Claudia S. Fung, Mark K. Grossman, Brenda J. Mintz, Paul D. O'Malley, Barbara A. Sesok-Pizzini, Deborah A. Shander, Aryeh Stack, Gary E. Webert, Kathryn E. Weinstein, Robert Welch, Babu G. Whitman, Glenn J. Wong, Edward C. Tobian, Aaron A. R. TI Platelet Transfusion: A Clinical Practice Guideline From the AABB SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; TRAUMATIC INTRACRANIAL HEMORRHAGE; PROGENITOR-CELL TRANSPLANT; VENOUS CATHETER PLACEMENT; BRAIN-INJURY PATIENTS; ACUTE LUNG INJURY; ACUTE-LEUKEMIA; LUMBAR PUNCTURE; ANTIPLATELET THERAPY; BLEEDING DIATHESES AB Background: The AABB (formerly, the American Association of Blood Banks) developed this guideline on appropriate use of platelet transfusion in adult patients. Methods: These guidelines are based on a systematic review of randomized, clinical trials and observational studies (1900 to September 2014) that reported clinical outcomes on patients receiving prophylactic or therapeutic platelet transfusions. An expert panel reviewed the data and developed recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Recommendation 1: The AABB recommends that platelets should be transfused prophylactically to reduce the risk for spontaneous bleeding in hospitalized adult patients with therapyinduced hypoproliferative thrombocytopenia. The AABB recommends transfusing hospitalized adult patients with a platelet count of 10 x 10(9) cells/L or less to reduce the risk for spontaneous bleeding. The AABB recommends transfusing up to a single apheresis unit or equivalent. Greater doses are not more effective, and lower doses equal to one half of a standard apheresis unit are equally effective. (Grade: strong recommendation; moderate-quality evidence) Recommendation 2: The AABB suggests prophylactic platelet transfusion for patients having elective central venous catheter placement with a platelet count less than 20 x 10(9) cells/L. (Grade: weak recommendation; low-quality evidence) Recommendation 3: The AABB suggests prophylactic platelet transfusion for patients having elective diagnostic lumbar puncture with a platelet count less than 50 x 10(9) cells/L. (Grade: weak recommendation; very-low-quality evidence) Recommendation 4: The AABB suggests prophylactic platelet transfusion for patients having major elective nonneuraxial surgery with a platelet count less than 50 x 10(9) cells/L. (Grade: weak recommendation; very-low-quality evidence) Recommendation 5: The AABB recommends against routine prophylactic platelet transfusion for patients who are nonthrombocytopenic and have cardiac surgery with cardiopulmonary bypass. The AABB suggests platelet transfusion for patients having bypass who exhibit perioperative bleeding with thrombocytopenia and/or evidence of platelet dysfunction. (Grade: weak recommendation; very-low-quality evidence) Recommendation 6: The AABB cannot recommend for or against platelet transfusion for patients receiving antiplatelet therapy who have intracranial hemorrhage (traumatic or spontaneous). (Grade: uncertain recommendation; very-low-quality evidence) C1 Brigham & Womens Hosp, Boston, MA 02115 USA. [Djulbegovic, Benjamin] Univ S Florida, Tampa, FL 33612 USA. [Gernsheimer, Terry] Univ Washington, Seattle, WA 98195 USA. [Kleinman, Steven] Univ British Columbia, Victoria, BC V9A 4W4, Canada. Ottawa Hosp Res Inst, Ottawa, ON, Canada. Childrens Hosp Colorado, Aurora, CO 80045 USA. Christiana Care Hlth Syst, Wilmington, DE USA. Univ Minnesota, Minneapolis, MN USA. Univ Vermont, Burlington, VT USA. Washington Univ, Sch Med, St Louis, MO USA. US FDA, Silver Spring, MD USA. Wayne State Univ, Detroit, MI USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Englewood Hosp & Med Ctr, Englewood, NJ USA. Yale Univ, Sch Med, West Haven, CT 06516 USA. McMaster Univ, Hamilton, ON, Canada. [Weinstein, Robert] Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. [Welch, Babu G.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Johns Hopkins Univ, Baltimore, MD USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Kaufman, RM (reprint author), Brigham & Womens Hosp, Dept Pathol, Blood Bank, Amory 260,75 Francis St, Boston, MA 02115 USA. EM rmkaufman@partners.org RI Djulbegovic, Benjamin/I-3661-2012; Stack, Gary/E-9646-2014; OI Djulbegovic, Benjamin/0000-0003-0671-1447; Stack, Gary/0000-0002-6501-7255; Grossman, Brenda/0000-0002-1500-8211 NR 72 TC 94 Z9 96 U1 3 U2 13 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 FEB 3 PY 2015 VL 162 IS 3 BP 205 EP U118 DI 10.7326/M14-1589 PG 17 WC Medicine, General & Internal SC General & Internal Medicine GA CC1NP UT WOS:000350108100006 PM 25383671 ER PT J AU Mudalige, TK Qu, HO Sanchez-Pomales, G Sisco, PN Linder, SW AF Mudalige, Thilak K. Qu, Haiou Sanchez-Pomales, Germane Sisco, Patrick N. Linder, Sean W. TI Simple Functionalization Strategies for Enhancing Nanoparticle Separation and Recovery with Asymmetric Flow Field Flow Fractionation SO ANALYTICAL CHEMISTRY LA English DT Article ID GOLD NANOPARTICLES; SILVER NANOPARTICLES; MULTIDETECTOR APPROACH; AU NANOPARTICLES; LIGHT-SCATTERING; ICP-MS; SIZE; MEMBRANES; CHANNEL; OPTIMIZATION AB Due to the increasing use of engineered nanomaterials in consumer products, regulatory agencies and other research organizations have determined that the development of robust, reliable, and accurate methodologies to characterize nanoparticles in complex matrices is a top priority. Of particular interest are methods that can separate and determine the size of nanomaterials in samples that contain polydisperse and/or multimodal nanoparticle populations. Asymmetric-flow field flow fractionation (AF4) has shown promise for the separation of nanoparticles with wide size range distributions; however, low analyte recoveries and decreased membrane lifetimes, due to membrane fouling, have limited its application. Herein, we report straightforward strategies to minimize membrane fouling and improve nanoparticle recovery by functionalizing the surface of the nanoparticles, as well as that of the AF4 membranes. Gold nanoparticles (AuNP) were stabilized through functionalization with a phosphine molecule, whereas the surface of the membranes was coated with a negatively charged polystyrenesulfonate polymer. Improved nanoparticle separation, recoveries of 99.1 (+/-0.5) %, and a detection limit of 6 mu g/kg were demonstrated by analyzing AuNP reference materials of different sizes (e.g., 10, 30, and 60 nm), obtained from the National Institute of Standards and Technology (NIST). Furthermore, the stability of the polymer coating and its specificity toward minimizing membrane fouling were demonstrated. C1 [Mudalige, Thilak K.; Qu, Haiou; Sanchez-Pomales, Germane; Sisco, Patrick N.; Linder, Sean W.] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, Jefferson, AR 72079 USA. RP Mudalige, TK (reprint author), US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Thilak.Mudalige@fda.hhs.gov; Sean.Linder@fda.hhs.gov FU Office of Regulatory Affairs/Arkansas Regional Laboratory, U.S. Food and Drug Administration FX These studies were conducted using the Nanotechnology Core Facility (NanoCore) located on the U.S. Food and Drug Administration's Jefferson Laboratories campus (Jefferson, AR), which houses the FDA National Center for Toxicological Research and the FDA Office of Regulatory Affairs Arkansas Regional Laboratory. We thank Dr. Selen Stromgren, Dr. Anil Pain, Dr. Paul C. Howard, Dr. Jin-Hee Lim, and Dr. Ivan Quevedo for their support and valuable comments on the draft manuscript. This project was supported in part by an appointment to the Research Participation Program at the Office of Regulatory Affairs/Arkansas Regional Laboratory, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA. The views expressed in this document are those of the researchers and should not be interpreted as the official opinion or policy of the U.S. Food and Drug Administration, Department of Health and Human Services, or any other agency or component of the U.S. government. The mention of trades names, commercial products, or organizations is for clarification of the methods used and should not be interpreted as an endorsement of a product or manufacturer. NR 51 TC 15 Z9 15 U1 6 U2 54 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 FEB 3 PY 2015 VL 87 IS 3 BP 1764 EP 1772 DI 10.1021/ac503683n PG 9 WC Chemistry, Analytical SC Chemistry GA CA6WX UT WOS:000349059000049 PM 25556296 ER PT J AU Li, YY He, X Yin, JJ Ma, YH Zhang, P Li, JY Ding, YY Zhang, J Zhao, YL Chai, ZF Zhang, ZY AF Li, Yuanyuan He, Xiao Yin, Jun-Jie Ma, Yuhui Zhang, Peng Li, Jingyuan Ding, Yayun Zhang, Jing Zhao, Yuliang Chai, Zhifang Zhang, Zhiyong TI Acquired Superoxide-Scavenging Ability of Ceria Nanoparticles SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE cerium; electron transfer; nanoparticles; oxides; surface chemistry ID OXIDE NANOPARTICLES; REDOX STATE; NANOMATERIALS; NANOMEDICINE AB Ceria nanoparticles (nanoceria) are well known as a superoxide scavenger. However, inherent superoxide-scavenging ability has only been found in the nanoceria with sizes of less than 5nm and with very limited shape diversity. Reported herein is a strategy to significantly improve the superoxide-scavenging activity of nanoceria sized at greater than 5nm. The nanoceria with sizes of greater than 5nm, with different shapes, and with a negligible Ce3+/Ce4+ ratio can acquire remarkable superoxide-scavenging abilities through electron transfer. This method will make it possible to develop nanoceria-based superoxide-scavengers with long-acting activity and tailorable characteristics. C1 [Li, Yuanyuan; He, Xiao; Ma, Yuhui; Zhang, Peng; Li, Jingyuan; Ding, Yayun; Zhao, Yuliang; Chai, Zhifang; Zhang, Zhiyong] Chinese Acad Sci, Inst High Energy Phys, Key Lab Nucl Radiat & Nucl Energy Technol, Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100049, Peoples R China. [Yin, Jun-Jie] US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Zhang, Jing] Chinese Acad Sci, Inst High Energy Phys, Beijing Synchrotron Radiat Facil, Beijing 100049, Peoples R China. RP He, X (reprint author), Chinese Acad Sci, Inst High Energy Phys, Key Lab Nucl Radiat & Nucl Energy Technol, Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100049, Peoples R China. EM hx421@ihep.ac.cn; zhangzhy@ihep.ac.cn RI Yin, Jun Jie /E-5619-2014; Li, Jingyuan/E-9009-2011; OI Li, Jingyuan/0000-0003-2926-1864; He, Xiao/0000-0002-5188-4382; Zhang, Peng/0000-0002-2774-5534 FU Chinese MOST 973 Program [2011CB933400, 2013CB932703, 2012CB932504]; National Natural Science Foundation of China [11275215, 11275218]; FDA Nanotechnology CORES Program; Office of Cosmetics and Colors, CFSAN/FDA FX This work was financially supported by the Chinese MOST 973 Program (2011CB933400, 2013CB932703 and 2012CB932504), the National Natural Science Foundation of China (11275215 and 11275218), and partially supported by a regulatory science grant under the FDA Nanotechnology CORES Program and by the Office of Cosmetics and Colors, CFSAN/FDA (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. We would like to thank Lili Fox Velez for the scientific editing. NR 15 TC 27 Z9 29 U1 16 U2 109 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD FEB 2 PY 2015 VL 54 IS 6 BP 1832 EP 1835 DI 10.1002/anie.201410398 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA CA8ZH UT WOS:000349209200026 PM 25515687 ER PT J AU Cooper, HA Najafi, AH Ghafourian, K Paixao, ARM Aljaabari, M Iantorno, M Canos, D Asch, FM Paza, JA AF Cooper, Howard A. Najafi, Amir H. Ghafourian, Kambiz Paixao, Andre R. M. Aljaabari, Mohamed Iantorno, Micaela Canos, Daniel Asch, Federico M. Paza, Julio A. TI Diagnosis of cardiogenic shock without the use of a pulmonary artery catheter SO EUROPEAN HEART JOURNAL-ACUTE CARDIOVASCULAR CARE LA English DT Article DE Shock; diagnosis; echocardiography ID RANDOMIZED CONTROLLED-TRIAL; RISK SURGICAL PATIENTS; VASCULAR-SURGERY; OUTCOMES; MANAGEMENT AB Background: Current diagnostic criteria for cardiogenic shock (CS) require the use of a pulmonary artery catheter (PAC), which is time-consuming and may cause complications. A set of simple yet accurate noninvasive diagnostic criteria would be of significant utility. Methods: Candidate components for the Noninvasive Parameters for Assessment of Cardiogenic Shock (N-PACS) criteria were required to be objective, readily available, and noninvasive. Variables encompassing hypotension, hypoperfusion, predisposing conditions, and elevated intracardiac filling pressures were optimized versus a PAC-based standard in a retrospective developmental cohort of 122 patients with acute myocardial infarction (AMI). The finalized criteria were validated in a prospective cohort of coronary care unit patients in whom a PAC was placed for clinical indications. Results: According to invasive criteria, CS was present in 32 of 217 consecutive patients undergoing PAC. Compared to the PAC-based standard, the N-PACS criteria had a sensitivity of 96.9% (95% confidence interval (CI) 82.0-99.8), specificity of 90.8% (95% CI 85.5-94.4), positive predictive value of 64.6% (95% CI 49.4-77.4), negative predictive value of 99.4% (95% CI 96.2-100), positive likelihood ratio of 10.5 (95% CI 6.7-16.7), negative likelihood ratio of 0.03 (95% CI 0.00-0.24), and diagnostic odds ratio of 306.4. Results were similar among patients with and without AMI. Conclusion: A simple, echocardiography-based set of noninvasive diagnostic criteria can be used to accurately diagnose CS. C1 [Cooper, Howard A.; Najafi, Amir H.; Ghafourian, Kambiz; Asch, Federico M.] Medstar Washington Hosp Ctr, MedStar Heart Inst, Washington, DC 20010 USA. [Paixao, Andre R. M.] Univ Texas, Dept Med, Houston, TX USA. [Aljaabari, Mohamed] Tufts Univ, Dept Internal Med, Medford, MA USA. [Iantorno, Micaela] NIH, Dept Crit Care Med, Bethesda, MD USA. [Canos, Daniel] US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. [Paza, Julio A.] New York Med Coll, Westchester Med Ctr, Valhalla, NY 10595 USA. RP Cooper, HA (reprint author), Medstar Washington Hosp Ctr, 110 Irving St NW,Suite NA-1103, Washington, DC 20010 USA. EM cooperh@verizon.net NR 25 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 2048-8726 EI 2048-8734 J9 EUR HEART J-ACUTE CA JI Eur. Heart J.-Acute Cardiovasc. Care PD FEB PY 2015 VL 4 IS 1 BP 88 EP 95 DI 10.1177/2048872614534564 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CW6NW UT WOS:000365115300013 PM 24833639 ER PT J AU Baraniuk, JN McGarvey, P Suzek, BE Rao, S Lababidi, S Sutherland, A Forshee, R Madhavan, S AF Baraniuk, James N. McGarvey, Peter Suzek, Baris E. Rao, Shruti Lababidi, Samir Sutherland, Andrea Forshee, Richard Madhavan, Subha TI In silico Analysis of Vaccination Adverse Events SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Baraniuk, James N.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [McGarvey, Peter; Suzek, Baris E.; Rao, Shruti; Madhavan, Subha] Georgetown Univ, Washington, DC USA. [Lababidi, Samir; Forshee, Richard] US FDA, White Oak, MD USA. [Sutherland, Andrea] Johns Hopkins Univ, Baltimore, MD USA. RI Suzek, Baris/K-3163-2014 OI Suzek, Baris/0000-0002-1521-4306 NR 0 TC 0 Z9 0 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 333 BP AB104 EP AB104 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600333 ER PT J AU Hamilton, RG Matsson, PN Hovanec-Burns, DL Van Cleve, M Chan, S Kober, A Kleine-Tebbe, JR Renz, H Magnusson, C Quicho, R Adkinson, NF AF Hamilton, Robert G. Matsson, Per N. Hovanec-Burns, Debra L. Van Cleve, Mark Chan, Sic Kober, Anita Kleine-Tebbe, Joerg R. Renz, Harald Magnusson, Carina Quicho, Ron Adkinson, N. Franklin, Jr. TI Analytical Performance Characteristics, Quality Assurance and Clinical Utility of Immunological Assays for Human IgE Antibodies of Defined Allergen Specificities. (CLSI-ILA20-A3) SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Hamilton, Robert G.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Matsson, Per N.] Thermo Fisher Sci, Portage, MI USA. [Hovanec-Burns, Debra L.] Siemens Healthcare Diagnost, Los Angeles, CA USA. [Van Cleve, Mark] Hycor Biomed, Garden Grove, CA USA. [Chan, Sic] US FDA, Silver Spring, MD USA. [Kober, Anita] Phadia AB, Thermo Fisher Sci, Uppsala, Sweden. [Kleine-Tebbe, Joerg R.] Allergy & Asthma Ctr Westend, Berlin, Germany. [Renz, Harald] Univ Marburg, Marburg, Germany. [Magnusson, Carina] Thermo Fisher Sci, Uppsala, Sweden. [Quicho, Ron] Clin Lab Stand Inst, Wayne, PA USA. [Adkinson, N. Franklin, Jr.] Johns Hopkins Asthma & Allergy Ctr, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 26 BP AB8 EP AB8 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600027 ER PT J AU Hillyer, P Shepard, RE Uehling, M Sheik, F Luongo, C Buchholz, UJ Collins, PL Donnelly, RP Rabin, RL AF Hillyer, Philippa Shepard, Rachel E. Uehling, Megan Sheik, Faruk Luongo, Cindy Buchholz, Ursula J. Collins, Peter L. Donnelly, Raymond P. Rabin, Ronald L. TI Respiratory Syncytial Virus-Induced Host IFN Signaling Differs Between A549 and BEAS-2B Epithelial Cell Lines SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Hillyer, Philippa; Shepard, Rachel E.; Uehling, Megan; Rabin, Ronald L.] US FDA, CBER, Silver Spring, MD USA. [Sheik, Faruk; Donnelly, Raymond P.] US FDA, CDER, Silver Spring, MD USA. [Luongo, Cindy; Buchholz, Ursula J.; Collins, Peter L.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 29 BP AB9 EP AB9 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600030 ER PT J AU Khurana, T Young, P Slater, JE AF Khurana, Taruna Young, Philip Slater, Jay E. TI Development of ELISA Assays for Measurement of Can f 1 and Can f 3 in Dog Allergen Extracts SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Khurana, Taruna; Young, Philip; Slater, Jay E.] FDA CBER OVRR DBPAP, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 181 BP AB57 EP AB57 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600182 ER PT J AU Kwegyir-Afful, EK Brookmire, L Shah, R Luccioli, S AF Kwegyir-Afful, Ernest K. Brookmire, Lauren Shah, Romina Luccioli, Stefano TI Assessing the Risk Reduction Achieved By Lowering the Regulatory Threshold for Sulfite Labeling in Foods to Asthmatics SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Kwegyir-Afful, Ernest K.; Brookmire, Lauren; Shah, Romina; Luccioli, Stefano] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 835 BP AB257 EP AB257 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600834 ER PT J AU Luccioli, S Zhu, JM Fleischer, DM Hiemstra, W Kim, EH Leung, SB Lindblad, RW Mudd, KE Reames, R Steele, PH Sampson, HA Sicherer, SH Vickery, BP Kwegyir-Afful, EK AF Luccioli, Stefano Zhu, Jianmei Fleischer, David Mark Hiemstra, Whitney Kim, Edwin H. Leung, Susan B. Lindblad, Robert W. Mudd, Kim E. Reames, Rene Steele, Pamela H. Sampson, Hugh A. Sicherer, Scott H. Vickery, Brian P. Kwegyir-Afful, Ernest K. TI Stratification of Health Risk Posed By Allergic Responses at Peanut Threshold Doses: A Pilot Study SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Luccioli, Stefano; Zhu, Jianmei; Kwegyir-Afful, Ernest K.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Fleischer, David Mark] Childrens Hosp Colorado, Aurora, CO USA. [Hiemstra, Whitney; Leung, Susan B.; Reames, Rene] Natl Jewish Hlth, Dept Pediat, Div Allergy Immunol, Denver, CO USA. [Kim, Edwin H.; Steele, Pamela H.] Univ N Carolina, Chapel Hill, NC USA. [Lindblad, Robert W.] EMMES Corp, Bangalore, Karnataka, India. [Mudd, Kim E.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Sampson, Hugh A.] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA. [Sicherer, Scott H.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Vickery, Brian P.] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 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 FEB PY 2015 VL 135 IS 2 SU S MA 834 BP AB256 EP AB256 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600833 ER PT J AU Renn, LA Theisen, TC Novatt, H Rabin, RL AF Renn, Lynnsey A. Theisen, Terence C. Novatt, Hilary Rabin, Ronald L. TI IFN-beta and IFN-lambda1 Induce Kinetically Distinct Patterns of Transcription Factor Interferon Stimulated Genes in Respiratory Epithelial Cells SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Renn, Lynnsey A.; Theisen, Terence C.; Novatt, Hilary; Rabin, Ronald L.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 355 BP AB110 EP AB110 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600355 ER PT J AU Zhu, JM Pouillot, R Kwegyir-Afful, EK Luccioli, S Gendel, SM AF Zhu, Jianmei Pouillot, Regis Kwegyir-Afful, Ernest K. Luccioli, Stefano Gendel, Steven M. TI The Relationship Between Eliciting Dose and Reaction Severity to Food Allergens SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Zhu, Jianmei; Pouillot, Regis; Kwegyir-Afful, Ernest K.; Luccioli, Stefano; Gendel, Steven M.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RI Pouillot, Regis/E-8103-2010 OI Pouillot, Regis/0000-0002-6107-5212 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 818 BP AB252 EP AB252 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600817 ER PT J AU Pava-Ripoll, M Pearson, REG Miller, AK Ziobro, GC AF Pava-Ripoll, Monica Pearson, Rachel E. G. Miller, Amy K. Ziobro, George C. TI Detection of Foodborne Bacterial Pathogens from Individual Filth Flies SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Environmental Sciences; Issue 96; Synanthropy; filth flies; Cronobacter; Listeria monocytogenes; Salmonella; Escherichia coli O157:H7; shiga-toxigenic E. coli; STEC; PCR-based methods; foodborne illness; foodborne outbreak investigations ID MUSCA-DOMESTICA L.; ENTEROBACTER-SAKAZAKII; SALMONELLA-ENTERICA; ESCHERICHIA-COLI; STABLE FLIES; HOUSE-FLY; MUSCIDAE; DIPTERA; SPP.; VECTORS AB There is unanimous consensus that insects are important vectors of foodborne pathogens. However, linking insects as vectors of the pathogen causing a particular foodborne illness outbreak has been challenging. This is because insects are not being aseptically collected as part of an environmental sampling program during foodborne outbreak investigations and because there is not a standardized method to detect foodborne bacteria from individual insects. To take a step towards solving this problem, we adapted a protocol from a commercially available PCR-based system that detects foodborne pathogens from food and environmental samples, to detect foodborne pathogens from individual flies. Using this standardized protocol, we surveyed 100 wild-caught flies for the presence of Cronobacter spp., Salmonella enterica, and Listeria monocytogenes and demonstrated that it was possible to detect and further isolate these pathogens from the body surface and the alimentary canal of a single fly. Twenty-two percent of the alimentary canals and 8% of the body surfaces from collected wild flies were positive for at least one of the three foodborne pathogens. The prevalence of Cronobacter spp. on either body part of the flies was statistically higher (19%) than the prevalence of S. enterica (7%) and L. monocytogenes (4%). No false positives were observed when detecting S. enterica and L. monocytogenes using this PCR-based system because pure bacterial cultures were obtained from all PCR-positive results. However, pure Cronobacter colonies were not obtained from about 50% of PCR-positive samples, suggesting that the PCR-based detection system for this pathogen cross-reacts with other Enterobacteriaceae present among the highly complex microbiota carried by wild flies. The standardized protocol presented here will allow laboratories to detect bacterial foodborne pathogens from aseptically collected insects, thereby giving public health officials another line of evidence to find out how the food was contaminated when performing foodborne outbreak investigations. C1 [Pava-Ripoll, Monica; Pearson, Rachel E. G.; Miller, Amy K.; Ziobro, George C.] US FDA, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. RP Pava-Ripoll, M (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. EM Monica.Pava-Ripoll@fda.hhs.gov NR 28 TC 0 Z9 0 U1 1 U2 8 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD FEB PY 2015 IS 96 AR e52372 DI 10.3791/52372 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR7MH UT WOS:000361533700029 PM 25742168 ER PT J AU Shariat, N Timme, RE Pettengill, JB Barrangou, R Dudley, EG AF Shariat, Nikki Timme, Ruth E. Pettengill, James B. Barrangou, Rodolphe Dudley, Edward G. TI Characterization and evolution of Salmonella CRISPR-Cas systems SO MICROBIOLOGY-SGM LA English DT Article ID ENTERICA SEROVAR ENTERITIDIS; ESCHERICHIA-COLI; H-NS; STREPTOCOCCUS-THERMOPHILUS; ACQUIRED-RESISTANCE; REPEATS CRISPRS; IMMUNE-SYSTEM; SEARCH TOOL; DNA; RNA AB Prokaryotic CRISPR-Cas (clustered regularly interspaced short palindromic repeats and CRISPR-associated genes) systems provide adaptive immunity from invasive genetic elements and encompass three essential features: (i) cas genes, (ii) a CRISPR array composed of spacers and direct repeats and (iii) an AT-rich leader sequence upstream of the array. We performed in-depth sequence analysis of the CRISPR-Cas systems in >600 Salmonella, representing four clinically prevalent serovars. Each CRISPR-Cas feature is extremely conserved in the Salmonella, and the CRISPR1 locus is more highly conserved than CRISPR2. Array composition is serovar-specific, although no convincing evidence of recent spacer acquisition against exogenous nucleic acids exists. Only 12% of spacers match phage and plasmid sequences and self-targeting spacers are associated with direct repeat variants. High nucleotide identity (>99.9%) exists across the cas operon among isolates of a single serovar and in some cases this conservation extends across divergent serovars. These observations reflect historical CRISPR-Cas immune activity, showing that this locus has ceased undergoing adaptive events. Intriguingly, the high level of conservation across divergent serovars shows that the genetic integrity of these inactive loci is maintained over time, contrasting with the canonical view that inactive CRISPR loci degenerate over time. This thorough characterization of Salmonella CRISPR-Cas systems presents new insights into Salmonella CRISPR evolution, particularly with respect to cas gene conservation, leader sequences, organization of direct repeats and protospacer matches. Collectively, our data suggest that Salmonella CRISPR-Cas systems are no longer immunogenic; rather, their impressive conservation indicates they may have an alternative function in Salmonella. C1 [Shariat, Nikki; Dudley, Edward G.] Penn State Univ, Dept Food Sci, Ctr Mol Immunol & Infect Dis, University Pk, PA 16802 USA. [Shariat, Nikki; Dudley, Edward G.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Timme, Ruth E.; Pettengill, James B.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Barrangou, Rodolphe] N Carolina State Univ, Dept Food Bioproc & Nutr Serv, Raleigh, NC 27695 USA. RP Dudley, EG (reprint author), Penn State Univ, Dept Food Sci, Ctr Mol Immunol & Infect Dis, University Pk, PA 16802 USA. EM egd100@psu.edu RI Barrangou, Rodolphe/I-2878-2014 OI Barrangou, Rodolphe/0000-0002-0648-3504 FU United States Army Research Office [W911NF-11-1-0442] FX We thank Dr Jennifer Mandel for helpful discussions and Dr Phillipe Horvath for sharing the macro (CRISPR DB II Excel Macro). This study was supported by a United States Army Research Office grant to E. G. D. (W911NF-11-1-0442). NR 53 TC 6 Z9 6 U1 4 U2 23 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1350-0872 J9 MICROBIOL-SGM JI Microbiology-(UK) PD FEB PY 2015 VL 161 BP 374 EP 386 DI 10.1099/mic.0.000005 PN 2 PG 13 WC Microbiology SC Microbiology GA CL0QR UT WOS:000356647800014 PM 25479838 ER PT J AU McNitt-Gray, MF Kim, GH Zhao, BS Schwartz, LH Clunie, D Cohen, K Petrick, N Fenimore, C Lu, ZQJ Buckler, AJ AF McNitt-Gray, Michael F. Kim, Grace Hyun Zhao, Binsheng Schwartz, Lawrence H. Clunie, David Cohen, Kristin Petrick, Nicholas Fenimore, Charles Lu, Z. Q. John Buckler, Andrew J. TI Determining the Variability of Lesion Size Measurements from CT Patient Data Sets Acquired under "No Change" Conditions SO TRANSLATIONAL ONCOLOGY LA English DT Article ID LUNG-CANCER; TUMOR MEASUREMENTS; SOLID TUMORS; TRUTH DATA; THERAPY; SEGMENTATION; EVALUATE; ERROR; SCANS AB PURPOSE: To determine the variability of lesion size measurements in computed tomography data sets of patients imaged under a "no change" ("coffee break") condition and to determine the impact of two reading paradigms on measurement variability. METHOD AND MATERIALS: Using data sets from 32 non-small cell lung cancer patients scanned twice within 15 minutes ("no change"), measurements were performed by five radiologists in two phases: (1) independent reading of each computed tomography dataset (timepoint): (2) a locked, sequential reading of datasets. Readers performed measurements using several sizing methods, including one-dimensional (1D) longest in-slice dimension and 3D semi-automated segmented volume. Change in size was estimated by comparing measurements performed on both timepoints for the same lesion, for each reader and each measurement method. For each reading paradigm, results were pooled across lesions, across readers, and across both readers and lesions, for each measurement method. RESULTS: The mean percent difference (+/- SD) when pooled across both readers and lesions for 1D and 3D measurements extracted from contours was 2.8 +/- 22.2% and 23.4 +/- 105.0%, respectively, for the independent reads. For the locked, sequential reads, the mean percent differences (+/- SD) reduced to 2.52 +/- 14.2% and 7.4 +/- 44.2% for the 1D and 3D measurements, respectively. CONCLUSION: Even under a "no change" condition between scans, there is variation in lesion size measurements due to repeat scans and variations in reader, lesion, and measurement method. This variation is reduced when using a locked, sequential reading paradigm compared to an independent reading paradigm. C1 [McNitt-Gray, Michael F.; Kim, Grace Hyun] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Zhao, Binsheng; Schwartz, Lawrence H.] Columbia Univ, Med Ctr, New York, NY USA. [Clunie, David] Pixel Med Publishing LLC, Bangor, PA USA. [Clunie, David] Core Lab Partners Inc, Princeton, NJ USA. [Cohen, Kristin] Janssen Pharmaceut Res & Dev, Titusville, NJ USA. [Cohen, Kristin] Core Lab Partners Inc, Titusville, NJ USA. [Petrick, Nicholas] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Fenimore, Charles] Image Qual Measurement Consultancy, Gaithersburg, MD USA. [Lu, Z. Q. John] NIST, Gaithersburg, MD 20899 USA. [Buckler, Andrew J.] Elucid Bioimaging Inc, Wenham, MA USA. RP McNitt-Gray, MF (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol Sci, 924 Westwood Blvd,Suite 650, Los Angeles, CA 90024 USA. EM mmcnittgray@mednet.ucla.edu OI Buckler, Andrew/0000-0002-0786-4835; McNItt-Gray, Michael/0000-0003-3004-4613 FU RSNA Quantitative Imaging Biomarker Alliance (QIBA) - National Institute of Biomedical Imaging and BIoengineering American Recovery and Reinvestment Act of funds FX The authors acknowledge the efforts of several key contributors to this work. CoreLab Partners, Inc conducted the reader study component of this investigation. They provided the reading facility, review workstations, software, and logistical support. CoreLab Partners radiologists also participated as readers. Therefore, we acknowledge CoreLab Partners for their support and specifically acknowledge CoreLab Partners radiologists Kevin Byrne, Steven Kaplan, Julie Barudin, Joyce Sherman, Kathy Slazak, George Edeburn, and J. Michael O'Neal for participating as readers in this study. Finally, we acknowledge financial support from the RSNA Quantitative Imaging Biomarker Alliance (QIBA) provided by National Institute of Biomedical Imaging and BIoengineering American Recovery and Reinvestment Act of 2009 funds. Certain commercial equipment, instruments, software, or materials are identified in this paper to foster understanding. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology nor does it imply that the materials or equipment identified are necessarily the best available for the purpose. Similarly, the mention of commercial entities, or commercial products, their sources, or their use in connection with materials reported herein is not to be construed as either an actual or implied endorsement of such entities or products by the Department of Health and Human Services or the United States Food and Drug Administration. NR 19 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1944-7124 EI 1936-5233 J9 TRANSL ONCOL JI Transl. Oncol. PD FEB PY 2015 VL 8 IS 1 BP 55 EP 64 DI 10.1016/j.tranon.2015.01.001 PG 10 WC Oncology SC Oncology GA CH9RE UT WOS:000354372900008 PM 25749178 ER PT J AU Phillips, AG Hongaard-Andersen, P Moscicki, RA Sahakian, B Quirion, R Krishnan, KRR Race, T AF Phillips, Anthony George Hongaard-Andersen, Peter Moscicki, Richard A. Sahakian, Barbara Quirion, Remi Krishnan, K. Ranga Rama Race, Tim TI Proceedings of the 2013 CINP Summit: Innovative Partnerships to Accelerate CNS Drug Discovery for Improved Patient Care SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Review DE brain health; clinical neuropsychopharmacology; CNS drug pipeline; public-private partnerships; science policy ID DISORDERS; EUROPE; BRAIN AB Central nervous system (CNS) diseases and, in particular, mental health disorders, are becoming recognized as the health challenge of the 21st century. Currently, at least 10% of the global population is affected by a mental health disorder, a figure that is set to increase year on year. Meanwhile, the rate of development of new CNS drugs has not increased for many years, despite unprecedented levels of investment. In response to this state of affairs, the Collegium Internationale Neuro-Psychopharmacologicum (CINP) convened a summit to discuss ways to reverse this disturbing trend through new partnerships to accelerate CNS drug discovery. The objectives of the Summit were to explore the issues affecting the value chain (i.e. the chain of activities or stakeholders that a company engages in/with to deliver a product to market) in brain research, thereby gaining insights from key stakeholders and developing actions to address unmet needs; to identify achievable objectives to address the issues; to develop action plans to bring about measurable improvements across the value chain and accelerate CNS drug discovery; and finally, to communicate recommendations to governments, the research and development community, and other relevant stakeholders. Summit outputs include the following action plans, aligned to the pressure points within the brain research-drug development value chain: Code of conduct dealing with conflict of interest issues, Prevention, early diagnosis, and treatment, Linking science and regulation, Patient involvement in trial design, definition of endpoints, etc., Novel trial design, Reproduction and confirmation of data, Update of intellectual property (IP) laws to facilitate repurposing and combination therapy (low priority), Large-scale, global patient registries, Editorials on nomenclature, biomarkers, and diagnostic tools, and Public awareness, with brain disease advocates to attend G8 meetings and World Economic Forum (WEF) Annual meetings in Davos, Switzerland. In this context Professor Barbara Sahakian recently made a formal presentation at the World Economic Forum (see Barbara Sahakian Blog from April 11, 2014, at https://forumblog.org/people/barbara-sahakian/) Full details of the discussions that formed the bases for these actions are presented in the main body of this document. C1 [Phillips, Anthony George] Coll Int Neuropsychopharmacol, Vancouver, BC, Canada. [Hongaard-Andersen, Peter] Innovat Fund Denmark, Copenhagen, Denmark. [Moscicki, Richard A.] US FDA, Silver Spring, MD USA. [Sahakian, Barbara] Univ Cambridge, Cambridge, England. [Quirion, Remi] McGill Univ, Montreal, PQ, Canada. [Krishnan, K. Ranga Rama] Duke NUS, Singapore, Singapore. [Race, Tim] Deutsch Bank, London, England. RP Phillips, AG (reprint author), 3402-2215 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada. EM aphillips@psych.ubc.ca FU European Brain Council FX The authors would like to acknowledge the continuing commitment of the CINP to stimulating dialogue on key issues relating to the field of neuropsychopharmacology as demonstrated by their sole sponsorship of the 2013 CINP Summit meeting. Generous financial support from the European Brain Council is gratefully acknowledged. The authors would also like to thank Mark Loughlin, Zoe Baxter, and Andy Grigg of Inspired Science, who contributed to the development of this report. The authors are entirely responsible for the content of the paper. NR 19 TC 0 Z9 0 U1 2 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD FEB PY 2015 VL 18 IS 3 DI 10.1093/ijnp/pyu100 PG 16 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CF4QQ UT WOS:000352535900018 ER PT J AU Bender, JB Barlam, TF Glore, RP Gumley, N Grayzel, SE Hoang, C Murphy, MJ Papich, MG Sykes, JE Watts, JL Whichard, JM AF Bender, Jeff B. Barlam, Tamar F. Glore, Reilly P. Gumley, Nigel Grayzel, Sharon E. Hoang, Christine Murphy, Michael J. Papich, Mark G. Sykes, Jane E. Watts, Jeffrey L. Whichard, Jean M. CA AVMA Task Force Antimicrobial Stew TI Antimicrobial stewardship in companion animal practice SO JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION LA English DT Editorial Material ID INFECTIOUS-DISEASES SOCIETY; HEALTH-CARE EPIDEMIOLOGY; THERAPY; GUIDELINES; HOSPITALS; PROGRAM; AMERICA C1 [Bender, Jeff B.] Univ Minnesota, Coll Vet Med, Dept Vet Populat Med, St Paul, MN 55108 USA. [Barlam, Tamar F.] Boston Med Ctr, Infect Dis Sect, Boston, MA 02118 USA. [Glore, Reilly P.] Brady Vet Hosp, Montesano, WA 98563 USA. [Gumley, Nigel] Canadian Vet Med Assoc, Ottawa, ON K1R 7K1, Canada. [Grayzel, Sharon E.] Columbia Vet Ctr, Vancouver, WA 98665 USA. [Hoang, Christine] AVMA, Schaumburg, IL 60173 USA. [Murphy, Michael J.] US FDA, Ctr Vet Med, Rockville, MD 20855 USA. [Papich, Mark G.] N Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC 27607 USA. [Sykes, Jane E.] Univ Calif Davis, Sch Vet Med, Dept Med & Epidemiol, Davis, CA 95616 USA. [Watts, Jeffrey L.] Zoetis, Antiinfect Res VMRD, Kalamazoo, MI 49009 USA. [Whichard, Jean M.] CDC, Atlanta, GA 30329 USA. RP Bender, JB (reprint author), Univ Minnesota, Coll Vet Med, Dept Vet Populat Med, St Paul, MN 55108 USA. EM Bende002@umn.edu NR 14 TC 1 Z9 1 U1 0 U2 2 PU AMER VETERINARY MEDICAL ASSOC PI SCHAUMBURG PA 1931 N MEACHAM RD SUITE 100, SCHAUMBURG, IL 60173-4360 USA SN 0003-1488 EI 1943-569X J9 JAVMA-J AM VET MED A JI JAVMA-J. Am. Vet. Med. Assoc. PD FEB 1 PY 2015 VL 246 IS 3 BP 287 EP 288 PG 2 WC Veterinary Sciences SC Veterinary Sciences GA CE8QA UT WOS:000352107400013 ER PT J AU Carroll, JD Shuren, J Jensen, TS Hernandez, J Holmes, D Marinac-Dabic, D Edwards, FH Zuckerman, BD Wood, LL Kuntz, RE Mack, MJ AF Carroll, John D. Shuren, Jeff Jensen, Tamara Syrek Hernandez, John Holmes, David Marinac-Dabic, Danica Edwards, Fred H. Zuckerman, Bram D. Wood, Larry L. Kuntz, Richard E. Mack, Michael J. TI Transcatheter Valve Therapy Registry Is A Model For Medical Device Innovation And Surveillance SO HEALTH AFFAIRS LA English DT Article ID HIGH-RISK PATIENTS; AORTIC-STENOSIS; MITRAL REGURGITATION; HEALTH-STATUS; REPLACEMENT; SURGERY; INFRASTRUCTURE; IMPLANTATION; ASSOCIATION; REPAIR AB Heart valve diseases are increasingly prevalent, especially in people older than age seventy. Many of these elderly people have other comorbid conditions, making them poor candidates for surgical treatment of heart valve diseases. Since 2011 such patients have been eligible to receive new nonsurgical heart valve treatments approved by the Food and Drug Administration (FDA) and covered by Medicare. This article examines the Transcatheter Valve Therapy Registry, which captures clinical information on all US patients undergoing new nonsurgical heart valve treatments. The registry has patient-level data from more than 27,000 patients treated with the novel devices. Patient-and procedure-related data are gathered from hospitals, patient-reported outcomes are assessed pre- and postprocedure, and longer-term data on mortality and repeat hospitalization are provided by linking the registry's data to Medicare patient data. The registry is a model of collaboration among professional societies, the FDA, the Centers for Medicare and Medicaid Services, hospitals, patients, and the medical device industry. It has been used to support Medicare coverage decisions, expand device indications, provide comprehensive device surveillance, and establish national quality benchmarks. Beyond having it serve as a collaborative model, future goals for the registry include shortening the FDA-approval timeline for devices, providing data for decision-making tools for patients, and public reporting of hospital performance. C1 [Carroll, John D.] Univ Colorado, Sch Med, Med, Aurora, CO 80045 USA. [Shuren, Jeff] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Jensen, Tamara Syrek] Ctr Medicare Serv, Ctr Clin Stand & Qual, Coverage & Anal Grp, Baltimore, MD USA. [Jensen, Tamara Syrek] Ctr Medicaid Serv, Ctr Clin Stand & Qual, Coverage & Anal Grp, Baltimore, MD USA. [Hernandez, John] Abbott Vasc, Hlth Econ & Outcomes Res, Santa Clara, CA USA. [Holmes, David] Mayo Clin, Coll Med, Med, Rochester, MN USA. [Marinac-Dabic, Danica] US FDA, Div Epidemiol, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Edwards, Fred H.] Univ Florida, Gainesville, FL 32611 USA. [Zuckerman, Bram D.] US FDA, Div Cardiovasc Devices, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Wood, Larry L.] Edwards Lifesci Corp, Irvine, CA USA. [Kuntz, Richard E.] Medtronic, Minneapolis, MN USA. [Mack, Michael J.] Baylor Scott & White Hlth, Plano, TX USA. RP Carroll, JD (reprint author), Univ Colorado, Sch Med, Med, Aurora, CO 80045 USA. EM john.carroll@ucdenver.edu NR 30 TC 9 Z9 9 U1 1 U2 4 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD FEB PY 2015 VL 34 IS 2 BP 328 EP 334 DI 10.1377/hlthaff.2014.1010 PG 7 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CE3HA UT WOS:000351716100020 PM 25646114 ER PT J AU Kessler, LG Barnhart, HX Buckler, AJ Choudhury, KR Kondratovich, MV Toledano, A Guimaraes, AR Filice, R Zhang, Z Sullivan, DC AF Kessler, Larry G. Barnhart, Huiman X. Buckler, Andrew J. Choudhury, Kingshuk Roy Kondratovich, Marina V. Toledano, Alicia Guimaraes, Alexander R. Filice, Ross Zhang, Zheng Sullivan, Daniel C. CA QIBA Terminology Working Grp TI The emerging science of quantitative imaging biomarkers terminology and definitions for scientific studies and regulatory submissions SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE Quantitative; terminology; definitions; bias; precision ID ASSESSING AGREEMENT; TUMOR RESPONSE; MEDICINE; PET AB The development and implementation of quantitative imaging biomarkers has been hampered by the inconsistent and often incorrect use of terminology related to these markers. Sponsored by the Radiological Society of North America, an interdisciplinary group of radiologists, statisticians, physicists, and other researchers worked to develop a comprehensive terminology to serve as a foundation for quantitative imaging biomarker claims. Where possible, this working group adapted existing definitions derived from national or international standards bodies rather than invent new definitions for these terms. This terminology also serves as a foundation for the design of studies that evaluate the technical performance of quantitative imaging biomarkers and for studies of algorithms that generate the quantitative imaging biomarkers from clinical scans. This paper provides examples of research studies and quantitative imaging biomarker claims that use terminology consistent with these definitions as well as examples of the rampant confusion in this emerging field. We provide recommendations for appropriate use of quantitative imaging biomarker terminological concepts. It is hoped that this document will assist researchers and regulatory reviewers who examine quantitative imaging biomarkers and will also inform regulatory guidance. More consistent and correct use of terminology could advance regulatory science, improve clinical research, and provide better care for patients who undergo imaging studies. C1 [Kessler, Larry G.] Univ Washington, Seattle, WA 98195 USA. [Barnhart, Huiman X.; Choudhury, Kingshuk Roy; Sullivan, Daniel C.] Duke Univ, Durham, NC USA. [Buckler, Andrew J.] Elucid Bioimaging Inc, Wenham, MA USA. [Kondratovich, Marina V.; Filice, Ross] US FDA, Silver Spring, MD USA. [Toledano, Alicia] Biostat Consulting LLC, Kensington, MD USA. [Guimaraes, Alexander R.] Harvard Massachusetts Gen Hosp, Boston, MA USA. [Zhang, Zheng] Brown Univ, Providence, RI 02912 USA. RP Kessler, LG (reprint author), Univ Washington, Seattle, WA 98195 USA. EM kesslerl@uw.edu OI Buckler, Andrew/0000-0002-0786-4835 FU Radiological Society of North America; NIH/NIBIB [HHSN268201000050C] FX The authors acknowledge and appreciate the Radiological Society of North America and NIH/NIBIB contract # HHSN268201000050C for supporting two workshops and numerous conference calls for the authors' Working Group. We would also like to thank Michael Boss of NIST and Jingjing Ye and Shashi Amur of the FDA for comments on earlier versions of the paper. NR 25 TC 27 Z9 27 U1 5 U2 14 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 FEB PY 2015 VL 24 IS 1 SI SI BP 9 EP 26 DI 10.1177/0962280214537333 PG 18 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA CE4ZZ UT WOS:000351840700002 PM 24919826 ER PT J AU Raunig, DL McShane, LM Pennello, G Gatsonis, C Carson, PL Voyvodic, JT Wahl, RL Kurland, BF Schwarz, AJ Gonen, M Zahlmann, G Kondratovich, MV O'Donnell, K Petrick, N Cole, PE Garra, B Sullivan, DC AF Raunig, David L. McShane, Lisa M. Pennello, Gene Gatsonis, Constantine Carson, Paul L. Voyvodic, James T. Wahl, Richard L. Kurland, Brenda F. Schwarz, Adam J. Goenen, Mithat Zahlmann, Gudrun Kondratovich, Marina V. O'Donnell, Kevin Petrick, Nicholas Cole, Patricia E. Garra, Brian Sullivan, Daniel C. CA QIBA Tech Performance Working Grp TI Quantitative imaging biomarkers: A review of statistical methods for technical performance assessment SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE quantitative imaging; imaging biomarkers; reliability; linearity; bias; precision; repeatability; reproducibility; agreement ID CONFIDENCE-INTERVALS; ASSESSING AGREEMENT; RELIABILITY; DEFINITIONS; COEFFICIENT; MEDICINE; POINTS AB Technological developments and greater rigor in the quantitative measurement of biological features in medical images have given rise to an increased interest in using quantitative imaging biomarkers to measure changes in these features. Critical to the performance of a quantitative imaging biomarker in preclinical or clinical settings are three primary metrology areas of interest: measurement linearity and bias, repeatability, and the ability to consistently reproduce equivalent results when conditions change, as would be expected in any clinical trial. Unfortunately, performance studies to date differ greatly in designs, analysis method, and metrics used to assess a quantitative imaging biomarker for clinical use. It is therefore difficult or not possible to integrate results from different studies or to use reported results to design studies. The Radiological Society of North America and the Quantitative Imaging Biomarker Alliance with technical, radiological, and statistical experts developed a set of technical performance analysis methods, metrics, and study designs that provide terminology, metrics, and methods consistent with widely accepted metrological standards. This document provides a consistent framework for the conduct and evaluation of quantitative imaging biomarker performance studies so that results from multiple studies can be compared, contrasted, or combined. C1 [Raunig, David L.] ICON Med Imaging, Warrington, PA 18976 USA. [McShane, Lisa M.] NCI, Bethesda, MD 20892 USA. [Pennello, Gene; Kondratovich, Marina V.; Petrick, Nicholas; Garra, Brian] US FDA, CDRH, Silver Spring, MD USA. [Gatsonis, Constantine] Brown Univ, Providence, RI 02912 USA. [Carson, Paul L.] Univ Michigan Hlth Syst, Ann Arbor, MI USA. [Voyvodic, James T.] Duke Univ BIAC, Durham, NC USA. [Wahl, Richard L.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Kurland, Brenda F.] Univ Pittsburgh, Pittsburgh, PA USA. [Schwarz, Adam J.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Goenen, Mithat] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Zahlmann, Gudrun] Hoffman La Roche Ltd, Basel, Switzerland. [O'Donnell, Kevin] Toshiba Med Res Inst, Vernon Hills, IL USA. [Cole, Patricia E.] Takaeda, Deerfield, IL USA. [Sullivan, Daniel C.] Duke Univ, Sch Med, Durham, NC 27706 USA. RP Raunig, DL (reprint author), ICON Med Imaging, 2800 Kelly Rd, Warrington, PA 18976 USA. EM David.Raunig@iconplc.com OI Kurland, Brenda/0000-0002-5669-0595 FU Radiological Society of North America; NIH/NIBIB [HHSN268201000050C] FX The authors acknowledge and appreciate the Radiological Society of North America and NIH/NIBIB contract #HHSN268201000050C for supporting two workshops and numerous conference calls for the authors' Working Group. NR 55 TC 20 Z9 20 U1 3 U2 11 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 FEB PY 2015 VL 24 IS 1 SI SI BP 27 EP 67 DI 10.1177/0962280214537344 PG 41 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA CE4ZZ UT WOS:000351840700003 PM 24919831 ER PT J AU Obuchowski, NA Reeves, AP Huang, EP Wang, XF Buckler, AJ Kim, HJ Barnhart, HX Jackson, EF Giger, ML Pennello, G Toledano, AY Kalpathy-Cramer, J Apanasovich, TV Kinahan, PE Myers, KJ Goldgof, DB Barboriak, DP Gillies, RJ Schwartz, LH Sullivan, DC AF Obuchowski, Nancy A. Reeves, Anthony P. Huang, Erich P. Wang, Xiao-Feng Buckler, Andrew J. Kim, Hyun J. (Grace) Barnhart, Huiman X. Jackson, Edward F. Giger, Maryellen L. Pennello, Gene Toledano, Alicia Y. Kalpathy-Cramer, Jayashree Apanasovich, Tatiyana V. Kinahan, Paul E. Myers, Kyle J. Goldgof, Dmitry B. Barboriak, Daniel P. Gillies, Robert J. Schwartz, Lawrence H. Sullivan, Daniel C. CA Algorithm Comparison Working Grp TI Quantitative imaging biomarkers: A review of statistical methods for computer algorithm comparisons SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE quantitative imaging; imaging biomarkers; image metrics; bias; precision; repeatability; reproducibility; agreement ID ASSESSING AGREEMENT; GOLD STANDARD; LUNG-CANCER; EVALUATE REPRODUCIBILITY; CONCORDANCE CORRELATION; REGRESSION PROCEDURES; INDIVIDUAL AGREEMENT; MALIGNANT-TUMORS; EM ALGORITHM; FDG-PET AB Quantitative biomarkers from medical images are becoming important tools for clinical diagnosis, staging, monitoring, treatment planning, and development of new therapies. While there is a rich history of the development of quantitative imaging biomarker (QIB) techniques, little attention has been paid to the validation and comparison of the computer algorithms that implement the QIB measurements. In this paper we provide a framework for QIB algorithm comparisons. We first review and compare various study designs, including designs with the true value (e.g. phantoms, digital reference images, and zero-change studies), designs with a reference standard (e.g. studies testing equivalence with a reference standard), and designs without a reference standard (e.g. agreement studies and studies of algorithm precision). The statistical methods for comparing QIB algorithms are then presented for various study types using both aggregate and disaggregate approaches. We propose a series of steps for establishing the performance of a QIB algorithm, identify limitations in the current statistical literature, and suggest future directions for research. C1 [Obuchowski, Nancy A.; Wang, Xiao-Feng] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Reeves, Anthony P.] Cornell Univ, Ithaca, NY USA. [Huang, Erich P.] NIH, Rockville, MD USA. [Buckler, Andrew J.] Elucid Bioimaging Inc, Wenham, MA USA. [Kim, Hyun J. (Grace)] Univ Calif Los Angeles, Los Angeles, CA USA. [Barnhart, Huiman X.; Barboriak, Daniel P.; Sullivan, Daniel C.] Duke Univ, Durham, NC USA. [Jackson, Edward F.] Univ Wisconsin, Madison, WI USA. [Giger, Maryellen L.] Univ Chicago, Chicago, IL 60637 USA. [Pennello, Gene; Myers, Kyle J.] US FDA, CDRH, Silver Spring, MD USA. [Toledano, Alicia Y.] Biostat Consulting LLC, Kensington, MD USA. [Kalpathy-Cramer, Jayashree] Harvard Univ, Sch Med, MGH, Boston, MA USA. [Apanasovich, Tatiyana V.] George Washington Univ, Washington, DC USA. [Kinahan, Paul E.] Univ Washington, Seattle, WA 98195 USA. [Goldgof, Dmitry B.] Univ S Florida, Tampa, FL USA. [Gillies, Robert J.] H Moffitt Canc Ctr, Tampa, FL USA. [Schwartz, Lawrence H.] Columbia Univ, New York, NY USA. RP Obuchowski, NA (reprint author), Cleveland Clin Fdn, Quantitat Hlth Sci JJN 3, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM obuchon@ccf.org OI Kalpathy-Cramer, Jayashree/0000-0001-8906-9618; Jackson, Edward/0000-0002-5958-0076; Gillies, Robert/0000-0002-8888-7747; Buckler, Andrew/0000-0002-0786-4835; Giger, Maryellen/0000-0001-5482-9728 FU Radiologic Society of North America (RSNA); NIH/NIBIB [HHSN268201000050C] FX The Radiologic Society of North America (RSNA) and NIH/NIBIB contract # HHSN268201000050C supported two workshops and numerous conference calls for the authors' Working Group. NR 75 TC 16 Z9 16 U1 1 U2 14 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 FEB PY 2015 VL 24 IS 1 SI SI BP 68 EP 106 DI 10.1177/0962280214537390 PG 39 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA CE4ZZ UT WOS:000351840700004 PM 24919829 ER PT J AU Obuchowski, NA Barnhart, HX Buckler, AJ Pennello, G Wang, XF Kalpathy-Cramer, J Kim, HJ Reeves, AP AF Obuchowski, Nancy A. Barnhart, Huiman X. Buckler, Andrew J. Pennello, Gene Wang, Xiao-Feng Kalpathy-Cramer, Jayashree Kim, Hyun J. (Grace) Reeves, Anthony P. CA Case Example Working Grp TI Statistical issues in the comparison of quantitative imaging biomarker algorithms using pulmonary nodule volume as an example SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE bias; repeatability; reproducibility; agreement; limits of agreement; coverage probability; intraclass correlation coefficient ID MODELS; CT; REPRODUCIBILITY; SEGMENTATION; VARIABILITY; AGREEMENT AB Quantitative imaging biomarkers are being used increasingly in medicine to diagnose and monitor patients' disease. The computer algorithms that measure quantitative imaging biomarkers have different technical performance characteristics. In this paper we illustrate the appropriate statistical methods for assessing and comparing the bias, precision, and agreement of computer algorithms. We use data from three studies of pulmonary nodules. The first study is a small phantom study used to illustrate metrics for assessing repeatability. The second study is a large phantom study allowing assessment of four algorithms' bias and reproducibility for measuring tumor volume and the change in tumor volume. The third study is a small clinical study of patients whose tumors were measured on two occasions. This study allows a direct assessment of six algorithms' performance for measuring tumor change. With these three examples we compare and contrast study designs and performance metrics, and we illustrate the advantages and limitations of various common statistical methods for quantitative imaging biomarker studies. C1 [Obuchowski, Nancy A.; Wang, Xiao-Feng] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Barnhart, Huiman X.] Duke Univ, Durham, NC USA. [Buckler, Andrew J.] Elucid Bioimaging Inc, Wenham, MA USA. [Pennello, Gene] US FDA, CDRH, Washington, DC 20204 USA. [Kalpathy-Cramer, Jayashree] Harvard Univ, MGH, Sch Med, Boston, MA USA. [Kim, Hyun J. (Grace)] Univ Calif Los Angeles, Los Angeles, CA USA. [Reeves, Anthony P.] Cornell Univ, Ithaca, NY USA. RP Obuchowski, NA (reprint author), Cleveland Clin Fdn, Quantitat Hlth Sci JJN 3, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM obuchon@ccf.org OI Kalpathy-Cramer, Jayashree/0000-0001-8906-9618; Buckler, Andrew/0000-0002-0786-4835 FU Radiologic Society of North America (RSNA); NIH/NIBIB [HHSN268201000050C] FX The authors acknowledge and appreciate the Radiologic Society of North America (RSNA) and NIH/NIBIB contract # HHSN268201000050C for supporting two workshops and numerous conference calls for the authors' Working Group. The authors appreciate the expert advice of Tatiyana V. Apanasovich on earlier drafts of this paper. NR 27 TC 8 Z9 8 U1 2 U2 8 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 FEB PY 2015 VL 24 IS 1 SI SI BP 107 EP 140 DI 10.1177/0962280214537392 PG 34 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA CE4ZZ UT WOS:000351840700005 PM 24919828 ER PT J AU Huang, EP Wang, XF Choudhury, KR McShane, LM Gonen, M Ye, JJ Buckler, AJ Kinahan, PE Reeves, AP Jackson, EF Guimaraes, AR Zahlmann, G AF Huang, Erich P. Wang, Xiao-Feng Choudhury, Kingshuk Roy McShane, Lisa M. Goenen, Mithat Ye, Jingjing Buckler, Andrew J. Kinahan, Paul E. Reeves, Anthony P. Jackson, Edward F. Guimaraes, Alexander R. Zahlmann, Gudrun CA Meta-Anal Working Grp TI Meta-analysis of the technical performance of an imaging procedure: Guidelines and statistical methodology SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE quantitative imaging; imaging biomarkers; technical performance; repeatability; reproducibility; meta-analysis; meta-regression; systematic review ID SEMIAUTOMATED VOLUME MEASUREMENTS; INDIVIDUAL PATIENT DATA; META-REGRESSION; SYSTEMATIC REVIEWS; ASSESSING AGREEMENT; LUNG-CANCER; FDG-PET; PULMONARY NODULES; MALIGNANT-TUMORS; PRISMA STATEMENT AB Medical imaging serves many roles in patient care and the drug approval process, including assessing treatment response and guiding treatment decisions. These roles often involve a quantitative imaging biomarker, an objectively measured characteristic of the underlying anatomic structure or biochemical process derived from medical images. Before a quantitative imaging biomarker is accepted for use in such roles, the imaging procedure to acquire it must undergo evaluation of its technical performance, which entails assessment of performance metrics such as repeatability and reproducibility of the quantitative imaging biomarker. Ideally, this evaluation will involve quantitative summaries of results from multiple studies to overcome limitations due to the typically small sample sizes of technical performance studies and/or to include a broader range of clinical settings and patient populations. This paper is a review of meta-analysis procedures for such an evaluation, including identification of suitable studies, statistical methodology to evaluate and summarize the performance metrics, and complete and transparent reporting of the results. This review addresses challenges typical of meta-analyses of technical performance, particularly small study sizes, which often causes violations of assumptions underlying standard meta-analysis techniques. Alternative approaches to address these difficulties are also presented; simulation studies indicate that they outperform standard techniques when some studies are small. The meta-analysis procedures presented are also applied to actual [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) test-retest repeatability data for illustrative purposes. C1 [Huang, Erich P.; McShane, Lisa M.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Wang, Xiao-Feng] Cleveland Clin Fdn, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. [Choudhury, Kingshuk Roy] Duke Univ, Dept Radiol, Sch Med, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Goenen, Mithat] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Ye, Jingjing] US FDA, Div Biostat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Buckler, Andrew J.] Elucid Biomed Imaging Inc, Wenham, MA USA. [Kinahan, Paul E.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Reeves, Anthony P.] Cornell Univ, Sch Elect & Comp Engn, Ithaca, NY USA. [Jackson, Edward F.] Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. [Guimaraes, Alexander R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Zahlmann, Gudrun] F Hoffmann La Roche Ltd, Basel, Switzerland. RP Huang, EP (reprint author), NCI, Div Canc Treatment & Diag, NIH, 9609 Med Ctr Dr,MSC 9735, Bethesda, MD 20892 USA. EM erich.huang@nih.gov OI Jackson, Edward/0000-0002-5958-0076; Buckler, Andrew/0000-0002-0786-4835 FU Radiological Society of North America; NIH/NIBIB [HHSN268201000050C] FX The authors acknowledge and appreciate the Radiological Society of North America and NIH/NIBIB contract # HHSN268201000050C for supporting two workshops and numerous conference calls for the authors' Working Group. The authors would also like to thank Huiman Barnhart and Daniel Sullivan from Duke University and Gene Pennello, Norberto Pantoja-Galicia, Robert Ochs, Shing Chun Benny Lam, and Mary Pastel from the FDA for their expert advice and comments on this manuscript. NR 77 TC 5 Z9 5 U1 1 U2 7 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 FEB PY 2015 VL 24 IS 1 SI SI BP 141 EP 174 DI 10.1177/0962280214537394 PG 34 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA CE4ZZ UT WOS:000351840700006 PM 24872353 ER PT J AU Beadling, CW Burkle, FM Koenig, KL Sharp, TW AF Beadling, Charles W. Burkle, Frederick M., Jr. Koenig, Kristi L. Sharp, Trueman W. TI Ebola Virus and Public Health INTRODUCTION SO DISASTER MEDICINE AND PUBLIC HEALTH PREPAREDNESS LA English DT Editorial Material C1 [Beadling, Charles W.] Uniformed Serv Univ Hlth Sci, Ctr Disaster & Humanitarian Assistance Med, Bethesda, MD 20814 USA. Harvard Univ, Harvard Humanitarian Initiat, Cambridge, MA 02138 USA. [Burkle, Frederick M., Jr.] Woodrow Wilson Int Ctr Scholars, Washington, DC 20560 USA. [Koenig, Kristi L.] Univ Calif Irvine, Ctr Disaster Med Sci, Irvine, CA USA. [Sharp, Trueman W.] US FDA, CDER, OGD, DCR, Silver Spring, MD USA. RP Beadling, CW (reprint author), Uniformed Serv Univ Hlth Sci, Ctr Disaster & Humanitarian Assistance Med, Bethesda, MD 20814 USA. NR 0 TC 0 Z9 0 U1 3 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1935-7893 EI 1938-744X J9 DISASTER MED PUBLIC JI Dis. Med. Public Health Prep. PD FEB PY 2015 VL 9 IS 1 BP 31 EP 31 DI 10.1017/dmp.2015.16 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CC9DR UT WOS:000350668600005 PM 25901336 ER PT J AU Seidman, JD Vang, R Ronnett, BM Yemelyanova, A Cosin, JA AF Seidman, Jeffrey D. Vang, Russell Ronnett, Brigitte M. Yemelyanova, Anna Cosin, Jonathan A. TI Distribution and case-fatality ratios by cell-type for ovarian carcinomas: A 22-year series of 562 patients with uniform current histological classification SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Ovarian carcinoma; Pathogenesis; Mortality; Serous carcinoma; Stage; Reproducibility ID GRADE SEROUS CARCINOMA; FALLOPIAN-TUBE; 2-TIER SYSTEM; TUMOR TYPE; CLEAR-CELL; STAGE-I; CANCER; ORIGIN; ADENOCARCINOMA; PATHOGENESIS AB Background. Ovarian carcinoma is comprised of several different cell types reflecting different clinicopathologic features. Pathologic criteria for distinguishing cell types have evolved, and therefore non-contemporary literature on ovarian cancer may have limited current relevance. A new dualistic model of pathogenesis that distinguishes type I (endometrioid, mucinous, clear cell and low grade serous carcinomas) from type II (high grade serous carcinomas and carcinosarcomas) tumors has become widely accepted. Methods. A cohort of 562 patients with invasive ovarian carcinoma from a large community hospital practice was reviewed. Cell type, FIGO stage, mortality and interpathologist diagnostic reproducibility were analyzed. Results. Advanced stage ovarian carcinomas were type II in 86% of cases while low stage tumors were most often type I. Only 1.7% of type II tumors were confirmed to be stage I with comprehensive surgical staging. Type H tumors accounted for 85% of deaths, and clear cell carcinomas, 5% of deaths. Cell type-specific casefatality ratios for type II tumors were 62% and 79% for high grade serous carcinoma and carcinosarcoma, respectively. For type I tumors, case-fatality ratios were 38%, 36%, 27% and 13% for low grade serous, clear cell, endometrioid and mucinous carcinomas, respectively. The kappa value for diagnostic reproducibility among 3 gynecologic pathologists was 0.83. Conclusions. Current diagnostic criteria confirm that high grade serous carcinoma and carcinosarcoma account for the vast majority (85%) of ovarian cancer deaths. Cell type designation is highly reproducible among gynecologic pathologists. Type II tumors are rarely stage I (<2%) when comprehensively staged by a gynecologic oncologist. (C) 2014 Elsevier Inc. All rights reserved. C1 [Seidman, Jeffrey D.] Washington Hosp Ctr, Dept Pathol, Washington, DC 20010 USA. [Vang, Russell; Ronnett, Brigitte M.; Yemelyanova, Anna] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21231 USA. [Vang, Russell; Ronnett, Brigitte M.; Yemelyanova, Anna] Johns Hopkins Med Inst, Dept Obstet & Gynecol, Baltimore, MD 21231 USA. [Cosin, Jonathan A.] Hosp Cent Connecticut, Dept Obstet & Gynecol, New Britain, CT 06050 USA. RP Seidman, JD (reprint author), US FDA, Mol Pathol & Cytol Branch, Div Mol Genet & Pathol, Off In Vitro Diagnost & Radiol Hlth,Ctr Devices &, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Jeffrey.Seidman@fda.hhs.gov NR 39 TC 4 Z9 4 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2015 VL 136 IS 2 BP 336 EP 340 DI 10.1016/j.ygyno.2014.12.018 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500027 PM 25528497 ER PT J AU Lara-Pezzi, E Menasche, P Trouvin, JH Badimon, L Ioannidis, JPA Wu, JC Hill, JA Koch, WJ De Felice, AF de Waele, P Steenwinckel, V Hajjar, RJ Zeiher, AM AF Lara-Pezzi, Enrique Menasche, Philippe Trouvin, Jean-Hugues Badimon, Lina Ioannidis, John P. A. Wu, Joseph C. Hill, Joseph A. Koch, Walter J. De Felice, Albert F. de Waele, Peter Steenwinckel, Valerie Hajjar, Roger J. Zeiher, Andreas M. TI Guidelines for Translational Research in Heart Failure SO JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH LA English DT Article DE Guidelines; Heart failure; Animal models; New therapies; Preclinical studies; Clinical trials; Good laboratory practice; Induced pluripotent stem cells; Toxicity ID PRESERVED EJECTION FRACTION; PLURIPOTENT STEM-CELLS; HEALED MYOCARDIAL-INFARCTION; IMPROVES CARDIAC-FUNCTION; DE-POINTES ARRHYTHMIAS; CHRONIC AV-BLOCK; MAGNETIC-RESONANCE; ANIMAL-MODELS; FAILING HEART; ISCHEMIA-REPERFUSION AB Heart failure (HF) remains a major cause of death and hospitalization worldwide. Despite medical advances, the prognosis of HF remains poor and new therapeutic approaches are urgently needed. The development of new therapies for HF is hindered by inappropriate or incomplete preclinical studies. In these guidelines, we present a number of recommendations to enhance similarity between HF animal models and the human condition in order to reduce the chances of failure in subsequent clinical trials. We propose different approaches to address safety as well as efficacy of new therapeutic products. We also propose that good practice rules are followed from the outset so that the chances of eventual approval by regulatory agencies increase. We hope that these guidelines will help improve the translation of results from animal models to humans and thereby contribute to more successful clinical trials and development of new therapies for HF. C1 [Lara-Pezzi, Enrique] CNIC, Cardiovasc Dev & Repair Dept, Madrid 28029, Spain. [Menasche, Philippe] Hop Europeen Georges Pompidou, AP HP, Dept Cardiovasc Surg, Paris, France. [Trouvin, Jean-Hugues] Univ Paris Sorbonne Cite, Sch Pharm, Dept Hlth Secur & Publ Hlth, Paris, France. [Trouvin, Jean-Hugues] European Med Agcy, Comm Adv Therapies, London, England. [Badimon, Lina] Hosp Santa Creu & Sant Pau, IIB St Pau, Cardiovasc Res Ctr, CSIC,ICCC, Barcelona, Spain. [Ioannidis, John P. A.] Stanford Univ, Dept Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Dept Hlth Res & Policy, Div Epidemiol, Stanford, CA 94305 USA. [Wu, Joseph C.] Stanford Univ, Sch Med, Stanford Cardiovasc Inst, Stanford, CA 94305 USA. [Hill, Joseph A.] Univ Texas SW Med Ctr Dallas, Dept Internal Med Cardiol, Dallas, TX 75390 USA. [Koch, Walter J.] Temple Univ, Dept Pharmacol, Ctr Translat Med, Philadelphia, PA 19122 USA. [De Felice, Albert F.] US FDA, Div Cardiovasc Drug Prod, Silver Spring, MD USA. [de Waele, Peter; Steenwinckel, Valerie] Cardio3 BioSci SA, Mt St Guibert, France. [Hajjar, Roger J.] Mt Sinai Sch Med, Dept Cardiol, Cardiovasc Res Ctr, New York, NY USA. [Zeiher, Andreas M.] JW Goethe Univ Hosp Frankfurt, Dept Cardiol, Internal Med 3, Frankfurt, Germany. [Hill, Joseph A.] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA. RP Lara-Pezzi, E (reprint author), CNIC, Cardiovasc Dev & Repair Dept, Melchor Fernandez Almagro 3, Madrid 28029, Spain. EM elara@cnic.es RI Lara-Pezzi, Enrique/E-2350-2015 OI Lara-Pezzi, Enrique/0000-0002-2743-1033 FU European Union [CardioNeT-ITN-289600, CardioNext-ITN-608027, FP7-IMI-JU-SAFET-115003]; Spanish Ministry of Economy [SAF2012-31451]; Regional Government of Madrid [2010-BMD-2321]; Spanish Ministry of Economy; Pro-CNIC Foundation; NIH [HL-120732, HL100401]; AHA [14SFRN20740000]; CPRIT [RP110486P3]; Leducq Foundation [11CVD04]; MINECO-SAF [2013-42962R]; Instituto Carlos III [TERCEL-RD-12/00190026, RIC12/00420024] FX E.L.-P. was supported by grants from the European Union's FP7 (CardioNeT-ITN-289600, CardioNext-ITN-608027), from the Spanish Ministry of Economy (SAF2012-31451), and from the Regional Government of Madrid (2010-BMD-2321 "Fibroteam"). The CNIC is supported by the Spanish Ministry of Economy and by the Pro-CNIC Foundation. J.A.H. was supported by grants from NIH (HL-120732; HL100401), AHA (14SFRN20740000), CPRIT (RP110486P3), and the Leducq Foundation (11CVD04). LB is supported by MINECO-SAF 2013-42962R, Instituto Carlos III (TERCEL-RD-12/00190026 and RIC12/00420024), and FP7-IMI-JU-SAFET-115003 by from the European Union. NR 121 TC 9 Z9 9 U1 2 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1937-5387 EI 1937-5395 J9 J CARDIOVASC TRANSL JI J. Cardiovasc. Transl. Res. PD FEB PY 2015 VL 8 IS 1 BP 3 EP 22 DI 10.1007/s12265-015-9606-8 PG 20 WC Cardiac & Cardiovascular Systems; Medicine, Research & Experimental SC Cardiovascular System & Cardiology; Research & Experimental Medicine GA CD1AJ UT WOS:000350805700002 PM 25604959 ER PT J AU Chen, K Freedberg, DI Keire, DA AF Chen, Kang Freedberg, Daron I. Keire, David A. TI NMR profiling of biomolecules at natural abundance using 2D H-1-N-15 and H-1-C-13 multiplicity-separated (MS) HSQC spectra SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE MS-HSQC; Multiplicity editing; Natural abundance; Triple-axis gradient water suppression ID HETERONUCLEAR SHIFT-CORRELATION; HIGHER-ORDER STRUCTURE; IMPROVED SENSITIVITY; CORRELATION SPECTROSCOPY; CAPSID PROTEIN; DEPT SEQUENCE; BIOPHARMACEUTICALS; THERAPEUTICS; RESONANCES; SELECTION AB 2D NMR H-1-X (X = N-15 or C-13) HSQC spectra contain cross-peaks for all XHn moieties. Multiplicity-edited H-1-C-13 HSQC pulse sequences generate opposite signs between peaks of CH2 and CH/CH3 at a cost of lower signal-to-noise due to the C-13 T-2 relaxation during an additional 1/(1)J(CH) period. Such CHn-editing experiments are useful in assignment of chemical shifts and have been successfully applied to small molecules and small proteins (e.g. ubiquitin) dissolved in deuterated solvents where, generally, peak overlap is minimal. By contrast, for larger biomolecules, peak overlap in 2D HSQC spectra is unavoidable and peaks with opposite phases cancel each other out in the edited spectra. However, there is an increasing need for using NMR to profile biomolecules at natural abundance dissolved in water (e.g., protein therapeutics) where NMR experiments beyond 2D are impractical. Therefore, the existing 2D multiplicity-edited HSQC methods must be improved to acquire data on nuclei other than C-13 (i.e. N-15), to resolve more peaks, to reduce T-2 losses and to accommodate water suppression approaches. To meet these needs, a multiplicity-separated H-1-X HSQC (MS-HSQC) experiment was developed and tested on 500 and 700 MHz NMR spectrometers equipped with room temperature probes using RNase A (14 kDa) and retroviral capsid (26 kDa) proteins dissolved in 95% H2O/5% D2O. In this pulse sequence, the 1/(1)J(XH) editing-period is incorporated into the semi-constant time (semi-CT) X resonance chemical shift evolution period, which increases sensitivity, and importantly, the sum and the difference of the interleaved (1)J(XH)-active and the (1)J(XH)-inactive HSQC experiments yield two separate spectra for XH2 and XH/XH3. Furthermore we demonstrate improved water suppression using triple xyz-gradients instead of the more widely used z-gradient only water-suppression approach. Published by Elsevier Inc. C1 [Chen, Kang; Keire, David A.] US FDA, Div Pharmaceut Anal, Off Testing & Res, Off Pharmaceut Qual,Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Freedberg, Daron I.] US FDA, Lab Bacterial Polysaccharides, Div Bacterial Prod & Allergen Prod, Off Vaccines Res & Review,Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Chen, K (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM kang.chen@fda.hhs.gov FU US FDA Critical Path funds FX We thank Hugo Azurmendi, Marcos Battistel and Jinfa Ying for helpful discussions. Support for this work from the US FDA Critical Path funds is gratefully acknowledged. NR 33 TC 3 Z9 3 U1 0 U2 23 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 EI 1096-0856 J9 J MAGN RESON JI J. Magn. Reson. PD FEB PY 2015 VL 251 BP 65 EP 70 DI 10.1016/j.jmr.2014.11.011 PG 6 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA CD7ED UT WOS:000351252700010 PM 25562571 ER PT J AU Cerreta, F Temple, R Asahina, Y Connaire, C AF Cerreta, F. Temple, R. Asahina, Y. Connaire, C. TI Regulatory activities to address the needs of older patients SO JOURNAL OF NUTRITION HEALTH & AGING LA English DT Article DE Older population; clinical development; regulators; pharmacokinetics; ICH E7 AB At the Drug Information Association (DIA) 49th annual meeting, for the first time regulators (Dr Francesca Cerreta, Dr Robert Temple and Dr Yasuko Asahina) from the three International Conference on Harmonization (ICH) co-sponsor regions came together in a forum to discuss their perspective on how the aging population impacts on drug development and on the design of clinical trials. In 2010, the ICH E7 Guideline (Studies in support of Special Populations: Geriatrics) was revised with the addition of a Questions and Answers document to take into account the rapidly changing world demographics. Regulators from the three ICH regions (Europe, USA and Japan) discuss here how they foresee the application of this guideline, and the impact that this might have on new drug development and clinical trial design. This article aims to summarize the discussions at the session for the benefit of a wider audience. C1 [Cerreta, F.; Connaire, C.] Sci Advice, Human Med Res & Dev Support Div, European Med Agcy, London, England. [Temple, R.] US FDA, Clin Sci, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Cerreta, F (reprint author), Sci Advice, Human Med Res & Dev Support Div, London, England. EM Francesca.Cerreta@ema.europa.eu NR 6 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER FRANCE PI PARIS PA 22 RUE DE PALESTRO, PARIS, 75002, FRANCE SN 1279-7707 EI 1760-4788 J9 J NUTR HEALTH AGING JI J. Nutr. Health Aging PD FEB PY 2015 VL 19 IS 2 BP 232 EP 233 DI 10.1007/s12603-014-0494-4 PG 2 WC Geriatrics & Gerontology; Nutrition & Dietetics SC Geriatrics & Gerontology; Nutrition & Dietetics GA CC4DH UT WOS:000350300500016 PM 25651451 ER PT J AU Ma, J Pawar, RS Grundel, E Mazzola, EP Ridge, CD Masaoka, T Le Grice, SFJ Wilson, J Beutler, JA Krynitsky, AJ AF Ma, Jun Pawar, Rahul S. Grundel, Erich Mazzola, Eugene P. Ridge, Clark D. Masaoka, Takashi Le Grice, Stuart F. J. Wilson, Jennifer Beutler, John A. Krynitsky, Alexander J. TI Sesquiterpenoid Tropolone Glycosides from Liriosma ovata SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID RIBONUCLEASE-H ACTIVITY; DULACIA-GUIANENSIS; MANICOL; ASSAY AB Two new sesquiterpenoid tropolone glycosides, liriosmasides A (1) and B (2), along with two known compounds, secoxyloganin and oplopanpheside C, were isolated from a methanol extract of the roots of Liriosma ovata. The structures of 1 and 2 were elucidated by spectroscopic methods including 1D and 2D NMR and by high-resolution mass spectrometry involving an ultra-high-performance liquid chromatography-quadrupole-orbital ion trap mass spectrometric (UHPLC-Q-Orbitrap MS) method. Compound 1 showed weak inhibitory activity against HIV RNase H. C1 [Ma, Jun; Pawar, Rahul S.; Grundel, Erich; Mazzola, Eugene P.; Ridge, Clark D.; Krynitsky, Alexander J.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. [Masaoka, Takashi; Le Grice, Stuart F. J.] Natl Canc Inst, HIV Drug Resistance Program, RT Biochem Sect, Frederick, MD 21702 USA. [Wilson, Jennifer; Beutler, John A.] Natl Canc Inst, Ctr Canc Res, Mol Targets Lab, Frederick, MD 21702 USA. RP Ma, J (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM jun.ma@fda.hhs.gov NR 17 TC 1 Z9 1 U1 1 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 EI 1520-6025 J9 J NAT PROD JI J. Nat. Prod. PD FEB PY 2015 VL 78 IS 2 BP 315 EP 319 DI 10.1021/np5006696 PG 5 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA CC4MX UT WOS:000350328600021 PM 25587934 ER PT J AU Alvarado-Facundo, E Gao, YM Ribas-Aparicio, RM Jimenez-Alberto, A Weiss, CD Wang, W AF Alvarado-Facundo, Esmeralda Gao, Yamei Maria Ribas-Aparicio, Rosa Jimenez-Alberto, Alicia Weiss, Carol D. Wang, Wei TI Influenza Virus M2 Protein Ion Channel Activity Helps To Maintain Pandemic 2009 H1N1 Virus Hemagglutinin Fusion Competence during Transport to the Cell Surface SO JOURNAL OF VIROLOGY LA English DT Article ID AMANTADINE RESISTANCE MUTATIONS; A VIRUS; MEMBRANE-FUSION; RECEPTOR-BINDING; PROTON CHANNEL; M(2) PROTEIN; LENTIVIRAL VECTOR; CYTOPLASMIC TAIL; PH CONFORMATION; GENE DELIVERY AB The influenza virus hemagglutinin (HA) envelope protein mediates virus entry by first binding to cell surface receptors and then fusing viral and endosomal membranes during endocytosis. Cleavage of the HA precursor (HA0) into a surface receptor-binding subunit (HA1) and a fusion-inducing transmembrane subunit (HA2) by host cell enzymes primes HA for fusion competence by repositioning the fusion peptide to the newly created N terminus of HA2. We previously reported that the influenza virus M2 protein enhances pandemic 2009 influenza A virus [(H1N1) pdm09] HA-pseudovirus infectivity, but the mechanism was unclear. In this study, using cell-cell fusion and HA-pseudovirus infectivity assays, we found that the ion channel function of M2 was required for enhancement of HA fusion and HA-pseudovirus infectivity. The M2 activity was needed only during HA biosynthesis, and proteolysis experiments indicated that M2 proton channel activity helped to protect (H1N1) pdm09 HA from premature conformational changes as it traversed low-pH compartments during transport to the cell surface. While M2 has previously been shown to protect avian influenza virus HA proteins of the H5 and H7 subtypes that have polybasic cleavage motifs, this study demonstrates that M2 can protect HA proteins from human H1N1 strains that lack a polybasic cleavage motif. This finding suggests that M2 proton channel activity may play a wider role in preserving HA fusion competence among a variety of HA subtypes, including HA proteins from emerging strains that may have reduced HA stability. IMPORTANCE Influenza virus infects cells when the hemagglutinin (HA) surface protein undergoes irreversible pH-induced conformational changes after the virus is taken into the cell by endocytosis. HA fusion competence is primed when host cell enzymes cleave the HA precursor. The proton channel function of influenza virus M2 protein has previously been shown to protect avian influenza virus HA proteins that contain a polybasic cleavage site from pH-induced conformational changes during biosynthesis, but this effect is less well understood for human influenza virus HA proteins that lack polybasic cleavage sites. Using assays that focus on HA entry and fusion, we found that the M2 protein also protects (H1N1) pdm09 influenza A virus HA from premature conformational changes as it transits low-pH compartments during biosynthesis. This work suggests that M2 may play a wider role in preserving HA function in a variety of influenza virus subtypes that infect humans and may be especially important for HA proteins that are less stable. C1 [Alvarado-Facundo, Esmeralda; Gao, Yamei; Weiss, Carol D.; Wang, Wei] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Alvarado-Facundo, Esmeralda; Maria Ribas-Aparicio, Rosa; Jimenez-Alberto, Alicia] Inst Politecn Nacl, Dept Microbiol, Escuela Nacl Ciencias Biol, Mexico City, DF, Mexico. RP Weiss, CD (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM carol.weiss@fda.hhs.gov; wei.wang@fda.hhs.gov RI Weiss, Carol/F-6438-2011 OI Weiss, Carol/0000-0002-9965-1289 FU U.S. FDA FX This work was supported by institutional funds from the U.S. FDA. NR 67 TC 8 Z9 8 U1 0 U2 7 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 FEB PY 2015 VL 89 IS 4 BP 1975 EP 1985 DI 10.1128/JVI.03253-14 PG 11 WC Virology SC Virology GA AZ9UT UT WOS:000348562800005 PM 25473053 ER PT J AU Coleman, BN Apelberg, BJ Ambrose, BK Green, KM Choiniere, CJ Bunnell, R King, BA AF Coleman, Blair N. Apelberg, Benjamin J. Ambrose, Bridget K. Green, Kerry M. Choiniere, Conrad J. Bunnell, Rebecca King, Brian A. TI Association Between Electronic Cigarette Use and Openness to Cigarette Smoking Among US Young Adults SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID NICOTINE DELIVERY-SYSTEMS; FUTURE SMOKING; ADOLESCENTS; AWARENESS; BEHAVIOR; TOBACCO AB Introduction: Use of electronic nicotine delivery systems (ENDS), including electronic cigarettes (e-cigarettes), is increasing. One concern is the appeal of these products to youth and young adults and the potential to influence perceptions and use of conventional cigarettes. Methods: Using data from the 2012-2013 National Adult Tobacco Survey, characteristics of adults aged 18-29 years who had never established cigarette smoking behavior were examined by ever use of e-cigarettes, demographics, and ever use of other tobacco products (smokeless tobacco, cigars, hookah, and cigarettes). Multivariate logistic regression was used to examine the relationship between e-cigarette use and openness to cigarette smoking among young adults, defined as the lack of a firm intention not to smoke soon or in the next year. Results: Among young adults who had never established cigarette smoking behavior (unweighted n = 4,310), 7.9% reported having ever tried e-cigarettes, and 14.6% of those who reported having ever tried e-cigarettes also reported current use of the product. Ever e-cigarette use was associated with being open to cigarette smoking (adjusted odds ratio = 2.4; 95% confidence interval = 1.7, 3.3), as was being male, aged 18-24 years, less educated, and having ever used hookah or experimented with conventional cigarettes. Conclusions: Ever use of e-cigarettes and other tobacco products was associated with being open to cigarette smoking. This study does not allow us to assess the directionality of this association, so future longitudinal research is needed to illuminate tobacco use behaviors over time as well as provide additional insight on the relationship between ENDS use and conventional cigarette use among young adult populations. C1 [Coleman, Blair N.; Apelberg, Benjamin J.; Ambrose, Bridget K.; Choiniere, Conrad J.] US FDA, Ctr Tobacco Prod, Off Sci, Silver Spring, MD 20993 USA. [Coleman, Blair N.; Green, Kerry M.] Univ Maryland, Sch Publ Hlth, Dept Behav & Community Hlth, College Pk, MD 20742 USA. [Bunnell, Rebecca; King, Brian A.] Ctr Dis Control & Prevent, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. RP Coleman, BN (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM blair.coleman@fda.hhs.gov NR 30 TC 33 Z9 33 U1 3 U2 21 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 FEB PY 2015 VL 17 IS 2 SI SI BP 212 EP 218 DI 10.1093/ntr/ntu211 PG 7 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA CC1YW UT WOS:000350142300016 PM 25378683 ER PT J AU Bunnell, RE Agaku, IT Arrazola, RA Apelberg, BJ Caraballo, RS Corey, CG Coleman, BN Dube, SR King, BA AF Bunnell, Rebecca E. Agaku, Israel T. Arrazola, Rene A. Apelberg, Benjamin J. Caraballo, Ralph S. Corey, Catherine G. Coleman, Blair N. Dube, Shanta R. King, Brian A. TI Intentions to Smoke Cigarettes Among Never-Smoking US Middle and High School Electronic Cigarette Users: National Youth Tobacco Survey, 2011-2013 SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID FUTURE SMOKING; PUBLIC-HEALTH; UNITED-STATES; U.S. ADULTS; SUSCEPTIBILITY; ADOLESCENTS; INITIATION; PREDICTOR; STUDENTS AB Introduction: Electronic cigarette (e-cigarette) use is increasing rapidly, and the impact on youth is unknown. We assessed associations between e-cigarette use and smoking intentions among US youth who had never smoked conventional cigarettes. Methods: We analyzed data from the nationally representative 2011, 2012, and 2013 National Youth Tobacco Surveys of students in grades 6-12. Youth reporting they would definitely not smoke in the next year or if offered a cigarette by a friend were defined as not having an intention to smoke; all others were classified as having positive intention to smoke conventional cigarettes. Demographics, pro-tobacco advertisement exposure, ever use of e-cigarettes, and ever use of other combustibles (cigars, hookah, bidis, kreteks, and pipes) and noncombustibles (chewing tobacco, snuff, dip, snus, and dissolvables) were included in multivariate analyses that assessed associations with smoking intentions among never-cigarette-smoking youth. Results: Between 2011 and 2013, the number of never-smoking youth who used e-cigarettes increased 3-fold, from 79,000 to more than 263,000. Intention to smoke conventional cigarettes was 43.9% among ever e-cigarette users and 21.5% among never users. Ever e-cigarette users had higher adjusted odds for having smoking intentions than never users (adjusted odds ratio = 1.70, 95% confidence interval = 1.24-2.32). Those who ever used other combustibles, ever used noncombustibles, or reported pro-tobacco advertisement exposure also had increased odds for smoking intentions. Conclusion: In 2013, more than a quarter million never-smoking youth used e-cigarettes. E-cigarette use is associated with increased intentions to smoke cigarettes, and enhanced prevention efforts for youth are important for all forms of tobacco, including e-cigarettes. C1 [Bunnell, Rebecca E.; Agaku, Israel T.; Arrazola, Rene A.; Caraballo, Ralph S.; King, Brian A.] Ctr Dis Control & Prevent, Off Smoking & Hlth, Atlanta, GA 30341 USA. [Apelberg, Benjamin J.; Corey, Catherine G.; Coleman, Blair N.] US FDA, Off Sci, Ctr Tobacco Prod, Rockville, MD 20857 USA. [Dube, Shanta R.] Georgia State Univ, Sch Publ Hlth, Div Epidemiol & Biostat, Atlanta, GA 30303 USA. RP Bunnell, RE (reprint author), Ctr Dis Control & Prevent, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Hwy,MS F-79, Atlanta, GA 30341 USA. EM rrb7@cdc.gov FU Intramural CDC HHS [CC999999] NR 37 TC 97 Z9 98 U1 6 U2 38 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 FEB PY 2015 VL 17 IS 2 SI SI BP 228 EP 235 DI 10.1093/ntr/ntu166 PG 8 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA CC1YW UT WOS:000350142300018 PM 25143298 ER PT J AU Walton, KM Abrams, DB Bailey, WC Clark, D Connolly, GN Djordjevic, MV Eissenberg, TE Fiore, MC Goniewicz, ML Haverkos, L Hecht, SS Henningfield, JE Hughes, JR Oncken, CA Postow, L Rose, JE Wanke, KL Yang, L Hatsukami, DK AF Walton, Kevin M. Abrams, David B. Bailey, William C. Clark, David Connolly, Gregory N. Djordjevic, Mirjana V. Eissenberg, Thomas E. Fiore, Michael C. Goniewicz, Maciej L. Haverkos, Lynne Hecht, Stephen S. Henningfield, Jack E. Hughes, John R. Oncken, Cheryl A. Postow, Lisa Rose, Jed E. Wanke, Kay L. Yang, Lucie Hatsukami, Dorothy K. TI NIH Electronic Cigarette Workshop: Developing a Research Agenda SO NICOTINE & TOBACCO RESEARCH LA English DT Review ID ABUSE LIABILITY ASSESSMENT; NICOTINE DELIVERY-SYSTEMS; TOBACCO PRODUCTS; CARBONYL-COMPOUNDS; SMOKING REDUCTION; PREGNANT SMOKERS; UNITED-STATES; USERS; EXPOSURE; HEALTH AB Background: Electronic cigarettes (e-cigarettes) represent an emerging public health issue. These devices deliver nicotine along with other constituents, including flavorants, via an inhalable aerosol. Their uptake is rapidly increasing in both adults and youths, primarily among current smokers. Public debate is increasing on how these devices should be regulated and used, yet only limited peer-reviewed research exists. To develop a informed policy for e-cigarettes, their effects on human behavior, physiology, and health need to be understood. Purpose: This paper describes proceedings from a National Institutes of Health-sponsored workshop, which was held in November 2013, to identify research needs related to the effects of e-cigarettes. Discussion topics included e-cigarette risks and abuse potential; the potential role for e-cigarettes in harm reduction and smoking cessation; unintended consequences of e-cigarette use, such as becoming a gateway to conventional cigarettes; and dual use of both e-cigarettes and conventional cigarettes. Results and Conclusions: The research needs identified by the workshop participants included the following: standards to measure the contents and emissions of e-cigarettes; biomarkers of exposure; physiological effects of e-cigarettes on tissues and organ systems, including pulmonary and cardiovascular; information on e-cigarette users, how the devices are used, and identification of the best tools to assess these measures; factors that drive use and influence patterns of use; and appropriate methods for evaluating a potential role for e-cigarettes in smoking or nicotine cessation. To understand fully the challenges and the opportunities that e-cigarettes represent, expertise will be needed in basic, behavioral, translational, and clinical sciences. C1 [Walton, Kevin M.] NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, Bethesda, MD 20892 USA. [Abrams, David B.] Schroeder Inst Legacy, Washington, DC USA. [Abrams, David B.] Johns Hopkins Sch Publ Hlth, Dept Hlth Behav & Soc, Baltimore, MD USA. [Bailey, William C.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Clark, David] Natl Inst Dent & Craniofacial Res, Behav & Social Sci Res Branch, NIH, Bethesda, MD USA. [Connolly, Gregory N.] Northeastern Univ, Sch Law, Boston, MA 02115 USA. [Connolly, Gregory N.] Northeastern Univ, Bouve Hlth Sci, Boston, MA 02115 USA. [Djordjevic, Mirjana V.] NCI, Tobacco Control Res Branch, NIH, Bethesda, MD 20892 USA. [Eissenberg, Thomas E.] Virginia Commonwealth Univ, Dept Psychol, Richmond, VA 23284 USA. [Fiore, Michael C.] Univ Wisconsin, Ctr Tobacco Res & Intervent, Madison, WI USA. [Goniewicz, Maciej L.] Roswell Pk Canc Inst, Dept Hlth Behav, Buffalo, NY 14263 USA. [Haverkos, Lynne] NICHHD, Child Dev & Behav Branch, NIH, Bethesda, MD 20892 USA. [Hecht, Stephen S.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Henningfield, Jack E.] Pinney Associates, Bethesda, MD USA. [Henningfield, Jack E.] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Hughes, John R.] Univ Vermont, Coll Med, Dept Psychol Sci, Burlington, VT USA. [Oncken, Cheryl A.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Postow, Lisa] NHLBI, Airway Biol & Dis Branch, NIH, Bethesda, MD 20892 USA. [Rose, Jed E.] Duke Univ, Med Ctr, Ctr Smoking Cessat, Durham, NC USA. [Wanke, Kay L.] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. [Yang, Lucie] US FDA, Div Nonprescript Clin Evaluat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Hatsukami, Dorothy K.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. RP Walton, KM (reprint author), NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM kevin.walton@nih.gov OI Hecht, Stephen/0000-0001-7228-1356 FU National Institutes of Health [P50 DA027840]; US Food and Drug Administration Center for Tobacco Products [U19 CA157345, P50 DA036105] FX This work was supported by the National Institutes of Health (P50 DA027840 to JER) and by the National Institutes of Health and US Food and Drug Administration Center for Tobacco Products (U19 CA157345 to DKH and P50 DA036105 to TEE). NR 103 TC 31 Z9 31 U1 7 U2 37 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 FEB PY 2015 VL 17 IS 2 SI SI BP 259 EP 269 DI 10.1093/ntr/ntu214 PG 11 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA CC1YW UT WOS:000350142300022 PM 25335949 ER PT J AU Vemula, SV Veerasamy, R Ragupathy, V Biswas, S Devadas, K Hewlett, I AF Vemula, Sai Vikram Veerasamy, Ravichandran Ragupathy, Viswanath Biswas, Santanu Devadas, Krishnakumar Hewlett, Indira TI HIV-1 Induced Nuclear Factor I-B (NF-IB) Expression Negatively Regulates HIV-1 Replication through Interaction with the Long Terminal Repeat Region SO VIRUSES-BASEL LA English DT Article ID GENE FAMILY; TRANSCRIPTION; INFECTION; PROTEINS; PROMOTER; CELLS; BIND AB Background: Retroviruses rely on host factors for cell entry, replication, transcription, and other major steps during their life cycle. Human Immunodeficiency Virus-1 (HIV-1) is well known for utilizing a plethora of strategies to evade the host immune response, including the establishment of latent infection within a subpopulation of susceptible cells. HIV-1 also manipulates cellular factors in latently infected cells and persists for long periods of time, despite the presence of successful highly active antiretroviral therapy (HAART). Results: In this study we demonstrate that Nuclear Factor-IB (NF-IB) is induced during HIV-1 infection and its expression negatively impacts viral replication. During HIV-1 infection in peripheral blood mononuclear cells (PBMCs), and the T cell line, Jurkat or during induction of virus replication in latently infected cells, ACH2 and J1.1, we observed a time-dependent alteration in NF-IB expression pattern that correlated with HIV-1 viral expression. Using the Chip assay, we observed an association of NF-IB with the long terminal repeat region of HIV-1 (LTR) (-386 to -453 nt), and this association negatively correlated with HIV-1 transcription. Furthermore, knock-down of NF-IB levels in J1.1 cells resulted in an increase of HIV-1 levels. Knock-down of NF-IB levels in J-Lat-Tat-GFP (A1), (a Jurkat cell GFP reporter model for latent HIV-1 infection) resulted in an increase in GFP levels, indicating a potential negative regulatory role of NF-IB in HIV-1 replication. Conclusion: Overall, our results suggest that NF-IB may play a role in intrinsic antiretroviral defenses against HIV-1. These observations may offer new insights into the correlation of the latently infected host cell types and HIV-1, and help to define new therapeutic approaches for triggering the switch from latency to active replication thereby eliminating HIV-1 latent infection. C1 [Vemula, Sai Vikram; Veerasamy, Ravichandran; Ragupathy, Viswanath; Biswas, Santanu; Devadas, Krishnakumar; Hewlett, Indira] US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Vemula, SV (reprint author), US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM saivikram.vemula@fda.hhs.gov; veerasamy.ravichandra@nih.gov; viswanath.ragupathy@fda.hhs.gov; santanu.biswas@fda.hhs.gov; krishnakumar.devadas@fda.hhs.gov; Indira.hewlett@fda.hhs.gov NR 14 TC 4 Z9 5 U1 0 U2 2 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD FEB PY 2015 VL 7 IS 2 BP 543 EP 558 DI 10.3390/v7020543 PG 16 WC Virology SC Virology GA CC9EL UT WOS:000350670800006 PM 25664610 ER PT J AU Nakamura, N Inselman, AL White, GA Chang, CW Trbojevich, RA Sephr, E Voris, KL Patton, RE Bryant, MS Harrouk, W McIntyre, BS Foster, PMD Hansen, DK AF Nakamura, Noriko Inselman, Amy L. White, Gene A. Chang, Ching-Wei Trbojevich, Raul A. Sephr, Estatira Voris, Kristie L. Patton, Ralph E. Bryant, Matthew S. Harrouk, Wafa McIntyre, Barry S. Foster, Paul M. D. Hansen, Deborah K. TI Effects of Maternal and Lactational Exposure to 2-Hydroxy-4-Methoxybenzone on Development and Reproductive Organs in Male and Female Rat Offspring SO BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY LA English DT Article DE 2-hydroxy-4-methoxybenzophenone; body weight; rats; offspring; testes; ovary; fetal exposure ID ENDOCRINE-DISRUPTING CHEMICALS; TANDEM MASS-SPECTROMETRY; BODY TOPICAL APPLICATION; UV FILTERS; CELL APOPTOSIS; LIQUID-CHROMATOGRAPHY; ESTROGENIC ACTIVITY; SURFACE WATERS; SWISS LAKES; BENZOPHENONE-3 AB BACKGROUND2-Hydroxy-4-methoxybenzophenone (HMB) is an ultraviolet (UV) absorbing compound used in many cosmetic products as a UV-protecting agent and in plastics for preventing UV-induced photodecomposition. HMB has been detected in over 95% of randomly collected human urine samples from adults and from premature infants, and it may have estrogenic potential. METHODSTo determine the effects of maternal and lactational exposure to HMB on development and reproductive organs of offspring, time-mated female Harlan Sprague-Dawley rats were dosed with 0, 1000, 3000, 10,000, 25,000, or 50,000 ppm HMB (seven to eight per group) added to chow from gestation day 6 until weaning on postnatal day (PND) 23. RESULTS AND CONCLUSIONExposure to HMB was associated with reduced body and organ weights in female and male offspring. No significant differences were observed in the number of implantation sites/litter, mean resorptions/litter, % litters with resorptions, number and weights of live fetuses, or sex ratios between the control and HMB dose groups. Normalized anogenital distance in male pups at PND 23 was decreased in the highest dose group. Spermatocyte development was impaired in testes of male offspring in the highest dose group. In females, follicular development was delayed in the highest dose group. However, by evaluating levels of the compound in rat serum, the doses at which adverse events occurred are much higher than usual human exposure levels. Thus, exposure to less than 10,000 ppm HMB does not appear to be associated with adverse effects on the reproductive system in rats C1 [Nakamura, Noriko; Inselman, Amy L.; White, Gene A.; Hansen, Deborah K.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Chang, Ching-Wei] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Trbojevich, Raul A.; Sephr, Estatira; Bryant, Matthew S.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Voris, Kristie L.; Patton, Ralph E.] Toxicol Pathol Associates, Jefferson, AR USA. [Harrouk, Wafa] US FDA, Ctr Drug Evaluat & Res, Jefferson, AR 72079 USA. [McIntyre, Barry S.; Foster, Paul M. D.] NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. RP Nakamura, N (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Noriko.Nakamura@fda.hhs.gov FU NCTR [E0745502]; FDA/NCTR [FDA 224-12-0003]; NIEHS/NTP [NIH AES12013] FX Grant sponsor: NCTR; Grant number: E0745502; Grant sponsor: FDA/NCTR; Grant number: FDA 224-12-0003; Grant sponsor: NIEHS/NTP; Grant number: NIH AES12013. NR 51 TC 2 Z9 2 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-9733 EI 1542-9741 J9 BIRTH DEFECTS RES B JI Birth Defects Res. Part B-Dev. Reprod. Toxicol. PD FEB PY 2015 VL 104 IS 1 BP 35 EP 51 DI 10.1002/bdrb.21137 PG 17 WC Oncology; Genetics & Heredity; Toxicology SC Oncology; Genetics & Heredity; Toxicology GA CC1ZX UT WOS:000350145200004 PM 25707689 ER PT J AU Scheife, RT Hines, LE Boyce, RD Chung, SP Momper, JD Sommer, CD Abernethy, DR Horn, JR Sklar, SJ Wong, SK Jones, G Brown, ML Grizzle, AJ Comes, S Wilkins, TL Borst, C Wittie, MA Malone, DC AF Scheife, Richard T. Hines, Lisa E. Boyce, Richard D. Chung, Sophie P. Momper, Jeremiah D. Sommer, Christine D. Abernethy, Darrell R. Horn, John R. Sklar, Stephen J. Wong, Samantha K. Jones, Gretchen Brown, Mary L. Grizzle, Amy J. Comes, Susan Wilkins, Tricia Lee Borst, Clarissa Wittie, Michael A. Malone, Daniel C. TI Consensus Recommendations for Systematic Evaluation of Drug-Drug Interaction Evidence for Clinical Decision Support SO DRUG SAFETY LA English DT Article ID INTERACTION SCREENING SOFTWARE; PHYSICIAN ORDER ENTRY; INTERACTION ALERTS; WARFARIN; INFORMATION; QUALITY; RISK; PERFORMANCE; TRIAZOLAM; RELEVANCE AB Background Healthcare organizations, compendia, and drug knowledgebase vendors use varying methods to evaluate and synthesize evidence on drug-drug interactions (DDIs). This situation has a negative effect on electronic prescribing and medication information systems that warn clinicians of potentially harmful medication combinations. Objective The aim of this study was to provide recommendations for systematic evaluation of evidence for DDIs from the scientific literature, drug product labeling, and regulatory documents. Methods A conference series was conducted to develop a structured process to improve the quality of DDI alerting systems. Three expert workgroups were assembled to address the goals of the conference. The Evidence Workgroup consisted of 18 individuals with expertise in pharmacology, drug information, biomedical informatics, and clinical decision support. Workgroup members met via webinar 12 times from January 2013 to February 2014. Two in-person meetings were conducted in May and September 2013 to reach consensus on recommendations. Results We developed expert consensus answers to the following three key questions. (i) What is the best approach to evaluate DDI evidence? (ii) What evidence is required for a DDI to be applicable to an entire class of drugs? (iii) How should a structured evaluation process be vetted and validated? Conclusion Evidence-based decision support for DDIs requires consistent application of transparent and systematic methods to evaluate the evidence. Drug compendia and clinical decision support systems in which these recommendations are implemented should be able to provide higher-quality information about DDIs. C1 [Scheife, Richard T.] Tufts Univ, Sch Med, Boston, MA USA. [Hines, Lisa E.; Brown, Mary L.; Grizzle, Amy J.; Malone, Daniel C.] Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA. [Boyce, Richard D.] Univ Pittsburgh, Dept Biomed Informat, Pittsburgh, PA USA. [Chung, Sophie P.; Jones, Gretchen; Comes, Susan] Epocrates,Athenahealth Inc, San Francisco, CA USA. [Momper, Jeremiah D.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA USA. [Sommer, Christine D.] FDB, South San Francisco, CA USA. [Abernethy, Darrell R.] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. [Horn, John R.] Univ Washington, Sch Pharm, Seattle, WA USA. [Sklar, Stephen J.] Wolters Kluwer Hlth, Indianapolis, IN USA. [Wong, Samantha K.] Cerner Multum, Denver, CO USA. [Wilkins, Tricia Lee; Wittie, Michael A.] US OFF, Natl Coordinator Hlth Informat Technol, Washington, DC USA. [Borst, Clarissa] Elsevier Clin Solut, Tampa, FL USA. RP Malone, DC (reprint author), Univ Arizona, Coll Pharm, 1295 N Martin Ave,POB 210202, Tucson, AZ 85721 USA. EM malone@pharmacy.arizona.edu FU Agency for Healthcare Research and Quality (AHRQ) [1R13HS021826-01]; AHRQ [K12 HS019461-01]; National Library of Medicine [R01 LM011838-01]; National Institute of Aging [K01 AG044433-01]; Cerner; Elsevier Clinical Solutions; Epocrates; athenahealth, Inc.; FDB (First Databank, Inc.); Truven Health Analytics; Wolters Kluwer FX This project was funded by the Agency for Healthcare Research and Quality (AHRQ) Grant No. 1R13HS021826-01 (Malone DC-PI). RDB received support to contribute to this project from AHRQ Grant No. K12 HS019461-01, National Library of Medicine Grant No. R01 LM011838-01, and National Institute of Aging Grant No. K01 AG044433-01. Additional support was provided by Cerner, Elsevier Clinical Solutions, Epocrates, athenahealth, Inc., FDB (First Databank, Inc.), Truven Health Analytics, and Wolters Kluwer. The authors would like to thank Alissa Rich for her participation in workgroup discussions and Loretta Peters for her editorial assistance in preparing this manuscript. We would like to acknowledge that John Horn developed the Drug Interaction Probability Scale that is recommended for use in evaluating drug interaction case reports. NR 63 TC 14 Z9 14 U1 1 U2 7 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 FEB PY 2015 VL 38 IS 2 BP 197 EP 206 DI 10.1007/s40264-014-0262-8 PG 10 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA CB6TB UT WOS:000349758500007 PM 25556085 ER PT J AU Church, RJ Gatti, DM Urban, TJ Long, N Yang, X Shi, Q Eaddy, JS Mosedale, M Ballard, S Churchill, GA Navarro, V Watkins, PB Threadgill, DW Harrill, AH AF Church, Rachel J. Gatti, Daniel M. Urban, Thomas J. Long, Nanye Yang, Xi Shi, Qiang Eaddy, J. Scott Mosedale, Merrie Ballard, Shawn Churchill, Gary A. Navarro, Victor Watkins, Paul B. Threadgill, David W. Harrill, Alison H. TI Sensitivity to hepatotoxicity due to epigallocatechin gallate is affected by genetic background in diversity outbred mice SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Green tea; Epigallocatechin gallate; Hepatotoxicity; Population variability; Herbal; Diversity outbred ID INDUCED LIVER-INJURY; ACETAMINOPHEN-INDUCED HEPATOTOXICITY; WEIGHT-LOSS SUPPLEMENTS; GREEN TEA EXTRACT; DIETARY-SUPPLEMENTS; MOUSE-POPULATION; TRAITS; MITOCHONDRIA; HYDROXYCUT; DISCOVERY AB Consumer use of herbal and dietary supplements has recently grown in the United States and, with increased use, reports of rare adverse reactions have emerged. One such supplement is green tea extract, containing the polyphenol epigallocatechin gallate (EGCG), which has been shown to be hepatotoxic at high doses in animal models. The Drug-Induced Liver Injury Network has identified multiple patients who have experienced liver injury ascribed to green tea extract consumption and the relationship to dose has not been straightforward, indicating that differences in sensitivity may contribute to the adverse response in susceptible people. The Diversity Outbred (DO), a genetically heterogeneous mouse population, provides a potential platform for study of interindividual toxicity responses to green tea extract. Within the DO population, an equal exposure to EGCG (50 mg/kg; daily for three days) was found to be tolerated in the majority of mice; however, a small fraction of the animals (16%; 43/272) exhibited severe hepatotoxicity (10-86.8% liver necrosis) that is analogous to the clinical cases. The data indicate that the DO mice may provide a platform for informing risk of rare, adverse reactions that may occur in consumer populations upon ingestion of concentrated herbal products. (C) 2014 The Authors. Published by Elsevier Ltd. C1 [Church, Rachel J.; Eaddy, J. Scott; Mosedale, Merrie; Watkins, Paul B.; Harrill, Alison H.] Hamner UNC Inst Drug Safety Sci, Durham, NC 27709 USA. [Gatti, Daniel M.; Churchill, Gary A.] Jackson Lab, Bar Harbor, ME 04609 USA. [Urban, Thomas J.; Long, Nanye] Duke Univ, Durham, NC 27708 USA. [Yang, Xi; Shi, Qiang] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Ballard, Shawn; Threadgill, David W.] N Carolina State Univ, Raleigh, NC 27607 USA. [Navarro, Victor] Einstein Healthcare Network, Philadelphia, PA 19141 USA. RP Harrill, AH (reprint author), Univ Arkansas Med Sci, Dept Environm & Occupat Hlth, 4301 W Markham St, Little Rock, AR 72205 USA. EM ahharrill@uams.edu OI Mosedale, Merrie/0000-0003-1968-6666 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institute of Health [1RC1DK087510-01]; Drug Induced Liver Injury Network [DKUO1 065201-10] FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institute of Health [1RC1DK087510-01 to P.B.W. and D.W.T] and the Drug Induced Liver Injury Network [DKUO1 065201-10 to P.B.W.]. The information in these materials is not a formal dissemination of information by FDA and does not represent agency position or policy. NR 41 TC 13 Z9 13 U1 2 U2 15 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 FEB PY 2015 VL 76 BP 19 EP 26 DI 10.1016/j.fct.2014.11.008 PG 8 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA CC1II UT WOS:000350094000003 PM 25446466 ER PT J AU Nonnemaker, JM Choiniere, CJ Farrelly, MC Kamyab, K Davis, KC AF Nonnemaker, James M. Choiniere, Conrad J. Farrelly, Matthew C. Kamyab, Kian Davis, Kevin C. TI Reactions to graphic health warnings in the United States SO HEALTH EDUCATION RESEARCH LA English DT Article ID SMOKING-BEHAVIOR; CIGARETTE PACK; IMPACT; MESSAGES; LABELS; ADOLESCENTS; PERSUASION; TEXT AB This study reports consumer reactions to the graphic health warnings selected by the Food and Drug Administration to be placed on cigarette packs in the United States. We recruited three sets of respondents for an experimental study from a national opt-in e-mail list sample: (i) current smokers aged 25 or older, (ii) young adult smokers aged 18-24 and (iii) youth aged 13-17 who are current smokers or who may be susceptible to initiation of smoking. Participants were randomly assigned to be exposed to a pack of cigarettes with one of nine graphic health warnings or with a text-only warning statement. All three age groups had overall strong negative emotional (beta = 4.7, P<0.001 for adults; beta = 4.6, P<0.001 for young adults and beta = 4.0, P<0.001 for youth) and cognitive (beta = 2.4, P<0.001 for adults; beta = 3.0, P<0.001 for young adults and beta = 4.6, P<0.001 for youth) reactions to the proposed labels. The strong negative emotional and cognitive reactions following a single exposure to the graphic health warnings suggest that, with repeated exposures over time, graphic health warnings may influence smokers' beliefs, intentions and behaviors. C1 [Nonnemaker, James M.; Farrelly, Matthew C.; Kamyab, Kian; Davis, Kevin C.] RTI Int, Res Triangle Pk, NC 27709 USA. [Choiniere, Conrad J.] US FDA, Ctr Tobacco Prod, Rockville, MD 20850 USA. RP Nonnemaker, JM (reprint author), RTI Int, Res Triangle Pk, NC 27709 USA. EM jnonnemaker@rti.org FU US Food and Drug Administration [HHSF223201010243G] FX This work was supported by US Food and Drug Administration (contract no. HHSF223201010243G). NR 26 TC 4 Z9 4 U1 4 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1153 EI 1465-3648 J9 HEALTH EDUC RES JI Health Educ. Res. PD FEB PY 2015 VL 30 IS 1 BP 46 EP 56 DI 10.1093/her/cyu036 PG 11 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA CC1SU UT WOS:000350124800005 PM 24974219 ER PT J AU Dauer, LT Miller, DL Schueler, B Silberzweig, J Balter, S Bartal, G Chambers, C Collins, JD Damilakis, J Dixon, RG Marx, MV Stocker, MS Vano, E Venkatesan, AM Nikolic, B AF Dauer, Lawrence T. Miller, Donald L. Schueler, Beth Silberzweig, James Balter, Stephen Bartal, Gabriel Chambers, Charles Collins, Jeremy D. Damilakis, John Dixon, Robert G. Marx, M. Victoria Stocker, Michael S. Vano, Eliseo Venkatesan, Aradhana M. Nikolic, Boris CA Soc Interventional Radiology Safet Cardiovasc & Interventional Radiol TI Occupational Radiation Protection of Pregnant or Potentially Pregnant Workers in IR: A Joint Guideline of the Society of Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID CARDIAC-CATHETERIZATION PROCEDURES; DIAGNOSTIC-RADIOLOGY; PROGRAM GUIDELINES; WOMEN-RADIOLOGISTS; SAFETY PROGRAM; HEALTH HAZARDS; EXPOSURE; PATIENT; CARDIOLOGY; STAFF C1 [Dauer, Lawrence T.] Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10021 USA. [Dauer, Lawrence T.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Silberzweig, James] Beth Israel Deaconess Med Ctr, Dept Radiol, New York, NY 10003 USA. [Balter, Stephen] Columbia Univ, Med Ctr, Dept Radiol, New York, NY 10003 USA. [Balter, Stephen] Columbia Univ, Med Ctr, Dept Med, New York, NY 10003 USA. [Nikolic, Boris] Stratton Med Ctr, Dept Radiol, Albany, NY USA. [Miller, Donald L.] Food & Drug Adm, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Venkatesan, Aradhana M.] Natl Inst Hlth Clin Ctr, Bethesda, MD USA. [Schueler, Beth] Mayo Clin, Dept Radiol, Rochester, MN USA. [Chambers, Charles] Penn State Hershey Med Ctr, Penn State Hershey Heart & Vasc Inst, Hershey, PA USA. [Collins, Jeremy D.] Northwestern Univ, Dept Radiol, Chicago, IL 60611 USA. [Dixon, Robert G.] Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. [Marx, M. Victoria] Los Angeles Cty & Univ So Calif, Med Ctr, Dept Radiol, Los Angeles, CA USA. [Stocker, Michael S.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Bartal, Gabriel] Meir Med Ctr, Dept Diagnost & Intervent Radiol, Kefar Sava, Israel. [Damilakis, John] Univ Crete, Fac Med, Dept Med Phys, Iraklion, Greece. [Vano, Eliseo] Univ Complutense, Dept Radiol, E-28040 Madrid, Spain. RP Dauer, LT (reprint author), SIR, 3975 Fair Ridge Dr,Suite 400 N, Fairfax, VA 22033 USA. EM dauerl@mskcc.org OI Dauer, Lawrence/0000-0002-5629-8462 NR 99 TC 2 Z9 2 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD FEB PY 2015 VL 26 IS 2 BP 171 EP 181 DI 10.1016/j.jvir.2014.11.026 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA CB6MZ UT WOS:000349742400004 PM 25645407 ER PT J AU Schure, MR Beaver, LA AF Schure, Mark R. Beaver (Guiochon), Lois Ann TI In Memoriam: Professor Georges A. Guiochon SO LC GC NORTH AMERICA LA English DT Biographical-Item C1 [Schure, Mark R.] Kroungold Analyt Blue, Bell, PA 19422 USA. [Beaver (Guiochon), Lois Ann] US FDA, Rockville, MD 20857 USA. RP Schure, MR (reprint author), Kroungold Analyt Blue, Bell, PA 19422 USA. EM mark.schure@gmail.com NR 1 TC 0 Z9 0 U1 0 U2 1 PU ADVANSTAR COMMUNICATIONS INC PI DULUTH PA 131 W 1ST STREET, DULUTH, MN 55802 USA SN 1527-5949 EI 1939-1889 J9 LC GC N AM JI LC GC N. AM. PD FEB PY 2015 SU S BP 32 EP 33 PG 2 WC Chemistry, Analytical SC Chemistry GA CB8MJ UT WOS:000349883400021 ER PT J AU Wan, HQ Yang, H Shore, DA Garten, RJ Couzens, L Gao, J Jiang, LL Carney, PJ Villanueva, J Stevens, J Eichelberger, MC AF Wan, Hongquan Yang, Hua Shore, David A. Garten, Rebecca J. Couzens, Laura Gao, Jin Jiang, Lianlian Carney, Paul J. Villanueva, Julie Stevens, James Eichelberger, Maryna C. TI Structural characterization of a protective epitope spanning A(H1N1)pdm09 influenza virus neuraminidase monomers SO NATURE COMMUNICATIONS LA English DT Article ID PANDEMIC H1N1 NEURAMINIDASE; MONOCLONAL-ANTIBODY; 3-DIMENSIONAL STRUCTURE; UNITED-STATES; A VIRUSES; COMPLEX; THERAPY; HEMAGGLUTININ; 150-CAVITY; LIKELIHOOD AB A(H1N1)pdm09 influenza A viruses predominated in the 2013-2014 USA influenza season, and although most of these viruses remain sensitive to Food and Drug Administration-approved neuraminidase (NA) inhibitors, alternative therapies are needed. Here we show that monoclonal antibody CD6, selected for binding to the NA of the prototypic A(H1N1) pdm09 virus, A/California/07/2009, protects mice against lethal virus challenge. The crystal structure of NA in complex with CD6 Fab reveals a unique epitope, where the heavy-chain complementarity determining regions (HCDRs) 1 and 2 bind one NA monomer, the light-chain CDR2 binds the neighbouring monomer, whereas HCDR3 interacts with both monomers. This 30-amino-acid epitope spans the lateral face of an NA dimer and is conserved among circulating A(H1N1) pdm09 viruses. These results suggest that the large, lateral CD6 epitope may be an effective target of antibodies selected for development as therapeutic agents against circulating H1N1 influenza viruses. C1 [Wan, Hongquan; Couzens, Laura; Gao, Jin; Jiang, Lianlian; Eichelberger, Maryna C.] Ctr Biol Evaluat & Res Food & Drug Adm, Div Viral Prod, Silver Spring, MD 20993 USA. [Yang, Hua; Shore, David A.; Garten, Rebecca J.; Carney, Paul J.; Villanueva, Julie; Stevens, James] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Influenza Div, Atlanta, GA 30333 USA. RP Stevens, J (reprint author), Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Influenza Div, 1600 Clifton Rd, Atlanta, GA 30333 USA. EM James.Stevens@cdc.hhs.gov; Maryna.Eichelberger@fda.hhs.gov FU Food and Drug Administration; Centers for Disease Control and Prevention; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357] FX This work was funded by the Food and Drug Administration and the Centers for Disease Control and Prevention. We thank Drs J. Taubenberger and M. Memoli (National Institute of Health, Bethesda, MD, USA) for providing the pCAGGS-CA/09NA plasmid and drug-resistant virus, and Dr R. Webster (St Jude Children's Research Hospital, Memphis, TN, USA) for providing plasmids used to generate influenza viruses by reverse genetics. Dr L. Jiang was supported by training funds administered by the Oak Ridge Institute for Science and Education. We are indebted to staff of the Division of Veterinary Services, Center for Biologics Evaluation and Research, Food and Drug Administration, for excellent animal care. We thank the WHO Global Influenza Surveillance and Response System (GISRS) for providing the virus sequences used to generate the NA expression clones described here, as well as all submitting laboratories, which have deposited their pH1N1 NA sequences to the GISAID Epiflu database (http://www.gisaid.org). Use of the Advanced Photon Source at Argonne National Laboratory was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. We thank the staff of SER-CAT sector 22 for their help with data collection. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Food and Drug Administration, the Centers for Disease Control and Prevention or the Agency for Toxic Substances and Disease Registry. NR 53 TC 8 Z9 8 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2015 VL 6 AR 6114 DI 10.1038/ncomms7114 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC2TJ UT WOS:000350197200002 PM 25668439 ER PT J AU Knudsen, TB Keller, DA Sander, M Carney, EW Doerrer, NG Eaton, DL Fitzpatrick, SC Hastings, KL Mendrick, DL Tice, RR Watkins, PB Whelan, M AF Knudsen, Thomas B. Keller, Douglas A. Sander, Miriam Carney, Edward W. Doerrer, Nancy G. Eaton, David L. Fitzpatrick, Suzanne Compton Hastings, Kenneth L. Mendrick, Donna L. Tice, Raymond R. Watkins, Paul B. Whelan, Maurice TI FutureTox II: In vitro Data and In Silico Models for Predictive Toxicology SO TOXICOLOGICAL SCIENCES LA English DT Editorial Material DE in vitro; in silico; modeling; predictive toxicology; risk assessment ID CELL-DERIVED CARDIOMYOCYTES; ADVERSE OUTCOME PATHWAYS; RISK-ASSESSMENT; ENVIRONMENTAL CHEMICALS; CONCEPTUAL-FRAMEWORK; 21(ST) CENTURY; STEM-CELLS; 21ST-CENTURY; SYSTEMS; VISION AB FutureTox II, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in January, 2014. The meeting goals were to review and discuss the state of the science in toxicology in the context of implementing the NRC 21st century vision of predicting in vivo responses from in vitro and in silico data, and to define the goals for the future. Presentations and discussions were held on priority concerns such as predicting and modeling of metabolism, cell growth and differentiation, effects on sensitive subpopulations, and integrating data into risk assessment. Emerging trends in technologies such as stem cell-derived human cells, 3D organotypic culture models, mathematical modeling of cellular processes and morphogenesis, adverse outcome pathway development, and high-content imaging of in vivo systems were discussed. Although advances in moving towards an in vitro/in silico based risk assessment paradigm were apparent, knowledge gaps in these areas and limitations of technologies were identified. Specific recommendations were made for future directions and research needs in the areas of hepatotoxicity, cancer prediction, developmental toxicity, and regulatory toxicology. C1 [Knudsen, Thomas B.] US EPA, Res Triangle Pk, NC 27711 USA. [Keller, Douglas A.] Sanofi, Bridgewater, NJ 08807 USA. [Sander, Miriam] Page One Editorial Serv, Boulder, CO 80304 USA. [Carney, Edward W.] Dow Chem Co USA, Midland, MI 48674 USA. [Doerrer, Nancy G.] Hlth & Environm Sci Inst, Washington, DC 20005 USA. [Eaton, David L.] Univ Washington, Seattle, WA 98105 USA. [Fitzpatrick, Suzanne Compton; Mendrick, Donna L.] US FDA, Silver Spring, MD 20993 USA. [Hastings, Kenneth L.] Sanofi, Bethesda, MD 20814 USA. [Tice, Raymond R.] NIEHS, Res Triangle Pk, NC 27709 USA. [Watkins, Paul B.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Watkins, Paul B.] Hamner Inst, Res Triangle Pk, NC 27709 USA. [Whelan, Maurice] European Commiss Joint Res Ctr, I-21027 Ispra, Italy. RP Keller, DA (reprint author), Sanofi, 55C 420A,55 Corp Dr, Bridgewater, NJ 08807 USA. EM douglas.keller@sanofi.com OI Keller, Douglas/0000-0002-6186-2881 NR 50 TC 17 Z9 17 U1 3 U2 39 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 FEB PY 2015 VL 143 IS 2 BP 256 EP 267 DI 10.1093/toxsci/kfu234 PG 12 WC Toxicology SC Toxicology GA CC1LK UT WOS:000350102000004 PM 25628403 ER PT J AU Hong, HX Branham, WS Ng, HW Moland, CL Dial, SL Fang, H Perkins, R Sheehan, D Tong, WD AF Hong, Huixiao Branham, William S. Ng, Hui Wen Moland, Carrie L. Dial, Stacey L. Fang, Hong Perkins, Roger Sheehan, Daniel Tong, Weida TI Human Sex Hormone-Binding Globulin Binding Affinities of 125 Structurally Diverse Chemicals and Comparison with Their Binding to Androgen Receptor, Estrogen Receptor, and alpha-Fetoprotein SO TOXICOLOGICAL SCIENCES LA English DT Article DE endocrine disruptor; sex hormone-binding globulin; binding affinity; estrogen receptor; androgen receptor; alpha-fetoprotein ID STEROID-HORMONES; ENVIRONMENTAL CHEMICALS; CRYSTAL-STRUCTURE; BREAST-CANCER; YOUNG-WOMEN; ESTRADIOL; LIGANDS; RISK; TESTOSTERONE; TRANSPORT AB One endocrine disruption mechanism is through binding to nuclear receptors such as the androgen receptor (AR) and estrogen receptor (ER) in target cells. The concentration of a chemical in serum is important for its entry into the target cells to bind the receptors, which is regulated by the serum proteins. Human sex hormone-binding globulin (SHBG) is the major transport protein in serum that can bind androgens and estrogens and thus change a chemical's availability to enter the target cells. Sequestration of an androgen or estrogen in the serum can alter the chemical elicited AR- and ER-mediated responses. To better understand the chemical-induced endocrine activity, we developed a competitive binding assay using human pregnancy plasma and measured the binding to the human SHBG for 125 structurally diverse chemicals, most of which were known to bind AR and ER. Eighty seven chemicals were able to bind the human SHBG in the assay, whereas 38 chemicals were nonbinders. Binding data for human SHBG are compared with that for rat alpha-fetoprotein, ER and AR. Knowing the binding profiles between serum and nuclear receptors will improve assessment of a chemical's potential for endocrine disruption. The SHBG binding data reported here represent the largest data set of structurally diverse chemicals tested for human SHBG binding. Utilization of the SHBG binding data with AR and ER binding data could enable better evaluation of endocrine disrupting potential of chemicals through AR- and ER-mediated responses since sequestration in serum could be considered. C1 [Hong, Huixiao; Ng, Hui Wen; Perkins, Roger; Tong, Weida] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Branham, William S.; Moland, Carrie L.] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. [Dial, Stacey L.; Sheehan, Daniel] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Fang, Hong] US FDA, Natl Ctr Toxicol Res, Off Sci Coordinat, Jefferson, AR 72079 USA. RP Hong, HX (reprint author), NCTR FDA, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM huixiao.hong@fda.hhs.gov FU National Center for Toxicological Research FX H.W.N. was supported through a post-doctoral training 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. NR 61 TC 17 Z9 18 U1 0 U2 16 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 FEB PY 2015 VL 143 IS 2 BP 333 EP 348 DI 10.1093/toxsci/kfu231 PG 16 WC Toxicology SC Toxicology GA CC1LK UT WOS:000350102000010 PM 25349334 ER PT J AU Menis, M Forshee, RA Anderson, SA McKean, S Gondalia, R Warnock, R Johnson, C Mintz, PD Worrall, CM Kelman, JA Izurieta, HS AF Menis, Mikhail Forshee, Richard A. Anderson, Steven A. McKean, Stephen Gondalia, Rahul Warnock, Rob Johnson, Chris Mintz, Paul D. Worrall, Christopher M. Kelman, Jeffrey A. Izurieta, Hector S. TI Posttransfusion purpura occurrence and potential risk factors among the inpatient US elderly, as recorded in large Medicare databases during 2011 through 2012 SO TRANSFUSION LA English DT Article ID POST-TRANSFUSION PURPURA; ADMINISTRATIVE DATA; BLOOD-TRANSFUSION; NONINFECTIOUS COMPLICATIONS; THROMBOCYTOPENIA; DIAGNOSIS; IMMUNOGLOBULIN; ANTIBODIES AB BackgroundPosttransfusion purpura (PTP) is a serious transfusion complication resulting in sudden thrombocytopenia with bleeding. The study's objective was to assess PTP occurrence and potential risk factors among the inpatient US elderly, ages 65 and older, during 2011 through 2012. Study Design and MethodsThis retrospective claims-based study utilized large Medicare databases for calendar years 2011 and 2012. Transfusions of blood and blood components were identified by recorded ICD-9-CM procedure codes and revenue center codes, and PTP was ascertained via ICD-9-CM diagnosis code. Our study evaluated PTP rates (per 100,000 inpatient transfusion stays) among elderly Medicare beneficiaries, overall and by age, sex, race, number of units, and blood components transfused. Multivariate regression analyses were used to assess potential risk factors. ResultsAmong 4,336,338 inpatient transfusion stays for elderly beneficiaries during the study period, 78 had a PTP diagnosis code recorded, an overall rate of 1.8 per 100,000 stays. PTP occurrence varied by the blood components, units transfused, and other characteristics. Significantly higher odds of PTP were found for platelet (PLT)-containing transfusions, with greater number of units transfused, as well as for elderly with histories of cardiac arrhythmias (odds ratio [OR],2.65; 95% confidence interval [CI], 1.43-4.93), coagulopathy (OR,1.79; 95% CI, 1.01-3.21), leukemia (OR,2.37; 95% CI, 1.07-5.26), transplant (OR,2.68; 95% CI, 1.41-5.09), and other conditions. ConclusionOur population-based study suggests a substantially higher PTP risk with PLT-containing transfusions. The study also suggests increased PTP risk with greater number of units transfused as well as the importance of underlying health conditions and prior recipient alloimmunization for PTP occurrence among the elderly. C1 [Menis, Mikhail; Forshee, Richard A.; Anderson, Steven A.; Mintz, Paul D.; Izurieta, Hector S.] US FDA, Silver Spring, MD 20993 USA. [McKean, Stephen; Gondalia, Rahul; Warnock, Rob; Johnson, Chris] 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, 10903 New Hampshire Ave, Silver Spring, MD 20993 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 44 TC 7 Z9 7 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 FEB PY 2015 VL 55 IS 2 BP 284 EP 295 DI 10.1111/trf.12782 PG 12 WC Hematology SC Hematology GA CB7PX UT WOS:000349820900010 PM 25065878 ER PT J AU McDowell, KL Nag, N Franco, Z Bu, M Piccardo, P Cervenak, J Deslys, JP Comoy, E Asher, DM Gregori, L AF McDowell, Kristy L. Nag, Nabanita Franco, Zulmarie Bu, Ming Piccardo, Pedro Cervenak, Juraj Deslys, Jean-Philippe Comoy, Emmanuel Asher, David M. Gregori, Luisa TI Blood reference materials from macaques infected with variant Creutzfeldt-Jakob disease agent SO TRANSFUSION LA English DT Article ID SPONGIFORM ENCEPHALOPATHY AGENT; ORAL INFECTION; PRION PROTEIN; TRANSFUSION; SHEEP; AMPLIFICATION; TRANSMISSION; PRIMATES; PATIENT; BRAIN AB BackgroundVariant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative infection that can be transmitted by blood and blood products from donors in the latent phase of the disease. Currently, there is no validated antemortem vCJD blood screening test. Several blood tests are under development. Any useful test must be validated with disease-relevant blood reference panels. Study Design and MethodsTo generate blood reference materials, we infected four cynomolgus macaques with macaque-adapted vCJD brain homogenates. Blood was collected throughout the preclinical and clinical phases of infection. In parallel, equivalent blood was collected from one uninfected macaque. For each blood collection, an aliquot was stored as whole blood and the remainder was separated into components. Aliquots of plasma from terminally ill macaques were assayed for the presence of PrPTSE with the protein misfolding cyclic amplification (PMCA) method. Infectivity of the macaque brain homogenate used to infect macaques was titrated in C57BL/6 and RIII J/S inbred wild-type mice. ResultsWe sampled blood 19 times from the inoculated monkeys at various stages of the disease over a period of 29 months, generating liters of vCJD-infected macaque blood. vCJD was confirmed in all inoculated macaques. After PMCA, PrPTSE was detected in plasma from infected monkeys, but not from uninfected animals. Both mouse models were more sensitive to infection with macaque-adapted vCJD agent than to primary human vCJD agent. ConclusionThe macaque vCJD blood panels generated in this study provide a unique resource to support vCJD assay development and to characterize vCJD infectivity in blood. C1 [McDowell, Kristy L.; Nag, Nabanita; Franco, Zulmarie; Bu, Ming; Piccardo, Pedro; Cervenak, Juraj; Asher, David M.; Gregori, Luisa] US FDA, Div Emerging & Transfus Transmitted Dis, Off Blood Res & Review, Silver Spring, MD USA. [Deslys, Jean-Philippe; Comoy, Emmanuel] Atom Energy Commiss, Div Prions & Related Dis SEPIA, Inst Emerging Dis & Innovat Therapies iMETI, Fontenay Aux Roses, France. RP Gregori, L (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Luisa.gregori@fda.hhs.gov FU US Food and Drug Administration; FDA Office of the Chief Scientist; Alliance BioSecure Foundation FX This work was supported by the US Food and Drug Administration and by an award from the FDA Office of the Chief Scientist. Part of this work was also funded by a grant from the Alliance BioSecure Foundation. NR 39 TC 3 Z9 3 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 FEB PY 2015 VL 55 IS 2 BP 405 EP 412 DI 10.1111/trf.12841 PG 8 WC Hematology SC Hematology GA CB7PX UT WOS:000349820900024 PM 25154296 ER PT J AU Bacot, SM Feldman, GM Yamada, KM Dhawan, S AF Bacot, Silvia M. Feldman, Gerald M. Yamada, Kenneth M. Dhawan, Subhash TI Pathogenic prion protein fragment (PrP106-126) promotes human immunodeficiency virus type-1 infection in peripheral blood monocyte-derived macrophages SO VIROLOGY LA English DT Article DE Blood; HIV-1; Prion protein; Peripheral blood monocytes; Macrophages ID CREUTZFELDT-JAKOB-DISEASE; NITRIC-OXIDE SYNTHASE; NF-KAPPA-B; HIV-1 INFECTION; VARIANT CJD; TRANSMISSION; TRANSFUSION; ACTIVATION; LIPOCORTIN-1; EXPRESSION AB Transfusion of blood and blood products contaminated with the pathogenic form of prion protein Prp(sc), thought to be the causative agent of variant a Creutzfeldt-Jakob disease (vCJD), may result in serious consequences in recipients with a compromised immune system, for example, as seen in HIV-1 infection. In the present study, we demonstrate that treatment of peripheral blood monocyte-derived macrophages (MDM) with PrP106-126, a synthetic domain of PrPSC that has intrinsic functional activities related to the full-length protein, markedly increased their susceptibility to HIV-1 infection, induced cytokine secretion, and enhanced their migratory behavior in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). Live-cell imaging of MDM cultured in the presence of PrP106-126 showed large cell clusters indicative of cellular activation. Tyrosine kinase inhibitor STI-571, protein kinase C inhibitor K252B, and cyclin-dependent kinase inhibitor olomoucine attenuated PrP106-126-induced altered MDM functions. These findings delineate a previously undefined functional role of PrP106-126-mediated host cell response in promoting HIV-1 pathogenesis. Published by Elsevier Inc. C1 [Dhawan, Subhash] US FDA, Ctr Biol Evaluat & Res, Div Transfus Transmitted Dis, Bethesda, MD USA. [Bacot, Silvia M.; Feldman, Gerald M.] US FDA, Ctr Drug Evaluat & Res, Div Monoclonal Antibodies, Bethesda, MD 20014 USA. [Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Dhawan, S (reprint author), US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Viral Immunol Sect, 10903 New Hampshire Ave,Bldg 52-72,Room 4306, Silver Spring, MD 20993 USA. EM subhash.dhawan@fda.hhs.gov FU FDA intramural research program; NIDCR intramural research program FX We thank Dr. Viswanath Ragupathy, Dr. Xue Wang, Dr. David Asher, and Dr. Pedro Piccardo for critical review of the manuscript. This work was supported by FDA and NIDCR intramural research programs. 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. NR 25 TC 0 Z9 0 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB PY 2015 VL 476 BP 372 EP 376 DI 10.1016/j.virol.2014.11.032 PG 5 WC Virology SC Virology GA CB8MF UT WOS:000349883000043 PM 25589240 ER PT J AU Deeds, JR Hoesch, RE Place, AR Kao, JPY AF Deeds, Jonathan R. Hoesch, Robert E. Place, Allen R. Kao, Joseph P. Y. TI The cytotoxic mechanism of karlotoxin 2 (KmTx 2) from Karlodinium veneficum (Dinophyceae) SO AQUATIC TOXICOLOGY LA English DT Article DE Pore-forming toxin; Non-selective membrane permeability; Colloid osmotic lysis; Fish kills; Karlotoxin ID DINOFLAGELLATE AMPHIDINIUM-KLEBSII; MEMBRANE-PERMEABILIZING ACTIVITIES; MARINE DINOFLAGELLATE; FLUORESCENT INDICATORS; ABSOLUTE-CONFIGURATION; STEROL COMPOSITION; PRACTICAL ASPECTS; ANTIFUNGAL; MICRUM; TOXIN AB This study demonstrates that the polyketide toxin karlotoxin 2 (KmTx 2) produced by Karlodinium veneficum, a dinoflagellate associated with fish kills in temperate estuaries world-wide, alters vertebrate cell membrane permeability. Microfluorimetric and electrophysiological measurements were used to determine that vertebrate cellular toxicity occurs through non-selective permeabilization of plasma membranes, leading to osmotic cell lysis. Previous studies showed that KmTx 2 is lethal to fish at naturally-occurring concentrations measured during fish kills, while sub-lethal doses severely damage gill epithelia. This study provides a mechanistic explanation for the association between K. veneficum blooms and fish kills that has long been observed in temperate estuaries worldwide. Published by Elsevier B.V. C1 [Deeds, Jonathan R.; Place, Allen R.] Univ Maryland, Ctr Environm Sci, Inst Marine & Environm Technol, Baltimore, MD 21202 USA. [Hoesch, Robert E.; Kao, Joseph P. Y.] Univ Maryland, Ctr Biomed Engn & Technol, Baltimore, MD 21201 USA. [Hoesch, Robert E.; Kao, Joseph P. Y.] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. RP Deeds, JR (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM jonathan.deeds@fda.hhs.gov; place@umces.edu OI Kao, Joseph/0000-0002-8875-2180 FU ECOHAB [NA04NOS4780276]; NIEHS [1RO1ES021949-01]; NIGMS [GM056481]; Ecology and Oceanography of Harmful Algal Blooms (ECOHAB) program [709] FX The authors wish to acknowledge Frederick Fry Jr. (US FDA) for the creation of Fig. 1. This work was funded in part by grants from ECOHAB [NA04NOS4780276] and NIEHS [1RO1ES021949-01] (to A.R.P.) and NIGMS [GM056481] (to J.P.Y.K.). This is contribution #4974 from the University of Maryland Center for Environmental Science (UMCES), #14-140 for the Institute of Marine and Environmental Technology (IMET), and #709 from the Ecology and Oceanography of Harmful Algal Blooms (ECOHAB) program. NR 43 TC 3 Z9 3 U1 1 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-445X EI 1879-1514 J9 AQUAT TOXICOL JI Aquat. Toxicol. PD FEB PY 2015 VL 159 BP 148 EP 155 DI 10.1016/j.aquatox.2014.11.028 PG 8 WC Marine & Freshwater Biology; Toxicology SC Marine & Freshwater Biology; Toxicology GA CB4IT UT WOS:000349592100016 PM 25546005 ER PT J AU Strawn, LK Brown, EW David, JRD Den Bakker, HC Vangay, P Yiannas, F Wiedmann, M AF Strawn, Laura K. Brown, Eric W. David, Jairus R. D. Den Bakker, Henk C. Vangay, Pajau Yiannas, Frank Wiedmann, Martin TI Big Data in Food Safety and Quality SO FOOD TECHNOLOGY LA English DT Article ID PATHOGENS; DISEASE C1 [Strawn, Laura K.] Virginia Polytech Inst & State Univ, Eastern Shore Agr Res & Extens Ctr, Dept Food Sci & Technol, Painter, VA USA. [Brown, Eric W.] US FDA, Div Microbiol, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [David, Jairus R. D.] ConAgra Foods Inc, Appl Sci & Technol, Res & Innovat, Omaha, NE USA. [Den Bakker, Henk C.] Texas Tech Univ, Dept Anim & Food Sci, Lubbock, TX 79409 USA. [Vangay, Pajau] Univ Minnesota, Dept Biomed Informat & Computat Biol, Minneapolis, MN USA. [Yiannas, Frank] Walmart, Food Safety, Bentonville, AR USA. [Wiedmann, Martin] Cornell Univ, Dept Food Sci, Ithaca, NY 14853 USA. RP Strawn, LK (reprint author), Virginia Polytech Inst & State Univ, Eastern Shore Agr Res & Extens Ctr, Dept Food Sci & Technol, Painter, VA USA. EM Lstrawn@vt.edu; eric.brown@fda.hhs.gov; jairus.david@canagrafoods.com; henk.C.den-bakker@ttu.edu; vanga015@umn.edu; frank.yiannas@walmart.com; mw16@cornell.edu RI Wiedmann, Martin/A-9683-2008 OI Wiedmann, Martin/0000-0002-4168-5662 NR 14 TC 1 Z9 1 U1 5 U2 39 PU INST FOOD TECHNOLOGISTS PI CHICAGO PA 525 WEST VAN BUREN, STE 1000, CHICAGO, IL 60607-3814 USA SN 0015-6639 J9 FOOD TECHNOL-CHICAGO JI Food Technol. PD FEB PY 2015 VL 69 IS 2 BP 42 EP + PG 7 WC Food Science & Technology SC Food Science & Technology GA CB5EX UT WOS:000349651400012 ER PT J AU Vallelian, F Gelderman-Fuhrmann, MP Schaer, CA Puglia, M Opitz, L Baek, JH Vostal, J Buehler, PW Schaer, DJ AF Vallelian, Florence Gelderman-Fuhrmann, Monique P. Schaer, Christian A. Puglia, Michele Opitz, Lennart Baek, Jin Hyen Vostal, Jaroslav Buehler, Paul W. Schaer, Dominik J. TI Integrative Proteome and Transcriptome Analysis of Extramedullary Erythropoiesis and Its Reversal by Transferrin Treatment in a Mouse Model of Beta-Thalassemia SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE thalasemia; therapy; transferrin; anenia erythropoiesis; spleer; LC-MSMS; mRNA sequencing ID ERYTHROID PRECURSORS; INEFFECTIVE ERYTHROPOIESIS; IRON-METABOLISM; BONE-MARROW; RECEPTOR 2; E DISEASE; EXPRESSION; GENE; MICE; EXPANSION AB Beta-thalassemia results from mutations of the beta-hemoglobin (Hbb) gene and reduced functional Hbb synthesis. Excess a-Hb causes globin chain aggregation, oxidation, cytoskeletal damage, and increased red blood cell clearance. These events result in anemia, altered iron homeostasis, and expansion of extramedullary erythropoiesis. Serum transferrin (Tf) is suggested to be an important regulator of erythropoiesis in murine models of thalassemia. The present study was conducted to establish a quantitative proteomic and transcriptomic analysis of transferrin-modulated extramedullary erythropoiesis in the spleen of wild type and thalassemic Hbb(th3/+) mice. Our LC-MS/MS protein analysis and mRNA sequencing data provide quantitative expression estimates of 1590 proteins and 24 581 transcripts of the murine spleen and characterize key processes of erythropoiesis and RBC homeostasis such as the whole heme synthesis pathway as well as critical components of the red blood cell antioxidant systems and the proliferative cell cycling pathway. The data confirm that Tf treatment of nontransfused Hbb(th3/+) mice induces a systematic correction of these processes at a molecular level. Tf treatment of Hbb(th3/+) mice for 60 days leads to a complete molecular restoration of the normal murine spleen phenotype. These findings support further investigation of plasma-derived Tf as a treatment for thalassemia. C1 [Vallelian, Florence; Schaer, Christian A.; Puglia, Michele; Schaer, Dominik J.] Univ Zurich, Div Internal Med, CH-8091 Zurich, Switzerland. [Gelderman-Fuhrmann, Monique P.; Vostal, Jaroslav] US FDA, Lab Cellular Hematol, CBER, Silver Spring, MD 20993 USA. [Puglia, Michele; Opitz, Lennart] Univ Zurich, Swiss Fed Inst Technol Zurich, Funct Genom Ctr Zurich, CH-8057 Zurich, Switzerland. [Baek, Jin Hyen; Buehler, Paul W.] US FDA, Lab Biochem & Vasc Biol, CBER, Silver Spring, MD 20993 USA. [Schaer, Dominik J.] Univ Zurich, Ctr Evolutionary Med, CH-8057 Zurich, Switzerland. RP Buehler, PW (reprint author), US FDA, Lab Biochem & Vasc Biol, CBER, Silver Spring, MD 20993 USA. EM paul.buehler@fda.hhs.gov; dominik.schaer@usz.ch FU Swiss National Science Foundation [310030/120658, 31003A/138500]; University of Zurich; Swiss Federal Commission for Technology and Innovation (CTI) FX This work was supported by the Swiss National Science Foundation (grants 310030/120658 and 31003A/138500 to DJ.S.), the University of Zurich Research Priority Program "Integrative Human Physiology" and the Swiss Federal Commission for Technology and Innovation (CTI). F.V. was supported by the University of Zurich funding programs "Research Time" and "Forschungskredit". NR 31 TC 0 Z9 0 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD FEB PY 2015 VL 14 IS 2 BP 1089 EP 1100 DI 10.1021/pr5010778 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CA9WV UT WOS:000349276400045 PM 25566950 ER PT J AU Wagner, C Pan, Y Hsu, V Sinha, V Zhao, P AF Wagner, C. Pan, Y. Hsu, V. Sinha, V. Zhao, P. TI PREDICTIVE PERFORMANCE OF PHYSIOLOGICALLY BASED PHARMACOKINETC (PBPK) MODELS FOR THE EFFECT OF CYP 3A INDUCERS ON SUBSTRATE DRUGS: ANALYSIS OF SUBMISSIONS TO THE FDA. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Wagner, C.; Hsu, V.; Sinha, V.; Zhao, P.] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. [Pan, Y.] US FDA, Off Gener Drugs, 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA OII-1 BP 101 EP 101 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500308 ER PT J AU Babiskin, A Kim, H Fang, L Lapteva, L Jiang, W Lionberger, R AF Babiskin, A. Kim, H. Fang, L. Lapteva, L. Jiang, W. Lionberger, R. TI USE OF PARTIAL AUC TO DEMONSTRATE BIOEQUIVALENCE OF GENERIC METHYLPHENIDATE EXTENDED-RELEASE PRODUCTS USING PHYSIOLOGICALLY BASED ABSORPTION MODELING AND SIMULATION. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Babiskin, A.; Kim, H.; Fang, L.; Lapteva, L.; Jiang, W.; Lionberger, R.] 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PI-076 BP S43 EP S43 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500129 ER PT J AU Bai, JP Babiskin, A Zhang, X Lionberger, RA Burckart, G Mulberg, AE Sinha, V Uno, T AF Bai, J. P. Babiskin, A. Zhang, X. Lionberger, R. A. Burckart, G. Mulberg, A. E. Sinha, V. Uno, T. TI PHYSIOLOGICALLY-BASED ABSORPTION MODELING AND SIMULATION FOR ASSESSING BIOAVAILABILITY IN ELDERLY, CHILDREN AND GASTROINTESTINAL DISEASES. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Bai, J. P.; Babiskin, A.; Zhang, X.; Lionberger, R. A.; Burckart, G.; Mulberg, A. E.; Sinha, V.] US FDA, Silver Spring, MD USA. [Uno, T.] Zikeikai Aoimori Hosp, Aomori, Japan. 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PI-084 BP S45 EP S45 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500137 ER PT J AU Bai, JP Babiskin, A Zhang, X Lionberger, RA Burckart, G Mulberg, AE Sinha, V Uno, T AF Bai, J. P. Babiskin, A. Zhang, X. Lionberger, R. A. Burckart, G. Mulberg, A. E. Sinha, V. Uno, T. TI PHYSIOLOGICALLY-BASED ABSORPTION MODELING AND SIMULATION FOR ASSESSING BIOAVAILABILITY IN ELDERLY, CHILDREN AND GASTROINTESTINAL DISEASES. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Bai, J. P.; Babiskin, A.; Zhang, X.; Lionberger, R. A.; Burckart, G.; Mulberg, A. E.; Sinha, V.] US FDA, Silver Spring, MD USA. [Uno, T.] Zikeikai Aoimori Hosp, Aomori, Japan. 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA QP-23 BP S9 EP S9 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500024 ER PT J AU Duan, P Zhao, P Zhang, L AF Duan, P. Zhao, P. Zhang, L. TI PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING (PBPK) OF PITAVASTATIN AND ATORVASTATIN TO PREDICT DRUG-DRUG INTERACTIONS (DDIS). SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Duan, P.] US FDA, Silver Spring, MD USA. [Zhao, P.; Zhang, L.] US FDA, Off Clin Pharmacol, Off Translat Sci, CDER, Silver Spring, MD 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PT-17 BP S16 EP S17 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500044 ER PT J AU Fan, J Zhang, X Lionberger, R AF Fan, J. Zhang, X. Lionberger, R. TI IMPACT OF ALTERED IN VITRO DISSOLUTION PROFILE ON WARFARIN IN VIVO PHARMACOKINETICS PERFORMANCE-POPULATION PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) SIMULATION. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Fan, J.; Zhang, X.; Lionberger, R.] US FDA, 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PI-081 BP S44 EP S44 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500134 ER PT J AU Fan, J Zhang, X Lionberger, R AF Fan, J. Zhang, X. Lionberger, R. TI IMPACT OF ALTERED IN VITRO DISSOLUTION PROFILE ON WARFARIN IN VIVO PHARMACOKINETICS PERFORMANCE-POPULATION PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) SIMULATION. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Fan, J.; Zhang, X.; Lionberger, R.] 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA QP-22 BP S8 EP S9 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500023 ER PT J AU Gronich, N Lavi, I Barnett, O Abernethy, DR Rennert, G AF Gronich, N. Lavi, I. Barnett, O. Abernethy, D. R. Rennert, G. TI TYROSINE KINASE TARGETING DRUGS-ASSOCIATED CONGESTIVE HEART FAILURE: TRASTUZUMAB, CETUXIMAB, PANITUMUMAB AND SUNITINIB ARE ASSOCIATED WITH INCREASED RISK. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Gronich, N.; Lavi, I.; Barnett, O.; Rennert, G.] Carmel Hosp, Haifa, Israel. [Abernethy, D. R.] 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PW-13 BP S99 EP S99 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500305 ER PT J AU Liu, J Corrigan, B Nicholas, T Ito, K Zhao, L Flockhart, DA AF Liu, J. Corrigan, B. Nicholas, T. Ito, K. Zhao, L. Flockhart, D. A. TI MARS (META-ANALYSIS USING R SHINY): A BROWSER BASED META-ANALYSIS MODELING VISUALIZATION APPLICATION. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Liu, J.; Flockhart, D. A.] Indiana Univ Sch Med, Dept Med, Div Clin Pharmacol, Indianapolis, IN 46202 USA. [Corrigan, B.; Nicholas, T.; Ito, K.] Pfizer Inc, Global Clin Pharmacol, Global Innovat Pharma, Groton, CT 06340 USA. [Zhao, L.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA OI-2 BP S19 EP S20 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500051 ER PT J AU Liu, J Corrigan, B Nicholas, T Ito, K Zhao, L Flockhart, DA AF Liu, J. Corrigan, B. Nicholas, T. Ito, K. Zhao, L. Flockhart, D. A. TI MARS (META-ANALYSIS USING R SHINY): A BROWSER BASED META-ANALYSIS MODELING VISUALIZATION APPLICATION. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Liu, J.; Flockhart, D. A.] Indiana Univ Sch Med, Dept Med, Div Clin Pharmacol, Indianapolis, IN 46202 USA. [Corrigan, B.; Nicholas, T.; Ito, K.] Pfizer Inc, Global Clin Pharmacol, Global Innovat Pharma, Groton, CT 06340 USA. [Zhao, L.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PT-03 BP S11 EP S12 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500030 ER PT J AU Liu, J Corrigan, B Nicholas, T Ito, K Zhao, L Flockhart, DA AF Liu, J. Corrigan, B. Nicholas, T. Ito, K. Zhao, L. Flockhart, D. A. TI MARS (META-ANALYSIS USING R SHINY): A BROWSER BASED META-ANALYSIS MODELING VISUALIZATION APPLICATION. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Liu, J.; Flockhart, D. A.] Indiana Univ Sch Med, Div Clin Pharmacol, Dept Med, Indianapolis, IN 46202 USA. [Corrigan, B.; Nicholas, T.; Ito, K.] Pfizer Inc, Global Clin Pharmacol, Global Innovat Pharma, Groton, CT 06340 USA. [Zhao, L.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA QP-21 BP S8 EP S8 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500022 ER PT J AU Marathe, A Jain, R Jain, L Hsu, C Pinheiro, J Winter, WD Sahajwalla, CG Sinha, V Mehrotra, N AF Marathe, A. Jain, R. Jain, L. Hsu, C. Pinheiro, J. Winter, W. D. Sahajwalla, C. G. Sinha, V. Mehrotra, N. TI EXPOSURE RESPONSE ANALYSIS AS EVIDENCE FOR APPROVAL OF CANAGLIFLOZIN-METFORMIN IMMEDIATE RELEASE FIXED-DOSE COMBINATION PRODUCT: A REGULATORY PERSPECTIVE. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Marathe, A.; Jain, R.; Jain, L.; Sahajwalla, C. G.; Sinha, V.; Mehrotra, N.] US FDA, Off Clin Pharmacol, OTS, CDER, Silver Spring, MD USA. [Hsu, C.; Pinheiro, J.; Winter, W. D.] Janssen Res & Dev LLC, Model Based Drug Dev, Raritan, NJ 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 FEB PY 2015 VL 97 SU 1 MA OI-1 BP S19 EP S19 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500050 ER PT J AU Ramamoorthy, A Bull, J Zhang, L Pacanowski, MA AF Ramamoorthy, A. Bull, J. Zhang, L. Pacanowski, M. A. TI PHARMACOGENETICS AND RACIAL COMPOSITION IN CLINICAL TRIALS FOR NON-SMALL CELL LUNG CANCER AND CHRONIC HEPATITIS C INFECTION. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Ramamoorthy, A.; Bull, J.; Zhang, L.; Pacanowski, M. A.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PW-05 BP S58 EP S59 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500178 ER PT J AU Ramamoorthy, A Bull, J Zhang, L Pacanowski, MA AF Ramamoorthy, A. Bull, J. Zhang, L. Pacanowski, M. A. TI PHARMACOGENETICS AND RACIAL COMPOSITION IN CLINICAL TRIALS FOR NON-SMALL CELL LUNG CANCER AND CHRONIC HEPATITIS C INFECTION. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Ramamoorthy, A.; Bull, J.; Zhang, L.; Pacanowski, M. A.] 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PT-10 BP S14 EP S14 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500037 ER PT J AU Shon, J Li, L Kim, M AF Shon, J. Li, L. Kim, M. TI THE EFFECTS OF BODY WEIGHT/BODY MASS INDEX ON THE DISPOSITION OF LEVONORGESTREL AFTER A SINGLE DOSE ADMINISTRATION OF LEVONORGESTREL CONTAINING EMERGENCY CONTRACTIVES. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Shon, J.; Li, L.; Kim, M.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PI-114 BP S53 EP S54 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500167 ER PT J AU Wagner, C Pan, Y Hsu, V Sinha, V Zhao, P AF Wagner, C. Pan, Y. Hsu, V. Sinha, V. Zhao, P. TI PREDICTIVE PERFORMANCE OF PHYSIOLOGICALLY BASED PHARMACOKINETC (PBPK) MODELS FOR THE EFFECT OF CYP 3A INDUCERS ON SUBSTRATE DRUGS: ANALYSIS OF SUBMISSIONS TO THE FDA. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Wagner, C.; Hsu, V.; Sinha, V.; Zhao, P.] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. [Pan, Y.] US FDA, Off Gener Drugs, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PT-05 BP S12 EP S13 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500032 ER PT J AU Yoshida, K Yeung, CK Kusama, M Zhang, H Ragueneau-Majlessi, I Argon, S Zhao, P Zhang, L Zineh, I Sugiyama, Y Huang, S AF Yoshida, K. Yeung, C. K. Kusama, M. Zhang, H. Ragueneau-Majlessi, I. Argon, S. Zhao, P. Zhang, L. Zineh, I. Sugiyama, Y. Huang, S. TI ANALYSIS OF THE EFFECT OF VARIOUS DEGREES OF RENAL IMPAIRMENT ON THE PHARMACOKINETICS OF NONRENALLY ELIMINATED DRUGS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Yoshida, K.; Zhang, H.; Zhao, P.; Zhang, L.; Zineh, I.; Huang, S.] US FDA, Silver Spring, MD USA. [Yeung, C. K.; Ragueneau-Majlessi, I.; Argon, S.] Univ Washington, Seattle, WA 98195 USA. [Kusama, M.] Univ Tokyo, Tokyo, Japan. [Sugiyama, Y.] Inst Phys & Chem Res RIKEN, Yokohama, Kanagawa, Japan. RI YOSHIDA, KENTA/B-3037-2012 OI YOSHIDA, KENTA/0000-0003-4967-3831 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PII-107 BP S92 EP S92 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500285 ER PT J AU Wunderlich, A Noo, F Gallas, BD Heilbrun, ME AF Wunderlich, Adam Noo, Frederic Gallas, Brandon D. Heilbrun, Marta E. TI Exact Confidence Intervals for Channelized Hotelling Observer Performance in Image Quality Studies SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Image quality assessment; linear discriminant analysis (LDA); Mahalanobis distance; model observers; noncentral F-distribution; noncentrality parameter ID MYOCARDIAL-PERFUSION SPECT; MODEL OBSERVERS; LESION DETECTABILITY; OBJECT VARIABILITY; DEFECT DETECTION; DETECTION TASKS; RECONSTRUCTION; OPTIMIZATION; COVARIANCE; PHANTOMS AB Task-based assessments of image quality constitute a rigorous, principled approach to the evaluation of imaging system performance. To conduct such assessments, it has been recognized that mathematical model observers are very useful, particularly for purposes of imaging system development and optimization. One type of model observer that has been widely applied in the medical imaging community is the channelized Hotelling observer (CHO), which is well-suited to known-location discrimination tasks. In the present work, we address the need for reliable confidence interval estimators of CHO performance. Specifically, we show that the bias associated with point estimates of CHO performance can be overcome by using confidence intervals proposed by Reiser for the Mahalanobis distance. In addition, we find that these intervals are well-defined with theoretically-exact coverage probabilities, which is a new result not proved by Reiser. The confidence intervals are tested with Monte Carlo simulation and demonstrated with two examples comparing X-ray CT reconstruction strategies. Moreover, commonly-used training/testing approaches are discussed and compared to the exact confidence intervals. MATLAB software implementing the estimators described in this work is publicly available at http://code.google.com/p/iqmodelo/. C1 [Wunderlich, Adam; Noo, Frederic; Heilbrun, Marta E.] Univ Utah, Dept Radiol, Salt Lake City, UT 84108 USA. [Wunderlich, Adam; Gallas, Brandon D.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Wunderlich, A (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM adam.wunderlich@fda.hhs.gov OI Wunderlich, Adam/0000-0002-8463-9156 FU National Institutes of Health [R01 EB007236, R21 EB009168]; Ben B. and Iris M. Margolis Foundation FX This work was supported in part by the National Institutes of Health under Grant R01 EB007236 and Grant R21 EB009168, and in part by a grant from the Ben B. and Iris M. Margolis Foundation. Asterisk indicates corresponding author. NR 49 TC 5 Z9 5 U1 2 U2 9 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 EI 1558-254X J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD FEB PY 2015 VL 34 IS 2 BP 453 EP 464 DI 10.1109/TMI.2014.2360496 PG 12 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA CB0TA UT WOS:000349338900008 PM 25265629 ER PT J AU Luccioli, S Kwegyir-Afful, E AF Luccioli, Stefano Kwegyir-Afful, Ernest TI Understanding food allergen thresholds requires careful analysis of the available clinical data Reply SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID PEANUT ALLERGY; NATURAL-HISTORY; CHILDREN; IGE C1 [Luccioli, Stefano; Kwegyir-Afful, Ernest] US FDA, Ctr Food Safety & Appl Nutr, Off Food Addit Safety, College Pk, MD 20740 USA. RP Luccioli, S (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Food Addit Safety, College Pk, MD 20740 USA. EM stefano.luccioli@fda.hhs.gov NR 10 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 BP 584 EP 585 DI 10.1016/j.jaci.2014.10.023 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA CB1FL UT WOS:000349372300043 PM 25468196 ER PT J AU Tong, MM Smith, JL Richlen, M Steidinger, KA Kulis, DM Fux, E Anderson, DM AF Tong, Mengmeng Smith, Juliette L. Richlen, Mindy Steidinger, Karen A. Kulis, David M. Fux, Elie Anderson, Donald M. TI CHARACTERIZATION AND COMPARISON OF TOXIN-PRODUCING ISOLATES OF DINOPHYSIS ACUMINATA FROM NEW ENGLAND AND CANADA SO JOURNAL OF PHYCOLOGY LA English DT Article DE cox1; Diarrhetic Shellfish Poisoning; Dinophysis acuminata; Dinophysis acuminata complex; morphology; okadaic acid; pectenotoxins; peduncle ID MULTIPLE SEQUENCE ALIGNMENT; OKADAIC ACID; GENETIC DIVERSITY; FOOD AVAILABILITY; SHELLFISH; PECTENOTOXIN-2; DINOFLAGELLATE; CULTURE; BLOOMS; GROWTH AB Following the identification of the first toxic isolate of Dinophysis acuminata from the northwestern Atlantic, we conducted detailed investigations into the morphology, phylogeny, physiology, and toxigenicity of three isolates from three sites within the northeastern U.S./Canada region: Eel Pond and Martha's Vineyard, Massachusetts, and the Bay of Fundy. Another isolate, collected from the Gulf of Mexico, was grown under the same light, temperature, and prey conditions for comparison. Despite observed phenotypic heterogeneity, morphometrics and molecular evidence classified the three northwestern Atlantic isolates as D. acuminata Claparede & Lachmann, whereas the isolate from the Gulf of Mexico was morphologically identified as D. cf. ovum. Physiological and toxin analyses supported these classifications, with the three northwestern Atlantic isolates being more similar to each other with respect to growth rate, toxin profile, and diarrhetic shellfish poisoning (DSP) toxin content (okadaic acid + dinophysistoxin 1/cell) than they were to the isolate from the Gulf of Mexico, which had toxin profiles similar to those published for D. cf. ovum F. Schutt. The DSP toxin content, 0.01-1.8 pg okadaic acid (OA) + dinophysistoxin (DTX1) per cell, of the three northwestern Atlantic isolates was low relative to other D. acuminata strains from elsewhere in the world, consistent with the relative scarcity of shellfish harvesting closures due to DSP toxins in the northeastern U. S. and Canada. If this pattern is repeated with the analyses of more geographically and temporally dispersed isolates from the region, it would appear that the risk of significant DSP toxin outbreaks in the northwestern Atlantic is low to moderate. Finally, the morphological, physiological, and toxicological variability within D. acuminata may reflect spatial (and/or temporal) population structure, and suggests that sub-specific resolution may be helpful in characterizing bloom dynamics and predicting toxicity. C1 [Tong, Mengmeng] Zhejiang Univ, Ocean Coll, Hangzhou 310058, Zhejiang, Peoples R China. [Tong, Mengmeng; Smith, Juliette L.; Richlen, Mindy; Kulis, David M.; Anderson, Donald M.] Woods Hole Oceanog Inst, Dept Biol, Woods Hole, MA 02543 USA. [Tong, Mengmeng; Smith, Juliette L.; Richlen, Mindy; Kulis, David M.; Anderson, Donald M.] Woods Hole Oceanog Inst, Woods Hole Ctr Oceans & Human Hlth, Woods Hole, MA 02543 USA. [Smith, Juliette L.] Coll William & Mary, Virginia Inst Marine Sci, Gloucester Point, VA 23062 USA. [Steidinger, Karen A.] Florida Fish & Wildlife Conservat Commiss, Fish & Wildlife Res Inst, St Petersburg, FL 33701 USA. [Fux, Elie] US FDA, Div Seafood Sci & Technol, Dauphin Isl, AL 36528 USA. RP Tong, MM (reprint author), Zhejiang Univ, Ocean Coll, Hangzhou 310058, Zhejiang, Peoples R China. EM mengmengtong@zju.edu.cn FU NSF [OCE-0850421]; Woods Hole Center for Oceans and Human Health through National Science Foundation (NSF) [OCE-1314642]; National Institute of Environmental Health Sciences (NIEHS) [1-P01-ES021923-01]; Natural Science Foundation of China [41306095]; Strategic Priority Research Program of the Chinese Academy of Science [XDA11020405]; CAS scientific project of innovation and interdisciplinary FX We are grateful to S.M. Plakas, U.S. FDA, and two anonymous reviewers for reviewing this manuscript and providing beneficial critiques. This work was funded by a NSF Grant OCE-0850421 to D.M.A. Additional support was provided by the Woods Hole Center for Oceans and Human Health through National Science Foundation (NSF) Grant OCE-1314642 and National Institute of Environmental Health Sciences (NIEHS) Grant 1-P01-ES021923-01, Natural Science Foundation of China (Grant No. 41306095), the Strategic Priority Research Program of the Chinese Academy of Science (No. XDA11020405) and CAS scientific project of innovation and interdisciplinary. This paper is Contribution No. 3419 of the Virginia Institute of Marine Science, College of William & Mary. NR 56 TC 2 Z9 2 U1 2 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3646 EI 1529-8817 J9 J PHYCOL JI J. Phycol. PD FEB PY 2015 VL 51 IS 1 BP 66 EP 81 DI 10.1111/jpy.12251 PG 16 WC Plant Sciences; Marine & Freshwater Biology SC Plant Sciences; Marine & Freshwater Biology GA CB1PU UT WOS:000349400900006 PM 26986259 ER PT J AU Kishnani, PS Sheets, KB Kazi, Z DeArmey, S Bali, D Rosenberg, A AF Kishnani, Priya S. Sheets, Kathryn Berrier Kazi, Zoheb DeArmey, Stephanie Bali, Deeksha Rosenberg, Amy TI Prophylactic immume modulation in infantile Pompe disease: Collective experience treating CRIM-positive and negative patients in the naive setting SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 11th Annual WORLD Symposium of the Lysosomal-Disease-Network CY FEB 09-13, 2015 CL Orlando, FL SP Lysosomal Dis Network C1 [Kishnani, Priya S.; Sheets, Kathryn Berrier; Kazi, Zoheb; DeArmey, Stephanie; Bali, Deeksha] Duke Univ, Med Ctr, Durham, NC USA. [Rosenberg, Amy] US FDA, Washington, DC 20204 USA. OI Berrier, Kathryn/0000-0003-3510-6836; Kazi, Zoheb/0000-0002-0447-2764 NR 0 TC 0 Z9 0 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2015 VL 114 IS 2 MA 133 BP S64 EP S64 DI 10.1016/j.ymgme.2014.12.136 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CA5UK UT WOS:000348973100132 ER PT J AU Catalfamo, M Mawle, A Verthelyi, D AF Catalfamo, Marta Mawle, Alison Verthelyi, Daniela TI Immunology careers at the NIH, FDA and CDC: different paths that focus on advancing public health SO NATURE IMMUNOLOGY LA English DT Article C1 [Catalfamo, Marta] NIAID, Immunoregulat Lab, US NIH, Bethesda, MD 20892 USA. [Mawle, Alison] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. [Verthelyi, Daniela] US FDA, Ctr Drug Evaluat & Res, Off Biotechnol Prod, Div Therapeut Prot, Silver Spring, MD USA. RP Catalfamo, M (reprint author), NIAID, Immunoregulat Lab, US NIH, Bldg 10, Bethesda, MD 20892 USA. EM catalfam@mail.nih.gov NR 9 TC 1 Z9 1 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2015 VL 16 IS 2 BP 129 EP 132 PG 4 WC Immunology SC Immunology GA AZ3QZ UT WOS:000348143100001 PM 25594454 ER PT J AU Miller, KL Lanthier, M AF Miller, Kathleen L. Lanthier, Michael TI Innovation in biologic new molecular entities: 1986-2014 SO NATURE REVIEWS DRUG DISCOVERY LA English DT News Item C1 [Miller, Kathleen L.; Lanthier, Michael] US FDA, Silver Spring, MD 20993 USA. RP Miller, KL (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM kathleen.miller@fda.hhs.gov; michael.lanthier@fda.hhs.gov NR 1 TC 8 Z9 9 U1 2 U2 4 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 FEB PY 2015 VL 14 IS 2 BP 83 EP 83 PG 1 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA CA5SM UT WOS:000348968100006 PM 25633785 ER PT J AU Ni, X Li, L Pan, GY AF Ni, Xuan Li, L. Pan, Guoyu TI HDAC inhibitor-induced drug resistance involving ATP-binding cassette transporters SO ONCOLOGY LETTERS LA English DT Review DE histone deacetylase inhibitors; cancer treatment; multidrug resistance; P-glycoprotein; breast cancer resistance protein; multidrug resistance protein 1/2; nuclear receptor ID HISTONE DEACETYLASE INHIBITORS; CONSTITUTIVE ANDROSTANE RECEPTOR; SUBEROYLANILIDE HYDROXAMIC ACID; PROMYELOCYTIC LEUKEMIA-CELLS; MDR1 GENE-EXPRESSION; COLON-CANCER CELLS; P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE; SODIUM-BUTYRATE; VALPROIC ACID AB Histone deacetylase (HDAC) inhibitors are becoming a novel and promising class of antineoplastic agents that have been used for cancer therapy in the clinic. Two HDAC inhibitors, vorinostat and romidepsin, have been approved by the Food and Drug Administration to treat T-cell lymphoma. Nevertheless, similar to common anticancer drugs, HDAC inhibitors have been found to induce multidrug resistance (MDR), which is an obstacle for the success of chemotherapy. The most common cause of MDR is considered to be the increased expression of adenosine triphosphate binding cassette (ABC) transporters. Numerous studies have identified that the upregulation of ABC transporters is often observed following treatment with HDAC inhibitors, particularly the increased expression of P-glycoprotein, which leads to drug efflux, reduces intracellular drug concentration and induces MDR. The present review summarizes the key ABC transporters involved in MDR following various HDAC inhibitor treatments in a range of cancer cell lines and also explored the potential mechanisms that result in MDR, including the effect of nuclear receptors, which are the upstream regulatory factors of ABC transporters. C1 [Ni, Xuan; Pan, Guoyu] Shanghai Inst Mat Medica, Chinese Acad Sci, Ctr Drug Safety Evaluat & Res, Shanghai 201203, Peoples R China. [Li, L.] Ctr Drug Evaluat & Res, Ffice Clin Pharmacol, US Food & Drug Adm, Silver Spring, MD 20993 USA. RP Pan, GY (reprint author), Shanghai Inst Mat Medica, Chinese Acad Sci, Ctr Drug Safety Evaluat & Res, 501 Haike Rd, Shanghai 201203, Peoples R China. EM guoyupan@hotmail.com NR 73 TC 7 Z9 7 U1 5 U2 17 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1792-1074 EI 1792-1082 J9 ONCOL LETT JI Oncol. Lett. PD FEB PY 2015 VL 9 IS 2 BP 515 EP 521 DI 10.3892/ol.2014.2714 PG 7 WC Oncology SC Oncology GA CB3CR UT WOS:000349506300001 ER PT J AU Uehara, H Rao, VA AF Uehara, Hiroshi Rao, V. Ashutosh TI Metal-Mediated Protein Oxidation: Applications of a Modified ELISA-Based Carbonyl Detection Assay for Complex Proteins SO PHARMACEUTICAL RESEARCH LA English DT Article DE biopharmaceuticals; carbonyl; leachables; polysorbates; stability ID HUMAN GROWTH-HORMONE; COLONY-STIMULATING FACTOR; CATALYZED OXIDATION; POSTTRANSLATIONAL MODIFICATIONS; METHIONINE RESIDUES; BIOLOGICAL CONSEQUENCES; THERAPEUTIC PROTEINS; INTERFERON BETA-1A; HEMOPHILIA-A; FACTOR-VIII AB Purpose Therapeutic proteins are prone to oxidative modification during manufacturing, processing, and storage that may lead to degradation, aggregation, and immunogenicity. Protein carbonylation is an irreversible oxidative modification and has been identified as a hallmark of severe oxidative stress but not extensively studied for its impact on the stability and activity of therapeutic proteins. Methods We describe the application of a modified ELISA-based method to quantify global levels of carbonyl modification of complex proteins. We investigated protein oxidation of large protein molecules (transferrin, rabbit IgG, or beta-glucosidase) and complex protein samples (human plasma) that were either stored in different buffer formulations, with varying amounts of divalent iron, or under different storage temperatures to determine the impact of different physicochemical stresses on carbonyl modifications. Results The modified ELISA allows for sensitive and specific carbonyl quantification with measurements that closely match those determined with the conventional spectrophotometric method. The method was useful for complex protein mixtures such as cell lysates without the need for additional procedures to remove DNA and RNA. Our findings demonstrate significant oxidative modification of each of the proteins stored in commonly used buffers and excipients at 37 degrees C, 23 degrees C, and 4 degrees C. The carbonyl levels were further exacerbated with addition of trace amounts of Fe2+. We also measured the extent of protein aggregation under oxidizing conditions. Conclusions Collectively, our results indicate the importance of better characterizing carbonyl modification of proteins during their storage and use. C1 [Uehara, Hiroshi; Rao, V. Ashutosh] US FDA, Chem Lab, Div Therapeut Prot, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. RP Rao, VA (reprint author), US FDA, Chem Lab, Div Therapeut Prot, Off Biotechnol Prod,Ctr Drug Evaluat & Res, 29 Lincoln Dr Bldg 29A,Room 2A-11, Bethesda, MD 20892 USA. EM ashutosh.rao@fda.hhs.gov FU CDER Critical Path Initiative FX This research was supported by the CDER Critical Path Initiative. We thank Dr. Joseph Kotarek (FDA) for help in analyzing protein aggregates. We would like to thank Elliot Rosen (FDA), Dr. Shen Luo (FDA), Dr. Nancy B. Wehr (NIH/NHLBI) and Dr. Rodney L. Levine (NIH/NHLBI) for critical reading of the manuscript or suggestions. The authors have no competing financial interests to disclose. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the U.S. Food and Drug Administration and the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 43 TC 4 Z9 4 U1 2 U2 12 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 FEB PY 2015 VL 32 IS 2 BP 691 EP 701 DI 10.1007/s11095-014-1496-y PG 11 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA CB1AB UT WOS:000349357700028 PM 25182973 ER PT J AU Tampal, N Mandula, H Zhang, HL Li, BV Nguyen, H Conner, DP AF Tampal, Nilufer Mandula, Haritha Zhang, Hongling Li, Bing V. Nguyen, Hoainhon Conner, Dale P. TI Biopharmaceutics Classification System-Based Biowaivers for Generic Oncology Drug Products: Case Studies SO AAPS PHARMSCITECH LA English DT Review DE Biopharmaceutics Classification System; bioequivalence; biowaiver; cancer; oncology AB Establishing bioequivalence (BE) of drugs indicated to treat cancer poses special challenges. For ethical reasons, often, the studies need to be conducted in cancer patients rather than in healthy volunteers, especially when the drug is cytotoxic. The Biopharmaceutics Classification System (BCS) introduced by Amidon (1) and adopted by the FDA, presents opportunities to avoid conducting the bioequivalence studies in humans. This paper analyzes the application of the BCS approach by the generic pharmaceutical industry and the FDA to oncology drug products. To date, the FDA has granted BCS-based biowaivers for several drug products involving at least four different drug substances, used to treat cancer. Compared to in vivo BE studies, development of data to justify BCS waivers is considered somewhat easier, faster, and more cost effective. However, the FDA experience shows that the approval times for applications containing in vitro studies to support the BCS-based biowaivers are often as long as the applications containing in vivo BE studies, primarily because of inadequate information in the submissions. This paper deliberates some common causes for the delays in the approval of applications requesting BCS-based biowaivers for oncology drug products. Scientific considerations of conducting a non-BCS-based in vivo BE study for generic oncology drug products are also discussed. It is hoped that the information provided in our study would help the applicants to improve the quality of ANDA submissions in the future. C1 [Tampal, Nilufer; Mandula, Haritha; Zhang, Hongling; Li, Bing V.; Nguyen, Hoainhon; Conner, Dale P.] US FDA, Div Bioequivalence, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Tampal, N (reprint author), US FDA, Div Bioequivalence, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Nilufer.Tampal@fda.hhs.gov NR 4 TC 1 Z9 1 U1 5 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-9932 J9 AAPS PHARMSCITECH JI AAPS PharmSciTech PD FEB PY 2015 VL 16 IS 1 BP 5 EP 9 DI 10.1208/s12249-014-0195-7 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA5EM UT WOS:000348931400003 PM 25245330 ER PT J AU Kona, R Fahmy, RM Claycamp, G Polli, JE Martinez, M Hoag, SW AF Kona, Ravikanth Fahmy, Raafat M. Claycamp, Gregg Polli, James E. Martinez, Marilyn Hoag, Stephen W. TI Quality-by-Design III: Application of Near-Infrared Spectroscopy to Monitor Roller Compaction In-process and Product Quality Attributes of Immediate Release Tablets SO AAPS PHARMSCITECH LA English DT Article DE chemometrics; crushing force; disintegration; near-infrared spectroscopy; partial least square; principal component analysis; quality by design; roller compaction ID CIPROFLOXACIN HYDROCHLORIDE; NIR SPECTROSCOPY; COMPRESSION; MOISTURE; STRENGTH; POWDER AB The objective of this study is to use near-infrared spectroscopy (NIRS) coupled with multivariate chemometric models to monitor granule and tablet quality attributes in the formulation development and manufacturing of ciprofloxacin hydrochloride (CIP) immediate release tablets. Critical roller compaction process parameters, compression force (CFt), and formulation variables identified from our earlier studies were evaluated in more detail. Multivariate principal component analysis (PCA) and partial least square (PLS) models were developed during the development stage and used as a control tool to predict the quality of granules and tablets. Validated models were used to monitor and control batches manufactured at different sites to assess their robustness to change. The results showed that roll pressure (RP) and CFt played a critical role in the quality of the granules and the finished product within the range tested. Replacing binder source did not statistically influence the quality attributes of the granules and tablets. However, lubricant type has significantly impacted the granule size. Blend uniformity, crushing force, disintegration time during the manufacturing was predicted using validated PLS regression models with acceptable standard error of prediction (SEP) values, whereas the models resulted in higher SEP for batches obtained from different manufacturing site. From this study, we were able to identify critical factors which could impact the quality attributes of the CIP IR tablets. In summary, we demonstrated the ability of near-infrared spectroscopy coupled with chemometrics as a powerful tool to monitor critical quality attributes (CQA) identified during formulation development. C1 [Kona, Ravikanth; Polli, James E.; Hoag, Stephen W.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. [Fahmy, Raafat M.; Claycamp, Gregg; Martinez, Marilyn] US FDA, Off New Anim Drug Evaluat, Ctr Vet Med, Rockville, MD 20855 USA. RP Hoag, SW (reprint author), Univ Maryland, Sch Pharm, 20 N Pine St, Baltimore, MD 21201 USA. EM shoag@rx.umaryland.edu FU FDA; CIPET FX The authors would like to acknowledge the financial assistance from the FDA and CIPET. Drs. Bancha Chuasuwan, Ramesh Dandu, and Walter Xie for their technical assistance with the CIP assay. Thanks to Ryan McCann for his assistance with roller compaction at Purdue University, School of Pharmacy. NR 26 TC 5 Z9 5 U1 5 U2 19 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-9932 J9 AAPS PHARMSCITECH JI AAPS PharmSciTech PD FEB PY 2015 VL 16 IS 1 BP 202 EP 216 DI 10.1208/s12249-014-0180-1 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA5EM UT WOS:000348931400024 PM 25319052 ER PT J AU Ayyadevara, S Balasubramaniam, M Gao, Y Yu, LR Alla, R Reis, RS AF Ayyadevara, Srinivas Balasubramaniam, Meenakshisundaram Gao, Yuan Yu, Li-Rong Alla, Ramani Reis, Robert Shmookler TI Proteins in aggregates functionally impact multiple neurodegenerative disease models by forming proteasome-blocking complexes SO AGING CELL LA English DT Article DE Alzheimer (disease); C; elegans; Huntington (disease); neurodegeneration; (protein) aggregation; proteasome ID CAENORHABDITIS-ELEGANS MODEL; POLYGLUTAMINE-EXPANSION; HUNTINGTONS-DISEASE; C. ELEGANS; LIFE-SPAN; AMYLOID-BETA; TOXICITY; STRESS; LENGTH; RNAI AB Age-dependent neurodegenerative diseases progressively form aggregates containing both shared components (e.g., TDP-43, phosphorylated tau) and proteins specific to each disease. We investigated whether diverse neuropathies might have additional aggregation-prone proteins in common, discoverable by proteomics. Caenorhabditis elegans expressing unc-54p/Q40::YFP, a model of polyglutamine array diseases such as Huntington's, accrues aggregates in muscle 2-6days posthatch. These foci, isolated on antibody-coupled magnetic beads, were characterized by high-resolution mass spectrometry. Three Q40::YFP-associated proteins were inferred to promote aggregation and cytotoxicity, traits reduced or delayed by their RNA interference knockdown. These RNAi treatments also retarded aggregation/cytotoxicity in Alzheimer's disease models, nematodes with muscle or pan-neuronal A(1-42) expression and behavioral phenotypes. The most abundant aggregated proteins are glutamine/asparagine-rich, favoring hydrophobic interactions with other random-coil domains. A particularly potent modulator of aggregation, CRAM-1/HYPK, contributed <1% of protein aggregate peptides, yet its knockdown reduced Q40::YFP aggregates 7286% (P<10(-6)). In worms expressing A(1-42), knockdown of cram-1 reduced -amyloid 60% (P<0.002) and slowed age-dependent paralysis >30% (P<10(-6)). In wild-type worms, cram-1 knockdown reduced aggregation and extended lifespan, but impaired early reproduction. Protection against seeded aggregates requires proteasome function, implying that normal CRAM-1 levels promote aggregation by interfering with proteasomal degradation of misfolded proteins. Molecular dynamic modeling predicts spontaneous and stable interactions of CRAM-1 (or human orthologs) with ubiquitin, and we verified that CRAM-1 reduces degradation of a tagged-ubiquitin reporter. We propose that CRAM-1 exemplifies a class of primitive chaperones that are initially protective and highly beneficial for early reproduction, but ultimately impair aggregate clearance and limit longevity. C1 [Ayyadevara, Srinivas; Alla, Ramani; Reis, Robert Shmookler] Cent Arkansas Vet Healthcare Serv, McClellan Vet Med Ctr, Little Rock, AR 72205 USA. [Ayyadevara, Srinivas; Balasubramaniam, Meenakshisundaram; Reis, Robert Shmookler] Univ Arkansas Med Sci, Dept Geriatr, Little Rock, AR 72205 USA. [Balasubramaniam, Meenakshisundaram] Univ Arkansas Med Sci, BioInformat Program, Little Rock, AR 72205 USA. [Balasubramaniam, Meenakshisundaram] Univ Arkansas, Little Rock, AR 72205 USA. [Gao, Yuan; Yu, Li-Rong] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Reis, Robert Shmookler] Univ Arkansas Med Sci, Dept Biochem & Mol Biol, Little Rock, AR 72205 USA. RP Reis, RS (reprint author), VA Med Ctr, 4300 West 7th St, Little Rock, AR 72205 USA. EM rjsr@uams.edu FU Life Extension Foundation; NIH/NIA [P30-AG028718]; NIH [P20 RR016460, P20 GM103429]; NSF [CRI CNS-0855248, EPS-0701890, EPS-0918970, MRI CNS-0619069, MRI 07266, OISE-0729792] FX Studies were supported by grants to RJSR (VA Merit, VA SRCSA) with additional support from the Life Extension Foundation (to RJSR); a subaward to SA from NIH/NIA Grant P30-AG028718 (J. Wei, P.I.); NIH Grants P20 RR016460 and P20 GM103429 supporting Arkansas INBRE; and NSF Grants CRI CNS-0855248, EPS-0701890, EPS-0918970, MRI CNS-0619069, MRI 07266, and OISE-0729792 supporting UAF high-performance computing. NR 46 TC 10 Z9 10 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD FEB PY 2015 VL 14 IS 1 BP 35 EP 48 DI 10.1111/acel.12296 PG 14 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA CA7KQ UT WOS:000349096600005 PM 25510159 ER PT J AU Seltzer, JH Turner, JR Geiger, MJ Rosano, G Mahaffey, KW White, WB Sabol, MB Stockbridge, N Sager, PT AF Seltzer, Jonathan H. Turner, J. Rick Geiger, Mary Jane Rosano, Giuseppe Mahaffey, Kenneth W. White, William B. Sabol, Mary Beth Stockbridge, Norman Sager, Philip T. TI Centralized adjudication of cardiovascular end points in cardiovascular and noncardiovascular pharmacologic trials: A report from the Cardiac Safety Research Consortium SO AMERICAN HEART JOURNAL LA English DT Article ID CLINICAL EVENTS COMMITTEE AB This white paper provides a summary of presentations and discussions at a cardiovascular (CV) end point adjudication think tank cosponsored by the Cardiac Safety Research Committee and the US Food and Drug Administration (FDA) that was convened at the FDA's White Oak headquarters on November 6, 2013. Attention was focused on the lack of clarity concerning the need for end point adjudication in both CV and non-CV trials: there is currently an absence of widely accepted academic or industry standards and a definitive regulatory policy on how best to structure and use clinical end point committees (CECs). This meeting therefore provided a forum for leaders in the fields of CV clinical trials and CV safety to develop a foundation of initial best practice recommendations for use in future CEC charters. Attendees included representatives from pharmaceutical companies, regulatory agencies, end point adjudication specialist groups, clinical research organizations, and active, academically based adjudicators. The manuscript presents recommendations from the think tank regarding when CV end point adjudication should be considered in trials conducted by cardiologists and by noncardiologists as well as detailing key issues in the composition of a CEC and its charter. In addition, it presents several recommended best practices for the establishment and operation of CECs. The science underlying CV event adjudication is evolving, and suggestions for additional areas of research will be needed to continue to advance this science. C1 [Seltzer, Jonathan H.] ACI Clin, Bala Cynwyd, PA 19004 USA. [Turner, J. Rick] Quintiles, Durham, NC USA. [Geiger, Mary Jane] Regeneron Pharmaceut Inc, Tarrytown, NY USA. [Rosano, Giuseppe] European Med Agcy, Cardiovasc Working Party, London, England. [Mahaffey, Kenneth W.; Sager, Philip T.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [White, William B.] Univ Connecticut, Sch Med, Farmington, CT USA. [Sabol, Mary Beth] GlaxoSmith Kline Pharmaceut Inc, Upper Providence, PA USA. [Stockbridge, Norman] US FDA, Silver Spring, MD USA. RP Seltzer, JH (reprint author), ACI Clin, 3 Bala Plaza West,Suite 402,251 St Asaphs Rd, Bala Cynwyd, PA 19004 USA. EM jseltzer@aciclinical.com FU National Institutes of Health (National Institute of Aging, National Institute of Drug Abuse) FX William B. White, MD, FASH, FAHA, has declared no stock ownership and is not a member of any speakers' bureaus. He receives research funding from the National Institutes of Health (National Institute of Aging, National Institute of Drug Abuse). Dr. White is a safety consultant (member of DSMB, CV end point committee, or advisory board) to Ardea Biosciences; Astra-Zeneca; Celgene, Forest Research Institute; Roche, Inc; Takeda, Inc; and Teva Pharmaceutical Industries. Dr White was the president of the American Society of Hypertension at the time of this CSRC meeting. NR 12 TC 5 Z9 5 U1 1 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 FEB PY 2015 VL 169 IS 2 BP 197 EP 204 DI 10.1016/j.ahj.2014.11.003 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CA9AN UT WOS:000349212800003 PM 25641528 ER PT J AU Mohammad, A Yang, Y Khan, MA Faustino, PJ AF Mohammad, A. Yang, Y. Khan, M. A. Faustino, P. J. TI Long-term stability study of Prussian blue-A quality assessment of water content and cyanide release SO CLINICAL TOXICOLOGY LA English DT Article DE Prussian blue; Long-term stability; Cyanide poisoning; Toxicity ID FERRIC-HEXACYANOFERRATE; QUANTITATIVE-DETERMINATION; THALLIUM BINDING AB Context. Prussian blue, ferric hexacyanoferrate is approved for (oral) treatment of internal contamination with radioisotopes of cesium or thallium. Cyanide makes up 35-40% of Prussian blue's molecular composition; thus, cyanide may be released during transit through the digestive tract under physiological pH conditions. Objectives. The purpose of this study is to assess the long-term stability of Prussian blue drug products and active pharmaceutical ingredients and its impact on cyanide release. The study involves the determination and comparison of the loss in water content and cyanide released from Prussian blue under pH conditions that bracket human physiological exposure. Methods. Test samples of active pharmaceutical ingredient and drug product were stored for 10 years at ambient temperatures that mimic warehouse storage conditions. Water loss from Prussian blue was measured using thermogravimetric analysis. An in vitro physiological pH model that brackets gastric exposure and gastrointestinal transit was utilized for cyanide release. Prussian blue was incubated in situ at pH: 1.0, 5.0, and 7.0 @ 37 degrees C for 1-24 h. Cyanide was measured using a validated colorimetric method by UV-Vis spectroscopy. Results. Although the water content (quality attribute) of Prussian blue active pharmaceutical ingredient and drug product decreased by about 10.5% and 13.8%, respectively, since 2003, the cyanide release remained comparable. At pH of 7.0 for 24 h cyanide released from active pharmaceutical ingredient-1 was 21.33 +/- 1.76 mu g/g in 2004, and 28.45 +/- 3.15 mu g/g in 2013; cyanide released from drug product-1 was 21.89 +/- 0.56 mu g/g in 2004, and 27.31 +/- 5.78 mu g/g in 2013. At gastric pH of 1.0 and upper gastrointestinal pH of 5.0, the data for active pharmaceutical ingredients and drug products were also comparable in 2013. The cyanide release is still pH-dependent and follows the same trend as observed in 2003 with minimum release at pH of 5.0 and maximal release at pH of 1.0. In summary, this is the long-term stability study of Prussian blue which correlates cyanide release to water loss. Cyanide released from Prussian blue was maximum at pH of 1.0 (47.47 mu g/g) and minimum at pH of 5.0-7.0 (20.01 mu g/g). Conclusions. Based on maximal dose, maximal residence time in stomach and intestine, the maximal cyanide released from Prussian blue is about 1.31 mg, which is far below the minimal lethal dose of cyanide of 50 mg, and therefore does not present a safety concern following long-term storage. C1 [Mohammad, A.; Yang, Y.; Khan, M. A.; Faustino, P. J.] Food & Drug Adm, Ctr Drug Evaluat & Res, Div Prod Qual Res, Silver Spring, MD 20993 USA. RP Faustino, PJ (reprint author), Food & Drug Adm, Ctr Drug Evaluat & Res, Div Prod Qual Res, Life Sci Bldg 64,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM patrick.faustino@fda.hhs.gov FU Food and Drug Administration Office of Counter Terrorism-Medical Counter Measures initiative (MCMi) FX This study was supported in part by a grant from the Food and Drug Administration Office of Counter Terrorism-Medical Counter Measures initiative (MCMi). The authors would also like to again thank HEYL Corporation and REACT/S (Oak Ridge, TN) for supplying Prussian blue active pharmaceutical ingredients and Prussian blue drug products in 2003. NR 11 TC 1 Z9 1 U1 1 U2 27 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1556-3650 EI 1556-9519 J9 CLIN TOXICOL JI Clin. Toxicol. PD FEB PY 2015 VL 53 IS 2 BP 102 EP 107 DI 10.3109/15563650.2014.998337 PG 6 WC Toxicology SC Toxicology GA CB1RR UT WOS:000349406200005 PM 25608705 ER PT J AU Beier, RC Foley, SL Davidson, MK White, DG McDermott, PF Bodeis-Jones, S Zhao, S Andrews, K Crippen, TL Sheffield, CL Poole, TL Anderson, RC Nisbet, DJ AF Beier, R. C. Foley, S. L. Davidson, M. K. White, D. G. McDermott, P. F. Bodeis-Jones, S. Zhao, S. Andrews, K. Crippen, T. L. Sheffield, C. L. Poole, T. L. Anderson, R. C. Nisbet, D. J. TI Characterization of antibiotic and disinfectant susceptibility profiles among Pseudomonas aeruginosa veterinary isolates recovered during 1994-2003 SO JOURNAL OF APPLIED MICROBIOLOGY LA English DT Article DE antibiotics; disinfectants; fluoroquinolone antibiotics; organic acids; Pseudomonas aeruginosa; susceptibility ID PATHOGENICITY ISLAND PAPI-1; GRAM-NEGATIVE BACTERIA; ESCHERICHIA-COLI O157; METABOLITE CIPROFLOXACIN; ANTIMICROBIAL RESISTANCE; STAPHYLOCOCCUS-AUREUS; METHICILLIN-RESISTANT; MICROBIAL-FLORA; OTITIS-MEDIA; DAIRY HERDS AB AimsTo evaluate susceptibility of Pseudomonas aeruginosa veterinary isolates to antibiotics and disinfectants. Methods and ResultsPseudomonas aeruginosa isolates collected from dogs (n=155) and other animals (n=20) from sixteen states during 1994-2003 were tested for susceptibility. Most isolates were resistant to twenty-one antimicrobials tested, and the highest prevalence of resistance was to -lactams (938%) and sulphonamides (935%). Fluoroquinolone resistance did not increase from 1994 to 2003. Ciprofloxacin and enrofloxacin had a 5 and 16% prevalence of resistance, respectively, while sarafloxacin and nalidixic acid had a prevalence of resistance of 97 and 98%, respectively. Strains were pan-resistant to triclosan and chlorhexidine, were highly resistant to benzalkonium chloride and demonstrated high susceptibility to other disinfectants. Didecyldimethylammonium chloride was the most active ammonium chloride. Inducible resistance was observed to cetyl ammonium halides, chlorhexidine and benzyl ammonium chlorides, which formulate disinfectants used in veterinary clinics and dairies. Organic acid inhibition was associated with the dissociated acid species. ConclusionsDissociated organic acids appear able to inhibit Ps.aeruginosa, and rates of fluoroquinolone resistance merit sustained companion animal isolate surveillance. Significance and Impact of the StudyThis is the first report of Ps.aeruginosa susceptibility to 24 disinfectants and illustrates the high resistance of Ps.aeruginosa to both antibiotics and disinfectants. C1 [Beier, R. C.; Andrews, K.; Crippen, T. L.; Sheffield, C. L.; Poole, T. L.; Anderson, R. C.; Nisbet, D. J.] ARS, Southern Plains Agr Res Ctr, USDA, College Stn, TX 77845 USA. [Foley, S. L.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Davidson, M. K.; White, D. G.; McDermott, P. F.; Bodeis-Jones, S.; Zhao, S.] US FDA, Res Off, Ctr Vet Med, Laurel, MD USA. RP Beier, RC (reprint author), ARS, Southern Plains Agr Res Ctr, USDA, 2881 F&B Rd, College Stn, TX 77845 USA. EM ross.beier@yahoo.com RI Grams, Michael/G-5197-2011 FU USDA, Agricultural Research Service FX The Authors thank Amir Karimloo and Seth Penny for technical support. This work was funded by the USDA, Agricultural Research Service. Mention of trade names, proprietary products or specific equipment is solely for the purpose of providing specific information and does not constitute a guarantee, warranty or endorsement by the U.S. Department of Agriculture or by the U.S. Food and Drug Administration and does not imply its approval to the exclusion of other products that may be suitable. Additionally, the views expressed in this article are those of the authors and do not necessarily reflect the official policy of the Department of Health and Human Services, the U.S. Food and Drug Administration or the U.S. Government. NR 86 TC 4 Z9 4 U1 6 U2 23 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 FEB PY 2015 VL 118 IS 2 BP 326 EP 342 DI 10.1111/jam.12707 PG 17 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA CA4DM UT WOS:000348854500007 PM 25431276 ER PT J AU Badano, A Revie, C Casertano, A Cheng, WC Green, P Kimpe, T Krupinski, E Sisson, C Skrovseth, S Treanor, D Boynton, P Clunie, D Flynn, MJ Heki, T Hewitt, S Homma, H Masia, A Matsui, T Nagy, B Nishibori, M Penczek, J Schopf, T Yagi, Y Yokoi, H AF Badano, Aldo Revie, Craig Casertano, Andrew Cheng, Wei-Chung Green, Phil Kimpe, Tom Krupinski, Elizabeth Sisson, Christye Skrovseth, Stein Treanor, Darren Boynton, Paul Clunie, David Flynn, Michael J. Heki, Tatsuo Hewitt, Stephen Homma, Hiroyuki Masia, Andy Matsui, Takashi Nagy, Balazs Nishibori, Masahiro Penczek, John Schopf, Thomas Yagi, Yukako Yokoi, Hideto TI Consistency and Standardization of Color in Medical Imaging: a Consensus Report SO JOURNAL OF DIGITAL IMAGING LA English DT Article DE Color imaging; Medical imaging; Color calibration; Color management ID PERFORMANCE; LESIONS; IMAGES; CAMERA AB This article summarizes the consensus reached at the Summit on Color in Medical Imaging held at the Food and Drug Administration (FDA) on May 8-9, 2013, co-sponsored by the FDA and ICC (International Color Consortium). The purpose of the meeting was to gather information on how color is currently handled by medical imaging systems to identify areas where there is a need for improvement, to define objective requirements, and to facilitate consensus development of best practices. Participants were asked to identify areas of concern and unmet needs. This summary documents the topics that were discussed at the meeting and recommendations that were made by the participants. Key areas identified where improvements in color would provide immediate tangible benefits were those of digital microscopy, telemedicine, medical photography (particularly ophthalmic and dental photography), and display calibration. Work in these and other related areas has been started within several professional groups, including the creation of the ICC Medical Imaging Working Group. C1 [Badano, Aldo; Cheng, Wei-Chung] US FDA, Div Imaging & Appl Math, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Revie, Craig] FFEI Ltd, London, England. [Revie, Craig] Int Color Consortium, London, England. [Casertano, Andrew] SAN Business Consultants LLP, New York, NY USA. [Green, Phil] Gjovik Univ Coll, Tromso, Norway. [Kimpe, Tom] Barco NV, Healthcare Div, Brussels, Belgium. [Krupinski, Elizabeth] Univ Arizona, Dept Med Imaging, Tucson, AZ USA. [Krupinski, Elizabeth] Univ Arizona, Arizona Telemed Program, Tucson, AZ USA. [Sisson, Christye] Rochester Inst Technol, Sch Photog Arts & Sci, Rochester, NY 14623 USA. [Skrovseth, Stein] Univ Hosp North Norway, Norwegian Ctr Integrated Care & Telemed, Tromso, Norway. [Treanor, Darren] Leeds Teaching Hosp NHS Trust, London, England. [Treanor, Darren] Univ Leeds, London, England. [Boynton, Paul] NIST, Gaithersburg, MD 20899 USA. [Clunie, David] PixelMed Publishing, Philadelphia, PA USA. [Flynn, Michael J.] Henry Ford Hlth Syst, New York, NY USA. [Heki, Tatsuo] Fujifilm Corp, Healthcare Business Dev Off, Tokyo, Japan. [Hewitt, Stephen] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Homma, Hiroyuki] Olympus Med Syst Corp, Tokyo, Japan. [Masia, Andy] X Rite, Boston, MA USA. [Matsui, Takashi] Eizo Corp, Tokyo, Japan. [Nagy, Balazs] Inst Psychol, Dept Expt Psychol, Sao Paulo, Brazil. [Nishibori, Masahiro] Int Univ Hlth & Welf, Dept Social Serv & Healthcare Management, Tokyo, Japan. [Penczek, John] NIST, Boulder, CO USA. [Penczek, John] Univ Colorado, Boulder, CO 80309 USA. [Schopf, Thomas] Univ Hosp North Norway, Norwegian Ctr Integrated Care & Telemed, Tromso, Norway. [Yokoi, Hideto] Kagawa Univ Hosp, Dept Med Informat, Tokyo, Japan. [Yagi, Yukako] Harvard Univ, Sch Med, Boston, MA USA. [Yagi, Yukako] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nagy, Balazs] Budapest Univ Technol & Econ, Ctr Neurosci & Behav, Budapest, Hungary. [Nagy, Balazs] Budapest Univ Technol & Econ, Dept Mechatron Opt & Engn Informat, Budapest, Hungary. RP Badano, A (reprint author), US FDA, Div Imaging & Appl Math, Ctr Devices & Radiol Hlth, 10993 New Hampshire Ave, Silver Spring, MD 20993 USA. EM aldo.badano@fda.hhs.gov RI NAGY, Balazs Vince/K-6546-2015; Clunie, David/Q-2777-2015; OI NAGY, Balazs Vince/0000-0002-8489-7200; Clunie, David/0000-0002-2406-1145; Skrovseth, Stein Olav/0000-0003-3568-867X; Hewitt, Stephen/0000-0001-8283-1788; badano, aldo/0000-0003-3712-6670 FU Research Council of Norway [174,934] FX SS and TS were funded by the Research Council of Norway grant no. 174,934, Tromso Telemedicine Laboratory. 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. NR 30 TC 11 Z9 11 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0897-1889 EI 1618-727X J9 J DIGIT IMAGING JI J. Digit. Imaging PD FEB PY 2015 VL 28 IS 1 BP 41 EP 52 DI 10.1007/s10278-014-9721-0 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AZ7KO UT WOS:000348398200007 PM 25005868 ER PT J AU Atwill, ER Chase, JA Oryang, D Bond, RF Koike, ST Cahn, MD Anderson, M Mokhtari, A Dennis, S AF Atwill, Edward R. Chase, Jennifer A. Oryang, David Bond, Ronald F. Koike, Steven T. Cahn, Michael D. Anderson, Maren Mokhtari, Amirhossein Dennis, Sherri TI Transfer of Escherichia coli O157:H7 from Simulated Wildlife Scat onto Romaine Lettuce during Foliar Irrigation SO JOURNAL OF FOOD PROTECTION LA English DT Article ID FRESH PRODUCE; WATER; SOIL; O157/H7; CONTAMINATION; PERSISTENCE; CALIFORNIA; SURVIVAL; O157-H7; FIELDS AB A field trial in Salinas Valley, California, was conducted during July 2011 to quantify the microbial load that transfers from wildlife feces onto nearby lettuce during foliar irrigation. Romaine lettuce was grown using standard commercial practices and irrigated using an impact sprinkler design. Five grams of rabbit feces was spiked with 1.29 x 10(8) CFU of Escherichia coli O157:H7 and placed -3, -2, and -1 days and immediately before a 2-h irrigation event. Immediately after irrigation, 168 heads of lettuce ranging from ca. 23 to 69 cm (from 9 to 27 in.) from the fecal deposits were collected, and the concentration of E. coli O157:H7 was determined. Thirty-eight percent of the collected lettuce heads had detectable E. coli O157:H7, ranging from 1 MPN to 2.30 x 10(5) MPN per head and a mean concentration of 7.37 x 10(3) MPN per head. Based on this weighted arithmetic mean concentration of 7.37 x 10(3) MPN of bacteria per positive head, only 0.00573% of the, original 5 g of scat with its mean load of 1.29 x 10(8) CFU was transferred to the positive heads of lettuce. Bacterial contamination was limited to the outer leaves of lettuce. In addition, factors associated with the transfer of E. coli O157:H7 from scat to lettuce were distance between the scat and lettuce, age of scat before irrigation, and mean distance between scat and the irrigation sprinkler heads. This study quantified the transfer coefficient between scat and adjacent heads of lettuce as a function of irrigation. The data can be used to populate a quantitative produce risk assessment model for E. coli O157:H7 in romaine lettuce to inform risk management and food safety policies. C1 [Atwill, Edward R.; Chase, Jennifer A.; Bond, Ronald F.] Univ Calif Davis, Western Ctr Food Safety, Davis, CA 95618 USA. [Oryang, David; Dennis, Sherri] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Koike, Steven T.; Cahn, Michael D.] Univ Calif Cooperat Extens Monterey Cty, Salinas, CA 93901 USA. [Anderson, Maren; Mokhtari, Amirhossein] RTI Int, Res Triangle Pk, NC 27709 USA. RP Atwill, ER (reprint author), Univ Calif Davis, Western Ctr Food Safety, 1477 Drew Ave,Suite 101, Davis, CA 95618 USA. EM ratwill@ucdavis.edu FU U.S. Food and Drug Administration [U01-003-572] FX This project was funded by contract U01-003-572 from the U.S. Food and Drug Administration. We thank Dr. Linda Harris and Anne-Laure Moyne for initial project planning and coordination of field logistics. We also thank Kerry Mello at University of California at Davis Center for Laboratory Animal Science (CLAS) for donating all rabbit scat used for this field trial. In addition, laboratory and field assistance was provided by David Ritchie, Stephanie Huang, Tran Nguyen, Elaine Wang, Yingjia Benson, Karissa Huang, Melissa Partyka, Chengling Xiao, Xunde Li, and Tamara Vodovoz. NR 24 TC 3 Z9 3 U1 1 U2 20 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 FEB PY 2015 VL 78 IS 2 BP 240 EP 247 DI 10.4315/0362-028X.JFP-14-277 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA CA6YW UT WOS:000349064800001 PM 25710137 ER PT J AU Costello, RB Saldanha, L Dwyer, J Andrews, K Bailen, R Bailey, R Betz, J Burt, V Chang, F Emenaker, N Gahche, J Hardy, C Pehrsson, P AF Costello, R. B. Saldanha, L. Dwyer, J. Andrews, K. Bailen, R. Bailey, R. Betz, J. Burt, V Chang, F. Emenaker, N. Gahche, J. Hardy, C. Pehrsson, P. TI NEW NATIONAL INSTITUTES OF HEALTH DIETARY SUPPLEMENT LABEL DATABASE CAN AID SEARCH FOR INGREDIENT INFORMATION SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract CT Southern Regional Meeting of the American-Federation-for-Medical-Research CY FEB 26-28, 2015 CL New Orleans, LA SP Amer Federat Med Res C1 [Costello, R. B.; Saldanha, L.; Dwyer, J.; Bailen, R.; Bailey, R.; Betz, J.; Chang, F.; Emenaker, N.] NIH, Bethesda, MD 20892 USA. [Andrews, K.; Pehrsson, P.] USDA, Beltsville, MD 20705 USA. [Burt, V; Gahche, J.] Ctr Dis Control & Prevent, Hyattsville, MD USA. [Hardy, C.] US FDA, College Pk, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD FEB PY 2015 VL 63 IS 2 MA 218 BP 386 EP 386 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA CA0GM UT WOS:000348595000229 ER PT J AU Majdi, JA Minnikanti, S Peixoto, N Agrawal, A Cohen, ED AF Majdi, Joseph A. Minnikanti, Saugandhika Peixoto, Nathalia Agrawal, Anant Cohen, Ethan D. TI Access resistance of stimulation electrodes as a function of electrode proximity to the retina SO JOURNAL OF NEURAL ENGINEERING LA English DT Article DE proximity; electrode; waveform; retina; prosthesis; fluopolymer; impedance spectroscopy ID OPTICAL COHERENCE TOMOGRAPHY; EPIRETINAL PROSTHESES; EYE-MOVEMENTS; IMPEDANCE; RABBIT; BLIND; MODEL; PLACEMENT; INTERFACE; DESIGN AB Objective. Epiretinal prostheses seek to effectively stimulate the retina by positioning electrode arrays close to its surface so current pulses generate narrow retinal electric fields. Our objective was to evaluate the use of the electrical impedance of insulated platinum electrodes as a measure of the proximity of insulated platinum electrodes to the inner surface of the retina. Approach. We examined the impedance of platinum disk electrodes, 0.25 mm in diameter, insulated with two widths (0.8 and 1.6 mm outer diameter) of transparent fluoropolymer in a rabbit retinal eyecup preparation. Optical coherence tomography measured the electrode's proximity to the retinal surface which was correlated with changes in the voltage waveform at the electrode. Electrode impedance changes during retinal deformation were also studied. Main results. When the 1.6 mm diameter insulated electrodes advanced towards the retinal surface from 1000 mu m, their voltage step at current pulse onset increased, reflecting an access resistance increase of 3880 +/- 630 Omega, with the 50% midpoint averaging 30 mu m, while thin 0.8 mm insulated electrode advancement showed an access resistance increase 50% midpoint averaging 16 mu m. Using impedance spectroscopy, electrode-retina proximity differences were seen in the 1.6 mm insulated electrode impedance modulus between 1 and 100 kHz and the waveform phase angle at 0.3-10 kHz, while thin 0.8 mm insulated electrode advancement produced smaller impedance modulus changes with retinal proximity between 3 and 100 kHz. These impedance changes with retinal proximity may reflect different sized zones of eye wall being coupled in series with the insulated platinum electrode. Significance. The proximity of stimulus electrodes to neural tissue in fluid-filled spaces can be estimated from access resistance changes in the stimulus pulse waveform. Because many prosthetic devices allow back telemetry communication of the stimulus electrode waveform, it is possible these series resistance increases observed with retinal proximity could be used as a metric of stimulus electrode placement. C1 [Majdi, Joseph A.; Agrawal, Anant; Cohen, Ethan D.] US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth,White Oak Fed Res Labs, Silver Spring, MD 20993 USA. [Minnikanti, Saugandhika; Peixoto, Nathalia] George Mason Univ, Volgenau Sch Elect Engn, Dept Elect & Comp Engn, Fairfax, VA 22030 USA. RP Majdi, JA (reprint author), US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth,White Oak Fed Res Labs, Rm 1204 Bldg 62, Silver Spring, MD 20993 USA. EM ethan.cohen@fda.hhs.gov FU US Food and Drug Administration: Critical Path Initiative; Oak Ridge Institute for Science and Education FX This work was made possible by a grant from the US Food and Drug Administration: Critical Path Initiative. We thank the George Mason University Engineering Department for use of their Gamry potentiostat, Daniel X Hammer for imaging assistance, and Bruce Fleharty for device fabrication, Victor Krauthamer for editorial assistance and Gene Hilmantel and Rajesh Nair for statistical consultation. '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'. This work was supported by the Oak Ridge Institute for Science and Education. NR 35 TC 0 Z9 0 U1 1 U2 6 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1741-2560 EI 1741-2552 J9 J NEURAL ENG JI J. Neural Eng. PD FEB PY 2015 VL 12 IS 1 AR 016006 DI 10.1088/1741-2560/12/1/016006 PG 14 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA CA2UE UT WOS:000348762500008 PM 25474329 ER PT J AU Mahmood, L Dozier, A Casey, D Dolan, J Korones, D AF Mahmood, Laila Dozier, Ann Casey, Denise Dolan, James Korones, David TI Early Palliative Care Involvement for Children with Cancer SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Meeting Abstract CT Annual Assembly of the American-Academy-of-Hospice-and-Palliative-Medicine and the Hospice-and-Palliative-Nurses-Association CY FEB 25-28, 2015 CL Philadelphia, PA SP Amer Acad Hosp & Palliat Med, Hosp & Palliat Nurses Assoc C1 [Mahmood, Laila] Univ Rochester, Med Ctr, Silver Spring, MD USA. [Dozier, Ann; Dolan, James] Univ Rochester, Rochester, NY USA. [Casey, Denise] US FDA, Bethesda, MD 20014 USA. [Korones, David] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD FEB PY 2015 VL 49 IS 2 MA S763 BP 439 EP 440 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA AZ8PU UT WOS:000348478200221 ER PT J AU Nillius, P Klamra, W Sibczynski, P Sharma, D Danielsson, M Badano, A AF Nillius, Peter Klamra, Wlodek Sibczynski, Pawel Sharma, Diksha Danielsson, Mats Badano, Aldo TI Light output measurements and computational models of microcolumnar CsI scintillators for x-ray imaging SO MEDICAL PHYSICS LA English DT Article DE CsI; scintillator; light transport; light output; blur ID SPATIAL-RESOLUTION; ENERGY RESOLUTION; PERFORMANCE; SYSTEMS; YIELD AB Purpose: The authors report on measurements of light output and spatial resolution of microcolumnar CsI:Tl scintillator detectors for x-ray imaging. In addition, the authors discuss the results of simulations aimed at analyzing the results of synchrotron and sealed-source exposures with respect to the contributions of light transport to the total light output. Methods: The authors measured light output from a 490-mu m CsI:Tl scintillator screen using two setups. First, the authors used a photomultiplier tube (PMT) to measure the response of the scintillator to sealed-source exposures. Second, the authors performed imaging experiments with a 27-keV monoenergetic synchrotron beam and a slit to calculate the total signal generated in terms of optical photons per keV. The results of both methods are compared to simulations obtained with hybrid MANTIS, a coupled x-ray, electron, and optical photon Monte Carlo transport package. The authors report line response (LR) and light output for a range of linear absorption coefficients and describe a model that fits at the same time the light output and the blur measurements. Comparing the experimental results with the simulations, the authors obtained an estimate of the absorption coefficient for the model that provides good agreement with the experimentally measured LR. Finally, the authors report light output simulation results and their dependence on scintillator thickness and reflectivity of the backing surface. Results: The slit images from the synchrotron were analyzed to obtain a total light output of 48 keV(-1) while measurements using the fast PMT instrument setup and sealed-sources reported a light output of 28 keV-1. The authors attribute the difference in light output estimates between the two methods to the difference in time constants between the camera and PMT measurements. Simulation structures were designed to match the light output measured with the camera while providing good agreement with the measured LR resulting in a bulk absorption coefficient of 5x10(-5) mu m(-1). Conclusions: The combination of experimental measurements for microcolumnar CsI:Tl scintillators using sealed-sources and synchrotron exposures with results obtained via simulation suggests that the time course of the emission might play a role in experimental estimates. The procedure yielded an experimentally derived linear absorption coefficient for microcolumnar Cs:Tl of 5x10(-5) mu m(-1). To the author's knowledge, this is the first time this parameter has been validated against experimental observations. The measurements also offer insight into the relative role of optical transport on the effective optical yield of the scintillator with microcolumnar structure. (C) 2015 American Association of Physicists in Medicine. C1 [Nillius, Peter; Klamra, Wlodek; Danielsson, Mats] Royal Inst Technol KTH, SE-10044 Stockholm, Sweden. [Sibczynski, Pawel] Natl Ctr Nucl Res, PL-05400 Otwock, Poland. [Sharma, Diksha; Badano, Aldo] US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Nillius, P (reprint author), Royal Inst Technol KTH, SE-10044 Stockholm, Sweden. EM nillius@mi.physics.kth.se OI badano, aldo/0000-0003-3712-6670 NR 16 TC 3 Z9 3 U1 0 U2 10 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD FEB PY 2015 VL 42 IS 2 BP 600 EP 605 DI 10.1118/1.4905096 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CA9GJ UT WOS:000349229600008 PM 25771557 ER PT J AU Alekel, DL Genschel, U Koehler, KJ Hofmann, H Van Loan, MD Beer, BS Hanson, LN Peterson, CT Kurzer, MS AF Alekel, D. Lee Genschel, Ulrike Koehler, Kenneth J. Hofmann, Heike Van Loan, Marta D. Beer, Bonnie S. Hanson, Laura N. Peterson, Charles T. Kurzer, Mindy S. TI Soy Isoflavones for Reducing Bone Loss Study: effects of a 3-year trial on hormones, adverse events, and endometrial thickness in postmenopausal women SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE Soy isoflavone supplements; Safety; Transvaginal ultrasound; 17 beta-Estradiol; Estrone sulfate; Thyroid-stimulating hormone ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; MENOPAUSAL SYMPTOMS; ALCOHOL-CONSUMPTION; PROTEIN ISOLATE; CANCER-RISK; HOT FLUSHES; US ADULTS; BREAST; NUTRITION AB Objective: This study aims to assess the overall safety and potential endometrium-stimulating effects of soy isoflavone tablets consumed (3 y) by postmenopausal women and to determine endometrial thickness response to treatment among compliant women, taking into account hormone concentrations and other hypothesized modifying factors. Methods: We randomized healthy postmenopausal women (aged 45.8-65.0 y) to placebo control or two doses (80 or 120 mg/d) of soy isoflavones at two sites. We used intent-to-treat analysis (N = 224) and compliant analysis (>95%; N = 208) to assess circulating hormone concentrations, adverse events, and endometrial thickness (via transvaginal ultrasound). Results: Median values for endometrial thickness (mm) declined from baseline through 36 months. Nonparametric analysis of variance for treatment differences among groups showed no differences in absolute (or percentage of change) endometrial thickness (chi(2) P ranged from 0.12 to 0.69) or in circulating hormones at any time point. A greater number of adverse events in the genitourinary system (P = 0.005) were noted in the 80 mg/day group compared with the 120 mg/day group, whereas other systems showed no treatment effects. The model predicting endometrial thickness response (using natural logarithm) to treatment among compliant women across time points was significant (P <= 0.0001), indicating that estrogen exposure (P = 0.0013), plasma 17 beta-estradiol (P = 0.0086), and alcohol intake (P = 0.023) contributed significantly to the response. Neither the 80 mg/day dose (P = 0.57) nor the 120 mg/day dose (P = 0.43) exerted an effect on endometrial thickness across time. Conclusions: Our randomized controlled trial verifies the long-term overall safety of soy isoflavone tablet intake by postmenopausal women who display excellent compliance. We find no evidence of treatment effects on endometrial thickness, adverse events, or circulating hormone concentrations, most notably thyroid function, across a 3-year period. C1 [Alekel, D. Lee] NIH, Bethesda, MD 20892 USA. [Genschel, Ulrike; Koehler, Kenneth J.; Hofmann, Heike] Iowa State Univ, Dept Stat, Ames, IA USA. [Van Loan, Marta D.] Univ Calif Davis, USDA, ARS, Western Human Nutr Res Ctr, Davis, CA 95616 USA. [Beer, Bonnie S.] McFarland Clin, Ames, IA USA. [Hanson, Laura N.] Mayo Validat Support Serv, Rochester, MN USA. [Peterson, Charles T.] US FDA, Ctr Devices & Radiol Hlth, White Oak, MD USA. [Kurzer, Mindy S.] Univ Minnesota, Dept Food Sci & Nutr, St Paul, MN USA. RP Alekel, DL (reprint author), NIH, Natl Ctr Complementary & Alternat Med, Suite 401,6707 Democracy Blvd 2, Bethesda, MD 20892 USA. EM Lee.Alekel@nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases [RO1 AR046922]; Nutrition and Wellness Research Center at Iowa State University; US Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center [5306-51530-006-00D]; Clinical and Translational Science Center, Clinical Research Center, University of California [1M01RR19975-01]; National Center for Medical Research [UL1 RR024146] FX Funding/support: This work was supported mainly by a grant (RO1 AR046922) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and was also supported by the Nutrition and Wellness Research Center at Iowa State University; US Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center (5306-51530-006-00D); Clinical and Translational Science Center, Clinical Research Center, University of California (1M01RR19975-01); and National Center for Medical Research (UL1 RR024146). NR 31 TC 14 Z9 14 U1 3 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD FEB PY 2015 VL 22 IS 2 BP 185 EP 197 DI 10.1097/gme.0000000000000280 PG 13 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CA2UY UT WOS:000348764600011 PM 25003624 ER PT J AU Lanzarotta, A AF Lanzarotta, Adam TI Approximating the Detection Limit of an Infrared Spectroscopic Imaging Microscope Operating in an Attenuated Total Reflection (ATR) Modality: Theoretical and Empirical Results for an Instrument Using a Linear Array Detector and a 1.5 Millimeter Germanium Hemisphere Internal Reflection Element SO APPLIED SPECTROSCOPY LA English DT Article DE Detection limit; Infrared; Attenuated total reflection; AIR; Imaging ID PHARMACEUTICAL FORMULATIONS; MAPPING MICROSPECTROSCOPY; SPECTROMETER; CRITERIA AB Theoretical and empirical detection limits have been estimated for aripiprazole (analyte) in alpha lactose monohydrate (matrix model pharmaceutical formulation) using a micro-attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopic imaging instrument equipped with a linear array detector and a 1.5 mm germanium hemisphere internal reflection element (IRE). The instrument yielded a theoretical detection limit of 0.0035% (35 parts per million (ppm)) when operating under diffraction-limited conditions, which was 49 times lower than what was achieved with a traditional macro-AIR instrument operating under practical conditions (0.17%, 1700 ppm). However, these results may not be achievable for most analyses because the detection limits will be particle size limited, rather than diffraction limited, for mixtures with average particle diameters greater than 8.3 mu m (most pharmaceutical samples). For example, a theoretical detection limit of 0.028% (280 ppm) was calculated for an experiment operating under particle size-limited conditions where the average particle size was 23.4 mu m. These conditions yielded a detection limit of 0.022% (220 ppm) when measured empirically, which was close to the theoretical value and only eight times lower than that of a faster, more simplistic macro-ATR instrument. Considering the longer data acquisition and processing times characteristic of the micro-ATR imaging approach (minutes or even hours versus seconds), the cost benefit ratio may not often be favorable for the analysis of analytes in matrices that exhibit only a few overlapping absorptions (low-interfering matrices such as alpha lactose monohydrate) using this technique compared to what can be achieved using macro-ATR. However, the advantage was significant for detecting analytes in more complex matrices (those that exhibited several overlapping absorptions with the analyte) because the detection limit of the macro-ATR approach was highly formulation dependent while that of the micro-AIR imaging technique was not. As a result, the micro-ATR imaging technique is expected to be more valuable than macro-ATR for detecting analytes in high-interfering matrices and in products with unknown ingredients (e.g., illicit tablets, counterfeit tablets, and unknown powders). C1 US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. RP Lanzarotta, A (reprint author), US FDA, Forens Chem Ctr, 6751 Steger Dr, Cincinnati, OH 45237 USA. EM Adam.Lanzarotta@fda.hhs.gov NR 43 TC 3 Z9 3 U1 0 U2 5 PU SOC APPLIED SPECTROSCOPY PI FREDERICK PA 5320 SPECTRUM DRIVE SUITE C, FREDERICK, MD 21703 USA SN 0003-7028 EI 1943-3530 J9 APPL SPECTROSC JI Appl. Spectrosc. PD FEB PY 2015 VL 69 IS 2 BP 205 EP 214 DI 10.1366/14-07538 PG 10 WC Instruments & Instrumentation; Spectroscopy SC Instruments & Instrumentation; Spectroscopy GA CA1TF UT WOS:000348693600003 PM 25588210 ER PT J AU Torosyan, Y Kurtz, SM Mihalko, WM Marinac-Dabic, D Rimnac, CM AF Torosyan, Yelizaveta Kurtz, Steven M. Mihalko, William M. Marinac-Dabic, Danica Rimnac, Clare M. TI Editorial: Arthroplasty Devices: Registries and Beyond SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Editorial Material C1 [Torosyan, Yelizaveta; Marinac-Dabic, Danica] US FDA, Div Epidemiol, Off Surveillance & Biometr, CDRH, Silver Spring, MD USA. [Kurtz, Steven M.] Drexel Univ, Implant Res Ctr, Philadelphia, PA 19104 USA. [Mihalko, William M.] Univ Tennessee, Campbell Clin, Dept Orthopaed Surg & Biomed Engn, Memphis, TN USA. [Rimnac, Clare M.] Case Western Reserve Univ, Case Sch Engn, Cleveland, OH 44106 USA. [Rimnac, Clare M.] Clin Orthopaed & Related Res, Philadelphia, PA 19103 USA. RP Rimnac, CM (reprint author), Clin Orthopaed & Related Res, Philadelphia, PA 19103 USA. EM crimnac@clinOrthop.org OI Mihalko, William/0000-0002-6229-1515 NR 9 TC 0 Z9 0 U1 0 U2 1 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 FEB PY 2015 VL 473 IS 2 BP 403 EP 405 DI 10.1007/s11999-014-4061-4 PG 3 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AZ6QY UT WOS:000348344900001 PM 25421957 ER PT J AU Gupta, A Chidambaram, N Khan, MA AF Gupta, Abhay Chidambaram, Nallaperumal Khan, Mansoor A. TI An index for evaluating difficulty of Chewing Index for chewable tablets SO DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY LA English DT Article DE Adverse events; chewable tablets; simulated salivary fluid; tablet breaking force; tablet hardness; tablet quality ID DIAMETRAL-COMPRESSION; TENSILE-STRENGTH; SALIVA AB Chewing difficulty index, a potential measure of difficulty in chewing the chewable tablets, has been described herein as the product of tablet thickness and tablet hardness measured under the diametral loading. The proposed index was evaluated by measuring the dimensions and mechanical strength of commercial and in-house prepared chewable tablets. Data collected on tablets with different thickness but same hardness or tensile strength suggests that the proposed index provides a good assessment of the force needed to chew the chewable tablets. Influence of brief exposure to salivary fluid during chewing on the mechanical strength of the chewable tablets was also evaluated. Thirty seconds exposure to the simulated salivary fluid was also found to significantly reduce (p < 0.05) the hardness and the chewing difficulty index of a number of evaluated chewable tablet drug products. C1 [Gupta, Abhay; Khan, Mansoor A.] US FDA, Ctr Drug Evaluat & Res, Div Prod Qual Res, Silver Spring, MD 20993 USA. [Chidambaram, Nallaperumal] US FDA, Ctr Drug Evaluat & Res, Off New Drug Qual Assessment, Silver Spring, MD 20993 USA. RP Gupta, A (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Prod Qual Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM abhay.gupta@fda.hhs.gov NR 13 TC 0 Z9 0 U1 1 U2 4 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 FEB PY 2015 VL 41 IS 2 BP 239 EP 243 DI 10.3109/03639045.2013.858736 PG 5 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA5BT UT WOS:000348923200010 PM 24252107 ER PT J AU Clotilde, LM Salvador, A Bernard, C Lin, A Lauzon, C Muldoon, M Xu, YC Carter, JM AF Clotilde, Laurie M. Salvador, Alexandra Bernard, Clay Lin, Andrew Lauzon, Carol Muldoon, Mark Xu, Yichun Carter, John Mark TI Comparison of Multiplex Immunochemical and Molecular Serotyping Methods for Shiga Toxin-Producing Escherichia coli SO Foodborne Pathogens and Disease LA English DT Article ID BEEF CARCASSES; UNITED-STATES; PREVALENCE; CATTLE AB Traditionally, serotyping of Escherichia coli has been performed via slide agglutination methods using antisera. More recently, multiplex immunoassays and "molecular serotyping" via polymerase chain reaction (PCR) have been validated for this purpose. In this study, the serogroups of 161 Shiga toxin-producing Escherichia coli (STEC) strains isolated from fecal samples of California cattle were typed by conventional methods using antisera as well as two newly developed multiplex PCR- and antibody-based microbead assays using the Luminex technology. Using the Luminex assays, we were capable of serotyping 11 STEC isolates that were previously determined untypeable for the O antigen by conventional methods using antisera. Except for 14 isolates, results from the 2 Luminex assays agreed. C1 [Clotilde, Laurie M.] MagArray, Milpitas, CA USA. [Salvador, Alexandra; Lauzon, Carol] Calif State Univ Hayward, Dept Biol Sci, Hayward, CA 94542 USA. [Salvador, Alexandra; Bernard, Clay; Carter, John Mark] ARS, USDA, Albany, CA USA. [Lin, Andrew] US FDA, Alameda, CA USA. [Muldoon, Mark] Romer Labs Technol Inc, Newark, DE USA. [Xu, Yichun] SDIX, Newark, DE USA. RP Carter, JM (reprint author), ARS, USDA, 800 Buchanan St, Albany, CA 94710 USA. EM j.mark.carter@usda.ars.gov RI Carter, John Mark/K-2485-2015 OI Carter, John Mark/0000-0001-8251-4168 FU FDA Commissioner's Fellow Program; San Francisco District Laboratory; USDA FX The authors would like to thank FDA Commissioner's Fellow Program and San Francisco District Laboratory for supporting this research. USDA funding was administrated through the Agricultural Research Service, National Program 108 Food Safety. NR 20 TC 2 Z9 2 U1 1 U2 2 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 FEB 1 PY 2015 VL 12 IS 2 BP 118 EP 121 DI 10.1089/fpd.2014.1827 PG 4 WC Food Science & Technology SC Food Science & Technology GA CA6GI UT WOS:000349008100004 PM 25646966 ER PT J AU Tillman, GE Simmons, M Wasilenko, JL Narang, N Cray, WC Bodeis-Jones, S Martin, G Gaines, S Seal, BS AF Tillman, G. E. Simmons, M. Wasilenko, J. L. Narang, N. Cray, W. C. Bodeis-Jones, S. Martin, G. Gaines, S. Seal, B. S. TI Development of a Real-Time PCR for Escherichia coli based on gadE, an acid response regulatory gene SO LETTERS IN APPLIED MICROBIOLOGY LA English DT Article DE acid resistance; E; coli; gadE; Non-O157 STEC; real-time PCR ID GROUND-BEEF; EVOLUTIONARY GENETICS; SHIGELLA-SONNEI; RESISTANCE; STRAINS; WATER; YHIE; STX2 AB Increasingly, molecular methods have become important in identification and confirmation of bacteria at the species level. Rapid molecular methods provide sensitivity and specificity while reducing cost and resources. The primary goal of this study was to develop a real-time PCR assay for identification of Escherichia coli from an agar plate. GadE (gadE) directly regulates the glutamate-dependent acid response system (GDAR) in E.coli and is responsible for survival of at pH 2. Based on gene sequence data, a real-time PCR assay targeting gadE was developed for this purpose. Seventy bacterial isolates recovered from ground beef enrichments and 714 isolates from caecal contents were identified biochemically and tested with the real-time PCR assay developed in this study. The PCR assay and the biochemical identification had 100% agreement on the tested isolates. The gadE real-time PCR assay was demonstrated in this study to be an inexpensive, reliable method for confirming E.coli colonies within 15h from an agar plate, thereby saving on final identification time. Significance and Impact of the StudyThere is always a need for rapid, inexpensive tests to identify bacterial cultures of public health concern at the species level. Recently, the numbers of tests performed to identify a culture as Escherichia coli have increased as regulations on pathogenic E.coli have increased as well as interest in the antibiotic resistance patterns of these organisms. The real-time PCR assay developed in this study provides a rapid, cost-effective way to identify E.coli from an agar plate without biochemical identification. This has importance for public health agencies in terms of analyst time and resource utilization. C1 [Tillman, G. E.; Simmons, M.; Wasilenko, J. L.; Narang, N.; Cray, W. C.] US Food Safety & Inspect Serv, USDA, Eastern Lab, Outbreaks Sect, Athens, GA USA. [Bodeis-Jones, S.; Martin, G.; Gaines, S.] US FDA, Ctr Vet Med, Res Off, Laurel, MD USA. [Seal, B. S.] ARS, USDA, Poultry Microbiol Safety Res Unit, Athens, GA USA. RP Tillman, GE (reprint author), USDA FSIS OPHS Eastern Lab, 950 Coll Stn Rd, Athens, GA 30605 USA. EM glenn.tillman@fsis.usda.gov NR 30 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0266-8254 EI 1472-765X J9 LETT APPL MICROBIOL JI Lett. Appl. Microbiol. PD FEB PY 2015 VL 60 IS 2 BP 196 EP 202 DI 10.1111/lam.12359 PG 7 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA CA2HA UT WOS:000348728200014 PM 25384850 ER PT J AU Gaddini, GW Grant, KA Woodall, A Stull, C Maddalozzo, GF Zhang, B Turner, RT Iwaniec, UT AF Gaddini, Gino W. Grant, Kathleen A. Woodall, Andrew Stull, Cara Maddalozzo, Gianni F. Zhang, Bo Turner, Russell T. Iwaniec, Urszula T. TI Twelve months of voluntary heavy alcohol consumption in male rhesus macaques suppresses intracortical bone remodeling SO BONE LA English DT Article DE Haversian remodeling; Histomorphometry; Microcomputed tomography; Ethanol; Non-human primate ID ADULT MALE RATS; MINERAL METABOLISM; CHRONIC-PANCREATITIS; MICRODAMAGE ACCUMULATION; BIOCHEMICAL MARKERS; SERUM OSTEOCALCIN; BODY-COMPOSITION; LIVER-DISEASE; CORTICAL BONE; HIP FRACTURE AB Chronic heavy alcohol consumption is a risk factor for cortical bone fractures in males. The increase in fracture risk may be due, in part, to reduced bone quality. Intracortical (osteonal) bone remodeling is the principle mechanism for maintaining cortical bone quality. However, it is not clear how alcohol abuse impacts intracortical bone remodeling. This study investigated the effects of long-duration heavy alcohol consumption on intracortical bone remodeling in a non-human primate model. Following a 4-month induction period, male rhesus macaques (Macaca mulatta, n = 21) were allowed to voluntarily self-administer water or alcohol (4% ethanol w/v) for 22 h/d, 7 d/wk for 12 months. Control monkeys (n = 13) received water and an isocaloric maltose-dextrin solution. Tetracycline hydrochloride was administered orally 17 and 3 days prior to sacrifice for determination of active mineralization sites. Animals in the alcohol group consumed 2.7 +/- 0.2 g alcohol/kg/d (mean +/- SE) during the 12 months of self-administration, resulting in a mean daily blood alcohol concentration of 77 +/- 9 mg/dl from samples taken at 7 h after the start of a daily session. However, blood alcohol concentration varied widely from day to day, with peak levels exceeding 250 mg/dl, modeling a binge-drinking pattern of alcohol consumption. The skeletal response to alcohol was determined by densitometry, microcomputed tomography and histomorphometry. Significant differences in tibial bone mineral content, bone mineral density, and cortical bone architecture (cross-sectional volume, cortical volume, marrow volume, cortical thickness, and polar moment of inertia) in the tibial diaphysis were not detected with treatment. However, cortical porosity was lower (1.8 +/- 0.5% versus 0.6 +/- 0.1 %, p = 0.021) and labeled osteon density was lower (0.41 +/- 0.2/mm(2) versus 0.04 +/- 0.01/mm(2), p < 0.003) in alcohol-consuming monkeys compared to controls, indicating a reduced rate of intracortical bone remodeling. In concordance, plasma CTx was lower (2.5 +/- 0.3 ng/ml versus 1.7 +/- 0.1 ng/ml, p = 0.028) in the alcohol group. These results suggest that chronic heavy alcohol consumption may negatively impact bone health, in part, by suppressing intracortical bone remodeling. (C) 2014 Elsevier Inc. All rights reserved. C1 [Gaddini, Gino W.; Maddalozzo, Gianni F.; Turner, Russell T.; Iwaniec, Urszula T.] Oregon State Univ, Coll Publ Hlth & Human Sci, Skeletal Biol Lab, Sch Biol & Populat Hlth Sci, Corvallis, OR 97331 USA. [Grant, Kathleen A.; Woodall, Andrew; Stull, Cara] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Neurosci, Beaverton, OR 97006 USA. [Zhang, Bo] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Turner, Russell T.; Iwaniec, Urszula T.] Oregon State Univ, Ctr Hlth Aging Res, Corvallis, OR 97331 USA. RP Iwaniec, UT (reprint author), Oregon State Univ, Coll Publ Hlth & Human Sci, Skeletal Biol Lab, Corvallis, OR 97331 USA. EM urszula.iwaniec@oregonstate.edu FU NIH [AA022454, AA109431, AA13510, OD11092] FX We thank Teresa L. Johnson for editorial assistance. This work was supported by NIH grants AA022454 (to UTI) and AA109431, AA13510, and OD11092 (to KAG). NR 73 TC 2 Z9 2 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD FEB PY 2015 VL 71 BP 227 EP 236 DI 10.1016/j.bone.2014.10.025 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AY7XU UT WOS:000347770000029 PM 25451322 ER PT J AU Shah, R Farris, S De Jager, LS Begley, TH AF Shah, Romina Farris, Samantha De Jager, Lowri S. Begley, Timothy H. TI A novel method for the simultaneous determination of 14 sweeteners of regulatory interest using UHPLC-MS/MS SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE UHPLC-MS/MS; non-nutritive sweeteners; challenging target analytes; foods ID HIGH-INTENSITY SWEETENERS; ARTIFICIAL SWEETENERS; LIQUID-CHROMATOGRAPHY; NONNUTRITIVE SWEETENERS; MASS-SPECTROMETRY; FOODS AB An improved, efficient, sensitive method for the determination of 14 non-nutritive sweeteners in food products was developed using electrospray ionisation (ESI) ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) in the negative-ion mode. Fourteen sweeteners and three internal standards were separated on a reversed-phase UHPLC column using a simple gradient programme. Analyte quantitation and confirmation were performed with data collection in multiple reaction monitoring (MRM) mode. Limits of detection (LODs) were determined in a representative drink, candy and yogurt sample and ranged from 0.1 to 1.8ngml(-1) (drinks) and from 0.1 to 2.5ngg(-1) (candy and yogurt). Repeatability at the limit of quantitation (LOQ) ranged from 1% to 13% relative standard deviation (RSD). Twenty-seven commercially available food products were tested using the optimised method showing that the majority of products contained sweetener concentrations below their assigned maximum usable dose. Recovery studies were performed and accuracy data are presented. C1 [Shah, Romina; Farris, Samantha; De Jager, Lowri S.; Begley, Timothy H.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Shah, R (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. EM romina.shah@fda.hhs.gov NR 19 TC 0 Z9 0 U1 3 U2 23 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PD FEB 1 PY 2015 VL 32 IS 2 BP 141 EP 151 DI 10.1080/19440049.2014.994111 PG 11 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA CA1FN UT WOS:000348658300002 PM 25482127 ER PT J AU Neal-Kluever, A Cooper, J Zebovitz, TC Butts, KM AF Neal-Kluever, April Cooper, Jessica Zebovitz, Thomas C. Butts, Kyla M. TI Ten-year retrospective assessment of the performance of the Food Contact Notification (FCN) programme SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE regulatory toxicology; regulatory chemistry; safety assessment; health policy; food contact AB The Food Contact Notification (FCN) programme was authorised by the US Food and Drug Administration (USFDA) Modernization Act of 1997. Manufacturers may file FCNs for food contact substances (FCSs) not already authorised or pre-sanctioned by the USFDA by demonstrating a reasonable certainty of no harm for their intended uses. The Division of Food Contact Notifications (DFCN) 10-year Retrospective Assessment Group was formed to collect and develop metrics associated with the first decade of the FCN Programme and determine the extent selected aspects of the review process contributed to the effective FCN. Comparative analysis of 924 FCNs revealed that 76% become effective, 23% were withdrawn and 1% received a not accepted status. The focus of the Group was to identify factors impacting the likelihood of an FCN becoming effective. C1 [Neal-Kluever, April; Cooper, Jessica; Zebovitz, Thomas C.] US FDA, Ctr Food Safety & Appl Nutr, Div Food Contact Notificat, College Pk, MD USA. [Butts, Kyla M.] ORISE, Oak Ridge, TN USA. RP Neal-Kluever, A (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Food Contact Notificat, College Pk, MD USA. EM April.kluever@fda.hhs.gov NR 1 TC 0 Z9 0 U1 0 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PD FEB 1 PY 2015 VL 32 IS 2 BP 261 EP 270 DI 10.1080/19440049.2014.994112 PG 10 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA CA1FN UT WOS:000348658300014 PM 25529924 ER PT J AU Boekhoudt, GH McGrath, AG Swisher, JFA Feldman, GM AF Boekhoudt, Gunther H. McGrath, Anna G. Swisher, Jennifer F. A. Feldman, Gerald M. TI Immune Complexes Suppress IFN-gamma-Induced Responses in Monocytes by Activating Discrete Members of the SRC Kinase Family SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERFERON-GAMMA; MYCOBACTERIAL INFECTION; INDUCED TRANSCRIPTION; ANTIVIRAL DEFENSE; IN-VITRO; RECEPTORS; EXPRESSION; BINDING; GENE; IGG AB The regulation of the innate and the adaptive immune responses are extensively intertwined and tightly regulated. Ag-driven immune responses that are modulated by immune complexes (ICs) are known to inhibit IFN-gamma-dependent MHC class II expression. We have previously demonstrated that ICs dramatically inhibit IFN-gamma-induced activation of human monocytes through the activation of the Fc gamma RI signaling pathway. In the present study we further explore the mechanisms by which ICs regulate IFN-gamma activation of human monocytes. We demonstrate that members of the SRC kinase family (SKF) are key mediators of IFN-gamma pathway suppression: inhibitors of the SKF reverse the ability of ICs to suppress IFN-gamma signaling. Small interfering RNA was used to target specific members of the SKF. The data indicate that SRC and LYN are both required for ICs to elicit their immunosuppressive activity, whereas FYN does not appear to contribute to this function. Similarly, the kinase SYK, though not a member of the SKF, is also demonstrated to be involved in this IC-mediated immunosuppression. Our data suggest a mechanism whereby ICs directly inhibit inflammatory signals by crosslinking Fc gamma RI, resulting in the activation of the specific phosphotyrosine kinases SRC, LYN, and SYK and the concomitant suppression of the IFN-gamma signaling pathway. C1 [Boekhoudt, Gunther H.; McGrath, Anna G.; Swisher, Jennifer F. A.; Feldman, Gerald M.] US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Feldman, GM (reprint author), US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Off Biotechnol Prod,Ctr Drug Evaluat & Res, 10903 New Hampshire Rd,HFD 123, Silver Spring, MD 20993 USA. EM gerald.feldman@fda.hhs.gov NR 34 TC 3 Z9 4 U1 0 U2 1 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 FEB 1 PY 2015 VL 194 IS 3 BP 983 EP 989 DI 10.4049/jimmunol.1401649 PG 7 WC Immunology SC Immunology GA AZ3NK UT WOS:000348134000018 PM 25512601 ER PT J AU Calhoun, WR Akpek, EK Weiblinger, R Ilev, IK AF Calhoun, William R. Akpek, Esen K. Weiblinger, Richard Ilev, Ilko K. TI Evaluation of Broadband Spectral Transmission Characteristics of Fresh and Gamma-Irradiated Corneal Tissues SO CORNEA LA English DT Article DE cornea; transmission; keratoplasty; gamma-irradiated ID WHOLE HUMAN EYES; PENETRATING KERATOPLASTY AB Purpose: The aim of this study was to evaluate the clarity of gamma-irradiated sterile corneal donor lenticules. Methods: Broadband UV, visible, and near-infrared (200-850 nm) light transmission was measured through gamma-irradiated, sterile partial-thickness, and full-thickness donor lenticules and fresh corneal tissues and compared with standard acrylic intraocular lens (IOL) implants using a conventional spectrophotometer technique. Results: All tissues had high light transmission (>= 90%) in the visible and near-infrared regions and very low (<2%) transmission below 290 nm. Differences in light transmission between irradiated and fresh cornea types were observed between 300 and 450 nm, which mirrored differences in light transmission through their respective storage solutions. Light transmission through partial-thickness irradiated donor lenticules was greatest across all wavelengths. All corneal tissues exhibited higher transmission than acrylic IOL implant across all wavelengths. Conclusions: Gamma-irradiated donor lenticules are comparable with fresh corneas regarding light transmission, with both partial-thickness and full-thickness lenticules having greater transmission than standard IOL. We would expect the optical performance of gamma-irradiated donor lenticules to be comparable to fresh cornea if used for lamellar corneal procedures that do not require a viable endothelium. C1 [Calhoun, William R.; Ilev, Ilko K.] US FDA, Opt Therapeut & Med Nanophoton Lab, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Calhoun, William R.] Virginia Commonwealth Univ, Dept Biomed Engn, Richmond, VA USA. [Akpek, Esen K.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Weiblinger, Richard] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Calhoun, WR (reprint author), US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 62, Silver Spring, MD 20993 USA. EM william.calhoun@fda.hhs.gov NR 28 TC 1 Z9 1 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD FEB PY 2015 VL 34 IS 2 BP 228 EP 234 PG 7 WC Ophthalmology SC Ophthalmology GA AY9ZU UT WOS:000347907100018 PM 25522222 ER PT J AU Williams, K Gokulan, K Shelman, D Akiyama, T Khan, A Khare, S AF Williams, Katherine Gokulan, Kuppan Shelman, Diamond Akiyama, Tatsuya Khan, Ashraf Khare, Sangeeta TI Cytotoxic Mechanism of Cytolethal Distending Toxin in Nontyphoidal Salmonella Serovar (Salmonella Javiana) During Macrophage Infection SO DNA AND CELL BIOLOGY LA English DT Article ID ENTERICA SEROTYPE TYPHIMURIUM; CELL-CYCLE PROGRESSION; CAMPYLOBACTER-JEJUNI; TUMOR-CELLS; HOST; AUTOPHAGY; INTERNALIZATION; VIRULENCE; PCR; INDUCTION AB Cytolethal distending toxin B (cdtB) is a conserved virulence factor in Salmonella enterica serovar Typhi. Here we report the presence and functionality of cdtB in some nontyphoidal Salmonella (NTS) serovars, including Salmonella Javiana (cdtB+wt S. Javiana), isolated from imported food. To understand the role of cdtB in NTS serovars, a deletion mutant (cdtB(-)Delta S. Javiana) was constructed. Macrophages were infected with cdtB+wt S. Javiana (wild type), cdtB(-)Delta S. Javiana (mutant), and cdtB-negative NTS serovar (S. Typhimurium). Cytotoxic activity and transcription level of genes involved in cell death (apoptosis, autophagy, and necrosis) were assessed in infected macrophages. The cdtB+wt S. Javiana caused cellular distension as well as high degree of vacuolization and presence of the autophagosome marker LC3 in infected macrophages as compared with cdtB(-)Delta S. Javiana. The mRNA expression of genes involved in the induction of autophagy in response to toxin (Esr1 and Pik3C3) and coregulators of autophagy and apoptosis (Bax and Cyld) were significantly upregulated in cdtB(+)wt S. Javiana-infected macrophages. As autophagy destroys internalized pathogens in addition to the infected cell, it may reduce the spread of infection. C1 [Williams, Katherine; Gokulan, Kuppan; Shelman, Diamond; Akiyama, Tatsuya; Khan, Ashraf; Khare, Sangeeta] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. RP Khare, S (reprint author), US FDA, Natl Ctr Toxicol Res, Div Microbiol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM sangeeta.khare@fda.hhs.gov FU Oak Ridge Institute for Science and Education; FDA Commissioner Fellowship Program FX Ms. Katherine Williams, Ms. Diamond Shelman, and Mr. Tatsuya Akiyama were supported by Oak Ridge Institute for Science and Education. Dr. Kuppan Gokulan was supported by FDA Commissioner Fellowship Program. The authors would like to thank Drs. Carl Cerniglia, Steven Foley, Doug Wagner, and Jyotsnabala Kanungo for their critical review of the article. The authors would like to acknowledge help provided by Dr. Dongryeoul Bae for identification of pltA and pltB genes in cdtB + wt S. Javiana and cdtB- Delta S. Javiana. NR 52 TC 7 Z9 8 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5498 EI 1557-7430 J9 DNA CELL BIOL JI DNA Cell Biol. PD FEB 1 PY 2015 VL 34 IS 2 BP 113 EP 124 DI 10.1089/dna.2014.2602 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity GA AZ9MM UT WOS:000348539000005 PM 25389664 ER PT J AU Allen, CE Schmitt, MP AF Allen, Courtni E. Schmitt, Michael P. TI Utilization of Host Iron Sources by Corynebacterium diphtheriae: Multiple Hemoglobin-Binding Proteins Are Essential for the Use of Iron from the Hemoglobin-Haptoglobin Complex SO JOURNAL OF BACTERIOLOGY LA English DT Article ID STAPHYLOCOCCUS-AUREUS; HEME-IRON; NEISSERIA-MENINGITIDIS; HAEMOPHILUS-INFLUENZAE; TRANSPORT-SYSTEM; VIBRIO-CHOLERAE; IDENTIFICATION; ACQUISITION; SIDEROPHORE; RECEPTOR AB The use of hemin iron by Corynebacterium diphtheriae requires the DtxR-and iron-regulated ABC hemin transporter HmuTUV and the secreted Hb-binding protein HtaA. We recently described two surface anchored proteins, ChtA and ChtC, which also bind hemin and Hb. ChtA and ChtC share structural similarities to HtaA; however, a function for ChtA and ChtC was not determined. In this study, we identified additional host iron sources that are utilized by C. diphtheriae. We show that several C. diphtheriae strains use the hemoglobin-haptoglobin (Hb-Hp) complex as an iron source. We report that an htaA deletion mutant of C. diphtheriae strain 1737 is unable to use the Hb-Hp complex as an iron source, and we further demonstrate that a chtA-chtC double mutant is also unable to use Hb-Hp iron. Single-deletion mutants of chtA or chtC use Hb-Hp iron in a manner similar to that of the wild type. These findings suggest that both HtaA and either ChtA or ChtC are essential for the use of Hb-Hp iron. Enzyme-linked immunosorbent assay (ELISA) studies show that HtaA binds the Hb-Hp complex, and the substitution of a conserved tyrosine (Y361) for alanine in HtaA results in significantly reduced binding. C. diphtheriae was also able to use human serum albumin (HSA) and myoglobin (Mb) but not hemopexin as iron sources. These studies identify a biological function for the ChtA and ChtC proteins and demonstrate that the use of the Hb-Hp complex as an iron source by C. diphtheriae requires multiple iron-regulated surface components. C1 [Allen, Courtni E.; Schmitt, Michael P.] US FDA, Lab Resp & Special Pathogens, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Schmitt, MP (reprint author), US FDA, Lab Resp & Special Pathogens, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. EM michael.schmitt@fda.hhs.gov FU intramural research program at the Center for Biologics Evaluation and Research, Food and Drug Administration FX This work was supported by the intramural research program at the Center for Biologics Evaluation and Research, Food and Drug Administration. NR 37 TC 9 Z9 9 U1 5 U2 19 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 FEB PY 2015 VL 197 IS 3 BP 553 EP 562 DI 10.1128/JB.02413-14 PG 10 WC Microbiology SC Microbiology GA AY6LD UT WOS:000347676800015 PM 25404705 ER PT J AU Lee, HW Carvell, J Brorson, K Yoon, S AF Lee, Hae Woo Carvell, John Brorson, Kurt Yoon, Seongkyu TI Dielectric spectroscopy-based estimation of VCD in CHO cell culture SO JOURNAL OF CHEMICAL TECHNOLOGY AND BIOTECHNOLOGY LA English DT Article DE dielectric spectroscopy; viable cell density; chinese hamster ovary (CHO) cells; chemometrics; locally-weighted partial least squares ID LOCALLY WEIGHTED REGRESSION; ANALYTICAL TECHNOLOGY PAT; EVOLVING FACTOR-ANALYSIS; HIGH-DENSITY CULTURE; FED-BATCH BIOPROCESS; IN-SITU MICROSCOPY; PERMITTIVITY MEASUREMENTS; ONLINE DETERMINATION; BIOMASS; PERFORMANCE AB BACKGROUNDIn mammalian cell culture processes, viable cell density (VCD) is one of the most crucial parameters for monitoring of the current status of cell growth and protein production. Among the various real-time monitoring tools available for VCD in Chinese hamster ovary (CHO) cell culture, dielectric spectroscopy is one of the more reliable due to its simplicity, robustness and accuracy. These attributes enable efficient monitoring and control of the corresponding processes. However, one of the major drawbacks of dielectric spectroscopy is frequent deterioration of accuracy during the late-growth phase of CHO cell culture. This can be caused by abrupt changes in the cell physiology, as well as environmental conditions. RESULTSIn this study, various kinds of chemometric tools were employed to understand the spectral dynamics of dielectric spectroscopy during extended CHO cell culture, including different cell growth phases. Then, the performance of different multivariate regression models were compared with conventional Cole-Cole equation-based approaches. The models were compared in their ability to estimate VCD in CHO cell culture from dielectric spectra from several batches of bioreactor operations. Multivariate analysis of dielectric spectral datasets clearly revealed the time-varying evolution of spectral dynamics during the transition between cell growth phases. The best prediction performance from the dielectric spectroscopy was realized using a regression model based on locally-weighted partial least squares (LWPLS). This estimation model best compensated for spectral dynamics observed during the different cell growth phases. CONCLUSIONDielectric spectroscopy combined with LWPLS allows achievement of optimal and stable estimation of VCD during CHO cell culture, regardless of inherent differences in cell growth phases. (c) 2014 Society of Chemical Industry C1 [Lee, Hae Woo] Daegu Gyeongbuk Med Innovat Fdn, Clin Drug Mfg Ctr, Taegu, South Korea. [Carvell, John] Aber Instruments Ltd, Aberystwyth, Dyfed, Wales. [Brorson, Kurt] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Yoon, Seongkyu] Univ Massachusetts, Dept Chem Engn, Lowell, MA USA. RP Yoon, S (reprint author), One Univ Ave, Lowell, MA 01854 USA. EM Seongkyu_Yoon@uml.edu FU Massachusetts Life Science Center; University of Massachusetts; Aber Instruments Ltd.; CDER Critical Path Project [1500] FX Financial support was provided by the Massachusetts Life Science Center, University of Massachusetts (New faculty start-up grant), and Aber Instruments Ltd. Aber Instruments Ltd provided the instrumentation and technical support for this feasibility study. CDER Critical Path Project # 1500 provided support for K.B. NR 56 TC 3 Z9 3 U1 5 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0268-2575 EI 1097-4660 J9 J CHEM TECHNOL BIOT JI J. Chem. Technol. Biotechnol. PD FEB PY 2015 VL 90 IS 2 SI SI BP 273 EP 282 DI 10.1002/jctb.4522 PG 10 WC Biotechnology & Applied Microbiology; Chemistry, Multidisciplinary; Engineering, Environmental; Engineering, Chemical SC Biotechnology & Applied Microbiology; Chemistry; Engineering GA AY8AZ UT WOS:000347778100008 ER PT J AU Lee, HW Christie, A Starkey, JA Read, EK Yoon, S AF Lee, Hae Woo Christie, Andrew Starkey, Jason A. Read, Erik K. Yoon, Seongkyu TI Intracellular metabolic flux analysis of CHO cells supplemented with wheat hydrolysates for improved mAb production and cell-growth SO JOURNAL OF CHEMICAL TECHNOLOGY AND BIOTECHNOLOGY LA English DT Article DE flux balance analysis; metabolic flux analysis; CHO cell culture; raw materials; wheat hydrolysates ID HAMSTER OVARY CELLS; RECOMBINANT PROTEIN THERAPEUTICS; PRINCIPAL COMPONENT ANALYSIS; CULTURE-MEDIA; HYBRIDOMA CELLS; LACTATE-DEHYDROGENASE; MALATE-DEHYDROGENASE; BALANCE ANALYSIS; MAMMALIAN-CELLS; NETWORKS AB BACKGROUNDIn the production of therapeutic proteins using Chinese hamster ovary (CHO) cell culture, the compositional variability in raw materials is often poorly understood. To elucidate the effects of raw material variability in regulating the intracellular metabolic pathways, plant-derived supplements of wheat hydrolysates were employed as a model system of raw materials having high compositional variability. The intracellular metabolic fluxes of antibody-producing GS-CHO cells supplemented with different lots of wheat hydrolysates were quantified using the techniques of flux balance analysis (FBA). RESULTSThe examination of the metabolic flux clearly illustrated several unique metabolic features. Specifically, under the given environmental conditions induced by the variability of the different wheat hydrolysate lots, the serine and glycine metabolism could be linked to improved cell growth, while the elevated levels of the anaplerotic reaction and the TCA cycle could be related to the increased specific antibody production. Multivariate data analysis revealed the detailed metabolic regulations of a GS-CHO cell line in response to the compositional variability of the given raw materials. The study result can be used for targeted optimization of cell growth and monoclonal antibody production. CONCLUSIONMetabolic flux analysis coupled with multivariate data analytics unravel the complicated effects of raw material variability on the cellular metabolism, and hence improve the overall productivity of an antibody-producing CHO cell culture. (c) 2014 Society of Chemical Industry C1 [Yoon, Seongkyu] Univ Massachusetts, Dept Chem Engn, Lowell, MA USA. [Christie, Andrew] SAFC Biosci, Lenexa, KS USA. [Starkey, Jason A.] Pfizer Inc, Chesterfield, MO USA. [Read, Erik K.] US FDA, Div Monoclonal Antibodies, OBP, OPS,CDER, Silver Spring, MD USA. [Lee, Hae Woo] Daegu Gyeongbuk Med Innovat Fdn, Clin Mfg Ctr, Taegu, South Korea. RP Yoon, S (reprint author), One Univ Ave, Lowell, MA 01854 USA. EM Seongkyu_Yoon@uml.edu FU Massachusetts Life Science Center; University of Massachusetts; Pfizer FX Financial support was provided by Massachusetts Life Science Center and University of Massachusetts (New faculty start-up grant). The authors thank SAFC for the datasets and the wheat hydrolysate samples used, and Pfizer for the partial funding of this research. NR 72 TC 3 Z9 3 U1 2 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0268-2575 EI 1097-4660 J9 J CHEM TECHNOL BIOT JI J. Chem. Technol. Biotechnol. PD FEB PY 2015 VL 90 IS 2 SI SI BP 291 EP 302 DI 10.1002/jctb.4523 PG 12 WC Biotechnology & Applied Microbiology; Chemistry, Multidisciplinary; Engineering, Environmental; Engineering, Chemical SC Biotechnology & Applied Microbiology; Chemistry; Engineering GA AY8AZ UT WOS:000347778100010 ER PT J AU Cook, AJ Wellman, RD Nelson, JC Jackson, LA Tiwari, RC AF Cook, Andrea J. Wellman, Robert D. Nelson, Jennifer C. Jackson, Lisa A. Tiwari, Ram C. TI Group sequential method for observational data by using generalized estimating equations: application to Vaccine Safety Datalink SO JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES C-APPLIED STATISTICS LA English DT Article DE Drug safety; Generalized estimating equations; Group sequential method for observational studies; Post-marketing surveillance; Vaccine safety ID CLINICAL-TRIALS; SURVEILLANCE; BOUNDARIES; PROJECT; DESIGNS; DRUG AB Post-market medical product surveillance is important for detecting rare adverse events that are not identified during preapproval. The goal of surveillance is to assess over time for elevated rates of adverse events for new medical products. These studies utilize administrative databases from multiple large health plans. We propose a group sequential method using a permutation approach with generalized estimating equations to account for confounding. A simulation study is conducted to evaluate the performance of the group sequential generalized estimating equation method compared with two other approaches. The methods are then applied to a vaccine safety application from the Vaccine Safety Datalink. C1 [Cook, Andrea J.; Wellman, Robert D.; Nelson, Jennifer C.; Jackson, Lisa A.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Cook, Andrea J.; Nelson, Jennifer C.] Univ Washington, Seattle, WA 98195 USA. [Tiwari, Ram C.] US FDA, Silver Spring, MD USA. RP Cook, AJ (reprint author), Grp Hlth Res Inst, Biostat Unit, Suite 1600,1730 Minor Ave, Seattle, WA 98101 USA. EM cook.aj@ghc.org FU America's Health Insurance Plans from the Centers for Disease Control and Prevention [200-2002-00732] FX This work was supported by a subcontract with America's Health Insurance Plans under contract 200-2002-00732 from the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Code in R and SAS for conducting the GSGEE method can be found at http://faculty.washington.edu/acook/. NR 18 TC 2 Z9 2 U1 1 U2 7 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 FEB PY 2015 VL 64 IS 2 BP 319 EP 338 DI 10.1111/rssc.12076 PG 20 WC Statistics & Probability SC Mathematics GA AY9TM UT WOS:000347893400005 ER PT J AU Schnaper, HW Furth, SL Yao, LP AF Schnaper, H. William Furth, Susan L. Yao, Lynne P. TI Defining new surrogate markers for CKD progression SO PEDIATRIC NEPHROLOGY LA English DT Editorial Material DE Surrogate markers; Chronic kidney disease; Kidney function; GFR; Pediatric CKD; Locusta migratoria ID CHRONIC KIDNEY-DISEASE; END-POINTS; RISK-FACTORS; CHILDREN; EPIDEMIOLOGY; BIOMARKERS; ALISKIREN; DECLINE; GFR AB At a recent meeting of international experts on clinical aspects of progressive chronic kidney disease (CKD), an extensive analysis of extant clinical trials was used to develop more effective and economical surrogate markers for CKD outcomes in adults. This article describes the reasons for this undertaking, the methods and conclusions of the meeting, and the relevance of these findings to pediatric nephrology. C1 [Schnaper, H. William] Northwestern Univ, Feinberg Sch Med, Dept Pediat, Chicago, IL 60611 USA. [Schnaper, H. William] Ann & Robert H Lurie Childrens Hosp Chicago, Div Kidney Dis, Chicago, IL USA. [Furth, Susan L.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Furth, Susan L.] Univ Penn, Dept Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Furth, Susan L.] Childrens Hosp Philadelphia, Div Nephrol, Philadelphia, PA 19104 USA. [Yao, Lynne P.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Schnaper, HW (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Pediat, Morton Bldg,Room 4-685G,320 E Super, Chicago, IL 60611 USA. EM schnaper@northwestern.edu FU NCATS NIH HHS [UL1 TR000150]; NIDDK NIH HHS [K24 DK078737, R01 DK049362, U01-DK066174, R01-DK049362, U01 DK066174, K24-DK078737] NR 22 TC 1 Z9 2 U1 0 U2 2 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 FEB PY 2015 VL 30 IS 2 BP 193 EP 198 DI 10.1007/s00467-014-2995-0 PG 6 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA AY0OG UT WOS:000347295200003 PM 25370779 ER PT J AU Singh, A Datta, S Sachdeva, A Maslanka, S Dykes, J Skinner, G Burr, D Whiting, RC Sharma, SK AF Singh, Ajay Datta, Shomik Sachdeva, Amita Maslanka, Susan Dykes, Janet Skinner, Guy Burr, Donald Whiting, Richard C. Sharma, Shashi K. TI EVALUATION OF AN ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA) KIT FOR THE DETECTION OF BOTULINUM NEUROTOXINS A, B, E, AND F IN SELECTED FOOD MATRICES SO HEALTH SECURITY LA English DT Article ID CLOSTRIDIUM-BOTULINUM; TOXINS; TECHNOLOGIES AB The mouse bioassay (MBA) is the only accepted standard method for detection of botulinum neurotoxins (BoNTs) in foods. The ELISA method has several advantages over the MBA and is therefore widely used for in vitro detection of BoNTs. The US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) conducted a precollaborative study to evaluate the applicability of Botulinum Toxin ELISA kits for the detection of BoNT serotypes A, B, E, and F in a variety of food matrices. In this study, food samples (eg, broccoli, salami, smoked salmon, green beans, orange juice, tomato juice, low-fat plain yogurt, whole milk, liquid infant formula milk, and liquid eggs) were spiked with high, medium, and low concentration BoNT serotypes A, B, E, and F. Samples (unspiked and spiked) were tested at both laboratories by the ELISA kits. All food samples were positive for BoNTs by ELISA in both laboratories at medium and high spiking levels; a positive ELISA result in low spiked samples was both serotype and laboratory dependent. Overall, the ELISA method appears to be an effective preliminary screening method for BoNT detection in food matrices. C1 [Singh, Ajay; Datta, Shomik; Sachdeva, Amita] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Singh, Ajay; Datta, Shomik; Sachdeva, Amita; Maslanka, Susan; Dykes, Janet; Skinner, Guy; Burr, Donald; Whiting, Richard C.; Sharma, Shashi K.] US Dept Energy Inst, Oak Ridge Inst Sci & Educ, Washington, DC USA. [Datta, Shomik] Vorsight LLC, Arlington, VA USA. [Sachdeva, Amita] Emergent Biosolut, Gaithersburg, MD USA. [Maslanka, Susan; Dykes, Janet] Ctr Dis Control & Prevent, CDC, Natl Botulism Lab Team, Atlanta, GA USA. [Skinner, Guy] US FDA, Inst Food Safety & Hlth, Ctr Food Safety & Appl Nutr, Bedford Pk, IL USA. [Burr, Donald] US FDA, Off Regulatory Affairs, Off Regulatory Sci, Rockville, MD USA. [Whiting, Richard C.] Exponent, Chem Regulat & Food Safety, Bowie, MD USA. [Sharma, Shashi K.] US FDA, Special Pathogen Team, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Sharma, SK (reprint author), FDA CFSAN, Div Microbiol, Off Regulatory Sci, Room 4E023,5100 Paint Branch Pkwy,HFS-711, College Pk, MD 20740 USA. EM Shashi.Sharma@fda.hhs.gov NR 16 TC 1 Z9 1 U1 3 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2326-5094 EI 2326-5108 J9 HEALTH SECUR JI Health Secur. PD FEB 1 PY 2015 VL 13 IS 1 BP 37 EP 44 DI 10.1089/hs.2014.0075 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DD0FT UT WOS:000369596500004 PM 25812427 ER PT J AU Smith, MA Reaman, GH AF Smith, Malcolm A. Reaman, Gregory H. TI Remaining Challenges in Childhood Cancer and Newer Targeted Therapeutics SO PEDIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Targeted therapy; Personalized medicine; Pediatric cancer drug development; Innovative clinical trials; Preclinical testing ID ACUTE LYMPHOBLASTIC-LEUKEMIA; LARGE-CELL LYMPHOMA; PRECLINICAL TESTING PROGRAM; ANAPLASTIC LYMPHOMA; ANTITUMOR-ACTIVITY; KINASE INHIBITION; PHASE-II; NEUROBLASTOMA; MODELS; METHYLATION AB Despite the enormously important and gratifying advances in cancer treatment outcomes for children with cancer, cancer remains the biggest cause of death from disease in children. Because the etiology and biology of cancers that occur in children differ dramatically from those that occur in adults, the immediate extrapolation of efficacy and safety of new cancer drugs to childhood cancer indications is not possible. We discuss factors that will play key roles in guiding pediatric oncologists as they select lines of research to pursue in their quest for more effective treatments for children with cancer. C1 [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Reaman, Gregory H.] US FDA, Off Hematol & Oncol Prod, OND, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 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 Intramural NIH HHS [Z99 CA999999] NR 43 TC 5 Z9 5 U1 0 U2 17 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0031-3955 EI 1557-8240 J9 PEDIATR CLIN N AM JI Pediatr. Clin. N. Am. PD FEB PY 2015 VL 62 IS 1 BP 301 EP + DI 10.1016/j.pcl.2014.09.018 PG 13 WC Pediatrics SC Pediatrics GA AX1BD UT WOS:000346682500019 PM 25435124 ER PT J AU Pouillot, R Chen, YH Hoelzer, K AF Pouillot, Regis Chen, Yuhuan Hoelzer, Karin TI Modeling number of bacteria per food unit in comparison to bacterial concentration in quantitative risk assessment: Impact on risk estimates SO FOOD MICROBIOLOGY LA English DT Article; Proceedings Paper CT 8th International Conference on Predictive Modelling in Food (ICPMF8) CY SEP 16-20, 2013 CL Paris, FRANCE SP Inst Pasteur DE Quantitative microbial risk assessment; Bacterial concentration; Bacterial number; Modeling process pathway; Simulation study ID ESCHERICHIA-COLI O157-H7; LISTERIA-MONOCYTOGENES; RAW-MILK; DOSE-RESPONSE; CONSUMPTION; SALMONELLA; INACTIVATION; EXPOSURE; SURVIVAL; CHEESES AB When developing quantitative risk assessment models, a fundamental consideration for risk assessors is to decide whether to evaluate changes in bacterial levels in terms of concentrations or in terms of bacterial numbers. Although modeling bacteria in terms of integer numbers may be regarded as a more intuitive and rigorous choice, modeling bacterial concentrations is more popular as it is generally less mathematically complex. We tested three different modeling approaches in a simulation study. The first approach considered bacterial concentrations; the second considered the number of bacteria in contaminated units, and the third considered the expected number of bacteria in contaminated units. Simulation results indicate that modeling concentrations tends to overestimate risk compared to modeling the number of bacteria. A sensitivity analysis using a regression tree suggests that processes which include drastic scenarios consisting of combinations of large bacterial inactivation followed by large bacterial growth frequently lead to a >10-fold overestimation of the average risk when modeling concentrations as opposed to bacterial numbers. Alternatively, the approach of modeling the expected number of bacteria in positive units generates results similar to the second method and is easier to use, thus potentially representing a promising compromise. Published by Elsevier Ltd. C1 [Pouillot, Regis; Chen, Yuhuan; Hoelzer, Karin] US FDA, Ctr Food Safety & Appl Nutr HFS 005, College Pk, MD 20740 USA. RP Pouillot, R (reprint author), US FDA, Ctr Food Safety & Appl Nutr HFS 005, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Regis.Pouillot@fda.hhs.gov RI Pouillot, Regis/E-8103-2010 OI Pouillot, Regis/0000-0002-6107-5212 FU U.S. Food and Drug Administration FX 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 34 TC 0 Z9 1 U1 2 U2 25 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 FEB PY 2015 VL 45 BP 245 EP 253 DI 10.1016/j.fm.2014.05.008 PN B PG 9 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA AW0NT UT WOS:000345990200012 PM 25500390 ER PT J AU Khuda, SE Jackson, LS Fu, TJ Williams, KM AF Khuda, Sefat E. Jackson, Lauren S. Fu, Tong-Jen Williams, Kristina M. TI Effects of processing on the recovery of food allergens from a model dark chocolate matrix SO FOOD CHEMISTRY LA English DT Article DE Food allergens; Processing effects; Extraction buffers; Antibody specificity; Allergenic proteins; Immunochemical staining; Chocolate matrix ID MAJOR PEANUT ALLERGEN; EXTRACTION BUFFERS; PROTEINS; STABILITY; PRODUCTS; ARA-H-1; ELISA; KITS; IGE AB To alleviate the risk to allergic consumers, it is crucial to improve factors affecting the detection of food allergens in processed chocolate products. This study evaluated processing effects on (1) recovery of peanut, egg, and milk allergens using five different extraction buffers, and (2) identification of specific allergenic proteins from extracts of incurred chocolate using allergen-specific antibodies and human allergic sera. Immunochemical staining with polyclonal antibodies showed that the addition of detergent or reducing agent improved extraction efficiency of peanut proteins, but not of egg and milk proteins. Tempering decreased antibody binding regardless of extractant. Detection of IgE-reactive peanut, egg, and milk allergens was differentially affected by tempering and extractant. Detection problems associated with matrix and processing effects may be overcome by the choice of extraction buffer and detecting antibody. Published by Elsevier Ltd. C1 [Khuda, Sefat E.; Williams, Kristina M.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Jackson, Lauren S.; Fu, Tong-Jen] US FDA, Ctr Food Safety & Appl Nutr, Bedford Pk, IL 60501 USA. RP Khuda, SE (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM sefat.khuda@fda.hhs.gov NR 42 TC 5 Z9 5 U1 1 U2 89 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 FEB 1 PY 2015 VL 168 BP 580 EP 587 DI 10.1016/j.foodchem.2014.07.084 PG 8 WC Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics SC Chemistry; Food Science & Technology; Nutrition & Dietetics GA AR5GJ UT WOS:000343612800077 PM 25172751 ER PT J AU Kwekel, JC Vijay, V Desai, VG Moland, CL Fuscoe, JC AF Kwekel, Joshua C. Vijay, Vikrant Desai, Varsha G. Moland, Carrie L. Fuscoe, James C. TI Age and sex differences in kidney microRNA expression during the life span of F344 rats SO BIOLOGY OF SEX DIFFERENCES LA English DT Article DE Kidney; miRNA expression; Sex; Age; Renal fibrosis; Renal inflammation; Biomarker ID RENAL-DISEASE; CIRCULATING MICRORNAS; TOXICOLOGICAL-RESEARCH; GENE-EXPRESSION; PROTECTIVE ROLE; LIVER-INJURY; GENDER; BIOMARKERS; CANCER; GLOMERULOSCLEROSIS AB Background: Growing evidence suggests that epigenetic mechanisms of gene regulation may play a role in susceptibilities to specific toxicities and adverse drug reactions. MiRNAs in particular have been shown to be important regulators in cancer and other diseases and show promise as predictive biomarkers for diagnosis and prognosis. In this study, we characterized the global kidney miRNA expression profile in untreated male and female F344 rats throughout the life span. These findings were correlated with sex-specific susceptibilities to adverse renal events, such as male-biased renal fibrosis and inflammation in old age. Methods: Kidney miRNA expression was examined in F344 rats at 2, 5, 6, 8, 15, 21, 78, and 104 weeks of age in both sexes using Agilent miRNA microarrays. Differential expression was determined using filtering criteria of >= 1.5 fold change and ANOVA or pairwise t-test (FDR <5%) to determine significant age and sex effects, respectively. Pathway analysis software was used to investigate the possible roles of these target genes in age-and sex-specific differences. Results: Three hundred eleven miRNAs were found to be expressed in at least one age and sex. Filtering criteria revealed 174 differentially expressed miRNAs in the kidney; 173 and 34 miRNAs exhibiting age and sex effects, respectively. Principal component analysis revealed age effects predominated over sex effects, with 2-week miRNA expression being much different from other ages. No significant sexually dimorphic miRNA expression was observed from 5 to 8 weeks, while the most differential expression (13 miRNAs) was observed at 21 weeks. Potential target genes of these differentially expressed miRNAs were identified. Conclusions: The expression of 56% of detected renal miRNAs was found to vary significantly with age and/or sex during the life span of F344 rats. Pathway analysis suggested that 2-week-expressed miRNAs may be related to organ and cellular development and proliferation pathways. Male-biased miRNA expression at older ages correlated with male-biased renal fibrosis and mononuclear cell infiltration. These miRNAs showed high representation in renal inflammation and nephritis pathways, and included miR-214, miR-130b, miR-150, miR-223, miR-142-5p, miR-185, and miR-296*. Analysis of kidney miRNA expression throughout the rat life span will improve the use of current and future renal biomarkers and inform our assessments of kidney injury and disease. C1 [Kwekel, Joshua C.; Vijay, Vikrant; Desai, Varsha G.; Moland, Carrie L.; Fuscoe, James C.] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Personalized Med Branch, Jefferson, AR 72079 USA. RP Kwekel, JC (reprint author), US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Personalized Med Branch, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Joshua.Kwekel@fda.hhs.gov; James.Fuscoe@fda.hhs.gov RI Vijay, Vikrant/E-7651-2010 OI Vijay, Vikrant/0000-0001-8425-1285 FU FDA Office of Women's Health; U.S. Department of Energy; U.S. Food and Drug Administration FX The thoughtful comments and critical reviews from Dr. Luisa Camacho and Dr. Igor Pogribny are greatly appreciated. We thank the FDA Office of Women's Health for support of this project. This research was supported in part by an appointment to the Research Participation 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 (W). The information in these materials is not a formal dissemination of information by FDA and does not represent agency position or policy. NR 65 TC 8 Z9 8 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2042-6410 J9 BIOL SEX DIFFER JI Biol. Sex Differ. PD JAN 28 PY 2015 VL 6 AR 1 DI 10.1186/s13293-014-0019-1 PG 16 WC Endocrinology & Metabolism; Genetics & Heredity SC Endocrinology & Metabolism; Genetics & Heredity GA CB7FF UT WOS:000349791500001 PM 25653823 ER PT J AU Khurana, S Coyle, EM Manischewitz, J King, LR Ishioka, G Alexander, J Smith, J Gurwith, M Golding, H AF Khurana, Surender Coyle, Elizabeth M. Manischewitz, Jody King, Lisa R. Ishioka, Glenn Alexander, Jeff Smith, Jon Gurwith, Marc Golding, Hana TI Oral Priming with Replicating Adenovirus Serotype 4 Followed by Subunit H5N1 Vaccine Boost Promotes Antibody Affinity Maturation and Expands H5N1 Cross-Clade Neutralization SO PLOS ONE LA English DT Article ID INFLUENZA-VIRUS INFECTION; MEMORY B-CELLS; SECRETING CELLS; WILD-TYPE; IMMUNOGENICITY; CHIMPANZEES; SAFETY; IMMUNIZATION; PERSISTENCE; CHALLENGE AB A Phase I trial conducted in 2009-2010 demonstrated that oral vaccination with a replication competent Ad4-H5 (A/Vietnam) vector with dosages ranging from 10(7)-10(11) viral particles was well tolerated. HA-specific T-cell responses were efficiently induced, but very limited hemagglutination-inhibiting (HI) humoral responses were measured. However, a single boost of Ad4-H5-Vtn vaccinated individuals with a unadjuvanted licensed H5N1 (A/Vietnam) subunit vaccine resulted in superior HI titers compared with unprimed subjects. In the current study, the impact of Ad4-H5 priming on the quality of the polyclonal humoral immune response was evaluated using a real-time kinetics assay by surface plasmon resonance (SPR). Total binding of serum polyclonal antibodies from the Ad4-H5-Vtn primed groups against both homologous H5N1-A/Vietnam/1194/2004 (clade 1) and heterologous A/Indonesia- 5/2005 (clade 2.1) HA1 head domain was significantly higher compared with sera from individuals that received subunit H5N1 vaccination alone. SPR measurements also demonstrated that the antigen-antibody complex dissociation rates (a surrogate for antibody affinity) of serum antibodies against the HA1 of H5N1-A/Vietnam were significantly higher in the Ad4-H5 primed groups compared with those from the unprimed group. Furthermore, strong correlations were observed between the antibody affinities for HA1 (but not HA2) and the virus neutralization titers against the homologous strain and a panel of heterologous clade 2 H5N1 strains. These findings support the concept of oral prime-boost vaccine approaches against pandemic influenza to elicit long-term memory B cells with high affinity capable of rapid response to variant pandemic viruses likely to emerge and adapt to human transmissions. C1 [Khurana, Surender; Coyle, Elizabeth M.; Manischewitz, Jody; King, Lisa R.; Golding, Hana] FDA, CBER, Div Viral Prod, Silver Spring, MD 20903 USA. [Ishioka, Glenn; Alexander, Jeff; Smith, Jon] PaxVax, San Diego, CA 92121 USA. [Gurwith, Marc] PaxVax, Redwood City, CA 94063 USA. RP Khurana, S (reprint author), FDA, CBER, Div Viral Prod, Silver Spring, MD 20903 USA. EM surender.khurana@fda.hhs.gov; hana.golding@fda.hhs.gov FU Wellcome Trust [Ad4-H5]; PaxVax FX Wellcome Trust funded the development of the Ad4-H5 vector through Phase I clinical trial for PaxVax. Co-authors Glenn Ishioka, Jeff Alexander, Jon Smith and Marc Gurwith are employed by PaxVax. PaxVax provided support in the form of salaries for authors GI, JA, JS and MG, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. NR 32 TC 5 Z9 5 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 JAN 28 PY 2015 VL 10 IS 1 AR e0115476 DI 10.1371/journal.pone.0115476 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA2IM UT WOS:000348732100018 PM 25629161 ER PT J AU Schmeisser, F Vasudevan, A Verma, S Wang, W Alvarado, E Weiss, C Atukorale, V Meseda, C Weir, JP AF Schmeisser, Falko Vasudevan, Anupama Verma, Swati Wang, Wei Alvarado, Esmeralda Weiss, Carol Atukorale, Vajini Meseda, Clement Weir, Jerry P. TI Antibodies to Antigenic Site A of Influenza H7 Hemagglutinin Provide Protection against H7N9 Challenge SO PLOS ONE LA English DT Article ID HUMAN CONJUNCTIVITIS; A VIRUS; VACCINE; SUBTYPE; CANDIDATE AB Identifying major antigenic and protective epitopes of the H7 hemagglutinin (HA) will be important for understanding the antibody response to vaccines developed against the novel influenza H7N9 viruses that emerged in China in 2013. To facilitate antigenic characterization of the H7N9 HA and to develop reagents for evaluation of H7N9 candidate vaccines, we generated a panel of murine monoclonal antibodies (mAbs) to the HA of A/Shanghai/2/2013 using mammalian cell-derived virus-like particles (VLP) containing the H7 HA. Neutralizing antibodies identified an HA epitope corresponding to antigenic site A on the structurally similar influenza H3 hemagglutinin. Importantly, the neutralizing antibodies protect against A/Shanghai/2/2013 challenge. This antigenic site is conserved among many H7 viruses, including strains of both Eurasian and North American lineage, and the isolated neutralizing antibodies are cross-reactive with older H7 vaccine strains. The results indicate that the identified antigenic site is a potentially important protective epitope and suggest the potential benefit of cross-reactive antibody responses to vaccination with H7 candidate vaccines. C1 [Schmeisser, Falko; Vasudevan, Anupama; Verma, Swati; Wang, Wei; Alvarado, Esmeralda; Weiss, Carol; Atukorale, Vajini; Meseda, Clement; Weir, Jerry P.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Weir, JP (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jerry.weir@fda.hhs.gov RI Weiss, Carol/F-6438-2011 OI Weiss, Carol/0000-0002-9965-1289 FU U.S. Food and Drug Administration; Biomedical Advanced Research and Development Authority, Department of Health and Human Services FX This work was supported by the U.S. Food and Drug Administration and by the Biomedical Advanced Research and Development Authority, Department of Health and Human Services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 4 Z9 4 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 28 PY 2015 VL 10 IS 1 AR e0117108 DI 10.1371/journal.pone.0117108 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA2IM UT WOS:000348732100065 PM 25629172 ER PT J AU Hategan, AP Steiner, J Bianchet, MA Karnaukhova, E Dimitriadis, EK Nath, A AF Hategan, Alina Popescu Steiner, Joseph Bianchet, Mario A. Karnaukhova, Elena Dimitriadis, Emilios K. Nath, Avindra TI HIV-Tat Protein-Amyloid Beta Complex: From Molecular Interaction to Increased Neurotoxicity SO BIOPHYSICAL JOURNAL LA English DT Meeting Abstract CT 59th Annual Meeting of the Biophysical-Society CY FEB 07-11, 2015 CL Baltimore, MD SP Biophys Soc C1 [Hategan, Alina Popescu; Steiner, Joseph; Nath, Avindra] NINDS, NIH, Bethesda, MD 20892 USA. [Bianchet, Mario A.] Johns Hopkins Sch Med, Baltimore, MD USA. [Karnaukhova, Elena] US FDA, CBER, Silver Spring, MD USA. [Dimitriadis, Emilios K.] NIBIB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD JAN 27 PY 2015 VL 108 IS 2 SU 1 MA 2505-Plat BP 496A EP 496A PG 1 WC Biophysics SC Biophysics GA CT5KV UT WOS:000362849600113 ER PT J AU Mohammad, A Yang, YS Khan, MA Faustino, PJ AF Mohammad, Adil Yang, Yongsheng Khan, Mansoor A. Faustino, Patrick J. TI A long-term stability study of Prussian blue: A quality assessment of water content and cesium binding SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Prussian blue; Stability; Moisture content; Product Quality; Cesium binding; Strategic National Stockpiles ID EFFECTIVE ANTIDOTE; RADIOCESIUM AB Prussian blue (PB) is the active pharmaceutical ingredient (API) of Radiogardase, the first approved medical countermeasure for the treatment of radiocesium poisoning in the event of a major radiological incident such as a "dirty bomb" or nuclear attack. The purpose of this study is to assess the long-term stability of Prussian blue drug products (DPs) and APIs under laboratory storage condition by monitoring the loss in water content and the in vitro cesium binding. The water content was measured by thermal gravimetric analysis (TGA). The in-vitro cesium binding study was conducted using a surrogate model to mimic gastric residence and intestinal transport. Free cesium was analyzed using a validated flame atomic emission spectroscopy (AES) method. The binding equilibrium was reached at 24 h. The Langmuir isotherm was plotted to calculate the maximum binding capacity (MBC). Comparison of the same PB samples with 2003 data samples, the water content of both APIs and DPs decreased on an average by approximately 12-24%. Consequently, the MBC of cesium was decreased from 358 mg/g in 2003 to 265 mg/g @ pH 7.5, a decrease of approximately 26%. The binding of cesium is also pH dependent with lowest binding at pH 1.0 and maximum binding at pH 7.5. At pH 7.5, the amount of cesium bound decreased by an average value of 7.9% for APIs and 8.9% for DPs (for 600 ppm initial cesium concentration). These findings of water loss, pH dependence and decrease in cesium binding are consistent with our previously published data in 2003. Over list 10-years the stored DPs and APIs of PB have. lost about 20% of water which has a negative impact on the PB cesium binding, however PB still meets the FDA specification of >150 mg/g at equilibrium. The study is the first quantitative assessment of the long-term stability of PB and directs that proper long-term and short-term storage of PB is required to ensure that it is safe and efficacious at the time of an emergency situation. Published by Elsevier B.V. C1 [Mohammad, Adil; Yang, Yongsheng; Khan, Mansoor A.; Faustino, Patrick J.] US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Prod Qual Res, Silver Spring, MD 20993 USA. RP Faustino, PJ (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Prod Qual Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM patrick.faustinop@fda.hhs.gov FU FDA Office of Counter Terrorism-Medical Counter Measures initiative (MCMi) FX This study was supported in part by a grant from the FDA Office of Counter Terrorism-Medical Counter Measures initiative (MCMi). The authors would also like to again thank HEYL Corporation and REACT/S (Oak Ridge, TN) for supplying PB API and PB drug products in 2003. NR 18 TC 2 Z9 2 U1 1 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 EI 1873-264X J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD JAN 25 PY 2015 VL 103 BP 85 EP 90 DI 10.1016/j.jpba.2014.10.030 PG 6 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA AX1EQ UT WOS:000346691300012 PM 25462125 ER PT J AU Kern, SE Nickum, EA Flurer, RA Toomey, VM Litzau, JJ AF Kern, Sara E. Nickum, Elisa A. Flurer, Rick A. Toomey, Valerie M. Litzau, Jonathan J. TI Isolation and structural characterization of a new tadalafil analog (2-hydroxyethylnortadalafil) found in a dietary supplement SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE PDE-5 inhibitor; Tadalafil analog; LC/MS ID SYNTHETIC PHOSPHODIESTERASE-5 INHIBITORS; PERFORMANCE LIQUID-CHROMATOGRAPHY; MASS-SPECTROMETRY; STRUCTURE ELUCIDATION; COUNTERFEIT PRODUCTS; SILDENAFIL; VARDENAFIL; ADULTERANT; MATRICES AB A screen for known PDE-5 inhibitors in a dietary supplement product marketed for "enhanced sexual performance" detected a compound that structurally resembled tadalafil. The compound was isolated from the supplement matrix using high-performance liquid chromatography with ultraviolet detection (HPLC-UV) and a fraction collector, and was further characterized using nuclear magnetic resonance (NMR), liquid chromatography-mass spectrometry (LC-MS), as well as high-resolution accurate mass mass spectrometry (HRAM-MS). The analog had an accurate mass of m/z420.15614 (error is 1.77235 ppm) for the protonated species [M + H](+), corresponding to a molecular formula of C23H22N3O5. Mass spectral fragmentation data suggested that the modification occurred in place of the -CH3 located on the pyrazinopyridoindole-1,4-dione of tadalafil. NMR was utilized to further elucidate the configuration of the substitution. The analysis indicated that the moiety is a -CH2CH2OH, hydroxyethyl group. The new analog has been named 2-hydroxyethylnortadalafil. (C) Published by Elsevier B.V. C1 [Kern, Sara E.; Nickum, Elisa A.; Flurer, Rick A.; Toomey, Valerie M.; Litzau, Jonathan J.] 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 FU Intramural FDA HHS [FD999999] NR 19 TC 6 Z9 6 U1 2 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 EI 1873-264X J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD JAN 25 PY 2015 VL 103 BP 99 EP 103 DI 10.1016/j.jpba.2014.10.021 PG 5 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA AX1EQ UT WOS:000346691300014 PM 25462127 ER PT J AU Vijay, V Han, T Moland, CL Kwekel, JC Fuscoe, JC Desai, VG AF Vijay, Vikrant Han, Tao Moland, Carrie L. Kwekel, Joshua C. Fuscoe, James C. Desai, Varsha G. TI Sexual Dimorphism in the Expression of Mitochondria-Related Genes in Rat Heart at Different Ages SO PLOS ONE LA English DT Article ID GENDER-RELATED DIFFERENCES; CARDIOVASCULAR-DISEASE; MOUSE MODEL; CARDIOMYOPATHY; MICE; DYSFUNCTION; APOPTOSIS; DEHYDROGENASE; HYPERTROPHY; FAILURE AB Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Moreover, sex and age are considered major risk factors in the development of CVDs. Mitochondria are vital for normal cardiac function, and regulation of mitochondrial structure and function may impact susceptibility to CVD. To identify potential role of mitochondria in sex-related differences in susceptibility to CVD, we analyzed the basal expression levels of mitochondria-related genes in the hearts of male and female rats. Whole genome expression profiling was performed in the hearts of young (8-week), adult (21-week), and old (78-week) male and female Fischer 344 rats and the expression of 670 unique genes related to various mitochondrial functions was analyzed. A significant (p<0.05) sexual dimorphism in expression levels of 46, 114, and 41 genes was observed in young, adult and old rats, respectively. Gene Ontology analysis revealed the influence of sex on various biological pathways related to cardiac energy metabolism at different ages. The expression of genes involved in fatty acid metabolism was significantly different between the sexes in young and adult rat hearts. Adult male rats also showed higher expression of genes associated with the pyruvate dehydrogenase complex compared to females. In young and adult hearts, sexual dimorphism was not noted in genes encoding oxidative phosphorylation. In old rats, however, a majority of genes involved in oxidative phosphorylation had higher expression in females compared to males. Such basal differences between the sexes in cardiac expression of genes associated with energy metabolism may indicate a likely involvement of mitochondria in susceptibility to CVDs. In addition, female rats showed lower expression levels of apoptotic genes in hearts compared to males at all ages, which may have implications for better preservation of cardiac mass in females than in males. C1 [Vijay, Vikrant; Han, Tao; Moland, Carrie L.; Kwekel, Joshua C.; Fuscoe, James C.; Desai, Varsha G.] US FDA, Personalized Med Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Desai, VG (reprint author), US FDA, Personalized Med Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM varsha.desai@fda.hhs.gov RI Vijay, Vikrant/E-7651-2010 OI Vijay, Vikrant/0000-0001-8425-1285 FU FDA Office of Women's Health; U.S. Department of Energy; U.S. Food and Drug Administration FX We thank the FDA Office of Women's Health for support of this project. This research was supported in part by an appointment to the Research Participation Program at the National Center for Toxicological 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 6 Z9 6 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 23 PY 2015 VL 10 IS 1 AR UNSP e0117047 DI 10.1371/journal.pone.0117047 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA7UF UT WOS:000349122100053 PM 25615628 ER PT J AU Li, Q Gavrielides, MA Zeng, RP Myers, KJ Sahiner, B Petrick, N AF Li, Qin Gavrielides, Marios A. Zeng, Rongping Myers, Kyle J. Sahiner, Berkman Petrick, Nicholas TI Volume estimation of low-contrast lesions with CT: a comparison of performances from a phantom study, simulations and theoretical analysis SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE volume estimation; phantom study; Cramer-Rao's lower bound; low-contrast lesion; computed tomography ID NODULE SIZE ESTIMATION; PULMONARY NODULES; SOLID TUMORS; CANCER; SCANS AB Measurements of lung nodule volume with multi-detector computed tomography (MDCT) have been shown to be more accurate and precise compared to conventional lower dimensional measurements. Quantifying the size of lesions is potentially more difficult when the object-to-background contrast is low as with lesions in the liver. Physical phantom and simulation studies are often utilized to analyze the bias and variance of lesion size estimates because a ground truth or reference standard can be established. In addition, it may also be useful to derive theoretical bounds as another way of characterizing lesion sizing methods. The goal of this work was to study the performance of a MDCT system for a lesion volume estimation task with object-to-background contrast less than 50 HU, and to understand the relation among performances obtained from phantom study, simulation and theoretical analysis. We performed both phantom and simulation studies, and analyzed the bias and variance of volume measurements estimated by a matched-filter-based estimator. We further corroborated results with a theoretical analysis to estimate the achievable performance bound, which was the Cramer-Rao's lower bound (CRLB) of minimum variance for the size estimates. Results showed that estimates of non-attached solid small lesion volumes with object-to- background contrast of 31-46 HU can be accurate and precise, with less than 10.8% in percent bias and 4.8% in standard deviation of percent error (SPE), in standard dose scans. These results are consistent with theoretical (CRLB), computational (simulation) and empirical phantom bounds. The difference between the bounds is rather small (for SPE less than 1.9%) indicating that the theoretical- and simulation-based performance bounds can be good surrogates for physical phantom studies. C1 [Li, Qin; Gavrielides, Marios A.; Zeng, Rongping; Myers, Kyle J.; Sahiner, Berkman; Petrick, Nicholas] US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Li, Q (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM qin.li1@fda.hhs.gov NR 23 TC 3 Z9 3 U1 0 U2 3 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 JAN 21 PY 2015 VL 60 IS 2 BP 671 EP 688 DI 10.1088/0031-9155/60/2/671 PG 18 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AY6KL UT WOS:000347675100014 PM 25555240 ER PT J AU Barrett, HH Myers, KJ Hoeschen, C Kupinski, MA Little, MP AF Barrett, Harrison H. Myers, Kyle J. Hoeschen, Christoph Kupinski, Matthew A. Little, Mark P. TI Task-based measures of image quality and their relation to radiation dose and patient risk SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE radiation dose; image quality; patient risk; ionizing radiation; tomography ID ATOMIC-BOMB SURVIVORS; ABDOMINAL COMPUTED-TOMOGRAPHY; DIGITAL BREAST TOMOSYNTHESIS; CONE-BEAM CT; ITERATIVE RECONSTRUCTION TECHNIQUES; OBSERVER DETECTION PERFORMANCE; POSITRON-EMISSION-TOMOGRAPHY; HOTELLING TRACE CRITERION; MONTE-CARLO CALCULATION; VISUAL SIGNAL-DETECTION AB The theory of task-based assessment of image quality is reviewed in the context of imaging with ionizing radiation, and objective figures of merit (FOMs) for image quality are summarized. The variation of the FOMs with the task, the observer and especially with the mean number of photons recorded in the image is discussed. Then various standard methods for specifying radiation dose are reviewed and related to the mean number of photons in the image and hence to image quality. Current knowledge of the relation between local radiation dose and the risk of various adverse effects is summarized, and some graphical depictions of the tradeoffs between image quality and risk are introduced. Then various dose-reduction strategies are discussed in terms of their effect on task-based measures of image quality. C1 [Barrett, Harrison H.; Kupinski, Matthew A.] Univ Arizona, Coll Opt Sci, Tucson, AZ 85721 USA. [Barrett, Harrison H.; Kupinski, Matthew A.] Univ Arizona, Dept Med Imaging, Ctr Gamma Ray Imaging, Tucson, AZ 85724 USA. [Myers, Kyle J.] US FDA, Div Imaging Diagnost & Software Reliabil, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Hoeschen, Christoph] Otto Von Guericke Univ, Dept Elect Engn & Informat Technol, D-39106 Magdeburg, Germany. [Hoeschen, Christoph] Helmholtz Zentrum Munchen, Res Unit Med Radiat Phys & Diagnost, D-85764 Oberschleissheim, Germany. [Little, Mark P.] NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP Barrett, HH (reprint author), Univ Arizona, Coll Opt Sci, Tucson, AZ 85721 USA. EM barrett@radiology.arizona.edu OI Little, Mark/0000-0003-0980-7567 FU National Institutes of Health at the University of Arizona [R01 EB000803, P41 EB002035]; Intramural Research Program of the National Institutes of Health FX This research was supported by the National Institutes of Health under grants R01 EB000803 and P41 EB002035 at the University of Arizona. This work was also supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 249 TC 17 Z9 17 U1 1 U2 10 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 JAN 21 PY 2015 VL 60 IS 2 BP R1 EP R75 DI 10.1088/0031-9155/60/2/R1 PG 75 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AY6KL UT WOS:000347675100002 PM 25564960 ER PT J AU Kurasawa, JH Shestopal, SA Woodle, SA Ovanesov, MV Lee, TK Sarafanov, AG AF Kurasawa, James H. Shestopal, Svetlana A. Woodle, Samuel A. Ovanesov, Mikhail V. Lee, Timothy K. Sarafanov, Andrey G. TI Cluster III of Low-Density Lipoprotein Receptor-Related Protein 1 Binds Activated Blood Coagulation Factor VIII SO BIOCHEMISTRY LA English DT Article ID VON-WILLEBRAND-FACTOR; CONSERVED ACIDIC RESIDUE; COMPLEMENT-TYPE REPEATS; LIGAND-BINDING; LIGHT-CHAIN; FACTOR IXA; APOLIPOPROTEIN-E; RAP COMPLEX; A2 DOMAIN; SITE AB Low-density lipoprotein receptor-related protein 1 (LRP) mediates clearance of blood coagulation factor VIII (FVIII). In LRP, FVIII binds the complement-type repeats (CRs) of clusters II and IV, which also bind a majority of other LRP ligands. No ligand is known for LRP cluster I, and only three ligands, including the LRP chaperone alpha-2 macroglobulin receptor-associated protein (RAP), bind cluster III. Using surface plasmon resonance, we found that in addition to clusters II and IV, activated FVIII (FVIIIa) binds cluster III. The specificity of this interaction was confirmed using an anti-FVIII antibody fragment, which inhibited the binding. Recombinant fragments of cluster III and its site-directed mutagenesis were used to localize the cluster's site for binding FVIIIa to CR.14-19. The interactive site of FVIIIa was localized within its A1/A3'-C1-C2 heterodimer (HDa), which is a major physiological remnant of FVIIIa. In mice, the clearance of HDa was faster than that of FVIII and prolonged in the presence of RAP, which is known to inhibit interactions of LRP with its ligands. In accordance with this, the cluster III site for RAP (CR.15-19) was found to overlap that for FVIIIa. Altogether, our findings support the involvement of LRP in FVIIIa catabolism and suggest a greater significance of the biological role of cluster III compared to that previously known. C1 [Kurasawa, James H.; Shestopal, Svetlana A.; Woodle, Samuel A.; Ovanesov, Mikhail V.; Lee, Timothy K.; Sarafanov, Andrey G.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Sarafanov, AG (reprint author), US FDA, 10903 New Hampshire Ave,WO 52-72-4208, Silver Spring, MD 20993 USA. EM andrey.sarafanov@fda.hhs.gov FU Center for Biologics Evaluation and Research (CBER) of the Food and Drug Administration (FDA) FX The study was supported by funds from the Center for Biologics Evaluation and Research (CBER) of the Food and Drug Administration (FDA) and also by an appointment to the Research Participation Program at the CBER administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the FDA. NR 61 TC 2 Z9 2 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 20 PY 2015 VL 54 IS 2 BP 481 EP 489 DI 10.1021/bi5011688 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AZ6MH UT WOS:000348333300036 PM 25486042 ER PT J AU Lee, SL Dou, JH Agarwal, R Temple, R Beitz, J Wu, C Mulberg, A Yu, LX Woodcock, J AF Lee, Sau L. Dou, Jinhui Agarwal, Rajiv Temple, Robert Beitz, Julie Wu, Charles Mulberg, Andrew Yu, Lawrence X. Woodcock, Janet TI Evolution of traditional medicines to botanical drugs SO SCIENCE LA English DT Article ID DIARRHEA C1 [Lee, Sau L.; Dou, Jinhui; Agarwal, Rajiv; Temple, Robert; Beitz, Julie; Wu, Charles; Mulberg, Andrew; Yu, Lawrence X.; Woodcock, Janet] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Lee, SL (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM sau.lee@fda.hhs.gov; jinhui.dou@fda.hhs.gov RI Yu, Lawrence/L-6280-2016 NR 8 TC 4 Z9 4 U1 3 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JAN 16 PY 2015 VL 347 IS 6219 BP S32 EP S34 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AZ0DA UT WOS:000347915300045 ER PT J AU Argaw, T Wilson, CA AF Argaw, Takele Wilson, Carolyn A. TI Mutations altering the gammaretrovirus endoproteolytic motif affect glycosylation of the envelope glycoprotein and early events of the virus life cycle SO VIROLOGY LA English DT Article DE Porcine endogenous retrovirus; Feline leukemia virus-B; Gammaretroviruses; Endoproteolytic cleavage signal; Glycosylation ID FELINE LEUKEMIA-VIRUS; PORCINE ENDOGENOUS RETROVIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; PROTEOLYTIC CLEAVAGE; MURINE RETROVIRUS; MEMBRANE-FUSION; CELL INFECTION; FURIN; RESIDUES; PROTEIN AB Previously, we found that mutation of glutamine to proline in the endoproteolytic cleavage signal of the PERV-C envelope (RQKK to RPKK) resulted in non-infectious vectors. Here, we show that RPKK results in a non-infectious vector when placed in not only a PERV envelope, but also the envelope of a related gammaretrovirus, FeLV-B. The amino acid substitutions do not prevent envelope precursor cleavage, viral core and genome assembly, or receptor binding. Rather, the mutations result in the formation of hyperglycosylated glycoprotein and a reduction in the reverse transcribed minus strand synthesis and undetectable 2-LTR circular DNA in cells exposed to vectors with these mutated envelopes. Our findings suggest novel functions associated with the cleavage signal sequence that may affect trafficking through the glycosylation machinery of the cell. Further, the glycosylation status of the envelope appears to impact post-binding events of the viral life cycle, either membrane fusion, internalization, or reverse transcription. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). C1 [Argaw, Takele; Wilson, Carolyn A.] US FDA, Gene Transfer & Immunogen Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Wilson, CA (reprint author), US FDA, Gene Transfer & Immunogen Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM carolyn.wilson@fda.hhs.gov FU FDA/CBER intramural research program FX The research described here was supported by the FDA/CBER intramural research program. We thank Maribeth V. Eiden of NIMH/NIH for constructive scientific discussions. We are also indebted to Winston Colon-Moran, May Shlash, Ou Wu, Josie Delisle, Howard Mostowski, and Fatima Abbasi for their technical support. We are grateful to Dr. John Elder for the gift of the plasmid encoding the cDNA for the FeLV-B (GA strain) envelope. Finally, we thank Drs. John Cipollo and Andrew Byrnes for their critical reading of the manuscript. NR 39 TC 0 Z9 0 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 0042-6822 J9 VIROLOGY JI Virology PD JAN 15 PY 2015 VL 475 BP 110 EP 119 DI 10.1016/j.virol.2014.11.010 PG 10 WC Virology SC Virology GA AZ4FE UT WOS:000348176500011 PM 25462351 ER PT J AU Duncan, TV Pillai, K AF Duncan, Timothy V. Pillai, Karthik TI Release of Engineered Nanomaterials from Polymer Nanocomposites: Diffusion, Dissolution, and Desorption SO ACS APPLIED MATERIALS & INTERFACES LA English DT Review DE nanocomposites; release; migration; environmental health and safety; nanoparticles; diffusion; exposure ID FOOD-CONTACT MATERIALS; SILVER NANOPARTICLES; EXPOSURE ASSESSMENT; CONSUMER PRODUCTS; HIGH-PRESSURE; MIGRATION; NANOSILVER; POLYLACTIDE; COMPOSITES; CONTAINERS AB Polymer nanocomposites-polymer-based materials that incorporate filler elements possessing at least one dimension in the nanometer range-are increasingly being developed for commercial applications ranging from building infrastructure to food packaging to biomedical devices and implants. Despite a wide range of intended applications, it is also important to understand the potential for exposure to these nanofillers, which could be released during routine use or abuse of these materials, so it can be determined whether they pose a risk to human health or the environment. This article is the first in a series of two that review the state of the science regarding the release of engineered nanomaterials (ENMs) from polymer nanocomposites. Two ENM release paradigms are considered in this series: the release of ENMs via passive diffusion, desorption, and dissolution into external liquid media and release of ENMs assisted by matrix degradation. The present article focuses primarily on the first paradigm and includes (1) an overview of basic interactions between polymers and liquid environments and a brief summary of diffusion physics as they apply to polymeric materials; (2) a summary of both experimental and theoretical methods to assess contaminant release (including ENMs) from polymers by diffusion, dissolution, and desorption; and (3) a thorough, critical review of the associated body of peer-reviewed literature on ENM release by these mechanisms. A short outlook section on knowledge gaps and future research needs is also provided. C1 [Duncan, Timothy V.; Pillai, Karthik] US FDA, Ctr Food Safety & Appl Nutr, Bedford Pk, IL 60501 USA. RP Duncan, TV (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM timothy.duncan@fda.hhs.gov NR 76 TC 18 Z9 18 U1 15 U2 95 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 JAN 14 PY 2015 VL 7 IS 1 BP 2 EP 19 DI 10.1021/am5062745 PG 18 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA AZ2TM UT WOS:000348085200002 PM 25485689 ER PT J AU Duncan, TV AF Duncan, Timothy V. TI Release of Engineered Nanomaterials from Polymer Nanocomposites: the Effect of Matrix Degradation SO ACS APPLIED MATERIALS & INTERFACES LA English DT Review DE nanocomposites; release; environmental health and safety; nanoparticles; exposure; mechanical abrasion; photodegradation; thermal degradation; hydrolysis ID LAYERED SILICATE NANOCOMPOSITES; ENHANCE THERMAL-STABILITY; EPOXY-BASED NANOCOMPOSITE; HYDROLYTIC DEGRADATION; CARBON NANOTUBES; NANOPARTICLE RELEASE; STRUCTURAL-CHANGES; POLYPROPYLENE NANOCOMPOSITES; FLAME RETARDANCY; FIRE RETARDANCY AB Polymer nanocomposites-polymer-based materials that incorporate filler elements possessing at least one dimension in the nanometer range-are increasingly being developed for commercial applications ranging from building infrastructure to food packaging to biomedical devices and implants. Despite a wide range of intended applications, it is also important to understand the potential for exposure to these nanofillers, which could be released during routine use or abuse of these materials so that it can be determined whether they pose a risk to human health or the environment. This article is the second of a pair that review what is known about the release of engineered nanomaterials (ENMs) from polymer nanocomposites. Two roughly separate ENM release paradigms are considered in this series: the release of ENMs via passive diffusion, desorption, and dissolution into external liquid media and the release of ENMs assisted by matrix degradation. The present article is focused primarily on the second paradigm and includes a thorough, critical review of the associated body of peer-reviewed literature on ENM release by matrix degradation mechanisms, including photodegradation, thermal decomposition, mechanical wear, and hydrolysis. These release mechanisms may be especially relevant to nanocomposites that are likely to be subjected to weathering, including construction and infrastructural materials, sporting equipment, and materials that might potentially end up in landfills. This review pays particular attention to studies that shed light on specific release mechanisms and synergistic mechanistic relationships. The review concludes with a short section on knowledge gaps and future research needs. C1 US FDA, Ctr Food Safety & Appl Nutr, Bedford Pk, IL 60501 USA. RP Duncan, TV (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM timothy.duncan@fda.hhs.gov NR 71 TC 11 Z9 11 U1 14 U2 88 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 JAN 14 PY 2015 VL 7 IS 1 BP 20 EP 39 DI 10.1021/am5062757 PG 20 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA AZ2TM UT WOS:000348085200003 PM 25397693 ER PT J AU Graham, DJ Reichman, ME Wernecke, M Zhang, RM Southworth, MR Levenson, M Sheu, TC Mott, K Goulding, MR Houstoun, M MaCurdy, TE Worrall, C Kelman, JA AF Graham, David J. Reichman, Marsha E. Wernecke, Michael Zhang, Rongmei Southworth, Mary Ross Levenson, Mark Sheu, Ting-Chang Mott, Katrina Goulding, Margie R. Houstoun, Monika MaCurdy, Thomas E. Worrall, Chris Kelman, Jeffrey A. TI Cardiovascular, Bleeding, and Mortality Risks in Elderly Medicare Patients Treated With Dabigatran or Warfarin for Nonvalvular Atrial Fibrillation SO CIRCULATION LA English DT Article DE anticoagulant; pharmacoepidemiology; safety; thrombin inhibitor; warfarin ID ACUTE MYOCARDIAL-INFARCTION; POSITIVE PREDICTIVE-VALUE; ADMINISTRATIVE DATA; CODING ACCURACY; STROKE; METAANALYSIS; VALIDATION; THERAPY; DIAGNOSIS; OLDER AB Background-The comparative safety of dabigatran versus warfarin for treatment of nonvalvular atrial fibrillation in general practice settings has not been established. Methods and Results-We formed new-user cohorts of propensity score-matched elderly patients enrolled in Medicare who initiated dabigatran or warfarin for treatment of nonvalvular atrial fibrillation between October 2010 and December 2012. Among 134 414 patients with 37 587 person-years of follow-up, there were 2715 primary outcome events. The hazard ratios (95% confidence intervals) comparing dabigatran with warfarin (reference) were as follows: ischemic stroke, 0.80 (0.67-0.96); intracranial hemorrhage, 0.34 (0.26-0.46); major gastrointestinal bleeding, 1.28 (1.14-1.44); acute myocardial infarction, 0.92 (0.78-1.08); and death, 0.86 (0.77-0.96). In the subgroup treated with dabigatran 75 mg twice daily, there was no difference in risk compared with warfarin for any outcome except intracranial hemorrhage, in which case dabigatran risk was reduced. Most patients treated with dabigatran 75 mg twice daily appeared not to have severe renal impairment, the intended population for this dose. In the dabigatran 150-mg twice daily subgroup, the magnitude of effect for each outcome was greater than in the combined-dose analysis. Conclusions-In general practice settings, dabigatran was associated with reduced risk of ischemic stroke, intracranial hemorrhage, and death and increased risk of major gastrointestinal hemorrhage compared with warfarin in elderly patients with nonvalvular atrial fibrillation. These associations were most pronounced in patients treated with dabigatran 150 mg twice daily, whereas the association of 75 mg twice daily with study outcomes was indistinguishable from warfarin except for a lower risk of intracranial hemorrhage with dabigatran. C1 [Graham, David J.; Reichman, Marsha E.; Mott, Katrina; Goulding, Margie R.; Houstoun, Monika] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Zhang, Rongmei; Levenson, Mark] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Southworth, Mary Ross] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Wernecke, Michael; Sheu, Ting-Chang; MaCurdy, Thomas E.] Acumen LLC, Burlingame, CA USA. [MaCurdy, Thomas E.] Stanford Univ, Dept Econ, Stanford, CA 94305 USA. [Worrall, Chris; Kelman, Jeffrey A.] Ctr Medicare Serv, Washington, DC USA. [Worrall, Chris; Kelman, Jeffrey A.] Ctr Medicaid Serv, Washington, DC USA. RP Graham, DJ (reprint author), Off Surveillance & Epidemiol, 10903 New Hampshire Ave,Bldg 22,Room 4314, Silver Spring, MD 20993 USA. EM david.graham1@fda.hhs.gov OI Mott, Katrina/0000-0001-8322-7830 FU Centers for Medicare & Medicaid Services; US Food and Drug Administration FX This study was funded through an intra-agency agreement between the Centers for Medicare & Medicaid Services and the US Food and Drug Administration. NR 33 TC 202 Z9 208 U1 5 U2 37 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 JAN 13 PY 2015 VL 131 IS 2 BP 157 EP 164 DI 10.1161/CIRCULATIONAHA.114.012061 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AY8FY UT WOS:000347791000012 PM 25359164 ER PT J AU Cortazar, P Geyer, CE Gianni, L Cameron, D von Minckwitz, G AF Cortazar, Patricia Geyer, Charles E., Jr. Gianni, Luca Cameron, David von Minckwitz, Gunter TI Pathological complete response in breast cancer Reply SO LANCET LA English DT Letter C1 [Cortazar, Patricia] US FDA, Silver Spring, MD 20993 USA. [Geyer, Charles E., Jr.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. [Gianni, Luca] Ist Sci San Raffaele, I-20132 Milan, Italy. [Cameron, David] Univ Edinburgh, Edinburgh Canc Res Ctr, Edinburgh, Midlothian, Scotland. [Cameron, David] NHS Lothian, Edinburgh, Midlothian, Scotland. [von Minckwitz, Gunter] German Breast Grp, Neu Isenburg, Germany. RP Cortazar, P (reprint author), US FDA, Silver Spring, MD 20993 USA. EM patricia.cortazar@fda.hhs.gov NR 3 TC 2 Z9 2 U1 0 U2 1 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 JAN 10 PY 2015 VL 385 IS 9963 BP 114 EP 115 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AY7BI UT WOS:000347715900020 PM 25706464 ER PT J AU Yang, XX Fisher, JW AF Yang, Xiaoxia Fisher, Jeffrey W. TI Unraveling bisphenol A pharmacokinetics using physiologically based pharmacokinetic modeling SO FRONTIERS IN PHARMACOLOGY LA English DT Review DE bisphenol A; PBPK; pharmacokinetics; age-dependent pharmacokinetics; species extrapolation; dosimetry ID ROUTE DEPENDENT DOSIMETRY; SPRAGUE-DAWLEY RATS; TISSUE DISTRIBUTION; PROTEIN-BINDING; CELL-LINES; CD-1 MICE; TRANSPORTER; INTESTINE; BPA; GLUCURONIDATION AB Physiologically based pharmacokinetic (PBPK) models integrate both chemical- and system-specific information into a mathematical framework, offering a mechanistic approach to predict the internal dose metrics of a chemical and an ability to perform species and dose extrapolations. Bisphenol A (BPA), because of its ubiquitous presence in a variety of consumer products, has received a considerable amount of attention from the public and regulatory bodies. PBPK models using deuterated BPA were developed for immature and adult rats and non-human primates and for adult humans to understand better the dosimetry of BPA. The focus of the present paper is to provide a rationale for interpreting species- and age-related pharmacokinetics of BPA. Gastrointestinal tract metabolism was an important consideration to predict unconjugated BPA serum kinetic profiles in adult and immature rats and monkeys. Biliary excretion and enterohepatic recirculation of BPA conjugates (BPA-c) accounted for the slowed systemic clearance of BPA-c in rats. For monkeys, renal reabsorption was proposed as a mechanism influencing systemic clearance of BPA-c. The quantitative understanding of the processes driving the pharmacokinetics of BPA across different species and life stages using a computational modeling approach provides more confidence in the interpretation of human biomonitoring data and the extrapolation of experimental animal findings to humans. C1 [Yang, Xiaoxia; Fisher, Jeffrey W.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Fisher, JW (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM jeffrey.fisher@fda.hhs.gov FU NCTR/FDA FX This manuscript does not necessarily reflect the views of the U.S. Food and Drug Administration. We appreciate Drs. Daniel Doerge Annie Lumen, Frederick Beland, and Jason Aungst for reviewing this manuscript and their critical comments and edits on the paper. This work was supported by NCTR/FDA. NR 50 TC 0 Z9 0 U1 4 U2 15 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-9812 J9 FRONT PHARMACOL JI Front. Pharmacol. PD JAN 9 PY 2015 VL 5 AR 292 DI 10.3389/fphar.2014.00292 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AZ4QX UT WOS:000348208600001 ER PT J AU Sauna, ZE Lozier, JN Kasper, CK Yanover, C Nichols, T Howard, TE AF Sauna, Zuben E. Lozier, Jay N. Kasper, Carol K. Yanover, Chen Nichols, Timothy Howard, Tom E. TI The intron-22-inverted F8 locus permits factor VIII synthesis: explanation for low inhibitor risk and a role for pharmacogenomics SO BLOOD LA English DT Article ID SEVERE HEMOPHILIA-A; ENDOGENOUS FACTOR-VIII; MHC CLASS-II; CENTRAL TOLERANCE; GENE; MUTATION; MILD; CELLS; IMMUNOGENICITY; INVERSIONS AB Intron-22-inversion patients express the entire Factor VIII (FVIII)-amino-acid sequence intracellularly as 2 non-secreted polypeptides and have a positive "intracellular (I)-FVIII-CRM" status. Mutations conferring a positive I-FVIII-CRM status are associated with low inhibitor risk and are pharmacogenetically relevant because inhibitor risk may be affected by the nature of the therapeutic FVIII-protein (tFVIII), the affinity of any tFVIII-derived foreign peptide (tFVIII-fp) for anyHLAclass-II isomer (HLA-II) comprising individual major histocompatibility complex (MHC) repertoires, and the stability of any tFVIII-fp/HLA-II complex. We hypothesize that mutations conferring a completely or substantially negative I-FVIII-CRM status are pharmacogenetically irrelevant because inhibitor risk is high with any tFVIII and individual MHC repertoire. C1 [Sauna, Zuben E.] US FDA, Lab Hemostasis, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Lozier, Jay N.] NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Kasper, Carol K.] Orthopaed Hemophilia Treatment Ctr, Los Angeles, CA USA. [Kasper, Carol K.] Univ So Calif, Keck Sch Med, Dept Med, Div Hematol, Los Angeles, CA 90033 USA. [Yanover, Chen] IBM Res Lab, Machine Learning Healthcare & Life Sci, Haifa, Israel. [Nichols, Timothy] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Nichols, Timothy] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Howard, Tom E.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Pathol & Lab Med, Los Angeles, CA 90073 USA. [Howard, Tom E.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Howard, Tom E.] Univ So Calif, Keck Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90033 USA. RP Howard, TE (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Dept Pathol & Lab Med, Bldg 500,Room 1258, Los Angeles, CA 90073 USA. EM zuben.sauna@fda.hhs.gov; Tom.Howard@va.gov RI Yanover, Chen/A-3754-2012 OI Yanover, Chen/0000-0003-3663-4286 FU Modernization of Science Program of the Center for Biologics Evaluation and Research, United States Food and Drug Administration; National Heart, Lung and Blood Institute, National Institutes of Health [1RC2-HL101851, HL-71130, HL-72533]; Bayer Healthcare Corporation; Bayer Hemophilia Awards Program; Baxter Healthcare Corporation; Clinical Translational Science Institute at the University of Southern California FX This study was supported by the Modernization of Science Program of the Center for Biologics Evaluation and Research, United States Food and Drug Administration (Z.E.S.); and grants from the National Heart, Lung and Blood Institute, National Institutes of Health (1RC2-HL101851, HL-71130, HL-72533), the Bayer Healthcare Corporation, Bayer Hemophilia Awards Program, Baxter Healthcare Corporation, and the Clinical Translational Science Institute at the University of Southern California (T.E.H.). NR 31 TC 3 Z9 4 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JAN 8 PY 2015 VL 125 IS 2 BP 223 EP 228 DI 10.1182/blood-2013-12-530113 PG 6 WC Hematology SC Hematology GA CD1CA UT WOS:000350810200010 PM 25406352 ER PT J AU Choi, CH Schoenfeld, BP Weisz, ED Bell, AJ Chambers, DB Hinchey, J Choi, RJ Hinchey, P Kollaros, M Gertner, MJ Ferrick, NJ Terlizzi, AM Yohn, N Koenigsberg, E Liebelt, DA Zukin, RS Woo, NH Tranfaglia, MR Louneva, N Arnold, SE Siegel, SJ Bolduc, FV McDonald, TV Jongens, TA McBride, SMJ AF Choi, Catherine H. Schoenfeld, Brian P. Weisz, Eliana D. Bell, Aaron J. Chambers, Daniel B. Hinchey, Joseph Choi, Richard J. Hinchey, Paul Kollaros, Maria Gertner, Michael J. Ferrick, Neal J. Terlizzi, Allison M. Yohn, Nicole Koenigsberg, Eric Liebelt, David A. Zukin, R. Suzanne Woo, Newton H. Tranfaglia, Michael R. Louneva, Natalia Arnold, Steven E. Siegel, Steven J. Bolduc, Francois V. McDonald, Thomas V. Jongens, Thomas A. McBride, Sean M. J. TI PDE-4 Inhibition Rescues Aberrant Synaptic Plasticity in Drosophila and Mouse Models of Fragile X Syndrome SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cAMP; Drosophila; fragile X; memory; mouse; phosphodiesterase 4 ID LONG-TERM DEPRESSION; MENTAL-RETARDATION PROTEIN; CYCLIC-AMP PHOSPHODIESTERASE; MUSHROOM BODY; PHARMACOLOGICAL RESCUE; COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; COURTSHIP BEHAVIOR; ADENYLATE-CYCLASE; MUTANT DROSOPHILA AB Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS. C1 [Choi, Catherine H.; Schoenfeld, Brian P.; Bell, Aaron J.; Hinchey, Joseph; Choi, Richard J.; Hinchey, Paul; Kollaros, Maria; Ferrick, Neal J.; Terlizzi, Allison M.; Koenigsberg, Eric; Liebelt, David A.; McDonald, Thomas V.; McBride, Sean M. J.] Albert Einstein Coll Med, Dept Med, Sect Mol Cardiol, Bronx, NY 10461 USA. [Choi, Catherine H.; Schoenfeld, Brian P.; Bell, Aaron J.; Hinchey, Joseph; Choi, Richard J.; Hinchey, Paul; Kollaros, Maria; Ferrick, Neal J.; Terlizzi, Allison M.; Koenigsberg, Eric; Liebelt, David A.; McDonald, Thomas V.; McBride, Sean M. J.] Albert Einstein Coll Med, Dept Mol Pharmacol, Sect Mol Cardiol, Bronx, NY 10461 USA. [Choi, Catherine H.] Lehigh Valley Hlth Syst, Dept Med, Allentown, PA 18103 USA. [Choi, Catherine H.] Drexel Univ, Coll Med, Dept Dermatol, Philadelphia, PA 19107 USA. [Schoenfeld, Brian P.; Weisz, Eliana D.; Bell, Aaron J.; Ferrick, Neal J.; Yohn, Nicole; Jongens, Thomas A.; McBride, Sean M. J.] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Chambers, Daniel B.; Bolduc, Francois V.] Univ Alberta, Ctr Neurosci, Dept Pediat, Edmonton, AB T6G 2N8, Canada. [Gertner, Michael J.; Zukin, R. Suzanne] Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Bronx, NY 10461 USA. [Woo, Newton H.] OND CDER FDA, Off Drug Evaluat 2, Div Anesthesia Analgesia & Addict Prod, Silver Spring, MD 20993 USA. [Tranfaglia, Michael R.] FRAXA Res Fdn, Newburyport, MA 01950 USA. [Louneva, Natalia; Arnold, Steven E.; Siegel, Steven J.; McBride, Sean M. J.] Univ Penn, Dept Psychiat, Sch Med, Philadelphia, PA 19104 USA. RP McDonald, TV (reprint author), Albert Einstein Coll Med, Dept Med & Mol Pharmacol, Sect Mol Cardiol, Bronx, NY 10461 USA. EM fbolduc@ualberta.ca; tom.mcdonald@einstein.yu.edu; jongens@mail.med.upenn.edu; smjmcbride@gmail.com OI Siegel, Steven/0000-0001-8058-9713 FU FRAXA Research Foundation; National Fragile X Foundation; Autism Speaks; Albert Einstein College of Medicine National Institutes of Health MSTP [R25 MH060490]; National Institutes of Health [GM086902]; DOD-Autism [AR1101189]; Canadian Institutes for Health Research; McMorris Autism Program FX This work was supported by the FRAXA Research Foundation to S.M.J.M., C.H.C., and T.A.J.; the National Fragile X Foundation for a summer fellowship award to Eric Koenigsberg; Autism Speaks to T.V.M. and S.M.J.M.; the Albert Einstein College of Medicine National Institutes of Health MSTP Grant R25 MH060490 (Clinical Research Scholars Program in Psychiatry) to S.M.J.M.; and National Institutes of Health Grant GM086902 and DOD-Autism Grant AR1101189 to T.A.J., D.B.C. and F.V.B. were supported by Canadian Institutes for Health Research. E.D.W. was supported by the McMorris Autism Program. We thank Efthimios Skoulakis, Myles Akabas, Thomas Dockendorff, Graham Ellis-Davies, Dan Kelley, Alex Harris, Boris Heifets, Kanji Takahashi, Diana Petit, Randi Hagerman, David Nelson, Elizabeth Berry-Kravis, Peter Davies, Peter Klein, Peter Vanderklish, Eric Klann, and Sumantra Chattarji for critical comments during this project; Mark Bear and Pablo Castillo for advice regarding the electrophysiology methods; Charles Rubin and Susan Horwitz for generously providing space and resources; Melanie Talent for the use of space and equipment; and the Animal Care Facility at Drexel College of Medicine and Albert Einstein College of Medicine, specifically Janet Schulenberg, Andy Nelson, Charlene Glenn, and Carlton Reed, for assistance with animal care. NR 91 TC 9 Z9 9 U1 3 U2 9 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 7 PY 2015 VL 35 IS 1 BP 396 EP 408 DI 10.1523/JNEUROSCI.1356-12.2015 PG 13 WC Neurosciences SC Neurosciences & Neurology GA CB1SB UT WOS:000349407200034 PM 25568131 ER PT J AU Chimalakonda, KC Pang, E Weaver, JL Howard, KE Patel, V Boyne, MT AF Chimalakonda, Krishna C. Pang, Eric Weaver, James L. Howard, Kristina E. Patel, Vikram Boyne, Michael T., II TI Development and validation of a liquid-chromatography tandem mass spectrometry method to determine in vitro and in vivo histamine release SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Histamine; LC-MS/MS; HILIC; Mast cell degranulation; Anaphylactic reactions ID BIOGENIC-AMINES; BRAIN; ASSAY; 1-METHYLHISTAMINE; METHYLHISTAMINE; METABOLITES; PEPTIDES; COLUMN; MS/MS; CELL AB Histamine is an important biogenic amine involved in regulating numerous physiological and pathophysiological processes in humans and animals. To date, there have been very few studies focused on developing and validating sensitive liquid-chromatography-tandem mass spectrometric (LC-MS/MS) assays capable of quantitative trace level histamine analysis in biological matrices. In the present study, a rapid and sensitive LC-MS/MS assay, amenable to high throughput analysis was developed and validated to characterize in vitro and in vivo histamine release. The LC-MS/MS procedure incorporating deuterium labeled internal standards provides rapid resolution of histamine with excellent sensitivity, precision, and accuracy. Histamine eluted at 1.5 min and was well separated from endogenous plasma peaks. The total run time of the assay was 8.0 min. A linear (r(2) >= 0.99) instrument response over the entire concentration range of 1.0-1000 ng/mL was observed. Excellent accuracy (error +/- 3.4%) and precision (CV +/- 10%) of the assay was demonstrated, with the lower limit of quantitation (LLOQ) at 15.6 ng/mL. The validated LC-MS/MS assay was applied to determine histamine release in both in vitro and in vivo models. Peritoneal mast cells treated with prototypical degranulating agents (Compound 48/80 and Teicoplanin) showed that the two chemicals caused approximately 40% histamine release. In rats, using this assay, basal histamine plasma levels were typically under 100 ng/mL. Treatment with an agent suspected of causing anaphylactic type reactions resulted in plasma histamine levels to increase above 3000 ng/mL. The LC-MS/MS assay presented in this study can be applied to further characterize the physiological and pathophysiological role of histamine release in complex in vitro and in vivo models. Importantly, the LC-MS/MS assay may be useful in assessing active pharmaceutical ingredient-mediated degranulation and anaphylaxis as part of either a pre-market or a post-market assessment of drug products. (C) 2014 Published by Elsevier B.V. C1 [Chimalakonda, Krishna C.; Pang, Eric; Weaver, James L.; Howard, Kristina E.; Patel, Vikram] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, 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. RP Boyne, MT (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Pharmaceut Anal, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Michael.Boyne@fda.hhs.gov FU CDER Critical Path Program; U.S. Food and Drug Administration FX Funding and support for this work was provided in part by the CDER Critical Path Program (MTB) and 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 Engineering and the U.S. Food and Drug Administration (EP). The authors also thank Sharron Stewart with assisting with the animal dosing experiments. NR 30 TC 3 Z9 3 U1 0 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 EI 1873-264X J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD JAN 5 PY 2015 VL 102 BP 494 EP 499 DI 10.1016/j.jpba.2014.10.016 PG 6 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA AY0HH UT WOS:000347277500059 PM 25459949 ER PT J AU Fiuza, JA Gannavaram, S Santiago, HD Selvapandiyan, A Souza, DM Passos, LSA de Mendonca, LZ Lemos-Giunchetti, DD Ricci, ND Bartholomeu, DC Giunchetti, RC Bueno, LL Correa-Oliveira, R Nakhasi, HL Fujiwara, RT AF Fiuza, Jacqueline Araujo Gannavaram, Sreenivas Santiago, Helton da Costa Selvapandiyan, Angamuthu Souza, Daniel Menezes Araujo Passos, Livia Silva de Mendonca, Ludmila Zanandreis Lemos-Giunchetti, Denise da Silveira Ricci, Natasha Delaqua Bartholomeu, Daniella Castanheira Giunchetti, Rodolfo Cordeiro Bueno, Lilian Lacerda Correa-Oliveira, Rodrigo Nakhasi, Hira L. Fujiwara, Ricardo Toshio TI Vaccination using live attenuated Leishmania donovani centrin deleted parasites induces protection in dogs against Leishmania infantum SO VACCINE LA English DT Article DE Vaccine; Leishmaniasis; Visceral leishmaniasis; Canine visceral leishmaniasis; Live attenuated; Vaccines; Leishmania ID CANINE VISCERAL LEISHMANIASIS; LUTZOMYIA-LONGIPALPIS; ASYMPTOMATIC DOGS; T-CELLS; CHAGASI; ANTIGENS; VACCINES; IMMUNOGENICITY; CHALLENGE; BRAZIL AB Live attenuated Leishmania donovani parasites such as LdCen(-/-) have been shown elicit protective immunity against leishmanial infection in mice and hamster models. Previously, we have reported on the induction of strong immunogenicity in dogs upon vaccination with LdCen(-/-) including an increase in immunoglobulin isotypes, higher lymphoproliferative response, higher frequencies of activated CD4(+) and CD8(+) T cells, IFN-gamma production by CD8(+) T cells, increased secretion of TNE-alpha and IL-12/1L-23p40 and, finally, decreased secretion of IL-4. To further explore the potential of LdCen(-/-) parasites as vaccine candidates, we performed a 24-month follow up of LdCen(-/-) immunized dogs after challenge with virulent Leishmania infantum, aiming determination of parasite burden by qPCR, antibody production (ELISA) and cellular responses (T cell activation and cytokine production) by flow cytometry and sandwich ELISA. Our data demonstrated that vaccination with a single dose of LdCen(-/-) (without any adjuvant) resulted in the reduction of up to 87.3% of parasite burden after 18 months of virulent challenge. These results are comparable to those obtained with commercially available vaccine in Brazil (Leishmunee). The protection was associated with antibody production and CD4(+) and CDS proliferative responses, as well as T cell activation and significantly higher production of IFN-gamma, IL-12/IL-23p40 and TNF-alpha, which was comparable to responses induced by immunization with Leishmune (R), with significant differences when compared to control animals (Placebo). Moreover, only animals immunized with LdCen(-/-) expressed lower levels of IL-4 when compared to animals vaccinated either with Leishmune (R) or PBS. Our results support further studies aiming to demonstrate the potential of genetically modified live attenuated L. donovani vaccine to control L. infantum transmission in endemic areas for CVL. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Fiuza, Jacqueline Araujo; Correa-Oliveira, Rodrigo] Fundacao Oswaldo Cruz, Lab Cellular & Mol Immunol, Ctr Pesquisas Rene Rachou, Belo Horizonte, MG, Brazil. [Fiuza, Jacqueline Araujo; Santiago, Helton da Costa; Souza, Daniel Menezes; Araujo Passos, Livia Silva; de Mendonca, Ludmila Zanandreis; Lemos-Giunchetti, Denise da Silveira; Ricci, Natasha Delaqua; Bartholomeu, Daniella Castanheira; Giunchetti, Rodolfo Cordeiro; Bueno, Lilian Lacerda; Fujiwara, Ricardo Toshio] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Fiuza, Jacqueline Araujo; Gannavaram, Sreenivas; Nakhasi, Hira L.] US FDA, Div Emerging & Transfus Transmitted Dis, Off Blood Res & Review, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Selvapandiyan, Angamuthu] Inst Mol Med, New Delhi 110020, India. RP Fujiwara, RT (reprint author), Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. EM fujiwara@icb.ufmg.br RI Bartholomeu, Daniella/J-4714-2015; Santiago, Helton/F-8704-2012; Fujiwara, Ricardo/J-7579-2012 OI Bartholomeu, Daniella/0000-0003-0974-7357; Santiago, Helton/0000-0002-5695-8256; Fujiwara, Ricardo/0000-0002-4713-575X FU Fundacao de Amparo a Pesquisa do Estado de Minas Gerais/FAPEMIG [CBB-PPM-00296-11]; Brazilian National Research Council (CNPq); CNPq fellowships FX This work was financially supported by the Fundacao de Amparo a Pesquisa do Estado de Minas Gerais/FAPEMIG (grant no. CBB-PPM-00296-11) and the Brazilian National Research Council (CNPq). HCS, DCB, RCG, RCO and RTF are supported by CNPq fellowships. NR 39 TC 16 Z9 16 U1 3 U2 13 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 JAN 3 PY 2015 VL 33 IS 2 BP 280 EP 288 DI 10.1016/j.vaccine.2014.11.039 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AZ5NX UT WOS:000348268500002 PM 25475955 ER PT J AU Cole, JB Heegaard, WG Deeds, JR McGrath, SC Handy, SM AF Cole, Jon B. Heegaard, William G. Deeds, Jonathan R. McGrath, Sara C. Handy, Sara M. TI Tetrodotoxin Poisoning Outbreak from Imported Dried Puffer - Fish Minneapolis, Minnesota, 2014 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID IDENTIFICATION C1 [Cole, Jon B.] Hennepin Reg Poison Ctr, Minneapolis, MN USA. [Cole, Jon B.; Heegaard, William G.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Deeds, Jonathan R.; McGrath, Sara C.; Handy, Sara M.] US FDA, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. RP Deeds, JR (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. EM jonathan.deeds@fda.hhs.gov RI Handy, Sara/C-6195-2008 NR 10 TC 6 Z9 7 U1 1 U2 12 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 JAN 2 PY 2015 VL 63 IS 51-52 BP 1222 EP 1225 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AY5FQ UT WOS:000347598800002 PM 25551594 ER PT J AU Weng, ZQ Luo, Y Yang, X Greenhaw, JJ Li, HB Xie, LM Mattes, WB Shi, Q AF Weng, Zuquan Luo, Yong Yang, Xi Greenhaw, James J. Li, Haibo Xie, Liming Mattes, William B. Shi, Qiang TI Regorafenib impairs mitochondrial functions, activates AMP-activated protein kinase, induces autophagy, and causes rat hepatocyte necrosis SO TOXICOLOGY LA English DT Article DE Regorafenib; Hepatotoxicity; Mitochondrion; Rat; Hepatocyte; Necrosis ID ACETAMINOPHEN-INDUCED HEPATOTOXICITY; CULTURED MOUSE HEPATOCYTES; PERMEABILITY TRANSITION; OXIDATIVE STRESS; LIVER-INJURY; INHIBITION; APOPTOSIS; CELLS; DYSFUNCTION; MECHANISMS AB The tyrosine kinase inhibitor regorafenib was approved by regulatory agencies for cancer treatment, albeit with strong warnings of severe hepatotoxicity included in the product label. The basis of this toxicity is unknown; one possible mechanism, that of mitochondrial damage, was tested. In isolated rat liver mitochondria, regorafenib directly uncoupled oxidative phosphorylation (OXPHOS) and promoted calcium overload-induced swelling, which were respectively prevented by the recoupler 6-ketocholestanol (KC) and the mitochondrial permeability transition (MPT) pore blocker cyclosporine A (CsA). In primary hepatocytes, regorafenib uncoupled OXPHOS, disrupted mitochondrial inner membrane potential (MMP), and decreased cellular ATP at 1 h, and triggered MPT at 3 h, which was followed by necrosis but not apoptosis at 7 h and 24 h, all of which were abrogated by K. The combination of the glycolysis enhancer fructose plus the mitochondrial ATPase synthase inhibitor oligomycin A abolished regorafenib induced necrosis at 7 h. This effect was not seen at 24 h nor with the fructose or oligomycin A separately. CsA in combination with trifluoperazine, both MPT blockers, showed similar effects. Two compensatory mechanisms, activation of AMP-activated protein kinase (AMPK) to ameliorate ATP shortage and induction of autophagy to remove dysfunctional mitochondria, were found to be mobilized. Hepatocyte necrosis was enhanced either by the AMPK inhibitor Compound C or the autophagy inhibitor chloroquine, while autophagy inducer rapamycin was strongly cytoprotective. Remarkably, all toxic effects were observed at clinically-relevant concentrations of 2.5-15 mu M. These data suggest that uncoupling of OXPHOS and the resulting ATP shortage and MPT induction are the key mechanisms for regorafenib induced hepatocyte injury, and AMPK activation and autophagy induction serve as pro-survival pathways against such toxicity. Published by Elsevier Ireland Ltd. C1 [Weng, Zuquan; Luo, Yong; Yang, Xi; Greenhaw, James J.; Li, Haibo; Xie, Liming; Shi, Qiang] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. [Mattes, William B.] PharmPoint Consulting, Poolesville, MD 20837 USA. RP Shi, Q (reprint author), US FDA, Natl Ctr Toxicol Res, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM qiang.shi@fda.hhs.gov FU U.S. FDA's Office of Women's Health; Research Participation Program at the National Center for Toxicological Research; Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. FDA; International Cooperation and Exchanges program from the Department of Health in Jiangsu Province, China FX This project is supported by the U.S. FDA's Office of Women's Health. Drs. Zuquan Weng and Haibo Li are supported by the Research Participation Program at the National Center for Toxicological Research administrated by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. FDA. Dr. Haibo Li is also partially supported by the International Cooperation and Exchanges (2012) program from the Department of Health in Jiangsu Province, China. The authors would like to thank Dr. Donna L. Mendrick for her critical review of this manuscript. NR 51 TC 6 Z9 7 U1 2 U2 16 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 JAN 2 PY 2015 VL 327 BP 10 EP 21 DI 10.1016/j.tox.2014.11.002 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AY9JJ UT WOS:000347866000002 PM 25445804 ER PT J AU Richards-Rissetto, H Plessing, R AF Richards-Rissetto, Heather Plessing, Rachel BE Guidi, G Torres, JC Scopigno, R Graf, H Remondino, F Brunet, P Barcelo, J Duranti, L Hazan, S TI Procedural Modeling for Ancient Maya Cityscapes Initial methodological challenges and solutions SO 2015 DIGITAL HERITAGE INTERNATIONAL CONGRESS, VOL 2: ANALYSIS & INTERPRETATION THEORY, METHODOLOGIES, PRESERVATION & STANDARDS DIGITAL HERITAGE PROJECTS & APPLICATIONS LA English DT Proceedings Paper CT Digital Heritage International Congress CY SEP 28-OCT 02, 2015 CL Granada, SPAIN SP VSMM, EG, IEEE, Sociedad Espanola Arqueologia Virtual, Univ Granada, Innova Virtual Archaeol, Archeo Virtual, CIPA, Comp Applicat & Quantitat Methods Archaeol, SPACE2PLACE, V-Must, Council Alhambra & Generalife, Andalusian Regional Minist Econ & Knowledge, Spanish Minist Econ & Competitiveness, AUTODESK, IBERIA, BARCO, Viajes & Corte Ingles, Escuela Tecnica Superior Ingenierias Informatica Telecomunicac, Oficina Software Libre, LST, Intl Campus Excellence Heritage, Sci Pk Museum DE Procedural Modeling; Landscape Archaeology; Ancient Maya; 3D Visualization; Architecture AB Digital reconstruction of 3D cityscapes is expensive, time-consuming, and requires significant expertise. We need a 3D modeling approach that streamlines the integration of multiple data types in a time-efficient and low-cost manner. Procedural modeling-rapid proto-typing of 3D models from a set of rules-offers a potential solution to this problem because it allows scholars to create digital reconstructions that can be quickly updated and used to test and formulate alternative hypotheses that are derived from and linked to underlying archaeological data. While procedural modeling is being used to visualize ancient Roman, Etruscan, and Greek cities, in the Maya region the approach has only been applied to reconstructions of individual buildings and not an entire city. In this paper, we present initial methodological challenges and solutions to procedural modeling of ancient Maya cityscapes using the UNESCO World Heritage Site of Copan, Honduras as a case study. C1 [Richards-Rissetto, Heather] Univ Lincoln Nebraska, Dept Anthropol, Lincoln, NE 68588 USA. [Richards-Rissetto, Heather] Univ Lincoln Nebraska, CDRH, Lincoln, NE USA. [Plessing, Rachel] Univ Lincoln Nebraska, Sch Architecture, Lincoln, NE USA. RP Richards-Rissetto, H (reprint author), Univ Lincoln Nebraska, Dept Anthropol, Lincoln, NE 68588 USA. EM richards-rissetto@unl.edu; rplessing@hotmail.com NR 13 TC 0 Z9 0 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-5090-0048-7 PY 2015 BP 85 EP 88 PG 4 WC Computer Science, Interdisciplinary Applications; Information Science & Library Science SC Computer Science; Information Science & Library Science GA BG0WW UT WOS:000386557900012 ER PT B AU Niederauer, CAP da Silva, M AF Pittaluga Niederauer, Carlos Alberto da Silva, Manuela BE Kamau, EC Winter, G Stoll, PT TI Research on genetic resources in the framework of the Brazilian ABS law SO RESEARCH AND DEVELOPMENT ON GENETIC RESOURCES: PUBLIC DOMAIN APPROACHES IN IMPLEMENTING THE NAGOYA PROTOCOL SE Routledge Research in International Environmental Law LA English DT Article; Book Chapter C1 [Pittaluga Niederauer, Carlos Alberto] Natl Council Sci & Technol Dev CNPq, Sci & Technol, Brasilia, DF, Brazil. [da Silva, Manuela] US FDA, NCTR, Rockville, MD 20857 USA. [da Silva, Manuela] FIOCRUZ Fundacao Oswaldo Cruz, Res & Reference Labs, Rio De Janeiro, Brazil. [da Silva, Manuela] FIOCRUZ Fundacao Oswaldo Cruz, Fiocruz Biol Collect, Rio De Janeiro, Brazil. [da Silva, Manuela] Natl Inst Hlth Qual Control INCQS FIOCRUZ, Rio De Janeiro, Brazil. RP Niederauer, CAP (reprint author), Natl Council Sci & Technol Dev CNPq, Sci & Technol, Brasilia, DF, Brazil. EM carlos.niederauer@cnpq.br; manueladasilva@fiocruz.br NR 10 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE PI ABINGDON PA 2 PARK SQ, MILTON PARK, ABINGDON OX14 4RN, OXFORD, ENGLAND BN 978-1-31571-783-8; 978-1-138-85861-9 J9 ROUT RES INT ENV LAW PY 2015 BP 93 EP 109 PG 17 WC Environmental Studies; Law SC Environmental Sciences & Ecology; Government & Law GA BF6QY UT WOS:000383591600007 ER PT S AU Park, SA Gray, RA AF Park, Sarah A. Gray, Richard A. BE Canepari, M Zecevic, D Bernus, O TI Optical Mapping of Ventricular Fibrillation Dynamics SO MEMBRANE POTENTIAL IMAGING IN THE NERVOUS SYSTEM AND HEART SE Advances in Experimental Medicine and Biology LA English DT Article; Book Chapter DE Fibrillation; Optical mapping; Spiral; Action potential; Conduction velocity ID ISOLATED RABBIT HEART; CONDUCTION-VELOCITY RESTITUTION; REENTRANT ATRIAL ARRHYTHMIAS; ACTION-POTENTIAL DURATION; ISOLATED CARDIAC-MUSCLE; SPIRAL WAVE BREAKUP; ELECTRICAL RESTITUTION; MULTIPLE MECHANISMS; SLOW CONDUCTION; TISSUE MASS AB There is very limited information regarding the dynamic patterns of the electrical activity during ventricular fibrillation (VF) in humans. Most of the data used to generate and test hypotheses regarding the mechanisms of VF come from animal models and computer simulations and the quantification of VF patterns is non-trivial. Many of the experimental recordings of the dynamic spatial patterns of VF have been obtained from mammals using "optical mapping" or "video imaging" technology in which "phase maps" are derived from high-resolution transmembrane recordings from the heart surface. The surface manifestation of the unstable reentrant waves sustaining VF can be identified as "phase singularities" and their number and location provide one measure of VF complexity. After providing a brief history of optical mapping of VF, we compare and contrast a quantitative analysis of VF patterns from the heart surface for four different animal models, hence providing physiological insight into the variety of VF dynamics among species. We found that in all four animal models the action potential duration restitution slope was actually negative during VF and that the spatial dispersion of electrophysiological parameters were not different during the first second of VF compared to pacing immediately before VF initiation. Surprisingly, our results suggest that APD restitution and spatial dispersion may not be essential causes of VF dynamics. Analyses of electrophysiological quantities in the four animal models are consistent with the idea that VF is essentially a two-dimensional phenomenon in small rabbit hearts whose size are near the boundary of the "critical mass" required to sustain VF, while VF in large pig hearts is three-dimensional and exhibits the maximal theoretical phase singularity density, and thus will not terminate spontaneously. C1 [Park, Sarah A.] Johns Hopkins Univ, Sch Med, FM Kirby Res Ctr Funct Brain Imaging, Kennedy Krieger Inst,Russell H Morgan Dept Radiol, Baltimore, MD 21205 USA. [Gray, Richard A.] US FDA, Div Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,WO62 Room 1114, Silver Spring, MD 20993 USA. RP Gray, RA (reprint author), US FDA, Div Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,WO62 Room 1114, Silver Spring, MD 20993 USA. EM Richard.Gray@fda.hhs.gov NR 74 TC 0 Z9 0 U1 3 U2 5 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 0065-2598 BN 978-3-319-17641-3; 978-3-319-17640-6 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2015 VL 859 BP 313 EP 342 DI 10.1007/978-3-319-17641-3_13 D2 10.1007/978-3-319-17641-3 PG 30 WC Cell Biology; Medicine, Research & Experimental; Physiology SC Cell Biology; Research & Experimental Medicine; Physiology GA BF4JM UT WOS:000381082700014 PM 26238059 ER PT S AU Daluwatte, C Scully, CG Kramer, GC Strauss, DG AF Daluwatte, Chathuri Scully, Christopher G. Kramer, George C. Strauss, David G. BE Murray, A TI A Robust Detection Algorithm to Identify Breathing Peaks in Respiration Signals from Spontaneously Breathing Subjects SO 2015 COMPUTING IN CARDIOLOGY CONFERENCE (CINC) SE Computing in Cardiology Conference LA English DT Proceedings Paper CT 2015 Comp in Cardiol Conference (CinC) CY SEP 06-09, 2015 CL Comp in Cardiol 2015, nice, FRANCE HO Comp in Cardiol 2015 ID SHOCK AB Assessing respiratory and cardiovascular system coupling can provide new insights into disease progression, but requires accurate analysis of each signal. Respiratory waveform data collected during spontaneous breathing are noisy and respiration rates from long term physiological experiments can vary over a wide range across time. There is a need for automatic and robust algorithms to detect breathing peaks in respiration signals for assessment of the coupling between the respiratory and cardiovascular systems. We developed an automatic algorithm to detect breathing peaks from a respiration signal. The algorithm was tested on respiration signals collected during hemorrhage in a conscious ovine model (N = 9, total length = 11.0h). The breathing rate varied from 15 to as high as 160 breaths/min for some animals during the hemorrhage protocol. The sensitivity of the algorithm to detect respiration peaks was 93.7% with a precision of 94.5%. The developed algorithm presents a promising approach to detect breathing peaks in respiration signals from spontaneously breathing subjects. The algorithm was able to consistently identify breathing peaks while the breathing rate varied from 15 to 160 breaths/min. C1 [Daluwatte, Chathuri; Scully, Christopher G.; Strauss, David G.] US FDA, Div Biomed Phys, Off Sci & Engn Labs, CDRH, Silver Spring, MD USA. [Kramer, George C.] Univ Texas Med Branch, Dept Anesthesiol, Galveston, TX 77555 USA. RP Daluwatte, C (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM chathuri.daluwatte@fda.hhs.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2325-887X BN 978-1-5090-0685-4 J9 COMPUT CARDIOL CONF PY 2015 VL 42 BP 297 EP 300 PG 4 WC Computer Science, Interdisciplinary Applications; Engineering, Multidisciplinary; Engineering, Biomedical SC Computer Science; Engineering GA BF1CZ UT WOS:000380374700076 ER PT S AU Daluwatte, C Johannesen, L Vicente, J Scully, CG Galeotti, L Strauss, DG AF Daluwatte, Chathuri Johannesen, Lars Vicente, Jose Scully, Christopher G. Galeotti, Loriano Strauss, David G. BE Murray, A TI Heartbeat Fusion Algorithm to Reduce False Alarms for Arrhythmias SO 2015 COMPUTING IN CARDIOLOGY CONFERENCE (CINC) SE Computing in Cardiology Conference LA English DT Proceedings Paper CT 2015 Comp in Cardiol Conference (CinC) CY SEP 06-09, 2015 CL Comp in Cardiol 2015, nice, FRANCE HO Comp in Cardiol 2015 ID CARE AB There is a need for patient monitoring algorithms to reduce alarm fatigue by rejecting clinically irrelevant alarms. We developed an algorithm using multimodal physiological waveforms (electrocardiogram, blood pressure, photoplethysmogram) and noise classifiers to improve arrhythmia detection by reducing the incidence of false alarms while maintaining a high true alarm rate as part of the Physionet Challenge 2015. Combining information from multiple physiological signals our algorithm was able to discard 362 of 456 false alarms (true negative rate [MR] of 79%), while correctly classifting 268 of the 294 true alarms (true positive rate [TPRI of 91%) on the training set, a score of 73.8. When applied to the test set which had 343 false alarms and 157 true alarms, we achieved a TNR of 81%, TPR of 86% and score of 70.2. Our results support the concept that false alarms can be reduced in the intensive care unit by removing noise segments in signals and combining information from multiple physiological signals. C1 [Daluwatte, Chathuri; Johannesen, Lars; Vicente, Jose; Scully, Christopher G.; Galeotti, Loriano; Strauss, David G.] US FDA, Div Biomed Phys, Off Sci & Engn Labs, CDRH, Silver Spring, MD USA. [Johannesen, Lars] Karolinska Inst, Dept Clin Physiol, Stockholm, Sweden. [Johannesen, Lars] Karolinska Univ Hosp, Stockholm, Sweden. [Vicente, Jose] US FDA, Div Cardiovasc & Renal Prod, Off New Drugs, CDER, Silver Spring, MD USA. [Vicente, Jose] Univ Zaragoza, BSICoS Grp, Aragon Inst Engn Res I3A, IIS Aragon, Zaragoza, Spain. RP Daluwatte, C (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM chathuri.daluwatte@fda.hhs.gov NR 11 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2325-887X BN 978-1-5090-0685-4 J9 COMPUT CARDIOL CONF PY 2015 VL 42 BP 745 EP 748 PG 4 WC Computer Science, Interdisciplinary Applications; Engineering, Multidisciplinary; Engineering, Biomedical SC Computer Science; Engineering GA BF1CZ UT WOS:000380374700188 ER PT J AU Huang, V Klepser, ME Gubbins, PO Bergman, SJ Chahine, EB Halilovic, J Hidayat, LK Matthias, KR Tesh, LD AF Huang, Vanthida Klepser, Michael E. Gubbins, Paul O. Bergman, Scott J. Chahine, Elias B. Halilovic, Jenana Hidayat, Levita K. Matthias, Kathryn R. Tesh, Lauren D. TI Quantification of curricular content devoted to point-of-care testing for infectious diseases in schools and colleges of pharmacy in the United States SO PHARMACY EDUCATION LA English DT Article DE infectious disease; point of care tests; pharmacy curriculum AB Background: Point of care (POC) testing for infectious diseases represents a potential pharmacy service, but how much education on these tests is included in the professional pharmacy curriculum in the United States (US) is unknown. The aim of this study was to determine the extent to which schools/colleges of pharmacy include such content in their curriculum. Methods: From August 2012 through June 2013, administrators from 128 schools/colleges of pharmacy were asked to complete an electronic survey. Results: Complete responses were received from 114 (89.1%) unique institutions. One third (n=38) of responding institutions reported including such content, but the majority (94.7%) of these institutions devoted less than 3 hours to the topic in their curriculum. Conclusions: United States professional pharmacy programs include little or no educational content regarding POC tests for infectious diseases. Academic pharmacy should explore ways to incorporate practical content regarding POC tests for infectious diseases into the professional curriculum. C1 [Huang, Vanthida] Midwestern Univ, Coll Pharm Glendale, Pharm Practice, Glendale Arizona, AZ USA. [Klepser, Michael E.] Ferris State Univ, Coll Pharm, Kalamazoo, MI USA. [Gubbins, Paul O.] SW Missouri State Univ, UMKC Sch Pharm, Pharm Practice & Adm, Springfield, MO 65806 USA. [Bergman, Scott J.] So Illinois Univ, Sch Pharm, Pharm Practice, Edwardsville, IL 62026 USA. [Chahine, Elias B.] Palm Beach Atlantic Univ, Lloyd L Gregory Sch Pharm, Pharm Practice, W Palm Beach, FL USA. [Halilovic, Jenana] Univ Pacific, Thomas J Long Sch Pharm & Hlth Sci, Pharm Practice, Stockton, CA 95211 USA. [Hidayat, Levita K.] Touro Coll Pharm, Pharm & Hlth Outcomes, New York, NY USA. [Matthias, Kathryn R.] Univ Arizona, Coll Pharm, Pharm Practice & Sci, Tucson, AZ 85721 USA. [Tesh, Lauren D.] CDER, OEP, DACCM, Silver Spring, MD USA. RP Gubbins, PO (reprint author), SW Missouri State Univ, UMKC Sch Pharm, Div Pharm Practice & Adm, Bldg One,327 West Mill St,Fourth Floor, Springfield, MO 65806 USA. EM gubbinsp@umkc.edu OI Bergman, Scott/0000-0002-6466-9518 NR 19 TC 0 Z9 0 U1 0 U2 0 PU INTERNATIONAL PHARMACEUTICAL FEDERATION PI THE HAGUE PA PO BOX 84200, THE HAGUE, 2508 AE, NETHERLANDS SN 1560-2214 EI 1477-2701 J9 PHARM EDUC JI Pharm. Educ. PY 2015 VL 15 IS 1 BP 1 EP 6 PG 6 WC Education, Scientific Disciplines SC Education & Educational Research GA DP4QT UT WOS:000378481400001 ER PT S AU Hughes, M Ghosh, T AF Hughes, Minerva Ghosh, Tapash BE Rathbone, MJ Senel, S Pather, I TI Pharmaceuticals for Oral Mucosal Drug Delivery: Regulatory Considerations SO ORAL MUCOSAL DRUG DELIVERY AND THERAPY SE Advances in Delivery Science and Technology LA English DT Article; Book Chapter C1 [Hughes, Minerva; Ghosh, Tapash] US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. RP Ghosh, T (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM Tapash.Ghosh@fda.hhs.gov NR 15 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 2192-6204 BN 978-1-4899-7558-4; 978-1-4899-7557-7 J9 ADV DEL SCI TECHNOL PY 2015 BP 247 EP 274 D2 10.1007/978-1-4899-7558-4 PG 28 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA BE9UO UT WOS:000378208700012 ER PT S AU Neufeld, E Oikonomidis, IV Iacono, MI Akinnagbe, E Angelone, LM Kainz, W Kuster, N AF Neufeld, Esra Oikonomidis, Ioannis V. Iacono, Maria I. Akinnagbe, Esther Angelone, Leonardo M. Kainz, Wolfgang Kuster, Niels GP IEEE TI Simulation Platform for Coupled Modeling of EM-Induced Neuronal Dynamics and Functionalized Anatomical Models SO 2015 7TH INTERNATIONAL IEEE/EMBS CONFERENCE ON NEURAL ENGINEERING (NER) SE International IEEE EMBS Conference on Neural Engineering LA English DT Proceedings Paper CT 7th Annual International IEEE EMBS Conference on Neural Engineering (NER) CY APR 22-24, 2015 CL Montpellier, FRANCE SP IEEE, EMBS AB A computational platform has been developed that is capable of simulating electromagnetic (EM) field interactions with neurons in complex tissue-structure environments. The platform has been tested in three case studies, namely: a) transcranial alternating current brain stimulation; b) MRI gradient coil switching induced nerve stimulation; and c) muscle activation by a neuroprosthetic implant. These applications were based on the use of a functionalized head and a whole-body model. Additionally a dedicated EM solver coupled with dynamic models of neuronal activity was also implemented. A high-resolution model of the head was developed for the analysis of EM-neuron interactions. Multimodal magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) data were acquired to guide neuron model placement and provide information on tissue anisotropy. The model, called "MIDA", features a large number of structures, particularly those (ears, eyes, and selected deep brain structures) relevant for applications such as DBS (Deep Brain Stimulation) and neuroprosthetics. A DBS application example is also shown. C1 [Neufeld, Esra; Oikonomidis, Ioannis V.; Kuster, Niels] ITIS Fdn Res Informat Technol Soc, Zurich, Switzerland. [Oikonomidis, Ioannis V.; Kuster, Niels] Swiss Fed Inst Technol ETHZ, Zurich, Switzerland. [Iacono, Maria I.; Akinnagbe, Esther; Angelone, Leonardo M.; Kainz, Wolfgang] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Neufeld, E (reprint author), ITIS Fdn Res Informat Technol Soc, Zurich, Switzerland. EM neufeld@itis.ethz.ch NR 13 TC 0 Z9 0 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1948-3546 BN 978-1-4673-6389-1 J9 I IEEE EMBS C NEUR E PY 2015 BP 517 EP 520 PG 4 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA BE9FT UT WOS:000377414600129 ER PT J AU Eigenberger, P Irwin, D Loomis, Z Maltzhan, J Anderson, M Lisk, C Buehler, P AF Eigenberger, P. Irwin, D. Loomis, Z. Maltzhan, J. Anderson, M. Lisk, C. Buehler, P. TI Hemoglobin Extravasation, Tissue Iron Accumulation And Oxidative Stress Contribute To Hemolysis Related Pulmonary Hypertenstion SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Eigenberger, P.] Univ Colorado, Denver, CO 80202 USA. [Irwin, D.; Loomis, Z.; Maltzhan, J.] Univ Colorado Denver, Aurora, CO USA. [Anderson, M.] Childrens Hosp Colorado, Aurora, CO USA. [Lisk, C.] Boston Univ, Boston, MA 02215 USA. [Buehler, P.] US FDA, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A5275 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582807094 ER PT J AU Lowers, HA Todorov, T Strand, MJ Breit, G Meeker, GP Plumlee, GS Robinson, M Miller, R Krefft, S Meehan, RT Groshong, SD Rose, C AF Lowers, H. A. Todorov, T. Strand, M. J. Breit, G. Meeker, G. P. Plumlee, G. S. Robinson, M. Miller, R. Krefft, S. Meehan, R. T. Groshong, S. D. Rose, C. TI Lung Biopsies From Symptomatic Military Deployers Have Variable Mineral Particle Types And Higher Abundances Of Silicon, Aluminum, Cadmium And Vanadium Compared To Controls SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT International Conference of the American-Thoracic-Society (ATS) CY MAY 15-20, 2015 CL Denver, CO SP Amer Thorac Soc C1 [Lowers, H. A.; Breit, G.; Meeker, G. P.; Plumlee, G. S.] US Geol Survey, Denver, CO 80225 USA. [Todorov, T.] US FDA, College Pk, MD USA. [Strand, M. J.; Robinson, M.; Krefft, S.; Meehan, R. T.; Groshong, S. D.] Natl Jewish Hlth, Denver, CO 80206 USA. [Miller, R.] Vanderbilt Univ, Nashville, TN 37235 USA. [Rose, C.] Univ Colorado, Sch Med, Colorado Sch Publ Hlth, Natl Jewish Hlth, Denver, CO USA. EM rosec@njhealth.org NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2015 VL 191 MA A2575 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DO2AW UT WOS:000377582802429 ER PT S AU Lin, A Salvador, A Carter, JM AF Lin, Andrew Salvador, Alexandra Carter, J. Mark BE Hnasko, R TI Multiplexed Microsphere Suspension Array-Based Immunoassays SO ELISA: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Microsphere; Bead-based assay; ELISA; Immunoassay; Antibody; Multiplex AB ELISA is an extremely powerful tool to detect analytes because of its sensitivity, selectivity, reproducibility and ease of use. Here we describe sandwich immunoassays performed in suspension on spectrally unique microspheres developed by Luminex. Luminex assays offer the benefit of multiplex analysis of large numbers of analytes in a single reaction. Because the microspheres are spectrally unique, many microspheres, each attached to various antibodies, can be added to a single sample. Luminex instruments can distinguish each microsphere and detect the intensity of a reporter signal for each microsphere. Results are reported in Median Fluorescent Intensities for each analyte. Luminex assays can be used to detect up to 500 analytes in a high-throughput format. Luminex refers to this technology as xMAP (R). Here we describe a routine protocol for a Luminex immunoassay. Other Luminex assays would have to be optimized for specific conditions according to their use. C1 [Lin, Andrew] US FDA, Alameda, CA USA. [Salvador, Alexandra; Carter, J. Mark] ARS, USDA, Albany, CA USA. RP Lin, A (reprint author), US FDA, Alameda, CA USA. NR 5 TC 3 Z9 5 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-4939-2742-5; 978-1-4939-2741-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2015 VL 1318 BP 107 EP 118 DI 10.1007/978-1-4939-2742-5_11 D2 10.1007/978-1-4939-2742-5 PG 12 WC Immunology SC Immunology GA BE7OP UT WOS:000375613000012 PM 26160569 ER PT S AU Atta-ur-Rahman Reitz, AB Choudhary, I Wang, JB AF Atta-ur-Rahman Reitz, Allen B. Choudhary, Iqbal Wang, Jizhou BE AttaUrRahman Reitz, AB Choudhary, MI Wang, J TI Frontiers in Medicinal Chemistry (Volume 7) PREFACE SO FRONTIERS IN MEDICINAL CHEMISTRY, VOL 7 SE Frontiers in Medicinal Chemistry LA English DT Editorial Material; Book Chapter C1 [Atta-ur-Rahman] Univ Cambridge, Kings Coll, Cambridge, England. [Reitz, Allen B.] Fox Chase Chem Divers Ctr Inc, Doylestown, PA 18902 USA. [Choudhary, Iqbal] Univ Karachi, HEJ Res Inst Chem, Karachi 75270, Pakistan. [Wang, Jizhou] US FDA, Silver Spring, MD USA. RP Atta-ur-Rahman (reprint author), Univ Cambridge, Kings Coll, Cambridge, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BENTHAM SCIENCE PUBL PI BUSUM PA PO BOX 294, BUSUM, 1400 AG, NETHERLANDS SN 1567-2042 BN 978-1-60805-970-6; 978-1-60805-971-3 J9 FRONT MED CHEM PY 2015 VL 7 BP I EP I PG 1 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA BE8MP UT WOS:000376601600001 ER PT S AU Agarabi, C Khan, MA Shah, RB AF Agarabi, Cyrus Khan, Mansoor A. Shah, Rakhi B. BE Jameel, F Hershenson, S Khan, MA MartinMoe, S TI Challenges and Opportunities for Biotech Quality by Design SO QUALITY BY DESIGN FOR BIOPHARMACEUTICAL DRUG PRODUCT DEVELOPMENT SE AAPS Advances in the Pharmaceutical Sciences Series LA English DT Article; Book Chapter ID NEAR-INFRARED SPECTROSCOPY; CULTURE; SYSTEMS; LINE C1 [Agarabi, Cyrus; Khan, Mansoor A.; Shah, Rakhi B.] US FDA, Div Prod Qual Res, Off Testing & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Agarabi, Cyrus; Khan, Mansoor A.; Shah, Rakhi B.] US FDA, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Shah, RB (reprint author), US FDA, Div Prod Qual Res, Off Testing & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM rakhi.shah@fda.hhs.gov NR 36 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 2210-7371 BN 978-1-4939-2316-8; 978-1-4939-2315-1 J9 AAPS ADV PHARM SCI PY 2015 VL 18 BP 1 EP 15 DI 10.1007/978-1-4939-2316-8_1 D2 10.1007/978-1-4939-2316-8 PG 15 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BE5RW UT WOS:000373343400002 ER PT S AU Rellahan, BL Kozlowski, S Swann, P AF Rellahan, Barbara L. Kozlowski, Steven Swann, Patrick BE Jameel, F Hershenson, S Khan, MA MartinMoe, S TI Lessons Learned from Monoclonal Antibody Applications to the Office of Biotechnology Products Quality by Design Pilot Program SO QUALITY BY DESIGN FOR BIOPHARMACEUTICAL DRUG PRODUCT DEVELOPMENT SE AAPS Advances in the Pharmaceutical Sciences Series LA English DT Article; Book Chapter C1 [Rellahan, Barbara L.] US FDA, Div Monoclonal Antibodies, Off Biotechnol Prod, Off Pharmaceut Sci,Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [Rellahan, Barbara L.] Amgen Inc, Rockville, MD 20850 USA. [Kozlowski, Steven] US FDA, Off Biotechnol Prod, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [Swann, Patrick] Biogen Idec Inc, Cambridge, MA USA. RP Rellahan, BL (reprint author), US FDA, Div Monoclonal Antibodies, Off Biotechnol Prod, Off Pharmaceut Sci,Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. EM rellahan@amgen.com NR 18 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 2210-7371 BN 978-1-4939-2316-8; 978-1-4939-2315-1 J9 AAPS ADV PHARM SCI PY 2015 VL 18 BP 17 EP 29 DI 10.1007/978-1-4939-2316-8_2 D2 10.1007/978-1-4939-2316-8 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BE5RW UT WOS:000373343400003 ER PT S AU Kim, DH AF Kim, Do-Hyun GP IEEE TI Multi-Spectral Imaging for Determining End-Point of Photothermal Damage of Tissue SO 2015 CONFERENCE ON LASERS AND ELECTRO-OPTICS (CLEO) SE Conference on Lasers and Electro-Optics LA English DT Proceedings Paper CT Conference on Lasers and Electro-Optics (CLEO) CY MAY 10-15, 2015 CL San Jose, CA AB Multi-spectral imaging (MSI) and its analysis methods were investigated to determine end-point of photothermal damage of tissue. MSI revealed denatured porcine tissue after irradiation of laser with irradiance lower than photothermal damage threshold. C1 [Kim, Do-Hyun] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Kim, DH (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM do-hyun.kim@fda.hhs.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2160-9020 BN 978-1-55752-968-8 J9 CONF LASER ELECTR PY 2015 PG 2 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA BE3EW UT WOS:000370627100076 ER PT S AU Le, HND Kim, DH Hassan, M Calhoun, W Huang, Y Ilev, IK Kang, JU AF Le, Hanh N. D. Kim, Do-Hyun Hassan, Moinuddin Calhoun, William Huang, Yong Ilev, Ilko K. Kang, Jin U. GP IEEE TI Transmittance of Ex vivo Bovine Lens Capsule from 800 cm(-1) to 40000 cm(-1) SO 2015 CONFERENCE ON LASERS AND ELECTRO-OPTICS (CLEO) SE Conference on Lasers and Electro-Optics LA English DT Proceedings Paper CT Conference on Lasers and Electro-Optics (CLEO) CY MAY 10-15, 2015 CL San Jose, CA AB Here we present detailed transmission measurements of ex-vivo lens capsule from 40,000 cm(-1) to 800 cm(-1). Time-dependent measurements were also performed to eliminate water absorption. C1 [Le, Hanh N. D.; Huang, Yong; Kang, Jin U.] Johns Hopkins Univ, Dept Elect & Comp Engn, 3400 North Charles St, Baltimore, MD 21218 USA. [Kim, Do-Hyun; Hassan, Moinuddin; Calhoun, William; Ilev, Ilko K.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Le, HND (reprint author), Johns Hopkins Univ, Dept Elect & Comp Engn, 3400 North Charles St, Baltimore, MD 21218 USA. EM jkang@jhu.edu NR 2 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2160-9020 BN 978-1-55752-968-8 J9 CONF LASER ELECTR PY 2015 PG 2 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA BE3EW UT WOS:000370627100058 ER PT S AU U-Thainual, P Kim, DH AF U-Thainual, Paweena Kim, Do-Hyun GP IEEE TI Characterization of optical resolution photoacoustic microscopy in comparison to confocal microscopy SO 2015 CONFERENCE ON LASERS AND ELECTRO-OPTICS (CLEO) SE Conference on Lasers and Electro-Optics LA English DT Proceedings Paper CT Conference on Lasers and Electro-Optics (CLEO) CY MAY 10-15, 2015 CL San Jose, CA AB Lateral resolution and depth discrimination in turbid samples was measured with optical resolution photoacoustic microscopy (ORPAM) and compared to confocal microscopy (CM). ORPAM signal strength and CM resolution were relatively less affected by scattering. C1 [U-Thainual, Paweena; Kim, Do-Hyun] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Kim, DH (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM do-hyun.kim@fda.hhs.gov NR 2 TC 0 Z9 0 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2160-9020 BN 978-1-55752-968-8 J9 CONF LASER ELECTR PY 2015 PG 2 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA BE3EW UT WOS:000370627100060 ER PT B AU Robkin, M Weininger, S Preciado, B Goldman, J AF Robkin, Michael Weininger, Sandy Preciado, Benjamin Goldman, Julian GP IEEE TI Levels of Conceptual Interoperability Model for Healthcare Framework for Safe Medical Device Interoperability SO 2015 IEEE SYMPOSIUM ON PRODUCT COMPLIANCE ENGINEERING (ISPCE 2015) LA English DT Proceedings Paper CT 12th IEEE Annual Symposium on Product Compliance Engineering (ISPCE) CY MAY 18-20, 2015 CL Chicago, IL SP IEEE, IEEE Prod Safety Engn Soc, UL, LiftMaster, Dell, Nemko, In Compliance DE Medical Device; Safety; Conceptual; Dynamic; Pragmatic; Semantic; Syntactic Interoperability; Standards; LCIM; Plug-and-Play; PNP; Healthcare Information Technology; HIT; MD PnP AB The Medical Device and Healthcare Information Technology (HIT) industries have not achieved safe PNP cross-manufacturer (heterogeneous) interoperability although it has been achieved decades ago in other safety critical industries. We believe that the Levels of Conceptual Interoperability Model (LCIM) [1] offers an essential account of the disparity and thereby offers insight for how to achieve safe PNP cross-manufacturer interoperability in HIT. The LCIM is a conceptual framework for interoperability first developed for military simulation and modeling. We have expanded its scope and detail while applying it to medical devices. Our results show that safe interoperability minimally requires system components that are aligned about a conceptual model (i.e. manufacturers are operating at level 6). Furthermore, such devices can be assured to be safely interoperable cross-manufacturer only if different manufacturers share the conceptual model embodied by the communicating devices. We identify some root causes preventing this realization. C1 [Robkin, Michael; Preciado, Benjamin] Anakena Solut Inc, Woodland Hills, CA USA. [Weininger, Sandy] US FDA, CDRH, Silver Spring, MD USA. [Goldman, Julian] Massachusetts Gen Hosp, MD PnP Program, Boston, MA 02114 USA. RP Robkin, M (reprint author), Anakena Solut Inc, Woodland Hills, CA USA. EM MikeRobkin@gmail.com; Sandy.Weininger@fda.hhs.gov; bpreciado@live.com; jgoldman@mdpnp.org NR 10 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4799-5930-3; 978-1-4799-5929-7 PY 2015 PG 8 WC Engineering, Industrial; Engineering, Electrical & Electronic SC Engineering GA BE3ZD UT WOS:000371412000004 ER PT J AU Merrill, SJ Ashrafi, S Subramanian, M Godar, DE AF Merrill, Stephen J. Ashrafi, Samira Subramanian, Madhan Godar, Dianne E. TI Exponentially increasing incidences of cutaneous malignant melanoma in Europe correlate with low personal annual UV doses and suggests 2 major risk factors SO DERMATO-ENDOCRINOLOGY LA English DT Article DE environment; HERV; HPV; latitude; melanoma; skin cancer; sunlight; ultraviolet; vitamin D-3 ID HUMAN-PAPILLOMAVIRUS HPV; DNA-POLYMERASE-ETA; SUN EXPOSURE; SKIN-CANCER; 1-ALPHA,25-DIHYDROXYVITAMIN D-3; IN-VIVO; ULTRAVIOLET-RADIATION; MELANOCYTIC NEVI; OUTDOOR WORKERS; CELL-GROWTH AB For several decades the incidence of cutaneous malignant melanoma (CMM) steadily increased in fair-skinned, indoor-working people around the world. Scientists think poor tanning ability resulting in sunburns initiate CMM, but they do not understand why the incidence continues to increase despite the increased use of sunscreens and formulations offering more protection. This paradox, along with lower incidences of CMM in outdoor workers, although they have significantly higher annual UV doses than indoor workers have, perplexes scientists. We found a temporal exponential increase in the CMM incidence indicating second-order reaction kinetics revealing the existence of 2 major risk factors. From epidemiology studies, we know one major risk factor for getting CMM is poor tanning ability and we now propose the other major risk factor may be the Human Papilloma Virus (HPV) because clinicians find beta HPVs in over half the biopsies. Moreover, we uncovered yet another paradox; the increasing CMM incidences significantly correlate with decreasing personal annual UV dose, a proxy for low vitamin D-3 levels. We also discovered the incidence of CMM significantly increased with decreasing personal annual UV dose from 1960, when it was almost insignificant, to 2000. UV and other DNA-damaging agents can activate viruses, and UV-induced cytokines can hide HPV from immune surveillance, which may explain why CMM also occurs in anatomical locations where the sun does not shine. Thus, we propose the 2 major risk factors for getting CMM are intermittent UV exposures that result in low cutaneous levels of vitamin D-3 and possibly viral infection. C1 [Merrill, Stephen J.] Marquette Univ, Dept Math Stat & Comp Sci, Milwaukee, WI 53233 USA. [Ashrafi, Samira] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. [Subramanian, Madhan] Northwest High Sch, Germantown, MD USA. [Godar, Dianne E.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Godar, DE (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. EM Dianne.Godar@FDA.HHS.GOV OI GODAR, DIANNE/0000-0002-7690-5223 NR 85 TC 3 Z9 3 U1 2 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1938-1972 EI 1938-1980 J9 DERM-ENDOCRINOL JI Derm.-Endocrinol. PD JAN-DEC PY 2015 VL 7 IS 1 DI 10.1080/19381980.2014.1004018 PG 8 WC Dermatology SC Dermatology GA DF4RJ UT WOS:000371337600003 ER PT S AU Lunn, G AF Lunn, George BE Town, WG Currano, JN TI PEPFAR - A US Government Program That Is Helping To Keep Millions Alive Around the World SO SCIENCE AND THE LAW: HOW THE COMMUNICATION OF SCIENCE AFFECTS POLICY DEVELOPMENT IN THE ENVIRONMENT, FOOD, HEALTH, AND TRANSPORT SECTORS SE ACS Symposium Series LA English DT Proceedings Paper CT Symp on Science and the Law: How the Communication of Science Affects Policy Development in the Evironment, Food, Health, and Transport Sectors CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc, Div Chem Informat ID DISEASE AB In 2003, the United States President's Emergency Plan For AIDS Relief (PEPFAR) was announced with the aim of bringing much-needed medications to the millions of people infected with human immunodeficiency virus (HIV) in resource-poor countries around the world. Over the years PEPFAR has been a great success. At the end of September, 2014, PEPFAR supported 7.7 million people on treatment. In this chapter 1 provide a brief history of PEPFAR and describe the role that the United States Food and Drug Administration (FDA) has played in the PEPFAR program. The way in which the FDA communicates its policy to manufacturers and other interested parties and modifies its expectations and requirements to deal with the changing nature of the problem are also examined. C1 [Lunn, George] US FDA, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Lunn, G (reprint author), US FDA, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM George.Lunn@FDA.HHS.GOV NR 31 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 SIXTEENTH ST NW, WASHINGTON, DC 20036 USA SN 0097-6156 BN 978-0-8412-3108-5 J9 ACS SYM SER JI ACS Symp. Ser. PY 2015 VL 1207 BP 175 EP 190 PG 16 WC Chemistry, Multidisciplinary; Public, Environmental & Occupational Health; Public Administration SC Chemistry; Public, Environmental & Occupational Health; Public Administration GA BE3FZ UT WOS:000370679500010 ER PT J AU Marchenko, O Jiang, Q Chakravarty, A Ke, CL Ma, HJ Maca, J Russek-Cohen, E Sanchez-Kam, M Zink, RC Chuang-Stein, C AF Marchenko, Olga Jiang, Qi Chakravarty, Aloka Ke, Chunlei Ma, Haijun Maca, Jeff Russek-Cohen, Estelle Sanchez-Kam, Matilde Zink, Richard C. Chuang-Stein, Christy TI Evaluation and Review of Strategies to Assess Cardiovascular Risk in Clinical Trials in Patients with Type 2 Diabetes Mellitus SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Review DE Cardiovascular risk; CVOT; Diabetes mellitus; Meta-analysis; Trial design ID CARE DECISION-MAKING; ISPOR TASK-FORCE; METAANALYSIS; DEATH AB This article is a result of the efforts of the American Statistical Association Biopharmaceutical Section Working Group on Safety. With representatives from different institutions, this group reviewed the drugs approved by the United States Food and Drug Administration (FDA) to treat Type 2 diabetes mellitus during 2002-2014 with a focus on the cardiovascular (CV) risk assessment. The main objective of this article is to understand the impact of FDA guidance of 2008 on assessment of CV risk in antidiabetes development programs, which are summarized and displayed in chronological order. Compared to New Drug Applications (NDAs) submitted prior to the FDA 2008 guidance, the number of patient-years significantly increased for NDAs approved in the post-guidance era. To meet guidance requirements on CV risk assessment, meta-analyses and large cardiovascular outcome trials (CVOTs) have been conducted. These CVOTs provide an opportunity to assess safety signals beyond CV risk and assess the benefit/risk ratio better in diabetic patients with a high risk for CV events, but they also present challenges. The advantages and disadvantages of different CV assessment strategies are summarized in this manuscript. Finally, we raise some emerging questions and discuss future opportunities for CV risk assessment research. Supplementary materials for this article are available online. C1 [Marchenko, Olga; Maca, Jeff] Quintiles, 5927 South Miami Blvd, Morrisville, NC 27560 USA. [Chakravarty, Aloka; Russek-Cohen, Estelle] US FDA, Ctr Drug Evaluat & Res, Div Biometr 7, Off Biostat, Silver Spring, MD 20993 USA. [Jiang, Qi; Ke, Chunlei] Amgen Inc, Global Biostat Sci, One Amgen Ctr Dr,24-2-C, Thousand Oaks, CA 91320 USA. [Sanchez-Kam, Matilde] Arena Pharmaceut, Biostat & Data Management, 6331 River Downs Rd, Alexandria, VA 22312 USA. [Zink, Richard C.] SAS Inst, JMP Life Sci, Cary, NC 27513 USA. [Zink, Richard C.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Chuang-Stein, Christy] Pfizer, Kalamazoo, MI 49009 USA. RP Marchenko, O (reprint author), Quintiles, 5927 South Miami Blvd, Morrisville, NC 27560 USA. EM olga.marchenko@quintiles.com; qjiang@amgen.com; Aloka.Chakravarty@fda.hhs.gov; cke@amgen.com; hma@amgen.com; jeff.maca@quintiles.com; Estelle.Russek-Cohen@fda.hhs.gov; MSanchez@arenapharm.com; Richard.Zink@jmp.com; christy.j.chuang-stein@pfizer.com NR 15 TC 1 Z9 1 U1 2 U2 2 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. PY 2015 VL 7 IS 4 BP 253 EP 266 DI 10.1080/19466315.2015.1077724 PG 14 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA DD4QW UT WOS:000369908700002 ER PT J AU Russek-Cohen, E AF Russek-Cohen, Estelle TI Untitled SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Editorial Material ID TRIAL C1 [Russek-Cohen, Estelle] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Russek-Cohen, E (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Estelle.Russek-Cohen@fda.hhs.gov NR 9 TC 0 Z9 0 U1 0 U2 0 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. PY 2015 VL 7 IS 4 BP 283 EP 285 DI 10.1080/19466315.2015.1093542 PG 3 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA DD4QW UT WOS:000369908700005 ER PT J AU Alosh, M Fritsch, K Huque, M Mahjoob, K Pennello, G Rothmann, M Russek-Cohen, E Smith, F Wilson, S Yue, L AF Alosh, Mohamed Fritsch, Kathleen Huque, Mohammad Mahjoob, Kooros Pennello, Gene Rothmann, Mark Russek-Cohen, Estelle Smith, Fraser Wilson, Stephen Yue, Lilly TI Statistical Considerations on Subgroup Analysis in Clinical Trials SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Bayesian subgroup analysis; Chance findings; Enrichment; Heterogeneity; Personalized medicine; Targeted and complementary subgroups ID HYPERSENSITIVITY; POPULATION; ABACAVIR; GENDER; BAYES AB The objective of subgroup analysis of a clinical trial is to investigate consistency or heterogeneity of the treatment effect across subgroups, defined based on background characteristics. As such, subgroup analysis plays an essential role in the interpretation of the clinical trial findings. Consistency of treatment effect across trial subgroups indicates that the average treatment effect is in general applicable regardless of the specific background characteristics. Substantial heterogeneity in treatment effect may be indicative that treatment benefit pertains only to a subset of the population. However, heterogeneity in the observed treatment effect across subgroups can arise due to chance as a result of partitioning the population into several subgroups. Furthermore, as it is known, clinical trials are generally not powered for detecting heterogeneity, thus statistical tests may miss detection of existing heterogeneity due to low power. In this article, we aim to: (i) outline the major issues underlying subgroup analysis in clinical trials and provide general statistical guidance for interpretation of its findings, (ii) provide statistical perspectives on the design and analysis of a clinical trial that aims for establishing efficacy in a targeted subgroup along with that of its overall population, and (iii) highlight some of the underlying assumptions and issues relevant to Bayesian subgroup analysis, subgroup considerations for noninferiority trials, personalized medicine, subgroup misclassification, and finally, subgroup analysis for safety assessment. C1 [Alosh, Mohamed; Fritsch, Kathleen; Wilson, Stephen] US FDA, Div Biometr 3, OB, OTS,CDER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Huque, Mohammad] US FDA, Off Biostat, OTS, CDER, Silver Spring, MD 20993 USA. [Smith, Fraser] US FDA, Div Biometr 4, OB, OTS,CDER, Silver Spring, MD 20993 USA. [Mahjoob, Kooros] US FDA, Div Biometr 1, OB, OTS,CDER, Silver Spring, MD 20993 USA. [Pennello, Gene; Yue, Lilly] US FDA, Div Biostat, OSB, CDRH, Silver Spring, MD 20993 USA. [Rothmann, Mark] US FDA, Div Biometr 2, OB, OTS,CDER, Silver Spring, MD 20993 USA. [Russek-Cohen, Estelle] US FDA, Div Biostat, OBE, CDER,Off Biostat, Silver Spring, MD 20993 USA. RP Alosh, M (reprint author), US FDA, Div Biometr 3, OB, OTS,CDER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Mohamed.Alosh@fda.hhs.gov; Kathleen.Fritsch@fda.hhs.gov; mohammad.huque@fda.hhs.gov; Kooros.Mahjoob@fda.hhs.gov; gene.pennello@fda.hhs.gov; Mark.Rothmann@fda.hhs.gov; Estelle.Russek-Cohen@fda.hhs.gov; fraser.smith@fda.hhs.gov; stephen.wilson@fda.hhs.gov; lilly.yue@fda.hhs.gov NR 33 TC 2 Z9 2 U1 1 U2 2 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. PY 2015 VL 7 IS 4 BP 286 EP 304 DI 10.1080/19466315.2015.1077726 PG 19 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA DD4QW UT WOS:000369908700006 ER PT J AU Scott, J AF Scott, John TI Untitled SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Editorial Material C1 [Scott, John] US FDA, Div Biostat, Ctr Biol Evaluat & Res, 1401 Rockville Pike,HFM 219, Rockville, MD 20852 USA. RP Scott, J (reprint author), US FDA, Div Biostat, Ctr Biol Evaluat & Res, 1401 Rockville Pike,HFM 219, Rockville, MD 20852 USA. EM John.Scott@fda.hhs.gov OI Scott, John/0000-0002-9116-948X NR 3 TC 0 Z9 0 U1 0 U2 0 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. PY 2015 VL 7 IS 4 BP 322 EP 324 DI 10.1080/19466315.2015.1099565 PG 3 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA DD4QW UT WOS:000369908700009 ER PT J AU Price, DL Rubin, DB Valappil, T AF Price, Dionne L. Rubin, Daniel B. Valappil, Thamban TI Antimicrobial Products: Statistical Challenges and Opportunities SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Bayesian analysis; Clinical trial; Hierarchical design; Master protocol; Noninferiority trial ID DRUGS AB According to a 2013 report of the Centers for Disease Control and Prevention, more than 2 million people in the United States develop illness from antibiotic-resistant infections yearly and at least 23,000 die as a direct result of antibiotic-resistant infections. Despite an alarming number of antibiotic-resistant infections, antibacterial drug development has been slow. The consequences of the lack of new effective antibiotics may be dire to our global public health. There are scientific, economic, and regulatory challenges that underpin the sparse antibiotic pipeline. In this article, we outline critical design and analysis elements that impact clinical trials of new antibiotics and include some of the complex scientific challenges unique to antibacterial products. The challenges also present opportunities for statisticians to provide innovative strategies to the design and analysis of these trials. C1 [Price, Dionne L.; Rubin, Daniel B.; Valappil, Thamban] US FDA, Div Biometr 4, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Price, DL (reprint author), US FDA, Div Biometr 4, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM dionne.price@fda.hhs.gov; daniel.rubin@fda.hhs.gov; Thamban.Valappil@fda.hhs.gov NR 15 TC 0 Z9 0 U1 0 U2 0 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. PY 2015 VL 7 IS 4 BP 325 EP 330 DI 10.1080/19466315.2015.1096824 PG 6 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA DD4QW UT WOS:000369908700010 ER PT J AU Grosser, S Park, M Raney, SG Rantou, E AF Grosser, Stella Park, Misook Raney, Sam G. Rantou, Elena TI Determining Equivalence for Generic Locally Acting Drug Products SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Bioequivalence; Clinical endpoint studies; In vitro studies; Nasal sprays; Topical dosage forms ID BIOEQUIVALENCE; ADHERENCE AB For regulatory purposes, bioequivalence (BE) is defined as the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. The U.S. Food and Drug Administration may accept evidence from various approaches for determining the bioavailability (BA) or BE of a drug product, including in vivo pharmacokinetic studies, certain in vitro studies that are correlated with and predictive of human in vivo BA, and well-controlled clinical endpoint studies. In this article, we describe some of the statistical approaches used in clinical endpoint studies of bioequivalence for generic drugs. We outline a conventional design and statistical analysis for such studies, including the equivalence criteria. We exemplify this approach with a more detailed discussion of studies of nasal spray products for allergic rhinitis, pointing out some of the statistical issues particular to this area. Finally, we describe a new statistical approach to evaluating BE for topical, locally acting dosage forms (e.g., creams, ointments, and gels) studied in vitro using excised human skin, with a specific focus on unique issues in the design and statistical analysis of data from such studies. C1 [Grosser, Stella; Park, Misook; Rantou, Elena] CDER FDA, Div Biometr 8, Off Biostat, OTS CDER FDA, 10903 New Hampshire, Silver Spring, MD 20993 USA. [Raney, Sam G.] CDER FDA, Topical & Transdermal Drug Prod, Div Therapeut Performance, Off Res & Stand,Off Gener Drugs, 10903 New Hampshire, Silver Spring, MD 20993 USA. RP Grosser, S (reprint author), CDER FDA, Div Biometr 8, Off Biostat, OTS CDER FDA, 10903 New Hampshire, Silver Spring, MD 20993 USA. EM stella.grosser@fda.hhs.gov; misook.park@fda.hhs.gov; sameersingh.raney@fda.hhs.gov; elena.rantou@fda.hhs.gov NR 22 TC 0 Z9 0 U1 5 U2 5 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. PY 2015 VL 7 IS 4 BP 337 EP 345 DI 10.1080/19466315.2015.1093541 PG 9 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA DD4QW UT WOS:000369908700012 ER PT J AU Sridhara, R He, K Nie, L Shen, YL Tang, SH AF Sridhara, Rajeshwari He, Kun Nie, Lei Shen, Yuan-Li Tang, Shenghui TI Current Statistical Challenges in Oncology Clinical Trials in the Era of Targeted Therapy SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Expansion cohorts; Master protocols; Non-proportional hazards; Treatment switch-over ID PROGRESSION-FREE SURVIVAL; LOG-RANK TEST; PHASE-II; PROPENSITY SCORE; LUNG-CANCER; DESIGNS; MALIGNANCIES; BENEFIT AB The mapping of the human genome has led to rapid advances in our understanding of diseases at the molecular level. This new knowledge is shifting the drug development paradigm in cancer trials. For example, traditional Phase 1 to 3 trials of dose finding, evaluating activity, and confirming efficacy are becoming less common with all the three objectives accomplished within one protocol. Molecular marker-based clinical trials are also on the rise in place of the traditional disease-based clinical trials. In addition, patients receiving control treatment are routinely switched to the experimental treatment after disease progression, complicating the final comparison of survival rates between treatment groups. In this article, we describe these and other challenges in the regulatory review of cancer therapies as a result of this paradigm shift and also describe some innovative ideas that have the potential to improve evaluation of new agents to treat cancer in clinical trials. C1 [Sridhara, Rajeshwari; He, Kun; Nie, Lei; Shen, Yuan-Li; Tang, Shenghui] US FDA, CDER OTS OB, 10903 New Hampshire Ave,WO21,Rm 3512, Silver Spring, MD 20993 USA. RP Sridhara, R (reprint author), US FDA, CDER OTS OB, 10903 New Hampshire Ave,WO21,Rm 3512, Silver Spring, MD 20993 USA. EM Rajeshwari.Sridhara@fda.hhs.gov; Kun.He@fda.hhs.gov; lei.nie@fda.hhs.gov; Yuan.Li.Shen@fda.hhs.gov; Shenghui.Tang@fda.hhs.gov NR 38 TC 0 Z9 0 U1 1 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. PY 2015 VL 7 IS 4 BP 348 EP 356 DI 10.1080/19466315.2015.1094673 PG 9 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA DD4QW UT WOS:000369908700014 ER PT B AU Chennasamudram, S Vann, WF AF Chennasamudram, Sudha Vann, Willie F. BE Wen, EP Ellis, R Pujar, NS TI CONJUGATE VACCINE PRODUCTION TECHNOLOGY SO VACCINE DEVELOPMENT AND MANUFACTURING SE Wiley Series in Biotechnology and Bioengineering LA English DT Article; Book Chapter ID INFLUENZAE TYPE-B; INVASIVE PNEUMOCOCCAL DISEASE; INDUCED EPITOPIC SUPPRESSION; HAEMOPHILUS-INFLUENZAE; NEISSERIA-MENINGITIDIS; CAPSULAR POLYSACCHARIDE; HYDROGEN-PEROXIDE; DIPHTHERIA-TOXIN; TETANUS TOXIN; GROUP-A C1 [Chennasamudram, Sudha; Vann, Willie F.] US FDA, Ctr Biol Evaluat & Res, Lab Bacterial Polysaccharides, Off Vaccine Res & Review, Bethesda, MD USA. RP Chennasamudram, S (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Bacterial Polysaccharides, Off Vaccine Res & Review, Bethesda, MD USA. NR 71 TC 0 Z9 0 U1 1 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA BN 978-1-118-87091-4; 978-0-470-26194-1 J9 WILEY SER BIOTECHNOL PY 2015 BP 217 EP 235 PG 19 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA BE2TB UT WOS:000370009700008 ER PT J AU Chan-Tack, KM Kim, C Moruf, A Birnkrant, DB AF Chan-Tack, Kirk M. Kim, Christine Moruf, Alicia Birnkrant, Debra B. TI Clinical experience with intravenous zanamivir under an Emergency IND program in the United States (2011-2014) SO ANTIVIRAL THERAPY LA English DT Article ID CRITICALLY-ILL PATIENTS; INFLUENZA; VIRUS AB Background: Since the emergence of 2009 H1N1 virus, intravenous (IV) zanamivir has been authorized as an investigational treatment for patients with serious and life-threatening influenza through an Emergency Investigational New Drug application (EIND). This review encompasses the FDA's EIND database from May 2011 to June 2014. Methods: This is a retrospective descriptive review of patient clinical data in the FDA's IV zanamivir EIND database from May 2011 to June 2014. Results: Of 364 IV zanamivir EIND requests, most (83%) patients were aged 18-64 years, 8 (2%) were pregnant, and 29 (8%) were children. 234 (64%) patients had >= 1 comorbidity reported. The majority (87%) were receiving oseltamivir when IV zanamivir was requested, and 33% had suspected (n=120; no improvement or worsening on oseltamivir) H275Y oseltamivir resistance. Influenza A was reported for 300 patients: confirmed 2009 H1N1 (n=163), suspected 2009 H1N1 (n=8), confirmed H3N2 (n=4) and not subtyped (n=125). Influenza B was reported for 25 patients. Many patients (87%) required invasive mechanical ventilation, 23 (6%) received high frequency oscillatory ventilation, and 74 (20%) received extracorporeal membrane oxygenation (ECMO). 289 (79%) patients had >= 1 complication such as renal failure (n=124; 77/124 required dialysis), bacteraemia (n=18), shock (n=95) or pneumonia (n=159). Of 134 (37%) patients with available outcome data, 83 died and 51 survived. Conclusions: IV zanamivir EIND authorizations were for treatment of critically ill adult patients with 2009 H1N1, including a substantial number with suspected oseltamivir resistance. Data from prospective, randomized controlled trials are needed and are ongoing to assess the safety and efficacy of IV zanamivir for treatment of hospitalized patients with severe influenza. C1 [Chan-Tack, Kirk M.; Kim, Christine; Moruf, Alicia; Birnkrant, Debra B.] US FDA, Div Antiviral Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Chan-Tack, KM (reprint author), US FDA, Div Antiviral Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM kirk.chan-tack@fda.hhs.gov NR 6 TC 3 Z9 3 U1 1 U2 1 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PY 2015 VL 20 IS 5 BP 561 EP 564 DI 10.3851/IMP2944 PG 4 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA DC7KD UT WOS:000369397800014 PM 25667992 ER PT J AU Luo, H Ye, H Ng, HW Shi, LM Tong, WD Mendrick, DL Hong, HX AF Luo, Heng Ye, Hao Ng, Hui Wen Shi, Leming Tong, Weida Mendrick, Donna L. Hong, Huixiao TI Machine Learning Methods for Predicting HLA-Peptide Binding Activity SO BIOINFORMATICS AND BIOLOGY INSIGHTS LA English DT Article DE HLA; peptide; binding; prediction; machine learning; MHC ID MAJOR HISTOCOMPATIBILITY COMPLEX; CLASS-I MOLECULES; T-CELL EPITOPES; HUMAN-LEUKOCYTE ANTIGENS; HIDDEN MARKOV-MODELS; MHC-BINDING; QUANTITATIVE PREDICTION; DRUG HYPERSENSITIVITY; COMPUTATIONAL SYSTEM; VACCINE RESEARCH AB As major histocompatibility complexes in humans, the human leukocyte antigens (HLAs) have important functions to present antigen peptides onto T-cell receptors for immunological recognition and responses. Interpreting and predicting HLA-peptide binding are important to study T-cell epitopes, immune reactions, and the mechanisms of adverse drug reactions. We review different types of machine learning methods and tools that have been used for HLA-peptide binding prediction. We also summarize the descriptors based on which the HLA-peptide binding prediction models have been constructed and discuss the limitation and challenges of the current methods. Lastly, we give a future perspective on the HLA-peptide binding prediction method based on network analysis. C1 [Luo, Heng; Ye, Hao; Ng, Hui Wen; Tong, Weida; Mendrick, Donna L.; Hong, Huixiao] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Luo, Heng] Univ Arkansas, Med Sci Bioinformat Grad Program, Little Rock, AR 72204 USA. [Shi, Leming] Fudan Univ, Sch Pharm, Ctr Pharmacogen, Shanghai 200433, Peoples R China. RP Hong, HX (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Donna.Mendrick@fda.hhs.gov; Huixiao.Hong@fda.hhs.gov RI Luo, Heng/D-3616-2016 OI Luo, Heng/0000-0001-5192-8878 FU NCRR NIH HHS [P20 RR016460]; NIGMS NIH HHS [P20 GM103429] NR 81 TC 10 Z9 10 U1 0 U2 6 PU LIBERTAS ACAD PI AUCKLAND PA PO BOX 300-874, ALBANY 0752, AUCKLAND, 00000, NEW ZEALAND SN 1177-9322 J9 BIOINFORM BIOL INSIG JI Bioinform. Biol. Insights PY 2015 VL 9 SU 3 BP 21 EP 29 DI 10.4137/BBI.S29466 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DB5UF UT WOS:000368578400003 PM 26512199 ER PT J AU Lo, SC Hung, GC Li, BJ Lei, HY Li, TW Nagamine, K Tsai, S Zucker, MJ Olesnicky, L AF Lo, Shyh-Ching Hung, Guo-Chiuan Li, Bingjie Lei, Haiyan Li, Tianwei Nagamine, Kenjiro Tsai, Shien Zucker, Mark J. Olesnicky, Ludmilla TI Mixed group of Rhizobiales microbes in lung and blood of a patient with fatal pulmonary illness SO INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY LA English DT Article DE Microbiome; MPS; HTS; Rhizobiales; alphaproteobacteria; Bradyrhizobiaceae; Phyllobacteriaceae; Methylobacteriaceae; Sphingomonadaceae; Afipia; Mesorhizobium ID MYCOPLASMA-FERMENTANS; SEQUENCE; PROBES AB We examined the microbial composition in the diseased lung and early-phase microbial cultures from the blood of a patient with a rapidly progressing fatal pulmonary illness. Although no microbes could be isolated from such cultures during the initial study, the HTS-microbiome study revealed the presence of a unique mixture of alphaproteobacteria, composed mainly of different families of Rhizobiales microbes. Microbial 16S rDNA sequences matching closely to Afipia cberi were identified mainly in the patient's diseased lung tissue, but only rarely in the early-phase blood cultures. Conversely, the high abundance of sequences found in early-phase blood cultures of different broth media matched closely with those of the families Methylobacteriaceae, Phyllobacteriaceae and Sphingomonadaceae. The two species that successfully adapted to grow in a laboratory culture system were A. cberi and Mesorhizobium hominis, which eventually were isolated from a previously cryopreserved blood culture of SP4 broth. Many other species, including members of the Bradyrhizobiaceae and Phyllobacteriaceae families, and all members of the Methylobacteriaceae and Sphingomonadaceae families identified by HTS remained non-cultivated. We developed specific PCR primers and FISH probes, which detected the target Rhizobiales microbes in former blood cultures and autopsy lung tissues. It is unclear what role these Rhizobiales microbes might have played in the patient's complex disease process. However, the above mentioned assays should help in rapidly detecting and identifying these previously unrecognized Rhizobiales microbes in patients. C1 [Lo, Shyh-Ching; Hung, Guo-Chiuan; Li, Bingjie; Lei, Haiyan; Li, Tianwei; Nagamine, Kenjiro; Tsai, Shien] US FDA, Tissue Microbiol Lab, Div Cellular & Gene Therapies, Off Cellular Tissue & Gene Therapies,Ctr Biol Eva, Silver Spring, MD 20993 USA. [Zucker, Mark J.] Newark Beth Israel Med Ctr, Dept Med, Newark, NJ 07112 USA. [Olesnicky, Ludmilla] Newark Beth Israel Med Ctr, Dept Pathol, Newark, NJ 07112 USA. RP Lo, SC (reprint author), US FDA, Tissue Microbiol Lab, Div Cellular & Gene Therapies, Off Cellular Tissue & Gene Therapies,Ctr Biol Eva, Silver Spring, MD 20993 USA. EM shyhching.lo@fda.hhs.gov FU FDA Modernizing Science Grant FX This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). The authors thank Drs. Jakob Reiser and Syed R. Husain for critical review and editing of the manuscript. Mr. Philip Yang drew the schematic of workflow. The study is supported in part by an FDA Modernizing Science Grant. NR 25 TC 1 Z9 1 U1 0 U2 0 PU E-CENTURY PUBLISHING CORP PI MADISON PA 40 WHITE OAKS LN, MADISON, WI 53711 USA SN 1936-2625 J9 INT J CLIN EXP PATHO JI Int. J. Clin. Exp. Pathol. PY 2015 VL 8 IS 11 BP 13834 EP 13852 PG 19 WC Oncology; Pathology SC Oncology; Pathology GA DA9OX UT WOS:000368140100006 PM 26823697 ER PT J AU Amaravadi, L Song, A Myler, H Thway, T Kirshner, S Devanarayan, V Ni, YG Garofolo, F Birnboeck, H Richards, S Gupta, S Luo, LL Kingsley, C Salazar-Fontana, L Fraser, S Gorovits, B Allinson, J Barger, T Chilewski, S Fjording, MS Haidar, S Islam, R Jaitner, B Kamerud, J Katori, N Krinos-Fiorotti, C Lanham, D Ma, M McNally, J Morimoto, A Mytych, D da Costa, AN Papadimitriou, A Pillutla, R Ray, S Safavi, A Savoie, N Schaefer, M Shih, J Smeraglia, J Skelly, MF Spond, J Staack, RF Stouffer, B Tampal, N Torri, A Welink, J Yang, TY Zoghbi, J AF Amaravadi, Lakshmi Song, An Myler, Heather Thway, Theingi Kirshner, Susan Devanarayan, Viswanath Ni, Yan G. Garofolo, Fabio Birnboeck, Herbert Richards, Susan Gupta, Shalini Luo, Linlin Kingsley, Clare Salazar-Fontana, Laura Fraser, Stephanie Gorovits, Boris Allinson, John Barger, Troy Chilewski, Shannon Fjording, Marianne Scheel Haidar, Sam Islam, Rafiqul Jaitner, Birgit Kamerud, John Katori, Noriko Krinos-Fiorotti, Corinna Lanham, David Ma, Mark McNally, Jim Morimoto, Alyssa Mytych, Daniel da Costa, Andre Nogueira Papadimitriou, Apollon Pillutla, Renuka Ray, Soma Safavi, Afshin Savoie, Natasha Schaefer, Martin Shih, Judy Smeraglia, John Skelly, Michael F. Spond, Jeffrey Staack, Roland F. Stouffer, Bruce Tampal, Nilufer Torri, Albert Welink, Jan Yang, Tong-Yuan Zoghbi, Jad TI 2015 White Paper on recent issues in bioanalysis: focus on new technologies and biomarkers (Part 3-LBA, biomarkers and immunogenicity) SO BIOANALYSIS LA English DT Article ID VALIDATION GROUP WORKSHOP; LIGAND-BINDING ASSAYS; LIFE-CYCLE MANAGEMENT; DRUG DEVELOPMENT; CRITICAL REAGENTS; FULL IMMERSION; BIOTECHNOLOGY PRODUCTS; REGULATED BIOANALYSIS; BISPECIFIC ANTIBODIES; GLOBAL HARMONIZATION AB The 2015 9th Workshop on Recent Issues in Bioanalysis (9th WRIB) took place in Miami, Florida with participation of 600 professionals from pharmaceutical and biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5 day, week-long event - A Full Immersion Bioanalytical Week - specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS and LBA approaches, including the focus on biomarkers and immunogenicity. This 2015 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2015 edition of this comprehensive White Paper has been divided into three parts. Part 3 discusses the recommendations for large molecule bioanalysis using LBA, biomarkers and immunogenicity. Part 1 (small molecule bioanalysis using LCMS) and Part 2 (hybrid LBA/LCMS and regulatory inputs from major global health authorities) have been published in volume 7, issues 22 and 23 of Bioanalysis, respectively. C1 [Amaravadi, Lakshmi; Ray, Soma] Biogen Idec Inc, Cambridge, MA USA. [Song, An; Morimoto, Alyssa] Genentech Inc, San Francisco, CA USA. [Myler, Heather; Ni, Yan G.; Luo, Linlin; Pillutla, Renuka; Stouffer, Bruce] Bristol Myers Squibb Co, Princeton, NJ USA. [Thway, Theingi; Gupta, Shalini; Barger, Troy; Ma, Mark; Mytych, Daniel; Shih, Judy] Amgen Inc, Thousand Oaks, CA USA. [Kirshner, Susan; Haidar, Sam; Skelly, Michael F.; Tampal, Nilufer] US FDA, Silver Spring, MD USA. [Devanarayan, Viswanath] Abbvie, Souderton, PA USA. [Garofolo, Fabio] Angelini Pharma, Pomezia, RM, Italy. [Birnboeck, Herbert] Roche Innovat Ctr, Roche Pharma Res & Early Dev, Basel, Switzerland. [Richards, Susan; Salazar-Fontana, Laura; Zoghbi, Jad] Sanofi, Framingham, MA USA. [Kingsley, Clare; Allinson, John] LGC, Cambridge, England. [Fraser, Stephanie] Pfizer Inc, Groton, CT 06340 USA. [Gorovits, Boris; Krinos-Fiorotti, Corinna; McNally, Jim] Pfizer, Andover, MA USA. [Chilewski, Shannon; Fjording, Marianne Scheel; Safavi, Afshin] Bristol Myers Squibb Co, Philadelphia, PA USA. [Fjording, Marianne Scheel] Novo Nordisk AS, Malov, Denmark. [Islam, Rafiqul] Celerion, Lincoln, NE USA. [Jaitner, Birgit] Novartis Pharmaceut, Basel, Switzerland. [Kamerud, John] Eurofins Bioanalyt Serv, St Charles, MO USA. [Katori, Noriko] Japan MHLW NIHS, Tokyo, Japan. [Lanham, David] Eurofins Bioanalyt Serv, Abingdon, Oxon, England. [da Costa, Andre Nogueira; Smeraglia, John] UCB Biopharma, Braine Lalleud, Belgium. [Papadimitriou, Apollon; Schaefer, Martin; Staack, Roland F.] Roche Innovat Ctr, Roche Pharma Res & Early Dev, Penzberg, Germany. [Safavi, Afshin] Bioagilytix Labs, Durham, NC USA. [Savoie, Natasha] CFABS, Laval, PQ, Canada. [Spond, Jeffrey] Merck, Rahway, NJ USA. [Torri, Albert] Regeneron Pharmaceut, Tarrytown, NY USA. [Welink, Jan] Dutch MEB, Utrecht, Netherlands. [Yang, Tong-Yuan] Janssen R&D, Spring House, PA USA. RP Garofolo, F (reprint author), Angelini Pharma, Pomezia, RM, Italy. EM f.garofolo@angelini.it FU US FDA; Europe EMA; France ANSM; Netherlands MEB; UK MHRA; Germany BfArM; Brazil ANVISA; Health Canada; Japan MHWL FX The authors would like to acknowledge the US FDA, Europe EMA, France ANSM, The Netherlands MEB, UK MHRA, Germany BfArM, Brazil ANVISA, Health Canada, and Japan MHWL for supporting this workshop. E Fluhler (Pfizer), J Welink (EMA/Dutch MEB), B Ackermann (Eli Lilly), N Hughes (Life Labs), F Garofolo (Angelini Pharma), A Song (Genentech), T Thway (Amgen), L Amaravadi (Biogen Idec) and H Myler (Bristol-Myers Squibb) for chairing the workshop and/or the white paper discussions. All the workshop attendees and members of the bioanalytical community who have sent comments and suggestions to complete this White Paper. W Garofolo, L Lu, X Wang, M Losauro, N Savoie, A Hernandezand, S Schonert, D Cohen, K Kalaydjian, P de Souza for the assistance in the organization of the event. Future Science Group as a trusted partner. NR 48 TC 6 Z9 6 U1 1 U2 3 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1757-6180 EI 1757-6199 J9 BIOANALYSIS JI Bioanalysis PY 2015 VL 7 IS 24 BP 3107 EP 3124 DI 10.4155/bio.15.226 PG 18 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CY4SS UT WOS:000366399200007 PM 26635247 ER PT S AU Rosenberg, A Demeule, B AF Rosenberg, Amy Demeule, Barthelemy BE Rosenberg, A Demeule, B TI Biobetters Protein Engineering to Approach the Curative Preface SO BIOBETTERS: PROTEIN ENGINEERING TO APPROACH THE CURATIVE SE AAPS Advances in the Pharmaceutical Sciences Series LA English DT Editorial Material; Book Chapter C1 [Rosenberg, Amy] US FDA, Div Biotechnol Review & Res 3, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Demeule, Barthelemy] Genentech Inc, San Francisco, CA 94080 USA. RP Rosenberg, A (reprint author), US FDA, Div Biotechnol Review & Res 3, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 2210-7371 BN 978-1-4939-2543-8; 978-1-4939-2542-1 J9 AAPS ADV PHARM SCI PY 2015 VL 19 BP V EP VII D2 10.1007/978-1-4939-2543-8 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA BE0RT UT WOS:000366803200001 ER PT S AU Rao, VA AF Rao, V. Ashutosh BE Rosenberg, A Demeule, B TI Perspectives on Engineering Biobetter Therapeutic Proteins with Greater Stability in Inflammatory Environments SO BIOBETTERS: PROTEIN ENGINEERING TO APPROACH THE CURATIVE SE AAPS Advances in the Pharmaceutical Sciences Series LA English DT Article; Book Chapter ID COLONY-STIMULATING FACTOR; SYSTEMIC-LUPUS-ERYTHEMATOSUS; HUMAN GROWTH-HORMONE; IN-VIVO POTENCY; OXIDATIVE STRESS; MUTANT P53; POLYETHYLENE-GLYCOL; HYDROGEN-PEROXIDE; ALBUMIN FUSION; HALF-LIFE C1 [Rao, V. Ashutosh] US FDA, Div Biotechnol Review & Res 3, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Rao, VA (reprint author), US FDA, Div Biotechnol Review & Res 3, Off Biotechnol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,52-72-2212, Silver Spring, MD 20993 USA. EM Ashutosh.Rao@fda.hhs.gov NR 137 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 2210-7371 BN 978-1-4939-2543-8; 978-1-4939-2542-1 J9 AAPS ADV PHARM SCI PY 2015 VL 19 BP 183 EP 202 DI 10.1007/978-1-4939-2543-8_11 D2 10.1007/978-1-4939-2543-8 PG 20 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA BE0RT UT WOS:000366803200012 ER PT S AU Lacana, E Yao, L Pariser, A Rosenberg, A Woodcock, J AF Lacana, Emanuela Yao, Lynne Pariser, Anne Rosenberg, Amy Woodcock, Janet BE Rosenberg, A Demeule, B TI Building Biobetters: The Regulatory Landscape SO BIOBETTERS: PROTEIN ENGINEERING TO APPROACH THE CURATIVE SE AAPS Advances in the Pharmaceutical Sciences Series LA English DT Article; Book Chapter ID CYSTIC-FIBROSIS C1 [Lacana, Emanuela] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Rosenberg, Amy] US FDA, Div Biotechnol Review & Res 3, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Yao, Lynne] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Pariser, Anne] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Woodcock, Janet] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Rosenberg, A (reprint author), US FDA, Div Biotechnol Review & Res 3, Off Biotechnol Prod, Ctr Drug Evaluat & Res, 71-2338 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM amy.rosenberg@fda.hhs.gov NR 4 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 2210-7371 BN 978-1-4939-2543-8; 978-1-4939-2542-1 J9 AAPS ADV PHARM SCI PY 2015 VL 19 BP 361 EP 370 DI 10.1007/978-1-4939-2543-8_16 D2 10.1007/978-1-4939-2543-8 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA BE0RT UT WOS:000366803200017 ER PT B AU Brainerd, CJ Reyna, VF AF Brainerd, Charles J. Reyna, Valerie F. BE Raaijmakers, JGW Criss, AH Goldstone, RL Nosofsky, RM Steyvers, M TI Memory and Knowledge Memory and Knowledge in Theories of Episodic Memory SO COGNITIVE MODELING IN PERCEPTION AND MEMORY: A FESTSCHRIFT FOR RICHARD M. SHIFFRIN SE Psychology Press Festschrift Series LA English DT Proceedings Paper CT Conference on Cognitive Modeling in Perception and Memory - Festschrift in Honor of Richard M. Shiffrin CY MAY, 2012 CL Indiana Univ, Bloomington, IN HO Indiana Univ ID FUZZY-TRACE THEORY; COGNITIVE-DEVELOPMENT; RECOGNITION MEMORY; WORKING MEMORY; FALSE MEMORIES; EVENT MEMORY; MODEL; CHILDREN; INDEPENDENCE; ABSTRACTION C1 [Brainerd, Charles J.] Cornell Univ, Dept Human Dev, Ithaca, NY 14853 USA. [Brainerd, Charles J.] Cornell Univ, PhD JD Program Law Psychol & Human Dev, Ithaca, NY 14853 USA. [Brainerd, Charles J.] Assoc Psychol Sci, Washington, DC USA. [Brainerd, Charles J.] Amer Psychol Assoc, Washington, DC USA. [Reyna, Valerie F.] Cornell Univ, Human Neurosci Inst, Ithaca, NY 14853 USA. [Reyna, Valerie F.] Cornell Univ, Magnet Resonance Imaging Facil, Ithaca, NY 14853 USA. [Reyna, Valerie F.] Amer Assoc Advancement Sci, Washington, DC USA. [Reyna, Valerie F.] Soc Judgment & Decis Making, Chicago, IL USA. [Reyna, Valerie F.] Natl Acad Sci, Sci Panels, Washington, DC USA. [Reyna, Valerie F.] Natl Sci Fdn, Sci Panels, Arlington, VA 22230 USA. [Reyna, Valerie F.] NIH, Sci Panels, Bethesda, MD USA. [Reyna, Valerie F.] US FDA, Sci Panels, Rockville, MD 20857 USA. [Reyna, Valerie F.] MacArthur Fdn, Sci Panels, Chicago, IL USA. RP Brainerd, CJ (reprint author), Cornell Univ, Dept Human Dev, Ithaca, NY 14853 USA. NR 47 TC 0 Z9 0 U1 1 U2 1 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH ROAD, HOVE BN3 2FA, E SUSSEX, ENGLAND BN 978-1-315-88558-2; 978-0-415-70938-5 J9 PSYCHOL PR FESTSCHR PY 2015 BP 173 EP 185 PG 13 WC Psychology, Experimental SC Psychology GA BE0SG UT WOS:000366823800011 ER PT J AU Smith, RE Tran, K Richards, KM AF Smith, Robert E. Tran, Kevin Richards, Kristy M. TI Recent Advances in Metabolomics SO CURRENT METABOLOMICS LA English DT Article DE Metabolomics; receiver operator characteristic (ROC) curves; capillary electrophoresis; gas chromatography; liquid chromatography; mass spectrometry; MS imaging ID RESONANCE MASS-SPECTROMETRY; METABOLITE IDENTIFICATION; HIGH-THROUGHPUT; NANOELECTROSPRAY IONIZATION; DIAGNOSTIC BIOMARKERS; QUANTITATIVE-ANALYSIS; COLORECTAL-CANCER; FATTY-ACIDS; HUMAN SERUM; CHROMATOGRAPHY AB The field of metabolomics has continued to expand rapidly in the past two years. It has become an important part of personalized, predictive, preventive, and participatory (P4) medicine. In this article, recent advances in analytical methods (capillary electrophoresis, gas chromatography, liquid chromatography, mass spectrometry and MS imaging) are described. Advances in data analysis, quality control and receiver operator characteristic (ROC) curves are also described. The recent uses of metabolomics in disease diagnosis, epidemiology, epigenetics, hypertension, cancer, toxicology, drug discovery and the understanding of biological processes are also presented. C1 [Smith, Robert E.; Tran, Kevin; Richards, Kristy M.] US FDA, Lenexa, KS 66214 USA. [Smith, Robert E.] Pk Univ, Parkville, MO 64152 USA. RP Smith, RE (reprint author), Pk Univ, 8700 NW River Pk Dr, Parkville, MO 64152 USA. EM robert.smith@fda.hhs.gov NR 78 TC 1 Z9 1 U1 7 U2 12 PU BENTHAM SCIENCE PUBL PI BUSUM PA PO BOX 294, BUSUM, 1400 AG, NETHERLANDS SN 2213-235X EI 2213-2368 J9 CURR METABOL JI Curr. Metabol. PY 2015 VL 3 IS 1 BP 54 EP 64 DI 10.2174/2213235X03666150402230203 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CY9AT UT WOS:000366700500007 ER PT J AU Wang, T Feldman, GM Herlyn, M Kaufman, RE AF Wang, Tao Feldman, Gerald M. Herlyn, Meenhard Kaufman, Russel E. TI The macrophage: Switches from a passenger to a driver during anticancer therapy SO ONCOIMMUNOLOGY LA English DT Editorial Material DE BRAF inhibitor; macrophage; melanoma; targeted therapy ID INHIBITORS; BRAF; RESISTANCE AB We have recently discovered that BRAF inhibitors induce potent macrophage responses that confer melanoma resistance to therapy. Our studies lay a foundation for the hypothesis that macrophages switch their role from a passenger to a driver for tumor survival during therapeutic treatment, suggesting that agents that target macrophages can be an important component of "cocktail" anticancer therapy. C1 [Wang, Tao; Feldman, Gerald M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Herlyn, Meenhard; Kaufman, Russel E.] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. RP Wang, T (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM tao.wang@fda.hhs.gov FU NCI NIH HHS [P30 CA010815] NR 10 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 2162-402X J9 ONCOIMMUNOLOGY JI OncoImmunology PY 2015 VL 4 IS 12 AR e1052929 DI 10.1080/2162402X.2015.1052929 PG 3 WC Oncology; Immunology SC Oncology; Immunology GA CY5AP UT WOS:000366420500015 PM 26587324 ER PT S AU Palmeri, M Nightingale, K Fielding, S Rouze, N Deng, YF Lynch, T Chen, SG Song, PF Urban, M Xie, H Wear, K Garra, B Milkowski, A Rosenzweig, S Carson, P Barr, R Shamdasani, V Macdonald, M Wang, M Guenette, G Miyajima, Y Okamura, Y Dhyani, M Samir, A Hah, Z McLaughlin, G Gee, A Chen, YL Napolitano, D McAleavey, S Obuchowski, N Hall, T AF Palmeri, Mark Nightingale, Kathy Fielding, Shana Rouze, Ned Deng, Yufeng Lynch, Ted Chen, Shigao Song, Pengfei Urban, Matthew Xie, Hua Wear, Keith Garra, Brian Milkowski, Andy Rosenzweig, Stephen Carson, Paul Barr, Richard Shamdasani, Vijay Macdonald, Michael Wang, Michael Guenette, Gilles Miyajima, Yasuo Okamura, Yoko Dhyani, Manish Samir, Anthony Hah, Zaegyoo McLaughlin, Glen Gee, Albert Chen, Yuling Napolitano, David McAleavey, Steve Obuchowski, Nancy Hall, Timothy GP IEEE TI RSNA QIBA Ultrasound Shear Wave Speed Phase II Phantom Study in Viscoelastic Media SO 2015 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS) SE IEEE International Ultrasonics Symposium LA English DT Proceedings Paper CT IEEE International Ultrasonics Symposium (IUS) CY OCT 21-24, 2015 CL Taipei, TAIWAN SP IEEE ID WFUMB GUIDELINES; CLINICAL-USE; LIVER; RECOMMENDATIONS; FIBROSIS AB Using ultrasonic shear wave speed (SWS) estimates has become popular to noninvasively evaluate liver fibrosis, but significant inter-system variability in liver SWS measurements can preclude meaningful comparison of measurements performed with different systems. The RSNA Quantitative Imaging Biomarker Alliance (QIBA) ultrasound SWS committee has been developing elastic and viscoelastic (VE) phantoms to evaluate system dependencies of SWS estimates. The objective of this study is to compare SWS measurements between commercially-available systems using phantoms that have viscoelastic properties similar to those observed in normal and fibrotic liver. CIRS, Inc. fabricated three phantoms using a proprietary oil-water emulsion infused in a Zerdine (R) hydrogel that were matched in viscoelastic behavior to healthy and fibrotic human liver data. Phantoms were measured at academic, clinical, government and vendor sites using different systems with curvilinear arrays at multiple focal depths (3.0, 4.5 & 7.0 cm). The results of this study show that current-generation ultrasound SWS measurement systems are able to differentiate viscoelastic materials that span healthy to fibrotic liver. The deepest focal depth (7.0 cm) yielded the greatest inter-system variability for each phantom (maximum of 17.7%) as evaluated by IQR. Inter-system variability was consistent across all 3 phantoms and was not a function of stiffness. Median SWS estimates for the greatest outlier system for each phantom/ focal depth combination ranged from 12.7-17.6%. Future efforts will include performing more robust statistical analyses of these data, comparing these phantom data trends with viscoelastic digital phantom data, providing vendors with study site data to refine their systems to have more consistent measurements, and integrating these data into the QIBA ultrasound shear wave speed measurement profile. C1 [Palmeri, Mark; Nightingale, Kathy; Fielding, Shana; Rouze, Ned; Deng, Yufeng] Duke Univ, Durham, NC 27708 USA. [Lynch, Ted] CIRS, Norfolk, VA USA. [Chen, Shigao; Song, Pengfei; Urban, Matthew] Mayo Clin, Rochester, MN USA. [Xie, Hua] Philips Res, Cambridge, MA USA. [Wear, Keith; Garra, Brian] US FDA, Rockville, MD 20857 USA. [Milkowski, Andy; Rosenzweig, Stephen] Siemens Ultrasound, Issaquah, WA USA. [Carson, Paul] Univ Michigan, Ann Arbor, MI 48109 USA. [Barr, Richard] Surg Hosp Southwoods, Boardman, OH USA. [Shamdasani, Vijay] Philips Ultrasound, Bothell, WA USA. [Macdonald, Michael; Wang, Michael] Gen Elect, Milwaukee, WI USA. [Guenette, Gilles; Miyajima, Yasuo; Okamura, Yoko] Toshiba Med Res Inst, Redmond, WA USA. [Dhyani, Manish; Samir, Anthony] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hah, Zaegyoo] Samsung Medison, Seoul, South Korea. [McLaughlin, Glen; Gee, Albert; Chen, Yuling; Napolitano, David] Zonare Med Syst, Mountain View, CA USA. [McAleavey, Steve] Univ Rochester, Rochester, NY USA. [Obuchowski, Nancy] Cleveland Clin, Cleveland, OH 44106 USA. [Hall, Timothy] Univ Wisconsin, Madison, WI USA. RP Palmeri, M (reprint author), Duke Univ, Durham, NC 27708 USA. NR 6 TC 0 Z9 0 U1 1 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1948-5719 BN 978-1-4799-8182-3 J9 IEEE INT ULTRA SYM PY 2015 DI 10.1109/ULTSYM.2015.0283 PG 4 WC Engineering, Electrical & Electronic SC Engineering GA BE0HK UT WOS:000366045700401 ER PT S AU Shi, W Anand, A Sethuraman, S Huang, SW Xie, H Agarwal, H Yan, P Azevedo, J Kruecker, J Ng, G Shamdasani, V Pritchard, W Karanian, J Wood, B AF Shi, William Anand, Ajay Sethuraman, Shriram Huang, Sheng-Wen Xie, Hua Agarwal, Harsh Yan, Pingkun Azevedo, Jose Kruecker, Jochen Ng, Gary Shamdasani, Vijay Pritchard, William Karanian, John Wood, Bradford GP IEEE TI Monitoring of Radiofrequency Ablation with Shear Wave Delay Mapping SO 2015 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS) SE IEEE International Ultrasonics Symposium LA English DT Proceedings Paper CT IEEE International Ultrasonics Symposium (IUS) CY OCT 21-24, 2015 CL Taipei, TAIWAN SP IEEE DE ablation monitoring; radiofrequency ablation; shear wave imaging; stiffness; elasticity; time-to-peak AB Real-time monitoring of radiofrequency ablation is important to ensure adequate treatment coverage of liver tumors as well as protection of healthy tissues. The high stiffness contrast between ablated and non-treated tissues has led to the use of ultrasound elastography for coagulation zone visualization. A highly sensitive shear wave delay mapping approach was developed for ablation boundary detection, especially, in the presence of a rigid ablation needle. The shear wave technique was evaluated using ex-vivo bovine and porcine liver samples as well as whole livers from sedated live and fresh cadaver pigs. Initial tissue softening was seen ex-vivo for non-perfused livers, but not observed in-vivo for live livers with 'cooling' blood perfusion. The lesion sizes (lateral radii) determined by the shear wave technique were generally in good agreement with those from gross pathology. In addition, T2-weighted MR images were acquired in 3D for direct assessments of ablated tissue volumes. Overall the shear wave technique appears feasible for defining and monitoring the progression of thermal lesion boundary. C1 [Shi, William; Anand, Ajay; Sethuraman, Shriram; Huang, Sheng-Wen; Xie, Hua; Agarwal, Harsh; Yan, Pingkun; Azevedo, Jose; Kruecker, Jochen] Philips Res North Amer, Cambridge, MA 02141 USA. [Ng, Gary; Shamdasani, Vijay] Philips Ultrasound, Bothell, WA 98021 USA. [Pritchard, William; Karanian, John] US FDA, Rockville, MD 20857 USA. [Wood, Bradford] NIH, Bethesda, MD 20892 USA. RP Shi, W (reprint author), Philips Res North Amer, Cambridge, MA 02141 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1948-5719 BN 978-1-4799-8182-3 J9 IEEE INT ULTRA SYM PY 2015 DI 10.1109/ULTSYM.2015.0040 PG 4 WC Engineering, Electrical & Electronic SC Engineering GA BE0HK UT WOS:000366045700412 ER PT J AU Bouhifd, M Beger, R Flynn, T Guo, LN Harris, G Hogberg, H Kaddurah-Daouk, R Kamp, H Kleensang, A Maertens, A Odwin-DaCosta, S Pamies, D Robertson, D Smirnova, L Sun, JC Zhao, L Hartung, T AF Bouhifd, Mounir Beger, Richard Flynn, Thomas Guo, Lining Harris, Georgina Hogberg, Helena Kaddurah-Daouk, Rima Kamp, Hennicke Kleensang, Andre Maertens, Alexandra Odwin-DaCosta, Shelly Pamies, David Robertson, Donald Smirnova, Lena Sun, Jinchun Zhao, Liang Hartung, Thomas TI Quality Assurance of Metabolomics SO ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION LA English DT Article DE metabolomics; toxicometabolomics; quality assurance; human toxome ID CELL-CULTURE PRACTICE; SYSTEMS TOXICOLOGY; METABOLITE IDENTIFICATION; HUMAN TOXOME; INTRACELLULAR METABOLITES; METABONOMIC ANALYSIS; TASK-FORCE; VALIDATION; PROTEOMICS; PLASMA AB Metabolomics promises a holistic phenotypic characterization of biological responses to toxicants. This technology is based on advanced chemical analytical tools with reasonable throughput, including mass-spectroscopy and NMR. Quality assurance, however from experimental design, sample preparation, metabolite identification, to bioinformatics data-mining is urgently needed to assure both quality of metabolomics data and reproducibility of biological models. In contrast to microarray-based transcriptomics, where consensus on quality assurance and reporting standards has been fostered over the last two decades, quality assurance of metabolomics is only now emerging. Regulatory use in safety sciences, and even proper scientific use of these technologies, demand quality assurance. In an effort to promote this discussion, an expert workshop discussed the quality assurance needs of metabolomics. The goals for this workshop were 1) to consider the challenges associated with metabolomics as an emerging science, with an emphasis on its application in toxicology and 2) to identify the key issues to be addressed in order to establish and implement quality assurance procedures in metabolomics-based toxicology. Consensus has still to be achieved regarding best practices to make sure sound, useful, and relevant information is derived from these new tools. C1 [Bouhifd, Mounir; Harris, Georgina; Hogberg, Helena; Kleensang, Andre; Maertens, Alexandra; Odwin-DaCosta, Shelly; Pamies, David; Smirnova, Lena; Zhao, Liang; Hartung, Thomas] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Ctr Alternat Anim Testing, Baltimore, MD USA. [Beger, Richard; Sun, Jinchun] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. [Flynn, Thomas] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD USA. [Guo, Lining] Metabolon Inc, Durham, NC USA. [Kaddurah-Daouk, Rima] Duke Univ, Duke Inst Brain Sci, Dept Psychiat & Behav Sci, Durham, NC USA. [Kamp, Hennicke] BASF SE, Expt Toxicol & Ecol, Ludwigshafen, Germany. [Robertson, Donald] Bristol Myers Squibb Pharmaceut Co, Princeton, NJ USA. [Hartung, Thomas] Univ Konstanz, CAAT Europe, Constance, Germany. RP Hartung, T (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Alternat Anim Testing, 615 North Wolfe St,W7032, Baltimore, MD 21205 USA. EM thartun1@jhu.edu OI Kleensang, Andre/0000-0002-4564-7399 FU NIH [R01ES020750] FX This CAAT workshop on Quality assurance of metabolomics was made possible by support from the Doerenkamp-Zbinden-Foundation, Agilent Technologies, and BASF, and was part of the NIH transformative research project on "Mapping the Human Toxome by Systems Toxicology" (R01ES020750). NR 58 TC 7 Z9 7 U1 5 U2 12 PU SPEKTRUM AKADEMISCHER VERLAG-SPRINGER-VERLAG GMBH PI HEILDEBERG PA TIERGARTENSTRASSE 17, HEILDEBERG, 69121, GERMANY SN 1868-596X EI 1868-8551 J9 ALTEX-ALTERN ANIM EX JI ALTEX-Altern. Anim. Exp. PY 2015 VL 32 IS 4 BP 319 EP 326 DI 10.14573/altex.1509161 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CY2EJ UT WOS:000366221300008 PM 26536290 ER PT J AU Gordon, S Daneshian, M Bouwstra, J Caloni, F Constant, S Davies, DE Dandekar, G Guzman, CA Fabian, E Haltner, E Hartung, T Hasiwa, N Hayden, P Kandarova, H Khare, S Krug, HF Kneuer, C Leist, M Lian, GP Marx, U Metzger, M Ott, K Prieto, P Roberts, MS Roggen, EL Tralau, T van den Braak, C Walles, H Lehr, CM AF Gordon, Sarah Daneshian, Mardas Bouwstra, Joke Caloni, Francesca Constant, Samuel Davies, Donna E. Dandekar, Gudrun Guzman, Carlos A. Fabian, Eric Haltner, Eleonore Hartung, Thomas Hasiwa, Nina Hayden, Patrick Kandarova, Helena Khare, Sangeeta Krug, Harald F. Kneuer, Carsten Leist, Marcel Lian, Guoping Marx, Uwe Metzger, Marco Ott, Katharina Prieto, Pilar Roberts, Michael S. Roggen, Erwin L. Tralau, Tewes van den Braak, Claudia Walles, Heike Lehr, Claus-Michael TI Non-Animal Models of Epithelial Barriers (Skin, Intestine and Lung) in Research, Industrial Applications and Regulatory Toxicology SO ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION LA English DT Article DE in vitro models; epithelial cell culture; permeability; transport studies; cytotoxicity ID IN-VITRO MODEL; AIR-LIQUID INTERFACE; EMBRYONIC STEM-CELLS; ON-A-CHIP; ARTIFICIAL MEMBRANE-PERMEABILITY; RECONSTRUCTED HUMAN EPIDERMIS; RESPIRATORY SYNCYTIAL VIRUS; PULMONARY DRUG-DELIVERY; VESICLE-BASED BARRIER; ASTHMATIC BRONCHIAL EPITHELIUM AB Models of the outer epithelia of the human body namely the skin, the intestine and the lung have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report. C1 [Gordon, Sarah; Lehr, Claus-Michael] Univ Saarland, Helmholtz Ctr Infect Res HZI, Helmholtz Inst Pharmaceut Res Saarland HIPS, Dept Drug Delivery DDEL, D-66123 Saarbrucken, Germany. [Gordon, Sarah; Lehr, Claus-Michael] Univ Saarland, Dept Pharm, D-66123 Saarbrucken, Germany. [Daneshian, Mardas; Hartung, Thomas; Hasiwa, Nina; Leist, Marcel] Univ Konstanz, Ctr Alternat Anim Testing Europe, Constance, Germany. [Bouwstra, Joke] Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Delivery Technol, Leiden, Netherlands. [Caloni, Francesca] Univ Milan, Dept Hlth Anim Sci & Food Safety VESPA, Milan, Italy. [Constant, Samuel] Epithelix Sarl, Geneva, Switzerland. [Davies, Donna E.] Univ Southampton, Fac Med, Clin & Expt Sci, Southampton SO9 5NH, Hants, England. [Davies, Donna E.] Southampton Univ Hosp, NIHR Resp Biomed Res Unit, Southampton, Hants, England. [Dandekar, Gudrun; Metzger, Marco; Walles, Heike] Univ Hosp Wurzburg, Fraunhofer Inst Interfacial Engn & Biotechnol IGB, Translat Ctr Regenerat Therapies Oncol & Musculos, Wurzburg Branch, Wurzburg, Germany. [Dandekar, Gudrun; Metzger, Marco; Walles, Heike] Univ Hosp Wurzburg, Dept Tissue Engn & Regenerat Med, Wurzburg, Germany. [Guzman, Carlos A.] Helmholtz Ctr Infect Res HZI, Dept Vaccinol & Appl Microbiol, Braunschweig, Germany. [Fabian, Eric; Ott, Katharina] BASF SE, Expt Toxicol & Ecol, Ludwigshafen, Germany. [Haltner, Eleonore] Across Barriers GmbH, Saarbrucken, Germany. [Hartung, Thomas] Johns Hopkins Univ, Ctr Alternat Anim Testing, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Hayden, Patrick] MatTek Corp, Ashland, MA USA. [Kandarova, Helena] MatTek In Vitro Life Sci Labs, Bratislava, Slovakia. [Khare, Sangeeta] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. [Krug, Harald F.] Empa Swiss Fed Inst Mat Sci Technol, St Gallen, Switzerland. [Kneuer, Carsten] German Fed Inst Risk Assessment BfR, Dept Pesticide Safety, Berlin, Germany. [Lian, Guoping] Unilever Res Colworth, Sharnbrook, Beds, England. [Lian, Guoping] Univ Surrey, Dept Chem & Proc Engn, Guildford GU2 5XH, Surrey, England. [Marx, Uwe] Tech Univ Berlin, Berlin, Germany. [Marx, Uwe] TissUse Inc, Spreenhagen, Berlin, Germany. [Prieto, Pilar] Commiss European Communities, Joint Res Ctr, Inst Hlth & Consumer Protect, EURL ECVAM,Syst Toxicol Unit, I-21020 Ispra, Italy. [Roberts, Michael S.] Univ Queensland, Sch Med, Therapeut Res Ctr, Brisbane, Qld, Australia. [Roberts, Michael S.] Univ S Australia, Adelaide, SA 5001, Australia. [Roggen, Erwin L.] 3Rs Management & Consulting ApS, Lyngby, Denmark. [Tralau, Tewes] German Fed Inst Risk Assessment BfR, Dept Chem & Prod Safety, Berlin, Germany. [van den Braak, Claudia] Danone Corp, Nutricia Res, Utrecht, Netherlands. RP Lehr, CM (reprint author), Univ Saarland, Helmholtz Ctr Infect Res HZI, Helmholtz Inst Pharmaceut Res Saarland HIPS, Dept Drug Delivery DDEL, Campus E 8, D-66123 Saarbrucken, Germany. EM claus-michael.lehr@helmholtz-hzi.de RI Davies, Donna/H-2993-2012; Roberts, Michael/C-5247-2014; Walles, Prof. Dr. Heike/M-1289-2015; Leist, Marcel/D-2133-2010; OI Roberts, Michael/0000-0003-3894-5301; Leist, Marcel/0000-0002-3778-8693; Kandarova, Helena/0000-0002-6926-1343 FU Medical Research Council (UK); Biotechnology and Biological Sciences Research Council; British Lung Foundation; Asthma, Allergy and Inflammation Research (AAIR) Charity; National Centre for Replacement, Refinement and Reduction of Animals in Research (NC3Rs); National Institute for Health Research (UK) FX D. E. Davies is supported by grants from Medical Research Council (UK), Biotechnology and Biological Sciences Research Council, British Lung Foundation, Asthma, Allergy and Inflammation Research (AAIR) Charity, National Centre for Replacement, Refinement and Reduction of Animals in Research (NC3Rs) and National Institute for Health Research (UK). NR 512 TC 9 Z9 9 U1 11 U2 26 PU SPEKTRUM AKADEMISCHER VERLAG-SPRINGER-VERLAG GMBH PI HEILDEBERG PA TIERGARTENSTRASSE 17, HEILDEBERG, 69121, GERMANY SN 1868-596X EI 1868-8551 J9 ALTEX-ALTERN ANIM EX JI ALTEX-Altern. Anim. Exp. PY 2015 VL 32 IS 4 BP 327 EP 378 DI 10.14573/altex.1510051 PG 52 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CY2EJ UT WOS:000366221300009 PM 26536291 ER PT S AU Dickinson, GS Akkoyunlu, M Bram, RJ Alugupalli, KR AF Dickinson, Gregory S. Akkoyunlu, Mustafa Bram, Richard J. Alugupalli, Kishore R. BA Ghosn, E BF Ghosn, E BE Rothstein, TL Herzenberg, LA Holodick, NE TI BAFF receptor and TACI in B-1b cell maintenance and antibacterial responses SO B-1 CELL DEVELOPMENT AND FUNCTION SE Annals of the New York Academy of Sciences LA English DT Article; Proceedings Paper CT Merinoff World Congress - B-1 Cell Development and Function CY JUN 16-19, 2014 CL Tarrytown, NY SP Panasonic, Beckman Coulter, Life Sciences, BioLegend, Sony, BD, Cellular Technol Ltd, Genentech DE B-1b cells; Borrelia hermsii; BAFF receptor; Toll-like receptor; X-linked immunodeficiency; polysaccharide vaccines; TACI ID BORRELIA-HERMSII INFECTION; INDEPENDENT TYPE-2 ANTIGENS; BRUTONS-TYROSINE KINASE; APRIL-DEFICIENT MICE; B-CELLS; XID MICE; B1B LYMPHOCYTES; ANTIBODY-RESPONSES; HUMORAL IMMUNITY; RELAPSING FEVER AB Although evidence of the protective immunity conferred by B-1b cells (CD19(+)B220(+)IgM(hi)Mac1(+)CD5(-)) has been established, the mechanisms governing the maintenance and activation of B-1b cells following pathogen encounter remain unclear. B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) mediate their function in mature B cells through the BAFF receptor (BAFFR) and transmembrane activator and CAML interactor (TACI). BAFFR-deficient mice have lower numbers of B-1b cells, and this reduction is directly proportional to BAFFR levels. The generation of B-1b cells is also dependent on the strength of B cell receptor (BCR) signaling. Mice with impaired BCR signaling, such as X-linked immunodeficient (xid) mice, have B-1b cell deficiency, indicating that both BCR- and BAFFR-mediated signaling are critical for B-1b cell homeostasis. Borrelia hermsii induces expansion and persistence of B-1b cells in xid mice, and these B-1b cells provide a heightened protective response. Toll-like receptor (TLR)-mediated stimulation of xid B cells results in a significant increase in TACI expression and restoration of TACI-mediated functions. The activation of TLR signaling by B. hermsii and BCR/TLR costimulation-mediated upregulation of BAFFR and TACI on B-1b cells suggests that B-1b cell maintenance and function following bacterial exposure may depend on BAFFR- and TACI-mediated signaling. In fact, the loss of both BAFFR and TACI results in a greater impairment in anti-B. hermsii responses compared to deficiency of BAFFR or TACI alone. C1 [Dickinson, Gregory S.; Alugupalli, Kishore R.] Thomas Jefferson Univ, Dept Microbiol & Immunol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Akkoyunlu, Mustafa] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Bram, Richard J.] Mayo Clin, Dept Pediat & Adolescent Med, Coll Med, Rochester, MN USA. RP Alugupalli, KR (reprint author), Thomas Jefferson Univ, Dept Microbiol & Immunol, Kimmel Canc Ctr, 233 South 10th St,BLSB 726, Philadelphia, PA 19107 USA. EM kishore.alugupalli@jefferson.edu FU NIH [RO3 AI109217, AI115412] FX This work was supported by NIH Grants RO3 AI109217 and AI115412 to K.R.A. NR 75 TC 2 Z9 2 U1 0 U2 1 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND SN 0077-8923 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2015 VL 1362 BP 57 EP 67 DI 10.1111/nyas.12772 PG 11 WC Cell Biology; Immunology SC Cell Biology; Immunology GA BE0LZ UT WOS:000366286200009 PM 25962322 ER PT J AU Ackermann, B Neubert, H Hughes, N Garofolo, F Abberley, L Alley, SC Brown-Augsburger, P Bustard, M Chen, LZ Heinrich, J Katori, N Kaur, S Kirkovsky, L Laterza, OF Le Blaye, O Levesque, A Santos, GML Olah, T Savoie, N Skelly, M Spitz, S Szapacs, M Tampal, N Wang, J Welink, J Wieling, J Haidar, S Vinter, S Whale, E Witte, B AF Ackermann, Brad Neubert, Hendrik Hughes, Nicola Garofolo, Fabio Abberley, Lee Alley, Stephen C. Brown-Augsburger, Patricia Bustard, Mark Chen, Lin-zhi Heinrich, Julia Katori, Noriko Kaur, Surinder Kirkovsky, Leo Laterza, Omar F. Le Blaye, Olivier Levesque, Ann Lima Santos, Gustavo Mendes Olah, Timothy Savoie, Natasha Skelly, Michael Spitz, Susan Szapacs, Matthew Tampal, Nilufer Wang, Jian Welink, Jan Wieling, Jaap Haidar, Sam Vinter, Stephen Whale, Emma Witte, Baerbel TI 2015 White Paper on recent issues in bioanalysis: focus on new technologies and biomarkers (Part 2-hybrid LBA/LCMS and input from regulatory agencies) SO BIOANALYSIS LA English DT Article ID VALIDATION GROUP WORKSHOP; LC-MS/MS; FULL IMMERSION; MASS-SPECTROMETRY; PROTEIN; IMMUNOGENICITY; GLUCAGON; ANTIBODY; DRUG; QUANTIFICATION AB The 2015 9th Workshop on Recent Issues in Bioanalysis (9th WRIB) took place in Miami, Florida with participation of over 600 professionals from pharmaceutical and biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. It is once again a 5-day week long event - a full immersion bioanalytical week - specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches including the focus on biomarkers and immunogenicity. This 2015 White Paper encompasses recommendations that emerged from the extensive discussions held during the workshop, and is aimed at providing the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to advance scientific excellence, improve quality and deliver better regulatory compliance. Due to its length, the 2015 edition of this comprehensive White Paper has been divided into three parts. Part 2 covers the recommendations for hybrid LBA/LCMS and regulatory agencies' inputs. Part 1 (small molecule bioanalysis using LCMS) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) will be published in volume 7 of Bioanalysis, issues 22 and 24, respectively. C1 [Ackermann, Brad; Brown-Augsburger, Patricia] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Neubert, Hendrik] Pfizer, Andover, MA USA. [Hughes, Nicola] Bioanalyt Lab Serv, Toronto, ON, Canada. [Garofolo, Fabio] Angelini Pharma, I-0040 S Palomba Pomezia, RM, Italy. [Abberley, Lee; Szapacs, Matthew] GlaxoSmithKline, King Of Prussia, PA USA. [Alley, Stephen C.] Seattle Genet, Seattle, WA USA. [Bustard, Mark] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Chen, Lin-zhi] Boehringer Ingelheim KG, Ridgefield, CT USA. [Heinrich, Julia] pRED Pharmaceut Sci, Roche Innovat Ctr Penzberg, Berlin, Germany. [Katori, Noriko] Japan MHLW NIHS, Tokyo, Japan. [Kaur, Surinder] Genentech Inc, San Francisco, CA 94080 USA. [Kirkovsky, Leo] Pfizer, San Diego, CA USA. [Laterza, Omar F.] Merck & Co Inc, Rahway, NJ 07065 USA. [Le Blaye, Olivier] France ANSM, St Denis, France. [Levesque, Ann] InVentiv Hlth Clin, Quebec City, PQ, Canada. [Lima Santos, Gustavo Mendes] Brazil ANVISA, Brasilia, DF, Brazil. [Olah, Timothy; Wang, Jian] Bristol Myers Squibb Co, Princeton, NJ USA. [Savoie, Natasha] CFABS, Montreal, PQ, Canada. [Skelly, Michael; Tampal, Nilufer; Haidar, Sam] US FDA, Silver Spring, MD USA. [Spitz, Susan] MedImmune, Gaithersburg, MD USA. [Welink, Jan] Dutch MEB, Utrecht, Netherlands. [Wieling, Jaap] Antaeus Biopharma, Fochteloo, Netherlands. [Vinter, Stephen; Whale, Emma] UK MHRA, London, England. [Witte, Baerbel] Germany BfArM, Bonn, Germany. RP Garofolo, F (reprint author), Angelini Pharma, Piazzale Staz,SNC, I-0040 S Palomba Pomezia, RM, Italy. EM f.garofolo@angelini.it FU US FDA; Europe EMA; France ANSM; Netherlands MEB; UK MHRA; Germany BfArM; Brazil ANVISA; Health Canada; Japan MHWL FX The authors acknowledge the US FDA, Europe EMA, France ANSM, The Netherlands MEB, UK MHRA, Germany BfArM, Brazil ANVISA, Health Canada and Japan MHWL for supporting this workshop. E Fluhler (Pfizer), J Welink (EMA/Dutch MEB), B Ackermann (Eli Lilly), N Hughes (Life Labs), F Garofolo (Angelini Pharma), A Song (Genentech), T Thway (Amgen), L Amaravadi (Biogen Idec) and H Myler (Bristol-Myers Squibb) for chairing the workshop and/or the White Paper discussions. All the workshop attendees and members of the bioanalytical community who have sent comments and suggestions to complete this White Paper. W Garofolo, L Lu, X Wang, M Losauro, N Savoie, A Hernandezand, S Schonert, D Cohen, K Kalaydjian, P de Souza for the assistance in the organization of the event. Future Science Group as a trusted partner. NR 31 TC 8 Z9 8 U1 1 U2 2 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1757-6180 EI 1757-6199 J9 BIOANALYSIS JI Bioanalysis PY 2015 VL 7 IS 23 BP 3019 EP 3034 DI 10.4155/bio.15.214 PG 16 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CY1RH UT WOS:000366184800007 PM 26627049 ER PT J AU Guan, A Li, ZY Phillips, KS AF Guan, Allan Li, Zhenyu Phillips, K. Scott TI The effects of non-ionic polymeric surfactants on the cleaning of biofouled hydrogel materials SO BIOFOULING LA English DT Article DE detergency; hydrogel; block copolymer; critical micelle concentration (CMC); contact lens; multipurpose solution (MPS) ID OXIDE BLOCK-COPOLYMERS; CONTACT-LENSES; FLUORESCENCE PROBE; PROTEIN ADSORPTION; GLOBULAR-PROTEINS; AQUEOUS-SOLUTIONS; SOIL REMOVAL; SURFACES; TENSION; DRUG AB Block co-polymer surfactants have been used for cleaning hydrogel medical devices that contact the body (eg contact lenses) because of their biocompatibility. This work examined the relationship between concentration and detergency of two non-ionic polymeric surfactants (Pluronic F127 and Triton X-100) for cleaning protein soil, with anionic surfactants (sodium dodecyl sulfate and sodium laureth sulfate) as positive controls. Surface plasmon resonance was used to quantify removal of simulated tear soil from self-assembled monolayer surfaces, and a microplate format was used to study the removal of fluorescently labeled soil proteins from contact lenses. While detergency increased as a function of concentration for anionic surfactants, it decreased with concentration for the two polymeric surfactants. The fact that the protein detergency of some non-ionic polymeric surfactants did not increase with concentration above the critical micelle concentration could have implications for optimizing the tradeoff between detergency and biocompatibility. C1 [Guan, Allan; Li, Zhenyu] George Washington Univ, Dept Biomed Engn, Washington, DC USA. [Phillips, K. Scott] US FDA, Div Biol Chem & Mat Sci, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth,Off Sci & Engn Labs, Silver Spring, MD 20993 USA. RP Phillips, KS (reprint author), US FDA, Div Biol Chem & Mat Sci, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth,Off Sci & Engn Labs, Silver Spring, MD 20993 USA. EM kenneth.phillips@fda.hhs.gov RI Phillips, Kenneth/A-2156-2013; OI Phillips, Kenneth/0000-0002-6552-0694; Guan, Allan/0000-0001-9292-4582 FU FDA Medical Countermeasures Initiative (MCMi); Center for Devices and Radiological Health (CDRH) FX The authors acknowledge the FDA Medical Countermeasures Initiative (MCMi) and the Center for Devices and Radiological Health (CDRH) for support. NR 62 TC 1 Z9 1 U1 3 U2 12 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0892-7014 EI 1029-2454 J9 BIOFOULING JI Biofouling PY 2015 VL 31 IS 9-10 BP 689 EP 697 DI 10.1080/08927014.2015.1094690 PG 9 WC Biotechnology & Applied Microbiology; Marine & Freshwater Biology SC Biotechnology & Applied Microbiology; Marine & Freshwater Biology GA CY5AA UT WOS:000366418900002 PM 26469384 ER PT S AU Twomey, JD Hallett, W Zhang, BL AF Twomey, Julianne D. Hallett, William Zhang, Baolin BE Bonavida, B Chouaib, S TI Overcoming Cancer Cell Resistance to Death Receptor Targeted Therapies SO RESISTANCE OF CANCER CELLS TO CTL-MEDIATED IMMUNOTHERAPY SE Resistance to Targeted Anti-Cancer Therapeutics LA English DT Article; Book Chapter DE Death receptors; Apoptosis; Targeted therapies; Drug resistance; Predictive biomarkers; Combinational therapies ID TUMOR-NECROSIS-FACTOR; APOPTOSIS-INDUCING LIGAND; TRAIL-INDUCED APOPTOSIS; METASTATIC COLORECTAL-CANCER; AGONISTIC MONOCLONAL-ANTIBODY; PLACEBO-CONTROLLED PHASE-2; HISTONE DEACETYLASE INHIBITORS; RECOMBINANT HUMAN APO2L/TRAIL; ADVANCED SOLID MALIGNANCIES; FOLFOX6 PLUS BEVACIZUMAB AB Death receptors (DRs) are promising targets for cancer therapies because of their ability to induce apoptosis in cancer cells. These receptors are characterized by an intracellular death domain, which transmits a death signal from their cognate ligands, including TNF-related apoptosis inducing ligand (TRAIL). Currently, multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL and agonistic antibodies to its receptors DR4 and DR5. Although the products have shown a tolerated safety profile in the completed phase 1 studies, a large number of cancer cell lines are found to be resistant to these agents, raising a concern about their clinical efficacy. This review provides an update of recent advances in understanding the molecular mechanisms involved in cancer cell resistance to DR4/DR5 targeted therapies. This information will be further discussed with respect to combinational strategies to overcome or bypass resistance mechanisms towards a better treatment outcome. C1 [Twomey, Julianne D.; Hallett, William; Zhang, Baolin] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. RP Zhang, BL (reprint author), US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. EM Baolin.Zhang@fda.hhs.gov NR 124 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2196-5501 BN 978-3-319-17807-3; 978-3-319-17806-6 J9 RESIST TARGET ANTI-C PY 2015 VL 7 BP 209 EP 233 DI 10.1007/978-3-319-17807-3_10 D2 10.1007/978-3-319-17807-3 PG 25 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA BE0FJ UT WOS:000365951300011 ER PT S AU Formolo, T Ly, M Levy, M Kilpatrick, L Lute, S Phinney, K Marzilli, L Brorson, K Boyne, M Davis, D Schiel, J AF Formolo, Trina Ly, Mellisa Levy, Michaella Kilpatrick, Lisa Lute, Scott Phinney, Karen Marzilli, Lisa Brorson, Kurt Boyne, Michael Davis, Darryl Schiel, John BE Schiel, JE Davis, DL Borisov, OV TI Determination of the NISTmAb Primary Structure SO STATE-OF-THE-ART AND EMERGING TECHNOLOGIES FOR THERAPEUTIC MONOCLONAL ANTIBODY CHARACTERIZATION, VOL 2: BIOPHARMACEUTICAL CHARACTERIZATION: THE NISTMAB CASE STUDY SE ACS Symposium Series LA English DT Article; Book Chapter ID TANDEM MASS-SPECTROMETRY; ELECTRON-TRANSFER DISSOCIATION; FAST-ATOM-BOMBARDMENT; AMINO ACID SEQUENCES; C-TERMINAL LYSINE; RECOMBINANT MONOCLONAL-ANTIBODY; ACHROMOBACTER-LYTICUS M497-1; HUMAN GAMMA-GLOBULIN; TOP-DOWN; IMMUNOGLOBULIN-G AB The primary structure of a protein, including therapeutic monoclonal antibodies (mAbs), is a critical quality attribute that determines a great deal of its structure, function, and stability. Significant effort is devoted to determining the complete amino acid sequence of recombinant proteins of potential therapeutic benefit. The focus of this chapter is to demonstrate current, state-of-the-art, mass spectrometry-based primary structure confirmation using the recombinant human IgG 1 k NISTmAb as a representative example. A combination of intact mass analysis, top-down sequencing, IdeS fragment mass analysis, IdeS fragment (or "middle-down") sequencing, and peptide mapping are discussed with respect to their orthogonality and limitations. A historical review of the methods employed to determine the primary structure of proteins is also included for completeness. C1 [Formolo, Trina; Kilpatrick, Lisa; Phinney, Karen; Schiel, John] NIST, Biomol Measurement Div, Gaithersburg, MD 20899 USA. [Ly, Mellisa; Marzilli, Lisa] Pfizer Inc, Mass Spectrometry & Biophys Characterizat, Analyt Res & Dev, BioTherapeut Pharmaceut Sci, Andover, MA 01810 USA. [Davis, Darryl] Janssen Res & Dev LLC, Spring House, PA 19002 USA. [Levy, Michaella; Boyne, Michael] US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Pharmaceut Anal, St Louis, MO 63110 USA. [Lute, Scott; Brorson, Kurt] US FDA, Ctr Drug Evaluat & Res, Off Biotechnol Prod, Div Monoclonal Antibodies, Silver Spring, MD 20993 USA. RP Formolo, T (reprint author), NIST, Biomol Measurement Div, Gaithersburg, MD 20899 USA. EM john.schiel@nist.gov NR 113 TC 0 Z9 0 U1 3 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 SIXTEENTH ST NW, WASHINGTON, DC 20036 USA SN 0097-6156 BN 978-0-8412-3029-3 J9 ACS SYM SER JI ACS Symp. Ser. PY 2015 VL 1201 BP 1 EP 62 D2 10.1021/bk-2015-1201 PG 62 WC Biochemical Research Methods; Chemistry, Analytical; Immunology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Immunology; Pharmacology & Pharmacy GA BE0LG UT WOS:000366231800001 ER PT S AU Michels, DA Ip, AY Dillon, TM Brorson, K Lute, S Chavez, B Prentice, KM Brady, LJ Miller, KJ AF Michels, David A. Ip, Anna Y. Dillon, Thomas M. Brorson, Kurt Lute, Scott Chavez, Brittany Prentice, Ken M. Brady, Lowell J. Miller, Karen J. BE Schiel, JE Davis, DL Borisov, OV TI Separation Methods and Orthogonal Techniques SO STATE-OF-THE-ART AND EMERGING TECHNOLOGIES FOR THERAPEUTIC MONOCLONAL ANTIBODY CHARACTERIZATION, VOL 2: BIOPHARMACEUTICAL CHARACTERIZATION: THE NISTMAB CASE STUDY SE ACS Symposium Series LA English DT Article; Book Chapter ID SODIUM DODECYL-SULFATE; PERFORMANCE LIQUID-CHROMATOGRAPHY; RECOMBINANT MONOCLONAL-ANTIBODY; SIZE-EXCLUSION CHROMATOGRAPHY; IONIZATION MASS-SPECTROMETRY; CAPILLARY-ELECTROPHORESIS; LIGHT-SCATTERING; CHARGE HETEROGENEITY; OPERATING-CONDITIONS; STRUCTURAL-ANALYSIS AB Chromatographic and electrophoretic separation methods are key tools for the characterization of monoclonal antibodies. The objective of these methods for characterization is to resolve and identify critical quality attributes. Several orthogonal separation methods are often required in order to fully characterize the critical quality attributes of a particular monoclonal antibody preparation. Throughout this chapter, the use of separation methods and orthogonal techniques for monoclonal antibody characterization is demonstrated by the analysis of a monoclonal antibody material available from the NIST. The analysis of the material described in this chapter serves as characterization of the material to enable its use as a standard and exemplifies the steps that may be taken to characterize a therapeutic monoclonal antibody. Recent advances described in this chapter include the use of high pressure systems in combination with small particle size columns to accomplish rapid separations which save time and reduce solvent consumption. In addition, the use of software tools for the development and optimization of methods is described. C1 [Michels, David A.] Genentech Inc, Dept Prot Analyt Chem, San Francisco, CA 94080 USA. [Ip, Anna Y.; Dillon, Thomas M.] Amgen Inc, Dept Proc & Prod Dev, Thousand Oaks, CA 91361 USA. [Brorson, Kurt; Lute, Scott; Chavez, Brittany] US FDA, Div Monoclonal Antibodies, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. [Prentice, Ken M.; Brady, Lowell J.] Amgen Inc, Dept Proc & Prod Dev, Seattle, WA 98119 USA. [Miller, Karen J.] Amgen Inc, Global Analyt Sci, Thousand Oaks, CA 91320 USA. RP Michels, DA (reprint author), Genentech Inc, Dept Prot Analyt Chem, San Francisco, CA 94080 USA. EM karen@amgen.com NR 60 TC 0 Z9 0 U1 2 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 SIXTEENTH ST NW, WASHINGTON, DC 20036 USA SN 0097-6156 BN 978-0-8412-3029-3 J9 ACS SYM SER JI ACS Symp. Ser. PY 2015 VL 1201 BP 237 EP 284 D2 10.1021/bk-2015-1201 PG 48 WC Biochemical Research Methods; Chemistry, Analytical; Immunology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Immunology; Pharmacology & Pharmacy GA BE0LG UT WOS:000366231800005 ER PT J AU Welink, J Fluhler, E Hughes, N Arnold, M Garofolo, F Bustard, M Coppola, L Dhodda, R Evans, C Gleason, C Haidar, S Hayes, R Heinig, K Katori, N Le Blaye, O Li, WK Liu, GW Santos, GML Meng, M Nicholson, B Savoie, N Skelly, M Sojo, L Tampal, N van De Merbel, N Verhaeghe, T Vinter, S Wickremsinhe, E Whale, E Wilson, A Witte, B Woolf, E AF Welink, Jan Fluhler, Eric Hughes, Nicola Arnold, Mark Garofolo, Fabio Bustard, Mark Coppola, Laura Dhodda, Raj Evans, Christopher Gleason, Carol Haidar, Sam Hayes, Roger Heinig, Katja Katori, Noriko Le Blaye, Olivier Li, Wenkui Liu, Guowen Santos, Gustavo Mendes Lima Meng, Min Nicholson, Bob Savoie, Natasha Skelly, Michael Sojo, Luis Tampal, Nilufer van de Merbel, Nico Verhaeghe, Tom Vinter, Stephen Wickremsinhe, Enaksha Whale, Emma Wilson, Amanda Witte, Baerbel Woolf, Eric TI 2015 White Paper on recent issues in bioanalysis: focus on new technologies and biomarkers (Part 1-small molecules by LCMS) SO BIOANALYSIS LA English DT Article ID MASS-SPECTROMETRIC ANALYSIS; VALIDATION GROUP WORKSHOP; REGULATED BIOANALYSIS; FULL IMMERSION; ELECTROSPRAY-IONIZATION; CALIBRATION; RECOMMENDATIONS; STABILITY; LIPEMIA; ADDRESS AB The 2015 9th Workshop on Recent Issues in Bioanalysis (9th WRIB) took place in Miami, Florida with participation of over 600 professionals from pharmaceutical and biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. It is once again a 5-day week long event - a full immersion bioanalytical week - specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches including the focus on biomarkers and immunogenicity. This 2015 White Paper encompasses recommendations that emerged from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to advance scientific excellence, improve quality and deliver better regulatory compliance. Due to its length, the 2015 edition of this comprehensive White Paper has been divided into three parts. Part 1 covers the recommendations for small molecule bioanalysis using LCMS. Part 2 (hybrid LBA/LCMS and regulatory agencies' inputs) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) will also be published in volume 7 of Bioanalysis, issues 23 and 24, respectively. C1 [Welink, Jan] Dutch MEB, Utrecht, Netherlands. [Fluhler, Eric] Pfizer, Pearl River, NY USA. [Hughes, Nicola] LifeLabs LP, Bioanalyt Lab Serv Div, Toronto, ON, Canada. [Arnold, Mark; Liu, Guowen] Bristol Myers Squibb, Princeton, NJ USA. [Garofolo, Fabio] Angelini Pharma, Pomezia, RM, Italy. [Bustard, Mark; Tampal, Nilufer] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Coppola, Laura] Apotex, Toronto, ON, Canada. [Dhodda, Raj] AbbVie Inc, N Chicago, IL USA. [Evans, Christopher] GlaxoSmithKline, King Of Prussia, PA USA. [Gleason, Carol] Bristol Myers Squibb, Tully, NY USA. [Haidar, Sam; Skelly, Michael] US FDA, Silver Spring, MD USA. [Hayes, Roger] MPI Res, Mattawan, MI USA. [Heinig, Katja] F Hoffmann La Roche Ltd, Basel, Switzerland. [Katori, Noriko] Japan MHLW NIHS, Tokyo, Japan. [Le Blaye, Olivier] France ANSM, St Denis, France. [Li, Wenkui] Novartis, E Hanover, NJ USA. [Santos, Gustavo Mendes Lima] Brazil Anvisa, Brasilia, DF, Brazil. [Meng, Min] Covance, Salt Lake City, UT USA. [Nicholson, Bob] PPD, Richmond, VA USA. [Savoie, Natasha] CFABS, Montreal, PQ, Canada. [Sojo, Luis] Xenon Pharmaceut Inc, Burnaby, BC, Canada. [van de Merbel, Nico] PRA Hlth Sci, Assen, Netherlands. [Verhaeghe, Tom] Janssen Res & Dev, Beerse, Belgium. [Vinter, Stephen; Whale, Emma] UK MHRA, London, England. [Wickremsinhe, Enaksha] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Wilson, Amanda] AstraZeneca, Cambridge, England. [Witte, Baerbel] Germany BfArM, Bonn, Germany. [Woolf, Eric] Merck Res Labs, West Point, PA USA. RP Garofolo, F (reprint author), Angelini Pharma, Piazzale Staz,Snc 0040 S Palomba, Pomezia, RM, Italy. EM f.garofolo@angelini.it NR 37 TC 3 Z9 3 U1 0 U2 1 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1757-6180 EI 1757-6199 J9 BIOANALYSIS JI Bioanalysis PY 2015 VL 7 IS 22 BP 2913 EP 2925 DI 10.4155/bio.15.204 PG 13 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CX3UU UT WOS:000365625700008 PM 26573485 ER PT J AU Hong, HX Slikker, W AF Hong, Huixiao Slikker, William, Jr. TI Advancing translation of biomarkers into regulatory science Foreword SO BIOMARKERS IN MEDICINE LA English DT Editorial Material DE biomarkers; regulatory science; safety; translation ID NEGATIVE BREAST-CANCER C1 [Hong, Huixiao] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Slikker, William, Jr.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 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; william.slikker@fda.hhs.gov NR 23 TC 2 Z9 2 U1 0 U2 3 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PY 2015 VL 9 IS 11 BP 1043 EP 1046 DI 10.2217/bmm.15.104 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX0RD UT WOS:000365403400001 PM 26573514 ER PT J AU Donaldson, EF Deming, DJ O'Rear, JJ Naeger, LK AF Donaldson, Eric F Deming, Damon J. O'Rear, Julian J. Naeger, Lisa K. TI Regulatory evaluation of antiviral drug resistance in the era of next-generation sequencing SO BIOMARKERS IN MEDICINE LA English DT Editorial Material DE antiviral drug resistance; next-generation sequencing; resistance-associated substitutions; treatment-emergent substitutions ID VIROLOGY C1 [Donaldson, Eric F; Deming, Damon J.; O'Rear, Julian J.; Naeger, Lisa K.] US FDA, Div Antiviral Prod, FDA OMPT CDER OND OAP Div Antiviral Prod, Silver Spring, MD 20993 USA. RP Donaldson, EF (reprint author), US FDA, Div Antiviral Prod, FDA OMPT CDER OND OAP Div Antiviral Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Eric.Donaldson@fda.hhs.gov NR 14 TC 1 Z9 1 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PY 2015 VL 9 IS 11 BP 1047 EP 1051 DI 10.2217/bmm.15.63 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX0RD UT WOS:000365403400002 PM 26508693 ER PT J AU Wu, LH Liu, ZC Xu, J Chen, MJ Fang, H Tong, WD Xiao, WM AF Wu, Leihong Liu, Zhichao Xu, Joshua Chen, Minjun Fang, Hong Tong, Weida Xiao, Wenming TI NETBAGs: a network-based clustering approach with gene signatures for cancer subtyping analysis SO BIOMARKERS IN MEDICINE LA English DT Article DE cancer subtyping; cluster; expression; gene network; microarray; RNA-seq ID NEGATIVE BREAST-CANCER; PROTEIN NETWORKS; HUMAN-DISEASE; CELLS; BIOLOGY; CLASSIFICATION; PREDICTOR; SURVIVAL; PROJECT; MODELS AB To evaluate gene signature and network-based approach for cancer subtyping and classification. Materials & methods: Here we introduced NETwork Based clustering Approach with Gene signatures (NETBAGs) algorithm, which clustered samples based on gene signatures and identified molecular markers based on their significantly expressed gene network profiles. Results: Applying NETBAGs to multiple independent breast cancer datasets, we demonstrated that the clustering results were highly associated with the clinical subtypes and clearly revealed the genomic diversity of breast cancer samples. Conclusion: NETBAGs algorithm is able to classify samples by their genomic signatures into clinically significant phenotypes so that potential biomarkers can be identified. The approach may contribute to cancer research and clinical study of complex diseases. C1 [Wu, Leihong; Liu, Zhichao; Xu, Joshua; Chen, Minjun; Tong, Weida; Xiao, Wenming] 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. RP Xiao, WM (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. EM weida.tong@fda.hhs.gov; wenming.xiao@fda.hhs.gov NR 39 TC 1 Z9 1 U1 2 U2 4 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PY 2015 VL 9 IS 11 BP 1053 EP 1065 DI 10.2217/bmm.15.96 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX0RD UT WOS:000365403400003 PM 26501477 ER PT J AU Du, TT Yang, L Luo, H Zhou, P Mei, H Xuan, JK Xing, QH Ning, BT Mendrick, DL Shi, LM AF Du, Tingting Yang, Lun Luo, Heng Zhou, Peng Mei, Hu Xuan, Jiekun Xing, Qinghe Ning, Baitang Mendrick, Donna L. Shi, Leming TI HLADR: a database system for enhancing the discovery of biomarkers for predicting human leukocyte antigen-mediated idiosyncratic adverse drug reactions SO BIOMARKERS IN MEDICINE LA English DT Article DE association; biomarkers; human leukocyte antigen; idiosyncratic drug reactions; pharmacogenomics ID STEVENS-JOHNSON-SYNDROME; INDUCED HYPERSENSITIVITY REACTIONS; ABACAVIR HYPERSENSITIVITY; GENETIC SUSCEPTIBILITY; PEPTIDE REPERTOIRE; LIVER-INJURY; T-CELLS; HLA-B-ASTERISK-5701; MARKER; ASSOCIATION AB To establish a database for the associations between idiosyncratic drug reactions (IDRs) and human leukocyte antigens (HLAs) and to systematically assess the characteristics of the drug-HLA associations. Materials & methods: Electronic databases were searched to extensively identify drug-HLA association studies from 1966 to present. Results: A drug-HLA-IDR database, HLADR, was created. The drug-HLA relationship network clearly reflected an ethnicity dependency of the associations. The positive predictive values and the negative predictive values demonstrated that other potential factors may also regulate the occurrence of HLA-specific IDRs. Conclusions: Constructing studies with samples from homogeneous ethnic groups and identifying cofactors that affect negative predictive values and positive predictive values will become necessary to enhance the predictability of HLA biomarkers for future research on IDRs. C1 [Du, Tingting; Xuan, Jiekun; Shi, Leming] Fudan Univ, Ctr Pharmacogen, Shanghai 201203, Peoples R China. [Du, Tingting; Xuan, Jiekun; Shi, Leming] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 201203, Peoples R China. [Du, Tingting; Xuan, Jiekun; Shi, Leming] Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China. [Yang, Lun; Luo, Heng; Zhou, Peng; Mei, Hu; Xuan, Jiekun; Ning, Baitang; Mendrick, Donna L.; Shi, Leming] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Luo, Heng; Shi, Leming] Univ Arkansas, Med Sci Joint Bioinformat Grad Program, Little Rock, AR 72204 USA. [Xing, Qinghe] Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China. RP Shi, LM (reprint author), Fudan Univ, Ctr Pharmacogen, 826 Zhangheng Rd, Shanghai 201203, Peoples R China. EM lun.yang@gmail.com; donna.mendrick@fda.hhs.gov; lemingshi@fudan.edu.cn RI Luo, Heng/D-3616-2016 OI Luo, Heng/0000-0001-5192-8878 FU National High Technology Research and Development Program of China [2015AA020104]; National Science Foundation of China [31471239]; 111 Project [B13016] FX This research was supported, in part, by the National High Technology Research and Development Program of China (2015AA020104), the National Science Foundation of China (31471239), the 111 Project (B13016) and by an appointment to the Research Participation Program at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. The 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 48 TC 3 Z9 3 U1 1 U2 8 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PY 2015 VL 9 IS 11 BP 1079 EP 1093 DI 10.2217/bmm.15.98 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX0RD UT WOS:000365403400005 PM 26501190 ER PT J AU Amur, SG Sanyal, S Chakravarty, AG Noone, MH Kaiser, J McCune, S Buckman-Garner, SY AF Amur, Shashi G. Sanyal, Sarmistha Chakravarty, Aloka G. Noone, Marianne H. Kaiser, James McCune, Susan Buckman-Garner, ShaAvhree Y. TI Building a roadmap to biomarker qualification: challenges and opportunities SO BIOMARKERS IN MEDICINE LA English DT Article DE biomarker; context of use; critical path innovation meeting; evidentiary considerations; international harmonization; letter of support; qualification; regulatory science; statistical considerations; submitter ID DRUG DEVELOPMENT AB The traditional route for regulatory acceptance of biomarkers in drug development is through submission of biomarker data in drug approval submissions in the context of a single drug development program. The US FDA's Critical Path Initiative called for establishment of a biomarker qualification process to enable progress in the drug development paradigm. In response to this, the Center for Drug Evaluation and Research (CDER) established a Biomarker Qualification Program (BQP) to qualify a biomarker for a specific context of use (COU). The qualified biomarker can then be used in multiple drug development programs for this COU without re-review. Here, we describe some of the features of the BQP and two new initiatives that have the potential to aid biomarker development through early interactions with the FDA. Finally, we discuss some of the feedback the FDA has received from submitters and the BQP's actions to strengthen the program. C1 [Amur, Shashi G.; Sanyal, Sarmistha; Noone, Marianne H.; Kaiser, James; McCune, Susan; Buckman-Garner, ShaAvhree Y.] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Chakravarty, Aloka G.] US FDA, Office Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Amur, SG (reprint author), US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Shashi.Amur@fda.hhs.gov NR 27 TC 9 Z9 9 U1 2 U2 4 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PY 2015 VL 9 IS 11 BP 1095 EP 1104 DI 10.2217/bmm.15.90 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX0RD UT WOS:000365403400006 PM 26526897 ER PT J AU Lababidi, S Sutherland, A Krasnicka, B Forshee, RA Anderson, SA AF Lababidi, Samir Sutherland, Andrea Krasnicka, Barbara Forshee, Richard A. Anderson, Steven A. TI Overall conceptual framework for studying the genetics of autoimmune diseases following vaccination: a regulatory perspective SO BIOMARKERS IN MEDICINE LA English DT Article DE biologic plausibility; genetics of autoimmune diseases; molecular biomarkers; rare adverse events; vaccine safety; vaccinomics ID IMMUNE THROMBOCYTOPENIC PURPURA; SYSTEMIC-LUPUS-ERYTHEMATOSUS; GUILLAIN-BARRE-SYNDROME; RHEUMATOID-ARTHRITIS; EULAR RECOMMENDATIONS; ADVERSE EVENTS; SAFETY; IMMUNIZATION; VACCINES; ASSOCIATIONS AB The US Vaccine Adverse Event Reporting System contains case reports of autoimmune diseases (ADs) occurring following vaccinations. ADs are rare and occur in unvaccinated people, making the potential association between vaccines and ADs challenging to evaluate. Developing mechanistic pathways that link genes, immune mediators, vaccine components and ADs would be helpful for hypothesis generation, enhancing theories of biologic plausibility and grouping rare autoimmune adverse events to increase the ability to detect and evaluate safety signals. Here, we propose a conceptual framework for investigating the genetics of ADs as safety signals following vaccination, potentially contributing to the identification of relevant biomarkers. We also discuss a study design that incorporates genetic information into postmarket clinical evaluation of autoimmune adverse events following vaccination. C1 [Lababidi, Samir; Forshee, Richard A.; Anderson, Steven A.] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Sutherland, Andrea] Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. [Krasnicka, Barbara] US FDA, Div Biostat, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Lababidi, S (reprint author), US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Samir.Lababidi@fda.hhs.gov NR 60 TC 1 Z9 1 U1 0 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PY 2015 VL 9 IS 11 BP 1107 EP 1120 DI 10.2217/bmm.15.67 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX0RD UT WOS:000365403400007 PM 26526761 ER PT J AU Chen, JJ Lu, TP Chen, YC Lin, WJ AF Chen, James J. Lu, Tzu-Pin Chen, Yu-Chuan Lin, Wei-Jiun TI Predictive biomarkers for treatment selection: statistical considerations SO BIOMARKERS IN MEDICINE LA English DT Article DE biomarker adaptive design; personalized and precision medicine; predictive biomarker; predictive classifier; subgroup analysis; subgroup selection ID SURROGATE END-POINTS; FALSE DISCOVERY RATE; MICROARRAY EXPRESSION DATA; ADAPTIVE SIGNATURE DESIGN; METASTATIC BREAST-CANCER; CLINICAL-TRIALS; GENE-EXPRESSION; DRUG DEVELOPMENT; BONFERRONI PROCEDURE; DECISION-MAKING AB Predictive biomarkers are developed for treatment selection to identify patients who are likely to benefit from a particular therapy. This review describes statistical methods and discusses issues in the development of predictive biomarkers to enhance study efficiency for detection of treatment effect on the selected responder patients in clinical studies. The statistical procedure for treatment selection consists of three components: biomarker identification, subgroup selection and clinical utility assessment. Major statistical issues discussed include biomarker designs, procedures to identify predictive biomarkers, classification models for subgroup selection, subgroup analysis and multiple testing for clinical utility assessment and evaluation. C1 [Chen, James J.; Chen, Yu-Chuan] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Chen, James J.] China Med Univ, Grad Inst Biostat, Taichung, Taiwan. [Lu, Tzu-Pin] Natl Taiwan Univ, Inst Epidemiol & Prevent Med, Dept Publ Hlth, Taipei 10764, Taiwan. [Lin, Wei-Jiun] Feng Chia Univ, Dept Appl Math, Taichung 40724, 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 NR 94 TC 0 Z9 1 U1 0 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PY 2015 VL 9 IS 11 BP 1121 EP 1135 DI 10.2217/bmm.15.84 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX0RD UT WOS:000365403400008 PM 26507127 ER PT J AU Koturbash, I Tolleson, WH Guo, L Yu, DK Chen, S Hong, HX Mattes, W Ning, BT AF Koturbash, Igor Tolleson, William H. Guo, Lei Yu, Dianke Chen, Si Hong, Huixiao Mattes, William Ning, Baitang TI microRNAs as pharmacogenomic biomarkers for drug efficacy and drug safety assessment SO BIOMARKERS IN MEDICINE LA English DT Review DE biomarker; cardiotoxicity; drug efficacy; drug metabolizing enzymes; drug safety; hepatotoxicity; microRNA; nephrotoxicity ID CELL LUNG-CANCER; MODULATES MULTIDRUG-RESISTANCE; DIHYDROFOLATE-REDUCTASE GENE; CHRONIC LYMPHOCYTIC-LEUKEMIA; INDUCED LIVER-INJURY; HUMAN OVARIAN-CANCER; PREGNANE-X RECEPTOR; BREAST-CANCER; DOWN-REGULATION; CIRCULATING MICRORNAS AB Much evidence has documented that microRNAs (miRNAs) play an important role in the modulation of interindividual variability in the production of drug metabolizing enzymes and transporters (DMETs) and nuclear receptors (NRs) through multidirectional interactions involving environmental stimuli/stressors, the expression of miRNA molecules and genetic polymorphisms. MiRNA expression has been reported to be affected by drugs and miRNAs themselves may affect drug metabolism and toxicity. In cancer research, miRNA biomarkers have been identified to mediate intrinsic and acquired resistance to cancer therapies. In drug safety assessment, miRNAs have been found associated with cardiotoxicity, hepatotoxicity and nephrotoxicity. This review article summarizes published studies to show that miRNAs can serve as early biomarkers for the evaluation of drug efficacy and drug safety. C1 [Koturbash, Igor] Univ Arkansas Med Sci, Dept Environm & Occupat Hlth, Little Rock, AR 72205 USA. [Tolleson, William H.; Guo, Lei; Yu, Dianke; Chen, Si; Hong, Huixiao; Mattes, William; Ning, Baitang] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Koturbash, I (reprint author), Univ Arkansas Med Sci, Dept Environm & Occupat Hlth, Little Rock, AR 72205 USA. EM IKoturbash@uams.edu; baitang.ning@fda.hhs.gov FU National Institutes of Health Center of Biological Research Excellence [1P20GM109005]; NIH UAMS Clinical and Translational Science Award [UL1TR000039, KL2TR000063]; Arkansas Biosciences Institute FX I Koturbash would like to acknowledge financial support from the National Institutes of Health Center of Biological Research Excellence (grant number 1P20GM109005); NIH UAMS Clinical and Translational Science Award (grant numbers UL1TR000039, KL2TR000063) and Arkansas Biosciences Institute. 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 238 TC 7 Z9 8 U1 9 U2 18 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PY 2015 VL 9 IS 11 BP 1153 EP 1176 DI 10.2217/bmm.15.89 PG 24 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX0RD UT WOS:000365403400010 PM 26501795 ER PT J AU Wang, WJ Shi, Q Mattes, WB Mendrick, DL Yang, X AF Wang, Wenjun Shi, Qiang Mattes, Williams B. Mendrick, Donna L. Yang, Xi TI Translating extracellular microRNA into clinical biomarkers for drug-induced toxicity: from high-throughput profiling to validation SO BIOMARKERS IN MEDICINE LA English DT Review DE biomarkers; cardiotoxicity; extracellular; hepatotoxicity; microRNA; nephrotoxicity ID DROPLET-DIGITAL PCR; ACUTE MYOCARDIAL-INFARCTION; INDUCED LIVER-INJURY; ACUTE KIDNEY INJURY; CIRCULATING MICRORNAS; HEART-FAILURE; TUBULAR INJURY; PLASMA MIR-208; SMALL RNAS; IDENTIFICATION AB Over the past 5 years, extracellular microRNAs (miRNAs) are being vigorously explored as injury biomarkers, including drug-induced cardiotoxicity, hepatotoxicity and nephrotoxicity. Currently, the development of miRNAs as clinical biomarkers has been hindered by the lack of standardization. Therefore, extracellular miRNA-based biomarkers have not been embraced as diagnostic tools. Each platform has its strengths and weaknesses when working with low-input-amount RNA samples from body fluids; the selection of a miRNA quantification approach should be based on the study design. The following review provides a summary of the extracellular miRNA release and stability in body fluids, performances of different miRNA quantification platforms, existing clinical gold standards for drug-induced tissue damage and translation of the miRNA biomarkers from the nonclinical to clinical setting. C1 [Wang, Wenjun] South Cent Univ Nationalities, Coll Life Sci, Wuhan 430074, Peoples R China. [Wang, Wenjun; Shi, Qiang; Mattes, Williams B.; Mendrick, Donna L.; Yang, Xi] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. RP Yang, X (reprint author), US FDA, Natl Ctr Toxicol Res, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Xi.Yang@fda.hhs.gov NR 73 TC 2 Z9 2 U1 2 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PY 2015 VL 9 IS 11 BP 1177 EP 1188 DI 10.2217/bmm.15.86 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX0RD UT WOS:000365403400011 PM 26501984 ER PT J AU Wang, YP Liu, ZC Zou, W Hong, HX Fang, H Tong, WD AF Wang, Yuping Liu, Zhichao Zou, Wen Hong, Huixiao Fang, Hong Tong, Weida TI Molecular regulation of miRNAs and potential biomarkers in the progression of hepatic steatosis to NASH SO BIOMARKERS IN MEDICINE LA English DT Review DE biomarker; drug-induced liver disease; fibrosis; miRNA; nonalcoholic fatty liver disease; steatohepatitis; steatosis ID FATTY LIVER-DISEASE; CIRCULATING MICRORNAS; LIPID-METABOLISM; UP-REGULATION; INDUCED STEATOHEPATITIS; GENE-EXPRESSION; PPAR-ALPHA; FACTOR-I; FIBROSIS; INJURY AB Increasing evidence suggests that microRNAs regulate diverse biological functions in the liver and play a very important function in metabolic-related disorders such as nonalcoholic fatty liver disease via regulating their target genes expression. In this review, we summarized the most recent progress in identification of miRNAs involving in the progression of liver steatosis and discussed the possible mechanisms by which miRNAs contribute to the diverse pathogenic liver injuries. We provide insights into the functional network of miRNAs by connecting miRNAs, their targets and biological pathways associated to hepatic steatosis and fibrosis, with important implications for our understanding of phenotypic-based disease pathogenesis. We also discuss the possible roles and challenges of miRNAs as biomarkers for drug-induced liver injury. C1 [Wang, Yuping; Liu, Zhichao; Zou, Wen; Hong, Huixiao; 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. RP Wang, YP (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Yuping.wang@fda.hhs.gov; Weida.tong@fda.hhs.gov NR 72 TC 2 Z9 2 U1 2 U2 7 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PY 2015 VL 9 IS 11 BP 1189 EP 1200 DI 10.2217/bmm.15.70 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX0RD UT WOS:000365403400012 PM 26506944 ER PT J AU Shi, Q Yang, X Mattes, WB Mendrick, DL Harrill, AH Beger, RD AF Shi, Qiang Yang, Xi Mattes, William B. Mendrick, Donna L. Harrill, Alison H. Beger, Richard D. TI Circulating mitochondrial biomarkers for drug-induced liver injury SO BIOMARKERS IN MEDICINE LA English DT Review DE acetaminophen; biomarker; drug-induced liver injury; hepatotoxicity; mitochondrion ID ACETAMINOPHEN-INDUCED HEPATOTOXICITY; ACUTE HEPATIC-INJURY; ALANINE AMINOTRANSFERASE; CYTOCHROME-C; ORNITHINE CARBAMYLTRANSFERASE; GLUTAMATE-DEHYDROGENASE; NONINVASIVE BIOMARKER; HEALTHY-VOLUNTEERS; PROTEIN-KINASE; I ARGINASE AB Liver mitochondria affected by drugs can be released into circulation and serve as biomarkers for drug-induced liver injury (DILI). The tissue specificity of ALT was improved by differentiating cytosolic ALT1 and mitochondrial ALT2 isoforms released in circulation. Prior to ALT elevation, mitochondrial cytochrome c, OCT, GLDH, CPS1 and DNA were increased in circulation following DILI. The baseline expression of mt-Nd6 was predictive of individual DILI susceptibility in animals. As mitochondrial DILI biomarkers appeared to be drug or species dependent, they might have value in clinical scenarios when culprit drugs are established, but may not be ideal tools to assess DILI potentials of new drugs. C1 [Shi, Qiang; Yang, Xi; Mattes, William B.; Beger, Richard D.] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. [Mendrick, Donna L.] US FDA, Natl Ctr Toxicol Res, Regulatory Activ, Jefferson, AR 72079 USA. [Harrill, Alison H.] Univ Arkansas Med Sci, Dept Environm & Occupat Hlth, Little Rock, AR USA. RP Shi, Q (reprint author), US FDA, Natl Ctr Toxicol Res, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM qiang.shi@fda.hhs.gov FU US FDA's Office of Women's Health; Chief Scientist's Challenge Grant FX This project was supported by the US FDA's Office of Women's Health and Chief Scientist's Challenge Grant. 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 50 TC 3 Z9 3 U1 2 U2 4 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PY 2015 VL 9 IS 11 BP 1215 EP 1223 DI 10.2217/bmm.15.59 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX0RD UT WOS:000365403400014 PM 26507261 ER PT J AU Gong, P Hong, HX Perkins, EJ AF Gong, Ping Hong, Huixiao Perkins, Edward J. TI Ionotropic GABA receptor antagonism-induced adverse outcome pathways for potential neurotoxicity biomarkers SO BIOMARKERS IN MEDICINE LA English DT Review DE adverse outcome pathway; antagonist; chloride channel; cross-species extrapolation; epileptic seizure; ionotropic gamma-aminobutyric acid receptor; metabotropic GABA receptor; neurotransmission; neurotoxicity biomarker; risk assessment ID GAMMA-AMINOBUTYRIC-ACID; GATED ION-CHANNEL; PITUITARY-ADRENAL AXIS; CENTRAL-NERVOUS-SYSTEM; CHARACTERIZE ADAPTIVE RESPONSES; REPRODUCTIVE ENDOCRINE AXIS; BENZODIAZEPINE BINDING-SITE; INDUCED STATUS EPILEPTICUS; RAT CEREBRAL-CORTEX; RISK-ASSESSMENT AB Antagonism of ionotropic GABA receptors (iGABARs) can occur at three distinct types of receptor binding sites causing chemically induced epileptic seizures. Here we review three adverse outcome pathways, each characterized by a specific molecular initiating event where an antagonist competitively binds to active sites, negatively modulates allosteric sites or noncompetitively blocks ion channel on the iGABAR. This leads to decreased chloride conductance, followed by depolarization of affected neurons, epilepsy-related death and ultimately decreased population. Supporting evidence for causal linkages from the molecular to population levels is presented and differential sensitivity to iGABAR antagonists in different GABA receptors and organisms discussed. Adverse outcome pathways are poised to become important tools for linking mechanism-based biomarkers to regulated outcomes in next-generation risk assessment. C1 [Gong, Ping; Perkins, Edward J.] US Army Engn Res & Dev Ctr, Environm Lab, Vicksburg, MS 39180 USA. [Hong, Huixiao] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. RP Gong, P (reprint author), US Army Engn Res & Dev Ctr, Environm Lab, 3909 Halls Ferry Rd, Vicksburg, MS 39180 USA. EM ping.gong@usace.army.mil FU US Army Environmental Quality and Installations Basic Research Program; "Rapid Hazard Risk Assessment" Focus Area Research Project FX The authors (P Gong and EJ Perkins) would like to acknowledge the US Army Environmental Quality and Installations Basic Research Program and the "Rapid Hazard Risk Assessment" Focus Area Research Project for financial support. 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 133 TC 3 Z9 3 U1 1 U2 5 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PY 2015 VL 9 IS 11 BP 1225 EP 1239 DI 10.2217/bmm.15.58 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX0RD UT WOS:000365403400015 PM 26508561 ER PT J AU Zhang, C Hong, HX Mendrick, DL Tang, Y Cheng, FX AF Zhang, Chen Hong, Huixiao Mendrick, Donna L. Tang, Yun Cheng, Feixiong TI Biomarker-based drug safety assessment in the age of systems pharmacology: from foundational to regulatory science SO BIOMARKERS IN MEDICINE LA English DT Review DE biomarker; drug safety assessment; regulatory science; systems biology; systems pharmacology ID IN-SILICO PREDICTION; INDUCED LIVER-INJURY; GENOME-WIDE ASSOCIATION; INTERACTION NETWORKS; POLYPHARMACOLOGICAL PROFILES; ENVIRONMENTAL TOXICITY; TARGET IDENTIFICATION; INTERACTION DATABASE; BINDING AFFINITIES; CHEMICAL BIOLOGY AB Improved biomarker-based assessment of drug safety is needed in drug discovery and development as well as regulatory evaluation. However, identifying drug safety-related biomarkers such as genes, proteins, miRNA and single-nucleotide polymorphisms remains a big challenge. The advances of 'omics' and computational technologies such as genomics, transcriptomics, metabolomics, proteomics, systems biology, network biology and systems pharmacology enable us to explore drug actions at the organ and organismal levels. Computational and experimental systems pharmacology approaches could be utilized to facilitate biomarker-based drug safety assessment for drug discovery and development and to inform better regulatory decisions. In this article, we review the current status and advances of systems pharmacology approaches for the development of predictive models to identify biomarkers for drug safety assessment. C1 [Zhang, Chen; Tang, Yun; Cheng, Feixiong] E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China. [Hong, Huixiao; Mendrick, Donna L.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Cheng, Feixiong] Sichuan Univ, West China Med Sch, West China Hosp, State Key Lab Biotherapy,Collaborat Innovat Ctr, Chengdu 610041, Peoples R China. RP Tang, Y (reprint author), E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Meilong Rd, Shanghai 200237, Peoples R China. EM ytang234@ecust.edu.cn; fxcheng1985@gmail.com FU National Natural Science Foundation of China [81373329, 81573020]; Fundamental Research Funds for the Central Universities [WY1113007]; 863 Project [2012AA020308] FX This work was supported by the National Natural Science Foundation of China (grant no. 81373329 and 81573020), the Fundamental Research Funds for the Central Universities (grant no. WY1113007) and the 863 Project (grant no. 2012AA020308). 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 96 TC 7 Z9 7 U1 5 U2 12 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PY 2015 VL 9 IS 11 BP 1241 EP 1252 DI 10.2217/bmm.15.81 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX0RD UT WOS:000365403400016 PM 26506997 ER PT J AU Zhao, WZ Chen, JJ Foley, S Wang, YP Zhao, SH Basinger, J Zou, W AF Zhao, Weizhong Chen, James J. Foley, Steven Wang, Yuping Zhao, Shaohua Basinger, John Zou, Wen TI Biomarker identification from next-generation sequencing data for pathogen bacteria characterization and surveillance SO BIOMARKERS IN MEDICINE LA English DT Review DE bioinformatics pipeline; biomarker; fliC gene; gene diversity; next-generation sequencing analysis; Salmonella serotypes ID DRAFT GENOME SEQUENCES; SALMONELLA-ENTERICA; UNITED-STATES; STRAINS; MICROARRAY; NEWPORT AB Aim: The purpose was to develop an analytical pipeline for specific gene analysis and biomarker discovery from next generation sequencing (NGS) data. Materials & methods: As a test case, the fliC gene reference sequences of 24 Salmonella enterica strains of 13 serotypes and NGS reads of 32 serovar Newport, 48 Montevideo and 115 Enteritidis outbreak isolates were retrieved from the National Center for Biotechnology Information database. Results: Establishment of an analytical pipeline consisting of four steps: reference sequences retrieval and template sequence determination; NGS sequence reads retrieval; multiple sequence alignments and phylogenetic analysis; data mining and biomarker discovery. Conclusion: The pipeline developed provides an effective bioinformatics tool for genetic diversity clarification and marker sequences discovery for pathogen characterization and surveillance. C1 [Zhao, Weizhong; Chen, James J.; Wang, Yuping; Basinger, John; Zou, Wen] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Foley, Steven] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. [Zhao, Shaohua] US FDA, Ctr Vet Med, Div Anim & Food Microbiol, Res Off, Laurel, MD 20993 USA. RP Zou, W (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM wen.zou@fda.hhs.gov NR 33 TC 2 Z9 2 U1 1 U2 4 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PY 2015 VL 9 IS 11 BP 1253 EP 1264 DI 10.2217/bmm.15.88 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CX0RD UT WOS:000365403400017 PM 26501894 ER PT J AU Blumenthal, GM AF Blumenthal, Gideon M. TI Accelerate the Development of Highly Effective and Safe Anticancer Agents in the Era of Precision Medicine SO ONCOLOGIST LA English DT Meeting Abstract CT Chabner Colloquium: Collaboration in Cancer Drug Trials CY OCT 26-27, 2015 CL Boston, MA C1 [Blumenthal, Gideon M.] US FDA, Off Hematol & Oncol Prd, Ctr Drug Evaluat & Res, White Oak, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 PY 2015 VL 20 SU 2 MA 15 BP S7 EP S7 PG 1 WC Oncology SC Oncology GA CX9RJ UT WOS:000366042700016 ER PT J AU Roth-Cline, M Nelson, RM AF Roth-Cline, Michelle Nelson, Robert M. TI Ethical Considerations in Conducting Pediatric and Neonatal Research in Clinical Pharmacology SO CURRENT PHARMACEUTICAL DESIGN LA English DT Article DE Ethics; pediatrics; children; neonates; subpart D; parental permission; child assent; clinical research ID ADVERSE DRUG-REACTIONS; INTENSIVE-CARE-UNIT; OFF-LABEL; CHILD ASSENT; PARENTAL PERMISSION; FEDERAL-REGULATIONS; EMPIRICAL-FINDINGS; CONTROLLED-TRIALS; DIRECT BENEFIT; MINIMAL RISK AB The critical need for pediatric research on drugs and biological products underscores the responsibility to ensure that children are enrolled in clinical research that is both scientifically necessary and ethically sound. In this chapter, we review key ethical considerations concerning the participation of children. We review a basic ethical framework to guide pediatric research, and suggest how this framework might be operationalized in linking science and ethics. Topics examined include: the status of children as a vulnerable population; the appropriate balance of risk and potential benefit in research; and parental permission and child assent to participate in research. C1 [Roth-Cline, Michelle; Nelson, Robert M.] US FDA, US Dept HHS, Off Commissioner, Off Pediat Therapeut, Silver Spring, MD 20993 USA. RP Roth-Cline, M (reprint author), US FDA, Off Pediat Therapeut, 10903 New Hampshire Ave,Bldg 32 Rm 5121, Silver Spring, MD 20993 USA. EM Michelle.Roth-Cline@fda.hhs.gov NR 104 TC 3 Z9 3 U1 4 U2 5 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 EI 1873-4286 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PY 2015 VL 21 IS 39 BP 5619 EP 5635 DI 10.2174/1381612821666150901105146 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CW5OF UT WOS:000365044900002 PM 26323417 ER PT J AU He, XJ Aker, WG Fu, PP Hwang, HM AF He, Xiaojia Aker, Winfred G. Fu, Peter P. Hwang, Huey-Min TI Toxicity of engineered metal oxide nanomaterials mediated by nano-bio-eco-interactions: a review and perspective SO ENVIRONMENTAL SCIENCE-NANO LA English DT Review ID TITANIUM-DIOXIDE NANOPARTICLES; TIO2 NANOPARTICLES; ESCHERICHIA-COLI; ZINC-OXIDE; ZNO NANOPARTICLES; PROTEIN CORONA; BIOPHYSICOCHEMICAL INTERACTIONS; MANUFACTURED NANOMATERIALS; INORGANIC NANOPARTICLES; CEO2 NANOPARTICLES AB Along with the expanding use of engineered metal oxide nanomaterials (MONMs), there is a growing concern over their unintentional adverse toxicological effects on human health and the environment upon release and exposure. It is inevitable that biota will be exposed to nanomaterials, through intentional administration or inadvertent contact under such circumstances. Therefore, a thorough investigation of the potential nanotoxicity of MONMs at the nano-bio-eco interface is urgently needed. In general, nanomaterials interact with their surrounding environments, biotic and abiotic, immediately upon introduction into the environment. The behavior and fate of MONMs are influenced by the dynamics of the environment. Thus, understanding the interactions at the nano-bio-eco interface is necessary for selecting and designing MONMs with minimum adverse impacts. Despite the limitations of currently available techniques, careful characterization of nanomaterials and the choosing of methodologies that promote further risk assessment promise more reliable and accurate data output. Conventional toxicological analysis techniques lack the power to handle the large datasets generated from in vitro/in vivo observations. This paper provides a comprehensive review of the recent experimental and theoretical studies on the toxicity of MONMs mediated by two-way or three-way interactions. In the Perspectives, we also call for more open collaborations between industry, academia, and research labs to facilitate nano-toxicological studies focused specifically on interactions at the nano-bio-eco interface, leading to safe and effective nanotechnology for commercial, environmental, and medicinal use. C1 [He, Xiaojia; Aker, Winfred G.; Hwang, Huey-Min] Jackson State Univ, Jackson, MS 39217 USA. [Fu, Peter P.] Natl Ctr Toxicol Res, Jefferson, AR USA. RP Hwang, HM (reprint author), Jackson State Univ, Jackson, MS 39217 USA. EM huey-min.hwang@jsums.edu FU NSF-CREST program (National Science Foundation-Centers of Research Excellence in Science and Technology) [HRD-0833178] FX This study was supported by the NSF-CREST program (National Science Foundation-Centers of Research Excellence in Science and Technology) with grant # HRD-0833178. This article is not an official U.S. Food and Drug Administration (FDA) guidance or policy statement. No official support or endorsement by the U.S. FDA is intended or should be inferred. The authors declare no competing financial interest. NR 149 TC 4 Z9 4 U1 23 U2 51 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2051-8153 EI 2051-8161 J9 ENVIRON SCI-NANO JI Environ.-Sci. Nano PY 2015 VL 2 IS 6 BP 564 EP 582 DI 10.1039/c5en00094g PG 19 WC Chemistry, Multidisciplinary; Environmental Sciences; Nanoscience & Nanotechnology SC Chemistry; Environmental Sciences & Ecology; Science & Technology - Other Topics GA CX0RO UT WOS:000365404600002 ER PT J AU Pathmanathan, P Gray, RA AF Pathmanathan, Pras Gray, Richard A. TI Filament Dynamics during Simulated Ventricular Fibrillation in a High-Resolution Rabbit Heart SO BIOMED RESEARCH INTERNATIONAL LA English DT Article ID ISOLATED CARDIAC-MUSCLE; EXCITABLE MEDIA; SPIRAL WAVES; COMPUTATIONAL MODELS; REENTRANT ACTIVITY; ROTATING WAVES; ORGANIZATION; TACHYCARDIA; MECHANISM; TRANSITION AB The mechanisms underlying ventricular fibrillation (VF) are not well understood. The electrical activity on the heart surface during VF has been recorded extensively in the experimental setting and in some cases clinically; however, corresponding transmural activation patterns are prohibitively difficult to measure. In this paper, we use a high-resolution biventricular heart model to study three-dimensional electrical activity during fibrillation, focusing on the driving sources of VF: "filaments," the organising centres of unstable reentrant scroll waves. We show, for the first time, specific 3D filament dynamics during simulated VF in a whole heart geometry that includes fine-scale anatomical structures. Our results suggest that transmural activity is much more complex than what would be expected from surface observations alone. We present examples of complex intramural activity, including filament breakup and reattachment, anchoring to the thin right ventricular apex; rapid transitions among various filament shapes; and filament lengths much greater than wall thickness. We also present evidence for anatomy playing a major role in VF development and coronary vessels and trabeculae influencing filament dynamics. Overall, our results indicate that intramural activity during simulated VF is extraordinarily complex and suggest that further investigation of 3D filaments is necessary to fully comprehend recorded surface patterns. C1 [Pathmanathan, Pras; Gray, Richard A.] US FDA, Silver Spring, MD 20993 USA. RP Pathmanathan, P (reprint author), US FDA, 10903 New Hampshire Ave WO 62, Silver Spring, MD 20993 USA. EM pras.pathmanathan@fda.hhs.gov NR 59 TC 2 Z9 2 U1 1 U2 6 PU HINDAWI PUBLISHING CORP PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 2314-6133 EI 2314-6141 J9 BIOMED RES INT JI Biomed Res. Int. PY 2015 AR 720575 DI 10.1155/2015/720575 PG 14 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA CW0PW UT WOS:000364692600001 ER PT B AU Ostroff, SM AF Ostroff, Stephen M. BE MIkanatha, NM Iskander, JK TI Concepts and methods in infectious disease surveillance Foreword SO Concepts and Methods in Infectious Disease Surveillance LA English DT Editorial Material; Book Chapter C1 US FDA, Rockville, MD 20857 USA. RP Ostroff, SM (reprint author), US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, WEST SUSSEX, ENGLAND BN 978-0-470-65939-7; 978-1-118-92864-6 PY 2015 BP X EP XII PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA BD6GN UT WOS:000362202500001 ER PT J AU Treadwell, EL Wiley, K Word, B Melchior, W Tolleson, WH Gopee, N Hammons, G Lyn-Cook, BD AF Treadwell, Edward L. Wiley, Kenneth Word, Beverly Melchior, William Tolleson, William H. Gopee, Neera Hammons, George Lyn-Cook, Beverly D. TI Prolactin and Dehydroepiandrosterone Levels in Women with Systemic Lupus Erythematosus: The Role of the Extrapituitary Prolactin Promoter Polymorphism at-1149G/T SO JOURNAL OF IMMUNOLOGY RESEARCH LA English DT Article ID PATHOGENESIS AB Systemic lupus erythematosus (SLE) has shown an association with high levels of prolactin, low levels of dehydroepiandrosterone (DHEA), and induction of inflammatory cytokines in the serum of patients with the disease. This preliminary study examined the relevance of a -1149G/T functional single-nucleotide polymorphism (SNP) (rs1341239) in the promoter of the extrapituitary prolactin gene in a cohort of African American and European American women with lupus. Examination of this SNP revealed that the -1149TT genotype was correlated with higher levels of prolactin in serum and prolactin gene expression (p = 0.0001) in peripheral blood mononuclear cells (PBMCs). Lower levels of DHEA in serum were demonstrated in lupus patients (p = 0.001); those with the -1149TT genotype had the lowest levels of DHEA. Furthermore, a small subset of women who were on DHEA therapy and had a TT genotype showed a significant decrease in prolactin gene expression and lower disease activity scores (SLEDAI). Lupus patients, particularly African Americans, had significantly higher levels of IL-6 (p = 0.0001) and TNF-alpha (p = 0.042). This study suggests that the -1149TT genotype may be a risk factor for lupus and may predict who could possibly benefit from DHEA therapy; therefore, these results should be validated in a larger cohort with all ethnic groups. C1 [Treadwell, Edward L.] E Carolina Univ, Brody Sch Med, Greenville, NC 27834 USA. [Wiley, Kenneth] NHGRI, Bethesda, MD 20892 USA. [Word, Beverly; Melchior, William; Tolleson, William H.; Gopee, Neera; Hammons, George; Lyn-Cook, Beverly D.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Lyn-Cook, BD (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM beverly.lyn-cook@fda.hhs.gov NR 32 TC 0 Z9 0 U1 1 U2 3 PU HINDAWI PUBLISHING CORP PI NEW YORK PA 315 MADISON AVE 3RD FLR, STE 3070, NEW YORK, NY 10017 USA SN 2314-8861 EI 2314-7156 J9 J IMMUNOL RES JI J Immunol. Res. PY 2015 AR 435658 DI 10.1155/2015/435658 PG 10 WC Immunology SC Immunology GA CW0YA UT WOS:000364714900001 ER PT S AU Masci, P Oladimeji, P Zhang, Y Jones, P Curzon, P Thimbleby, H AF Masci, Paolo Oladimeji, Patrick Zhang, Yi Jones, Paul Curzon, Paul Thimbleby, Harold BE Kroening, D Pasareanu, CS TI PVSio-web 2.0: Joining PVS to HCI SO COMPUTER AIDED VERIFICATION, PT I SE Lecture Notes in Computer Science LA English DT Proceedings Paper CT 27th International Conference on Computer-Aided Verification (CAV) CY JUL 18-24, 2015 CL San Francisco, CA SP Google, NASA, Fujitsu, SGT, Facebook, Microsoft, IBM, Cadence, Intel, Samsung DE Prototyping; User interface analysis; Practical formal tools ID SYSTEMS AB PVSio-web is a graphical environment for facilitating the design and evaluation of interactive (human-computer) systems. Using PVSio-web, one can generate and evaluate realistic interactive prototypes from formal models. PVSio-web has been successfully used over the last two years for analyzing commercial, safety-critical medical devices. It has been used to create training material for device developers and device users. It has also been used for medical device design, by both formal methods experts and non-technical end users. This paper presents the latest release of PVSio-web 2.0, which will be part of the next PVS distribution. The new tool architecture is discussed, and the rationale behind its design choices are presented. PVSio-web Tool: http://www.pvsioweb.org C1 [Masci, Paolo; Curzon, Paul] Queen Mary Univ London, London, England. [Zhang, Yi; Jones, Paul] US FDA, Silver Spring, MD USA. [Oladimeji, Patrick; Thimbleby, Harold] Swansea Univ, Swansea, W Glam, Wales. RP Masci, P (reprint author), Queen Mary Univ London, London, England. EM p.m.masci@qmul.ac.uk; p.oladimeji@swansea.ac.uk; yi.zhang2@fda.hhs.gov; paul.jones@fda.hhs.gov; p.curzon@qmul.ac.uk; h.thimbleby@swansea.ac.uk OI Masci, Paolo/0000-0002-0667-7763 NR 44 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0302-9743 BN 978-3-319-21690-4; 978-3-319-21689-8 J9 LECT NOTES COMPUT SC PY 2015 VL 9206 BP 470 EP 478 DI 10.1007/978-3-319-21690-4_30 PG 9 WC Computer Science, Hardware & Architecture; Computer Science, Software Engineering; Computer Science, Theory & Methods; Logic SC Computer Science; Science & Technology - Other Topics GA BD8QC UT WOS:000364182900030 ER PT S AU Dokmanovic, M Wu, WJ AF Dokmanovic, Milos Wu, Wen Jin BE Makowski, GS TI Monitoring Trastuzumab Resistance and Cardiotoxicity: A Tale of Personalized Medicine SO ADVANCES IN CLINICAL CHEMISTRY, VOL 70 SE Advances in Clinical Chemistry LA English DT Review; Book Chapter ID METASTATIC BREAST-CANCER; GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; CIRCULATING TUMOR-CELLS; GASTRIC-CANCER; COLORECTAL-CANCER; DRUG-RESISTANCE; MOUSE MODELS; MONOCLONAL-ANTIBODY; TARGETED THERAPIES AB While approval of trastuzumab, a recombinant monoclonal antibody directed against HER2, along with a diagnostic kit to detect breast cancers which are positive for HER2 overexpression, has advanced a new era of stratified and personalized medicine, it also created several challenges to our scientific and clinical practice. These problems include trastuzumab resistance and trastuzumab-induced cardiotoxicity. In this review, we will summarize data from the literature regarding mechanisms of trastuzumab resistance and trastuzumab-induced cardiotoxicity and present some promising model systems that may advance our understanding of these mechanisms. Our discussion will include development of circulating tumor cells and circulating tumor DNA for monitoring tumor burden, of patient-derived xenograft models for preclinical testing of novel therapies, and of novel therapeutic strategies for trastuzumab-resistance and possible integration of these strategies in the design of co-clinical studies for testing in relevant patient subpopulations. C1 [Dokmanovic, Milos; Wu, Wen Jin] US FDA, Mol Oncol Lab, Div Monoclonal Antibodies, Off Biotechnol Prod,Off Pharmaceut Sci,Ctr Drug E, Silver Spring, MD 20993 USA. RP Dokmanovic, M (reprint author), US FDA, Mol Oncol Lab, Div Monoclonal Antibodies, Off Biotechnol Prod,Off Pharmaceut Sci,Ctr Drug E, Silver Spring, MD 20993 USA. EM Milos.Dokmanovic@fda.hhs.gov; Wen.Wu@fda.hhs.gov NR 167 TC 0 Z9 0 U1 3 U2 5 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-2423 BN 978-0-12-803317-3; 978-0-12-803316-6 J9 ADV CLIN CHEM JI Advan. Clin. Chem. PY 2015 VL 70 BP 95 EP 130 DI 10.1016/bs.acc.2015.03.006 PG 36 WC Medical Laboratory Technology SC Medical Laboratory Technology GA BD7ND UT WOS:000363328700004 PM 26231486 ER PT J AU Sarkar, S Raymick, J Ray, B Lahiri, DK Paule, MG Schmued, L AF Sarkar, Sumit Raymick, James Ray, Balmiki Lahiri, Debomoy K. Paule, Merle G. Schmued, Larry TI Oral Administration of Thioflavin T Prevents Beta Amyloid Plaque Formation in Double Transgenic AD Mice SO CURRENT ALZHEIMER RESEARCH LA English DT Article DE AD; Amylo-Glo; astrocytes; CD68; GFAP; microglia; neuroprotection; thioflavin T ID ALZHEIMERS-DISEASE; NEUROFIBRILLARY CHANGES; BINDING; ACCUMULATION; AGGREGATION; DEPOSITION; PROTEINS AB Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the fourth leading cause of death in the United States and most common cause of adult-onset dementia. The major hallmarks of AD are the formation of senile amyloid plaques made of beta amyloid and neurofibrillary tangles (NFT) which are primarily composed of phosphorylated tau protein. Although numerous agents have been considered as providing protection against AD, identification of potential agents with neuroprotective ability is limited. Thioflavin T has been used in the past to stain amyloid beta plaques in brain. In this study, Thioflavin T (ThT) and vehicle (infant formula) were administered orally by gavage to transgenic (B6C3 APP PS1; AD-Tg) mice beginning at 4 months age and continuing until sacrifice at 9 months of age at 40mg/kg dose. The number of amyloid plaques was reduced dramatically by ThT treatment in both male and female transgenic mice compared to those in control mice. Additionally, GFAP and Amylo-Glo labeling suggest that astrocytic hypertrophy is minimized in ThT-treated animals. Similarly, CD68 labeling, which detects activated microglia, along with Amylo-Glo labeling, suggests that microglial activation is significantly less in ThT-treated mice. Both A beta-40 and A beta-42 concentrations in blood rose significantly in the ThT-treated animals suggesting that ThT may inhibit the deposition, degradation, and/or clearance of A beta plaques in brain. C1 [Sarkar, Sumit; Raymick, James; Paule, Merle G.; Schmued, Larry] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Ray, Balmiki; Lahiri, Debomoy K.] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN 46222 USA. RP Sarkar, S (reprint author), US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 132, Jefferson, AR 72079 USA. EM sumit.sarkar@fda.hhs.gov FU National Center for Toxicological Research/FDA [E07273] FX This study was supported by the National Center for Toxicological Research/FDA (E07273). NR 33 TC 1 Z9 1 U1 2 U2 4 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 EI 1875-5828 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PY 2015 VL 12 IS 9 BP 837 EP 846 DI 10.2174/156720501209151019105647 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CU1ZP UT WOS:000363321300004 PM 26510980 ER PT J AU Harjivan, SG Pinheiro, PF Martins, IL Godinho, AL Wanke, R Santos, PP Pereira, SA Beland, FA Marques, MM Antunes, AMM AF Harjivan, Shrika G. Pinheiro, Pedro F. Martins, Ines L. Godinho, Ana L. Wanke, Riccardo Santos, Pedro P. Pereira, Sofia A. Beland, Frederick A. Matilde Marques, M. Antunes, Alexandra M. M. TI Quinoid derivatives of the nevirapine metabolites 2-hydroxy- and 3-hydroxy-nevirapine: activation pathway to amino acid adducts SO TOXICOLOGY RESEARCH LA English DT Article ID INDUCED SKIN RASH; REVERSE-TRANSCRIPTASE INHIBITOR; TOXIC EPIDERMAL NECROLYSIS; TANDEM MASS-SPECTROMETRY; STEVENS-JOHNSON-SYNDROME; UDP-GLUCURONOSYLTRANSFERASE; PARKINSONS-DISEASE; DRUG NEVIRAPINE; SEX-DIFFERENCES; LIVER-INJURY AB Nevirapine (NVP) is the non-nucleoside HIV-1 reverse transcriptase inhibitor most commonly used in developing countries, both as a component of combined antiretroviral therapy and to prevent mother-to-child transmission of the virus; however, severe hepatotoxicity and serious adverse cutaneous effects raise concerns about its safety. NVP metabolism yields several phenolic derivatives conceivably capable of undergoing further metabolic oxidation to electrophilic quinoid derivatives prone to react with bionucleophiles and initiate toxic responses. We investigated the ability of two phenolic NVP metabolites, 2-hydroxy-NVP and 3-hydroxy-NVP, to undergo oxidation and subsequent reaction with bionucleophiles. Both metabolites yielded the same ring-contraction product upon oxidation with Fremy's salt in aqueous medium. This is consistent with the formation of a 2,3-NVP-quinone intermediate, which upon stabilization by reduction was fully characterized by mass spectrometry and nuclear magnetic resonance spectroscopy. Additionally, we established that the oxidative activation of 2-hydroxy-NVP involved the transient formation of both the quinone and a quinone-imine, whereas 3-hydroxy-NVP was selectively converted into 2,3-NVP-quinone. The oxidations of 2-hydroxy-NVP and 3-hydroxy-NVP in the presence of the model amino acids ethyl valinate (to mimic the highly reactive N-terminal valine of hemoglobin) and N-acetylcysteine were also investigated. Ethyl valinate reacted with both 2,3-NVP-quinone and NVP-quinone-imine, yielding covalent adducts. By contrast, neither 2,3-NVP-quinone nor NVP-derived quinone-imine reacted with N-acetylcysteine. The product profile observed upon Fremy's salt oxidation of 2-hydroxy-NVP in the presence of ethyl valinate was replicated with myeloperoxidase-mediated oxidation. Additionally, tyrosinase-mediated oxidations selectively yielded 2,3-NVP-quinone-derived products, while quinone-imine-derived products were obtained upon lactoperoxidase catalysis. These observations suggest that the metabolic conversion of phenolic NVP metabolites into quinoid electrophiles is biologically plausible. Moreover, the lack of reaction with sulfhydryl groups might hamper the in vivo detoxification of NVP-derived quinone and quinone-imine metabolites via glutathione conjugation. As a result, these metabolites could be available for reaction with nitrogen-based bionucleophiles (e.g., lysine residues of proteins) ultimately eliciting toxic events. C1 [Harjivan, Shrika G.; Pinheiro, Pedro F.; Martins, Ines L.; Godinho, Ana L.; Wanke, Riccardo; Santos, Pedro P.; Matilde Marques, M.; Antunes, Alexandra M. M.] Univ Lisbon, Inst Super Tecn, Ctr Quim Estrutural, P-1049001 Lisbon, Portugal. [Pereira, Sofia A.] Nova Univ, NOVA Med Sch, Ctr Estudos Doencas Cron CEDOC, P-1169056 Lisbon, Portugal. [Beland, Frederick A.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Harjivan, SG (reprint author), Univ Lisbon, Inst Super Tecn, Ctr Quim Estrutural, P-1049001 Lisbon, Portugal. EM matilde.marques@tecnico.ulisboa.pt; alexandra.antunes@tecnico.ulisboa.pt RI Marques, M. Matilde/E-2535-2012; PTMS, RNEM/C-1589-2014; Antunes, Alexandra/B-7871-2009; Santos, Pedro Paulo/P-1769-2016; Faculdade de Ciencias Medicas, Nova Medical School/K-6209-2013; OI Marques, M. Matilde/0000-0002-7526-4962; Antunes, Alexandra/0000-0003-1827-7369; Santos, Pedro Paulo/0000-0003-3045-4591; Lanca Martins, Ines/0000-0003-0797-7642 FU Fundacao para a Ciencia e a Tecnologia (FCT), Portugal [PTDC/QUI-QUI/113910/2009, RECI/QEQ-MED/0330/2012, UID/QUI/00100/2013, IF/01091/2013/CP1163/CT0001]; National Center for Toxicological Research/Food and Drug Administration [Y1ES1027]; National Institute of Environmental Health Sciences/National Toxicology Program [Y1ES1027]; FCT [SFRH/BPD/70953/2010, SFRH/BD/72301/2010, SFRH/BD/75426/2010, SFRH/BD/80690/2011]; Operacional Potencial Humano from FCT; European Social Fund [IF/01091/2013]; LRI Innovative Science Award FX This work was supported in part by Fundacao para a Ciencia e a Tecnologia (FCT), Portugal (PTDC/QUI-QUI/113910/2009, RECI/QEQ-MED/0330/2012, UID/QUI/00100/2013 and IF/01091/2013/CP1163/CT0001), and by Interagency Agreement Y1ES1027 between the National Center for Toxicological Research/Food and Drug Administration and the National Institute of Environmental Health Sciences/National Toxicology Program. The opinions expressed in this paper do not necessarily represent those of the U.S. Food and Drug Administration. RW, ALG, ILM and SGH thank FCT for postdoctoral and doctoral fellowships (SFRH/BPD/70953/2010, SFRH/BD/72301/2010, SFRH/BD/75426/2010 and SFRH/BD/80690/2011, respectively). AMM also acknowledges Programa Operacional Potencial Humano from FCT and the European Social Fund (IF/01091/2013), and the LRI Innovative Science Award. We thank the Portuguese NMR and MS networks (IST nodes) for providing access to the facilities. NR 61 TC 0 Z9 0 U1 0 U2 6 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. PY 2015 VL 4 IS 6 BP 1565 EP 1577 DI 10.1039/c5tx00176e PG 13 WC Toxicology SC Toxicology GA CU1DR UT WOS:000363260200013 ER PT J AU Loethen, YL Kauffman, JF Buhse, LF Rodriguez, JD AF Loethen, Yvette L. Kauffman, John F. Buhse, Lucinda F. Rodriguez, Jason D. TI Rapid screening of anti-infective drug products for counterfeits using Raman spectral library-based correlation methods SO ANALYST LA English DT Article ID INFRARED-SPECTROSCOPY; IDENTIFICATION; CHEMOMETRICS; MEDICINES; COMBINATION; QUALITY AB A new spectral library-based approach that is capable of screening a diverse set of finished drug products using only an active pharmaceutical ingredient spectral library is described in this paper. This approach obviates the need for a comprehensive drug product library, thereby streamlining the use of spectral library-based tests for anti-counterfeiting efforts, specifically to target finished drug products containing the wrong active ingredient or no active ingredient at all. Both laboratory-based and portable spectrometers are used in the study to demonstrate the usefulness and transferability of the spectral correlation method for field screening. The spectral correlation between the active pharmaceutical ingredient and finished drug product spectra is calculated using both full spectral analysis and targeted spectral regions analysis of six types of antimalarial, antibiotic and antiviral products. The spectral regions were determined using a moving window spectral correlation algorithm, and the use of specific spectral regions is shown to be crucial in screening finished drug products using only the active pharmaceutical ingredient spectrum. This comprehensive screening spectral correlation method is tested on seven different validation samples from different manufacturers as those used to develop the method, as well as simulated counterfeits which were prepared to mimic falsified drugs containing no active ingredient. The spectral correlation method is successful in correctly identifying 100% of the authentic products and simulated counterfeit samples tested. C1 [Loethen, Yvette L.; Kauffman, John F.; Buhse, Lucinda F.; Rodriguez, Jason D.] US FDA, Ctr Drug Evaluat & Res, Div Pharmaceut Anal, St Louis, MO 63110 USA. RP Rodriguez, JD (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Pharmaceut Anal, St Louis, MO 63110 USA. EM Jason.Rodriguez@fda.hhs.gov NR 27 TC 4 Z9 4 U1 4 U2 15 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 PY 2015 VL 140 IS 21 BP 7225 EP 7233 DI 10.1039/c5an01679g PG 9 WC Chemistry, Analytical SC Chemistry GA CT4RT UT WOS:000362795100019 PM 26401527 ER PT J AU Cokic, VP Mitrovic-Ajtic, O Beleslin-Cokic, BB Markovic, D Buac, M Diklic, M Kraguljac-Kurtovic, N Damjanovic, S Milenkovic, P Gotic, M Raj, PK AF Cokic, Vladan P. Mitrovic-Ajtic, Olivera Beleslin-Cokic, Bojana B. Markovic, Dragana Buac, Marijana Diklic, Milos Kraguljac-Kurtovic, Nada Damjanovic, Svetozar Milenkovic, Pavle Gotic, Mirjana Raj, Puri K. TI Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms SO MEDIATORS OF INFLAMMATION LA English DT Article ID REFRACTORY MULTIPLE-MYELOMA; NF-KAPPA-B; POLYCYTHEMIA-VERA; PRIMARY MYELOFIBROSIS; ESSENTIAL THROMBOCYTHEMIA; IDIOPATHIC MYELOFIBROSIS; BONE-MARROW; INFLAMMATORY CYTOKINES; SILTUXIMAB ANTI-IL-6; INTERLEUKIN-6 IL-6 AB The recent JAK1/2 inhibitor trial in myeloproliferative neoplasms (MPNs) showed that reducing inflammation can be more beneficial than targeting gene mutants. We evaluated the proinflammatory IL-6 cytokine and JAK-STAT signaling pathway related genes in circulating CD34(+) cells of MPNs. Regarding laboratory data, leukocytosis has been observed in polycythemia vera (PV) and JAK2V617F mutation positive versus negative primary myelofibrosis (PMF) patients. Moreover, thrombocytosis was reduced by JAK2V617F allele burden in essential thrombocythemia (ET) and PMF. 261 significantly changed genes have been detected in PV, 82 in ET, and 94 genes in PMF. The following JAK-STAT signaling pathway related genes had augmented expression in CD34(+) cells of MPNs: CCND3 and IL23A regardless of JAK2V617F allele burden; CSF3R, IL6ST, and STAT1/2 in ET and PV with JAK2V617F mutation; and AKT2, IFNGR2, PIM1, PTPN11, and STAT3 only in PV. STAT5A gene expression was generally reduced in MPNs. IL-6 cytokine levels were increased in plasma, as well as IL-6 protein levels in bone marrow stroma of MPNs, dependent on JAK2V617F mutation presence in ET and PMF patients. Therefore, the JAK2V617F mutant allele burden participated in inflammation biomarkers induction and related signaling pathways activation in MPNs. C1 [Cokic, Vladan P.; Mitrovic-Ajtic, Olivera; Markovic, Dragana; Buac, Marijana; Diklic, Milos; Milenkovic, Pavle] Univ Belgrade, Inst Med Res, Belgrade 11129, Serbia. [Beleslin-Cokic, Bojana B.; Damjanovic, Svetozar] Clin Ctr Serbia, Clin Endocrinol Diabet & Dis Metab, Belgrade 11000, Serbia. [Kraguljac-Kurtovic, Nada; Gotic, Mirjana] Clin Ctr Serbia, Clin Hematol, Belgrade 11000, Serbia. [Damjanovic, Svetozar; Gotic, Mirjana] Univ Belgrade, Fac Med, Belgrade 11000, Serbia. [Raj, Puri K.] US FDA, Div Cellular & GeneTherapies, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Cokic, VP (reprint author), Univ Belgrade, Inst Med Res, Belgrade 11129, Serbia. EM vl@imi.bg.ac.rs FU National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda; Serbian Ministry of Education, Science and Technological Development [175053] FX This research was supported by Intramural Research Program of Alan N. Schechter at the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, and by a Grant from the Serbian Ministry of Education, Science and Technological Development (no. 175053). NR 48 TC 1 Z9 1 U1 2 U2 6 PU HINDAWI PUBLISHING CORP PI NEW YORK PA 315 MADISON AVE 3RD FLR, STE 3070, NEW YORK, NY 10017 USA SN 0962-9351 EI 1466-1861 J9 MEDIAT INFLAMM JI Mediat. Inflamm. PY 2015 AR 453020 DI 10.1155/2015/453020 PG 13 WC Cell Biology; Immunology SC Cell Biology; Immunology GA CT3VV UT WOS:000362735900001 ER PT B AU Narayan, R Goering, P AF Narayan, Roger Goering, Peter BE Balani, K Verma, V Agarwal, A Narayan, R TI LASER ENGINEERING OF SURFACE STRUCTURES SO BIOSURFACES: A MATERIALS SCIENCE AND ENGINEERING PERSPECTIVE LA English DT Article; Book Chapter ID OPTICAL MASER OSCILLATION; TRANSDERMAL DRUG-DELIVERY; DIAMOND-LIKE; THIN-FILMS; 2-PHOTON POLYMERIZATION; MICRONEEDLE ARRAY; ANTIMICROBIAL PROPERTIES; MEDICAL DEVICES; MEMORY ALLOY; NANOPARTICLES C1 [Narayan, Roger] UNC NCSU Joint Dept Biomed Engn, Chapel Hill, NC 27514 USA. [Goering, Peter] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Narayan, R (reprint author), UNC NCSU Joint Dept Biomed Engn, Chapel Hill, NC 27514 USA. NR 97 TC 0 Z9 0 U1 1 U2 6 PU AMER CERAMIC SOC PI WESTERVILLE PA 735 CERAMIC PLACE, WESTERVILLE, OH 43081-8720 USA BN 978-1-118-95062-3; 978-1-118-29997-5 PY 2015 BP 239 EP 259 PG 21 WC Materials Science, Biomaterials SC Materials Science GA BD6GD UT WOS:000362197300010 ER PT S AU Bailey, AM Arcidiacono, J Benton, KA Taraporewala, Z Winitsky, S AF Bailey, Alexander M. Arcidiacono, Judith Benton, Kimberly A. Taraporewala, Zenobia Winitsky, Steve BE Galli, MC Serabian, M TI United States Food and Drug Administration Regulation of Gene and Cell Therapies SO REGULATORY ASPECTS OF GENE THERAPY AND CELL THERAPY PRODUCTS: A GLOBAL PERSPECTIVE SE Advances in Experimental Medicine and Biology LA English DT Article; Book Chapter DE US Food and Drug Administration (US FDA); Cell therapy; Gene therapy; Public health; Clinical trial; Marketing application; Product licensure; Clinical development AB The United States (US) Food and Drug Administration (FDA) is a regulatory agency that has oversight for a wide range of products entering the US market, including gene and cell therapies. The regulatory approach for these products is similar to other medical products within the United States and consists of a multitiered framework of statutes, regulations, and guidance documents. Within this framework, there is considerable flexibility which is necessary due to the biological and technical complexity of these products in general. This chapter provides an overview of the US FDA regulatory oversight of gene and cell therapy products. C1 [Bailey, Alexander M.; Arcidiacono, Judith; Benton, Kimberly A.; Taraporewala, Zenobia; Winitsky, Steve] US FDA, OCTGT, CBER, Silver Spring, MD 20993 USA. RP Bailey, AM (reprint author), US FDA, OCTGT, CBER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM alexander.bailey@fda.hhs.gov NR 19 TC 2 Z9 2 U1 3 U2 4 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0065-2598 BN 978-3-319-18618-4; 978-3-319-18617-7 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2015 VL 871 BP 1 EP 29 DI 10.1007/978-3-319-18618-4_1 D2 10.1007/978-3-319-18618-4 PG 29 WC Biology; Medicine, Research & Experimental SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine GA BD5TJ UT WOS:000361809700002 PM 26374210 ER PT S AU Galli, MC Serabian, M AF Galli, Maria Cristina Serabian, Mercedes BE Galli, MC Serabian, M TI Regulatory Aspects of Gene Therapy and Cell Therapy Products A Global Perspective Preface SO REGULATORY ASPECTS OF GENE THERAPY AND CELL THERAPY PRODUCTS: A GLOBAL PERSPECTIVE SE Advances in Experimental Medicine and Biology LA English DT Editorial Material; Book Chapter C1 [Galli, Maria Cristina] Ist Super Sanita, Dept Cell Biol & Neurosci, I-00161 Rome, Italy. [Serabian, Mercedes] US FDA, Ctr Biol Evaluat & Res, Off Cellular Tissue & Gene Therapies, Silver Spring, MD USA. RP Galli, MC (reprint author), Ist Super Sanita, Dept Cell Biol & Neurosci, Viale Regina Elena 299, I-00161 Rome, Italy. NR 0 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0065-2598 BN 978-3-319-18618-4; 978-3-319-18617-7 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2015 VL 871 BP V EP VI D2 10.1007/978-3-319-18618-4 PG 2 WC Biology; Medicine, Research & Experimental SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine GA BD5TJ UT WOS:000361809700001 PM 26677465 ER PT J AU Stephenson, D Hu, MT Romero, K Breen, K Burn, D Ben-Shlomo, Y Bhattaram, A Isaac, M Venuto, C Kubota, K Little, MA Friend, S Lovestone, S Morris, HR Grosset, D Sutherland, M Gallacher, J Williams-Gray, C Bain, LJ Aviles, E Marek, K Toga, AW Stark, Y Gordon, MF Ford, S AF Stephenson, Diane Hu, Michele T. Romero, Klaus Breen, Kieran Burn, David Ben-Shlomo, Yoav Bhattaram, Atul Isaac, Maria Venuto, Charles Kubota, Ken Little, Max A. Friend, Stephen Lovestone, Simon Morris, Huw R. Grosset, Donald Sutherland, Margaret Gallacher, John Williams-Gray, Caroline Bain, Lisa J. Aviles, Enrique Marek, Ken Toga, Arthur W. Stark, Yafit Gordon, Mark Forrest Ford, Steve TI Precompetitive Data Sharing as a Catalyst to Address Unmet Needs in Parkinson's Disease SO JOURNAL OF PARKINSONS DISEASE LA English DT Article DE Data standards; privacy; data integration; collaboration; quantitative disease progression; regulatory science ID MILD COGNITIVE IMPAIRMENT; POPULATION-BASED COHORT; NONMOTOR FEATURES; CRITICAL PATH; DISORDER; PD; RECOMMENDATIONS; PERSPECTIVE; SYMPTOMS; CAMPAIGN AB Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of collaboration. At a workshop hosted by Parkinson's UK and co-organized by Critical Path Institute's (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contribute to disease progression heterogeneity. Novel therapeutic targets and trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination are required. The integration of robust clinical data sets is viewed as a powerful approach to hasten medical discovery and therapies, as is being realized across diverse disease conditions employing big data analytics for healthcare. The application of lessons learned from parallel efforts is critical to identify barriers and enable a viable path forward. A roadmap is presented for a regulatory, academic, industry and advocacy driven integrated initiative that aims to facilitate and streamline new drug trials and registrations in Parkinson's disease. C1 [Stephenson, Diane; Romero, Klaus; Aviles, Enrique] CAMD, Crit Path Inst, Tucson, AZ USA. [Hu, Michele T.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Dept Neurol, Oxford OX3 9DU, England. [Lovestone, Simon] Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford, England. [Breen, Kieran] Sci Consultant, London, England. [Burn, David] Newcastle Univ, Fac Med Sci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Ben-Shlomo, Yoav] Univ Bristol, Bristol, Avon, England. [Bhattaram, Atul] US FDA, Silver Spring, MD USA. [Isaac, Maria] EMA, London, England. [Venuto, Charles] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Kubota, Ken] Michael J Fox Fdn Parkinsons Res, New York, NY USA. [Little, Max A.] Aston Univ, Cambridge, MA USA. [Little, Max A.] Aston Univ, MIT, Media Lab, Cambridge, MA USA. [Friend, Stephen] Sage Bionetworks, Seattle, WA USA. [Morris, Huw R.] UCL Inst Neurol, Dept Clin Neurosci, London, England. [Morris, Huw R.] Royal Free Hosp, Dept Neurol, London NW3 2QG, England. [Morris, Huw R.] Natl Hosp Neurol, Neurol, London, England. [Grosset, Donald] Univ Glasgow, Inst Neurosci & Psychol, Glasgow G12 8QQ, Lanark, Scotland. [Sutherland, Margaret] NINDS, Neurosci Ctr, Bethesda, MD 20892 USA. [Gallacher, John] Univ Oxford Hosp, Dept Psychiat, Oxford, England. [Williams-Gray, Caroline] Univ Cambridge, John Van Geest Ctr Brain Repair, Dept Clin Neurosci, Cambridge, England. [Bain, Lisa J.] Independent Sci & Med Writer, Elverson, PA USA. [Marek, Ken] Parkinsons Progress Markers Initiat, Inst Neurodegenerat Dis, New Haven, CT USA. [Toga, Arthur W.] Univ So Calif, Keck Sch Med, Lab Neuro Imaging, Los Angeles, CA 90089 USA. [Stark, Yafit] Teva Pharmaceut Ind Ltd, Petah Tiqwa, Israel. [Gordon, Mark Forrest] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. [Ford, Steve] Parkinsons UK, London, England. RP Stephenson, D (reprint author), Crit Path Inst, 1730 E River Rd, Tucson, AZ 85718 USA. EM dstephenson@c-path.org RI Morris, Huw/B-8527-2008; Breen, Kieran/N-4644-2014 OI Morris, Huw/0000-0002-5473-3774; Breen, Kieran/0000-0003-3974-4237 FU NIBIB NIH HHS [P41 EB015922]; NINDS NIH HHS [T32 NS007338]; Parkinson's UK [J-1301] NR 40 TC 2 Z9 2 U1 6 U2 11 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1877-7171 EI 1877-718X J9 J PARKINSON DIS JI J. Parkinsons Dis. PY 2015 VL 5 IS 3 BP 581 EP 594 DI 10.3233/JPD-150570 PG 14 WC Neurosciences SC Neurosciences & Neurology GA CR8LE UT WOS:000361602500018 PM 26406139 ER PT J AU Wen, T He, WW Chong, Y Liu, Y Yin, JJ Wu, XC AF Wen, Tao He, Weiwei Chong, Yu Liu, Yi Yin, Jun-Jie Wu, Xiaochun TI Exploring environment-dependent effects of Pd nanostructures on reactive oxygen species (ROS) using electron spin resonance (ESR) technique: implications for biomedical applications SO PHYSICAL CHEMISTRY CHEMICAL PHYSICS LA English DT Article ID SINGLET OXYGEN; PALLADIUM NANOCRYSTALS; PHOTOTHERMAL THERAPY; HYDROGEN-PEROXIDE; OXIDATIVE STRESS; NANOPARTICLES; SUPEROXIDE; GENERATION; RADICALS; GOLD AB Recently, because of the great advances in tailoring their shape and structure, palladium nanoparticles (Pd NPs) have been receiving increasing attention in biomedical fields apart from their traditional application as industrial catalysts. When considering the potential uses of Pd NPs in biomedicine, their catalytic properties need to be evaluated under physiologically relevant conditions. In this article, we demonstrate that Pd nanostructures (NSs, both commercial Pd NPs and in-house-prepared Au@Pd nanorods) can induce O-2 or (OH)-O-center dot production depending on pH values in the presence of H2O2. We observed that O-2 is produced under neutral and alkaline conditions but (OH)-O-center dot under acidic conditions. We also found that Pd NSs can scavenge superoxide and singlet oxygen, which may provide protection in biological systems. On the other hand, their oxidase-like activity may accelerate the oxidation of ascorbic acid and thus may produce negative biological effects. The presented study will provide useful guidance for designing noble metal nanostructures with desired catalytic and biological properties in biomedical applications. C1 [Wen, Tao; Wu, Xiaochun] Natl Ctr Nanosci & Technol, CAS Key Lab Standardizat & Measurement Nanotechno, Beijing 100190, Peoples R China. [Wen, Tao; He, Weiwei; Chong, Yu; Liu, Yi; Yin, Jun-Jie] US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Wen, Tao] Univ Chinese Acad Sci, Beijing 100190, Peoples R China. [He, Weiwei] Xuchang Univ, Inst Surface Micro & Nano Mat, Key Lab Micronano Mat Energy Storage & Convers H, Xuchang 461000, Henan, Peoples R China. RP Yin, JJ (reprint author), US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM JunJie.Yin@fda.hhs.gov; wuxc@nanoctr.cn RI chen, jiaqi/D-5526-2016 FU National Natural Science Foundation of China [21173056, 21303153]; FDA Nanotechnology CORES Program; Program for Science & Technology Innovation Talents in Universities of Henan Province [14HASTIT008] FX The work was supported by the National Natural Science Foundation of China (Grant No. 21173056) and partially supported by a regulatory science grant under the FDA Nanotechnology CORES Program. W. He thanks the support from National Natural Science Foundation of China (Grant No. 21303153) and Program for Science & Technology Innovation Talents in Universities of Henan Province (14HASTIT008). We are also grateful to Wayne G. Wamer (the Center for Food Safety & Applied Nutrition/US FDA) for his significant input in this study. 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 43 TC 5 Z9 5 U1 6 U2 16 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1463-9076 EI 1463-9084 J9 PHYS CHEM CHEM PHYS JI Phys. Chem. Chem. Phys. PY 2015 VL 17 IS 38 BP 24937 EP 24943 DI 10.1039/c5cp04046a PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA CR9SR UT WOS:000361697400042 PM 26344402 ER PT J AU Howland, H Fahmy, R Hoag, SW AF Howland, Harris Fahmy, Raafat Hoag, Stephen W. TI Analysis of curing of a sustained release coating formulation by application of NIR spectroscopy to monitor changes associated with glyceryl monostearate SO DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY LA English DT Article DE Curing; film coat; glyceryl monostearate and ammonio methacrylate copolymer; near infrared; polymer; spectroscopy; sustained release ID FLUIDIZED-BED; QUALITY; DESIGN; CHEMOMETRICS; TEMPERATURE; TABLETS; LATEX AB For controlled release, latex or pseudolatex coatings to function as designed, it must be cured at temperatures at or slightly above the polymer's glass transition temperature. The focus of this study is to develop an understanding of the curing process and to develop near infrared spectroscopy as a tool for monitoring curing. Differential scanning calorimetry studies were used to determine how the thermal properties of glyceryl monostearate (GMS) and its polymorphic forms relate to the extent of Eudragit (R) polymer coat curing at different curing temperatures. The different GMS melting endotherms were used to monitor the extent of curing and as references for model development. The calculated melting peak areas for the GMS were plotted versus time and found to be dependent on time and temperature used for curing. Principal component analysis and parallel factor analysis were used to investigate the effect of curing on the films and showed that spectral changes could be could be directly related to the changes associated with the GMS during curing. Partial least square models developed could predict the extent of curing and the final state of GMS post curing. C1 [Howland, Harris; Fahmy, Raafat; Hoag, Stephen W.] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Fahmy, Raafat] US FDA, Off New Anim Drug Evaluat, Rockville, MD 20857 USA. RP Hoag, SW (reprint author), Univ Maryland, Sch Pharm, 20 N Pine St, Baltimore, MD 21201 USA. EM shoag@rx.umaryland.edu FU Consortium for Industrial Pharmaceutics Education and Training (CIPET) FX The authors gratefully acknowledge Consortium for Industrial Pharmaceutics Education and Training (CIPET) for financial support for this research. NR 23 TC 1 Z9 1 U1 1 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0363-9045 EI 1520-5762 J9 DRUG DEV IND PHARM JI Drug Dev. Ind. Pharm. PY 2015 VL 41 IS 8 BP 1263 EP 1273 DI 10.3109/03639045.2014.947505 PG 11 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CR4TS UT WOS:000361332800006 PM 25138350 ER PT J AU Moolchandani, V Augsburger, LL Gupta, A Khan, M Langridge, J Hoag, SW AF Moolchandani, Vikas Augsburger, Larry L. Gupta, Abhay Khan, Mansoor Langridge, John Hoag, Stephen W. TI Characterization and selection of suitable grades of lactose as functional fillers for capsule filling: part 1 SO DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY LA English DT Article DE alpha-Lactose monohydrate; beta-anhydrous lactose; capsule filling; filler characterization; plug mechanical strength ID PLUG FORMATION; MACHINE; FORMULATIONS; WEIGHT; SIZE AB The purpose of this work is to characterize thermal, physical and mechanical properties of different grades of lactose and better understand the relationships between these properties and capsule filling performance. Eight grades of commercially available lactose were evaluated: Pharmatose 110 M, 125 M, 150 M, 200 M, 350 M (alpha-lactose monohydrate), AL (anhydrous lactose containing similar to 80% beta-AL), DCL11 (spray dried cc-lactose monohydrate containing 15% amorphous lactose) and DCL15 (granulated alpha-lactose monohydrate containing similar to 12% (3-AL). In this study, different lactose grades were characterized by thermal, solid state, physical and mechanical properties and later evaluated using principal component analysis (PCA) to assess the inter-relationships among some of these properties. The lactose grades were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray diffraction (XRD), moisture sorption/desorption isotherms, particle size distribution; the flow was characterized by Carr Index (Cl), critical orifice diameter (COD) and angle of friction. Plug mechanical strength was estimated from its diametric crushing strength. The first and second principal components (PC) captured 47.6% and 27.4% of variation in the physical and mechanical property data, respectively. The PCA plot grouped together 110 M, AL, DCL11 and DCL15 on the one side of plot which possessed superior properties for capsule formulation and these grades were selected for future formulation development studies (part II of this work). C1 [Moolchandani, Vikas; Augsburger, Larry L.; Hoag, Stephen W.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. [Gupta, Abhay; Khan, Mansoor] US FDA, Div Prod Qual Res, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Langridge, John] DMV Fonterra Excipients, Goch, Germany. RP Moolchandani, V (reprint author), Nutrilite Hlth Inst Amway, 5600 Beach Blvd, Buena Pk, CA 90622 USA. EM Moolchandani.rx@gmail.com FU DMV-Fonterra Excipients (Goch, Germany); University of Maryland Department of Pharmaceutical Sciences FX The views and opinions expressed in this paper are only of the authors, and do not necessarily reflect the views or policies of the FDA. Authors thank the financial support of this research provided by DMV-Fonterra Excipients (Goch, Germany). This work was also supported by University of Maryland Department of Pharmaceutical Sciences predoctoral Dr. Frank J. Slam and H. A. B. Dunning fellowship. NR 50 TC 1 Z9 1 U1 4 U2 7 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0363-9045 EI 1520-5762 J9 DRUG DEV IND PHARM JI Drug Dev. Ind. Pharm. PY 2015 VL 41 IS 9 BP 1452 EP 1463 DI 10.3109/03639045.2014.957703 PG 12 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CR4TY UT WOS:000361333500007 PM 25212639 ER PT J AU Lefebvre, DE Venema, K Gombau, L Valerio, LG Raju, J Bondy, GS Bouwmeester, H Singh, RP Clippinger, AJ Collnot, EM Mehta, R Stone, V AF Lefebvre, David E. Venema, Koen Gombau, Lourdes Valerio, Luis G., Jr. Raju, Jayadev Bondy, Genevieve S. Bouwmeester, Hans Singh, R. Paul Clippinger, Amy J. Collnot, Eva-Maria Mehta, Rekha Stone, Vicki TI Utility of models of the gastrointestinal tract for assessment of the digestion and absorption of engineered nanomaterials released from food matrices SO NANOTOXICOLOGY LA English DT Review DE Alimentary canal; bioaccessibility; bioavailability; nanotechnology ID IN-VITRO DIGESTION; ORAL-DRUG ABSORPTION; ABERRANT CRYPT FOCI; INTESTINAL EPITHELIAL-CELLS; INFLAMMATORY-BOWEL-DISEASE; SOLID LIPID NANOPARTICLES; ZINC-OXIDE NANOPARTICLES; SILVER NANOPARTICLES; CACO-2 CELLS; ANIMAL-MODELS AB Engineered metal/mineral, lipid and biochemical macromolecule nanomaterials (NMs) have potential applications in food. Methodologies for the assessment of NM digestion and bioavailability in the gastrointestinal tract are nascent and require refinement. A working group was tasked by the International Life Sciences Institute NanoRelease Food Additive project to review existing models of the gastrointestinal tract in health and disease, and the utility of these models for the assessment of the uptake of NMs intended for food. Gastrointestinal digestion and absorption could be addressed in a tiered approach using in silico computational models, in vitro non-cellular fluid systems and in vitro cell culture models, after which the necessity of ex vivo organ culture and in vivo animal studies can be considered. Examples of NM quantification in gastrointestinal tract fluids and tissues are emerging; however, few standardized analytical techniques are available. Coupling of these techniques to gastrointestinal models, along with further standardization, will further strengthen methodologies for risk assessment. C1 [Lefebvre, David E.; Raju, Jayadev; Bondy, Genevieve S.; Mehta, Rekha] Hlth Canada, Food Directorate, Regulatory Toxicol Res Div, Ottawa, ON K1A 0L2, Canada. [Venema, Koen] Beneficial Microbes Consultancy, Wageningen, Netherlands. [Gombau, Lourdes] Leitat Technol Ctr, Barcelona, Spain. [Valerio, Luis G., Jr.] US FDA, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Bouwmeester, Hans] RIKILT Wageningen UR, Wageningen, Netherlands. [Singh, R. Paul] Univ Calif Davis, Dept Biol & Agr Engn, Davis, CA 95616 USA. [Clippinger, Amy J.] PETA Int Sci Consortium Ltd, London, England. [Collnot, Eva-Maria] URSAPHARM Ind, Saarbrucken, Germany. [Stone, Vicki] Heriot Watt Univ, Sch Life Sci, Edinburgh EH14 4AS, Midlothian, Scotland. RP Stone, V (reprint author), Heriot Watt Univ, Sch Life Sci, Riccarton Campus, Edinburgh EH14 4AS, Midlothian, Scotland. EM v.stone@hw.ac.uk OI Stone, Vicki/0000-0001-8346-7471 FU Unilever; Pew Charitable Trusts; US Food and Drug Administration; Health Canada; ILSI North America; Coca-Cola Company; Illinois Institute of Technology's Institute for Food Safety and Health; ILSI Research Foundation FX The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper. In the past, Vicki Stone had received research funding from Unilever. The initial convening Steering Committee phase of the NanoRelease Food Additive project was funded by the Pew Charitable Trusts, the US Food and Drug Administration, Health Canada, ILSI North America, the Coca-Cola Company, the Illinois Institute of Technology's Institute for Food Safety and Health and the ILSI Research Foundation. Substantial in-kind support was provided by the Nanotechnology Industries Association. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This paper reflects the current thinking and experience of the authors. NR 184 TC 10 Z9 10 U1 9 U2 40 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1743-5390 EI 1743-5404 J9 NANOTOXICOLOGY JI Nanotoxicology PY 2015 VL 9 IS 4 BP 523 EP 542 DI 10.3109/17435390.2014.948091 PG 20 WC Nanoscience & Nanotechnology; Toxicology SC Science & Technology - Other Topics; Toxicology GA CR4SQ UT WOS:000361329100013 PM 25119418 ER PT J AU Fares, RCG Souza, KPR Anez, G Rios, M AF Fares, Rafaelle C. G. Souza, Katia P. R. Anez, German Rios, Maria TI Epidemiological Scenario of Dengue in Brazil SO BIOMED RESEARCH INTERNATIONAL LA English DT Review ID RIO-DE-JANEIRO; SHOCK SYNDROME DHF/DSS; VIRUS SEROTYPE 4; HEMORRHAGIC-FEVER; AEDES-ALBOPICTUS; COST-EFFECTIVENESS; NEUROLOGICAL MANIFESTATIONS; GLOBAL DISTRIBUTION; ANTIBODY-RESPONSE; AGE PATTERN AB Dengue is the most important reemerging mosquito-borne viral disease worldwide. It is caused by any of four Dengue virus types or serotypes (DENV-1 to DENV-4) and is transmitted by mosquitoes from the genus Aedes. Ecological changes have favored the geographic expansion of the vector and, since the dengue pandemic in the Asian and Pacific regions, the infection became widely distributed worldwide, reaching Brazil in 1845. The incidence of dengue in Brazil has been frequently high, and the number of cases in the country has at some point in time represented up to 60% of the dengue reported cases worldwide. This review addresses vector distribution, dengue outbreaks, circulating serotypes and genotypes, and prevention approaches being utilized in Brazil. C1 [Fares, Rafaelle C. G.; Souza, Katia P. R.; Anez, German; Rios, Maria] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Rios, M (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM maria.rios@fda.hhs.gov OI Anez, German/0000-0001-5361-3001 NR 120 TC 2 Z9 2 U1 0 U2 2 PU HINDAWI PUBLISHING CORP PI NEW YORK PA 315 MADISON AVE 3RD FLR, STE 3070, NEW YORK, NY 10017 USA SN 2314-6133 EI 2314-6141 J9 BIOMED RES INT JI Biomed Res. Int. PY 2015 AR 321873 DI 10.1155/2015/321873 PG 13 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA CR3AE UT WOS:000361201500001 ER PT J AU Pandey, SN Kesari, A Yokota, T Pandey, GS AF Pandey, Sachchida Nand Kesari, Akanchha Yokota, Toshifumi Pandey, Gouri Shankar TI Muscular Dystrophy: Disease Mechanisms and Therapies SO BIOMED RESEARCH INTERNATIONAL LA English DT Editorial Material C1 [Pandey, Sachchida Nand] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. [Kesari, Akanchha] Miami Childrens Hosp, Miami, FL 33155 USA. [Yokota, Toshifumi] Univ Alberta, Dept Med Genet, Fac Med & Dent, Edmonton, AB T6G 2H7, Canada. [Pandey, Gouri Shankar] US FDA, Bethesda, MD 20993 USA. RP Pandey, SN (reprint author), Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. EM spandey@childrensnational.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 2314-6133 EI 2314-6141 J9 BIOMED RES INT JI Biomed Res. Int. PY 2015 AR 456348 DI 10.1155/2015/456348 PG 2 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA CQ6RK UT WOS:000360731400001 ER PT J AU Li, H Cui, S Wang, S Jiang, X Zhang, S Zhang, R Fu, PP Sun, X AF Li, H. Cui, S. Wang, S. Jiang, X. Zhang, S. Zhang, R. Fu, P. P. Sun, X. TI Ultrasensitive UPLC-MS/MS method for analysis of etheno-DNA adducts in human white blood cells SO FREE RADICAL RESEARCH LA English DT Article DE UPLC-MS/MS; 1, N-6-etheno-2'-deoxyadenosine; 3, N-4-etheno-2'-deoxycytidine; lipid peroxidation; human biomonitoring ID TANDEM MASS-SPECTROMETRY; ETHYL CARBAMATE URETHANE; NUCLEIC-ACID BASES; LIPID-PEROXIDATION; LIQUID-CHROMATOGRAPHY; VINYL-CHLORIDE; RETINYL PALMITATE; QUANTIFICATION; PRODUCTS; LIVER AB Etheno-DNA adducts are generated by interaction of cellular DNA with exogenous environmental carcinogens and end products of lipid peroxidation. It has been determined that 1,N-6-etheno-2'-deoxyadenosine (epsilon dA) and 3,N-4-etheno-2'-deoxycytidine (epsilon dC) adducts formed in human white blood cells can be used to serve as biomarkers of genetic damage mediated by oxidative stress. In this study, we developed an ultrasensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method used to detect and quantify epsilon dA and epsilon dC adducts in human white blood cells. The percent recoveries of epsilon dA and epsilon dC adducts were found to be 88.9% + 2.8 and 95.7% +/- 3.7, respectively. The detection limits were similar to 1.45 fmol for epsilon dA and similar to 1.27 fmol for epsilon dC in 20 mu g of human white blood cell DNA samples, both epsilon dA and epsilon dC adducts could be detected using only similar to 5 mu g of DNA per sample. For validation of the method, 34 human blood cell DNA samples were assayed and the results revealed a significant difference (P < 0.01) between levels (fmol/mu g DNA) of 0.82 +/- 0.83 (standard deviation [SD]) (range: 0.15-3.11) for epsilon dA, 3.28 +/- 3.15 (SD) (range: 0.05-9.6) for epsilon dC in benzene-exposed workers; and 0.04 +/- 0.08 (SD) (range: 0.0-0.27) for epsilon dA and 0.77 +/- 1.02 (SD) (range: 0.10-4.11) for epsilon dC in non-benzene-exposed workers. Our method shows a high sensitivity and specificity when applied to small amounts of human white blood cell DNA samples; background levels of epsilon dA and epsilon dC could be reproducibly detected. The ultrasensitive and simple detection method is thus suitable for applications in human biomonitoring and molecular epidemiology studies. C1 [Li, H.; Cui, S.; Wang, S.; Jiang, X.; Sun, X.] Chinese Ctr Dis Control & Prevent, Key Lab Chem Safety & Hlth, Beijing, Peoples R China. [Li, H.; Cui, S.; Wang, S.; Jiang, X.; Sun, X.] Chinese Ctr Dis Control & Prevent, Natl Inst Occupat Hlth & Poison Control, Beijing, Peoples R China. [Li, H.; Cui, S.; Zhang, S.] Zhengzhou Univ, Dept Chem, Zhengzhou 450052, Peoples R China. [Wang, S.] Hebei United Univ, Coll Publ Hlth, Tangshan, Hebei Province, Peoples R China. [Zhang, R.] Henan Ctr Dis Control & Prevent, Zhengzhou, Henan Province, Peoples R China. [Fu, P. P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Sun, X (reprint author), 27 Nan Wei Rd, Beijing 100050, Peoples R China. EM sunxin@chinacdc.cn FU National Natural Foundation of China [30771790]; National Science and Technology Infrastructure Program [2013BAI12B03] FX The research work was supported by the National Natural Foundation of China (30771790) and the National Science and Technology Infrastructure Program (2013BAI12B03). This article is not an official guidance or policy statement of U.S. Food and Drug Administration (FDA). No official support or endorsement by the U.S. FDA is intended or should be inferred. NR 28 TC 1 Z9 1 U1 2 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1071-5762 EI 1029-2470 J9 FREE RADICAL RES JI Free Radic. Res. PY 2015 VL 49 IS 9 BP 1049 EP 1054 DI 10.3109/10715762.2015.1006213 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CQ6KW UT WOS:000360714300001 PM 25968941 ER PT J AU Sheikh, F Dickensheets, H Pedras-Vasconcelos, J Ramalingam, T Helming, L Gordon, S Donnelly, RP AF Sheikh, Faruk Dickensheets, Harold Pedras-Vasconcelos, Joao Ramalingam, Thirumalai Helming, Laura Gordon, Siamon Donnelly, Raymond P. TI The Interleukin-13 Receptor-alpha 1 Chain Is Essential for Induction of the Alternative Macrophage Activation Pathway by IL-13 but Not IL-4 SO JOURNAL OF INNATE IMMUNITY LA English DT Article DE Alternative macrophage activation; Arginase; Interleukin-4; Interleukin-13; Interleukin-13 receptor-alpha 1; STAT6 ID COMMON GAMMA-CHAIN; INTERFERON-GAMMA; GENE-EXPRESSION; IN-VITRO; DIFFERENTIAL EXPRESSION; CYTOKINE SIGNALING-1; HUMAN MONOCYTES; MICE LACKING; STAT6; CELLS AB Macrophages coexpress both the interleukin (IL)-2R gamma chain (gamma(c)) and IL-13R alpha 1. These receptor chains can heterodimerize with IL-4R alpha to form type I or type II IL-4 receptor complexes, respectively. We used macrophages derived from Il2rg and Il13ra1 knockout (KO) mice to evaluate the requirements for these receptor chains for induction of the alternative macrophage activation (AMA) pathway by IL-4 and IL-13. Absence of gamma(c) significantly decreased activation of STAT6 by IL-4 but not IL-13. However, although activation of STAT6 by IL-4 was markedly reduced in gamma(c) KO macrophages, it was not abolished, indicating that IL-4 can still signal through type II IL-4 receptors via the IL-13R alpha 1 chain. IL-13 failed to activate STAT6 in macrophages derived from Il13ra1 KO mice; however, these cells remained fully responsive to IL-4. The inability of IL-13 but not IL-4 to signal in Il13ra1(-/-) macrophages correlated with the inability of IL-13 but not IL-4 to induce expression of genes such as Arg1, Retnla and Ccl11 that are characteristically expressed by alternatively activated macrophages. In addition, IL-13 but not IL-4 failed to induce membrane fusion and giant cell formation by Il13ra1 KO macrophages. These findings demonstrate that the IL-13R alpha 1 chain is essential for induction of the AMA pathway by IL-13 but not IL-4. (C) 2015 S. Karger AG, Basel C1 [Sheikh, Faruk; Dickensheets, Harold; Pedras-Vasconcelos, Joao; Donnelly, Raymond P.] US FDA, Div Therapeut Proteins, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Ramalingam, Thirumalai] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Helming, Laura] Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-80290 Munich, Germany. [Gordon, Siamon] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. RP Donnelly, RP (reprint author), Div Biotechnol Res & Review, FFDA CDER WO Bldg 52,Room 2106, Silver Spring, MD 20993 USA. EM raymond.donnelly@fda.hhs.gov FU Intramural NIH HHS [Z99 OD999999] NR 46 TC 5 Z9 5 U1 1 U2 3 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1662-811X EI 1662-8128 J9 J INNATE IMMUN JI J. Innate Immun. PY 2015 VL 7 IS 5 BP 494 EP 505 DI 10.1159/000376579 PG 12 WC Immunology SC Immunology GA CQ2YU UT WOS:000360469300007 PM 25766112 ER PT J AU Lee, WJ Lee, TA Pickard, AS Shoaibi, A Schumock, GT AF Lee, Wan-Ju Lee, Todd A. Pickard, Alan Simon Shoaibi, Azadeh Schumock, Glen T. TI Using linked electronic data to validate algorithms for health outcomes in administrative databases SO JOURNAL OF COMPARATIVE EFFECTIVENESS RESEARCH LA English DT Article DE administrative database; algorithm; health outcome of interest; linked database; validation ID MEDICARE CLAIMS DATA; HOSPITAL DISCHARGE REGISTRY; INCIDENT BREAST-CANCER; RHEUMATOID-ARTHRITIS; DIAGNOSIS; QUALITY; RHABDOMYOLYSIS; INFORMATION; IDENTIFY; STROKE AB The validity of algorithms used to identify health outcomes in claims-based and administrative data is critical to the reliability of findings from observational studies. The traditional approach to algorithm validation, using medical charts, is expensive and time-consuming. An alternative method is to link the claims data to an external, electronic data source that contains information allowing confirmation of the event of interest. In this paper, we describe this external linkage validation method and delineate important considerations to assess the feasibility and appropriateness of validating health outcomes using this approach. This framework can help investigators decide whether to pursue an external linkage validation method for identifying health outcomes in administrative/claims data. C1 [Lee, Wan-Ju; Lee, Todd A.; Pickard, Alan Simon; Schumock, Glen T.] Univ Illinois, Coll Pharm, Dept Pharm Syst Outcomes & Policy, Chicago, IL 60607 USA. [Lee, Todd A.; Pickard, Alan Simon; Schumock, Glen T.] Univ Illinois, Coll Pharm, Ctr Pharmacoepidemiol & Pharmacoecon Res, Chicago, IL USA. [Shoaibi, Azadeh] US FDA, Ctr Drug Evaluat & Res, Off Med Policy, Silver Spring, MD USA. RP Schumock, GT (reprint author), Univ Illinois, Coll Pharm, Dept Pharm Syst Outcomes & Policy, Chicago, IL 60607 USA. EM schumock@uic.edu OI Lee, Wan-Ju/0000-0001-9263-6943 FU US FDA through the Department of Health and Human Services (HHS) [HHSF223200910006] FX The Mini-Sentinel program is funded by the US FDA through the Department of Health and Human Services (HHS) Contract number HHSF223200910006. The concepts discussed here stem from experience gained from a project conducted under the Mini-Sentinel program. 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 37 TC 0 Z9 0 U1 3 U2 5 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 2042-6305 EI 2042-6313 J9 J COMP EFFECT RES JI J. Comp. Eff. Res. PY 2015 VL 4 IS 4 BP 359 EP 366 DI 10.2217/CER.15.14 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CP1AP UT WOS:000359608500009 PM 26274797 ER PT S AU Briguglio, S Chirtel, S Spungen, J Rabbani, PI Hoffman-Pennesi, D Wirtz, M AF Briguglio, Stephanie Chirtel, Stuart Spungen, Judith Rabbani, P. Isaac Hoffman-Pennesi, Dana Wirtz, Mark BE Mitchell, DC Braithwaite, E TI Sodium Trends in Selected US Total Diet Study Foods, 2003-2011 SO 38TH NATIONAL NUTRIENT DATABANK CONFERENCE SE Procedia Food Science LA English DT Proceedings Paper CT 38th National Nutrient Databank Conference (NNDC) CY MAY, 2014 CL Oregon Hlth Sci Univ, Portland, OR HO Oregon Hlth Sci Univ DE Total diet study; sodium AB Objective: Characterize trends in sodium concentrations in the general categories of foods analyzed in the U.S. FDA Total Diet Study (TDS) program from 2003 through 2011. Methods: Trends were assessed for sodium concentrations in a small convenience sample of TDS foods from 2003 to 2011 using simple linear regression with the SAS regression procedure, focusing on sodium concentrations in foods in USDA's sentinel food categories. Results: Levels of sodium in various TDS foods varied over time. Overall, 75 TDS foods did not have statistically significant linear changes in sodium content during that time, and 23 TDS foods did. Certain sentinel foods such as ramen-style noodles showed gradually increasing sodium content from 2003 through 2011. Significance: Over three quarters of foods show no statistically significant linear changes over time. Although a number of selected foods had a statistically significant decline, a limitation to this study is that specific brands of TDS foods were not necessarily the same for each period. The results suggest that some sodium reduction has been occurring in some foods and supports the idea that commercially viable reductions are possible. Such reductions in the sodium content of foods could have large public health implications-rates of hypertension and related health consequences would likely decline-thus saving thousands of lives and billions of dollars each year. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). C1 [Briguglio, Stephanie; Chirtel, Stuart; Spungen, Judith; Rabbani, P. Isaac; Hoffman-Pennesi, Dana; Wirtz, Mark] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Briguglio, S (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Stephanie.briguglio@fda.hhs.gov NR 8 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2211-601X J9 PROC FOOD SCI PY 2015 VL 4 BP 27 EP 38 DI 10.1016/j.profoo.2015.06.006 PG 12 WC Food Science & Technology; Nutrition & Dietetics SC Food Science & Technology; Nutrition & Dietetics GA BD2HB UT WOS:000358738000005 ER PT S AU Hoffman-Pennesi, D Spungen, J Rabbani, PI Briguglio, S Wirtz, M AF Hoffman-Pennesi, Dana Spungen, Judith Rabbani, P. Isaac Briguglio, Stephanie Wirtz, Mark BE Mitchell, DC Braithwaite, E TI Evaluation of US Total Diet Study Data on Selenium SO 38TH NATIONAL NUTRIENT DATABANK CONFERENCE SE Procedia Food Science LA English DT Proceedings Paper CT 38th National Nutrient Databank Conference (NNDC) CY MAY, 2014 CL Oregon Hlth Sci Univ, Portland, OR HO Oregon Hlth Sci Univ DE US FDA Total Diet Study; selenium; USDA Standard Reference 26; whole wheat bread; boiled eggs AB The potential usefulness of FDA's U.S. Total Diet Study (TDS) selenium (Sc) data to the nutrition community was evaluated as part of the TDS modernization program. TDS Sc data collected from 2003 - 2010 was evaluated by comparing these data to Se concentration data in USDA's Standard Reference 26 (SR26) Database. We also evaluated trends in Sc concentrations over tone and differences in Se concentrations by Market Basket (MB). Comparable SR26 foods were identified for most TDS foods; however, for many TDS foods, there was more than one match in SR26. TDS was found to be a unique source of analytical Se concentration data for four food mixtures and for several SR26 foods with imputed Se concentrations. Sc concentrations in TDS foods were similar to analyzed Se concentrations in most corresponding SR26 foods. Se concentrations in whole wheat bread were significantly higher in MB 2 (U.S. West Region, collected in the winter) than in MB 1 (U.S. North Central Region, collected in the fall), 3 (U.S. South Region, collected in the spring), and 4 (U.S. North East Region, collected in the summer). Se concentrations in whole wheat bread were also significantly higher in MB 4 than in MB 3. Se concentrations in boiled eggs were significantly higher in MB 2 than in other market baskets. The U.S. Total Diet Study suspended analysis of Se in 2010, but FDA is evaluating the potential benefits of adding Se analysis back to the TDS program. Results of this study demonstrate the potential value of TDS concentration data for Sc and other nutrients to the U.S. nutrition community. However, it is clear that 'WS data on generic foods (e.g. tuna, canned in water) are less useful than TDS data on more specifically defined foods (e.g. tuna, white, canned in water). Potential geographical and/or seasonal differences in Sc contents of some foods may warrant additional investigation. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativeconunons.or2/licc.nsc.s/by-nc-nd/4.0/). Peer-review under responsibility of the National Nutrient Databank Steering Conunittee C1 [Hoffman-Pennesi, Dana; Spungen, Judith; Rabbani, P. Isaac; Briguglio, Stephanie; Wirtz, Mark] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Hoffman-Pennesi, D (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM dana.pennesi@fda.hhs.gov NR 2 TC 0 Z9 0 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2211-601X J9 PROC FOOD SCI PY 2015 VL 4 BP 79 EP 85 DI 10.1016/j.profoo.2015.06.012 PG 7 WC Food Science & Technology; Nutrition & Dietetics SC Food Science & Technology; Nutrition & Dietetics GA BD2HB UT WOS:000358738000011 ER PT S AU Juan, WY Yamini, S Britten, P AF Juan, WenYen Yamini, Sedigheh Britten, Patricia BE Mitchell, DC Braithwaite, E TI Food Intake Patterns of Self-identified Vegetarians among the US Population, 2007-2010 SO 38TH NATIONAL NUTRIENT DATABANK CONFERENCE SE Procedia Food Science LA English DT Proceedings Paper CT 38th National Nutrient Databank Conference (NNDC) CY MAY, 2014 CL Oregon Hlth Sci Univ, Portland, OR HO Oregon Hlth Sci Univ DE self-identified vegetarian; vegetarian Ibod intake pattern; NHANES ID WEIGHT-LOSS; NONVEGETARIAN WOMEN; MANAGEMENT; HEALTH; DIETS AB Vegetarians' food intake patterns vary in the extent that they exclude all or some animal products (e.g., meat, poultry, fish/seafood, eggs, and dairy). We examined the differences of consumption of selected USDA Food Patterns food groups, subgroups, and food components, total calorie intake, and the number of food items between self-identified vegetarians and non-vegetarians in the U.S. population aged 1 year and older. Weighted reliable food consumption data from day 1 of the National Health and Nutrition Examination Survey, 2007-2010 and the USDA Food Patterns Equivalents Database, 2007-2010 were analyzed in the U.S. population (n=15,453) using SAS 9.3. Only 3% of the self-identified vegetarians (total 2.1%; n=323) did not consume any animal products. Compared to non-vegetarians, vegetarians consumed significantly fewer calories (1862 kcal vs. 2058 kcal; p<0.05) with the same number of food items (n=16) per day, and they consumed significantly less meat, poultry, solid fats and added sugars, and more soy, legumes, and whole grains than non-vegetarians. Both groups consumed about the same amounts of eggs, dairy, seafood, fruits, and vegetables. After energy adjustment, vegetarians consumed significantly more fruits, vegetables, whole grains, and total grains than non-vegetarians per 1000 kcal. Although a large proportion of self-identified vegetarians report consuming some type of animal products, such as meat, poultry and/or seafood, their dietary patterns contain more plant-based foods and whole grains with less solid fats and added sugars. Caution is needed in interpreting the term "vegetarian" front self-reports. Increasing fruit, vegetable, and whole grain consumption remains a targeted message for all populations. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license jhup://creativeconunons.org/licenses/by-ne-nd/4.0/4 Peer-review under responsibility of the National Nutrient Databank Steering Committee C1 [Juan, WenYen; Yamini, Sedigheh] US FDA, Off Nutr Labeling & Dietary Supplements, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Britten, Patricia] USDA, Ctr Nutr Policy & Promot, Alexandria, VA 22302 USA. RP Juan, WY (reprint author), US FDA, Off Nutr Labeling & Dietary Supplements, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM wenyen.juan@fda.hhs.gov NR 17 TC 1 Z9 1 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2211-601X J9 PROC FOOD SCI PY 2015 VL 4 BP 86 EP 93 DI 10.1016/j.profoo.2015.06.013 PG 8 WC Food Science & Technology; Nutrition & Dietetics SC Food Science & Technology; Nutrition & Dietetics GA BD2HB UT WOS:000358738000012 ER PT S AU Shimakawa, T Ferguson, M AF Shimakawa, Tomoko Ferguson, Martine BE Mitchell, DC Braithwaite, E TI Prevalence of Structure Function Claims: 2006-2007 Food Label and Package Survey SO 38TH NATIONAL NUTRIENT DATABANK CONFERENCE SE Procedia Food Science LA English DT Proceedings Paper CT 38th National Nutrient Databank Conference (NNDC) CY MAY, 2014 CL Oregon Hlth Sci Univ, Portland, OR HO Oregon Hlth Sci Univ DE Food Label; FLAPS; Structure Function Claims AB The Food and Drug Administration (FDA) studies product labels from the United States (U.S.) food supply through the Food Label and Package Survey (FLAPS) to monitor industry responses to FDA regulations and policies on foods. The 2006-2007 FLAPS data were analyzed to obtain prevalence, food sources, and claim types of structure function (SF) claims. The SF claims describe the role of a nutrient or food component intended to maintain the normal structure or function of body (e.g., calcium builds strong bones). FDA selected regulated food products from the ACNielsen Strategic Planner sales database of the U.S. retail stores using a stratified, two-stage design with selection probabilities proportional to nationally estimated sales dollars. Products were purchased from retail stores across the U.S. and the detailed product label information was recorded. FDA calculated product sampling weights based On sales data so that the FLAPS estimate will be generalizable to the foods sold in all U.S. retail stores The FLAPS database contains label information for 1,227 foods in 57 product groups. The weighted prevalence of the FLAPS foods with at least one SF claim was 5.5%, of which approximately 1/3 had two or more SF claims. There were about 30 different types of SF claims and commonly found SF claims include claims about healthy bones and teeth, baby's brain and eye development, healthy weight, immune system, and healthy cholesterol level. The SF claims were found commonly in the following product groups: infant formulas, cheeses, yogurts, cold cereals, refrigerated and shelf-stable juices and drinks. These results demonstrate the usefulness of the FLAPS data as an FDA's monitoring tool to assess compliance with food label-related laws and regulations and to plan for future policy making. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativeconimons.org/licenses/by-nc-nd/4.07). Peer-review under responsibility of the National Nutrient Databank Steering Committee C1 [Shimakawa, Tomoko; Ferguson, Martine] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Shimakawa, T (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM Tomoko.Shimakawa@fda.hhs.gov NR 5 TC 1 Z9 1 U1 3 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2211-601X J9 PROC FOOD SCI PY 2015 VL 4 BP 133 EP 137 DI 10.1016/j.profoo.2015.06.018 PG 5 WC Food Science & Technology; Nutrition & Dietetics SC Food Science & Technology; Nutrition & Dietetics GA BD2HB UT WOS:000358738000017 ER PT J AU Melas, IN Sakellaropoulos, T Iorio, F Alexopoulos, LG Loh, WY Lauffenburger, DA Saez-Rodriguez, J Bai, JPF AF Melas, Ioannis N. Sakellaropoulos, Theodore Iorio, Francesco Alexopoulos, Leonidas G. Loh, Wei-Yin Lauffenburger, Douglas A. Saez-Rodriguez, Julio Bai, Jane P. F. TI Identification of drug-specific pathways based on gene expression data: application to drug induced lung injury SO INTEGRATIVE BIOLOGY LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; RESPIRATORY-DISTRESS-SYNDROME; TRANSCRIPTION FACTORS; REGULATORY NETWORKS; SIGNALING PATHWAYS; OXIDATIVE STRESS; MICE; CANCER; EDEMA; ACID AB Identification of signaling pathways that are functional in a specific biological context is a major challenge in systems biology, and could be instrumental to the study of complex diseases and various aspects of drug discovery. Recent approaches have attempted to combine gene expression data with prior knowledge of protein connectivity in the form of a PPI network, and employ computational methods to identify subsets of the protein-protein-interaction (PPI) network that are functional, based on the data at hand. However, the use of undirected networks limits the mechanistic insight that can be drawn, since it does not allow for following mechanistically signal transduction from one node to the next. To address this important issue, we used a directed, signaling network as a scaffold to represent protein connectivity, and implemented an Integer Linear Programming (ILP) formulation to model the rules of signal transduction from one node to the next in the network. We then optimized the structure of the network to best fit the gene expression data at hand. We illustrated the utility of ILP modeling with a case study of drug induced lung injury. We identified the modes of action of 200 lung toxic drugs based on their gene expression profiles and, subsequently, merged the drug specific pathways to construct a signaling network that captured the mechanisms underlying Drug Induced Lung Disease (DILD). We further demonstrated the predictive power and biological relevance of the DILD network by applying it to identify drugs with relevant pharmacological mechanisms for treating lung injury. C1 [Melas, Ioannis N.; Bai, Jane P. F.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Sakellaropoulos, Theodore; Alexopoulos, Leonidas G.] Natl Tech Univ Athens, Sch Mech Engn, Athens, Greece. [Iorio, Francesco; Saez-Rodriguez, Julio] European Bioinformat Inst EMBL EBI, European Mol Biol Lab, Hinxton, Cambs, England. [Alexopoulos, Leonidas G.] ProtATonce Ltd, Athens, Greece. [Loh, Wei-Yin] Univ Wisconsin, Dept Stat, Madison, WI 53706 USA. [Lauffenburger, Douglas A.] MIT, Sch Biol Engn, Cambridge, MA 02139 USA. RP Bai, JPF (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM saezrodriguez@ebi.ac.uk; jane.bai@fda.hhs.gov OI Iorio, Francesco/0000-0001-7063-8913; Saez-Rodriguez, Julio/0000-0002-8552-8976 FU Medical Countermeasures grant; Institute for Collaborative Biotechnologies [ARO W911NF-09-D-0001] FX The core methodology of this paper on the integration of gene expression data into signaling pathways, by leveraging prior knowledge or protein connectivity and transcription regulation via regular optimization formulations, was conceptualized and motivated by INM, DAL, LGA and JSR. The ILP formulation was developed by INM, TS and JSR. The prior knowledge of transcription regulation in the form of TF regulons and the rewired versions of the original network, used for null model simulations, were provided by FI. All aspects of the DILD application were conceptualised, developed and implemented by INM and JPFB. The GUIDE algorithm was developed and implemented by WYL. Computational infrastructure was provided by EMBL-EBI. All authors edited the manuscript. We gratefully acknowledge IBM for providing the IBM ILOG CPLEX, free of charge. INM was supported as an ORISE fellow through 2013 Medical Countermeasures grant to JPFB. DAL was partially supported by ARO W911NF-09-D-0001 Institute for Collaborative Biotechnologies. NR 59 TC 5 Z9 5 U1 1 U2 4 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1757-9694 EI 1757-9708 J9 INTEGR BIOL-UK JI Integr. Biol. PY 2015 VL 7 IS 8 BP 904 EP 920 DI 10.1039/c4ib00294f PG 17 WC Cell Biology SC Cell Biology GA CO1LD UT WOS:000358915500007 PM 25932872 ER PT J AU Simhadri, VL Banerjee, AS Simon, J Kimchi-Sarfaty, C Sauna, ZE AF Simhadri, Vijaya L. Banerjee, Aditi Sengupta Simon, Jonathan Kimchi-Sarfaty, Chava Sauna, Zuben E. TI Personalized approaches to the treatment of hemophilia A and B SO PERSONALIZED MEDICINE LA English DT Review DE coagulation factors; hemophilia; immunogenicity; personalized dosing; pharmacogenetics; protein therapeutics ID RECOMBINANT FACTOR-VIII; MILD HEMOPHILIA; FACTOR-IX; PROTEIN THERAPEUTICS; IMMUNOGENICITY; PHARMACOGENETICS; INHIBITORS; PLASMA; THERAPY; FVIII AB The recognition that individuals respond differently to the same medication is not new and dates almost to the founding of western medicine. In the last century it came to be recognized that genetic factors influence the heterogeneity of individual responses to medications with respect to both toxicity and effectiveness. Nonetheless, it has been challenging to integrate pharmacogenetic approaches in the routine practice of medicine as the identification of biomarkers is difficult due to the inherent complexity of biological systems. Here, we present potential applications of pharmacogenetics in managing hemophilia A and B. We discuss how predicting and circumventing immunogenicity, an important impediment to treating hemophilia patients, particularly lends itself to a pharmacogenetic approach. In addition, we discuss new trends toward personalizing the management of hemophilia in clinical settings. C1 [Simhadri, Vijaya L.; Banerjee, Aditi Sengupta; Simon, Jonathan; Kimchi-Sarfaty, Chava; Sauna, Zuben E.] US FDA, Lab Hemostasis, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Sauna, ZE (reprint author), US FDA, Lab Hemostasis, Div Hematol Res & Review, Ctr Biol Evaluat & Res, New Hampshire Ave, Silver Spring, MD 20993 USA. EM zuben.sauna@fda.hhs.gov FU Laboratory of Hemostasis; Center for Biologics Evaluation and Research, Food and Drug Administration's Modernization of Science program FX This work was supported by funds from the Laboratory of Hemostasis and the Center for Biologics Evaluation and Research, Food and Drug Administration's Modernization of Science program (ZE Sauna). 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 50 TC 1 Z9 1 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 EI 1744-828X J9 PERS MED JI Pers. Med. PY 2015 VL 12 IS 4 BP 403 EP 415 DI 10.2217/PME.15.6 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CO1VY UT WOS:000358945300009 ER PT J AU Jain, HV Verthelyi, D Beaucage, SL AF Jain, H. V. Verthelyi, D. Beaucage, S. L. TI Amphipathic trans-acting phosphorothioate DNA elements mediate the delivery of uncharged nucleic acid sequences in mammalian cells SO RSC ADVANCES LA English DT Article ID ANTISENSE MORPHOLINO OLIGOMERS; EFFICIENT SPLICING CORRECTION; DUCHENNE MUSCULAR-DYSTROPHY; PENETRATING PEPTIDES; MDX MOUSE; CELLULAR DELIVERY; VIVO-MORPHOLINOS; GENE DELIVERY; EXON; PNA AB A convenient approach to the delivery of uncharged peptide nucleic acids (PNA) or phosphorodiamidate morpholino (PMO) oligomers in mammalian cells is presented and consists of extending the sequence of these oligomers with a short (6-mer) PNA-polyA or PMO-polyA tail. Recognition of the polyA-tailed PNA or PMO oligomers by an 8-mer amphipathic trans-acting polythymidylic thiophosphate triester element (dTtaPS) results in efficient internalization of these oligomers in several cell lines. Our findings indicate that internalization of the oligomers occurs through an energy-dependent mechanism and macropinocytosis appears to be the prevailing endocytic pathway used for cellular uptake. The functionality of the internalized oligomers is demonstrated by alternate splicing of the pre-mRNA encoding luciferase in HeLa pLuc 705 cells. C1 [Jain, H. V.; Beaucage, S. L.] US FDA, Div Biotechnol Review & Res 4, CDER, Silver Spring, MD 20933 USA. [Verthelyi, D.] US FDA, Div Biotechnol Review & Res 3, CDER, Silver Spring, MD 20933 USA. RP Beaucage, SL (reprint author), US FDA, Div Biotechnol Review & Res 4, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20933 USA. EM Harsh.Jain@fda.hhs.gov; Serge.Beaucage@fda.hhs.gov NR 33 TC 2 Z9 2 U1 0 U2 12 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2046-2069 J9 RSC ADV JI RSC Adv. PY 2015 VL 5 IS 80 BP 65245 EP 65254 DI 10.1039/c5ra12038a PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA CO4NC UT WOS:000359136500053 ER PT J AU Van der Heiden, E Delmarcelle, M Simon, P Counson, M Galleni, M Freedberg, DI Thompson, J Joris, B Battistel, MD AF Van der Heiden, Edwige Delmarcelle, Michael Simon, Patricia Counson, Melody Galleni, Moreno Freedberg, Daron I. Thompson, John Joris, Bernard Battistel, Marcos D. TI Synthesis and Physicochemical Characterization of D-Tagatose-1-Phosphate: The Substrate of the Tagatose-1-Phosphate Kinase in the Phosphotransferase System-Mediated D-Tagatose Catabolic Pathway of Bacillus licheniformis SO JOURNAL OF MOLECULAR MICROBIOLOGY AND BIOTECHNOLOGY LA English DT Article DE Tagatose; Phosphoenolpyruvate:sugar phosphotransferase system; Tagatose-1-phosphate kinase; Bacillus licheniformis; Klebsiella pneumoniae; P-31 and H-1 nuclear magnetic resonance; Nuclear magnetic resonance characterization of tagatose phosphate ID D-GALACTOSE METABOLISM; PHOSPHORYL TRANSFER COMPLEX; GLUCOSYL-D-FRUCTOSES; STAPHYLOCOCCUS-AUREUS; ESCHERICHIA-COLI; STREPTOCOCCUS-MUTANS; 6-PHOSPHATE PATHWAY; LACTOSE METABOLISM; BACTERIAL PHOSPHOENOLPYRUVATE; KLEBSIELLA-PNEUMONIAE AB We report the first enzymatic synthesis of D-tagatose-1-phosphate (Tag-1P) by the multicomponent phosphoenolpyruvate: sugar phosphotransferase system (PEP-PTS) present in tagatose-grown cells of Klebsiella pneumoniae. Physicochemical characterization by P-31 and H-1 nuclear magnetic resonance spectroscopy reveals that, in solution, this derivative is primarily in the pyranose form. Tag-1P was used to characterize the putative tagatose-1-phosphate kinase (TagK) of the Bacillus licheniformis PTS-mediated D-tagatose catabolic pathway (Bli -TagP). For this purpose, a soluble protein fusion was obtained with the 6 His-tagged trigger factor (TFHis6) of Escherichia coli. The active fusion enzyme was named TagK-TFHis6. Tag-1P and D-fructose-1-phosphate are substrates for the TagK-TFHis6 enzyme, whereas the isomeric derivatives D-tagatose-6-phosphate and D-fructose-6-phosphate are inhibitors. Studies of catalytic efficiency (k(cat)/K-m) reveal that the enzyme specificity is markedly in favor of Tag-1P as the substrate. Importantly, we show in vivo that the transfer of the phosphate moiety from PEP to the B. licheniformis tagatose-specific Enzyme II in E. coli is inefficient. The capability of the PTS general cytoplasmic components of B. subtilis, HPr and Enzyme I to restore the phosphate transfer is demonstrated. (C) 2015 S. Karger AG, Basel C1 [Van der Heiden, Edwige; Delmarcelle, Michael; Simon, Patricia; Galleni, Moreno; Joris, Bernard] Univ Liege, Inst Chim, Ctr Prot Engn, Sart Tilman Par Liege, Belgium. [Counson, Melody] NUTRILAB NV, Heusden Zolder, Belgium. [Freedberg, Daron I.; Battistel, Marcos D.] US FDA, Lab Bacterial Polysaccharides, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Thompson, John] NIDCR, Microbial Biochem & Genet Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Delmarcelle, M (reprint author), Univ Liege, Inst Chim B6a, CIP, BE-4000 Sart Tilman Par Liege, Belgium. EM michael.delmarcelle@ulg.ac.be FU Intramural Research Program of the NIDCR, National Institutes of Health, Bethesda, Md., USA; FRIA (Fonds de la Recherche pour l'Industrie et l'Agriculture) fellowship FX This work was supported in part by the Intramural Research Program of the NIDCR, National Institutes of Health, Bethesda, Md., USA. Edwige Van der Heiden was the recipient of a FRIA (Fonds de la Recherche pour l'Industrie et l'Agriculture) fellowship. We thank Eric Anderson, Noel Whittaker and Andreas Pikis for mass spectrometry data and technical assistance. We thank Regine Freichels for the gift of LacD enzyme. NR 40 TC 0 Z9 0 U1 0 U2 7 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1464-1801 EI 1660-2412 J9 J MOL MICROB BIOTECH JI J. Mol. Microbiol. Biotechnol. PY 2015 VL 25 IS 2-3 BP 106 EP 119 DI 10.1159/000370115 PG 14 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA CM6XO UT WOS:000357834900004 PM 26159072 ER PT S AU Boehm, KM Wang, SJ Burtt, KE Turkbey, B Weisenthal, S Pinto, P Choyke, P Wood, BJ Petrick, N Sahiner, B Summers, RM AF Boehm, Kevin M. Wang, Shijun Burtt, Karen E. Turkbey, Baris Weisenthal, Samuel Pinto, Peter Choyke, Peter Wood, Bradford J. Petrick, Nicholas Sahiner, Berkman Summers, Ronald M. BE Hadjiiski, LM Tourassi, GD TI Efficient Hilbert transform-based alternative to Tofts physiological models for representing MRI dynamic contrast-enhanced images in computer-aided diagnosis of prostate cancer SO MEDICAL IMAGING 2015: COMPUTER-AIDED DIAGNOSIS SE Proceedings of SPIE LA English DT Proceedings Paper CT Computer-Aided Diagnosis (CAD) Conference at the SPIE Medical Imaging Symposium CY FEB 22-25, 2015 CL Orlando, FL SP SPIE, ALIO Ind, Alpin Med Syst, Modus Med Dev Inc, Bruker DE Feature selection; prostate cancer; computer-aided diagnosis; multi-parametric MRI; DCE; Ktrans ID MANAGEMENT; TRACER AB In computer-aided diagnosis (CAD) systems for prostate cancer, dynamic contrast enhanced (DCE) magnetic resonance imaging is useful for distinguishing cancerous and benign tissue. The Tofts physiological model is a commonly used representation of the DCE image data, but the parameters require extensive computation. Hence, we developed an alternative representation based on the Hilbert transform of the DCE images. The time maximum of the Hilbert transform, a binary metric of early enhancement, and a pre-DCE value was assigned to each voxel and appended to a standard feature set derived from T2-weighted images and apparent diffusion coefficient maps. A cohort of 40 patients was used for training the classifier, and 20 patients were used for testing. The AUC was calculated by pooling the voxel-wise prediction values and comparing with the ground truth. The resulting AUC of 0.92 (95% CI [0.87 0.97]) is not significantly different from an AUC calculated using Tofts physiological models of 0.92 (95% CI [0.87 0.97]), as validated by a Wilcoxon signed rank test on each patient's AUC (p = 0.19). The time required for calculation and feature extraction is 11.39 seconds (95% CI [10.95 11.82]) per patient using the Hilbert-based feature set, two orders of magnitude faster than the 1319 seconds (95% CI [1233 1404]) required for the Tofts parameter-based feature set (p<0.001). Hence, the features proposed herein appear useful for CAD systems integrated into clinical workflows where efficiency is important. C1 [Boehm, Kevin M.; Wang, Shijun; Burtt, Karen E.; Weisenthal, Samuel; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Turkbey, Baris; Pinto, Peter; Choyke, Peter] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Intervent Radiol Sect, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Petrick, Nicholas; Sahiner, Berkman] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Summers, RM (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci, Ctr Clin, Bldg 10 Room 1C224 MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov NR 13 TC 0 Z9 0 U1 1 U2 2 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-504-9 J9 PROC SPIE PY 2015 VL 9414 AR 94140S DI 10.1117/12.2082309 PG 8 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BD0US UT WOS:000357728600027 ER PT S AU He, X Samuelson, F Zeng, RP Sahiner, B AF He, Xin Samuelson, Frank Zeng, Rongping Sahiner, Berkman BE Hadjiiski, LM Tourassi, GD TI Potential Reasons for Differences in CAD Effectiveness Evaluated using Laboratory and Clinical Studies SO MEDICAL IMAGING 2015: COMPUTER-AIDED DIAGNOSIS SE Proceedings of SPIE LA English DT Proceedings Paper CT Computer-Aided Diagnosis (CAD) Conference at the SPIE Medical Imaging Symposium CY FEB 22-25, 2015 CL Orlando, FL SP SPIE, ALIO Ind, Alpin Med Syst, Modus Med Dev Inc, Bruker DE CAD; cueing; learning; Bayes update; prevalence effects; equivalent ideal observer ID COMPUTER-AIDED DETECTION; BREAST-CANCER DETECTION; SCREENING MAMMOGRAPHY; DETECTION SYSTEM; VISUAL-SEARCH; PERFORMANCE; SENSITIVITY; IMPACT; SPECIFICITY; PREVALENCE AB Research studies have investigated a number of factors that may impact the performance assessment of computer aided detection (CAD) effectiveness, such as the inherent design of the CAD, the image and reader samples, and the assessment methods. In this study, we focused on the effect of prevalence on cue validity (co-occurrence of cue and signal) and learning as potentially important factors in CAD assessment. For example, the prevalence of cases with breast cancer is around 50% in laboratory CAD studies, which is 100 times higher than that in breast cancer screening. Although ROC is prevalence-independent, an observer's use of CAD involves tasks that are more complicated than binary classification, including: search, detection, classification, cueing and learning. We developed models to investigate the potential impact of prevalence on cue validity and the learning of cue validity tasks. We hope this work motivates new studies that investigate previously under-explored factors involved in image interpretation with a new modality in its assessment. C1 [He, Xin; Samuelson, Frank; Zeng, Rongping; Sahiner, Berkman] US FDA, Rockville, MD 20857 USA. RP He, X (reprint author), US FDA, Rockville, MD 20857 USA. NR 39 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-504-9 J9 PROC SPIE PY 2015 VL 9414 AR 94141V DI 10.1117/12.2082811 PG 11 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BD0US UT WOS:000357728600065 ER PT S AU Li, Q Gavrielides, MA Zeng, RP Myers, KJ Sahiner, B Petrick, N AF Li, Qin Gavrielides, Marios A. Zeng, Rongping Myers, Kyle J. Sahiner, Berkman Petrick, Nicholas BE Hadjiiski, LM Tourassi, GD TI Factors affecting uncertainty in lung nodule volume estimation with CT: comparisons of findings from two estimation methods in a phantom study SO MEDICAL IMAGING 2015: COMPUTER-AIDED DIAGNOSIS SE Proceedings of SPIE LA English DT Proceedings Paper CT Computer-Aided Diagnosis (CAD) Conference at the SPIE Medical Imaging Symposium CY FEB 22-25, 2015 CL Orlando, FL SP SPIE, ALIO Ind, Alpin Med Syst, Modus Med Dev Inc, Bruker DE volume estimation; thoracic computed tomography; phantom study; segmentation; matched-filter; repeatability; reproducibility ID THORACIC CT AB This work aimed to compare two different types of volume estimation methods (a model-based and a segmentation-based method) in terms of identifying factors affecting measurement uncertainty. Twenty-nine synthetic nodules with varying size, radiodensity, and shape were placed in an anthropomorphic thoracic phantom and scanned with a 16-detector row CT scanner. Ten repeat scans were acquired using three exposures and two slice collimations, and were reconstructed with varying slice thicknesses. Nodule volumes were estimated from the reconstructed data using a matched-filter and a segmentation approach. Log transformed volumes were used to obtain measurement error with truth obtained through micro-CT. ANOVA and multiple linear regression were applied to measurement error to identify significant factors affecting volume estimation for each method. Root mean square of measurement errors (RMSE) for meaningful subgroups, repeatability coefficients (RC) for different imaging protocols, and reproducibility coefficients (RDC) for thin and thick collimation conditions were evaluated. Results showed that for both methods, nodule size, shape and slice thickness were significant factors. Collimation was significant for the matched-filter method. RMSEs for matched-filter measurements were in general smaller than segmentation. To achieve RMSE on the order of 15% or less for {5, 8, 9, 10mm} nodules, the corresponding maximum allowable slice thicknesses were {3, 5, 5, 5mm} for the matched-filter and {0.8, 3, 3, 3mm} for the segmentation method. RCs showed similar patterns for both methods, increasing with slice thickness. For 8-10mm nodules, the measurements were highly repeatable provided the slice thickness was <= 3mm, regardless of method and across varying acquisition conditions. RDCs were lower for thin collimation than thick collimation protocols. While RDC of matched filter volume estimation results was always lower than segmentation results, for 8-10mm nodules with thin collimation protocols, the measurements for both approaches were highly reproducible (RDC on the order of 15% or less). These findings are valuable for validating lung nodule volume as a quantitative imaging biomarker. C1 [Li, Qin; Gavrielides, Marios A.; Zeng, Rongping; Myers, Kyle J.; Sahiner, Berkman; Petrick, Nicholas] US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Li, Q (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM qin.li1@fda.hhs.gov NR 6 TC 2 Z9 2 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-504-9 J9 PROC SPIE PY 2015 VL 9414 AR 94140C DI 10.1117/12.2081489 PG 7 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BD0US UT WOS:000357728600011 ER PT S AU Pezeshk, A Sahiner, B Chen, WJ Petrick, N AF Pezeshk, Aria Sahiner, Berkman Chen, Weijie Petrick, Nicholas BE Hadjiiski, LM Tourassi, GD TI Improving CAD Performance by Seamless Insertion of Pulmonary Nodules in Chest CT Exams SO MEDICAL IMAGING 2015: COMPUTER-AIDED DIAGNOSIS SE Proceedings of SPIE LA English DT Proceedings Paper CT Computer-Aided Diagnosis (CAD) Conference at the SPIE Medical Imaging Symposium CY FEB 22-25, 2015 CL Orlando, FL SP SPIE, ALIO Ind, Alpin Med Syst, Modus Med Dev Inc, Bruker DE Computer aided diagnosis; Reference library creation; Lesion insertion; Chest CT; Poisson image editing ID LUNG NODULES; SAMPLE-SIZE; SIMULATION AB The availability of large medical image datasets is critical in training and testing of computer aided diagnosis (CAD) systems. However, collection of data and establishment of ground truth for medical images are both costly and difficult. To address this problem, we have developed an image composition tool that allows users to modify or supplement existing datasets by seamlessly inserting a clinical lesion extracted from a source image into a different location on a target image. In this study we focus on the application of this tool to the training of a CAD system designed to detect pulmonary nodules in chest CT. To compare the performance of a CAD system without and with the use of our image composition tool, we trained the system on two sets of data. The first training set was obtained from original CT cases, while the second set consisted of the first set plus nodules in the first set inserted into new locations. We then compared the performance of the two CAD systems in differentiating nodules from normal areas by testing each trained system against a fixed dataset containing natural nodules, and using the area under the ROC curve (AUC) as the figure of merit. The performance of the system trained with the augmented dataset was found to be significantly better than that trained with the original dataset under several training scenarios. C1 [Pezeshk, Aria; Sahiner, Berkman; Chen, Weijie; Petrick, Nicholas] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Pezeshk, A (reprint author), WO62-4110,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM aria.pezeshk@fda.hhs.gov NR 20 TC 0 Z9 0 U1 0 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-504-9 J9 PROC SPIE PY 2015 VL 9414 AR 94140A DI 10.1117/12.2082200 PG 6 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BD0US UT WOS:000357728600009 ER PT B AU Morales, JP Reidy, J AF Morales, Jose Pablo Reidy, John BE Sievert, H Qureshi, SA Wilson, N Hijazi, ZM TI Thoracic aortic aneurysms SO INTERVENTIONS IN STRUCTURAL, VALVULAR, AND CONGENITAL HEART DISEASE LA English DT Article; Book Chapter ID REPAIR; SURGERY; EXPERIENCE C1 [Morales, Jose Pablo] US FDA, Div Cardiovasc Devices, Silver Spring, MD 20993 USA. [Reidy, John] Guys Hosp, Dept Radiol, London SE1 9RT, England. RP Morales, JP (reprint author), US FDA, Div Cardiovasc Devices, Silver Spring, MD 20993 USA. NR 13 TC 0 Z9 0 U1 1 U2 1 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4822-1564-9; 978-1-4822-1563-2 PY 2015 BP 741 EP 744 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA BC7ZN UT WOS:000355441100090 ER PT J AU Brennan, JM Zhao, Y Williams, J O'Brien, S Dokholyan, R Gammie, J Edwards, F Loyo-Berrios, N Canos, D Gross, T Marinac-Dabic, D Peterson, E AF Brennan, J. Matthew Zhao, Yue Williams, Judson O'Brien, Sean Dokholyan, Rachel Gammie, James Edwards, Fred Loyo-Berrios, Nilsa Canos, Daniel Gross, Thomas Marinac-Dabic, Danica Peterson, Eric TI Long-Term Clinical Outcomes of Silzone Era St. Jude Medical Mechanical Heart Valves SO JOURNAL OF HEART VALVE DISEASE LA English DT Article ID CARDIAC-SURGERY DATABASE; REDUCTION TRIAL AVERT; PROPENSITY-SCORE; ENDOCARDITIS; RISK; SOCIETY; LINKING; LEAK AB Background and aim of the study: Since the voluntary recall of St. Jude Medical (SJM) Silzone impregnated heart valves, no large-scale study has examined their long-term outcomes. Methods: Using Medicare-linked records from the Society of Thoracic Surgeons Adult Cardiac Surgery Database (1993-2004), the clinical outcomes were evaluated through eight years among those patients who received SJM mechanical heart valves during the Silzone era (March 1998 to December 1999; n = 3,775), relative to those in both the pre-Silzone era (January 1993 to February 1998; n = 13,570) and the post-Silzone era (January 2000 to December 2004; n = 6,882). An inverse probability weighting was used to balance the observed differences in case mix. Results: During the Silzone era, 79% of all implanted mechanical heart valves were manufactured by SJM. By eight years post-implantation, the most common adverse events in this Medicare-linked cohort (median age 71 years) were death (43.5%) and thromboembolism (14.7%), while valve reoperation (1.7%) and endocarditis (1.4%) were less common. Patients treated during the Silzone era experienced a lower associated risk of mortality to eight years than those in both the pre-Silzone era (adjusted hazards ratio (HR) 0.93, 95% confidence interval (CI) 0.88-0.98) and post-Silzone era (adjusted HR 0.92, CI 0.67-0.98), while the adjusted eight-year risks of reoperation, thromboembolism and endocarditis were similar across the three eras for the overall cohort and among both aortic valve and mitral valve patients. Conclusion: Medicare patients who received SJM mechanical heart valves during the Silzone era experienced similar clinical outcomes as those treated before or after the Silzone era. These data do not substantiate continued public health concerns associated with Silzone era valve prostheses among older individuals. C1 [Brennan, J. Matthew; Zhao, Yue; Williams, Judson; O'Brien, Sean; Dokholyan, Rachel; Peterson, Eric] Duke Clin Res Inst, Durham, NC USA. [Gammie, James] Univ Maryland, Med Ctr, Div Cardiothorac Surg, Baltimore, MD 21201 USA. [Edwards, Fred] Univ Florida, Hlth Sci Ctr, Div Cardiothorac Surg, Jacksonville, FL 32209 USA. [Loyo-Berrios, Nilsa; Canos, Daniel; Gross, Thomas; Marinac-Dabic, Danica] US FDA, Rockville, MD 20857 USA. RP Brennan, JM (reprint author), Duke Univ, Med Ctr, Div Cardiol, 2400 Pratt St,Rm 0311 Terrace Level, Durham, NC 27705 USA. EM j.matthew.brennan@dm.duke.edu NR 18 TC 0 Z9 0 U1 0 U2 0 PU I C R PUBLISHERS PI NORTHWOOD PA CRISPIN HOUSE, 12/A SOUTH APPROACH, MOOR PARK, NORTHWOOD HA6 2ET, ENGLAND SN 0966-8519 J9 J HEART VALVE DIS JI J. Heart Valve Dis. PD JAN PY 2015 VL 24 IS 1 BP 66 EP 73 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CL4FV UT WOS:000356908900010 PM 26182622 ER PT J AU Yager, KG Forrey, C Singh, G Satija, SK Page, KA Patton, DL Douglas, JF Jones, RL Karim, A AF Yager, Kevin G. Forrey, Christopher Singh, Gurpreet Satija, Sushil K. Page, Kirt A. Patton, Derek L. Douglas, Jack F. Jones, Ronald L. Karim, Alamgir TI Thermally-induced transition of lamellae orientation in block-copolymer films on 'neutral' nanoparticle-coated substrates SO SOFT MATTER LA English DT Article ID SYMMETRIC DIBLOCK COPOLYMER; MOVING TEMPERATURE-GRADIENT; ORDER-DISORDER TRANSITION; SELECTIVELY ASSOCIATING HOMOPOLYMER; THIN-FILMS; PHASE-BEHAVIOR; CYLINDRICAL DOMAINS; PERPENDICULAR ORIENTATION; PATTERN-FORMATION; ELECTRIC-FIELD AB Block-copolymer orientation in thin films is controlled by the complex balance between interfacial free energies, including the inter-block segregation strength, the surface tensions of the blocks, and the relative substrate interactions. While block-copolymer lamellae orient horizontally when there is any preferential affinity of one block for the substrate, we recently described how nanoparticle-roughened substrates can be used to modify substrate interactions. We demonstrate how such 'neutral' substrates can be combined with control of annealing temperature to generate vertical lamellae orientations throughout a sample, at all thicknesses. We observe an orientational transition from vertical to horizontal lamellae upon heating, as confirmed using a combination of atomic force microscopy (AFM), neutron reflectometry (NR) and rotational small-angle neutron scattering (RSANS). Using molecular dynamics (MD) simulations, we identify substrate-localized distortions to the lamellar morphology as the physical basis of the novel behavior. In particular, under strong segregation conditions, bending of horizontal lamellae induce a large energetic cost. At higher temperatures, the energetic cost of conformal deformations of lamellae over the rough substrate is reduced, returning lamellae to the typical horizontal orientation. Thus, we find that both surface interactions and temperature play a crucial role in dictating block-copolymer lamellae orientation. Our combined experimental and simulation findings suggest that controlling substrate roughness should provide a useful and robust platform for controlling block-copolymer orientation in applications of these materials. C1 [Yager, Kevin G.] Brookhaven Natl Lab, Ctr Funct Nanomat, Upton, NY 11973 USA. [Forrey, Christopher] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Singh, Gurpreet; Karim, Alamgir] Univ Akron, Dept Polymer Engn, Akron, OH 44325 USA. [Satija, Sushil K.] NIST, Ctr Neutron Res, Gaithersburg, MD 20899 USA. [Page, Kirt A.; Douglas, Jack F.; Jones, Ronald L.] NIST, Div Polymers, Gaithersburg, MD 20899 USA. [Patton, Derek L.] Univ So Mississippi, Sch Polymers & High Performance Mat, Hattiesburg, MS 39406 USA. RP Yager, KG (reprint author), Brookhaven Natl Lab, Ctr Funct Nanomat, Upton, NY 11973 USA. EM kyager@bnl.gov; alamgir@uakron.edu RI Yager, Kevin/F-9804-2011 OI Yager, Kevin/0000-0001-7745-2513 FU U.S. Department of Energy, Office of Basic Energy Sciences [DE-AC02-98CH10886] FX Work carried out in part in the Center for Functional Nanomaterials, Brookhaven National Laboratory, which is supported by the U.S. Department of Energy, Office of Basic Energy Sciences, under Contract No. DE-AC02-98CH10886. We thank the Division of Electrical and Software Engineering (FDA) for use of the high performance computing facilities and the Division of Imaging and Applied Mathematics (FDA) for additional computational time. Acknowledgment by AK is made to the Donors of the American Chemical Society Petroleum Research Fund, New Directions (ACS-PRF ND) for partial support of this research. NR 85 TC 6 Z9 6 U1 5 U2 29 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1744-683X EI 1744-6848 J9 SOFT MATTER JI Soft Matter PY 2015 VL 11 IS 25 BP 5154 EP 5167 DI 10.1039/c5sm00896d PG 14 WC Chemistry, Physical; Materials Science, Multidisciplinary; Physics, Multidisciplinary; Polymer Science SC Chemistry; Materials Science; Physics; Polymer Science GA CK7EM UT WOS:000356394400020 PM 26053660 ER PT J AU Fang, JL Vanlandingham, MM Juliar, BE Olson, GR Patton, RE Beland, FA AF Fang, Jia-Long Vanlandingham, Michelle M. Juliar, Beth E. Olson, Greg R. Patton, Ralph E. Beland, Frederick A. TI Dose-response assessment of the dermal toxicity of triclosan in B6C3F1 mice SO TOXICOLOGY RESEARCH LA English DT Article ID PERSONAL CARE PRODUCTS; WASTE-WATER; AQUATIC ENVIRONMENT; NEONATAL THYROXINE; PERIPHERAL-BLOOD; SURFACE WATERS; IN-VITRO; EXPOSURE; RATS; TESTS AB Triclosan [5-chloro-2-(2,4-dichlorophenoxy) phenol] is a widely used antimicrobial agent in personal care products, household items, medical devices, and clinical settings. Due to its extensive use, there is potential for humans in all age groups to receive life-time exposures to triclosan, yet data on the chronic dermal toxicity/carcinogenicity of triclosan are still lacking. The present study evaluated the toxicity of triclosan administered dermally to B6C3F1 mice for 13 weeks. Groups of 10 male and 10 female B6C3F1 mice received dermal applications of 0, 5.8, 12.5, 27, 58, or 125 mg triclosan per kg body weight (bw) daily for 13 weeks. The doses were administered in 1 ml ethanol per kg bw. All mice survived the 13-week treatment period. Body weights of female mice receiving 125 mg triclosan per kg bw per day weighed 94% (p < 0.05) of the female control mice; male mice administered 58 and 125 mg triclosan per kg bw per day weighed 91% (p < 0.05) and 82% (p < 0.01) of the control male mice. Liver weights were significantly increased in females receiving 58 and 125 mg triclosan per kg bw per day and in males in the 125 mg triclosan per kg bw per day dose group. A significant dose-dependent decrease in the levels of thyroxine and cholesterol was observed in both sexes. The highest dose of triclosan increased the percentage of reticulocytes in both sexes; in addition, the 58 mg triclosan per kg bw per day dose increased the percentage of reticulocytes in females. Skin lesions (dermal fibrosis and inflammation; epidermal hyperplasia, inflammation, necrosis, and ulceration, and parakeratosis) were observed in both sexes, with a dose-dependent increase in severity and incidence. C1 [Fang, Jia-Long; Vanlandingham, Michelle M.; Beland, Frederick A.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Juliar, Beth E.] Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Olson, Greg R.] Toxicol Pathol Associates Inc, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Fang, JL (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM jia-long.fang@fda.hhs.gov FU National Toxicology Program, National Institute of Environmental Health Sciences [224-12-0003]; U.S. Food and Drug Administration, National Center for Toxicological Research FX We are indebted to Wafa A. Harrouk, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, for excellent advices during the course of this study. We thank James Carson, Andy Matson, and Mark Moore for providing dose formulations, animal diets, and animal care; Matthew Bryant, Goncalo Gamboa da Costa, and Mani Chidambaram for assessing the identity and purity of the triclosan and vehicle as well as conducting dose stability and certification analyses; Mason G. Pearce for helping peripheral blood micronucleus analyses. This work was supported by an Interagency Agreement (224-12-0003) between the National Toxicology Program, National Institute of Environmental Health Sciences, and the U.S. Food and Drug Administration, National Center for Toxicological Research. The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration. NR 51 TC 2 Z9 2 U1 4 U2 16 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. PY 2015 VL 4 IS 4 BP 867 EP 877 DI 10.1039/c4tx00152d PG 11 WC Toxicology SC Toxicology GA CL0EL UT WOS:000356612300008 ER PT S AU Ghammraoui, B Popescu, LM Badal, A AF Ghammraoui, B. Popescu, L. M. Badal, A. BE Hoeschen, C Kontos, D TI Monte Carlo Evaluation of the Relationship between Absorbed Dose and Contrast-to-Noise Ratio in Coherent Scatter Breast CT SO MEDICAL IMAGING 2015: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 22-25, 2015 CL Orlando, FL SP SPIE, ALIO Ind, Alpin Med Syst, Modus Med Devices Inc, Bruker, Carestream Health Inc, GE Healthcare, American Assoc Physicists Med, American Physiolog Soc, Comp Assisted Radiol & Surg, Med Image Percept Soc, Radiolog Soc N America, Soc Imaging Informat Med, World Mol Imaging Soc, DICOM Stand Comm DE Coherent-scatter; X-ray scattering; Monte Carlo simulation; Breast cancer; Energy Dispersive X-Ray Diffraction ID X-RAY-SCATTERING; COMPUTED-TOMOGRAPHY; TISSUES AB Purpose: The objective of this work was to evaluate the advantages and shortcomings associated with Coherent Scatter Computed Tomography (CSCT) systems for breast imaging and study possible alternative configurations. The relationship between dose in a breast phantom and a simple surrogate of image quality in pencil-beam and fan-beam CSCT geometries was evaluated via Monte Carlo simulation, and an improved pencil-beam setup was proposed for faster CSCT data acquisition. Methods: CSCT projection datasets of a simple breast phantom have been simulated using a new version of the MC-GPU code that includes an improved model of x-ray coherent scattering using experimentally measured molecular interference functions. The breast phantom was composed of an 8 cm diameter cylinder of 50/50 glandular/adipose material and nine rods with different diameters of cancerous, adipose and glandular tissues. The system performance has been assessed in terms of the contrast-to-noise ratio (CNR) in multiple regions of interest within the reconstructed images, for a range of exposure levels. The enhanced pencil-beam setup consisted of multiplexed pencil beams and specific postprocessing of the projection data to calculate the scatter intensity coming from each beam separately. Results: At reconstruction spatial resolution of 1 x 1 x 1 mm(3) and from 1 to 10 mGy of received breast dose, fan-beam geometry showed higher statistical noise and lower CNR than pencil-beam geometry. Conventional CT acquisition had the highest CNR per dose. However, the CNR figure of merit did not combine yet all the information available at different scattering angles in the CSCT, which has potential for increased discrimination of materials with similar attenuation properties. Preliminary evaluation of the multiplexed pencil-beam geometry showed that the scattering profiles simulated with the new approach are similar to those of the single pencil-beam geometry. Conclusion: It has been shown that the GPU-accelerated MC-GPU code is a practical tool to simulate complete CSCT scans with different acquisition geometries and exposure levels. The simulation showed better performance in terms of the received dose and CNR with pencil-beam geometry in comparison to the fan-beam geometry. Finally, we demonstrated that the proposed multiplexed-beam geometry might be useful for faster acquisition of CSCT while providing comparable image quality as the pencil-beam geometry. C1 [Ghammraoui, B.; Popescu, L. M.; Badal, A.] US FDA, OSEL, Div Imaging Diagnost & Software Reliabil, Silver Spring, MD 20993 USA. RP Ghammraoui, B (reprint author), US FDA, OSEL, Div Imaging Diagnost & Software Reliabil, Silver Spring, MD 20993 USA. EM bahaa.ghammraoui@fda.hhs.gov NR 10 TC 0 Z9 0 U1 4 U2 4 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-502-5 J9 PROC SPIE PY 2015 VL 9412 AR 94121G DI 10.1117/12.2082696 PG 7 WC Optics; Physics, Applied; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BC8EX UT WOS:000355581700048 ER PT S AU Makeev, A Rodrigues, M Wang, GC Glick, SJ AF Makeev, Andrey Rodrigues, Miesher Wang, Gin-Chung Glick, Stephen J. BE Hoeschen, C Kontos, D TI Modeling CZT/CdTe X-ray Photon-Counting Detectors SO MEDICAL IMAGING 2015: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 22-25, 2015 CL Orlando, FL SP SPIE, ALIO Ind, Alpin Med Syst, Modus Med Devices Inc, Bruker, Carestream Health Inc, GE Healthcare, American Assoc Physicists Med, American Physiolog Soc, Comp Assisted Radiol & Surg, Med Image Percept Soc, Radiolog Soc N America, Soc Imaging Informat Med, World Mol Imaging Soc, DICOM Stand Comm DE semiconductor detector modeling; Monte Carlo; charge induction efficiency; photon counting ID SEMICONDUCTOR RADIATION DETECTORS; CHARGE-TRANSPORT AB Software for modeling x-ray signals, as detected by a semiconductor radiation detector has been developed. We model a generic signal generation/collection/processing sequence using Monte Carlo and finite element analysis software. The suggested framework will allow one to simulate x-ray pulse-height spectrum, various triggering schemes, and can be used for detector optimization. C1 [Makeev, Andrey; Glick, Stephen J.] US FDA, Silver Spring, MD 20993 USA. [Rodrigues, Miesher; Wang, Gin-Chung] Toshiba Med Res Inst USA Inc, Vernon Hills, IL 60061 USA. RP Glick, SJ (reprint author), US FDA, Silver Spring, MD 20993 USA. EM Andrey.Makeev@fda.hhs.gov; Stephen.Glick@fda.hhs.gov NR 8 TC 0 Z9 0 U1 0 U2 4 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-502-5 J9 PROC SPIE PY 2015 VL 9412 AR 94124V DI 10.1117/12.2082039 PG 9 WC Optics; Physics, Applied; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BC8EX UT WOS:000355581700158 ER PT S AU Wang, QZ Castro, K Desai, VN Cheng, WC Pfefer, J AF Wang, Quanzeng Castro, Kurt Desai, Viraj N. Cheng, Wei-Chung Pfefer, Joshua BE Hoeschen, C Kontos, D TI Comparison of Methods for Quantitative Evaluation of Endoscopic Distortion SO MEDICAL IMAGING 2015: PHYSICS OF MEDICAL IMAGING SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Physics of Medical Imaging CY FEB 22-25, 2015 CL Orlando, FL SP SPIE, ALIO Ind, Alpin Med Syst, Modus Med Devices Inc, Bruker, Carestream Health Inc, GE Healthcare, American Assoc Physicists Med, American Physiolog Soc, Comp Assisted Radiol & Surg, Med Image Percept Soc, Radiolog Soc N America, Soc Imaging Informat Med, World Mol Imaging Soc, DICOM Stand Comm DE endoscope; optical performance; local magnification; radial distortion; optical imaging; standardization AB Endoscopy is a well-established paradigm in medical imaging, and emerging endoscopic technologies such as high resolution, capsule and disposable endoscopes promise significant improvements in effectiveness, as well as patient safety and acceptance of endoscopy. However, the field lacks practical standardized test methods to evaluate key optical performance characteristics (OPCs), in particular the geometric distortion caused by fisheye lens effects in clinical endoscopic systems. As a result, it has been difficult to evaluate an endoscope's image quality or assess its changes over time. The goal of this work was to identify optimal techniques for objective, quantitative characterization of distortion that are effective and not burdensome. Specifically, distortion measurements from a commercially available distortion evaluation/ correction software package were compared with a custom algorithm based on a local magnification (ML) approach. Measurements were performed using a clinical gastroscope to image square grid targets. Recorded images were analyzed with the ML approach and the commercial software where the results were used to obtain corrected images. Corrected images based on the ML approach and the software were compared. The study showed that the ML method could assess distortion patterns more accurately than the commercial software. Overall, the development of standardized test methods for characterizing distortion and other OPCs will facilitate development, clinical translation, manufacturing quality and assurance of performance during clinical use of endoscopic technologies. C1 [Wang, Quanzeng; Castro, Kurt; Desai, Viraj N.; Cheng, Wei-Chung; Pfefer, Joshua] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Castro, Kurt] George Washington Univ, Washington, DC 20052 USA. [Desai, Viraj N.] Univ Maryland, College Pk, MD 20740 USA. RP Wang, QZ (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM Quanzeng.Wang@fda.hhs.gov NR 8 TC 0 Z9 0 U1 0 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-502-5 J9 PROC SPIE PY 2015 VL 9412 AR 94123A DI 10.1117/12.2082077 PG 7 WC Optics; Physics, Applied; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BC8EX UT WOS:000355581700107 ER PT J AU Hammond, M Cleveland, JN O'Neill, JW Stawski, RS Tate, AJ AF Hammond, Michelle Cleveland, Jeanette N. O'Neill, John W. Stawski, Robert S. Tate, April Jones TI Mediators of transformational leadership and the work-family relationship SO JOURNAL OF MANAGERIAL PSYCHOLOGY LA English DT Article DE Transformational leadership; Resources; Work-family enrichment; Work-family conflict ID JOB CHARACTERISTICS; ORGANIZATIONAL COMMITMENT; POSITIVE EMOTIONS; FIELD EXPERIMENT; CONFLICT; ENRICHMENT; SUPERVISOR; RESOURCES; IMPACT; CONSEQUENCES AB Purpose - The purpose of this paper is to examine the ways in which leaders influence follower's work-life management. Specifically, the authors propose that personal (positive affect), social (managerial support for work-family balance), and job (autonomy) resources mediate the relationships between transformational leadership and work-family conflict (WFC) and enrichment. Design/methodology/approach - The sample included 411 managers in 37 hotel properties across the USA. Findings - The relationship between TL and WFC was mediated by autonomy, positive affect and managerial support for work-family balance, whereas the relationship between TL and WFE was mediated by managerial support for work-family balance and positive affect. Research limitations/implications - This study constructs a foundation for future integration of leadership and work and family literatures. It also provides preliminary support for work-family enrichment theory (Greenhaus and Powell, 2006), as well as the value of examining leadership through a resource-based perspective. Practical implications - Interventions designed to enhance leadership may be effective not only in the workplace, but also for reducing WFC and promoting enrichment. Originality/value - This study is the first to directly examine the effect of transformational leadership and both WFC and enrichment. Further, it specifies mediating variables that underlie these relationships. C1 [Hammond, Michelle] Univ Limerick, Kemmy Business Sch, Org Behav, Limerick, Ireland. [Cleveland, Jeanette N.] Colorado State Univ, Dept Psychol, Doctoral Program Ind & Org Psychol, Ft Collins, CO 80523 USA. [O'Neill, John W.] Penn State Univ, Sch Hospitality Management, University Pk, PA 16802 USA. [Stawski, Robert S.] Oregon State Univ, Coll Publ Hlth & Human Sci, Corvallis, OR 97331 USA. [Tate, April Jones] US FDA, Dept Human Capital, Ctr Vet Med, Rockville, MD 20857 USA. RP Hammond, M (reprint author), Univ Limerick, Kemmy Business Sch, Org Behav, Limerick, Ireland. EM Michelle.Hammond@ul.ie RI Hammond, Michelle/F-5631-2014 OI Hammond, Michelle/0000-0003-1011-9155 FU National Institutes of Health; Centers for Disease Control and Prevention: National Institute of Child Health and Human Development [U01HD051217, U01HD051218, U01HD051256, U01HD051276]; National Institute on Aging [U01AG027669]; Office of Behavioral and Science Sciences Research; National Institute for Occupational Safety and Health [U010H008788]; Alfred P. Sloan Foundation FX This research was conducted as part of the Work, Family and Health Network, which is funded by a cooperative agreement through the National Institutes of Health and the Centers for Disease Control and Prevention: National Institute of Child Health and Human Development (Grant No. U01HD051217, U01HD051218, U01HD051256, U01HD051276), National Institute on Aging (Grant No. U01AG027669), Office of Behavioral and Science Sciences Research, and National Institute for Occupational Safety and Health (Grant No. U010H008788). We would like to thank the Alfred P. Sloan Foundation (2004-12-4) for providing support for this research. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of these institutes and offices. Special acknowledgement goes to Extramural Staff Science Collaborator, Rosalind Berkowitz King, PhD (NICHD) and Lynne Casper, PhD (University of Southern California) for design of the original Workplace, Family, Health and Well-Being Network Initiative. Persons interested in learning more about the Network should go to www.kpchr.org/workplacenetwork NR 64 TC 3 Z9 3 U1 6 U2 25 PU EMERALD GROUP PUBLISHING LIMITED PI BINGLEY PA HOWARD HOUSE, WAGON LANE, BINGLEY BD16 1WA, W YORKSHIRE, ENGLAND SN 0268-3946 EI 1758-7778 J9 J MANAGE PSYCHOL JI J. Manage. Psychol. PY 2015 VL 30 IS 4 BP 454 EP 469 DI 10.1108/JMP-10-2011-0090 PG 16 WC Psychology, Applied; Management SC Psychology; Business & Economics GA CK0VJ UT WOS:000355923000006 ER PT J AU Saeed, LM Mahmood, M Xu, Y Nima, ZA Kannarpady, GK Bratton, SM Dervishi, E Casciano, D Ali, S Crooks, PA Radominska-Pandya, A Biris, AS AF Saeed, L. M. Mahmood, M. Xu, Y. Nima, Z. A. Kannarpady, G. K. Bratton, S. M. Dervishi, E. Casciano, D. Ali, S. Crooks, P. A. Radominska-Pandya, A. Biris, A. S. TI Nanodelivery of gambogic acid by functionalized graphene enhances inhibition of cell proliferation and induces G(0)/G(1) cell cycle arrest in cervical, ovarian, and prostate cancer cells SO RSC ADVANCES LA English DT Article ID CARBON NANOTUBES; DRUG-DELIVERY; MAGNETIC NANOPARTICLES; CARCINOMA CELLS; LEUKEMIA-CELLS; APOPTOSIS; CYTOTOXICITY; BREAST; OXIDE; FE3O4 AB Functionalized graphene (fGn) has been used to deliver the low toxicity plant product, gambogic acid (GA), to cervical, ovarian, and prostate cancer cells, and the relative cytotoxicity of this complex when compared to delivery of drug alone has been evaluated. In this study, we analyzed the characteristics of the GA + fGn complex, including pH-sensitive release of the drug from the nanomaterial. We then compared the in vitro effects of GA and GA + fGn on the growth inhibition and apoptosis in the above three cancer cell types. We found that GA, when delivered as a GA/fGn complex was more effective at inhibiting cell proliferation, initiating cell cycle arrest and inducing apoptosis in HeLa, NCI/ADR-RES, and PC-3 cancer cell lines compared to delivery of drug alone. Overall, our results indicate that this novel GA/fGn nanocomplex has the ability to inhibit proliferation and induce apoptosis in several different organ-derived cancer cells, and could have potential as a new drug delivery strategy in cancer chemotherapy. C1 [Saeed, L. M.; Mahmood, M.; Xu, Y.; Nima, Z. A.; Kannarpady, G. K.; Dervishi, E.; Casciano, D.; Biris, A. S.] Univ Arkansas, Ctr Integrat Nanotechnol Sci, Little Rock, AR 72204 USA. [Bratton, S. M.; Radominska-Pandya, A.] Univ Arkansas Med Sci, Coll Med, Dept Biochem & Mol Biol, Little Rock, AR 72205 USA. [Ali, S.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Crooks, P. A.] Univ Arkansas Med Sci, Coll Pharm, Dept Pharmaceut Sci, Little Rock, AR 72205 USA. RP Biris, AS (reprint author), Univ Arkansas, Ctr Integrat Nanotechnol Sci, Little Rock, AR 72204 USA. EM radominskaanna@uams.edu; asbiris@ualr.edu FU DOD TATRC FX The financial support of DOD TATRC is highly appreciated. We acknowledge the Arkansas Research Alliance Memorandum of Understanding with the Food and Drug Administration (FDA) with the focus on graphene science. The editorial assistance of Dr Marinelle Ringer is also acknowledged. NR 57 TC 1 Z9 1 U1 7 U2 23 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2046-2069 J9 RSC ADV JI RSC Adv. PY 2015 VL 5 IS 55 BP 44022 EP 44030 DI 10.1039/c5ra00833f PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA CI7SM UT WOS:000354964900015 ER PT S AU Abbey, CK Samuelson, FW Wunderlich, A Popescu, LM Eckstein, MP Boone, JM AF Abbey, Craig K. Samuelson, Frank W. Wunderlich, Adam Popescu, Lucretiu M. Eckstein, Miguel P. Boone, John M. BE MelloThoms, CR Kupinski, MA TI Approximate Maximum Likelihood Estimation of Scanning Observer Templates SO MEDICAL IMAGING 2015: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY FEB 25-26, 2015 CL Orlando, FL SP SPIE, Alpin Med Syst, Modus Med Devices Inc, Bruker, ALIO Ind DE Scanning linear template; search models; localization task; ramp-spectrum noise; and observer modeling ID FORCED-CHOICE EXPERIMENTS; CLASSIFICATION IMAGE-ANALYSIS; SEARCH; LROC; NOISE; MODEL AB In localization tasks, an observer is asked to give the location of some target or feature of interest in an image. Scanning linear observer models incorporate the search implicit in this task through convolution of an observer template with the image being evaluated. Such models are becoming increasingly popular as predictors of human performance for validating medical imaging methodology. In addition to convolution, scanning models may utilize internal noise components to model inconsistencies in human observer responses. In this work, we build a probabilistic mathematical model of this process and show how it can, in principle, be used to obtain estimates of the observer template using maximum likelihood methods. The main difficulty of this approach is that a closed form probability distribution for a maximal location response is not generally available in the presence of internal noise. However, for a given image we can generate an empirical distribution of maximal locations using Monte-Carlo sampling. We show that this probability is well approximated by applying an exponential function to the scanning template output. We also evaluate log-likelihood functions on the basis of this approximate distribution. Using 1,000 trials of simulated data as a validation test set, we find that a plot of the approximate log-likelihood function along a single parameter related to the template profile achieves its maximum value near the true value used in the simulation. This finding holds regardless of whether the trials are correctly localized or not. In a second validation study evaluating a parameter related to the relative magnitude of internal noise, only the incorrect localization images produces a maximum in the approximate log-likelihood function that is near the true value of the parameter. C1 [Abbey, Craig K.; Eckstein, Miguel P.] UC Santa Barbara, Dept Psychol & Brain Sci, Santa Barbara, CA 93106 USA. [Samuelson, Frank W.; Wunderlich, Adam; Popescu, Lucretiu M.] US FDA, CDRH, OSEL, Div Imaging & Appl Math, Silver Spring, MD 20993 USA. [Boone, John M.] UC Davis Med Ctr, Dept Radiol, Sacramento, CA USA. RP Abbey, CK (reprint author), UC Santa Barbara, Dept Psychol & Brain Sci, Santa Barbara, CA 93106 USA. NR 22 TC 0 Z9 0 U1 3 U2 3 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-506-3 J9 PROC SPIE PY 2015 VL 9416 AR 94160O DI 10.1117/12.2082874 PG 9 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BC6OS UT WOS:000354266600020 ER PT S AU Chen, WJ Sahiner, B Samuelson, F Pezeshk, A Petrick, N AF Chen, Weijie Sahiner, Berkman Samuelson, Frank Pezeshk, Aria Petrick, Nicholas BE MelloThoms, CR Kupinski, MA TI Investigation of Methods for Calibration of Classifier Scores to Probability of Disease SO MEDICAL IMAGING 2015: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY FEB 25-26, 2015 CL Orlando, FL SP SPIE, Alpin Med Syst, Modus Med Devices Inc, Bruker, ALIO Ind DE classifier evaluation; scale transformation; likelihood ratio; pool-adjacent-violators algorithm AB Classifier scores in many diagnostic devices, such as computer-aided diagnosis systems, are usually on an arbitrary scale, the meaning of which is unclear. Calibration of classifier scores to a meaningful scale such as the probability of disease is potentially useful when such scores are used by a physician or another algorithm. In this work, we investigated the properties of two methods for calibrating classifier scores to probability of disease. The first is a semiparametric method in which the likelihood ratio for each score is estimated based on a semiparametric proper receiver operating characteristic model, and then an estimate of the probability of disease is obtained using the Bayes theorem assuming a known prevalence of disease. The second method is nonparametric in which isotonic regression via the pool-adjacent-violators algorithm is used. We employed the mean square error (MSE) and the Brier score to evaluate the two methods. We evaluate the methods under two paradigms: (a) the dataset used to construct the score-to-probability mapping function is used to calculate the performance metric (MSE or Brier score) (resubstitution); (b) an independent test dataset is used to calculate the performance metric (independent). Under our simulation conditions, the semiparametric method is found to be superior to the nonparametric method at small to medium sample sizes and the two methods appear to converge at large sample sizes. Our simulation results also indicate that the resubstitutionbias may depend on the performance metric and for the semiparametricmethod, the resubstitutionbias is small when a reasonable number of cases (>100 cases per class) are available. C1 [Chen, Weijie; Sahiner, Berkman; Samuelson, Frank; Pezeshk, Aria; Petrick, Nicholas] US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Chen, WJ (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM weijie.chen@fda.hhs.gov NR 11 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-506-3 J9 PROC SPIE PY 2015 VL 9416 AR 94161E DI 10.1117/12.2082142 PG 8 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BC6OS UT WOS:000354266600044 ER PT S AU He, X Samuelson, F Zeng, RP Sahiner, B AF He, Xin Samuelson, Frank Zeng, Rongping Sahiner, Berkman BE MelloThoms, CR Kupinski, MA TI Prevalence Learning and Decision Making in a Visual Search Task: An equivalent ideal observer approach SO MEDICAL IMAGING 2015: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY FEB 25-26, 2015 CL Orlando, FL SP SPIE, Alpin Med Syst, Modus Med Devices Inc, Bruker, ALIO Ind DE prevalence effects; visual search; equivalent ideal observer ID READER VARIABILITY; SIGNAL-DETECTION; RARE TARGETS; MAMMOGRAPHY AB Research studies have observed an influence of target prevalence on observer performance for visual search tasks. The goal of this work is to develop models for prevalence effects on visual search. In a recent study by Wolfe et. al, a large scale observer study was conducted to understand the effects of varying target prevalence on visual search. Particularly, a total of 12 observers were recruited to perform 1000 trials of simulated baggage search as target prevalence varied sinusoidally from high to low and back to high. We attempted to model observers' behavior in prevalence learning and decision making. We modeled the observer as an equivalent ideal observer (EIO) with a prior belief of the signal prevalence. The use of EIO allows the application of ideal observer mathematics to characterize real observers' performance reading real-life images. For every given new image, the observer updates the belief on prevalence and adjusts his/her decision threshold according to utility theory. The model results agree well with the experimental results from the Wolfe study. The proposed models allow theoretical insights into observer behavior in learning prevalence and adjusting their decision threshold. C1 [He, Xin; Samuelson, Frank; Zeng, Rongping; Sahiner, Berkman] US FDA, Rockville, MD 20857 USA. RP He, X (reprint author), US FDA, Rockville, MD 20857 USA. NR 23 TC 0 Z9 0 U1 0 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-506-3 J9 PROC SPIE PY 2015 VL 9416 AR 94160Q DI 10.1117/12.2082800 PG 8 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BC6OS UT WOS:000354266600022 ER PT S AU Pezeshk, A Popescu, LM Sahiner, B AF Pezeshk, Aria Popescu, Lucretiu M. Sahiner, Berkman BE MelloThoms, CR Kupinski, MA TI CT image quality evaluation for detection of signals with unknown location, size, contrast and shape using unsupervised methods SO MEDICAL IMAGING 2015: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY FEB 25-26, 2015 CL Orlando, FL SP SPIE, Alpin Med Syst, Modus Med Devices Inc, Bruker, ALIO Ind DE Image Quality Assessment; Saliency Detection ID DESCRIPTOR; MODEL AB The advent of new image reconstruction and image processing techniques for CT images has increased the need for robust objective image quality assessment methods. One of the most common quality assessment methods is the measurement of signal detect ability for a known signal at a known location using supervised classification techniques. However, this method requires a large number of simulations or physical measurements, and its underlying assumptions may be considered clinically unrealistic. In this study we focus on objective assessment of image quality in terms of detection of a signal with unknown location, size, shape, and contrast. We explore several unsupervised saliency detection methods which assume no knowledge about the signal, along with a template matching technique which uses information about the signal's size and shape in the object domain, for simulated phantoms that have been reconstructed using filtered back projection (FBP) and iterative reconstruction algorithms (IRA). The performance of each of the image reconstruction algorithms is then measured using the area under the localization receiver operating characteristic curve (LROC) and exponential transformation of the free response operating characteristic curve (EFROC). Our results indicate that unsupervised saliency detection methods can be effectively used to determine image quality in terms of signal detectability for unknown signals given only a small number of sample images. C1 [Pezeshk, Aria; Popescu, Lucretiu M.; Sahiner, Berkman] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Pezeshk, A (reprint author), WO62-4110,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM aria.pezeshk@fda.hhs.gov NR 14 TC 1 Z9 1 U1 0 U2 4 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-506-3 J9 PROC SPIE PY 2015 VL 9416 AR 94160J DI 10.1117/12.2082254 PG 7 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BC6OS UT WOS:000354266600016 ER PT S AU Sahiner, B Chen, WJ Pezeshk, A Petrick, N AF Sahiner, Berkman Chen, Weijie Pezeshk, Aria Petrick, Nicholas BE MelloThoms, CR Kupinski, MA TI Comparison of Two Stand-alone CADe Systems at Multiple Operating Points SO MEDICAL IMAGING 2015: IMAGE PERCEPTION, OBSERVER PERFORMANCE, AND TECHNOLOGY ASSESSMENT SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Image Perception, Observer Performance, and Technology Assessment CY FEB 25-26, 2015 CL Orlando, FL SP SPIE, Alpin Med Syst, Modus Med Devices Inc, Bruker, ALIO Ind DE Multiple hypothesis testing; computer-aided detection; familywise error rate; power AB Computer-aided detection (CADe) systems are typically designed to work at a given operating point: The device displays a mark if and only if the level of suspiciousness of a region of interest is above a fixed threshold. To compare the standalone performances of two systems, one approach is to select the parameters of the systems to yield a target false-positive rate that defines the operating point, and to compare the sensitivities at that operating point. Increasingly, CADe developers offer multiple operating points, which necessitates the comparison of two CADe systems involving multiple comparisons. To control the Type I error, multiple-comparison correction is needed for keeping the familywise error rate (FWER) less than a given alpha-level. The sensitivities of a single modality at different operating points are correlated. In addition, the sensitivities of the two modalities at the same or different operating points are also likely to be correlated. It has been shown in the literature that when test statistics are correlated, well-known methods for controlling the FWER are conservative. In this study, we compared the FWER and power of three methods, namely the Bonferroni, step-up, and adjusted step-up methods in comparing the sensitivities of two CADe systems at multiple operating points, where the adjusted step-up method uses the estimated correlations. Our results indicate that the adjusted step-up method has a substantial advantage over other the two methods both in terms of the FWER and power. C1 [Sahiner, Berkman; Chen, Weijie; Pezeshk, Aria; Petrick, Nicholas] US FDA, CDRH, Silver Spring, MD 20993 USA. RP Sahiner, B (reprint author), US FDA, CDRH, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Berkman.sahiner@fda.hhs.gov NR 6 TC 0 Z9 0 U1 0 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-506-3 J9 PROC SPIE PY 2015 VL 9416 AR 941612 DI 10.1117/12.2082123 PG 6 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BC6OS UT WOS:000354266600033 ER PT S AU Vogt, WC Jia, CX Wear, KA Garra, BS Pfefer, J AF Vogt, William C. Jia, Congxian Wear, Keith A. Garra, Brian S. Pfefer, Joshua BE Oraevsky, AA Wang, LV TI Quantitative Assessment of Photoacoustic Tomography Systems Integrating Clinical Ultrasound Transducers Using Novel Tissue-Simulating Phantoms SO PHOTONS PLUS ULTRASOUND: IMAGING AND SENSING 2015 SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Photons Plus Ultrasound - Imaging and Sensing CY FEB 08-10, 2015 CL San Francisco, CA SP SPIE, Seno Med Instruments Inc DE optoacoustics; image quality; plastisol; system evaluation ID LABORATORY PROTOTYPE; MIMICKING PHANTOMS; OPTICAL-PROPERTIES; BREAST; MAMMOGRAPHY; RESOLUTION AB Photoacoustic Tomography (PAT) systems based on commercial ultrasound instruments have the benefit of dualmodality imaging, which increases their appeal from a clinical standpoint. However, factors that influence PAT system performance have not been thoroughly investigated and standardized test methods have not been established for image quality evaluation. To address these issues we have adapted phantom-based approaches from ultrasound imaging standards and implemented them to assess a PAT system developed for vascular imaging. Our system comprises a tunable near-infrared pulsed laser and a commercial ultrasound imaging system, including four interchangeable linear array clinical ultrasound transducers with varying center frequencies, acoustic bandwidths and geometries. Phantoms consisted of a customized polyvinyl chloride (PVC) plastisol gel that simulates both optical and acoustic properties of breast tissue. One phantom incorporates a sub-resolution filament array suitable for bimodal ultrasound-photoacoustic imaging, while another contains an array of hemoglobin-filled cylindrical inclusions at various depths. Key performance characteristics were evaluated, including spatial resolution, signal uniformity, contrast, and penetration depth. These characteristics were evaluated at 750 nm at radiant exposures below ANSI safety limits. Effects of transducer properties on imaging performance were evaluated. Axial and lateral resolution ranged from 0.27-0.83 mm and 0.28-1.8 mm, respectively, and penetration depths from 1.9-4.2 cm were achieved. These results demonstrate variation in PAT system performance based on clinical transducer selection, as well as the utility of realistic phantom-based test methods in performing benchtop evaluations of system performance. C1 [Vogt, William C.; Jia, Congxian; Wear, Keith A.; Garra, Brian S.; Pfefer, Joshua] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Vogt, WC (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. NR 38 TC 2 Z9 2 U1 3 U2 5 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-413-4 J9 PROC SPIE PY 2015 VL 9323 AR 932333 DI 10.1117/12.2080283 PG 11 WC Optics; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BC6WE UT WOS:000354517500072 ER PT S AU Gavrielidesi, MA Ronnett, BM Vang, R Seidman, JD AF Gavrielidesi, Marios A. Ronnett, Brigitte M. Vang, Russell Seidman, Jeffrey D. BE Gurcan, MN Madabhushi, A TI Inter-observer variability in the classification of ovarian cancer cell type using microscopy: a pilot study SO MEDICAL IMAGING 2015: DIGITAL PATHOLOGY SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Digital Pathology CY FEB 25-26, 2015 CL Orlando, FL SP SPIE, ALIO Ind, Alpin Med Syst, Modus Med Devices Inc, Bruker DE ovarian cancer; cell type; diagnosis; observer variability; agreement; microscopy; pathology ID CARCINOMA; PATHOLOGY AB Studies have shown that different cell types of ovarian carcinoma have different molecular profiles, exhibit different behavior, and that patients could benefit from type-specific treatment. Different cell types display different histopathology features, and different criteria are used for each cell type classification. Inter-observer variability for the task of classifying ovarian cancer cell types is an under-examined area of research. This study served as a pilot study to quantify observer variability related to the classification of ovarian cancer cell types and to extract valuable data for designing a validation study of digital pathology (DP) for this task. Three observers with expertise in gynecologic pathology reviewed 114 cases of ovarian cancer with optical microscopy, with specific guidelines for classifications into distinct cell types. For 93 cases all 3 pathologists agreed on the same cell type, for 18 cases 2 out of 3 agreed, and for 3 cases there was no agreement. Across cell types with a minimum sample size of 10 cases, agreement between all three observers was {91.1%, 80.0%, 90.0%, 78.6%, 100.0%, 61.5%} for the high grade serous carcinoma, low grade serous carcinoma, endometrioid, mucinous, clear cell, and carcinosarcoma cell types respectively. These results indicate that unanimous agreement varied over a fairly wide range. However, additional research is needed to determine the importance of these differences in comparison studies. These results will be used to aid in the design and sizing of such a study comparing optical and digital pathology. In addition, the results will help in understanding the potential role computer-aided diagnosis has in helping to improve the agreement of pathologists for this task. C1 [Gavrielidesi, Marios A.] US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Ronnett, Brigitte M.; Vang, Russell] Johns Hopkins Univ Hosp, Dept Pathol, Div Gynecol Pathol, Baltimore, MD 21287 USA. [Seidman, Jeffrey D.] US FDA, Mol Pathol & Cytol Branch, Off In Vitro Diagnost & Radiol Hlth, Div Mol Genet & Pathol,Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Gavrielidesi, MA (reprint author), US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. NR 11 TC 0 Z9 0 U1 0 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-510-0 J9 PROC SPIE PY 2015 VL 9420 AR 94200D DI 10.1117/12.2082264 PG 9 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BC6QB UT WOS:000354372500010 ER PT S AU Gavrielidesl, MA Gallas, BD Hewitt, SM AF Gavrielidesl, Marios A. Gallas, Brandon D. Hewitt, Stephen M. BE Gurcan, MN Madabhushi, A TI Uncertainty in the assessment of immunohistochemical staining with optical and digital microscopy: lessons from a reader study SO MEDICAL IMAGING 2015: DIGITAL PATHOLOGY SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Digital Pathology CY FEB 25-26, 2015 CL Orlando, FL SP SPIE, ALIO Ind, Alpin Med Syst, Modus Med Devices Inc, Bruker ID SURGICAL PATHOLOGY; VIRTUAL MICROSCOPY; BREAST-CANCER; SLIDE; TELEPATHOLOGY; DIAGNOSIS; RECOMMENDATIONS; VALIDATION; GUIDELINE; ROUTINE AB We recently completed a reader study to compare optical and digital pathology (DP) for the assessment of two tissue-based biomarkers with immunohistochemistry. Eight pathologists reviewed 50 breast cancer whole slides (25 stained with HER2 and 25 with Ki-67) and 2 TMAs (1 stained with HER2, 1 with Ki-67, 97 cores each), using digital and optical microscopy. All reviews took place in a single office, using the same microscope, same computer/color calibrated monitor combination, and the same ambient light, in order to eliminate sources of variability due to these parameters. Agreement analysis was performed using the Kendall's tau-b metric and percent correct agreement. Results showed relatively high overall inter-observer and inter-modality agreement. However, significant uncertainty was observed for the whole slide evaluation with 95% confidence intervals (CI) in the order of 0.30 for the Kendall's tau-b metric, despite taking care to reduce sources of uncertainty. For the better-sampled TMAs, CIs were in the order of 0.15. It can be deduced that the sample size of 25 slides for each biomarker was not adequate even though it is in line with recent guidelines for the validation of DP from the College of American Pathologists (20 slides for immunohistochemistry without specifying task). Significant uncertainty was observed in our study, despite controlling for several variables. Further work is needed to identify sources of uncertainty for observer tasks in DP, and to account for it in study designs to assess DP. C1 [Gavrielidesl, Marios A.; Gallas, Brandon D.] US FDA, Ctr Devices & Radiol Hlth, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gavrielidesl, MA (reprint author), US FDA, Ctr Devices & Radiol Hlth, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. OI Hewitt, Stephen/0000-0001-8283-1788 NR 25 TC 0 Z9 0 U1 0 U2 3 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-510-0 J9 PROC SPIE PY 2015 VL 9420 AR 94200V DI 10.1117/12.2082243 PG 12 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BC6QB UT WOS:000354372500028 ER PT J AU Luo, H Du, TT Zhou, P Yang, L Mei, H Ng, HW Zhang, WQ Shu, M Tong, WD Shi, LM Mendrick, DL Hong, HX AF Luo, Heng Du, Tingting Zhou, Peng Yang, Lun Mei, Hu Ng, Huiwen Zhang, Wenqian Shu, Mao Tong, Weida Shi, Leming Mendrick, Donna L. Hong, Huixiao TI Molecular Docking to Identify Associations Between Drugs and Class I Human Leukocyte Antigens for Predicting Idiosyncratic Drug Reactions SO COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING LA English DT Article DE Adverse drug reaction; docking; personalized medicine; human leukocyte antigen; idiosyncratic drug reaction; modelling ID MAJOR HISTOCOMPATIBILITY COMPLEX; STEVENS-JOHNSON-SYNDROME; INDUCED LIVER-INJURY; T-CELLS PROVIDES; PEPTIDE REPERTOIRE; HLA-B; HYPERSENSITIVITY; HLA-B-ASTERISK-5701; ACTIVATION; ABACAVIR AB Idiosyncratic drug reactions (IDRs) are rare, somewhat dose-independent, patient-specific and hard to predict. Human leukocyte antigens (HLAs) are the major histocompatibility complex (MHC) in humans, are highly polymorphic and are associated with specific IDRs. Therefore, it is important to identify potential drug-HLA associations so that individuals who would develop IDRs can be identified before drug exposure. We harvested the associations between drugs and class I HLAs from the literature. The results revealed that there are many drug-HLA pairs without clinical data. For better potential interactions of the drug-HLA pairs, molecular docking was used to explore the potential of associations between the drugs and HLAs. From the analysis of docking scores between the 17 drugs and 74 class I HLAs, it was observed that the known significantly associated drug-HLA pairs had statistically lower docking scores than those not reported to be significantly associated (t-test p < 0.05). This indicates that molecular docking could be utilized for screening drug-HLA interactions and predicting potential IDRs. Examining the binding modes of drugs in the docked HLAs suggested several distinct binding sites inside class I HLAs, expanding our knowledge of the underlying interaction mechanisms between drugs and HLAs. C1 [Luo, Heng; Yang, Lun; Ng, Huiwen; Zhang, Wenqian; Shu, Mao; Tong, Weida; Mendrick, Donna L.; Hong, Huixiao] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Luo, Heng] Univ Arkansas, Univ Arkansas Med Sci, Bioinformat Grad Program, Little Rock, AR 72204 USA. [Du, Tingting; Shi, Leming] Fudan Univ, Sch Pharm, Ctr Pharmacogen, Shanghai 201203, Peoples R China. [Zhou, Peng] Univ Elect Sci & Technol China, Ctr Bioinformat COBI, Chengdu 610054, Peoples R China. [Zhou, Peng] Univ Elect Sci & Technol China, Minist Educ, Sch Life Sci & Technol, Key Lab Neuroinformat, Chengdu 610054, Peoples R China. [Mei, Hu] Chongqing Univ, Coll Bioengn, Minist Educ, Key Lab Biorheol Sci & Technol, Chongqing 400044, Peoples R China. RP Mendrick, DL (reprint author), US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM donna.mendrick@fda.hhs.gov; huixiao.hong@fda.hhs.gov RI Luo, Heng/D-3616-2016 OI Luo, Heng/0000-0001-5192-8878 FU U.S. Department of Energy; U.S. Food and Drug Administration; National Center for Research Resources [P20RR016460]; National Institute of General Medical Sciences from the National Institutes of Health [P20GM103429] FX We thank Dr. Cesar Compadre from University of Arkansas for Medical Sciences for his help to this project. This research was supported in part by an appointment to the Research Participation Program at the National Center for Toxicological Research (Heng Luo, Hui Wen Ng and Wenqian Zhang) 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 project was partially supported by grants from the National Center for Research Resources (P20RR016460) and the National Institute of General Medical Sciences (P20GM103429) from the National Institutes of Health. NR 44 TC 8 Z9 8 U1 2 U2 12 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1386-2073 EI 1875-5402 J9 COMB CHEM HIGH T SCR JI Comb. Chem. High Throughput Screen PY 2015 VL 18 IS 3 BP 296 EP 304 PG 9 WC Biochemical Research Methods; Chemistry, Applied; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA CG9JA UT WOS:000353629800006 PM 25747444 ER PT S AU Wang, JT Ghassemi, P Melchiorri, A Ramella-Roman, J Mathews, SA Coburn, J Sorg, B Chen, Y Pfefer, J AF Wang, Jianting Ghassemi, Pejhman Melchiorri, Anthony Ramella-Roman, Jessica Mathews, Scott A. Coburn, James Sorg, Brian Chen, Yu Pfefer, Joshua BE Allen, DW Bouchard, JP TI 3D Printed Biomimetic Vascular Phantoms for Assessment of Hyperspectral Imaging Systems SO DESIGN AND PERFORMANCE VALIDATION OF PHANTOMS USED IN CONJUNCTION WITH OPTICAL MEASUREMENT OF TISSUE VII SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Design and Performance Validation of Phantoms Used in Conjunction with Optical Measurement of Tissue VII CY FEB 07, 2015 CL San Francisco, CA SP SPIE DE 3D printing; biomimetic vascular phantoms; biophotonic imaging; hyperspectral reflectance imaging; tissue oximetry ID TISSUE OPTICAL-PROPERTIES; OXYGEN-SATURATION; TURBID MEDIA; RETINA AB The emerging technique of three-dimensional (3D) printing provides a revolutionary way to fabricate objects with biologically realistic geometries. Previously we have performed optical and morphological characterization of basic 3D printed tissue-simulating phantoms and found them suitable for use in evaluating biophotonic imaging systems. In this study we assess the potential for printing phantoms with irregular, image-defined vascular networks that can be used to provide clinically-relevant insights into device performance. A previously acquired fundus camera image of the human retina was segmented, embedded into a 3D matrix, edited to incorporate the tubular shape of vessels and converted into a digital format suitable for printing. A polymer with biologically realistic optical properties was identified by spectrophotometer measurements of several commercially available samples. Phantoms were printed with the retinal vascular network reproduced as similar to 1.0 mm diameter channels at a range of depths up to similar to 3 mm. The morphology of the printed vessels was verified by volumetric imaging with mu-CT. Channels were filled with hemoglobin solutions at controlled oxygenation levels, and the phantoms were imaged by a near-infrared hyperspectral reflectance imaging system. The effect of vessel depth on hemoglobin saturation estimates was studied. Additionally, a phantom incorporating the vascular network at two depths was printed and filled with hemoglobin solution at two different saturation levels. Overall, results indicated that 3D printed phantoms are useful for assessing biophotonic system performance and have the potential to form the basis of clinically-relevant standardized test methods for assessment of medical imaging modalities. C1 [Wang, Jianting; Ghassemi, Pejhman; Coburn, James; Pfefer, Joshua] US FDA, Silver Spring, MD 20993 USA. [Wang, Jianting; Melchiorri, Anthony; Chen, Yu] Univ Maryland, College Pk, MD 20742 USA. [Ramella-Roman, Jessica] Florida Int Univ, Dept Biomed Engn, Miami, FL 33174 USA. [Mathews, Scott A.] Catholic Univ Amer, Dept Elect Engn & Comp Sci, Washington, DC 20064 USA. [Sorg, Brian] NCI, NIH, Rockville, MD 20852 USA. RP Wang, JT (reprint author), US FDA, Silver Spring, MD 20993 USA. EM Joshua.Pfefer@fda.hhs.gov NR 21 TC 1 Z9 1 U1 5 U2 10 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-415-8 J9 PROC SPIE PY 2015 VL 9325 AR 932508 DI 10.1117/12.2084720 PG 9 WC Cell & Tissue Engineering; Biophysics; Optics SC Cell Biology; Biophysics; Optics GA BC6EX UT WOS:000353883600005 ER PT J AU Johnson, GE Slob, W Doak, SH Fellows, MD Gollapudi, BB Heflich, RH Rees, BJ Soeteman-Hernandez, LG Verma, JR Wills, JW Jenkins, GJS White, PA AF Johnson, George E. d Slob, Wout Doak, Shareen H. Fellows, Mick D. Gollapudi, Bhaskar B. Heflich, Robert H. Rees, Ben J. Soeteman-Hernandez, Lya G. Verma, Jatin R. Wills, John W. Jenkins, Gareth J. S. White, Paul A. TI New approaches to advance the use of genetic toxicology analyses for human health risk assessment SO TOXICOLOGY RESEARCH LA English DT Article ID RED-BLOOD-CELLS; DOSE-RESPONSE RELATIONSHIPS; MUTATION ASSAY TRIAL; IN-VIVO GENOTOXICITY; ETHYL METHANESULFONATE; FOLLOW-UP; CARCINOGENIC POTENCY; HUMAN-LYMPHOCYTES; TRANSGENIC MICE; ECVAM WORKSHOP AB Genetic toxicology testing has a crucial role in the safety assessment of new and existing substances of societal value by reducing/eliminating human exposure to potential somatic and germ cell mutagens. Genetic toxicology assays have historically been used in a qualitative manner to arrive at the binary decision of 'yes' or 'no' with regards to the mutagenic potential. However, the field is currently at a crossroads, with new methods being developed and new proposals being made to use genetic toxicity data in a more quantitative manner. Technological advances have made it possible to perform high-content, high-throughput and high-precision analysis to increase the number of "scored" events leading to increased statistical precision of the endpoint under evaluation. Automated flow cytometry and image analysis are providing significant advantages for the evaluation of gene mutations as well as cytogenetic damage both in vitro and in vivo. In addition, statistical methods such as the benchmark dose (BMD) approach can be used to identify point of departure (PoD) metrics for use in human health risk assessments, including estimation of reference dose (RfD) and margins of exposure (MOE) from in vivo data. Here we provide new data to compare different in vitro micronucleus approaches, observing that the flow based assay performs very well in defining a PoD for methyl methanesulfonate. We also present reanalysis of published in vivo Pig-a gene mutation data, to show how covariate analysis increases precision and reduces the effects of outliers when defining BMD values. Furthermore, we show how in vivo BMD metrics can be used to define RfD values, and then provide comparisons to other human exposure limit values such as permitted daily exposure (PDE). Finally, the principles of empirical correlation using BMD metrics are presented, with methods for derivation of BMD values for endpoint B, when using data from only endpoint A. These developments are opening the possibility of genetic toxicity data being used as an apical endpoint to define negligible risk in human health risk assessments. Expert groups consisting of stakeholders representing academia, industry and the government are now developing guidance on transforming genetic toxicology testing from a qualitative to a quantitative science, keeping in mind the 3R principles of animal welfare. C1 [Johnson, George E. d; Slob, Wout; Doak, Shareen H.; Rees, Ben J.; Verma, Jatin R.; Wills, John W.; Jenkins, Gareth J. S.] Swansea Univ, Inst Life Sci, Coll Med, Swansea, W Glam, Wales. [Fellows, Mick D.] AstraZeneca, Discovery Safety, Cambridge, England. [Gollapudi, Bhaskar B.] Ctr Toxicol & Mech Biol, Midland, MI USA. [Heflich, Robert H.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Soeteman-Hernandez, Lya G.] Natl Inst Publ Hlth & Environm RIVM, Ctr Hlth Protect, Bilthoven, Netherlands. [White, Paul 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, Inst Life Sci, Coll Med, Swansea, W Glam, Wales. EM g.johnson@swansea.ac.uk OI white, paul/0000-0001-5853-4759; Johnson, George/0000-0001-5643-9942; Doak, Shareen/0000-0002-6753-1987 FU National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [NC/K500033/1]; Engineering and Physical Science Research Council and GlaxoSmithKline (EPSRC-GSK) [EP/J502248/1]; government of Canada under the Chemicals Management Plan FX The authors would like to thank the HESI Genetic Toxicology Technical Committee for is intellectual support. Dr Andreas Zeller and Dr Melanie Guerard for their expert input. National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs, contract number NC/K500033/1) provided funding for Dr Johnson. Engineering and Physical Science Research Council and GlaxoSmithKline (EPSRC-GSK case studentship EP/J502248/1) provided funding for Ben Rees. We thank the two anonymous Health Canada reviewers for helpful comments on the draft manuscript. Jatin Verma would like to thank Dr Lila A. Lodha for providing his funding. Additional funding was provided by the government of Canada under the Chemicals Management Plan. We would like to acknowledge Litron laboratories for their gifts of the Microflow kits as well as expert input from Dr Steve Bryce and colleagues during this work. NR 47 TC 7 Z9 7 U1 4 U2 11 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. PY 2015 VL 4 IS 3 BP 667 EP 676 DI 10.1039/c4tx00118d PG 10 WC Toxicology SC Toxicology GA CG8TY UT WOS:000353587200012 ER PT B AU Lampel, KA AF Lampel, Keith A. BE Ozer, BH AkdemirEvrendilek, G TI Strategies for Rapid Detection of Milk-borne Pathogens SO Dairy Microbiology and Biochemistry: Recent Developments LA English DT Article; Book Chapter ID REAL-TIME PCR; MASTITIS-CAUSING PATHOGENS; DAIRY FARM ENVIRONMENT; ESCHERICHIA-COLI O157; RAW-MILK; LISTERIA-MONOCYTOGENES; FOODBORNE PATHOGENS; SALMONELLA SPP.; BOVINE-MILK; FOOD SAFETY C1 US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Lampel, KA (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Keith.lampel@fda.hhs.gov NR 35 TC 0 Z9 0 U1 2 U2 5 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4822-3504-3; 978-1-4822-3502-9 PY 2015 BP 390 EP 403 PG 14 WC Agriculture, Dairy & Animal Science; Biochemistry & Molecular Biology; Food Science & Technology; Microbiology SC Agriculture; Biochemistry & Molecular Biology; Food Science & Technology; Microbiology GA BC5FW UT WOS:000353241600016 ER PT S AU Jang, H Singh, K Wang, HW Pfefer, TJ Chen, Y AF Jang, Hyounguk Singh, Karam Wang, Hsing-Wen Pfefer, T. Joshua Chen, Yu BE Raghavachari, R Liang, R TI Oximetry system performance assessment with POM (acetal) phantoms incorporating hemoglobin calibration standards and customized saturation levels SO DESIGN AND QUALITY FOR BIOMEDICAL TECHNOLOGIES VIII SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Design and Quality for Biomedical Technologies VIII CY FEB 07-08, 2015 CL San Francisco, CA SP SPIE DE near-infrared spectroscopy; oximetry; phantom ID NEAR-INFRARED SPECTROSCOPY; TISSUE OPTICAL-PROPERTIES; BRAIN; MODEL AB Standardized approaches for performance assessment of biophotonic devices have the potential to facilitate system development and intercomparison, clinical trial standardization, recalibration, manufacturing quality control and quality assurance during clinical use. Evaluation of devices based on near-infrared spectroscopy (NIRS) for detection of hemoglobin (Hb) content and oxygenation have often involved tissue-simulating phantoms incorporating artificial dyes or flow systems. Towards the development of simple, effective techniques for objective, quantitative evaluation of basic NIRS system performance, we have developed and evaluated two test methods. These methods are based on cuvette inserts in solid turbid phantoms for measuring commercially-available Hb oximetry standards and custom-formulated oxy/deoxy-Hb solutions. Both approaches incorporate solid acetal, or polyoxymethylene (POM), as a tissue-simulating matrix material. First, inverse-adding-doubling (IAD) based on measurements with a spectrophotometer and an integrating sphere was used to measure POM optical properties and their stability over time. Second, two fiberoptic-probe-based NIRS systems were used to measure concentration change of oxy- and deoxy-Hb in standard Hb solutions and customized Hb solutions by adding yeast. Differences in system performance were likely due to differences in light source outputs and fiberoptic probe design. Our preliminary results indicate that simple phantom-based approaches based on commercially available polymers and inclusions containing Hb standards, or controlled oxygenation levels may be useful for benchtop assessment of NIRS device quality for a variety of biophotonic devices. C1 [Jang, Hyounguk; Singh, Karam; Wang, Hsing-Wen; Chen, Yu] Univ Maryland, Dept Bioengn, College Pk, MD 20742 USA. [Jang, Hyounguk; Pfefer, T. Joshua] US FDA, Silver Spring, MD 20902 USA. RP Jang, H (reprint author), Univ Maryland, Dept Bioengn, College Pk, MD 20742 USA. NR 22 TC 1 Z9 1 U1 0 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-405-9 J9 PROC SPIE PY 2015 VL 9315 AR 931503 DI 10.1117/12.2087095 PG 7 WC Engineering, Biomedical; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Optics; Radiology, Nuclear Medicine & Medical Imaging GA BC5OM UT WOS:000353415800002 ER PT S AU Vogt, WC Jia, CX Wear, KA Garra, BS Pfefer, J AF Vogt, William C. Jia, Congxian Wear, Keith A. Garra, Brian S. Pfefer, Joshua BE Raghavachari, R Liang, R TI Design and Phantom-based Validation of a Bimodal Ultrasound-Photoacoustic Imaging System for Spectral Detection of Optical Biomarkers SO Design and Quality for Biomedical Technologies VIII SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Design and Quality for Biomedical Technologies VIII CY FEB 07-08, 2015 CL San Francisco, CA SP SPIE DE Oximetry; optoacoustics; photoacoustic tomography; spectroscopy; contrast agent; hemoglobin ID IMAGES AB The construction of photoacoustic tomography (PAT) systems that combine tunable laser sources and ultrasound systems for bimodal imaging and spectroscopic applications such as oximetry presents novel challenges to the biophotonics researcher. We address some of the design issues, including system synchronization, cross-platform integration, and image reconstruction algorithms, and present techniques for device performance validation. Our system comprises a pulsed Nd: YAG laser-pumped optical parametric oscillator for near-infrared tunability and a research-grade ultrasound acquisition system compatible with multiple clinical transducers to enable wide variation in operating parameters. Considerations such as pulse energy variability, ultrasound transducer properties, and spectral energy compensation, and their impact on measurements are presented. Spectral imaging was performed on tissue-simulating phantoms made of a custom polyvinyl chloride (PVC) plastisol gel designed to mimic both the optical properties (absorption, scattering) and acoustic properties (sound velocity, attenuation) of human breast tissue. Phantoms contained fluid channels at various depths which were injected with either oxyhemoglobin or organic dye solutions as absorptive targets. Spectral analysis of these solutions was performed for channel depths from 0.5 to 3 cm and at radiant exposures up to the ANSI maximum permissible exposure. Recovered photoacoustic spectra are compared with absorption spectra measured using spectrophotometry. Results provide insight into the influence of factors that impact the quality of spectroscopic measurements and reconstructed images in ultrasound-PAT systems. C1 [Vogt, William C.; Jia, Congxian; Wear, Keith A.; Garra, Brian S.; Pfefer, Joshua] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Vogt, WC (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Joshua.Pfefer@fda.hhs.gov NR 21 TC 2 Z9 2 U1 0 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-405-9 J9 PROC SPIE PY 2015 VL 9315 AR 931502 DI 10.1117/12.2082847 PG 7 WC Engineering, Biomedical; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Optics; Radiology, Nuclear Medicine & Medical Imaging GA BC5OM UT WOS:000353415800001 ER PT J AU Faris, O Shuren, J AF Faris, Owen Shuren, Jeffrey TI A CDRH Priority: Clinical Trials in the US SO MANUFACTURING ENGINEERING LA English DT Editorial Material C1 [Faris, Owen] US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Silver Spring, MD 20993 USA. [Shuren, Jeffrey] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Faris, O (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Silver Spring, MD 20993 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU SOC MANUFACTURING ENGINEERS PI DEARBORN PA ONE SME DRIVE, PO BOX 930, DEARBORN, MI 48121-0930 USA SN 0361-0853 J9 MANUF ENG JI Manuf. Eng. PY 2015 SU S BP 23 EP 23 PG 1 WC Engineering, Manufacturing SC Engineering GA CG4JU UT WOS:000353252200005 ER PT S AU Le, HND U-Thainual, P Kim, DH AF Le, Hanh N. D. U-Thainual, Paweena Kim, Do-Hyun BE Gannot, I TI Photoacoustic spectroscopy of gaseous biomarker in simulated breath SO OPTICAL FIBERS AND SENSORS FOR MEDICAL DIAGNOSTICS AND TREATMENT APPLICATIONS XV SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Optical Fibers and Sensors for Medical Diagnostics and Treatment Applications XV CY FEB 07-08, 2015 CL San Francisco, CA SP SPIE DE Photoacoustic spectroscopy; biomarkers; breath analysis ID GAS-ANALYSIS; PENTANE; ETHANE; AIR AB In this study, a photoacoustic detector integrated with Fourier-transform infrared spectroscopy was used to measure biomarkers in gas samples independently. Simulated exhaled breath samples were created by mixing varying concentrations of acetone, ammonia and ethane. The results of these measurements demonstrate the potential of photoacoustic spectroscopy to detect biomarkers from human breath. C1 [Le, Hanh N. D.; U-Thainual, Paweena; Kim, Do-Hyun] US FDA, Silver Spring, MD 20993 USA. RP Le, HND (reprint author), Johns Hopkins Univ, 3400 N Charles St, Baltimore, MD 21218 USA. NR 16 TC 0 Z9 0 U1 1 U2 12 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-62841-407-3 J9 PROC SPIE PY 2015 VL 9317 AR 931704 DI 10.1117/12.2082703 PG 8 WC Engineering, Biomedical; Remote Sensing; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Remote Sensing; Optics; Radiology, Nuclear Medicine & Medical Imaging GA BC5QF UT WOS:000353482300002 ER PT J AU Chancey, C Grinev, A Volkova, E Rios, M AF Chancey, Caren Grinev, Andriyan Volkova, Evgeniya Rios, Maria TI The Global Ecology and Epidemiology of West Nile Virus SO BIOMED RESEARCH INTERNATIONAL LA English DT Review ID TICK-BORNE ENCEPHALITIS; NONSTRUCTURAL PROTEIN NS1; TRANSFUSION-ASSOCIATED TRANSMISSION; MURRAY-VALLEY-ENCEPHALITIS; FATAL NEUROLOGIC DISEASE; FLAVIVIRUS CELL ENTRY; LINEAGE 2; UNITED-STATES; NEW-YORK; KUNJIN-VIRUS AB Since its initial isolation in Uganda in 1937 through the present, West Nile virus (WNV) has become an important cause of human and animal disease worldwide. WNV, an enveloped virus of the genus Flavivirus, is naturally maintained in an enzootic cycle between birds and mosquitoes, with occasional epizootic spillover causing disease in humans and horses. The mosquito vectors for WNV are widely distributed worldwide, and the known geographic range of WNV transmission and disease has continued to increase over the past 77 years. While most human infections with WNV are asymptomatic, severe neurological disease may develop resulting in long-term sequelae or death. Surveillance and preventive measures are an ongoing need to reduce the public health impact of WNV in areas with the potential for transmission. C1 [Chancey, Caren; Grinev, Andriyan; Volkova, Evgeniya; Rios, Maria] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Rios, M (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM maria.rios@fda.hhs.gov NR 316 TC 8 Z9 8 U1 3 U2 32 PU HINDAWI PUBLISHING CORP PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 2314-6133 EI 2314-6141 J9 BIOMED RES INT JI Biomed Res. Int. PY 2015 AR 376230 DI 10.1155/2015/376230 PG 20 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA CF2XC UT WOS:000352410100001 ER PT J AU Lindblom, EN AF Lindblom, Eric N. TI Effectively Regulating E-Cigarettes and Their Advertising-And the First Amendment SO FOOD AND DRUG LAW JOURNAL LA English DT Article ID ELECTRONIC CIGARETTES; SMOKING REDUCTION; DARK MARKET; FOLLOW-UP; TOBACCO; US; ASSOCIATION; STATEMENT; EXPOSURE; REASONS C1 [Lindblom, Eric N.] US FDA, Off Policy, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Lindblom, EN (reprint author), Georgetown Univ, Ctr Law, ONeill Inst Natl & Global Hlth Law, Washington, DC 20057 USA. OI Lindblom, Eric/0000-0003-0627-0987 NR 106 TC 5 Z9 5 U1 0 U2 8 PU FOOD DRUG LAW INST PI WASHINGTON PA 1000 VERMONT AVE NW, SUITE 1200, WASHINGTON, DC 20005-4903 USA SN 1064-590X J9 FOOD DRUG LAW J JI Food Drug Law J. PY 2015 VL 70 IS 1 BP 55 EP 92 PG 38 WC Food Science & Technology; Law; Nutrition & Dietetics; Pharmacology & Pharmacy SC Food Science & Technology; Government & Law; Nutrition & Dietetics; Pharmacology & Pharmacy GA CF6LQ UT WOS:000352668600006 PM 26292472 ER PT J AU Brown, MS AF Brown, Mark S. TI 2nd Annual Eric M. Blumberg Memorial Lecture SO FOOD AND DRUG LAW JOURNAL LA English DT Article C1 [Brown, Mark S.] King & Spaldings FDA, Washington, DC 20006 USA. [Brown, Mark S.] US FDA, Rockville, MD 20857 USA. RP Brown, MS (reprint author), King & Spaldings FDA, Washington, DC 20006 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FOOD DRUG LAW INST PI WASHINGTON PA 1000 VERMONT AVE NW, SUITE 1200, WASHINGTON, DC 20005-4903 USA SN 1064-590X J9 FOOD DRUG LAW J JI Food Drug Law J. PY 2015 VL 70 IS 1 BP 93 EP 99 PG 7 WC Food Science & Technology; Law; Nutrition & Dietetics; Pharmacology & Pharmacy SC Food Science & Technology; Government & Law; Nutrition & Dietetics; Pharmacology & Pharmacy GA CF6LQ UT WOS:000352668600007 PM 26292473 ER PT J AU Nickum, EA Flurer, CL AF Nickum, Elisa A. Flurer, Cheryl L. TI Determination of Phosphodiesterase-5 Inhibitors and Analogs Using High-Performance Liquid Chromatography with Ultraviolet Detection SO JOURNAL OF CHROMATOGRAPHIC SCIENCE LA English DT Article ID HERBAL DIETARY-SUPPLEMENT; TANDEM MASS-SPECTROMETRY; STRUCTURE ELUCIDATION; ELECTROSPRAY-IONIZATION; STRUCTURAL ELUCIDATION; ERECTILE DYSFUNCTION; SILDENAFIL CITRATE; HUMAN PLASMA; IDENTIFICATION; ADULTERANT AB A considerable number of erectile dysfunction products, and dietary supplements suspected of containing phosphodiesterase-5 (PDE-5) inhibitors, have been analyzed by the US Food and Drug Administration. Often these samples are found to contain the approved active pharmaceutical ingredients (APIs) such as sildenafil, tadalafil or vardenafil. However, analogs of these APIs have also been identified in many samples and products containing multiple PDE-5 inhibitors have also been found. A single high-performance liquid chromatography with ultraviolet detection method has been developed for the determination of sildenafil, tadalafil, vardenafil and a number of commonly encountered analogs in pharmaceutical dosage forms and dietary supplement products, including tablets, capsules, bulk powders, troches and liquids. This method was designed as an alternative to methods developed for the determination of a single PDE-5 inhibitor. Using this protocol, 14 PDE-5 inhibitor compounds can be separated and determined in a single analysis. C1 [Nickum, Elisa A.; Flurer, Cheryl L.] US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. RP Nickum, EA (reprint author), US FDA, Forens Chem Ctr, 6751 Steger Dr, Cincinnati, OH 45237 USA. EM elisa.nickum@fda.hhs.gov NR 35 TC 3 Z9 3 U1 1 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0021-9665 EI 1945-239X J9 J CHROMATOGR SCI JI J. Chromatogr. Sci. PD JAN PY 2015 VL 53 IS 1 BP 38 EP 46 DI 10.1093/chromsci/bmu010 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CE8OA UT WOS:000352101300006 PM 24668043 ER PT J AU Myers, MB McKim, KL Meng, FX Parsons, BL AF Myers, Meagan B. McKim, Karen L. Meng, Fanxue Parsons, Barbara L. TI Low-frequency KRAS mutations are prevalent in lung adenocarcinomas SO PERSONALIZED MEDICINE LA English DT Article DE carcinogenesis; epidermal growth factor receptor; mutation; mutation detection; non-small-cell lung cancer; oncogene; oncogene-induced senescence; personalized medicine; polyclonal tumor origin; targeted molecular therapy ID TYROSINE KINASE INHIBITORS; GROWTH-FACTOR RECEPTOR; K-RAS MUTATIONS; PERSONALIZED CANCER-TREATMENT; ACB-PCR QUANTIFICATION; ACQUIRED-RESISTANCE; COLORECTAL-CANCER; MUTANT FRACTION; PHASE-III; EGFR AB Aim: This study quantified low-frequency KRAS mutations in normal lung and lung adenocarcinomas, to understand their potential significance in the development of acquired resistance to EGFR-targeted therapies. Materials & Methods: Allele-specific Competitive Blocker-PCR was used to quantify KRAS codon 12 GAT (G12D) and GTT (G12V) mutation in 19 normal lung and 21 lung adenocarcinoma samples. Results: Lung adenocarcinomas had KRAS codon 12 GAT and GTT geometric mean mutant fractions of 1.94 x 10(-4) and 1.16 x 10(-3), respectively. For 76.2% of lung adenocarcinomas, the level of KRAS mutation was greater than the upper 95% confidence interval of that in normal lung. Conclusion: KRAS mutant tumor subpopulations, not detectable by DNA sequencing, may drive resistance to EGFR blockade in lung adenocarcinoma patients. C1 [Myers, Meagan B.; McKim, Karen L.; Meng, Fanxue; Parsons, Barbara L.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Parsons, BL (reprint author), US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM barbara.parsons@fda.hhs.gov FU NIH [5 U42 RR006042] FX MB Myers, KL McKim, F Meng and BL Parsons are employees of the US FDA. The opinions and information presented are those of the authors, and do not represent the views and/or policies of the US FDA, no does the mention of trade names or commercial products constitute endorsement or recommendation for use The authors acknowledge use of tissues procured by the National Disease Research Interchange (NDRI; with support from NIH grant 5 U42 RR006042). 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 61 TC 1 Z9 1 U1 1 U2 3 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 EI 1744-828X J9 PERS MED JI Pers. Med. PY 2015 VL 12 IS 2 BP 83 EP 98 DI 10.2217/PME.14.69 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CE1YR UT WOS:000351609500005 PM 27795727 ER PT J AU Pathmanathan, P Shotwell, MS Gavaghan, DJ Cordeiro, JM Gray, RA AF Pathmanathan, Pras Shotwell, Matthew S. Gavaghan, David J. Cordeiro, Jonathan M. Gray, Richard A. TI Uncertainty quantification of fast sodium current steady-state inactivation for multi-scale models of cardiac electrophysiology SO PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY LA English DT Review DE Cardiac modelling; Uncertainty quantification; Population variability; Nonlinear mixed effects modelling ID COMPUTATIONAL MODELS; ION CHANNELS; RANOLAZINE; PATHOPHYSIOLOGY; CONSEQUENCES; FIBRILLATION; SIMULATIONS; VARIABILITY; DEPRESSION; TARGET AB Perhaps the most mature area of multi-scale systems biology is the modelling of the heart. Current models are grounded in over fifty years of research in the development of biophysically detailed models of the electrophysiology (EP) of cardiac cells, but one aspect which is inadequately addressed is the incorporation of uncertainty and physiological variability. Uncertainty quantification (UQ) is the identification and characterisation of the uncertainty in model parameters derived from experimental data, and the computation of the resultant uncertainty in model outputs. It is a necessary tool for establishing the credibility of computational models, and will likely be expected of EP models for future safety-critical clinical applications. The focus of this paper is formal UQ of one major sub-component of cardiac EP models, the steady-state inactivation of the fast sodium current, I-Na. To better capture average behaviour and quantify variability across cells, we have applied for the first time an 'individual-based' statistical methodology to assess voltage clamp data. Advantages of this approach over a more traditional 'population-averaged' approach are highlighted. The method was used to characterise variability amongst cells isolated from canine epi and endocardium, and this variability was then 'propagated forward' through a canine model to determine the resultant uncertainty in model predictions at different scales, such as of upstroke velocity and spiral wave dynamics. Statistically significant differences between epi and endocardial cells (greater half-inactivation and less steep slope of steady state inactivation curve for endo) was observed, and the forward propagation revealed a lack of robustness of the model to underlying variability, but also surprising robustness to variability at the tissue scale. Overall, the methodology can be used to: (i) better analyse voltage clamp data; (ii) characterise underlying population variability; (iii) investigate consequences of variability; and (iv) improve the ability to validate a model. To our knowledge this article is the first to quantify population variability in membrane dynamics in this manner, and the first to perform formal UQ for a component of a cardiac model. The approach is likely to find much wider applicability across systems biology as current application domains reach greater levels of maturity. Published by Elsevier Ltd. C1 [Pathmanathan, Pras; Gray, Richard A.] US FDA, Silver Spring, MD 20993 USA. [Shotwell, Matthew S.] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN 37203 USA. [Gavaghan, David J.] Univ Oxford, Dept Comp Sci, Oxford OX1 3QD, England. [Cordeiro, Jonathan M.] Masonic Med Res Lab, Utica, NY 13501 USA. RP Pathmanathan, P (reprint author), US FDA, 10903 New Hampshire Ave WO 62, Silver Spring, MD 20993 USA. EM pras.pathmanathan@fda.hhs.gov; matt.shotwell@vanderbilt.edu; gavaghan@cs.ox.ac.uk; jcordeiro@mmrl.edu; richard.gray@fda.hhs.gov RI Gray, Richard/F-3916-2015; OI Gray, Richard/0000-0003-2798-6378; gavaghan, david/0000-0001-8311-3200 FU UK EPSRC [EP/I017909/1]; NIH/NHLBI [1R01HL118392-01] FX The authors would like to thank Leonardo Angelone and Tina M. Morrison (Center for Devices and Radiological Health, FDA) for their feedback. PP would like to acknowledge support from the UK EPSRC-funded '2020 Science' programme (grant number: EP/I017909/1). MS would like to acknowledge grant NIH/NHLBI 1R01HL118392-01. Tissues simulations were carried out using FDA supercomputing resources, and PP would like to thank Mike Mikailov (FDA Supercomputing Laboratory) for technical assistance. NR 41 TC 5 Z9 5 U1 3 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6107 J9 PROG BIOPHYS MOL BIO JI Prog. Biophys. Mol. Biol. PD JAN PY 2015 VL 117 IS 1 BP 4 EP 18 DI 10.1016/j.pbiomolbio.2015.01.008 PG 15 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CE4NK UT WOS:000351807100002 PM 25661325 ER PT J AU Bozza, WP Tolleson, WH Rosado, LAR Zhang, BL AF Bozza, William P. Tolleson, William H. Rosado, Leslie A. Rivera Zhang, Baolin TI Ricin detection: Tracking active toxin SO BIOTECHNOLOGY ADVANCES LA English DT Review DE Ricin; Bioterrorism; Detection methods; Plant toxins ID RIBOSOME-INACTIVATING PROTEINS; SURFACE-PLASMON RESONANCE; RNA N-GLYCOSIDASE; TANDEM MASS-SPECTROMETRY; CHAIN-REACTION ASSAY; A-CHAIN; ENZYMATIC-ACTIVITY; LECTINS ABRIN; B-CHAIN; BIOLOGICAL TOXINS AB Ricin is a plant toxin with high bioterrorism potential due to its natural abundance and potency in inducing cell death. Early detection of the active toxin is essential for developing appropriate countermeasures. Here we review concepts for designing ricin detection methods, including mechanism of action of the toxin, advantages and disadvantages of current detection assays, and perspectives on the future development of rapid and reliable methods for detecting ricin in environmental samples. Published by Elsevier Inc. C1 [Bozza, William P.; Rosado, Leslie A. Rivera; Zhang, Baolin] US FDA, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Tolleson, William H.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Rosado, Leslie A. Rivera] US Publ Hlth Serv Commissioned Corps, Rockville, MD USA. RP Zhang, BL (reprint author), US FDA, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. EM Baolin.zhang@fda.hhs.gov FU US Food and Drug Administration (FDA) Medical Countermeasure Initiatives FX We thank Drs. Amy Rosenberg, Serge Beaucage, and Xu Di for critical reading of the manuscript. This work is funded by the US Food and Drug Administration (FDA) Medical Countermeasure Initiatives. The views presented in this article do not necessarily reflect those of the Food and Drug Administration. NR 78 TC 12 Z9 13 U1 5 U2 34 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0734-9750 EI 1873-1899 J9 BIOTECHNOL ADV JI Biotechnol. Adv. PD JAN-FEB PY 2015 VL 33 IS 1 BP 117 EP 123 DI 10.1016/j.biotechadv.2014.11.012 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA CD8BY UT WOS:000351321400008 PM 25481398 ER PT J AU Majdi, JA Qian, HH Li, YC Langsner, RJ Shea, KI Agrawal, A Hammer, DX Hanig, JP Cohen, ED AF Majdi, Joseph A. Qian, Haohua Li, Yichao Langsner, Robert J. Shea, Katherine I. Agrawal, Anant Hammer, Daniel X. Hanig, Joseph P. Cohen, Ethan D. TI The Use of Time-Lapse Optical Coherence Tomography to Image the Effects of Microapplied Toxins on the Retina SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE microperfusion; optical coherence tomography; retinotoxins ID ALPHA-AMINOADIPIC ACID; CENTRAL-NERVOUS-SYSTEM; IN-VIVO; SPREADING DEPRESSION; PIGMENT-EPITHELIUM; SCATTERING CHANGES; OCULAR TOXICITY; HYDROXYCHLOROQUINE RETINOPATHY; CHLOROQUINE RETINOPATHY; RABBIT RETINA AB PURPOSE. We developed a novel technique for accelerated drug screening and retinotoxin characterization using time-lapse optical coherence tomography (OCT) and a drug microapplication device. METHODS. Using an ex vivo rabbit eyecup preparation, we studied retinotoxin effects in real-time by microperfusing small retinal areas under a transparent fluoropolymer tube. Known retinotoxic agents were applied to the retina for 5-minute periods, while changes in retinal structure, thickness, and reflectance were monitored with OCT. The OCT images of two agents with dissimilar mechanisms, cyanide and kainic acid, were compared to their structural changes seen histologically. RESULTS. We found the actions of retinotoxic agents tested could be classified broadly into two distinct types: (1) agents that induce neuronal depolarization, such as kainic acid, causing increases in OCT reflectivity or thickness of the inner plexiform and nuclear layers, and decreased reflectivity of the outer retina; and (2) agents that disrupt mitochondrial function, such as cyanide, causing outer retinal structural changes as evidenced by a reduction in the OCT reflectivity of the photoreceptor outer segment and pigment epithelium layers. CONCLUSIONS. Retinotoxin-induced changes in retinal layer reflectivity and thickness under the microperfusion tube in OCT images closely matched the histological evidence of retinal injury. Time-lapse OCT imaging of the microperfused local retina has the potential to accelerate drug retinotoxicological screening and expand the use of OCT as an evaluation tool for preclinical animal testing. C1 [Majdi, Joseph A.; Langsner, Robert J.; Agrawal, Anant; Hammer, Daniel X.; Cohen, Ethan D.] US FDA, Div Biomed Phys, Off Sci & Engn Lab, Ctr Devices & Radiol Hlth,White Oak Fed Res Labs, Silver Spring, MD 20993 USA. [Qian, Haohua; Li, Yichao] NEI, Visual Funct Core, NIH, Bethesda, MD 20892 USA. [Shea, Katherine I.; Hanig, Joseph P.] US FDA, Off Testing & Res, Ctr Drug Evaluat & Res, White Oak Fed Res Labs, Silver Spring, MD 20993 USA. RP Cohen, ED (reprint author), US FDA, Div Biomed Phys, Off Sci & Engn Lab, Ctr Devices & Radiol Hlth,White Oak Fed Res Labs, Room 1204,Bldg 62, Silver Spring, MD 20993 USA. EM ethan.cohen@fda.hhs.gov FU FDA Critical Path Initiative FX Supported by a grant from the FDA Critical Path Initiative. The content of this publication represents solely the authors' views and may not reflect any position of the United States Government or the Food and Drug Administration. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. NR 73 TC 2 Z9 2 U1 0 U2 3 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 JAN PY 2015 VL 56 IS 1 BP 587 EP 597 DI 10.1167/iovs.14-15594 PG 11 WC Ophthalmology SC Ophthalmology GA CE0TQ UT WOS:000351519800066 PM 25525175 ER PT J AU Yen, CW de Puig, H Tam, JO Gomez-Marquez, J Bosch, I Hamad-Schifferli, K Gehrke, L AF Yen, Chun-Wan de Puig, Helena Tam, Justina O. Gomez-Marquez, Jose Bosch, Irene Hamad-Schifferli, Kimberly Gehrke, Lee TI Multicolored silver nanoparticles for multiplexed disease diagnostics: distinguishing dengue, yellow fever, and Ebola viruses SO LAB ON A CHIP LA English DT Article ID PROTEIN NS1; GOLD; ANTIGEN AB Rapid point-of-care (POC) diagnostic devices are needed for field-forward screening of severe acute systemic febrile illnesses. Multiplexed rapid lateral flow diagnostics have the potential to distinguish among multiple pathogens, thereby facilitating diagnosis and improving patient care. Here, we present a platform for multiplexed pathogen detection using multi-colored silver nanoplates. This design requires no external excitation source and permits multiplexed analysis in a single channel, facilitating integration and manufacturing. C1 [Yen, Chun-Wan; Tam, Justina O.; Bosch, Irene; Gehrke, Lee] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Yen, Chun-Wan; Tam, Justina O.; Bosch, Irene] US FDA, Winchester Engn Analyt Ctr, Winchester, MA 01890 USA. [de Puig, Helena; Hamad-Schifferli, Kimberly] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Gomez-Marquez, Jose] MIT, Little Devices Lab, Cambridge, MA 02139 USA. [Gomez-Marquez, Jose] MIT SUTD Int Design Ctr, Cambridge, MA USA. [Hamad-Schifferli, Kimberly] MIT, Lincoln Lab, Lexington, MA 02420 USA. [Gehrke, Lee] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. RP Hamad-Schifferli, K (reprint author), MIT, Dept Mech Engn, Cambridge, MA 02139 USA. EM schiffer@mit.edu; lgehrke@mit.edu FU NIH NIAID [AI100190]; Research Participation Program at the Winchester Engineering and Analytical Center, U.S. Food and Drug Administration; MIT/SUTD International Design Centre; Rafael del Pino Fellowship FX Funding was from the NIH NIAID (AI100190). CWY and IB were supported by appointments to the Research Participation Program at the Winchester Engineering and Analytical Center, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA. JOT is a Commissioner's Fellow of the U.S. Food and Drug Administration. HdP was supported by the MIT/SUTD International Design Centre and a Rafael del Pino Fellowship. We thank CMSE at MIT for use of TEM imaging facilities, and Dr. Michael Diamond (Washington University School of Medicine) for providing the 9NS1 antibody. NR 20 TC 31 Z9 31 U1 8 U2 61 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1473-0197 EI 1473-0189 J9 LAB CHIP JI Lab Chip PY 2015 VL 15 IS 7 BP 1638 EP 1641 DI 10.1039/c5lc00055f PG 4 WC Biochemical Research Methods; Chemistry, Multidisciplinary; Nanoscience & Nanotechnology SC Biochemistry & Molecular Biology; Chemistry; Science & Technology - Other Topics GA CE0KO UT WOS:000351493100003 PM 25672590 ER PT J AU Phillips, JA McLaughlin, MM Gettig, JP Fajiculay, JR Advincula, MR AF Phillips, Jennifer A. McLaughlin, Milena M. Gettig, Jacob P. Fajiculay, Jay R. Advincula, M. Renee TI An Analysis of Motivation Factors for Students' Pursuit of Leadership Positions SO AMERICAN JOURNAL OF PHARMACEUTICAL EDUCATION LA English DT Article DE leadership; students; organizations ID CRISIS AB Objective. To identify factors that influence student involvement and leadership within organizations and to assess the impact of involvement in organizations on professional skill development. Methods. A printed survey was administered to fourth-year pharmacy students at one college of pharmacy (N=202). Results. Most students (82%) indicated they were involved in at least one organization during pharmacy school and 58% reported holding a leadership position at some point. Factors with the largest impact on involvement in organizations were desire to present a well-rounded image to employers, ability to network, and interest in the activities sponsored by the organization. Involvement in professional organizations had a strong influence on their leadership, teamwork, confidence, and time-management skills. Conclusion. That presenting a well-rounded image to employers and having the ability to network with mentors and peers drove student involvement in professional organizations may be reflective of increasing competition for residencies and jobs. C1 [Phillips, Jennifer A.; McLaughlin, Milena M.; Gettig, Jacob P.] Midwestern Univ Chicago, Coll Pharm, Downers Grove, IL 60515 USA. [McLaughlin, Milena M.] NW Mem Hosp, Chicago, IL 60611 USA. [Fajiculay, Jay R.] Purdue Univ, Coll Pharm, W Lafayette, IN 47907 USA. [Fajiculay, Jay R.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Fajiculay, Jay R.] US FDA, Silver Spring, MD USA. [Advincula, M. Renee] NorthShore Univ Hlth Syst, Evanston, IL USA. [Phillips, Jennifer A.] Advocate Lutheran Gen Hosp, Park Ridge, IL USA. RP Phillips, JA (reprint author), Midwestern Univ Chicago, Coll Pharm, Pharm Practice, 555 31st St, Downers Grove, IL 60515 USA. EM jennifer.a.phillips@gmail.com NR 15 TC 2 Z9 2 U1 0 U2 4 PU AMER ASSOC COLL PHARMACY PI ALEXANDRIA PA 1426 PRINCE STREET, ALEXANDRIA, VA 22314-2815 USA SN 0002-9459 EI 1553-6467 J9 AM J PHARM EDUC JI Am. J. Pharm. Educ. PY 2015 VL 79 IS 1 AR 08 PG 5 WC Education, Scientific Disciplines; Pharmacology & Pharmacy SC Education & Educational Research; Pharmacology & Pharmacy GA CC7WN UT WOS:000350579200008 PM 25741024 ER PT J AU Cross, K Kruhlak, N Myatt, G Stavitskaya, L White, A AF Cross, K. Kruhlak, N. Myatt, G. Stavitskaya, L. White, A. TI Ensuring Regulatory Acceptable (Q)SAR Models and Expert Alerts for ICH M7 Reflect Proprietary Chemical Space SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Meeting Abstract CT 35th Annual Meeting of the American-College-of-Toxicology (ACT) CY NOV 09-12, 2014 CL Orlando, FL SP Amer Coll Toxicol C1 [Cross, K.; Myatt, G.] Leadscope, Columbus, OH USA. [White, A.] GlaxoSmithKline, Ware, Herts, England. [Kruhlak, N.; Stavitskaya, L.] US FDA, Silver Spring, MD USA. 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 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD JAN-FEB PY 2015 VL 34 IS 1 MA P205 BP 83 EP 84 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CB9WZ UT WOS:000349986200030 ER PT J AU Valerio, LG Yeager, RP AF Valerio, L. G., Jr. Yeager, R. P. TI Investigating the Performance of an In Silico Salmonella Mutagenicity Model with HPHCs from Tobacco Products and Tobacco Smoke SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Meeting Abstract CT 35th Annual Meeting of the American-College-of-Toxicology (ACT) CY NOV 09-12, 2014 CL Orlando, FL SP Amer Coll Toxicol C1 [Valerio, L. G., Jr.; Yeager, R. P.] US FDA, CTP, Off Sci, Div Nonclin Sci, Silver Spring, MD USA. 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 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD JAN-FEB PY 2015 VL 34 IS 1 MA P304 BP 85 EP 85 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CB9WZ UT WOS:000349986200034 ER PT J AU Wang, Y Castro, C Gong, B Morikawa, Y Yan, J Uehara, T Chen, T Tong, W AF Wang, Y. Castro, C. Gong, B. Morikawa, Y. Yan, J. Uehara, T. Chen, T. Tong, W. TI Characterization of microRNA Expression Patterns and their Target Genes to Discover Potential Biomarkers for Hepatacaciongenesis after Exposed to Thioacetamide in Rats SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Meeting Abstract CT 35th Annual Meeting of the American-College-of-Toxicology (ACT) CY NOV 09-12, 2014 CL Orlando, FL SP Amer Coll Toxicol C1 [Wang, Y.; Gong, B.; Yan, J.; Chen, T.; Tong, W.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Castro, C.] Univ N Carolina, Charlotte, NC 28223 USA. [Morikawa, Y.; Uehara, T.] Shinonogi & Co Ltd, Osaka, Japan. RI Gong, Binsheng/E-2306-2015 OI Gong, Binsheng/0000-0002-8724-5435 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 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD JAN-FEB PY 2015 VL 34 IS 1 MA P306 BP 86 EP 86 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CB9WZ UT WOS:000349986200036 ER PT J AU Zhang, J Mathis, MV Sellers, JW Kordzakhia, G Jackson, AJ Dow, A Yang, P Fossom, L Zhu, H Patel, H Unger, EF Temple, RJ AF Zhang, Jing Mathis, Mitchell V. Sellers, Jenn W. Kordzakhia, George Jackson, Andre J. Dow, Antonia Yang, Peiling Fossom, Linda Zhu, Hao Patel, Hiren Unger, Ellis F. Temple, Robert J. TI The US Food and Drug Administration's Perspective on the New Antidepressant Vortioxetine SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID MAJOR DEPRESSIVE DISORDER; GEPIRONE EXTENDED-RELEASE; 5 MG VORTIOXETINE; DOUBLE-BLIND; LU AA21004; PLACEBO; EFFICACY; TRIAL; ONDANSETRON; ADULTS AB Objective: This article summarizes the US Food and Drug Administration's (FDA's) review of the New Drug Application for vortioxetine, especially the clinical efficacy and safety data. It emphasizes the issues that were important to the FDA's approval decision, particularly the difference in the effective dose in domestic and foreign studies, and notes several new labeling features, specifically, description of time course of treatment response and detailed sexual dysfunction evaluation. Data Sources: The data sources were the original raw data sets for all clinical trials included in the development program for vortioxetine, as well as the sponsor's original analyses of these data. Data were available from 51 human trials involving vortioxetine, and included a total of 7,666 healthy volunteers and patients with a diagnosis of major depressive disorder (MDD) or generalized anxiety disorder who were exposed to at least 1 dose of vortioxetine for a total of 2,743 patient-years. Results: Vortioxetine was effective in treating MDD in the United States at a dose of 20 mg/d. The recommended starting dose is 10 mg once daily without regard to food, with increase to 20 mg/d if the 10 mg/d dose is tolerated. For patients who do not tolerate 20 mg/d, 10 mg/d can be used and 5-mg/d dose can be considered. Vortioxetine can be discontinued abruptly, but it is recommended that doses of 15 mg/d or 20 mg/d be reduced to 10 mg/d for 1 week prior to full discontinuation to avoid potential withdrawal symptoms. Although the non-US maintenance study showed that maintenance doses of 5 to 10 mg/d were effective, a clinical judgment needs to be made to decide the maintenance dose in the United States. The applicant has agreed to conduct a US maintenance dose-response study covering the US-approved dose range. Vortioxetine's adverse event profile is similar to that of other selective serotonin reuptake inhibitors (SSRIs). Nausea is the most common adverse event and is dose dependent. No dose adjustment is needed based on age, gender, or the presence of renal or mild to moderate hepatic impairment. The maximum recommended dose is 10 mg/d in known cytochrome P450 2D6 poor metabolizers. Conclusions: Vortioxetine is a new treatment for MDD, and its adverse event profile is similar to that of other SSRIs. (C) Copyright 2014 Physicians Postgraduate Press, Inc. C1 [Zhang, Jing; Mathis, Mitchell V.; Sellers, Jenn W.; Dow, Antonia; Fossom, Linda; Patel, Hiren] US FDA, Div Psychiat Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Kordzakhia, George; Yang, Peiling] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Jackson, Andre J.; Zhu, Hao] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Unger, Ellis F.; Temple, Robert J.] US FDA, Off Drug Evaluat 1, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Zhang, J (reprint author), US FDA, Div Psychiat Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jing.zhang@fda.hhs.gov NR 20 TC 11 Z9 11 U1 0 U2 8 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JAN PY 2015 VL 76 IS 1 BP 8 EP 14 DI 10.4088/JCP.14r09164 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA CD3JC UT WOS:000350973400014 PM 25562777 ER PT J AU Azad, BB Banerjee, SR Pullambhatla, M Lacerda, S Foss, CA Wang, YC Ivkov, R Pomper, MG AF Azad, Babak Behnam Banerjee, Sangeeta R. Pullambhatla, Mrudula Lacerda, Silvia Foss, Catherine A. Wang, Yuchuan Ivkov, Robert Pomper, Martin G. TI Evaluation of a PSMA-targeted BNF nanoparticle construct SO NANOSCALE LA English DT Article ID MEMBRANE ANTIGEN PSMA; DRUG-DELIVERY; MULTIFUNCTIONAL NANOPARTICLES; MAGNETIC NANOPARTICLES; CANCER; NANOMEDICINE; THERAPY; NANOTECHNOLOGY; STRATEGIES; PROTEIN AB Early detection enables improved prognosis for prostate cancer (PCa). A promising target for imaging and therapy of PCa is the prostate-specific membrane antigen (PSMA), which exhibits both expression within the epithelium of PCa cells, and becomes internalized upon ligand binding. Here we report the synthesis of a PSMA-targeted bionized nanoferrite (BNF) nanoparticle and its biological evaluation in an experimental model of PCa. The BNF nanoparticle formulation exhibits properties conducive to targeted imaging such as stealth, prolonged circulation time and enhanced clearance from non-target sites. Optical imaging of the targeted BNF in vivo indicates preferential accumulation in PSMA+ tumors 4 h post-injection, suggesting target specificity. On the other hand, non-targeted nanoparticles exhibit lower uptake with similar accumulation in both PSMA+ and PSMA-tumors indicating tumor access without preferential accumulation. Imaging with single photon emission computed tomography (SPECT) and bio-distribution studies of a modified construct indicate highest tumor accumulation at 48 h post-injection [4.3 +/- 0.4 percentage injected dose per gram of tissue (% ID g(-1))], with tumor/blood and tumor/muscle ratios of 7.5 +/- 2.4 and 11.6 +/- 1.2 % ID g(-1), respectively. Ex vivo fluorescence microscopy, Prussian blue staining, immunohistochemistry and biodistribution studies confirm enhanced nanoparticle uptake in PSMA+ tumors compared to those not expressing PSMA. The BNF nano-formulation described is promising for PSMA-targeted imaging applications in vivo. C1 [Azad, Babak Behnam; Banerjee, Sangeeta R.; Pullambhatla, Mrudula; Foss, Catherine A.; Wang, Yuchuan; Pomper, Martin G.] Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21205 USA. [Lacerda, Silvia] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Ivkov, Robert; Pomper, Martin G.] Johns Hopkins Med Inst, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD 21205 USA. RP Pomper, MG (reprint author), Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, 600 N Wolfe St, Baltimore, MD 21205 USA. EM mpomper@jhmi.edu RI Ivkov, Robert/A-3902-2015; OI Ivkov, Robert/0000-0002-2930-5276; Wang, Yuchuan/0000-0001-5111-6562 FU A. David Mazzone Award Program of the Prostate Cancer Foundation; [CA151838]; [CA134675]; [CA184228] FX This study was supported by CA151838, CA134675, CA184228 and the A. David Mazzone Award Program of the Prostate Cancer Foundation. We thank Dr. Bert Vogelstein for use of equipment from his laboratory. NR 35 TC 9 Z9 9 U1 0 U2 21 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PY 2015 VL 7 IS 10 BP 4432 EP 4442 DI 10.1039/c4nr06069e PG 11 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA CC9ED UT WOS:000350669900018 ER PT J AU Wu, HH Liu, Y Li, M Chong, Y Zeng, MY Lo, YM Yin, JJ AF Wu, Haohao Liu, Yi Li, Meng Chong, Yu Zeng, Mingyong Lo, Y. Martin Yin, Jun-Jie TI Size-dependent tuning of horseradish peroxidase bioreactivity by gold nanoparticles SO NANOSCALE LA English DT Article ID CYTOCHROME-C PEROXIDASE; HYDROGEN-PEROXIDE; COMPOUND-I; HEME-PROTEINS; OXIDATION; REDUCTION; SUPEROXIDE; ENZYME; OXYGEN; NADH AB Molecules with diverse biological functions, such as heme peroxidases, can be useful tools for identifying potential biological effects of gold nanoparticles (AuNPs) at the molecular level. Here, using UV-Vis, circular dichroism, dynamic light scattering, and electron spin resonance spectroscopy, we report tuning of horseradish peroxidase (HRP) bioactivity by reactant-free AuNPs with diameters of 5, 10, 15, 30 and 60 nm (Au-5 nm, Au-10 nm, Au-15 nm, Au-30 nm and Au-60 nm). HRP conjugation to AuNPs was observed with only Au-5 nm and Au-10 nm prominently increasing the a-helicity of the enzyme to extents inversely related to their size. Au-5 nm inhibited both HRP peroxidase activity toward 3,3',5,5'-tetramethylbenzidine and HRP compound I/II reactivity toward 5,5-dimethyl-1-pyrroline N-oxide. Au-5 nm enhanced the HRP peroxidase activity toward ascorbic acid and the HRP compound I/II reactivity toward redox-active residues in the HRP protein moiety. Further, Au-5 nm also decreased the catalase-and oxidase-like activities of HRP. Au-10 nm showed similar, but weaker effects, while Au-15 nm, Au-30 nm and Au-60 nm had no effect. Results suggest that AuNPs can size-dependently enhance or inhibit HRP bioreactivity toward substrates with different redox potentials via a mechanism involving extension of the HRP substrate access channel and decline in the redox potentials of HRP catalytic intermediates. C1 [Wu, Haohao; Zeng, Mingyong] Ocean Univ China, Coll Food Sci & Engn, Qingdao 266003, Shandong, Peoples R China. [Wu, Haohao; Liu, Yi; Li, Meng; Chong, Yu; Yin, Jun-Jie] US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Wu, Haohao; Lo, Y. Martin] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. RP Yin, JJ (reprint author), US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM junjie.yin@fda.hhs.gov RI Yin, Jun Jie /E-5619-2014; OI Zeng, Mingyong/0000-0002-3580-9139; Wu, Haohao/0000-0003-3852-2608 FU Maryland NanoCenter; Nanoscale Imaging Spectroscopy and Properties (NISP) Laboratory; regulatory science grant under the FDA Nanotechnology CORES Program; National Natural Science Foundation of China [31371758]; National Key Technology Research and Development Program of China [2012BAD28B05]; China Scholarship Council [201306330015] FX 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. We acknowledge the support of the Maryland NanoCenter and its Nanoscale Imaging Spectroscopy and Properties (NISP) Laboratory. This work was supported by a regulatory science grant under the FDA Nanotechnology CORES Program. H. Wu and M. Zeng appreciate the support from the National Natural Science Foundation of China (no. 31371758), the National Key Technology Research and Development Program of China (no. 2012BAD28B05), and the China Scholarship Council (no. 201306330015). We thank Dr Wayne G. Wamer (CFSAN/FDA) for valuable suggestions and comments on this manuscript, and Dr Lili Fox Velez for her scientific editing support. NR 48 TC 4 Z9 4 U1 9 U2 43 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PY 2015 VL 7 IS 10 BP 4505 EP 4513 DI 10.1039/c4nr07056a PG 9 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA CC9ED UT WOS:000350669900027 PM 25684572 ER PT B AU Aubin, Y Freedberg, DI Keire, DA AF Aubin, Yves Freedberg, Daron I. Keire, David A. BE Houde, DJ Berkowitz, SA TI One- and Two-Dimensional NMR Techniques for Biopharmaceuticals SO BIOPHYSICAL CHARACTERIZATION OF PROTEINS IN DEVELOPING BIOPHARMACEUTICALS LA English DT Article; Book Chapter ID MAGNETIC-RESONANCE-SPECTROSCOPY; RESIDUAL WATER SUPPRESSION; CHEMICAL-SHIFT ANISOTROPY; LIQUID-CRYSTALLINE MEDIUM; HUMAN GROWTH-HORMONE; COVARIANCE NMR; H-1-NMR SPECTROSCOPY; PROTEIN NMR; PROTON NMR; POLARIZATION TRANSFER C1 [Aubin, Yves] Hlth Canada, Ctr Biol Evaluat, Biol & Genet Therapies Directorate, Hlth Prod & Food Branch, Ottawa, ON K1A 0L2, Canada. [Freedberg, Daron I.] US FDA, Struct Biol Sect, Lab Bacterial Polysaccharides, DBPAP,OVRR,CBER, Silver Spring, MD USA. [Keire, David A.] US FDA, Div Pharmaceut Anal, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Aubin, Y (reprint author), Hlth Canada, Ctr Biol Evaluat, Biol & Genet Therapies Directorate, Hlth Prod & Food Branch, Ottawa, ON K1A 0L2, Canada. NR 89 TC 2 Z9 2 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS BN 978-0-444-59590-4; 978-0-444-59573-7 PY 2015 BP 341 EP 383 DI 10.1016/B978-0-444-59573-7.00013-0 PG 43 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA BC0HX UT WOS:000349046900014 ER PT J AU Gollenberg, AL Addo, OY Zhang, ZW Hediger, ML Himes, JH Lee, PA AF Gollenberg, Audra L. Addo, O. Yaw Zhang, Zhiwei Hediger, Mary L. Himes, John H. Lee, Peter A. TI In utero Exposure to Cigarette Smoking, Environmental Tobacco Smoke and Reproductive Hormones in US Girls Approaching Puberty SO HORMONE RESEARCH IN PAEDIATRICS LA English DT Article DE Endocrine disruptors; Puberty; Tobacco; Adolescence; Environmental tobacco smoke ID FOR-GESTATIONAL-AGE; FOLLICLE-STIMULATING-HORMONE; INHIBIN-B; LUTEINIZING-HORMONE; REDUCED UTERINE; PUBLIC-HEALTH; OVARIAN SIZE; MENARCHE; PREGNANCY; WOMEN AB Background/Aims: Evidence is unclear whether prenatal smoking affects age at menarche and pubertal development, and its impact upon hormones has not been well studied. We aim to identify potential pathways through which prenatal smoking and environmental tobacco smoke (ETS) affect reproductive hormones in girls approaching puberty. Methods: We examined the association between prenatal smoking, current ETS and luteinizing hormone (LH) and inhibin B (InB) in 6- to 11-year-old girls in the 3rd National Health and Nutrition Examination Survey, 1988-1994. Parents/guardians completed interviewer-assisted questionnaires on health and demographics at the time of physical examination. Residual blood samples were analyzed for reproductive hormones in 2008. Results: Of 660 girls, 19 and 39% were exposed to prenatal smoke and current ETS, respectively. Accounting for multiple pathways in structural equation models, prenatally exposed girls had significantly lower LH (beta = -0.205 log-mlU/ml, p < 0.0001) and InB (beta = -0.162, log-pg/ml, p < 0.0001). Prenatal smoking also influenced LH positively and InB negatively indirectly through BMI-for-age. ETS was positively associated with LH, but not with InB. Conclusion: Exposure to maternal smoking may disrupt reproductive development manifesting in altered hormone levels near puberty. (C) 2015 S. Karger AG, Basel C1 [Gollenberg, Audra L.] Shenandoah Univ, Coll Arts & Sci, Publ Hlth Program, Winchester, VA 22601 USA. [Addo, O. Yaw] Emory Univ, Rollins Sch Publ Hlth, Hubert Dept Global Hlth, Atlanta, GA 30322 USA. [Zhang, Zhiwei] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Hediger, Mary L.] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Philadelphia, PA USA. [Himes, John H.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Lee, Peter A.] Milton S Hershey Med Ctr, Penn State Coll Med, Dept Pediat, Hershey, PA USA. [Lee, Peter A.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. RP Gollenberg, AL (reprint author), Shenandoah Univ, Coll Arts & Sci, Publ Hlth Program, Winchester, VA 22601 USA. EM agollenb@su.edu OI Gollenberg, Audra/0000-0001-7542-0390; Addo, O.Yaw/0000-0003-1269-759X FU Intramural NIH HHS [ZIA HD008803-05] NR 43 TC 0 Z9 0 U1 2 U2 3 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1663-2818 EI 1663-2826 J9 HORM RES PAEDIAT JI Horm. Res. Paediatr. PY 2015 VL 83 IS 1 BP 36 EP 44 DI 10.1159/000369168 PG 9 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA CC7VS UT WOS:000350577100005 PM 25633306 ER PT J AU Oka, S Kaspar, O Tokarova, V Sowrirajan, K Wu, HQ Khan, M Muzzio, F Stepanek, F Ramachandran, R AF Oka, Sarang Kaspar, Ondrej Tokarova, Viola Sowrirajan, Koushik Wu, Huiquan Khan, Mansoor Muzzio, Fernando Stepanek, Frantisek Ramachandran, Rohit TI A quantitative study of the effect of process parameters on key granule characteristics in a high shear wet granulation process involving a two component pharmaceutical blend SO ADVANCED POWDER TECHNOLOGY LA English DT Article DE Wet granulation; High-shear; DOE; QbD; Particle size; Porosity; Process parameter ID LIQUID-BOUND GRANULES; REGIME MAP; GROWTH; NUCLEATION; QUALITY; POWDERS; DESIGN; MIXER AB The objective of the current work was to investigate the effect of liquid to solid ratio (L/S), impeller speed and the wet massing time on the critical quality attributes of granules in a high shear wet granulation process for a two component (API and excipient) system. The parameters were evaluated for their effect on granule properties using a design of experiment based approach. Granules were characterized for their particle size distribution, content uniformity, morphology and porosity. The liquid to solid (L/S) ratio was found to have a dominant effect on the median particle size and exhibited a clear trend. The system was found to be extremely well mixed for all conditions thus implying robust composition uniformity within and between batches, independent of process parameters. The release kinetics of granules within the batch were found to be identical, independent of particle size. The granules were found to be fairly spherical as observed through a scanning electron microscope with no distinct agglomeration. The images indicate granulation by layering and consolidation. All three process parameters were found to have an effect on granule porosity, with the wet massing time having the most pronounced effect. A judicious selection of the afore mentioned process parameters will enable a balance between granule growth and porosity to be achieved without compromising on the mixing efficiency of the process thereby allowing one to build quality into the final product. (C) 2014 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved. C1 [Oka, Sarang; Sowrirajan, Koushik; Muzzio, Fernando; Ramachandran, Rohit] Rutgers State Univ, Dept Chem & Biochem Engn, Piscataway, NJ 08855 USA. [Kaspar, Ondrej; Tokarova, Viola; Stepanek, Frantisek] Inst Chem Technol, Dept Chem Engn, CR-16628 Prague, Czech Republic. [Wu, Huiquan; Khan, Mansoor] US FDA, Div Prod Qual Res, Off Testing & Res, Off Pharmaceut Sci,CDER, Silver Spring, MD USA. RP Ramachandran, R (reprint author), Rutgers State Univ, Dept Chem & Biochem Engn, Piscataway, NJ 08855 USA. EM rohitrr@rci.rutgers.edu RI Stepanek, Frantisek/C-1218-2009 OI Stepanek, Frantisek/0000-0001-9288-4568 FU Ministry of Education [LH12115-MultiGRAN]; Specific University Research (Project MSMT) [20/2013]; National Institute for Pharmaceutical Technology and Education (NIPTE); U.S. Food and Drug Administration (FDA) via the FDA [5U01FD004275-02]; Engineering Research Center for Structured Organic Particulate Systems (ERC C-SOPS) [NSF-ECC 0540855] FX The authors would like to acknowledge funding from the Ministry of Education (Project LH12115-MultiGRAN) and the Specific University Research (Project MSMT No. 20/2013). S. Oka, K. Sowrirajan and R. Ramachandran are grateful to the National Institute for Pharmaceutical Technology and Education (NIPTE) and the U.S. Food and Drug Administration (FDA) for providing funds for this research via the FDA-sponsored Grant "Critical Path Manufacturing Sector Research Initiative (5U01FD004275-02). They would also like to thank the Engineering Research Center for Structured Organic Particulate Systems (ERC C-SOPS) through grant NSF-ECC 0540855. The authors are also grateful to Dr. Preetanshu Pandey of Bristol-Myers Squibb for useful discussions and suggestions pertaining to this work. The support from various FDA managers including Dr. Richard Lostritto, Dr. Vincent Vilker, Cheryl Kaiser and Mr. Jon E. Clark and insightful FDA internal review by Dr. Cindy Buhse are acknowledged. NR 21 TC 5 Z9 5 U1 4 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0921-8831 EI 1568-5527 J9 ADV POWDER TECHNOL JI Adv. Powder Technol. PD JAN PY 2015 VL 26 IS 1 BP 315 EP 322 DI 10.1016/j.apt.2014.10.012 PG 8 WC Engineering, Chemical SC Engineering GA CB6TC UT WOS:000349758600041 ER PT S AU Jones, JL AF Jones, J. L. BE Bhunia, AK Kim, MS Taitt, CR TI High throughput screening of seafood for foodborne pathogens SO HIGH THROUGHPUT SCREENING FOR FOOD SAFETY ASSESSMENT: BIOSENSOR TECHNOLOGIES, HYPERSPECTRAL IMAGING AND PRACTICAL APPLICATIONS SE Woodhead Publishing Series in Food Science Technology and Nutrition LA English DT Article; Book Chapter ID POLYMERASE-CHAIN-REACTION; REAL-TIME PCR; MEDIATED ISOTHERMAL AMPLIFICATION; VIBRIO-PARAHAEMOLYTICUS; LISTERIA-MONOCYTOGENES; UNITED-STATES; IMMUNOMAGNETIC SEPARATION; QUANTITATIVE DETECTION; IDENTIFICATION; VULNIFICUS C1 US FDA, Dauphin Isl, AL 36528 USA. RP Jones, JL (reprint author), US FDA, Dauphin Isl, AL 36528 USA. NR 51 TC 0 Z9 0 U1 0 U2 1 PU WOODHEAD PUBL LTD PI CAMBRIDGE PA ABINGTON HALL ABINGTON, CAMBRIDGE CB1 6AH, CAMBS, ENGLAND SN 2042-8049 BN 978-0-85709-807-8; 978-0-85709-801-6 J9 WOODHEAD PUBL FOOD S JI Woodhead Publ. Food Sci. Technol. Nutr. PY 2015 IS 262 BP 491 EP 505 DI 10.1016/B978-0-85709-801-6.00020-4 PG 15 WC Food Science & Technology SC Food Science & Technology GA BC0DI UT WOS:000348925600020 ER PT J AU Sanlorenzo, M Wehner, MR Linos, E Kornak, J Kainz, WG Posch, C Vujic, I Johnston, K Gho, D Monico, G McGrath, JT Osella-Abate, S Quaglino, P Cleaver, JE Ortiz-Urda, S AF Sanlorenzo, Martina Wehner, Mackenzie R. Linos, Eleni Kornak, John Kainz, Wolfgang Posch, Christian Vujic, Igor Johnston, Katia Gho, Deborah Monico, Gabriela McGrath, James T. Osella-Abate, Simona Quaglino, Pietro Cleaver, James E. Ortiz-Urda, Susana TI The Risk of Melanoma in Airline Pilots and Cabin Crew A Meta-analysis SO JAMA DERMATOLOGY LA English DT Article ID CAUSE-SPECIFIC MORTALITY; CANCER INCIDENCE; COSMIC-RADIATION; FLIGHT ATTENDANTS; UNITED-STATES; MALIGNANT-MELANOMA; CUTANEOUS MELANOMA; COHORT; POPULATION; EXPOSURE AB IMPORTANCE Airline pilots and cabin crew are occupationally exposed to higher levels of cosmic and UV radiation than the general population, but their risk of developing melanoma is not yet established. OBJECTIVE To assess the risk of melanoma in pilots and airline crew. DATA SOURCES PubMed (1966 to October 30, 2013), Web of Science (1898 to January 27, 2014), and Scopus (1823 to January 27, 2014). STUDY SELECTION All studies were included that reported a standardized incidence ratio (SIR), standardized mortality ratio (SMR), or data on expected and observed cases of melanoma or death caused by melanoma that could be used to calculate an SIR or SMR in any flight-based occupation. DATA EXTRACTION AND SYNTHESIS Primary random-effectmeta-analyses were used to summarize SIR and SMR for melanoma in any flight-based occupation. Heterogeneity was assessed using the X-2 test and I-2 statistic. To assess the potential bias of small studies, we used funnel plots, the Begg rank correlation test, and the Egger weighted linear regression test. MAIN OUTCOMES AND MEASURES Summary SIR and SMR of melanoma in pilots and cabin crew. RESULTS Of the 3527 citations retrieved, 19 studies were included, with more than 266 431 participants. The overall summary SIR of participants in any flight-based occupation was 2.21 (95% CI, 1.76-2.77; P < .001; 14 records). The summary SIR for pilots was 2.22 (95% CI, 1.67-2.93; P = .001; 12 records). The summary SIR for cabin crew was 2.09 (95% CI, 1.67-2.62; P = .45; 2 records). The overall summary SMR of participants in any flight-based occupation was 1.42 (95% CI, 0.89-2.26; P = .002; 6 records). The summary SMR for pilots was 1.83 (95% CI, 1.27-2.63, P = .33; 4 records). The summary SMR for cabin crew was 0.90 (95% CI, 0.80-1.01; P = .97; 2 records). CONCLUSIONS AND RELEVANCE Pilots and cabin crew have approximately twice the incidence of melanoma compared with the general population. Further research on mechanisms and optimal occupational protection is needed. C1 [Sanlorenzo, Martina; Wehner, Mackenzie R.; Linos, Eleni; Posch, Christian; Vujic, Igor; Johnston, Katia; Gho, Deborah; Monico, Gabriela; McGrath, James T.; Cleaver, James E.; Ortiz-Urda, Susana] Univ Calif San Francisco, Dept Dermatol, Mt Zion Canc Res Ctr, San Francisco, CA 94115 USA. [Sanlorenzo, Martina; Osella-Abate, Simona; Quaglino, Pietro] Univ Turin, Dept Med Sci, Dermatol Sect, Turin, Italy. [Wehner, Mackenzie R.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Kornak, John] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kainz, Wolfgang] US FDA, Ctr Devices & Radiol Hlth, Div Phys, Silver Spring, MD USA. [Posch, Christian; Vujic, Igor] Rudolfstiftung Hosp, Dept Dermatol, Vienna, Austria. RP Ortiz-Urda, S (reprint author), Univ Calif San Francisco, Dept Dermatol, Mt Zion Canc Res Ctr, 2340 Sutter St, San Francisco, CA 94115 USA. EM ortizsm@derm.ucsf.edu OI Linos, Eleni/0000-0002-5856-6301; Posch, Christian/0000-0003-0296-3567; , Eleni/0000-0003-2538-0700 FU National Cancer Institute of the National Institutes of Health [KO8CA155O35]; Melanoma Research Alliance, and Timothy Dattels, MBA; Dermatology Foundation Career Development Award; National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI [KL2TROOO14] FX This study was supported in part by the National Cancer Institute of the National Institutes of Health under award No. KO8CA155O35 (Dr Ortiz-Urda), the Melanoma Research Alliance (Dr Ortiz-Urda), and Timothy Dattels, MBA, and the Dermatology Foundation Career Development Award, the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI grant No. KL2TROOO14 (Dr Linos) also provided generous support. NR 44 TC 17 Z9 17 U1 3 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD JAN PY 2015 VL 151 IS 1 BP 51 EP 58 DI 10.1001/jamadermatol.2014.1077 PG 8 WC Dermatology SC Dermatology GA CB6RI UT WOS:000349753900010 PM 25188246 ER PT J AU Wang, YH Avonto, C Avula, B Wang, M Rua, D Khan, IA AF Wang, Yan-Hong Avonto, Cristina Avula, Bharathi Wang, Mei Rua, Diego Khan, Ikhlas A. TI Quantitative Determination of alpha-Arbutin, beta-Arbutin, Kojic Acid, Nicotinamide, Hydroquinone, Resorcinol, 4-Methoxyphenol, 4-Ethoxyphenol, and Ascorbic Acid from Skin Whitening Products by HPLC-UV SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; COSMETIC PRODUCTS; LIGHTENING AGENTS; TYROSINASE; VALIDATION; CREAMS AB An HPLC-UV method was developed for the quantitative analysis of nine skin whitening agents in a single injection. These compounds are a-arbutin, beta-arbutin, kojic acid, nicotinamide, resorcinol, ascorbic acid, hydroquinone, 4-methoxyphenol, and 4-ethoxyphenol. The separation was achieved on a reversed-phase C-18 column within 30 min. The mobile phase was composed of water and methanol, both containing 0.1% acetic acid (v/v). The stability of the analytes was evaluated at different pH values between 2.3 and 7.6, and the extraction procedure was validated for different types of skin whitening product matrixes, which included two creams, a soap bar, and a capsule. The best solvent system for sample preparation was 20 mM NaH2PO4 containing 10% methanol at pH 2.3. The analytical method was validated for accuracy, precision, LOD, and LOQ. The developed HPLC-UV method was applied for the quantitation of the nine analytes in 59 skin whitening products including creams, lotions, sera, foams, gels, mask sheets, soap bars, tablets, and capsules. C1 [Wang, Yan-Hong; Avonto, Cristina; Avula, Bharathi; Wang, Mei; Khan, Ikhlas A.] Univ Mississippi, Sch Pharm, Pharmaceut Sci Res Inst, Natl Ctr Nat Prod Res, University, MS 38677 USA. [Rua, Diego] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Khan, Ikhlas A.] Univ Mississippi, Sch Pharm, Dept BioMol Sci, Div Pharmacogmosy, University, MS 38677 USA. [Khan, Ikhlas A.] King Saud Univ, Coll Pharm, Dept Pharmacognosy, Riyadh, Saudi Arabia. RP Khan, IA (reprint author), Univ Mississippi, Sch Pharm, Pharmaceut Sci Res Inst, Natl Ctr Nat Prod Res, University, MS 38677 USA. EM ikhan@olemiss.edu FU "Science Based Authentication of Dietary Supplements" - U.S. Food and Drug Administration [1U01FD004246-003]; U.S. Department of Agriculture, Agricultural Research Service [58-6408-02-1-162-04] FX This research is supported in part by "Science Based Authentication of Dietary Supplements" funded by the U.S. Food and Drug Administration Grant No. 1U01FD004246-003, and the U.S. Department of Agriculture, Agricultural Research Service, Specific Cooperative Agreement No. 58-6408-02-1-162-04. NR 26 TC 4 Z9 4 U1 7 U2 42 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 JAN-FEB PY 2015 VL 98 IS 1 BP 5 EP 12 DI 10.5740/jaoacint.14-123 PG 8 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA CB4JE UT WOS:000349593200002 PM 25857872 ER PT J AU Hepp, NM AF Hepp, Nancy Morris TI Determination of Arsenic, Chromium, Lead, Manganese, and Mercury in Certifiable Color Additives by Inductively Coupled Plasma/Mass Spectrometry SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID ATOMIC-ABSORPTION-SPECTROMETRY; X-RAY-FLUORESCENCE; MASS-SPECTROMETRY AB Specifications in the Code of Federal Regulations limit the levels of As, Pb, and Hg in most certifiable color additives, and some have additional specification limits for Cr and Mn. A new ICP/MS method was developed and validated for the quantitative determination of these elements in various certifiable color additives. One dissolution and two microwave-assisted digestion sample preparation procedures were optimized to address initial low Hg and enhanced As recoveries. Results using the three sample preparation procedures were generally equivalent for all of the elements determined. LOQ values were 0.3 mg/kg for As, 0.7 mg/kg for Cr, 0.4 mg/kg for Pb, 0.7 mg/kg for Mn, and 0.1 mg/kg for Hg. C1 US FDA, Ctr Food Safety & Appl Nutr, Off Cosmet & Colors, College Pk, MD 20740 USA. RP Hepp, NM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Cosmet & Colors, College Pk, MD 20740 USA. EM Nancy.Hepp@fda.hhs.gov NR 9 TC 4 Z9 4 U1 2 U2 15 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 JAN-FEB PY 2015 VL 98 IS 1 BP 160 EP 164 DI 10.5740/jaoacint.13-284 PG 5 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA CB4JE UT WOS:000349593200022 PM 25857892 ER PT J AU Wang, B Zhou, XY Wang, DQ Yin, JJ Chen, HQ Gao, XF Zhang, J Ibrahim, K Chai, ZF Feng, WY Zhao, YL AF Wang, Bing Zhou, Xiaoyan Wang, Dongqi Yin, Jun-Jie Chen, Hanqing Gao, Xingfa Zhang, Jing Ibrahim, Kurash Chai, Zhifang Feng, Weiyue Zhao, Yuliang TI Structure and catalytic activities of ferrous centers confined on the interface between carbon nanotubes and humic acid SO NANOSCALE LA English DT Article ID MOLECULAR-ORBITAL METHODS; OXYGEN REDUCTION REACTION; GAUSSIAN-TYPE BASIS; ORGANIC-MOLECULES; HYDROXYL RADICALS; METAL CENTERS; BASIS-SET; IRON; ACTIVATION; OXIDATION AB Preparation of heterogeneous catalysts with active ferrous centers is of great significance for industrial and environmental catalytic processes. Nanostructured carbon materials (NCM), which possess free-flowing p electrons, can coordinate with transition metals, provide a confinement environment for catalysis, and act as potential supports or ligands to construct analogous complexes. However, designing such catalysts using NCM is still seldom studied to date. Herein, we synthesized a sandwich structured ternary complex via the coordination of Fe-loaded humic acid (HA) with C=C bonds in the aromatic rings of carbon nanotubes (CNTs), in which the O/N-Fe-C interface configuration provides the confinement environment for the ferrous sites. The experimental and theoretical results revealed octahedrally/tetra-hedrally coordinated geometry at Fe centers, and the strong hybridization between CNT C pi* and Fe 3d orbitals induces discretization of the atomic charges on aromatic rings of CNTs, which facilitates O-2 adsorption and electron transfer from carbon to O-2, which enhances O-2 activation. The O-2 activation by the novel HA/Fe-CNT complex can be applied in the oxidative degradation of phenol red (PR) and bisphenol A (BPA) in aqueous media. C1 [Wang, Bing; Zhou, Xiaoyan; Wang, Dongqi; Chen, Hanqing; Gao, Xingfa; Chai, Zhifang; Feng, Weiyue; Zhao, Yuliang] Chinese Acad Sci, Inst High Energy Phys, CAS Key Lab Nucl Radiat & Nucl Energy Technol, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100049, Peoples R China. [Yin, Jun-Jie] US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Zhang, Jing; Ibrahim, Kurash] Chinese Acad Sci, Inst High Energy Phys, Beijing Synchrotron Radiat Facil, Beijing 100049, Peoples R China. [Chai, Zhifang] Soochow Univ, Sch Radiat Med & Protect, Suzhou 215123, Peoples R China. [Zhao, Yuliang] Natl Ctr Nanosci & Technol China, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100190, Peoples R China. RP Wang, DQ (reprint author), Chinese Acad Sci, Inst High Energy Phys, CAS Key Lab Nucl Radiat & Nucl Energy Technol, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100049, Peoples R China. EM dwang@ihep.ac.cn; fengwy@ihep.ac.cn RI Yin, Jun Jie /E-5619-2014; Gao, Xingfa/E-5691-2010; Wang, Dongqi/A-8977-2012; Feng, Wei-Yue/H-3390-2016 OI Gao, Xingfa/0000-0002-1636-6336; FU National Basic Research Program (973 program) [2011CB933403]; National Natural Science Foundation of China [11275214, 11375211] FX The authors are grateful for the financial support of the National Basic Research Program (973 program, 2011CB933403) and the National Natural Science Foundation of China (11275214, 11375211). NR 46 TC 4 Z9 4 U1 12 U2 46 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PY 2015 VL 7 IS 6 BP 2651 EP 2658 DI 10.1039/c4nr06665k PG 8 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA CB2QH UT WOS:000349472300057 PM 25580558 ER PT J AU Cedarbaum, JM Stephenson, D Rudick, R Carrillo, MC Stebbins, G Kerr, D Heemskerk, J Galpern, WR Kaufmann, P Cella, D Isaac, M Walton, MK AF Cedarbaum, Jesse M. Stephenson, Diane Rudick, Richard Carrillo, Maria C. Stebbins, Glenn Kerr, Douglas Heemskerk, Jill Galpern, Wendy R. Kaufmann, Petra Cella, David Isaac, Maria Walton, Marc K. TI Commonalities and Challenges in the Development of Clinical Trial Measures in Neurology SO NEUROTHERAPEUTICS LA English DT Article DE Clinical trials; Clinical outcome assessments ID DISEASE RATING-SCALE; ALZHEIMERS ASSOCIATION WORKGROUPS; AMYOTROPHIC-LATERAL-SCLEROSIS; SOCIETY-SPONSORED REVISION; PARKINSONS-DISEASE; MDS-UPDRS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; RECOMMENDATIONS; DEXPRAMIPEXOLE AB As neurologists and neuroscientists, we are trained to evaluate disorders of the nervous system by thinking systematically. Clinically, we think in terms of cognition, behavior, motor function, sensation, balance and co-ordination, and autonomic system function. But when we assess symptoms of neurological disorders for the purpose of drug development, we tend to create disease-specific outcome measures, often using a variety of methods to assess the same types of dysfunction in overlapping, related disorders. To begin to explore the potential to simplify and harmonize the assessment of dysfunction across neurological disorders, a symposium, entitled, "Commonalities in the Development of Outcome Measures in Neurology" was held at the 16th annual meeting of the American Society for Experimental NeuroTherapeutics (ASENT), in February 2014. This paper summarizes the presentations at the symposium. The authors hope that readers will begin to view Clinical Outcome Assessment (COA) development in a new light. We hope that in presenting this material, we will stimulate discussions and collaborations across disease areas to develop common concepts of neurological COA development and construction. C1 [Cedarbaum, Jesse M.] Biogen Idec Inc, Neurol Early Clin Dev, Cambridge, MA 02142 USA. [Stephenson, Diane] Crit Path Inst, Tucson, AZ USA. [Rudick, Richard] Biogen Idec Inc, Value Based Med, Cambridge, MA 02142 USA. [Carrillo, Maria C.] Alzheimers Assoc, Chicago, IL USA. [Stebbins, Glenn] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Kerr, Douglas] Biogen Idec Inc, Clin & Safety Sci, Cambridge, MA 02142 USA. [Heemskerk, Jill] NIMH, Div Adult Translat Res, NIH, Bethesda, MD 20892 USA. [Galpern, Wendy R.] NINDS, Off Clin Res, Bethesda, MD 20892 USA. [Kaufmann, Petra] NIH, Div Clin Innovat, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Cella, David] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Isaac, Maria] European Med Agcy, London, England. [Walton, Marc K.] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Cedarbaum, JM (reprint author), Biogen Idec Inc, Neurol Early Clin Dev, 14 Cambridge Ctr, Cambridge, MA 02142 USA. EM jesse.cedarbaum@biogenidec.com NR 26 TC 2 Z9 2 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 EI 1878-7479 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JAN PY 2015 VL 12 IS 1 BP 151 EP 169 DI 10.1007/s13311-014-0310-1 PG 19 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA CB3PX UT WOS:000349541800017 PM 25384682 ER PT J AU Cedarbaum, JM Stephenson, D Rudick, R Carrillo, MC Stebbins, G Kerr, D Heemskerk, J Galpern, WR Kaufmann, P Cella, D Isaac, M Walton, MK AF Cedarbaum, Jesse M. Stephenson, Diane Rudick, Richard Carrillo, Maria C. Stebbins, Glenn Kerr, Douglas Heemskerk, Jill Galpern, Wendy R. Kaufmann, Petra Cella, David Isaac, Maria Walton, Marc K. TI Commonalities and Challenges in the Development of Clinical Trial Measures in Neurology (vol 12, pg 151, 2015) SO NEUROTHERAPEUTICS LA English DT Correction C1 [Cedarbaum, Jesse M.] Biogen Idec Inc, CambridgeCtr 14, Neurol Early Clin Dev, Cambridge, MA 02142 USA. [Stephenson, Diane] Crit Path Inst, Tucson, AZ USA. [Rudick, Richard] Biogen Idec Inc, Value Based Med, Cambridge, MA USA. [Carrillo, Maria C.] Alzheimers Assoc, Med & Sci Relat, Chicago, IL USA. [Stebbins, Glenn] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Kerr, Douglas] Biogen Idec Inc, Clin & Safety Sci, Cambridge, MA USA. [Heemskerk, Jill] NIMH, Div Adult Translat Res, NIH, Bethesda, MD 20892 USA. [Galpern, Wendy R.] NINDS, Off Clin Res, Bethesda, MD 20892 USA. [Kaufmann, Petra] NIH, Div Clin Innovat, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Cella, David] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Isaac, Maria] European Med Agcy, London, England. [Walton, Marc K.] Ctr Drug Evaluat & Res Food & Drug Adm, Off Translat Sci, Silver Spring, MD USA. RP Cedarbaum, JM (reprint author), Biogen Idec Inc, CambridgeCtr 14, Neurol Early Clin Dev, Cambridge, MA 02142 USA. EM jesse.cedarbaum@biogenidec.com NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 EI 1878-7479 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JAN PY 2015 VL 12 IS 1 BP 285 EP 285 DI 10.1007/s13311-014-0323-9 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA CB3PX UT WOS:000349541800074 PM 25608934 ER PT J AU Pouillot, R Hoelzer, K Chen, YH Dennis, SB AF Pouillot, Regis Hoelzer, Karin Chen, Yuhuan Dennis, Sherri B. TI Listeria monocytogenes Dose Response Revisited-Incorporating Adjustments for Variability in Strain Virulence and Host Susceptibility SO RISK ANALYSIS LA English DT Article DE Dose response; Listeria monocytogenes; risk assessment ID SURVEILLANCE NETWORK FOODNET; COLD-SMOKED SALMON; TO-EAT FOODS; UNITED-STATES; RISK-ASSESSMENT; OUTBREAK; ILLNESS; MODELS; CONSUMPTION; INTERNALIN AB Evaluations of Listeria monocytogenes dose-response relationships are crucially important for risk assessment and risk management, but are complicated by considerable variability across population subgroups and L. monocytogenes strains. Despite difficulties associated with the collection of adequate data from outbreak investigations or sporadic cases, the limitations of currently available animal models, and the inability to conduct human volunteer studies, some of the available data now allow refinements of the well-established exponential L. monocytogenes dose response to more adequately represent extremely susceptible population subgroups and highly virulent L. monocytogenes strains. Here, a model incorporating adjustments for variability in L. monocytogenes strain virulence and host susceptibility was derived for 11 population subgroups with similar underlying comorbidities using data from multiple sources, including human surveillance and food survey data. In light of the unique inherent properties of L. monocytogenes dose response, a lognormal-Poisson dose-response model was chosen, and proved able to reconcile dose-response relationships developed based on surveillance data with outbreak data. This model was compared to a classical beta-Poisson dose-response model, which was insufficiently flexible for modeling the specific case of L. monocytogenes dose-response relationships, especially in outbreak situations. Overall, the modeling results suggest that most listeriosis cases are linked to the ingestion of food contaminated with medium to high concentrations of L. monocytogenes. While additional data are needed to refine the derived model and to better characterize and quantify the variability in L. monocytogenes strain virulence and individual host susceptibility, the framework derived here represents a promising approach to more adequately characterize the risk of listeriosis in highly susceptible population subgroups. C1 [Pouillot, Regis; Hoelzer, Karin; Chen, Yuhuan; Dennis, Sherri 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 RI Pouillot, Regis/E-8103-2010 OI Pouillot, Regis/0000-0002-6107-5212 FU Center for Food Safety and Applied Nutrition FX This work was supported, in part, by an appointment 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. We thank Eric Ebel (USDA-FSIS) and the anonymous reviewers for their constructive comments on the first draft of the article. NR 58 TC 6 Z9 6 U1 0 U2 15 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 JAN PY 2015 VL 35 IS 1 BP 90 EP 108 DI 10.1111/risa.12235 PG 19 WC Public, Environmental & Occupational Health; Mathematics, Interdisciplinary Applications; Social Sciences, Mathematical Methods SC Public, Environmental & Occupational Health; Mathematics; Mathematical Methods In Social Sciences GA CB5XJ UT WOS:000349701000012 PM 24975545 ER PT J AU Louie, A Boyne, MT Patel, V Huntley, C Liu, W Fikes, S Kurhanewicz, S Rodriquez, J Robbins, N Brown, D Baluya, D Drusano, GL AF Louie, Arnold Boyne, Michael T., II Patel, Vikram Huntley, Clayton Liu, Weiguo Fikes, Steven Kurhanewicz, Stephanie Rodriquez, Jaime Robbins, Nichole Brown, David Baluya, Dodge Drusano, G. L. TI Pharmacodynamic Evaluation of the Activities of Six Parenteral Vancomycin Products Available in the United States SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; QUALITY AB A recent report found that generic parenteral vancomycin products may not have in vivo efficacies equivalent to those of the innovator in a neutropenic murine thigh infection model despite having similar in vitro microbiological activities and murine serum pharmacokinetics. We compared the in vitro and in vivo activities of six of the parenteral vancomycin products available in the United States. The in vitro assessments for the potencies of the vancomycin products included MIC/minimal bactericidal concentration (MBC) determinations, quantifying the impact of human and murine serum on the MIC values, and time-kill studies. Also, the potencies of the vancomycin products were quantified with a biological assay, and the human and mouse serum protein binding rates for the vancomycin products were measured. The in vivo studies included dose-ranging experiments with the 6 vancomycin products for three isolates of Staphylococcus aureus in a neutropenic mouse thigh infection model. The pharmacokinetics of the vancomycin products were assessed in infected mice by population pharmacokinetic modeling. No differences were seen across the vancomycin products with regard to any in vitro evaluation. Inhibitory sigmoid maximal bacterial kill (E-max) modeling of the relationship between vancomycin dosage and the killing of the bacteria in mice in vivo yielded similar E-max and EC50 (drug exposure driving one-half E-max) values for bacterial killing. Further, there were no differences in the pharmacokinetic clearances of the 6 vancomycin products from infected mice. There were no important pharmacodynamic differences in the in vitro or in vivo activities among the six vancomycin products evaluated. C1 [Louie, Arnold; Fikes, Steven; Kurhanewicz, Stephanie; Rodriquez, Jaime; Robbins, Nichole; Brown, David; Baluya, Dodge; Drusano, G. L.] Univ Florida, Coll Med, Inst Therapeut Innovat, Orlando, FL 32827 USA. [Boyne, Michael T., II] US FDA, Div Pharmaceut Anal, Off Testing & Res, Off Pharmaceut Sci, Silver Spring, MD USA. [Patel, Vikram] US FDA, Div Appl Regulatory Sci, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Huntley, Clayton] NIAID, NIH, Bacteriol & Mycol Branch, Div Microbiol & Infect Dis, Bethesda, MD 20892 USA. RP Louie, A (reprint author), Univ Florida, Coll Med, Inst Therapeut Innovat, Orlando, FL 32827 USA. EM Arnold.Louie@medicine.ufl.edu FU National Institutes of Health, National Institute of Allergy and Infectious Diseases [R01AI090802] FX This work was supported by grant R01AI090802 from the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 13 TC 3 Z9 3 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JAN PY 2015 VL 59 IS 1 BP 622 EP 632 DI 10.1128/AAC.03710-14 PG 11 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA CA0LO UT WOS:000348609500076 PM 25385113 ER PT S AU Eichelberger, MC Wan, HQ AF Eichelberger, Maryna C. Wan, Hongquan BE Oldstone, MBA Compans, RW TI Influenza Neuraminidase as a Vaccine Antigen SO INFLUENZA PATHOGENESIS AND CONTROL - VOL II SE Current Topics in Microbiology and Immunology LA English DT Review; Book Chapter ID DIVALENT-CATION REQUIREMENTS; PANDEMIC H1N1 NEURAMINIDASE; A VIRUS NEURAMINIDASE; VIRAL NEURAMINIDASE; IMMUNOLOGICAL RESPONSE; INHIBITING ANTIBODIES; ZONAL CENTRIFUGATION; CRYSTAL-STRUCTURE; 2.2-A RESOLUTION; PRIOR EXPERIENCE AB Neuraminidase (NA) is the second most abundant influenza surface glycoprotein and contributes to virus replication in several ways, most notably by removing sialic acids from the host and viral glycoproteins, releasing newly formed virus particles from infected cells. Antibodies that block this enzyme activity restrict virus replication in vitro. This chapter describes foundational epidemiologic and human influenza challenge studies that provide evidence of an association between NA inhibiting antibodies and resistance to disease. Mouse challenge studies show that while NA immunity is infection-permissive, NA-specific antibodies attenuate infection and prevent severe disease. NA immunity is most effective against homologous viruses but there is substantial protection against viruses with a heterologous NA (different lineage within a NA subtype). Monoclonal antibodies specific for conserved antigenic domains of subtype N1 protect against seasonal and pandemic H1N1 as well as H5N1 virus challenge. Clinical studies demonstrate that licensed seasonal vaccines contain immunogenic amounts of NA, but the contribution of this immunity to vaccine efficacy is currently not known. New types of influenza vaccines could be designed to elicit NA immunity. Because NA induces heterologous immunity, it could be an important constituent of universal influenza vaccines that aim to protect against unexpected emerging viruses. C1 [Eichelberger, Maryna C.; Wan, Hongquan] US FDA, Div Viral Prod, Off Vaccine Res & Review, Ctr Biol Res & Regulat, Silver Spring, MD 20892 USA. RP Eichelberger, MC (reprint author), US FDA, Div Viral Prod, Off Vaccine Res & Review, Ctr Biol Res & Regulat, HFM445, Silver Spring, MD 20892 USA. EM Maryna.Eichelberger@fda.hhs.gov; Hongquan.Wan@fda.hhs.gov NR 99 TC 11 Z9 11 U1 3 U2 19 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0070-217X BN 978-3-319-11158-2; 978-3-319-11157-5 J9 CURR TOP MICROBIOL JI Curr.Top.Microbiol.Immunol. PY 2015 VL 386 BP 275 EP 299 DI 10.1007/82_2014_398 D2 10.1007/978-3-319-11158-2 PG 25 WC Immunology; Microbiology SC Immunology; Microbiology GA BC0EE UT WOS:000348984400011 PM 25033754 ER PT J AU de Araujo, FF Nagarkatti, R Gupta, C Marino, AP Debrabant, A AF de Araujo, Fernanda Fortes Nagarkatti, Rana Gupta, Charu Marino, Ana Paula Debrabant, Alain TI Aptamer-Based Detection of Disease Biomarkers in Mouse Models for Chagas Drug Discovery SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID TRYPANOSOMA-CRUZI; AMERICAN TRYPANOSOMIASIS; MURINE HOSTS; VACCINE; MICE; INFECTION; STRAINS; HEART; PCR AB Drug discovery initiatives, aimed at Chagas treatment, have been hampered by the lack of standardized drug screening protocols and the absence of simple pre-clinical assays to evaluate treatment efficacy in animal models. In this study, we used a simple Enzyme Linked Aptamer (ELA) assay to detect T. cruzi biomarker in blood and validate murine drug discovery models of Chagas disease. In two mice models, Apt-29 ELA assay demonstrated that biomarker levels were significantly higher in the infected group compared to the control group, and upon Benznidazole treatment, their levels reduced. However, biomarker levels in the infected treated group did not reduce to those seen in the non-infected treated group, with 100% of the mice above the assay cutoff, suggesting that parasitemia was reduced but cure was not achieved. The ELA assay was capable of detecting circulating biomarkers in mice infected with various strains of T. cruzi parasites. Our results showed that the ELA assay could detect residual parasitemia in treated mice by providing an overall picture of the infection in the host. They suggest that the ELA assay can be used in drug discovery applications to assess treatment efficacy in-vivo. C1 [de Araujo, Fernanda Fortes; Nagarkatti, Rana; Gupta, Charu; Debrabant, Alain] US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Marino, Ana Paula] NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP de Araujo, FF (reprint author), US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM alain.debrabant@fda.hhs.gov OI Gupta, Charu/0000-0002-7437-6559 FU US Food and Drug Administration FX Research was supported by intramural grants from the US Food and Drug Administration to AD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 6 Z9 6 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JAN PY 2015 VL 9 IS 1 AR e3451 DI 10.1371/journal.pntd.0003451 PG 10 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CB0LR UT WOS:000349318100048 PM 25569299 ER PT J AU Phillips, KS Patwardhan, D Jayan, G AF Phillips, K. Scott Patwardhan, Dinesh Jayan, Geetha TI Biofilms, medical devices, and antibiofilm technology: Key messages from a recent public workshop SO AMERICAN JOURNAL OF INFECTION CONTROL LA English DT Editorial Material ID INFECTIONS C1 [Phillips, K. Scott] US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth,Off Med Prod & Tobacco, Silver Spring, MD 20993 USA. [Patwardhan, Dinesh] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Off Med Prod & Tobacco, Silver Spring, MD 20993 USA. [Jayan, Geetha] US FDA, Off Ctr Director, Ctr Devices & Radiol Hlth, Off Med Prod & Tobacco, Silver Spring, MD 20993 USA. RP Phillips, KS (reprint author), US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, 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 NR 11 TC 3 Z9 3 U1 1 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-6553 EI 1527-3296 J9 AM J INFECT CONTROL JI Am. J. Infect. Control PD JAN PY 2015 VL 43 IS 1 BP 2 EP 3 DI 10.1016/j.ajic.2014.09.019 PG 2 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA AY6CG UT WOS:000347654600001 PM 25448303 ER PT J AU Furtak, VA Dabrazhynetskaya, A Volokhov, DV Chizhikov, V AF Furtak, Vyacheslav A. Dabrazhynetskaya, Alena Volokhov, Dmitriy V. Chizhikov, Vladimir TI Use of tangential flow filtration for improving detection of viral adventitious agents in cell substrates SO BIOLOGICALS LA English DT Article DE Cell substrates; Adventitious agents; Ultrafiltration; Concentration; Detection ID VIRUS; SAMPLES; CULTURES; WATER; PCR; DNA; ULTRAFILTRATION; IDENTIFICATION; AMPLIFICATION; PURIFICATION AB In this study, we assessed the feasibility of tangential flow filtration (TFF) for primary concentration of viral adventitious agents (AAs) from large volumes of cell substrate-derived samples, such as cell-free Chinese hamster ovary (CHO) culture supernatants (500 mL) and CHO cell lysates (50 mL), prior to virus detection in them by nucleic acid-based methods (i.e., qPCR and massively parallel sequencing (MPS). The study was conducted using the samples spiked with four model DNA viruses (bovine herpesvirus type 4, human adenovirus type 5, simian polyomavirus SV-40, and bovine parvovirus). The results showed that the combined TFF/MPS approach enables reliable detection of as low as 1000 genome equivalents (GE) of each of the four viruses spiked into the cell substrate samples. The final achieved sensitivities of 2 GE/mL for cell culture supernatant and 20 GE/mL for cell lysate make this approach more sensitive than virus-specific PCR and qPCR assays. The study results allowed us to propose that TFF might be useful and valuable method for simple and rapid concentration of potential AAs in cell substrate samples prior to AAs detection by conventional in vivo, in vitro, or molecular methods. Published by Elsevier Ltd on behalf of The International Alliance for Biological Standardization. C1 [Furtak, Vyacheslav A.; Dabrazhynetskaya, Alena; Volokhov, Dmitriy V.; Chizhikov, Vladimir] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Chizhikov, V (reprint author), US FDA, Ctr Biol Evaluat & Res, Off Vaccine Res & Review, Div Viral Prod,Lab Methods Dev, 10903 New Hampshire Ave,Bldg 52,Room 1118, Silver Spring, MD 20993 USA. EM vladimir.chizhikov@fda.hhs.gov FU Medical Counter-measures Initiative, FDA FX This work was financially supported by the Medical Counter-measures Initiative, FDA. NR 49 TC 1 Z9 1 U1 3 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1045-1056 EI 1095-8320 J9 BIOLOGICALS JI Biologicals PD JAN PY 2015 VL 43 IS 1 BP 23 EP 30 DI 10.1016/j.biologicals.2014.10.005 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA CA5LO UT WOS:000348950100004 PM 25432087 ER PT J AU Klontz, KC Singh, N AF Klontz, Karl C. Singh, Nalini TI Treatment of drug-resistant Shigella infections SO EXPERT REVIEW OF ANTI-INFECTIVE THERAPY LA English DT Review DE bacillary dysentery; diarrheal disease; multidrug resistance; Shigella; shigellosis ID SPECTRUM BETA-LACTAMASE; TRIMETHOPRIM-SULFAMETHOXAZOLE THERAPY; REDUCED AZITHROMYCIN SUSCEPTIBILITY; TRANSFERABLE ANTIBIOTIC RESISTANCE; RANDOMIZED CLINICAL-TRIAL; ACUTE INVASIVE DIARRHEA; DYSENTERIAE TYPE-1; NALIDIXIC-ACID; DOUBLE-BLIND; ANTIMICROBIAL-RESISTANCE AB Since the introduction of sulfonamides in the late 1930s, selective pressure and the widespread dissemination of mobile genetic elements conferring antimicrobial resistance have forced clinicians to seek successive agents for the treatment of multidrug-resistant shigellosis. Over the decades, the principal antibiotics used to treat Shigella infections have included tetracycline, chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, and nalidixic acid. Presently, ciprofloxacin, azithromycin, and ceftriaxone serve as the mainstays of treatment, although growing evidence has documented decreased susceptibility or full resistance to these agents in some regions. With diminishing pharmaceutical options available, there is an enhanced need for preventive measures in the form of improved sanitation and hygiene standards, strict use of currently effective agents, and a safe and effective licensed vaccine. C1 [Klontz, Karl C.] US FDA, Off Analyt & Outreach, Ctr Food Safety & Appl Nutr, College Pk, MD 20814 USA. [Singh, Nalini] George Washington Univ, Washington, DC USA. RP Klontz, KC (reprint author), US FDA, Off Analyt & Outreach, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20814 USA. EM karl.klontz@fda.hhs.gov NR 193 TC 10 Z9 10 U1 0 U2 19 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1478-7210 EI 1744-8336 J9 EXPERT REV ANTI-INFE JI Expert Rev. Anti-Infect. Ther. PD JAN PY 2015 VL 13 IS 1 BP 69 EP 80 DI 10.1586/14787210.2015.983902 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA4FK UT WOS:000348859700007 PM 25399653 ER PT J AU Grabias, B Zheng, H Mlambo, G Tripathi, AK Kumar, S AF Grabias, Bryan Zheng, Hong Mlambo, Godfree Tripathi, Abhai K. Kumar, Sanjai TI A sensitive enhanced chemiluminescent-ELISA for the detection of Plasmodium falciparum circumsporozoite antigen in midguts of Anopheles stephensi mosquitoes SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Article DE ELISA; Plasmodium; Oocyst; Malaria; Vector screening ID LINKED-IMMUNOSORBENT-ASSAY; HUMAN MALARIA PARASITES; LACTATE-DEHYDROGENASE; INFECTED MOSQUITOS; TRANSMISSION; SPOROZOITES; PROTEIN; QUANTIFICATION; DIAGNOSIS; CAMEROON AB Efforts to develop a successful malaria vaccine are hampered due to lack of assays that are predictive of protective immunity without conducting large clinical studies. The effect of experimental vaccines and drugs on malaria transmission is yet more difficult to measure. Knowledge on the Plasmodium infection rate in mosquito populations will aid the measurement of effects from intervention measures for malaria control. Here, we report the development of a chemiluminescent sandwich ELISA (ECL-ELISA) that can detect Plasmodium falciparum circumsporozoite protein (Pf CSP) produced in recombinant form at concentrations of 4.4 pg and in P. falciparum sporozoites (Pf SPZ) derived from mosquito salivary glands at levels corresponding to 5 Pf SPZ. Most importantly, we demonstrate reliable Pf CSP-based detection of 0.056 day 8 P. falciparum oocysts developing inside mosquito midguts in whole mosquito lysates. Cumulatively, the ECL-ELISA is 47 x more sensitive for the detection of Pf CSP than a colorimetric ELISA while greatly simplifying sample preparation, obviating the need for cumbersome midgut dissections and allowing high throughput screening of Plasmodium infection in mosquito populations. The ECL-ELISA may also have broader application in diagnosis of infectious diseases and the prognostic value in cancer and other diseases such as auto-immunity and genetic disorders based on antigen detection, or quality validation of biological vaccine components. Published by Elsevier B.V. C1 [Grabias, Bryan; Zheng, Hong; Kumar, Sanjai] Ctr Biol Evaluat & Res, Off Blood Res & Review, Div Emerging & Transfus Transmitted Dis, Lab Emerging Pathogens, Rockville, MD 20852 USA. [Mlambo, Godfree; Tripathi, Abhai K.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Johns Hopkins Malaria Res Inst, Baltimore, MD 21205 USA. [Mlambo, Godfree; Tripathi, Abhai K.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. RP Grabias, B (reprint author), 10903 New Hampshire Ave,Bldg 52-72 Rm 5304, Silver Spring, MD 20993 USA. EM Bryan.Grabias@fda.hhs.gov; Hong.Theng@fda.hhs.gov; gmlambo1@jhu.edu; atripat2@jhu.edu; Sanjai.Kumar@fda.hhs.gov FU FDA FX This research was funded through Intramural Research Grants provided by the FDA. NR 28 TC 2 Z9 2 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7012 EI 1872-8359 J9 J MICROBIOL METH JI J. Microbiol. Methods PD JAN PY 2015 VL 108 BP 19 EP 24 DI 10.1016/j.mimet.2014.10.006 PG 6 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA CA0TB UT WOS:000348628200004 PM 25455023 ER PT J AU Schure, MR Beaver, LA AF Schure, Mark R. Beaver (Guiochon), Lois Ann TI In Memoriam: Professor Georges A. Guiochon SO LC GC NORTH AMERICA LA English DT Biographical-Item C1 [Schure, Mark R.] Kroungold Analyt, St Petersburg 194223, Russia. [Beaver (Guiochon), Lois Ann] US FDA, Rockville, MD 20857 USA. RP Schure, MR (reprint author), Kroungold Analyt, St Petersburg 194223, Russia. EM mark.schure@gmail.com NR 1 TC 0 Z9 0 U1 0 U2 1 PU ADVANSTAR COMMUNICATIONS INC PI DULUTH PA 131 W 1ST STREET, DULUTH, MN 55802 USA SN 1527-5949 EI 1939-1889 J9 LC GC N AM JI LC GC N. AM. PD JAN PY 2015 VL 33 IS 1 BP 50 EP 52 PG 3 WC Chemistry, Analytical SC Chemistry GA CA0XL UT WOS:000348636700007 ER PT J AU Kucuk, C Jiang, B Hu, XZ Zhang, WY Chan, JKC Xiao, WM Lack, N Alkan, C Williams, JC Avery, KN Kavak, P Scuto, A Sen, E Gaulard, P Staudt, L Iqbal, J Zhang, WW Cornish, A Gong, Q Yang, QP Sun, H d'Amore, F Leppa, S Liu, WP Fu, K de Leval, L McKeithan, T Chan, WC AF Kucuk, Can Jiang, Bei Hu, Xiaozhou Zhang, Wenyan Chan, John K. C. Xiao, Wenming Lack, Nathan Alkan, Can Williams, John C. Avery, Kendra N. Kavak, Pinar Scuto, Anna Sen, Emel Gaulard, Philippe Staudt, Lou Iqbal, Javeed Zhang, Weiwei Cornish, Adam Gong, Qiang Yang, Qunpei Sun, Hong d'Amore, Francesco Leppa, Sirpa Liu, Weiping Fu, Kai de Leval, Laurence McKeithan, Timothy Chan, Wing C. TI Activating mutations of STAT5B and STAT3 in lymphomas derived from gamma delta-T or NK cells SO NATURE COMMUNICATIONS LA English DT Article ID GRANULAR LYMPHOCYTIC-LEUKEMIA; TUMOR-SUPPRESSOR GENE; SEQUENCING DATA; EXPRESSION; MALIGNANCIES; NEOPLASMS; FREQUENT; PATHOGENESIS; DISORDERS; LANDSCAPE AB Lymphomas arising from NK or gamma delta-T cells are very aggressive diseases and little is known regarding their pathogenesis. Here we report frequent activating mutations of STAT3 and STAT5B in NK/T-cell lymphomas (n - 51), gamma delta-T-cell lymphomas (n - 43) and their cell lines (n = 9) through next generation and/or Sanger sequencing. STAT5B N642H is particularly frequent in all forms of gamma delta-T-cell lymphomas. STAT3 and STAT5B mutations are associated with increased phosphorylated protein and a growth advantage to transduced cell lines or normal NK cells. Growth-promoting activity of the mutants can be partially inhibited by a JAK1/2 inhibitor. Molecular modelling and surface plasmon resonance measurements of the N642H mutant indicate a marked increase in binding affinity of the phosphotyrosine-Y699 with the mutant histidine. This is associated with the prolonged persistence of the mutant phosphoSTAT5B and marked increase of binding to target sites. Our findings suggest that JAK-STAT pathway inhibition may represent a therapeutic strategy. C1 [Kucuk, Can; Jiang, Bei; Hu, Xiaozhou; Scuto, Anna; McKeithan, Timothy; Chan, Wing C.] City Hope Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Zhang, Wenyan; Yang, Qunpei; Sun, Hong; Liu, Weiping; Fu, Kai] Sichuan Univ, West China Hosp, Dept Pathol, Chengdu 610041, Peoples R China. [Chan, John K. C.] Queen Elizabeth Hosp, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Xiao, Wenming] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Rockville, MD 20857 USA. [Lack, Nathan; Sen, Emel] Koc Univ, Dept Pharmacol, TR-34450 Istanbul, Turkey. [Alkan, Can] Bilkent Univ, Dept Comp Engn, TR-06800 Ankara, Turkey. [Williams, John C.; Avery, Kendra N.] Beckman Res Inst City Hope, Dept Mol Med, Duarte, CA 91010 USA. [Kavak, Pinar] Bogazici Univ, Dept Comp Engn, TR-34342 Istanbul, Turkey. [Gaulard, Philippe] Univ Paris Est, INSERM, U955, Dept Pathol,Grp Henri Mondor Albert Chenevier, F-94000 Creteil, France. [Staudt, Lou] NCI, Ctr Canc Res, Mol Biol Lymphoid Malignancies Sect, Bethesda, MD 20892 USA. [Iqbal, Javeed; Zhang, Weiwei] Univ Nebraska, Ctr Med, Dept Pathol & Microbiol, Omaha, NE 68198 USA. [Cornish, Adam] Univ Nebraska, Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE 68198 USA. [Gong, Qiang] Chinese Acad Sci, Beijing Inst Genom, Beijing 100029, Peoples R China. [d'Amore, Francesco] Aarhus Univ Hosp, Dept Hematol, DK-8000 Aarhus, Denmark. [Leppa, Sirpa] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki 00029, Finland. [de Leval, Laurence] Univ Pathol, Pathol Clin Inst, CH-1011 Lausanne, Switzerland. RP Chan, WC (reprint author), City Hope Med Ctr, Dept Pathol, Duarte, CA 91010 USA. EM jochan@coh.org RI Alkan, Can/D-2982-2009; Kucuk, Can/K-3913-2015; OI Alkan, Can/0000-0002-5443-0706; Leppa, Sirpa/0000-0002-8265-511X; Kucuk, Can/0000-0001-5540-9012; McKeithan, Timothy/0000-0003-2242-3074 NR 44 TC 47 Z9 48 U1 9 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN PY 2015 VL 6 AR 6025 DI 10.1038/ncomms7025 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA3TP UT WOS:000348829800003 PM 25586472 ER PT J AU Goodwin, AK Lantz-McPeak, SM Robinson, BL Law, CD Ali, SF Ferguson, SA AF Goodwin, Amy K. Lantz-McPeak, Susan M. Robinson, Bonnie L. Law, C. Delbert Ali, Syed F. Ferguson, Sherry A. TI Effects of adolescent treatment with nicotine, harmane, or norharmane in male Sprague-Dawley rats SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Nicotine; Harmane; Norharmane; Adolescence; Behavior; Rat ID BETA-CARBOLINES NORHARMAN; VENTRAL TEGMENTAL AREA; CIGARETTE-SMOKE; FEMALE RATS; EXTRACELLULAR CONCENTRATIONS; LOCOMOTOR-ACTIVITY; NUCLEUS-ACCUMBENS; BRAIN-DEVELOPMENT; SEX-DIFFERENCES; WISTAR RATS AB The initiation of tobacco use occurs most often in adolescence and may be especially detrimental as the adolescent brain is undergoing substantial development. In addition to nicotine, there are over 9000 other compounds present in tobacco products, including the beta-carbolines harmane and norharmane. The present study aimed to determine the long-term effects of adolescent exposure to nicotine (NIC), harmane (HAR), or norharmane (NOR) on locomotor activity, learning and memory, anxiety-like behavior, motor coordination, and monoamine/metabolite concentrations in the striatum and nucleus accumbens of male Sprague-Dawley rats. Beginning on postnatal day (PND) 27 and continuing through PND 55, subjects received twice daily intraperitoneal injections of 1 ml/kg saline (CON), 0.5 mg NIC/kg, 0.5 mg HAR/kg, or 0.5 mg NOR/kg. Body weight, food, and water intake were measured daily (PNDs 27-96). Locomotor activity was assessed on PND 40 or 41, PND 55, and PNDs 81 and 82. Other behaviors (anxiety-like behavior, motor coordination, and spatial learning and memory) were assessed at least 25 days after drug exposure ended (PNDs 80-91). On PND 97, subjects were decapitated and the striatum and nucleus accumbens were dissected and frozen for analysis. NIC treatment significantly decreased food intake, but did not alter locomotor activity during or after treatment. MAR and NOR treatment, however, caused significant open field hypoactivity. Motor coordination, water maze performance, and concentrations of monoamines and metabolites in the striatum and nucleus accumbens were unaltered by any drug treatment. These results indicate a long-lasting effect on activity levels from adolescent MAR or NOR treatment; however, there were few long-lasting NIC effects. Given the paucity of data describing effects of HAR or NOR exposure, these data should encourage additional studies of these tobacco constituents as well as constituent combination studies. Published by Elsevier Inc. C1 [Goodwin, Amy K.; Lantz-McPeak, Susan M.; Law, C. Delbert; Ali, Syed F.; Ferguson, Sherry A.] US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. [Robinson, Bonnie L.] Toxicol Pathol Associates Inc, Jefferson, AR 72079 USA. RP Ferguson, SA (reprint author), Natl Ctr Toxicol Res, Div Neurotoxicol, 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 [E7452] FX This work was supported by the National Center for Toxicological Research/Food and Drug Administration [Protocol # E7452 to S.F.A.]. The authors are grateful for the technical expertise provided by the animal care staff of the Priority One Corporation. NR 77 TC 2 Z9 2 U1 0 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 JAN-FEB PY 2015 VL 47 BP 25 EP 35 DI 10.1016/j.ntt.2014.10.005 PG 11 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA CA5NL UT WOS:000348955000004 PM 25450662 ER PT J AU Ferguson, SA Law, CD Sahin, L Montenegro, SV AF Ferguson, Sherry A. Law, C. Delbert Sahin, Leyla Montenegro, Susan V. TI Effects of perinatal methylphenidate (MPH) treatment on postweaning behaviors of male and female Sprague-Dawley rats SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Methylphenidate; Ritalinic acid; Hormone; Behavior; Pregnancy; Rat ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; CONDITIONED PLACE PREFERENCE; PRENATAL COCAINE EXPOSURE; PLUS-MAZE BEHAVIOR; YOUNG-ADULT RATS; DEVELOPMENTAL TREATMENT; UNITED-STATES; BISPHENOL-A; DOPAMINE-D1 RECEPTORS AB Methylphenidate (MPH) is a common treatment for adult Attention Deficit Hyperactivity Disorder (ADHD). However, little information exists regarding its safety during pregnancy and thus, women with ADHD face difficult decisions regarding continued use during pregnancy. Thus, Sprague-Dawley rats were orally treated 3x/day with 0 (control), 6 (low), 18 (mid), or 42 (high) mg MPH/kg/day (i.e., 0, 2, 6, or 14 mg/kg at each treatment time) on gestational days 6-21. All offspring/litter were orally treated with the same dose their dam had received on postnatal days (PNDs) 1-21. After weaning, offspring were assessed for adolescent play behavior, locomotor activity, motor coordination, Barnes maze performance, acoustic startle response, novel object recognition, residential running wheel activity, flavored solution intake, home cage behavior, water maze performance, elevated plus maze behavior, locomotor response to an MPH challenge, and passive avoidance. At euthanasia, whole brain and striatal weights as well as serum hormone levels were measured. Body weights of the high MPH group were reduced in both sexes. Males of the high MPH group were less active than control males in open field assessments on PNDs 40-42. Latency to maximum acoustic startle was significantly altered in females of the medium and high MPH groups and residential running wheel activity of females of the low and medium MPH groups was lower than control females. Open arm entries in the elevated plus maze were increased in subjects of the medium MPH group. Females of the low MPH group were less sensitive to the locomotor-increasing effects of an acute 5 mg/kg MPH challenge. Serum hormone levels and whole brain and striatal weights were not altered by prior MPH treatment. These results indicate that MPH treatment during development has sporadic effects on postweaning behaviors and those effects were generally exhibited by females. Published by Elsevier Inc. C1 [Ferguson, Sherry A.; Law, C. Delbert] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Sahin, Leyla] US FDA, Pediat & Maternal Hlth Staff, Off New Drugs, Ctr Drug Evaluat Res, Silver Spring, MD 20993 USA. [Montenegro, Susan V.] US FDA, Div Epidemiol 2, Off Pharmacovigilance & Epidemiol, Off Suiveillance & Epidemiol,Ctr Drug Evaluat Res, Silver Spring, MD 20993 USA. RP Ferguson, SA (reprint author), HFT-132,3900 NCTR Rd, Jefferson, AR 72079 USA. EM Sherry.Ferguson@fda.hhs.gov OI Ferguson, Sherry/0000-0002-5120-0219 FU National Center for Toxicological Research/Food and Drug Administration [E7318] FX This work was supported by the National Center for Toxicological Research/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. We especially are indebted to expert statistician Mr. Robert Paul Felton of the Division of Bioinformatics and Biostatistics for his careful analyses and for the scoring assistance of Ms. Leah Fisher, Ms. Kaitlyn Maier, Ms. Caitlyn Masterson, and Mr. Alton (Jay) Withers. NR 84 TC 2 Z9 2 U1 1 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 JAN-FEB PY 2015 VL 47 BP 125 EP 136 DI 10.1016/j.ntt.2014.12.002 PG 12 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA CA5NL UT WOS:000348955000014 PM 25514582 ER PT J AU Hoenerhoff, MJ Silverman, L Francke, S AF Hoenerhoff, Mark J. Silverman, Lee Francke, Sabine TI A Brief Overview of the 33rd Annual STP Symposium on the Translational Pathology: Relevance of Toxicologic Pathology to Human Health SO TOXICOLOGIC PATHOLOGY LA English DT Article DE translational pathology; preclinical; nonclinical; technologies; regulatory; epigenetics; environmental; human health; safety evaluations; comorbidities AB The 33rd Society of Toxicologic Pathology's Annual Symposium focused on translational science and the relevance of toxicologic pathology to human health. Toxicologic pathologists work in diverse settings studying changes elicited by pharmacological, chemical, and environmental agents and factors that modify these responses. Regardless of the work setting, society members are dedicated to the integration of toxicologic pathology into hazard identification, risk assessment, and risk communication regarding human and animal exposure to potentially toxic substances. Toxicologic pathologists routinely face not only questions regarding pathological changes related to compound exposure but also questions concerning what translational relevance those lesions and exposures have to a human population or organ system. This symposium provided a basis for the membership to understand the variety of roles the toxicologic pathologist plays in translational science, where our gaps in translational science are, and how we can move forward to better address the challenges in the field translational science in order to continue to positively impact human health. C1 [Hoenerhoff, Mark J.] Univ Michigan, Sch Med, Unit Lab Anim Med, In Vivo Anim Core, Ann Arbor, MI 48109 USA. [Silverman, Lee] Agios Pharmaceut, Cambridge, MA USA. [Francke, Sabine] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Hoenerhoff, MJ (reprint author), Univ Michigan, Sch Med, Unit Lab Anim Med, In Vivo Anim Core, North Campus Res Complex,2800 Plymouth Rd,Bldg 36, Ann Arbor, MI 48109 USA. EM hoenerho@med.umich.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JAN PY 2015 VL 43 IS 1 BP 41 EP 47 DI 10.1177/0192623314555525 PG 7 WC Pathology; Toxicology SC Pathology; Toxicology GA CA4ZT UT WOS:000348917300002 PM 25351921 ER PT J AU Gucinski, AC Boyne, MT Keire, DA AF Gucinski, Ashley C. Boyne, Michael T., II Keire, David A. TI Modern analytics for naturally derived complex drug substances: NMR and MS tests for protamine sulfate from chum salmon SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE NMR; LC-MS; Peptide drug quality ID ELECTRON-TRANSFER DISSOCIATION; INTACT MASS-SPECTROMETRY; QUANTITATIVE-ANALYSIS; QUALITY; HEPARIN; THERAPEUTICS; BIOACTIVITY; PEPTIDES; ASSAYS AB This work describes orthogonal NMR and MS tests for the structure and composition of the drug protamine sulfate derived from chum salmon. The spectral response pattern obtained by 1D-H-1-NMR and MS methods from salmon protamine, a mixture of four predominant peptide chains, is dependent on the amino acid sequence and abundance of each peptide. Thus, an assay was developed based on the ratios of alanine, glycine and arginine amino acid residue NMR peaks (relative to the arginine C delta H proton signal) in this mixture that are unique to the salmon source. In addition, MS analysis provided sensitive sequence determination and impurity analysis based on shifts from exact masses. Spectra from protamine sulfate active pharmaceutical ingredient (API) suppliers and from a formulated drug product purchased from the US market were examined. Based on these marketplace survey data, NMR acceptance criteria for chum salmon derived protamine sulfate could be based on the absence of aromatic amino acid signals and on ratios of Ala beta H/Arg delta H, Gly alpha H/Arg delta H and Arg alpha H/Arg delta H integrated areas of 2.4 +/- 1 %, 9.4 +/- 3 % and 50 +/- 5 %, respectively. For MS, acceptance criteria based on the presence of specific mass to charge (m/z) ratio peaks (m/z = +8 of 530.455, 540.841, 532.208 and 508.950) could be used for the four major peptides present in the mixture with relative abundances of 17 +/- 1 %, 31 +/- 2 %, 27 +/- 1 % and 25 +/- 3 %, respectively. The specificity of the combined NMR and MS assay was tested by comparison to data obtained from herring protamine which contains a different mixture of peptides with related amino acid sequences. Both assays were able to clearly distinguish protamine derived from these different natural sources. C1 [Gucinski, Ashley C.; Boyne, Michael T., II; Keire, David A.] US FDA, Div Pharmaceut Res, Off Testing & Res, Ctr Drug Evaluat & Res, St Louis, MO 63110 USA. RP Keire, DA (reprint author), US FDA, Div Pharmaceut Res, Off Testing & Res, Ctr Drug Evaluat & Res, 645 S Newstead Ave, St Louis, MO 63110 USA. EM david.keire@fda.hhs.gov FU CDER Critical Path Program FX Funding and support for this work was provided by the CDER Critical Path Program and is gratefully acknowledged. 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 25 TC 4 Z9 4 U1 1 U2 9 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD JAN PY 2015 VL 407 IS 3 BP 749 EP 759 DI 10.1007/s00216-014-8172-2 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AZ7ZY UT WOS:000348435600013 PM 25260409 ER PT J AU Lee, EY Shen, HCJ AF Lee, Eunice Y. Shen, Hsin-Chieh Jennifer TI Regulatory considerations for companion diagnostic devices SO BIOMARKERS IN MEDICINE LA English DT Review DE assay; biomarker; codevelopment; in vitro companion diagnostic; medical device; personalized medicine; precision medicine; regulation ID DRUG DEVELOPMENT; DECISION-MAKING; PHARMACOGENOMICS AB The emergence of companion diagnostic devices has been spurred by drug discovery and development efforts towards targeted therapies, particularly in oncology. Companion diagnostics and their corresponding therapeutics are often codeveloped, or developed in parallel, to ensure the safe and effective use of the products. The regulatory framework for companion diagnostics has gradually evolved as a result of the essential role of diagnostic tests to identify the intended population for a corresponding treatment. Here, we describe the current regulatory model for companion diagnostics in the US and outline key strategies for a successful codevelopment program from the device perspective. We also discuss how technological advances and changes in clinical management may challenge the regulatory model in the future. C1 [Lee, Eunice Y.; Shen, Hsin-Chieh Jennifer] US FDA, Div Mol Genet & Pathol, Off Vitro Diagnost & Radiol Hlth, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Lee, EY (reprint author), US FDA, Div Mol Genet & Pathol, Off Vitro Diagnost & Radiol Hlth, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM eunice.lee@fda.hhs.gov; jennifer.shen@fda.hhs.gov NR 24 TC 2 Z9 2 U1 0 U2 8 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PY 2015 VL 9 IS 1 BP 67 EP 75 DI 10.2217/BMM.14.98 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AZ6EQ UT WOS:000348312000008 PM 25605456 ER PT J AU Dal Pan, GJ Arlett, PR AF Dal Pan, Gerald J. Arlett, Peter R. TI The US Food and Drug Administration-European Medicines Agency Collaboration in Pharmacovigilance: Common Objectives and Common Challenges SO DRUG SAFETY LA English DT Article AB On 19 February 2014, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) announced the formation of a cluster on pharmacovigilance topics. The cluster is designed to complement, and not replace, other international activities in this field. It builds upon years of interactions between the two agencies. The creation of the cluster formalizes this longstanding and productive relationship and facilitates more systematic exchange of information and expertise. C1 [Dal Pan, Gerald J.] US FDA, Silver Spring, MD 20993 USA. [Arlett, Peter R.] European Med Agcy, London, England. RP Dal Pan, GJ (reprint author), US FDA, Silver Spring, MD 20993 USA. EM gerald.dalpan@fda.hhs.gov NR 1 TC 1 Z9 1 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 JAN PY 2015 VL 38 IS 1 BP 13 EP 15 DI 10.1007/s40264-014-0259-3 PG 3 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA AZ6PJ UT WOS:000348341000002 PM 25539878 ER PT J AU Simon, LL Pataki, H Marosi, G Meemken, F Hungerbuhler, K Baiker, A Tummala, S Glennon, B Kuentz, M Steele, G Kramer, HJM Rydzak, JW Chen, ZP Morris, J Kjell, F Singh, R Gani, R Gernaey, KV Louhi-Kultanen, M O'Reilly, J Sandler, N Antikainen, O Yliruusi, J Frohberg, P Ulrich, J Braatz, RD Leyssens, T von Stosch, M Oliveira, R Tan, RBH Wu, HQ Khan, M O'Grady, D Pandey, A Westra, R Delle-Case, E Pape, D Angelosante, D Maret, Y Steiger, O Lenner, M Abbou-Oucherif, K Nagy, ZK Litster, JD Kamaraju, VK Chiu, MS AF Simon, Levente L. Pataki, Hajnalka Marosi, Gyoergy Meemken, Fabian Hungerbuehler, Konrad Baiker, Alfons Tummala, Srinivas Glennon, Brian Kuentz, Martin Steele, Gerry Kramer, Herman J. M. Rydzak, James W. Chen, Zengping Morris, Julian Kjell, Francois Singh, Ravendra Gani, Rafiqul Gernaey, Krist V. Louhi-Kultanen, Marjatta O'Reilly, John Sandler, Niklas Antikainen, Osmo Yliruusi, Jouko Frohberg, Patrick Ulrich, Joachim Braatz, Richard D. Leyssens, Tom von Stosch, Moritz Oliveira, Rui Tan, Reginald B. H. Wu, Huiquan Khan, Mansoor O'Grady, Des Pandey, Anjan Westra, Remko Delle-Case, Emmanuel Pape, Detlef Angelosante, Daniele Maret, Yannick Steiger, Olivier Lenner, Miklos Abbou-Oucherif, Kaoutar Nagy, Zoltan K. Litster, James D. Kamaraju, Vamsi Krishna Chiu, Min-Sen TI Assessment of Recent Process Analytical Technology (PAT) Trends: A Multiauthor Review SO ORGANIC PROCESS RESEARCH & DEVELOPMENT LA English DT Review ID BATCH COOLING CRYSTALLIZATION; NEAR-INFRARED SPECTROSCOPY; L-GLUTAMIC ACID; ATR-FTIR SPECTROSCOPY; BEAM REFLECTANCE MEASUREMENT; MEDIATED POLYMORPHIC TRANSFORMATION; MODEL-PREDICTIVE CONTROL; METASTABLE ZONE WIDTH; IN-SITU RAMAN; ULTRASONIC RESONATOR TECHNOLOGY AB This multiauthor review article aims to bring readers up to date with some of the current trends in the field of process analytical technology (PAT) by summarizing each aspect of the subject (sensor development, PAT based process monitoring and control methods) and presenting applications both in industrial laboratories and in manufacture e.g. at GSK, AstraZeneca and Roche. Furthermore, the paper discusses the PAT paradigm from the regulatory science perspective. Given the multidisciplinary nature of PAT, such an endeavour would be almost impossible for a single author, so the concept of a multiauthor review was born. Each section of the multiauthor review has been written by a single expert or group of experts with the aim to report on its own research results. This paper also serves as a comprehensive source of information on PAT topics for the novice reader. C1 [Simon, Levente L.] BASF Schweiz AG, CH-4133 Schweizerhalle, Switzerland. [Pataki, Hajnalka; Marosi, Gyoergy] Budapest Univ Technol & Econ, Dept Organ Chem & Technol, H-1111 Budapest, Hungary. [Meemken, Fabian; Hungerbuehler, Konrad; Baiker, Alfons] ETH, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland. [Tummala, Srinivas] Bristol Myers Squibb Co, Chem Dev, New Brunswick, NJ 08903 USA. [Glennon, Brian; Kamaraju, Vamsi Krishna] Univ Coll Dublin, Sch Chem & Bioproc Engn, Synth & Solid State Pharmaceut Ctr, Dublin 4, Ireland. [Glennon, Brian] APC Ltd, Dublin 4, Ireland. [Kuentz, Martin] Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharma Technol, Sch Life Sci, CH-4132 Muttenz, Switzerland. [Steele, Gerry] PharmaCryst Consulting Ltd, Loughborough LE11 3HN, Leics, England. [Kramer, Herman J. M.] Delft Univ Technol, Intensified React & Separat Syst, NL-2628 CB Delft, Netherlands. [Rydzak, James W.] GlaxoSmithKline, King Of Prussia, PA 19406 USA. [Chen, Zengping] Hunan Univ, Coll Chem & Chem Engn, State Key Lab Chemo Biosensing & Chemometr, Changsha 410082, Hunan, Peoples R China. [Morris, Julian] Newcastle Univ, Sch Chem Engn & Adv Mat, Ctr Proc Analyt & Control Technol, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Kjell, Francois] Siemens Nv Sa, Ind Automat SIPAT Ind Software, B-1070 Brussels, Belgium. [Singh, Ravendra; Gani, Rafiqul; Gernaey, Krist V.] Tech Univ Denmark DTU, Dept Chem & Biochem Engn, CAPEC PROC, DK-2800 Lyngby, Denmark. [Louhi-Kultanen, Marjatta] Lappeenranta Univ Technol, Dept Chem Technol, FI-53851 Lappeenranta, Finland. [O'Reilly, John] Roche Ireland Ltd, Clarecastle, Clare, Ireland. [Sandler, Niklas] Abo Akad Univ, Dept Biosci, Pharmaceut Sci Lab, FIN-20520 Turku, Finland. [Antikainen, Osmo; Yliruusi, Jouko] Univ Helsinki, Fac Pharm, Div Pharmaceut Technol, SF-00100 Helsinki, Finland. [Frohberg, Patrick; Ulrich, Joachim] Univ Halle Wittenberg, Ctr Engn Sci, D-06099 Halle, Saale, Germany. [Braatz, Richard D.] MIT, Cambridge, MA 02139 USA. [Leyssens, Tom] Catholic Univ Louvain, Inst Condensed Matter & Nanosci, B-1348 Louvain La Neuve, Belgium. [von Stosch, Moritz; Oliveira, Rui] Univ Nova Lisboa, EQUIMTE Dept Quim, Fac Ciencias & Tecnol, P-1099085 Caparica, Portugal. [von Stosch, Moritz; Oliveira, Rui] HybPAT, Caparica, Portugal. [Tan, Reginald B. H.] ASTAR, Inst Chem & Engn Sci, Singapore 627833, Singapore. [Tan, Reginald B. H.; Kamaraju, Vamsi Krishna; Chiu, Min-Sen] Natl Univ Singapore, Dept Chem & Biomol Engn, Singapore 117576, Singapore. [Wu, Huiquan; Khan, Mansoor] US FDA, Div Prod Qual Res, Off Testing & Res, Off Pharmaceut Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [O'Grady, Des; Pandey, Anjan] Mettler Toledo AutoChem, Columbia, MD 20146 USA. [Westra, Remko] FMC Technol BV, NL-6825 MN Arnhem, Netherlands. [Delle-Case, Emmanuel] Univ Tulsa, Tulsa, OK 74104 USA. [Pape, Detlef; Angelosante, Daniele; Maret, Yannick; Steiger, Olivier; Lenner, Miklos] ABB Corp Res Ctr, CH-5405 Baden, Switzerland. [Abbou-Oucherif, Kaoutar; Nagy, Zoltan K.; Litster, James D.] Purdue Univ, Sch Chem Engn, W Lafayette, IN 47906 USA. [Nagy, Zoltan K.] Loughborough Univ Technol, Dept Chem Engn, Loughborough LE11 3TU, Leics, England. RP Simon, LL (reprint author), BASF Schweiz AG, CH-4133 Schweizerhalle, Switzerland. EM levente.simon@basf.com RI Gani, Rafiqul/A-4865-2011; Louhi-Kultanen, Marjatta/G-2067-2016; OI Gani, Rafiqul/0000-0002-6719-9283; Louhi-Kultanen, Marjatta/0000-0002-0987-1406; Oliveira, Rui/0000-0001-8077-4177; Gernaey, Krist/0000-0002-0364-1773 FU DTI [GR/R19366/01, GR/R43853/01]; EPSRC [GR/R19366/01, GR/R43853/01]; CPACT; National Natural Science Foundation of China [21075034, 21275046]; Program for New Century Excellent Talents in University [NCET-12-0161]; Academy of Finland [260141]; European Research Council [280106-CrySys] FX L.L.S. acknowledges the American Chemical Society and the Editor of Organic Process Research and Development, Dr. Trevor Laird, for supporting this multiauthor review paper, Dr. Pataki Hajnalka for managing the references, and Professor A. S. Myerson at MIT, U.S.A. for providing Figure 40, and the reviewers' comments. Z.C. and J.M. acknowledge the financial support of the DTI and the EPSRC grant GR/R19366/01 (KNOW-HOW) and GR/R43853/01 (Chemicals Behaving Badly II) and CPACT. Z.C. also thanks the National Natural Science Foundation of China (grant no. 21075034, no. 21275046) and the Program for New Century Excellent Talents in University (NCET-12-0161). M.L.-K. would like to thank The Academy of Finland (Project No. 260141) for financial support. Z.K.N. acknowledges the financial support provided by the European Research Council grant no. 280106-CrySys. NR 432 TC 43 Z9 44 U1 23 U2 149 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1083-6160 EI 1520-586X J9 ORG PROCESS RES DEV JI Org. Process Res. Dev. PD JAN PY 2015 VL 19 IS 1 BP 3 EP 62 DI 10.1021/op500261y PG 60 WC Chemistry, Applied; Chemistry, Organic SC Chemistry GA AZ6LT UT WOS:000348332000002 ER PT J AU Wu, HQ Dong, ZD Li, HT Khan, M AF Wu, Huiquan Dong, Zedong Li, Haitao Khan, Mansoor TI An Integrated Process Analytical Technology (PAT) Approach for Pharmaceutical Crystallization Process Understanding to Ensure Product Quality and Safety: FDA Scientist's Perspective SO ORGANIC PROCESS RESEARCH & DEVELOPMENT LA English DT Review ID INDUCTION TIME; CARBAMAZEPINE TABLETS; NUCLEATION; PRECIPITATION; POLYMORPHS; RITONAVIR; MECHANISM; SULFATE; DESIGN AB In this review, a brief overview of the current regulatory science framework pertinent to pharmaceutical crystallization and process characterization is made first. The FDAs scientific research on pharmaceutical crystallization process understanding and product characterization is then illustrated via several aspects: (1) Combined real-time PAT monitoring and process chemometrics for mapping the state of a pharmaceutical crystallization process; (2) Combined real-time PAT process monitoring and first-principle modeling for elucidating the nucleation mechanisms of a dynamic pharmaceutical crystallization process; (3) Combined real-time PAT process monitoring, Design of Experiments (DOE), and General Linear Modeling (GLM) to establish a hybrid approach for process characterization and process design space development; and (4) Integrated PAT approach for nucleation induction time measurement. Finally, some of the current challenges and future outlook on pharmaceutical crystallization process and product characterization across the pipeline, from drug substance to drug product development, manufacturing, and process scale-up to ensure product quality and safety, and ultimately to protect and promote public health is discussed from both a regulatory science and process engineering point of view. C1 [Wu, Huiquan; Khan, Mansoor] US FDA, DPQR, Off Testing & Res, Off Pharmaceut Sci, Silver Spring, MD 20993 USA. [Dong, Zedong] US FDA, Div New Drug Qual Assessment 1, Off New Drug Qual Assessment, Off Pharmaceut Sci, Silver Spring, MD USA. [Li, Haitao] US FDA, Div DMF Review, Off Gener Drugs, Off Pharmaceut Sci,Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Wu, HQ (reprint author), US FDA, DPQR, Off Testing & Res, Off Pharmaceut Sci, Silver Spring, MD 20993 USA. EM Huiquan.wu@fda.hhs.gov FU FDA CDER Regulatory Science and Review (RSR) [RSR04-16, RSR12-42, RSR13-32]; FDA CDER OTR [OTR-12 PAT]; FDA CDER OTR DPQR; Mettler-Toledo AutoChem; Brimrose of America; Broker Optics; Chemglass; Camo Technologies; Rohm America; Spectral Dimensions; FOSS NIRSystems FX We thank Dr. Lucinda Buhse (Acting Director, Office of Testing and Research), Dr. Robert Lionberger (Acting Deputy Director for Science, Office of Generic Drugs), and Dr. Xiaohui Jiang (Scientist, Office of Generic Drugs), Center for Drug Evaluation and Research, FDA, for proofing the manuscript and thoughtful inputs. H. Wu is grateful for the help and encouragement provided by Maury White (former ORISE fellow who worked for DPQR), Dr. Vince Vilker (retired), and Dr. Robbe Lyon (retired), Dr. Patrick Faustino (DPQR), and Dr. Ke Liu (CBER). H. Wu is grateful for funding supports from FDA CDER Regulatory Science and Review (RSR), Projects RSR04-16, RSR12-42, and RSR13-32, FDA CDER OTR Intramural Funding OTR-12 PAT, and FDA CDER OTR DPQR Intramural Funding from 2006 to 2014. The support from Mettler-Toledo AutoChem, Brimrose of America, Broker Optics, Chemglass, Camo Technologies, Rohm America, Spectral Dimensions, FOSS NIRSystems, Dr. San Kiang at BMS, Dr. Richard Braatz at MIT, and Dr. Thomas Wheelock at Iowa State University are acknowledged. NR 50 TC 5 Z9 5 U1 2 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1083-6160 EI 1520-586X J9 ORG PROCESS RES DEV JI Org. Process Res. Dev. PD JAN PY 2015 VL 19 IS 1 BP 89 EP 101 DI 10.1021/op500056a PG 13 WC Chemistry, Applied; Chemistry, Organic SC Chemistry GA AZ6LT UT WOS:000348332000005 ER PT J AU Wu, HQ White, M Khan, M AF Wu, Huiquan White, Maury Khan, Mansoor TI An Integrated Process Analytical Technology (PAT) Approach for Process Dynamics-Related Measurement Error Evaluation and Process Design Space Development of a Pharmaceutical Powder Blending Bed SO ORGANIC PROCESS RESEARCH & DEVELOPMENT LA English DT Article ID NEAR-INFRARED SPECTROSCOPY; HOMOGENEITY; QUALITY; SEGREGATION; MECHANISMS; UNIFORMITY; QBD AB In this work, a model pharmaceutical powder blending system consisting of ibuprofen (drug), MCC, and lactose anhydrous was monitored in real-time via inline near-infrared (NIR) spectroscopy for dual purposes: (1) to examine the effects of formulation variables (drug and MCC contents) and a process variable (impeller rotation speed) on powder blending process kinetics via a 33 full factorial design, and (2) to examine the measurement errors associated with the real-time NIR monitoring environment. The NIR probe was in direct contact with the powder bed for process monitoring. Selected powder blend samples were collected at certain prespecified time points for UV analysis. Three consecutive spectra were used to calculate the standard deviation (stdev) of NIR absorbance at each wavelength. A moving window average was applied to establish the evolution of stdev over the course of powder blending. Two distinct process segments were found: an initial period during which the stdev rapidly decreases and a following fluctuation period during which both the mean and the stdev vary with the formulation and process parameters. Analysis of the process thermodynamics indicated that the initial period of rapid decrease was due to rapid decrease of the thermodynamic driving force, i.e., the powder component concentration gradient. Analysis of the moving powder bed dynamics suggested that the subsequent period of relative stability punctuated by minor fluctuation corresponds to the powder beds microstructure fluctuation, i.e., dynamics in compactness, density, and porosity, due to mechanic rotation of the impeller. The analysis was confirmed by ANOVA results. ANOVA shows that the formulation compositions are primary factors dictating how fast the powder system could achieve the macro-homogeneity (often within 12 min); both the impeller rotation speed and the formulation composition are the primary factors dictating both the powder blending homogeneity at microlevel and the measurement error associated with real-time dynamic PAT monitoring environment. General Linear Models (GLM) were used to link the critical formulation and process parameters (CPPs) with the derived response variables and to construct a powder blending process design space. For the model powder blending system, it was shown that selection of appropriate impeller rotation speed range is critical to ensure optimal powder blending performance with practically acceptable dynamic noise. Therefore, this work provided an integrated PAT approach and methodology to address practical powder blending challenges from both process engineering and regulatory science perspectives. C1 [Wu, Huiquan; White, Maury; Khan, Mansoor] US FDA, DPQR, OTR, OPS,CDER, Silver Spring, MD 20993 USA. RP Wu, HQ (reprint author), US FDA, DPQR, OTR, OPS,CDER, HFD 940,FDA White Oak Campus Bldg 64, Silver Spring, MD 20993 USA. EM Huiquan.wu@fda.hhs.gov FU FDA CDER Regulatory Science and Review Program [RSR-04-16] FX The authors wish to acknowledge Dr. Meiyu Shen, Senior Mathematical Statistician, Division of Biometrics VI, Office of Biostatistics, Office of Translational Science, Center for Drug Evaluation and Research, FDA, for strong statistical support. H. Wu wishes to acknowledge Dr. Robbe Lyon (retired from the FDA in 2009) for his mentorship. This project was partially supported by FDA CDER Regulatory Science and Review Program (project code: RSR-04-16) for research focused on exploring the regulatory science utility of integrating DOE and PAT for the 21st Century CGMP Initiative. The OTR internship which allowed M. White to carry out some experiments for this work is acknowledged. The constructive suggestions from two unanimous reviewers of this manuscript are greatly appreciated. NR 32 TC 4 Z9 4 U1 4 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1083-6160 EI 1520-586X J9 ORG PROCESS RES DEV JI Org. Process Res. Dev. PD JAN PY 2015 VL 19 IS 1 BP 215 EP 226 DI 10.1021/op500085m PG 12 WC Chemistry, Applied; Chemistry, Organic SC Chemistry GA AZ6LT UT WOS:000348332000018 ER PT J AU Wear, KA Liu, YB Gammell, PM Maruvada, S Harris, GR AF Wear, Keith A. Liu, Yunbo Gammell, Paul M. Maruvada, Subha Harris, Gerald R. TI Correction for Frequency-Dependent Hydrophone Response to Nonlinear Pressure Waves Using Complex Deconvolution and Rarefactional Filtering: Application With Fiber Optic Hydrophones SO IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL LA English DT Article; Proceedings Paper CT 23rd International Symposium on the Applications of Ferroelectrics (ISAF) CY MAY 12-16, 2014 CL Pennsylvania State Univ, Univ Pk, PA HO Pennsylvania State Univ ID FOCUSED ULTRASOUND FIELDS; TIME-DELAY SPECTROMETRY; PHASE CALIBRATION; AMPLITUDE; SIMULATION; SENSOR; MODEL AB Nonlinear acoustic signals contain significant energy at many harmonic frequencies. For many applications, the sensitivity (frequency response) of a hydrophone will not be uniform over such a broad spectrum. In a continuation of a previous investigation involving deconvolution methodology, deconvolution (implemented in the frequency domain as an inverse filter computed from frequency-dependent hydrophone sensitivity) was investigated for improvement of accuracy and precision of nonlinear acoustic output measurements. Time-delay spectrometry was used to measure complex sensitivities for 6 fiber-optic hydrophones. The hydrophones were then used to measure a pressure wave with rich harmonic content. Spectral asymmetry between compressional and rarefactional segments was exploited to design filters used in conjunction with deconvolution. Complex deconvolution reduced mean bias (for 6 fiber-optic hydrophones) from 163% to 24% for peak compressional pressure (p(+)), from 113% to 15% for peak rarefactional pressure (p(-)), and from 126% to 29% for pulse intensity integral (PII). Complex deconvolution reduced mean coefficient of variation (COV) (for 6 fiber optic hydrophones) from 18% to 11% (p(+)), 53% to 11% (p(-)), and 20% to 16% (PII). Deconvolution based on sensitivity magnitude or the minimum phase model also resulted in significant reductions in mean bias and COV of acoustic output parameters but was less effective than direct complex deconvolution for p+ and p-. Therefore, deconvolution with appropriate filtering facilitates reliable nonlinear acoustic output measurements using hydrophones with frequency-dependent sensitivity. C1 [Wear, Keith A.; Liu, Yunbo; Maruvada, Subha; Harris, Gerald R.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Gammell, Paul M.] Gammell Appl Technol LLC, Exmore, VA USA. RP Wear, KA (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM keith.wear@fda.hhs.gov NR 25 TC 3 Z9 3 U1 0 U2 11 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0885-3010 EI 1525-8955 J9 IEEE T ULTRASON FERR JI IEEE Trans. Ultrason. Ferroelectr. Freq. Control PD JAN PY 2015 VL 62 IS 1 BP 152 EP 164 DI 10.1109/TUFFC.2014.006578 PG 13 WC Acoustics; Engineering, Electrical & Electronic SC Acoustics; Engineering GA AZ0PU UT WOS:000347948000015 PM 25585399 ER PT J AU Gould, AL Lystig, TC Lu, Y Fu, HD Ma, HJ AF Gould, A. Lawrence Lystig, Theodore C. Lu, Yun Fu, Haoda Ma, Haijun TI Methods and Issues to Consider for Detection of Safety Signals From Spontaneous Reporting Databases: A Report of the DIA Bayesian Safety Signal Detection Working Group SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE pharmacovigilance; risk identification; empirical Bayes; Bayes; propensity; score ID PROBABILITY RATIO TEST; ADVERSE DRUG-REACTIONS; FALSE DISCOVERY RATES; PHARMACOVIGILANCE; STRATIFICATION; SURVEILLANCE; SYSTEM; MULTIPLICITY; ASSOCIATIONS; PERSPECTIVE AB Spontaneous reporting (SR) adverse event system databases, large observational databases, large clinical trials, and large health records databases comprise repositories of information that may be useful for early detection of potential harms associated with drugs, devices, and vaccines. All of the data sources include many different adverse events and many medical products, so that any approach designed to detect important signals of potential harm must have adequate specificity to protect against false alarms yet provide satisfactory sensitivity for detecting issues that really need further investigation. Algorithms for evaluating potential risks using information from these sources, especially SR databases, have been described in the literature. The algorithms may seek to identify potential product-event associations without any prior specifications, to identify events associated with a particular product or set of products, or to identify products associated with a particular event or set of events. This article provides recommendations for using information from postmarketing spontaneous adverse event reporting databases to provide insight into risks of potential harm expressed by safety signals and offers guidance regarding appropriate methods, both frequentist and Bayesian, to use in various situations as a function of the objective of the analysis. C1 [Gould, A. Lawrence] Merck Res Labs, N Wales, PA 19454 USA. [Lystig, Theodore C.] Medtronic Inc, Minneapolis, MN USA. [Lu, Yun] US FDA, Rockville, MD 20857 USA. [Fu, Haoda] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Ma, Haijun] Amgen Inc, Thousand Oaks, CA 91320 USA. RP Gould, AL (reprint author), Merck Res Labs, 351 North Sumneytown Pike, N Wales, PA 19454 USA. EM goulda@merck.com RI Lystig, Theodore/E-4149-2015 OI Lystig, Theodore/0000-0002-4523-0761 NR 60 TC 0 Z9 0 U1 2 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD JAN PY 2015 VL 49 IS 1 BP 65 EP 75 DI 10.1177/2168479014533114 PG 11 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA AZ0XL UT WOS:000347965200009 ER PT J AU Bashaw, ED Tran, DC Shukla, CG Liu, XM AF Bashaw, Edward Dennis Tran, Doanh C. Shukla, Chinmay G. Liu, Xiaomei TI Maximal Usage Trial: An Overview of the Design of Systemic Bioavailability Trial for Topical Dermatological Products SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE Dermatology; Topical Drug Delivery; Absorption; Clinical Pharmacology; Maximal Use ID PHARMACOKINETICS; SUPPRESSION; SKIN AB Dermatologic diseases can present in varying forms and severity, ranging from the individual lesion and up to almost total skin involvement. Pharmacokinetic assessment of topical drug products has previously been plagued by bioanalytical assay limitations and the lack of a standardized study design. Since the mid-1990's the US Food and Drug Administration has developed and implemented a pharmacokinetic maximal usage trial (MUsT) design to help address these issues. The MUsT design takes into account the following elements: the enrollment of patients rather than normal volunteers, the frequency of dosing, duration of dosing, use of highest proposed strength, total involved surface area to be treated at one time, amount applied per square centimeter, application method and site preparation, product formulation, and use of a sensitive bioanalytical method that has been properly validated. This paper provides a perspective of pre-MUsT study designs and a discussion of the individual elements that make up a MUsT. C1 [Bashaw, Edward Dennis; Tran, Doanh C.; Shukla, Chinmay G.; Liu, Xiaomei] US FDA, Silver Spring, MD 20993 USA. RP Bashaw, ED (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 51,Room 3134, Silver Spring, MD 20993 USA. EM edward.bashaw@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 24 TC 1 Z9 1 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 JAN PY 2015 VL 49 IS 1 BP 108 EP 115 DI 10.1177/2168479014539157 PG 8 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA AZ0XL UT WOS:000347965200015 PM 26634191 ER PT J AU Hayes, RP Blum, SI Gordon, MF Piault, E Burke, LB Slagle, AF Coons, SJ AF Hayes, Risa P. Blum, Steven I. Gordon, Mark Forrest Piault, Elisabeth Burke, Laurie B. Slagle, Ashley F. Coons, Stephen Joel TI The Patient-Reported Outcome (PRO) Consortium: Lessons Learned Along the Path to PRO Instrument Qualification SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE patient-reported outcome measure; drug development tool; PRO Consortium AB Established in 2008, the Patient-Reported Outcome (PRO) Consortium is a collaboration among the US Food and Drug Administration's Center for Drug Evaluation and Research, the Critical Path Institute, the pharmaceutical/biotechnology industry, and other stakeholders. The purpose of the consortium is to qualify PRO instruments through the Center for Drug Evaluation and Research's drug development tool qualification process for use as clinical trial endpoints to support drug approval and product labeling claims. The PRO Consortium has made notable progress toward collaborative development of PRO instruments in the following areas: asthma, mild cognitive impairment, depression, functional dyspepsia, irritable bowel syndrome, non-small cell lung cancer, and rheumatoid arthritis. This progress has come with considerable challenges, including navigating a new and evolving regulatory initiative, gaining consensus on key issues, and maintaining communication and engagement in a precompetitive environment. The purpose of this paper is to describe some of the challenges and lessons learned since the creation of the PRO Consortium in hopes that this information may provide direction and insight for similar collaborations. C1 [Hayes, Risa P.] Eli Lilly & Co, Global Patient Outcomes & Real World Evidence, Indianapolis, IN 46237 USA. [Blum, Steven I.] GlaxoSmithKline, Collegeville, PA USA. [Gordon, Mark Forrest] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. [Piault, Elisabeth] Genentech Inc, San Francisco, CA 94080 USA. [Burke, Laurie B.] LORA Grp LLC, Royal Oak, MD USA. [Slagle, Ashley F.] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Coons, Stephen Joel] Crit Path Inst, Patient Reported Outcome Consortium, Tucson, AZ USA. RP Hayes, RP (reprint author), Eli Lilly & Co, 6441 Bastani Pl, Indianapolis, IN 46237 USA. EM hayesrisa2013@gmail.com FU US Food and Drug Administration [U01FD003865]; AbbVie; Actelion; Allergan; Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; CTI BioPharma; Daiichi Sankyo; Eisai; Eli Lilly and Company; Forest Laboratories Inc; GlaxoSmithKline; Horizon Pharma; Ironwood; Johnson Johnson; Merck Sharp Dohme Corp; Novartis; Novo Nordisk; Pfizer; Roche; Sanofi; Shire; Sunovion; Takeda; UCB FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Critical Path Institute's PRO Consortium is supported by grant No. U01FD003865 from the US Food and Drug Administration. Additional support for the PRO Consortium comes from membership fees paid by the following firms: AbbVie, Actelion, Allergan, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CTI BioPharma, Daiichi Sankyo, Eisai, Eli Lilly and Company, Forest Laboratories Inc, GlaxoSmithKline, Horizon Pharma, Ironwood, Johnson & Johnson, Merck Sharp & Dohme Corp, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Shire, Sunovion, Takeda, and UCB. NR 6 TC 1 Z9 1 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 JAN PY 2015 VL 49 IS 1 BP 132 EP 138 DI 10.1177/2168479014549858 PG 7 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA AZ0XL UT WOS:000347965200018 ER PT J AU Chen, RT Carbery, B Mac, L Berns, KI Chapman, L Condit, RC Excler, JL Gurwith, M Hendry, M Khan, AS Khuri-Bulos, N Klug, B Robertson, JS Seligman, SJ Sheets, R Williamson, AL AF Chen, Robert T. Carbery, Baevin Mac, Lisa Berns, Kenneth I. Chapman, Louisa Condit, Richard C. Excler, Jean-Louis Gurwith, Marc Hendry, Michael Khan, Arifa S. Khuri-Bulos, Najwa Klug, Bettina Robertson, James S. Seligman, Stephen J. Sheets, Rebecca Williamson, Anna-Lise CA V3SWG TI The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) SO VACCINE LA English DT Article DE Vaccines; Viral Vector; Safety; Immunization ID ROTAVIRUS VACCINE; HIV-1 VACCINE; DOUBLE-BLIND; RISK; EFFICACY; IMMUNIZATION; INFECTION; TRIAL; STEP; H1N1 AB Recombinant viral vectors provide an effective means for heterologous antigen expression in vivo and thus represent promising platforms for developing novel vaccines against human pathogens from Ebola to tuberculosis. An increasing number of candidate viral vector vaccines are entering human clinical trials. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to improve our ability to anticipate potential safety issues and meaningfully assess or interpret safety data, thereby facilitating greater public acceptance when licensed. Published by Elsevier Ltd. C1 [Chen, Robert T.; Carbery, Baevin; Mac, Lisa; Chapman, Louisa; Hendry, Michael] Ctr Dis Control & Prevent, DHAP, NCHHSTP, Atlanta, GA 30333 USA. [Carbery, Baevin] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Berns, Kenneth I.; Condit, Richard C.] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA. [Excler, Jean-Louis] Int AIDS Vaccine Initiat, New York, NY USA. US Mil HIV Res Program MHRP, Bethesda, MD 20817 USA. [Gurwith, Marc] PaxVax, San Diego, CA 92121 USA. [Khan, Arifa S.] US FDA, Lab Retroviruses, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Khuri-Bulos, Najwa] Jordan Univ Hosp, Div Infect Dis, Amman, Jordan. [Klug, Bettina] Paul Ehrlich Inst, D-63225 Langen, Germany. [Robertson, James S.] Natl Inst Biol Stand & Controls, Potters Bar EN6 3QG, Herts, England. [Seligman, Stephen J.] New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA. [Sheets, Rebecca] NIAID, Div Aids, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Williamson, Anna-Lise] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Williamson, Anna-Lise] Natl Hlth Lab Serv, Cape Town, South Africa. RP Chen, RT (reprint author), Ctr Dis Control & Prevent, DHAP, NCHHSTP, 1600 Clifton Rd, Atlanta, GA 30333 USA. EM brightoncollaborationv3swg@gmail.com FU Intramural CDC HHS [CC999999] NR 35 TC 5 Z9 5 U1 2 U2 13 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 JAN 1 PY 2015 VL 33 IS 1 BP 73 EP 75 DI 10.1016/j.vaccine.2014.09.035 PG 3 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AY6FX UT WOS:000347663700013 PM 25305565 ER PT J AU Derrick, SC Yang, A Parra, M Kolibab, K Morris, SL AF Derrick, Steven C. Yang, Amy Parra, Marcela Kolibab, Kristopher Morris, Sheldon L. TI Effect of cationic liposomes on BCG trafficking and vaccine-induced immune responses following a subcutaneous immunization in mice SO VACCINE LA English DT Article DE BCG; Tuberculosis; Immunity; Adjuvants ID MYCOBACTERIUM-BOVIS BCG; ORAL VACCINATION; PUBLISHED LITERATURE; GUINEA-BISSAU; TUBERCULOSIS; INFECTION; EFFICACY; PERSISTENCE; SURVIVAL; PREVENTION AB While formulating Mycobacterium bovis BCG in lipid-based adjuvants has been shown to increase the vaccine's protective immunity, the biological mechanisms responsible for the enhanced potency of lipid encapsulated BCG are unknown. To assess whether mixing BCG in adjuvant increases its immunogenicity by altering post-vaccination organ distribution and persistence, mice were immunized subcutaneously with conventional BCG Pasteur or BCG formulated in DDA/TDB adjuvant and the bio-distribution of BCG bacilli was evaluated in mouse lungs, spleens, lymph nodes, and livers for up to I year. Although BCG was rarely detected in mouse livers, mycobacteria were found in mouse lungs, spleens, and lymph nodes for at least 1 year post-vaccination. However, at various time points during the 1 year study, the frequency of lung and spleen infections and the number of mycobacteria in infected organs of individual mice were highly variable. In contrast, mycobacteria were nearly always detected in the lymph nodes of vaccinated mice. While the frequency and extent of lymph node infections generally were not significantly different between mice vaccinated with adjuvanted or nonadjuvanted BCG preparations, multiparameter flow cytometry analysis of lymph node cells showed significantly higher frequencies of CD4+ and CD8+ T cells expressing IFN-gamma and IFN-gamma/TNF-alpha in mice immunized with adjuvanted BCG. Overall, our data suggest that the relationship between lymph node infection and the generation of anti-tuberculosis protective responses following BCG vaccination should be further investigated. Published by Elsevier C1 [Derrick, Steven C.; Yang, Amy; Parra, Marcela; Morris, Sheldon L.] Ctr Biol Evaluat & Res, Lab Mycobacterial Dis & Cellular Immunol, Silver Spring, MD 20993 USA. [Kolibab, Kristopher] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Derrick, SC (reprint author), Bldg 52-72, Silver Spring, MD 20993 USA. EM steven.derrick@fda.hhs.gov NR 36 TC 3 Z9 3 U1 2 U2 12 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 JAN 1 PY 2015 VL 33 IS 1 BP 126 EP 132 DI 10.1016/j.vaccine.2014.11.004 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AY6FX UT WOS:000347663700021 PM 25448108 ER PT J AU Venkatakrishnan, K Friberg, LE Ouellet, D Mettetal, JT Stein, A Troconiz, IF Bruno, R Mehrotra, N Gobburu, J Mould, DR AF Venkatakrishnan, K. Friberg, L. E. Ouellet, D. Mettetal, J. T. Stein, A. Troconiz, I. F. Bruno, R. Mehrotra, N. Gobburu, J. Mould, D. R. TI Optimizing Oncology Therapeutics Through Quantitative Translational and Clinical Pharmacology: Challenges and Opportunities SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID PROGRESSION-FREE SURVIVAL; RENAL-CELL CARCINOMA; METASTATIC COLORECTAL-CANCER; CHEMOTHERAPY-INDUCED MYELOSUPPRESSION; TUMOR-GROWTH INHIBITION; SIZE RESPONSE METRICS; SURROGATE END-POINT; BODY-SURFACE AREA; DRUG DEVELOPMENT; BREAST-CANCER AB Despite advances in biomedical research that have deepened our understanding of cancer hallmarks, resulting in the discovery and development of targeted therapies, the success rates of oncology drug development remain low. Opportunities remain for objective dose selection informed by exposure-response understanding to optimize the benefit-risk balance of novel therapies for cancer patients. This review article discusses the principles and applications of modeling and simulation approaches across the lifecycle of development of oncology therapeutics. Illustrative examples are used to convey the value gained from integration of quantitative clinical pharmacology strategies from the preclinical-translational phase through confirmatory clinical evaluation of efficacy and safety. C1 [Venkatakrishnan, K.] Takeda Pharmaceut Int Co, Clin Pharmacol, Cambridge, MA 02139 USA. [Friberg, L. E.] Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden. [Ouellet, D.] GlaxoSmithKline, Clin Pharmacol Modeling & Simulat, Res Triangle Pk, NC USA. [Mettetal, J. T.] AstraZeneca R&D, Drug Safety & Metab, Waltham, MA USA. [Stein, A.] Novartis Inst Biochem Res, Cambridge, MA USA. [Troconiz, I. F.] Univ Navarra, Dept Pharm & Pharmaceut Technol, E-31080 Pamplona, Spain. [Bruno, R.] Pharsight, Pharsight Consulting Serv, Marseille, France. [Mehrotra, N.] US FDA, Div Pharmacometr, Off Clin Pharmacol, Silver Spring, MD USA. [Gobburu, J.] Univ Maryland, Sch Pharm, Ctr Translat Med, Baltimore, MD 21201 USA. [Mould, D. R.] Project Res Inc, Phoenixville, PA USA. RP Venkatakrishnan, K (reprint author), Takeda Pharmaceut Int Co, Clin Pharmacol, Cambridge, MA 02139 USA. EM karthik.venkatakrishnan@takeda.com FU ASCPT PMK FX This article represents a work product of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) Oncology I-Promote initiative of the Society's Pharmacometrics and Pharmacokinetics (PMK) section. The authors are grateful to ASCPT PMK section leadership for their support of this initiative. The authors thank Ms. Zina Deretsky for artwork contributions to this article. Disclaimer: The views presented in this article by N.M. are the author's personally and do not reflect any position or policy of the government or the Food and Drug Administration. NR 99 TC 14 Z9 15 U1 3 U2 13 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 JAN PY 2015 VL 97 IS 1 BP 37 EP 54 DI 10.1002/cpt.7 PG 18 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AY9SF UT WOS:000347889900012 PM 25670382 ER PT J AU Stephenson, D Perry, D Bens, C Bain, LJ Berry, D Krams, M Sperling, R Dilts, D Luthman, J Hanna, D McKew, J Temple, R Fields, FO Salloway, S Katz, R AF Stephenson, Diane Perry, Dan Bens, Cynthia Bain, Lisa J. Berry, Donald Krams, Michael Sperling, Reisa Dilts, David Luthman, Johan Hanna, Debra McKew, John Temple, Robert Fields, F. Owen Salloway, Stephen Katz, Russell TI Charting a path toward combination therapy for Alzheimer's disease SO EXPERT REVIEW OF NEUROTHERAPEUTICS LA English DT Review DE Alzheimer's disease; combination therapy; collaboration; novel therapy; co-development ID DRUG DEVELOPMENT; BREAST-CANCER; CLINICAL-TRIALS; MAJOR DISEASES; BIOMARKERS; CHEMOTHERAPY; MEMANTINE; RECOMMENDATIONS; PERSPECTIVES; COALITION AB It is acknowledged that progress in combined therapeutic approaches for Alzheimer's disease (AD) will require an unprecedented level of collaboration. At a meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer's Disease Coalition and the Critical Path Institute, investigators from industry, academia and regulatory agencies agreed on the need for combinatorial approaches to treating AD. The need for advancing multiple targets includes recognition for novel adaptive trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination. A combination trial now being planned may test drugs targeting different pathogenic pathways or multiple targets along a common pathway. Collaborations and consortia-based strategies are pivotal for success and a regulatory framework is recommended for success. C1 [Stephenson, Diane] Crit Path Inst, CAMD, Tucson, AZ 85718 USA. [Perry, Dan; Bens, Cynthia] Alliance Aging Res, Accelerate Cure Treatments Alzheimers Dis ACT AD, Washington, DC USA. [Berry, Donald] Berry Consultants LLC, Austin, TX 78746 USA. [Krams, Michael] Janssen Pharmaceut, Neurol Franchise, Titusville, NJ USA. [Sperling, Reisa] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Alzheimer Res & Treatment, Boston, MA 02115 USA. [Dilts, David] OHSU Knight Canc Inst, Div Management, Ctr Management Res Healthcare, Portland, OR USA. [Luthman, Johan] Eisai Pharmaceut, Visakhapatnam, Andhra Pradesh, India. [Hanna, Debra] Crit Path TB Drug Regimens Regulatory Sci Consort, Tucson, AZ USA. [McKew, John] NIH, Therapeut Dev Branch, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Temple, Robert] US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Fields, F. Owen] Pfizer, Worldwide Res & Dev, Regulatory Strategy, New York, NY USA. [Salloway, Stephen] Butler Hosp, Memory & Aging Program, Providence, RI 02906 USA. RP Stephenson, D (reprint author), Crit Path Inst, CAMD, Tucson, AZ 85718 USA. EM DStephenson@c-path.org RI Akbar, Afrah/C-2001-2016 FU Eli Lily; Eisai; Avid; Janssen; Biogen Idec; Merck Lilly; Roche Genentech FX M Krams is an employee of Janssen R&D. R Sperling is a consultant to Roche, Isis, Genentech, Janssen and has received research support from Eli Lily, Eisai, Avid and Janssen. J Luthman is an employee of Eisai Inc and owns shares in AstraZeneca & Merck Inc. F Owen Fields is employed by Pfizer and has stock options in Pfizer. S Salloway has received research support from Biogen Idec, Merck Lilly, Roche & Genentech. 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 30 TC 10 Z9 10 U1 1 U2 6 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1473-7175 EI 1744-8360 J9 EXPERT REV NEUROTHER JI Expert Rev. Neurother. PD JAN PY 2015 VL 15 IS 1 SI SI BP 107 EP 113 DI 10.1586/14737175.2015.995168 PG 7 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AY8KQ UT WOS:000347802800009 PM 25540951 ER PT J AU Pouillot, R Gallagher, D Tang, J Hoelzer, K Kause, J Dennis, SB AF Pouillot, Regis Gallagher, Daniel Tang, Jia Hoelzer, Karin Kause, Janell Dennis, Sherri B. TI Listeria monocytogenes in Retail Delicatessens: An Interagency Risk Assessment-Model and Baseline Results SO JOURNAL OF FOOD PROTECTION LA English DT Article ID TURKEY BREAST; UNITED-STATES; CROSS-CONTAMINATION; GROWTH BOUNDARY; DELI MEATS; ILLNESS; SALAMI; ESTABLISHMENTS; ENVIRONMENTS; PREVALENCE AB The Interagency Risk Assessment Listeria monocytogenes (Lm) in Retail Delicatessens provides a scientific assessment of the risk of listeriosis associated with the consumption of ready-to-eat (RTE) foods commonly prepared and sold in the delicatessen (deli) of a retail food store. The quantitative risk assessment (QRA) model simulates the behavior of retail employees in a deli department and tracks the Lm potentially present in this environment and in the food. Bacterial growth, bacterial inactivation (following washing and sanitizing actions), and cross-contamination (from object to object, from food to object, or from object to food) are evaluated through a discrete event modeling approach. The QRA evaluates the risk per serving of deli-prepared RTE food for the susceptible and general population, using a dose-response model from the literature. This QRA considers six separate retail baseline conditions and provides information on the predicted risk of listeriosis for each. Among the baseline conditions considered, the model predicts that (i) retail delis without an environmental source of Lm (such as niches), retail delis without niches that do apply temperature control, and retail delis with niches that do apply temperature control lead to lower predicted risk of listeriosis relative to retail delis with niches and (ii) retail delis with incoming RTE foods that are contaminated with Lm lead to higher predicted risk of listeriosis, directly or through cross-contamination, whether the contaminated incoming product supports growth or not. The risk assessment predicts that listeriosis cases associated with retail delicatessens result from a sequence of key events: (i) the contaminated RTE food supports Lm growth; (ii) improper retail and/or consumer storage temperature or handling results in the growth of Lm on the RTE food; and (iii) the consumer of this RTE food is susceptible to listeriosis. The risk assessment model, therefore, predicts that cross-contamination with Lm at retail predominantly results in sporadic cases. C1 [Pouillot, Regis; Hoelzer, Karin; Dennis, Sherri B.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Gallagher, Daniel; Tang, Jia] Virginia Polytech Inst & State Univ, Civil & Environm Engn Dept, Blacksburg, VA 24061 USA. [Kause, Janell] USDA, Off Publ Hlth Sci, Food Safety & Inspect Serv, Washington, DC 20228 USA. RP Pouillot, R (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Regis.Pouillot@fda.hhs.gov RI Pouillot, Regis/E-8103-2010 OI Pouillot, Regis/0000-0002-6107-5212 FU Virginia Tech; U.S. Department of Agriculture, Food Safety and Inspection Service (FSIS) [AG-3A94-P-08-0166]; Center for Food Safety and Applied Nutrition FX Support for this work was provided by Virginia Tech in collaboration with the U.S. Department of Agriculture, Food Safety and Inspection Service (FSIS contract AG-3A94-P-08-0166). This work was also supported by an appointment 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 42 TC 4 Z9 4 U1 5 U2 23 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 JAN PY 2015 VL 78 IS 1 BP 134 EP 145 DI 10.4315/0362-028X.JFP-14-235 PG 12 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA AZ1QB UT WOS:000348012000018 PM 25581188 ER PT J AU Marshall, KM Nowaczyk, L Morrissey, TR Loeza, V Halik, LA Skinner, GE Reddy, NR Fleischman, GJ Larkin, JW AF Marshall, Kristin M. Nowaczyk, Louis, II Morrissey, Travis R. Loeza, Viviana Halik, Lindsay A. Skinner, Guy E. Reddy, N. Rukma Fleischman, Gregory J. Larkin, John W. TI Effect of Sporulation Temperature on the Resistance of Clostridium botulinum Type A Spores to Thermal and High Pressure Processing SO JOURNAL OF FOOD PROTECTION LA English DT Article ID HEAT-RESISTANCE; BACILLUS-CEREUS; INACTIVATION; STRAIN AB The purpose of this study was to determine the effect of sporulation temperature on the resistance of Clostridium botulinum type A spores of strains 62A and GiorgioA to thermal and high pressure processing (HPP). Spore crops produced in Trypticase peptone glucose yeast extract broth at four incubation temperatures (20, 27, 37, and 41 degrees C) were harvested, and heat resistance studies were conducted at 105 degrees C (strain 62A) and 100 degrees C (strain GiorgioA). Resistance to HPP was evaluated by subjecting the spores to a high pressure (700 MPa) and temperature combination (105 degrees C, strain 62A; 100 degrees C strain GiorgioA) in a laboratory-scale pressure test system. The decimal reduction time (D-value) was calculated using the log-linear model. Although the time to sporulation for GiorgioA was shorter and resulted in higher spore concentrations than for 62A at 20, 27, and 37 degrees C, GiorgioA did not produce a sufficient spore crop at 41 degrees C to be evaluated. The heat resistance of 62A spores was greatest when produced at 27 degrees C and decreased for spore crops produced above or below 27 degrees C (D-105 degrees C-values: 20 degrees C, 1.9 min; 27 degrees C, 4.03 min; 37 degrees C, 3.66 min; and 41 degrees C, 3.5 min; P < 0.05). Unlike 62A, the heat resistance behavior of GiorgioA spores increased with rising sporulation temperature, and spores formed at the organism's optimum growth temperature of 37 degrees C were the most resistant (D-100 degrees C-values: 20 degrees C, 3.4 min; 27 degrees C, 5.08 min; and 37 degrees C, 5.65 min; P < 0.05). Overall, all spore crops were less resistant to pressure-assisted thermal processing than thermal treatment alone. Sporulation temperature has an effect on the resistance of C. botulinum spores to heat and HPP, and is characteristic to a particular strain. Knowledge of the effect of sporulation temperature on the resistance of C. botulinum spores is vital for the production of spores utilized in thermal and high pressure inactivation studies. C1 [Marshall, Kristin M.; Nowaczyk, Louis, II; Morrissey, Travis R.; Skinner, Guy E.; Reddy, N. Rukma; Fleischman, Gregory J.; Larkin, John W.] US FDA, Ctr Food Safety & Appl Nutr, Bedford Pk, IL 60501 USA. [Loeza, Viviana; Halik, Lindsay A.] IIT, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. RP Marshall, KM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM kristin.marshall@fda.hhs.gov NR 20 TC 4 Z9 4 U1 1 U2 27 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 JAN PY 2015 VL 78 IS 1 BP 146 EP 150 DI 10.4315/0362-028X.JFP-14-186 PG 5 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA AZ1QB UT WOS:000348012000019 PM 25581189 ER PT J AU Eischeid, AC Kasko, SM AF Eischeid, Anne C. Kasko, Sasha M. TI Quantitative Multiplex Real-Time PCR Assay for Shrimp Allergen: Comparison of Commercial Master Mixes and PCR Platforms in Rapid Cycling SO JOURNAL OF FOOD PROTECTION LA English DT Article ID POLYMERASE-CHAIN-REACTION; ROCHE LIGHTCYCLER; VIRUS DETECTION; DNA; RNA AB Real-time PCR has been used widely in numerous fields. In food safety, it has been applied to detection of microbes and other contaminants, including food allergens. Interest in rapid (fast) cycling real-time PCR has grown because it yields results in less time than does conventional cycling. However, fast cycling can adversely affect assay performance. Here we report on tests of commercial master mixes specifically designed for fast real-time PCR using a shrimp allergen assay we previously developed and validated. The objective of this work was to determine whether specialized commercial master mixes lead to improved assay performance in rapid cycling. Real-time PCR assays were carried out using four different master mixes and two different rapid cycling protocols. Results indicated that specialized master mixes did yield quality results. In many cases, linear ranges spanned up to 7 orders of magnitude, R-2 values were at least 0.95, and reaction efficiencies were within or near the optimal range of 90 to 110%. In the faster of the two rapid cycling protocols tested, assay performance and PCR amplification were markedly better for the shorter PCR product. In conclusion, specialized commercial master mixes were effective as part of rapid cycling protocols, but conventional cycling as used in our previous work is more reliable for the shrimp assay tested. C1 [Eischeid, Anne C.; Kasko, Sasha M.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Eischeid, AC (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM anne.eischeid@fda.hhs.gov NR 19 TC 1 Z9 1 U1 4 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 JAN PY 2015 VL 78 IS 1 BP 230 EP 234 DI 10.4315/0362-028X.JFP-14-203 PG 5 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA AZ1QB UT WOS:000348012000032 PM 25581202 ER PT J AU Gewandter, JS McKeown, A McDermott, MP Dworkin, JD Smith, SM Gross, RA Hunsinger, M Lin, AH Rappaport, BA Rice, ASC Rowbotham, MC Williams, MR Turk, DC Dworkin, RH AF Gewandter, Jennifer S. McKeown, Andrew McDermott, Michael P. Dworkin, Jordan D. Smith, Shannon M. Gross, Robert A. Hunsinger, Matthew Lin, Allison H. Rappaport, Bob A. Rice, Andrew S. C. Rowbotham, Michael C. Williams, Mark R. Turk, Dennis C. Dworkin, Robert H. TI Data Interpretation in Analgesic Clinical Trials With Statistically Nonsignificant Primary Analyses: An ACTTION Systematic Review SO JOURNAL OF PAIN LA English DT Review DE Spin; misrepresentation; randomized clinical trials; ACTTION; systematic review ID RANDOMIZED CONTROLLED-TRIALS; SECONDARY END-POINTS; PRIMARY OUTCOMES; RECOMMENDATIONS; BIAS; PUBLICATION; PROTOCOLS; EFFICACY; CANCER; IF AB Peer-reviewed publications of randomized clinical trials (RCTs) are the primary means of disseminating research findings. "Spin" in RCT publications is misrepresentation of statistically nonsignificant research findings to suggest treatment benefit. Spin can influence the way readers interpret clinical trials and use the information to make decisions about treatments and medical policies. The objective of this study was to determine the frequency with which 4 types of spin were used in publications of analgesic RCTs with nonsignificant primary analyses in 6 major pain journals. In the 76 articles included in our sample, 28% of the abstracts and 29% of the main texts emphasized secondary analyses with P values <.05; 22% of abstracts and 29% of texts emphasized treatment benefit based on nonsignificant primary results; 14% of abstracts and 18% of texts emphasized within-group improvements over time, rather than primary between-group comparisons; and 13% of abstracts and 10% of texts interpreted a nonsignificant difference between groups in a superiority study as comparable effectiveness. When considering the article conclusion sections, 21% did not mention the nonsignificant primary result, 22% were presented with no uncertainty or qualification, 30% did not acknowledge that future research was required, and 8% recommended the intervention for clinical use. Perspective: This article identifies relatively frequent "spin" in analgesic RCTs. These findings highlight a need for authors, reviewers, and editors to be more cognizant of how analgesic RCT results are presented and attempt to minimize spin in future clinical trial publications. (C) 2015 by the American Pain Society. Published by Elsevier Inc. All rights reserved C1 [Gewandter, Jennifer S.; McKeown, Andrew; Smith, Shannon M.; Williams, Mark R.; Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Dept Anesthesiol, Rochester, NY 14642 USA. [McDermott, Michael P.] Univ Rochester, Sch Med & Dent, Dept Biostat & Computat Biol, Rochester, NY 14642 USA. [McDermott, Michael P.; Gross, Robert A.] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA. [Gross, Robert A.] Univ Rochester, Sch Med & Dent, Dept Pharmacol & Physiol, Rochester, NY 14642 USA. [Dworkin, Jordan D.] Haverford Coll, Haverford, PA 19041 USA. [Hunsinger, Matthew] Univ Pacific, Sch Profess Psychol, Hillsboro, OR USA. [Lin, Allison H.; Rappaport, Bob A.] United States Food & Drug Adm, Silver Spring, MD USA. [Rice, Andrew S. C.] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London, England. [Rowbotham, Michael C.] Calif Pacific Med Ctr, San Francisco, CA USA. [Turk, Dennis C.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. RP Gewandter, JS (reprint author), Univ Rochester, Sch Med & Dent, Dept Anesthesiol, Rochester, NY 14642 USA. EM Jennifer_gewandter@urmc.rochester.edu OI Dworkin, Jordan/0000-0002-5720-1298 FU Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership; ACTTION public-private partnership; FDA [U01 FD004187]; Annovation; Astellas; Collegium; Depomed; Jazz; John- son Johnson; Lilly; Olatec; Pfizer; Purdue; Spinifex; Teva FX The views expressed in this article are those of the authors and no official endorsement by the Food and Drug Administration (FDA) or the pharmaceutical companies that provided unrestricted grants to support the activities of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership should be inferred. Financial support for this project was provided by the ACTTION public-private partnership, which has received research contracts, grants, or other revenue from the FDA (U01 FD004187), Annovation, Astellas, Collegium, Depomed, Jazz, John- son & Johnson, Lilly, Olatec, Pfizer, Purdue, Spinifex, and Teva. None of the authors have financial disclosures that are relevant to this article. NR 25 TC 8 Z9 8 U1 0 U2 3 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD JAN PY 2015 VL 16 IS 1 BP 3 EP 10 DI 10.1016/j.jpain.2014.10.003 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AY6FO UT WOS:000347662900002 PM 25451621 ER PT J AU Kang, EM Pinheiro, SP Hammad, TA Abou-Ali, A AF Kang, Elizabeth M. Pinheiro, Simone P. Hammad, Tarek A. Abou-Ali, Adel TI Evaluating the validity of clinical codes to identify cataract and glaucoma in the UK Clinical Practice Research Datalink SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE clinical practice research datalink; read codes; validation of cataract; validation of glaucoma; eye disorders; pharmacoepidemiology ID PRACTICE RESEARCH DATABASE; PREDICTIVE-VALUE; RISK; POPULATION; STATINS; CORTICOSTEROIDS; DISEASE; USERS AB PurposeThe aim of this study is to determine (i) the positive predictive value (PPV) of an algorithm using clinical codes to identify incident glaucoma and cataract events in the Clinical Practice Research Datalink (CPRD) and (ii) the ability to capture the correct timing of these clinical events. MethodsA total of 21339 and 5349 potential cataract and glaucoma cases, respectively, were identified in CPRD between 1 January 1990 and 31 December 2010. Questionnaires were sent to the general practitioners (GP) of 1169 (5.5%) cataract and 1163 (21.7%) glaucoma cases for validation. GPs were asked to verify the diagnosis and the timing of the diagnosis and to provide other supporting information. ResultsA total of 986 (84.3%) valid cataract questionnaires and 863 (74.2%) glaucoma questionnaires were completed. 92.1% and 92.4% of these used information beyond EMR to verify the diagnosis. Cataract and glaucoma diagnoses were confirmed in the large majority of the cases. The PPV (95% CI) of the cataract and glaucoma Read code algorithm were 92.0% (90.3-93.7%) and 84.1% (81.7-86.6%), respectively. However, timing of diagnosis was incorrect for a substantial proportion of the cases (20.3% and 32.8% of the cataract and glaucoma cases, respectively) among whom 30.4% and 49.2% had discrepancies in diagnosis timing greater than 1year. ConclusionsHigh PPV suggests that the algorithms based on the clinical Read codes are sufficient to identify the cataract and glaucoma cases in CPRD. However, these codes alone may not be able to accurately identify the timing of the diagnosis of these eye disorders. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Kang, Elizabeth M.; Pinheiro, Simone P.; Hammad, Tarek A.; Abou-Ali, Adel] US FDA, Silver Spring, MD 20993 USA. RP Kang, EM (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Elizabeth.Kang@fda.hhs.gov RI CPRD, CPRD/B-9594-2017 FU US Food and Drug Administration (FDA); US Department of Energy's Oak Ridge Institute for Science and Education (ORISE) FX Funding for this study came from the US Food and Drug Administration (FDA). AA received a stipend from the US Department of Energy's Oak Ridge Institute for Science and Education (ORISE). NR 17 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 JAN PY 2015 VL 24 IS 1 BP 38 EP 44 DI 10.1002/pds.3726 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AY6ZC UT WOS:000347710100006 PM 25425327 ER PT J AU Levin, D Golding, B Strome, SE Sauna, ZE AF Levin, Ditza Golding, Basil Strome, Scott E. Sauna, Zuben E. TI Fc fusion as a platform technology: potential for modulating immunogenicity SO TRENDS IN BIOTECHNOLOGY LA English DT Review DE therapeutic proteins; Fe-fusion technology; immunogenicity; neutralizing antidrug antibodies; Fc receptors; drug development ID IDIOPATHIC THROMBOCYTOPENIC PURPURA; INTRAVENOUS GAMMA-GLOBULIN; NECROSIS-FACTOR-ALPHA; MONOCLONAL-ANTIBODIES; DENDRITIC CELLS; IN-VIVO; RHEUMATOID-ARTHRITIS; BASOPHIL ACTIVATION; RECEPTOR ANTAGONIST; AUTOIMMUNE-DISEASE AB The platform technology of fragment crystallizable (Fc) fusion, in which the Fc region of an antibody is genetically linked to an active protein drug, is among the most successful of a new generation of bioengineering strategies. Immunogenicity is a critical safety concern in the development of any protein therapeutic. While the therapeutic goal of generating Fc-fusion proteins has been to extend half-life, there is a critical mass of literature from immunology indicating that appropriate design of the Fc component has the potential to engage the immune system for product-specific outcomes. In the context of Fc-fusion therapeutics, a review of progress in understanding Fc biology suggests the prospect of engineering products that have an extended half-life and are able to modulate the immune system. C1 [Levin, Ditza; Sauna, Zuben E.] Ctr Biol Evaluat & Res, Food & Drug Adm, Lab Hemostasis, Div Hematol Res & Review, Silver Spring, MD 20993 USA. [Golding, Basil] Food & Drug Adm, Ctr Biol Evaluat & Res, Div Hematol Res & Review, Silver Spring, MD 20993 USA. [Strome, Scott E.] Univ Maryland, Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Baltimore, MD 21201 USA. RP Sauna, ZE (reprint author), Ctr Biol Evaluat & Res, Food & Drug Adm, Lab Hemostasis, Div Hematol Res & Review, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM zuben.sauna@fda.hhs.gov FU Laboratory of Hemostasis, Center for Biologics Evaluation and Research; FDA's Modernization of Science Program; Critical Path initiative; FDA Chief Scientist's Challenge Grant FX The authors thank Jonathan Simon for assistance with Figure 1. This work was supported by funds from the Laboratory of Hemostasis, Center for Biologics Evaluation and Research (B.G. and Z.E.S.), the FDA's Modernization of Science Program (Z.E.S), The Critical Path initiative (Z.E.S.), and the FDA Chief Scientist's Challenge Grant (Z.E.S.). NR 88 TC 20 Z9 21 U1 3 U2 25 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0167-7799 J9 TRENDS BIOTECHNOL JI Trends Biotechnol. PD JAN PY 2015 VL 33 IS 1 BP 27 EP 34 DI 10.1016/j.tibtech.2014.11.001 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AY9II UT WOS:000347863400005 PM 25488117 ER PT J AU Bartlett, JA Brewster, M Brown, P Cabral-Lilly, D Cruz, CN David, R Eickhoff, WM Haubenreisser, S Jacobs, A Malinoski, F Morefield, E Nalubola, R Prud'homme, RK Sadrieh, N Sayes, CM Shahbazian, H Subbarao, N Tamarkin, L Tyner, K Uppoor, R Whittaker-Caulk, M Zamboni, W AF Bartlett, Jeremy A. Brewster, Marcus Brown, Paul Cabral-Lilly, Donna Cruz, Celia N. David, Raymond Eickhoff, W. Mark Haubenreisser, Sabine Jacobs, Abigail Malinoski, Frank Morefield, Elaine Nalubola, Ritu Prud'homme, Robert K. Sadrieh, Nakissa Sayes, Christie M. Shahbazian, Hripsime Subbarao, Nanda Tamarkin, Lawrence Tyner, Katherine Uppoor, Rajendra Whittaker-Caulk, Margaret Zamboni, William TI Summary Report of PQRI Workshop on Nanomaterial in Drug Products: Current Experience and Management of Potential Risks SO AAPS JOURNAL LA English DT Article DE nanomaterials; nanomedicine; nanotechnology; PQRI; risk management; USFDA ID PEGYLATED LIPOSOMAL DOXORUBICIN; CKD-602 S-CKD602; DELIVERY SYSTEMS; PHARMACEUTICAL DEVELOPMENT; POLYMERIC NANOPARTICLES; ANTICANCER AGENTS; COLLOIDAL GOLD; SOLID TUMORS; IN-VIVO; PHARMACOKINETICS AB At the Product Quality Research Institute (PQRI) Workshop held last January 14-15, 2014, participants from academia, industry, and governmental agencies involved in the development and regulation of nanomedicines discussed the current state of characterization, formulation development, manufacturing, and nonclinical safety evaluation of nanomaterial-containing drug products for human use. The workshop discussions identified areas where additional understanding of material attributes, absorption, biodistribution, cellular and tissue uptake, and disposition of nanosized particles would continue to inform their safe use in drug products. Analytical techniques and methods used for in vitro characterization and stability testing of formulations containing nanomaterials were discussed, along with their advantages and limitations. Areas where additional regulatory guidance and material characterization standards would help in the development and approval of nanomedicines were explored. Representatives from the US Food and Drug Administration (USFDA), Health Canada, and European Medicines Agency (EMA) presented information about the diversity of nanomaterials in approved and newly developed drug products. USFDA, Health Canada, and EMA regulators discussed the applicability of current regulatory policies in presentations and open discussion. Information contained in several of the recent EMA reflection papers was discussed in detail, along with their scope and intent to enhance scientific understanding about disposition, efficacy, and safety of nanomaterials introduced in vivo and regulatory requirements for testing and market authorization. Opportunities for interaction with regulatory agencies during the lifecycle of nanomedicines were also addressed at the meeting. This is a summary of the workshop presentations and discussions, including considerations for future regulatory guidance on drug products containing nanomaterials. C1 [Bartlett, Jeremy A.] Pfizer Inc, Groton Labs, Groton, CT 06340 USA. [Brewster, Marcus] Johnson & Johnson, Janssen Pharmaceut, Beerse, Belgium. [Brown, Paul; Cruz, Celia N.; Jacobs, Abigail; Tyner, Katherine; Uppoor, Rajendra; Whittaker-Caulk, Margaret] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. [Cabral-Lilly, Donna] Celator Pharmaceut Inc, Ewing, NJ 08628 USA. [Cruz, Celia N.] US FDA, Silver Spring, MD 20993 USA. [David, Raymond] BASF Corp, Ecol & Safety, Florham Pk, NJ 07932 USA. [Eickhoff, W. Mark] Merck & Co Inc, West Point, PA 19486 USA. [Haubenreisser, Sabine] European Med Agcy, Canary Wharf, London E14 5EU, England. [Malinoski, Frank] Nanomed Alliance, Washington, DC USA. [Morefield, Elaine] Vertex Pharmaceut Inc, Boston, MA 02210 USA. [Nalubola, Ritu] US FDA, Off Commissioner, Silver Spring, MD 20903 USA. [Prud'homme, Robert K.] Princeton Univ, Sch Engn & Appl Sci, Princeton, NJ 08544 USA. [Sadrieh, Nakissa] US FDA, Ctr Food Safety & Appl Nutr, Silver Spring, MD 20903 USA. [Sayes, Christie M.] RTI Int, Res Triangle Pk, NC 27709 USA. [Shahbazian, Hripsime] Hlth Canada, Hlth Protect Branch, Ottawa, ON K1A 0L2, Canada. [Subbarao, Nanda] Biol Consulting Grp, Alexandria, VA 22314 USA. [Tamarkin, Lawrence] CytImmune, Rockville, MD 20850 USA. [Zamboni, William] Univ N Carolina, Carolina Ctr Canc Nanotechnol Excellence, UNC Lineberger Comprehens Canc Ctr, UNC Eshelman Sch Pharm, Chapel Hill, NC 27514 USA. [Zamboni, William] Wildcat Pharmaceut Dev Ctr, Houston, TX 77389 USA. RP Cruz, CN (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. EM celia.cruz@fda.hhs.gov RI Sayes, Christie/C-1333-2016 OI Sayes, Christie/0000-0002-5529-4101 FU USFDA; USP; AAPS FX The workshop was cosponsored by USFDA, USP, and AAPS and endorsed by the Society of Toxicology. NR 76 TC 3 Z9 3 U1 4 U2 27 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD JAN PY 2015 VL 17 IS 1 BP 44 EP 64 DI 10.1208/s12248-014-9701-9 PG 21 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AY2XG UT WOS:000347448900005 PM 25421459 ER PT J AU Zhang, J Kale, V Chen, MN AF Zhang, Jin Kale, Vijay Chen, Mingnan TI Gene-Directed Enzyme Prodrug Therapy SO AAPS JOURNAL LA English DT Review DE bystander effects; gene delivery; gene-directed enzyme; prodrug; stem cell-based targeting ID CYTOSINE DEAMINASE GENE; VIRUS THYMIDINE KINASE; ADENOVIRUS-MEDIATED TRANSFER; MESENCHYMAL STEM-CELLS; URACIL PHOSPHORIBOSYLTRANSFERASE GENE; ADVANCED HEPATOCELLULAR-CARCINOMA; I CLINICAL-TRIAL; HSV-TK GENE; SUICIDE GENE; PHASE-I AB As one targeting strategy of prodrug delivery, gene-directed enzyme prodrug therapy (GDEPT) promises to realize the targeting through its three key features in cancer therapy-cell-specific gene delivery and expression, controlled conversion of prodrugs to drugs in target cells, and expanded toxicity to the target cells' neighbors through bystander effects. After over 20 years of development, multiple GDEPT systems have advanced into clinical trials. However, no GDEPT product is currently marketed as a drug, suggesting that there are still barriers to overcome before GDEPT becomes a standard therapy. In this review, we first provide a general introduction of this prodrug targeting strategy. Then, we utilize the four most thoroughly studied systems to illustrate components, mechanisms, preclinical and clinical results, and further development directions of GDEPT. These four systems are herpes simplex virus thymidine kinase/ganciclovir, cytosine deaminase/5-fluorocytosine, cytochrome P450/oxazaphosphorines, and nitroreductase/CB1954 system. Later, we focus our discussion on bystander effects including local and distant bystander effects. Lastly, we discuss carriers that are used to deliver genes for GDEPT including virus carriers and non-virus carriers. Among these carriers, the stem cell-based gene delivery system represents one of the newest carriers under development, and may brought about a breakthrough to the gene delivery issue of GDEPT. C1 [Zhang, Jin] US FDA, Silver Spring, MD 20993 USA. [Kale, Vijay] Roseman Univ Hlth Sci, Coll Pharm, South Jordan, UT 84095 USA. [Chen, Mingnan] Univ Utah, Dept Pharmaceut & Pharmaceut Chem, Salt Lake City, UT 84112 USA. RP Zhang, J (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jinzhang526@gmail.com; mingnan.chen@utah.edu NR 103 TC 11 Z9 12 U1 11 U2 59 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD JAN PY 2015 VL 17 IS 1 BP 102 EP 110 DI 10.1208/s12248-014-9675-7 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AY2XG UT WOS:000347448900009 PM 25338741 ER PT J AU Braddy, AC Davit, BM Stier, EM Conner, DP AF Braddy, April C. Davit, Barbara M. Stier, Ethan M. Conner, Dale P. TI Survey of International Regulatory Bioequivalence Recommendations for Approval of Generic Topical Dermatological Drug Products SO AAPS JOURNAL LA English DT Review DE bioequivalence; bioequivalence studies with clinical endpoints; biowaivers; dermatopharmacokinetics; topical dermatological drug products; vasoconstrictor assay ID PERSPECTIVES AB The objective of this article is to discuss the similarities and differences in accepted bioequivalence (BE) approaches for generic topical dermatological drug products between international regulatory authorities and organizations. These drug products are locally applied and not intended for systemic absorption. Therefore, the BE approaches which serve as surrogates to establish safety and efficacy for topical dosage forms tend to differ from the traditional solid oral dosage forms. We focused on 15 different international jurisdictions and organizations that currently participate in the International Generic Drug Regulators Pilot Project. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Association (EMA), Japan, Mexico, New Zealand, Singapore (a member of the Association of Southeast Asian Nations), South Africa, South Korea, Switzerland, the USA and the World Health Organization (WHO). Upon evaluation, we observed that currently only Canada, the EMA, Japan, and the USA have specific guidance documents for topical drug products. Across all jurisdictions and organizations, the three approaches consistently required are (1) BE studies with clinical endpoints for most topical drug products; (2) in vivo pharmacodynamic studies, in particular the vasoconstrictor assay for topical corticosteroids; and (3) waivers from BE study requirements for topical solutions. Japan, South Africa, the USA, and the WHO are also making strides to accept other BE approaches such as in vivo pharmacokinetic studies for BE assessment, in vivo dermatopharmacokinetic studies and/or BE studies with in vitro endpoints. C1 [Braddy, April C.; Davit, Barbara M.; Stier, Ethan M.] US FDA, Div Bioequivalence 3, Off Bioequivalence, Off Gener Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Conner, Dale P.] US FDA, Off Bioequivalence, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Braddy, AC (reprint author), US FDA, Div Bioequivalence 3, Off Bioequivalence, Off Gener Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM april.braddy@fda.hhs.gov NR 59 TC 2 Z9 4 U1 2 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD JAN PY 2015 VL 17 IS 1 BP 121 EP 133 DI 10.1208/s12248-014-9679-3 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AY2XG UT WOS:000347448900011 PM 25344440 ER PT J AU Subramaniam, S Patel, D Davit, BM Conner, DP AF Subramaniam, Sriram Patel, Devvrat Davit, Barbara M. Conner, Dale P. TI Analysis of Imprecision in Incurred Sample Reanalysis for Small Molecules SO AAPS JOURNAL LA English DT Article DE bias; imprecision; incurred sample reanalysis; sample size; small molecules ID BIOANALYSIS; VALIDATION; IMPACT AB Over the years, incurred sample (IS) reanalysis (ISR) has become a tool to confirm the reliability of bioanalytical measurements. The recommendation for ISR acceptance criterion for small molecules is at least 67% of ISR samples that have reanalyzed concentrations within 20% of their original concentrations when normalized to their means. To understand the relevance of the ISR acceptance criterion and sample size requirements, simulated ISR studies evaluated the probability of ISR studies passing the acceptance criterion (ISR pass rate) as a function of IS imprecision and sample size. When IS imprecision (percent coefficient of variation: %CV) is low (a parts per thousand currency sign10 or 1-10% CV), high ISR pass rate (a parts per thousand yen99%) is attained with < 50 samples. At intermediate IS imprecision (e.g., 12% CV or 7-12% CV range), 80-160 samples are required for a high ISR pass rate. When IS imprecision is at the higher end of the acceptance limit, ISR pass rate decreases significantly, and increasing sample size fails to achieve high ISR pass rate. The effect of systematic bias (e.g., instability, interconversion) on ISR pass rate is strongly dependent on sample size at intermediate IS imprecision. The results provide an understanding of the effect of IS imprecision on ISR pass rates and a framework for selection of ISR sample sizes. C1 [Subramaniam, Sriram; Patel, Devvrat] US FDA, Div Bioequivalence 3, Off Bioequivalence, Off Gener Drugs, Silver Spring, MD 20993 USA. [Davit, Barbara M.] Merck Sharp & Dohme Corp, Whitehouse Stn, NJ USA. [Conner, Dale P.] US FDA, Off Bioequivalence, Off Gener Drugs, Silver Spring, MD 20993 USA. RP Subramaniam, S (reprint author), US FDA, Div Bioequivalence 3, Off Bioequivalence, Off Gener Drugs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM sriram.subramaniam@fda.hhs.gov NR 18 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD JAN PY 2015 VL 17 IS 1 BP 206 EP 215 DI 10.1208/s12248-014-9689-1 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AY2XG UT WOS:000347448900019 PM 25354732 ER PT J AU Rump, LV Gonzalez-Escalona, N Ju, WT Wang, F Cao, GJ Meng, SA Meng, JH AF Rump, Lydia V. Gonzalez-Escalona, Narjol Ju, Wenting Wang, Fei Cao, Guojie Meng, Sean Meng, Jianghong TI Genomic Diversity and Virulence Profiles of Historical Escherichia coli O157 Strains Isolated from Clinical and Environmental Sources SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID HEMOLYTIC-UREMIC-SYNDROME; TELLURITE RESISTANCE; MULTIPLEX PCR; UNITED-STATES; SEROTYPE O157-H7; CLONAL STRUCTURE; OUTBREAKS; PLASMID; INFECTIONS; SEQUENCE AB Escherichia coli O157:H7 is, to date, the major E. coli serotype causing food-borne human disease worldwide. Strains of O157 with other H antigens also have been recovered. We analyzed a collection of historic O157 strains (n = 400) isolated in the late 1980s to early 1990s in the United States. Strains were predominantly serotype O157:H7 (55%), and various O157:non-H7 (41%) serotypes were not previously reported regarding their pathogenic potential. Although lacking Shiga toxin (stx) and eae genes, serotypes O157:H1, O157:H2, O157:H11, O157:H42, and O157:H43 carried several virulence factors (iha, terD, and hlyA) also found in virulent serotype E. coli O157:H7. Pulsed-field gel electrophoresis (PFGE) showed the O157 serogroup was diverse, with strains with the same H type clustering together closely. Among non-H7 isolates, serotype O157:H43 was highly prevalent (65%) and carried important enterohemorrhagic E. coli (EHEC) virulence markers (iha, terD, hlyA, and espP). Isolates from two particular H types, H2 and H11, among the most commonly found non-O157 EHEC serotypes (O26:H11, O111:H11, O103:H2/H11, and O45:H2), unexpectedly clustered more closely with O157:H7 than other H types and carried several virulence genes. This suggests an early divergence of the O157 serogroup to clades with different pathogenic potentials. The appearance of important EHEC virulence markers in closely related H types suggests their virulence potential and suggests further monitoring of those serotypes not implicated in severe illness thus far. C1 [Rump, Lydia V.; Ju, Wenting; Wang, Fei; Cao, Guojie; Meng, Sean; Meng, Jianghong] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Gonzalez-Escalona, Narjol] US FDA, Div Microbiol, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Meng, Jianghong] Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 USA. RP Meng, JH (reprint author), Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. EM jmeng@umd.edu OI Gonzalez-Escalona, Narjol/0000-0003-4568-0022 NR 47 TC 2 Z9 2 U1 1 U2 20 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 JAN PY 2015 VL 81 IS 2 BP 569 EP 577 DI 10.1128/AEM.02616-14 PG 9 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA AY1UL UT WOS:000347377500012 PM 25381234 ER PT J AU Hampton, D Tarver, ME Eydelman, MB AF Hampton, Denise Tarver, Michelle E. Eydelman, Malvina B. TI Latest Food and Drug Administration's Efforts to Improve Safe Contact Lens Use SO EYE & CONTACT LENS-SCIENCE AND CLINICAL PRACTICE LA English DT Editorial Material ID SOLUTION DISINFECTION ACTIVITY; ACANTHAMOEBA-KERATITIS; STAPHYLOCOCCUS-AUREUS C1 [Hampton, Denise; Tarver, Michelle E.; Eydelman, Malvina B.] US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Div Ophthalm & Ear Nose & Throat Devices, Silver Spring, MD USA. RP Hampton, D (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Div Ophthalm & Ear Nose & Throat Devices, Silver Spring, MD USA. NR 14 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1542-2321 EI 1542-233X J9 EYE CONTACT LENS JI Eye Contact Lens-Sci. Clin. Pra. PD JAN PY 2015 VL 41 IS 1 BP 1 EP 2 DI 10.1097/ICL.0000000000000117 PG 2 WC Ophthalmology SC Ophthalmology GA AY2ZT UT WOS:000347455200003 PM 25536527 ER PT J AU Feng, S Qiang, R Kainz, W Chen, J AF Feng, Shi Qiang, Rui Kainz, Wolfgang Chen, Ji TI A Technique to Evaluate MRI-Induced Electric Fields at the Ends of Practical Implanted Lead SO IEEE TRANSACTIONS ON MICROWAVE THEORY AND TECHNIQUES LA English DT Article DE Magnetic resonance imaging (MRI); pacemaker; reciprocity; transfer functions ID IN-VIVO; RESONANCE; PACEMAKERS; TEMPERATURE; APPARATUS; SAFETY; VITRO AB This paper presents a novel technique for efficient evaluation of magnetic resonance imaging (MRI)-induced electric fields or induced voltages in the vicinity of implanted metallic leads. The technique is based on the reciprocity theorem in conjunction with the Huygens Principle. This approach allows one to decouple the micro-scale metallic lead simulation/measurement from the macro-level phantom human simulations within the MRI scanners. Consequently, the estimation of MRI-induced heating on an implanted lead, and the induced voltage on the pacemaker device can be greatly simplified. In addition, this method clearly explains the induced lead heating mechanism during MRI procedures. Several numerical examples, as well as measurement results are given to demonstrate the efficiency and accuracy of this method. C1 [Feng, Shi; Chen, Ji] Univ Houston, Dept Elect & Comp Engn, Houston, TX 77204 USA. [Qiang, Rui] Micro Syst Engn Inc, Lake Oswego, OR 97035 USA. [Kainz, Wolfgang] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Feng, S (reprint author), Univ Houston, Dept Elect & Comp Engn, Houston, TX 77204 USA. EM sfeng5@uh.edu; jchen18@uh.edu NR 28 TC 8 Z9 8 U1 3 U2 11 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9480 EI 1557-9670 J9 IEEE T MICROW THEORY JI IEEE Trans. Microw. Theory Tech. PD JAN PY 2015 VL 63 IS 1 BP 305 EP 313 DI 10.1109/TMTT.2014.2376523 PG 9 WC Engineering, Electrical & Electronic SC Engineering GA AY4CB UT WOS:000347524700030 ER PT J AU Li, J Goulding, M Seymour, S Starke, P AF Li, Jie Goulding, Margie Seymour, Sally Starke, Peter TI EXCELS study results do not rule out potential cancer risk with omalizumab SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter C1 [Li, Jie; Goulding, Margie] US FDA, CDER, Div Epidemiol 2, Off Surveillance & Epidemiol, Silver Spring, MD 20993 USA. [Seymour, Sally; Starke, Peter] US FDA, CDER, Div Pulm Allergy & Rheumatol, Off New Drugs, Silver Spring, MD USA. RP Li, J (reprint author), US FDA, CDER, Div Epidemiol 2, Off Surveillance & Epidemiol, Silver Spring, MD 20993 USA. EM jie.j.li@fda.hhs.gov NR 1 TC 2 Z9 2 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JAN PY 2015 VL 135 IS 1 BP 289 EP 289 DI 10.1016/j.jaci.2014.09.017 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA AY0PG UT WOS:000347298200044 PM 25441294 ER PT J AU Harman, C Zhong, LL Ma, L Liu, P Deng, L Zhao, Z Yan, HL Struble, E Virata-Theimer, ML Zhang, P AF Harman, Christine Zhong, Lilin Ma, Li Liu, Peter Deng, Lu Zhao, Zhong Yan, Hailing Struble, Evi Virata-Theimer, Maria Luisa Zhang, Pei TI A View of the E2-CD81 Interface at the Binding Site of a Neutralizing Antibody against Hepatitis C Virus SO JOURNAL OF VIROLOGY LA English DT Article ID E2 ENVELOPE GLYCOPROTEIN; MONOCLONAL-ANTIBODIES; CD81 BINDING; MEDIATED NEUTRALIZATION; EXTRACELLULAR DOMAIN; HCV INFECTION; IDENTIFICATION; PROTEIN; EPITOPE; ENTRY AB Hepatitis C virus (HCV) glycoprotein E2 is considered a major target for generating neutralizing antibodies against HCV, primarily due to its role of engaging host entry factors, such as CD81, a key cell surface protein associated with HCV entry. Based on a series of biochemical analyses in combination with molecular docking, we present a description of a potential binding interface formed between the E2 protein and CD81. The virus side of this interface includes a hydrophobic helix motif comprised of residues W(437)LAGLF(442), which encompasses the binding site of a neutralizing monoclonal antibody, mAb41. The helical conformation of this motif provides a structural framework for the positioning of residues F442 and Y443, serving as contact points for the interaction with CD81. The cell side of this interface likewise involves a surface-exposed hydrophobic helix, namely, the D-helix of CD81, which coincides with the binding site of 1D6, a monoclonal anti-CD81 antibody known to block HCV entry. Our illustration of this virus-host interface suggests an important role played by the W(437)LAGLF(442) helix of the E2 protein in the hydrophobic interaction with the D-helix of CD81, thereby facilitating our understanding of the mechanism for antibody-mediated neutralization of HCV. IMPORTANCE Characterization of the interface established between a virus and host cells can provide important information that may be used for the control of virus infections. The interface that enables hepatitis C virus (HCV) to infect human liver cells has not been well understood because of the number of cell surface proteins, factors, and conditions found to be associated with the infection process. Based on a series of biochemical analyses in combination with molecular docking, we present such an interface, consisting of two hydrophobic helical structures, from the HCV E2 surface glycoprotein and the CD81 protein, a major host cell receptor recognized by all HCV strains. Our study reveals the critical role played by hydrophobic interactions in the formation of this virus-host interface, thereby contributing to our understanding of the mechanism for antibody-mediated neutralization of HCV. C1 [Harman, Christine; Zhong, Lilin; Ma, Li; Liu, Peter; Deng, Lu; Zhao, Zhong; Yan, Hailing; Struble, Evi; Virata-Theimer, Maria Luisa; Zhang, Pei] FDA, Div Hematol Res & Review, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Zhang, P (reprint author), FDA, Div Hematol Res & Review, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM pei.zhang@fda.hhs.gov FU FDA CBER FX This study was funded by a Modernizing Science grant from FDA CBER. NR 42 TC 3 Z9 3 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2015 VL 89 IS 1 BP 492 EP 501 DI 10.1128/JVI.01661-14 PG 10 WC Virology SC Virology GA AX8RL UT WOS:000347176100041 PM 25339761 ER PT J AU Wang, MO Vorwald, CE Dreher, ML Mott, EJ Cheng, MH Cinar, A Mehdizadeh, H Somo, S Dean, D Brey, EM Fisher, JP AF Wang, Martha O. Vorwald, Charlotte E. Dreher, Maureen L. Mott, Eric J. Cheng, Ming-Huei Cinar, Ali Mehdizadeh, Hamidreza Somo, Sami Dean, David Brey, Eric M. Fisher, John P. TI Evaluating 3D-Printed Biomaterials as Scaffolds for Vascularized Bone Tissue Engineering SO ADVANCED MATERIALS LA English DT Article ID IN-VITRO DEGRADATION; OSTEOGENIC SIGNAL EXPRESSION; MARROW STROMAL CELLS; POLY(PROPYLENE FUMARATE); CROSS-LINKING; ANGIOGENESIS; DESIGN; MODEL; NEOVASCULARIZATION; DIFFERENTIATION C1 [Wang, Martha O.; Vorwald, Charlotte E.; Fisher, John P.] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [Dreher, Maureen L.] US FDA, Div Solid & Fluid Mech, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Mott, Eric J.; Dean, David] Ohio State Univ, Dept Plast Surg, Columbus, OH 43210 USA. [Cheng, Ming-Huei] Chang Gung Univ, Chang Gung Mem Hosp, Dept Plast & Reconstruct Surg, Div Reconstruct Microsurg,Coll Med, Taoyuan, Taiwan. [Cinar, Ali; Mehdizadeh, Hamidreza] IIT, Dept Chem & Biol Engn, Chicago, IL 60616 USA. [Somo, Sami; Brey, Eric M.] IIT, Dept Biomed Engn, Chicago, IL 60616 USA. [Brey, Eric M.] Hines VA Hosp, Res Serv, Hines, IL USA. RP Fisher, JP (reprint author), Univ Maryland, Fischell Dept Bioengn, 3238 Jeong H Kim Engn Bldg, College Pk, MD 20742 USA. EM jpfisher@umd.edu OI Cinar, Ali/0000-0002-1607-9943 FU National Institutes of Health [R01-DE013740]; National Science Foundation [IIS-1125412]; Veterans Administration; Chang Gung Memorial Hospital [CMRPG300201]; Food and Drug Administration Center of Excellence in Regulatory Science and Innovation (CERSI) FX This research was supported, in part, by the National Institutes of Health (R01-DE013740) National Science Foundation (IIS-1125412), Veterans Administration, the Chang Gung Memorial Hospital (CMRPG300201), and a Food and Drug Administration Center of Excellence in Regulatory Science and Innovation (CERSI) grant. Animal studies were performed under the direction of Chih-Wei Wu, assisted by Shu-Wei Kao. Srinidhi Nagaraja provided mu CT support and guidance. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 36 TC 34 Z9 35 U1 36 U2 217 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 0935-9648 EI 1521-4095 J9 ADV MATER JI Adv. Mater. PD JAN PY 2015 VL 27 IS 1 BP 138 EP 144 DI 10.1002/adma.201403943 PG 7 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 AX9RL UT WOS:000347239600019 PM 25387454 ER PT J AU Hmiel, LK Brorson, KA Boyne, MT AF Hmiel, Laura K. Brorson, Kurt A. Boyne, Michael T., II TI Post-translational structural modifications of immunoglobulin G and their effect on biological activity SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE IgG; Post-translational modifications; Bioprocess; Monoclonal antibodies; Effector function ID RECOMBINANT MONOCLONAL-ANTIBODY; FC-GAMMA-RIII; N-GLYCOLYLNEURAMINIC ACID; HAMSTER OVARY CELLS; LIQUID CHROMATOGRAPHY/MASS SPECTROMETRY; RHEUMATOID-ARTHRITIS PATIENTS; IONIZATION MASS-SPECTROMETRY; HIGH-AFFINITY BINDING; ALPHA-GALACTOSYL IGG; FAB-ARM EXCHANGE AB The size, heterogeneity, and biological production process of protein therapeutics like monoclonal antibodies create unique challenges for their analysis and regulation compared with small molecules. Complete structural characterization of a molecule 1000-fold heavier than aspirin is no small feat. Biological post-translational modifications such as glycosylation further complicate their characterization and regulation. Even approved protein therapeutics are known to contain multiple structural variants in differing amounts. Structural modification occurs during production and storage as well as within patients after administration. Thus, the goals of manufacturers and regulators are to control and characterize this heterogeneity, not take on the impossible task of eliminating it. The aim of this review is to describe the structural heterogeneities known to occur with immunoglobulin G (IgG), note current detection and analytical strategies, establish their causes, and define their potential effects on the ultimate safety, purity, and potency of antibody therapeutics when known. C1 [Hmiel, Laura K.; Boyne, Michael T., II] US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Pharmaceut Anal, St Louis, MO 63110 USA. [Brorson, Kurt A.] US FDA, Ctr Drug Evaluat & Res, Off Biotechnol Prod, Div Monoclonal Antibodies, Silver Spring, MD 20993 USA. RP Boyne, MT (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Pharmaceut Anal, St Louis, MO 63110 USA. EM michael.boyne@fda.hhs.gov NR 182 TC 10 Z9 11 U1 6 U2 36 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD JAN PY 2015 VL 407 IS 1 BP 79 EP 94 DI 10.1007/s00216-014-8108-x PG 16 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AX8GM UT WOS:000347148100006 PM 25200070 ER PT J AU Wagner, C Pan, YZ Hsu, V Grillo, J Zhang, L Reynolds, K Sinha, V Zhao, P AF Wagner, Christian Pan, Yuzhuo Hsu, Vicky Grillo, Joseph A. Zhang, Lei Reynolds, Kellie S. Sinha, Vikram Zhao, Ping TI Predicting the Effect of Cytochrome P450 Inhibitors on Substrate Drugs: Analysis of Physiologically Based Pharmacokinetic Modeling Submissions to the US Food and Drug Administration SO CLINICAL PHARMACOKINETICS LA English DT Article ID PHARMACOLOGY; VARIABILITY; SIMULATION AB Background and Objective The US Food and Drug Administration (FDA) has seen a recent increase in the application of physiologically based pharmacokinetic (PBPK) modeling towards assessing the potential of drugdrug interactions (DDI) in clinically relevant scenarios. To continue our assessment of such approaches, we evaluated the predictive performance of PBPK modeling in predicting cytochrome P450 (CYP)-mediated DDI. Methods This evaluation was based on 15 substrate PBPK models submitted by nine sponsors between 2009 and 2013. For these 15 models, a total of 26 DDI studies (cases) with various CYP inhibitors were available. Sponsors developed the PBPK models, reportedly without considering clinical DDI data. Inhibitor models were either developed by sponsors or provided by PBPK software developers and applied with minimal or no modification. The metric for assessing predictive performance of the sponsors' PBPK approach was the R-predicted/observed value (R-predicted/observed = [predicted mean exposure ratio]/ [observed mean exposure ratio], with the exposure ratio defined as [C-max (maximum plasma concentration) or AUC (area under the plasma concentration-time curve) in the presence of CYP inhibition]/[C-max or AUC in the absence of CYP inhibition]). Results In 81 % (21/26) and 77 % (20/26) of cases, respectively, the R-predicted/observed values for AUC and Cmax ratios were within a pre-defined threshold of 1.25-fold of the observed data. For all cases, the R-predicted/observed values for AUC and Cmax were within a 2-fold range. Conclusion These results suggest that, based on the submissions to the FDA to date, there is a high degree of concordance between PBPK-predicted and observed effects of CYP inhibition, especially CYP3A-based, on the exposure of drug substrates. C1 [Wagner, Christian; Hsu, Vicky; Grillo, Joseph A.; Zhang, Lei; Reynolds, Kellie S.; Sinha, Vikram; Zhao, Ping] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Pan, Yuzhuo] US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Zhao, P (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM ping.zhao@fda.hhs.gov FU FDA Office of Commissioner, Office of Chief Scientist, and Office of Scientific Professional Development; ORISE Research Participation Program at the Center for Drug Evaluation and Research (CDER) FX This project was supported in part by an appointment to the ORISE Research Participation Program at the Center for Drug Evaluation and Research (CDER) administered by the Oak Ridge Institute for Science and Education through an agreement between the US Department of Energy and CDER.; This project was supported in part by the Commissioner Fellowship Program from the FDA Office of Commissioner, Office of Chief Scientist, and Office of Scientific Professional Development. NR 12 TC 21 Z9 21 U1 3 U2 10 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0312-5963 EI 1179-1926 J9 CLIN PHARMACOKINET JI Clin. Pharmacokinet. PD JAN PY 2015 VL 54 IS 1 BP 117 EP 127 DI 10.1007/s40262-014-0188-4 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AX8GE UT WOS:000347147300007 PM 25260695 ER PT J AU Win, TT Venkatesh, BA Volpe, GJ Mewton, N Rizzi, P Sharma, RK Strauss, DG Lima, JA Tereshchenko, LG AF Win, Theingi Tiffany Venkatesh, Bharath Ambale Volpe, Gustavo J. Mewton, Nathan Rizzi, Patricia Sharma, Ravi K. Strauss, David G. Lima, Joao A. Tereshchenko, Larisa G. TI Associations of electrocardiographic P-wave characteristics with left atrial function, and diffuse left ventricular fibrosis defined by cardiac magnetic resonance: The PRIMERI Study SO HEART RHYTHM LA English DT Article DE P-terminal force in V-1; Left atrium function; Fibrosis; Left ventricle; Atrial fibrillation ID QRS-T ANGLE; LATE GADOLINIUM ENHANCEMENT; ATHEROSCLEROSIS RISK; MYOCARDIAL FIBROSIS; HEART-FAILURE; PROGNOSTIC VALUE; ISCHEMIC-STROKE; FIBRILLATION; MORTALITY; DEATH AB BACKGROUND Abnormal P-terminal force in lead V-1 (PTEv(1)) is associated with an increased risk of heart failure, stroke, atrial fibrillation, and death. OBJECTIVE Our goal was to explore associations of left ventricular (LV) diffuse fibrosis with left atrial (LA) function and electrocardiographic (ECG) measures of LA electrical activity. METHODS Patients without atrial fibrillation (n = 91; mean age 59.5 years; 61.5% men; 65.9% white) with structural heart disease (spatial QRS-T angle >= 105 degrees and/or Selvester ORS score >= 5 on ECG) but LV ejection fraction >35 /a underwent clinical evaluation, cardiac magnetic resonance, and resting ECG. LA function indices were obtained by multimodality tissue tracking using 2- and 4-chamber long-axis images. T-1 mapping and late gadolinium enhancement were used to assess diffuse LV fibrosis and presence of scar. P-prime in V-1 amplitude (PPaV1) and duration (PPdV1), averaged P-wave-duration, PR interval, and P-wave axis were automatically measured using 12 SLIM algorithm. PTFv1 was calculated as a product of PPaVi and PPdV1. RESULTS In linear regression after adjustment for demographic characteristics, body mass index, maximum LA volume index, presence of scar, and LV mass index, each decile increase in LV interstitial fibrosis was associated with 0.76 mV*ms increase in negative abnormal PTFv1 (95% confidence interval [CI] 1.42 to 0.09; P = .025), 15.3 ms prolongation of PPdV1 (95% CI 6.9 to 23.8; P = .001) and 5.4 ms prolongation of averaged P-duration (95% CI 0.9-10.0; P = .020). LV fibrosis did not affect LA function. PTFV1 and PPdv(1) were associated with an increase in LA volumes and decrease in LA emptying fraction and LA reservoir function. CONCLUSION LV interstitial fibrosis is associated with abnormal PTEvi, prolonged PPdV1, and P-duration, but does not affect LA function. C1 [Win, Theingi Tiffany; Venkatesh, Bharath Ambale; Volpe, Gustavo J.; Mewton, Nathan; Rizzi, Patricia; Sharma, Ravi K.; Lima, Joao A.; Tereshchenko, Larisa G.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Win, Theingi Tiffany] Univ New Mexico, Dept Med, Div Cardiol, Albuquerque, NM 87131 USA. [Strauss, David G.] US FDA, Silver Spring, MD USA. [Tereshchenko, Larisa G.] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR 97239 USA. RP Tereshchenko, LG (reprint author), Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, 3181 SW Sam Jackson Pk Rd,UHN62, Portland, OR 97239 USA. EM tereshch@ohsu.edu RI Ambale Venkatesh, Bharath/F-4941-2016; OI Ambale Venkatesh, Bharath/0000-0002-2330-2373; Tereshchenko, Larisa/0000-0002-6976-1313 FU National Institutes of Health [P20HL101397, 1R01HL118277] FX This research was supported in part by the National Institutes of Health (grant #P20HL101397 to Dr Lima and grant #1R01HL118277 to Dr Tereshchenko) NR 43 TC 3 Z9 4 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD JAN PY 2015 VL 12 IS 1 BP 155 EP 162 DI 10.1016/j.hrthm.2014.09.044 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AX3RR UT WOS:000346857100028 ER PT J AU Donaldson, EF Harrington, PR O'Rear, JJ Naeger, LK AF Donaldson, Eric F. Harrington, Patrick R. O'Rear, Julian J. Naeger, Lisa K. TI Clinical Evidence and Bioinformatics Characterization of Potential Hepatitis C Virus Resistance Pathways for Sofosbuvir SO HEPATOLOGY LA English DT Article ID NONNUCLEOSIDE POLYMERASE INHIBITORS; MECHANISM; GENOTYPE; RNA AB Sofosbuvir (Sovaldi, SOF) is a nucleotide analog prodrug that targets the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase and inhibits viral replication. High sustained virological response rates are achieved when SOF is used in combination with ribavirin with or without pegylated interferon in subjects with chronic HCV infection. Potential mechanisms of HCV resistance to SOF and other nucleos(t)ide analog NS5B polymerase inhibitors are not well understood. SOF was the first U.S. Food and Drug Administration (FDA)-approved antiviral drug for which genotypic resistance analyses were based almost entirely on next-generation sequencing (NGS), an emerging technology that lacks a standard data analysis pipeline. The FDA Division of Antiviral Products developed an NGS analysis pipeline and performed independent analyses of NGS data from five SOF clinical trials. Additionally, structural bioinformatics approaches were used to characterize potential resistance-associated substitutions. Using protocols we developed, independent analyses of the NGS data reproduced results that were comparable to those reported by Gilead Sciences, Inc. Low-frequency, treatment-emergent substitutions occurring at conserved NS5B amino acid positions in subjects who experienced virological failure were also noted and further evaluated. The NS5B substitutions, L159F (sometimes in combination with L320F or C316N) and V321A, emerged in 2.2%-4.4% of subjects who failed SOF treatment across clinical trials. Moreover, baseline polymorphisms at position 316 were potentially associated with reduced response rates in HCV genotype 1b subjects. Analyses of these variants modeled in NS5B crystal structures indicated that all four substitutions could feasibly affect SOF anti-HCV activity. Conclusion: SOF has a high barrier to resistance; however, low-frequency NS5B substitutions associated with treatment failure were identified that may contribute to resistance of this important drug for chronic HCV infection. (Hepatology 2015;61:56-65) C1 [Donaldson, Eric F.; Harrington, Patrick R.; O'Rear, Julian J.; Naeger, Lisa K.] US FDA, Div Antiviral Prod, Silver Spring, MD 20993 USA. RP Donaldson, EF (reprint author), US FDA, Div Antiviral Prod, 10903 New Hampshire Ave,WO22,Off 6336, Silver Spring, MD 20993 USA. EM Eric.Donaldson@fda.hhs.gov RI Luan, Gan/B-3211-2015 NR 15 TC 52 Z9 54 U1 3 U2 39 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD JAN PY 2015 VL 61 IS 1 BP 56 EP 65 DI 10.1002/hep.27375 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AX6AF UT WOS:000347005100013 PM 25123381 ER PT J AU Bijwaard, K Dickey, JS Kelm, K Tezak, Z AF Bijwaard, Karen Dickey, Jennifer S. Kelm, Kellie Tezak, Zivana TI The first FDA marketing authorizations of next-generation sequencing technology and tests: challenges, solutions and impact for future assays SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE assay; cystic fibrosis; diagnostic; high throughput sequencing; instrument; medical device; next generation sequencing; regulation; sequencing by synthesis AB The rapid emergence and clinical translation of novel high-throughput sequencing technologies created a need to clarify the regulatory pathway for the evaluation and authorization of these unique technologies. Recently, the US FDA authorized for marketing four next generation sequencing (NGS)-based diagnostic devices which consisted of two heritable disease-specific assays, library preparation reagents and a NGS platform that are intended for human germline targeted sequencing from whole blood. These first authorizations can serve as a case study in how different types of NGS-based technology are reviewed by the FDA. In this manuscript we describe challenges associated with the evaluation of these novel technologies and provide an overview of what was reviewed. Besides making validated NGS-based devices available for in vitro diagnostic use, these first authorizations create a regulatory path for similar future instruments and assays. C1 [Bijwaard, Karen; Dickey, Jennifer S.] US FDA, Div Mol Genet & Pathol, Off In Vitro Diagnost & Radiol Hlth OIR, CDRH, Silver Spring, MD 20993 USA. [Kelm, Kellie] US FDA, Div Chem & Toxicol Devices, OIR, CDRH, Silver Spring, MD 20993 USA. [Tezak, Zivana] Ctr Devices & Radiol Hlth CDRH, OIR, Silver Spring, MD 20993 USA. RP Tezak, Z (reprint author), Ctr Devices & Radiol Hlth CDRH, OIR, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM zivana.tezak@fda.hhs.gov NR 7 TC 3 Z9 3 U1 6 U2 14 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 JAN PY 2015 VL 15 IS 1 BP 33 EP 40 DI 10.1586/14737159.2015.979795 PG 8 WC Pathology SC Pathology GA AX4KF UT WOS:000346900900005 PM 25370936 ER PT J AU Bancos, S Stevens, DL Tyner, KM AF Bancos, Simona Stevens, David L. Tyner, Katherine M. TI Effect of silica and gold nanoparticles on macrophage proliferation, activation markers, cytokine production, and phagocytosis in vitro SO INTERNATIONAL JOURNAL OF NANOMEDICINE LA English DT Article DE bioaccumulation; phagocytosis; gold nanoparticles; silica nanoparticles; macrophage function ID CARBON NANOTUBES; TNF-ALPHA; RAW 264.7; TOXICITY; MODEL; NANOMEDICINE; INFLAMMATION; MECHANISMS; EXPOSURE AB The accumulation of durable nanoparticles (NPs) in macrophages following systemic administration is well described. The ultimate biological impact of this accumulation on macrophage function, however, is not fully understood. In this study, nontoxic doses of two durable NPs, SiO2 and Au, at particle sizes of similar to 10 nm and 300 nm were used to evaluate the effect of bioaccumulation on macrophage function in vitro using RAW 264.7 mouse macrophage-like cells as a model system. Cell proliferation, cell cycle, cytokine production, surface marker activation, and phagocytosis responses were evaluated through a panel of assays using flow cytometry and confocal microscopy. The most dramatic change in RAW 264.7 cell function was a reduction in phagocytosis as monitored by the uptake of Escherichia coli. Cells exposed to both 10 nm Au NPs and 10 nm SiO2 NPs showed similar to 50% decrease in phagocytosis, while the larger NPs caused a less dramatic reduction. In addition to modifying phagocytosis profiles, 10 nm SiO2 NPs caused changes in proliferation, cell cycle, and cell morphology. Au NPs had no effect on cell cycle, cytokine production, or surface markers and caused interference in phagocytosis in the form of quenching when the assay was performed via flow cytometry. Confocal microscopy analysis was used to minimize this interference and demonstrated that both sizes of Au NPs decreased the phagocytosis of E. coli. Overall, our results demonstrate that Au and SiO2 NP uptake by macrophages can influence macrophage phagocytosis in vitro without altering surface markers and cytokine production in vitro. While the biological impact of these findings remains unclear, our results indicate that bioaccumulation of durable NPs within the macrophages may lead to a suppression of bacterial uptake and possibly impair bactericidal activity. C1 [Bancos, Simona; Stevens, David L.; Tyner, Katherine M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Tyner, KM (reprint author), US FDA, Ctr Drug Evaluat & Res, Bldg 51,Room 4159,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM katherine.tyner@fda.hhs.gov FU US Department of Energy; US Food and Drug Administration FX The authors acknowledge the Office of Science and Engineering Laboratories, CDRH FDA, for the use of their TGA. This project 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. The authors would like to acknowledge the FDA White Oak Nanotechnology Core Facility for instrument use and scientific and technical assistance. NR 50 TC 9 Z9 9 U1 4 U2 30 PU DOVE MEDICAL PRESS LTD PI ALBANY PA PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND SN 1178-2013 J9 INT J NANOMED JI Int. J. Nanomed. PY 2015 VL 10 BP 183 EP 206 DI 10.2147/IJN.S72580 PG 24 WC Nanoscience & Nanotechnology; Pharmacology & Pharmacy SC Science & Technology - Other Topics; Pharmacology & Pharmacy GA AX3KO UT WOS:000346838500003 PM 25565813 ER PT J AU Ross, MM AF Ross, Mark M. TI Joseph E. Campana (1952-2014) OBITUARY SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Biographical-Item C1 US FDA, College Pk, MD 20740 USA. RP Ross, MM (reprint author), US FDA, College Pk, MD 20740 USA. EM markm.ross@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 1044-0305 EI 1879-1123 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD JAN PY 2015 VL 26 IS 1 BP 5 EP 6 DI 10.1007/s13361-014-1023-8 PG 2 WC Biochemical Research Methods; Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA AX3SN UT WOS:000346859200002 PM 25380776 ER PT J AU Roessler, S Lin, GL Forgues, M Budhu, A Hoover, S Simpson, RM Wu, XL He, P Qin, LX Tang, ZY Ye, QH Wang, XW AF Roessler, Stephanie Lin, Guoling Forgues, Marshonna Budhu, Anuradha Hoover, Shelley Simpson, R. Mark Wu, Xiaolin He, Ping Qin, Lun-Xiu Tang, Zhao-You Ye, Qing-Hai Wang, Xin Wei TI Integrative Genomic and Transcriptomic Characterization of Matched Primary and Metastatic Liver and Colorectal Carcinoma SO INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES LA English DT Article DE Liver cancer; Colon cancer; Organ site-specific metastasis; Profiling ID IN-VIVO SELECTION; ARRAY CGH DATA; HEPATOCELLULAR-CARCINOMA; TUMOR-METASTASIS; CANCER-CELLS; RECURRENCE; SIGNATURE; SURVIVAL; GENES; IDENTIFICATION AB Metastasis is the main cause of cancer mortality but its process remains poorly understood and thus hampers more effective treatment and improved cancer prognosis. To search for metastasis driver genes responsible for tumor spread, we integrated genomic and transcriptomic profiles of 61 matched primary tumors and distant metastases of liver or colorectal carcinoma isolated by laser-capture microdissection and assayed by array-based technologies. We found that primary tumor lesions and their matched distant metastases were largely similar at the genomic and transcriptomic levels, but substantial differences could be found between primary tumors with or without accompanying metastases. Interestingly, metastasis genes were principally tumor type and organ site-specific. Despite distinct pathway enrichment, different metastasis gene sets shared common prognostic capacity and were predictive of hepatocellular carcinoma survival in an independent cohort. Thus, the metastatic propensity is inherent to the primary tumor and the lack of general metastasis genes necessitates the development of specific treatment modalities. C1 [Roessler, Stephanie; Lin, Guoling; Forgues, Marshonna; Budhu, Anuradha; Wang, Xin Wei] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Lin, Guoling; Qin, Lun-Xiu; Tang, Zhao-You; Ye, Qing-Hai] Fudan Univ, Liver Canc Inst, Shanghai 200032, Peoples R China. [Hoover, Shelley; Simpson, R. Mark] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Wu, Xiaolin] NCI, Lab Mol Technol, SAIC Frederick, Frederick, MD 21701 USA. [He, Ping] US FDA, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Wang, XW (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ye.qinghai@zs-hospital.sh.cn; xw3u@nih.gov RI Wang, Xin/B-6162-2009 FU Intramural Research Program of the Center for Cancer Research; National Cancer Institute [Z01 BC 010313, Z01 BC 010877, Z01 BC 010876]; National Key Project for Infectious Disease of China [2012ZX10002012-003]; State Key Basic Research Program of China [2009CB521701]; National Natural Science Foundation of China [81071993] FX This work was supported in part by the Intramural Research Program of the Center for Cancer Research, the National Cancer Institute (Z01 BC 010313, Z01 BC 010877 and Z01 BC 010876). QHY was supported by the Grants of the National Key Project for Infectious Disease of China (2012ZX10002012-003), the State Key Basic Research Program of China (2009CB521701) and the National Natural Science Foundation of China (81071993). NR 26 TC 3 Z9 3 U1 0 U2 3 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1449-2288 J9 INT J BIOL SCI JI Int. J. Biol. Sci. PY 2015 VL 11 IS 1 BP 88 EP 98 DI 10.7150/ijbs.10583 PG 11 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA AW7FR UT WOS:000346430600010 PM 25552933 ER PT J AU Sine, J Urban, C Thayer, D Charron, H Valim, N Tata, DB Schiff, R Blumenthal, R Joshi, A Puri, A AF Sine, Jessica Urban, Cordula Thayer, Derek Charron, Heather Valim, Niksa Tata, Darrell B. Schiff, Rachel Blumenthal, Robert Joshi, Amit Puri, Anu TI Photo activation of HPPH encapsulated in "Pocket" liposomes triggers multiple drug release and tumor cell killing in mouse breast cancer xenografts SO INTERNATIONAL JOURNAL OF NANOMEDICINE LA English DT Article DE laser-triggered payload release; photo-agents; photopolymerizable phospholipids; tumor regression; phototriggering ID LIPID-BASED NANOPARTICLES; PHOTODYNAMIC THERAPY; PHOTOSENSITIVE LIPOSOMES; PYROPHEOPHORBIDE-A; DELIVERY SYSTEMS; SOLUTE RELEASE; LIGHT; CARRIERS; PHOSPHATIDYLCHOLINE; EFFICIENCY AB We recently reported laser-triggered release of photosensitive compounds from liposomes containing dipalmitoylphosphatidylcholine (DPPC) and 1,2 bis(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC8,9PC). We hypothesized that the permeation of photoactivated compounds occurs through domains of enhanced fluidity in the liposome membrane and have thus called them "Pocket" liposomes. In this study we have encapsulated the red light activatable anticancer photodynamic therapy drug 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) (Ex/Em410/670 nm) together with calcein (Ex/Em490/517 nm) as a marker for drug release in Pocket liposomes. A mole ratio of 7.6:1 lipid: HPPH was found to be optimal, with > 80% of HPPH being included in the liposomes. Exposure of liposomes with a cw-diode 660 nm laser (90 mW, 0-5 minutes) resulted in calcein release only when HPPH was included in the liposomes. Further analysis of the quenching ratios of liposome-entrapped calcein in the laser treated samples indicated that the laser-triggered release occurred via the graded mechanism. In vitro studies with MDA-MB-231-LM2 breast cancer cell line showed significant cell killing upon treatment of cell-liposome suspensions with the laser. To assess in vivo efficacy, we implanted MDA-MB-231-LM2 cells containing the luciferase gene along the mammary fat pads on the ribcage of mice. For biodistribution experiments, trace amounts of a near infrared lipid probe DiR (Ex/Em745/840 nm) were included in the liposomes. Liposomes were injected intravenously and laser treatments (90 mW, 0.9 cm diameter, for an exposure duration ranging from 5-8 minutes) were done 4 hours postinjection (only one tumor per mouse was treated, keeping the second flank tumor as control). Calcein release occurred as indicated by an increase in calcein fluorescence from laser treated tumors only. The animals were observed for up to 15 days postinjection and tumor volume and luciferase expression was measured. A significant decrease in luciferase expression and reduction in tumor volume was observed only in laser treated animal groups injected with liposomes containing HPPH. Histopathological examination of tumor tissues indicated tumor necrosis resulting from laser treatment of the HPPH-encapsulated liposomes that were taken up into the tumor area. C1 [Sine, Jessica; Thayer, Derek; Blumenthal, Robert; Puri, Anu] NCI, Membrane Struct & Funct Sect, Basic Res Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Urban, Cordula; Charron, Heather; Valim, Niksa; Joshi, Amit] Baylor Coll Med, Dept Radiol, Houston, TX 77030 USA. [Tata, Darrell B.] US FDA, CDRH, OSEL, Div Phys, Rockville, MD 20857 USA. [Schiff, Rachel] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. RP Puri, A (reprint author), NCI, Membrane Struct & Funct Sect, Basic Res Lab, Ctr Canc Res, Bldg 469 Room 216A,1050 Boyles St, Frederick, MD 21702 USA. EM amitj@bcm.edu; puria@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; National Institute of Health [NIH-ROI 5R01 CA151962]; Dan L Duncan Cancer Center [P30CA125123]; SPORE from the National Cancer Institute, Breast Cancer Research Foundation [P50 CA58183] FX We thank Roberta Smith and Dr Diana Haines (Pathology/Histotechnology Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research) for their help with tumor images. We thank Dr Ulrich Baxa (Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research) for electron microscopy analysis of the liposomes. Mr Patrick Hall and Mr Joseph Bergman are duly acknowledged for their assistance in assembly of liposome formulations. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Dr Thomas Dougherty, Roswell Park Memorial Institute, for the kind gift of HPPH. We gratefully acknowledge the funding support provided by the National Institute of Health for grants NIH-ROI 5R01 CA151962 (A Joshi). This work was also supported in part by Dan L Duncan Cancer Center Grant15 P30CA125123 and SPORE Grant No P50 CA58183 from the National Cancer Institute, Breast Cancer Research Foundation (R Schiff). We also thank Dr Shawn Zhang from Lester and Sue Smith Breast Center for providing the MDA-MB-231-LM2 cells. NR 48 TC 5 Z9 5 U1 7 U2 38 PU DOVE MEDICAL PRESS LTD PI ALBANY PA PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND SN 1178-2013 J9 INT J NANOMED JI Int. J. Nanomed. PY 2015 VL 10 BP 125 EP 145 DI 10.2147/IJN.S72143 PG 21 WC Nanoscience & Nanotechnology; Pharmacology & Pharmacy SC Science & Technology - Other Topics; Pharmacology & Pharmacy GA AW9SH UT WOS:000346597000001 PM 25565809 ER PT J AU Day, JB Basavanna, U AF Day, J. B. Basavanna, U. TI Real-time PCR detection of Listeria monocytogenes in infant formula and lettuce following macrophage-based isolation and enrichment SO JOURNAL OF APPLIED MICROBIOLOGY LA English DT Article DE detection; Listeria; polymerase chain reaction; food; identification ID POLYMERASE-CHAIN-REACTION; CELL-CULTURE METHOD; FOOD SAMPLES; EPIDEMIC LISTERIOSIS; SUBSEQUENT DETECTION; MOLECULAR-DETECTION; ESCHERICHIA-COLI; UNITED-STATES; SOFT CHEESE; MILK AB AimsTo develop a rapid detection procedure for Listeria monocytogenes in infant formula and lettuce using a macrophage-based enrichment protocol and real-time PCR. Methods and ResultsA macrophage cell culture system was employed for the isolation and enrichment of L.monocytogenes from infant formula and lettuce for subsequent identification using real-time PCR. Macrophage monolayers were exposed to infant formula and lettuce contaminated with a serial dilution series of L.monocytogenes. As few as approx. 10CFUml(-1) or g(-1) of L.monocytogenes were detected in infant formula and lettuce after 16h postinfection by real-time PCR. Internal positive PCR controls were utilized to eliminate the possibility of false-negative results. Co-inoculation with Listeria innocua did not reduce the L.monocytogenes detection sensitivity. Intracellular L.monocytogenes could also be isolated on Listeria selective media from infected macrophage lysates for subsequent confirmation. ConclusionsThe detection method is highly sensitive and specific for L.monocytogenes in infant formula and lettuce and establishes a rapid identification time of 20 and 48h for presumptive and confirmatory identification, respectively. Significance and Impact of the StudyThe method is a promising alternative to many currently used q-PCR detection methods which employ traditional selective media for enrichment of contaminated food samples. Macrophage enrichment of L.monocytogenes eliminates PCR inhibitory food elements and contaminating food microflora which produce cleaner samples that increase the rapidity and sensitivity of detection. C1 [Day, J. B.; Basavanna, U.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Day, JB (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM james.day@fda.hhs.gov NR 65 TC 1 Z9 1 U1 5 U2 17 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 JAN PY 2015 VL 118 IS 1 BP 233 EP 244 DI 10.1111/jam.12674 PG 12 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA AW5UP UT WOS:000346339500024 PM 25346434 ER PT J AU Rubin, S Eckhaus, M Rennick, LJ Bamford, CGG Duprex, WP AF Rubin, Steven Eckhaus, Michael Rennick, Linda J. Bamford, Connor G. G. Duprex, W. Paul TI Molecular biology, pathogenesis and pathology of mumps virus SO JOURNAL OF PATHOLOGY LA English DT Review DE mumps; mumps virus; pathogenesis; neurovirulence; vaccine ID CENTRAL-NERVOUS-SYSTEM; ACUTE CEREBELLAR-ATAXIA; AQUEDUCTAL STENOSIS; COMPLICATING MUMPS; UNITED-STATES; INNER-EAR; CONGENITAL HYDROCEPHALUS; INTRAUTERINE INFECTION; CORNEAL ENDOTHELIITIS; UNIVERSITY-STUDENTS AB Mumps is caused by the mumps virus (MuV), a member of the Paramyxoviridae family of enveloped, non-segmented, negative-sense RNA viruses. Mumps is characterized by painful inflammatory symptoms, such as parotitis and orchitis. The virus is highly neurotropic, with laboratory evidence of central nervous system (CNS) infection in approximately half of cases. Symptomatic CNS infection occurs less frequently; nonetheless, prior to the introduction of routine vaccination, MuV was a leading cause of aseptic meningitis and viral encephalitis in many developed countries. Despite being one of the oldest recognized diseases, with a worldwide distribution, surprisingly little attention has been given to its study. Cases of aseptic meningitis associated with some vaccine strains and a global resurgence of cases, including in highly vaccinated populations, has renewed interest in the virus, particularly in its pathogenesis and the need for development of clinically relevant models of disease. In this review we summarize the current state of knowledge on the virus, its pathogenesis and its clinical and pathological outcomes. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Rubin, Steven] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Eckhaus, Michael] NIH, Div Vet Resources, Bethesda, MD 20892 USA. [Bamford, Connor G. G.] Univ Glasgow, MRC, Ctr Virus Res, Glasgow, Lanark, Scotland. [Rennick, Linda J.; Duprex, W. Paul] Boston Univ, Dept Microbiol, Sch Med, Boston, MA 02215 USA. RP Rubin, S (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Steven.rubin@fda.hhs.gov OI /0000-0001-5974-6921 FU NIH [R01 AI105063]; Oak Ridge Institute for Science and Education FX This work was supported by the NIH R01 AI105063 to WPD and by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. We wish to thank Christian Sauder and Laurie Ngo (FDA, Silver Spring, MD) for critical reading of the manuscript, and Jan Johannessen (FDA, Silver Spring, MD) for providing the MRI rat brain images. We dedicate this work to the memory of the late Dr Philip Snoy, DVM, Director, CBER Veterinary Services, respected scientist, admired leader and treasured friend, who laid much of the groundwork towards development of improved preclinical MuV neurotoxicity tests. NR 169 TC 12 Z9 13 U1 4 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3417 EI 1096-9896 J9 J PATHOL JI J. Pathol. PD JAN PY 2015 VL 235 IS 2 BP 242 EP 252 DI 10.1002/path.4445 PG 11 WC Oncology; Pathology SC Oncology; Pathology GA AW3MH UT WOS:000346190300009 PM 25229387 ER PT J AU Chaturvedi, S Cockrell, E Espinola, R Hsi, L Fulton, S Khan, M Li, L Fonseca, F Kundu, S McCrae, KR AF Chaturvedi, Shruti Cockrell, Erin Espinola, Ricardo Hsi, Linda Fulton, Stacey Khan, Mohammad Li, Liang Fonseca, Fabio Kundu, Suman McCrae, Keith R. TI Circulating microparticles in patients with antiphospholipid antibodies: Characterization and associations SO THROMBOSIS RESEARCH LA English DT Article DE Microparticles; Antiphospholipid; Thrombosis; Endothelial cell; Platelet; Thrombosis ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; TISSUE FACTOR ACTIVITY; FACTOR-BEARING MICROPARTICLES; PROTEIN-C PATHWAY; ENDOTHELIAL-CELLS; ANTI-BETA(2)-GLYCOPROTEIN-I ANTIBODIES; VENOUS THROMBOEMBOLISM; BETA(2)-GLYCOPROTEIN I; AUTOIMMUNE-DISEASE; DOMAIN I AB The antiphospholipid syndrome is characterized by venous or arterial thrombosis and/or recurrent fetal loss in the presence of circulating antiphospholipid antibodies. These antibodies cause activation of endothelial and other cell types leading to the release of microparticles with procoagulant and pro-inflammatory properties. The aims of this study were to characterize the levels of endothelial cell, monocyte or platelet derived, and tissue factor-bearing microparticles in patients with antiphospholipid antibodies, to determine the association of circulating microparticles with anticardiolipin and anti-beta(2)-glycoprotein antibodies, and to define the cellular origin of microparticles that express tissue factor. Microparticle content within citrated blood from 47 patients with antiphospholipid antibodies and 144 healthy controls was analyzed within 2 hours of venipuncture. Levels of Annexin-V, CD105 and CD144 (endothelial derived), CD41 (platelet derived) and tissue factor positive microparticles were significantly higher in patients than controls. Though levels of CD14 (monocyte-derived) microparticles in patient plasma were not significantly increased, increased levels of CD14 and tissue factor positive microparticles were observed in patients. Levels of microparticles that stained for CD105 and CD144 showed a positive correlation with IgG (R = 0.60, p = 0.006) and IgM anti-beta2(-)glycoprotein I antibodies (R = 0.58, p = 0.006). The elevation of endothelial and platelet derived microparticles in patients with antiphospholipid antibodies and their correlation with anti-beta(2)-glycoprotein I antibodies suggests a chronic state of vascular cell activation in these individuals and an important role for beta(2)-glycoprotein I in development of the pro-thrombotic state associated with antiphospholipid antibodies. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Chaturvedi, Shruti] Cleveland Clin, Dept Internal Med, Cleveland, OH 44195 USA. [Cockrell, Erin] St Joseph Canc Inst, Tampa, FL USA. [Espinola, Ricardo] US FDA, Rockville, MD 20857 USA. [McCrae, Keith R.] Cleveland Clin, Dept Hematol & Med Oncol, Cleveland, OH 44195 USA. [Hsi, Linda; Fulton, Stacey; Khan, Mohammad; Fonseca, Fabio; Kundu, Suman; McCrae, Keith R.] Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44195 USA. [Li, Liang] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. RP McCrae, KR (reprint author), Cleveland Clin, Taussig Canc Inst, R4-018, Cleveland, OH 44195 USA. EM mccraek@ccf.org OI Chaturvedi, Shruti/0000-0001-6832-2389; McCrae, Keith/0000-0001-7340-475X; Cockrell, Erin/0000-0003-3016-4471 FU National Heart, Lung and Blood Institute [P50HL081011]; American Society of Hematology FX This work was supported by P50HL081011 from the National Heart, Lung and Blood Institute, and by a bridge grant from the American Society of Hematology. NR 56 TC 8 Z9 8 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PD JAN PY 2015 VL 135 IS 1 BP 102 EP 108 DI 10.1016/j.thromres.2014.11.011 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AW7GK UT WOS:000346432600019 PM 25467081 ER PT J AU Sokolic, R Oden, N Candotti, F AF Sokolic, Robert Oden, Neal Candotti, Fabio TI Assessment of immature platelet fraction in the diagnosis of Wiskott-Aldrich syndrome SO FRONTIERS IN PEDIATRICS LA English DT Article DE thrombocytopenia; differential diagnosis; immature platelet fraction; Wiskott Aldrich syndrome; immune thrombocytopenic purpura AB Children with Wiskott Aldrich syndrome (WAS) are often first diagnosed with immune thrombocytopenia (ITP), potentially leading to both inappropriate treatment and the delay of life-saving definitive therapy. WAS is traditionally differentiated from ITP based on the small size of WAS platelets. In practice, microthrombocytopenia is often not present or not appreciated in children with WAS. To develop an alternative method of differentiating WAS from ITP, we retrospectively reviewed all complete blood counts and measurements of immature platelet fraction (IPF) in 18 subjects with WAS and 38 subjects with a diagnosis of ITP treated at our hospital. Examination of peripheral blood smears revealed a wide range of platelet sizes in subjects with WAS. Mean platelet volume (MPV) was not reported in 26% of subjects, and subjects in whom MPV was not reported had lower platelet counts than did subjects in whom MPV was reported. Subjects with WAS had a lower IPF than would be expected for their level of thrombocytopenia, and the IPF in subjects with WAS was significantly lower than in subjects with a diagnosis of ITP. Using logistic regression, we developed and validated a rule based on platelet count and IPF that was more sensitive for the diagnosis of WAS than was the MPV, and was applicable regardless of the level of platelets or the availability of the MPV. Our observations demonstrate that MPV is often not available in severely thrombocytopenic subjects, which may hinder the diagnosis of WAS. In addition, subjects with WAS have a low IPF, which is consistent with the notion that a platelet production defect contributes to the thrombocytopenia of WAS. Knowledge of this detail of WAS pathophysiology allows to differentiate WAS from ITP with increased sensitivity, thereby allowing a physician to spare children with WAS from inappropriate treatment, and make definitive therapy available in a timely manner. C1 [Sokolic, Robert] US FDA, Off Cellular Tissue & Gene Therapies, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 71,Room 5261, Silver Spring, MD 20993 USA. [Oden, Neal] Emmes Corp, Rockville, MD USA. [Sokolic, Robert; Candotti, Fabio] NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Candotti, Fabio] CHU Vaudois, Div Immunol & Allergy, Lausanne, Switzerland. RP Sokolic, R (reprint author), US FDA, Off Cellular Tissue & Gene Therapies, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 71,Room 5261, Silver Spring, MD 20993 USA. EM Robert.Sokolic@fda.hhs.gov FU National Institutes of Health; Food and Drug Administration FX The collection of this data was funded as part of the intramural research program of the National Institutes of Health. Funding to analyze the data and write the manuscript was provided by the Food and Drug Administration. We thank Dr. James Cimino and Ms. Andrea Beri for assistance in extracting data from BTRIS. We thank principal investigators of protocols on which ITP subjects were enrolled for permission to use their clinical research data. We thank Dr. Wilson Bryan for thoughtful review of the manuscript and suggestions for improvement. We thank the nurses, fellows, residents and clinical staff of the institutes and nursing units that provided care for the patients. We thank the patients for their time, their blood samples, and the privilege of caring for them. NR 30 TC 2 Z9 3 U1 3 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2296-2360 J9 FRONT PEDIATR JI Front. Pediatr. PY 2015 VL 3 AR 49 DI 10.3389/fped.2015.00049 PG 10 WC Pediatrics SC Pediatrics GA V46PZ UT WOS:000209897400047 PM 26082919 ER PT J AU Tall, BD Gangiredla, J Gopinath, GR Yan, QQ Chase, HR Lee, B Hwang, S Trach, L Park, E Yoo, Y Chung, TJ Jackson, SA Patel, IR Sathyamoorthy, V Pava-Ripoll, M Kotewicz, ML Carter, L Iversen, C Pagotto, F Stephan, R Lehner, A Fanning, S Grim, CJ AF Tall, Ben Davies Gangiredla, Jayanthi Gopinath, Gopal R. Yan, Qiongqiong Chase, Hannah R. Lee, Boram Hwang, Seongeun Trach, Larisa Park, Eunbi Yoo, YeonJoo Chung, TaeJung Jackson, Scott A. Patel, Isha R. Sathyamoorthy, Venugopal Pava-Ripoll, Monica Kotewicz, Michael L. Carter, Laurenda Iversen, Carol Pagotto, Franco Stephan, Roger Lehner, Angelika Fanning, Seamus Grim, Christopher J. TI Development of a custom-designed, pan genomic DNA microarray to characterize strain-level diversity among Cronobacter spp. SO FRONTIERS IN PEDIATRICS LA English DT Article DE Cronobacter; microarray; genomic diversity; pan genomic; phylogenic divergence AB Cronobacter species cause infections in all age groups; however neonates are at highest risk and remain the most susceptible age group for life-threatening invasive disease. The genus contains seven species: Cronobacter sakazakii, Cronobacter malonaticus, Cronobacter turicensis, Cronobacter muytjensii, Cronobacter dublinensis, Cronobacter universalis, and Cronobacter condimenti. Despite an abundance of published genomes of these species, genomics-based epidemiology of the genus is not well established. The gene content of a diverse group of 126 unique Cronobacter and taxonomically related isolates was determined using a pan genomic-based DNA microarray as a genotyping tool and as a means to identify outbreak isolates for food safety, environmental, and clinical surveillance purposes. The microarray constitutes 19,287 independent genes representing 15 Cronobacter genomes and 18 plasmids and 2,371 virulence factor genes of phylogenetically related Gram-negative bacteria. The Cronobacter microarray was able to distinguish the seven Cronobacter species from one another and from non-Cronobacter species; and within each species, strains grouped into distinct clusters based on their genomic diversity. These results also support the phylogenic divergence of the genus and clearly highlight the genomic diversity among each member of the genus. The current study establishes a powerful platform for further genomics research of this diverse genus, an important prerequisite toward the development of future countermeasures against this foodborne pathogen in the food safety and clinical arenas. C1 [Tall, Ben Davies; Gangiredla, Jayanthi; Gopinath, Gopal R.; Chase, Hannah R.; Lee, Boram; Hwang, Seongeun; Trach, Larisa; Park, Eunbi; Yoo, YeonJoo; Chung, TaeJung; Jackson, Scott A.; Patel, Isha R.; Sathyamoorthy, Venugopal; Kotewicz, Michael L.; Carter, Laurenda; Grim, Christopher J.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD USA. [Yan, Qiongqiong; Fanning, Seamus] Univ Coll Dublin, Ctr Food Safety, Sch Publ Hlth Physiotherapy & Populat Sci, Dublin, Ireland. [Yan, Qiongqiong; Fanning, Seamus] WHO, Collaborating Ctr Cronobacter, Dublin, Ireland. [Pava-Ripoll, Monica] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Iversen, Carol] Univ Dundee, Coll Life Sci, Dundee, Scotland. [Pagotto, Franco] Hlth Canada, Bur Microbial Hazards, Food Directorate, Ottawa, ON, Canada. [Stephan, Roger; Lehner, Angelika] Univ Zurich, Inst Food Safety & Hyg, Zurich, Switzerland. RP Tall, BD (reprint author), US FDA, Ctr Food Safety & Appl Nutr, OARSA,MOD Facil 1,Lab 3408,Off 3607, Div Virulence Assessment,Virulence Mechanisms Bra, 8301 MuirKirk Rd, Laurel, MD 20708 USA. EM ben.tall@fda.hhs.gov FU International Offices of Kyungpook National University, Daegu; Gachon University, Gyeonggi, Republic of Korea; office of Undergraduate Research and Internship Programs, Joint institute of Food Safety and Applied Nutrition, University of Maryland, College Park, MD, USA; U.S. FDA FX We thank the student internship programs of the International Offices of Kyungpook National University, Daegu, and Gachon University, Gyeonggi, Republic of Korea for sponsoring student interns: B. Lee, S. Hwang, E. Park, Y. J. Yoo, T. J. Chung. We thank the office of Undergraduate Research and Internship Programs, Joint institute of Food Safety and Applied Nutrition, University of Maryland, College Park, MD, USA for sponsoring student interns: H. R. Chase and L. Trach. We thank E. Strain of the Office of Analytics and Outreach, Division of Public Health and Biostatistics, CFSAN for providing us the 454 whole genome sequence of C. malonaticus strain ENBT0334. Funds supporting this work were obtained internally through U.S. FDA appropriations. If readers would like the Excel version of Table S3 in Supplementary Material, and the full data set of CEL files, they are available upon request. NR 33 TC 3 Z9 3 U1 0 U2 5 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2296-2360 J9 FRONT PEDIATR JI Front. Pediatr. PY 2015 VL 3 AR 36 DI 10.3389/fped.2015.00036 PG 11 WC Pediatrics SC Pediatrics GA V46PZ UT WOS:000209897400034 PM 25984509 ER PT S AU Pezeshk, A Petrick, N Sahiner, B AF Pezeshk, Aria Petrick, Nicholas Sahiner, Berkman BE Tourassi, GD Armato, SG TI Seamless Lesion Insertion in Digital Mammography: Methodology and Reader Study SO MEDICAL IMAGING 2016: COMPUTER-AIDED DIAGNOSIS SE Proceedings of SPIE LA English DT Proceedings Paper CT Conference on Medical Imaging - Computer-Aided Diagnosis CY FEB 28-MAR 02, 2016 CL San Diego, CA SP SPIE, Modus Med Devices Inc, Bruker, Poco Graphite, ImXPAD DE Computer aided diagnosis; Reference library creation; Lesion insertion; Digital Mammography; Poisson image editing ID PULMONARY NODULES; CHEST; TOOL AB Collection of large repositories of clinical images containing verified cancer locations is costly and time consuming due to difficulties associated with both the accumulation of data and establishment of the ground truth. This problem poses a significant challenge to the development of machine learning algorithms that require large amounts of data to properly train and avoid overfitting. In this paper we expand the methods in our previous publications by making several modifications that significantly increase the speed of our insertion algorithms, thereby allowing them to be used for inserting lesions that are much larger in size. These algorithms have been incorporated into an image composition tool that we have made publicly available. This tool allows users to modify or supplement existing datasets by seamlessly inserting a real breast mass or micro-calcification cluster extracted from a source digital mammogram into a different location on another mammogram. We demonstrate examples of the performance of this tool on clinical cases taken from the University of South Florida Digital Database for Screening Mammography (DDSM). Finally, we report the results of a reader study evaluating the realism of inserted lesions compared to clinical lesions. Analysis of the radiologist scores in the study using receiver operating characteristic (ROC) methodology indicates that inserted lesions cannot be reliably distinguished from clinical lesions. C1 [Pezeshk, Aria; Petrick, Nicholas; Sahiner, Berkman] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Pezeshk, A (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM aria.pezeshk@fda.hhs.gov NR 13 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-1-5106-0020-1 J9 PROC SPIE PY 2015 VL 9785 AR UNSP 97850J DI 10.1117/12.2217056 PG 6 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA BG5QJ UT WOS:000389678800018 ER PT J AU Bellayr, IH Marklein, RA Lo Surdo, JL Bauer, SR Puri, RK AF Bellayr, I. H. Marklein, R. A. Lo Surdo, J. L. Bauer, S. R. Puri, R. K. TI Identification of Predictive Gene Markers for Multipotent Stromal Cell Proliferation SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract C1 [Bellayr, I. H.; Marklein, R. A.; Lo Surdo, J. L.; Bauer, S. R.; Puri, R. K.] US FDA, Div Cellular & Gene Therapies, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PY 2015 VL 26 MA P2267 PG 1 WC Cell Biology SC Cell Biology GA V47BZ UT WOS:000209928600531 ER PT J AU Wang, SJ Li, D Petrick, N Sahiner, B Linguraru, MG Summers, RM AF Wang, Shijun Li, Diana Petrick, Nicholas Sahiner, Berkman Linguraru, Marius George Summers, Ronald M. TI Optimizing area under the ROC curve using semi-supervised learning SO PATTERN RECOGNITION LA English DT Article DE Receiver operating characteristic; AUC; Semi-supervised learning; Transfer learning; Semidefinite programming; RankBoost; SVMROC; SSLROC ID SUPPORT VECTOR MACHINES; CT COLONOGRAPHY; CLASSIFICATION; ALGORITHMS; AUC; TESTS AB Receiver operating characteristic (ROC) analysis is a standard methodology to evaluate the performance of a binary classification system. The area under the ROC curve (AUC) is a performance metric that summarizes how well a classifier separates two classes. Traditional AUC optimization techniques are supervised learning methods that utilize only labeled data (i.e., the true class is known for all data) to train the classifiers. In this work, inspired by semi-supervised and transductive learning, we propose two new AUC optimization algorithms hereby referred to as semi-supervised learning receiver operating characteristic (SSLROC) algorithms, which utilize unlabeled test samples in classifier training to maximize AUC. Unlabeled samples are incorporated into the AUC optimization process, and their ranking relationships to labeled positive and negative training samples are considered as optimization constraints. The introduced test samples will cause the learned decision boundary in a multidimensional feature space to adapt not only to the distribution of labeled training data, but also to the distribution of unlabeled test data. We formulate the semi-supervised AUC optimization problem as a semi-definite programming problem based on the margin maximization theory. The proposed methods SSLROC1 (1-norm) and SSLROC2 (2-norm) were evaluated using 34 (determined by power analysis) randomly selected datasets from the University of California, Irvine machine learning repository. Wilcoxon signed rank tests showed that the proposed methods achieved significant improvement compared with state-of-the-art methods. The proposed methods were also applied to a CT colonography dataset for colonic polyp classification and showed promising results.(1) Published by Elsevier Ltd. C1 [Wang, Shijun; Li, Diana; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. [Petrick, Nicholas; Sahiner, Berkman] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Linguraru, Marius George] Childrens Natl Hlth Syst, Sheikh Zayed Inst Pediat Surg Innovat, Washington, DC 20010 USA. [Linguraru, Marius George] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20037 USA. RP Summers, RM (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bldg 10 Room 1C224D MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov FU Intramural NIH HHS [ZIA CL040003-11] NR 54 TC 4 Z9 4 U1 1 U2 17 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0031-3203 EI 1873-5142 J9 PATTERN RECOGN JI Pattern Recognit. PD JAN PY 2015 VL 48 IS 1 BP 276 EP 287 DI 10.1016/j.patcog.2014.07.025 PG 12 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA AS3UR UT WOS:000344204000021 PM 25395692 ER PT J AU Dobhal, S Zhang, GD Gautam, D Fletcher, J Ma, LM AF Dobhal, Shefali Zhang, Guodong Gautam, Dhiraj Fletcher, Jacqueline Ma, Li Maria TI Uneven distribution of microorganisms on the surface of field-grown cantaloupes SO FOOD CONTROL LA English DT Article DE Cantaloupe; Microbial contamination; Food safety; Soil contamination; Washing ID FRESH PRODUCE; SALMONELLA; CONTAMINATION; WATER; TYPHIMURIUM; EFFICACY; QUALITY; MANURE AB Cantaloupes have been implicated in a number of foodborne illness outbreaks due to contamination with human pathogens. However, we have limited understanding on the potential microbial contamination routes, especially in the production fields. We hypothesized that the soil upon which cantaloupe fruit rest can be a source of microbial contamination. Microbial populations on the surfaces of field-grown cantaloupes were enumerated and the effect of washing on the removal of microorganisms from the cantaloupe surfaces was evaluated. The microbial populations on the lower surface (in direct contact with soil) of the cantaloupes were significantly higher (p < 0.05), averaging 2.21 log CFU/cm(2) (aerobic bacteria); 1.62 log CFU/cm(2) (coliforms); and 2.02 log CFU/cm(2) (molds and yeasts), compared to those on the upper surface (exposed to the air). Washing significantly reduced only the populations of yeasts and molds on the lower surfaces of cantaloupes. Scanning electron micrographs showed more microbe-like bodies on the lower surface of cantaloupe than on the top. This study revealed an uneven distribution of microbial populations on the surfaces of field-grown cantaloupes, suggesting that direct contact with soil can be a major source of microbial contamination to fruits. Field production practices that minimize direct contact of cantaloupes with the soil may serve as a control strategy for ensuring a safer product. Also, more effective surface cleaning methods should be explored. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Dobhal, Shefali; Gautam, Dhiraj; Fletcher, Jacqueline; Ma, Li Maria] Oklahoma State Univ, Dept Entomol & Plant Pathol, Natl Inst Microbial Forens & Food & Agr Biosecur, Stillwater, OK 74078 USA. [Zhang, Guodong] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Ma, LM (reprint author), Oklahoma State Univ, Dept Entomol & Plant Pathol, Natl Inst Microbial Forens & Food & Agr Biosecur, 127 Noble Res Ctr, Stillwater, OK 74078 USA. EM li.ma@okstate.edu FU Oklahoma Agricultural Experiment Station, Oklahoma State University FX This work was partially supported by the Oklahoma Agricultural Experiment Station, Oklahoma State University. We also thank Dr. Astri Wayadande and Dr. Trenna Blagden for reviewing the manuscript. No conflict of interest exists. NR 23 TC 1 Z9 1 U1 1 U2 25 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-7135 EI 1873-7129 J9 FOOD CONTROL JI Food Control PD JAN PY 2015 VL 47 BP 185 EP 189 DI 10.1016/j.foodcont.2014.07.002 PG 5 WC Food Science & Technology SC Food Science & Technology GA AR5GI UT WOS:000343612700028 ER PT J AU Kou, LP Luo, YG Ingram, DT Yan, SL Jurick, WM AF Kou, Liping Luo, Yaguang Ingram, David T. Yan, Shoulei Jurick, Wayne M., II TI Open-refrigerated retail display case temperature profile and its impact on product quality and microbiota of stored baby spinach SO FOOD CONTROL LA English DT Article DE Baby spinach; Temperature profile; Display case; Product quality; Retail storage ID ESCHERICHIA-COLI O157H7; STORAGE-TEMPERATURE; SHELF-LIFE; FRESH; CABINETS; ROMAINE; LETTUCE; PERFORMANCE; LEAVES; TIME AB Maintaining proper storage temperature is critical for ensuring the quality and safety of fresh-cut products. The US Food and Drug Administration Food Code recommend that packaged fresh-cut leafy green vegetables be kept no warmer than 5 C at all times to ensure food safety. Substantial temperature variations, however, within the widely used open refrigerated display cases used in retail stores are known to present the technical challenge of complying with this federal guidance for industry. This study determined the extent of the spatial and temporal temperature variations within two commercial open-refrigerated display cases under different operating conditions, and their impact on the quality and microbial growth of packaged baby spinach products. The packaged products were received within 2 d of commercial processing and temperature data loggers were placed inside-and-outside of each bag. All bags were immediately loaded in the display cases and the overall visual quality, tissue electrolyte leakage, total aerobic mesophilic bacteria and psychrotrophic bacteria were evaluated for each bag. Results from this study showed that the temperature variation in the cases was dependent on spatial location, thermostat setting, and defrost cycle interval and duration of defrost. The largest temperature differentials were found for samples located in the front and back rows of the display cases. Samples located in the front rows had the highest temperature due to heat penetration from the surrounding ambient environment, while those in the back were damaged as temperatures fell below freezing. These products received low quality scores and had higher tissue electrolyte leakage. In order to reduce the large temperature variations in the display cases, insulating foam boards were installed which significantly (P < 0.05) decreased the temperature variation by 3.5 degrees C and enabled samples in the front rows of the cases to remain less than 5 degrees C as recommended by the FDA. These results suggest that the quality and safety of packaged ready-to-eat spinach at retail will benefit from improvements in open refrigerated case design or the utilization of insulation, doors or curtains. Published by Elsevier Ltd. C1 [Kou, Liping] Northwest A&F Univ, Coll Food Sci & Engn, Yangling 712100, Shaanxi, Peoples R China. [Kou, Liping; Luo, Yaguang; Yan, Shoulei; Jurick, Wayne M., II] USDA ARS, Food Qual Lab, Beltsville, MD 20705 USA. [Luo, Yaguang] USDA ARS, Environm Microbiol & Food Safety Lab, Beltsville, MD 20705 USA. [Ingram, David T.] US FDA, College Pk, MD 20740 USA. [Yan, Shoulei] Huazhong Agr Univ, Coll Food Sci & Technol, Wuhan 430070, Hubei, Peoples R China. RP Luo, YG (reprint author), USDA ARS, Environm Microbiol & Food Safety Lab, 10300 Baltimore Ave, Beltsville, MD 20705 USA. EM Yaguang.Luo@ars.usda.gov FU USDA-NIFA (Specialty Crop Initiative) [2010-51181-21230]; USDA-ARS [1275-43440-004-00D] FX The authors wish to thank Dr. Roger Billingsley at Dole Fresh Vegetables (Salinas, CA, USA) for donating packaged baby spinach products, Dr. Jose Atilio de Frias for reviewing and revising the manuscript prior to its submission. This research is supported by USDA-NIFA (Specialty Crop Initiative Award No. 2010-51181-21230) and USDA-ARS (Project No. 1275-43440-004-00D). NR 22 TC 3 Z9 5 U1 14 U2 51 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-7135 EI 1873-7129 J9 FOOD CONTROL JI Food Control PD JAN PY 2015 VL 47 BP 686 EP 692 DI 10.1016/j.foodcont.2014.07.054 PG 7 WC Food Science & Technology SC Food Science & Technology GA AR5GI UT WOS:000343612700096 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 (Retraction of vol 157, pg 540, 2014) SO FOOD CHEMISTRY LA English DT Correction 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 1 TC 0 Z9 0 U1 4 U2 19 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 JAN 1 PY 2015 VL 166 BP 514 EP 514 DI 10.1016/j.foodchem.2014.06.074 PG 1 WC Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics SC Chemistry; Food Science & Technology; Nutrition & Dietetics GA AQ2XV UT WOS:000342654200069 ER PT J AU Zhang, YZ Du, WX Fregevu, C Kothary, MH Harden, L McHugh, TH AF Zhang, Yuzhu Du, Wen-Xian Fregevu, Cecile Kothary, Mahendra H. Harden, Leslie McHugh, Tara H. TI Expression, Purification, and Characterization of Almond (Prunus dulcis) Allergen Pru du 4 SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE food allergy; sumo; tree nut allergy; stability; almond; allergen ID FOOD ALLERGY; PROFILIN; PROTEIN; SOLUBILITY; STABILITY; CLONING C1 [Zhang, Yuzhu; Du, Wen-Xian; Fregevu, Cecile; Harden, Leslie; McHugh, Tara H.] ARS, USDA, Pacific West Area, Western Reg Res Ctr, Albany, CA 94710 USA. [Kothary, Mahendra H.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Zhang, YZ (reprint author), ARS, USDA, Pacific West Area, Western Reg Res Ctr, 800 Buchanan St, Albany, CA 94710 USA. EM yuzhu.zhang@ars.usda.gov NR 26 TC 3 Z9 3 U1 3 U2 18 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 DEC 31 PY 2014 VL 62 IS 52 BP 12695 EP 12700 DI 10.1021/jf5045102 PG 6 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA AY2RS UT WOS:000347437500027 PM 25437489 ER PT J AU Madon-Simon, M Cowley, M Garfield, AS Moorwood, K Bauer, SR Ward, A AF Madon-Simon, Marta Cowley, Michael Garfield, Alastair S. Moorwood, Kim Bauer, Steven R. Ward, Andrew TI Antagonistic roles in fetal development and adult physiology for the oppositely imprinted Grb10 and Dlk1 genes SO BMC BIOLOGY LA English DT Article DE Adiposity; Body proportions; Genomic imprinting; Glucose-regulated metabolism; Growth; Mouse genetics AB Background: Despite being a fundamental biological problem the control of body size and proportions during development remains poorly understood, although it is accepted that the insulin-like growth factor (IGF) pathway has a central role in growth regulation, probably in all animals. The involvement of imprinted genes has also attracted much attention, not least because two of the earliest discovered were shown to be oppositely imprinted and antagonistic in their regulation of growth. The Igf2 gene encodes a paternally expressed ligand that promotes growth, while maternally expressed Igf2r encodes a cell surface receptor that restricts growth by sequestering Igf2 and targeting it for lysosomal degradation. There are now over 150 imprinted genes known in mammals, but no other clear examples of antagonistic gene pairs have been identified. The delta-like 1 gene (Dlk1) encodes a putative ligand that promotes fetal growth and in adults restricts adipose deposition. Conversely, Grb10 encodes an intracellular signalling adaptor protein that, when expressed from the maternal allele, acts to restrict fetal growth and is permissive for adipose deposition in adulthood. Results: Here, using knockout mice, we present genetic and physiological evidence that these two factors exert their opposite effects on growth and physiology through a common signalling pathway. The major effects are on body size (particularly growth during early life), lean: adipose proportions, glucose regulated metabolism and lipid storage in the liver. A biochemical pathway linking the two cell signalling factors remains to be defined. Conclusions: We propose that Dlk1 and Grb10 define a mammalian growth axis that is separate from the IGF pathway, yet also features an antagonistic imprinted gene pair. C1 [Madon-Simon, Marta; Cowley, Michael; Garfield, Alastair S.; Moorwood, Kim; Ward, Andrew] Univ Bath, Dept Biol & Biochem, Bldg 4 South, Bath BA2 7AY, Avon, England. [Madon-Simon, Marta; Cowley, Michael; Garfield, Alastair S.; Moorwood, Kim; Ward, Andrew] Univ Bath, Ctr Regenerat Med, Bath BA2 7AY, Avon, England. [Bauer, Steven R.] US FDA, Ctr Biol Evaluat & Res, Cellular & Tissue Therapies Branch, Div Cellular & Gene Therapies, Silver Spring, MD 20993 USA. [Cowley, Michael] N Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. [Cowley, Michael] N Carolina State Univ, Ctr Human Hlth & Environm, Raleigh, NC 27695 USA. RP Ward, A (reprint author), Univ Bath, Dept Biol & Biochem, Bldg 4 South, Bath BA2 7AY, Avon, England. EM bssaw@bath.ac.uk OI Moorwood, Kim/0000-0003-0943-6161; Cowley, Michael/0000-0001-8564-4224 FU Medical Research Council UK; University of Bath FX We thank Mark Perry, Adrian Rogers and Iryna Withington for technical assistance, and Anne Ferguson-Smith and Marika Charalambous for discussions during the course of the work. We are grateful for funding for the work from the Medical Research Council UK (studentship to ASG and research grant award to AW) and the University of Bath (studentships to MM-S and MC; post-doctoral funds to KM). NR 85 TC 4 Z9 4 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD DEC 31 PY 2014 VL 12 AR 771 DI 10.1186/s12915-014-0099-8 PG 22 WC Biology SC Life Sciences & Biomedicine - Other Topics GA V42LH UT WOS:000209614800001 PM 25551289 ER PT J AU Krishnaiah, YSR Yang, Y Hunt, RL Khan, MA AF Krishnaiah, Yellela S. R. Yang, Yang Hunt, Robert L. Khan, Mansoor A. TI Cold flow of estradiol transdermal systems: Influence of drug loss on the in vitro flux and drug transfer across human epidermis SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Cold flow; Transdermal; Flux; In vitro permeation; Human epidermis; Estradiol ID PRESSURE-SENSITIVE ADHESIVE; DELIVERY SYSTEMS; SKIN ADHESION; QUANTIFICATION; PRINCIPLES; ABSORPTION; PRODUCTS; PATCHES AB The objective was to quantify drug loss due to cold flow (CF) in marketed estradiol transdermal drug delivery systems (TDDS), and study its influence on the in vitro flux and drug transfer across contacting skin. TDDS samples (products-A and B) were induced with CF at 25 and 32 degrees C/60% RH by applying 1-kg force for 72 h. CF was measured as percent dimensional change and amount of drug loss/migration in CF region. In vitro drug permeation studies were conducted across human epidermis from TDDS excluding CF region, and CF region alone against control (without CF). In both products, significantly higher percentage of CF (dimensional change and drug migration) was observed at 32 degrees C compared to 25 degrees C. In vitro flux from both products excluding CF region either at 25 or 32 degrees C was the same, but significantly lower compared to control. Drug transferred from CF region of product-A after 8 h was the same at 25 and 32 degrees C, but significantly higher in product-B. Flux from both products together with CF region at 32 degrees C was significantly lower than that observed at 25 degrees C. Results showed that excessive CF at storage (25 degrees C) and clinical usage (32 degrees C) conditions may have implications on product performance and safety of estradiol TDDS. Published by Elsevier B.V. C1 [Krishnaiah, Yellela S. R.; Yang, Yang; Hunt, Robert L.; Khan, Mansoor A.] US FDA, Div Prod Qual Res, Off Testing & Res, Off Pharmaceut Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Krishnaiah, YSR (reprint author), US FDA, CDER, OPS, OTR,DPQR, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM krishnaiah.yellela@fda.hhs.gov FU Office of Women's Health, US Food and Drug Administration [750312CDR] FX This part of the research work was funded by Office of Women's Health, US Food and Drug Administration (Grant ID: 750312CDR). NR 25 TC 0 Z9 0 U1 2 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD DEC 30 PY 2014 VL 477 IS 1-2 BP 73 EP 80 DI 10.1016/j.ijpharm.2014.10.013 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AY5PG UT WOS:000347623800009 PM 25311180 ER PT J AU Mohammad, A Faustino, PJ Khan, MA Yang, YS AF Mohammad, Adil Faustino, Patrick J. Khan, Mansoor A. Yang, Yongsheng TI Long-term stability study of Prussian blue - A quality assessment of water content and thallium binding SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Prussian blue; Thallium binding; Particle size; Water content loss; Hydration; Product quality ID RADIOCAESIUM; PRODUCTS; DRUG; EXCRETION; MEAL AB The purpose of this study is to assess the long-term stability of Prussian blue (PB) drug product (DP) and active pharmaceutical ingredient (API) under laboratory storage conditions by monitoring the loss in water content and the corresponding change of the in vitro thallium binding capacity that represents product performance. The bound water content and the in vitro thallium binding capacity of PB DPs and APIs were measured in 2003 and 2013, respectively. Water content, a critical quality attribute that directly correlates to the thallium (Tl) binding capacity was measured by thermal gravimetric analysis (TGA). The thallium binding study was conducted by testing PB in buffered solutions over the human gastrointestinal pH range with thallium concentrations ranging from 600 to 1500 ppm. Samples were incubated at physiological temperature of 37 degrees C in a shaking water bath to mimic gastric flux and intestinal transport. The binding equilibrium was reached at 24 h. Following incubation, each sample was filtered and the free thallium was analyzed using a validated inductively coupled plasma spectroscopic method (ICP). The Langmuir isotherm was plotted to calculate maximum binding capacity (MBC). Compared with 2003, the water content of DP-1 decreased by about 14.1% (from 15.6 to 13.4 mol), and the MBC of DP-1 decreased by about 12.5% (from 714 to 625 mg/g) at pH 7.5. When low concentration of thallium (600 ppm) was used at pH 7.5, the Tl binding remained comparable for both API-1 (286 vs 276 mg/g) and DP-1 (286 vs 268 mg/g). Similarly, the Tl binding remained unchanged for both API-1 (237 vs 255 mg/g) and DP-1 (234 vs 236 mg/g) at pH 5.0. However, at pH 1.0 the binding was reduced 32.3% and 25.9% for API-1 and DP-1, respectively. Since the majority of binding takes place in the upper GI tract where pH around 5 can be expected, and therefore, the Tl binding capacity of PB should be comparable for new and aged samples. The findings that Tl binding changes with the water loss of PB and pH conditions are consistent with our previously published data. The study also represents the first quantitative assessment of the long-term stability of PB. Over last 10 years, PB DPs and APIs have lost about 20% water under ambient laboratory storage conditions which are consistent with a controlled warehouse environment. While the maximum binding capacity of PB to thallium was decreased after about 10 years of long-term storage, it is still very effective, suggesting that the shelf life of PB should be much longer than the manufacturer ascribed expiration date of 2008 under proper storage conditions. Published by Elsevier B.V. C1 [Mohammad, Adil; Faustino, Patrick J.; Khan, Mansoor A.; Yang, Yongsheng] US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Prod Qual Res, Silver Spring, MD 20993 USA. RP Yang, YS (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Prod Qual Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Yongsheng.Yang@fda.hhs.gov FU FDA Office of Counter Terrorism-Medical Counter Measures initiative (MCMi); intramural FDA Office of Testing and Research funds FX This study was supported in part by a grant from the FDA Office of Counter Terrorism-Medical Counter Measures initiative (MCMi) and from intramural FDA Office of Testing and Research funds. The authors would also like to again thank HEYL Corporation and REACT/S (Oak Ridge, TN) for supplying API and PB drug products in 2003. NR 23 TC 3 Z9 3 U1 4 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD DEC 30 PY 2014 VL 477 IS 1-2 BP 122 EP 127 DI 10.1016/j.ijpharm.2014.10.020 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AY5PG UT WOS:000347623800015 PM 25311178 ER PT J AU Ouyang, Q Wang, LR Mu, Y Xie, XQ AF Ouyang, Qin Wang, Lirong Mu, Ying Xie, Xiang-Qun TI Modeling skin sensitization potential of mechanistically hard-to-be-classified aniline and phenol compounds with quantum mechanistic properties SO BMC PHARMACOLOGY & TOXICOLOGY LA English DT Article DE Chemical mechanisms; Structure-activity relationship; Skin sensitizer; Anilines; Phenols; Quantum mechanism ID LYMPH-NODE ASSAY; CONTACT ALLERGENS; KNOWLEDGE GENERATION; METABOLIC-ACTIVATION; RISK-ASSESSMENT; IN-VITRO; PREDICTION; REACTIVITY; TOXICITY; POTENCY AB Background: Advanced structure-activity relationship (SAR) modeling can be used as an alternative tool for identification of skin sensitizers and in improvement of the medical diagnosis and more effective practical measures to reduce the causative chemical exposures. It can also circumvent ethical concern of using animals in toxicological tests, and reduce time and cost. Compounds with aniline or phenol moieties represent two large classes of frequently skin sensitizing chemicals but exhibiting very variable, and difficult to predict, potency. The mechanisms of action are not well-understood. Methods: A group of mechanistically hard-to-be-classified aniline and phenol chemicals were collected. An in silico model was established by statistical analysis of quantum descriptors for the determination of the relationship between their chemical structures and skin sensitization potential. The sensitization mechanisms were investigated based on the features of the established model. Then the model was utilized to analyze a subset of FDA approved drugs containing aniline and/or phenol groups for prediction of their skin sensitization potential. Results and discussion: A linear discriminant model using the energy of the highest occupied molecular orbital (epsilon(HOMO)) as the descriptor yielded high prediction accuracy. The contribution of epsilon(HOMO) as a major determinant may suggest that autoxidation or free radical binding could be involved. The model was further applied to predict allergic potential of a subset of FDA approved drugs containing aniline and/or phenol moiety. The predictions imply that similar mechanisms (autoxidation or free radical binding) may also play a role in the skin sensitization caused by these drugs. Conclusions: An accurate and simple quantum mechanistic model has been developed to predict the skin sensitization potential of mechanistically hard-to-be-classified aniline and phenol chemicals. The model could be useful for the skin sensitization potential predictions of a subset of FDA approved drugs. C1 [Ouyang, Qin; Wang, Lirong; Xie, Xiang-Qun] Univ Pittsburgh, Sch Pharm,Dept Pharmaceut Sci,Drug Discovery Inst, Natl Ctr Excellence Computat Drug Abuse Res, Computat Chem Genom Screening Ctr,NIH, Pittsburgh, PA 15261 USA. [Xie, Xiang-Qun] Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA 15261 USA. [Mu, Ying] US FDA, Div Biol, Off Sci & Engn Labs, Ctr Devices & Radiobiol Hlth, Silver Spring, MD 20993 USA. [Ouyang, Qin] Third Mil Med Univ, Coll Pharm, Chongqing 400038, Peoples R China. RP Xie, XQ (reprint author), Univ Pittsburgh, Sch Pharm,Dept Pharmaceut Sci,Drug Discovery Inst, Natl Ctr Excellence Computat Drug Abuse Res, Computat Chem Genom Screening Ctr,NIH, 718 Salk Hall, Pittsburgh, PA 15261 USA. EM xix15@pitt.edu FU National Natural Science Foundation of China [NSFC21202201] FX OQ would like to acknowledge the support from the National Natural Science Foundation of China (NSFC21202201). NR 45 TC 1 Z9 1 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2210 J9 BMC PHARMACOL TOXICO JI BMC Pharmacol. Toxicol. PD DEC 24 PY 2014 VL 15 AR 76 DI 10.1186/2050-6511-15-76 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AZ3UL UT WOS:000348152000001 PM 25539579 ER PT J AU Kumar, S Zheng, H Deng, BB Mahajan, B Grabias, B Kozakai, Y Morin, MJ Locke, E Birkett, A Miura, K Long, C AF Kumar, Sanjai Zheng, Hong Deng, Bingbing Mahajan, Babita Grabias, Bryan Kozakai, Yukiko Morin, Merribeth J. Locke, Emily Birkett, Ashley Miura, Kazutoyo Long, Carole TI A Slot Blot Immunoassay for Quantitative Detection of Plasmodium falciparum Circumsporozoite Protein in Mosquito Midgut Oocyst SO PLoS One LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; MALARIA TRANSMISSION; FALSE POSITIVITY; SPOROZOITES; VIVAX; ANTIBODIES; PFS48/45; ANTIGEN; VACCINE; VECTOR AB There is still a need for sensitive and reproducible immunoassays for quantitative detection of malarial antigens in preclinical and clinical phases of vaccine development and in epidemiology and surveillance studies, particularly in the vector host. Here we report the results of sensitivity and reproducibility studies for a research-grade, quantitative enhanced chemiluminescent-based slot blot assay (ECL-SB) for detection of both recombinant Plasmodium falciparum circumsporozoite protein (rPfCSP) and native PfCSP from Oocysts (Pf Oocyst) developing in the midguts of Anopheles stephensi mosquitoes. The ECL-SB detects as little as 1.25 pg of rPfCSP (linear range of quantitation 2.5-20 pg; R-2 = 0.9505). We also find the earliest detectable expression of native PfCSP in Pf Oocyst by ECL-SB occurs on day 7 post feeding with infected blood meal. The ECL-SB was able to detect approximately as few as 0.5 day 8 Pf Oocysts (linear quantitation range 1-4, R-2 = 0.9795) and determined that one Pf Oocyst expressed approximately 2.0 pg (0.5-3 pg) of native PfCSP, suggesting a similar range of detection for recombinant and native forms of PfCSP. The ECL-SB is highly reproducible; the Coefficient of Variation (CV) for inter-assay variability for rPfCSP and native PfCSP were 1.74% and 1.32%, respectively. The CVs for intra-assay variability performed on three days for rPfCSP were 2.41%, 0.82% and 2% and for native PfCSP 1.52%, 0.57%, and 1.86%, respectively. In addition, the ECL-SB was comparable to microscopy in determining the P. falciparum prevalence in mosquito populations that distinctly contained either high and low midgut Pf Oocyst burden. In whole mosquito samples, estimations of positivity for P. falciparum in the high and low burden groups were 83.3% and 23.3% by ECL-SB and 85.7% and 27.6% by microscopy. Based on its performance characteristics, ECL-SB could be valuable in vaccine development and to measure the parasite prevalence in mosquitoes and transmission-blocking interventions in endemic areas. C1 [Kumar, Sanjai; Zheng, Hong; Mahajan, Babita; Grabias, Bryan; Kozakai, Yukiko] Ctr Biol Evaluat & Res Food & Drug Adm, Div Emerging & Transfus Transmitted Dis, Lab Emerging Pathogens, Silver Spring, MD 20993 USA. [Deng, Bingbing; Miura, Kazutoyo; Long, Carole] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Morin, Merribeth J.; Locke, Emily; Birkett, Ashley] PATH Malaria Vaccine Initiat, Washington, DC 20001 USA. RP Kumar, S (reprint author), Ctr Biol Evaluat & Res Food & Drug Adm, Div Emerging & Transfus Transmitted Dis, Lab Emerging Pathogens, Silver Spring, MD 20993 USA. EM Sanjai.kumar@fda.hhs.gov FU PATH Malaria Vaccine Initiative; US Food and Drug Administration [CRADA 145-08]; National Institute of Allergy and Infectious Diseases FX This research was funded, in part, through financial support from the PATH Malaria Vaccine Initiative (http://www.malariavaccine.org, SK) and intramural funding from the US Food and Drug Administration (http://www.FDA.gov, SK, CRADA 145-08) and the National Institute of Allergy and Infectious Diseases (http://www.NIAID.NIH.gov, CL). The Path Malaria Vaccine initiative was extensively involved in the design of the study, data collection and analysis, decision to publish, and the preparation of the manuscript. All other funders had no such involvement. NR 25 TC 2 Z9 2 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 DEC 22 PY 2014 VL 9 IS 12 AR e115807 DI 10.1371/journal.pone.0115807 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA3ZY UT WOS:000348845100110 PM 25531543 ER PT J AU U-Thainual, P Yang, Y Le, HND Kim, DH AF U-Thainual, Paweena Yang, Yi Le, Hanh N. D. Kim, Do-Hyun TI Radiant exposure level comparison between Gaussian and top hat beams in various scanning patterns SO APPLIED OPTICS LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; RESOLUTION PHOTOACOUSTIC MICROSCOPY; LASER; VASCULATURE; NM AB The radiant exposure of optical irradiation beams with different scanning parameters has been theoretically studied. We analyzed the difference in radiant exposure introduced by Gaussian and top hat beams. Various parameters such as scanning pattern, aperture position, beam size and scan spacing were also introduced in this study. We found that Gaussian beams introduce higher calculated radiant exposure to the aperture than top hat beams for certain beam size to aperture size ratios. However, as the scan spacing decreases, the radiant exposure difference calculated from Gaussian and top hat beams diminishes. (C) 2014 Optical Society of America C1 [U-Thainual, Paweena; Yang, Yi; Le, Hanh N. D.; Kim, Do-Hyun] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Kim, DH (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM do-hyun.kim@fda.hhs.gov FU Critical Path Initiative of the U.S. Food and Drug Administration FX This work was in part supported by the Critical Path Initiative of the U.S. Food and Drug Administration. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. NR 24 TC 0 Z9 0 U1 0 U2 4 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1559-128X EI 2155-3165 J9 APPL OPTICS JI Appl. Optics PD DEC 20 PY 2014 VL 53 IS 36 BP 8585 EP 8592 DI 10.1364/AO.53.008585 PG 8 WC Optics SC Optics GA AX3ED UT WOS:000346822300026 PM 25608209 ER PT J AU Ali, N Nakhasi, HL Valenzuela, JG Reis, AB AF Ali, Nahid Nakhasi, Hira L. Valenzuela, Jesus G. Reis, Alexandre Barbosa TI largetec immunology for prevention and cure of VL SO FRONTIERS IN IMMUNOLOGY LA English DT Editorial Material DE visceral leishmaniasis; immunotherapy; vaccine; immuno-modulator; Thl response ID HYDROLASE TERMINAL DOMAINS; VISCERAL LEISHMANIASIS; SALIVARY PROTEIN; IMMUNE-RESPONSE; IMMUNOTHERAPY; AMAZONENSIS; PROTECTION; GAMMA C1 [Ali, Nahid] Indian Inst Chem Biol, Infect Dis & Immunol, Kolkata, India. [Nakhasi, Hira L.] US FDA, Silver Spring, MD USA. [Valenzuela, Jesus G.] NIAID, Rockville, MD USA. [Reis, Alexandre Barbosa] Univ Fed Ouro Preto, Ouro Preto, Brazil. RP Ali, N (reprint author), Indian Inst Chem Biol, Infect Dis & Immunol, Kolkata, India. EM nali@iicb.res.in NR 25 TC 1 Z9 1 U1 0 U2 6 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD DEC 19 PY 2014 VL 5 AR 660 DI 10.3389/fimmu.2014.00660 PG 2 WC Immunology SC Immunology GA CI1YC UT WOS:000354540100001 PM 25566268 ER PT J AU Cox, E Borio, L Temple, R AF Cox, Edward Borio, Luciana Temple, Robert TI Evaluating Ebola Therapies - The Case for RCTs SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID EPIDEMIC C1 [Cox, Edward; Temple, Robert] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Borio, Luciana] US FDA, Off Commissioner, Silver Spring, MD USA. RP Cox, E (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. NR 4 TC 32 Z9 32 U1 1 U2 16 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 DEC 18 PY 2014 VL 371 IS 25 BP 2350 EP 2351 DI 10.1056/NEJMp1414145 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AW7DX UT WOS:000346425800003 PM 25470568 ER PT J AU Sedrakyan, A Paxton, E Graves, S Love, R Marinac-Dabic, D AF Sedrakyan, Art Paxton, Elizabeth Graves, Stephen Love, Rebecca Marinac-Dabic, Danica TI National and International Postmarket Research and Surveillance Implementation Achievements of the International Consortium of Orthopaedic Registries Initiative SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID UNIQUE DEVICE IDENTIFICATION; HEALTH; JOINT C1 [Sedrakyan, Art] Weill Cornell Med Coll, New York, NY 10065 USA. [Paxton, Elizabeth; Love, Rebecca] Kaiser Permanente, Surg Outcomes & Anal Dept, San Diego, CA 92108 USA. [Graves, Stephen] Univ Adelaide, Discipline Publ Hlth, Australian Orthopaed Assoc, Natl Joint Replacement Registry, Adelaide, SA 5005, Australia. [Marinac-Dabic, Danica] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Sedrakyan, A (reprint author), Weill Cornell Med Coll, 402 East 67th St, New York, NY 10065 USA. RI Graves, Stephen/A-9463-2016 OI Graves, Stephen/0000-0002-1629-319X FU U.S. Food and Drug Administration (FDA), Silver Spring, Maryland [HHSF223201110172C] FX The ICOR initiative, including the coordinating center at Weill Cornell Medical College and Kaiser Permanente, is financed by contract HHSF223201110172C from the U.S. Food and Drug Administration (FDA), Silver Spring, Maryland; one of the authors (A.S.) was the principal investigator. NR 26 TC 4 Z9 4 U1 9 U2 11 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD DEC 17 PY 2014 VL 96A SU S1 BP 1 EP 6 DI 10.2106/JBJS.N.00739 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AY3IG UT WOS:000347477000001 PM 25520412 ER PT J AU Banerjee, S Cafri, G Isaacs, AJ Graves, S Paxton, E Marinac-Dabic, D Sedrakyan, A AF Banerjee, Samprit Cafri, Guy Isaacs, Abby J. Graves, Stephen Paxton, Elizabeth Marinac-Dabic, Danica Sedrakyan, Art TI A Distributed Health Data Network Analysis of Survival Outcomes The International Consortium of Orthopaedic Registries Perspective SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID METAANALYSIS AB The International Consortium for Orthopaedic Registries is a multinational initiative established by the United States Food and Drug Administration to develop a health data network aimed at providing a robust infrastructure to facilitate evidence-based decision-making on performance of medical devices. Through the International Consortium for Orthopaedic Registries, individual data holders have complete control of their data and can choose to participate in studies of their choice. In this article, we present an overview of the data extraction process and the analytic strategy employed to answer several device performance-related questions in total hip arthroplasty and total knee arthroplasty. In the process, we discuss some nuances pertinent to International Consortium for Orthopaedic Registries data that pose certain statistical challenges, and we briefly suggest strategies to be adopted to address them. C1 [Banerjee, Samprit; Isaacs, Abby J.; Sedrakyan, Art] Weill Cornell Med Coll, New York, NY 10065 USA. [Cafri, Guy; Paxton, Elizabeth] Kaiser Permanente, Surg Outcomes & Anal Dept, San Diego, CA 92108 USA. [Graves, Stephen] Univ Adelaide, Discipline Publ Hlth, Natl Joint Replacement Registry, Australian Orthopaed Assoc, Adelaide, SA 5005, Australia. [Marinac-Dabic, Danica] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Banerjee, S (reprint author), Weill Cornell Med Coll, 402 East 67th St, New York, NY 10065 USA. RI Graves, Stephen/A-9463-2016 OI Graves, Stephen/0000-0002-1629-319X NR 14 TC 2 Z9 2 U1 2 U2 3 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD DEC 17 PY 2014 VL 96A SU S1 BP 7 EP 11 DI 10.2106/JBJS.N.00642 PG 5 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AY3IG UT WOS:000347477000002 PM 25520413 ER PT J AU Alonso, AN Perry, KJ Regeimbal, JM Regan, PM Higgins, DE AF Alonso, Almaris N. Perry, Kyle J. Regeimbal, James M. Regan, Patrick M. Higgins, Darren E. TI Identification of Listeria monocytogenes Determinants Required for Biofilm Formation SO PLOS ONE LA English DT Article ID ALANYL-LIPOTEICHOIC ACID; MARINER-BASED TRANSPOSON; BACILLUS-SUBTILIS; VIRULENCE; MUTAGENESIS; EXPRESSION; HEMOLYSIN; SURFACES; SYSTEM; GROWTH AB Listeria monocytogenes is a Gram-positive, food-borne pathogen of humans and animals. L. monocytogenes is considered to be a potential public health risk by the U.S. Food and Drug Administration (FDA), as this bacterium can easily contaminate ready-to-eat (RTE) foods and cause an invasive, life-threatening disease (listeriosis). Bacteria can adhere and grow on multiple surfaces and persist within biofilms in food processing plants, providing resistance to sanitizers and other antimicrobial agents. While whole genome sequencing has led to the identification of biofilm synthesis gene clusters in many bacterial species, bioinformatics has not identified the biofilm synthesis genes within the L. monocytogenes genome. To identify genes necessary for L. monocytogenes biofilm formation, we performed a transposon mutagenesis library screen using a recently constructed Himar1 mariner transposon. Approximately 10,000 transposon mutants within L. monocytogenes strain 10403S were screened for biofilm formation in 96-well polyvinyl chloride (PVC) microtiter plates with 70 Himar1 insertion mutants identified that produced significantly less biofilms. DNA sequencing of the transposon insertion sites within the isolated mutants revealed transposon insertions within 38 distinct genetic loci. The identification of mutants bearing insertions within several flagellar motility genes previously known to be required for the initial stages of biofilm formation validated the ability of the mutagenesis screen to identify L. monocytogenes biofilm-defective mutants. Two newly identified genetic loci, dltABCD and phoPR, were selected for deletion analysis and both Delta dltABCD and Delta phoPR bacterial strains displayed biofilm formation defects in the PVC microtiter plate assay, confirming these loci contribute to biofilm formation by L. monocytogenes. C1 [Alonso, Almaris N.; Perry, Kyle J.; Regeimbal, James M.; Higgins, Darren E.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Alonso, Almaris N.; Regan, Patrick M.] US FDA, Winchester Engn & Analyt Ctr, Winchester, MA 01890 USA. RP Alonso, AN (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, 10903 New Hampshire Ave,Bldg 32,Rm 5160, Silver Spring, MD 20993 USA. EM Almaris.Alonso@fda.hhs.gov; dhiggins@hms.harvard.edu RI Luan, Gan/B-3211-2015 FU United States Public Health Service Grant from the National Institutes of Health [AI53669]; FDA Office of Regulatory Affairs, Division of Field Science FX This work was supported by United States Public Health Service Grant AI53669 from the National Institutes of Health (DEH) and has been funded in part by the FDA Office of Regulatory Affairs, Division of Field Science (ANA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 5 Z9 5 U1 0 U2 36 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 DEC 17 PY 2014 VL 9 IS 12 AR e113696 DI 10.1371/journal.pone.0113696 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AX9IA UT WOS:000347215600008 PM 25517120 ER PT J AU Yang, JY Dunker, AK Liu, JS Qin, X Arabnia, HR Yang, W Niemierko, A Chen, ZX Luo, ZJ Wang, LJ Liu, YL Xu, D Deng, YP Tong, WD Yang, MQ AF Yang, Jack Y. Dunker, A. Keith Liu, Jun S. Qin, Xiang Arabnia, Hamid R. Yang, William Niemierko, Andrzej Chen, Zhongxue Luo, Zuojie Wang, Liangjiang Liu, Yunlong Xu, Dong Deng, Youping Tong, Weida Yang, Mary Qu TI Advances in translational bioinformatics facilitate revealing the landscape of complex disease mechanisms SO BMC BIOINFORMATICS LA English DT Editorial Material AB Advances of high-throughput technologies have rapidly produced more and more data from DNAs and RNAs to proteins, especially large volumes of genome-scale data. However, connection of the genomic information to cellular functions and biological behaviours relies on the development of effective approaches at higher systems level. In particular, advances in RNA-Seq technology has helped the studies of transcriptome, RNA expressed from the genome, while systems biology on the other hand provides more comprehensive pictures, from which genes and proteins actively interact to lead to cellular behaviours and physiological phenotypes. As biological interactions mediate many biological processes that are essential for cellular function or disease development, it is important to systematically identify genomic information including genetic mutations from GWAS (genome-wide association study), differentially expressed genes, bidirectional promoters, intrinsic disordered proteins (IDP) and protein interactions to gain deep insights into the underlying mechanisms of gene regulations and networks. Furthermore, bidirectional promoters can co-regulate many biological pathways, where the roles of bidirectional promoters can be studied systematically for identifying co-regulating genes at interactive network level. Combining information from different but related studies can ultimately help revealing the landscape of molecular mechanisms underlying complex diseases such as cancer. C1 [Yang, Jack Y.] Univ Arkansas, George W Dougherty Coll Engn & Informat Technol, Joint Bioinformat PhD Program, Little Rock, AR 72204 USA. [Yang, Jack Y.] Univ Arkansas Med Sci, Little Rock, AR 72204 USA. [Yang, Jack Y.; Niemierko, Andrzej] Massachusetts Gen Hosp, Dept Radiat Oncol, Div Biostat & Biomath, Boston, MA 02114 USA. [Yang, Jack Y.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Dunker, A. Keith] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA. [Liu, Jun S.] Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. [Qin, Xiang] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Qin, Xiang] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Arabnia, Hamid R.] Univ Georgia, Dept Comp Sci, Athens, GA 30602 USA. [Yang, William] Univ Arkansas, George W Donaghey Coll Engn & Informat Technol, Dept Comp Sci, Little Rock, AR 72204 USA. [Chen, Zhongxue] Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN 47405 USA. [Luo, Zuojie] Guangxi Med Univ, Affiliated Hosp 1, Dept Endocrinol, Nanning 530021, Guangxi, Peoples R China. [Wang, Liangjiang] Clemson Univ, Dept Biochem & Genet, Clemson, SC 29634 USA. [Liu, Yunlong; Deng, Youping] Univ Missouri, Dept Comp Sci, Columbia, MO 65211 USA. [Xu, Dong] Rush Univ, Ctr Canc, Chicago, IL 60612 USA. [Xu, Dong] Rush Univ, Med Ctr, Dept Internal Med, Chicago, IL 60612 USA. [Xu, Dong] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA. [Tong, Weida] US FDA, Div Bioinformat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Tong, Weida] US FDA, Div Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Yang, Mary Qu] Univ Arkansas, George W Donaghey Coll Engn & Informat Technol, MidSouth Bioinformat Ctr, Dept Informat Sci, Little Rock, AR 72204 USA. [Yang, Mary Qu] Univ Arkansas, Joint Bioinformat Grad Program, Little Rock, AR 72204 USA. [Yang, Mary Qu] Univ Arkansas Med Sci, Little Rock, AR 72204 USA. RP Arabnia, HR (reprint author), Univ Georgia, Dept Comp Sci, Athens, GA 30602 USA. EM hra@uga.edu; youping_deng@rush.edu FU PHS HHS [NIH/NIGMS 5P20GM10342913, NIH/NHGRI 5U54HG003273-11] NR 6 TC 2 Z9 2 U1 0 U2 5 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 DEC 16 PY 2014 VL 15 SU 17 AR I1 DI 10.1186/1471-2105-15-S17-I1 PG 5 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA CH4AS UT WOS:000353973500001 PM 25559210 ER PT J AU Yang, W Yoshigoe, K Qin, X Liu, JS Yang, JY Niemierko, A Deng, YP Liu, YL Dunker, AK Chen, ZX Wang, LJ Xu, D Arabnia, HR Tong, WD Yang, MQ AF Yang, William Yoshigoe, Kenji Qin, Xiang Liu, Jun S. Yang, Jack Y. Niemierko, Andrzej Deng, Youping Liu, Yunlong Dunker, A. Keith Chen, Zhongxue Wang, Liangjiang Xu, Dong Arabnia, Hamid R. Tong, Weida Yang, Mary Qu TI Identification of genes and pathways involved in kidney renal clear cell carcinoma SO BMC BIOINFORMATICS LA English DT Article ID HISTONE DEMETHYLASE RBP2; CANCER; NEPHRECTOMY; METASTASIS; ACTIVATION; INFECTION; DISEASE AB Background: Kidney Renal Clear Cell Carcinoma (KIRC) is one of fatal genitourinary diseases and accounts for most malignant kidney tumours. KIRC has been shown resistance to radiotherapy and chemotherapy. Like many types of cancers, there is no curative treatment for metastatic KIRC. Using advanced sequencing technologies, The Cancer Genome Atlas (TCGA) project of NIH/NCI-NHGRI has produced large-scale sequencing data, which provide unprecedented opportunities to reveal new molecular mechanisms of cancer. We combined differentially expressed genes, pathways and network analyses to gain new insights into the underlying molecular mechanisms of the disease development. Results: Followed by the experimental design for obtaining significant genes and pathways, comprehensive analysis of 537 KIRC patients' sequencing data provided by TCGA was performed. Differentially expressed genes were obtained from the RNA-Seq data. Pathway and network analyses were performed. We identified 186 differentially expressed genes with significant p-value and large fold changes (P < 0.01, |log(FC)| > 5). The study not only confirmed a number of identified differentially expressed genes in literature reports, but also provided new findings. We performed hierarchical clustering analysis utilizing the whole genome-wide gene expressions and differentially expressed genes that were identified in this study. We revealed distinct groups of differentially expressed genes that can aid to the identification of subtypes of the cancer. The hierarchical clustering analysis based on gene expression profile and differentially expressed genes suggested four subtypes of the cancer. We found enriched distinct Gene Ontology (GO) terms associated with these groups of genes. Based on these findings, we built a support vector machine based supervised-learning classifier to predict unknown samples, and the classifier achieved high accuracy and robust classification results. In addition, we identified a number of pathways (P < 0.04) that were significantly influenced by the disease. We found that some of the identified pathways have been implicated in cancers from literatures, while others have not been reported in the cancer before. The network analysis leads to the identification of significantly disrupted pathways and associated genes involved in the disease development. Furthermore, this study can provide a viable alternative in identifying effective drug targets. Conclusions: Our study identified a set of differentially expressed genes and pathways in kidney renal clear cell carcinoma, and represents a comprehensive computational approach to analysis large-scale next-generation sequencing data. The pathway and network analyses suggested that information from distinctly expressed genes can be utilized in the identification of aberrant upstream regulators. Identification of distinctly expressed genes and altered pathways are important in effective biomarker identification for early cancer diagnosis and treatment planning. Combining differentially expressed genes with pathway and network analyses using intelligent computational approaches provide an unprecedented opportunity to identify upstream disease causal genes and effective drug targets. C1 [Yang, William; Yoshigoe, Kenji] Univ Arkansas, George W Donaghey Coll Engn & Informat Technol, Dept Comp Sci, Little Rock, AR 72204 USA. [Qin, Xiang] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Qin, Xiang] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Liu, Jun S.] Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. [Yang, Jack Y.; Niemierko, Andrzej] Massachusetts Gen Hosp, Dept Radiat Oncol, Div Biostat & Biomath, Boston, MA 02114 USA. [Yang, Jack Y.; Niemierko, Andrzej] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Deng, Youping] Rush Univ, Med Ctr, Ctr Canc, Chicago, IL 60612 USA. [Deng, Youping] Rush Univ, Med Ctr, Dept Internal Med, Chicago, IL 60612 USA. [Deng, Youping] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA. [Yang, Jack Y.; Liu, Yunlong; Dunker, A. Keith] Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA. [Chen, Zhongxue] Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN 47405 USA. [Wang, Liangjiang] Clemson Univ, Dept Biochem & Genet, Clemson, SC 29634 USA. [Xu, Dong] Univ Missouri, Dept Comp Sci, Columbia, MO 65211 USA. [Arabnia, Hamid R.] Univ Georgia, Dept Comp Sci, Athens, GA 30602 USA. [Tong, Weida] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Yang, Mary Qu] Univ Arkansas, George W Donaghey Coll Engn & Informat Technol, Dept Informat Sci, MidSouth Bioinformat Ctr, Little Rock, AR 72204 USA. [Yang, Mary Qu] Univ Arkansas, Joint Bioinformat Grad Program, Little Rock, AR 72204 USA. [Yang, Mary Qu] Univ Arkansas Med Sci, Little Rock, AR 72204 USA. RP Yang, MQ (reprint author), Univ Arkansas, George W Donaghey Coll Engn & Informat Technol, Dept Informat Sci, MidSouth Bioinformat Ctr, 2801 S Univ Ave, Little Rock, AR 72204 USA. EM mqyang@ualr.edu FU National Institutes of Health (NIH); Arkansas Science and Technology Authority (ASTA); National Science Foundation (NSF); NIH/NIGMS [5P20GM10342913]; ASTA [15-B-23]; NIH/NHGRI [5U54HG003273-11]; NSF [1359323, 1429160] FX The research was supported by the National Institutes of Health (NIH), Arkansas Science and Technology Authority (ASTA), and National Science Foundation (NSF). Specifically, MQY was supported by NIH/NIGMS 5P20GM10342913 and ASTA Award # 15-B-23. XQ was supported by NIH/NHGRI 5U54HG003273-11. KY and WY were supported by NSF Award # 1359323 and NSF Award # 1429160. NR 23 TC 14 Z9 14 U1 6 U2 15 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 DEC 16 PY 2014 VL 15 SU 17 AR S2 DI 10.1186/1471-2105-15-S17-S2 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA CH4AS UT WOS:000353973500003 PM 25559354 ER PT J AU Yu, K Zhang, J Chen, MJ Xu, XW Suzuki, A Ilic, K Tong, WD AF Yu, Ke Zhang, Jie Chen, Minjun Xu, Xiaowei Suzuki, Ayako Ilic, Katarina Tong, Weida TI Mining hidden knowledge for drug safety assessment: topic modeling of LiverTox as a case study SO BMC BIOINFORMATICS LA English DT Article ID FAILURE; DISEASE; INJURY; LABELS AB Background: Given the significant impact on public health and drug development, drug safety has been a focal point and research emphasis across multiple disciplines in addition to scientific investigation, including consumer advocates, drug developers and regulators. Such a concern and effort has led numerous databases with drug safety information available in the public domain and the majority of them contain substantial textual data. Text mining offers an opportunity to leverage the hidden knowledge within these textual data for the enhanced understanding of drug safety and thus improving public health. Methods: In this proof-of-concept study, topic modeling, an unsupervised text mining approach, was performed on the LiverTox database developed by National Institutes of Health (NIH). The LiverTox structured one document per drug that contains multiple sections summarizing clinical information on drug-induced liver injury (DILI). We hypothesized that these documents might contain specific textual patterns that could be used to address key DILI issues. We placed the study on drug-induced acute liver failure (ALF) which was a severe form of DILI with limited treatment options. Results: After topic modeling of the "Hepatotoxicity" sections of the LiverTox across 478 drug documents, we identified a hidden topic relevant to Hy's law that was a widely-accepted rule incriminating drugs with high risk of causing ALF in humans. Using this topic, a total of 127 drugs were further implicated, 77 of which had clear ALF relevant terms in the "Outcome and management" sections of the LiverTox. For the rest of 50 drugs, evidence supporting risk of ALF was found for 42 drugs from other public databases. Conclusion: In this case study, the knowledge buried in the textual data was extracted for identification of drugs with potential of causing ALF by applying topic modeling to the LiverTox database. The knowledge further guided identification of drugs with the similar potential and most of them could be verified and confirmed. This study highlights the utility of topic modeling to leverage information within textual drug safety databases, which provides new opportunities in the big data era to assess drug safety. C1 [Yu, Ke; Zhang, Jie; Chen, Minjun; Xu, Xiaowei; Tong, Weida] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Xu, Xiaowei] Univ Arkansas, Dept Informat Sci, Little Rock, AR 72204 USA. [Suzuki, Ayako] Univ Arkansas Med Sci, Div Gastroenterol, Little Rock, AR 72205 USA. [Ilic, Katarina] Univ Belgrade, Fac Pharm, Dept Pharmacol, Belgrade 11221, Serbia. RP Ilic, K (reprint author), Univ Belgrade, Fac Pharm, Dept Pharmacol, 450 Vojvode Stepe, Belgrade 11221, Serbia. EM katarina.v.ilic@gmail.com; weida.tong@fda.hhs.gov FU HHS/FDA/NCTR; National Center for Toxicological Research (NCTR) of U.S. Food and Drug Administration (FDA) through the Oak Ridge Institute for Science and Education (ORISE); ORISE; Ministry of Education and Science, Republic of Serbia [175064] FX This is research was funded by HHS/FDA/NCTR (to WT). We thank Reagan Kelly, Qiang Shi, Yuping Wang, and Hong Fang for comments and discussion. KY 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). KI worked during her summer sabbatical at NCTR, which was supported through ORISE and by the Ministry of Education and Science, Republic of Serbia (project 175064, 2011-2014). NR 21 TC 2 Z9 3 U1 3 U2 12 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 DEC 16 PY 2014 VL 15 SU 17 AR S6 DI 10.1186/1471-2105-15-S17-S6 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA CH4AS UT WOS:000353973500007 PM 25559675 ER PT J AU Yang, MQ Yoshigoe, K Yang, W Tong, WD Qin, X Dunker, AK Chen, ZX Arbania, HR Liu, JS Niemierko, A Yang, JY AF Yang, Mary Qu Yoshigoe, Kenji Yang, William Tong, Weida Qin, Xiang Dunker, A. Keith Chen, Zhongxue Arbania, Hamid R. Liu, Jun S. Niemierko, Andrzej Yang, Jack Y. TI The emerging genomics and systems biology research lead to systems genomics studies SO BMC GENOMICS LA English DT Article AB Synergistically integrating multi-layer genomic data at systems level not only can lead to deeper insights into the molecular mechanisms related to disease initiation and progression, but also can guide pathway-based biomarker and drug target identification. With the advent of high-throughput next-generation sequencing technologies, sequencing both DNA and RNA has generated multi-layer genomic data that can provide DNA polymorphism, non-coding RNA, messenger RNA, gene expression, isoform and alternative splicing information. Systems biology on the other hand studies complex biological systems, particularly systematic study of complex molecular interactions within specific cells or organisms. Genomics and molecular systems biology can be merged into the study of genomic profiles and implicated biological functions at cellular or organism level. The prospectively emerging field can be referred to as systems genomics or genomic systems biology. The Mid-South Bioinformatics Centre (MBC) and Joint Bioinformatics Ph.D. Program of University of Arkansas at Little Rock and University of Arkansas for Medical Sciences are particularly interested in promoting education and research advancement in this prospectively emerging field. Based on past investigations and research outcomes, MBC is further utilizing differential gene and isoform/exon expression from RNA-seq and co-regulation from the ChiP-seq specific for different phenotypes in combination with protein-protein interactions, and protein-DNA interactions to construct high-level gene networks for an integrative genome-phoneme investigation at systems biology level. C1 [Yang, Mary Qu] Univ Arkansas, George W Donaghey Coll Engn & Informat Technol, MidSouth Bioinformat Ctr, Dept Informat Sci, Little Rock, AR 72204 USA. [Yang, Mary Qu] Univ Arkansas, Joint Bioinformat Grad Program, Little Rock, AR 72204 USA. [Yang, Mary Qu] Univ Arkansas Med Sci, Little Rock, AR 72204 USA. [Yoshigoe, Kenji; Yang, William] Univ Arkansas, Dept Comp Sci, George W Donaghey Coll Engn & Informat Technol, Little Rock, AR 72204 USA. [Tong, Weida] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Qin, Xiang] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Qin, Xiang] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Dunker, A. Keith; Yang, Jack Y.] Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA. [Chen, Zhongxue] Indiana Univ, Sch Med, Dept Epidemiol & Biostat, Bloomington, IN 47405 USA. [Arbania, Hamid R.] Univ Georgia, Dept Comp Sci, Athens, GA 30602 USA. [Liu, Jun S.; Yang, Jack Y.] Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. [Niemierko, Andrzej] Massachusetts Gen Hosp, Dept Radiat Oncol, Div Biostat & Biomath, Boston, MA 02114 USA. [Niemierko, Andrzej] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Yang, MQ (reprint author), Univ Arkansas, George W Donaghey Coll Engn & Informat Technol, MidSouth Bioinformat Ctr, Dept Informat Sci, 2801 S Univ Ave, Little Rock, AR 72204 USA. EM mqyang@ualr.edu FU National Institutes of Health (NIH); Arkansas Science and Technology Authority (ASTA); National Science Foundation (NSF); NIH/NIGMS [5P20GM10342913]; ASTA [15-B-23]; NIH/NHGRI [5U54HG003273-11]; NSF [1359323, 1429160] FX The research at MBC was supported by the National Institutes of Health (NIH), Arkansas Science and Technology Authority (ASTA), and National Science Foundation (NSF). MQY was supported by NIH/NIGMS 5P20GM10342913 and ASTA Award # 15-B-23. XQ was supported by NIH/NHGRI 5U54HG003273-11. KY and WY were supported by NSF Award # 1359323 and NSF Award # 1429160. NR 4 TC 0 Z9 0 U1 2 U2 5 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 DEC 16 PY 2014 VL 15 SU 11 AR I1 DI 10.1186/1471-2164-15-S11-I1 PG 4 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CH4CE UT WOS:000353978200001 PM 25558922 ER PT J AU Newsome, GA Ackerman, LK Johnson, KJ AF Newsome, G. Asher Ackerman, Luke K. Johnson, Kevin J. TI Humidity Affects Relative Ion Abundance in Direct Analysis in Real Time Mass Spectrometry of Hexamethylene Triperoxide Diamine SO ANALYTICAL CHEMISTRY LA English DT Article ID DIELECTRIC BARRIER DISCHARGE; TEMPERATURE PLASMA PROBE; AMBIENT CONDITIONS; IONIZATION SOURCE; VAPOR-PRESSURES; HMTD AB Unstable explosive hexamethylene triperoxide diamine (HMTD) is dangerous in quantity and benefits from the minimal sampling handling associated with atmospheric pressure chemical ionization for mass spectral analysis. Seasonal variation observed in HMTD mass spectra suggested a humidity dependence. Therefore, direct analysis in real time (DART) ionization mass spectra were acquired at a range of humidity values. An enclosure was designed to fit around the ion source and mass spectrometer inlet at atmospheric pressure. The enclosure was supplied with controlled amounts of humidified air from a test atmosphere generator to create programmable conditions for ambient analysis. The relative abundance and fragmentation of analyte ions were observed to change reliably with changing humidity values and, to a lesser degree, temperature. Humidity at such plasma-based ion sources should be regulated to avoid similar to 90% shifts in relative ion abundance and provide stability and reproducibility of HMTD analysis. C1 [Newsome, G. Asher] Nova Res Inc, Alexandria, VA 22308 USA. [Ackerman, Luke K.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, Div Analyt Chem, College Pk, MD 20740 USA. [Johnson, Kevin J.] US Naval Res Lab, Naval Tech Ctr Safety & Survivabil, Washington, DC 20375 USA. RP Newsome, GA (reprint author), Nova Res Inc, 1900 Elkin St,Suite 230, Alexandria, VA 22308 USA. EM graham.newsome.ctr@nrl.navy.mil RI Newsome, G. Asher/J-8970-2012; Ackerman, Luke/E-4597-2011 OI Newsome, G. Asher/0000-0003-1683-2197; Ackerman, Luke/0000-0001-6626-3039 FU Office of Naval Research (ONR) through the Naval Research Laboratory's Basic Research Program FX The authors wish to thank Michael Malito of Nova Research, Inc., for assistance with designing the source enclosure and Lauryn DeGreeff-Silk of the Naval Research Laboratory for preparing the HMTD solution. Funding for this project was provided by the Office of Naval Research (ONR) through the Naval Research Laboratory's Basic Research Program. NR 25 TC 6 Z9 6 U1 4 U2 39 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 DEC 16 PY 2014 VL 86 IS 24 BP 11977 EP 11980 DI 10.1021/ac503652x PG 4 WC Chemistry, Analytical SC Chemistry GA AX1BR UT WOS:000346683900011 PM 25419648 ER PT J AU Beigi, RH Fortner, KB Munoz, FM Roberts, J Gordon, JL Han, HH Glenn, G Dormitzer, PR Gu, XX Read, JS Edwards, K Patel, SM Swamy, GK AF Beigi, Richard H. Fortner, Kimberly B. Munoz, Flor M. Roberts, Jeff Gordon, Jennifer L. Han, Htay Htay Glenn, Greg Dormitzer, Philip R. Gu, Xing Xing Read, Jennifer S. Edwards, Kathryn Patel, Shital M. Swamy, Geeta K. TI Maternal Immunization: Opportunities for Scientific Advancement SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE maternal; immunization; vaccines; pregnancy; research ID PREGNANT-WOMEN; INFLUENZA IMMUNIZATION; DEVELOPING-COUNTRIES; TETANUS-DIPHTHERIA; ANTIBODY-RESPONSE; IMMUNE-RESPONSE; BREAST-MILK; VACCINE; INFANTS; MOTHERS AB Maternal immunization is an effective strategy to prevent and/or minimize the severity of infectious diseases in pregnant women and their infants. Based on the success of vaccination programs to prevent maternal and neonatal tetanus, maternal immunization has been well received in the United States and globally as a promising strategy for the prevention of other vaccine-preventable diseases that threaten pregnant women and infants, such as influenza and pertussis. Given the promise for reducing the burden of infectious conditions of perinatal significance through the development of vaccines against relevant pathogens, the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) sponsored a series of meetings to foster progress toward clinical development of vaccines for use in pregnancy. A multidisciplinary group of stakeholders convened at the NIH in December 2013 to identify potential barriers and opportunities for scientific advancement in maternal immunization. C1 [Beigi, Richard H.] Univ Pittsburgh, Med Ctr, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15260 USA. [Fortner, Kimberly B.] Vanderbilt Univ, Dept Obstet & Gynecol, Nashville, TN 37235 USA. [Munoz, Flor M.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Munoz, Flor M.; Patel, Shital M.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Roberts, Jeff] US FDA, Ctr Biol Evaluat & Res, Off Vaccines Res & Review, Silver Spring, MD USA. [Gordon, Jennifer L.] US Dept HHS, Natl Vaccine Program Off, Off Assistant Secretary Hlth, Washington, DC 20201 USA. [Han, Htay Htay] GlaxoSmithKline Vaccines, King Of Prussia, PA USA. [Glenn, Greg] Novavax Inc, Gaithersburg, MD USA. [Dormitzer, Philip R.] Novartis Vaccines & Diagnost Inc, Cambridge, MA USA. [Gu, Xing Xing; Read, Jennifer S.] NIAID, NIH, Bethesda, MD 20892 USA. [Edwards, Kathryn] Vanderbilt Univ, Dept Pediat, Vanderbilt Vaccine Res Program, Nashville, TN USA. [Patel, Shital M.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Swamy, Geeta K.] Duke Univ, Dept Obstet & Gynecol, Durham, NC USA. RP Beigi, RH (reprint author), UPMC, Magee Womens Hosp, Dept Ob Gyn RS, 300 Halket St, Pittsburgh, PA 15213 USA. EM rbeigi@magee.edu FU Bill & Melinda Gates Foundation FX This article appears as part of the supplement "Including Pregnant Women in Clinical Trials of Antimicrobials and Vaccines," sponsored by the Bill & Melinda Gates Foundation. NR 53 TC 7 Z9 7 U1 1 U2 14 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 DEC 15 PY 2014 VL 59 SU 7 BP S408 EP S414 DI 10.1093/cid/ciu708 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AU9LB UT WOS:000345913100003 PM 25425719 ER PT J AU Gruber, MF AF Gruber, Marion F. TI Global and National Initiatives to Facilitate Studies of Vaccines in Pregnant Women SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE vaccines; pregnancy; maternal immunization; pregnancy labeling ID INFLUENZA IMMUNIZATION C1 [Gruber, Marion F.] US Dept HHS, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, US FDA, Silver Spring, MD 20993 USA. RP Gruber, MF (reprint author), US Dept HHS, 10903 New Hampshire Ave,Bldg 71,Rm 3230, Silver Spring, MD 20993 USA. EM marion.gruber@fda.hhs.gov FU Bill & Melinda Gates Foundation FX This article appears as part of the supplement "Including Pregnant Women in Clinical Trials of Antimicrobials and Vaccines," sponsored by the Bill & Melinda Gates Foundation. NR 29 TC 3 Z9 3 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2014 VL 59 SU 7 BP S395 EP S399 DI 10.1093/cid/ciu707 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AU9LB UT WOS:000345913100001 PM 25425717 ER PT J AU Rasmussen, SA Hernandez-Diaz, S Abdul-Rahman, OA Sahin, L Petrie, CR Keppler-Noreuil, KM Frey, SE Mason, RM Nesin, M Carey, JC AF Rasmussen, Sonja A. Hernandez-Diaz, Sonia Abdul-Rahman, Omar A. Sahin, Leyla Petrie, Carey R. Keppler-Noreuil, Kim M. Frey, Sharon E. Mason, Robin M. Nesin, Mirjana Carey, John C. TI Assessment of Congenital Anomalies in Infants Born to Pregnant Women Enrolled in Clinical Trials SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE congenital anomalies; birth defects; clinical trials; pregnant women ID MORPHOLOGY STANDARD TERMINOLOGY; FETAL ALCOHOL SYNDROME; BIRTH-DEFECTS; POSTMARKETING SURVEILLANCE; MAJOR MALFORMATIONS; EXCLUSION CRITERIA; TERATOGEN UPDATE; PREDICTIVE VALUE; NEWBORN-INFANTS; MINOR ANOMALIES AB In 2011 and 2012, the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, held a series of meetings to provide guidance to investigators regarding study design of clinical trials of vaccines and antimicrobial medications that enroll pregnant women. Assessment of congenital anomalies among infants born to women enrolled in these trials was recognized as a challenging issue, and a workgroup with expertise in epidemiology, pediatrics, genetics, dysmorphology, clinical trials, and infectious diseases was formed to address this issue. The workgroup considered 3 approaches for congenital anomalies assessment that have been developed for use in other studies: (1) maternal report combined with medical records review, (2) standardized photographic assessment and physical examination by a health professional who has received specific training in congenital anomalies, and (3) standardized physical examination by a trained dysmorphologist (combined with maternal interview and medical records review). The strengths and limitations of these approaches were discussed with regard to their use in clinical trials. None of the approaches was deemed appropriate for use in all clinical trials. Instead, the workgroup acknowledged that decisions regarding the optimal method of assessment of congenital anomalies will likely vary depending on the clinical trial, its setting, and the agent under study; in some cases, a combination of approaches may be appropriate. The workgroup recognized the need for more research on approaches to the assessment of congenital anomalies to better guide investigators in optimal design of clinical trials that enroll pregnant women. C1 [Rasmussen, Sonja A.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Hernandez-Diaz, Sonia] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Abdul-Rahman, Omar A.] Univ Mississippi, Med Ctr, University, MS 38677 USA. [Sahin, Leyla] US FDA, Silver Spring, MD USA. [Petrie, Carey R.] EMMES Corp, Rockville, MD USA. [Keppler-Noreuil, Kim M.; Mason, Robin M.; Nesin, Mirjana] NIH, Bethesda, MD 20892 USA. [Frey, Sharon E.] St Louis Univ, Sch Med, St Louis, MO 63103 USA. [Carey, John C.] Univ Utah, Sch Med, Salt Lake City, UT USA. RP Rasmussen, SA (reprint author), CDC, 1600 Clifton Rd,MS A-28, Atlanta, GA 30333 USA. EM skr9@cdc.gov FU NIAID (HHS) [HHSN272200800013C] FX C. R. P.'s work on the article was supported by NIAID contract (HHS contract HHSN272200800013C). NR 40 TC 1 Z9 1 U1 1 U2 12 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 DEC 15 PY 2014 VL 59 SU 7 BP S428 EP S436 DI 10.1093/cid/ciu738 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AU9LB UT WOS:000345913100005 PM 25425721 ER PT J AU Sheffield, JS Siegel, D Mirochnick, M Heine, RP Nguyen, C Bergman, KL Savic, RM Long, J Dooley, KE Nesin, M AF Sheffield, Jeanne S. Siegel, David Mirochnick, Mark Heine, R. Phillips Nguyen, Christine Bergman, Kimberly L. Savic, Rada M. Long, Jill Dooley, Kelly E. Nesin, Mirjana TI Designing Drug Trials: Considerations for Pregnant Women SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE pregnancy; drug trials; pharmacokinetics ID MEDICATIONS AB Clinical pharmacology studies that describe the pharmacokinetics and pharmacodynamics of drugs in pregnant women are critical for informing on the safe and effective use of drugs during pregnancy. That being said, multiple factors have hindered the ability to study drugs in pregnant patients. These include concerns for maternal and fetal safety, ethical considerations, the difficulty in designing appropriate trials to assess the study objectives, and funding limitations. This document summarizes the recommendations of a panel of experts convened by the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. These experts were charged with reviewing the issues related to the development of preclinical and clinical drug studies in pregnant women and to develop strategies for addressing these issues. These findings may also be utilized in the development of future drug studies involving pregnant women and their fetus/neonate. C1 [Sheffield, Jeanne S.] Univ Texas SW Med Ctr Dallas, Div Maternal Fetal Med, Dallas, TX 75390 USA. [Siegel, David] NICHHD, NIH, Bethesda, MD 20892 USA. [Mirochnick, Mark] Boston Univ, Div Neonatol, Boston, MA 02215 USA. [Heine, R. Phillips] Duke Univ, Div Maternal Fetal Med, Durham, NC USA. [Nguyen, Christine] Ctr Drug Evaluat & Res, Div Bone Reprod & Urol Prod, Off Drug Evaluat 3, Silver Spring, MD USA. [Bergman, Kimberly L.] US FDA, Off Clin Pharmacol, Off Translat Sci, Silver Spring, MD USA. [Savic, Rada M.] Univ Calif San Francisco, Dept Bioengn, San Francisco, CA 94143 USA. [Long, Jill; Nesin, Mirjana] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. [Dooley, Kelly E.] Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. RP Sheffield, JS (reprint author), 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM jeanne.sheffield@utsouthwestern.edu FU Bill & Melinda Gates Foundation; Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This article was supported by an unrestricted grant from the Bill & Melinda Gates Foundation and the Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 17 TC 6 Z9 6 U1 0 U2 8 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 DEC 15 PY 2014 VL 59 SU 7 BP S437 EP S444 DI 10.1093/cid/ciu709 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AU9LB UT WOS:000345913100006 PM 25425722 ER PT J AU Couzens, L Gao, J Westgeest, K Sandbulte, M Lugovtsev, V Fouchier, R Eichelberger, M AF Couzens, Laura Gao, Jin Westgeest, Kim Sandbulte, Matthew Lugovtsev, Vladimir Fouchier, Ron Eichelberger, Maryna TI An optimized enzyme-linked lectin assay to measure influenza A virus neuraminidase inhibition antibody titers in human sera SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE Influenza; Neuraminidase; Enzyme-linked lectin assay; Serology; Antibody ID ANTIGENIC-COMPETITION; HEMAGGLUTININ; RESISTANCE; VACCINE AB Antibodies to neuraminidase (NA), the second most abundant surface protein on influenza virus, contribute toward protection against influenza. The traditional thiobarbituric acid (TBA) method to quantify NA inhibiting antibodies is cumbersome and not suitable for routine serology. An enzyme-linked lectin assay (ELLA) described by Lambre et al. (1990) is a practical alternative method for measuring NA inhibition (NI) titers. This report describes optimization of the ELLA for measuring NI titers in human sera against influenza A viruses, using H6N1 and H6N2 viruses as antigens. The optimized ELLA is subtype-specific and reproducible. While the titers measured by ELLA are somewhat greater than those measured by a miniaturized TBA method, seroconversion rates are the same, suggesting similarity in assay sensitivity under these optimized conditions. The ELLA described in this report provides a practical format for routine evaluation of human antibody responses to NA. Published by Elsevier B.V. C1 [Couzens, Laura; Gao, Jin; Sandbulte, Matthew; Lugovtsev, Vladimir; Eichelberger, Maryna] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Westgeest, Kim; Fouchier, Ron] Erasmus MC, Dept Virosci, NL-3000 CA Rotterdam, Netherlands. RP Eichelberger, M (reprint author), 10903 New Hampshire Ave,Bldg 72,Room 1328,HFM445, Silver Spring, MD 20993 USA. EM Laura.Couzens@fda.hhs.gov; Jin.Gao@fda.hhs.gov; k.westgeest@erasmusmc.nl; sandbult@iastate.edu; Vladimir.Lugovtsev@fda.hhs.gov; r.fouchier@erasmusmc.nl; Maiyna.Eichelberger@fda.hhs.gov RI Fouchier, Ron/A-1911-2014 OI Fouchier, Ron/0000-0001-8095-2869 FU intramural PanFlu funds (CBER); ORISE; NOW VICI grant [91896613] FX This project was funded by intramural PanFlu funds (CBER); LC was supported by funds administered through an ORISE training fecllowship; KW was supported by NOW VICI grant 91896613 (awarded to RAMF). We are indebted to Miranda de Graaf, Wei Wang and Freya Lynn for critical reading of the manuscript, and Lev Sirota for guidance in statistical analysis. NR 26 TC 19 Z9 19 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 EI 1879-0984 J9 J VIROL METHODS JI J. Virol. Methods PD DEC 15 PY 2014 VL 210 BP 7 EP 14 DI 10.1016/j.jviromet.2014.09.003 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA AU2ZK UT WOS:000345482700002 PM 25233882 ER PT J AU Holland, RD Wilkes, JG Cooper, WM Alusta, P Williams, A Pearce, B Beaudoin, M Buzatu, D AF Holland, Ricky D. Wilkes, Jon G. Cooper, Willie M. Alusta, Pierre Williams, Anna Pearce, Bruce Beaudoin, Michael Buzatu, Dan TI Thymol treatment of bacteria prior to matrix-assisted laser desorption/ionization time-of-flight mass spectrometric analysis aids in identifying certain bacteria at the subspecies level SO RAPID COMMUNICATIONS IN MASS SPECTROMETRY LA English DT Article ID DESORPTION IONIZATION-TIME; PROBE SAMPLE PRETREATMENT; RAPID IDENTIFICATION; WHOLE CELLS; PROTEINS; SPECTRA; MALDI; OIL; KDA AB RATIONALE: The identification of bacteria based on mass spectra produced by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) has become routine since its introduction in 1996. The major drawback is that bacterial patterns produced by MALDI are dependent on sample preparation prior to analysis. This results in poor reproducibility in identifying bacterial types and between laboratories. The need for a more broadly applicable and useful sample handling procedure is warranted. METHODS: Thymol was added to the suspension solvent of bacteria prior to MALDI analysis. The suspension solvent consisted of ethanol, water and TFA. The bacterium was added to the thymol suspension solvent and heated. An aliquot of the bacterial suspension was mixed directly with the matrix solution at a 9: 1 ratio, matrix/bacteria solution, respectively. The mixture was then placed on the MALDI plate and allowed to air dry before MALDI analysis. RESULTS: The thymol method improved the quality of spectra and number of peaks when compared to other sample preparation procedures studied. The bacterium-identifying biomarkers assigned to four strains of E. coli were statistically 95% reproducible analyzed on three separate days. The thymol method successfully differentiated between the four E. coli strains. In addition, the thymol procedure could identify nine out of ten S. enterica serovars over a 3-day period and nine S. Typhimurium strains from the other ten serovars 90% of the time over the same period. CONCLUSIONS: The thymol method can identify certain bacteria at the sub-species level and yield reproducible results over time. It improves the quality of spectra by increasing the number of peaks when compared to the other sample preparation methods assessed in this study. Published in 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Holland, Ricky D.; Wilkes, Jon G.; Cooper, Willie M.; Alusta, Pierre; Williams, Anna; Pearce, Bruce; Buzatu, Dan] US FDA, Div Syst Biol, Innovat Safety & Technol Branch, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Beaudoin, Michael] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Holland, RD (reprint author), US FDA, Div Syst Biol, Innovat Safety & Technol Branch, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM ricky.holland@fda.hhs.gov NR 26 TC 3 Z9 3 U1 1 U2 11 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 DEC 15 PY 2014 VL 28 IS 23 BP 2617 EP 2626 DI 10.1002/rcm.7060 PG 10 WC Biochemical Research Methods; Chemistry, Analytical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA AT0HH UT WOS:000344617100014 PM 25366408 ER PT J AU McClenahan, SD Uhlenhaut, C Krause, PR AF McClenahan, Shasta D. Uhlenhaut, Christine Krause, Philip R. TI Evaluation of cells and biological reagents for adventitious agents using degenerate primer PCR and massively parallel sequencing SO VACCINE LA English DT Article DE Cell substrate; Adventitious agent; Virus; Degenerate PCR; Massively parallel sequencing (MPS) ID VIRUS DETECTION; CANINE GENOME; LINE; IDENTIFICATION; PLATFORM; SAMPLES AB We employed a massively parallel sequencing (MPS)-based approach to test reagents and model cell substrates including Chinese hamster ovary (CHO), Madin-Darby canine kidney (MDCK), African green monkey kidney (Vero), and High Five insect cell lines for adventitious agents. RNA and DNA were extracted either directly from the samples or from viral capsid-enriched preparations, and then subjected to MPS-based non-specific virus detection with degenerate oligonucleotide primer (DOP) PCR. MPS by 454, Illumina MiSeq, and Illumina HiSeq was compared on independent samples. Virus detection using these methods was reproducibly achieved. Unclassified sequences from CHO cells represented cellular sequences not yet submitted to the databases typically used for sequence identification. The sensitivity of MPS-based virus detection was consistent with theoretically expected limits based on dilution of virus in cellular nucleic acids. Capsid preparation increased the number of viral sequences detected. Potential viral sequences were detected in several samples; in each case, these sequences were either artifactual or (based on additional studies) shown not to be associated with replication-competent viruses. Virus-like sequences were more likely to be identified in BLAST searches using virus-specific databases that did not contain cellular sequences. Detected viral sequences included previously described retrovirus and retrovirus-like sequences in CHO, Vero, MDCK and High Five cells, and nodavirus and endogenous bracovirus sequences in High Five insect cells. Bovine viral diarrhea virus, bovine hokovirus, and porcine circovirus sequences were detected in some reagents. A recently described parvo-like virus present in some nucleic acid extraction resins was also identified in cells and extraction controls from some samples. The present study helps to illustrate the potential for MPS-based strategies in evaluating the presence of viral nucleic acids in various sample types, including cell culture substrates and vaccines. (C) 2014 Published by Elsevier Ltd. C1 [McClenahan, Shasta D.; Krause, Philip R.] Ctr Biol Evaluat & Res Food & Drug Adm, Silver Spring, MD 20993 USA. [Uhlenhaut, Christine] Robert Koch Inst, Ctr Biol Threats & Special Pathogens, Berlin, Germany. RP Krause, PR (reprint author), Ctr Biol Evaluat & Res Food & Drug Adm, Silver Spring, MD 20993 USA. EM Philip.krause@fda.hhs.gov OI Krause, Philip/0000-0002-1045-7536 FU FDA FX The authors have no financial or personal relationships that influenced this research. Funding was provided by FDA. NR 37 TC 4 Z9 4 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 DEC 12 PY 2014 VL 32 IS 52 BP 7115 EP 7121 DI 10.1016/j.vaccine.2014.10.022 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AZ1TI UT WOS:000348020200015 PM 25454874 ER PT J AU Li, M He, WW Liu, Y Wu, HH Wamer, WG Lo, YM Yin, JJ AF Li, Meng He, Weiwei Liu, Yi Wu, Haohao Wamer, Wayne G. Lo, Y. Martin Yin, Jun-Jie TI FD&C Yellow No. 5 (Tartrazine) Degradation via Reactive Oxygen Species Triggered by TiO2 and Au/TiO2 Nanoparticles Exposed to Simulated Sunlight SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE TiO2 nanoparticles; ROS; ED&C Yellow No. 5; ESR; color degradation; tartrazine ID SINGLET MOLECULAR-OXYGEN; ELECTRON-SPIN-RESONANCE; TITANIUM-DIOXIDE; PHOTOCATALYTIC DEGRADATION; DYE-TARTRAZINE; AZO DYES; FOOD; GENERATION; PHOTODEGRADATION; PARTICLES AB When exposed to light, TiO2 nanoparticles (NPs) become photoactivated and create electron/hole pairs as well as reactive oxygen species (ROS). We examined the ROS production and degradation of a widely used azo dye, FD&C Yellow No. 5 (tartrazine), triggered by photoactivated TiO2 NPs. Degradation was found to follow pseudo-first order reaction kinetics where the rate constant increased with TiO2 NP concentration. Depositing Au on the surface of TiO2 largely enhanced electron transfer and ROS generation, which consequently accelerated dye degradation. Alkaline conditions promoted ROS generation and dye degradation. Results from electron spin resonance spin-trap spectroscopy suggested that at pH 7.4, both hydroxyl radical (center dot OH) and singlet oxygen (O-1(2)) were responsible for dye discoloration, whereas at pH 5, the consumption of O-1(2) became dominant. Implications for dye degradation in foods and other consumer products that contain both TiO2 and FD&C Yellow No. 5 as ingredients are discussed. C1 [Li, Meng; He, Weiwei; Liu, Yi; Wu, Haohao; Yin, Jun-Jie] US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Wamer, Wayne G.] US FDA, Div Bioanalyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Li, Meng; Wu, Haohao; Lo, Y. Martin] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. RP Yin, JJ (reprint author), US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM junjie.yin@fda.hhs.gov RI Yin, Jun Jie /E-5619-2014 FU FDA Nanotechnology CORES Program; Office of Cosmetics and Colors, CFSAN/FDA; National Natural Science, Foundation of China [21303153]; Program for Science and Technology Innovation Talents in Universities of Henan Province [14HASTIT008] FX 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. appreciates the support from the National Natural Science, Foundation of China (Grant No. 21303153) and the Program for Science and Technology Innovation Talents in Universities of Henan Province (Grant No. 14HASTIT008). NR 41 TC 5 Z9 5 U1 6 U2 39 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 DEC 10 PY 2014 VL 62 IS 49 BP 12052 EP 12060 DI 10.1021/jf5045052 PG 9 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA AW5NJ UT WOS:000346321400033 PM 25393426 ER PT J AU McGarvey, PB Suzek, BE Baraniuk, JN Rao, S Conkright, B Lababidi, S Sutherland, A Forshee, R Madhavan, S AF McGarvey, Peter B. Suzek, Baris E. Baraniuk, James N. Rao, Shruti Conkright, Brian Lababidi, Samir Sutherland, Andrea Forshee, Richard Madhavan, Subha TI In silico analysis of autoimmune diseases and genetic relationships to vaccination against infectious diseases SO BMC IMMUNOLOGY LA English DT Article ID GUILLAIN-BARRE-SYNDROME; INFLUENZA-VIRUS INFECTION; DATA INTEGRATION; SMALL MOLECULES; PROTEIN; DATABASE; PATHWAY; IMMUNE; CELLS; ASSOCIATION AB Background: Near universal administration of vaccines mandates intense pharmacovigilance for vaccine safety and a stringently low tolerance for adverse events. Reports of autoimmune diseases (AID) following vaccination have been challenging to evaluate given the high rates of vaccination, background incidence of autoimmunity, and low incidence and variable times for onset of AID after vaccinations. In order to identify biologically plausible pathways to adverse autoimmune events of vaccine-related AID, we used a systems biology approach to create a matrix of innate and adaptive immune mechanisms active in specific diseases, responses to vaccine antigens, adjuvants, preservatives and stabilizers, for the most common vaccine-associated AID found in the Vaccine Adverse Event Reporting System. Results: This report focuses on Guillain-Barre Syndrome (GBS), Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), and Idiopathic (or immune) Thrombocytopenic Purpura (ITP). Multiple curated databases and automated text mining of PubMed literature identified 667 genes associated with RA, 448 with SLE, 49 with ITP and 73 with GBS. While all data sources provided valuable and unique gene associations, text mining using natural language processing (NLP) algorithms provided the most information but required curation to remove incorrect associations. Six genes were associated with all four AIDs. Thirty-three pathways were shared by the four AIDs. Classification of genes into twelve immune system related categories identified more "Th17T-cell subtype" genes in RA than the other AIDs, and more "Chemokine plus Receptors" genes associated with RA than SLE. Gene networks were visualized and clustered into interconnected modules with specific gene clusters for each AID, including one in RA with ten C-X-C motif chemokines. The intersection of genes associated with GBS, GBS peptide auto-antigens, influenza A infection, and influenza vaccination created a subnetwork of genes that inferred a possible role for the MAPK signaling pathway in influenza vaccine related GBS. Conclusions: Results showing unique and common gene sets, pathways, immune system categories and functional clusters of genes in four autoimmune diseases suggest it is possible to develop molecular classifications of autoimmune and inflammatory events. Combining this information with cellular and other disease responses should greatly aid in the assessment of potential immune- mediated adverse events following vaccination. C1 [McGarvey, Peter B.; Suzek, Baris E.; Rao, Shruti; Conkright, Brian; Madhavan, Subha] Georgetown Univ, Med Ctr, Innovat Ctr Biomed Informat, Washington, DC 20007 USA. [McGarvey, Peter B.; Suzek, Baris E.] Georgetown Univ, Med Ctr, Dept Biochem & Mol & Cellular Biol, Washington, DC 20007 USA. [Baraniuk, James N.] Georgetown Univ, Med Ctr, Dept Med, Div Rheumatol Immunol & Allergy, Washington, DC 20007 USA. [Lababidi, Samir; Sutherland, Andrea; Forshee, Richard] US FDA, Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, Silver Spring, MD 20993 USA. [Sutherland, Andrea] Johns Hopkins Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. [Suzek, Baris E.] Mugla Sitki Kocman Univ, Dept Comp Engn, Mugla, Turkey. RP McGarvey, PB (reprint author), Georgetown Univ, Med Ctr, Innovat Ctr Biomed Informat, 2115 Wisconsin Ave NW,Suite 110, Washington, DC 20007 USA. EM pbm9@georgetown.edu RI Suzek, Baris/K-3163-2014 OI Suzek, Baris/0000-0002-1521-4306 FU FDA though the CERSI (Centers in Excellence in Regulatory Sciences) program [1U01FD004319-01] FX We thank Simina Boca for advice on the statistical analysis. This work was partly funded by the FDA though the CERSI (Centers in Excellence in Regulatory Sciences) program 1U01FD004319-01. NR 67 TC 7 Z9 7 U1 0 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD DEC 9 PY 2014 VL 15 AR 61 DI 10.1186/s12865-014-0061-0 PG 12 WC Immunology SC Immunology GA AX0ZA UT WOS:000346677200002 PM 25486901 ER PT J AU Kang, KA Wang, JT AF Kang, Kyung Aih Wang, Jianting TI Conditionally activating optical contrast agent with enhanced sensitivity via gold nanoparticle plasmon energy transfer: feasibility study SO JOURNAL OF NANOBIOTECHNOLOGY LA English DT Article DE Optical contrast agent; Fluorescence enhancement; Fluorescence quenching; Gold nanoparticle; Molecular imaging; NanoPPET ID FLUORESCENCE; DEPENDENCE; DISTANCE; NANOBEACONS; PARTICLES; UROKINASE; CELLS AB Background: Molecular sensing/imaging utilizing fluorophores has been one of the most frequently used techniques in biomedical research. As for any molecular imaging techniques, fluorescence mediated sensing always seeks for greater specificity and sensitivity. Since fluorophores emit fluorescence while their electron energy state changes, manipulating the local electromagnetic field around the fluorophores may be a way to enhance the specificity and sensitivity. Gold nanoparticles (GNPs) are known to form a very strong electromagnetic field on their surface [i.e., surface plasmon field (SPF)], upon receiving photonic energy. The level of fluorescence change by GNP-SPF may range from complete quenching to extensive enhancement, depending upon the SPF strength, excitation and emission wavelengths, and quantum yield of the fluorophore. Method: Here, we report a novel design that utilizes BOTH fluorescence quenching and enhancement abilities of the GNP in one single nano-entity, providing high specificity and sensitivity. The construct utilizes a specially designed molecular dual-spacer that places the fluorphore at the location with an appropriate GNP-SFP strength before and after exposed to the biomarker. A model system to test the concept was an optical signal mediator activated by urokinase-type plasminogen activator (uPA; breast cancer secreting enzyme). Results: The resulting contrast agent shows less than 10% of the natural fluorescence but, in the presence of uPA, its fluorescence emission is triggered and emits its fluorescence approximately twice of the natural form. Conclusion: This study demonstrated that our novel design of an optical contrast agent can be conditionally activated with enhanced sensitivity, using both quenching and enhancement phenomena of fluorophores in the electromagnetic field of the appropriate strengths (in this case, locally generated by the GNP-SPF). This entity is similar to molecular beacon in terms of specificity but with greater sensitivity. In addition, it is not restricted to only DNA or RNA sensing but for any designs that cause the change in the distance between the fluorophore and GNP, upon the time of encountering biomarker of interest. C1 [Kang, Kyung Aih; Wang, Jianting] Univ Louisville, Dept Chem Engn, Louisville, KY 40292 USA. [Wang, Jianting] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Kang, KA (reprint author), Univ Louisville, Dept Chem Engn, Louisville, KY 40292 USA. EM kyung.kang@louisville.edu FU U.S. Army (DOD) Breast Cancer Program [BC074387]; Institute for Molecular Diversity and Drug Design (IMD3) for the Spatola Endowment Graduate Research Fellowship Award FX The authors acknowledge the U.S. Army (DOD) Breast Cancer Program (BC074387) for the financial support. The authors also would like to acknowledge the support from the Institute for Molecular Diversity and Drug Design (IMD3) for the Spatola Endowment Graduate Research Fellowship Award. NR 36 TC 2 Z9 2 U1 5 U2 24 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-3155 J9 J NANOBIOTECHNOL JI J. Nanobiotechnol. PD DEC 7 PY 2014 VL 12 AR 56 DI 10.1186/s12951-014-0056-2 PG 9 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA AW7IB UT WOS:000346436700001 PM 25481683 ER PT J AU Lei, HY Li, TW Tsai, S Biggar, RJ Nkrumah, F Neequayee, J Gutierrez, M Epelman, S Lo, SC Mbulaiteye, SM Bhatia, K AF Lei, Haiyan Li, Tianwei Tsai, Shien Biggar, Robert J. Nkrumah, Francis Neequayee, Janet Gutierrez, Marina Epelman, Sidnei Lo, Shyh-Ching Mbulaiteye, Sam M. Bhatia, Kishor TI Whole Genome Sequences of Epstein-Barr Viruses Associated with Burkitt Lymphoma Tissues SO BLOOD LA English DT Meeting Abstract C1 [Lei, Haiyan; Li, Tianwei; Tsai, Shien; Lo, Shyh-Ching] US FDA, Bethesda, MD 20014 USA. [Biggar, Robert J.] Queensland Univ Technol, Brisbane, Qld 4001, Australia. [Nkrumah, Francis] Noguchi Mem Inst, Accra, Ghana. [Neequayee, Janet] Univ Ghana, Accra, Ghana. [Gutierrez, Marina] Lab Stamboulian, Buenos Aires, DF, Argentina. [Epelman, Sidnei] St Marcelina Hosp, Sao Paulo, Brazil. [Mbulaiteye, Sam M.; Bhatia, Kishor] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD DEC 6 PY 2014 VL 124 IS 21 PG 3 WC Hematology SC Hematology GA CA9KQ UT WOS:000349242706051 ER PT J AU Kane, RC Xu, Q Sridhara, R Earp, J AF Kane, Robert C. Xu, Qing Sridhara, Rajeshwari Earp, Justin TI Poor ESA Responders As Defined By Week 4 Hemoglobin Response Have Greater ESA Dosing but Worse Cardiovascular Outcomes in Patients with Anemia of Chronic Kidney Disease (CKD) Not on Dialysis SO BLOOD LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Society-of-Hematology CY DEC 06-09, 2014 CL San Francisco, CA SP Amer Soc Hematol C1 [Kane, Robert C.; Xu, Qing; Sridhara, Rajeshwari; Earp, Justin] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD DEC 6 PY 2014 VL 124 IS 21 PG 3 WC Hematology SC Hematology GA CA9KX UT WOS:000349243506079 ER PT J AU Karnaukhova, E Rutardottir, S Rajabi, M Rosenlof, LW Alayash, AI Akerstrom, B AF Karnaukhova, Elena Rutardottir, Sigurbjorg Rajabi, Mohsen Rosenlof, Lena Wester Alayash, Abdu I. Akerstrom, Bo TI Characterization of heme binding to recombinant alpha(1)-microglobulin SO FRONTIERS IN PHYSIOLOGY LA English DT Article DE alpha-1-microglobulin; heme binding; surface plasmon resonance; circular dichroism ID SURFACE-PLASMON RESONANCE; HUMAN SERUM-ALBUMIN; LIPOCALIN ALPHA(1)-MICROGLOBULIN; CIRCULAR-DICHROISM; COVALENT IMMOBILIZATION; TAGGED PROTEINS; LIGAND-BINDING; HEMOGLOBIN; MECHANISMS; ACID AB Background: Alpha-1-microglobulin (A1M), a small lipocalin protein found in plasma and tissues, has been identified as a heme and radical scavenger that may participate in the mitigation of toxicities caused by degradation of hemoglobin. The objective of this work was to investigate heme interactions with A1M in vitro using various analytical techniques and to optimize analytical methodology suitable for rapid evaluation of the ligand binding properties of recombinant A1M versions. Methods: To examine heme binding properties of A1M we utilized UV/Vis absorption spectroscopy, visible circular dichroism (CD), catalase-like activity, migration shift electrophoresis, and surface plasmon resonance (SPR), which was specifically developed for the assessment of His-tagged A1M. Results: The results of this study confirm that A1M is a heme binding protein that can accommodate heme at more than one binding site and/or in coordination with different amino acid residues depending upon heme concentration and ligand-to-protein molar ratio. UV/Vis titration of A1M with heme revealed an unusually large bathochromic shift, up to 38 nm, observed for heme binding to a primary binding site. UV/Vis spectroscopy, visible CD and catalase-like activity suggested that heme is accommodated inside His-tagged (tgA1M) and tagless A1M (ntA1M) in a rather similar fashion although the His-tag is very likely involved into coordination with iron of the heme molecule. SPR data indicated kinetic rate constants and equilibrium binding constants with K-D values in a mu M range. Conclusions: This study provided experimental evidence of the A1M heme binding properties by aid of different techniques and suggested an analytical methodology for a rapid evaluation of ligand-binding properties of recombinant A1M versions, also suitable for other His-tagged proteins. C1 [Karnaukhova, Elena; Alayash, Abdu I.] US FDA, Ctr Biol Evaluat & Res, Div Hematol Res & Review, Lab Biochem & Vasc Biol, Silver Spring, MD 20993 USA. [Rutardottir, Sigurbjorg; Rosenlof, Lena Wester] Lund Univ, Dept Clin Sci Lund, Div Infect Med, Lund, Sweden. [Rajabi, Mohsen] US FDA, Ctr Biol Evaluat & Res, Off Pharmaceut Sci, Off Biotechnol Prod,Div Therapeut Proteins, Silver Spring, MD 20993 USA. RP Karnaukhova, E (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM elena.karnaukhova@fda.hhs.gov; bo.akerstrom@med.lu.se FU National Institutes of Health (NIH) [HL110900]; U.S. Food and Drug Administration (MODSCI); governmental ALF research grants; Royal Physiographic Society in Lund; Foundations of Greta; Johan Kock, Alfred Osterlund; Blood and Defence Network, Lund University; Crafoord Foundation [20081029]; Oak Ridge Institute for Science and Education (ORISE) FX This work was supported in part by the National Institutes of Health (NIH) under grants HL110900 (Abdu I. Alayash), and U.S. Food and Drug Administration (MODSCI 2013), and by governmental ALF research grants to Lund University and Lund University Hospital, the Royal Physiographic Society in Lund, the Foundations of Greta and Johan Kock, Alfred Osterlund, the Blood and Defence Network, Lund University, and the Crafoord Foundation (20081029). Mohsen Rajabi is grateful to the Oak Ridge Institute for Science and Education (ORISE) for fellowship. NR 48 TC 3 Z9 3 U1 4 U2 12 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD DEC 4 PY 2014 VL 5 AR 465 DI 10.3389/fphys.2014.00465 PG 11 WC Physiology SC Physiology GA AY8ME UT WOS:000347806900002 PM 25538624 ER PT J AU Comertpay, S Pastorino, S Tanji, M Mezzapelle, R Strianese, O Napolitano, A Baumann, F Weigel, T Friedberg, J Sugarbaker, P Krausz, T Wang, E Powers, A Gaudino, G Kanodia, S Pass, HI Parsons, BL Yang, HN Carbone, M AF Comertpay, Sabahattin Pastorino, Sandra Tanji, Mika Mezzapelle, Rosanna Strianese, Oriana Napolitano, Andrea Baumann, Francine Weigel, Tracey Friedberg, Joseph Sugarbaker, Paul Krausz, Thomas Wang, Ena Powers, Amy Gaudino, Giovanni Kanodia, Shreya Pass, Harvey I. Parsons, Barbara L. Yang, Haining Carbone, Michele TI Evaluation of clonal origin of malignant mesothelioma SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Malignant mesothelioma; Clonal origin; HUMARA assay; Carcinogenesis; Polyclonal tumors ID X-CHROMOSOME INACTIVATION; CANCER; TISSUE; GENE; EVOLUTION; PROSTATE; ASBESTOS; TUMORS; CELLS; FOXP3 AB Background: The hypothesis that most cancers are of monoclonal origin is often accepted as a fact in the scientific community. This dogma arose decades ago, primarily from the study of hematopoietic malignancies and sarcomas, which originate as monoclonal tumors. The possible clonal origin of malignant mesothelioma (MM) has not been investigated. Asbestos inhalation induces a chronic inflammatory response at sites of fiber deposition that may lead to malignant transformation after 30-50 years latency. As many mesothelial cells are simultaneously exposed to asbestos fibers and to asbestos-induced inflammation, it may be possible that more than one cell undergoes malignant transformation during the process that gives rise to MM, and result in a polyclonal malignancy. Methods and results: To investigate the clonality patterns of MM, we used the HUMARA (Human Androgen Receptor) assay to examine 16 biopsies from 14 women MM patients. Out of 16 samples, one was non-informative due to skewed Lyonization in its normal adjacent tissue. Fourteen out of the 15 informative samples revealed two electrophoretically distinct methylated HUMARA alleles, the Corrected Allele Ratio (CR) calculated on the allele peak areas indicating polyclonal origin MM. Conclusions: Our results show that MM originate as polyclonal tumors and suggest that the carcinogenic "field effect" of mineral fibers leads to several premalignant clones that give rise to these polyclonal malignancies. C1 [Comertpay, Sabahattin; Pastorino, Sandra; Tanji, Mika; Strianese, Oriana; Napolitano, Andrea; Baumann, Francine; Powers, Amy; Gaudino, Giovanni; Yang, Haining; Carbone, Michele] Univ Hawaii Manoa, Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Mezzapelle, Rosanna] Univ Piemonte Orientale Amedeo Avogadro, Dept Hlth Sci, Novara, Italy. [Napolitano, Andrea] Univ Hawaii Manoa, Dept Melocular Biol & Bioengn, Honolulu, HI 96822 USA. [Weigel, Tracey] Maine Med Ctr, Portland, ME 04102 USA. [Friedberg, Joseph] Penn Presbyterian Med Ctr, Philadelphia, PA USA. [Sugarbaker, Paul] MedStar Washington Hosp Ctr, Program Peritoneal Surface Malignancy, Washington, DC USA. [Krausz, Thomas] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Wang, Ena] Sidra Med & Res Ctr, Doha, Qatar. [Kanodia, Shreya] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA. [Kanodia, Shreya] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Pass, Harvey I.] NYU, Dept Cardiothorac Surg, New York, NY USA. [Parsons, Barbara L.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Carbone, Michele] Univ Hawaii Manoa, Dept Pathol, John A Burns Sch Med, Honolulu, HI 96822 USA. RP Carbone, M (reprint author), Univ Hawaii Manoa, Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. EM mcarbone@cc.hawaii.edu OI Baumann, Francine/0000-0003-1726-489X; Napolitano, Andrea/0000-0002-7509-1555 FU National Institute of Health [R01CA106567, P01CA114047, P30CA071789, R01CA160715-0A]; DoD CDMRP PRCRP Career Development Award; V Foundation; UHCC Pathology Shared Resource [P30 CA071789]; Mesothelioma Applied Research Foundation; United-4 A Cure; Hawai'i Community Foundation; University of Hawai'i Foundation FX We thank Dr. Patricia Ward for advice, Ms. Kimberly Theos and Dr. Masaki Nasu for technical support. This work was supported by National Institute of Health [grant numbers R01CA106567, P01CA114047, P30CA071789 to MC and R01CA160715-0A to HY]; the DoD CDMRP PRCRP Career Development Award to HY, and the V Foundation to MC and HY, the P30 CA071789 (UHCC Pathology Shared Resource); the Mesothelioma Applied Research Foundation to HY, the United-4 A Cure, the Hawai'i Community Foundation to HY, and the University of Hawai'i Foundation, which received donations to support mesothelioma research from Honeywell International Inc., to MC. The contents of this manuscript do not necessarily reflect the views or polices of the U.S. FDA, nor does the mention of trade names or commercial products constitute endorsement or recommendation for use. NR 26 TC 16 Z9 16 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD DEC 4 PY 2014 VL 12 AR 301 DI 10.1186/s12967-014-0301-3 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AX9CR UT WOS:000347202100001 PM 25471750 ER PT J AU Bond, MR Ghosh, SK Wang, P Hanover, JA AF Bond, Michelle R. Ghosh, Salil K. Wang, Peng Hanover, John A. TI Conserved Nutrient Sensor O-GlcNAc Transferase Is Integral to C. elegans Pathogen-Specific Immunity SO PLOS ONE LA English DT Article ID CAENORHABDITIS-ELEGANS; BETA-CATENIN; SIGNALING PATHWAY; INNATE IMMUNITY; STRESS-RESPONSE; LIFE-SPAN; MODEL; ACTIVATION; GLYCOSYLATION; GLCNACYLATION AB Discriminating pathogenic bacteria from bacteria used as a food source is key to Caenorhabidits elegans immunity. Using mutants defective in the enzymes of O-linked N-acetylglucosamine (O-GlcNAc) cycling, we examined the role of this nutrient-sensing pathway in the C. elegans innate immune response. Genetic analysis showed that deletion of O-GlcNAc transferase (ogt-1) yielded animals hypersensitive to the human pathogen S. aureus but not to P. aeruginosa. Genetic interaction studies revealed that nutrient-responsive OGT-1 acts through the conserved beta-catenin (BAR-1) pathway and in concert with p38 MAPK (PMK-1) to modulate the immune response to S. aureus. Moreover, whole genome transcriptional profiling revealed that O-GlcNAc cycling mutants exhibited deregulation of unique stress-and immune-responsive genes. The participation of nutrient sensor OGT-1 in an immunity module evolutionarily conserved from C. elegans to humans reveals an unexplored nexus between nutrient availability and a pathogen-specific immune response. C1 [Bond, Michelle R.; Hanover, John A.] NIDDK, NIH, Bethesda, MD 20892 USA. [Ghosh, Salil K.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Wang, Peng] Medstar Georgetown Univ Hosp, Dept Pathol, Washington, DC USA. RP Hanover, JA (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM jah@helix.nih.gov FU NIDDK intramural funds (NIH) FX This work was supported by NIDDK intramural funds (NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 5 Z9 5 U1 4 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 DEC 4 PY 2014 VL 9 IS 12 AR e113231 DI 10.1371/journal.pone.0113231 PG 26 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AW6MB UT WOS:000346382500079 PM 25474640 ER PT J AU MacMahon, S Ridge, CD Begley, TH AF MacMahon, Shaun Ridge, Clark D. Begley, Timothy H. TI Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Method for the Direct Detection of 2-Monochloropropanediol (2-MCPD) Esters in Edible Oils SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article ID FATTY-ACID ESTERS; 3-CHLOROPROPANE-1,2-DIOL 3-MCPD; PROCESSING CONTAMINANTS; GLYCIDYL ESTERS; 3-MONOCHLOROPROPANE-1,2-DIOL AB A new analytical method has been developed and validated for the detection and quantification of 2-monochloropropanediol (2-MCPD) esters in edible oils. The target compounds are potentially carcinogenic contaminants formed during the processing of edible oils. As the 2-MCPD esters that occur most frequently in refined edible oils were not commercially available, standards were synthesized with identity and purity (95+%) confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and 1H NMR. Target analytes are separated from edible oil matrices using a two-step solid-phase extraction (SPE) procedure. The extracts are then analyzed using LC-MS/MS with electrospray ionization (ESI). The method has been validated for 11 2-MCPD diesters and 3 2-MCPD monoesters in soybean oil, olive oil, and palm oil using an external calibration curve. The ranges of average recoveries and relative standard deviations (RSD) across the three oil matrices at three spiking concentrations are 79-106% (3-13% RSD) for the 2-MCPD diesters and 72-108% (4-17% RSD) for the 2-MCPD monoesters, with limits of quantitation at or below 30 ng/g for the diesters and 90 ng/g for the monoesters. C1 [MacMahon, Shaun; Ridge, Clark D.; Begley, Timothy H.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP MacMahon, S (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM shaun.macmahon@fda.hhs.gov NR 24 TC 4 Z9 4 U1 3 U2 42 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 DEC 3 PY 2014 VL 62 IS 48 BP 11647 EP 11656 DI 10.1021/jf503994m PG 10 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA AU9AH UT WOS:000345883800005 PM 25383913 ER PT J AU Hill, JM Quenelle, DC Cardin, RD Vogel, JL Clement, C Bravo, FJ Foster, TP Bosch-Marce, M Raja, P Lee, JS Bernstein, DI Krause, PR Knipe, DM Kristie, TM AF Hill, James M. Quenelle, Debra C. Cardin, Rhonda D. Vogel, Jodi L. Clement, Christian Bravo, Fernando J. Foster, Timothy P. Bosch-Marce, Marta Raja, Priya Lee, Jennifer S. Bernstein, David I. Krause, Philip R. Knipe, David M. Kristie, Thomas M. TI Inhibition of LSD1 reduces herpesvirus infection, shedding, and recurrence by promoting epigenetic suppression of viral genomes SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID SIMPLEX-VIRUS 1; HISTONE DEMETHYLASE LSD1; GENE-EXPRESSION; SELECTIVE-INHIBITION; TRIGEMINAL GANGLIA; HIV-1 ACQUISITION; CHROMATIN CONTROL; LATENT INFECTION; SUPER-ENHANCERS; CELLS AB Herpesviruses are highly prevalent and maintain lifelong latent reservoirs, thus posing challenges to the control of herpetic disease despite the availability of antiviral pharmaceuticals that target viral DNA replication. The initiation of herpes simplex virus infection and reactivation from latency is dependent on a transcriptional coactivator complex that contains two required histone demethylases, LSD1 (lysine-specific demethylase 1) and a member of the JMJD2 family (Jumonji C domain-containing protein 2). Inhibition of either of these enzymes results in heterochromatic suppression of the viral genome and blocks infection and reactivation in vitro. We demonstrate that viral infection can be epigenetically suppressed in three animal models of herpes simplex virus infection and disease. Treating animals with the monoamine oxidase inhibitor tranylcypromine to inhibit LSD1 suppressed viral lytic infection, subclinical shedding, and reactivation from latency in vivo. This phenotypic suppression was correlated with enhanced epigenetic suppression of the viral genome and suggests that, even during latency, the chromatin state of the virus is dynamic. Therefore, epi-pharmaceuticals may represent a promising approach to treat herpetic diseases. C1 [Hill, James M.; Clement, Christian; Foster, Timothy P.] Louisiana State Univ, Dept Ophthalmol, LSU Eye Ctr, Hlth Sci Ctr,Sch Med, New Orleans, LA 70112 USA. [Quenelle, Debra C.] Louisiana State Univ, Dept Microbiol Immunol & Parasitol, LSU Eye Ctr, Hlth Sci Ctr,Sch Med, New Orleans, LA 70112 USA. [Cardin, Rhonda D.; Bravo, Fernando J.; Bernstein, David I.] Univ Alabama Birmingham, Dept Pediat Infect Dis, Birmingham, AL 35294 USA. [Vogel, Jodi L.; Kristie, Thomas M.] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Div Infect Dis, Cincinnati, OH 45229 USA. [Bosch-Marce, Marta; Krause, Philip R.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20852 USA. [Raja, Priya; Lee, Jennifer S.; Knipe, David M.] Harvard Univ, Dept Microbiol & Immunol, Sch Med, Boston, MA 02115 USA. [Lee, Jennifer S.; Knipe, David M.] Harvard Univ, Harvard Program Virol, Sch Med, Boston, MA 02115 USA. RP Kristie, TM (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM tkristie@niaid.nih.gov OI Krause, Philip/0000-0002-1045-7536; Lee, Jennifer/0000-0003-1324-6846 FU Laboratory of Viral Diseases, Division of Intramural Research, NIAID, NIH; National Eye Institute [R01-EY006311]; Research to Prevent Blindness (RPB); RPB; LSUHSC; U.S. Food and Drug Administration Intramural Funding; NIH [P01-AI098681]; [HHSN272201000027I]; [HHSN2720001]; [HHSN27220100008I] FX These studies were supported by the Laboratory of Viral Diseases, Division of Intramural Research, NIAID, NIH (T.M.K.); contract HHSN272201000027I, Task Order HHSN2720001 (D.C.Q.); National Eye Institute R01-EY006311 (J.M.H.), Research to Prevent Blindness (RPB) Senior Investigator Award (J.M.H.), RPB unrestricted grant to the LSU Eye Center (J.M.H.), LSUHSC unrestricted grant to J.M.H.; U.S. Food and Drug Administration Intramural Funding (P.R.K.); contract HHSN27220100008I (D.I.B. and R.D.C.); and NIH P01-AI098681 (D.M.K.). NR 63 TC 17 Z9 17 U1 3 U2 23 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD DEC 3 PY 2014 VL 6 IS 265 AR 265ra169 DI 10.1126/scitranslmed.3010643 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AU9MD UT WOS:000345916300004 PM 25473037 ER PT J AU Uhl, K Peters, JR AF Uhl, Kathleen Peters, John R. TI Burden of Changes in Generic Pill Appearance SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 [Uhl, Kathleen; Peters, John R.] US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Uhl, K (reprint author), US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 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 DEC 2 PY 2014 VL 161 IS 11 BP 839 EP 839 DI 10.7326/L14-5028 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AX9UJ UT WOS:000347247200017 PM 25437414 ER PT J AU Qu, HO Mudalige, TK Linder, SW AF Qu, Haiou Mudalige, Thilak K. Linder, Sean W. TI Capillary Electrophoresis/Inductively-Coupled Plasma-Mass Spectrometry: Development and Optimization of a High Resolution Analytical Tool for the Size-Based Characterization of Nanomaterials in Dietary Supplements SO ANALYTICAL CHEMISTRY LA English DT Article ID SODIUM DODECYL-SULFATE; ICP-MS; SILVER NANOPARTICLES; GOLD NANOPARTICLES; SEPARATION; SPECIATION; TRANSFORMATION; FRACTIONATION; DISTRIBUTIONS; MONOLAYERS AB We report the development and optimization of a system consisting of capillary electrophoresis (CE) interfaced with inductively coupled plasma mass spectrometry (ICPMS) for rapid and high resolution speciation and characterization of metallic (e.g., gold, platinum, and palladium) nanoparticles in a dietary supplement. Multiple factors, including surfactant type and concentration, pH of running buffer, and applied voltage, were investigated to optimize the separation conditions. It was found that by using the anionic surfactant sodium dodecyl benzenesulfonate (SDBS) in the running buffer the separation resolution was significantly improved, allowing for easy distinction of adjacent size fractions in a gold nanoparticle mixture with very small size differences (e.g., 5, 15, 20, and 30 nm). The type and concentration of the surfactant was found to be critical in obtaining sufficient separation while applied voltage and pH values of the running buffers largely affected the elution times by varying the electroosmotic flow. Quantum dots were used as mobility markers to eliminate the run-to-run variation. The diameters of the nanoparticles followed a linear relationship with their relative electrophoretic mobility, and size information on unknown samples could be extrapolated from a standard curve. The accuracy and precision of this method was confirmed using 10 and 30 nm gold nanoparticle standard reference materials. Furthermore, the method was successfully applied to the analysis of commercially available metallic nanoparticle-based dietary supplements, as evidenced by good agreement between the particle sizes calculated by CE/ICPMS and transmission electron microscopy (TEM). C1 [Qu, Haiou; Mudalige, Thilak K.; Linder, Sean W.] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, Jefferson, AR 72079 USA. RP Mudalige, TK (reprint author), US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM thilak.mudalige@fda.hhs.gov; sean.linder@fda.hhs.gov FU Office of Regulatory Affairs/Arkansas Regional Laboratory, U.S. Food and Drug Administration FX These studies were conducted using the Nanotechnology Core Facility (Nano Core) located on the U.S. Food and Drug Administration's Jefferson Laboratories campus (Jefferson, AR), which houses the FDA National Center for Toxicological Research and the FDA Office of Regulatory Affairs Arkansas Regional Laboratory. We thank Dr. Anthony Adeuya, Dr. Paul Howard, Dr. Patrick Sisco, Dr. Jin-Hee Lim, and Dr. Ivan Quevedo for their support and valuable comments on the draft manuscript. This project was supported in part by an appointment to the Research Participation Program at the Office of Regulatory Affairs/Arkansas Regional Laboratory, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA. The views expressed in this document are those of the authors and should not be interpreted as the official opinion or policy of the U.S. Food and Drug Administration, Department of Health and Human Services, or any other agency or component of the U.S. government. The mention of trades names, commercial products, or organizations is for clarification of the methods used and should not be interpreted as an endorsement of a product or manufacturer. NR 42 TC 26 Z9 26 U1 13 U2 95 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 DEC 2 PY 2014 VL 86 IS 23 BP 11620 EP 11627 DI 10.1021/ac5025655 PG 8 WC Chemistry, Analytical SC Chemistry GA AU7TK UT WOS:000345803300025 PM 25354835 ER PT J AU Liu, ZC Borlak, J Tong, WD AF Liu, Zhichao Borlak, Juergen Tong, Weida TI Deciphering miRNA transcription factor feed-forward loops to identify drug repurposing candidates for cystic fibrosis SO GENOME MEDICINE LA English DT Article ID TRANSMEMBRANE CONDUCTANCE REGULATOR; AIRWAY EPITHELIAL-CELLS; HIGH-DOSE IBUPROFEN; FACTOR-KAPPA-B; MICRORNA EXPRESSION; GENE-REGULATION; THERAPEUTIC TARGET; ANTITUMORAL DRUGS; SMALL MOLECULES; NITRIC-OXIDE AB Background: Cystic fibrosis (CF) is a fatal genetic disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that primarily affects the lungs and the digestive system, and the current drug treatment is mainly able to alleviate symptoms. To improve disease management for CF, we considered the repurposing of approved drugs and hypothesized that specific microRNA (miRNA) transcription factors (TF) gene networks can be used to generate feed-forward loops (FFLs), thus providing treatment opportunities on the basis of disease specific FFLs. Methods: Comprehensive database searches revealed significantly enriched TFs and miRNAs in CF and CFTR gene networks. The target genes were validated using ChIPBase and by employing a consensus approach of diverse algorithms to predict miRNA gene targets. STRING analysis confirmed protein-protein interactions (PPIs) among network partners and motif searches defined composite FFLs. Using information extracted from SM2miR and Pharmaco-miR, an in silico drug repurposing pipeline was established based on the regulation of miRNA/TFs in CF/CFTR networks. Results: In human airway epithelium, a total of 15 composite FFLs were constructed based on CFTR specific miRNA/TF gene networks. Importantly, nine of them were confirmed in patient samples and CF epithelial cells lines, and STRING PPI analysis provided evidence that the targets interacted with each other. Functional analysis revealed that ubiquitin-mediated proteolysis and protein processing in the endoplasmic reticulum dominate the composite FFLs, whose major functions are folding, sorting, and degradation. Given that the mutated CFTR gene disrupts the function of the chloride channel, the constructed FFLs address mechanistic aspects of the disease and, among 48 repurposing drug candidates, 26 were confirmed with literature reports and/or existing clinical trials relevant to the treatment of CF patients. Conclusion: The construction of FFLs identified promising drug repurposing candidates for CF and the developed strategy may be applied to other diseases as well. C1 [Liu, Zhichao; Tong, Weida] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Borlak, Juergen] Hannover Med Sch, Ctr Pharmacol & Toxicol, D-30625 Hannover, Germany. RP Borlak, J (reprint author), Hannover Med Sch, Ctr Pharmacol & Toxicol, Carl Neuberg Str 1, D-30625 Hannover, Germany. EM Borlak.Juergen@mh-hannover.de; weida.tong@fda.hhs.gov RI Liu, Zhichao/C-4035-2011 FU German Federal Ministry for Education and Research, Virtual Liver Network initiative [031 6154]; ORISE Stipend of the FDA FX JB receives funding from the German Federal Ministry for Education and Research as part of the Virtual Liver Network initiative (Grant number 031 6154). Furthermore, JB is recipient of an ORISE Stipend of the FDA which is gratefully acknowledged. NR 94 TC 5 Z9 5 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD DEC 2 PY 2014 VL 6 AR 94 DI 10.1186/s13073-014-0094-2 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA AU6ML UT WOS:000345717000001 PM 25484921 ER PT J AU Roth-Cline, M Nelson, R AF Roth-Cline, Michelle Nelson, Robert TI The Ethical Principle of Scientific Necessity in Pediatric Research 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 5121, Silver Spring, MD 20993 USA. EM robert.nelson@fda.hhs.gov NR 7 TC 1 Z9 1 U1 0 U2 2 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 DEC 2 PY 2014 VL 14 IS 12 BP 14 EP 15 DI 10.1080/15265161.2014.964874 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA AS1SD UT WOS:000344060400005 PM 25369406 ER PT J AU Chen, JJ Di, X Zhang, YQ Bozza, W Zhang, BL AF Chen, Jun-jie Di, Xu Zhang, Yaqin Bozza, William Zhang, Baolin TI H-Ras regulates the dynamics of TRAIL death receptors SO MOLECULAR CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on RAS Oncogenes - From Biology to Therapy CY FEB 24-27, 2014 CL Lake Buena Vista, FL SP Amer Assoc Canc Res C1 [Chen, Jun-jie; Di, Xu; Zhang, Yaqin; Bozza, William; Zhang, Baolin] US FDA, Bethesda, MD 20014 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 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD DEC PY 2014 VL 12 SU 12 MA A42 DI 10.1158/1557-3125.RASONC14-A42 PG 1 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CQ9IZ UT WOS:000360929000037 ER PT J AU Myers, MB McKim, KL Meng, FX Parsons, BL AF Myers, Meagan B. McKim, Karen L. Meng, Fanxue Parsons, Barbara L. TI High sensitivity characterization of KRAS mutant subpopulations in normal lung tissue and adenocarcinomas of the lung SO MOLECULAR CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on RAS Oncogenes - From Biology to Therapy CY FEB 24-27, 2014 CL Lake Buena Vista, FL SP Amer Assoc Canc Res C1 [Myers, Meagan B.; McKim, Karen L.; Meng, Fanxue; Parsons, Barbara L.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD DEC PY 2014 VL 12 SU 12 MA B56 DI 10.1158/1557-3125.RASONC14-B56 PG 1 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CQ9IZ UT WOS:000360929000093 ER PT J AU Zafar, F Badano, A AF Zafar, Fahad Badano, Aldo TI Characterization of crosstalk in stereoscopic display devices SO JOURNAL OF THE SOCIETY FOR INFORMATION DISPLAY LA English DT Article DE stereoscopic displays; medical imaging; crosstalk AB Many different types of stereoscopic display devices are used for commercial and research applications. Stereoscopic displays offer the potential to improve performance in detection tasks for medical imaging diagnostic systems. Due to the variety of stereoscopic display technologies, it remains unclear how these compare with each other for detection and estimation tasks. Different stereo devices have different performance trade-offs due to their display characteristics. Among them, crosstalk is known to affect observer perception of 3D content and might affect detection performance. We measured and report the detailed luminance output and crosstalk characteristics for three different types of stereoscopic display devices. We recorded the effect of other issues on recorded luminance profiles such as viewing angle, use of different eye wear, and screen location. Our results show that the crosstalk signature for viewing 3D content can vary considerably when using different types of 3D glasses for active stereo displays. We also show that significant differences are present in crosstalk signatures when varying the viewing angle from 0 degrees to 20 degrees for a stereo mirror 3D display device. Our detailed characterization can help emulate the effect of crosstalk in conducting computational observer image quality assessment evaluations that minimize costly and time-consuming human reader studies. C1 [Zafar, Fahad] Univ Maryland Baltimore Cty, Dept Elect & Comp Engn, Baltimore, MD 21228 USA. [Badano, Aldo] US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Zafar, F (reprint author), Univ Maryland Baltimore Cty, Dept Elect & Comp Engn, Baltimore, MD 21228 USA. EM zoalord12@gmail.com 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 Peter Liu and Asumi Yamazaki for helping with the measurements. The mention of commercial products herein is not to be construed as either an actual or an 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. NR 23 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1071-0922 EI 1938-3657 J9 J SOC INF DISPLAY JI J. Soc. Inf. Disp. PD DEC PY 2014 VL 22 IS 12 BP 613 EP 622 DI 10.1002/jsid.279 PG 10 WC Engineering, Electrical & Electronic; Materials Science, Multidisciplinary; Optics; Physics, Applied SC Engineering; Materials Science; Optics; Physics GA CK7ZX UT WOS:000356457800003 ER PT J AU Kuo, J Huang, I Hsiao, C Wu, J Shen, R Liu, C Wang, Y Chen, Y Huang, C Del Alamo, J Chang, Z Tang, M Khoo, K AF Kuo, J. Huang, I. Hsiao, C. Wu, J. Shen, R. Liu, C. Wang, Y. Chen, Y. Huang, C. Del Alamo, J. Chang, Z. Tang, M. Khoo, K. TI GEF-H1 controls focal adhesion signaling that regulates mesenchymal stem cell lineage commitment SO MOLECULAR BIOLOGY OF THE CELL LA English DT Meeting Abstract CT ASCB/IFCB Meeting CY DEC 06-10, 2014 CL Philadelphia, PA SP Amer Soc Cell Biol, Int Federat Cell Biol C1 [Kuo, J.; Wu, J.; Huang, C.; Chang, Z.] Natl Yang Ming Univ, Inst Biochem & Mol Biol, Taipei 112, Taiwan. [Huang, I.] Natl Yang Ming Univ, Taipei 112, Taiwan. [Hsiao, C.; Khoo, K.] Natl Taiwan Univ, Inst Biochem Sci, Taipei, Taiwan. [Hsiao, C.; Khoo, K.] Acad Sin, Inst Biol Chem, Taipei, Taiwan. [Shen, R.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Liu, C.] Natl Cheng Kung Univ Hosp, Inst Basic Med Sci, Tainan 70428, Taiwan. [Liu, C.] Natl Cheng Kung Univ Hosp, Dept Physiol, Tainan 70428, Taiwan. [Wang, Y.] Natl Cheng Kung Univ Hosp, Dept Cell Biol & Anat, Tainan 70428, Taiwan. [Wang, Y.] Taipei Med Univ, Ctr Neurotrauma & Neuroregenerat, Taipei, Taiwan. [Del Alamo, J.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Tang, M.] Natl Cheng Kung Univ, Coll Med, Tainan 70101, Taiwan. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD DEC PY 2014 VL 25 MA P1465 PG 1 WC Cell Biology SC Cell Biology GA CE8LP UT WOS:000352094103316 ER PT J AU Said, M AF Said, Maria TI In Liberia, the End of the Ebola Epidemic will be the Beginning SO ECOHEALTH LA English DT Editorial Material C1 [Said, Maria] US PHS, LCDR, Washington, DC 20201 USA. [Said, Maria] NIH, Div Int Training & Res, Fogarty Int Ctr, Rockville, MD 20852 USA. [Said, Maria] US FDA, Div Epidemiol, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Said, M (reprint author), US PHS, LCDR, Washington, DC 20201 USA. EM said.maria@gmail.com NR 1 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1612-9202 EI 1612-9210 J9 ECOHEALTH JI EcoHealth PD DEC PY 2014 VL 11 IS 4 BP 459 EP 460 DI 10.1007/s10393-015-1017-4 PG 2 WC Biodiversity Conservation; Ecology; Environmental Sciences SC Biodiversity & Conservation; Environmental Sciences & Ecology GA CE5HB UT WOS:000351860800003 PM 25691142 ER PT J AU Zhu, M Ming, Y Swaim, H Swain, MD Myers, MJ Deaver, C Wu, XL Jones, YL Yancy, HF AF Zhu, Min Ming, Yi Swaim, Heidi Swain, Marla D. Myers, Michael J. Deaver, Christine Wu, Xiaolin Jones, Yolanda L. Yancy, Haile F. TI Identification of potential biomarkers of P-glycoprotein substrate neurotoxicity in transgenic mice expressing the mutated canine ABCB1 gene SO AMERICAN JOURNAL OF VETERINARY RESEARCH LA English DT Article ID TARGETED INSERTION; CHLORIDE CHANNELS; IVERMECTIN; COLLIES; INSECTICIDES; SENSITIVITY; MDR1-1-DELTA; BRAIN AB Objective To identify biomarkers of P-glycoprotein (P-gp) substrate neurotoxicity in transgenic mice expressing the mutant canine ABCB1 gene (ABCB1-1 Delta). Animals-8 ABCB1 knock-in and knock-out transgenic mice expressing the ABCB1-1 Delta gene and 8 control mice expressing the wild-type canine ABCB1 gene (ABCB1-WI). Procedures Groups including 2 ABCB1-1 Delta mutant mice and 2 ABC81-WT mice were administered the P-gp substrates ivermectin (10 mg/kg, SC), doramectin (10 mg/kg, SC), moxidectin (10 mg/kg, PO), or digoxin (1.53 mg/kg, SC). A toxicogenomic approach based on DNA microarrays was used to examine whole-genome expression changes in mice administered P-gp substrates. Results Compared with control ABC81-WT mice, ABCB1-1 Delta mutant mice developed neurotoxic signs including ataxia, lethargy, and tremors similar to those reported for dogs with the ABCB1-1 Delta mutation. Microarray analysis revealed that gene expression was altered in ABCB1-1 Delta mutant mice, compared with findings for ABCB1-WT mice, following administration of the same P-gp substrates. Gene pathway analysis revealed that genes with a >= 2-fold gene expression change were associated with behavior and nervous system development and function. Moreover, 34 genes were altered in the ABCB1-1 Delta mutant mice in all 4 drug treatment groups. These genes were also associated with behavior, which was identified as the top-ranked gene network. Conclusions and Clinical Relevance These study data have facilitated understanding of the molecular mechanisms of neurotoxicosis in ABCB1-1 Delta mutant mice following exposure to various P-gp substrates. Some genes appear to be potential biomarkers of P-gp substrate neurotoxicity that might be used to predict C1 [Zhu, Min; Swaim, Heidi; Swain, Marla D.; Myers, Michael J.; Deaver, Christine; Jones, Yolanda L.; Yancy, Haile F.] US FDA, Res Off, Ctr Vet Med, Laurel, MD 20708 USA. [Ming, Yi] SAIC Frederick Inc, Adv Biomed Comp Ctr, Informat Syst Program, NIH, Frederick, MD 21702 USA. [Wu, Xiaolin] SAIC Frederick Inc, NIH, Lab Mol Technol, Frederick, MD 21701 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 NR 23 TC 2 Z9 2 U1 0 U2 3 PU AMER VETERINARY MEDICAL ASSOC PI SCHAUMBURG PA 1931 N MEACHAM RD SUITE 100, SCHAUMBURG, IL 60173-4360 USA SN 0002-9645 EI 1943-5681 J9 AM J VET RES JI Am. J. Vet. Res. PD DEC PY 2014 VL 75 IS 12 BP 1104 EP 1110 PG 7 WC Veterinary Sciences SC Veterinary Sciences GA CA6EL UT WOS:000349001800010 PM 25419811 ER PT J AU Simonyan, V Mazumder, R AF Simonyan, Vahan Mazumder, Raja TI High-Performance Integrated Virtual Environment (HIVE) Tools and Applications for Big Data Analysis SO Genes LA English DT Article DE big data; bioinformatics; high-performance cloud computing; high-throughput sequencing; next-generation sequencing; genomics ID SEQUENCING DATA; READ ALIGNMENT; COMPUTATIONAL CHALLENGES; PROTEIN FAMILIES; BIOINFORMATICS; GENOMES; WEB; DNA; IDENTIFICATION; TECHNOLOGY AB The High-performance Integrated Virtual Environment (HIVE) is a high-throughput cloud-based infrastructure developed for the storage and analysis of genomic and associated biological data. HIVE consists of a web-accessible interface for authorized users to deposit, retrieve, share, annotate, compute and visualize Next-generation Sequencing (NGS) data in a scalable and highly efficient fashion. The platform contains a distributed storage library and a distributed computational powerhouse linked seamlessly. Resources available through the interface include algorithms, tools and applications developed exclusively for the HIVE platform, as well as commonly used external tools adapted to operate within the parallel architecture of the system. HIVE is composed of a flexible infrastructure, which allows for simple implementation of new algorithms and tools. Currently, available HIVE tools include sequence alignment and nucleotide variation profiling tools, metagenomic analyzers, phylogenetic tree-building tools using NGS data, clone discovery algorithms, and recombination analysis algorithms. In addition to tools, HIVE also provides knowledgebases that can be used in conjunction with the tools for NGS sequence and metadata analysis. C1 [Simonyan, Vahan] Ctr Biol Evaluat & Res Food & Drug Adm, Silver Spring, MD 20993 USA. [Mazumder, Raja] George Washington Univ, Dept Biochem & Mol Med, Washington, DC 20037 USA. RP Simonyan, V (reprint author), Ctr Biol Evaluat & Res Food & Drug Adm, Silver Spring, MD 20993 USA. EM vahan.simonyan@fda.hhs.gov; mazumder@gwu.edu NR 72 TC 7 Z9 7 U1 2 U2 22 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2073-4425 J9 GENES-BASEL JI Genes PD DEC PY 2014 VL 5 IS 4 BP 957 EP 981 DI 10.3390/genes5040957 PG 25 WC Genetics & Heredity SC Genetics & Heredity GA CA4EX UT WOS:000348858000004 PM 25271953 ER PT J AU Sharma, K Goehe, RW Di, X Hicks, MA Torti, SV Torti, FM Harada, H Gewirtz, DA AF Sharma, Khushboo Goehe, Rachel W. Di, Xu Hicks, Mark Anthony, II Torti, Suzy V. Torti, Frank M. Harada, Hisashi Gewirtz, David A. TI A novel cytostatic form of autophagy in sensitization of non-small cell lung cancer cells to radiation by vitamin D and the vitamin D analog, EB 1089 SO AUTOPHAGY LA English DT Article DE autophagy; cytostatic; cytoprotective; NSCLC; radiation ID BREAST-TUMOR CELLS; IN-VIVO; CONCURRENT CHEMORADIOTHERAPY; ACCELERATED SENESCENCE; RECEPTOR EXPRESSION; CYTOTOXIC AUTOPHAGY; IONIZING-RADIATION; ENERGY HOMEOSTASIS; DNA-DAMAGE; P53 AB The standard of care for unresectable lung cancer is chemoradiation. However, therapeutic options are limited and patients are rarely cured. We have previously shown that vitamin D and vitamin D analogs such as EB 1089 can enhance the response to radiation in breast cancer through the promotion of a cytotoxic form of autophagy. In A549 and H460 non-small cell lung cancer (NSCLC) cells, 1,25-D-3 (the hormonally active form of vitamin D) and EB 1089 prolonged the growth arrest induced by radiation alone and suppressed proliferative recovery, which translated to a significant reduction in clonogenic survival. In H838 or H358 NSCLC cells, which lack VDR/vitamin D receptor or functional TP53, respectively, 1,25-D-3 failed to modify the extent of radiation-induced growth arrest or suppress proliferative recovery post-irradiation. Sensitization to radiation in H1299 NSCLC cells was evident only when TP53 was induced in otherwise tp53-null H1299 NSCLC cells. Sensitization was not associated with increased DNA damage, decreased DNA repair or an increase in apoptosis, necrosis, or senescence. Instead sensitization appeared to be a consequence of the conversion of the cytoprotective autophagy induced by radiation alone to a novel cytostatic form of autophagy by the combination of 1,25-D-3 or EB 1089 with radiation. While both pharmacological and genetic suppression of autophagy or inhibition of AMPK phosphorylation sensitized the NSCLC cells to radiation alone, inhibition of the cytostatic autophagy induced by the combination treatment reversed sensitization. Evidence for selectivity was provided by lack of radiosensitization in normal human bronchial cells and cardiomyocytes. Taken together, these studies have identified a unique cytostatic function of autophagy that appears to be mediated by VDR, TP53, and possibly AMPK in the promotion of an enhanced response to radiation by 1,25-D-3 and EB 1089 in NSCLC. C1 [Sharma, Khushboo; Gewirtz, David A.] Virginia Commonwealth Univ, Dept Pharmacol & Pharmacol, Massey Canc Ctr, Richmond, VA 23284 USA. [Goehe, Rachel W.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Di, Xu] US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, Off Biotechnol Prod, Bethesda, MD USA. [Hicks, Mark Anthony, II; Harada, Hisashi] Virginia Commonwealth Univ, Massey Canc Ctr, Dept Oral & Craniofacial Mol Biol, Richmond, VA USA. [Torti, Suzy V.] Univ Connecticut Hlth Sci, Dept Mol Biol & Biophys, Farmington, CT USA. [Torti, Frank M.] Univ Connecticut Hlth Sci, Dept Med, Farmington, CT USA. RP Gewirtz, DA (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Pharmacol, Massey Canc Ctr, Richmond, VA 23284 USA. EM gewirtz@vcu.edu FU NIH [P30 CA16059]; NIH-NINDS Center core grant [5P30NS047463]; CTSA award from the National Center for Advancing Translational Sciences [UL1TR000058]; American Cancer Society [IRG-14-192-40]; [R01 CA171101]; [5R21 CA171974] FX Quantification of PtdIns staining for cell cycle, ANXA5 and PI staining, GLB staining, and acridine orange staining were conducted at the Virginia Commonwealth University Flow Cytometry and Imaging Shared Resource Facility supported in part by NIH Grant P30 CA16059. Confocal microscopy was performed at the VCU Department of Anatomy and Neurobiology Microscopy Facility, supported, in part, with funding from the NIH-NINDS Center core grant 5P30NS047463. These studies were supported in part by R01 CA171101 (SVT, FMT), 5R21 CA171974 (DAG) and CTSA award No. UL1TR000058 from the National Center for Advancing Translational Sciences (DAG). David A. Gewirtz, Ph.D., was supported by an Institutional Research Grant, IRG-14-192-40 from the American Cancer Society. NR 53 TC 9 Z9 9 U1 0 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PD DEC PY 2014 VL 10 IS 12 BP 2346 EP 2361 DI 10.4161/15548627.2014.993283 PG 16 WC Cell Biology SC Cell Biology GA CA0HN UT WOS:000348598200019 PM 25629933 ER PT J AU Joshi, BH Leland, P Lababidi, S Varrichio, F Puri, RK AF Joshi, Bharat H. Leland, Pamela Lababidi, Samir Varrichio, Frederick Puri, Raj K. TI Interleukin-4 receptor alpha overexpression in human bladder cancer correlates with the pathological grade and stage of the disease SO CANCER MEDICINE LA English DT Article DE Biomarker; grade and clinical stage; IL-4R alpha; bladder cancer-associated protein; tumor aggressiveness ID RENAL-CELL CARCINOMA; HUMAN PLEURAL MESOTHELIOMA; CD4(+) T-CELLS; PSEUDOMONAS EXOTOXIN; PULMONARY METASTASIS; ANTITUMOR IMMUNITY; CYTOTOXIN THERAPY; MALIGNANT GLIOMA; TUMOR-GROWTH; IN-VITRO AB Previously, we have demonstrated that interleukin-4 receptor alpha (IL-4R alpha) is over-expressed on a variety of human cancers and can serve as target for IL-4 immunotoxin comprised of IL-4 and a mutated Pseudomonas exotoxin. However, its expression and association with grade and clinical stage of bladder cancer has not been studied. IL-4R alpha expression was examined in human bladder cancer cell lines, mouse xenografts, and biopsy specimens at mRNA and protein levels by real-time RT-PCR and IHC/ISH techniques. We also examined the effect of IL-4 on proliferation and invasion of bladder carcinoma cell lines. For tissue microarray (TMA) results, we analyzed the precision data using exact binomial proportion with exact two-sided P-values. We used Cochran-Armitage Statistics with exact two-sided P-values to examine the trend analysis of IL-4R alpha over grade or stage of the bladder cancer specimens. The influence of age and gender covariates was also analyzed using multiple logistic regression models. IL-4R alpha is overexpressed in five bladder cancer cell lines, while normal bladder and human umbilical vein cell lines (HUVEC) expressed at low levels. Two other chains of IL-4 receptor complex, IL-2R gamma C and IL-13R alpha 1, were absent or weakly expressed. IL-4 modestly inhibited the cell proliferation, but enhanced cell invasion of bladder cancer cell lines in a concentration-dependent manner. Bladder cancer xenografts in immunodeficient mice also maintained IL-4R alpha overexpression in vivo. Analysis of tumor biopsy specimens in TMAs revealed significantly higher IL-4R alpha immunostaining (>= 2+) in Grade 2 (85%) and Grade 3 (97%) compared to Grade 1 tumors (0%) (P <= 0.0001). Similarly, 9% stage I tumors were positive for IL-4R alpha (>= 2+) compared to 84% stage II (P <= 0.0001) and 100% stages III-IV tumors (P <= 0.0001). IL-13R alpha 1 was also expressed in tumor tissues but at low levels and it did not show any correlation with the grade and stage of disease. However, the IL-2R gamma C was not expressed. Ten normal bladder specimens demonstrated <= 1+ staining for IL-4R alpha and IL-13R alpha 1 and no staining for IL-2R gamma C. These results demonstrate that IL-4R alpha is overexpressed in human bladder cancer, which correlates with advanced grade and stage of the disease. Thus, IL-4R alpha may be a bladder tumor-associated protein and a prognostic biomarker. C1 [Joshi, Bharat H.; Leland, Pamela; Puri, Raj K.] US FDA, Ctr Biol Evaluat & Res, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies,Off Cellular Tissue, Bethesda, MD 20892 USA. [Lababidi, Samir; Varrichio, Frederick] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Joshi, BH (reprint author), Ctr Biol Evaluat & Res, Tumor Vaccines & Biotechnol Branch, 10903 New Hampshire Ave,White Oak Bldg 52, Silver Spring, MD 20993 USA. EM bharat.joshi@fda.hhs.gov NR 50 TC 8 Z9 8 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD DEC PY 2014 VL 3 IS 6 BP 1615 EP 1628 DI 10.1002/cam4.330 PG 14 WC Oncology SC Oncology GA AZ4YB UT WOS:000348226000017 PM 25208941 ER PT J AU Zhang, ZW Nie, L Soon, GX Liu, AY AF Zhang, Zhiwei Nie, Lei Soon, Guoxing Liu, Aiyi TI THE USE OF COVARIATES AND RANDOM EFFECTS IN EVALUATING PREDICTIVE BIOMARKERS UNDER A POTENTIAL OUTCOME FRAMEWORK SO ANNALS OF APPLIED STATISTICS LA English DT Article DE Conditional independence; counterfactual; ROC regression; sensitivity analysis; treatment effect heterogeneity; treatment selection ID TREATMENT-SELECTION; TRIAL; CANCER AB Predictive or treatment selection biomarkers are usually evaluated in a subgroup or regression analysis with focus on the treatment-by-marker interaction. Under a potential outcome framework (Huang, Gilbert and Janes [Biometrics 68 (2012) 687-696]), a predictive biomarker is considered a predictor for a desirable treatment benefit (defined by comparing potential outcomes for different treatments) and evaluated using familiar concepts in prediction and classification. However, the desired treatment benefit is unobservable because each patient can receive only one treatment in a typical study. Huang et al. overcome this problem by assuming monotonicity of potential outcomes, with one treatment dominating the other in all patients. Motivated by an HIV example that appears to violate the monotonicity assumption, we propose a different approach based on covariates and random effects for evaluating predictive biomarkers under the potential outcome framework. Under the proposed approach, the parameters of interest can be identified by assuming conditional independence of potential outcomes given observed covariates, and a sensitivity analysis can be performed by incorporating an unobserved random effect that accounts for any residual dependence. Application of this approach to the motivating example shows that baseline viral load and CD4 cell count are both useful as predictive biomarkers for choosing antiretroviral drugs for treatment-naive patients. C1 [Zhang, Zhiwei] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Nie, Lei] US FDA, Div Biometr 5, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Soon, Guoxing] US FDA, Div Biometr 4, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Population Hlth Res, NIH, Bethesda, MD 20892 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; lei.nie@fda.hhs.gov; guoxing.soon@fda.hhs.gov; liua@mail.nih.gov OI Liu, Aiyi/0000-0002-6618-5082 FU Intramural NIH HHS [ZIA HD008875-01] NR 25 TC 1 Z9 1 U1 0 U2 5 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 1932-6157 J9 ANN APPL STAT JI Ann. Appl. Stat. PD DEC PY 2014 VL 8 IS 4 BP 2336 EP 2355 DI 10.1214/14-AOAS773 PG 20 WC Statistics & Probability SC Mathematics GA AY4EF UT WOS:000347530200021 PM 26779295 ER PT J AU Parshikov, IA Sutherland, JB AF Parshikov, Igor A. Sutherland, John B. TI The use of Aspergillus niger cultures for biotransformation of terpenoids SO PROCESS BIOCHEMISTRY LA English DT Review DE Aspergillus niger; Biotransformation; Epoxides; Saponins; Terpenes ID MICROBIAL TRANSFORMATION; MICROBIOLOGICAL TRANSFORMATIONS; FUNGAL TRANSFORMATION; NATURAL-PRODUCTS; HYDROXYLATION; ACID; SESQUITERPENOIDS; MICROORGANISMS; BIOCONVERSION; ARTEMISININ AB Aspergillus niger is a well-known fungus that has been used for many different biotransformations of organic compounds. The terpenoids include a large variety of natural hydrocarbons and their derivatives, mostly obtained from plant essential oils, but some obtained from animals or fungi. They may be acyclic or have one or more rings of various sizes, and they show a variety of biological activities that include antibacterial, antifungal, antiparasitic, antiviral, and anticancer activities. Terpenoids are classified as monoterpenoids (C-10), sesquiterpenoids (C-15), diterpenoids (C-20), triterpenoids (C-30), and others. This review summarizes experimental processes that use cultures of various A. niger strains to carry out stereoselective biochemical reactions in terpenoids, including related epoxides, lactones, N-phenylcarbamates, and saponins, to produce metabolites that may be useful as flavors and fragrances or as new experimental drug candidates. Cultures of A. niger that add hydroxyl, carbonyl, and other groups at specific positions or reduce double bonds have resulted in the production of valuable new compounds. Published by Elsevier Ltd. C1 [Parshikov, Igor A.] Russian Acad Sci, Inst Appl Mech, Moscow 119991, Russia. [Sutherland, John B.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Sutherland, JB (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM john.sutherland@fda.hhs.gov OI Sutherland, John/0000-0003-4823-9822; Parshikov, Igor/0000-0003-1466-1128 NR 98 TC 3 Z9 3 U1 4 U2 59 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-5113 EI 1873-3298 J9 PROCESS BIOCHEM JI Process Biochem. PD DEC PY 2014 VL 49 IS 12 BP 2086 EP 2100 DI 10.1016/j.procbio.2014.09.005 PG 15 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Engineering, Chemical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Engineering GA AY7TG UT WOS:000347761100010 ER PT J AU Chappell, G Kobets, T O'Brien, B Tretyakova, N Sangaraju, D Kosyk, O Sexton, KG Bodnar, W Pogribny, IP Rusyn, I AF Chappell, Grace Kobets, Tetyana O'Brien, Bridget Tretyakova, Natalia Sangaraju, Dewakar Kosyk, Oksana Sexton, Kenneth G. Bodnar, Wanda Pogribny, Igor P. Rusyn, Ivan TI Epigenetic Events Determine Tissue-Specific Toxicity of Inhalational Exposure to the Genotoxic Chemical 1,3-Butadiene in Male C57BL/6J Mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE 1,3-butadiene; epigenetics; genotoxicity ID HISTONE LYSINE METHYLATION; DNA CROSS-LINKS; MAMMALIAN-CELLS; DAMAGE RESPONSE; CANCER-CELLS; B6C3F1 MICE; ACETYLATION; RATS; ACETYLTRANSFERASE; REPLICATION AB 1,3-Butadiene (BD), a widely used industrial chemical and a ubiquitous environmental pollutant, is a known human carcinogen. Although genotoxicity is an established mechanism of the tumorigenicity of BD, epigenetic effects have also been observed in livers of mice exposed to the chemical. To better characterize the diverse molecular mechanisms of BD tumorigenicity, we evaluated genotoxic and epigenotoxic effects of BD exposure in mouse tissues that are target (lung and liver) and non-target (kidney) for BD-induced tumors. We hypothesized that epigenetic alterations may explain, at least in part, the tissue-specific differences in BD tumorigenicity in mice. We evaluated the level of N-7-(2,3,4-trihydroxybut-1-yl)guanine adducts and 1,4-bis-(guan-7-yl)-2,3-butanediol crosslinks, DNA methylation, and histone modifications in male C57BL/6 mice exposed to filtered air or 425 ppm of BD by inhalation (6 h/day, 5 days/week) for 2 weeks. Although DNA damage was observed in all three tissues of BD-exposed mice, variation in epigenetic effects clearly existed between the kidneys, liver, and lungs. Epigenetic alterations indicative of genomic instability, including demethylation of repetitive DNA sequences and alterations in histone-lysine acetylation, were evident in the liver and lung tissues of BD-exposed mice. Changes in DNA methylation were insignificant in the kidneys of treated mice, whereas marks of condensed heterochromatin and transcriptional silencing (histone-lysine trimethylation) were increased. These modifications may represent a potential mechanistic explanation for the lack of tumorigenesis in the kidney. Our results indicate that differential tissue susceptibility to chemical-induced tumorigenesis may be attributed to tissue-specific epigenetic alterations. C1 [Chappell, Grace; Kobets, Tetyana; O'Brien, Bridget; Kosyk, Oksana; Sexton, Kenneth G.; Bodnar, Wanda; Rusyn, Ivan] Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. [Kobets, Tetyana; Pogribny, Igor P.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Tretyakova, Natalia; Sangaraju, Dewakar] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA. RP Rusyn, I (reprint author), Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. EM iir@unc.edu RI Rusyn, Ivan/S-2426-2016 FU National Institutes of Health [R01 ES023195, P30 ES010126] FX The National Institutes of Health (R01 ES023195 and P30 ES010126), and appointment (T.K.) to the Postgraduate Research Program at the NCTR administered by the Oak Ridge Institute for Science and Education (ORISE). NR 45 TC 6 Z9 6 U1 0 U2 11 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 DEC PY 2014 VL 142 IS 2 BP 375 EP 384 DI 10.1093/toxsci/kfu191 PG 10 WC Toxicology SC Toxicology GA AY5MZ UT WOS:000347617800007 PM 25237060 ER PT J AU Spindel, S Sapsford, KE AF Spindel, Samantha Sapsford, Kim E. TI Evaluation of Optical Detection Platforms for Multiplexed Detection of Proteins and the Need for Point-of-Care Biosensors for Clinical Use SO SENSORS LA English DT Review DE immunoassay; fluorescent; ELISA; multiplex; protein; biomarker; point-of-care; in vitro diagnostics; quantum dot ID SURFACE-PLASMON RESONANCE; ON-A-CHIP; PHYSICOCHEMICALLY MODIFIED SILICON; IONIZATION MASS-SPECTROMETRY; LINKED-IMMUNOSORBENT-ASSAY; QUANTUM DOTS; CARDIAC BIOMARKERS; ENERGY-TRANSFER; CHEST-PAIN; PERSONALIZED MEDICINE AB This review investigates optical sensor platforms for protein multiplexing, the ability to analyze multiple analytes simultaneously. Multiplexing is becoming increasingly important for clinical needs because disease and therapeutic response often involve the interplay between a variety of complex biological networks encompassing multiple, rather than single, proteins. Multiplexing is generally achieved through one of two routes, either through spatial separation on a surface (different wells or spots) or with the use of unique identifiers/labels (such as spectral separation-different colored dyes, or unique beads-size or color). The strengths and weaknesses of conventional platforms such as immunoassays and new platforms involving protein arrays and lab-on-a-chip technology, including commercially-available devices, are discussed. Three major public health concerns are identified whereby detecting medically-relevant markers using Point-of-Care (POC) multiplex assays could potentially allow for a more efficient diagnosis and treatment of diseases. C1 [Spindel, Samantha; Sapsford, Kim E.] US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. RP Spindel, S (reprint author), US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Samantha.spindel@fda.hhs.gov; kim.sapsford@fda.hhs.gov NR 150 TC 14 Z9 14 U1 12 U2 85 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1424-8220 J9 SENSORS-BASEL JI Sensors PD DEC PY 2014 VL 14 IS 12 BP 22313 EP 22341 DI 10.3390/s141222313 PG 29 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation SC Chemistry; Electrochemistry; Instruments & Instrumentation GA AX2SK UT WOS:000346794300010 PM 25429414 ER PT J AU O'Donoghue, AC Sullivan, HW Aikin, KJ AF O'Donoghue, Amie C. Sullivan, Helen W. Aikin, Kathryn J. TI Randomized Study of Placebo and Framing Information in Direct-to-Consumer Print Advertisements for Prescription Drugs SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE DTC advertising; Placebo; Mixed frame; Quantitative ID NUMERACY; BENEFITS; TRIALS AB Background Research suggests that quantitative information in direct-to-consumer (DTC) prescription drug ads may be helpful for consumers. Purpose The objective was to examine the effect of adding placebo rates and framing to DTC ads. Methods In study 1, 2,000 Internet panel members with chronic pain participated in a randomized controlled experiment of DTC ads varying in placebo rate and framing. In study 2, 596 physicians ranked DTC ads varying in placebo rate and framing by how well they conveyed scientific information and their usefulness for patients. Results In study 1, participants who viewed placebo rates were able to recall them and use them to form certain perceptions. A mixed frame led to lower placebo rate recall and perceived efficacy. In study 2, overall, physicians preferred a placebo/single frame ad. Conclusions Adding placebo rates to DTC ads may be useful for consumers. The evidence does not support using a mixed frame. C1 [O'Donoghue, Amie C.; Sullivan, Helen W.; Aikin, Kathryn J.] US FDA, Silver Spring, MD 20993 USA. RP O'Donoghue, AC (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 51,Rm 3236, Silver Spring, MD 20993 USA. EM amie.odonoghue@fda.hhs.gov NR 24 TC 3 Z9 3 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD DEC PY 2014 VL 48 IS 3 BP 311 EP 322 DI 10.1007/s12160-014-9603-1 PG 12 WC Psychology, Multidisciplinary SC Psychology GA AX4RP UT WOS:000346919400006 PM 24682975 ER PT J AU Santillo, MF AF Santillo, Michael F. TI Inhibition of monoamine oxidase (MAO) by alpha-ethylphenethylamine and N,alpha-diethylphenethylamine, two compounds related to dietary supplements SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Monoamine oxidase (MAO); N-ethyl-1-phenyl-2-butanamine; 1-phenyl-2-butanamine; Enzyme inhibition; Amphetamines; Diethylphenethylamines ID D-METHAMPHETAMINE; AMPHETAMINE; IDENTIFICATION; PHARMACOKINETICS; ALMOTRIPTAN; XENOBIOTICS; MECHANISMS; INVIVO; DRUG; SAR AB Phenethylamines can interact with the metabolic enzyme monoamine oxidase (MAO), which can cause neurochemical dysfunction or changes in drug potency. A methamphetamine analog, N,alpha-diethylphenethylamine (N,alpha-DEPEA), was recently discovered in athletic performance-enhancing supplements, along with discovery of its metabolite, alpha-ethylphenethylamine (AEPEA). In vitro inhibition of human recombinant MAO by AEPEA and N,alpha-DEPEA was evaluated by measuring the fluorescence of 4-hydroxyquinoline produced from MAO substrate, kynuramine. AEPEA competitively inhibited human recombinant MAO A (K-i =14.0 mu M), which was 17-fold stronger compared to MAO B (K-i= 234 mu M). Furthermore, N,alpha-DEPEA was a weak inhibitor of both MAO A (K-i=251 mu M) and MAO B (K-i = 159 mu M). Trends regarding MAO A inhibition were explored among structural analogs, yielding the following ranking: amphetamine (K-i=5.3 AEPEA (K-i =14.0 mu M), methamphetamine (K-i = 17.2 mu M), phentermine (K-i = 196 mu M), and N,alpha-DEPEA (K-i= 251 mu M). This study provides important data relating chemical structures and biochemical effects for two emerging compounds associated with dietary supplements. Published by Elsevier Ltd. C1 US FDA, Div Toxicol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Santillo, MF (reprint author), US FDA, Div Toxicol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM michael.santillo@fda.hhs.gov RI Santillo, Michael/B-5081-2009 OI Santillo, Michael/0000-0001-8087-5859 FU U.S. Food and Drug Administration (FDA) FX The author thanks Drs. Yitong Liu and Paddy Wiesenfeld for feedback and assistance with this study. This research was funded by the U.S. Food and Drug Administration (FDA). NR 42 TC 2 Z9 2 U1 1 U2 10 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 DEC PY 2014 VL 74 BP 265 EP 269 DI 10.1016/j.fct.2014.10.009 PG 5 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA AY0GD UT WOS:000347274600035 PM 25455893 ER PT J AU Bandele, OJ Stine, CB Ferguson, M Black, T Olejnik, N Keltner, Z Evans, ER Crosby, TC Reimschuessel, R Sprando, RL AF Bandele, O. J. Stine, C. B. Ferguson, M. Black, T. Olejnik, N. Keltner, Z. Evans, E. R. Crosby, T. C. Reimschuessel, R. Sprando, R. L. TI Use of urinary renal biomarkers to evaluate the nephrotoxic effects of melamine or cyanuric acid in non-pregnant and pregnant rats SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Melamine; Cyanuric acid; Kidney; Nephrotoxicity; Biomarkers; Luminex ID KIDNEY INJURY MOLECULE-1; CRYSTAL-FORMATION; EPITHELIAL-CELLS; CLUSTERIN; TOXICITY; OSTEOPONTIN; EXPRESSION; PROTEIN; IDENTIFICATION; CARCINOGENICITY AB Although traditional assessments of renal damage detect loss of kidney function, urinary renal biomarkers are proposed to indicate early changes in renal integrity. The recent adulteration of infant formula and other milk-based foods with melamine revealed a link between melamine ingestion and nephropathy. Thus, the effects of melamine and related analogs (e.g., cyanuric acid) should be assessed in other potentially sensitive groups. We evaluated whether urinary Kim-1, clusterin, and osteopontin could detect the effects of high doses of melamine-or cyanuric acid in pregnant and non-pregnant female rats gavaged with 1000 mg/kg bw/day for 10 days. We demonstrate that these biomarkers can differentiate the severity of effects induced by melamine or cyanuric acid. All melamine-treated animals experienced adverse effects; however, pregnant rats were most sensitive as indicated by increased SCr, BUN, and kidney weights, decreased body weight, and presence of renal crystals. These effects coincided with elevated urinary biomarker levels as early as day 2 of exposure. One cyanuric acid-treated rat displayed effects similar to melamine, including increased urinary biomarker levels. This work illustrates that these biomarkers can detect early effects of melamine or cyanuric acid crystal-induced nephropathy and further supports the use of urinary protein immunoassays as a powerful, non-invasive method to assess nephrotoxicity. Published by Elsevier Ltd. C1 [Bandele, O. J.; Black, T.; Olejnik, N.; Keltner, Z.; Sprando, R. L.] US FDA, Div Toxicol, Off Appl Res & Safety Assessment, CFSAN, Laurel, MD USA. [Stine, C. B.; Ferguson, M.; Evans, E. R.; Crosby, T. C.; Reimschuessel, R.] US FDA, Div Appl Vet Res, Res Off, CVM, Laurel, MD USA. RP Bandele, OJ (reprint author), US FDA, Ctr Food Safety & Appl Nutr, OFAS DFCN, HFS-275,4300 River Rd, College Pk, MD 20740 USA. EM omari.bandele@fda.hhs.gov NR 58 TC 2 Z9 2 U1 0 U2 6 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 DEC PY 2014 VL 74 BP 301 EP 308 DI 10.1016/j.fct.2014.10.013 PG 8 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA AY0GD UT WOS:000347274600040 PM 25455896 ER PT J AU Ting, HY Li, Q Ye, LJ Yang, H Xue, XP Zhang, MJ Huang, QS Yin, DC Shang, P AF Ting Huyan Li, Qi Ye, Lin-Jie Yang, Hui Xue, Xiao-Ping Zhang, Ming-Jie Huang, Qing-Sheng Yin, Da-Chuan Shang, Peng TI Inhibition of human natural killer cell functional activity by human aspartyl beta-hydroxylase SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Article DE Human aspartyl beta-hydroxylase (HAAH); Human natural killer (NK) cells; Cytotoxicity; Tumor immune surveillance ID NK CELLS; HEPATOCELLULAR-CARCINOMA; EXPRESSION; CYTOTOXICITY; CHOLANGIOCARCINOMA; GENE; ASPARTYL(ASPARAGINYL)BETA-HYDROXYLASE; OVEREXPRESSION; ACTIVATION; CLONING AB Natural killer (NK) cells are a key component of the innate immune system and play pivotal roles as inflammatory regulators and in tumor surveillance. Human aspartyl beta-hydroxylase (HAAH) is a plasma membrane and endoplasmic reticulum protein with hydroxylation activity, which is over-expressed in many malignant neoplasms and can be detected from the sera of tumor patients. HAAH is involved in regulating tumor cell infiltration and metastasis. Escaping from immune surveillance may help tumor cell infiltration and metastasis. However, the effects of HAAH on tumor immune surveillance have not yet been investigated carefully. The present study investigated the potential use of HAAH as an immune regulator of human NK cells. We assessed the effects of recombinant HAAH (r-HAAH) on primary human NK cell morphology, viability, cytotoxicity, apoptosis, receptors expression and cytokine/cytolytic proteins production. Our results demonstrated that r-HAAH negatively affects NK cell activity in a time and dose-dependent manner. It noticeably reduces the viability of the NK cells by increasing apoptosis and necrosis via caspase signaling pathways. Moreover, r-HAAH reduces the NK cell cytotoxicity by inhibiting surface expression of NKG2D, NKp44 and IFN-gamma secretion. These findings suggest that one of the ways by which HAAH actively promotes tumor formation and proliferation is by inhibiting NK cell-surveillance activity. (C) 2014 Elsevier B.V. All rights reserved. C1 [Ting Huyan; Li, Qi; Ye, Lin-Jie; Yang, Hui; Xue, Xiao-Ping; Zhang, Ming-Jie; Huang, Qing-Sheng; Yin, Da-Chuan; Shang, Peng] Northwestern Polytech Univ, Sch Life Sci, Key Lab Space Biosci & Space Biotechnol, Xian 710072, Shaanxi, Peoples R China. [Zhang, Ming-Jie] USDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Rockville, MD USA. RP Yin, DC (reprint author), Northwestern Polytech Univ, Sch Life Sci, 127 YouyiXilu, Xian 710072, Shaanxi, Peoples R China. EM yindc@nwpu.edu.cn FU National Basic Research Program of China [2011CB710903]; Natural Science Foundation of Shaanxi Province [2014JM4171]; China Postdoctoral Science Foundation [2014M560804]; Fundamental Research Funds for the Central Universities [3102014JKY15008] FX We gratefully acknowledge financial support from the National Basic Research Program of China (Grant No. 2011CB710903), the Natural Science Foundation of Shaanxi Province (Grant No. 2014JM4171), the China Postdoctoral Science Foundation (Grant No. 2014M560804), and Fundamental Research Funds for the Central Universities (Grant No. 3102014JKY15008). NR 29 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 EI 1878-1705 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD DEC PY 2014 VL 23 IS 2 BP 452 EP 459 DI 10.1016/j.intimp.2014.09.018 PG 8 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA AX5GF UT WOS:000346954000012 ER PT J AU Jernigan, AM Chen, CCG Sewell, C AF Jernigan, Amelia M. Chen, Chi Chiung Grace Sewell, Catherine TI A randomized trial of chewing gum to prevent postoperative ileus after laparotomy for benign gynecologic surgery SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Article DE Chewing gum; Gynecologic surgery; Ileus; Laparotomy ID TOTAL ABDOMINAL HYSTERECTOMY; PHASE-III; DOUBLE-BLIND; MOTILITY; ALVIMOPAN; METAANALYSIS; MANAGEMENT; RESECTION AB Objective: To assess whether chewing gum prevents postoperative ileus after laparotomy for benign gynecologic surgery. Methods: A randomized study was conducted from December 1, 2010, to February 29, 2012. Patients scheduled to undergo laparotomy were randomly assigned to receive chewing gum or routine care after surgery. A chart review was performed to establish incidence of nausea and vomiting, use of antiemetics, cases of postoperative ileus (>= 2 episodes of emesis of 100 mL or more, with abdominal distention and absence of bowel sounds), and time to discharge. Inpatient surveys recorded the time to specific events. Results: A total of 109 patients were randomly assigned to receive chewing gum (n = 51) or routine postoperative care (n = 58). Fewer participants assigned to receive chewing gum than routine care experienced postoperative nausea (16 [31.4%] versus 29 [50.0%]; P = 0.049) and postoperative ileus (0 vs 5 [8.6%]; P = 0.032). There were no differences in the need for postoperative antiemetics, episodes of postoperative vomiting, readmissions, repeat surgeries, time to first hunger, time to toleration of clear liquids, time to regular diet, time to first flatus, or time to discharge. Conclusion: Chewing gum after laparotomy for gynecologic surgery is safe and lowers the incidence of postoperative ileus and nausea. (C) 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Jernigan, Amelia M.; Sewell, Catherine] Johns Hopkins Med Inst, Dept Gynecol & Obstet, Baltimore, MD 21205 USA. [Chen, Chi Chiung Grace] Johns Hopkins Bayview Med Ctr, Dept Gynecol & Obstet, Baltimore, MD USA. [Sewell, Catherine] US FDA, Ctr Devices & Radiol Hlth, Div Reprod Gastrorenal & Urol Devices, Obstet & Gynecol Devices Branch, Silver Spring, MD USA. RP Jernigan, AM (reprint author), 9500 Euclid Ave,Desk A81, Cleveland, OH 44195 USA. EM amelia.jernigan@gmail.com NR 23 TC 5 Z9 5 U1 1 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 EI 1879-3479 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD DEC PY 2014 VL 127 IS 3 BP 279 EP 282 DI 10.1016/j.ijgo.2014.06.008 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AX7ZI UT WOS:000347129700012 PM 25147092 ER PT J AU He, WW Jia, HM Wamer, WG Zheng, Z Li, PJ Callahan, JH Yin, JJ AF He, Weiwei Jia, Huimin Wamer, Wayne G. Zheng, Zhi Li, Pinjiang Callahan, John H. Yin, Jun-Jie TI Predicting and identifying reactive oxygen species and electrons for photocatalytic metal sulfide micro-nano structures SO JOURNAL OF CATALYSIS LA English DT Article DE Reactive oxygen species; Electrons transfer; Photocatalytic; Electron spin resonance; Metal sulfides ID ANTIBACTERIAL PROPERTIES; OXIDE NANOPARTICLES; OXIDATIVE STRESS; SEMICONDUCTOR; TITANIUM; WATER; NANOSTRUCTURES; DEGRADATION; MECHANISMS; GENERATION AB A broadly applicable theoretical and experimental framework was developed for understanding the photocatalytic mechanism of semiconductors. Using this framework, we found that it is possible to predict the type and reactivity of reactive oxygen species and electrons produced during photoexcitation of semiconductors by comparing the band edge energies of semiconductors with the redox potentials of relevant species. In addition, we could experimentally verify these predictions using electron spin resonance spectroscopy (ESR) with spin trapping and spin labeling techniques. We selected four types of metal sulfides (CdS, ZnS, In2S3, and Bi2S3) to elucidate the applicability of this model system. Using ESR technique, we found that these four sulfides are significantly different in the types of produced reactive oxygen species. When irradiated, ZnS can generate superoxide (O-2(-center dot)), hydroxyl radicals ((OH)-O-center dot), and singlet oxygen (O-1(2)); CdS and In2S3 can produce O-2(-center dot), while irradiation of Bi2S3 generates none of these reactive oxygen species. These results are correlated with the photocatalytic oxidation and reduction activities of metal sulfide structures. (C) 2014 Elsevier Inc. All rights reserved. C1 [He, Weiwei; Jia, Huimin; Zheng, Zhi; Li, Pinjiang] Xuchang Univ, Inst Surface Micro & Nano Mat, Key Lab Micronano Mat Energy Storage & Convers He, Xuchang 461000, Henan, Peoples R China. [He, Weiwei; Callahan, John H.; Yin, Jun-Jie] US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Wamer, Wayne G.] US FDA, Div Bioanalyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Zheng, Z (reprint author), Xuchang Univ, Inst Surface Micro & Nano Mat, Key Lab Micronano Mat Energy Storage & Convers He, Xuchang 461000, Henan, Peoples R China. EM 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]; regulatory science grant under the FDA Nanotechnology CORES Program; Office of Cosmetics and Colors, CFSAN/FDA FX This work was supported by National Natural Science Foundation of China (Grant Nos. 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 (Grant No. 144200510014), and a regulatory science grant under the FDA Nanotechnology CORES Program and by the Office of Cosmetics and Colors, CFSAN/FDA. We appreciate Dr. Wang Li for her assistance with TOC measurement. NR 40 TC 6 Z9 6 U1 10 U2 53 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0021-9517 EI 1090-2694 J9 J CATAL JI J. Catal. PD DEC PY 2014 VL 320 BP 97 EP 105 DI 10.1016/j.jcat.2014.10.004 PG 9 WC Chemistry, Physical; Engineering, Chemical SC Chemistry; Engineering GA AX8AZ UT WOS:000347134100012 ER PT J AU Swisher, JFA Haddad, DA McGrath, AG Boekhoudt, GH Feldman, GM AF Swisher, Jennifer F. A. Haddad, Devin A. McGrath, Anna G. Boekhoudt, Gunther H. Feldman, Gerald M. TI IgG4 can induce an M2-like phenotype in human monocyte-derived macrophages through Fc gamma RI SO MABS LA English DT Article DE IgG4; Fc gamma receptors; immune complex; monocyte-derived macrophage; alternatively activated M2 macrophage ID MONOCLONAL-ANTIBODY THERAPY; IMMUNE-COMPLEXES; CRYSTAL-STRUCTURE; IN-VITRO; RECEPTOR; INFLAMMATION; AFFINITY; BINDING; INFECTION; RESPONSES AB Antibodies evoke cellular responses through the binding of their Fc region to Fc receptors, most of which contain immunoreceptor tyrosine-based activation motif domains and are thus considered "activating." However, there is a growing appreciation of these receptors for their ability to deliver an inhibitory signal as well. We previously described one such phenomenon whereby interferon (IFN) gamma signaling is inhibited by immune complex signaling through Fc gamma RI. To understand the implications of this in the context of therapeutic antibodies, we assessed individual IgG subclasses to determine their ability to deliver this anti-inflammatory signal in monocyte-derived macrophages. Like IgG1, we found that IgG4 is fully capable of inhibiting IFN gamma-mediated events. In addition, F(ab ') 2 fragments that interfere with Fc gamma RI signaling reversed this effect. For mAbs developed with either an IgG1 or an IgG4 constant region for indications where inflammation is undesirable, further examination of a potential Fc-dependent contribution to their mechanism of action is warranted. C1 [Swisher, Jennifer F. A.; Haddad, Devin A.; McGrath, Anna G.; Boekhoudt, Gunther H.; Feldman, Gerald M.] US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. RP Feldman, GM (reprint author), US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. EM gerald.feldman@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration FX This project was supported in part by an appointment of DAH and AGM 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 interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 55 TC 3 Z9 3 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1942-0862 EI 1942-0870 J9 MABS-AUSTIN JI mAbs PD DEC PY 2014 VL 6 IS 6 BP 1377 EP 1384 DI 10.4161/19420862.2014.975657 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AX4BH UT WOS:000346878600004 PM 25484046 ER PT J AU Price, GA Holmes, RK AF Price, Gregory A. Holmes, Randall K. TI Immunizing Adult Female Mice with a TcpA-A2-CTB Chimera Provides a High Level of Protection for Their Pups in the Infant Mouse Model of Cholera SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID TOXIN-COREGULATED PILUS; OUTER-MEMBRANE VESICLES; MANNOSE-SENSITIVE HEMAGGLUTININ; ORAL KILLED CHOLERA; TEXAS STAR-SR; VIBRIO-CHOLERAE; CELLULAR MECHANISMS; ESCHERICHIA-COLI; VACCINE; O139 AB Vibrio cholerae expresses two primary virulence factors, cholera toxin (CT) and the toxin-coregulated pilus (TCP). CT causes profuse watery diarrhea, and TCP (composed of repeating copies of the major pilin TcpA) is required for intestinal colonization by V. cholerae. Antibodies to CT or TcpA can protect against cholera in animal models. We developed a TcpA holotoxin-like chimera (TcpA-A2-CTB) to elicit both anti-TcpA and anti-CTB antibodies and evaluated its immunogenicity and protective efficacy in the infant mouse model of cholera. Adult female CD-1 mice were immunized intraperitoneally three times with the TcpA-A2-CTB chimera and compared with similar groups immunized with a TcpA+CTB mixture, TcpA alone, TcpA with Salmonella typhimurium flagellin subunit FliC as adjuvant, or CTB alone. Blood and fecal samples were analyzed for antigen-specific IgG or IgA, respectively, using quantitative ELISA. Immunized females were mated; their reared offspring were challenged orogastrically with 10 or 20 LD50 of V. cholerae El Tor N16961; and vaccine efficacy was assessed by survival of the challenged pups at 48 hrs. All pups from dams immunized with the TcpA-A2-CTB chimera or the TcpA+ CTB mixture survived at both challenge doses. In contrast, no pups from dams immunized with TcpA+ FliC or CTB alone survived at the 20 LD50 challenge dose, although the anti-TcpA or anti-CTB antibody level elicited by these immunizations was comparable to the corresponding antibody level achieved by immunization with TcpA-A2-CTB or TcpA+ CTB. Taken together, these findings comprise strong preliminary evidence for synergistic action between anti-TcpA and anti-CTB antibodies in protecting mice against cholera. Weight loss analysis showed that only immunization of dams with TcpA-A2CTB chimera or TcpA+ CTB mixture protected their pups against excess weight loss from severe diarrhea. These data support the concept of including both TcpA and CTB as immunogens in development of an effective multivalent subunit vaccine against V. cholerae. C1 [Price, Gregory A.; Holmes, Randall K.] Univ Colorado, Sch Med, Dept Immunol & Microbiol, Aurora, CO USA. RP Price, GA (reprint author), US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM randall.holmes@ucdenver.edu FU NIH [Grant R01 AI031940] FX This work was supported in part by NIH Grant R01 AI031940. No other research grant supported this work. 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 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD DEC PY 2014 VL 8 IS 12 AR e3356 DI 10.1371/journal.pntd.0003356 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AX1IM UT WOS:000346701000034 PM 25474636 ER PT J AU McGregor, AJ Barr, H Greenberg, MR Safdar, B Wildgoose, P Wright, DW Hollander, JE AF McGregor, Alyson J. Barr, Helen Greenberg, Marna R. Safdar, Basmah Wildgoose, Peter Wright, David W. Hollander, Judd E. TI Gender-specific Regulatory Challenges to Product Approval: A Panel Discussion SO ACADEMIC EMERGENCY MEDICINE LA English DT Article AB On May 13, 2014, a 1-hour panel discussion session titled Gender-specific Regulatory Challenges to Product Approval was held during the Academic Emergency Medicine consensus conference, Gender-specific Research in Emergency Medicine: Investigate, Understand, and Translate How Gender Affects Patient Outcomes. The session sought to bring together leaders in emergency medicine (EM) research, authors, and reviewers in EM research publications, as well as faculty, fellows, residents, and students engaged in research and clinical practice. A panel was convened involving a representative from the Office of Women's Health of the U.S. Food and Drug Administration, two pharmaceutical executives, and a clinical EM researcher. The moderated discussion also involved audience members who contributed significantly to the dialogue. Historical background leading up to the session along with the main themes of the discussion are reproduced in this article. These revolve around sex- and gender-specific research, statistical analysis of sex and gender, clinical practice, financial costs associated with pharmaceutical development, adaptive design, and specific recommendations on the regulatory process as it affects the specialty of EM. C1 [McGregor, Alyson J.] Brown Univ, Dept Emergency Med, Warren Alpert Med Sch, Providence, RI 02912 USA. [Greenberg, Marna R.] Lehigh Valley Hosp, USF Morsani Coll Med, Dept Emergency Med, Allentown, PA USA. [Safdar, Basmah] Yale Univ, Sch Med, Dept Emergency Med, New Haven, CT USA. [Wright, David W.] Emory Univ, Sch Med, Dept Emergency Med, Atlanta, GA USA. [Hollander, Judd E.] Sidney Kimmel Med Coll, Dept Emergency Med, Philadelphia, PA USA. [Barr, Helen] US FDA, Off Womens Heath, Washington, DC 20204 USA. [Wildgoose, Peter] Johnson & Johnson, Janssen Pharmaceut, New Brunswick, NJ USA. RP McGregor, AJ (reprint author), Brown Univ, Dept Emergency Med, Warren Alpert Med Sch, Providence, RI 02912 USA. EM amcgregor@lifespan.org OI Hollander, Judd/0000-0002-1318-2785 FU National Institute of Neurological Disorders and Stroke [1R13NS087861-01]; Office of Research on Women's Health at the National Institutes of Health FX The consensus conference was supported by grant 1R13NS087861-01 from the National Institute of Neurological Disorders and Stroke and the Office of Research on Women's Health at the National Institutes of Health. Additional funding was provided by several organizational, institutional, and individual donors. Non-CME events were supported by Janssen Pharmaceuticals and Besins Critical Care/BH Pharma. See the executive summary elsewhere in this issue for full funding information. NR 12 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1069-6563 EI 1553-2712 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2014 VL 21 IS 12 BP 1334 EP 1338 DI 10.1111/acem.12531 PG 5 WC Emergency Medicine SC Emergency Medicine GA AW9KS UT WOS:000346576700006 PM 25443664 ER PT J AU Sun, SQ Anderson, NM Keller, S AF Sun, Shengqian Anderson, Nathan M. Keller, Susanne TI Atmospheric Pressure Plasma Treatment of Black Peppercorns Inoculated with Salmonella and Held Under Controlled Storage SO JOURNAL OF FOOD SCIENCE LA English DT Article DE cold plasma; microbial inactivation; nonthermal; Salmonella; spices ID DECONTAMINATION; RESISTANCE; SPICES; INACTIVATION; PATHOGENS; SURFACE; FOODS; EGGS AB Spices, including black pepper, are a source of microbial contamination and have been linked to outbreaks of salmonellosis when added to products that undergo no further processing. Traditional thermal processing employed to reduce microbial contamination can lead to losses of heat-sensitive compounds. Thus, alternative processes such as atmospheric pressure plasma (APP) are desirable. The purpose of this research was to determine the efficacy of APP in the destruction of Salmonella inoculated on the surface of peppercorns. Secondarily, we examined the effect of storage on the subsequent inactivation of Salmonella on the surfaces of black peppercorns by APP. Black peppercorns inoculated with a cocktail of Salmonella enterica serotypes Oranienburg, Tennessee, Anatum, and Enteritidis were stored at 25 degrees C, 33% relative humidity (RH); 25 degrees C, 97% RH; and, 37 degrees C, 33% RH for 10 d and additionally at 25 degrees C, 33% RH for 1 and 30 d then treated with APP. Results showed that Salmonella populations decreased significantly (P < 0.05) with respect to the treatment time, but where not related to previous storage conditions (P > 0.05). Approximately a 4.5- to 5.5-log(10) reduction in population was achieved after 60 to 80 s treatment. A combination of treatments, storage and 80 s of plasma, may achieve a total reduction on the order of 7-log(10)CFU/g. These findings support the potential of APP to decontaminate Salmonella on the surfaces of black peppercorns and other dry foods and illustrate that a multiple hurdle approach may prove effective for achieving significant reductions of Salmonella in many low-moisture foods. Practical Application Spices, including black pepper, which often is added to ready-to-eat food as final decoration or flavoring, has raised public health concerns due to outbreaks of salmonellosis. APP is a desirable and effective technology that is able to decontaminate pathogens while maintaining product quality. In this research, APP was shown to significantly reduce levels of Salmonella on the surfaces of black peppercorns. About a 5-log(10) reduction could be achieved with 80-s treatment by APP. Storage conditions did not significantly affect the application of APP. C1 [Sun, Shengqian] IIT, IFSH, Bedford Pk, IL 60501 USA. [Anderson, Nathan M.; Keller, Susanne] US FDA, Bedford Pk, IL 60501 USA. RP Anderson, NM (reprint author), US FDA, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM nathan.anderson@fda.hhs.gov FU U.S. Food and Drug Administration [5U01FD003801] FX This work was supported in part by grant number 5U01FD003801 from the U.S. Food and Drug Administration to the Illinois Institute of Technology Institute for Food Safety and Health; and by appointments to the Research Participation Program 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. The authors also thank Lindsay Halik for her technical assistance with experiments. NR 25 TC 3 Z9 3 U1 3 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-1147 EI 1750-3841 J9 J FOOD SCI JI J. Food Sci. PD DEC PY 2014 VL 79 IS 12 BP E2441 EP E2446 DI 10.1111/1750-3841.12696 PG 6 WC Food Science & Technology SC Food Science & Technology GA AX0PS UT WOS:000346654800005 PM 25393920 ER PT J AU Sharfstein, JM AF Sharfstein, Joshua M. TI The Strange Journey of Population Health SO MILBANK QUARTERLY LA English DT Editorial Material C1 [Sharfstein, Joshua M.] Maryland Dept Hlth & Mental Hyg, Baltimore, MD USA. [Sharfstein, Joshua M.] US FDA, Rockville, MD 20857 USA. [Sharfstein, Joshua M.] US House Representat, Comm Govt Reform, Washington, DC USA. [Sharfstein, Joshua M.] US Dept HHS, Hlth Informat Technol Policy Comm, Washington, DC 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 5 TC 6 Z9 6 U1 0 U2 4 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 DEC PY 2014 VL 92 IS 4 BP 640 EP 643 DI 10.1111/1468-0009.12082 PG 4 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AW9PC UT WOS:000346588500002 PM 25492595 ER PT J AU Liu, Y Yin, JJ Nie, ZH AF Liu, Yi Yin, Jun-Jie Nie, Zhihong TI Harnessing the collective properties of nanoparticle ensembles for cancer theranostics SO NANO RESEARCH LA English DT Article DE vesicle; nanoparticle; self-assembly; cancer theranostics ID AMPHIPHILIC TRIBLOCK COPOLYMERS; CELL LUNG-CANCER; GOLD NANOPARTICLES; PLASMONIC VESICLES; DRUG-DELIVERY; IN-VIVO; INORGANIC NANOPARTICLES; QUANTUM DOTS; LIVE CELLS; DRIVEN AB Individual inorganic nanoparticles (NPs) have been widely used in the fields of drug delivery, cancer imaging and therapy. There are still many hurdles that limit the performance of individual NPs for these applications. The utilization of highly ordered NP ensembles opens a door to resolve these problems, as a result of their new or advanced collective properties. The assembled NPs show several advantages over individual NP-based systems, such as improved cell internalization and tumor targeting, enhanced multimodality imaging capability, superior combination therapy arising from synergistic effects, possible complete clearance from the whole body by degradation of assemblies into original small NP building blocks, and so on. In this review, we discuss the potential of utilizing assembled NP ensembles for cancer imaging and treatment by taking plasmonic vesicular assemblies of Au NPs as an example. We first summarize the recent developments in the self-assembly of plasmonic vesicular structures of NPs from amphiphilic polymer-tethered NP building blocks. We further review the utilization of plasmonic vesicles of NPs for cancer imaging (e.g. multi-photon induced luminescence, photothermal, and photoacoustic imaging), and cancer therapy (e.g., photothermal therapy, and chemotherapy). Finally, we outline current challenges and our perspectives along this line. C1 [Liu, Yi; Nie, Zhihong] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Liu, Yi; Yin, Jun-Jie] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Nie, ZH (reprint author), Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. EM znie@umd.edu RI Yin, Jun Jie /E-5619-2014; Nie, Zhihong/D-7495-2011 OI Nie, Zhihong/0000-0001-9639-905X FU NSF Career Award [DMR-1255377]; startup funds from the University of Maryland; Joint Institute for Food Safety and Nutrition, University of Maryland, College Park, MD - FDA [5U01FD001418] FX This work is supported by a NSF Career Award (DMR-1255377), startup funds from the University of Maryland, and the Joint Institute for Food Safety and Nutrition, University of Maryland, College Park, MD through a cooperative agreement funded by FDA, Grant No. 5U01FD001418 (Yi Liu). 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 59 TC 17 Z9 17 U1 7 U2 86 PU TSINGHUA UNIV PRESS PI BEIJING PA TSINGHUA UNIV, RM A703, XUEYAN BLDG, BEIJING, 10084, PEOPLES R CHINA SN 1998-0124 EI 1998-0000 J9 NANO RES JI Nano Res. PD DEC PY 2014 VL 7 IS 12 BP 1719 EP 1730 DI 10.1007/s12274-014-0541-9 PG 12 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA AX0KM UT WOS:000346641400001 ER PT J AU Taylor, MR AF Taylor, Michael R. TI Keeping Foods Safe Through Global Partnerships SO FOOD TECHNOLOGY LA English DT Editorial Material C1 US FDA, Rockville, MD 20857 USA. RP Taylor, MR (reprint author), US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU INST FOOD TECHNOLOGISTS PI CHICAGO PA 525 WEST VAN BUREN, STE 1000, CHICAGO, IL 60607-3814 USA SN 0015-6639 J9 FOOD TECHNOL-CHICAGO JI Food Technol. PD DEC PY 2014 VL 68 IS 12 BP 108 EP 108 PG 1 WC Food Science & Technology SC Food Science & Technology GA AW6RU UT WOS:000346397000017 ER PT J AU Dong, H Sharma, D Badano, A AF Dong, Han Sharma, Diksha Badano, Aldo TI Web-based, GPU-accelerated, Monte Carlo simulation and visualization of indirect radiation imaging detector performance SO MEDICAL PHYSICS LA English DT Article DE Monte Carlo simulation; GPU acceleration; indirect detector; CsI; detector models ID X-RAY; SYSTEMS AB Purpose: Monte Carlo simulations play a vital role in the understanding of the fundamental limitations, design, and optimization of existing and emerging medical imaging systems. Efforts in this area have resulted in the development of a wide variety of open-source software packages. One such package, hybridMANTIS, uses a novel hybrid concept to model indirect scintillator detectors by balancing the computational load using dual CPU and graphics processing unit (GPU) processors, obtaining computational efficiency with reasonable accuracy. In this work, the authors describe two open-source visualization interfaces, webMANTIS and visualMANTIS to facilitate the setup of computational experiments via hybridMANTIS. Methods: The visualization tools visualMANTIS and webMANTIS enable the user to control simulation properties through a user interface. In the case of webMANTIS, control via a web browser allows access through mobile devices such as smartphones or tablets. webMANTIS acts as a server back-end and communicates with an NVIDIA GPU computing cluster that can support multiuser environments where users can execute different experiments in parallel. Results: The output consists of point response and pulse-height spectrum, and optical transport statistics generated by hybridMANTIS. The users can download the output images and statistics through a zip file for future reference. In addition, webMANTIS provides a visualization window that displays a few selected optical photon path as they get transported through the detector columns and allows the user to trace the history of the optical photons. Conclusions: The visualization tools visualMANTIS and webMANTIS provide features such as on the fly generation of pulse-height spectra and response functions for microcolumnar x-ray imagers while allowing users to save simulation parameters and results from prior experiments. The graphical interfaces simplify the simulation setup and allow the user to go directly from specifying input parameters to receiving visual feedback for the model predictions. (C) 2014 American Association of Physicists in Medicine. C1 [Dong, Han; Sharma, Diksha; Badano, Aldo] US FDA, Ctr Devices & Radiol Hlth, Div Imaging Diagnost & Software Reliabil, Silver Spring, MD 20993 USA. RP Badano, A (reprint author), US FDA, Ctr Devices & Radiol Hlth, Div Imaging Diagnost & Software Reliabil, Silver Spring, MD 20993 USA. EM aldo.badano@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 NR 13 TC 0 Z9 0 U1 1 U2 12 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 DEC PY 2014 VL 41 IS 12 AR 121907 DI 10.1118/1.4901516 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AW3HE UT WOS:000346176300023 PM 25471967 ER PT J AU Desai, VG Kwekel, JC Vijay, V Moland, CL Herman, EH Lee, T Han, T Lewis, SM Davis, KJ Muskhelishvili, L Kerr, S Fuscoe, JC AF Desai, Varsha G. Kwekel, Joshua C. Vijay, Vikrant Moland, Carrie L. Herman, Eugene H. Lee, Taewon Han, Tao Lewis, Sherry M. Davis, Kelly J. Muskhelishvili, Levan Kerr, Susan Fuscoe, James C. TI Early biomarkers of doxorubicin-induced heart injury in a mouse model SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Doxorubicin; Heart; MicroRNA profiling; Biomarker; Mouse ID CARDIAC TROPONIN-T; MYOCARDIAL-INFARCTION; INDUCED CARDIOTOXICITY; CARDIOVASCULAR-DISEASE; INDUCED CARDIOMYOPATHY; MOLECULAR-MECHANISMS; GENE-EXPRESSION; MUSCLE CELLS; MICRORNAS; FAILURE AB Cardiac troponins, which are used as myocardial injury markers, are released in plasma only after tissue damage has occurred. Therefore, there is a need for identification of biomarkers of earlier events in cardiac injury to limit the extent of damage. To accomplish this, expression profiling of 1179 unique microRNAs (miRNAs) was performed in a chronic cardiotoxicity mouse model developed in our laboratory. Male B6C3F(1) mice were injected intravenously with 3 mg/kg doxorubicin (DOX; an anti-cancer drug), or saline once a week for 2, 3, 4, 6, and 8 weeks, resulting in cumulative DOX doses of 6, 9, 12, 18, and 24 mg/kg, respectively. Mice were euthanized a week after the last dose. Cardiac injury was evidenced in mice exposed to 18 mg/kg and higher cumulative DOX dose whereas examination of hearts by light microscopy revealed cardiac lesions at 24 mg/kg DOX. Also, 24 miRNAs were differentially expressed in mouse hearts, with the expression of 1, 1, 2, 8, and 21 miRNAs altered at 6, 9, 12, 18, and 24 mg/kg DOX, respectively. A pro-apoptotic miR-34a was the only miRNA that was upregulated at all cumulative DOX doses and showed a significant dose-related response. Up-regulation of miR-34a at 6 mg/kg DOX may suggest apoptosis as an early molecular change in the hearts of DOX-treated mice. At 12 mg/kg DOX, up-regulation of miR-34a was associated with down-regulation of hypertrophy-related miR-150; changes observed before cardiac injury. These findings may lead to the development of biomarkers of earlier events in DOX-induced cardiotoxicity that occur before the release of cardiac troponins. Published by Elsevier Inc. C1 [Desai, Varsha G.; Kwekel, Joshua C.; Vijay, Vikrant; Moland, Carrie L.; Han, Tao; Fuscoe, James C.] US FDA, Personalized Med Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Herman, Eugene H.] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Rockville, MD 20850 USA. [Lee, Taewon] Korea Univ, Dept Math, Sejong 339700, Chungnam, South Korea. [Lewis, Sherry M.] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Davis, Kelly J.; Muskhelishvili, Levan] Natl Ctr Toxicol Res, Toxicol Pathol Associates, Jefferson, AR 72079 USA. [Kerr, Susan] Arkansas Heart Hosp, Little Rock, AR 72211 USA. RP Desai, VG (reprint author), US FDA, Personalized Med Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM varsha.desai@fda.hhs.gov RI Vijay, Vikrant/E-7651-2010 OI Vijay, Vikrant/0000-0001-8425-1285 NR 63 TC 20 Z9 21 U1 2 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD DEC 1 PY 2014 VL 281 IS 2 BP 221 EP 229 DI 10.1016/j.taap.2014.10.006 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AW4BR UT WOS:000346227000008 PM 25448438 ER PT J AU Chen, JP Kettermann, A Rostron, BL Day, HR AF Chen, Jiping Kettermann, Anna Rostron, Brian L. Day, Hannah R. TI Biomarkers of Exposure among US Cigar Smokers: An Analysis of 1999-2012 National Health and Nutrition Examination Survey (NHANES) Data SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ADULT SMOKERS; PIPE SMOKING; TOBACCO USE; CANCER; COTININE; RISK; LUNG; RACE/ETHNICITY; ELIMINATION; POPULATION AB Background: Cigar consumption is increasing in the United States, but little information is available about exposure to toxic constituents from cigar smoking. Methods: We conducted a cross-sectional analysis of biomarkers of tobacco exposure among 25,522 participants from the National Health and Nutrition Examination Survey (NHANES, 1999-2012). The biomarkers analyzed were serum cotinine, urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), blood lead, blood cadmium, and urinary arsenic. We calculated geometric mean concentrations for each biomarker by tobacco use category and geometric mean ratios controlling for demographic factors. Results: Cigar smokers had higher cotinine, NNAL, and lead concentrations than nontobacco users. The geometric mean concentration [95% confidence interval (CI)] of cotinine for primary cigar smokers (i.e., current cigar/never cigarette smokers) was 6.2 (4.2-9.2) ng/mL versus 0.045 (0.043-0.048) ng/mL for nontobacco users, and the NNAL concentration was 19.1 (10.6-34.3) pg/mg creatinine for primary cigar smokers versus 1.01 (0.95-1.07) pg/mg creatinine for nontobacco users. Secondary cigar smokers (i.e., current cigar/former cigarette smokers) and dual cigar/cigarette smokers had higher cadmium concentrations than nontobacco users. Cigar smoking was associated with significantly higher concentrations of cotinine, NNAL, cadmium, and lead, after adjusting for demographic factors. Secondary cigar smokers had significantly higher cotinine and NNAL concentrations than primary cigar smokers. The NNAL concentrations in daily cigar smokers were comparable with those in daily cigarette smokers. Conclusions: Cigar smokers have higher concentrations of several toxic and carcinogenic substances than nontobacco users. Impact: Our results are consistent with epidemiologic evidence demonstrating cigar smoking as a cause of disease and premature death. (C) 2014 AACR. C1 [Chen, Jiping; Kettermann, Anna; Rostron, Brian L.; Day, Hannah R.] US FDA, Ctr Tobacco Prod, Off Sci, Silver Spring, MD 20993 USA. RP Chen, JP (reprint author), US FDA, Ctr Tobacco Prod, Document Control Ctr, Bldg 71,Room G335,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jiping.chen@fda.hhs.gov NR 29 TC 5 Z9 5 U1 3 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2014 VL 23 IS 12 BP 2906 EP 2915 DI 10.1158/1055-9965.EPI-14-0849 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AW0FU UT WOS:000345967300032 PM 25380733 ER PT J AU Walsh, KA Bennett, SD Mahovic, M Gould, LH AF Walsh, Kelly A. Bennett, Sarah D. Mahovic, Michael Gould, L. Hannah TI Outbreaks Associated with Cantaloupe, Watermelon, and Honeydew in the United States, 1973-2011 SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article ID LISTERIA-MONOCYTOGENES; MULTISTATE OUTBREAK; FRESH PRODUCE; SALMONELLA; MELONS; ILLNESS; GROWTH AB Fresh fruits and vegetables are an important part of a healthy diet. Melons have been associated with enteric infections. We reviewed outbreaks reported to the Centers for Disease Control and Prevention's Foodborne Disease Outbreak Surveillance System during 1973-2011 in which the implicated food was a single melon type. We also reviewed published literature and records obtained from investigating agencies. During 1973-2011, 34 outbreaks caused by a single melon type were reported, resulting in 3602 illnesses, 322 hospitalizations, 46 deaths, and 3 fetal losses. Cantaloupes accounted for 19 outbreaks (56%), followed by watermelons (13, 38%) and honeydew (2, 6%). Melon-associated outbreaks increased from 0.5 outbreaks per year during 1973-1991 to 1.3 during 1992-2011. Salmonella was the most common etiology reported (19, 56%), followed by norovirus (5, 15%). Among 13 outbreaks with information available, melons imported from Mexico and Central America were implicated in 9 outbreaks (69%) and domestically grown melons were implicated in 4 outbreaks (31%). The point of contamination was known for 20 outbreaks; contamination occurred most commonly during growth, harvesting, processing, or packaging (13, 65%). Preventive measures focused on reducing bacterial contamination of melons both domestically and internationally could decrease the number and severity of melon-associated outbreaks. C1 [Walsh, Kelly A.; Bennett, Sarah D.; Gould, L. Hannah] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Atlanta, GA 30333 USA. [Mahovic, Michael] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Walsh, KA (reprint author), Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, 1600 Clifton Rd NE,Mailstop C-09, Atlanta, GA 30333 USA. EM kwalsh@cdc.gov FU Intramural CDC HHS [CC999999] NR 35 TC 12 Z9 12 U1 3 U2 30 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 DEC 1 PY 2014 VL 11 IS 12 BP 945 EP 952 DI 10.1089/fpd.2014.1812 PG 8 WC Food Science & Technology SC Food Science & Technology GA AW4LZ UT WOS:000346253800005 PM 25407556 ER PT J AU Hariharan, P Dibaji, SAR Banerjee, RK Nagaraja, S Myers, MR AF Hariharan, Prasanna Dibaji, Seyed Ahmad Reza Banerjee, Rupak K. Nagaraja, Srinidhi Myers, Matthew R. TI Localization of Focused-Ultrasound Beams in a Tissue Phantom, Using Remote Thermocouple Arrays SO IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL LA English DT Article ID BACKSCATTER AB In focused-ultrasound procedures such as vessel cauterization or clot lysis, targeting accuracy is critical. To investigate the targeting accuracy of the focused-ultrasound systems, tissue phantoms embedded with thermocouples can be employed. This paper describes a method that utilizes an array of thermocouples to localize the focused ultrasound beam. All of the thermocouples are located away from the beam, so that thermocouple artifacts and sensor interference are minimized. Beam propagation and temperature rise in the phantom are simulated numerically, and an optimization routine calculates the beam location that produces the best agreement between the numerical temperature values and those measured with thermocouples. The accuracy of the method was examined as a function of the array characteristics, including the number of thermocouples in the array and their orientation. For exposures with a 3.3-MHz source, the remote-thermocouple technique was able to predict the focal position to within 0.06 mm. Once the focal location is determined using the localization method, temperatures at desired locations (including the focus) can be estimated from remote thermocouple measurements by curve fitting an analytical solution to the heat equation. Temperature increases in the focal plane were predicted to within 5% agreement with measured values using this method. C1 [Hariharan, Prasanna; Dibaji, Seyed Ahmad Reza; Myers, Matthew R.] US FDA, Div Solid & Fluid Mech, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Banerjee, Rupak K.; Nagaraja, Srinidhi] Univ Cincinnati, Coll Engn & Appl Sci, Dept Mech & Mat Engn, Cincinnati, OH USA. RP Hariharan, P (reprint author), US FDA, Div Solid & Fluid Mech, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM matthew.myers@fda.hhs.gov FU National Science Foundation [1041508, 1137166] FX Manuscript received August 20, 2014; accepted September 24, 2014. This study was funded by National Science Foundation grants 1041508 and 1137166. NR 19 TC 2 Z9 2 U1 2 U2 8 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0885-3010 EI 1525-8955 J9 IEEE T ULTRASON FERR JI IEEE Trans. Ultrason. Ferroelectr. Freq. Control PD DEC PY 2014 VL 61 IS 12 BP 2019 EP 2031 DI 10.1109/TUFFC.2014.006702 PG 13 WC Acoustics; Engineering, Electrical & Electronic SC Acoustics; Engineering GA AU9XF UT WOS:000345944300009 PM 25474777 ER PT J AU Eydelman, MB AF Eydelman, Malvina B. TI The US Food and Drug Administration's Efforts to Support Ophthalmology Clinical Trials SO JAMA OPHTHALMOLOGY LA English DT Editorial Material ID END-POINTS SYMPOSIUM C1 US FDA, Div Ophthalm & Ear Nose & Throat Devices, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Eydelman, MB (reprint author), US FDA, Div Ophthalm & Ear Nose & Throat Devices, Off Device Evaluat, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 66, Silver Spring, MD 20993 USA. EM malvina.eydelman@fda.hhs.gov NR 6 TC 3 Z9 3 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD DEC PY 2014 VL 132 IS 12 BP 1391 EP 1392 DI 10.1001/jamaophthalmol.2014.2826 PG 2 WC Ophthalmology SC Ophthalmology GA AW3HF UT WOS:000346176400001 PM 25171671 ER PT J AU Shpyleva, S Pogribna, M Cozart, C Bryant, MS Muskhelishvili, L Tryndyak, VP Ross, SA Beland, FA Pogribny, IP AF Shpyleva, Svitlana Pogribna, Marta Cozart, Christy Bryant, Matthew S. Muskhelishvili, Levan Tryndyak, Volodymyr P. Ross, Sharon A. Beland, Frederick A. Pogribny, Igor P. TI Interstrain differences in the progression of nonalcoholic steatohepatitis to fibrosis in mice are associated with altered hepatic iron metabolism SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE NAFLD; Methyl-deficient diet; Liver fibrogenesis; Iron metabolism; IRP1; miR-200a ID FATTY LIVER-DISEASE; FOLATE-DEFICIENT DIET; ENDOPLASMIC-RETICULUM STRESS; REGULATORY PROTEINS; LIPID-METABOLISM; OXIDATIVE STRESS; STELLATE CELLS; FERRITIN; CHOLINE; INJURY AB Nonalcoholic fatty liver disease (NAFLD) is a major health problem worldwide. Currently, there is a lack of conclusive information to clarify the molecular events and mechanisms responsible for the progression of NAFLD to fibrosis and cirrhosis and, more importantly, for differences in interindividual disease severity. The aim of this study was to investigate a role of interindividual differences in iron metabolism among inbred mouse strains in the pathogenesis and severity of fibrosis in a model of NAFLD. Feeding male A/J, 129S1/SvImJ and WSB/EiJ mice a choline- and folate-deficient diet caused NAFLD-associated liver injury and iron metabolism abnormalities, especially in WSB/EiJ mice. NAFLD-associated fibrogenesis was correlated with a marked strain- and injury-dependent increase in the expression of iron metabolism genes, especially transferrin receptor (Tfrc), ferritin heavy chain (Fth1), and solute carrier family 40 (iron-regulated transporter), member 1 (Slc40a1, Fpn1) and their related proteins, and pronounced down-regulation of the iron regulatory protein 1 (IRP1), with the magnitude being A/J<129S1/SvImJ 7 days, 3) used parallel-group or crossover designs, 4) included patients with OA of the knee, hip, and/or hand, and 5) were placebo controlled and double blind. Crossover trials were excluded, because complete information was available for only 2 of 20 treatment conditions. Results. There was considerable heterogeneity in the SES among the examined trials. A multiple metaregression analysis indicated that trials with shorter treatment period durations and those that did not permit concomitant analgesics had significantly greater assay sensitivity. In univariate analyses of efficacious treatments, trials conducted outside North America and those with a minimum baseline pain intensity score (as defined by the inclusion criterion) of > 40 (0-100 scale) had a significantly larger SES, although these relationships were not significant in the multiple metaregression analysis. Conclusion. The analyses examined potentially modifiable correlates of study SES and showed that longer treatment durations and allowing concomitant analgesics in randomized clinical trials of OA pain are associated with reduced assay sensitivity. These data provide a foundation for investigating strategies to improve assay sensitivity and thereby decrease the likelihood of false-negative outcomes in randomized clinical trials of efficacious treatments for OA pain. C1 [Dworkin, Robert H.; Peirce-Sandner, Sarah; He, Hua; McDermott, Michael P.] Univ Rochester, Rochester, NY 14642 USA. [Turk, Dennis C.] Univ Washington, Seattle, WA 98195 USA. [Hochberg, Marc C.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Jordan, Joanne M.] Univ N Carolina, Chapel Hill, NC USA. [Katz, Nathaniel P.] Analges Solut, Natick, MA USA. [Lin, Allison H.; Rappaport, Bob A.] US FDA, Silver Spring, MD USA. [Neogi, Tuhina] Boston Univ, Sch Med, Boston, MA 02118 USA. [Simon, Lee S.] SDG LLC, Cambridge, MA USA. RP Dworkin, RH (reprint author), Univ Rochester, Sch Med & Dent, 601 Elmwood Ave,Box 604, Rochester, NY 14642 USA. EM robert_dworkin@urmc.rochester.edu OI Neogi, Tuhina/0000-0002-9515-1711 FU FDA [HHSF 223201000078C]; US Food and Drug Administration (FDA) FX The views expressed herein are those of the authors and no official endorsement by the US Food and Drug Administration (FDA) or the pharmaceutical companies that provided unrestricted grants to support the activities of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership should be inferred.; The impetus for this project was provided by the Osteoarthritis Research Society International-FDA Osteoarthritis Initiative. Financial support was provided by a research contract (HHSF 223201000078C) from the FDA to the University of Rochester and by the ACTTION public-private partnership, which has received research grants and/or other revenue from the FDA, multiple pharmaceutical companies, and other sources. NR 15 TC 6 Z9 6 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD DEC PY 2014 VL 66 IS 12 BP 3327 EP 3336 DI 10.1002/art.38869 PG 10 WC Rheumatology SC Rheumatology GA AU4HK UT WOS:000345571200010 PM 25186636 ER PT J AU Brorson, K Jia, AY AF Brorson, Kurt Jia, Audrey Y. TI Therapeutic monoclonal antibodies and consistent ends: terminal heterogeneity, detection, and impact on quality SO CURRENT OPINION IN BIOTECHNOLOGY LA English DT Review ID LIQUID CHROMATOGRAPHY/MASS SPECTROMETRY; IONIZATION MASS-SPECTROMETRY; ISOELECTRIC-FOCUSING METHOD; CHARGE HETEROGENEITY; POSTTRANSLATIONAL MODIFICATIONS; CELL-CULTURE; HEAVY-CHAIN; VARIANTS; LYSINE; IGG1 AB Monoclonal antibodies (mAbs) are biological macromolecules with complex post-translational modifications that can be observed when assessing product variants. The N- and C-terminal heterogeneities of commercially produced antibodies have been observed and extensively studied over the past 30 years. This review summarizes the current literature on detectable antibody termini variants from cultured cells. The presence of these heterogeneities can be detected by many different analytical methods, mostly based on sequence, charge and size differences. Examples are presented that highlight terminal heterogeneities, methods of detection, and their impact on the quality of mAbs. Regulatory considerations are also discussed regarding the potential impact on product quality, safety, and efficacy. C1 [Brorson, Kurt; Jia, Audrey Y.] US FDA, Off Biotechnol Prod, CDER, Silver Spring, MD 20903 USA. RP Brorson, K (reprint author), US FDA, Off Biotechnol Prod, CDER, Silver Spring, MD 20903 USA. EM Kurt.Brorson@fda.hhs.gov NR 50 TC 10 Z9 13 U1 5 U2 29 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0958-1669 EI 1879-0429 J9 CURR OPIN BIOTECH JI Curr. Opin. Biotechnol. PD DEC PY 2014 VL 30 BP 140 EP 146 DI 10.1016/j.copbio.2014.06.012 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA AU8BS UT WOS:000345822300022 PM 25022603 ER PT J AU Diack, AB Ritchie, DL Peden, AH Brown, D Boyle, A Morabito, L Maclennan, D Burgoyne, P Jansen, C Knight, RS Piccardo, P Ironside, JW Manson, JC AF Diack, Abigail B. Ritchie, Diane L. Peden, Alexander H. Brown, Deborah Boyle, Aileen Morabito, Laura Maclennan, David Burgoyne, Paul Jansen, Casper Knight, Richard S. Piccardo, Pedro Ironside, James W. Manson, Jean C. TI Variably Protease-Sensitive Prionopathy, a Unique Prion Variant with Inefficient Transmission Properties SO EMERGING INFECTIOUS DISEASES LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; BLOOD-TRANSFUSION; SPONGIFORM ENCEPHALOPATHY; PATIENT; SCRAPIE; VCJD; CLASSIFICATION; INFECTIVITY; DIAGNOSIS; PATHOLOGY AB Variably protease-sensitive prionopathy (VPSPr) can occur in persons of all codon 129 genotypes in the human prion protein gene (PRNP) and is characterized by a unique biochemical profile when compared with other human prion diseases. We investigated transmission properties of VPSPr by inoculating transgenic mice expressing human PRNP with brain tissue from 2 persons with the valine-homozygous (VV) and 1 with the heterozygous methionine/valine codon 129 genotype. No clinical signs or vacuolar pathology were observed in any inoculated mice. Small deposits of prion protein accumulated in the brains of inoculated mice after challenge with brain material from VV VPSPr patients. Some of these deposits resembled microplaques that occur in the brains of VPSPr patients. Comparison of these transmission properties with those of sporadic Creutzfeldt-Jakob disease in the same lines of mice indicated that VPSPr has distinct biological properties. Moreover, we established that VPSPr has limited potential for human-to-human transmission. C1 [Diack, Abigail B.; Brown, Deborah; Boyle, Aileen; Morabito, Laura; Maclennan, David; Burgoyne, Paul; Manson, Jean C.] Univ Edinburgh, Roslin Inst, Easter Bush EH25 9RG, Midlothian, Scotland. [Ritchie, Diane L.; Peden, Alexander H.; Knight, Richard S.; Ironside, James W.] Univ Edinburgh, Sch Clin Sci, Edinburgh, Midlothian, Scotland. [Piccardo, Pedro] US FDA, Rockville, MD 20857 USA. [Jansen, Casper] Univ Med Ctr Utrecht, Utrecht, Netherlands. RP Manson, JC (reprint author), Univ Edinburgh, Roslin Inst, Easter Bush EH25 9RG, Midlothian, Scotland. EM jean.manson@roslin.ed.ac.uk OI Ironside, James/0000-0001-5869-2108 FU Department of Health Policy Research Programme FX The Edinburgh Brain Bank, a source of material for this study, is supported by the Medical Research Council (MR/L016400/1). This report is independent research commissioned and funded by the Department of Health Policy Research Programme (Strain typing and investigation of transmission potential of unusual cases of CJD). NR 28 TC 6 Z9 6 U1 0 U2 9 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 DEC PY 2014 VL 20 IS 12 BP 1969 EP 1979 DI 10.3201/eid2012.140214 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AU6RP UT WOS:000345729900001 PM 25418327 ER PT J AU Rostron, BL Chang, CM Pechacek, TF AF Rostron, Brian L. Chang, Cindy M. Pechacek, Terry F. TI Estimation of Cigarette Smoking-Attributable Morbidity in the United States SO JAMA INTERNAL MEDICINE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; AIRWAY-OBSTRUCTION; LUNG-DISEASE; COPD; DIAGNOSIS; UNDERDIAGNOSIS; POPULATION; PREVALENCE; MANAGEMENT; MORTALITY AB IMPORTANCE Cigarette smoking has been found to harm nearly every bodily organ and is a leading cause of preventable disease, but current estimates of smoking-attributable morbidity by condition for the United States are generally unavailable. OBJECTIVE To estimate the burden of major medical conditions attributable to cigarette smoking in the United States. DESIGN, SETTING, AND PARTICIPANTS The disease burden of smoking was estimated using population-attributable risk calculations, taking into account the uncertainty of estimates. Population estimates came from 2009 US Census Bureau data and smoking prevalence, disease prevalence, and disease relative risk estimates came from National Health Interview Survey data for surveyed adults from 2006 through 2012. National Health and Nutrition Examination Survey spirometry data obtained from medical examination of surveyed adults from 2007 through 2010 was used to adjust for underreporting of chronic obstructive pulmonary disease. EXPOSURES Smoking status was assessed from self-reported National Health Interview Survey data. MAIN OUTCOMES AND MEASURES The number of adults 35 years and older who had had a major smoking-attributable disease by sex and condition and the total number of these conditions were estimated for the United States in 2009. RESULTS Using National Health Interview Survey data, we estimated that 6.9 million (95% CI, 6.5-7.4 million) US adults had had a combined 10.9 million (95% CI, 10.3-11.5 million) self-reported smoking-attributable medical conditions. Using chronic obstructive pulmonary disease prevalence estimates obtained from National Health and Nutrition Examination Survey self-reported and spirometry data, we estimated that US adults had had a combined 14.0 million (95% CI, 12.9-15.1 million) smoking-attributable conditions in 2009. CONCLUSIONS AND RELEVANCE We estimate that US adults have had approximately 14 million major medical conditions that were attributable to smoking. This figure is generally conservative owing to the existence of other diseases and medical events that were not included in these estimates. Cigarette smoking remains a leading cause of preventable disease in the United States, underscoring the need for continuing and vigorous smoking-prevention efforts. C1 [Rostron, Brian L.; Chang, Cindy M.] US FDA, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. [Pechacek, Terry F.] Ctr Dis Control & Prevent, Off Smoking & Hlth, Atlanta, GA USA. RP Rostron, BL (reprint author), US FDA, Ctr Tobacco Prod, 10903 New Hampshire Ave,Bldg 75,Room 4404, Silver Spring, MD 20993 USA. EM brian.rostron@fda.hhs.gov NR 30 TC 23 Z9 23 U1 3 U2 10 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 DEC PY 2014 VL 174 IS 12 BP 1922 EP 1928 DI 10.1001/jamainternmed.2014.5219 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AU9KI UT WOS:000345911000013 PM 25317719 ER PT J AU Skinner, GE Marshall, KM Morrissey, TR Loeza, V Patazca, E Reddy, NR Larkin, JW AF Skinner, Guy E. Marshall, Kristin M. Morrissey, Travis R. Loeza, Viviana Patazca, Eduardo Reddy, N. Rukma Larkin, John W. TI Combined High Pressure and Thermal Processing on Inactivation of Type E and Nonproteolytic Type B and F Spores of Clostridium botulinum SO JOURNAL OF FOOD PROTECTION LA English DT Article ID FIELD GEL-ELECTROPHORESIS; BACILLUS-AMYLOLIQUEFACIENS SPORES; ELEVATED-TEMPERATURES; HEAT-RESISTANCE; SHELF-LIFE; FOODS; ENDOSPORES; STRAINS; SALMONELLA; PROTOCOLS AB The aim of this study was to determine the resistance of multiple strains of the three nonproteolytic types of Clostridium botulinum (seven strains of type E, eight of type B, and two of type F) spores exposed to combined high pressure and thermal processing. The resistance of spores suspended in N-(2-acetamido)-2-aminoethanesulfonic acid (ACES) buffer (0.05 M, pH 7) was determined at a process temperature of 80 degrees C with high pressures of 600, 650, and 700 MPa using a laboratory-scale pressure test system. Spores of C. botulinum serotype E strains demonstrated less resistance than nonproteolytic spores of type B or F strains when processed at 80 degrees C and 600 MPa for up to 15 min All C. botulinum type E strains were reduced by >6.0 log units within 5 min under these conditions. Among the nonproteolytic type B strains, KAP 9-B was the most resistant, resulting in reductions of 2.7, 5.3, and 5.5 log, coinciding with D-values of 7.7, 3.4, and 1.8 min at 80 degrees C and 600, 650, and 700 MPa, respectively. Of the two nonproteolytic type F strains, 610F was the most resistant, showing 2.6-, 4.5-, and 5.3-log reductions with D-values of 8.9, 4.3, and 1.8 min at 80 degrees C and 600, 650, and 700 MPa, respectively. Pulsed-field gel electrophoresis was performed to examine the genetic relatedness of strains tested and to determine if strains with similar banding patterns also exhibited similar D-values. No correlation between the genetic fingerprint of a particular strain and its resistance to high pressure processing was observed. C1 [Skinner, Guy E.; Marshall, Kristin M.; Morrissey, Travis R.; Reddy, N. Rukma; Larkin, John W.] US FDA, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. [Loeza, Viviana; Patazca, Eduardo] IIT, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. RP Skinner, GE (reprint author), US FDA, Inst Food Safety & Hlth, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM guy.skinner@fda.hhs.gov; kristin.marshall@fda.hhs.gov; rukma.reddy@fda.hhs.gov FU FDA FX We acknowledge the assistance of Louis Nowaczyk for preparing samples and performing PFGE. The work was supported by a grant from the FDA to the Institute for Food Safety and Health at Illinois Institute of Technology. NR 39 TC 4 Z9 4 U1 2 U2 24 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 DEC PY 2014 VL 77 IS 12 BP 2054 EP 2061 DI 10.4315/0362-028X.JFP-14-259 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA AU9ZK UT WOS:000345950200006 PM 25474050 ER PT J AU Kirshner, SL AF Kirshner, Susan L. TI Mechanisms Underlying the Immunogenicity of Therapeutic Proteins: Risk Assessment and Management Strategies SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Review ID ANTI-NATALIZUMAB ANTIBODIES; HUMAN GAMMA-GLOBULIN; NEUTRALIZING ANTIBODIES; BIOTECHNOLOGY PRODUCTS; HETEROGENEOUS NUCLEATION; BIOLOGICAL THERAPEUTICS; MULTIPLE-SCLEROSIS; IMMUNE-RESPONSES; GAUCHER-DISEASE; HOST ANTIBODIES AB Antibodies to therapeutic proteins have caused serious adverse events and loss of efficacy in patients. Therefore, it is critical to manage the risk of antitherapeutic antibodies (ATA) during drug development and in the postmarketing environment. Risk assessments are an important tool for managing immunogenicity risk because they provide a format for considering the consequences and likelihood of ATA development. Because many factors influence both the severity of the consequences and likelihood of ATA development, successful risk assessments require input from all relevant disciplines, including product quality, manufacturing, nonclinical, pharmacology, and clinical. The results of risk assessments are used to develop appropriate risk reduction strategies, which may include product quality and manufacturing controls and elements of clinical trial design. This article discusses considerations for immunogenicity risk assessments and management. C1 US FDA, Div Therapeut Proteins, Bethesda, MD 20892 USA. RP Kirshner, SL (reprint author), US FDA, Div Therapeut Proteins, 29 Lincoln Dr,Bldg 29A,Room 2D,16 HFD 120, Bethesda, MD 20892 USA. EM susan.kirshner@fda.hhs.gov NR 79 TC 0 Z9 0 U1 1 U2 7 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 DEC 1 PY 2014 VL 34 IS 12 SI SI BP 923 EP 930 DI 10.1089/jir.2013.0011 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA AW0EC UT WOS:000345962100002 ER PT J AU Pandey, GS Sauna, ZE AF Pandey, Gouri S. Sauna, Zuben E. TI Pharmacogenetics and the Immunogenicity of Protein Therapeutics SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Review ID RISK-BASED APPROACH; RECOMBINANT FACTOR-VIII; MILD HEMOPHILIA-A; INHIBITOR DEVELOPMENT; PRODUCTS; FVIII; GENE; F8; METAANALYSIS; PREVENTION AB The recognition that genetic factors influence the heterogeneity of individual responses to medications with respect to both toxicity and efficacy is not new. However, only following dramatic advances in functional genomics during the last decade did the development of so-called personalized medicine become a realistic possibility. Although drug development approaches that integrate pharmacogenetic information about both the protein drug and its protein target appear logical, given the complexity of biological systems, the selection of appropriate biomarkers and the study design remain daunting tasks. Here we present potential applications of pharmacogenetics in the development of recombinant coagulation factors. In addition, we highlight the potential utility of a personalized approach to predicting and eventually circumventing immunogenicity using the recombinant Factor VIII in the treatment of hemophilia A as a model system. The immunogenicity of protein therapeutics is of increasing concern during the development and licensure of biologics and clearly calls for a pharmacogenetic approach. This is because, with immunogenicity, the predicament is not that all patients develop inhibitory antibodies but that some individuals, ethnicities, or other subpopulations have a stronger immunogenic reaction than others do. C1 [Pandey, Gouri S.; Sauna, Zuben E.] US FDA, Lab Hemostasis, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Sauna, ZE (reprint author), US FDA, Lab Hemostasis, Div Hematol, Ctr Biol Evaluat & Res, 29 Lincoln Dr, Bethesda, MD 20892 USA. EM zuben.sauna@fda.hhs.gov FU Laboratory of Hemostasis; Center for Biologics Evaluation and Research, Food and Drug Administration's Modernization of Science program FX We thank Dr. Chava Kimchi-Sarfaty and Dr. Basil Golding for helpful discussions. This work was supported by funds from the Laboratory of Hemostasis and the Center for Biologics Evaluation and Research, Food and Drug Administration's Modernization of Science program (ZES). Our contributions are an informal communication and represent our own best judgment. These comments do not bind or obligate FDA. NR 40 TC 4 Z9 4 U1 2 U2 15 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 DEC 1 PY 2014 VL 34 IS 12 SI SI BP 931 EP 937 DI 10.1089/jir.2012.0136 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA AW0EC UT WOS:000345962100003 ER PT J AU Winter, HS Krzeski, P Heyman, MB Ibarguen-Secchia, E Iwanczak, B Kaczmarski, M Kierkus, J Kolacek, S Osuntokun, B Quiros, JA Shah, M Yacyshyn, B Dunnmon, PM AF Winter, Harland S. Krzeski, Piotr Heyman, Melvin B. Ibarguen-Secchia, Eduardo Iwanczak, Barbara Kaczmarski, Maciej Kierkus, Jaroslaw Kolacek, Sanja Osuntokun, Bankole Quiros, J. Antonio Shah, Manoj Yacyshyn, Bruce Dunnmon, Preston M. TI High- and Low-Dose Oral Delayed-Release Mesalamine in Children With Mild-to-Moderately Active Ulcerative Colitis SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE children; inflammatory bowel disease; mild-to-moderate ulcerative colitis; oral mesalamine; Pediatric Ulcerative Colitis Activity Index ID INFLAMMATORY-BOWEL-DISEASE; MULTICENTER; MANAGEMENT; TRIAL; G/DAY AB Objective: The aim of the study was to assess the safety and efficacy of high-and low-dose oral, delayed-release mesalamine in a randomized, double-blind, active control study of children with mild-to-moderately active ulcerative colitis. Methods: Patients ages 5 to 17 years, with a Pediatric Ulcerative Colitis Activity Index (PUCAI) score of >= 10 to <= 55 and a truncated Mayo Score of >= 1 for both rectal bleeding and stool frequency, were enrolled. They received body weight-dependent doses of oral, delayed-release mesalamine for 6 weeks in a low- (27-71 mg . g(-1) . day(-1)) or high-dose group (53-118 mg . g(-1) . day(-1)). The primary endpoint was treatment success, defined as the proportion of patients who achieved remission (PUCAI score <10) or partial response (PUCAI score >= 10 with a decrease from baseline by >= 20 points). Secondary endpoints included truncated Mayo Score and global assessment of change of disease activity. Results: The modified intent-to-treat population included 81 of 83 patients enrolled. Treatment success by PUCAI was achieved by 23 of 41 (56%) and 22 of 40 (55%) patients in the mesalamine low-and high-dose groups, respectively (P = 0.924). Truncated Mayo Score (low-dose 30 [73%] and high-dose 28 [70%] patients) and other efficacy results did not differ between the groups. The type and severity of adverse events were consistent with those reported in previous studies of adults with ulcerative colitis and did not differ between groups. Conclusions: Both low-and high-dose oral, delayed-release mesalamine doses were equally effective as short-term treatment of mild-to-moderately active ulcerative colitis in children, without a specific benefit or risk to using either dose. C1 [Winter, Harland S.] MassGen Hosp Children, Boston, MA 02114 USA. [Krzeski, Piotr] Medpace, Warsaw, Poland. [Heyman, Melvin B.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Ibarguen-Secchia, Eduardo] Methodist Childrens Hosp, San Antonio, TX USA. [Iwanczak, Barbara] Med Acad Wroclaw, Dept Pediat Gastroenterol & Nutr, Wroclaw, Poland. [Kaczmarski, Maciej] Med Univ Bialystok, Dept Pediat Gastroenterol & Allergol, Bialystok, Poland. [Kierkus, Jaroslaw] Childrens Mem Hlth Inst, Dept Gastroenterol Hepatol & Immunol, Warsaw, Poland. [Kolacek, Sanja] Univ Childrens Hosp Zagreb, Zagreb, Croatia. [Osuntokun, Bankole] Cook Childrens Med Ctr, Ft Worth, TX USA. [Quiros, J. Antonio] MUSC Pediat Ctr Inflammatory Bowel Disorders, Charleston, SC USA. [Shah, Manoj] Loma Linda Univ Childrens Hosp, Loma Linda, CA USA. [Yacyshyn, Bruce] Univ Cincinnati, Div Digest Dis, Cincinnati, OH USA. [Dunnmon, Preston M.] US FDA, Silver Spring, MD USA. RP Winter, HS (reprint author), MassGen Hosp Children, 175 Cambridge St,CRPZ 5-560, Boston, MA 02114 USA. EM hwinter@mgh.harvard.edu FU Warner Chilcott (US) LLC.; Janssen Pharmaceuticals; Prometheus Laboratories; UCB Pharmaceuticals; Autism Research Institute; Pediatric IBD Foundation; Nutricia; Shire; Salix Pharmaceuticals; Procter&Gamble Pharmaceuticals; CCFA; NIH [DK060617]; Chr. Hansen; FALK; Abbott; BioGaia; Nestle; Merck FX Financial support for the study and for writing and editorial services was provided by Warner Chilcott (US) LLC.; H.S.W.: consultant for Janssen Pharmaceuticals, Prometheus Laboratories, Mead Johnson, Salix, Shire, and AstraZeneca; grant support from Janssen Pharmaceuticals, Prometheus Laboratories, UCB Pharmaceuticals, Autism Research Institute, Pediatric IBD Foundation, and Nutricia. P.K.: employee of Procter&Gamble Pharmaceuticals and Warner Chilcott at the time of the study. M.B.H.: grant support from Shire, Salix Pharmaceuticals, Procter&Gamble Pharmaceuticals, UCB Pharmaceuticals, Janssen Pharmaceuticals, CCFA, and NIH (DK060617). M.K.: scientific board member of Mead Johnson Nutrition research grant "ALERNI Education Programme." S.K.: sponsored research for Chr. Hansen; lectures provided for Abbott, Arla Foods, BioGaia, JGL, Nestle, Nutricia, and MSD; grant support from FALK, Abbott, BioGaia, and Nestle. J.A.Q.: consultant for Sigma-Tau, Prometheus Laboratories, and Santarus. B.Y.: employee of Procter&Gamble Pharmaceuticals at time of study; speakers bureau for Optimer, Santarus, and Forest; consultant to N-8, GlaxoSmithKline, Sucampo, and Procter&Gamble Pharmaceuticals; and grant funding (ISP) from Merck. The remaining authors report no conflicts of interest. NR 16 TC 1 Z9 1 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 EI 1536-4801 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD DEC PY 2014 VL 59 IS 6 BP 767 EP 772 DI 10.1097/MPG.0000000000000530 PG 6 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA AU8NS UT WOS:000345853800021 PM 25419597 ER PT J AU Matlashewski, G Arana, B Kroeger, A Be-Nazir, A Mondal, D Nabi, SG Banjara, MR Das, ML Marasini, B Das, P Medley, G Satoskar, A Nakhasi, H Argaw, D Reeder, J Olliaro, P AF Matlashewski, Greg Arana, Byron Kroeger, Axel Be-Nazir, Ahmed Mondal, Dinesh Nabi, Shan Golam Banjara, Megha Raj Das, Murari Lal Marasini, Baburam Das, Pradeep Medley, Graham Satoskar, Abhay Nakhasi, Hira Argaw, Daniel Reeder, John Olliaro, Piero TI Research priorities for elimination of visceral leishmaniasis SO LANCET GLOBAL HEALTH LA English DT Editorial Material C1 [Matlashewski, Greg] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ H3A 2B4, Canada. [Arana, Byron; Kroeger, Axel; Reeder, John; Olliaro, Piero] WHO Special Program Res & Training Trop Dis, Geneva, Switzerland. [Mondal, Dinesh] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. [Banjara, Megha Raj] Tribhuvan Univ, Kathmandu, Nepal. [Das, Murari Lal] Koirala Inst Hlth Sci, Dept Microbiol, Dharan, Nepal. [Das, Pradeep] Rajendra Mem Res Inst Med Sci, Patna, Bihar, India. [Medley, Graham] Univ Warwick, Sch Life Sci, Coventry CV4 7AL, W Midlands, England. [Satoskar, Abhay] Ohio State Univ, Dept Pathol & Microbiol, Columbus, OH 43210 USA. [Nakhasi, Hira] US FDA, Ctr Biol Evaluat & Res, Silver Spring, WA USA. [Argaw, Daniel] WHO NTD, Neglected Trop Dis, Geneva, Switzerland. RP Matlashewski, G (reprint author), McGill Univ, Dept Microbiol & Immunol, 3775 Univ St, Montreal, PQ H3A 2B4, Canada. EM greg.matlashewski@mcgill.ca RI Medley, Graham/B-7289-2008 OI Medley, Graham/0000-0002-0030-7278 FU World Health Organization [001] NR 1 TC 9 Z9 9 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD DEC PY 2014 VL 2 IS 12 BP E683 EP E684 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AU5SB UT WOS:000345665600007 PM 25433617 ER PT J AU Alekel, DL Genschel, U Koehler, KJ Hofmann, H Van Loan, MD Beer, BS Hanson, LN Peterson, CT Kurzer, MS AF Alekel, D. Lee Genschel, Ulrike Koehler, Kenneth J. Hofmann, Heike Van Loan, Marta D. Beer, Bonnie S. Hanson, Laura N. Peterson, Charles T. Kurzer, Mindy S. TI Soy Isoflavones for Reducing Bone Loss (SIRBL) Study: Effect of a three-year trial on hormones, adverse events, and endometrial thickness in postmenopausal women SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Meeting Abstract CT 25th Annual Meeting of the North-American-Menopause-Society CY OCT 15-18, 2014 CL Washington, DC SP N Amer Menopause Soc C1 [Alekel, D. Lee] NIH, NCCAM, Bethesda, MD 20892 USA. [Genschel, Ulrike; Koehler, Kenneth J.; Hofmann, Heike] Iowa State Univ, Ames, IA USA. [Van Loan, Marta D.] Univ Calif Davis, USDA, ARS, Western Human Nutr Res Ctr, Davis, CA 95616 USA. [Beer, Bonnie S.] McFarland Clin, Ames, IA USA. [Hanson, Laura N.] Mayo Validat Support Serv, Rochester, MN USA. [Peterson, Charles T.] US FDA, Ctr Devices & Radiol Hlth, White Oak, MD USA. [Kurzer, Mindy S.] Univ Minnesota, St Paul, MN 55108 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD DEC PY 2014 VL 21 IS 12 MA S-8 BP 1328 EP 1329 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AU8KY UT WOS:000345846600047 ER PT J AU Andersen, PH Moscicki, R Sahakian, B Quirion, R Krishnan, R Race, T Phillips, A AF Andersen, Peter Hongaard Moscicki, Richard Sahakian, Barbara Quirion, Remi Krishnan, Ranga Race, Tim Phillips, Anthony CA 2013 CINP Summit Grp TI Securing the future of drug discovery for central nervous system disorders SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material C1 [Andersen, Peter Hongaard] Innovat Fund Denmark, DK-1100 Copenhagen K, Denmark. [Moscicki, Richard] US FDA, Silver Spring, MD 20993 USA. [Sahakian, Barbara] Univ Cambridge, Dept Psychiat, Cambridge CB2 2QQ, England. [Sahakian, Barbara] Univ Cambridge, Med Res Council, Cambridge CB2 2QQ, England. [Sahakian, Barbara] Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 2QQ, England. [Quirion, Remi] McGill Univ, Montreal, PQ H3G 2M1, Canada. [Krishnan, Ranga] Duke Univ, Singapore 169857, Singapore. [Krishnan, Ranga] Duke NUS Grad Med Sch, Singapore 169857, Singapore. [Race, Tim] Deutsch Bank, London EC2N 2EQ, England. [Phillips, Anthony] Univ British Columbia, Vancouver, BC V6T 1Z3, Canada. RP Andersen, PH (reprint author), Innovat Fund Denmark, Ostergade 26a, DK-1100 Copenhagen K, Denmark. EM peter.hongaard@innofond.dk FU Medical Research Council [G0701748] NR 2 TC 1 Z9 1 U1 0 U2 8 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 DEC PY 2014 VL 13 IS 12 BP 871 EP 872 DI 10.1038/nrd4489 PG 2 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA AU8HR UT WOS:000345837800001 PM 25435203 ER PT J AU Secora, AM Dormitzer, CM Staffa, JA Dal Pan, GJ AF Secora, Alex M. Dormitzer, Catherine M. Staffa, Judy A. Dal Pan, Gerald J. TI Measures to quantify the abuse of prescription opioids: a review of data sources and metrics SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Review DE prescription opioid; abuse; diversion; measurement; metrics; data sources; pharmacoepidemiology ID EXTENDED-RELEASE OXYCODONE; POISON DATA SYSTEM; UNITED-STATES; POSTMARKETING SURVEILLANCE; MONITORING PROGRAMS; TRAMADOL HYDROCHLORIDE; CONTROL CENTERS; THERAPEUTIC-USE; NONMEDICAL USE; DRUG-ABUSE AB PurposeThe abuse and nonmedical use of prescription opioids and its subsequent consequences are an important public health concern. This phenomenon has paralleled the increase in the therapeutic use of opioids for pain management. There is thus a need to measure prescription opioid abuse to understand trends over time and to compare abuse of one product to another. The purpose of this review is to provide an overview of the strengths and weaknesses of frequently used numerators and denominators in abuse ratios (ARs). MethodsFor this review, we critically evaluated the various measures to quantify drug availability and the available data sources to measure prescription opioid abuse. ResultsThere are currently no commonly adopted metrics for measuring either the prevalence of opioid abuse, or abuse relative to drug availability. Because the settings, manifestations, and severity of abuse can vary from one person to the next, no one measure of abuse, abuse-related outcome, or drug exposure is ideal. Each measure of abuse captures a specific facet of abuse, but not the whole spectrum. Reliable estimation of population-adjusted or utilization-adjusted rates of abuse can be accomplished with a prescription opioid AR. This metric estimates the prevalence of abuse in a given population or abuse relative to how much drug is available, and, in certain cases, can be used to compare abuse among various opioid drugs. AR measurements in the literature vary in the inclusion of specific measures of abuse and availability, and there is little consensus in the field regarding which measures allow for the most appropriate approximation of the extent of abuse, and for comparisons among opioids. Crude numbers of outcomes related to abuse (e.g., emergency department visits, treatment admissions, and overdoses) cannot be properly understood without context as these may overestimate or underestimate the true scope and severity of prescription opioid abuse. They can, however, serve as numerators in properly constructed ARs. The denominator of the AR provides the necessary context by accounting for populations at risk or drug availability (e.g., prescriptions or tablets dispensed, unique recipients of dispensed drug, total patient days of therapy, or kilograms sold), and each comes with its own set of assumptions to consider. ConclusionsMoving forward, it is important that there be a common understanding in the scientific community regarding how to select appropriate measures to serve as numerators and denominators in AR calculations, and how to interpret the resultant findings. There is no single best measure of abuse for use as a numerator in an AR, and each must be chosen and interpreted in the context of what it measures. For public health considerations, one must always look at both absolute numbers and adjusted numbers. When conducting multiple analyses using different measures of exposure as denominators, differences in ARs are not unexpected, but one should explore why there are differences and assess the appropriateness of each of the denominators. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Secora, Alex M.; Dormitzer, Catherine M.; Staffa, Judy A.; Dal Pan, Gerald J.] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Secora, AM (reprint author), US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, WO22,Room 24510903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Alex.Secora@fda.hhs.gov FU Oak Ridge Institute for Science and Education (ORISE) FX The authorship of this article was supported, in part, by the Oak Ridge Institute for Science and Education (ORISE), managed by Oak Ridge Associated Universities (ORAU). The principle author (AMS) had an ORISE fellowship at FDA during the initial part of its preparation. A special thanks to those in OSE's Division of Epidemiology who contributed to the thinking in this area, especially James Trinidad, Elizabeth Maloney, and Cynthia Kornegay. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. NR 61 TC 7 Z9 7 U1 1 U2 7 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 DEC PY 2014 VL 23 IS 12 BP 1227 EP 1237 DI 10.1002/pds.3711 PG 11 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AU9MS UT WOS:000345918200001 PM 25257660 ER PT J AU Hanig, J Paule, MG Ramu, J Schmued, L Konak, T Chigurupati, S Slikker, W Sarkar, S Liachenko, S AF Hanig, Joseph Paule, Merle G. Ramu, Jaivijay Schmued, Larry Konak, Tetyana Chigurupati, Srinivasulu Slikker, William, Jr. Sarkar, Sumit Liachenko, Serguei TI The use of MRI to assist the section selections for classical pathology assessment of neurotoxicity SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE MRI; MRS; T-2 signal; Neurotoxicity ID MAGNETIC-RESONANCE; DOMOIC ACID; RAT; DEGENERATION; MYELIN; EDEMA AB MRI was utilized to probe T-2 changes in living brain following exposure of rats to one of ten classical neurotoxicants. Brains were subsequently perfused for classical neuropathology examination. This approach was predicated on the assumption that the T-2 changes represent lad of neurotoxicity encompassing those seen using neuropathology techniques. The traditional neurotoxicologic approach of selecting a few arbitrary brain sections is dramatically improved by MRI targeting that can indicate the location(s) at which to collect "smart sections" for subsequent workup. MRI scans can provide the equivalent of 64 coronal sections; the number estimated for full coverage of the rat brain if only traditional neuropathology is utilized. Use of MRI allows each animal to serve as its own control as well as longitudinal observations of the life cycle of the neurotoxic lesion(s) (inception, apex and regression). Optimization of time of sacrifice and selection of an appropriate stain based on MRI-identified brain areas could be greatly enhanced should this approach prove successful. The application of full brain MRI imaging that informs neuropathology offers the potential to dramatically improve detection of neurotoxicity produced by new drugs and facilitate new drug development, review and approval processes, and to qualify an imaging biomarker of neuropathology. Published by Elsevier Inc. C1 [Hanig, Joseph] US FDA, Off Testing & Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Paule, Merle G.; Ramu, Jaivijay; Schmued, Larry; Konak, Tetyana; Chigurupati, Srinivasulu; Sarkar, Sumit; Liachenko, Serguei] Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. [Slikker, William, Jr.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Hanig, J (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 22,Room 2134, Silver Spring, MD 20993 USA. EM joseph.hanig@fda.hhs.gov FU FDA - Center for Drug Evaluation & Research (CDER) Critical Path Program, CDER Office of Research Testing; National Center for Toxicological Research/FDA [E0741801] FX FDA - Center for Drug Evaluation & Research (CDER) Critical Path Program, CDER Office of Research & Testing and National Center for Toxicological Research/FDA (E0741801) for support. NR 23 TC 4 Z9 4 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD DEC PY 2014 VL 70 IS 3 BP 641 EP 647 DI 10.1016/j.yrtph.2014.09.010 PG 7 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA AU7ZO UT WOS:000345816900008 PM 25265367 ER PT J AU Howard, PC Tong, WD Weichold, F Healy, M Slikker, W AF Howard, Paul C. Tong, Weida Weichold, Frank Healy, Marion Slikker, William TI Global Summit on Regulatory Science 2013 SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Regulatory science; Regulatory agencies; Global Summit on Regulatory Science AB Regulatory science has been defined as the science that is used to develop regulatory decisions by government bodies. Regulatory science encompasses many scientific disciplines that oversee many studies producing a wide array of data. These may include fundamental research into the cellular interaction or response to a particular chemical or substance, hazard-assessment and dose-response studies in animal species, neurophysiological or neurobehavioral studies, best practices for the generation and analysis of genomics data, bioinformatics approaches, and mathematical modeling of risk. The Global Summit on Regulatory Science is an international conference with a mission to explore emerging and innovative technologies, and provide a platform to enhance translation of basic science into regulatory applications. The Third Global Summit on Regulatory Science which focused on nanotechnology is discussed. Published by Elsevier Inc. C1 [Howard, Paul C.; Tong, Weida; Slikker, William] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Weichold, Frank] US FDA, Off Chief Scientist, Silver Spring, MD USA. [Healy, Marion] Food Stand Australia New Zealand, Canberra, BC, Australia. RP Howard, PC (reprint author), US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Paul.Howard@fda.hhs.gov FU U.S. Food and Drug Administration including The Office of the Commissioner; Office of International Programs; National Center for Toxicological Research; State of Arkansa FX The conference would not be possible without support from components of the U.S. Food and Drug Administration including The Office of the Commissioner (Dr. Margaret Hamburg), Office of International Programs (Ms. Mary Lou Valdez), National Center for Toxicological Research (Dr. William Slikker), and the State of Arkansas (Hon. Mike Beebee). The conference organizing and planning committee were indispensable in conducting the micro and macro details of logistics and organization, with special thanks to Ms. Roben Brooks. We are sincerely grateful to the presenters at the conference, including Margaret A. Hamburg, M.D. (Director, U.S. Food & Drug Administration, Washington DC USA), Jay Gandy, Ph.D. (Professor & Chair, Department of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR USA), Alexandru S. Bins, Ph.D. (Director, Center for Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, Little Rock, AR USA), Sally S. Tinkle, Ph.D. (Science and Technology Policy Institute, Washington DC USA), Vincent A. Hackley, Ph.D. (Materials Science Division, Nanomechanical Properties Group, National Institute of Standards and Technology, Gaithersburg, MD USA), Martin A. Philbert, Ph.D. (Dean, School of Public Health, University of Michigan, Ann Arbor, MI USA), Steve T. Stern, Ph.D. (Nanotechnology Characterization Laboratory, National Cancer Institute, Frederick, MD USA), Hongda Chen, Ph.D. (National Program Leader, Bioprocess Engineering and Nanotechnology, National Institute of Food Agriculture, U.S. Department of Agriculture, Washington DC USA), Vladimir P. Zharov, Ph.D., D.Sc. (Director, Arkansas Nanomedicine Center, University of Arkansas for Medical Sciences, Little Rock, AR USA), David B. Warheit, Ph.D. (Senior Research Toxicologist, Acute and Developmental Toxicology Division, E.I. DuPont de Nemours and Co., Inc., Dover, DE USA), Nigel J. Walker, Ph.D. (Deputy Director for Science, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC USA), Kevin L. Dreher, Ph.D. (Cardiopulmonary and Immunotoxicology Branch, U.S. Environmental Protection Agency, Research Triangle Park, NC USA), Jong Kwon Lee, D.V.M., Ph.D. (Deputy Director, Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Seol, Korea), Frank F. Weichold, M.D. (Office of Chief Scientist, U.S. Food and Drug Administration, Silver Spring, MD USA), Asif Rasheed, Ph.D. (Office of New Animal Drug Evaluation, Division of Manufacturing Technologies, Center for Veterinary Medicine, U.S. Food and Drug Administration, Laurel MD USA), Michael M. Landa, Esq. (Director, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, MD USA), Subhas G. Malghan, Ph.D. (Deputy Director, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD USA), Paul C. Howard, Ph.D. (National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR USA), and Jan Simak, Ph.D. (Division of Hematology, Office of Blood Research and Review, Center for Biologics and Experimental Research, U.S. Food and Drug Administration, Bethesda MD USA). NR 6 TC 1 Z9 1 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 DEC PY 2014 VL 70 IS 3 BP 728 EP 732 DI 10.1016/j.yrtph.2014.08.004 PG 5 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA AU7ZO UT WOS:000345816900018 PM 25128336 ER PT J AU Landgren, O Gormley, N Turley, D Owen, RG Rawstron, A Paiva, B Barnett, D Arroz, M Wallace, P Durie, B Yuan, C Dogan, A Stetler-Stevenson, M Marti, GE AF Landgren, Ola Gormley, Nicole Turley, Danielle Owen, Roger G. Rawstron, Andy Paiva, Bruno Barnett, David Arroz, Maria Wallace, Paul Durie, Brian Yuan, Constance Dogan, Ahmet Stetler-Stevenson, Maryalice Marti, Gerald E. TI Flow cytometry detection of minimal residual disease in multiple myeloma: Lessons learned at FDA-NCI roundtable symposium SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter ID STEM-CELL TRANSPLANTATION C1 [Landgren, Ola; Yuan, Constance; Stetler-Stevenson, Maryalice] NCI, Bethesda, MD 20892 USA. [Gormley, Nicole; Turley, Danielle; Marti, Gerald E.] US FDA, Silver Spring, MD USA. [Owen, Roger G.; Rawstron, Andy] St Jamess Inst Oncol, HMDS Lab, Leeds, W Yorkshire, England. [Paiva, Bruno] Univ Navarra Clin, Pamplona, Spain. [Paiva, Bruno] CIMA, Pamplona, Spain. [Barnett, David] Royal Hallamshire Hosp, UK NEQAS Leucocyte Immunophenotyping, Shefield, England. [Arroz, Maria] CHLO, HSFX, Dept Clin Pathol, Lisbon, Portugal. [Wallace, Paul] Roswell Pk Canc Inst, Dept Flow & Image Cytometry, Buffalo, NY 14263 USA. [Durie, Brian] Cedars Sinai Comprehens Canc Ctr, Los Angeles, CA USA. [Dogan, Ahmet] Mem Sloan Kettering Canc Ctr, Hematopathol Serv, New York, NY 10021 USA. RP Landgren, O (reprint author), NCI, Bethesda, MD 20892 USA. EM landgrec@mskcc.org OI Rawstron, Andy/0000-0003-0798-9790 NR 8 TC 21 Z9 21 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2014 VL 89 IS 12 BP 1159 EP 1160 DI 10.1002/ajh.23831 PG 2 WC Hematology SC Hematology GA AU1CK UT WOS:000345358600026 PM 25132630 ER PT J AU Thompson, A Lawrence, J Stockbridge, N AF Thompson, Aliza Lawrence, John Stockbridge, Norman TI GFR Decline as an End Point in Trials of CKD: A Viewpoint From the FDA SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material C1 [Thompson, Aliza; Lawrence, John; Stockbridge, Norman] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Thompson, A (reprint author), US FDA, Ctr Drug Evaluat & Res, White Oak Campus,Bldg 22,Room 4109, Silver Spring, MD 20993 USA. EM Aliza.Thompson@fda.hhs.gov NR 6 TC 7 Z9 8 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD DEC PY 2014 VL 64 IS 6 BP 836 EP 837 DI 10.1053/j.ajkd.2014.09.006 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA AU1TZ UT WOS:000345404200002 PM 25446026 ER PT J AU Jones, JL Ludeke, CHM Bowers, JC DeRosia-Banick, K Carey, DH Hastback, W AF Jones, Jessica L. Luedeke, Catharina H. M. Bowers, John C. DeRosia-Banick, Kristin Carey, David H. Hastback, William TI Abundance of Vibrio cholerae, V-vulnificus, and V-parahaemolyticus in Oysters (Crassostrea virginica) and Clams (Mercenaria mercenaria) from Long Island Sound SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID UNITED-STATES; CHESAPEAKE BAY; GULF-COAST; SHELLFISH; INFECTIONS; DIARRHEA; ECOLOGY; STORAGE; WATERS; SAFETY AB Vibriosis is a leading cause of seafood-associated morbidity and mortality in the United States. Typically associated with consumption of raw or undercooked oysters, vibriosis associated with clam consumption is increasingly being reported. However, little is known about the prevalence of Vibrio spp. in clams. The objective of this study was to compare the levels of Vibrio cholerae, Vibrio vulnificus, and Vibrio parahaemolyticus in oysters and clams harvested concurrently from Long Island Sound (LIS). Most probable number (MPN)-real-time PCR methods were used for enumeration of total V. cholerae, V. vulnificus, V. parahaemolyticus, and pathogenic (tdh(+) and/or trh(+)) V. parahaemolyticus. V. cholerae was detected in 8.8% and 3.3% of oyster (n = 68) and clam (n = 30) samples, with levels up to 1.48 and 0.48 log MPN/g in oysters and clams, respectively. V. vulnificus was detected in 97% and 90% of oyster and clam samples, with median levels of 0.97 and - 0.08 log MPN/g, respectively. V. parahaemolyticus was detected in all samples, with median levels of 1.88 and 1.07 log MPN/g for oysters and clams, respectively. The differences between V. vulnificus and total and pathogenic V. parahaemolyticus levels in the two shellfish species were statistically significant (P < 0.001). These data indicate that V. vulnificus and total and pathogenic V. parahaemolyticus are more prevalent and are present at higher levels in oysters than in hard clams. Additionally, the data suggest differences in vibrio populations between shellfish harvested from different growing area waters within LIS. These results can be used to evaluate and refine illness mitigation strategies employed by risk managers and shellfish control authorities. C1 [Jones, Jessica L.; Luedeke, Catharina H. M.] US FDA, Gulf Coast Seafood Lab, Div Seafood Sci & Technol, Dauphin Isl, AL 36528 USA. [Luedeke, Catharina H. M.] Univ Hamburg, Hamburg Sch Food Sci, Hamburg, Germany. [Bowers, John C.] US FDA, Ctr Food Safety & Appl Nutr, Div Publ Hlth Informat & Analyt, College Pk, MD USA. [DeRosia-Banick, Kristin; Carey, David H.] Bur Aquaculture, Dept Agr, Milford, CT USA. [Hastback, William] Bur Marine Resources, Dept Environm Conservat, East Setauket, NY USA. RP Jones, JL (reprint author), US FDA, Gulf Coast Seafood Lab, Div Seafood Sci & Technol, Dauphin Isl, AL 36528 USA. EM Jessica.Jones@fda.hhs.gov FU FDA FX This project was supported, in part, by an appointment to the Research Fellowship Program for the Center for Food Safety and Applied Nutrition administered by the Oak Ridge Associated Universities through a contract with the FDA. NR 33 TC 12 Z9 12 U1 0 U2 25 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 DEC PY 2014 VL 80 IS 24 BP 7667 EP 7672 DI 10.1128/AEM.02820-14 PG 6 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA AT9BS UT WOS:000345223500024 PM 25281373 ER PT J AU Handy, SM Chizhikov, V Yakes, BJ Paul, SZ Deeds, JR Mossoba, MM AF Handy, Sara M. Chizhikov, Vladimir Yakes, Betsy Jean Paul, Stephen Z. Deeds, Jonathan R. Mossoba, Magdi M. TI Microarray Chip Development Using Infrared Imaging for the Identification of Catfish Species SO APPLIED SPECTROSCOPY LA English DT Article DE Catfish; Mid-infrared; Chemical imaging; Deoxyribonucleic acid; DNA microarrays; Raman spectroscopy; DNA oligoprobes ID ENHANCED RAMAN-SPECTROSCOPY; NANOPARTICLE PROBES; DNA MICROARRAYS; FISHES; PRODUCTS; BARCODE; IRCI AB Several families of catfish species are extensively aquacultured around the world; however, only those from the family Ictaluridae can be labeled as catfish in the United States. Non-lctalurid catfish species that are marketed as "catfish" in the USA are considered misbranded. Misbranding in general has led to an increased interest in developing deoxyribonucleic acid (DNA)-based methods such as DNA barcoding, polymerase chain reaction restriction fragment length polymorphism, and DNA microarrays with fluorescence detection for the identification of fish species. In this proof-of-concept study, DNA microarrays coupled with a newly developed mid-infrared imaging detection method were applied to the identification of seven species of catfish for the first time. Species-specific DNA probes targeting three regions per species of the cytochrome c oxidase 1 (barcoding) gene were developed and printed as microarrays on glass slides. Deoxyribonucleic acid targets labeled with biotin were hybridized to their complementary probes using a strategy that allowed the selective formation of a silver layer on hybridized spots needed for detection. Using this three-probe format, the seven species were all identified correctly, even when a limited number of false positive spots were observed. Raman spectroscopy was employed to further characterize the arrays. C1 [Handy, Sara M.; Yakes, Betsy Jean; Paul, Stephen Z.; Deeds, Jonathan R.; Mossoba, Magdi M.] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Chizhikov, Vladimir] US FDA, Lab Methods Dev, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Handy, SM (reprint author), US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Sara.Handy@fda.hhs.gov RI Handy, Sara/C-6195-2008 NR 36 TC 1 Z9 1 U1 0 U2 14 PU SOC APPLIED SPECTROSCOPY PI FREDERICK PA 5320 SPECTRUM DRIVE SUITE C, FREDERICK, MD 21703 USA SN 0003-7028 EI 1943-3530 J9 APPL SPECTROSC JI Appl. Spectrosc. PD DEC PY 2014 VL 68 IS 12 BP 1365 EP 1373 DI 10.1366/14-07505 PG 9 WC Instruments & Instrumentation; Spectroscopy SC Instruments & Instrumentation; Spectroscopy GA AU3ZB UT WOS:000345547900007 PM 25356840 ER PT J AU Hoch, U Staschen, CM Johnson, RK Eldon, MA AF Hoch, Ute Staschen, Carl-Michael Johnson, Randall K. Eldon, Michael A. TI Nonclinical pharmacokinetics and activity of etirinotecan pegol (NKTR-102), a long-acting topoisomerase 1 inhibitor, in multiple cancer models SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Topoisomerase 1 inhibition; Anticancer activity; Etirinotecan pegol; SN38; Pharmacokinetics ID METASTATIC COLORECTAL-CANCER; MULTICENTER PHASE-II; CELL LUNG-CANCER; SOLID TUMORS; IRINOTECAN CPT-11; ANTICANCER AGENTS; XENOGRAFT MODELS; OVARIAN-CANCER; BREAST-CANCER; 2 SCHEDULES AB The aim of the study was to demonstrate the activity of etirinotecan pegol, a polymer conjugate of irinotecan, in multiple human tumor models and to establish both the pharmacokinetic/pharmacodynamics (PK/PD) relationship and clinical relevance of the findings. Anti-tumor activity was evaluated in mouse models of human lung, colorectal, breast, ovarian, and gastric cancers. Etirinotecan pegol was administered intravenously (once or every 3-7 days) to animals with established tumors. Activity was assessed by tumor growth delay (TGD) and regression. Mice bearing established colorectal and lung tumors were treated with etirinotecan pegol or irinotecan, and serial blood and tumor samples were collected at planned times between 0 and 60 days post-treatment for quantitation of etirinotecan pegol and SN38. For PK analysis, analyte concentration-time data were fit with compartmental models; PK/PD analysis was based on an inhibitory E (max) response model. Etirinotecan pegol was active in all tumor models. TGD was sustained for 2-10 weeks after last dose, while conventional irinotecan resulted in little suppression of tumor growth. Etirinotecan pegol was eliminated very slowly from the tumor (t (1/2) = 17 days), achieving higher and more sustained tumor exposure when compared with conventional irinotecan. The increased tumor exposure following etirinotecan pegol correlated with strong and prolonged suppression of tumor growth. Sustained plasma exposure to active SN38 was consistently observed across nonclinical species (including mouse, rat, and dog) and translated to cancer patients. Etirinotecan pegol is the first long-acting topoisomerase 1 inhibitor that provides sustained exposure, which results in prolonged anti-tumor activity in a wide variety of cancer models. C1 [Hoch, Ute; Eldon, Michael A.] Nektar Therapeut, San Francisco, CA 94158 USA. [Staschen, Carl-Michael] US FDA, Rockville, MD 20857 USA. RP Hoch, U (reprint author), Nektar Therapeut, 455 Mission Bay Blvd South, San Francisco, CA 94158 USA. EM uhoch@nektar.com FU Nektar Therapeutics FX The authors thank Ron Wolff, Elizabeth Tonkin, and Heather Persson for their help and assistance in our experiments. They also thank Yuan Song for help with analyzing the samples and Janice Y. Ahn for editorial assistance. This research was supported by Nektar Therapeutics. NR 48 TC 12 Z9 13 U1 1 U2 12 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 DEC PY 2014 VL 74 IS 6 BP 1125 EP 1137 DI 10.1007/s00280-014-2577-7 PG 13 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA AU0RB UT WOS:000345330400003 PM 25228368 ER PT J AU Mishra, P Florian, J Qi, KR Zeng, W Naeger, LK Donaldson, E Connelly, S O'Rear, J Price, D Murray, J Birnkrant, D AF Mishra, Poonam Florian, Jeffry Qi, Karen Zeng, Wen Naeger, Lisa K. Donaldson, Eric Connelly, Sarah O'Rear, Jules Price, Dionne Murray, Jeffrey Birnkrant, Debra TI FDA Perspective on Sofosbuvir Therapy for Patients With Chronic Hepatitis C Virus Genotype 1 Infection Who Did Not Respond to Treatment With Pegylated Interferon and Ribavirin SO GASTROENTEROLOGY LA English DT Editorial Material ID ALPHA-2A; UPDATE C1 [Mishra, Poonam; Florian, Jeffry; Qi, Karen; Zeng, Wen; Naeger, Lisa K.; Donaldson, Eric; Connelly, Sarah; O'Rear, Jules; Price, Dionne; Murray, Jeffrey; Birnkrant, Debra] US FDA, Silver Spring, MD 20993 USA. RP Mishra, P (reprint author), US FDA, Silver Spring, MD 20993 USA. NR 13 TC 5 Z9 7 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2014 VL 147 IS 6 BP 1196 EP 1200 DI 10.1053/j.gastro.2014.10.027 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU3PC UT WOS:000345524800009 PM 25449024 ER PT J AU Mishra, P Jason, M Cao, KY Singer, M Murray, JS Birnkrant, D AF Mishra, Poonam Jason, Mihaela Cao, Kelly Y. Singer, Mary Murray, Jeffrey S. Birnkrant, Debra TI Concomitant Use of Simeprevir and Sofosbuvir for Treatment of Chronic Hepatitis C: A Review of Post-marketing Surveillance Using the FDA Adverse Event Reporting System (FAERS) SO HEPATOLOGY LA English DT Meeting Abstract C1 [Mishra, Poonam; Jason, Mihaela; Cao, Kelly Y.; Singer, Mary; Murray, Jeffrey S.; Birnkrant, Debra] US FDA, Siver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD DEC PY 2014 VL 60 IS 6 MA LB-35 BP 1287A EP 1288A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU3MI UT WOS:000345517000036 ER PT J AU Mishra, P Florian, J Murray, J AF Mishra, Poonam Florian, Jeffry Murray, Jeffrey TI FDA Bridging Analyses Confirmed in Clinical Trial SO HEPATOLOGY LA English DT Letter C1 [Mishra, Poonam; Murray, Jeffrey] US FDA, Div Antiviral Prod, Silver Spring, MD 20993 USA. [Florian, Jeffry] US FDA, Div Pharmacometr, Silver Spring, MD USA. RP Mishra, P (reprint author), US FDA, Div Antiviral Prod, Silver Spring, MD 20993 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD DEC PY 2014 VL 60 IS 6 BP 2134 EP 2134 DI 10.1002/hep.27107 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU3MI UT WOS:000345517000086 PM 24591059 ER PT J AU Calderon, SN Klein, M AF Calderon, Silvia N. Klein, Michael TI A regulatory perspective on the abuse potential evaluation of novel stimulant drugs in the United States SO NEUROPHARMACOLOGY LA English DT Review DE Abuse potential stimulants; Drug scheduling; Eight factor analysis ID LIABILITY ASSESSMENT; PRINCIPLES; AMPHETAMINE AB In the United States of America (USA), the abuse potential assessment of a drug is performed as part of the safety evaluation of a drug under development, and to evaluate if the drug needs to be subject to controls that would minimize the abuse of the drug once on the market. The assessment of the abuse potential of new drugs consists of a scientific and medical evaluation of all data related to abuse of the drug. This paper describes the regulatory framework for evaluating the abuse potential of new drugs, in general, including novel stimulants. The role of the United States Food and Drug Administration (FDA) in the evaluation of the abuse potential of drugs, and its role in drug control are also discussed. A definition of abuse potential, an overview of the currently accepted approaches to evaluating the abuse potential of a drug, as well as a description of the criteria that applies when recommending a specific level of control (i.e., a Schedule) for a drug under the Controlled Substances Act (CSA). This article is part of the Special Issue entitled 'CNS Stimulants'. Published by Elsevier Ltd. C1 [Calderon, Silvia N.; Klein, Michael] US FDA, Controlled Subst Staff, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Calderon, SN (reprint author), US FDA, Controlled Subst Staff, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM silvia.calderon@fda.hhs.gov NR 24 TC 6 Z9 6 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD DEC PY 2014 VL 87 SI SI BP 97 EP 103 DI 10.1016/j.neuropharm.2014.04.001 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AU2XR UT WOS:000345478400011 PM 24727212 ER PT J AU Durai, P Ferlin, KM Fisher, JP Kaplan, DS AF Durai, Priyanka Ferlin, Kimberly M. Fisher, John P. Kaplan, David S. TI Characterization of Chondrocyte Adhesion on Protein-Coated 2D and 3D Substrates SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS-AM Conference CY DEC 13-16, 2014 CL Washington, DC SP TERMIS AM C1 [Durai, Priyanka; Kaplan, David S.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Ferlin, Kimberly M.; Fisher, John P.] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC 1 PY 2014 VL 20 SU 1 MA U-6 BP S135 EP S135 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AU6AK UT WOS:000345684300531 ER PT J AU Ferlin, KM Kaplan, DS Fisher, JP AF Ferlin, K. M. Kaplan, D. S. Fisher, J. P. TI Optimization of Surface-Modified Biodegradable Scaffolds for Mesenchymal Stem Cell Adhesion and Differentiation SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS-AM Conference CY DEC 13-16, 2014 CL Washington, DC SP TERMIS AM C1 [Ferlin, K. M.; Fisher, J. P.] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [Kaplan, D. S.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC 1 PY 2014 VL 20 SU 1 MA O-362 BP S29 EP S29 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AU6AK UT WOS:000345684300107 ER PT J AU Miller, ML Ferlin, KM Kaplan, DS Fisher, JP AF Miller, Makenzie L. Ferlin, Kimberly M. Kaplan, David S. Fisher, John P. TI The Influence of Protein-Modified Surfaces on Mesenchymal Stem Cell Adhesion and Isolation SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS-AM Conference CY DEC 13-16, 2014 CL Washington, DC SP TERMIS AM C1 [Miller, Makenzie L.; Ferlin, Kimberly M.; Fisher, John P.] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [Kaplan, David S.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC 1 PY 2014 VL 20 SU 1 MA U-15 BP S137 EP S137 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AU6AK UT WOS:000345684300540 ER PT J AU Prendergast, ME Ferlin, KM Kaplan, DS Fisher, JP AF Prendergast, Margaret E. Ferlin, Kimberly M. Kaplan, David S. Fisher, John P. TI Influence of 3D-Printed Pore Architecture on Mesenchymal Stem Cell Proliferation and Differentiation SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS-AM Conference CY DEC 13-16, 2014 CL Washington, DC SP TERMIS AM C1 [Prendergast, Margaret E.; Ferlin, Kimberly M.; Fisher, John P.] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [Kaplan, David S.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. NR 1 TC 0 Z9 0 U1 2 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC 1 PY 2014 VL 20 SU 1 MA U-17 BP S138 EP S138 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AU6AK UT WOS:000345684300542 ER PT J AU Gauger, PC Loving, CL Khurana, S Lorusso, A Perez, DR Kehrli, ME Roth, JA Golding, H Vincent, AL AF Gauger, Phillip C. Loving, Crystal L. Khurana, Surender Lorusso, Alessio Perez, Daniel R. Kehrli, Marcus E., Jr. Roth, James A. Golding, Hana Vincent, Amy L. TI Live attenuated influenza A virus vaccine protects against A(H1N1) pdm09 heterologous challenge without vaccine associated enhanced respiratory disease SO VIROLOGY LA English DT Article DE Swine; Influenza A; Pandemic H1N1; Live attenuated influenza virus; Whole inactivated virus; Enhanced pneumonia ID PANDEMIC H1N1 2009; CROSS-PROTECTION; UNITED-STATES; H3N2 VIRUS; SWINE; PIGS; INFECTION; ANTIBODIES; EFFICACY; HUMANS AB Live-attenuated influenza virus (LAIV) vaccines may provide cross-protection against contemporary influenza A virus (IAV) in swine. Conversely, whole inactivated virus (WIV) vaccines have the potential risk of vaccine-associated enhanced respiratory disease (VAERD) when challenged with IAV of substantial antigenic drift. A temperature sensitive, intranasal H1N2 LAIV was compared to wild type exposure (WT) and an intramuscular WIV vaccine in a model shown to induce VAERD. WIV vaccinated swine challenged with pandemic A/H1N1 (H1N1pdm09) were not protected from infection and demonstrated severe respiratory disease consistent with VAERD. Lung lesions were mild and challenge virus was not detected in the respiratory tract of LAIV vaccinates. High levels of post-vaccination IgG serum antibodies targeting the H1N1pdm09 HA2 stalk domain were exclusively detected in the WIV group and associated with increased H1N1pdm09 virus infectivity in MDCK cells. In contrast, infection-enhancing antibodies were not detected in the serum of LAIV vaccinates and VAERD was not observed. Published by Elsevier Inc. C1 [Gauger, Phillip C.; Loving, Crystal L.; Lorusso, Alessio; Kehrli, Marcus E., Jr.; Vincent, Amy L.] ARS, Virus & Prion Res Unit, Natl Anim Dis Ctr, USDA, Ames, IA 50010 USA. [Gauger, Phillip C.] Iowa State Univ, Dept Vet Diagnost & Prod Anim Med, Coll Vet Med, Ames, IA 50011 USA. [Khurana, Surender; Golding, Hana] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Perez, Daniel R.] Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. [Perez, Daniel R.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Roth, James A.] Iowa State Univ, Dept Vet Microbiol & Prevent Med, Coll Vet Med, Ames, IA 50011 USA. RP Vincent, AL (reprint author), Natl Anim Dis Ctr, 1920 Dayton Ave,POB 70, Ames, IA 50010 USA. EM amy.vincent@ars.usda.gov RI Roth, James/A-7122-2009; Lorusso, Alessio/A-7311-2016; OI Roth, James/0000-0003-3562-668X; Lorusso, Alessio/0000-0001-7933-7367; Perez, Daniel/0000-0002-6569-5689; Lorusso, Alessio/0000-0001-6156-8212 FU USDA-ARS FX This work was supported by USDA-ARS. The sponsor had no role in the study design, data collection, analysis and interpretation of data, writing of the manuscript or the decision to submit for publication. The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this manuscript. NR 52 TC 9 Z9 9 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD DEC PY 2014 VL 471 BP 93 EP 104 DI 10.1016/j.virol.2014.10.003 PG 12 WC Virology SC Virology GA AU3FJ UT WOS:000345497600011 PM 25461535 ER PT J AU Slavov, SH Wilkes, JG Buzatu, DA Kruhlak, NL Willard, JM Hanig, JP Beger, RD AF Slavov, Svetoslav H. Wilkes, Jon G. Buzatu, Dan A. Kruhlak, Naomi L. Willard, James M. Hanig, Joseph P. Beger, Richard D. TI Computational identification of a phospholipidosis toxicophore using C-13 and N-15 NMR-distance based fingerprints SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Phospholipidosis; Toxicophore; Fingerprint; Quantitative spectral data-activity relationship (3D-QSDAR); Molecular modeling ID DRUG-INDUCED PHOSPHOLIPIDOSIS; CONSTRUCTION; ALGORITHMS; MECHANISM; TOXICITY; BINDING; MODELS AB Modified 3D-SDAR fingerprints combining C-13 and N-15 NMR chemical shifts augmented with inter-atomic distances were used to model the potential of chemicals to induce phospholipidosis (PLD). A curated dataset of 328 compounds (some of which were cationic amphiphilic drugs) was used to generate 3D-QSDAR models based on tessellations of the 3D-SDAR space with grids of different density. Composite PLS models averaging the aggregated predictions from 100 fully randomized individual models were generated. On each of the 100 runs, the activities of an external blind test set comprised of 294 proprietary chemicals were predicted and averaged to provide composite estimates of their PLD-inducing potentials (PLD+ if PLD is observed, otherwise PLD-). The best performing 3D-QSDAR model utilized a grid with a density of 8 ppm x 8 ppm in the C-C region, 8 ppm x 20 ppm in the C-N region and 20 ppm x 20 ppm in the N-N region. The classification predictive performance parameters of this model evaluated on the basis of the external test set were as follows: accuracy = 0.70, sensitivity = 0.73 and specificity = 0.66. A projection of the most frequently occurring bins on the standard coordinate space suggested a toxicophore composed of an aromatic ring with a centroid 3.5-7.5 angstrom distant from an amino-group. The presence of a second aromatic ring separated by a 4-5 angstrom spacer from the first ring and at a distance of between 5.5 angstrom and 7 angstrom from the amino-group was also associated with a PLD+ effect. These models provide comparable predictive performance to previously reported models for PLD with the added benefit of being based entirely on non-confidential, publicly available training data and with good predictive performance when tested in a rigorous, external validation exercise. 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 [Slavov, Svetoslav H.; Wilkes, Jon G.; Buzatu, Dan A.; Beger, Richard D.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Kruhlak, Naomi L.; Willard, James M.; Hanig, Joseph P.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Beger, RD (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Richard.Beger@fda.hhs.gov FU National Center for Toxicological Research (FDA); Center for Drug Evaluation and Research (FDA) FX This work was supported by the National Center for Toxicological Research (FDA) and the Center for Drug Evaluation and Research (FDA). The authors thank Ms. Barbara Minnier for assistance in identifying and providing external validation case studies. NR 27 TC 6 Z9 6 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD DEC 1 PY 2014 VL 22 IS 23 BP 6706 EP 6714 DI 10.1016/j.bmc.2014.08.021 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA AU0BE UT WOS:000345287300017 PM 25228124 ER PT J AU Cowley, SC AF Cowley, Siobhan C. TI MAIT cells and pathogen defense SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Invariant T cells; Innate T cells; MR1; Innate immunity; Mucosal immunity ID INVARIANT T-CELLS; BACTERIAL-INFECTION; ADAPTIVE IMMUNITY; PERIPHERAL-BLOOD; ALPHA-CHAIN; IN-VIVO; INNATE; ACTIVATION; INFLAMMATION; LYMPHOCYTES AB Mucosa-associated invariant T (MAIT) cells are a unique population of innate T cells that are abundant in humans. These cells possess an evolutionarily conserved invariant T cell receptor alpha chain restricted by the nonpolymorphic class Ib major histocompatibility (MHC) molecule, MHC class I-related protein (MR1). The recent discovery that MAIT cells are activated by MR1-bound riboflavin metabolite derivatives distinguishes MAIT cells from all other alpha beta T cells in the immune system. Since mammals lack the capacity to synthesize riboflavin, intermediates from the riboflavin biosynthetic pathway are distinct microbial molecular patterns that provide a unique signal to the immune system. Multiple lines of evidence suggest that MAIT cells, which produce important cytokines such as IFN-gamma, TNF, and IL-17A, have the potential to influence immune responses to a broad range of pathogens. Here we will discuss our current understanding of MAIT cell biology and their role in pathogen defense. C1 US FDA, Div Bacterial Parasit & Allergen Prod, Lab Mycobacterial Dis & Cellular Immunol, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Cowley, SC (reprint author), US FDA, Div Bacterial Parasit & Allergen Prod, Lab Mycobacterial Dis & Cellular Immunol, Ctr Biol Evaluat & Res, 1401 Rockville Pike HFM-431, Rockville, MD 20852 USA. EM siobhan.cowley@fda.hhs.gov NR 52 TC 8 Z9 8 U1 1 U2 9 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD DEC PY 2014 VL 71 IS 24 BP 4831 EP 4840 DI 10.1007/s00018-014-1708-y PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AT6ZM UT WOS:000345085600009 PM 25164578 ER PT J AU Zhang, L Lee, SC Zhao, H Wu, F AF Zhang, L. Lee, S. C. Zhao, H. Wu, F. TI Response to "Erlotinib and Gastric Acid-Reducing Agents: A Combination to Avoid or to Support?" SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Letter C1 [Zhang, L.; Lee, S. C.; Zhao, H.; Wu, F.] 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 NR 4 TC 2 Z9 2 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 DEC PY 2014 VL 96 IS 6 BP 659 EP 659 DI 10.1038/clpt.2014.192 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AT8RS UT WOS:000345200400023 PM 25247623 ER PT J AU Dill, S Ahn, J AF Dill, Susie Ahn, Jin TI Drug shortages in developed countries-reasons, therapeutic consequences, and handling SO EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Review DE Sterile injectables; Manufacturers; Drug shortages AB Drug shortages in developed countries pose a serious public health problem and have far-reaching implications for healthcare providers and their patients. Given the current state of the market, with the limited number of manufacturers and the array of manufacturing quality issues, drug shortages have become a global concern, forcing regulatory authorities to explore and implement strategies to prevent and mitigate drug shortages. C1 [Dill, Susie; Ahn, Jin] US FDA, Silver Spring, MD 20993 USA. RP Dill, S (reprint author), US FDA, Silver Spring, MD 20993 USA. EM susie.dill@fda.hhs.gov NR 9 TC 2 Z9 2 U1 0 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0031-6970 EI 1432-1041 J9 EUR J CLIN PHARMACOL JI Eur. J. Clin. Pharmacol. PD DEC PY 2014 VL 70 IS 12 BP 1405 EP 1412 DI 10.1007/s00228-014-1747-1 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AT7SY UT WOS:000345138700001 PM 25228250 ER PT J AU Zhou, EH Kang, EM Seymour, S Iyasu, S AF Zhou, Esther H. Kang, Elizabeth M. Seymour, Sally Iyasu, Solomon TI Long-acting beta(2)-adrenergic agonist in pediatric and adolescent asthma patients, 2003-2011 SO JOURNAL OF ASTHMA LA English DT Article DE Asthma; FDA regulatory activity; LABA dispensing patterns ID BETA-AGONISTS; PRESCRIPTION PATTERNS; MEDICATION USE; DRUG SAMPLES; SAFE USE; RISKS; SALMETEROL; EDUCATION; BEHAVIOR; CHILDREN AB Objectives: To evaluate changes in the dispensing patterns of long-acting beta(2)-adrenergic agonist (LABA) in pediatric and adolescent asthma patients in relation to multiple Food and Drug Administration (FDA) regulatory activities from 2003 to 2011. Methods: We estimated LABA dispensing to pediatric asthma patients across three periods: 2003-2004 (after the first labeling change), 2005-2009 (after regulatory activities in 2005 and before 2010 LABA labeling change) and 2010-2011 (after 2010 LABA labeling change), using the IMS Health Plan Claims database. We estimated dispensing patterns over time for single-ingredient (SI) LABA and fixed-dose combination (FDC) of inhaled corticosteroid (ICS) and LABA (FDC-ICS/LABA). We also evaluated prior use of non-LABA asthma-control medication (ACM) before LABA initiation. Results: Of the 147 862 pediatric and adolescent asthma patients who initiated a LABA during the entire study period, the majority (96%) were FDC-ICS/LABA initiators. The proportion of SI-LABA among any LABA initiators was small and declined (9%, 4% and 2%, trend test p<0.001) for the three periods. Among the patients who initiated, the proportions with prior use of an ACM (1-90 days prior) were 35%, 36% and 39% for the three periods. Conclusions: The significant decline in the proportion of SI-LABA initiation over these years is consistent with FDA's recommendations. However, the favorable trend cannot be solely attributed to FDA activities as changes to clinical practice guidelines, and media publicity may have played a role. Investigating the reasons for the low ACM use before LABA initiation may inform approaches to further improve appropriate use of LABA in young asthma patients. C1 [Zhou, Esther H.; Kang, Elizabeth M.; Iyasu, Solomon] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Seymour, Sally] US FDA, Off New Drugs, Silver Spring, MD USA. RP Iyasu, S (reprint author), US FDA, Off Pharmacovigilance & Epidemiol, 10903 New Hampshire Ave,Bldg 22,Rm 2472, Silver Spring, MD 20993 USA. EM Solomon.Iyasu@fda.hhs.gov NR 25 TC 1 Z9 1 U1 0 U2 2 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0277-0903 EI 1532-4303 J9 J ASTHMA JI J. Asthma PD DEC PY 2014 VL 51 IS 10 BP 1061 EP 1067 DI 10.3109/02770903.2014.936452 PG 7 WC Allergy; Respiratory System SC Allergy; Respiratory System GA AT9HG UT WOS:000345238200010 PM 24945885 ER PT J AU Zhang, PH Vemula, SV Zhao, JQ Du, BC Mohan, H Liu, JK El Mubarak, HS Landry, ML Hewlett, I AF Zhang, Panhe Vemula, Sai Vikram Zhao, Jiangqin Du, Bingchen Mohan, Haleyurgirisetty Liu, Jikun El Mubarak, Haja Sittana Landry, Marie L. Hewlett, Indira TI A Highly Sensitive Europium Nanoparticle-Based Immunoassay for Detection of Influenza A/B Virus Antigen in Clinical Specimens SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID CAPSID P24 ANTIGEN; A H1N1 VIRUS; DIAGNOSTIC-TESTS; UNITED-STATES; CYTOSPIN-IMMUNOFLUORESCENCE; HOSPITALIZED-PATIENTS; EMERGENCE; PCR AB We report the development of a novel europium nanoparticle-based immunoassay (ENIA) for rapid detection of influenza A and influenza B viruses. The ENIA demonstrated sensitivities of 90.7% (147/162) for influenza A viruses and 81.80% (9/11) for influenza B viruses compared to those for an in-house reverse transcription (RT)-PCR assay in testing of influenza-positive clinical samples. C1 [Zhang, Panhe; Vemula, Sai Vikram; Zhao, Jiangqin; Du, Bingchen; Mohan, Haleyurgirisetty; Liu, Jikun; Hewlett, Indira] US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [El Mubarak, Haja Sittana] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Landry, Marie L.] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06510 USA. RP Vemula, SV (reprint author), US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. EM saivikram.vemula@fda.hhs.gov; indira.hewlett@fda.hhs.gov FU CBER; FDA MCMi funds FX This work was funded through CBER intramural and FDA MCMi funds. NR 22 TC 5 Z9 5 U1 1 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD DEC PY 2014 VL 52 IS 12 BP 4385 EP 4387 DI 10.1128/JCM.02635-14 PG 3 WC Microbiology SC Microbiology GA AT9BM UT WOS:000345222900047 PM 25297327 ER PT J AU Storey, JM Clark, SB Johnson, AS Andersen, WC Turnipseed, SB Lohne, JJ Burger, RJ Ayres, PR Carr, JR Madson, MR AF Storey, Joseph M. Clark, Susan B. Johnson, Aaron S. Andersen, Wendy C. Turnipseed, Sherri B. Lohne, Jack J. Burger, Robert J. Ayres, Patrick R. Carr, Justin R. Madson, Mark R. TI Analysis of sulfonamides, trimethoprim, fluoroquinolones, quinolones, triphenylmethane dyes and methyltestosterone in fish and shrimp using liquid chromatography-mass spectrometry SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Multi-residue; Seafood; LC-MS/MS; Triphenylmethane dyes; Sulfonamides; Fluoroquinolones ID MALACHITE GREEN; GENTIAN-VIOLET; VETERINARY DRUGS; BRILLIANT GREEN; RAINBOW-TROUT; RESIDUES; MUSCLE; ANTIBIOTICS; METABOLITES; SALMON AB A liquid chromatography-tandem mass spectrometry (LC-MS/MS) screening method is described for the detection and identification of 26 veterinary drugs in fish and other aquaculture products. The analytes include: 13 sulfonamides, trimethoprim, 3 fluoroquinolones, 3 quinolones, 3 triphenylmethane dyes, 2 leuco dye metabolites, and 1 hormone. In this method, tissue is mixed with EDTA-Mcllvaine buffer, double-extracted with acetonitrile, p-toluenesulfonic (p-TSA) acid and N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride (TMPD), and analyzed using LC-MS/MS. Inclusion of p-TSA and TMPD in the extraction procedure was critical for simultaneous analysis of dyes with the other groups of veterinary drugs. The proposed procedure was validated as both a quantitative analysis method and as a semi-quantitative screening method for multiple fish and shrimp matrices. The method was applied to eight types of fish (catfish, eel, pangasius, sablefish, tilapia, swai, salmon, and trout) and shrimp at the appropriate level of concern: 10 ng/g for sulfonamides, trimethoprim, and quinolones, 5 ng/g for fluoroquinolones, 1 ng/g for dyes and their metabolites, and 0.4 ng/g for methyltestosterone. Published by Elsevier B.V. C1 [Storey, Joseph M.; Andersen, Wendy C.; Turnipseed, Sherri B.; Lohne, Jack J.; Madson, Mark R.] USDA, Anim Drugs Res Ctr, Denver Fed Ctr, Denver, CO 80225 USA. [Clark, Susan B.; Johnson, Aaron S.; Burger, Robert J.; Ayres, Patrick R.; Carr, Justin R.; Madson, Mark R.] US FDA, Denver Lab, Denver Fed Ctr, Denver, CO 80225 USA. RP Storey, JM (reprint author), USDA, Anim Drugs Res Ctr, Denver Fed Ctr, POB 25087, Denver, CO 80225 USA. EM joseph.storey@fda.hhs.gov NR 25 TC 12 Z9 15 U1 9 U2 87 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 EI 1873-376X J9 J CHROMATOGR B JI J. Chromatogr. B PD DEC 1 PY 2014 VL 972 BP 38 EP 47 DI 10.1016/j.jchromb.2014.09.009 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AT3HQ UT WOS:000344826800006 PM 25310706 ER PT J AU Agarwal, S Qiu, W Sahajwalla, C AF Agarwal, Sheetal Qiu, Wei Sahajwalla, Chandrahas TI Overview of Recently Approved 505(b)(2) New Drug Applications (2010-2012): Role of Clinical Pharmacology SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE 505(b)(2); regulatory; drug development AB The role of clinical pharmacology (CP) in the approval of 505(b)(2) NDAs was explored with the goal of sharing with the drug development community, some of the critical CP aspects that need to be considered and addressed during the planning and submission of a 505(b)(2) NDA. Among the 106 505(b)(2) NDAs approved in 2010-2012 (excluding those that were approved under the PEPFAR program), 25% included only CP information, no supportive clinical safety/efficacy was necessary for their approval and 43% included both clinical and CP information. A review of the pre-submission interaction discussion held for 58% of the non-PEPFAR NDAs, indicated that CP-related aspects discussed at this avenue included study design of the pivotal BA/BE study, biowaiver related discussion, need for additional or supportive pharmacokinetic information to be included in the NDA, selection of the most appropriate reference drug product for 505(b)(2) purpose, as well as acceptability of publicly available information to address data gaps in knowledge. Further, we also noted that 505(b)(2) NDAs that did not report having a pre-submission interaction with the Agency had twice the rate of receiving a complete response action in the first cycle as compared to the NDAs that did meet with the Agency. C1 [Agarwal, Sheetal; Qiu, Wei; Sahajwalla, Chandrahas] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Agarwal, S (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Bldg 51,Room 3160,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Sheetal.Agarwal@fda.hhs.gov NR 5 TC 0 Z9 0 U1 2 U2 4 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 DEC PY 2014 VL 54 IS 12 BP 1330 EP 1336 DI 10.1002/jcph.350 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AT2SU UT WOS:000344786900002 PM 24958449 ER PT J AU Romero, K Sinha, V Allerheiligen, S Danhof, M Pinheiro, J Kruhlak, N Wang, YN Wang, SJ Sauer, JM Marier, JF Corrigan, B Rogers, J Heerspink, HJL Gumbo, T Vis, P Watkins, P Morrison, T Gillespie, W Gordon, MF Stephenson, D Hanna, D Pfister, M Lalonde, R Colatsky, T AF Romero, Klaus Sinha, Vikram Allerheiligen, Sandra Danhof, Meindert Pinheiro, Jose Kruhlak, Naomi Wang, Yaning Wang, Sue-Jane Sauer, John-Michael Marier, J. F. Corrigan, Brian Rogers, James Heerspink, H. J. Lambers Gumbo, Tawanda Vis, Peter Watkins, Paul Morrison, Tina Gillespie, William Gordon, Mark Forrest Stephenson, Diane Hanna, Debra Pfister, Marc Lalonde, Richard Colatsky, Thomas TI Modeling and simulation for medical product development and evaluation: highlights from the FDA-C-Path-ISOP 2013 workshop SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Article DE Regulatory science; Modeling and simulation; Quantitative drug development; Pre-competitive research; (Q)SAR; Pharmacometrics; Biostatistics ID PHARMACOKINETICS-PHARMACODYNAMICS; TUBERCULOSIS AB Medical-product development has become increasingly challenging and resource-intensive. In 2004, the Food and Drug Administration (FDA) described critical challenges facing medical-product development by establishing the critical path initiative [1]. Priorities identified included the need for improved modeling and simulation tools, further emphasized in FDA's 2011 Strategic Plan for Regulatory Science [Appendix]. In an effort to support and advance model-informed medical-product development (MIMPD), the Critical Path Institute (C-Path) [www.cpath.org], FDA, and International Society of Pharmacometrics [www.go-isop.org] co-sponsored a workshop in Washington, D. C. on September 26, 2013, to examine integrated approaches to developing and applying model-MIMPD. The workshop brought together an international group of scientists from industry, academia, FDA, and the European Medicines Agency to discuss MIMPD strategies and their applications. A commentary on the proceedings of that workshop is presented here. C1 [Romero, Klaus; Sauer, John-Michael; Stephenson, Diane; Hanna, Debra] Crit Path Inst, Tucson, AZ 85718 USA. [Sinha, Vikram; Kruhlak, Naomi; Wang, Yaning; Wang, Sue-Jane; Morrison, Tina; Colatsky, Thomas] US FDA, Silver Spring, MD 20993 USA. [Allerheiligen, Sandra] Merck Sharp & Dohme Corp Pharmaceutical Co, Whitehouse Stn, NJ 08889 USA. [Danhof, Meindert] Leiden Acad Ctr Drug Res, Fac Sci, Gorlaeus Labs, NL-2333 CC Leiden, Netherlands. [Pinheiro, Jose] Janssen, Raritan, NJ 08869 USA. [Marier, J. F.] Certara, St Louis, MO 63144 USA. [Corrigan, Brian; Lalonde, Richard] Pfizer Inc, Groton, CT 06340 USA. [Rogers, James; Gillespie, William] Metrum Res Grp, Tariffville, CT 06081 USA. [Heerspink, H. J. Lambers] Univ Groningen, Univ Med Ctr Groningen, NL-9700 RB Groningen, Netherlands. [Gumbo, Tawanda] Univ Texas SW Med Ctr Dallas, Dallas, TX 75235 USA. [Vis, Peter] Lap & P Consultants BV, NL-2333 CM Leiden, Netherlands. [Watkins, Paul] Hamner Inst Hlth Sci, Res Triangle Pk, NC 27709 USA. [Gordon, Mark Forrest] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. [Pfister, Marc] Univ Basel, CH-4003 Basel, Switzerland. RP Romero, K (reprint author), Crit Path Inst, 1730 East River Rd, Tucson, AZ 85718 USA. EM kromero@c-path.org OI Gumbo, Tawanda/0000-0001-7592-8012 NR 10 TC 5 Z9 5 U1 0 U2 6 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 DEC PY 2014 VL 41 IS 6 BP 545 EP 552 DI 10.1007/s10928-014-9390-0 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AT2YJ UT WOS:000344800200001 PM 25288257 ER PT J AU Jin, YY Bies, R Gastonguay, MR Wang, YN Stockbridge, N Gobburu, J Madabushi, R AF Jin, Yuyan Bies, Robert Gastonguay, Marc R. Wang, Yaning Stockbridge, Norman Gobburu, Jogarao Madabushi, Rajanikanth TI Predicted impact of various clinical practice strategies on cardiovascular risk for the treatment of hypertension: a clinical trial simulation study SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Article DE Clinical trial simulation; Hypertension; Clinical practice; Cardiovascular risk; Public health; Pharmacometrics ID BLOOD-PRESSURE; VASCULAR MORTALITY; INDIVIDUAL DATA; PRIMARY-CARE; METAANALYSIS; COUNTRIES; ERROR; AGE AB Hypertension control rate in the US is low with the current clinical practice (JNC 7) and cardiovascular disease (CVD) remain is the leading cause of morbidity and mortality. A 6-month clinical trial simulation case study testing different virtual clinical practice strategies was performed in an attempt to increase the control rate. The CVD risk was calculated using the Framingham CVD risk model at baseline and 6 months post-treatment. The estimated CVD events for the baseline patient sample without any treatment was 998 (95 % CI: 967-1,026) over 6 months in 100,000 patients. Treating these patients for 6 months with current clinical practice, high dose strategy, high dose with low target BP strategy resulted in a reduction in CVD events of 191(95 % CI: 169-205), 284 (95 % CI: 261-305), and 353 (95 % CI: 331-375), respectively. Hence the two alternative strategies resulted in an increase in treatment effect by 49 % (95 %CI: 44-59 %) and 85 % (95 %CI: 79-99 %), respectively. The increased safety with the current low dose strategy may potentially be offset by increased CVD risk in the time necessary to control hypertension. C1 [Jin, Yuyan] F Hoffmann La Roche Ltd, Roche Innovat Ctr Shanghai, Clin Pharmacol, Shanghai 201203, Peoples R China. [Bies, Robert] Indiana Univ, Indiana Clin & Translat Sci Inst, Div Clin Pharmacol, Indianapolis, IN 46204 USA. [Gastonguay, Marc R.] Metrum Inst, Tariffville, CT USA. [Wang, Yaning; Stockbridge, Norman; Madabushi, Rajanikanth] US FDA, Silver Spring, MD 20903 USA. [Gobburu, Jogarao] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. [Gobburu, Jogarao] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Madabushi, Rajanikanth] US FDA, CDER, Silver Spring, MD 20903 USA. RP Madabushi, R (reprint author), US FDA, CDER, WO51,RM2172,10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM Rajnikanth.Madabushi@fda.hhs.gov FU FDA-Pharmacometrics Critical Path Fellowship; Indiana Clinical and Translational Sciences Institute FX The study was funded by FDA-Pharmacometrics Critical Path Fellowship. The authors would like to thank Dr. Karen A. Matthews (Distinguished Professor of Psychiatry, Professor of Epidemiology and Psychology, Director, Pittsburgh Mind-Body Center Director, Cardiovascular Behavioral Medicine Research Program, Department of Psychiatry, University of Pittsburgh School of Medicine) for providing ABPM data to evaluate baseline BP model. The project was also supported by Indiana Clinical and Translational Sciences Institute (Dr. Robert Bies). NR 30 TC 0 Z9 0 U1 0 U2 5 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 DEC PY 2014 VL 41 IS 6 BP 693 EP 704 DI 10.1007/s10928-014-9394-9 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AT2YJ UT WOS:000344800200011 PM 25326066 ER PT J AU Huang, Y Gregori, L Anderson, SA Asher, DM Yang, H AF Huang, Yin Gregori, Luisa Anderson, Steven A. Asher, David M. Yang, Hong TI Development of Dose-Response Models of Creutzfeldt-Jakob Disease Infection in Nonhuman Primates for Assessing the Risk of Transfusion-Transmitted Variant Creutzfeldt-Jakob Disease SO JOURNAL OF VIROLOGY LA English DT Article ID TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY; BLOOD COMPONENTS; PRION PROTEIN; PLASMA; ASSAY AB Estimates for the risk of transmitting variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion have relied largely on data from rodent experiments, but the relationship between dose (amount of infected blood) and response (vCJD infection) has never been well quantified. The goal of this study was to develop a dose-response model based on nonhuman primate data to better estimate the likelihood of transfusion-transmitted vCJD (TTvCJD) in humans. Our model used dose-response data from nonhuman primates inoculated intracerebrally (i.c.) with brain tissues of patients with sporadic and familial CJD. We analyzed the data statistically by using a beta-Poisson dose-response model. We further adjusted model parameters to account for the differences in infectivity between blood and brain tissue and in transmission efficiency between intravenous (i.v.) and i.c. routes to estimate dose-dependent TTvCJD infection. The model estimates a mean infection rate of 76% among recipients who receive one unit of whole blood collected from an infected donor near the end of the incubation period. The nonhuman primate model provides estimates that are more consistent with those derived from a risk analysis of transfused nonleukoreduced red blood cells in the United Kingdom than prior estimates based on rodent models. IMPORTANCE TTvCJD was recently identified as one of three emerging infectious diseases posing the greatest immediate threat to the safety of the blood supply. Cases of TTvCJD were reported in recipients of nonleukoreduced red blood cells and coagulation factor VIII manufactured from blood of United Kingdom donors. As the quantity of abnormal prions (the causative agent of TTvCJD) varies significantly in different blood components and products, it is necessary to quantify the dose-response relationship for a wide range of doses for the vCJD agent in transfused blood and plasma derivatives. In this paper, we suggest the first mechanistic dose-response model for TTvCJD infection based on data from experiments with nonhuman primates. This new model may improve estimates of the possible risk to humans. C1 [Huang, Yin; Anderson, Steven A.; Yang, Hong] US FDA, Off Biostat & Epidemiol, Silver Spring, MD 20993 USA. [Gregori, Luisa; Asher, David M.] US FDA, Off Blood Res & Review, Silver Spring, MD USA. RP Huang, Y (reprint author), US FDA, Off Biostat & Epidemiol, Silver Spring, MD 20993 USA. EM Yin.Huang@fda.hhs.gov; Hong.Yang@fda.hhs.gov FU U.S. Food and Drug Administration through the Oak Ridge Institute for Science and Education FX This research was funded by the U.S. Food and Drug Administration through the Oak Ridge Institute for Science and Education. NR 20 TC 0 Z9 0 U1 0 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD DEC PY 2014 VL 88 IS 23 BP 13732 EP 13736 DI 10.1128/JVI.01805-14 PG 5 WC Virology SC Virology GA AT3CI UT WOS:000344812800018 PM 25231313 ER PT J AU Sun, JC Schmitt, T Schnackenberg, LK Pence, L Ando, Y Greenhaw, J Yang, X Slavov, S Davis, K Salminen, WF Mendrick, DL Beger, RD AF Sun, Jinchun Schmitt, Thomas Schnackenberg, Laura K. Pence, Lisa Ando, Yosuke Greenhaw, James Yang, Xi Slavov, Svetoslav Davis, Kelly Salminen, William F. Mendrick, Donna L. Beger, Richard D. TI Comprehensive analysis of alterations in lipid and bile acid metabolism by carbon tetrachloride using integrated transcriptomics and metabolomics SO METABOLOMICS LA English DT Article DE Metabolomics; Transcriptomics; Carbon tetrachloride; Hepatotoxicity; Lipid pathway; Bile acid pathway ID RAT-LIVER; PEROXIDATION; HEPATOTOXICITY; MICE; PROFILES; HEPATOCYTES; ANTIOXIDANT; CHLOROFORM; EXPRESSION; COLCHICINE AB Understanding mechanisms of liver injury can enable better preclinical testing and clinical management of patients. Carbon tetrachloride (CCl4), used extensively as a model hepatotoxicant, induces lipid perturbation and increases in plasma bile acids (BAs). An integrated transcriptomics and metabolomics approach was employed to investigate CCl4-induced alterations in lipid and BA metabolism. Sprague-Dawley rats were treated orally with corn oil, 50 (low dose, LD) or 2,000 mg CCl4/kg/d (high dose, HD). Animals were sacrificed at 6, 24 or 72 h. Terminal blood was collected for clinical chemistry and metabolomics analyses. Livers were harvested for histopathology, metabolomics and transcriptomics analyses. Both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased in the treated groups with the greatest increases observed in the HD group at 24 and 72 h. Blood cholesterol and triglycerides (TGs) were significantly decreased in the HD group at both 24 and 72 h, and hepatocyte vacuolization was observed at these timepoints. Consistent with the clinical chemistry and histopathological data, metabolomics results showed that levels of total fatty acids increased in the liver but decreased in the blood in the HD group at the 24 and 72 h timepoints. This suggested that lipids accumulate in the liver. Primary BAs increased in both liver and blood, while secondary and conjugated BAs decreased in the liver and increased in the blood, which indicated that the BA conjugation pathway and that BA uptake by the liver were inhibited by CCl4. Results from this study provide a better understanding of the mechanisms of CCl4-induced hepatotoxicity. C1 [Sun, Jinchun; Schmitt, Thomas; Schnackenberg, Laura K.; Pence, Lisa; Ando, Yosuke; Greenhaw, James; Yang, Xi; Slavov, Svetoslav; Salminen, William F.; Mendrick, Donna L.; Beger, Richard D.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Davis, Kelly] US FDA, Toxicol Pathol Associates Inc TPA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Sun, JC (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Jinchun.Sun@fda.hhs.gov NR 28 TC 1 Z9 1 U1 1 U2 26 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 DEC PY 2014 VL 10 IS 6 BP 1293 EP 1304 DI 10.1007/s11306-014-0665-7 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS9IA UT WOS:000344555300022 ER PT J AU Markowitz, S Cuellar, A Conrad, RM Grossman, M AF Markowitz, Sara Cuellar, Alison Conrad, Ryan M. Grossman, Michael TI Alcohol control and foster care SO REVIEW OF ECONOMICS OF THE HOUSEHOLD LA English DT Article DE Alcohol policy; Alcohol prices; Alcohol outlets; Foster care; Child abuse ID LEGAL DRINKING AGE; MARIJUANA USE EVIDENCE; OF-HOME CARE; CHILD MALTREATMENT; BEVERAGE PRICES; CONSUMPTION; DEMAND; RATES; AVAILABILITY; OUTCOMES AB Parental alcohol consumption is often associated with an increased likelihood of child abuse. As consumption is related to price, the purpose of this paper is to investigate the propensity for increases in the full price of alcohol to influence entry rates and the length of time spent in foster care. Using alcoholic beverage prices and a measure of availability in combination with data on foster care cases, we find that higher alcohol prices are not effective in reducing foster care entry rates; however, once in foster care, the duration of stay may be shortened by higher prices and reduced availability. C1 [Markowitz, Sara] Emory Univ, Dept Econ, Atlanta, GA 30322 USA. [Markowitz, Sara; Cuellar, Alison; Grossman, Michael] NBER, Cambridge, MA 02138 USA. [Cuellar, Alison] George Mason Univ, Fairfax, VA 22030 USA. [Conrad, Ryan M.] US FDA, Silver Spring, MD USA. [Grossman, Michael] CUNY, New York, NY 10021 USA. RP Markowitz, S (reprint author), Emory Univ, Dept Econ, Atlanta, GA 30322 USA. EM sara.markowitz@emory.edu FU NIAAA NIH HHS [R03 AA016836] NR 44 TC 0 Z9 0 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1569-5239 EI 1573-7152 J9 REV ECON HOUSEHOLD JI Rev. Econ. Househ. PD DEC PY 2014 VL 12 IS 4 BP 589 EP 612 DI 10.1007/s11150-013-9198-5 PG 24 WC Economics SC Business & Economics GA AT0AP UT WOS:000344599600001 PM 25506296 ER PT J AU Luan, Y Qi, XM Xu, L Ren, J Chen, T AF Luan, Yang Qi, Xinming Xu, Liang Ren, Jin Chen, Tao TI Absence of mature microRNAs inactivates the response of gene expression to carcinogenesis induced by N-ethyl-N-nitrosourea in mouse liver SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE microRNAs; gene expression; microarray; carcinogenesis; Dicer1 knockout ID EMBRYONIC STEM-CELLS; CHEMICAL CARCINOGENESIS; RAT-LIVER; PROFILES; EXPOSURE; DICER; DIFFERENTIATION; APOPTOSIS; MIR-34A; TUMORS AB This study aims to evaluate the role of microRNAs (miRNAs) in chemical tumorigenesis by evaluating genomic gene expression in miRNA knockout mice. Previous studies showed that mice without mature miRNAs due to hepatocyte-specific Dicer1 knockout (KO) had a much higher liver tumor incidence than wild-type mice. In this study, Dicer1 KO or the wild-type mice were treated intraperitoneally with genotoxic carcinogen N-ethyl-N-nitrosourea (ENU) at a single dose (150 mg kg(-1) that resulted in liver tumorigenesis) or the vehicle at 3 weeks of age. The animals were killed 2 weeks after treatment and the liver samples were collected for the gene expression study. Principal components analysis and hierarchical cluster analysis showed that gene expression was globally altered by the Dicer1 KO and ENU exposure. There were 5621, 3286 and 2565 differentially expressed genes for Dicer1 disruption, ENU treatment in wild-type mice and ENU treatment in Dicer1 KO mice, respectively. Functional analysis of the differentially expressed genes suggests that the Dicer1 KO mouse liver lost their capability to suppress the carcinogenesis induced by ENU exposure in genomic level. In addition, the miRNA-mediated BRCA1 and P53 signaling pathways were identified as the main pathways responsible for the tumorigenesis. We conclude that the mouse livers in the absence of mature miRNAs could not appropriately respond to carcinogenic insults from ENU treatment, indicating that miRNAs play a critical role in chemical carcinogenesis. Copyright (c) 2014 John Wiley & Sons, Ltd. This study evaluates the role of microRNAs in chemical tumorigenesis by evaluating genomic gene expression in microRNA knockout mice treated with carcinogen N-ethyl-N-nitrosourea. The results demonstrate that the mouse liver in the absence of mature microRNAs could not appropriately respond to the carcinogenic insults to suppress the carcinogenesis induced by the carcinogen. Many tumor-suppressor functions, especially BRCA1 and P53 signaling pathways, were lost due to the absence of mature microRNAs. Thus, microRNAs play a critical role in chemical carcinogenesis. C1 [Luan, Yang] Shanghai Jiao Tong Univ, Sch Publ Hlth, Shanghai 200025, Peoples R China. [Qi, Xinming; Ren, Jin] Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, State Key Lab New Drug Res, Shanghai 201203, Peoples R China. [Xu, Liang] Shanghai Integrated Biotech Solut Co Ltd, Shanghai 201203, Peoples R China. [Chen, Tao] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. RP Luan, Y (reprint author), Shanghai Jiao Tong Univ, Sch Publ Hlth, Shanghai 200025, Peoples R China. EM luan_tihiro@hotmail.com; tao.chen@fda.hhs.gov NR 36 TC 2 Z9 2 U1 0 U2 4 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 DEC PY 2014 VL 34 IS 12 BP 1409 EP 1417 DI 10.1002/jat.2973 PG 9 WC Toxicology SC Toxicology GA AS3AA UT WOS:000344146300016 PM 24478143 ER PT J AU Mahmood, L Dozier, A Dolan, J Casey, D Mullen, C Korones, D AF Mahmood, L. Dozier, A. Dolan, J. Casey, D. Mullen, C. Korones, D. TI EARLY PALLIATIVE CARE CONSULTATION FOR HIGH RISK PEDIATRIC ONCOLOGY PATIENTS: A FEASIBILITY STUDY SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Mahmood, L.] Univ Rochester, Strong Mem Hosp, Golisanos Children Hosp, Rochester, NY 14627 USA. [Dozier, A.; Dolan, J.] Univ Rochester, Rochester, NY 14627 USA. [Casey, D.] US FDA, US Dept Hlth & Human Serv, Rockville, MD 20857 USA. [Mullen, C.; Korones, D.] Univ Rochester, Golisanos Children Hosp, Rochester, NY 14627 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA EP-641 BP S395 EP S395 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932101292 ER PT J AU Alonso, D Plourde, J Weininger, S Goldman, JM AF Alonso, Diego Plourde, Jeffrey Weininger, Sandy Goldman, Julian M. TI Web-Based Clinical Scenario Repository (TM) (CSR (TM)) SO ANESTHESIA AND ANALGESIA LA English DT Meeting Abstract C1 [Alonso, Diego; Plourde, Jeffrey; Goldman, Julian M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Goldman, Julian M.] Harvard Med Sch, Boston, MA USA. [Weininger, Sandy] US FDA, Rockville, MD 20857 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 2014 VL 119 SU 1 PG 2 WC Anesthesiology SC Anesthesiology GA V45PE UT WOS:000209827700065 ER PT J AU Goldman, JM Jaffe, MB Osborn, D Weininger, S AF Goldman, Julian M. Jaffe, Michael B. Osborn, David Weininger, Sandy TI The Integrated Clinical Environment (ICE) Standards (ASTM F2761-09) - The First Ten Years SO ANESTHESIA AND ANALGESIA LA English DT Meeting Abstract C1 [Goldman, Julian M.; Jaffe, Michael B.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Osborn, David] Philips Healthcare, Andover, MA USA. [Weininger, Sandy] US FDA, Silver Spring, MD USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 2014 VL 119 SU 1 PG 2 WC Anesthesiology SC Anesthesiology GA V45PE UT WOS:000209827700063 ER PT J AU Jaffe, M Arney, D Weininger, S Dain, S Goldman, JM AF Jaffe, Michael Arney, David Weininger, Sandy Dain, Steven Goldman, Julian M. TI The Integrated Clinical Environment (ICE) Data Logger-Opportunities and Advantages Relative to Individual Device Data Logging SO ANESTHESIA AND ANALGESIA LA English DT Meeting Abstract C1 [Jaffe, Michael; Arney, David; Goldman, Julian M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Weininger, Sandy; Goldman, Julian M.] Harvard Med Sch, Boston, MA USA. [Weininger, Sandy; Goldman, Julian M.] US FDA, Rockville, MD 20857 USA. [Dain, Steven] Western Univ, Schulich Med & Dent, London, ON, Canada. NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 2014 VL 119 SU 1 PG 2 WC Anesthesiology SC Anesthesiology GA V45PE UT WOS:000209827700061 ER PT J AU Nodora, J Hartman, SJ Strong, DR Messer, K Vera, LE White, MM Portnoy, DB Choiniere, CJ Vullo, GC Pierce, JP AF Nodora, Jesse Hartman, Sheri J. Strong, David R. Messer, Karen Vera, Lisa E. White, Martha M. Portnoy, David B. Choiniere, Conrad J. Vullo, Genevieve C. Pierce, John P. TI Curiosity predicts smoking experimentation independent of susceptibility in a US national sample SO ADDICTIVE BEHAVIORS LA English DT Article DE Curiosity; Susceptibility to smoking; Smoking experimentation; Adolescent smoking ID UNITED-STATES; ELECTRONIC CIGARETTES; TOBACCO PRODUCTS; ADOLESCENTS; SCHOOL; INITIATION; BEHAVIORS; GIRLS AB Purpose: To improve smoking prevention efforts, better methods for identifying at-risk youth are needed. The widely used measure of susceptibility to smoking identifies at-risk adolescents; however, it correctly identifies only about one third of future smokers. Adding curiosity about smoking to this susceptibility index may allow us to identify a greater proportion of future smokers while they are still pre-teens. Methods: We use longitudinal data from a recent national study on parenting to prevent problem behaviors. Only oldest children between 10 and 13 years of age were eligible. Participants were identified by RDD survey and followed for 6 years. All baseline never smokers with at least one follow-up assessment were included (n = 878). The association of curiosity about smoking with future smoking behavior was assessed. Then, curiosity was added to form an enhanced susceptibility index and sensitivity, specificity and positive predictive value were calculated. Results: Among committed never smokers at baseline, those who were 'definitely not curious' were less likely to progress toward smoking than both those who were 'probably not curious' (ORadj = 1.89; 95% Cl = 1.03-3.47) or 'probably/definitely curious' (ORadj = 2.88; 95% Cl = 1.11-7.45). Incorporating curiosity into the susceptibility index increased the proportion identified as at-risk to smoke from 25.1% to 46.9%. The sensitivity (true positives) for this enhanced susceptibility index for both experimentation and established smoking increased from 37-40% to over 50%, although the positive predictive value did not improve. Conclusion: The addition of curiosity significantly improves the identification and classification of which adolescents will experiment with smoking or become established smokers. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Nodora, Jesse; Hartman, Sheri J.; Strong, David R.; Messer, Karen; Vera, Lisa E.; White, Martha M.; Pierce, John P.] Univ Calif San Diego, Moores UCSD Canc Ctr, Canc Prevent & Control Program, La Jolla, CA 92093 USA. [Nodora, Jesse; Hartman, Sheri J.; Strong, David R.; Messer, Karen; Vera, Lisa E.; White, Martha M.; Pierce, John P.] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Portnoy, David B.; Choiniere, Conrad J.] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. [Vullo, Genevieve C.] Kelly Govt Solut, Bethesda, MD USA. RP Pierce, JP (reprint author), Univ Calif San Diego, Moores UCSD Canc Ctr, Canc Prevent & Control Program, La Jolla, CA 92093 USA. EM jppierce@ucsd.edu OI Portnoy, David/0000-0003-2175-9457 FU National Cancer Institute [CA093982, 1R01CA172058-01]; American Legacy Foundation grant; University of California [17RT-0088, 15RT-0238]; National Institute on Drug Abuse, National Institutes of Health; Food and Drug Administration, Department of Health and Human Services [HHSN271201100027C]; Tobacco Related Disease Research Program [21RT-01335] FX Funding for the primary data collection was provided by the National Cancer Institute grant CA093982, an American Legacy Foundation grant, and Tobacco Related Disease Research Program grants 17RT-0088 and 15RT-0238 from the University of California. Funding for this analysis and manuscript preparation has been funded with Federal funds from the National Institute on Drug Abuse, National Institutes of Health, the Food and Drug Administration, Department of Health and Human Services, under Contract No. HHSN271201100027C, and the Tobacco Related Disease Research Program grant 21RT-01335 and National Cancer Institute Grant 1R01CA172058-01. NR 39 TC 7 Z9 8 U1 0 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD DEC PY 2014 VL 39 IS 12 BP 1695 EP 1700 DI 10.1016/j.addbeh.2014.06.002 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA AR1LI UT WOS:000343346300002 PM 25117844 ER PT J AU Farahani, M Clochard, MC Gifford, I Barkatt, A Al-Sheikhly, M AF Farahani, Mahnaz Clochard, Marie-Claude Gifford, Ian Barkatt, Aaron Al-Sheikhly, Mohamad TI Differences in fundamental reaction mechanisms between high and low-LET in recent advancements and applications of ionizing radiation SO RADIATION PHYSICS AND CHEMISTRY LA English DT Article; Proceedings Paper CT 17th International Meeting on Radiation Processing (IMRP) CY NOV 04-08, 2013 CL IIA, Shanghai, PEOPLES R CHINA SP Jaingsu Dasheng Electron Accelerator Co Ltd, SQHL HO IIA DE High-LET; Low-LET ID NEUTRON-CAPTURE THERAPY; ANNIHILATION LIFETIME SPECTROSCOPY; MOLECULAR-WEIGHT POLYETHYLENE; POLYCHLORINATED-BIPHENYLS; TRANSFORMER OIL; MARINE SEDIMENT; CROSS-LINKING; HEAVY-IONS; FUEL-CELL; MEMBRANES AB Differences among the mechanisms of energy deposition by high-linear energy transfer (LET) radiation, consisting of neutrons, protons, alpha particles, and heavy ions on one hand, and low-LET radiation, exemplified by electron beam and gamma radiation on the other, are utilized in the selection of types of radiation used for specific applications. Thus, high-LET radiation is used for modification of carbon nanotubes, ion track grafting, and the synthesis of membranes and nanowires, as well as for characterization of materials by means of neutron scattering. Recent applications of low-LET irradiation include minimization of radiolytic degradation upon sterilization of ultra-high molecular weight polyethylene (UHMWPE), radiolytic synthesis of nanogels for drug delivery systems, grafting of polymers in the synthesis of adsorbents for uranium from seawater, and reductive remediation of PCBs.(1) (C) 2014 Elsevier Ltd. All rights reserved. C1 [Farahani, Mahnaz] US FDA, Off Gener Drugs, Rockville, MD 20857 USA. [Clochard, Marie-Claude] Ecole Polytech, CEA CNRS X, Solides Irradies Lab, UMR7642, F-91128 Palaiseau, France. [Gifford, Ian] Armed Forces Radiobiol Res Inst, Bethesda, MD USA. [Barkatt, Aaron] Catholic Univ Amer, Dept Chem, Washington, DC 20064 USA. [Al-Sheikhly, Mohamad] Univ Maryland, Coll Engn, Dept Mat Sci & Technol, College Pk, MD 20742 USA. EM mohamad@umd.edu NR 69 TC 0 Z9 0 U1 1 U2 35 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0969-806X J9 RADIAT PHYS CHEM JI Radiat. Phys. Chem. PD DEC PY 2014 VL 105 BP 39 EP 47 DI 10.1016/j.radphyschem.2014.05.032 PG 9 WC Chemistry, Physical; Nuclear Science & Technology; Physics, Atomic, Molecular & Chemical SC Chemistry; Nuclear Science & Technology; Physics GA AQ7TO UT WOS:000343022300009 ER PT J AU Marshall, KM Nowaczyk, L Raphael, BH Skinner, GE Reddy, NR AF Marshall, Kristin M. Nowaczyk, Louis, II Raphael, Brian H. Skinner, Guy E. Reddy, N. Rukma TI Identification and genetic characterization of Clostridium botulinum serotype A strains from commercially pasteurized carrot juice SO FOOD MICROBIOLOGY LA English DT Article DE Clostridium botulinum DNA microarray; PFGE (pulsed-field gel electrophoresis); Botulinum neurotoxin (BoNT); Plasmids; Bacteriophage ID FIELD GEL-ELECTROPHORESIS; INFANT BOTULISM; GENOME SEQUENCE; PLASMID; TOXIN; CLUSTERS; DNA; DIFFERENTIATION; NEUROTOXINS; PREVALENCE AB Clostridium botulinum is an important foodborne pathogen capable of forming heat resistant endospores and producing deadly botulinum neurotoxins (BoNTs). In 2006, C. botulinum was responsible for an international outbreak of botulism attributed to the consumption of commercially pasteurized carrot juice. The purpose of this study was to isolate and characterize strains of C. botulinum from the adulterated product. Carrot juice bottles retrieved from the manufacturing facility were analyzed for the presence of BoNT and BoNT-producing isolates using DIG-ELISA. Toxigenic isolates from the carrot juice were analyzed using pulsed-field gel electrophoresis (PFGE) and DNA microarray analysis to determine their genetic relatedness to the original outbreak strains CDC51348 and CDC51303. PFGE revealed that isolates CJ4-1 and CJ10-1 shared an identical pulsotype with strain CDC51303, whereas isolate CJ5-1 displayed a unique restriction banding pattern. DNA microarray analysis identified several phage related genes unique to strain CJ5-1, and Southern hybridization analysis of Xhol digested and non-digested DNA showed their chromosomal location, while a homolog to pCLI_A009 of plasmid pCLI of C botulinum serotype Langeland F, was located on a small plasmid. The acquisition or loss of bacterio-phages and other mobile genetic elements among C. botulinum strains has epidemiological and evolutionary implications. Published by Elsevier Ltd. C1 [Marshall, Kristin M.; Nowaczyk, Louis, II; Skinner, Guy E.; Reddy, N. Rukma] USDA, Ctr Food Safety & Appl Nutr, Bedford Pk, IL 60501 USA. [Raphael, Brian H.] Ctr Dis Control & Prevent, Atlanta, GA 30329 USA. RP Marshall, KM (reprint author), USDA, Ctr Food Safety & Appl Nutr, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM Kristin.Marshall@fda.hhs.gov; Nowaczyk@gmail.com; BRaphael@cdc.gov; Skinner@fda.hhs.gov; Rukma.Reddy@fda.hhs.gov OI Raphael, Brian/0000-0003-2778-2623 NR 39 TC 0 Z9 0 U1 2 U2 73 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 DEC PY 2014 VL 44 BP 149 EP 155 DI 10.1016/j.fm.2014.05.009 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA AN8JS UT WOS:000340851100020 PM 25084657 ER PT J AU Dailey, RC Martin, KG Smiley, RD AF Dailey, Rachel C. Martin, Keely G. Smiley, R. Derike TI The effects of competition from non-pathogenic foodborne bacteria during the selective enrichment of Listeria monocytogenes using buffered Listeria enrichment broth SO FOOD MICROBIOLOGY LA English DT Article DE Regulatory microbiology; Foodborne pathogen; Microbial competition; PCR; Real-time PCR; Lateral flow device; Automated immunofluorescence assay; Molecular screen; Analytical microbiology ID INNOCUA; FOOD; SAMPLES; CULTURES; GROWTH AB The growth of Listeria monocytogenes during the pathogen specific enrichment of food samples can be limited by the presence of additional microorganisms that are resistant to the selective conditions being applied. If growth is severely limited and minimum post-enrichment threshold levels are not met then the presence of L. monocytogenes may go undetected. Several food products were screened for non-pathogenic commensal or spoilage microorganisms that are capable of growth under the conditions commonly used by regulatory testing laboratories to select for Listeria species. The effect of these potential competitor microorganisms on the ability to detect L. monocytogenes by several common molecular screening assays was then determined. Eight species of bacteria were isolated from foods that demonstrated the ability to grow in buffered Listeria enrichment broth under selective conditions. Growth of these competitor microorganisms during the enrichment incubation resulted in a decrease ranging from 1 to 4 logs in the 48 h population of L monocytogenes. Three strains of L monocytogenes representing serotypes 1/2a, 1/2b, and 4b were included in this study but no one serotype appeared to be most or least sensitive to the presence of competitor microorganisms. One additional strain of L monocytogenes was identified as displaying minimal growth during the enrichment period in the presence of the Citrobacter braakii with the final population only reaching approximately 2.6 log CFU/ml after 48 h which was a 2 log increase over the initial population. This particular strain was subsequently shown to be difficult to detect following enrichment by an automated immunofluorescence assay and an antibody-based lateral flow device assay. In some enrichments, this strain was also difficult to detect by real-time PCR. Published by Elsevier Ltd. C1 [Dailey, Rachel C.; Martin, Keely G.; Smiley, R. Derike] US FDA, Arkansas Reg Lab, Off Regulatory Affairs, Jefferson, AR 72079 USA. RP Smiley, RD (reprint author), US FDA, Arkansas Reg Lab, Off Regulatory Affairs, 3900 NCTR Rd,Bldg 26, Jefferson, AR 72079 USA. EM Ronald.Smiley@fda.hhs.gov FU U.S. FDA's Office of Regulatory Affairs; Arkansas Regional Laboratory FX The authors thank the U.S. FDA's Office of Regulatory Affairs and the Arkansas Regional Laboratory for their support of this research. NR 12 TC 10 Z9 11 U1 4 U2 56 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 DEC PY 2014 VL 44 BP 173 EP 179 DI 10.1016/j.fm.2014.05.004 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA AN8JS UT WOS:000340851100023 PM 25084660 ER PT J AU Hoelzer, K Pouillot, R Van Doren, JM Dennis, S AF Hoelzer, K. Pouillot, R. Van Doren, J. M. Dennis, S. TI Reduction of Listeria monocytogenes contamination on produce - A quantitative analysis of common liquid fresh produce wash compounds SO FOOD CONTROL LA English DT Article DE Liquid produce wash compound; Listeria monocytogenes; Efficacy; Systematic review; Meta-analysis; Antimicrobial substance ID ESCHERICHIA-COLI O157-H7; AQUEOUS CHLORINE DIOXIDE; PRECUT ICEBERG LETTUCE; ORGANIC-ACID TREATMENT; SALMONELLA-TYPHIMURIUM; HYDROGEN-PEROXIDE; FOODBORNE PATHOGENS; GAMMA-IRRADIATION; UNITED-STATES; LACTIC-ACID AB Contaminated produce has been identified as the cause of several listeriosis outbreaks in recent years. Listeria monocytogenes is widely distributed in the environment and complete prevention of produce contamination is therefore challenging. Mitigation options that reduce contamination on produce are valuable, especially for produce commodities that are commonly consumed fresh or minimally processed. We performed a systematic review and meta-analysis of the available peer-reviewed literature to evaluate the efficacy of liquid fresh produce wash compounds in reducing produce contamination with L. monocytogenes, and derive quantitative estimates of treatment efficacy for a variety of common liquid fresh produce wash compounds. Treatment efficacy differed considerably across produce commodities, with liquid fresh produce wash compounds generally showing considerably greater efficacy for some tested commodities than for other commodities. Most but not all of the evaluated liquid fresh produce wash compounds were significantly more effective in reducing L monocytogenes contamination than water alone, with mean reductions in L. monocytogenes levels ranging from less than 1 log(10) cfu to more than 5 log(10) cfu. Liquid fresh produce wash compounds are therefore a possible tool for reducing contamination with L. monocytogenes, for certain produce commodities. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Hoelzer, K.; Pouillot, R.; Van Doren, J. M.; Dennis, S.] US FDA, Ctr Food Safety & Appl Nutr HFS 005, College Pk, MD 20740 USA. RP Hoelzer, K (reprint author), US FDA, Ctr Food Safety & Appl Nutr HFS 005, 5100 Paint Branch Pkwy,Room 2A-031, College Pk, MD 20740 USA. EM Karin.Hoelzer@fda.hhs.gov RI Pouillot, Regis/E-8103-2010 OI Pouillot, Regis/0000-0002-6107-5212 FU U.S. Food and Drug Administration [100000038]; Research Participation Program at the Center for Food Safety and Applied Nutrition FX The authors acknowledge and thank Dr. M. Parish for his insights and advice in reviewing an earlier version of this manuscript. This work was supported by the U.S. Food and Drug Administration (100000038) 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 US Department of Energy and the US Food and Drug Administration. NR 95 TC 6 Z9 6 U1 1 U2 50 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-7135 EI 1873-7129 J9 FOOD CONTROL JI Food Control PD DEC PY 2014 VL 46 BP 430 EP 440 DI 10.1016/j.foodcont.2014.06.011 PG 11 WC Food Science & Technology SC Food Science & Technology GA AN0UU UT WOS:000340300300058 ER PT J AU Bancos, S Tyner, KM AF Bancos, Simona Tyner, Katherine M. TI Evaluating the effect of assay preparation on the uptake of gold nanoparticles by RAW264.7 cells SO JOURNAL OF NANOBIOTECHNOLOGY LA English DT Article DE Gold nanoparticle; Nanoparticle uptake; In vitro assay; Nanoparticle dosimetry; Macrophage ID ENGINEERED NANOMATERIALS; IN-VITRO; CYTOTOXICITY; DOSIMETRY; LINES AB Background: Cell culture conditions can greatly influence the results of nanoparticle (NP) uptake assays. In this study, 10 nm gold nanoparticles (AuNPs) and RAW 264.7 macrophages were used as a model system, while instrumental neutron activation analysis (NAA) was used as the elemental analysis technique to determine AuNP levels produced by the various culturing conditions. Static plate-based and insert-based culture conditions were compared with a dynamic suspension culture to evaluate the conditions' effect on the rate and extent of AuNP uptake. Results: The results indicate that a dynamic culturing condition allows for the greatest NP uptake (approximately 3-5 times over the adherent conditions), whereas the plate-based assays have the initial highest rate of NP incorporation. Conclusions: These data highlight the importance of judiciously choosing the assay conditions prior to evaluating NP uptake. C1 [Bancos, Simona; Tyner, Katherine M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Tyner, KM (reprint author), US FDA, Ctr Drug Evaluat & Res, Bldg 51 Room 4159,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Katherine.Tyner@fda.hhs.gov FU Center for Drug Evaluation and Research; U.S. Department of Energy; U.S. Food and Drug Administration FX The authors acknowledge the invaluable help of David Stevens CDER/FDA and Oleg Vesnovsky CDRH/FDA for assistance in cutting up the cell culture dishes. The authors acknowledge the Office of Science and Engineering Laboratories, FDA, for the use of their TGA. The authors would also like to acknowledge the FDA White Oak Nanotechnology Core Facility for instrument use, scientific and technical assistance. This project 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 U.S. Department of Energy and the U.S. Food and Drug Administration. NR 16 TC 1 Z9 1 U1 2 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-3155 J9 J NANOBIOTECHNOL JI J. Nanobiotechnol. PD NOV 26 PY 2014 VL 12 AR 45 DI 10.1186/s12951-014-0045-5 PG 11 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA AX9DU UT WOS:000347204900001 PM 25424488 ER PT J AU Sanad, YM Jung, K Kashoma, I Zhang, XL Kassem, II Saif, YM Rajashekara, G AF Sanad, Yasser M. Jung, Kwonil Kashoma, Isaac Zhang, Xiaoli Kassem, Issmat I. Saif, Yehia M. Rajashekara, Gireesh TI Insights into potential pathogenesis mechanisms associated with Campylobacter jejuni-induced abortion in ewes SO BMC VETERINARY RESEARCH LA English DT Article DE Campylobacter jejuni; Sheep abortion; Pathogenesis; Public health; Pregnant ewes ID UNITED-STATES; GENETIC DIVERSITY; SHEEP; INTERLEUKIN-15; CLONE; SUSCEPTIBILITY; HELICOBACTER; APOPTOSIS; EMERGENT; PRETERM AB Background: Campylobacter jejuni is commonly found in the gastrointestinal tract of many food-animals including sheep without causing visible clinical symptoms of disease. However, C. jejuni has been implicated in ovine abortion cases worldwide. Specifically, in the USA, the C. jejuni sheep abortion (SA) clone has been increasingly associated with sheep abortion. In vivo studies in sheep (the natural host) are needed to better characterize the virulence potential and pathogenesis of this clone. Results: Pregnant ewes intravenously (IV) or orally inoculated with ovine or bovine abortion-associated C. jejuni SA clones exhibited partial or complete uterine prolapse with retained placenta, and abortion or stillbirth, whereas delivery of healthy lambs occurred in pregnant ewes inoculated with C. jejuni 81-176 or in the uninfected group. In sheep inoculated with the SA clone, histopathological lesions including suppurative necrotizing placentitis and/or endometritis coincided with: 1) increased apoptotic death of trophoblasts, 2) increased expression of the host genes (e.g. genes encoding interleukin IL-6 and IL-15) related to cellular necrosis and pro-inflammatory responses in uterus, and 3) decreased expression of the genes encoding GATA binding protein 6, chordin, and insulin-like 3 (INSL3) that account for embryonic development in uterus. Immunohistochemistry revealed localization of bacterial antigens in trophoblasts lining the chorioallantoic membrane of ewes inoculated with the C. jejuni SA clone. Conclusions: The results showed that C. jejuni SA clones are capable of causing abortion or stillbirth in experimentally infected sheep. Furthermore, down-or up-regulation of specific genes in the uterus of infected pregnant ewes might implicate host genes in facilitating the disease progression. Since the C. jejuni SA strains share genotypic similarities with clones that have been isolated from human clinical cases of gastroenteritis, these strains might represent a potential public health risk. C1 [Sanad, Yasser M.; Jung, Kwonil; Kashoma, Isaac; Kassem, Issmat I.; Saif, Yehia M.; Rajashekara, Gireesh] Ohio State Univ, Ohio Agr Res & Dev Ctr, FAHRP, Wooster, OH 44691 USA. [Zhang, Xiaoli] Ohio State Univ, Ctr Biostat, Columbus, OH 43220 USA. [Rajashekara, Gireesh] Ohio State Univ, Dept Vet Prevent Med, Columbus, OH 43220 USA. [Sanad, Yasser M.] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. RP Rajashekara, G (reprint author), Ohio State Univ, Ohio Agr Res & Dev Ctr, FAHRP, 1680 Madison Ave, Wooster, OH 44691 USA. EM rajashekara.2@osu.edu RI Rajashekara, Gireesh/E-3913-2011 FU Ohio Agricultural Research and Development Center (OARDC); Ohio State University; Agriculture and Food Research Initiative (AFRI), U. S. Department of Agriculture; Ohio State University Open Access Fund FX We gratefully acknowledge the technical assistance of Dr. Juliette Hanson with sheep experiments and Ms. Anne E Parkinson for providing C. jejuni abortion-associated isolates. Research in Dr. Rajashekara's laboratory is supported by the Ohio Agricultural Research and Development Center (OARDC), The Ohio State University, and the Agriculture and Food Research Initiative (AFRI), U. S. Department of Agriculture. Partial funding for Open Access provided by The Ohio State University Open Access Fund. NR 38 TC 0 Z9 0 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1746-6148 J9 BMC VET RES JI BMC Vet. Res. PD NOV 25 PY 2014 VL 10 AR 274 DI 10.1186/s12917-014-0274-8 PG 13 WC Veterinary Sciences SC Veterinary Sciences GA AX6DW UT WOS:000347014500001 PM 25420712 ER PT J AU Shpyleva, S Ivanovsky, S de Conti, A Melnyk, S Tryndyak, V Beland, FA James, SJ Pogribny, IP AF Shpyleva, Svitlana Ivanovsky, Samuil de Conti, Aline Melnyk, Stepan Tryndyak, Volodymyr Beland, Frederick A. James, S. Jill Pogribny, Igor P. TI Cerebellar Oxidative DNA Damage and Altered DNA Methylation in the BTBR T plus tf/J Mouse Model of Autism and Similarities with Human Post Mortem Cerebellum SO PLOS ONE LA English DT Article ID TUBEROUS SCLEROSIS COMPLEX; GLUTATHIONE REDOX IMBALANCE; SPECTRUM DISORDERS; REPAIR; EXPRESSION; STRESS; CELLS; MICE; OGG1; GENE AB The molecular pathogenesis of autism is complex and involves numerous genomic, epigenomic, proteomic, metabolic, and physiological alterations. Elucidating and understanding the molecular processes underlying the pathogenesis of autism is critical for effective clinical management and prevention of this disorder. The goal of this study is to investigate key molecular alterations postulated to play a role in autism and their role in the pathophysiology of autism. In this study we demonstrate that DNA isolated from the cerebellum of BTBR T+tf/J mice, a relevant mouse model of autism, and from human post-mortem cerebellum of individuals with autism, are both characterized by an increased levels of 8-oxo-7-hydrodeoxyguanosine (8-oxodG), 5-methylcytosine (5mC), and 5-hydroxymethylcytosine (5hmC). The increase in 8-oxodG and 5mC content was associated with a markedly reduced expression of the 8-oxoguanine DNA-glycosylase 1 (Ogg1) and increased expression of de novo DNA methyltransferases 3a and 3b (Dnmt3a and Dnmt3b). Interestingly, a rise in the level of 5hmC occurred without changes in the expression of ten-eleven translocation expression 1 (Tet1) and Tet2 genes, but significantly correlated with the presence of 8-oxodG in DNA. This finding and similar elevation in 8-oxodG in cerebellum of individuals with autism and in the BTBR T+tf/J mouse model warrant future large-scale studies to specifically address the role of OGG1 alterations in pathogenesis of autism. C1 [Shpyleva, Svitlana; de Conti, Aline; Melnyk, Stepan; James, S. Jill] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. [Shpyleva, Svitlana; Ivanovsky, Samuil; Tryndyak, Volodymyr; Beland, Frederick A.; Pogribny, Igor P.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP James, SJ (reprint author), Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. EM james.jill@uams.edu; igor.pogribny@fda.hhs.gov FU Jane Botsford Johnson Foundation FX Funding support for this study was provided by the Jane Botsford Johnson Foundation. Recipient of funding - SS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 13 Z9 13 U1 2 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 NOV 25 PY 2014 VL 9 IS 11 AR e113712 DI 10.1371/journal.pone.0113712 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU9GL UT WOS:000345899700058 PM 25423485 ER PT J AU Romano, A Inbar, E Debrabant, A Charmoy, M Lawyer, P Ribeiro-Gomes, F Barhoumi, M Grigg, M Shaik, J Dobson, D Beverley, SM Sacks, DL AF Romano, Audrey Inbar, Ehud Debrabant, Alain Charmoy, Melanie Lawyer, Phillip Ribeiro-Gomes, Flavia Barhoumi, Mourad Grigg, Michael Shaik, Jahangheer Dobson, Deborah Beverley, Stephen M. Sacks, David L. TI Cross-species genetic exchange between visceral and cutaneous strains of Leishmania in the sand fly vector SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Leishmania; genetic exchange; sand fly ID POPULATION-STRUCTURE; OLD-WORLD; A2 GENE; DONOVANI; INFECTION; INFANTUM; HYBRIDIZATION; CHROMOSOME; EVOLUTION; SURVIVAL AB Genetic exchange between Leishmania major strains during their development in the sand fly vector has been experimentally shown. To investigate the possibility of genetic exchange between different Leishmania species, a cutaneous strain of L. major and a visceral strain of Leishmania infantum, each bearing a different drug-resistant marker, were used to coinfect Lutzomyia longipalpis sand flies. Eleven double-drug-resistant progeny clones, each the product of an independent mating event, were generated and submitted to genotype and phenotype analyses. The analysis of multiple allelic markers across the genome suggested that each progeny clone inherited at least one full set of chromosomes from each parent, with loss of heterozygosity at some loci, and uniparental retention of maxicircle kinetoplast DNA. Hybrids with DNA contents of approximately 2n, 3n, and 4n were observed. In vivo studies revealed clear differences in the ability of the hybrids to produce pathology in the skin or to disseminate to and grow in the viscera, suggesting polymorphisms and differential inheritance of the gene(s) controlling these traits. The studies, to our knowledge, represent the first experimental confirmation of cross-species mating in Leishmania, opening the way toward genetic linkage analysis of important traits and providing strong evidence that genetic exchange is responsible for the generation of the mixed-species genotypes observed in natural populations. C1 [Romano, Audrey; Inbar, Ehud; Charmoy, Melanie; Lawyer, Phillip; Ribeiro-Gomes, Flavia; Barhoumi, Mourad; Grigg, Michael; Sacks, David L.] NIAID, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. [Debrabant, Alain] US FDA, Div Emerging & Transfus Transmitted Dis, Off Blood Res & Review, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Shaik, Jahangheer; Dobson, Deborah; Beverley, Stephen M.] Washington Univ, Dept Mol Microbiol, Sch Med, St Louis, MO 63110 USA. RP Sacks, DL (reprint author), NIAID, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. EM dsacks@nih.gov RI Ribeiro-Gomes, Flavia/F-7609-2015; OI Beverley, Stephen/0000-0001-5319-0811 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); NIH [AI-R01-29646] FX We thank Kim Beacht for assistance with the animal studies. This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); and by NIH Grant AI-R01-29646 (to S.M.B.). NR 39 TC 6 Z9 6 U1 3 U2 11 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 25 PY 2014 VL 111 IS 47 BP 16808 EP 16813 DI 10.1073/pnas.1415109111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU5QX UT WOS:000345662700045 PM 25385616 ER PT J AU He, Y Fisher, R Chowdhury, S Sultana, I Pereira, CP Bray, M Reed, JL AF He, Yong Fisher, Robert Chowdhury, Soma Sultana, Ishrat Pereira, Claudia P. Bray, Mike Reed, Jennifer L. TI Vaccinia Virus Induces Rapid Necrosis in Keratinocytes by a STAT3-Dependent Mechanism SO PLOS ONE LA English DT Article ID CELL-DEATH; STAT3 ACTIVATION; PROTEIN; PHOSPHORYLATION; INFLAMMATION; NECROPTOSIS; MITOCHONDRIA; APOPTOSIS; KINASE AB Rationale: Humans with a dominant negative mutation in STAT3 are susceptible to severe skin infections, suggesting an essential role for STAT3 signaling in defense against cutaneous pathogens. Methods: To focus on innate antiviral defenses in keratinocytes, we used a standard model of cutaneous infection of severe combined immunodeficient mice with the current smallpox vaccine, ACAM-2000. In parallel, early events post-infection with the smallpox vaccine ACAM-2000 were investigated in cultured keratinocytes of human and mouse origin. Results: Mice treated topically with a STAT3 inhibitor (Stattic) developed larger vaccinia lesions with higher virus titers and died more rapidly than untreated controls. Cultured human and murine keratinocytes infected with ACAM-2000 underwent rapid necrosis, but when treated with Stattic or with inhibitors of RIP1 kinase or caspase-1, they survived longer, produced higher titers of virus, and showed reduced activation of type I interferon responses and inflammatory cytokines release. Treatment with inhibitors of RIP1 kinase and STAT3, but not caspase-1, also reduced the inflammatory response of keratinocytes to TLR ligands. Vaccinia growth properties in Vero cells, which are known to be defective in some antiviral responses, were unaffected by inhibition of RIP1K, caspase-1, or STAT3. Conclusions: Our findings indicate that keratinocytes suppress the replication and spread of vaccinia virus by undergoing rapid programmed cell death, in a process requiring STAT3. These data offer a new framework for understanding susceptibility to skin infection in patients with STAT3 mutations. Interventions which promote prompt necroptosis/pyroptosis of infected keratinocytes may reduce risks associated with vaccination with live vaccinia virus. C1 [He, Yong; Fisher, Robert; Chowdhury, Soma; Sultana, Ishrat; Pereira, Claudia P.; Reed, Jennifer L.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. RP Reed, JL (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM jennifer.reed@fda.hhs.gov FU Medical Countermeasures Initiative and Modernization of Science - Food and Drug Administration, Center for Biologics Evaluation and Research FX This work was supported by Medical Countermeasures Initiative and Modernization of Science funding awarded by the Food and Drug Administration, Center for Biologics Evaluation and Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 2 Z9 2 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 24 PY 2014 VL 9 IS 11 AR e113690 DI 10.1371/journal.pone.0113690 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AX2IM UT WOS:000346766900066 PM 25419841 ER PT J AU Krishnaiah, YSR Xu, XM Rahman, Z Yang, Y Katragadda, U Lionberger, R Peters, JR Uhl, K Khan, MA AF Krishnaiah, Yellela S. R. Xu, Xiaoming Rahman, Ziyaur Yang, Yang Katragadda, Usha Lionberger, Robert Peters, John R. Uhl, Kathleen Khan, Mansoor A. TI Development of performance matrix for generic product equivalence of acyclovir topical creams SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Acyclovir; Topical cream; Process variables; Quality metrics; Sameness; Q1/Q2/Q3 ID DERMATOLOGICAL DRUG PRODUCTS; MEMBRANE-TRANSPORT; YIELD-STRESS; BIOEQUIVALENCE; SUPERSATURATION; DERMATOPHARMACOKINETICS; BIOAVAILABILITY; SPREADABILITY; FORMULATIONS; ENHANCEMENT AB The effect of process variability on physicochemical characteristics and in vitro performance of qualitatively (Q1) and quantitatively (Q2) equivalent generic acyclovir topical dermatological creams was investigated to develop a matrix of standards for determining their in vitro bioequivalence with reference listed drug (RLD) product (Zovirax (R)). A fractional factorial design of experiment (DOE) with triplicate center point was used to create 11 acyclovir cream formulations with manufacturing variables such as pH of aqueous phase, emulsification time, homogenization speed, and emulsification temperature. Three more formulations (F-12-F-14) with drug particle size representing RLD were also prepared where the pH of the final product was adjusted. The formulations were subjected to physicochemical characterization (drug particle size, spreadability, viscosity, pH, and drug concentration in aqueous phase) and in vitro drug release studies against RLD. The results demonstrated that DOE formulations were structurally and functionally (e.g., drug release) similar (Q3) to RLD. Moreover, in vitro drug permeation studies showed that extent of drug bioavailability/retention in human epidermis from F-12-F- 14 were similar to RLD, although differed in rate of permeation. The results suggested generic acyclovir creams can be manufactured to obtain identical performance as that of RLD with Q1/Q2/Q3. Published by Elsevier B.V. C1 [Krishnaiah, Yellela S. R.; Xu, Xiaoming; Rahman, Ziyaur; Yang, Yang; Katragadda, Usha; Khan, Mansoor A.] US FDA, Div Prod Qual Res, Off Testing & Res, Off Pharmaceut Sci,Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Lionberger, Robert; Peters, John R.; Uhl, Kathleen] US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Khan, MA (reprint author), FDA CDER OPS OTR DPQR, LS Bldg 64,Room 1070,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM mansoor.khan@fda.hhs.gov OI Xu, Xiaoming/0000-0003-1672-0830; Rahman, Ziyaur/0000-0002-0402-825X FU Office of Generic Drugs FX Office of Generic Drugs is gratefully acknowledged for providing funding to carry out this research. The authors would like to thank Robert Hunt for his help with the in vitro drug release studies. The National Disease Research Interchange (NDRI, Philadelphia, PA, USA) is also acknowledged for providing the human cadaver skin. NR 37 TC 6 Z9 6 U1 0 U2 10 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 110 EP 122 DI 10.1016/j.ijpharm.2014.07.034 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AU0FR UT WOS:000345299500011 PM 25089511 ER EF