FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Li, HL Hitchins, VM Wickramasekara, S AF Li, Hongli Hitchins, Victoria M. Wickramasekara, Samanthi TI Rapid detection of bacterial endotoxins in ophthalmic viscosurgical device materials by direct analysis in real time mass spectrometry SO ANALYTICA CHIMICA ACTA LA English DT Article DE Endotoxin; Sodium hyaluronate; Perfluoro-n-octane; Silicone oil; Direct analysis in real time; Mass spectrometry ID ANTERIOR SEGMENT SYNDROME; LIMULUS AMEBOCYTE LYSATE; PERFLUORO-N-OCTANE; DART-MS; RETINAL-DETACHMENT; CATARACT-SURGERY; GC-MS; SILICONE; LIPOPOLYSACCHARIDES; CONTAMINATION AB Bacterial endotoxins are lipopolysaccharides bound to the bacterial cell wall and released when bacteria rupture or disintegrate. Possible contamination of endotoxin in ophthalmic devices can cause a painful eye inflammation or result in toxic anterior segment syndrome after cataract surgery. Measurement of bacterial endotoxin in medical device materials is difficult since endotoxin binds with polymer matrix and some of the materials are very viscous and non-water soluble, where traditional enzyme-based Limulus amebocyte lysate (LAL) assay cannot be applied. Here we propose a rapid and high throughput ambient ionization mass spectrometric (MS) method using direct analysis in real time (DART) for the evaluation of endotoxin contamination in medical device materials. Large and structurally complex endotoxin instantaneously breaks down into low-mass characteristic fragment ions using DART and is detected by MS in both positive and negative ion modes. This method enables the identification and separation of endotoxin from medical materials with a detection limit of 0.03 ng mL(-1) endotoxins in aqueous solution. Ophthalmic viscosurgical device materials including sodium hyaluronate (NaHA), non-water soluble perfluoro-n-octane (PFO) and silicone oil (SO) were spiked with different known concentrations of endotoxin and analyzed by DART MS, where the presence of endotoxin was successfully detected and featured small mass fragment ions were generated for NaHA, PFO and SO as well. Current findings showed the feasibility of measuring endotoxin contamination in medical device materials using DART-MS, which can lead to a one-step analysis of endotoxins in different matrices, avoiding any potential contamination during sample pre-treatment steps. Published by Elsevier B.V. C1 [Li, Hongli; Hitchins, Victoria M.; Wickramasekara, Samanthi] US FDA, Div Biol Chem & Mat Sci, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 64,Rm 3064, Silver Spring, MD 20993 USA. [Li, Hongli] Nanjing Normal Univ, Coll Chem & Mat Sci, Jiangsu Collaborat Innovat Ctr Biomed Funct Mat, Jiangsu Key Lab Biomed Mat, Nanjing 210023, Jiangsu, Peoples R China. RP Wickramasekara, S (reprint author), US FDA, Div Biol Chem & Mat Sci, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 64,Rm 3064, Silver Spring, MD 20993 USA. EM Samanthi.Wickramasekara@fda.hhs.gov FU FDA Medical Countermeasure Initiative (MCMi) program; Division of Biology, Chemistry and Materials Science (DBCMS) fund; appointment to the Research Participation Program at the Center for Devices and Radiological Health FX This work was supported by FDA Medical Countermeasure Initiative (MCMi) program and Division of Biology, Chemistry and Materials Science (DBCMS) fund. We thank Jason Brookbank for coordinating the grant for the DART source in this study as well as management support from Dr. Jose Centeno and Dr. Benita J. Dair. This project was supported in part by an appointment to the Research Participation Program at the Center for Devices and Radiological Health administrated by the Oak Ridge Institute for Science and Education through an inter-agency agreement between US Department of Energy and the US food and Drug Administration. NR 60 TC 0 Z9 0 U1 16 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0003-2670 EI 1873-4324 J9 ANAL CHIM ACTA JI Anal. Chim. Acta PD NOV 2 PY 2016 VL 943 BP 98 EP 105 DI 10.1016/j.aca.2016.09.030 PG 8 WC Chemistry, Analytical SC Chemistry GA DZ1QV UT WOS:000385614700011 PM 27769383 ER PT J AU Dharmasena, MN Osorio, M Filipova, S Marsh, C Stibitz, S Kopecko, DJ AF Dharmasena, Madushini N. Osorio, Manuel Filipova, Svetlana Marsh, Christina Stibitz, Scott Kopecko, Dennis J. TI Stable expression of Shigella dysenteriae serotype 1 O-antigen genes integrated into the chromosome of live Salmonella oral vaccine vector Ty21a SO PATHOGENS AND DISEASE LA English DT Article DE combination oral vaccine; lambda red-mediated recombineering; stable expression of inserted antigenic genes; shigellosis-enteric fever combination vaccine; Ty21a vector expressing Shigella dysenteriae 1 O-antigen ID ESCHERICHIA-COLI; TYPHOID VACCINE; BIVALENT VACCINE; SONNEI VACCINE; PROTECTION; STRAIN; POLYSACCHARIDE; RESPONSES; IMMUNITY; CLONING AB Typhoid fever and shigellosis cause high morbidity and mortality worldwide, yet no anti-Shigella vaccine is currently available. However, to protect against typhoid fever, an approved vaccine, based on the attenuated Salmonella enterica serovar Typhi strain Ty21a is available. We have investigated Ty21a as a live oral vaccine vector for expression of heterologous foreign antigens to protect against other diseases (e.g. shigellosis, anthrax and plague). Shigella lipopolysccharide (LPS) is a potent vaccine antigen for serotype-specific protection against Shigellae. We previously reported the construction of a Ty21a derivative expressing Shigella sonnei O-antigen by insertion of a large (similar to 12.5 kb) operon comprising the S. sonnei O-antigen biosynthetic genes into a targeted site within the Ty21a chromosome using modified lambda red recombineering methods. In the current study, S. dysenteriae 1 O-antigen biosynthetic genes from two separate genetic loci, rfp and rfb, were assembled and inserted into the Ty21a chromosome by lambda red-mediated recombineering to construct strain Ty21a-Sd. To obtain a high level of heterologous LPS expression, the native upstream promoter was replaced with the constitutive lpp promoter, which resulted in Ty21a-Sdl with enhanced heterologous LPS expression. Both Ty21a-Sd and Ty21a-Sdl elicited significant serum antibody responses in mice against both Ty21a and this heterologous Shigella LPS, and conferred protection against virulent S. dysenteriae 1 challenge. This work represents progress toward the goal of a safe and effective vaccine against Shigella. C1 [Dharmasena, Madushini N.; Osorio, Manuel; Filipova, Svetlana; Marsh, Christina; Stibitz, Scott; Kopecko, Dennis J.] US FDA, Lab Mucosal Pathogens & Cellular Immunol, Ctr Biol Evaluat & Res, New Hampshire Ave,Bldg 72-52,HFM 440, Silver Spring, MD 20903 USA. [Kopecko, Dennis J.] CombiVax LLC, 16325 Whitehaven Rd,Suite A, Silver Spring, MD 20906 USA. RP Dharmasena, MN (reprint author), US FDA, Lab Mucosal Pathogens & Cellular Immunol, Ctr Biol Evaluat & Res, New Hampshire Ave,Bldg 72-52,HFM 440, Silver Spring, MD 20903 USA. EM madushini.dharmasena@fda.hhs.gov NR 36 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2049-632X J9 PATHOG DIS JI Pathog. Dis. PD NOV PY 2016 VL 74 IS 8 AR ftw098 DI 10.1093/femspd/ftw098 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EL5VV UT WOS:000394690300009 ER PT J AU Rodriguez, DA Pfefer, TJ Wang, QZ Lopez, PF Ramella-Roman, JC AF Rodriguez, Daniel A. Pfefer, T. Joshua Wang, Quanzeng Lopez, Pedro F. Ramella-Roman, Jessica C. TI A Monte Carlo Analysis of Error Associated With Two-Wavelength Algorithms for Retinal Oximetry SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE oximetry; two-wavelength; Monte Carlo ID VESSEL OXYGEN-SATURATION; VISION-THREATENING RETINOPATHY; OPEN-ANGLE GLAUCOMA; DIABETIC-RETINOPATHY; OPTICAL-PROPERTIES; VEIN OCCLUSION; HUMAN EYE; HEALTHY; BLOOD; LIGHT AB PURPOSE. Two-wavelength algorithms aimed at the extrapolation of retinal vasculature optical properties are being used in the clinical setting. Although robust, this approach has some clear mathematical limitations. We have conducted an in-depth study of this methodology and report on the limits and benefit of this approach. METHODS. We used a well-tested, voxel-based Monte Carlo model of light transfer into biological tissue combined with a seven-layer model of the human fundus to create reflectance maps of retina vessels at different oxygenation levels. RESULTS. This study shows that the two-wavelength approach works remarkably well in the optimal scenario of known calibration arteries and veins. Errors as a result of choroidal pigmentation and discrepancies in vessel size can be minimized with numerical approaches. When the calibration process deviates largely from physiological values, the technique fails with large errors. CONCLUSIONS. The two-wavelength approach is convenient, easy to implement, and suitable in studies where relative rather than absolute knowledge of retinal oximetry is necessary. A robust calibration step is paramount when using this approach. C1 [Rodriguez, Daniel A.; Ramella-Roman, Jessica C.] Florida Int Univ, Dept Biomed Engn, 10555 W Flagler St,EC-2610, Miami, FL 33174 USA. [Pfefer, T. Joshua; Wang, Quanzeng] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Lopez, Pedro F.; Ramella-Roman, Jessica C.] Florida Int Univ, Herbert Wertheim Coll Med, Miami, FL 33174 USA. RP Ramella-Roman, JC (reprint author), Florida Int Univ, Dept Biomed Engn, 10555 W Flagler St,EC-2610, Miami, FL 33174 USA. EM jramella@fiu.edu FU Herbert Wertheim College of Medicine; Herbert and Nicole Wertheim Professorship Endowment FX Supported by the Herbert Wertheim College of Medicine and the Herbert and Nicole Wertheim Professorship Endowment. NR 62 TC 0 Z9 0 U1 1 U2 1 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 NOV PY 2016 VL 57 IS 14 BP 6474 EP 6481 DI 10.1167/iovs.16-20138 PG 8 WC Ophthalmology SC Ophthalmology GA EI3HG UT WOS:000392380000080 PM 27893889 ER PT J AU Ahn, Y Kim, JM Kweon, O Kim, SJ Jones, RC Woodling, K da Costa, GG LiPuma, JJ Hussong, D Marasa, BS Cerniglia, CE AF Ahn, Youngbeom Kim, Jeong Myeong Kweon, Ohgew Kim, Seong-Jae Jones, Richard C. Woodling, Kellie da Costa, Gonalo Gamboa LiPuma, John J. Hussong, David Marasa, Bernard S. Cerniglia, Carl E. TI Intrinsic Resistance of Burkholderia cepacia Complex to Benzalkonium Chloride SO MBIO LA English DT Article ID QUATERNARY AMMONIUM-COMPOUNDS; MYCOBACTERIUM-VANBAALENII PYR-1; RING-HYDROXYLATING OXYGENASES; HYDROCARBON METABOLIC NETWORK; SERRATIA-MARCESCENS; PSEUDOMONAS-PUTIDA; DISTILLED WATER; LISTERIA-MONOCYTOGENES; DRUG-RESISTANCE; CYSTIC-FIBROSIS AB Pharmaceutical products that are contaminated with Burkholderia cepacia complex (BCC) bacteria may pose serious consequences to vulnerable patients. Benzyldimethylalkylammonium chloride (BZK) cationic surfactants are extensively used in medical applications and have been implicated in the coselection of antimicrobial resistance. The ability of BCC to degrade BZK, tetradecyldimethylbenzylammonium chloride (C(14)BDMA-Cl), dodecyldimethylbenzylammonium chloride (C(12)BDMA-Cl), decyldimethylbenzylammonium chloride (C(10)BDMA-Cl), hexyldimethylbenzylammonium chloride, and benzyltrimethylammonium chloride was determined by incubation in 1/10-diluted tryptic soy broth (TSB) to determine if BCC bacteria have the ability to survive and inactivate these disinfectants. With BZK, C(14)BDMA-Cl, and C(12)BDMA-Cl, inhibition of the growth of 20 BCC strains was observed in disinfectant solutions that ranged from 64 to 256 mu g/ml. The efflux pump inhibitor carbonyl cyanidem-chlorophenylhydrazone increased the sensitivity of bacteria to 64 mu g/ml BZK. The 20 BCC strains grew well in 1/10-diluted TSB medium with BZK, C(12)BDMA-Cl, and C(10)BDMA-Cl; they absorbed and degraded the compounds in 7 days. Formation of benzyldimethylamine and benzylmethylamine as the initial metabolites suggested that the cleavage of the C alkyl-N bond occurred as the first step of BZK degradation by BCC bacteria. Proteomic data confirmed the observed efflux activity and metabolic inactivation via biodegradation in terms of BZK resistance of BCC bacteria, which suggests that the two main resistance mechanisms are intrinsic and widespread. IMPORTANCE Benzyldimethylalkylammonium chloride is commonly used as an antiseptic in the United States. Several recent microbial outbreaks were linked to antiseptics that were found to contain strains of the Burkholderia cepacia complex. Burkholderia species survived in antiseptics, possibly because of the degradation of antiseptic molecules or regulation of relevant gene expression. In this study, we assessed the efflux pump and the potential of B. cepacia complex bacteria to degrade benzyldimethylalkylammonium chloride and improved our understanding of the resistance mechanisms, by using proteomic and metabolic information. To our knowledge, this is the first systematic report of the intrinsic mechanisms of B. cepacia complex strain resistance to benzyldimethylalkylammonium chloride, based on the metabolic and proteomic evidence for efflux pumps and the complete biodegradation of benzyldimethylalkylammonium chloride. C1 [Ahn, Youngbeom; Kim, Jeong Myeong; Kweon, Ohgew; Kim, Seong-Jae; Cerniglia, Carl E.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Jones, Richard C.] MS Bioworks LLC, Ann Arbor, MI USA. [Woodling, Kellie; da Costa, Gonalo Gamboa] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [LiPuma, John J.] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Hussong, David] US FDA, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Marasa, Bernard S.] US FDA, Div Microbiol Assessment, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Cerniglia, CE (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Carl.Cerniglia@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration FX This work was supported in part by an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration to the Postgraduate Research Fellow Program (J. M. Kim) at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science and Education. The views presented in this article do not necessarily reflect those of the Food and Drug Administration. NR 65 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2016 VL 7 IS 6 AR e01716 DI 10.1128/mBio.01716-16 PG 11 WC Microbiology SC Microbiology GA EH9GK UT WOS:000392079500041 ER PT J AU Manangeeswaran, M Ireland, DDC Verthelyi, D AF Manangeeswaran, Mohanraj Ireland, Derek D. C. Verthelyi, Daniela TI Zika (PRVABC59) Infection Is Associated with T cell Infiltration and Neurodegeneration in CNS of Immunocompetent Neonatal C57Bl/6 Mice SO PLOS PATHOGENS LA English DT Article ID VIRUS-INFECTION; ALPHAVIRUS ENCEPHALOMYELITIS; MOUSE MODEL; ARENAVIRUS; BRAIN; INTERLEUKIN-10; PATHOGENICITY; ENCEPHALITIS; ORGANOIDS; PREGNANCY AB The recent spread of Zika virus (ZIKV) and its association with increased rates of Guillain Barre and other neurological disorders as well as congenital defects that include microcephaly has created an urgent need to develop animal models to examine the pathogenesis of the disease and explore the efficacy of potential therapeutics and vaccines. Recently developed infection models for ZIKV utilize mice defective in interferon responses. In this study we establish and characterize a new model of peripheral ZIKV infection using immunocompetent neonatal C57BL/6 mice and compare its clinical progression, virus distribution, immune response, and neuropathology with that of C57BL/6-IFNAR KO mice. We show that while ZIKV infected IFNAR KO mice develop bilateral hind limb paralysis and die 5-6 days post-infection (dpi), immunocompetent B6 WT mice develop signs of neurological disease including unsteady gait, kinetic tremors, severe ataxia and seizures by 13 dpi that subside gradually over 2 weeks. Immunohistochemistry show viral antigen predominantly in cerebellum at the peak of the disease in both models. However, whereas IFNAR KO mice showed infiltration by neutrophils and macrophages and higher expression of IL-1, IL-6 and Cox2, B6 WT mice show a cellular infiltration in the CNS composed predominantly of T cells, particularly CD8+ T cells, and increased mRNA expression levels of IFNg, GzmB and Prf1 at peak of disease. Lastly, the CNS of B6 WT mice shows evidence of neurodegeneration predominantly in the cerebellum that are less prominent in mice lacking the IFN response possibly due to the difference in cellular infiltrates and rapid progression of the disease in that model. The development of the B6 WT model of ZIKV infection will provide insight into the immunopathology of the virus and facilitate assessments of possible therapeutics and vaccines. C1 [Manangeeswaran, Mohanraj; Ireland, Derek D. C.; Verthelyi, Daniela] US FDA, Div Biotechnol Review & Res 3, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Verthelyi, D (reprint author), US FDA, Div Biotechnol Review & Res 3, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Daniela.Verthelyi@fda.hhs.gov OI Verthelyi, Daniela/0000-0002-5450-3071 FU FDA Medical Countermeasures Initiative FX This work was partly funded by the FDA Medical Countermeasures Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 3 Z9 3 U1 5 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD NOV PY 2016 VL 12 IS 11 AR e1006004 DI 10.1371/journal.ppat.1006004 PG 20 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EI0VO UT WOS:000392193200033 PM 27855206 ER PT J AU Meierovics, AI Cowley, SC AF Meierovics, Anda I. Cowley, Siobhan C. TI MAIT cells promote inflammatory monocyte differentiation into dendritic cells during pulmonary intracellular infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID INVARIANT T-CELLS; CYTOKINE GM-CSF; COLONY-STIMULATING FACTOR; MR1 ANTIGEN PRESENTATION; LIVE VACCINE STRAIN; MOUSE BONE-MARROW; IMMUNE-RESPONSES; FRANCISELLA-TULARENSIS; BACTERIAL-INFECTION; MYCOBACTERIUM-TUBERCULOSIS AB Mucosa-associated invariant T (MAIT) cells are a unique innate T cell subset that is necessary for rapid recruitment of activated CD4(+) T cells to the lungs after pulmonary F. tularensis LVS infection. Here, we investigated the mechanisms behind this effect. We provide evidence to show that MAIT cells promote early differentiation of CCR2-dependent monocytes into monocyte- derived DCs (Mo-DCs) in the lungs after F. tularensis LVS pulmonary infection. Adoptive transfer of Mo-DCs to MAIT cell-deficient mice (MR1(-/-) mice) rescued their defect in the recruitment of activated CD4(+) T cells to the lungs. We further demonstrate that MAIT cell-dependent GM-CSF production stimulated monocyte differentiation in vitro, and that in vivo production of GM-CSF was delayed in the lungs of MR1(-/-) mice. Finally, GM-CSF-deficient mice exhibited a defect in monocyte differentiation into Mo-DCs that was phenotypically similar to MR1(-/-) mice. Overall, our data demonstrate that MAIT cells promote early pulmonary GM-CSF production, which drives the differentiation of inflammatory monocytes into Mo-DCs. Further, this delayed differentiation of Mo-DCs in MR1(-/-) mice was responsible for the delayed recruitment of activated CD4(+) T cells to the lungs. These findings establish a novel mechanism by which MAIT cells function to promote both innate and adaptive immune responses. C1 [Meierovics, Anda I.; Cowley, Siobhan C.] US FDA, Lab Mucosal Pathogens & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Cowley, SC (reprint author), US FDA, Lab Mucosal Pathogens & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM siobhan.cowley@fda.hhs.gov FU internal Center for Biologics Evaluation and Research/Food and Drug Administration (U.S. government) FX This work was funded by internal Center for Biologics Evaluation and Research/Food and Drug Administration (U.S. government) operating funds. NR 64 TC 0 Z9 0 U1 2 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD NOV PY 2016 VL 213 IS 12 BP 2793 EP 2809 DI 10.1084/jem.20160637 PG 17 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EG5ZC UT WOS:000391122400018 PM 27799620 ER PT J AU Durmowicz, AG AF Durmowicz, Anthony G. TI Cystic fibrosis biomarker - Commentary SO JOURNAL OF CYSTIC FIBROSIS LA English DT Editorial Material C1 [Durmowicz, Anthony G.] US FDA, Div Pulm Allergy & Rheumatol Prod, Off New Drugs, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Durmowicz, AG (reprint author), US FDA, Div Pulm Allergy & Rheumatol Prod, Off New Drugs, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. EM Anthony.Durmowicz@fda.hhs.gov NR 4 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-1993 EI 1873-5010 J9 J CYST FIBROS JI J. Cyst. Fibros PD NOV PY 2016 VL 15 IS 6 BP 712 EP 713 DI 10.1016/j.jcf.2016.10.010 PG 2 WC Respiratory System SC Respiratory System GA EF7OA UT WOS:000390517700005 PM 27842897 ER PT J AU Bonhomme, MG Holder-Hayes, E Ambrose, BK Tworek, C Feirman, SP King, BA Apelberg, BJ AF Bonhomme, Michele G. Holder-Hayes, Enver Ambrose, Bridget K. Tworek, Cindy Feirman, Shari P. King, Brian A. Apelberg, Benjamin J. TI Flavoured non-cigarette tobacco product use among US adults: 2013-2014 SO TOBACCO CONTROL LA English DT Article DE Non-cigarette tobacco products; Surveillance and monitoring; Priority; special populations; Disparities; Electronic nicotine delivery devices ID HIGH-SCHOOL-STUDENTS; UNITED-STATES; ELECTRONIC CIGARETTES; YOUNG-ADULTS; SMOKERS; SMOKING; BRANDS; TRENDS; CIGARILLOS; SMOKELESS AB Introduction Limited data exist on flavoured non-cigarette tobacco product (NCTP) use among US adults. Methods Data from the 2013 to 2014 National Adult Tobacco Survey (N=75233), a landline and cellular telephone survey of US adults aged 18, were assessed to estimate past 30-day NCTP use, flavoured NCTP use and flavour types using bivariate analyses. Results During 2013-2014, 14.4% of US adults were past 30-day NCTP users. Nationally, an estimated 10.2 million e-cigarette users (68.2%), 6.1 million hookah users (82.3%), 4.1 million cigar smokers (36.2%) and 4.0 million smokeless tobacco users (50.6%) used flavoured products in the past 30days. The most prevalent flavours reported were menthol/mint (76.9%) for smokeless tobacco; fruit (74.0%) for hookah; fruit (52.4%), candy/chocolate/other sweet flavours (22.0%) and alcohol (14.5%) for cigars/cigarillos/filtered little cigars; fruit (44.9%), menthol/mint (43.9%) and candy/chocolate/other sweet flavours (25.7%) for e-cigarettes and fruit (56.6%), candy/chocolate/other sweet flavours (26.5%) and menthol/mint (24.8%) for pipes. Except for hookah and pipes, past 30-day flavoured product use was highest among 18-24-year olds. By cigarette smoking, never smoking e-cigarette users (84.8%) were more likely to report flavoured e-cigarette use, followed by recent former smokers (78.1%), long-term former smokers (70.4%) and current smokers (63.2%). Conclusions Flavoured NCTP use is prominent among US adult tobacco users, particularly among e-cigarette, hookah and cigar users. Flavoured product use, especially fruit and sweet-flavoured products, was higher among younger adults. It is important for tobacco prevention and control strategies to address all forms of tobacco use, including flavoured tobacco products. C1 [Bonhomme, Michele G.; Holder-Hayes, Enver; Ambrose, Bridget K.; Tworek, Cindy; Feirman, Shari P.; Apelberg, Benjamin J.] US FDA, Ctr Tobacco Prod, Off Sci, Bldg WO75,Room 4476,10903 New Hampshire, Silver Spring, MD 20903 USA. [King, Brian A.] Ctr Dis Control & Prevent, Off Smoking & Hlth, Atlanta, GA USA. RP Bonhomme, MG (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, Bldg WO75,Room 4476,10903 New Hampshire, Silver Spring, MD 20903 USA. EM Michele.Bonhomme@fda.hhs.gov FU Food and Drug Administration's Center for Tobacco Products; Centers for Disease Control and Prevention's Office of Smoking and Health FX This work was supported by the Food and Drug Administration's Center for Tobacco Products and the Centers for Disease Control and Prevention's Office of Smoking and Health. NR 28 TC 1 Z9 1 U1 2 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 EI 1468-3318 J9 TOB CONTROL JI Tob. Control PD NOV PY 2016 VL 25 SU 2 BP ii4 EP ii13 DI 10.1136/tobaccocontrol-2016-053373 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EF8OZ UT WOS:000390589800002 PM 27794065 ER PT J AU Hoffman, AC Salgado, RV Dresler, C Faller, RW Bartlett, C AF Hoffman, Allison C. Salgado, Raydel Valdes Dresler, Carolyn Faller, Rachel Williams Bartlett, Christopher TI Flavour preferences in youth versus adults: a review SO TOBACCO CONTROL LA English DT Review DE Non-cigarette tobacco products; End game; Priority; special populations ID TASTE PREFERENCES; SWEET TASTE; DEVELOPMENTAL-CHANGES; SENSORY PERCEPTION; EUROPEAN CHILDREN; SOUR PREFERENCES; FOOD PREFERENCES; HUMAN INFANTS; WEIGHT STATUS; AGE AB Objective To understand the available evidence of how children and adults differ in their preferences for flavours that may be used in tobacco products. Data sources A total of 474 articles published between 1931 and August 2015 were retrieved through searches conducted in PubMed, EMBASE, Web of Science and PsycINFO. Study selection and extraction A 2-phase relevancy review process resulted in the identification of 59 articles and information was extracted by 2 independent reviewers. Data synthesis Findings were grouped by taste and smell preferences, which are important components of overall flavour. For taste, evidence is summarised in the following categories: sweet, salty, sour, bitter, umami and fat; within each of them, findings are organised by age categories. For smell, evidence is summarised as follows: fruit/herbal/spices, tobacco and coffee and other odours. Major findings from this search indicated that sweet preference in children and adolescents was higher than in adults. Examples of preferred food-related tastes and odours for young people included cherry, candy, strawberry, orange, apple and cinnamon. Currently, all these are used to flavour cigars, cartridges for electronic cigarettes, hookah (waterpipe) and smokeless tobacco products. Conclusions Infants and children exhibited elevated sweet and salty preference relative to adults. Age-related changes in bitter, sour, umami and fat taste were not clear and more research would be useful. Sweet' food odours were highly preferred by children. Tobacco products in flavours preferred by young people may impact tobacco use and initiation, while flavours preferred by adults may impact product switching or dual use. C1 [Hoffman, Allison C.; Dresler, Carolyn] Ctr Tobacco Prod, Bldg 75,Rm 5426,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Salgado, Raydel Valdes; Faller, Rachel Williams; Bartlett, Christopher] SciMetrika LLC, Div Populat Hlth Sci, Silver Spring, MD USA. RP Hoffman, AC (reprint author), Ctr Tobacco Prod, Bldg 75,Rm 5426,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM allison.hoffman@fda.hhs.gov FU Food and Drug Administration [HHSF223201310024I] FX This work was supported by funding from the Food and Drug Administration (Contract no. HHSF223201310024I). NR 70 TC 0 Z9 0 U1 7 U2 7 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 EI 1468-3318 J9 TOB CONTROL JI Tob. Control PD NOV PY 2016 VL 25 SU 2 BP ii32 EP ii39 DI 10.1136/tobaccocontrol-2016-053192 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EF8OZ UT WOS:000390589800005 PM 27633764 ER PT J AU Dadhania, VP Muskhelishvili, L Latendresse, JR Mehendale, HM AF Dadhania, Vivekkumar P. Muskhelishvili, Levan Latendresse, John R. Mehendale, Harihara M. TI Hepatic Overexpression of Annexin A1 and A2 in Thioacetamide-Primed Mice Protects Them Against Acetaminophen-Induced Liver Failure and Death SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Article DE Heteroprotection; Secretory phospholipase A2; Annexin A1; Annexin A2; Tissue repair; Liver failure ID PHOSPHOLIPASE A(2) ACTIVITY; TISSUE-REPAIR; MEDIATES PROGRESSION; CCL4 AUTOPROTECTION; GENE-EXPRESSION; INJURY; MODEL; HEPATOTOXICITY; REGENERATION; HEPATOCYTES AB Compensatory tissue repair (CTR) in thioacetamide (TA)-primed rats protects them against acetaminophen (APAP)-induced lethality. This study was aimed at investigating the mechanisms of CTR-mediated heteroprotection in mice. Male Swiss Webster mice received a priming dose of TA (40 mg/kg body weight [BW] in 10 mL distilled water [DW]/kg BW, intraperitoneally [IP]). Thioacetamide-induced liver injury, CTR, and expression of annexin A1 and A2 (ANX1 and ANX2), the endogenous inhibitors of the death protein secretory phospholipase A2 (sPLA(2)), were measured over a time course of 84 hours after TA priming. Both centrilobular necrosis and CTR peaked at 36 hours after TA priming as indicated by significantly increased plasma alanine transaminase (ALT) and aspartate transaminase (AST) activities, liver histology, and proliferating cell nuclear antigen immunostaining. Thioacetamide priming resulted in the overexpression of ANX1 and ANX2 at 36 to 84 hours and 12 to 60 hours, respectively. A lethal dose of APAP (600 mg/kg BW in 10 mL 0.45% NaCl/kg BW, IP) was given at 12, 24, or 36 hours after TA-priming. Thioacetamide priming did not affect the rise in plasma ALT, AST, sPLA(2), and arachidonic acid levels seen at 2 hours after the APAP overdose. Neither these biochemical parameters nor histology suggested any escalation of hepatic injury at later time points (12 and 24 hours after APAP overdose), consistent with 100% survival of the TA + APAP-treated mice compared to DW + APAP-treated mice, which had 100% mortality. Inhibition of ANX1 and ANX2 biosynthesis using cycloheximide (40 mg/kg BW in 5 mL DW/kg BW, IP) abolished this heteroprotection. Our data indicate that hepatic overexpression of ANX1 and ANX2 inhibits APAP-induced expansion of liver injury. C1 [Dadhania, Vivekkumar P.; Mehendale, Harihara M.] ULM, Dept Toxicol, Coll Hlth & Pharmaceut Sci, 700 Univ Ave,Bienville 259, Monroe, LA 71209 USA. [Muskhelishvili, Levan; Latendresse, John R.] Natl Ctr Toxicol Res, Toxicol Pathol Associates, Jefferson, AR 72079 USA. RP Mehendale, HM (reprint author), ULM, Dept Toxicol, Coll Hlth & Pharmaceut Sci, 700 Univ Ave,Bienville 259, Monroe, LA 71209 USA. EM mehendale@ulm.edu NR 30 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD NOV-DEC PY 2016 VL 35 IS 6 BP 654 EP 665 DI 10.1177/1091581816659067 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE9CI UT WOS:000389922900004 PM 27451051 ER PT J AU Buseyne, F Gessain, A Soares, MA Santos, AF Materniak-Kornas, M Lesage, P Zamborlini, A Lochelt, M Qiao, WT Lindemann, D Wohrl, BM Stoye, JP Taylor, IA Khan, AS AF Buseyne, Florence Gessain, Antoine Soares, Marcelo A. Santos, Andre F. Materniak-Kornas, Magdalena Lesage, Pascale Zamborlini, Alessia Loechelt, Martin Qiao, Wentao Lindemann, Dirk Woehrl, Birgitta M. Stoye, Jonathan P. Taylor, Ian A. Khan, Arifa S. TI Eleventh International Foamy Virus ConferenceMeeting Report SO VIRUSES-BASEL LA English DT Article DE foamy virus; cross-species virus transmission; zoonosis; restriction factors; immune responses; FV vectors; virus replication; latent infection ID IN-VITRO; MOLECULAR VIROLOGY; RHESUS MACAQUES; TRANSMISSION; HUMANS; REPLICATION; INFECTION; GORILLA; VECTOR; CELLS AB The Eleventh International Foamy Virus Conference took place on 9-10 June 2016 at the Institut Pasteur, Paris, France. The meeting reviewed progress on foamy virus (FV) research, as well as related current topics in retrovirology. FVs are complex retroviruses that are widespread in several animal species. Several research topics on these viruses are relevant to human health: cross-species transmission and viral emergence, vectors for gene therapy, development of antiretroviral drugs, retroviral evolution and its influence on the human genome. In this article, we review the conference presentations on these viruses and highlight the major questions to be answered. C1 [Buseyne, Florence; Gessain, Antoine] Inst Pasteur, Unite Epidemiol & Physiopathol Virus Oncogenes, F-75015 Paris, France. [Buseyne, Florence; Gessain, Antoine] CNRS, UMR3569, F-75015 Paris, France. [Soares, Marcelo A.; Santos, Andre F.] Univ Fed Rio de Janeiro, Dept Genet, BR-21949570 Rio De Janeiro, Brazil. [Soares, Marcelo A.] Inst Nacl Canc, Oncovirol Program, BR-20231050 Rio De Janeiro, Brazil. [Materniak-Kornas, Magdalena] Natl Inst Vet Res, Dept Biochem, PL-24100 Pulawy, Poland. [Lesage, Pascale; Zamborlini, Alessia] Univ Paris Diderot, CNRS UMR 7212, Inst Univ Hematol, Hop St Louis,Sorbonne Paris Cite,INSERM U944, F-75010 Paris, France. [Zamborlini, Alessia] Conservatoire Natl Arts & Metiers, Lab Pathol & Virol Mol, F-75003 Paris, France. [Loechelt, Martin] Res Program Infect Inflammat & Canc, Dept Mol Diagnost Oncogen Infect, D-69120 Heidelberg, Germany. [Qiao, Wentao] Nankai Univ, Coll Life Sci, Key Lab Mol Microbiol & Technol, Minist Educ, Tianjin 300071, Peoples R China. [Lindemann, Dirk] Tech Univ Dresden, Med Fac Carl Gustav Carus, Inst Virol, D-01307 Dresden, Germany. [Woehrl, Birgitta M.] Univ Bayreuth, Dept Biopolymers, D-95447 Bayreuth, Germany. [Stoye, Jonathan P.; Taylor, Ian A.] Francis Crick Inst, London NW1 1AT, England. [Khan, Arifa S.] US FDA, Lab Retroviruses, Div Viral Prod, OVRR,CBER, Silver Spring, MD 20993 USA. RP Buseyne, F (reprint author), Inst Pasteur, Unite Epidemiol & Physiopathol Virus Oncogenes, F-75015 Paris, France.; Buseyne, F (reprint author), CNRS, UMR3569, F-75015 Paris, France. EM florence.buseyne@pasteur.fr; antoine.gessain@pasteur.fr; masoares@biologia.ufrj.br; andre.santos@ufrj.br; magdalena.materniak@piwet.pulawy.pl; pascale.lesage@inserm.fr; alessia.zamborlini@univ-paris-diderot.fr; m.loechelt@dkfz.de; wentaoqiao@nankai.edu.cn; dirk.lindemann@tu-dresden.de; birgitta.woehrl@uni-bayreuth.de; jonathan.stoye@crick.ac.uk; ian.taylor@crick.ac.uk; arifa.khan@fda.hhs.gov OI Buseyne, Florence/0000-0002-9323-7837; Lindemann, Dirk/0000-0002-0320-4223; TAYLOR, IAN/0000-0002-6763-3852 FU LabEx IBEID; Pasteur-Maladies infectieuses Carnot Institute FX Florence Buseyne and Antoine Gessain would like to thank Isma Ziani, Caroline Lambert and Lea Richard for the organization of the meeting, and Thomas Montange, Delia Djuicy, Mathilde Couteaudier and other members from the research unit for their help in welcoming the participants. The meeting was supported by grants from the LabEx IBEID (https://research.pasteur.fr/fr/program project/integrative-biology-of-emerging-infectious-diseases) and Pasteur-Maladies infectieuses Carnot Institute (http://www.instituts-carnot.eu/en/carnot-institute/pasteur-mi). Organizers would like to thank Thierry Planchenault, Pascale Cossart, Philippe Sansonetti, Cecile Peltekian, Jean-Christophe Olivo-Marin and Daniel Larzul for their support. No funding was received for covering the costs to publish in open access. NR 45 TC 0 Z9 0 U1 2 U2 2 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD NOV PY 2016 VL 8 IS 11 AR 318 DI 10.3390/v8110318 PG 14 WC Virology SC Virology GA EF1UA UT WOS:000390109100026 ER PT J AU Hepp, NM James, IC AF Hepp, Nancy M. James, India C. TI Application of high-energy polarized energy-dispersive x-ray fluorescence spectrometry to the determination of trace levels of As, Hg, and Pb in certifiable color additives SO X-RAY SPECTROMETRY LA English DT Article ID EDXRF; SAMPLES; SOILS; RADIATION; ELEMENTS AB Advances in x-ray fluorescence (XRF) using high-energy polarized energy-dispersive (ED) XRF spectrometry (PEDXRF) were applied to the determination of trace As, Hg, and Pb in various color additives subject to batch certification by the U.S. Food and Drug Administration (FDA). The objectives of this study were to simplify sample preparation for quantitative determination of these elements and, if possible, to achieve improved sensitivity and detection limits compared to techniques currently used for certification. PEDXRF was compared with wavelength-dispersive x-rayfluorescence spectrometry (WDXRF) and inductively coupled plasma - mass spectrometry (ICP-MS) for the analysis of trace levels of As, Hg, and Pb in certifiable color additives. For these light matrices, PEDXRF provided better signal-to-noise and allowed quantitation in smaller amounts of color additive relative to WDXRF and equal or better precision to ICP-MS. Determination of these trace elements in a variety of color additives was possible relative to calibrations generated from one color additive using specimens prepared simply by pouring the color additive powder into an XRF sample cup. Published 2016. This article is a U.S. Government work and is in the public domain in the USA C1 [Hepp, Nancy M.; James, India C.] US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Hepp, NM (reprint author), US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM Nancy.Hepp@FDA.HHS.GOV NR 14 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0049-8246 EI 1097-4539 J9 X-RAY SPECTROM JI X-Ray Spectrom. PD NOV-DEC PY 2016 VL 45 IS 6 BP 330 EP 338 DI 10.1002/xrs.2709 PG 9 WC Spectroscopy SC Spectroscopy GA EF0TB UT WOS:000390037800005 ER PT J AU Kutanzi, KR Lumen, A Koturbash, I Miousse, IR AF Kutanzi, Kristy R. Lumen, Annie Koturbash, Igor Miousse, Isabelle R. TI Pediatric Exposures to Ionizing Radiation: Carcinogenic Considerations SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Review DE radiation; children's health; cancer; computed tomography ID CHILDHOOD-CANCER SURVIVOR; ATOMIC-BOMB SURVIVORS; NATURAL BACKGROUND-RADIATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; COMPUTED-TOMOGRAPHY SCANS; THYROID-CANCER; BREAST-CANCER; CT SCANS; CHERNOBYL ACCIDENT; SUBSEQUENT RISK AB Children are at a greater risk than adults of developing cancer after being exposed to ionizing radiation. Because of their developing bodies and long life expectancy post-exposure, children require specific attention in the aftermath of nuclear accidents and when radiation is used for diagnosis or treatment purposes. In this review, we discuss the carcinogenic potential of pediatric exposures to ionizing radiation from accidental, diagnostic, and therapeutic modalities. Particular emphasis is given to leukemia and thyroid cancers as consequences of accidental exposures. We further discuss the evidence of cancers that arise as a result of radiotherapy and conclude the review with a summary on the available literature on the links between computer tomography (CT) and carcinogenesis. Appropriate actions taken to mitigate or minimize the negative health effects of pediatric exposures to ionizing radiation and future considerations are discussed. C1 [Kutanzi, Kristy R.; Koturbash, Igor; Miousse, Isabelle R.] Univ Arkansas Med Sci, Coll Publ Hlth, Dept Environm & Occupat Hlth, Little Rock, AR 72205 USA. [Lumen, Annie] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Kutanzi, KR; Miousse, IR (reprint author), Univ Arkansas Med Sci, Coll Publ Hlth, Dept Environm & Occupat Hlth, Little Rock, AR 72205 USA. EM kristy.kutanzi@gmail.com; Annie.Lumen@fda.hhs.gov; ikoturbash@uams.edu; iracinemiousse@uams.edu FU National Institute of General Medical Sciences of the National Institutes of Health [1P20GM109005] FX Research reported in this publication was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (grant number 1P20GM109005). The authors are thankful to Christopher Fettes for editing this manuscript. NR 102 TC 1 Z9 1 U1 6 U2 6 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD NOV PY 2016 VL 13 IS 11 AR 1057 DI 10.3390/ijerph13111057 PG 14 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA EE4KR UT WOS:000389571300016 ER PT J AU Goodwin, AK AF Goodwin, Amy K. TI An intravenous self-administration procedure for assessing the reinforcing effects of hallucinogens in nonhuman primates SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Article DE Lysergic acid diethylamide (LSD); Abuse liability; Hallucinogen; Reinforcing effects; Intravenous (IV) self-administration; Operant behavior ID PLACE PREFERENCE; RHESUS-MONKEYS; BABOONS; LSD; COCAINE; GHB; ANIMALS; HUMANS; DRUGS; ABUSE AB Introduction: Self-administration procedures are the gold standard for investigating the reinforcing effects of drugs. The notable exception to good correspondence between laboratory self-administration studies and human drug taking behavior has historically been the classic hallucinogens. Method: The present study used a well-established daily access procedure, followed by a novel intermittent access procedure, to investigate the reinforcing effects of LSD in baboons. Results: Rates of self-injection in the daily access procedure were minimal. One baboon self-administered 0.001 mg/kg and a second baboon self-administered 0.0032 mg/kg above vehicle levels, though rates of self-injection were clearly low and neither of the two remaining baboons self-administered any LSD dose tested in the daily access procedure. Rates of self-injection using an intermittent access procedure with discriminative stimuli resulted in two doses of LSD being self-administered above vehicle levels in two of three baboons tested (0.01 and 0.032 mg/kg in one baboon; 0.0032 and 0.01 mg/kg in a second). In addition, the number of self-injections at these doses was higher (range = 3-6 injections) in the intermittent access procedure than in the daily access procedure (range = 1-2 injections). Discussion: The present study is the first to demonstrate LSD self-administration in a laboratory animal, and though the results are limited, they indicate intermittent access procedures with discriminative stimuli may provide a reliable and valid method for investigating the reinforcing effects of IV self-administered hallucinogens in laboratory animals. The usefulness of such procedures should be further evaluated in a larger number of subjects. (C) 2016 Published by Elsevier Inc. C1 [Goodwin, Amy K.] US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Silver Spring, MD 20993 USA. [Goodwin, Amy K.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Behav Biol, Baltimore, MD 21218 USA. [Goodwin, Amy K.] US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 132, Jefferson, AR 72079 USA. RP Goodwin, AK (reprint author), US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Silver Spring, MD 20993 USA.; Goodwin, AK (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Behav Biol, Baltimore, MD 21218 USA.; Goodwin, AK (reprint author), US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 132, Jefferson, AR 72079 USA. EM Amy.Goodwin@FDA.HHS.GOV FU National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA) [R03 DA026905] FX This work was supported by the National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA) grant R03 DA026905 and drugs were provided by the NIDA drug supply program. The funding source had no involvement in study design, data collection or analysis, or in the writing of this manuscript. The author would like to acknowledge the excellent technical assistance of Kelly Lane and Heather Wilmoth. NR 35 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD NOV-DEC PY 2016 VL 82 BP 31 EP 36 DI 10.1016/j.vascn.2016.07.004 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE3YC UT WOS:000389537200005 PM 27473331 ER PT J AU Bottomley, A Pe, M Sloan, J Basch, E Bonnetain, F Calvert, M Campbell, A Cleeland, C Cocks, K Collette, L Dueck, AC Devlin, N Flechtner, HH Gotay, C Greimel, E Griebsch, I Groenvold, M Hamel, JF King, M Kluetz, PG Koller, M Malone, DC Martinelli, F Mitchell, SA Moinpour, CM Musoro, J O'Connor, D Oliver, K Piault-Louis, E Piccart, M Pimentel, FL Quinten, C Reijneveld, JC Schurmann, C Smith, AW Soltys, KM Taphoorn, MJB Velikova, G Coens, C AF Bottomley, Andrew Pe, Madeline Sloan, Jeff Basch, Ethan Bonnetain, Franck Calvert, Melanie Campbell, Alicyn Cleeland, Charles Cocks, Kim Collette, Laurence Dueck, Amylou C. Devlin, Nancy Flechtner, Hans-Henning Gotay, Carolyn Greimel, Eva Griebsch, Ingolf Groenvold, Mogens Hamel, Jean-Francois King, Madeleine Kluetz, Paul G. Koller, Michael Malone, Daniel C. Martinelli, Francesca Mitchell, Sandra A. Moinpour, Carol M. Musoro, Jammbe O'Connor, Daniel Oliver, Kathy Piault-Louis, Elisabeth Piccart, Martine Pimentel, Francisco L. Quinten, Chantal Reijneveld, Jaap C. Schuermann, Christoph Smith, Ashley Wilder Soltys, Katherine M. Taphoorn, Martin J. B. Velikova, Galina Coens, Corneel CA Setting Int Stand Analyzing TI Analysing data from patient-reported outcome and quality of life endpoints for cancer clinical trials: a start in setting international standards SO LANCET ONCOLOGY LA English DT Article ID EVEROLIMUS PLUS EXEMESTANE; BREAST-CANCER AB Measures of health-related quality of life (HRQOL) and other patient-reported outcomes generate important data in cancer randomised trials to assist in assessing the risks and benefits of cancer therapies and fostering patient-centred cancer care. However, the various ways these measures are analysed and interpreted make it difficult to compare results across trials, and hinders the application of research findings to inform publications, product labelling, clinical guidelines, and health policy. To address these problems, the Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL) initiative has been established. This consortium, directed by the European Organisation for Research and Treatment of Cancer (EORTC), was convened to provide recommendations on how to standardise the analysis of HRQOL and other patient-reported outcomes data in cancer randomised trials. This Personal View discusses the reasons why this project was initiated, the rationale for the planned work, and the expected benefits to cancer research, patient and provider decision making, care delivery, and policy making. C1 [Bottomley, Andrew; Pe, Madeline; Collette, Laurence; Martinelli, Francesca; Musoro, Jammbe; Coens, Corneel] EORTC Headquarters, 83-11 Ave E Mounier, B-1200 Brussels, Belgium. [Sloan, Jeff] Mayo Clin, Alliance Stat & Data Ctr, Rochester, MN USA. [Basch, Ethan] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Bonnetain, Franck] Univ Hosp Besancon, Methodol & Qual Life Unit Canc, INSERM, U1098, Besancon, France. [Calvert, Melanie] Univ Birmingham, Coll Med & Dent Sci, Inst Appl Hlth Res, Ctr Patient Reported Outcomes Res, Birmingham, W Midlands, England. [Campbell, Alicyn; Piault-Louis, Elisabeth] Genentech Inc, San Francisco, CA USA. [Cleeland, Charles] Univ Texas MD Anderson Canc Ctr, Dept Symptom Res, Houston, TX 77030 USA. [Cocks, Kim] Adelphi Values, Bollington, Cheshire, England. [Dueck, Amylou C.] Mayo Clin, Alliance Stat & Data Ctr, Scottsdale, AZ USA. [Devlin, Nancy] Off Hlth Econ, London, England. [Flechtner, Hans-Henning] Univ Magdeburg, Clin Child & Adolescent Psychiat & Psychotherapy, Magdeburg, Germany. [Gotay, Carolyn] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada. [Greimel, Eva] Med Univ Graz, Obstet & Gynecol, Graz, Austria. [Griebsch, Ingolf] Boehringer Ingelheim GmbH & Co KG, Frankfurt, Germany. [Groenvold, Mogens] Univ Copenhagen, Dept Publ Hlth, Copenhagen, Denmark. [Groenvold, Mogens] Univ Copenhagen, Bispebjerg Hosp, Copenhagen, Denmark. [Hamel, Jean-Francois] Univ Hosp Angers UNAM, Methodol & Biostat Dept, Angers, France. [King, Madeleine] Univ Sydney, Sch Psychol, Sydney, NSW, Australia. [King, Madeleine] Univ Sydney, Sydney Med Sch, Sydney, NSW, Australia. [Kluetz, Paul G.] US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Koller, Michael] Univ Hosp Regensburg, Ctr Clin Studies, Regensburg, Germany. [Malone, Daniel C.] Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA. [Mitchell, Sandra A.; Smith, Ashley Wilder] NCI, Outcomes Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Moinpour, Carol M.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [O'Connor, Daniel] Med & Healthcare Prod Regulatory Agcy, London, England. [Oliver, Kathy] Int Brain Tumour Alliance, Tadworth, Surrey, England. [Piccart, Martine] Inst Jules Bordet, Internal Med Oncol, Brussels, Belgium. [Pimentel, Francisco L.] Univ Aveiro, Hlth Sci, Aveiro, Portugal. [Pimentel, Francisco L.] Lenitudes Med Ctr & Res, Santa Maria Feira, Portugal. [Quinten, Chantal] European Ctr Dis Prevent & Control, Surveillance & Response Support Unit, Epidemiol Methods Sect, Stockholm, Sweden. [Reijneveld, Jaap C.] Vrije Univ Amsterdam Med Ctr, Dept Neurol, Amsterdam, Netherlands. [Reijneveld, Jaap C.] Vrije Univ Amsterdam Med Ctr, Brain Tumor Ctr, Amsterdam, Netherlands. [Schuermann, Christoph] Inst Qual & Efficiency Hlth Care, Cologne, Germany. [Soltys, Katherine M.] Hlth Canada, Ottawa, ON, Canada. [Taphoorn, Martin J. B.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Taphoorn, Martin J. B.] Med Ctr Haaglanden, The Hague, Netherlands. [Velikova, Galina] Univ Leeds, St Jamess Hosp, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England. RP Bottomley, A (reprint author), EORTC Headquarters, 83-11 Ave E Mounier, B-1200 Brussels, Belgium. EM andrew.bottomley@eortc.be OI Pimentel, Francisco Luis/0000-0001-5993-5132 FU Boehringer Ingelheim GmbH; EORTC Cancer Research Fund; Fonds Cancer (FOCA) from Belgium FX EORTC received an unrestricted education grant from Boehringer Ingelheim GmbH to initiate this work and additional financial support was provided by the EORTC Cancer Research Fund and Fonds Cancer (FOCA) from Belgium. Andrew Bottomley confirms final responsibility for the decision to submit for publication. This publication reflects the views of the individual authors and should not be construed to represent official views or policies of the US Food and Drug Administration, US National Cancer Institute, Medicines and Healthcare products Regulatory Agency, or Health Canada. NR 26 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD NOV PY 2016 VL 17 IS 11 BP E510 EP E514 DI 10.1016/S1470-2045(16)30510-1 PG 5 WC Oncology SC Oncology GA EE3YF UT WOS:000389537600021 PM 27769798 ER PT J AU Barone, A Casey, D Reaman, G AF Barone, A. Casey, D. Reaman, G. TI The Impact of Paediatric Legislative Initiatives on Approval and Paediatric Labeling Information for Cancer Drugs Approved for use in the US SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Barone, A.; Casey, D.; Reaman, G.] US FDA, Off Oncol & Haematol Prod, 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2016 VL 63 SU 3 MA PD-089 BP S83 EP S83 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DY0XF UT WOS:000384818800682 ER PT J AU Reaman, G Herold, R Norga, K Donoghue, M Casey, D Chuk, M Dinndorf, P Leighton, J Sterba, J Paulo, P Baiardi, P van den Berg, H Carleer, J Suzanne, M Temeck, J Murphy, D AF Reaman, G. Herold, R. Norga, K. Donoghue, M. Casey, D. Chuk, M. Dinndorf, P. Leighton, J. Sterba, J. Paulo, P. Baiardi, P. van den Berg, H. Carleer, J. Suzanne, M. Temeck, J. Murphy, D. TI Impact of the Food and Drug Administration (FDA)-European Medicines Agency (EMA) Common Commentary (CC) on Paediatric Cancer Drug Development SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Reaman, G.; Donoghue, M.; Casey, D.; Chuk, M.; Dinndorf, P.; Leighton, J.] US FDA, Off Haematol & Oncol Prod, Silver Spring, MD USA. [Herold, R.; Norga, K.; Sterba, J.; Paulo, P.; Baiardi, P.; van den Berg, H.; Carleer, J.] European Med Agcy, Paediat Comm, London, England. [Suzanne, M.; Temeck, J.; Murphy, D.] US FDA, Off Paediat Therapeut, 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2016 VL 63 SU 3 MA P-0577 BP S212 EP S212 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DY0XF UT WOS:000384818801285 ER PT J AU Tegenge, MA Von Tungeln, LS Mitkus, RJ Anderson, SA Vanlandingham, MM Forshee, RA Beland, FA AF Tegenge, Million A. Von Tungeln, Linda S. Mitkus, Robert J. Anderson, Steven A. Vanlandingham, Michelle M. Forshee, Richard A. Beland, Frederick A. TI Pharmacokinetics and biodistribution of squalene-containing emulsion adjuvant following intramuscular injection of H5N1 influenza vaccine in mice SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE MF59; AS03; Pre-pandemic; NONMEM; Safety; Lymphatic delivery ID POPULATION PHARMACOKINETICS; DIETARY SQUALENE; ALPHA-TOCOPHEROL; PBPK MODEL; SAFETY; DESIGN; MF59; IMMUNOGENICITY; PERFORMANCE; RAT AB Squalene is a component of oil-in-water emulsion adjuvants developed for potential use in some influenza vaccines. The biodistribution of the squalene-containing emulsion adjuvant (AddaVax (TM)) alone and as part of complete H5N1 vaccine was quantified in mechanistically and toxicologically relevant target tissues up to 336 h (14 days) following injection into quadriceps muscle. At 1 h, about 55% of the intramuscularly injected dose of squalene was detected in the local quadriceps muscles and this decreased to 26% at 48 h. Twenty-four hours after the injection, approximately 5%, 1%, and 0.6% of the injected dose was detected in inguinal fat, draining lymph nodes, and sciatic nerve, respectively. The peak concentration for kidney, brain, spinal cord, bone marrow, and spleen was each less than 1% of the injected dose, and H5N1 antigen did not significantly alter the biodistribution of squalene to these tissues. The area-under-blood-concentration curve (AUC) and peak blood concentration (Cmax) of squalene were slightly higher (20-25%) in the presence of H5N1 antigen. A population pharmacokinetic model based statistical analysis identified body weight and H5N1 antigen as covariates influencing the clearance of squalene. The results contribute to the body of knowledge informing benefit-risk analyses of squalene-containing emulsion vaccine adjuvants. Published by Elsevier Inc. C1 [Tegenge, Million A.; Mitkus, Robert J.; Anderson, Steven A.; Forshee, Richard A.] US FDA, Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Von Tungeln, Linda S.; Vanlandingham, Michelle M.; Beland, Frederick A.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Rockville, MD 20857 USA. RP Tegenge, MA (reprint author), US FDA, Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM million.tegenge@fda.hhs.gov FU CBER; FDA MCMi FX We thank Biomedical Advanced Research and Development Authority (BARDA) for the provision of the flu vaccine H5N1 A/Indonesia (Sanofi Pasteur Inc.; via HHS/OS/ASPR/BARDA). We thank Dr. Sorell Schwartz for his helpful suggestions of PK modeling approaches at the initial stage of the study. This study was supported by internal funds from CBER and the FDA MCMi. NR 28 TC 0 Z9 0 U1 3 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD NOV PY 2016 VL 81 BP 113 EP 119 DI 10.1016/j.yrtph.2016.08.003 PG 7 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA EE8HF UT WOS:000389865600013 PM 27498239 ER PT J AU Saber, H Gudi, R Manning, M Wearne, E Leighton, JK AF Saber, Haleh Gudi, Ramadevi Manning, Michael Wearne, Emily Leighton, John K. TI An FDA oncology analysis of immune activating products and first-in-human dose selection SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE MABEL; Immune oncology; First-in-human dose ID IMMUNOMODULATORY MONOCLONAL-ANTIBODIES; CYTOKINE RELEASE; CANCER-IMMUNOTHERAPY; TGN1412; TRIALS; SAFETY; STORM AB As sub-therapeutic doses are not medically justifiable in patients with cancer, we retrospectively analyzed data on immune activating products, to assess approaches used in first-in-human (FIH) dose selection, the utility of animal toxicology studies in dose selection, and the length of time to complete FIH trials. The information collected included pharmacology and toxicology data, FIH dose and rationale, and dose-finding trial design. We used the principles of the Hill equation to estimate the FIH doses for antibodies and compared them to the doses administered to patients with acceptable toxicities. For approximately half the antibodies (44%) examined, the FIH doses were at least a hundred-fold lower than the doses safely administered to patients, indicating optimization of FIH dose selection and/or optimization of dose-finding trial design is needed to minimize patient exposure to sub-therapeutic doses. However, selection of the FIH dose for antibodies based on animal toxicology studies using 1/6th the HNSTD or 1/10th the NOAEL resulted in human doses that were unsafe for several antibodies examined. We also concluded that antibodies with Fc-modifications for increased effector function may be less tolerated, resulting in toxicities at lower doses than those without such modifications. There was insufficient information to evaluate CD3 bispecific products. Published by Elsevier Inc. C1 [Saber, Haleh; Gudi, Ramadevi; Manning, Michael; Wearne, Emily; Leighton, John K.] US FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. RP Saber, H (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM haleh.saber@fda.hhs.gov NR 22 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD NOV PY 2016 VL 81 BP 448 EP 456 DI 10.1016/j.yrtph.2016.10.002 PG 9 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA EE8HF UT WOS:000389865600049 PM 27743776 ER PT J AU Thompson, KL Boitier, E Chen, T Couttet, P Ellinger-Ziegelbauer, H Goetschy, M Guillemain, G Kanki, M Kelsall, J Mariet, C de La Moureyre-Spire, C Mouritzen, P Nassirpour, R O'Lone, R Pine, PS Rosenzweig, BA Sharapova, T Smith, A Uchiyama, H Yan, J Yuen, PS Wolfinger, R AF Thompson, Karol L. Boitier, Eric Chen, Tao Couttet, Philippe Ellinger-Ziegelbauer, Heidrun Goetschy, Manuela Guillemain, Gregory Kanki, Masayuki Kelsall, Janet Mariet, Claire de La Moureyre-Spire, Catherine Mouritzen, Peter Nassirpour, Rounak O'Lone, Raegan Pine, P. Scott Rosenzweig, Barry A. Sharapova, Tatiana Smith, Aaron Uchiyama, Hidefumi Yan, Jian Yuen, Peter S. Wolfinger, Russ TI Absolute Measurement of Cardiac Injury-Induced microRNAs in Biofluids across Multiple Test Sites SO TOXICOLOGICAL SCIENCES LA English DT Article DE interlaboratory; microRNA; variance; biomarker ID ACUTE MYOCARDIAL-INFARCTION; REAL-TIME PCR; CIRCULATING MICRORNAS; HEART-FAILURE; BIOMARKERS; PLASMA; RAT; QUANTIFICATION; HEPATOTOXICITY; IDENTIFICATION AB Extracellular microRNAs (miRNAs) represent a promising new source of toxicity biomarkers that are sensitive indicators of site of tissue injury. In order to establish reliable approaches for use in biomarker validation studies, the HESI technical committee on genomics initiated a multi-site study to assess sources of variance associated with quantitating levels of cardiac injury induced miRNAs in biofluids using RT-qPCR. Samples were generated at a central site using a model of acute cardiac injury induced in male Wistar rats by 0.5 mg/kg isoproterenol. Biofluid samples were sent to 11 sites for measurement of 3 cardiac enriched miRNAs (miR-1-3p, miR-208a-3p, and miR-499-5p) and 1 miRNA abundant in blood (miR-16-5p) or urine (miR-192-5p) by absolute quantification using calibration curves of synthetic miRNAs. The samples included serum and plasma prepared from blood collected at 4 h, urine collected from 6 to 24 h, and plasma prepared from blood collected at 24 h post subcutaneous injection. A 3 parameter logistic model was utilized to fit the calibration curve data and estimate levels of miRNAs in biofluid samples by inverse prediction. Most sites observed increased circulating levels of miR-1-3p and miR-208a-3p at 4 and 24 h after isoproterenol treatment, with no difference seen between serum and plasma. The biological differences in miRNA levels and sample type dominated as sources of variance, along with outlying performance by a few sites. The standard protocol established in this study was successfully implemented across multiple sites and provides a benchmark method for further improvements in quantitative assays for circulating miRNAs. C1 [Thompson, Karol L.; Rosenzweig, Barry A.] Food & Drug Adm, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Boitier, Eric; Mariet, Claire] Sanofi R&D, Disposit Safety & Anim Res, Vitry Sur Seine, France. [Chen, Tao; Yan, Jian] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Couttet, Philippe; Goetschy, Manuela; Guillemain, Gregory] Novartis Pharma AG, CH-4057 Basel, Switzerland. [Ellinger-Ziegelbauer, Heidrun] Bayer Pharma, Toxicol, D-42096 Wuppertal, AG, Germany. [Kanki, Masayuki] Astellas Pharma Inc, Osaka 5328514, Japan. [Kelsall, Janet] AstraZeneca Ltd, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England. [de La Moureyre-Spire, Catherine] Inst Rech Servier, F-78290 Croissy Sur Seine, France. [Mouritzen, Peter] Exiqon, DK-2950 Vedbaek, Denmark. [Nassirpour, Rounak] Pfizer, Andover, MA 01810 USA. [O'Lone, Raegan] ILSI Hlth & Environm Sci Inst, Washington, DC 20005 USA. [Pine, P. Scott] Natl Inst Stand & Technol, Stanford, CA 94305 USA. [Sharapova, Tatiana] AbbVie, Abbott Pk, N Chicago, IL 60064 USA. [Smith, Aaron] Eli Lilly, Indianapolis, IN 46285 USA. [Uchiyama, Hidefumi] Takeda Pharmaceut Co Ltd, Fujisawa, Kanagawa 2518555, Japan. [Yuen, Peter S.] NIH NIDDK, Bethesda, MD 20892 USA. [Wolfinger, Russ] SAS Inst Inc Cary, Cary, NC 27513 USA. [Nassirpour, Rounak; Pine, P. Scott] Momenta Pharmaceut Inc, Cambridge, MA 02142 USA. RP O'Lone, R (reprint author), ILSI Hlth & Environm Sci Inst, Washington, DC 20005 USA. EM Rolone@hesiglobal.org FU HESI FX This HESI scientific initiative is primarily supported by in-kind contributions (from public and private sector participants) of time, expertise, and experimental effort. These contributions are supplemented by direct funding (that largely supports program infrastructure and management) that was provided by HESI's corporate sponsors. A list of supporting organizations (public and private) is available at http://hesiglobal.org/application-of-genomics-to-mechanism-based-risk-as sessment-technical-committee/3311. NR 40 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD NOV PY 2016 VL 154 IS 1 BP 115 EP 125 DI 10.1093/toxsci/kfw143 PG 11 WC Toxicology SC Toxicology GA ED6CA UT WOS:000388940900012 PM 27605421 ER PT J AU Banerjee, A Bhattacharya, P Joshi, AB Ismail, N Dey, R Nakhasi, HL AF Banerjee, Antara Bhattacharya, Parna Joshi, Amritanshu B. Ismail, Nevien Dey, Ranadhir Nakhasi, Hira L. TI Role of pro-inflammatory cytokine IL-17 in Leishmania pathogenesis and in protective immunity by Leishmania vaccines SO CELLULAR IMMUNOLOGY LA English DT Article DE Th17 cells; Leishmania; Vaccine; IL-17 ID EXPERIMENTAL VISCERAL LEISHMANIASIS; AZAR DERMAL LEISHMANIASIS; DENDRITIC CELL SUBSETS; CD8+ T-CELLS; CUTANEOUS LEISHMANIASIS; CANDIDA-ALBICANS; GAMMA-INTERFERON; HOST-DEFENSE; TH17 CELLS; C57BL/6 MICE AB The clinical outcome of Leishmania pathogenesis ranges from active skin lesions to fatal visceral dissemination and severely impaired T cell immunity. It is well established that a strong Th1 immune response is protective against cutaneous forms of the disease, however a mixed Th1/Th2 response is most commonly observed against visceral infections as evident from previous studies. Aside from Th1/Th2 cytokines, the pro-inflammatory IL-17 cytokine family plays an important role in the clearance of intracellular pathogens. In Leishmania induced skin lesions, IL-17 produced by Th17 cells is shown to exacerbate the disease, suggesting a role in pathogenesis. However, a protective role for IL-17 is indicated by the expansion of IL-17 producing cells in vaccine-induced immunity. In human visceral leishmaniasis (VL) it has been demonstrated that IL-17 and IL-22 are associated with protection against re-exposure to Leishmania, which further suggests the involvement of IL-17 in vaccine induced protective immunity. Although there is no vaccine against any form of leishmaniasis, the development of genetically modified live attenuated parasites as vaccine candidates prove to be promising, as they successfully induce a robust protective immune response in various animal models. However, the role of IL-17 producing cells and Th17 cells in response to these vaccine candidates remains unexplored. In this article, we review the role of IL-17 in Leishmania pathogenesis and the potential impact on vaccine induced immunity, with a special focus on live attenuated Leishmania parasites. Published by Elsevier Inc. C1 [Banerjee, Antara; Bhattacharya, Parna; Joshi, Amritanshu B.; Ismail, Nevien; Dey, Ranadhir; Nakhasi, Hira L.] US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Banerjee, Antara] Bangabasi Coll, Dept Zool, 19 Rajkumar Chakraborty Sarani, Kolkata 700009, W Bengal, India. RP Dey, R (reprint author), US FDA, Ctr Biol Evaluat & Res, Bldg 52-72,Rm 4358,10903 New Hampshire Ave, Silver Spring, MD 20993 USA.; Nakhasi, HL (reprint author), US FDA, Ctr Biol Evaluat & Res, Bldg 71,Rm 4266,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Ranadhir.Dey@fda.hhs.gov; Hira.Nakhasi@fda.hhs.gov NR 86 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 EI 1090-2163 J9 CELL IMMUNOL JI Cell. Immunol. PD NOV PY 2016 VL 309 SI SI BP 37 EP 41 DI 10.1016/j.cellimm.2016.07.004 PG 5 WC Cell Biology; Immunology SC Cell Biology; Immunology GA ED4MP UT WOS:000388823300006 PM 27444130 ER PT J AU Raevsky, AV Sharifi, M Samofalova, DA Karpov, PA Blume, YB AF Raevsky, A. V. Sharifi, M. Samofalova, D. A. Karpov, P. A. Blume, Y. B. TI 3D structure prediction of histone acetyltransferase proteins of the MYST family and their interactome in Arabidopsis thaliana SO JOURNAL OF MOLECULAR MODELING LA English DT Article DE Histone acetylation; HAM1/HAM2; MYST; Arabidopsis thaliana ID MULTIPLE SEQUENCE ALIGNMENT; ACETYLATION; ROLES; DNA; MODELS; REPAIR; MOF AB Histone lysine acetylation is a reversible post-translational modification that does not involve changes in DNA sequences. Enzymes play an important role in developmental processes and their deregulation has been linked to the progression of diverse disorders. The HAT enzyme family fulfills an important role in various developmental processes mediated by the state of chromatin, and have been attributed to its deregulation. To understand acetylation mechanisms and their role in cell signaling, transcriptional regulation, and apoptosis, it is crucial to identify and analyze acetylation sites. Bioinformatics methods can be used to generate relatively precise predictions. Here we applied classical bioinformatics methods-sequence alignment, homology modeling, and docking-to compare approved and predicted lysine acetylation processes in different organisms. HAM1 and HAM2 are analogs of KAT8 and KAT7 (MYST1 and MYST2), members of the MYST histone acetyltransferase family, and our results show that HAM1 and HAM2 have much in common with other representatives of MYST families from various organisms. One function of acetyl-CoA binding was predicted with a high level of probability by computational methods. Based on our data, we conclude that, despite huge genetic distances and some structural differences between animal and plant species, a closer look at acetylation mechanism shows that they have much in common. C1 [Raevsky, A. V.; Samofalova, D. A.; Karpov, P. A.; Blume, Y. B.] Natl Acad Sci Ukraine, Inst Food Biotechnol & Genom, Struct Biol Lab, UA-04123 Kiev, Ukraine. [Sharifi, M.] Univ Kent, Medway Sch Pharm, Chatham ME4 4TB, Kent, England. [Sharifi, M.] Univ Greenwich, Medway Sch Pharm, Chatham ME4 4TB, Kent, England. [Sharifi, M.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Raevsky, AV (reprint author), Natl Acad Sci Ukraine, Inst Food Biotechnol & Genom, Struct Biol Lab, UA-04123 Kiev, Ukraine. EM rayevsky85@gmail.com OI Blume, Yaroslav/0000-0001-7078-7548 FU Oak Ridge Institute for Science and Education (ORISE) FX The authors gratefully acknowledge Dr. Priyanka Chitranshi and Beth Juliar for their constructive comments and careful review of this manuscript, as well as the Oak Ridge Institute for Science and Education (ORISE) for its support. NR 27 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1610-2940 EI 0948-5023 J9 J MOL MODEL JI J. Mol. Model. PD NOV PY 2016 VL 22 IS 11 DI 10.1007/s00894-016-3103-0 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Multidisciplinary; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Chemistry; Computer Science GA ED4US UT WOS:000388847900002 PM 27709438 ER PT J AU Dwivedi, RS AF Dwivedi, Rama S. TI A new diagnostic algorithm for an early diagnosis of patients with fragile X syndrome SO NEUROLOGY INDIA LA English DT Editorial Material C1 [Dwivedi, Rama S.] US FDA, 10903 New Hampshire Ave,Bldg 22,Room 4191, Silver Spring, MD 20993 USA. RP Dwivedi, RS (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 22,Room 4191, Silver Spring, MD 20993 USA. EM Rama.Dwivedi@fda.hhs.gov NR 7 TC 0 Z9 0 U1 1 U2 1 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 0028-3886 EI 1998-4022 J9 NEUROL INDIA JI Neurol. India PD NOV-DEC PY 2016 VL 64 IS 6 BP 1136 EP 1137 DI 10.4103/0028-3886.193774 PG 2 WC Neurosciences SC Neurosciences & Neurology GA ED5IT UT WOS:000388885800005 PM 27841171 ER PT J AU Jenkins, GR Lee, T Moland, CL Vijay, V Herman, EH Lewis, SM Davis, KJ Muskhelishvili, L Kerr, S Fuscoe, JC Desai, VG AF Jenkins, G. Ronald Lee, Taewon Moland, Carrie L. Vijay, Vikrant Herman, Eugene H. Lewis, Sherry M. Davis, Kelly J. Muskhelishvili, Levan Kerr, Susan Fuscoe, James C. Desai, Varsha G. TI Sex-related differential susceptibility to doxorubicin-induced cardiotoxicity in B6C3F(1) mice SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Doxorubicin; Cardiotoxicity; Sex-based differences; Mouse model; Apoptosis; DNA damage ID CARDIAC TROPONIN-T; SPONTANEOUSLY HYPERTENSIVE-RATS; CONGESTIVE-HEART-FAILURE; DOUBLE-STRAND BREAKS; RISK-FACTORS; IN-VIVO; INDUCED CARDIOMYOPATHY; RADICAL FORMATION; CHILDHOOD-CANCER; ORGAN WEIGHT AB Sex is a risk factor for development of cardiotoxicity, induced by the anti-cancer drug, doxorubicin (DOX), in humans. To explore potential mechanisms underlying differential susceptibility to DOX between sexes, 8-week old male and female B6C3F(1) mice were dosed with 3 mg/kg body weight DOX or an equivalent volume of saline via tail vein once a week for 6, 7, 8, and 9 consecutive weeks, resulting in 18, 21, 24, and 27 mg/kg cumulative DOX doses, respectively. At necropsy, one week after each consecutive final dose, the extent of myocardial injury was greater in male mice compared to females as indicated by higher plasma concentrations of cardiac troponin T at all cumulative DOX doses with statistically significant differences between sexes at the 21 and 24 mg/kg cumulative doses. A greater susceptibility to DOX in male mice was further confirmed by the presence of cytoplasmic vacuolization in cardiomyocytes, with left atrium being more vulnerable to DOX cardiotoxicity. The number of TUNEL-positive cardiomyocytes was mostly higher in DOX-treated male mice compared to female counterparts, showing a statistically significant sex-related difference only in left atrium at 21 mg/kg cumulative dose. DOX-treated male mice also had an increased number of gamma-H2A.X-positive (measure of DNA double-strand breaks) cardiomyocytes compared to female counterparts with a significant sex effect in the ventricle at 27 mg/kg cumulative dose and right atrium at 21 and 27 mg/kg cumulative doses. This newly established mouse model provides a means to identify biomarkers and access potential mechanisms underlying sex-related differences in DOX-induced cardiotoxicity. Published by Elsevier Inc. C1 [Jenkins, G. Ronald; Moland, Carrie L.; Vijay, Vikrant; Fuscoe, James C.; Desai, Varsha G.] US FDA, Personalized Med Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Lee, Taewon] Korea Univ, Dept Math, Sejong, South Korea. [Herman, Eugene H.] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Rockville, MD 20850 USA. [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 74 TC 1 Z9 1 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD NOV 1 PY 2016 VL 310 BP 159 EP 174 DI 10.1016/j.taap.2016.09.012 PG 16 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EA6NM UT WOS:000386745900017 PM 27644598 ER PT J AU Ge, CC Fang, G Shen, XM Chong, Y Wamer, WG Gao, XF Chai, ZF Chen, CY Yin, JJ AF Ge, Cuicui Fang, Ge Shen, Xiaomei Chong, Yu Wamer, Wayne G. Gao, Xingfa Chai, Zhifang Chen, Chunying Yin, Jun-Jie TI Facet Energy versus Enzyme-like Activities: The Unexpected Protection of Palladium Nanocrystals against Oxidative Damage SO ACS NANO LA English DT Article DE palladium nanocrystals; surface facet; enzyme-like activity; antioxidants; computational chemistry; oxidative stress ID METAL-ORGANIC FRAMEWORKS; PEROXIDASE-LIKE ACTIVITY; AUGMENTED-WAVE METHOD; REACTIVE OXYGEN; CATALYTIC-ACTIVITY; ARTIFICIAL ENZYMES; DNA-DAMAGE; GLUTATHIONE-PEROXIDASE; OXIDE NANOPARTICLES; MOLECULAR-OXYGEN AB To develop nanomaterials as artificial enzymes, it is necessary to better understand how their physicochemical properties affect their enzyme-like activities. Although prior research has demonstrated that nanomaterials exhibit tunable enzyme-like activities depending on their size, structure, and composition, few studies have examined the effect of surface facets, which determine surface energy or surface reactivity. Here, we use electron spin-resonance spectroscopy to report that lower surface energy {111}-faceted Pd octahedrons have greater intrinsic antioxidant enzyme like activity than higher surface energy {100}-faceted Pd nanocubes. Our in vitro experiments found that those same Pd octahedrons are more effective than Pd nanocubes at scavenging reactive oxygen species (ROS). Those reductions in ROS preserve the homogeneity of mitochondrial membrane potential and attenuate damage to important biomolecules, thereby allowing a substantially higher number of cells to survive oxidative challenges. Our computations of molecular mechanisms for the antioxidant activities of {111}- and {100}-faceted Pd nanocrystals, as well as their activity order, agree well with experimental observations. These findings can guide the design of antioxidant-mimicking nanomaterials, which could have therapeutic or preventative potential against oxidative stress related diseases. C1 [Ge, Cuicui; Fang, Ge; Chong, Yu; Chai, Zhifang] Soochow Univ, Sch Radiol & Interdisciplinary Sci RAD X, Collaborat Innovat Ctr Radiat Med, Jiangsu Higher Educ Inst, Suzhou 215123, Peoples R China. [Ge, Cuicui; Chong, Yu; Wamer, Wayne G.; Yin, Jun-Jie] US FDA, Div Bioanalyt Chem, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. [Ge, Cuicui; Chong, Yu; Wamer, Wayne G.; Yin, Jun-Jie] US FDA, Div Analyt Chem, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. [Chen, Chunying] Chinese Acad Sci, Key Lab Biomed Effects Nanomat & Nanosafety, Natl Ctr Nanosci & Technol China, Beijing 100190, Peoples R China. [Chen, Chunying] Chinese Acad Sci, Inst High Energy Phys, Beijing 100190, Peoples R China. [Shen, Xiaomei; Gao, Xingfa] Jiangxi Normal Univ, Coll Chem & Chem Engn, Nanchang 330022, Peoples R China. RP Yin, JJ (reprint author), US FDA, Div Bioanalyt Chem, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA.; Yin, JJ (reprint author), US FDA, Div Analyt Chem, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA.; Chen, CY (reprint author), Chinese Acad Sci, Key Lab Biomed Effects Nanomat & Nanosafety, Natl Ctr Nanosci & Technol China, Beijing 100190, Peoples R China.; Chen, CY (reprint author), Chinese Acad Sci, Inst High Energy Phys, Beijing 100190, Peoples R China.; Gao, XF (reprint author), Jiangxi Normal Univ, Coll Chem & Chem Engn, Nanchang 330022, Peoples R China. EM gaox@ihep.ac.cn; chenchy@nanoctr.cn; junjie.yin@fda.hhs.gov RI Yin, Jun Jie /E-5619-2014; OI Gao, Xingfa/0000-0002-1636-6336 FU National Basic Research Program of China (973 Program) [2014CB931900, 2016YFA0201600]; National Natural Science Foundation of China [21207164, 11575123, 21373226]; Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection; Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); FDA Nanotechnology CORES Program; NSFC Distinguished Young Scholars [11425520] FX Dedicated to the memory of Wayne G. Warner. This work is partially supported by the National Basic Research Program of China (973 Program Grant Nos. 2014CB931900 and 2016YFA0201600), National Natural Science Foundation of China (Nos. 21207164, 11575123, and 21373226), Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and a regulatory science grant under the FDA Nanotechnology CORES Program. C.C. appreciates support from the NSFC Distinguished Young Scholars (11425520).We thank Dr. Lili Fox Velez for editorial and scientific writing support. 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 66 TC 0 Z9 0 U1 28 U2 28 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 EI 1936-086X J9 ACS NANO JI ACS Nano PD NOV PY 2016 VL 10 IS 11 BP 10436 EP 10445 DI 10.1021/acsnano.6b06297 PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA ED5SR UT WOS:000388913100075 PM 27934089 ER PT J AU Butler, J Hamo, CE Udelson, JE Pitt, B Yancy, C Shah, SJ Desvigne-Nickens, P Bernstein, HS Clark, RL Depre, C Dinh, W Hamer, A Kay-Mugford, P Kramer, F Lefkowitz, M Lewis, K Maya, J Maybaum, S Patel, MJ Pollack, PS Roessig, L Rotman, S Salsali, A Sims, JJ Senni, M Rosano, G Dunnmon, P Stockbridge, N Anker, SD Zile, MR Gheorghiade, M AF Butler, Javed Hamo, Carine E. Udelson, James E. Pitt, Bertram Yancy, Clyde Shah, Sanjiv J. Desvigne-Nickens, Patrice Bernstein, Harold S. Clark, Richard L. Depre, Christophe Dinh, Wilfried Hamer, Andrew Kay-Mugford, Patricia Kramer, Frank Lefkowitz, Martin Lewis, Kelly Maya, Juan Maybaum, Simon Patel, Mahesh J. Pollack, Pia S. Roessig, Lothar Rotman, Sarit Salsali, Afshin Sims, J. Jason Senni, Michele Rosano, Giuseppe Dunnmon, Preston Stockbridge, Norman Anker, Stefan D. Zile, Michael R. Gheorghiade, Mihai TI Exploring New Endpoints for Patients With Heart Failure With Preserved Ejection Fraction SO CIRCULATION-HEART FAILURE LA English DT Article DE aging; drug approval; heart failure; hospitalization; quality of life ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS; QUALITY-OF-LIFE; CLINICAL-TRIALS; FUNCTIONAL-CAPACITY; I-PRESERVE; WALK TEST; HOSPITALIZATION; PREFERENCES; SURVIVAL; OUTCOMES AB The epidemiological, clinical, and societal implications of the heart failure (HF) epidemic cannot be overemphasized. Approximately half of all HF patients have HF with preserved ejection fraction (HFpEF). HFpEF is largely a syndrome of the elderly, and with aging of the population, the proportion of patients with HFpEF is expected to grow. Currently, there is no drug known to improve mortality or hospitalization risk for these patients. Besides mortality and hospitalization, it is imperative to realize that patients with HFpEF have significant impairment in their functional capacity and their quality of life on a daily basis, underscoring the need for these parameters to ideally be incorporated within a regulatory pathway for drug approval. Although attempts should continue to explore therapies to reduce the risk of mortality or hospitalization for these patients, efforts should also be directed to improve other patient-centric concerns, such as functional capacity and quality of life. To initiate a dialogue about the compelling need for and the challenges in developing such alternative endpoints for patients with HFpEF, the US Food and Drug Administration on November 12, 2015, facilitated a meeting represented by clinicians, academia, industry, and regulatory agencies. This document summarizes the discussion from this meeting. C1 [Butler, Javed; Hamo, Carine E.] SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USA. [Udelson, James E.] Tufts Univ, Sch Med, Tufts Med Ctr, Div Cardiol, Boston, MA 02111 USA. [Pitt, Bertram] Univ Michigan, Sch Med, Div Cardiol, Ann Arbor, MI USA. [Yancy, Clyde; Shah, Sanjiv J.] Northwestern Univ, Feinberg Sch Med, Div Cardiol, Chicago, IL 60611 USA. [Gheorghiade, Mihai] Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. [Desvigne-Nickens, Patrice] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Bernstein, Harold S.] Merck & Co Inc, Kenilworth, NJ USA. [Clark, Richard L.; Sims, J. Jason] Medtronic, Mounds View, MN USA. [Depre, Christophe; Hamer, Andrew; Maya, Juan] Amgen Inc, Thousand Oaks, CA 91320 USA. [Dinh, Wilfried; Kramer, Frank; Lewis, Kelly; Roessig, Lothar; Rotman, Sarit] Bayer Pharma AG, Wuppertal, Germany. [Dinh, Wilfried] Univ Hosp Witten Herdecke, Dept Cardiol, HELIOS Clin Wuppertal, Witten, Germany. [Kay-Mugford, Patricia; Lefkowitz, Martin; Maybaum, Simon] Novartis Pharmaceut Inc, E Hanover, NJ USA. [Patel, Mahesh J.] Merck Res Labs, Clin Res Cardiovasc Dis Div, Rahway, NJ USA. [Pollack, Pia S.] AstraZeneca Global Med Dev, Gaithersburg, MD USA. [Salsali, Afshin] Boehringer Ingelheim Pharmaceut Inc, 90 E Ridge POB 368, Ridgefield, CT 06877 USA. [Senni, Michele] Azienda Osped Papa Giovannni XXIII, Dipartimento Cardiovasc, Bergamo, Italy. [Rosano, Giuseppe] IRCCS San Raffaele Pisana, Dept Med Sci, Rome, Italy. [Rosano, Giuseppe] St Georges Univ London, Cardiovasc & Cell Sci Inst, London, England. [Dunnmon, Preston; Stockbridge, Norman] US FDA, Div Cardiovasc & Renal Prod, Silver Spring, MD USA. [Anker, Stefan D.] Univ Med Ctr Gottingen UMG, Innovat Clin Trials, Dept Cardiol & Pneumol, Gottingen, Germany. [Zile, Michael R.] Med Univ South Carolina, Charleston, SC USA. [Zile, Michael R.] RHJ Dept Vet Adm Med Ctr, Charleston, SC USA. RP Butler, J (reprint author), SUNY Stony Brook, Div Cardiol, T-16,Room 080, Stony Brook, NY 11794 USA. EM javed.butler@stonybrookmedicine.edu FU National Institutes of Health; European Union; American Heart Association; Novartis; Abbott Vascular; Vifor; Bayer Pharma; Lonestar Heart; Respicardia; ZS Pharma; Relypsa; Biotronik; Cardiorentis; Servier; National Heart, Lung, and Blood Institute; Veteran Affairs; Alere; Bayer; CVRx; Medtronic; Sanofi-Aventis FX Dr Butler reports receiving research support from the National Institutes of Health and European Union and serves as a consultant to Amgen, Bayer, Boehringer Ingelheim, Cardiocell, Celladon, Novartis, Trevena, Relypsa, Z Pharma, and Zensun. Dr Shah reports research support from the National Institutes of Health and the American Heart Association and has served as an advisory board member for Actelion, Bayer, Merck, and Novartis. Dr Bernstein is an employee of Merck. R. Clark and J.J. Sims are employees of Medtronic. Drs Depre, Hamer, and Maya are employees of Amgen. Dr Dinh, Dr Kramer, Kelly Lewis, S. Rotman, and Dr Roessig are employees of Bayer Pharma AG. P. Kay-Mugford and Dr Lefkowitz are employees of Novartis. Dr Patel is an employee of Merck. Dr Pitt has served as a consultant for Pfizer, Merck, Bayer, Relypsa, Stealth Peptides, AstraZeneca, Boehringer Ingelheim, scPharmaceuticals, PharMain, Tricida, DaVinci Therapeutics, Kbp Biosciences, and Takeda and has stock options in Tricida, Relypsa, Stealth Peptides, PharMain, scPharmaceuticals, Kbp Biosciences, and a patent pending, site-specific delivery of eplerenone to the myocardium. Dr Pollack is an employee of AstraZeneca. Dr Salsali is an employee of Boehringer Ingelheim. Dr Senni reports consulting fees for Novartis and Abbott Vascular. Dr Anker has received research grants from Vifor and Abbott Vascular and personal fees from Vifor, Abbott Vascular, Bayer Pharma, Novartis, Lonestar Heart, Respicardia, ZS Pharma, Relypsa, Biotronik, Cardiorentis, and Servier. Dr Zile has received research support from National Heart, Lung, and Blood Institute, Veteran Affairs, Alere, Bayer, CVRx, Medtronic, Novartis, Sanofi-Aventis and has served as a consultant for Abbott, Alere, Bayer, BG Med, Bristol Myers Squib, Cardiome, Celledon, CorAssist, CVRx, GE Health, HDL, Idenex, Intersection Medical, Medtronic, MicroVide, Novartis, ONO Pharma, Sanofi-Aventis, and Up-To-Date. Dr Gheorghiade reports consulting relationships with Abbott, Astellas, AstraZeneca, Bayer, Cardiorentis, CorThera, Cytokinetics, CytoPherx, DebioPharm SA, Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, Johnson & Johnson, Medtronic, Merck, Novartis, Ono Pharmaceuticals, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda, and Trevena Therapeutics. The other authors report no conflicts. NR 37 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD NOV PY 2016 VL 9 IS 11 AR e003358 DI 10.1161/CIRCHEARTFAILURE.116.003358 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ED2HH UT WOS:000388664100006 ER PT J AU He, K Chen, HY Gwise, T Casak, S Lemery, S Keegan, P Pazdur, R Sridhara, R AF He, Kun Chen, Huanyu Gwise, Thomas Casak, Sandra Lemery, Steven Keegan, Patricia Pazdur, Richard Sridhara, Rajeshwari TI Statistical Considerations in Evaluating a Biosimilar Product in an Oncology Clinical Study SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; RANDOMIZED PHASE-II; NON-INFERIORITY; BEVACIZUMAB; CARBOPLATIN; PACLITAXEL AB The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) established an abbreviated approval pathway for biosimilar and interchangeable biological products that was intended to balance innovation and consumer interests. The FDA has published several guidance documents to facilitate implementation of the BPCI Act. Here we discuss the role of comparative clinical studies in the assessment of clinically meaningful differences and illustrate the underlying scientific concepts with a hypothetical example of a clinical study comparing a product to US-licensed bevacizumab. (C)2016 AACR. C1 [He, Kun; Chen, Huanyu; Gwise, Thomas; Sridhara, Rajeshwari] US FDA, Ctr Drug Evaluat & Res, Off Biostat, Silver Spring, MD USA. [Casak, Sandra; Lemery, Steven; Keegan, Patricia; Pazdur, Richard] US FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, Silver Spring, MD USA. RP He, K (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 21,Room 3523, Silver Spring, MD 20993 USA. EM kun.he@fda.hhs.gov NR 14 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 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 1 PY 2016 VL 22 IS 21 BP 5167 EP 5170 DI 10.1158/1078-0432.CCR-16-1010 PG 4 WC Oncology SC Oncology GA EB5VY UT WOS:000387450000003 PM 27582485 ER PT J AU Larkins, E Blumenthal, GM Chen, HY He, K Agarwal, R Gieser, G Stephens, O Zahalka, E Ringgold, K Helms, W Shord, S Yu, JY Zhao, H Davis, G Mckee, AE Keegan, P Pazdur, R AF Larkins, Erin Blumenthal, Gideon M. Chen, Huanyu He, Kun Agarwal, Rajiv Gieser, Gerlie Stephens, Olen Zahalka, Eias Ringgold, Kimberly Helms, Whitney Shord, Stacy Yu, Jingyu Zhao, Hong Davis, Gina McKee, Amye E. Keegan, Patricia Pazdur, Richard TI FDA Approval: Alectinib for the Treatment of Metastatic, ALK-Positive Non-Small Cell Lung Cancer Following Crizotinib SO CLINICAL CANCER RESEARCH LA English DT Article ID BRAIN METASTASES; INHIBITOR; CH5424802/RO5424802; CARCINOMA; NSCLC AB On December 11, 2015, the FDA granted accelerated approval to alectinib (Alecensa; Genentech) for the treatment of patients with anaplastic lymphoma receptor tyrosine kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This approval was based on two single-arm trials including 225 patients treated with alectinib 600 mg orally twice daily. The objective response rates (ORR) by an independent review committee in these studies were 38% [95% confidence interval (CI), 28-49] and 44% (95% CI, 36-53); the median durations of response (DOR) were 7.5 months and 11.2 months. In a pooled analysis of 51 patients with measurable disease in the central nervous system(CNS) at baseline, the CNS ORR was 61%(95% CI, 46-74); the CNSDOR was 9.1 months. The primary safety analysis population included 253 patients. The most common adverse reactions were fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). The most common laboratory abnormalities were anemia (56%), increased aspartate aminotransferase (51%), increased alkaline phosphatase (47%), increased creatine phosphokinase (43%), hyperbilirubinemia (39%), hyperglycemia (36%), increased alanine aminotransferase (34%), and hypocalcemia (32%). Dose reductions due to adverse reactions occurred in 12% of patients, whereas 27% of patients had alectinib dosing interrupted for adverse reactions. Permanent discontinuation of alectinib due to adverse reactions occurred in only 6% of patients. With the clinically meaningful ORR and DOR as well as the safety profile observed in these trials, alectinib was determined to have a favorable benefit-risk profile for the treatment of the indicated population. (C) 2016 AACR. C1 [Larkins, Erin; Blumenthal, Gideon M.; Zahalka, Eias; Ringgold, Kimberly; Helms, Whitney; Davis, Gina; McKee, Amye E.; Keegan, Patricia; Pazdur, Richard] US FDA, Off Hematol & Oncol Prod, 10903 New Hampshire Ave,Bldg 22,Room 2346, Silver Spring, MD 20993 USA. [Chen, Huanyu; He, Kun] US FDA, Off Biostat, Silver Spring, MD USA. [Agarwal, Rajiv; Gieser, Gerlie; Stephens, Olen] US FDA, Off Pharmaceut Qual, Silver Spring, MD USA. [Shord, Stacy; Yu, Jingyu; Zhao, Hong] US FDA, Off Translat Sci, Silver Spring, MD USA. RP Larkins, E (reprint author), US FDA, Off Hematol & Oncol Prod, 10903 New Hampshire Ave,Bldg 22,Room 2346, Silver Spring, MD 20993 USA. EM erin.larkins@fda.hhs.gov NR 27 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 1 PY 2016 VL 22 IS 21 BP 5171 EP 5176 DI 10.1158/1078-0432.CCR-16-1293 PG 6 WC Oncology SC Oncology GA EB5VY UT WOS:000387450000004 PM 27413075 ER PT J AU Kruger, N Sauder, C Hoffmann, M Orvell, C Drexler, JF Rubin, S Herrler, G AF Krueger, Nadine Sauder, Christian Hoffmann, Markus Orvell, Claes Drexler, Jan Felix Rubin, Steven Herrler, Georg TI Recombinant mumps viruses expressing the batMuV fusion glycoprotein are highly fusion active and neurovirulent SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; HEMAGGLUTININ-NEURAMINIDASE; PARAMYXOVIRUS FUSION; AMINO-ACID; N-GLYCANS; PROTEIN; GENE; STRAINS; RNA; NEUTRALIZATION AB A recent study reported the detection of a bat-derived virus (BatPV/Epo_spe/AR1/DCR/2009, batMuV) with phylogenetic relatedness to human mumps virus (hMuV). Since all efforts to isolate infectious batMuV have reportedly failed, we generated recombinant mumps viruses (rMuVs) in which the open reading frames (ORFs) of the fusion (F) and haemagglutinin-neuraminidase (HN) glycoproteins of an hMuV strain were replaced by the corresponding ORFs of batMuV. The batMuV F and HN proteins were successfully incorporated into viral particles and the resultant chimeric virus was able to mediate infection of Vero cells. Distinct differences were observed between the fusogenicity of rMuVs expressing one or both batMuV glycoproteins: viruses expressing batMuV F were highly fusogenic, regardless of the origin of HN. In contrast, rMuVs expressing human F and bat-derived HN proteins were less fusogenic compared to hMuV. The growth kinetics of chimeric MuVs expressing batMuV HN in combination with either hMuV or batMuV F were similar to that of the backbone virus, whereas a delay in virus replication was obtained for rMuVs harbouring batMuV F and hMuV HN. Replacement of the hMuV F and HN genes or the HN gene alone by the corresponding batMuV genes led to a slight reduction in neurovirulence of the highly neurovirulent backbone strain. Neutralizing antibodies inhibited infection mediated by all recombinant viruses generated. Furthermore, group IV anti-MuV antibodies inhibited the neuraminidase activity of bat-derived HN. Our study reports the successful generation of chimeric MuVs expressing the F and HN proteins of batMuV, providing a means for further examination of this novel batMuV. C1 [Krueger, Nadine; Herrler, Georg] Univ Vet Med Hannover, Inst Virol, Hannover, Germany. [Sauder, Christian; Rubin, Steven] US FDA, CBER, Silver Spring, MD USA. [Hoffmann, Markus] German Primate Ctr Gottingen, Infect Biol Unit, Gottingen, Germany. [Orvell, Claes] Karolinska Inst, Div Lab Med, Stockholm, Sweden. [Drexler, Jan Felix] Univ Bonn, Inst Virol, Med Ctr, Bonn, Germany. RP Kruger, N (reprint author), Univ Vet Med Hannover, Inst Virol, Hannover, Germany. EM nadine.krueger@tiho-hannover.de FU German Research Foundation [HE 1168/14-1, HE 1168/16-1, KR 4762/2-1] FX We are grateful to Karl-Klaus Conzelmann (Ludwig Maximilian University of Munich) and Andrea Maisner (Philipps University Marburg) for providing BSR-T7/5 and Vero76 cells, respectively. This work was supported by grants from the German Research Foundation to G.H. (HE 1168/14-1 and HE 1168/16-1) and N.K. (KR 4762/2-1). NR 46 TC 0 Z9 0 U1 1 U2 1 PU MICROBIOLOGY SOC PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER ST, LONDON WC1N 2JU, ERKS, ENGLAND SN 0022-1317 EI 1465-2099 J9 J GEN VIROL JI J. Gen. Virol. PD NOV PY 2016 VL 97 BP 2837 EP 2848 DI 10.1099/jgv.0.000596 PN 11 PG 12 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA ED2LV UT WOS:000388677600005 PM 27590163 ER PT J AU Sargeant, JM O'Connor, AM Dohoo, IR Erb, HN Cevallos, M Egger, M Ersboll, AK Martin, SW Nielsen, LR Pearl, DL Pfeiffer, DU Sanchez, J Torrence, ME Vigre, H Waldner, C Ward, MP AF Sargeant, J. M. O'Connor, A. M. Dohoo, I. R. Erb, H. N. Cevallos, M. Egger, M. Ersboll, A. K. Martin, S. W. Nielsen, L. R. Pearl, D. L. Pfeiffer, D. U. Sanchez, J. Torrence, M. E. Vigre, H. Waldner, C. Ward, M. P. TI Methods and Processes of Developing the Strengthening the Reporting of Observational Studies in Epidemiology - Veterinary (STROBE-Vet) Statement SO JOURNAL OF VETERINARY INTERNAL MEDICINE LA English DT Article DE Animal Health; Animal welfare; Food Safety; Observational studies; Production; Animal Reporting guidelines ID EQUINE LEUKOENCEPHALOMALACIA; FUSARIUM-MONILIFORME; FUMONISIN; MYCOTOXINS AB Background: Reporting of observational studies in veterinary research presents challenges that often are not addressed in published reporting guidelines. Objective: To develop an extension of the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement that addresses unique reporting requirements for observational studies in veterinary medicine related to health, production, welfare, and food safety. Design: Consensus meeting of experts. Setting: Mississauga, Canada. Participants: Seventeen experts from North America, Europe, and Australia. Methods: Experts completed a pre-meeting survey about whether items in the STROBE statement should be modified or added to address unique issues related to observational studies in animal species with health, production, welfare, or food safety outcomes. During the meeting, each STROBE item was discussed to determine whether or not rewording was recommended and whether additions were warranted. Anonymous voting was used to determine consensus. Results: Six items required no modifications or additions. Modifications or additions were made to the STROBE items 1 (title and abstract), 3 (objectives), 5 (setting), 6 (participants), 7 (variables), 8 (data sources/measurement), 9 (bias), 10 (study size), 12 (statistical methods), 13 (participants), 14 (descriptive data), 15 (outcome data), 16 (main results), 17 (other analyses), 19 (limitations), and 22 (funding). Conclusion: The methods and processes used were similar to those used for other extensions of the STROBE statement. The use of this STROBE statement extension should improve reporting of observational studies in veterinary research by recognizing unique features of observational studies involving food-producing and companion animals, products of animal origin, aquaculture, and wildlife. C1 [Sargeant, J. M.] Univ Guelph, Ctr Publ Hlth & Zoonoses, 50 Stone Rd, Guelph, ON N1G 2W1, Canada. [Sargeant, J. M.; Martin, S. W.; Pearl, D. L.] Dept Populat Med, Ontario Vet Coll, Guelph, ON, Canada. [O'Connor, A. M.] Iowa State Univ, Dept Vet Diagnost & Prod Anim Med, Ames, IA USA. [Dohoo, I. R.] Univ Prince Edward Isl, Ctr Vet Epidemiol Res, Charlottetown, PE, Canada. [Erb, H. N.] Cornell Univ, Dept Populat Med & Diagnost Sci, Ithaca, NY USA. [Cevallos, M.; Egger, M.] Univ Bern, Inst Social & Prevent Med, Bern, Switzerland. [Ersboll, A. K.] Univ Southern Denmark, Natl Inst Publ Hlth, Copenhagen, Denmark. [Nielsen, L. R.] Univ Copenhagen, Sect Anim Welf & Dis Control, Copenhagen, Denmark. [Pfeiffer, D. U.] Royal Vet Coll, Dept Prod & Populat Hlth, London, England. [Sanchez, J.] Univ Prince Edward Isl, Dept Hlth Management, Charlottetown, PE, Canada. [Torrence, M. E.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Vigre, H.] Tech Univ Denmark, Unit Genom Epidemiol, Lyngby, Denmark. [Waldner, C.] Univ Saskatchewan, Western Coll Vet Med, Dept Large Anim Clin Sci, Saskatoon, SK, Canada. [Ward, M. P.] Univ Sydney, Fac Vet Sci, Sydney, NSW, Australia. RP Sargeant, JM (reprint author), Univ Guelph, Ctr Publ Hlth & Zoonoses, 50 Stone Rd, Guelph, ON N1G 2W1, Canada.; Sargeant, JM (reprint author), Dept Populat Med, Ontario Vet Coll, Guelph, ON, Canada. EM sargeanj@uoguelph.ca RI Pfeiffer, Dirk/C-5002-2009; Ward, Michael/C-5758-2009 OI Pfeiffer, Dirk/0000-0001-7000-0530; NR 18 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0891-6640 EI 1939-1676 J9 J VET INTERN MED JI J. Vet. Intern. Med. PD NOV PY 2016 VL 30 IS 6 BP 1887 EP 1895 DI 10.1111/jvim.14574 PG 9 WC Veterinary Sciences SC Veterinary Sciences GA ED0AX UT WOS:000388506500017 PM 27859753 ER PT J AU O'Connor, AM Sargeant, JM Dohoo, IR Erb, HN Cevallos, M Egger, M Ersboll, AK Martin, SW Nielsen, LR Pearl, DL Pfeiffer, DU Sanchez, J Torrence, ME Vigre, H Waldner, C Ward, MP AF O'Connor, A. M. Sargeant, J. M. Dohoo, I. R. Erb, H. N. Cevallos, M. Egger, M. Ersboll, A. K. Martin, S. W. Nielsen, L. R. Pearl, D. L. Pfeiffer, D. U. Sanchez, J. Torrence, M. E. Vigre, H. Waldner, C. Ward, M. P. TI Explanation and Elaboration Document for the STROBE-Vet Statement: Strengthening the Reporting of Observational Studies in Epidemiology-Veterinary Extension SO JOURNAL OF VETERINARY INTERNAL MEDICINE LA English DT Article DE Animal Health; Animal welfare; Food Safety; Observational studies; Production; Reporting guidelines ID PEROXYGEN DISINFECTANT; CONTAMINATION; INFECTION; HOSPITALS; EFFICACY; FOOTWEAR; OUTBREAK AB The STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement was first published in 2007 and again in 2014. The purpose of the original STROBE was to provide guidance for authors, reviewers, and editors to improve the comprehensiveness of reporting; however, STROBE has a unique focus on observational studies. Although much of the guidance provided by the original STROBE document is directly applicable, it was deemed useful to map those statements to veterinary concepts, provide veterinary examples, and highlight unique aspects of reporting in veterinary observational studies. Here, we present the examples and explanations for the checklist items included in the STROBE-Vet statement. Thus, this is a companion document to the STROBE-Vet statement methods and process document (JVIM_14575 "Methods and Processes of Developing the Strengthening the Reporting of Observational Studies in Epidemiology-Veterinary (STROBE-Vet) Statement" undergoing proofing), which describes the checklist and how it was developed. C1 [O'Connor, A. M.] Iowa State Univ, Dept Vet Diagnost & Prod Anim Med, Ames, IA 50011 USA. [Sargeant, J. M.] Univ Guelph, Ctr Publ Hlth & Zoonoses, Guelph, ON, Canada. [Sargeant, J. M.; Martin, S. W.; Pearl, D. L.] Ontario Vet Coll, Dept Populat Med, Guelph, ON, Canada. [Dohoo, I. R.] Univ Prince Edward Isl, Ctr Vet Epidemiol Res, Charlottetown, PE, Canada. [Erb, H. N.] Cornell Univ, Dept Populat Med & Diagnost Sci, Ithaca, NY USA. [Cevallos, M.; Egger, M.] Univ Bern, Inst Social & Prevent Med, Bern, Switzerland. [Ersboll, A. K.] Univ Southern Denmark, Natl Inst Publ Hlth, Copenhagen, Denmark. [Nielsen, L. R.] Univ Copenhagen, Sect Anim Welf & Dis Control, Copenhagen, Denmark. [Pfeiffer, D. U.] Royal Vet Coll, Dept Prod & Populat Hlth, London, England. [Sanchez, J.] Univ Prince Edward Isl, Dept Hlth Management, Charlottetown, PE, Canada. [Torrence, M. E.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Vigre, H.] Tech Univ Denmark, Natl Food Inst, Lyngby, Denmark. [Waldner, C.] Univ Saskatchewan, Dept Large Anim Clin Sci, Western Coll Vet Med, Saskatoon, SK, Canada. [Ward, M. P.] Univ Sydney, Fac Vet Sci, Sydney, NSW, Australia. RP O'Connor, AM (reprint author), Iowa State Univ, Dept Vet Diagnost & Prod Anim Med, Ames, IA 50011 USA.; O'Connor, AM (reprint author), Iowa State Univ, Epidemiol, Coll Vet Med, Lloyd Vet Med Ctr Rm 2424,1809 S Riverside Dr, Ames, IA 50011 USA. EM oconnor@iastate.edu RI Pfeiffer, Dirk/C-5002-2009; Ward, Michael/C-5758-2009 OI Pfeiffer, Dirk/0000-0001-7000-0530; NR 15 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0891-6640 EI 1939-1676 J9 J VET INTERN MED JI J. Vet. Intern. Med. PD NOV PY 2016 VL 30 IS 6 BP 1896 EP 1928 DI 10.1111/jvim.14592 PG 33 WC Veterinary Sciences SC Veterinary Sciences GA ED0AX UT WOS:000388506500018 PM 27859752 ER PT J AU Balakumar, P Maung-U, K Jagadeesh, G AF Balakumar, Pitchai Maung-U, Khin Jagadeesh, Gowraganahalli TI Prevalence and prevention of cardiovascular disease and diabetes mellitus SO PHARMACOLOGICAL RESEARCH LA English DT Review DE Noncommunicable diseases; Cardiovascular risk factors; Cardiovascular disease prevalence; Diabetes mellitus; Disease prevention ID AMERICAN-HEART-ASSOCIATION; STROKE STATISTICS-2016 UPDATE; RISK-FACTORS; SCIENTIFIC STATEMENT; ARTERY-DISEASE; GLOBAL BURDEN; COUNTRIES; EPIDEMIOLOGY; METAANALYSIS; HYPERTENSION AB Noncommunicable diseases (NCDs) have become important causes of mortality on a global scale. According to the report of World Health Organization (WHO), NCDs killed 38 million people (out of 56 million deaths that occurred worldwide) during 2012. Cardiovascular diseases accounted for most NCD deaths (17.5 million NCD deaths), followed by cancers (8.2 million NCD deaths), respiratory diseases (4.0 million NCD deaths) and diabetes mellitus (1.5 million NCD deaths). Globally, the leading cause of death is cardiovascular diseases; their prevalence is incessantly progressing in both developed and developing nations. Diabetic patients with insulin resistance are even at a greater risk of cardiovascular disease. Obesity, high cholesterol, hypertriglyceridemia and elevated blood pressure are mainly considered as major risk factors for diabetic patients afflicted with cardiovascular disease. The present review sheds light on the global incidence of cardiovascular disease and diabetes mellitus. Additionally, measures to be taken to reduce the global encumbrance of cardiovascular disease and diabetes mellitus are highlighted. Published by Elsevier Ltd. C1 [Balakumar, Pitchai] AIMST Univ, Pharmacol Unit, Fac Pharm, Bedong 08100, Kedah Darul Ama, Malaysia. [Maung-U, Khin; Jagadeesh, Gowraganahalli] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Jagadeesh, G (reprint author), US FDA, Div Cardiovasc & Renal Prod, Off Drug Evaluat 1, Off New Drugs,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 22,Room 4128, Silver Spring, MD 20993 USA. EM pbala2006@gmail.com; Khin.U@fda.hhs.gov; gowra.jagadeesh@fda.hhs.gov NR 40 TC 2 Z9 2 U1 6 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD NOV PY 2016 VL 113 BP 600 EP 609 DI 10.1016/j.phrs.2016.09.040 PN A PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED7XU UT WOS:000389086800060 PM 27697647 ER PT J AU Sargeant, JM O'Connor, AM Dohoo, IR Erb, HN Cevallos, M Egger, M Ersboll, AK Martin, SW Nielsen, LR Pearl, DL Pfeiffer, DU Sanchez, J Torrence, ME Vigre, H Waldner, C Ward, MP AF Sargeant, J. M. O'Connor, A. M. Dohoo, I. R. Erb, H. N. Cevallos, M. Egger, M. Ersboll, A. K. Martin, S. W. Nielsen, L. R. Pearl, D. L. Pfeiffer, D. U. Sanchez, J. Torrence, M. E. Vigre, H. Waldner, C. Ward, M. P. TI Methods and processes of developing the strengthening the reporting of observational studies in epidemiology - veterinary (STROBE-Vet) statement SO PREVENTIVE VETERINARY MEDICINE LA English DT Article DE Reporting guidelines; Observational studies; Animal health; Animal production; Animal welfare; Food safety ID MOLECULAR EPIDEMIOLOGY; QUALITY; EXTENSION; DISEASES; TRIALS; TOOLS; BIAS AB Background: The reporting of observational studies in veterinary research presents many challenges that often are not adequately addressed in published reporting guidelines. Objective: To develop an extension of the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement that addresses unique reporting requirements for observational studies in veterinary medicine related to health, production, welfare, and food safety. Design: A consensus meeting of experts was organized to develop an extension of the STROBE statement to address observational studies in veterinary medicine with respect to animal health, animal production, animal welfare, and food safety outcomes. Setting: Consensus meeting May 11-13,2014 in Mississauga, Ontario, Canada. Participants: Seventeen experts from North America, Europe, and Australia attended the meeting. The experts were epidemiologists and biostatisticians, many of whom hold or have held editorial positions with relevant journals. Methods: Prior to the meeting, 19 experts completed a survey about whether they felt any of the 22 items of the STROBE statement should be modified and if items should be added to address unique issues related to observational studies in animal species with health, production, welfare, or food safety outcomes. At the meeting, the participants were provided with the survey responses and relevant literature concerning the reporting of veterinary observational studies. During the meeting, each STROBE item was discussed to determine whether or not re-wording was recommended, and whether additions were warranted. Anonymous voting was used to determine whether there was consensus for each item change or addition. Results: The consensus was that six items needed no modifications or additions. Modifications or additions were made to the STROBE items numbered: 1 (title and abstract), 3 (objectives), 5 (setting), 6 (participants), 7 (variables), 8 (data sources/measurement), 9 (bias), 10 (study size), 12 (statistical methods), 13 (participants), 14 (descriptive data), 15 (outcome data), 16 (main results), 17 (other analyses), 19 (limitations), and 22 (funding). Limitation: Published literature was not always available to support modification to, or inclusion of, an item. Conclusion: The methods and processes used in the development of this statement were similar to those used for other extensions of the STROBE statement. The use of this extension to the STROBE statement should improve the reporting of observational studies in veterinary research related to animal health, production, welfare, or food safety outcomes by recognizing the unique features of observational studies involving food-producing and companion animals, products of animal origin, aquaculture, and wildlife. (C) 2016 The Authors. Published by Elsevier B.V. C1 [Sargeant, J. M.] Univ Guelph, Ctr Publ Hlth & Zoonoses, Guelph, ON, Canada. [Sargeant, J. M.; Martin, S. W.; Pearl, D. L.] Ontario Vet Coll, Dept Populat Med, Guelph, ON, Canada. [O'Connor, A. M.] Iowa State Univ, Dept Vet Diagnost & Prod Anim Med, Ames, IA USA. [Dohoo, I. R.] Univ Prince Edward Isl, Ctr Vet Epidemiol Res, Charlottetown, PE, Canada. [Erb, H. N.] Cornell Univ, Dept Populat Med & Diagnost Sci, Ithaca, NY USA. [Cevallos, M.; Egger, M.] Univ Bern, Inst Social & Prevent Med, Bern, Switzerland. [Ersboll, A. K.] Univ Southern Denmark, Natl Inst Publ Hlth, Copenhagen, Denmark. [Nielsen, L. R.] Univ Copenhagen, Sect Anim Welf & Dis Control, Copenhagen, Denmark. [Pfeiffer, D. U.] Royal Vet Coll, Dept Prod & Populat Hlth, London, England. [Sanchez, J.] Univ Prince Edward Isl, Dept Hlth Management, Charlottetown, PE, Canada. [Torrence, M. E.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Vigre, H.] Tech Univ Denmark, Natl Food Inst, Unit Genom Epidemiol, Lyngby, Denmark. [Waldner, C.] Univ Saskatchewan, Western Coll Vet Med, Dept Large Anim Clin Sci, Saskatoon, SK, Canada. [Ward, M. P.] Univ Sydney, Fac Vet Sci, Sydney, NSW, Australia. RP Sargeant, JM (reprint author), Univ Guelph, Ctr Publ Hlth & Zoonoses, Guelph, ON, Canada. EM sargeanj@uoguelph.ca RI Pfeiffer, Dirk/C-5002-2009 OI Pfeiffer, Dirk/0000-0001-7000-0530 NR 23 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-5877 EI 1873-1716 J9 PREV VET MED JI Prev. Vet. Med. PD NOV 1 PY 2016 VL 134 BP 188 EP 196 DI 10.1016/j.prevetmed.2016.09.005 PG 9 WC Veterinary Sciences SC Veterinary Sciences GA ED8CV UT WOS:000389100500021 PM 27836042 ER PT J AU Pinheiro, SP Rivera, DR Graham, DJ Freedman, AN Major, JM Penberthy, L Levenson, M Bradley, MC Wong, HL Ouellet-Hellstrom, R AF Pinheiro, Simone P. Rivera, Donna R. Graham, David J. Freedman, Andrew N. Major, Jacqueline M. Penberthy, Lynne Levenson, Mark Bradley, Marie C. Wong, Hui-Lee Ouellet-Hellstrom, Rita TI Cancer pharmacoepidemiology symposium Challenges in evaluating cancer as a clinical outcome in postapproval studies of drug safety SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Cancer epidemiology; Pharmacoepidemiology; Drug safety ID COLORECTAL-CANCER; LATENCY ANALYSIS; LUNG-CANCER; ASSOCIATION; DATABASE; MINERS; GENOME; WOMEN; RISK AB Pharmaceuticals approved in the United States are largely not known human carcinogens. However, cancer signals associated with pharmaceuticals may be hypothesized or arise after product approval. There are many study designs that can be used to evaluate cancer as an outcome in the postapproval setting. Because prospective systematic collection of cancer outcomes from a large number of individuals may be lengthy, expensive, and challenging, leveraging data from large existing databases are an integral approach. Such studies have the capability to evaluate the clinical experience of a large number of individuals, yet there are unique methodological challenges involved in their use to evaluate cancer outcomes. To discuss methodological challenges and potential solutions, the Food and Drug Administration and the National Cancer Institute convened a two-day public meeting in 2014. This commentary summarizes the most salient issues discussed at the meeting. Published by Elsevier Inc. C1 [Pinheiro, Simone P.; Graham, David J.; Major, Jacqueline M.; Bradley, Marie C.; Wong, Hui-Lee; Ouellet-Hellstrom, Rita] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Rivera, Donna R.; Freedman, Andrew N.; Penberthy, Lynne; Bradley, Marie C.] NCI, Clin & Translat Epidemiol Branch, Epidemiol & Genom Res, Div Canc Control & Populat Sci, Rockville, MD USA. [Levenson, Mark] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Pinheiro, SP (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM simone.pinheiro@fda.hhs.gov NR 23 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD NOV PY 2016 VL 26 IS 11 BP 735 EP 740 DI 10.1016/j.annepidem.2016.04.012 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ED0QF UT WOS:000388546300001 PM 27663208 ER PT J AU Major, JM Penberthy, L McGlynn, KA AF Major, Jacqueline M. Penberthy, Lynne McGlynn, Katherine A. TI Cancer pharmacoepidemiology symposium Data systems and record linkage: considerations for pharmacoepidemiologic studies examining cancer risk SO ANNALS OF EPIDEMIOLOGY LA English DT Editorial Material C1 [Major, Jacqueline M.] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Penberthy, Lynne] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Major, JM (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Jacqueline.Major@fda.hhs.gov NR 12 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD NOV PY 2016 VL 26 IS 11 BP 746 EP 748 DI 10.1016/j.annepidem.2016.08.015 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ED0QF UT WOS:000388546300003 PM 27639347 ER PT J AU Jin, JS Hsieh, YH Cui, JM Damera, K Dai, CF Chaudhary, AS Zhang, H Yang, HC Cao, NN Jiang, C Vaara, M Wang, BH Tai, PC AF Jin, Jinshan Hsieh, Ying-Hsin Cui, Jianmei Damera, Krishna Dai, Chaofeng Chaudhary, Arpana S. Zhang, Hao Yang, Hsiuchin Cao, Nannan Jiang, Chun Vaara, Martti Wang, Binghe Tai, Phang C. TI Using Chemical Probes to Assess the Feasibility of Targeting SecA for Developing Antimicrobial Agents against Gram-Negative Bacteria SO CHEMMEDCHEM LA English DT Article DE antibiotics; Gram-negative bacteria; membrane permeability; multidrug resistance; SecA translocase ID PROTEIN-CONDUCTING CHANNELS; SIGNAL-PEPTIDE-SPECIFICITY; MULTIDRUG EFFLUX PUMP; 3 POSITIVE CHARGES; ESCHERICHIA-COLI; PSEUDOMONAS-AERUGINOSA; OUTER-MEMBRANE; ANTIBIOTIC EFFLUX; AZIDE-RESISTANCE; INHIBITORS AB With the widespread emergence of drug resistance, there is an urgent need to search for new antimicrobials, especially those against Gram-negative bacteria. Along this line, the identification of viable targets is a critical first step. The protein translocase SecA is commonly believed to be an excellent target for the development of broad-spectrum antimicrobials. In recent years, we developed three structural classes of SecA inhibitors that have proven to be very effective against Gram-positive bacteria. However, we have not achieved the same level of success against Gram-negative bacteria, despite the potent inhibition of SecA in enzyme assays by the same inhibitors. In this study, we use representative inhibitors as chemical probes to gain an understanding as to why these inhibitors were not effective against Gram-negative bacteria. The results validate our initial postulation that the major difference in effectiveness against Gram-positive and Gram-negative bacteria is in the additional permeability barrier posed by the outer membrane of Gram-negative bacteria. We also found that the expression of efflux pumps, which are responsible for multidrug resistance (MDR), have no effect on the effectiveness of these SecA inhibitors. Identification of an inhibitor-resistant mutant and complementation tests of the plasmids containing secA in a secAts mutant showed that a single secA-azi-9 mutation increased the resistance, providing genetic evidence that SecA is indeed the target of these inhibitors in bacteria. Such results strongly suggest SecA as an excellent target for developing effective antimicrobials against Gram-negative bacteria with the intrinsic ability to overcome MDR. A key future research direction should be the optimization of membrane permeability. C1 [Jin, Jinshan; Hsieh, Ying-Hsin; Zhang, Hao; Yang, Hsiuchin; Cao, Nannan; Jiang, Chun; Tai, Phang C.] Georgia State Univ, Dept Biol, Ctr Biotechnol & Drug Design, Ctr Diagnost & Therapeut, POB 4010, Atlanta, GA 30303 USA. [Cui, Jianmei; Damera, Krishna; Dai, Chaofeng; Chaudhary, Arpana S.; Wang, Binghe] Georgia State Univ, Dept Chem, Ctr Biotechnol & Drug Design, Ctr Diagnost & Therapeut, Atlanta, GA 30303 USA. [Vaara, Martti] Helsinki Univ Hosp, Div Clin Microbiol, HUSLAB, Helsinki 00029, Finland. [Vaara, Martti] Northern Antibiot Ltd, Helsinki 00720, Finland. [Jin, Jinshan] US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Tai, PC (reprint author), Georgia State Univ, Dept Biol, Ctr Biotechnol & Drug Design, Ctr Diagnost & Therapeut, POB 4010, Atlanta, GA 30303 USA.; Wang, BH (reprint author), Georgia State Univ, Dept Chem, Ctr Biotechnol & Drug Design, Ctr Diagnost & Therapeut, Atlanta, GA 30303 USA. EM wang@gsu.edu; biopct@gsu.edu FU Georgia Research Alliance; US National Institutes of Health (NIH) [AI104168]; GSU FX We thank Donald B. Oliver (Wesleyan University), Thomas J. Silhavy (Princeton University), Chung-Dar Lu (Georgia State University), Rajeev Misra (Arizona State University), and Herbert P. Schweizer (University of Florida) for strains and plasmids. We thank Ping Jiang for DNA sequencing in the Biology Core facilities at the Georgia State University Center of Biotechnology and Drug Design, which were supported in part by the Georgia Research Alliance. This work was supported by the US National Institutes of Health (NIH) (grant no. AI104168), and Fellowships of the Molecular Basis of Diseases Program at GSU (to J.S.J., Y.H.H., and A.S.C.). NR 70 TC 1 Z9 1 U1 5 U2 5 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1860-7179 EI 1860-7187 J9 CHEMMEDCHEM JI ChemMedChem PD NOV PY 2016 VL 11 IS 22 BP 2511 EP 2521 DI 10.1002/cmdc.201600421 PG 11 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED0BD UT WOS:000388507100006 PM 27753464 ER PT J AU Mahmood, I Tegenge, MA AF Mahmood, I. Tegenge, M. A. TI A bodyweight-dependent allometric exponent model for scaling clearance of clotting factor VIII and IX from infants to adults SO HAEMOPHILIA LA English DT Letter ID RECOMBINANT FACTOR-IX; PREDICTIVE PERFORMANCE; DRUG CLEARANCE; BODY-WEIGHT; AGE; PHARMACOKINETICS; CHILDREN C1 [Mahmood, I.] US FDA, Ctr Biol Evaluat & Res, OBRR, Div Hematol Clin Review Branch, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Tegenge, M. A.] US FDA, Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, Silver Spring, MD USA. RP Mahmood, I (reprint author), US FDA, Ctr Biol Evaluat & Res, OBRR, Div Hematol Clin Review Branch, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Iftekhar.mahmood@fda.hhs.gov NR 10 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-8216 EI 1365-2516 J9 HAEMOPHILIA JI Haemophilia PD NOV PY 2016 VL 22 IS 6 BP E570 EP E573 DI 10.1111/hae.13116 PG 4 WC Hematology SC Hematology GA EC9VS UT WOS:000388493000016 PM 27868371 ER PT J AU Graham, DJ Reichman, ME Wernecke, M Hsueh, H Izem, R Southworth, MR Wei, YQ Liao, JM Goulding, MR Mott, K Chillarige, Y MaCurdy, TE Worrall, C Kelman, JA AF Graham, David J. Reichman, Marsha E. Wernecke, Michael Hsueh, Hui Izem, Rima Southworth, Mary Ross Wei, Yuqin Liao, Jiemin Goulding, Margie R. Mott, Katrina Chillarige, Yoganand MaCurdy, Thomas E. Worrall, Chris Kelman, Jeffrey A. TI Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation SO JAMA INTERNAL MEDICINE LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; POSITIVE PREDICTIVE-VALUE; POPULATION-BASED COHORT; ORAL ANTICOAGULANTS; ADMINISTRATIVE DATA; CODING ACCURACY; WARFARIN; METAANALYSIS; VALIDATION; PREVENTION AB IMPORTANCE Dabigatran and rivaroxaban are non-vitamin K oral anticoagulants approved for stroke prevention in patients with nonvalvular atrial fibrillation (AF). There are no randomized head-to-head comparisons of these drugs for stroke, bleeding, or mortality outcomes. OBJECTIVE To compare risks of thromboembolic stroke, intracranial hemorrhage (ICH), major extracranial bleeding including major gastrointestinal bleeding, and mortality in patients with nonvalvular AF who initiated dabigatran or rivaroxaban treatment for stroke prevention. DESIGN, SETTING, AND PARTICIPANTS Retrospective new-user cohort study of 118 891 patients with nonvalvular AF who were 65 years or older, enrolled in fee-for-service Medicare, and who initiated treatment with dabigatran or rivaroxaban from November 4, 2011, through June 30, 2014. Differences in baseline characteristics were adjusted using stabilized inverse probability of treatment weights based on propensity scores. The data analysis was performed from May 7, 2015, through June 30, 2016. EXPOSURES Dabigatran, 150 mg, twice daily; rivaroxaban, 20 mg, once daily. MAIN OUTCOMES AND MEASURES Adjusted hazard ratios (HRs) for the primary outcomes of thromboembolic stroke, ICH, major extracranial bleeding including major gastrointestinal bleeding, and mortality, with dabigatran as reference. Adjusted incidence rate differences (AIRDs) were also estimated. RESULTS A total of 52 240 dabigatran-treated and 66 651 rivaroxaban-treated patients (47% female) contributed 15 524 and 20 199 person-years of on-treatment follow-up, respectively, during which 2537 primary outcome events occurred. Rivaroxaban use was associated with a statistically nonsignificant reduction in thromboembolic stroke (HR, 0.81; 95% CI, 0.65-1.01; P = .07; AIRD = 1.8 fewer cases/1000 person-years), statistically significant increases in ICH (HR, 1.65; 95% CI, 1.20-2.26; P = .002; AIRD = 2.3 excess cases/1000 person-years) and major extracranial bleeding (HR, 1.48; 95% CI, 1.32-1.67; P < .001; AIRD = 13.0 excess cases/1000 person-years), including major gastrointestinal bleeding (HR, 1.40; 95% CI, 1.23-1.59; P < .001; AIRD = 9.4 excess cases/1000 person-years), and with a statistically nonsignificant increase in mortality (HR, 1.15; 95% CI, 1.00-1.32; P = .051; AIRD = 3.1 excess cases/1000 person-years). In patients 75 years or older or with CHADS(2) score greater than 2, rivaroxaban use was associated with significantly increased mortality compared with dabigatran use. The excess rate of ICH with rivaroxaban use exceeded its reduced rate of thromboembolic stroke. CONCLUSIONS AND RELEVANCE Treatment with rivaroxaban 20 mg once daily was associated with statistically significant increases in ICH and major extracranial bleeding, including major gastrointestinal bleeding, compared with dabigatran 150mg twice daily. C1 [Graham, David J.; Reichman, Marsha E.; Goulding, Margie R.; Mott, Katrina] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 22,Room 4314, Silver Spring, MD 20993 USA. [Wernecke, Michael; Wei, Yuqin; Liao, Jiemin; Chillarige, Yoganand; MaCurdy, Thomas E.] Acumen LLC, Burlingame, CA USA. [Hsueh, Hui; Izem, Rima] 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. [MaCurdy, Thomas E.] Stanford Univ, Dept Econ, Stanford, CA 94305 USA. [Worrall, Chris; Kelman, Jeffrey A.] Ctr Medicare & Medicaid Serv, Washington, DC USA. RP Graham, DJ (reprint author), US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 22,Room 4314, Silver Spring, MD 20993 USA. EM david.graham1@fda.hhs.gov FU SafeRx project, a joint initiative of the Centers for Medicare & Medicaid Services (CMS); US Food and Drug Administration (FDA) FX This study was performed as part of the SafeRx project, a joint initiative of the Centers for Medicare & Medicaid Services (CMS) and the US Food and Drug Administration (FDA), and was funded through an interagency agreement. NR 49 TC 12 Z9 12 U1 6 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD NOV PY 2016 VL 176 IS 11 BP 1662 EP 1671 DI 10.1001/jamainternmed.2016.5954 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EC4KK UT WOS:000388097700019 PM 27695821 ER PT J AU Chen, Y Odumeru, J Ziemer, W AF Chen, Yi Odumeru, Joseph Ziemer, Wayne TI Validation of the ANSR (R) for Campylobacter Method for Detection of Thermophilic Campylobacter spp. in Chicken Carcass Rinse and Turkey Sponge Samples SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID SALMONELLA METHOD; ENVIRONMENTAL-SAMPLES; FOODS AB A performance validation of the ANSR (R) for Campylobacter method was conducted in selected matrixes. This assay used selective nicking enzyme amplification technology to amplify target genes. Samples were enriched for 20 to 24 h and then lysed. The assay was completed within 50 min using real-time detection in a combination incubator/fluorescence detector and software. When 50 distinct strains of Campylobacter jejuni, C. lari, or C. coli were tested for inclusivity, all 50 strains produced positive results. In exclusivity testing, 31 strains of related organisms, including seven nontarget Campylobacter strains and other common species, were evaluated. All 31 species generated negative ANSR assay results, including the nontarget Campylobacter strains. The ANSR for Campylobacter method was compared to the U.S. Department of Agriculture, Food Safety and Inspection Service Microbiology Laboratory Guidebook reference method using naturally contaminated chicken carcass rinse or turkey carcass sponge samples. ANSR method performance was not statistically different from the reference method using two different enrichment options. Equivalent results were observed at both time points (20 and 24 h) and in both atmospheres (microaerobic and aerobic) to reference methods. Method performance with chicken carcass rinse was confirmed in an independent laboratory study. Additionally, in robustness testing, small, deliberate changes to the assay parameters minimally affected ANSR method performance. Finally, accelerated stability results from three independently manufactured lots supported a shelf life of 6 months when stored at 4 degrees C. The ANSR assay offered greater efficiency and flexibility when compared to the reference method with a 20-24 h single-step enrichment in a microaerobic or an aerobic atmosphere. C1 [Chen, Yi] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Odumeru, Joseph] Univ Guelph, Lab Serv Div, 95 Stone Rd West, Guelph, ON H1H 8J7, Canada. [Ziemer, Wayne] 1301 Kristen Ln, Loganville, GA 30052 USA. RP Chen, Y (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM rviator@neogen.com NR 9 TC 0 Z9 0 U1 0 U2 0 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 EI 1944-7922 J9 J AOAC INT JI J. AOAC Int. PD NOV-DEC PY 2016 VL 99 IS 6 BP 1555 EP 1564 DI 10.5740/jaoacint.16-0241 PG 10 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA ED0SH UT WOS:000388551700020 ER PT J AU Dickinson, PA Kesisoglou, F Flanagan, T Martinez, MN Mistry, HB Crison, JR Polli, JE Cruanes, MT Serajuddin, ATM Mullertz, A Cook, JA Selen, A AF Dickinson, Paul A. Kesisoglou, Filippos Flanagan, Talia Martinez, Marilyn N. Mistry, Hitesh B. Crison, John R. Polli, James E. Cruanes, Maria T. Serajuddin, Abu T. M. Mullertz, Anette Cook, Jack A. Selen, Arzu TI Optimizing Clinical Drug Product Performance: Applying Biopharmaceutics Risk Assessment Roadmap (BioRAM) and the BioRAM Scoring Grid SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE quality by design (QbD); bioavailability; Biopharmaceutics Classification System (BCS); clinical trial simulations; drug delivery; in silico modeling; in vitro models; in vitro and in vivo correlations/relationships (IVIVC/R); Biopharmaceutics Risk Assessment Roadmap (BioRAM); pharmokinetic/pharmacodynamic models ID RESEARCH-AND-DEVELOPMENT; REAL-WORLD DATA; SODIUM BENZOATE; NONKETOTIC HYPERGLYCINEMIA; COATED GRANULES; FORMULATIONS; ACID; INFANTS; BINDER; TIME AB The aim of Biopharmaceutics Risk Assessment Roadmap (BioRAM) and the BioRAM Scoring Grid is to facilitate optimization of clinical performance of drug products. BioRAM strategy relies on therapy-driven drug delivery and follows an integrated systems approach for formulating and addressing critical questions and decision-making (J Pharm Sci. 2014,103(11): 3777-97). In BioRAM, risk is defined as not achieving the intended in vivo drug product performance, and success is assessed by time to decision-making and action. Emphasis on time to decision-making and time to action highlights the value of well-formulated critical questions and well-designed and conducted integrated studies. This commentary describes and illustrates application of the BioRAM Scoring Grid, a companion to the BioRAM strategy, which guides implementation of such an integrated strategy encompassing 12 critical areas and 6 assessment stages. Application of the BioRAM Scoring Grid is illustrated using published literature. Organizational considerations for implementing BioRAM strategy, including the interactions, function, and skillsets of the BioRAM group members, are also reviewed. As a creative and innovative systems approach, we believe that BioRAM is going to have a broad-reaching impact, influencing drug development and leading to unique collaborations influencing how we learn, and leverage and share knowledge. Published by Elsevier Inc. on behalf of the American Pharmacists Association. C1 [Dickinson, Paul A.] Seda Pharmaceut Dev Serv, Biohub Alderley Pk, Macclesfield SK10 4TG, Cheshire, England. [Kesisoglou, Filippos] Merck & Co Inc, Biopharmaceut Pharmaceut Sci & Clin Supply, West Point, PA 19486 USA. [Flanagan, Talia] AstraZeneca R&D, Pharmaceut Technol & Dev, Macclesfield SK10 2NA, Cheshire, England. [Martinez, Marilyn N.] US FDA, Ctr Vet Med, Off New Anim Drug Evaluat, Rockville, MD 20855 USA. [Mistry, Hitesh B.] Univ Manchester, Manchester Pharm Sch, Manchester M13 9PT, Lancs, England. [Crison, John R.] Pharmaceut Consulting LLC, Martindale, NJ 08836 USA. [Polli, James E.] Univ Maryland, Sch Pharm, Ind Pharm & Pharmaceut, Baltimore, MD 21201 USA. [Cruanes, Maria T.] Merck & Co Inc, Las Piedras Operat, Las Piedras, PR 00771 USA. [Serajuddin, Abu T. M.] St Johns Univ, Coll Pharm & Hlth Sci, Queens, NY 11439 USA. [Mullertz, Anette] Univ Copenhagen, Dept Pharm, Bioneer FARMA, DK-1165 Copenhagen, Denmark. [Cook, Jack A.] Pfizer Inc, Dept Clin Pharmacol, Global Prod Dev, Groton, CT 06340 USA. [Selen, Arzu] US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Qual, Off Testing & Res, Silver Spring, MD 20993 USA. RP Selen, A (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Qual, Off Testing & Res, Silver Spring, MD 20993 USA. EM arzu.selen@fda.hhs.gov OI Mistry, Hitesh/0000-0002-9683-1903 NR 48 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD NOV PY 2016 VL 105 IS 11 BP 3243 EP 3255 DI 10.1016/j.xphs.2016.07.024 PG 13 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA EC6SY UT WOS:000388268200003 PM 27659159 ER PT J AU Carbonetti, NH von Konig, CHW Lan, R Jacob-Dubuisson, F Cotter, PA Deora, R Merkel, TJ van Els, CA Locht, C Hozbor, D Rodriguez, ME AF Carbonetti, Nicholas H. von Koenig, Carl Heinz Wirsing Lan, Ruiting Jacob-Dubuisson, Francoise Cotter, Peggy A. Deora, Rajendar Merkel, Tod J. van Els, Cecile A. Locht, Camille Hozbor, Daniela Rodriguez, Maria E. TI Highlights of the 11th International Bordetella Symposium: from Basic Biology to Vaccine Development SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID PERTACTIN-DEFICIENT; PERTUSSIS VACCINES; UNITED-STATES; INFECTION; IMMUNITY; INFANTS; CHILDREN; STRAINS; FITNESS; COUGH AB Pertussis is a severe respiratory disease caused by infection with the bacterial pathogen Bordetella pertussis. The disease affects individuals of all ages but is particularly severe and sometimes fatal in unvaccinated young infants. Other Bordetella species cause diseases in humans, animals, and birds. Scientific, clinical, public health, vaccine company, and regulatory agency experts on these pathogens and diseases gathered in Buenos Aires, Argentina from 5 to 8 April 2016 for the 11th International Bordetella Symposium to discuss recent advances in our understanding of the biology of these organisms, the diseases they cause, and the development of new vaccines and other strategies to prevent these diseases. Highlights of the meeting included pertussis epidemiology in developing nations, genomic analysis of Bordetella biology and evolution, regulation of virulence factor expression, new model systems to study Bordetella biology and disease, effects of different vaccines on immune responses, maternal immunization as a strategy to prevent newborn disease, and novel vaccine development for pertussis. In addition, the group approved the formation of an International Bordetella Society to promote research and information exchange on bordetellae and to organize future meetings. A new Bordetella.org website will also be developed to facilitate these goals. C1 [Carbonetti, Nicholas H.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [von Koenig, Carl Heinz Wirsing] Lab Med Krefeld MVZ GmbH, Krefeld, Germany. [Lan, Ruiting] Univ New South Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia. [Jacob-Dubuisson, Francoise; Locht, Camille] Univ Lille, Ctr Infect & Immun Lille, Inserm U1019, Inst Pasteur Lille,CNRS UMR8204, Lille, France. [Cotter, Peggy A.] Univ N Carolina, Chapel Hill Sch Med, Chapel Hill, NC USA. [Deora, Rajendar] Wake Forest Sch Med, Winston Salem, NC USA. [Merkel, Tod J.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [van Els, Cecile A.] Natl Inst Publ Hlth & Environm, Ctr Infect Dis Control, Bilthoven, Netherlands. [Hozbor, Daniela] Univ Nacl La Plata, Fac Ciencias Exactas, IBBM, La Plata, Buenos Aires, Argentina. [Rodriguez, Maria E.] Univ Nacl La Plata, Fac Ciencias Exactas, CINDEFI CONICET UNLP, La Plata, Buenos Aires, Argentina. RP Carbonetti, NH (reprint author), Univ Maryland, Sch Med, Baltimore, MD 21201 USA. EM ncarbonetti@som.umaryland.edu OI Jacob-Dubuisson, Francoise/0000-0002-5102-1704 FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [R21 AI117095, R01 AI101055, R21 AI119566, R01 AI125560, R21 AI126147, R01 AI094991]; National Health and Medical Research Council (NHMRC) [APP1011942]; Agencia Nacional de Promocion Cientifica y Tecnologica (ANCPyT) [PICT2012/2719, PICT2014/3617]; L' Agence Nationale de la Recherche [ANR-13-BSV8-0002-01]; National Agency for Scientific and Technological Promotion (MINCyT) [PICT 2013 1937, RC 2015 0031]; National Institute of Allergy and Infectious Diseases, NIH [R13] FX This work, including the efforts of Nicholas H. Carbonetti, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R21 AI117095, R01 AI101055, and R21 AI119566). This work, including the efforts of Rajendar Deora, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R01 AI125560). This work, including the efforts of Rajendar Deora, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R21 AI126147). This work, including the efforts of Peggy A. Cotter, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R01 AI094991). This work, including the efforts of Ruiting Lan, was funded by the National Health and Medical Research Council (NHMRC) (APP1011942). This work, including the efforts of Daniela Hozbor, was funded by Agencia Nacional de Promocion Cientifica y Tecnologica (ANCPyT) (PICT2012/2719 and PICT2014/3617). This work, including the efforts of F. Jacob-Dubuisson, was funded by L' Agence Nationale de la Recherche (ANR-13-BSV8-0002-01). This work, including the efforts of Maria Eugenia Rodriguez, was funded by the National Agency for Scientific and Technological Promotion (MINCyT) (PICT 2013 1937).; The symposium was funded in part by conference grant RC 2015 0031 from the National Agency for Scientific and Technological Promotion (MINCyT) (to Maria Eugenia Rodriguez) and by an R13 conference grant from the National Institute of Allergy and Infectious Diseases, NIH (to Eric Hewlett). NR 33 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD NOV PY 2016 VL 23 IS 11 BP 842 EP 850 DI 10.1128/CVI.00388-16 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EC1HM UT WOS:000387855500001 PM 27655886 ER PT J AU Samuels-Reid, JH Cope, JU AF Samuels-Reid, Joy H. Cope, Judith U. TI Medical Devices and Adolescents Points to Consider SO JAMA PEDIATRICS LA English DT Editorial Material ID ADVERSE EVENTS; CHILDREN C1 [Samuels-Reid, Joy H.] US FDA, Div Anesthesiol Gen Hosp Resp Infect Control & De, Off Device Evaluat, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 66,Room 2608, Silver Spring, MD 20993 USA. [Cope, Judith U.] US FDA, Off Pediat Therapeut, Off Special Med Programs, Off Commissioner, Silver Spring, MD USA. RP Samuels-Reid, JH (reprint author), US FDA, Div Anesthesiol Gen Hosp Resp Infect Control & De, Off Device Evaluat, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 66,Room 2608, Silver Spring, MD 20993 USA. EM joy.samuels-reid@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 7 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD NOV PY 2016 VL 170 IS 11 BP 1035 EP 1036 DI 10.1001/jamapediatrics.2016.1351 PG 2 WC Pediatrics SC Pediatrics GA EC4KM UT WOS:000388097900004 PM 27618419 ER PT J AU Xu, J Gill, R Cruz, M Staffa, J Lurie, P AF Xu, Jing Gill, Rajdeep Cruz, Marisa Staffa, Judy Lurie, Peter TI Effect of US Food and Drug Administration-Approved Pediatric Labeling on Dispensing of Extended-Release Oxycodone in the Outpatient Retail Setting SO JAMA PEDIATRICS LA English DT Letter C1 [Xu, Jing; Cruz, Marisa; Lurie, Peter] US FDA, Off Publ Hlth Strategy & Anal, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Gill, Rajdeep; Staffa, Judy] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Xu, J (reprint author), US FDA, Off Publ Hlth Strategy & Anal, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jing.xu@fda.hhs.gov NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD NOV PY 2016 VL 170 IS 11 BP 1103 EP 1104 DI 10.1001/jamapediatrics.2016.3197 PG 2 WC Pediatrics SC Pediatrics GA EC4KM UT WOS:000388097900019 PM 27612007 ER PT J AU Guldenring, D Finlay, DD Bond, RR Kennedy, A McLaughlin, J Galeotti, L Strauss, DG AF Guldenring, Daniel Finlay, Dewar D. Bond, Raymond R. Kennedy, Alan McLaughlin, James Galeotti, Loriano Strauss, David G. TI Computing the spatial QRS-T angle using reduced electrocardiographic lead sets SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE Linear lead transformations; Estimation of the Frank VCG; Derivation of the Frank VCG; Spatial QRS-T angle; Mason-Likar 12-lead; ECG; Monitoring ID 12-LEAD ELECTROCARDIOGRAM; VENTRICULAR GRADIENT; VECTORCARDIOGRAM; MATRIX; SYSTEM; ECG AB The 'spatial QRS-T angle' (SA) is frequently determined using linear lead transformation matrices that require the entire 12-lead electrocardiogram (ECG). While this approach is adequate when using 12-lead ECG data that is recorded in the resting supine position, it is not optimal in monitoring applications. This is because maintaining a good quality recording of the complete 12-lead ECG in monitoring applications is difficult. In this research, we assessed the differences between the 'gold standard' SA as determined using the Frank VGG and the SA as determined using different reduced lead systems (RLSs). The random error component (span of the Bland-Altman 95% limits of agreement) of the differences between the 'gold standard' SA and the SA values based upon the different RLSs was quantified. This was performed for all 62 RLSs that can be constructed from Mason-Likar (ML) limb leads I, II and all possible precordial lead subsets that contain between one and five of the precordial leads VI to V6. The RLS with the smallest lead set size that produced SA estimates of a quality similar to what is achieved using the ML 12-lead ECG was based upon ML limb leads I, II and precordial leads V1, V3 and V6. The random error component (mean [95% confidence interval]) associated with this RLS and the ML 12-lead ECG were found to be 40.74 [35.56 degrees-49.29 degrees] and 39.57 degrees [33.78 degrees-45.70 degrees], respectively. Our findings suggest that a RLS that is based upon the ML limb leads I and II and the three best precordial leads can yield SA estimates of a quality similar to what is achieved when using the complete ML 12-lead ECG. (C) 2016 Elsevier Inc. All rights reserved. C1 [Guldenring, Daniel; Finlay, Dewar D.; Bond, Raymond R.; Kennedy, Alan; McLaughlin, James] Univ Ulster, Jordanstown Campus,Shore Rd, Newtownabbey, Antrim, North Ireland. [Galeotti, Loriano; Strauss, David G.] US FDA, Off Sci & Engn Labs, CDRH, Silver Spring, MD USA. RP Guldenring, D (reprint author), Univ Ulster, Jordanstown Campus,Shore Rd, Newtownabbey, Antrim, North Ireland. EM guldenring-d2@email.ulster.ac.uk OI Guldenring, Daniel/0000-0002-8847-2744; Bond, Raymond/0000-0002-1078-2232 NR 22 TC 0 Z9 0 U1 2 U2 2 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD NOV-DEC PY 2016 VL 49 IS 6 BP 794 EP 799 DI 10.1016/j.jelectrocard.2016.07.015 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EB8IA UT WOS:000387633500005 PM 27609012 ER PT J AU Vicente, J Stockbridge, N Strauss, DG AF Vicente, Jose Stockbridge, Norman Strauss, David G. TI Evolving regulatory paradigm for proarrhythmic risk assessment for new drugs SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE QTc prolongation; J-T(peak)c; T-wave morphology; Torsade de pointes; hERG block; Multi-ion channel block ID LONG QT SYNDROME; THOROUGH QT; SAFETY; PROLONGATION; RANOLAZINE; INTERVAL; BLOCK AB Fourteen drugs were removed from the market worldwide because their potential to cause torsade de pointes (torsade), a potentially fatal ventricular arrhythmia. The observation that most drugs that cause torsade block the potassium channel encoded by the human ether-a-go-go related gene (hERG) and prolong the heart rate corrected QT interval (QTc) on the ECG, led to a focus on screening new drugs for their potential to block the hERG potassium channel and prolong QTc. This has been a successful strategy keeping torsadogenic drugs off the market, but has resulted in drugs being dropped from development, sometimes inappropriately. This is because not all drugs that block the hERG potassium channel and prolong QTc cause torsade, sometimes because they block other channels. The regulatory paradigm is evolving to improve proarrhythmic risk prediction. ECG studies can now use exposure-response modeling for assessing the effect of a drug on the QTc in small sample size first-in-human studies. Furthermore, the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a new in vitro paradigm for cardiac safety evaluation of new drugs that provides a more accurate and comprehensive mechanistic-based assessment of proarrhythmic potential. Under CiPA, the prediction of proarrhythmic potential will come from in vitro ion channel assessments coupled with an in silico model of the human ventricular myocyte. The preclinical assessment will be checked with an assessment of human phase 1 ECG data to determine if there are unexpected ion channel effects in humans compared to preclinical ion channel data. While there is ongoing validation work, the heart rate corrected J-T-peak interval is likely to be assessed under CiPA to detect inward current block in presence of hERG potassium channel block. (C) 2016 Elsevier Inc. All rights reserved. C1 [Vicente, Jose; Strauss, David G.] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Stockbridge, Norman] US FDA, Div Cardiovasc & Renal Prod, Off New Drugs, Silver Spring, MD USA. RP Vicente, J (reprint author), US FDA, 10903 New Hampshire Ave,WO62-1125B, Silver Spring, MD 20993 USA. EM pepoviru@gmail.com OI Vicente, Jose/0000-0001-9963-1205 NR 28 TC 0 Z9 0 U1 1 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD NOV-DEC PY 2016 VL 49 IS 6 BP 837 EP 842 DI 10.1016/j.jelectrocard.2016.07.017 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EB8IA UT WOS:000387633500012 PM 27524478 ER PT J AU Azizian, H Mossoba, MM Fardin-Kia, AR Karunathilaka, SR Kramer, JKG AF Azizian, Hormoz Mossoba, Magdi M. Fardin-Kia, Ali Reza Karunathilaka, Sanjeewa R. Kramer, John K. G. TI Developing FT-NIR and PLS1 Methodology for Predicting Adulteration in Representative Varieties/Blends of Extra Virgin Olive Oils SO LIPIDS LA English DT Article DE FT-NIR; PLS; Extra virgin olive oil; FA markers; Volatile compounds ID NEAR-INFRARED SPECTROSCOPY; QUANTIFICATION; FATS AB It was previously demonstrated that Fourier transform near infrared (FT-NIR) spectroscopy and partial least squares (PLS1) were successfully used to assess whether an olive oil was extra virgin, and if adulterated, with which type of vegetable oil and by how much using previously developed PLS1 calibration models. This last prediction required an initial set of four PLS1 calibration models that were based on gravimetrically prepared mixtures of a specific variety of extra virgin olive oil (EVOO) spiked with adulterants. The current study was undertaken after obtaining a range of EVOO varieties grown in different countries. It was found that all the different types of EVOO varieties investigated belonged to four distinct groups, and each required the development of additional sets of specific PLS1 calibration models to ensure that they can be used to predict low concentrations of vegetable oils high in linoleic, oleic, or palmitic acid, and/or refined olive oil. These four distinct sets of PLS1 calibration models were required to cover the range of EVOO varieties with a linoleic acid content from 1.3 to 15.5 % of total fatty acids. An FT-NIR library was established with 66 EVOO products obtained from California and Europe. The quality and/or purity of EVOO were assessed by determining the FT-NIR Index, a measure of the volatile content of EVOO. The use of these PLS1 calibration models made it possible to predict the authenticity of EVOO and the identity and quantity of potential adulterant oils in minutes. C1 [Azizian, Hormoz] NIR Technol Inc, Oakville, ON L6M 2M2, Canada. [Mossoba, Magdi M.; Fardin-Kia, Ali Reza; Karunathilaka, Sanjeewa R.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD USA. [Kramer, John K. G.] Agr & Agri Food Canada, Guelph Food Res Ctr, Guelph, ON, Canada. RP Azizian, H (reprint author), NIR Technol Inc, Oakville, ON L6M 2M2, Canada.; Kramer, JKG (reprint author), Agr & Agri Food Canada, Guelph Food Res Ctr, Guelph, ON, Canada. EM hazizian@nirtechnologies.com; magdi.mossoba@fda.hhs.gov; jkgkramer@rogers.com NR 10 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0024-4201 EI 1558-9307 J9 LIPIDS JI Lipids PD NOV PY 2016 VL 51 IS 11 BP 1309 EP 1321 DI 10.1007/s11745-016-4195-0 PG 13 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA EC5OD UT WOS:000388184500009 PM 27677754 ER PT J AU Wu, BN Chung, S Jiang, XR McNally, J Pedras-Vasconcelos, J Pillutla, R White, JT Xu, YX Gupta, S AF Wu, Bonnie Chung, Shan Jiang, Xu-Rong McNally, Jim Pedras-Vasconcelos, Joao Pillutla, Renuka White, Joleen T. Xu, Yuanxin Gupta, Shalini TI Strategies to Determine Assay Format for the Assessment of Neutralizing Antibody Responses to Biotherapeutics SO AAPS JOURNAL LA English DT Article DE assay format; biotherapeutic; mechanism of action; neutralizing antibody ID CELL-BASED ASSAY; BIOTECHNOLOGY PRODUCTS; BIOLOGICAL THERAPEUTICS; IMMUNE-RESPONSES; HOST ANTIBODIES; I INTERFERON; RECOMMENDATIONS; RECEPTOR; IMMUNOGENICITY; VALIDATION AB Most biotherapeutics can elicit immune responses in dosed recipients generating anti-drug antibodies (ADAs). Neutralizing antibodies (NAbs) are a subpopulation of ADAs that can potentially impact patient safety and directly mediate loss of drug efficacy by blocking the biological activity of a therapeutic product. Therefore, NAb detection is an important aspect of immunogenicity assessment, requiring sensitive and reliable methods reflective of the therapeutic mechanism of action (MoA). Both cell-based and non cell-based assays are viable options for NAb assessment. However, the scientific approach for the selection of a suitable assay format (cell-based or non cell-based) for NAb assessment is not currently well defined. In this manuscript, the authors summarize the design and utility of cell-based and non cell-based NAb assays and recommend a NAb assay format selection approach that relies on a combination of three factors. These include (i) the therapeutic MoA, (ii) the evidence of desirable assay performance characteristics, and (iii) risk of immunogenicity. The utility of correlating NAb response with pharmacodynamic data is also discussed. The aim of this paper is to provide a consistent strategy that will guide the selection of scientifically justified assay formats capable of detecting clinically relevant NAbs for biotherapeutics with varying MoAs and diverse complexity. C1 [Wu, Bonnie] Johnson & Johnson, Janssen Res & Dev LLC, 1400 McKean Rd,POB 776, Spring House, PA 19477 USA. [Chung, Shan] Genentech Inc, 1 DNAWay, San Francisco, CA 94080 USA. [Jiang, Xu-Rong] AstraZeneca, 1 MedImmune Way, Gaithersburg, MD 20878 USA. [McNally, Jim] Pfizer, 1 Burtt Rd, Andover, MA 01810 USA. [McNally, Jim; White, Joleen T.] EMD Serono, 45A Middlesex Turnpike, Billerica, MA 01821 USA. [Pedras-Vasconcelos, Joao] US FDA, Ctr Drug Evaluat & Res, Off Biotechnol Prod, Div Biotech Review & Reseach 3, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Pillutla, Renuka] Bristol Myers Squibb, 206 & Provinceline Rd, Princeton, NJ 08543 USA. [White, Joleen T.] Biogen, 250 Binney St, Cambridge, MA 02142 USA. [Xu, Yuanxin] Alnylam Pharmaceut, 300 Third St, Cambridge, MA 02142 USA. [Gupta, Shalini] Amgen Inc, One Amgen Ctr Dr, Thousand Oaks, CA 91320 USA. RP Wu, BN (reprint author), Johnson & Johnson, Janssen Res & Dev LLC, 1400 McKean Rd,POB 776, Spring House, PA 19477 USA. EM bwu23@its.jnj.com FU Ligand Binding Assay Bioanalytical Focus Group (LBABFG) of the American Association of Pharmaceutical Scientists (AAPS) FX This work was sponsored by the Ligand Binding Assay Bioanalytical Focus Group (LBABFG) of the American Association of Pharmaceutical Scientists (AAPS). The authors would like to thank all the individuals for critical review and helpful discussion of the manuscript and would like to acknowledge Drs. Boris Gorovits (Pfizer), Gopi Shankar (Janssen Research and Development), Fabio Garoforo (Angelini Pharma), An Song (Genentech Inc.), Martin Schaefer (Roche), and Alvydas Mikulskis (Biogen). We particularly appreciate the regulatory input from Susan Kirshner (Food and Drug Administration), Meenu Wadhwa (National Institute for Biological Standards and Control), and Jiang Wang (Health Canada). NR 55 TC 2 Z9 2 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD NOV PY 2016 VL 18 IS 6 BP 1335 EP 1350 DI 10.1208/s12248-016-9954-6 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EB7DU UT WOS:000387547000001 PM 27495119 ER PT J AU Arnold, ME Booth, B King, L Ray, C AF Arnold, Mark E. Booth, Brian King, Lindsay Ray, Chad TI Workshop Report: Crystal City VI-Bioanalytical Method Validation for Biomarkers SO AAPS JOURNAL LA English DT Article ID IMPLEMENTATION AB With the growing focus on translational research and the use of biomarkers to drive drug development and approvals, biomarkers have become a significant area of research within the pharmaceutical industry. However, until the US Food and Drug Administration's (FDA) 2013 draft guidance on bioanalytical method validation included consideration of biomarker assays using LC-MS and LBA, those assays were created, validated, and used without standards of performance. This lack of expectations resulted in the FDA receiving data from assays of varying quality in support of efficacy and safety claims. The AAPS Crystal City VI (CC VI) Workshop in 2015 was held as the first forum for industry-FDA discussion around the general issues of biomarker measurements (e.g., endogenous levels) and specific technology strengths and weaknesses. The 2-day workshop served to develop a common understanding among the industrial scientific community of the issues around biomarkers, informed the FDA of the current state of the science, and will serve as a basis for further dialogue as experience with biomarkers expands with both groups. C1 [Arnold, Mark E.] Bioanalyt Solut Integrat, Burlington, NJ USA. [Booth, Brian] US FDA, Silver Spring, MD USA. [King, Lindsay] Pfizer Inc, Groton, CT 06340 USA. [Ray, Chad] Pfizer Inc, La Jolla, CA USA. RP Arnold, ME (reprint author), Bioanalyt Solut Integrat, Burlington, NJ USA. EM mark.arnoldcs@gmail.com NR 15 TC 8 Z9 8 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD NOV PY 2016 VL 18 IS 6 BP 1366 EP 1372 DI 10.1208/s12248-016-9946-6 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EB7DU UT WOS:000387547000004 PM 27514862 ER PT J AU Suarez-Sharp, S Li, M Duan, J Shah, H Seo, P AF Suarez-Sharp, Sandra Li, Min Duan, John Shah, Heta Seo, Paul TI Regulatory Experience with In Vivo In Vitro Correlations (IVIVC) in New Drug Applications SO AAPS JOURNAL LA English DT Review DE causes of failure; dissolution; in vitro in vivo correlations; QbD; regulatory submissions ID ORAL DOSAGE FORMS; PERFORMANCE; PREDICTION; ACCURACY; WORKSHOP; INVITRO AB In the past two decades, in vitro in vivo correlation (IVIVC) has been considered an important tool for supporting biowaivers, setting dissolution acceptance criteria, and more recently in the Quality by Design (QbD) framework promoting the establishment of clinically meaningful drug product specifications using dissolution as the endpoint. Based on our review experience at the FDA, for the purposes of this article, we analyzed the current state of regulatory submissions containing IVIVC approaches and discussed the successes and failures from the perspectives of study design to methodology. In the past decade, the overall acceptance rate of the IVIVC submissions is about 40%. Moreover, the number of IVIVC studies seen in the submissions per year is not increasing. Establishing clinically meaningful drug product specifications through the linkages between the identified critical quality attributes and in vivo performance is key for developing a quality drug product. To achieve this goal, there is an imminent need for addressing the issues behind a low success rate in IVIVC development. The results from the current analysis revealed that special considerations should be taken in areas such as (1) selection of appropriate number/kind of formulations for IVIVC development/validation, (2) construction of exploratory plots to guide model building and selection, (3) investigation of the reasons of inconclusive predictability, (4) improvement on the quality and richness of the data, and (5) avoidance of over parameterization. The development and incorporation of biopredictive dissolution methods and the use of non-conventional approaches, including mechanistic/physiologically based approaches, should be explored to increase the likelihood of IVIVC success. C1 [Suarez-Sharp, Sandra; Li, Min; Duan, John; Shah, Heta; Seo, Paul] US FDA, Div Biopharmaceut, Off New Drug Prod, Off Pharmaceut Qual,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Suarez-Sharp, S (reprint author), US FDA, Div Biopharmaceut, Off New Drug Prod, Off Pharmaceut Qual,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Sandra.Suarez@fda.hhs.gov NR 21 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD NOV PY 2016 VL 18 IS 6 BP 1379 EP 1390 DI 10.1208/s12248-016-9966-2 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EB7DU UT WOS:000387547000006 PM 27480319 ER PT J AU Li, M Sander, S Duan, J Rosencrance, S Miksinski, SP Yu, L Seo, P Rege, B AF Li, Min Sander, Sanna Duan, John Rosencrance, Susan Miksinski, Sarah Pope Yu, Lawrence Seo, Paul Rege, Bhagwant TI Scientific and Regulatory Considerations in Solid Oral Modified Release Drug Product Development SO AAPS JOURNAL LA English DT Review DE Biopharmaceutics; Clinically relevant specifications; Control strategy; Modified release; Product and process understanding ID WATER-SOLUBLE DRUGS; DOSAGE FORMS; ABSORPTION; DELIVERY; DISSOLUTION; QUALITY; DESIGN; SYSTEM; TOOL; FORMULATIONS AB This review presents scientific and regulatory considerations for the development of solid oral modified release (MR) drug products. It includes a rationale for patient-focused development based on Quality-by-Design (QbD) principles. Product and process understanding of MR products includes identification and risk-based evaluation of critical material attributes (CMAs), critical process parameters (CPPs), and their impact on critical quality attributes (CQAs) that affect the clinical performance. The use of various biopharmaceutics tools that link the CQAs to a predictable and reproducible clinical performance for patient benefit is emphasized. Product and process understanding lead to a more comprehensive control strategy that can maintain product quality through the shelf life and the lifecycle of the drug product. The overall goal is to develop MR products that consistently meet the clinical objectives while mitigating the risks to patients by reducing the probability and increasing the detectability of CQA failures. C1 [Li, Min; Duan, John; Seo, Paul] US FDA, Div Biopharmaceut, Off New Drug Prod, Off Pharmaceut Qual, Silver Spring, MD USA. [Sander, Sanna; Rege, Bhagwant] US FDA, Div Modified Release Prod, Off Lifecycle Drug Prod, Off Pharmaceut Qual, Silver Spring, MD 20993 USA. [Rosencrance, Susan] US FDA, Off Lifecycle Drug Prod, Off Pharmaceut Qual, Silver Spring, MD USA. [Miksinski, Sarah Pope] US FDA, Off New Drug Prod, Off Pharmaceut Qual, Silver Spring, MD USA. [Yu, Lawrence] US FDA, Off Pharmaceut Qual, Silver Spring, MD USA. RP Rege, B (reprint author), US FDA, Div Modified Release Prod, Off Lifecycle Drug Prod, Off Pharmaceut Qual, Silver Spring, MD 20993 USA. EM bhagwant.rege@fda.hhs.gov NR 48 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD NOV PY 2016 VL 18 IS 6 BP 1406 EP 1417 DI 10.1208/s12248-016-9974-2 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EB7DU UT WOS:000387547000008 PM 27650190 ER PT J AU Chow, ECY Talattof, A Tsakalozou, E Fan, JH Zhao, L Zhang, XY AF Chow, Edwin Chiu Yuen Talattof, Arjang Tsakalozou, Eleftheria Fan, Jianghong Zhao, Liang Zhang, Xinyuan TI Using Physiologically Based Pharmacokinetic (PBPK) Modeling to Evaluate the Impact of Pharmaceutical Excipients on Oral Drug Absorption: Sensitivity Analyses SO AAPS JOURNAL LA English DT Article DE Biopharmaceutics Classification System (BCS); excipients; gastrointestinal transporters; oral drug absorption; PBPK modeling ID BIOPHARMACEUTICS CLASSIFICATION-SYSTEM; PEPTIDE TRANSPORTER PEPT1; COMMONLY USED EXCIPIENTS; P-GLYCOPROTEIN; CREMOPHOR EL; CACO-2 CELLS; BIOAVAILABILITY; PERMEABILITY; SURFACTANTS; METABOLISM AB Drug solubility, effective permeability, and intestinal metabolism and transport are parameters that govern intestinal bioavailability and oral absorption. However, excipients may affect the systemic bioavailability of a drug by altering these parameters. Thus, parameter sensitivity analyses using physiologically based pharmacokinetic (PBPK) models were performed to examine the potential impact of excipients on oral drug absorption of different Biopharmaceutics Classification System (BCS) class drugs. The simulation results showed that changes in solubility had minimal impact on C-max and AUC(0-t) of investigated BCS class 1 and 3 drugs. Changes in passive permeability altered C-max more than AUC(0-t) for BCS class 1 drugs but were variable and drug-specific across different BCS class 2 and 3 drugs. Depending on the drug compounds for BCS class 1 and 2 drugs, changes in intestinal metabolic activity altered C-max and AUC(0-t). Reducing or increasing influx and efflux transporter activity might likely affect C-max and AUC(0-t) of BCS class 2 and 3 drugs, but the magnitude may be drug dependent. Changes in passive permeability and/or transporter activity for BCS class 2 and 3 drugs might also have a significant impact on fraction absorbed and systemic bioavailability while changes in intestinal metabolic activity may have an impact on gut and systemic bioavailability. Overall, we demonstrate that PBPK modeling can be used routinely to examine sensitivity of bioavailability based on physiochemical and physiological factors and subsequently assess whether biowaiver requirements need consideration of excipient effects for immediate release oral solid dosage forms. C1 [Chow, Edwin Chiu Yuen; Talattof, Arjang; Tsakalozou, Eleftheria; Fan, Jianghong; Zhao, Liang; Zhang, Xinyuan] US FDA, Div Quantitat Methods & Modeling, Off Res & Stand, Off Gener Drugs, Silver Spring, MD 20993 USA. [Chow, Edwin Chiu Yuen; Talattof, Arjang; Tsakalozou, Eleftheria; Fan, Jianghong; Zhao, Liang; Zhang, Xinyuan] 10903 New Hampshire Ave,Bldg 75,Room 4690, Silver Spring, MD 20993 USA. RP Zhang, XY (reprint author), US FDA, Div Quantitat Methods & Modeling, Off Res & Stand, Off Gener Drugs, Silver Spring, MD 20993 USA.; Zhang, XY (reprint author), 10903 New Hampshire Ave,Bldg 75,Room 4690, Silver Spring, MD 20993 USA. EM Xinyuan.Zhang@fda.hhs.gov NR 51 TC 0 Z9 0 U1 6 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD NOV PY 2016 VL 18 IS 6 BP 1500 EP 1511 DI 10.1208/s12248-016-9964-4 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EB7DU UT WOS:000387547000016 PM 27520379 ER PT J AU Martinez, M Mistry, B Lukacova, V Polli, JE Hoag, SW Dowling, T Kona, R Fahmy, R AF Martinez, Marilyn Mistry, Bipin Lukacova, Viera Polli, James E. Hoag, Stephen W. Dowling, Thomas Kona, Ravikanth Fahmy, Raafat TI Use of Modeling and Simulation Tools for Understanding the Impact of Formulation on the Absorption of a Low Solubility Compound: Ciprofloxacin (vol 18, pg 886, 2016) SO AAPS JOURNAL LA English DT Correction C1 [Martinez, Marilyn; Mistry, Bipin; Fahmy, Raafat] US FDA, Rockville, MD 20855 USA. [Lukacova, Viera] Simulat Plus Inc, Lancaster, CA 93534 USA. [Polli, James E.; Hoag, Stephen W.] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Dowling, Thomas] Ferris State Univ, Dept Pharm Practice, Big Rapids, MI 49307 USA. [Kona, Ravikanth] Actavis Inc, Div Formulat Dev, Parsippany, NJ 07054 USA. RP Martinez, M (reprint author), US FDA, Rockville, MD 20855 USA. EM marilyn.martinez@fda.hhs.gov NR 1 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD NOV PY 2016 VL 18 IS 6 BP 1584 EP 1584 DI 10.1208/s12248-016-9933-y PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EB7DU UT WOS:000387547000024 PM 27215600 ER PT J AU Biswas, B AF Biswas, Bipasa TI Clinical Performance Evaluation of Molecular Diagnostic Tests SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Review ID SAMPLE-SIZE; CHLAMYDIA-TRACHOMATIS; CONFIDENCE-INTERVALS; PREDICTIVE VALUES; MISSING DATA; PROPORTIONS; ACCURACY; DISEASE; DESIGN; CANCER AB Molecular diagnostic tests with application to clinical diagnostics involve studies in infectious diseases, inherited diseases, oncology, predisposition to disease, or the description of polymorphisms linked to disease states. General considerations in the design of evaluation of diagnostic test trials and statistical principles for reporting the results are discussed. A brief overview of the general statistical considerations related to the intent of use, test development versus validation, different types of biases, and issues with missing data are provided. Furthermore, issues related to commonly used but not necessarily correct methods to characterize the performance in the presence and absence of a clinical reference standard are discussed. These issues are broadly applicable to any molecular diagnostic test with a dichotomous result. This overview may help the clinical molecular diagnostic community to evaluate tests that provide a dichotomous result. C1 [Biswas, Bipasa] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Biswas, B (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM bipasa.biswas@fda.hhs.gov NR 64 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2016 VL 18 IS 6 BP 803 EP 812 DI 10.1016/j.jmoldx.2016.06.008 PG 10 WC Pathology SC Pathology GA EB2OF UT WOS:000387201000002 PM 27639547 ER PT J AU Dave, K Alsharif, FM Perumal, O AF Dave, Kaushalkumar Alsharif, Fand M. Perumal, Omathanu TI Transpapillary (Nipple) Delivery of Macromolecules to the Breast: Proof of Concept Study SO MOLECULAR PHARMACEUTICS LA English DT Article DE breast cancer; nipple; mammary papilla; topical; macromolecules; iontophoresis; transdermal; BSA ID TRANSDERMAL IONTOPHORESIS; DRUG-DELIVERY; CANCER; SKIN; TRANSPORT; ELECTROOSMOSIS; MANAGEMENT; GROWTH; CHARGE; WOMEN AB Localized drug delivery to the breast can maximize drug concentration at the target site and minimize systemic drug distribution. To this end, the study explored the feasibility of delivering macromolecules to the breast through mammary papilla (nipple). The in vitro penetration of model macromolecules (inulin, dextran, ovalbumin, and bovine serum albumin) varying in molecular weight from 5 to 67 kDa was studied using excised porcine and human mammary papilla. The penetration of macromolecules decreased with increase in molecular weight. The penetration of the macromolecules was significantly higher through the mammary papilla in comparison to breast skin. In vitro penetration of the macromolecules was similar in human and porcine mammary papilla. Iontophoresis was used to enhance the transport of bovine serum albumin (BSA) through the mammary papilla. The flux and cumulative amount permeated was increased by 2- to 4-fold by iontophoresis. The macromolecules were transported through the ducts and the surrounding connective tissue in the mammary papilla. Overall, the results from this study for the first time demonstrate the feasibility of delivering macromolecules through the mammary papilla. These findings have implications for developing safe and effective localized therapeutic approaches for breast cancer. C1 [Dave, Kaushalkumar; Alsharif, Fand M.; Perumal, Omathanu] South Dakota State Univ, Dept Pharmaceut Sci, Coll Pharm, Brookings, SD 57007 USA. [Dave, Kaushalkumar] US FDA, Div Biopharmaceut, Off New Drug Prod, Off Pharmaceut Qual,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Alsharif, Fand M.] Al Azhar Univ, Dept Pharmaceut & Ind Pharm, Coll Pharm, Assiut, Egypt. RP Perumal, O (reprint author), South Dakota State Univ, Dept Pharmaceut Sci, Coll Pharm, Brookings, SD 57007 USA. EM omathanu.perumal@sdstate.edu FU South Dakota Governor's Translational Cancer Research Center FX This work was funded by the South Dakota Governor's 2010 Translational Cancer Research Center. Human tissues were provided by National Disease Research Interchange (Philadelphia, PA, USA) and South Dakota Lions Eye and Tissue Bank (Sioux Falls, SD, USA). This is an exempt protocol as per the IRB guidelines at South Dakota State University. Porcine tissues were provided by Dr. Kelley Bruns and Adam Rhody from the Department of Animal Science, South Dakota State University, Brookings, SD, USA, and from Renner Corner Locker at Renner, SD, USA. NR 47 TC 0 Z9 0 U1 3 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD NOV PY 2016 VL 13 IS 11 BP 3842 EP 3851 DI 10.1021/acs.molpharmaceut.6b00634 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA EB5PK UT WOS:000387428300024 PM 27700111 ER PT J AU Wang, W Griswold, ME AF Wang, Wei Griswold, Michael E. TI Estimating overall exposure effects for the clustered and censored outcome using random effect Tobit regression models SO STATISTICS IN MEDICINE LA English DT Article DE random effects; Tobit model; marginalized model; model based prediction; overall exposure effect ID LONGITUDINAL BINARY DATA AB The random effect Tobit model is a regression model that accommodates both left- and/or right-censoring and within-cluster dependence of the outcome variable. Regression coefficients of random effect Tobit models have conditional interpretations on a constructed latent dependent variable and do not provide inference of overall exposure effects on the original outcome scale. Marginalized random effects model (MREM) permits likelihood-based estimation of marginal mean parameters for the clustered data. For random effect Tobit models, we extend the MREM to marginalize over both the random effects and the normal space and boundary components of the censored response to estimate overall exposure effects at population level. We also extend the 'Average Predicted Value' method to estimate the model-predicted marginal means for each person under different exposure status in a designated reference group by integrating over the random effects and then use the calculated difference to assess the overall exposure effect. The maximum likelihood estimation is proposed utilizing a quasi-Newton optimization algorithm with Gauss-Hermite quadrature to approximate the integration of the random effects. We use these methods to carefully analyze two real datasets. Copyright (C) 2016 John Wiley & Sons, Ltd. C1 [Wang, Wei] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, New Guyton Res Bldg G562,2500 North State St, Jackson, MS 39216 USA. [Griswold, Michael E.] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, New Guyton Res Bldg G651-07,2500 North State St, Jackson, MS 39216 USA. [Wang, Wei] US FDA, Ctr Devices & Radiol Hlth, Div Biostat, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Wang, W (reprint author), Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, New Guyton Res Bldg G562,2500 North State St, Jackson, MS 39216 USA.; Wang, W (reprint author), US FDA, Ctr Devices & Radiol Hlth, Div Biostat, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM wwang@umc.edu FU Jackson Heart Study from the National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities; National Institute on Aging [R01AG045255] FX Support for this research was provided in part by the Jackson Heart Study contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities, with additional support from the National Institute on Aging [grant number R01AG045255 (B.G. Windham)]. NR 24 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD NOV PY 2016 VL 35 IS 27 BP 4948 EP 4960 DI 10.1002/sim.7045 PG 13 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 EB4NA UT WOS:000387347400004 PM 27449636 ER PT J AU Sharma, K Harrington, A Worrell, S Bertha, A AF Sharma, Khushboo Harrington, Afi Worrell, Sallamar Bertha, Amy TI An FDA Analysis of Formal Dispute Resolution in the Center for Drug Evaluation and Research: 2003 Through 2014 SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE appeal; 30-day goal; formal dispute resolution; appeal issues; FDA deciding official AB Scientific and/or medical disputes will inevitably arise with regard to the US Food and Drug Administration's (FDA's) decision making related to drug development, new drug review, generic drug review, and postmarketing oversight. As these disputes can involve complex judgments and issues that are scientifically and commercially important, it is critical that FDA have procedures for effective and efficient resolution. FDA regulations allow a sponsor to obtain a review of an FDA decision by submitting a request for formal dispute resolution (an appeal). FDA's Center for Drug Evaluation and Research (CDER) received 137 appeal issues for fiscal years 2003 through 2014. However, sponsors can appeal the same issue multiple times, and each is considered a unique appeal; CDER received and analyzed 173 of these unique appeals. Of these 173 unique appeals, CDER accepted 140 (81%) for review and refused to accept for review 25 (14%). Eight (5%) were withdrawn by the sponsor prior to CDER making a decision whether to accept the appeal for review. Of the 140 unique appeals accepted and reviewed, CDER granted 23 (16%) appeals and denied 117 (84%). The analysis also examines an array of aspects of the process, such as (1) reasons why CDER rejected appeals, (2) reasons why sponsors submitted appeals, (3) the types of appeals that sponsors submitted, (4) the characteristics of the sponsors that submitted appeals (eg, size, past regulatory experience, legal representation), and (5) CDER's performance in meeting user fee goals associated with dispute resolution. C1 [Sharma, Khushboo] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Harrington, Afi; Worrell, Sallamar] US FDA, Off Strateg Programs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Bertha, Amy] US FDA, Off Execut Programs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Sharma, K (reprint author), Ctr Drug Evaluat & Res, Off New Drugs, 10903 New Hampshire Ave,Bldg 22,Room 6468, Silver Spring, MD 20903 USA. EM Khushboo.Sharma@fda.hhs.gov NR 0 TC 0 Z9 0 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 NOV PY 2016 VL 50 IS 6 BP 697 EP 704 DI 10.1177/2168479016651297 PG 8 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA EB2FJ UT WOS:000387173000003 ER PT J AU Jarow, JP Lemery, S Bugin, K Khozin, S Moscicki, R AF Jarow, Jonathan P. Lemery, Steven Bugin, Kevin Khozin, Sean Moscicki, Richard TI Expanded Access of Investigational Drugs: The Experience of the Center of Drug Evaluation and Research Over a 10-Year Period SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE expanded access; compassionate use; US Food and Drug Administration ID TO-TRY LAWS; CHALLENGES AB Background: The purpose of this study was to describe the experience of the Center of Drug Evaluation and Research (CDER) with expanded access of investigational drugs. Methods: Multiple searches of CDER's document tracking system were performed to identify the number, type, and indication for all expanded access requests over the 10-year time period of January 2005 through December 2014. An additional search was performed to identify all active commercial investigational drug development programs during that time period and whether or not the clinical program was placed on hold. The two searches were then cross-referenced to identify those commercial investigational drug development programs placed on clinical hold due to serious adverse events occurring within expanded access programs. Results: CDER receives over 1000 applications for expanded access each year. The majority are for single patients, roughly evenly split between emergency and nonemergency use. The vast majority, 99.7%, are allowed to proceed. The incidence of clinical holds for all commercial investigational drug development programs is 7.9%, as compared to only 0.2% related to adverse events observed in patients receiving drug treatments under expanded access. Conclusions: The expanded access program is viewed as a success from FDA's perspective based on the large number of applications processed and allowed to proceed each year. However, the actual number of patients and their health care providers that desire drug treatments available under expanded access is not known. It is exceedingly rare for a serious adverse event under expanded access to affect the development program for that drug. C1 [Jarow, Jonathan P.; Lemery, Steven; Bugin, Kevin; Khozin, Sean; Moscicki, Richard] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Jarow, JP (reprint author), US FDA, Off Ctr Director, Ctr Drug Evaluat & Res, WO51 RM6364,10903 New Hampshire Ave, Spring, MD 20993 USA. EM jonathan.jarow@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 10 TC 0 Z9 0 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 NOV PY 2016 VL 50 IS 6 BP 705 EP 709 DI 10.1177/2168479016656030 PG 5 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA EB2FJ UT WOS:000387173000004 PM 27917324 ER PT J AU Yang, XT Thompson, L Chu, JX Liu, S Lu, H Zhou, J Gomatam, S Tang, R Zhao, Y Ge, YJ Gray, GW AF Yang, Xiting Thompson, Laura Chu, Jianxiong Liu, Sherry Lu, Hong Zhou, Jie Gomatam, Shanti Tang, Rong Zhao, Yu Ge, Yunjiang Gray, Gerry W. TI Adaptive Design Practice at the Center for Devices and Radiological Health (CDRH), January 2007 to May 2013 SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE adaptive design; medical device; survey; FDA ID SAMPLE-SIZE REESTIMATION; GROUP RANDOMIZED-TRIALS; CLINICAL-TRIALS; UPDATED GUIDELINES AB Adaptive designs have generated great interest in the clinical trial community as a result of their versatility and efficiency. Recently, the Center for Devices and Radiological Health (CDRH) at the US Food and Drug Administration (FDA) surveyed all adaptive design applications submitted between 2007 and May 2013 for regulatory review. In this paper, we discuss the overall results and findings that emerged from an in-depth examination of the submissions. We summarize the current status of adaptive designs used in medical device studies. We also identify some of the lessons learned and common pitfalls that we encountered in our review of the designs. C1 [Yang, Xiting; Thompson, Laura; Chu, Jianxiong; Liu, Sherry; Lu, Hong; Zhou, Jie; Gomatam, Shanti; Tang, Rong; Zhao, Yu; Ge, Yunjiang; Gray, Gerry W.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Yang, XT (reprint author), Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM xiting.yang@fda.hhs.gov NR 22 TC 0 Z9 0 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 NOV PY 2016 VL 50 IS 6 BP 710 EP 717 DI 10.1177/2168479016656027 PG 8 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA EB2FJ UT WOS:000387173000005 ER PT J AU McMahon, AW Watt, K Wang, J Green, D Tiwari, R Burckart, GJ AF McMahon, Ann W. Watt, Kevin Wang, Jian Green, Dionna Tiwari, Ram Burckart, Gilbert J. TI Stratification, Hypothesis Testing, and Clinical Trial Simulation in Pediatric Drug Development SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE Kawasaki disease; age groups; modeling; pharmacokinetics pharmacodynamics ID ANTIDEPRESSANT DRUGS; PHARMACOLOGY; CHILDREN; DESIGN; ERROR AB Background: Pediatric drug development is plagued by small sample sizes, unvalidated clinical endpoints, and limited studies. Objectives: The objective of this study was to determine whether age stratification within the pediatric population could be used to (1) assess response to a pharmacologic intervention and to (2) design future trials based upon published stratified disease data using clinical trial simulation (CTS). Methods: Data available from the literature for Kawasaki disease (KD) was used in the model. Age-stratified CTS for a theoretical new drug was conducted. Results: Population-specific differences due to age might affect trial success if not taken into account. CTS predicted inflammatory indices, and inclusion cutoff significantly altered the trial outcome. Finally, altered pharmacokinetics/pharmacodynamics in varying age groups of KD patients may alter drug exposure and response. Conclusions: If assumptions regarding a pediatric disease process, such as KD, do not include age stratification with inclusion or response, then the wrong decision could result with regard to age-appropriateness or approval of a drug. C1 [McMahon, Ann W.] US FDA, Off Pediat Therapeut, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Watt, Kevin] Duke Univ, Med Ctr, Durham, NC USA. [Wang, Jian; Green, Dionna; Burckart, Gilbert J.] US FDA, Off Clin Pharmacol, Off Translat Sci, Silver Spring, MD USA. [Tiwari, Ram] US FDA, Off Biostat, Off Translat Sci, Silver Spring, MD USA. RP McMahon, AW (reprint author), US FDA, Off Pediat Therapeut, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM ann.mcmahon@fda.hhs.gov NR 13 TC 0 Z9 0 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 NOV PY 2016 VL 50 IS 6 BP 817 EP 822 DI 10.1177/2168479016651661 PG 6 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA EB2FJ UT WOS:000387173000017 ER PT J AU Duggan, MC Jochems, C Donahue, RN Richards, J Karpa, V Foust, E Paul, B Brooks, T Tridandapani, S Olencki, T Pan, XL Lesinski, GB Schlom, J Carson, WE AF Duggan, Megan C. Jochems, Caroline Donahue, Renee N. Richards, Jacob Karpa, Volodymyr Foust, Elizabeth Paul, Bonnie Brooks, Taylor Tridandapani, Susheela Olencki, Thomas Pan, Xueliang Lesinski, Gregory B. Schlom, Jeffrey Carson, William E., III TI A phase I study of recombinant (r) vaccinia-CEA(6D)-TRICOM and rFowlpox-CEA(6D)-TRICOM vaccines with GM-CSF and IFN-alpha-2b in patients with CEA-expressing carcinomas SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Vaccines; Carcinoembryonic antigen (CEA); Colorectal cancer; Immunotherapy; Interferon alpha-2b ID HUMAN CARCINOEMBRYONIC ANTIGEN; METASTATIC COLORECTAL-CANCER; TUMOR-ASSOCIATED ANTIGENS; MHC CLASS-I; ALPHA-INTERFERON TREATMENT; T-CELL-ACTIVATION; MONOCLONAL-ANTIBODY; SUPPRESSOR-CELLS; MELANOMA PATIENTS; HUMAN-BREAST AB Prime-boost vaccination with recombinant (r) vaccinia(V)-CEA(6D)-TRICOM (triad of co-stimulatory molecules B7.1, ICAM-1 and LFA-3) and rFowlpox(F)-CEA(6D)-TRICOM infect antigen-presenting cells and direct expression of co-stimulatory molecules. We hypothesized that co-administration of vaccine with GM-CSF and interferon alpha (IFN-alpha) would have efficacy in CEA-expressing cancers. Patients with CEA-expressing cancers received the rV-CEA(6D)-TRICOM vaccine subcutaneously (s.c.) on day 1 followed by GM-CSF s.c. to the injection site on days 1-4. In Cycle 1, patients received thrice weekly s.c. injections of IFN-alpha-2b the week after rV-CEA(6D)-TRICOM. In Cycles 2-4, patients received thrice weekly s.c. injections of IFN-alpha-2b the same week that rF-CEA(6D)-TRICOM was given. The first cohort received no IFN followed by dose escalation of IFN-alpha in subsequent cohorts. Thirty-three patients were accrued (mean 59.8 years). Grade 3 toxicities included fatigue and hyperglycemia. Grade 4-5 adverse events (unrelated to treatment) were confusion (1), elevated aspartate transaminase (AST)/alanine transaminase (ALT) (1), and sudden death (1). No patients had a partial response, and eight patients exhibited stable disease of aeyen3 months. Median progression-free survival and overall survival (OS) were 1.8 and 6.3 months, respectively. Significantly higher serum CD27 levels were observed after vaccine therapy (p = 0.006 post 1-2 cycles, p = 0.003 post 3 cycles, p = 0.03 post 4-7 cycles) and 42 % of patients assayed developed CEA-specific T cell responses. Pre-treatment levels of myeloid-derived suppressor cells correlated with overall survival (p = 0.04). Administration of IFN-alpha led to significantly increased OS (p = 0.02) compared to vaccine alone. While the vaccine regimen produced no clinical responses, IFN-alpha administration was associated with improved survival. C1 [Duggan, Megan C.; Karpa, Volodymyr; Foust, Elizabeth; Paul, Bonnie; Brooks, Taylor; Tridandapani, Susheela; Lesinski, Gregory B.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Jochems, Caroline; Donahue, Renee N.; Richards, Jacob; Schlom, Jeffrey] NCI, Lab Tumor Immunol & Biol, Bethesda, MD 20892 USA. [Olencki, Thomas] Ohio State Univ, Div Med Oncol, Columbus, OH 43210 USA. [Pan, Xueliang] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. [Carson, William E., III] Ohio State Univ, Div Surg Oncol, N924 Doan Hall,410 W 10th Ave, Columbus, OH 43210 USA. [Richards, Jacob] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Carson, WE (reprint author), Ohio State Univ, Div Surg Oncol, N924 Doan Hall,410 W 10th Ave, Columbus, OH 43210 USA. EM william.carson@osumc.edu FU NIH [P01 CA095426, P30 CA016058, T32 GM068412] FX This work was supported by NIH Grants: P01 CA095426 (W. Carson), P30 CA016058 (W. Carson), and T32 GM068412 (M. Duggan). NR 47 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 EI 1432-0851 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD NOV PY 2016 VL 65 IS 11 BP 1353 EP 1364 DI 10.1007/s00262-016-1893-7 PG 12 WC Oncology; Immunology SC Oncology; Immunology GA EA4UN UT WOS:000386610800007 PM 27581603 ER PT J AU Gagne, JJ Han, X Hennessy, S Leonard, CE Chrischilles, EA Carnahan, RM Wang, SV Fuller, C Iyer, A Katcoff, H Woodworth, TS Archdeacon, P Meyer, TE Schneeweiss, S Toh, S AF Gagne, J. J. Han, X. Hennessy, S. Leonard, C. E. Chrischilles, E. A. Carnahan, R. M. Wang, S. V. Fuller, C. Iyer, A. Katcoff, H. Woodworth, T. S. Archdeacon, P. Meyer, T. E. Schneeweiss, S. Toh, S. TI Successful Comparison of US Food and Drug Administration Sentinel Analysis Tools to Traditional Approaches in Quantifying a Known Drug-Adverse Event Association SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID INHIBITOR-ASSOCIATED ANGIOEDEMA; SAFETY MONITORING-SYSTEM; HEALTH DATA; ANGIOTENSIN; PROGRAM; DESIGN; MODELS; EDEMA AB The US Food and Drug Administration's Sentinel system has developed the capability to conduct active safety surveillance of marketed medical products in a large network of electronic healthcare databases. We assessed the extent to which the newly developed, semiautomated Sentinel Propensity Score Matching (PSM) tool could produce the same results as a customized protocol-driven assessment, which found an adjusted hazard ratio (HR) of 3.04 (95% confidence interval [CI], 2.81-3.27) comparing angioedema in patients initiating angiotensin-converting enzyme (ACE) inhibitors vs. beta-blockers. Using data from 13 Data Partners between 1 January 2008, and 30 September 2013, the PSM tool identified 2,211,215 eligible ACE inhibitor and 1,673,682 eligible beta-blocker initiators. The tool produced an HR of 3.14 (95% CI, 2.86-3.44). This comparison provides initial evidence that Sentinel analytic tools can produce findings similar to those produced by a highly customized protocol-driven assessment. C1 [Gagne, J. J.; Wang, S. V.; Schneeweiss, S.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. [Gagne, J. J.; Wang, S. V.; Schneeweiss, S.] Harvard Med Sch, Boston, MA USA. [Han, X.; Hennessy, S.; Leonard, C. E.] Univ Penn, Ctr Pharmacoepidemiol Res & Training, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Han, X.; Hennessy, S.; Leonard, C. E.] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Chrischilles, E. A.; Carnahan, R. M.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Fuller, C.; Iyer, A.; Katcoff, H.; Woodworth, T. S.; Toh, S.] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Fuller, C.; Iyer, A.; Katcoff, H.; Woodworth, T. S.; Toh, S.] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Archdeacon, P.] US FDA, Off Med Policy, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Meyer, T. E.] US FDA, Div Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Gagne, JJ (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA.; Gagne, JJ (reprint author), Harvard Med Sch, Boston, MA USA. EM jgagne1@partners.org RI Toh, Sengwee/D-7567-2017 OI Toh, Sengwee/0000-0002-5160-0810 FU US Food and Drug Administration through the Department of Health and Human Services [HHSF223200910006I] FX The authors thank the Data Partners who provided data used in the analysis: Aetna (Aetna Informatics, Blue Bell, PA), HealthCore, (HealthCore, Inc., Government & Academic Research, Alexandria, VA) Harvard Pilgrim, Health Partners (HealthPartners Institute for Education and Research, Saint Paul, MN), Humana (Humana, Inc., Comprehensive Health Insights, Miramar, FL), KPCO (Kaiser Permanente Colorado Institute for Health Research, Denver, CO), KPHI (Kaiser Permanente Center for Health Research Hawai'i, Honolulu, HI), KPNC (Kaiser Permanente Northern California, Division of Research, Oakland, CA), KPNW (Kaiser Permanente Northwest Center for Health Research, Portland, OR), Lovelace (Lovelace Clinic Research Foundation, Albuquerque, NM), Marshfield (Marshfield Clinic Research Foundation, Marshfield, WI), Optum (OptumInsight Life Sciences, Inc., Waltham, MA), Vanderbilt (Vanderbilt University School of Medicine, Department of Preventive Medicine, Nashville, TN [we are indebted to the Tennessee Bureau of TennCare of the Department of Finance and Administration, which provided data]). The authors thank Sophia Axtman, April Duddy, Lisa Ortendahl, and Jennifer Popovic for assistance. The Mini-Sentinel program is funded by the US Food and Drug Administration through the Department of Health and Human Services contract number HHSF223200910006I. The views expressed in this article are those of the authors and are not intended to convey official US Food and Drug Administration policy or guidance. NR 20 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD NOV PY 2016 VL 100 IS 5 BP 558 EP 564 DI 10.1002/cpt.429 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DZ8QL UT WOS:000386135800024 PM 27416001 ER PT J AU Cote, I Andersen, ME Ankley, GT Barone, S Birnbaum, LS Boekelheide, K Bois, F Burgoon, LD Chiu, WA Crawford-Brown, D Crofton, KM DeVito, M Devlin, RB Edwards, SW Guyton, KZ Hattis, D Judson, RS Knight, D Krewski, D Lambert, J Maull, EA Mendrick, D Paoli, GM Patel, CJ Perkins, EJ Poje, G Portier, CJ Rusyn, I Schulte, PA Simeonov, A Smith, MT Thayer, KA Thomas, RS Thomas, R Tice, RR Vandenberg, JJ Villeneuve, DL Wesselkamper, S Whelan, M Whittaker, C White, R Xia, M Yauk, C Zeise, L Zhao, J DeWoskin, RS AF Cote, Ila Andersen, Melvin E. Ankley, Gerald T. Barone, Stanley Birnbaum, Linda S. Boekelheide, Kim Bois, FredericY. Burgoon, Lyle D. Chiu, Weihsueh A. Crawford-Brown, Douglas Crofton, Kevin M. DeVito, Michael Devlin, Robert B. Edwards, Stephen W. Guyton, Kathryn Z. Hattis, Dale Judson, Richard S. Knight, Derek Krewski, Daniel Lambert, Jason Maull, Elizabeth Anne Mendrick, Donna Paoli, Gregory M. Patel, Chirag Jagdish Perkins, Edward J. Poje, Gerald Portier, Christopher J. Rusyn, Ivan Schulte, Paul A. Simeonov, Anton Smith, Martyn T. Thayer, Kristina A. Thomas, Russell S. Thomas, Reuben Tice, Raymond R. Vandenberg, John J. Villeneuve, Daniel L. Wesselkamper, Scott Whelan, Maurice Whittaker, Christine White, Ronald Xia, Menghang Yauk, Carole Zeise, Lauren Zhao, Jay DeWoskin, Robert S. TI The Next Generation of Risk Assessment Multi-Year Study-Highlights of Findings, Applications to Risk Assessment, and Future Directions SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review ID ADVERSE OUTCOME PATHWAYS; BRONCHIAL EPITHELIAL-CELLS; THROUGHPUT SCREENING DATA; IN-VIVO HAZARD; ENVIRONMENTAL CHEMICALS; HUMAN HEALTH; GENE-EXPRESSION; POPULATION VARIABILITY; PREDICTIVE TOXICOLOGY; ESTROGEN-RECEPTOR AB BACKGROUND: The Next Generation (NexGen) of Risk Assessment effort is a multi-year collaboration among several organizations evaluating new, potentially more efficient molecular, computational, and systems biology approaches to risk assessment. This article summarizes our findings, suggests applications to risk assessment, and identifies strategic research directions. OBJECTIVE: Our specific objectives were to test whether advanced biological data and methods could better inform our understanding of public health risks posed by environmental exposures. METHODS: New data and methods were applied and evaluated for use in hazard identification and dose-response assessment. Biomarkers of exposure and effect, and risk characterization were also examined. Consideration was given to various decision contexts with increasing regulatory and public health impacts. Data types included transcriptomics, genomics, and proteomics. Methods included molecular epidemiology and clinical studies, bioinformatic knowledge mining, pathway and network analyses, short-duration in vivo and in vitro bioassays, and quantitative structure activity relationship modeling. DISCUSSION: NexGen has advanced our ability to apply new science by more rapidly identifying chemicals and exposures of potential concern, helping characterize mechanisms of action that influence conclusions about causality, exposure-response relationships, susceptibility and cumulative risk, and by elucidating new biomarkers of exposure and effects. Additionally, NexGen has fostered extensive discussion among risk scientists and managers and improved confidence in interpreting and applying new data streams. CONCLUSIONS: While considerable uncertainties remain, thoughtful application of new knowledge to risk assessment appears reasonable for augmenting major scope assessments, forming the basis for or augmenting limited scope assessments, and for prioritization and screening of very data limited chemicals. C1 [Cote, Ila; Vandenberg, John J.; DeWoskin, Robert S.] US EPA, Natl Ctr Environm Assessment, Washington, DC 20460 USA. [Andersen, Melvin E.] ScitoVation, Res Triangle Pk, NC USA. [Ankley, Gerald T.; Villeneuve, Daniel L.] US EPA, Natl Hlth & Environm Effects Res Lab, Duluth, MN USA. [Barone, Stanley] US EPA, Off Chem Safety & Pollut Prevent, Washington, DC 20460 USA. [Birnbaum, Linda S.; DeVito, Michael; Maull, Elizabeth Anne; Thayer, Kristina A.; Tice, Raymond R.] NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.; DeVito, Michael; Maull, Elizabeth Anne; Thayer, Kristina A.; Tice, Raymond R.] NIH, Natl Toxicol Program, DHHS, Res Triangle Pk, NC USA. [Boekelheide, Kim] Brown Univ, Dept Pathol & Lab Med, Providence, RI 02912 USA. [Bois, FredericY.] Inst Natl Environm Ind & Risques, Unite Modeles Icotoxicol & Toxicol, Verneuil En Halatte, France. [Burgoon, Lyle D.] US Army, Engineer Res & Dev Ctr, Res Triangle Pk, NC USA. [Chiu, Weihsueh A.; Rusyn, Ivan] Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX USA. [Crawford-Brown, Douglas] Univ Cambridge, Dept Land Econ, Cambridge, England. [Crofton, Kevin M.; Judson, Richard S.; Thomas, Russell S.] Natl Ctr Computat Toxicol, Res Triangle Pk, NC USA. [Devlin, Robert B.; Edwards, Stephen W.] US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Guyton, Kathryn Z.] Int Agcy Res Canc, Lyon, France. [Hattis, Dale] Clark Univ, George Perkins Marsh Inst, Worcester, MA 01610 USA. [Knight, Derek] European Chem Agcy, Helsinki, Finland. [Krewski, Daniel] Univ Ottawa, McLaughlin Ctr Populat Hlth Risk Assessment, Ottawa, ON, Canada. [Lambert, Jason; Wesselkamper, Scott; Zhao, Jay] US EPA, Natl Ctr Environm Assessment, Cincinnati, OH 45268 USA. [Mendrick, Donna] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Paoli, Gregory M.] Risk Sci Int, Ottawa, ON, Canada. [Patel, Chirag Jagdish] Harvard Med Sch, Dept Biomed Informat, Boston, MA USA. [Perkins, Edward J.] US Army, Engineer Res & Dev Ctr, Vicksburg, MS USA. [Poje, Gerald] Grant Consulting Grp, Washington, DC USA. [Portier, Christopher J.] Environm Def Fund, Washington, DE USA. [Schulte, Paul A.; Whittaker, Christine] Ctr Dis Control & Prevent, Natl Inst Occupat Safety & Hlth, Educ & Informat Div, Cincinnati, OH USA. [Simeonov, Anton; Xia, Menghang] NIH, Natl Ctr Adv Translat Sci, DHHS, Bethesda, MD USA. [Smith, Martyn T.] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Thomas, Reuben] Univ Calif San Francisco, Gladstone Inst, San Francisco, CA 94143 USA. [Whelan, Maurice] European Commiss Joint Res Ctr, Syst Toxicol Unit, Ispra, Italy. [White, Ronald] Ctr Effect Govt, Washington, DE USA. [Yauk, Carole] Hlth Canada, Environm Hlth Sci & Res Bur, Ottawa, ON, Canada. [Zeise, Lauren] Calif EPA, Off Environm Hlth Hazard Assessment, Oakland, CA USA. RP Cote, I (reprint author), US EPA, Reg 8,Room 8152,1595 Wynkoop St, Denver, CO 80202 USA. EM cote.ila@epa.gov RI Bois, Frederic/E-9241-2012; Rusyn, Ivan/S-2426-2016; OI Bois, Frederic/0000-0002-4154-0391; Vandenberg, John/0000-0003-2619-9460; Burgoon, Lyle/0000-0003-4977-5352 FU NIEHS NIH HHS [P42 ES005948, R00 ES023504, K99 ES023504, R21 ES025052] NR 152 TC 0 Z9 0 U1 30 U2 30 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD NOV PY 2016 VL 124 IS 11 BP 1671 EP 1682 DI 10.1289/EHP233 PG 12 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA EA8UF UT WOS:000386913800010 PM 27091369 ER PT J AU Chen, Y Burall, LS Macarisin, D Pouillot, R Strain, E De Jesus, AJ Laasri, A Wang, H Ali, L Tatavarthy, A Zhang, GD Hu, LJ Day, J Kang, JH Sahu, S Srinivasan, D Klontz, K Parish, M Evans, PS Brown, EW Hammack, TS Zink, DL Datta, AR AF Chen, Yi Burall, Laurel S. Macarisin, Dumitru Pouillot, Regis Strain, Errol De Jesus, Antonio J. Laasri, Anna Wang, Hua Ali, Laila Tatavarthy, Aparna Zhang, Guodong Hu, Lijun Day, James Kang, Jihun Sahu, Surasri Srinivasan, Devayani Klontz, Karl Parish, Mickey Evans, Peter S. Brown, Eric W. Hammack, Thomas S. Zink, Donald L. Datta, Atin R. TI Prevalence and Level of Listeria monocytogenes in Ice Cream Linked to a Listeriosis Outbreak in the United States SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Enumeration; Ice cream; Listeriosis outbreak ID SURVIVAL AB A most-probable-number (MPN) method was used to enumerate Listeria monocytogenes in 2,320 commercial ice cream scoops manufactured on a production line that was implicated in a 2015 listeriosis outbreak in the United States. The analyzed samples were collected from seven lots produced in November 2014, December 2014, January 2015, and March 2015. L. monocytogenes was detected in 99% (2,307 of 2,320) of the tested samples (lower limit of detection, 0.03 MPN/g), 92% of which were contaminated at <20 MPN/g. The levels of L. monocytogenes in these samples had a geometric mean per lot of 0.15 to 7.1 MPN/g. The prevalence and enumeration data from an unprecedented large number of naturally contaminated ice cream products linked to a listeriosis outbreak provided a unique data set for further understanding the risk associated with L. monocytogenes contamination for highly susceptible populations. C1 [Chen, Yi; Macarisin, Dumitru; De Jesus, Antonio J.; Laasri, Anna; Wang, Hua; Ali, Laila; Tatavarthy, Aparna; Zhang, Guodong; Hu, Lijun; Day, James; Evans, Peter S.; Brown, Eric W.; Hammack, Thomas S.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. [Pouillot, Regis; Strain, Errol; Klontz, Karl] Off Analyt & Outreach, College Pk, MD 20740 USA. [Parish, Mickey; Zink, Donald L.] Off Ctr Director, College Pk, MD 20740 USA. [Burall, Laurel S.; Kang, Jihun; Sahu, Surasri; Srinivasan, Devayani; Datta, Atin R.] US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. RP Chen, Y (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA.; Datta, AR (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. EM yi.chen@fda.hhs.gov; atin.datta@fda.hhs.gov RI Pouillot, Regis/E-8103-2010 OI Pouillot, Regis/0000-0002-6107-5212 FU University of Maryland Joint Institute for Food Safety and Applied Nutrition; U.S. Food and Drug Administration (FDA) [FDU001418]; U.S. Department of Energy; FDA FX This research was funded in part by the University of Maryland Joint Institute for Food Safety and Applied Nutrition through a cooperative agreement with the U.S. Food and Drug Administration (FDA; FDU001418) and in part by an appointment to the Research Participation Program at the FDA 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 FDA. The authors thank D. Charles Hunt (Kansas Bureau of Epidemiology and Public Health Informatics, Department of Health and the Environment, Topeka, KS) for providing information on hospital kitchen sampling. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the FDA. NR 14 TC 4 Z9 4 U1 11 U2 11 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD NOV PY 2016 VL 79 IS 11 BP 1828 EP 1832 DI 10.4315/0362-028X.JFP-16-208 PG 5 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EB1FG UT WOS:000387094400001 PM 28221903 ER PT J AU Tyson, GH Tate, HP Abbott, J Tran, TT Kabera, C Crarey, E Young, SN McDermott, PF Sprague, G Campbell, M Adeyemo, O Browne-Silva, J Myers, M Thitaram, S Zhao, SH AF Tyson, Gregory H. Tate, Heather P. Abbott, Jason Thu-Thuy Tran Kabera, Claudine Crarey, Emily Young, Shenia McDermott, Patrick F. Sprague, Grisselle Campbell, Mark Adeyemo, Oyewole Browne-Silva, Johnette Myers, Michael Thitaram, Sutawee Zhao, Shaohua TI Molecular Subtyping and Source Attribution of Campylobacter Isolated from Food Animals SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Campylobacter; Food animals; Pulsed-field gel electrophoresis; Source attribution ID FIELD GEL-ELECTROPHORESIS; UNITED-STATES; ANTIMICROBIAL RESISTANCE; JEJUNI CLONE; RETAIL MEATS; OUTBREAK; PATHOGENS; COLI; INFECTIONS; PREVALENCE AB Campylobacter spp. commonly cause gastrointestinal illness in humans. Poultry meats have long been considered the predominant source of these infections, but few in-depth Campylobacter source attribution studies have been completed. We analyzed more than 1,300 Campylobacter isolates recovered from a number of animal and food sources, including dairy and beef cattle, pigs, poultry, and retail poultry meat, and compared them with Campylobacter isolates recovered from human clinical samples. Each isolate was subtyped using pulsed-field gel electrophoresis (PFGE) with SmaI and queried against the Centers for Disease Control and Prevention PulseNet database to identify human isolates with indistinguishable patterns. Half (49.5%) of the PFGE patterns from poultry animal and retail meat isolates were indistinguishable from patterns of at least one human isolate. Among the isolates from beef and dairy cows, 56.6 and 65.0%, respectively, of their PFGE patterns were indistinguishable from those of human isolates. Only a small portion of the PFGE patterns of Campylobacter isolated from pigs (9.5%) were found to have PFGE patterns in common with human isolates. These data imply that cattle may be larger contributors to Campylobacter infections than previously recognized and help further our understanding of potential sources of human campylobacteriosis. C1 [Tyson, Gregory H.; Tate, Heather P.; Abbott, Jason; Thu-Thuy Tran; Kabera, Claudine; Crarey, Emily; Young, Shenia; McDermott, Patrick F.; Zhao, Shaohua] US FDA, Ctr Vet Med, 8401 Muirkirk Rd, Laurel, MD 20708 USA. [Sprague, Grisselle; Campbell, Mark; Adeyemo, Oyewole; Browne-Silva, Johnette; Myers, Michael; Thitaram, Sutawee] US Food Safety & Inspect Serv, USDA, 950 Coll Stn Rd, Athens, GA 30601 USA. RP Tyson, GH (reprint author), US FDA, Ctr Vet Med, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM Gregory.Tyson@fda.hhs.gov NR 32 TC 0 Z9 0 U1 6 U2 6 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD NOV PY 2016 VL 79 IS 11 BP 1891 EP 1897 DI 10.4315/0362-028X.JFP-16-195 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EB1FG UT WOS:000387094400010 PM 28221911 ER PT J AU Keys, AL Hitchins, AD Smiley, RD AF Keys, Ashley L. Hitchins, Anthony D. Smiley, R. Derike TI Contribution of Selective Conditions to Microbial Competition in Four Listeria Selective Enrichment Formulations SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Foodborne pathogen; Listeria; Listeria monocytogenes; Microbial competition; Regulatory microbiology; Selective enrichment ID NALIDIXIC-ACID; MONOCYTOGENES; INNOCUA; SAMPLES; GROWTH; MEDIA; BROTH; DIFFERENTIATION; ACRIFLAVINE; BACTERIA AB Microbial competition during selective enrichment negatively affects Listeria monocytogenes populations and may hinder the subsequent detection or recovery of this organism. Competition assays among 10 selected strains of Listeria and Citrobacter braakii were performed in buffered Listeria enrichment broth, 3-(N-morpholino)propanesulfonic acid buffered Listeria enrichment broth, University of Vermont medium modified Listeria enrichment broth, and Fraser broth. The individual contributions of each selective agent in these media were also assessed, as well as the contribution of incubation temperature. Acriflavine hydrochloride and sodium nalidixate were ineffective at preventing the overgrowth of C. braakii; this resulted in substantially lower populations of Listeria than when the competitor was absent. At the higher levels, both of these selective agents were detrimental to Listeria populations. The highest enrichment populations of Listeria were observed when either NaCl or LiCl was present. In the absence of selective agents, the final populations of Listeria following competitive growth with C. braakii were not substantially affected by temperature; however, in the presence of selective agents, the Listeria populations were statistically higher at the higher incubation temperature. There are a limited number of selective agents available for use in Listeria-specific enrichment media, resulting in formulations that are only somewhat selective for this species. The optimization of current formulations may help researchers to improve Listeria recovery, particularly from products with a high microbial load. The understanding of the behavior and interactions between target and nontarget microorganisms in the presence of these available selective agents is a necessary step in the optimization of Listeria selective enrichment formulations. C1 [Keys, Ashley L.; Smiley, R. Derike] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd,Bldg 26, Jefferson, AR 72079 USA. [Hitchins, Anthony D.] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20705 USA. RP Smiley, RD (reprint author), US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd,Bldg 26, Jefferson, AR 72079 USA. EM Ronald.Smiley@fda.hhs.gov FU FDA Office of Regulatory Affairs; Arkansas Regional Laboratory FX The authors thank Kristin Butler and Kristin Schill from the FDA Center for Food Safety and Applied Nutrition for kindly reviewing the manuscript and for their insightful comments. The authors acknowledge the FDA Office of Regulatory Affairs and the Arkansas Regional Laboratory for their support of the study. This study is the opinion of the authors and not that of the FDA. References to commercial technologies or brands do not imply endorsement nor does omission of similar technologies or brands imply criticism by the FDA. NR 22 TC 0 Z9 0 U1 4 U2 4 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD NOV PY 2016 VL 79 IS 11 BP 1904 EP 1910 DI 10.4315/0362-028X.JFP-16-216 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EB1FG UT WOS:000387094400012 PM 28221922 ER PT J AU Lindemann, S Kmet, M Reddy, R Uhlig, S AF Lindemann, Samantha Kmet, Matthew Reddy, Ravinder Uhlig, Steffen TI Matrix-Specific Method Validation of an Automated Most-Probable-Number System for Use in Measuring Bacteriological Quality of Grade "A" Milk Products SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Method validation; Microbiology; Milk; Most probable number ID AEROBIC COUNT PLATES; ESCHERICHIA-COLI; PASTEURIZED MILK; WATER SAMPLES; FOOD SAFETY; ENUMERATION; COLIFORMS; PETRIFILM; BACTERIA; MICROORGANISMS AB The U.S. Food and Drug Administration (FDA) oversees a long-standing cooperative federal and state milk sanitation program that uses the grade "A" Pasteurized Milk Ordinance standards to maintain the safety of grade "A" milk sold in the United States. The Pasteurized Milk Ordinance requires that grade "A" milk samples be tested using validated total aerobic bacterial and coliform count methods. The objective of this project was to conduct an interlaboratory method validation study to compare performance of a film plate method with an automated most-probable-number method for total aerobic bacterial and coliform counts, using statistical approaches from international data standards. The matrix-specific validation study was administered concurrently with the FDA's annual milk proficiency test to compare method performance in five milk types. Eighteen analysts from nine laboratories analyzed test portions from 12 samples in triplicate. Statistics, including mean bias and matrix standard deviation, were calculated. Sample-specific bias of the alternative method for total aerobic count suggests that there are no large deviations within the population of samples considered. Based on analysis of 648 data points, mean bias of the alternative method across milk samples for total aerobic count was 0.013 log CFU/ml and the confidence interval for mean deviation was 0.066 to 0.009 log CFU/ml. These results indicate that the mean difference between the selected methods is small and not statistically significant. Matrix standard deviation was 0.077 log CFU/ml, showing that there is a low risk for large sample-specific bias based on milk matrix. Mean bias of the alternative method was 0.160 log CFU/ml for coliform count data. The 95% confidence interval was 0.210 to 0.100 log CFU/ml, indicating that mean deviation is significantly different from zero. The standard deviation of the sample-specific bias for coliform data was 0.033 log CFU/ml, indicating no significant effect of milk type. C1 [Lindemann, Samantha; Reddy, Ravinder] US FDA, Div Food Proc Sci & Technol, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. [Kmet, Matthew] Illinois Inst Technol Moffett Campus, Inst Food Safety & Hlth, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. [Uhlig, Steffen] QuoData GmbH, Prellerstr 14, D-01309 Dresden, Germany. RP Lindemann, S (reprint author), US FDA, Div Food Proc Sci & Technol, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM samantha.lindemann@fda.hhs.gov NR 38 TC 0 Z9 0 U1 2 U2 2 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD NOV PY 2016 VL 79 IS 11 BP 1911 EP 1918 DI 10.4315/0362-028X.JFP-16-141 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EB1FG UT WOS:000387094400013 PM 28221923 ER PT J AU Kim, YJ Whan, CJ Kim, HS Kim, KY Yim, JH Cho, SH Seo, KH AF Kim, Young-Ji Whan, Chon-Jung Kim, Hong-Seok Kim, Kwang-Yeop Yim, Jin-Hyeok Cho, Seung-Hak Seo, Kun-Ho TI Improvement of Karmali Agar by Supplementation with Tazobactam for Detecting Campylobacter in Raw Poultry SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Campylobacter; Chicken carcass rinse; Detection; Karmali agar; Tazobactam ID CEFOPERAZONE-DEOXYCHOLATE AGAR; CHICKEN CARCASS RINSE; C. COLI; POTASSIUM CLAVULANATE; BOLTON BROTH; POLYMYXIN-B; BLOOD-FREE; JEJUNI; SPP.; IDENTIFICATION AB In this study, Karmali agar was modified by adding tazobactam (T-Karmali agar) to suppress the growth of extended-spectrum beta-lactamase (ESBL) producing Escherichia coli, which frequently contaminates raw poultry meat. By inoculating 30 Campylobacter spp. strains and 25 ESBL-producing E. coli strains onto Karmali agar and T-Karmali agar containing various concentrations of the antibacterial agent, we determined the optimum concentration of tazobactam to be 4 mg/liter. The Campylobacter spp. isolation rate on T-Karmali agar (13.3%) was higher than that on Karmali agar (8.3%), although the difference was not significant (P > 0.05). However, T-Karmali agar showed a significantly greater selectivity than Karmali agar, as evaluated by comparing the numbers of contaminated agar plates (20.8 versus 82.5%; P < 0.05) and the growth indexes (1.36 versus 2.83) of competing flora. The predominant competing flora on Karmali and T-Karmali agar were identified as ESBL-producing E. coli. Thus, T-Karmali agar might be effective for determining the real prevalence of Campylobacter in raw poultry and, especially, contamination with ESBL-producing E. coli. C1 [Kim, Young-Ji; Whan, Chon-Jung; Kim, Hong-Seok; Kim, Kwang-Yeop; Yim, Jin-Hyeok; Seo, Kun-Ho] Konkuk Univ, Coll Vet Med, Ctr One Hlth, Seoul 143701, South Korea. [Cho, Seung-Hak] Korea Natl Inst Hlth, Ctr Infect Dis, Div Enter Dis, Cheongju 363951, South Korea. [Whan, Chon-Jung] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Seo, KH (reprint author), Konkuk Univ, Coll Vet Med, Ctr One Hlth, Seoul 143701, South Korea. EM bracstu3@konkuk.ac.kr FU National Research Foundation of Korea - Korean government (MSIP) [2015R1A2A2A05001288]; Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries (IPET) through Agriculture, Food and Rural Affairs Research Center Support Program; Ministry of Agriculture, Food and Rural Affairs (MAFRA) [716002-7] FX This work was supported by a National Research Foundation of Korea grant (2015R1A2A2A05001288) funded by the Korean government (MSIP), and by the Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries (IPET) through the Agriculture, Food and Rural Affairs Research Center Support Program, funded by the Ministry of Agriculture, Food and Rural Affairs (MAFRA) (716002-7). NR 19 TC 0 Z9 0 U1 2 U2 2 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD NOV PY 2016 VL 79 IS 11 BP 1982 EP 1985 DI 10.4315/0362-028X.JFP-16-105 PG 4 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EB1FG UT WOS:000387094400023 PM 28221899 ER PT J AU Fleischman, GJ AF Fleischman, Gregory J. TI Nonuniformity of Temperatures in Microwave Steam Heating of Lobster Tail SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Cooking; Food Code; Lobster tail; Microwave; Steam AB The biennial Conference for Food Protection provides a formal process for all interested parties to influence food safety guidance. At a recent conference, an issue was raised culminating in a formal request to the U.S. Food and Drug Administration to change its Food Code recommendation for safe cooking of seafood using microwave energy when steaming was also employed. The request was to treat microwave steam cooked seafood as a conventionally cooked raw animal product rather than a microwave cooked product, for which the safe cooking recommendation is more extensive owing to the complex temperature distributions in microwave heating. The request was motivated by a literature study that revealed a more uniform temperature distribution in microwave steam cooked whole lobster. In that study, single-point temperatures were recorded in various sections of the whole lobster, but only one temperature was recorded in the tail, although the large size of the tail could translate to multiple hot and cold points. The present study was conducted to examine lobster tail specifically, measuring temperatures at multiple points during microwave steam cooking. Large temperature differences, greater than 60 degrees C at times, were found throughout the heating period. To compensate for such differences, the Food Code recommends a more extensive level of cooking when microwave energy, rather than conventional heat sources, is used. Therefore, a change in the Food Code regarding microwave steam heating cannot be recommended. C1 [Fleischman, Gregory J.] US FDA, Inst Food Safety & Hlth, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. RP Fleischman, GJ (reprint author), US FDA, Inst Food Safety & Hlth, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM gregory.fleischman@fda.hhs.gov NR 11 TC 0 Z9 0 U1 2 U2 2 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD NOV PY 2016 VL 79 IS 11 BP 2000 EP 2004 DI 10.4315/0362-028X.JFP-16-099 PG 5 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EB1FG UT WOS:000387094400027 PM 28221915 ER PT J AU Camp, KM Krotoski, D Parisi, MA Gwinn, KA Cohen, BH Cox, CS Enns, GM Falk, MJ Goldstein, AC Gopal-Srivastava, R Gorman, GS Hersh, SP Hirano, M Hoffman, FA Karaa, A MacLeod, EL McFarland, R Mohan, C Mulberg, AE Odenkirchen, JC Parikh, S Rutherford, PJ Suggs-Anderson, SK Tang, WHW Vockley, J Wolfe, LA Yannicelli, S Yeske, PE Coates, PM AF Camp, Kathryn M. Krotoski, Danuta Parisi, Melissa A. Gwinn, Katrina A. Cohen, Bruce H. Cox, Christine S. Enns, Gregory M. Falk, Marni J. Goldstein, Amy C. Gopal-Srivastava, Rashmi Gorman, Grainne S. Hersh, Stephen P. Hirano, Michio Hoffman, Freddie Ann Karaa, Amel MacLeod, Erin L. McFarland, Robert Mohan, Charles Mulberg, Andrew E. Odenkirchen, Joanne C. Parikh, Sumit Rutherford, Patricia J. Suggs-Anderson, Shawne K. Tang, W. H. Wilson Vockley, Jerry Wolfe, Lynne A. Yannicelli, Steven Yeske, Philip E. Coates, Paul M. TI Nutritional interventions in primary mitochondrial disorders: Developing an evidence base SO MOLECULAR GENETICS AND METABOLISM LA English DT Review DE Primary mitochondrial disorders; Mitochondrial disease; Nutritional interventions; Dietary supplements; Medical foods; OXPHOS ID RESPIRATORY-CHAIN DEFECTS; COMPLEX-I-DEFICIENCY; KETOGENIC DIET; METHYLMALONIC ACIDEMIA; CARDIOVASCULAR-DISEASE; PRACTICE PATTERNS; INBORN-ERRORS; C. ELEGANS; CHILDREN; EPILEPSY AB In December 2014, a workshop entitled "Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base" was convened at the NIH with the goals of exploring the use of nutritional interventions in primary mitochondrial disorders (PMD) and identifying knowledge gaps regarding their safety and efficacy; identifying research opportunities; and forging collaborations among researchers, clinicians, patient advocacy groups, and federal partners. Sponsors included the NIH, the Wellcome Trust, and the United Mitochondrial Diseases Foundation. Dietary supplements have historically been used in the management of PMD due to their potential benefits and perceived low risk, even though little evidence exists regarding their effectiveness. PMD are rare and clinically, phenotypically, and genetically heterogeneous. Thus patient recruitment for randomized controlled trials (RCTs) has proven to be challenging. Only a few RCTs examining dietary supplements, singly or in combination with other vitamins and cofactors, are reported in the literature. Regulatory issues pertaining to the use of dietary supplements as treatment modalities further complicate the research and patient access landscape. As a preface to exploring a research agenda, the workshop included presentations and discussions on what PMD are; how nutritional interventions are used in PMD; challenges and barriers to their use; new technologies and approaches to diagnosis and treatment; research opportunities and resources; and perspectives from patient advocacy, industry, and professional organizations. Seven key areas were identified during the workshop. These areas were: 1) defining the disease, 2) clinical trial design, 3) biomarker selection, 4) mechanistic approaches, 5) challenges in using dietary supplements, 6) standards of clinical care, and 7) collaboration issues. Short- and long-term goals within each of these areas were identified. An example of an overarching goal is the enrollment of all individuals with PMD in a natural history study and a patient registry to enhance research capability. The workshop demonstrates an effective model for fostering and enhancing collaborations among NIH and basic research, clinical, patient, pharmaceutical industry, and regulatory stakeholders in the mitochondrial disease community to address research challenges on the use of dietary supplements in PMD. (C) 2016 Elsevier Inc. All rights reserved. C1 [Camp, Kathryn M.; Coates, Paul M.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. [Krotoski, Danuta; Parisi, Melissa A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Gwinn, Katrina A.; Odenkirchen, Joanne C.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Cohen, Bruce H.] Akron Childrens Hosp, Dept Pediat, Akron, OH 44308 USA. [Cox, Christine S.] MitoAction, Boston, MA 02205 USA. [Enns, Gregory M.] Stanford Univ, Div Med Genet, Stanford, CA 94305 USA. [Falk, Marni J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Falk, Marni J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Goldstein, Amy C.] Childrens Hosp Pittsburgh, Div Child Neurol, Pittsburgh, PA 15224 USA. [Gopal-Srivastava, Rashmi] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Gorman, Grainne S.; McFarland, Robert] Newcastle Univ, Wellcome Trust Ctr Mitochondrial Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Hersh, Stephen P.] J Willard & Alice S Marriott Fdn, Bethesda, MD 20817 USA. [Hirano, Michio] Columbia Univ, Med Ctr, New York, NY 10032 USA. [Hoffman, Freddie Ann] HeteroGeneity LLC, Washington, DC 20011 USA. [Karaa, Amel] Massachusetts Gen Hosp, Genet Unit, Boston, MA 02114 USA. [MacLeod, Erin L.] Childrens Natl Hlth Syst, Div Genet & Metab, Washington, DC 20010 USA. [Mohan, Charles; Yeske, Philip E.] United Mitochondrial Dis Fdn, Pittsburgh, PA 15239 USA. [Mulberg, Andrew E.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. [Parikh, Sumit] Cleveland Clin, Neurosci, Cleveland, OH 44195 USA. [Rutherford, Patricia J.] Vitaflo Int Ltd, Liverpool L3 4BQ, Merseyside, England. [Suggs-Anderson, Shawne K.] US FDA, Off Nutr & Food Labeling, College Pk, MD 20740 USA. [Tang, W. H. Wilson] Cleveland Clin, Ctr Clin Genom, Cleveland, OH 44195 USA. [Vockley, Jerry] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15224 USA. [Wolfe, Lynne A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Yannicelli, Steven] Nutricia North Amer, Med & Sci Affairs, Rockville, MD 20850 USA. [Mulberg, Andrew E.] US FDA, Rockville, MD 20857 USA. RP Camp, KM (reprint author), 6100 Execut Blvd, Rockville, MD 20892 USA. EM campkm@od.nih.gov; krotoskd@mail.nih.gov; parisima@mail.nih.gov; gwinnk@ninds.nih.gov; bcohen@chmca.org; outreach@mitoaction.org; genns@stanford.edu; falkm@email.chop.edu; amy.goldstein@chp.edu; rashmi.gopal-srivastava@nih.gov; grainne.gorman@newcastle.ac.uk; hershs@starpower.net; mh29@cumc.columbia.edu; fhoffman@heterogeneity-LLC.com; akaraa@mgh.harvard.edu; emacleod@childrensnational.org; robert.mcfarland@newcastle.ac.uk; chuckm@umdf.org; amulberg@amicusrx.com; jo21x@nih.gov; parikhs@ccf.org; triciarutherford@vitaflo.co.uk; shawne.suggs-anderson@fda.hhs.gov; tangw@ccf.org; gerard.vockley@chp.edu; lynne.wolfe@nih.gov; steven.yannicelli@nutricia.com; philip.yeske@umdf.org; coatesp@od.nih.gov OI Gwinn, Katrina/0000-0002-8277-651X FU Edison; Raptor; Reata Pharmaceutical companies; Stealth Peptides; Raptor Pharmaceuticals; Vitaflo; NIH; Neurovive; Stealth Biopeptides; Muscular Dystrophy Association; Santhera Pharmaceuticals; Edison Pharmaceuticals; BioMarin; Medical Research Council; Wellcome Trust; Ryan Stanford Appeal; Lily Foundation; International Foundation for CDKL5 Research (IFCR); Edison Pharmaceutical company; Reata Pharmaceutical company FX The following authors declared financial relationships: B.H. Cohen receives research funding from Edison, Raptor, and Reata Pharmaceutical companies, research funding from and consults to Stealth Peptides, was a consultant to Transgenomic labs and on the speakers board for Courtagen labs; G.M. Enns was a consultant to Mitobridge and runs clinical trials for Edison and Raptor Pharmaceutical companies; M.J. Falk consults to MitoBridge and the KC Group, receives or received research funding from Raptor Pharmaceuticals, Vitaflo, NIH, Neurovive, and Stealth Biopeptides, and has stock options from Perlstein Labs, Inc., LLC; A.C. Goldstein was a consultant to Stealth Biotherapeutics; M. Hirano has been a consultant to MitoBridge, Raptor, Stealth Biopeptides Pharmaceuticals and has received research funding from NIH, Muscular Dystrophy Association, Santhera Pharmaceuticals and Edison Pharmaceuticals; A. Karaa is on the advisory board of Stealth Biotherapeutics and consults to and is on the advisory board of Genzyme; E.L. MacLeod is on the advisory board for Nutricia North America, receives honoraria from Nutricia North America and Cambrooke Therapeutics, and research funding from BioMarin; R. McFarland receives research funding from the Medical Research Council, the Wellcome Trust, the Ryan Stanford Appeal, and the Lily Foundation; S. Parikh receives research funding from NIH, Edison Pharmaceuticals, and International Foundation for CDKL5 Research (IFCR); P.J. Rutherford is employed by VitaFlo Intl, LTD.; W.H. Wilson Tang receives research funding from NIH; J. Vockley participates in clinical trials sponsored by Edison and Reata Pharmaceutical companies, and Stealth Peptides; S. Yannicelli is employed by and owns stock in Nutricia North America. NR 108 TC 1 Z9 1 U1 6 U2 6 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 NOV PY 2016 VL 119 IS 3 BP 187 EP 206 DI 10.1016/j.ymgme.2016.09.002 PG 20 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EA9TH UT WOS:000386987100001 PM 27665271 ER PT J AU Chan, HT Xiao, YH Weldon, WC Oberste, SM Chumakov, K Daniell, H AF Chan, Hui-Ting Xiao, Yuhong Weldon, William C. Oberste, Steven M. Chumakov, Konstantin Daniell, Henry TI Cold chain and virus-free chloroplast-made booster vaccine to confer immunity against different poliovirus serotypes SO PLANT BIOTECHNOLOGY JOURNAL LA English DT Article DE human infectious diseases; molecular farming; chloroplast transformation; bioencapsulation; oral delivery; mucosal immunity ID TOXIN B-SUBUNIT; ORAL DELIVERY; PLANT-CELLS; TOBACCO CHLOROPLASTS; INHIBITOR FORMATION; TRANSGENIC PLANTS; UNITED-STATES; HEMOPHILIA-B; HEPATITIS-B; EXPRESSION AB The WHO recommends complete withdrawal of oral polio vaccine (OPV) type 2 by April 2016 globally and replacing with at least one dose of inactivated poliovirus vaccine (IPV). However, high-cost, limited supply of IPV, persistent circulating vaccine-derived polioviruses transmission and need for subsequent boosters remain unresolved. To meet this critical need, a novel strategy of a low-cost cold chain-free plant-made viral protein 1 (VP1) subunit oral booster vaccine after single IPV dose is reported. Codon optimization of the VP1 gene enhanced expression by 50-fold in chloroplasts. Oral boosting of VP1 expressed in plant cells with plant-derived adjuvants after single priming with IPV significantly increased VP1-IgG1 and VP1-IgA titres when compared to lower IgG1 or negligible IgA titres with IPV injections. IgA plays a pivotal role in polio eradication because of its transmission through contaminated water or sewer systems. Neutralizing antibody titres (similar to 3.17-10.17 log(2) titre) and seropositivity (70-90%) against all three poliovirus Sabin serotypes were observed with two doses of IPV and plant-cell oral boosters but single dose of IPV resulted in poor neutralization. Lyophilized plant cells expressing VP1 stored at ambient temperature maintained efficacy and preserved antigen folding/assembly indefinitely, thereby eliminating cold chain currently required for all vaccines. Replacement of OPV with this booster vaccine and the next steps in clinical translation of FDA-approved antigens and adjuvants are discussed. C1 [Chan, Hui-Ting; Xiao, Yuhong; Daniell, Henry] Univ Penn, Sch Dent Med, Dept Biochem, Philadelphia, PA 19104 USA. [Weldon, William C.; Oberste, Steven M.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Chumakov, Konstantin] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Daniell, H (reprint author), Univ Penn, Sch Dent Med, Dept Biochem, Philadelphia, PA 19104 USA. EM hdaniell@upenn.edu FU Bill and Melinda Gates Foundation [OPP1031406]; NIH [R01 HL107904, R01 HL109442] FX This study was supported by Bill and Melinda Gates Foundation (OPP1031406), NIH grants R01 HL107904 and R01 HL109442 to Henry Daniell. 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. NR 57 TC 6 Z9 6 U1 16 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1467-7644 EI 1467-7652 J9 PLANT BIOTECHNOL J JI Plant Biotechnol. J. PD NOV PY 2016 VL 14 IS 11 BP 2190 EP 2200 DI 10.1111/pbi.12575 PG 11 WC Biotechnology & Applied Microbiology; Plant Sciences SC Biotechnology & Applied Microbiology; Plant Sciences GA DZ8TB UT WOS:000386143400010 PM 27155248 ER PT J AU Lorenz, SC Monday, SR Hoffmann, M Fischer, M Kase, JA AF Lorenz, Sandra C. Monday, Steven R. Hoffmann, Maria Fischer, Markus Kase, Julie A. TI Plasmids from Shiga Toxin-Producing Escherichia coli Strains with Rare Enterohemolysin Gene (ehxA) Subtypes Reveal Pathogenicity Potential and Display a Novel Evolutionary Path SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID VI-SECRETION-SYSTEM; SERINE-PROTEASE AUTOTRANSPORTERS; HEMOLYTIC-UREMIC SYNDROME; COMPLETE GENOME SEQUENCE; HEAT-STABLE ENTEROTOXIN; ENTEROCYTE EFFACEMENT; EPITHELIAL-CELLS; TSH AUTOTRANSPORTER; VIRULENCE PLASMIDS; TRANSFER REGION AB Most Shiga toxin-producing Escherichia coli (STEC) strains associated with severe disease, such as hemolytic-uremic syndrome (HUS), carry large enterohemolysin-encoding (ehxA) plasmids, e.g., pO157 and pO103, that contribute to STEC clinical manifestations. Six ehxA subtypes (A through F) exist that phylogenetically cluster into eae-positive (B, C, F), a mix of eae-positive (E) and eae-negative (A), and a third, more distantly related, cluster of eae-negative (D) STEC strains. While subtype B, C, and F plasmids share a number of virulence traits that are distinct from those of subtype A, sequence data have not been available for subtype D and E plasmids. Here, we determined and compared the genetic composition of four subtype D and two subtype E plasmids to establish their evolutionary relatedness among ehxA subtypes and define their potential role in pathogenicity. We found that subtype D strains carry one exceptionally large plasmid (> 200 kbp) that carries a variety of virulence genes that are associated with enterotoxigenic and enterohemorrhagic E. coli, which, quite possibly, enables these strains to cause disease despite being food isolates. Our data offer further support for the hypothesis that this subtype D plasmid represents a novel virulence plasmid, sharing very few genetic features with other plasmids; we conclude that these plasmids have evolved from a different evolutionary lineage than the plasmids carrying the other ehxA subtypes. In contrast, the 50-kbp plasmids of subtype E (pO145), although isolated from HUS outbreak strains, carried only few virulence-associated determinants, suggesting that the clinical presentation of subtype E strains is largely a result of chromosomally encoded virulence factors. IMPORTANCE Bacterial plasmids are known to be key agents of change in microbial populations, promoting the dissemination of various traits, such as drug resistance and virulence. This study determined the genetic makeup of virulence plasmids from rare enterohemolysin subtype D and E Shiga toxin-producing E. coli strains. We demonstrated that ehxA subtype D plasmids represent a novel E. coli virulence plasmid, and although subtype D plasmids were derived from nonclinical isolates, they encoded a variety of virulence determinants that are associated with pathogenic E. coli. In contrast, subtype E plasmids, isolated from strains recovered from severely ill patients, carry only a few virulence determinants. The results of this study reemphasize the plasticity and vast diversity among E. coli plasmids. This work demonstrates that, although E. coli strains of certain serogroups may not be frequently associated with disease, they should not be underestimated in protecting human health and food safety. C1 [Lorenz, Sandra C.; Monday, Steven R.; Hoffmann, Maria; Kase, Julie A.] US FDA, Ctr Food Safety & Appl Nutr, Div Microbiol, College Pk, MD 20740 USA. [Lorenz, Sandra C.; Fischer, Markus] Univ Hamburg, Hamburg Sch Food Sci, Inst Food Chem, Hamburg, Germany. RP Kase, JA (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Microbiol, College Pk, MD 20740 USA. EM julie.kase@fda.hhs.gov FU Research Fellowship Program for the Center for Food Safety FX This project was supported by the appointment of S.C.L. 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. This project is further part of the Ph.D. program (S.C.L.) at the University of Hamburg, Germany under the supervision of Markus Fischer. NR 87 TC 0 Z9 0 U1 6 U2 6 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 NOV PY 2016 VL 82 IS 21 BP 6367 EP 6377 DI 10.1128/AEM.01839-16 PG 11 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DZ7UI UT WOS:000386072300008 PM 27542930 ER PT J AU Yang, E Welink, J Cape, S Woolf, E Sydor, J James, C Goykhman, D Arnold, M Addock, N Bauer, R Buonarati, M Ciccimaro, E Dodda, R Evans, C Garofolo, F Hughes, N Islam, R Nehls, C Wilson, A Briscoe, C Bustard, M Coppola, L Croft, S Drexler, D Ferrari, L Fraier, D Jenkins, R Kadavil, J King, L Li, WK Santos, GML Musuku, A Ramanathan, R Saito, Y Savoie, N Summerfield, S Sun, R Tampal, N Vinter, S Wakelin-Smith, J Yue, Q AF Yang, Eric Welink, Jan Cape, Stephanie Woolf, Eric Sydor, Jens James, Christopher Goykhman, Dina Arnold, Mark Addock, Neil Bauer, Ronald Buonarati, Michael Ciccimaro, Eugene Dodda, Raj Evans, Christopher Garofolo, Fabio Hughes, Nicola Islam, Rafiq Nehls, Corey Wilson, Amanda Briscoe, Chad Bustard, Mark Coppola, Laura Croft, Stephanie Drexler, Dieter Ferrari, Luca Fraier, Daniela Jenkins, Rand Kadavil, John King, Lloyd Li, Wenkui Lima Santos, Gustavo Mendes Musuku, Adrien Ramanathan, Ragu Saito, Yoshiro Savoie, Natasha Summerfield, Scott Sun, Rachel Tampal, Nilufer Vinter, Steve Wakelin-Smith, Jason Yue, Qin TI 2016 White Paper on recent issues in bioanalysis: focus on biomarker assay validation (BAV) (Part 1-small molecules, peptides and small molecule biomarkers by LCMS) SO BIOANALYSIS LA English DT Article ID REGULATED BIOANALYSIS; FULL IMMERSION; 2-HYBRID LBA/LCMS; GROUP WORKSHOP; MATRIX; GCC; MS; TECHNOLOGIES; QUANTITATION; CALIBRATION AB The 2016 10th Workshop on Recent Issues in Bioanalysis (10th WRIB) took place in Orlando, Florida with participation of close to 700 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. WRIB was once again a 5-day, weeklong event - A Full Immersion Week of Bioanalysis including Biomarkers and Immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecule analysis involving LCMS, hybrid LBA/LCMS, and LBA approaches, with the focus on biomarkers and immunogenicity. This 2016 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. This white paper is published in 3 parts due to length. This part (Part 1) discusses the recommendations for small molecules, peptides and small molecule biomarkers by LCMS. Part 2 (Hybrid LBA/LCMS and regulatory inputs from major global health authorities) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) will be published in the Bioanalysis journal, issue 23. C1 [Yang, Eric; Evans, Christopher] GlaxoSmithKline, King Of Prussia, PA USA. [Welink, Jan] Dutch MEB, Utrecht, Netherlands. [Cape, Stephanie] Covance, Madison, WI USA. [Woolf, Eric; Goykhman, Dina] Merck Res Labs, West Point, PA USA. [Sydor, Jens; Dodda, Raj] AbbVie Inc, N Chicago, IL USA. [James, Christopher] Amgen Inc, Thousand Oaks, CA USA. [Arnold, Mark] Bristol Myers Squibb, Princeton, NJ USA. [Arnold, Mark] Bioanalyt Solut Integrat LLC, Burlington, NJ USA. [Addock, Neil] LGC, Cambridge, England. [Bauer, Ronald] Austria AGES, Vienna, Austria. [Buonarati, Michael] Intertek, San Diego, CA USA. [Ciccimaro, Eugene] Bristol Myers Squibb, Princeton, NJ USA. [Garofolo, Fabio] Angelini Pharma, Pomezia, RM, Italy. [Hughes, Nicola] Bioanalyt Lab Serv, Toronto, ON, Canada. [Islam, Rafiq] Celerion, Lincoln, NE USA. [Nehls, Corey] PPD, Middleton, WI USA. [Wilson, Amanda] AstraZeneca, Cambridge, England. [Briscoe, Chad] PRA Hlth Sci, Overland Pk, KS USA. [Bustard, Mark] Hlth Canada, Ottawa, ON, Canada. [Coppola, Laura] Apotex, Toronto, ON, Canada. [Croft, Stephanie] WHO, Geneva, Switzerland. [Drexler, Dieter] Bristol Myers Squibb, Wallingford, CT USA. [Ferrari, Luca; Fraier, Daniela] F Hoffmann La Roche, Basel, Switzerland. [Jenkins, Rand] PPD, Richmond, VA USA. [Kadavil, John; Tampal, Nilufer] US FDA, Silver Spring, MD USA. [King, Lloyd] UCB, Slough, Berks, England. [Li, Wenkui] Novartis, E Hanover, NJ USA. [Lima Santos, Gustavo Mendes] Brazil Anvisa, Brasilia, DF, Brazil. [Musuku, Adrien] Pharmascience, Montreal, PQ, Canada. [Ramanathan, Ragu] Pfizer, Groton, CT USA. [Saito, Yoshiro] Japan MHLW NIHS, Tokyo, Japan. [Savoie, Natasha] CFABS, Montreal, PQ, Canada. [Summerfield, Scott] GlaxoSmithKline, Ware, Herts, England. [Sun, Rachel] BASi, W Lafayette, IN USA. [Vinter, Steve; Wakelin-Smith, Jason] UK MHRA, London, England. [Yue, Qin] Novartis, Emeryville, CA USA. RP Garofolo, F (reprint author), Angelini Pharma, Pomezia, RM, Italy. EM f.garofolo@angelini.it FU US FDA; Europe EMA; UK MHRA; Austria AGES; Italy AIFA; Brazil ANVISA; Health Canada; Japan MHWL; WHO FX The authors would like to acknowledge the US FDA, Europe EMA, UK MHRA, Austria AGES, Italy AIFA, Brazil ANVISA, Health Canada, Japan MHWL and WHO for supporting this workshop. S Richards (Sanofi), L Amaravadi (Sanofi/Genzyme), R Pillutla (Bristol-Myers Squibb), H Birnboeck (F. Hoffmann-La Roche Ltd.), F Garofolo (Angelini Pharma) 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 Hernandez, K Kalaydjian and J. Conception for the assistance in the organization of the event. Future Science Group as a trusted partner. NR 45 TC 2 Z9 2 U1 6 U2 6 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 PD NOV PY 2016 VL 8 IS 22 BP 2363 EP 2378 DI 10.4155/bio-2016-4992 PG 16 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DZ7LR UT WOS:000386047600011 ER PT J AU Page, SJ Rivera, M Kleiner, DE Zhao, X Auh, S Remmers, EF Heller, T AF Page, Sandra J. Rivera, Maria Kleiner, David E. Zhao, Xiongce Auh, Sungyoung Remmers, Elaine F. Heller, Theo TI Polymorphisms in the NADPH Oxidase Complex are Associated with Hepatitis C-induced Fibrosis and Inflammation SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 24-26, 2016 CL Toronto, CANADA SP Int Genet Epidemiol Soc C1 [Page, Sandra J.; Rivera, Maria; Heller, Theo] NIDDK, Translat Hepatol Unit, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Zhao, Xiongce] FDA, Ctr Vet Med, Rockville, MD USA. [Auh, Sungyoung] NIDDK, Off Clin Director, Liver Dis Branch, Bethesda, MD 20892 USA. [Remmers, Elaine F.] NHGRI, Inflammatory Dis Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2016 VL 40 IS 7 MA 126 BP 655 EP 655 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA DZ7HF UT WOS:000386034800132 ER PT J AU Seidman, JD Krishnan, J AF Seidman, Jeffrey D. Krishnan, Jayashree TI Non-Neoplastic Conditions of the Ovaries in Grossly Normal Adnexa: A Clinicopathologic Study of 403 Completely Embedded Cases SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Ovary; Granuloma; Stromal hyperplasia; Mucinous metaplasia; Endometriosis; BRCA; Brenner tumor; Transitional metaplasia; Fatty metaplasia; Walthard nest ID FALLOPIAN-TUBE; SMOOTH-MUSCLE; CARCINOGENESIS; TUMORS; ORIGIN; SITE AB Most non-neoplastic lesions of the ovaries have not been comprehensively examined in the contemporary literature. We evaluated completely embedded ovaries from 403 unselected, consecutive patients who had grossly normal adnexa. These included prophylactic specimens in high-risk women with BRCA mutations (38 women) and women with a personal history of breast cancer or a family history of breast and/or ovarian cancer (79 women). Transitional cell (Brenner) nests were found in 9.1%; 31% of these lesions were smaller than 1 mm, and 8 were solitary nests. Cortical granulomas were found in 20.5%, fatty metaplasia in 5.3%, mucinous metaplasia of surface epithelial inclusions in 5.5%, and smooth muscle stromal metaplasia in 2%. One or more types of stromal hyperplasia were found in 24.3%. Endometriosis was found in 22% of adnexa. There were no significant differences in the findings in high-risk women compared with non-high-risk except those attributable to age differences between the groups. These findings establish baseline frequencies for non-neoplastic ovarian lesions, and suggest that transitional cell nests are so common that they can be regarded as a normal finding. C1 [Seidman, Jeffrey D.] US FDA, Div Mol Genet & Pathol, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Krishnan, Jayashree] Washington Hosp Ctr, Dept Pathol, Washington, DC 20010 USA. RP Seidman, JD (reprint author), US FDA, Off In Vitro Diagnost & Radiol Hlth, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jdseidman@hotmail.com NR 16 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-1691 EI 1538-7151 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD NOV PY 2016 VL 35 IS 6 BP 544 EP 548 DI 10.1097/PGP.0000000000000281 PG 5 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA EA2IH UT WOS:000386415500007 PM 26974997 ER PT J AU Hakovirta, JR Prezioso, S Hodge, D Pillai, SP Weigel, LM AF Hakovirta, Janetta R. Prezioso, Samantha Hodge, David Pillai, Segaran P. Weigel, Linda M. TI Identification and Analysis of Informative Single Nucleotide Polymorphisms in 16S rRNA Gene Sequences of the Bacillus cereus Group SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article AB Analysis of 16S rRNA genes is important for phylogenetic classification of known and novel bacterial genera and species and for detection of uncultivable bacteria. PCR amplification of 16S rRNA genes with universal primers produces a mixture of amplicons from all rRNA operons in the genome, and the sequence data generally yield a consensus sequence. Here we describe valuable data that are missing from consensus sequences, variable effects on sequence data generated from nonidentical 16S rRNA amplicons, and the appearance of data displayed by different software programs. These effects are illustrated by analysis of 16S rRNA genes from 50 strains of the Bacillus cereus group, i.e., Bacillus anthracis, Bacillus cereus, Bacillus mycoides, and Bacillus thuringiensis. These species have 11 to 14 rRNA operons, and sequence variability occurs among the multiple 16S rRNA genes. A single nucleotide polymorphism (SNP) previously reported to be specific to B. anthracis was detected in some B. cereus strains. However, a different SNP, at position 1139, was identified as being specific to B. anthracis, which is a biothreat agent with high mortality rates. Compared with visual analysis of the electropherograms, basecaller software frequently missed gene sequence variations or could not identify variant bases due to overlapping basecalls. Accurate detection of 16S rRNA gene sequences that include intragenomic variations can improve discrimination among closely related species, improve the utility of 16S rRNA databases, and facilitate rapid bacterial identification by targeted DNA sequence analysis or by whole-genome sequencing performed by clinical or reference laboratories. C1 [Hakovirta, Janetta R.; Prezioso, Samantha; Weigel, Linda M.] Ctr Dis Control & Prevent, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Hodge, David] US Dept Homeland Secur, Sci & Technol Directorate, Washington, DC USA. [Pillai, Segaran P.] US FDA, Off Lab Sci & Safety, Silver Spring, MD USA. [Prezioso, Samantha] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. RP Weigel, LM (reprint author), Ctr Dis Control & Prevent, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. EM lweigel@cdc.gov FU Department of Homeland Security USA [HSHQDC-09-X-00240] FX This work was funded by Department of Homeland Security USA (HSHQDC-09-X-00240). NR 33 TC 0 Z9 0 U1 6 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD NOV PY 2016 VL 54 IS 11 BP 2749 EP 2756 DI 10.1128/JCM.01267-16 PG 8 WC Microbiology SC Microbiology GA DZ8ID UT WOS:000386113200019 PM 27582514 ER PT J AU Mulugeta, Y Barrett, JS Nelson, R Eshete, AT Mushtaq, A Yao, L Glasgow, N Mulberg, AE Gonzalez, D Green, D Florian, J Krudys, K Seo, S Kim, I Chilukuri, D Burckart, GJ AF Mulugeta, Yeruk Barrett, Jeffrey S. Nelson, Robert Eshete, Abel Tilahun Mushtaq, Alvina Yao, Lynne Glasgow, Nicole Mulberg, Andrew E. Gonzalez, Daniel Green, Dionna Florian, Jeffry Krudys, Kevin Seo, Shirley Kim, Insook Chilukuri, Dakshina Burckart, Gilbert J. TI Exposure Matching for Extrapolation of Efficacy in Pediatric Drug Development SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Review DE pediatrics; drug development; dosing; exposure matching; extrapolation ID PHARMACOKINETICS; DISPOSITION; ONTOGENY AB During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully extrapolated. This is a systematic review of approaches used for matching adult systemic exposures as the basis for dose selection in pediatric trials submitted to the US Food and Drug Administration (FDA) between 1998 and 2012. The trial design of pediatric pharmacokinetic (PK) studies and the pediatric and adult systemic exposure data were obtained from FDA publicly available databases containing reviews of pediatric trials. Exposure-matching approaches that were used as the basis for pediatric dose selection were reviewed. The PK data from the adult and pediatric populations were used to quantify exposure agreement between the 2 patient populations. The main measures were the pediatric PK studies' trial design elements and drug systemic exposures (adult and pediatric). There were 31 products (86 trials) with full or partial extrapolation of efficacy with an available PK assessment. Pediatric exposures had a range of mean C-max and AUC ratios (pediatric/adult) of 0.63 to 4.19 and 0.36 to 3.60, respectively. Seven of the 86 trials (8.1%) had a predefined acceptance boundary used to match adult exposures. The key PK parameter was consistently predefined for antiviral and anti-infective products. Approaches to match exposure in children and adults varied across products. A consistent approach for systemic exposure matching and evaluating pediatric PK studies is needed to guide future pediatric trials. C1 [Mulugeta, Yeruk; Green, Dionna; Florian, Jeffry; Krudys, Kevin; Seo, Shirley; Kim, Insook; Chilukuri, Dakshina; Burckart, Gilbert J.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Barrett, Jeffrey S.] Childrens Hosp Philadelphia, Div Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA. [Nelson, Robert] US FDA, Off Pediat Therapeut, Off Commissioner, Silver Spring, MD USA. [Eshete, Abel Tilahun] US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Mushtaq, Alvina] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Yao, Lynne] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Glasgow, Nicole] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. [Mulberg, Andrew E.] US FDA, Div Gastroenterol & Inborn Errors Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Gonzalez, Daniel] Univ N Carolina, Div Pharmacotherapy & Expt Therapeut, UNC Eshelman Sch Pharm, Chapel Hill, NC USA. RP Burckart, GJ (reprint author), US FDA, White Oak Bldg 51, Silver Spring, MD 20903 USA. EM gilbert.burckart@fda.hhs.gov FU NICHD [K23HD083465]; Thrasher Research Fund FX Dr. Gonzalez is funded by K23HD083465 from the NICHD and by the nonprofit Thrasher Research Fund (www.thrasherresearch.org). NR 20 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD NOV PY 2016 VL 56 IS 11 BP 1326 EP 1334 DI 10.1002/jcph.744 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DZ7XY UT WOS:000386083200002 PM 27040726 ER PT J AU Nascimento, FS Wei-Pridgeon, Y Arrowood, MJ Moss, D da Silva, AJ Talundzic, E Qvarnstrom, Y AF Nascimento, Fernanda S. Wei-Pridgeon, Yuping Arrowood, Michael J. Moss, Delynn da Silva, Alexandre J. Talundzic, Eldin Qvarnstrom, Yvonne TI Evaluation of library preparation methods for Illumina next generation sequencing of small amounts of DNA from foodborne parasites SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Article DE Next generation sequencing; Illumina; MiSeq; Library preparation; Angiostrongylus cantonensis; Cyclospora cayetanensis ID ANGIOSTRONGYLUS-CANTONENSIS; CYCLOSPORA-CAYETANENSIS; CRYPTOSPORIDIUM-PARVUM; GENOME; CONSTRUCTION; OOCYSTS; BIAS AB Illumina library preparation methods for ultra-low input amounts were compared using genomic DNA from two foodborne parasites (Angiostrongylus cantonensis and Cyclospora cayetanensis) as examples. The Ovation Ultralow method resulted in libraries with the highest concentration and produced quality sequencing data, even when the input DNA was in the picogram range. Published by Elsevier B.V. C1 [Nascimento, Fernanda S.; Wei-Pridgeon, Yuping; da Silva, Alexandre J.; Qvarnstrom, Yvonne] Ctr Dis Control & Prevent, Parasit Dis Branch, Div Parasit Dis & Malaria, Ctr Global Hlth, 1600 Clifton Rd NE, Atlanta, GA 30329 USA. [Wei-Pridgeon, Yuping] IHRC Inc, 2 Ravinia Dr,Suite 1750, Atlanta, GA 30346 USA. [Arrowood, Michael J.; Moss, Delynn] Ctr Dis Control & Prevent, Waterborne Dis Prevent Branch, Div Foodborne Waterborne & Environm Dis, Natl Ctr Enter & Zoonot Infect Dis, 1600 Clifton Rd NE, Atlanta, GA 30329 USA. [Talundzic, Eldin] Ctr Dis Control & Prevent, Malaria Branch, Div Parasit Dis & Malaria, Ctr Global Hlth, 1600 Clifton Rd NE, Atlanta, GA 30329 USA. [Talundzic, Eldin] Atlanta Res & Educ Fdn, 1670 Clairmont Rd,Suite 5A104, Decatur, GA 30033 USA. [da Silva, Alexandre J.] US FDA, Off Appl Res & Safety Assessment, Ctr Food Safety & Nutr, Laurel, MD 20708 USA. RP Qvarnstrom, Y (reprint author), Ctr Dis Control & Prevent, Parasit Dis Branch, Div Parasit Dis & Malaria, Ctr Global Hlth, 1600 Clifton Rd NE, Atlanta, GA 30329 USA. EM yeb7@cdc.gov; saaspservices@gmail.com; mja0@cdc.gov; dmm3@cdc.gov; Alexandre.DaSilva@fda.hhs.gov; wrj5@cdc.gov; bvp2@cdc.gov NR 23 TC 1 Z9 1 U1 16 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7012 EI 1872-8359 J9 J MICROBIOL METH JI J. Microbiol. Methods PD NOV PY 2016 VL 130 BP 23 EP 26 DI 10.1016/j.mimet.2016.08.020 PG 4 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA EA2EZ UT WOS:000386406900004 PM 27553132 ER PT J AU Sargeant, JM O'Connor, AM Dohoo, IR Erb, HN Cevallos, M Egger, M Ersboll, AK Martin, SW Nielsen, LR Pearl, DL Pfeiffer, DU Sanchez, J Torrence, ME Vigre, H Waldner, C Ward, MP AF Sargeant, J. M. O'Connor, A. M. Dohoo, I. R. Erb, H. N. Cevallos, M. Egger, M. Ersboll, A. K. Martin, S. W. Nielsen, L. R. Pearl, D. L. Pfeiffer, D. U. Sanchez, J. Torrence, M. E. Vigre, H. Waldner, C. Ward, M. P. TI Methods and processes of developing the Strengthening the Reporting of Observational Studies in Epidemiology - Veterinary (STROBE-Vet) statement SO JOURNAL OF SWINE HEALTH AND PRODUCTION LA English DT Article DE reporting guidelines; veterinary; observational study; animal ID MOLECULAR EPIDEMIOLOGY; QUALITY; EXTENSION; TRIALS; GUIDELINES; DISEASES; TOOLS; BIAS AB Background: Reporting of observational studies in veterinary research presents challenges that often are not addressed in published reporting guidelines. Objective: To develop an extension of the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement that addresses unique reporting requirements for observational studies in veterinary medicine related to health, production, welfare, and food safety. Design: Consensus meeting of experts. Setting: Mississauga, Canada. Participants: Seventeen experts from North America, Europe, and Australia. Methods: Experts, completed a pre-meeting survey about whether items in the STROBE statement should be added to or modified to address unique issues related to observational studies in animal species with health, production, welfare, or food safety outcomes. During the meeting, each STROBE item was discussed to determine whether or not re-wording was recommended and whether additions were warranted. Anonymous voting was used to determine consensus. Results: Six items required no modifications or additions. Modifications or additions were made to the STROBE items 1 (title and abstract), 3 (objectives), 5 (setting), 6 (participants), 7 (variables), 8 (data sources-measurement), 9 (bias), 10 (study size), 12 (statistical methods), 13 (participants), 14 (descriptive data), 15 (outcome data), 16 (main results), 17 (other analyses), 19 (limitations), and 22 (funding). Conclusion: The methods and processes used were similar to those used for other extensions of the STROBE statement. The use of this STROBE statement extension should improve reporting of observational studies in veterinary research by recognizing unique features of observational studies involving food-producing and companion animals, products of animal origin, aquaculture, and wildlife. C1 [Sargeant, J. M.] Univ Guelph, Ontario Vet Coll, Ctr Publ Hlth & Zoonoses, Guelph, ON N1G 2W1, Canada. [Sargeant, J. M.; Martin, S. W.; Pearl, D. L.] Univ Guelph, Ontario Vet Coll, Dept Populat Med, Guelph, ON N1G 2W1, Canada. [O'Connor, A. M.] Iowa State Univ, Vet Diagnost & Prod Anim Med, Ames, IA USA. [Dohoo, I. R.; Sanchez, J.] Univ Prince Edward Isl, Atlantic Vet Coll, Dept Hlth Management, Charlottetown, PE, Canada. [Erb, H. N.] Cornell Univ, Coll Vet Med, Dept Populat Med & Diagnost Sci, Ithaca, NY 14853 USA. [Ersboll, A. K.] Univ Southern Denmark, Natl Inst Publ Hlth, Copenhagen, Denmark. [Nielsen, L. R.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Large Anim Sci, Copenhagen, Denmark. [Pfeiffer, D. U.] Univ London, Royal Vet Coll, Dept Prod & Populat Hlth, London, England. [Torrence, M. E.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Vigre, H.] Tech Univ Denmark, Natl Food Inst, Unit Genom Epidemiol, Lyngby, Denmark. [Waldner, C.] Univ Saskatchewan, Western Coll Vet Med, Dept Clin Sci, Saskatoon, SK, Canada. [Ward, M. P.] Univ Sydney, Fac Vet Sci, Sydney, NSW 2006, Australia. [Cevallos, M.] Univ Bern, Inst Social & Prevent Med, Bern, Switzerland. [Egger, M.] Univ Bern, ISPM, Epidemiol & Publ Hlth, Bern, Switzerland. RP Sargeant, JM (reprint author), Univ Guelph, Ontario Vet Coll, Ctr Publ Hlth & Zoonoses, Guelph, ON N1G 2W1, Canada.; Sargeant, JM (reprint author), Univ Guelph, Ontario Vet Coll, Dept Populat Med, Guelph, ON N1G 2W1, Canada. EM sargeanj@uoguelph.ca RI Pfeiffer, Dirk/C-5002-2009 OI Pfeiffer, Dirk/0000-0001-7000-0530 NR 23 TC 0 Z9 0 U1 5 U2 5 PU AMER ASSOC SWINE VETERINARIANS PI PERRY PA 902 1ST AVE, PERRY, IA 50220-1703 USA SN 1537-209X J9 J SWINE HEALTH PROD JI J. Swine. Health Prod. PD NOV-DEC PY 2016 VL 24 IS 6 BP 315 EP 325 PG 11 WC Veterinary Sciences SC Veterinary Sciences GA EA2HL UT WOS:000386413300009 ER PT J AU Ilyushina, NA Sheikh, F Bovin, NV Donnelly, RP AF Ilyushina, N. A. Sheikh, F. Bovin, N. V. Donnelly, R. P. TI GENERATION AND CHARACTERIZATION OF INTERFERON-LAMBDA 1-RESISTANT H1N1 INFLUENZA A VIRUSES SO CYTOKINE LA English DT Meeting Abstract CT 4th Annual Meeting of The International-Cytokine-and-Interferon-Society (ICIS) CY OCT 16-19, 2016 CL San Francisco, CA SP Int Cytokine & Interferon Soc C1 [Ilyushina, N. A.; Sheikh, F.; Donnelly, R. P.] FDA CDER, Silver Spring, MD USA. [Bovin, N. V.] Shemyakin Bioorgan Chem, Moscow, Russia. NR 0 TC 0 Z9 0 U1 3 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD NOV PY 2016 VL 87 MA P144 BP 122 EP 122 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA DY7PH UT WOS:000385321100177 ER PT J AU Stanifer, M Pervolaraki, K Rippert, A Renn, L Odendall, C Theisen, T Rabin, R Kagan, J Boulant, S AF Stanifer, M. Pervolaraki, K. Rippert, A. Renn, L. Odendall, C. Theisen, T. Rabin, R. Kagan, J. Boulant, S. TI CELLULAR POLARITY AND TYPE III INTERFERONS ARE KEY REGULATORS OF ANTIVIRAL INNATE IMMUNITY IN HUMAN INTESTINAL EPITHELIAL CELLS SO CYTOKINE LA English DT Meeting Abstract CT 4th Annual Meeting of The International-Cytokine-and-Interferon-Society (ICIS) CY OCT 16-19, 2016 CL San Francisco, CA SP Int Cytokine & Interferon Soc C1 [Stanifer, M.; Pervolaraki, K.; Rippert, A.; Boulant, S.] Heidelberg Univ, Heidelberg, Germany. [Renn, L.; Theisen, T.; Rabin, R.] USFDA, Silver Spring, MD USA. [Odendall, C.; Kagan, J.] Boston Childrens Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD NOV PY 2016 VL 87 MA P192 BP 142 EP 142 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA DY7PH UT WOS:000385321100225 ER PT J AU Onabajo, OO Rao, N Obajemu, AA Kari, DA Sheikh, F Donnelly, R Shabman, RS Prokunina-Olsson, L AF Onabajo, O. O. Rao, N. Obajemu, A. A. Kari, D. A. Sheikh, F. Donnelly, R. Shabman, R. S. Prokunina-Olsson, L. TI IFNL4 INDUCES A FASTER BUT MORE TRANSIENT ANTIVIRAL RESPONSE COMPARED TO OTHER TYPE III INTERFERONS SO CYTOKINE LA English DT Meeting Abstract CT 4th Annual Meeting of The International-Cytokine-and-Interferon-Society (ICIS) CY OCT 16-19, 2016 CL San Francisco, CA SP Int Cytokine & Interferon Soc C1 [Onabajo, O. O.; Rao, N.; Obajemu, A. A.; Prokunina-Olsson, L.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kari, D. A.; Shabman, R. S.] J Craig Venter Inst, Virol Grp, Rockville, MD USA. [Sheikh, F.; Donnelly, R.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD NOV PY 2016 VL 87 MA P193 BP 143 EP 143 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA DY7PH UT WOS:000385321100226 ER PT J AU Huang, YZ Li, W Liu, K Xiong, CR Cao, P Tao, JP AF Huang, Yuzheng Li, Wei Liu, Kun Xiong, Chunrong Cao, Peng Tao, Jianping TI New detection method in experimental mice for schistosomiasis: ClinProTool and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry SO PARASITOLOGY RESEARCH LA English DT Article DE Schistosomiasis; ClinProTool; MALDI-TOF mass spectrometry; Sentinel mice; Early surveillance ID ENDEMIC AREAS; YANGTZE-RIVER; TOF MS; CHINA; SURVEILLANCE; JAPONICA; WATER; CANCER; SERUM; RISK AB Oncomelania hupensis snails along the Yangtze River and the low positive rate and infectiosity of human and livestock schistosomiasis still pose a threat to public health in China. Adult blood flukes were recognized as Schistosoma japonicum, which are found in the portal system of the sentinel mice bred in the laboratory for 35 days after contact with the water. However, 35 days was too long from the field test to dissection, and the dissection in the laboratory was also time-consuming and labor-intensive. Serum peptides in mice at different times after infection were measured by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. ClinProTool was used to establish the proteomic detection pattern (PDP), based on the differentially expressed peptide between the infection and healthy control groups. Under experimental conditions, characteristic PDP were detected in 5 % (3/60), 35 % (21/60), 75 % (45/60), 87.93 % (51/58), and 98.15 % (53/54) of infected mice from weeks 1 to 5 post-infection, whereas ELISA and dissection examination for adult blood flukes missed the first 2 weeks. At 35 days post-infection, the infectiosity assay showed 40 % (4/10), 50 % (5/10), and 80 % (8/10) positivity with the PDP test in mice infected with 4, 6, and 10 cercariae, respectively, as well as 100 % (10/10) positivity in mice infected with 14, 18, and 22 cercariae. Five stored sera of positive sentinel mice with parasite detection were verified correctly in the PDP test. The results confirm that PDP can be used as a rapid and early detection method for S. japonicum infection in experimental mice, which are expected to apply in early surveillance for schistosomiasis. C1 [Huang, Yuzheng; Cao, Peng] Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing 210028, Jiangsu, Peoples R China. [Huang, Yuzheng; Cao, Peng] Jiangsu Prov Acad Tradit Chinese Med, 100 Hongshan Rd, Nanjing 210028, Jiangsu, Peoples R China. [Li, Wei; Xiong, Chunrong] Minist Hlth, Jiangsu Inst Parasit Dis, Key Lab Technol Parasit Dis Prevent & Control, Wuxi 214064, Jiangsu, Peoples R China. [Liu, Kun] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Johns Hopkins Malaria Res Inst, Baltimore, MD 21205 USA. [Liu, Kun] US FDA, Pacific Reg Lab Northwest, 22201 23rd DR SE, Bothell, WA 98021 USA. [Tao, Jianping] Yangzhou Univ, Coll Vet Med, Jiangsu Coinnovat Ctr Prevent & Control Major Ani, 12 Wenhui Rd, Yangzhou 225009, Jiangsu, Peoples R China. RP Cao, P (reprint author), Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing 210028, Jiangsu, Peoples R China.; Cao, P (reprint author), Jiangsu Prov Acad Tradit Chinese Med, 100 Hongshan Rd, Nanjing 210028, Jiangsu, Peoples R China.; Tao, JP (reprint author), Yangzhou Univ, Coll Vet Med, Jiangsu Coinnovat Ctr Prevent & Control Major Ani, 12 Wenhui Rd, Yangzhou 225009, Jiangsu, Peoples R China. EM yzhyz01@163.com; iambigsnail@163.com; kunliuphd@gmail.com; maiya711@163.com; njpcao@126.com; yzjptao@126.com FU Natural Science Foundation of China [31201893]; Special Program of Jiangsu Clinical Medicine [BL2014020]; Jiangsu Province's Key Medical Centre [201108]; Natural Science Foundation of Jiangsu Province [BK2011164]; Jiangsu Health Science Project [X201416, X201110, X201505]; Project of Preventive Medicine Association of Jiangsu Province [Y2015071]; Open Project of Key Laboratory of Jiangsu Preventive Veterinary Medicine [K13045]; project of Jiangsu branch of CACMS [H1604]; Jiangsu Health International Exchange Program; Johns Hopkins University Malaria Research Institute FX This study was supported by the Natural Science Foundation of China (grant no. 31201893), the Special Program of Jiangsu Clinical Medicine (grant no. BL2014020), Jiangsu Province's Key Medical Centre (grant no. 201108), the Natural Science Foundation of Jiangsu Province (grant no. BK2011164), the Jiangsu Health Science Project (grant nos. X201416, X201110, and X201505), the Project of Preventive Medicine Association of Jiangsu Province (grant no. Y2015071), the Open Project of Key Laboratory of Jiangsu Preventive Veterinary Medicine (grant no. K13045), the project of Jiangsu branch of CACMS (grant no. H1604), the Jiangsu Health International Exchange Program to Y Huang, and a pilot grant to K Liu from the Johns Hopkins University Malaria Research Institute. The funders had no role in study design, data collection, management, analysis and interpretation, decision to publish, as well as the preparation, review, or approval of this manuscript. NR 39 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0932-0113 EI 1432-1955 J9 PARASITOL RES JI Parasitol. Res. PD NOV PY 2016 VL 115 IS 11 BP 4173 EP 4181 DI 10.1007/s00436-016-5193-0 PG 9 WC Parasitology SC Parasitology GA DY5LU UT WOS:000385142100011 PM 27469535 ER PT J AU Schnackenberg, LK Pence, L Vijay, V Moland, CL George, N Cao, ZJ Yu, LR Fuscoe, JC Beger, RD Desai, VG AF Schnackenberg, Laura K. Pence, Lisa Vijay, Vikrant Moland, Carrie L. George, Nysia Cao, Zhijun Yu, Li-Rong Fuscoe, James C. Beger, Richard D. Desai, Varsha G. TI Early metabolomics changes in heart and plasma during chronic doxorubicin treatment in B6C3F(1) mice SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE Biomarkers; Cardiotoxicity; Doxorubicin; Metabolomics ID CARDIAC MITOCHONDRIA; NITRIC-OXIDE; THERAPEUTIC IMPLICATIONS; INDUCED CARDIOTOXICITY; BREAST-CANCER; FAILURE; PATHWAY; RATS; CARDIOMYOPATHY; ANTHRACYCLINES AB The present study aimed to identify molecular markers of early stages of cardiotoxicity induced by a potent chemotherapeutic agent, doxorubicin (DOX). Male B6C3F(1) mice were dosed with 3mgkg(-1) DOX or saline via tail vein weekly for 2, 3, 4, 6 or 8weeks (cumulative DOX doses of 6, 9, 12, 18 or 24mgkg(-1), respectively) and euthanized a week after the last dose. Mass spectrometry-based and nuclear magnetic resonance spectrometry-based metabolic profiling were employed to identify initial biomarkers of cardiotoxicity before myocardial injury and cardiac pathology, which were not noted until after the 18 and 24mgkg(-1) cumulative doses, respectively. After a cumulative dose of 6mgkg(-1), 18 amino acids and four biogenic amines (acetylornithine, kynurenine, putrescine and serotonin) were significantly increased in cardiac tissue; 16 amino acids and two biogenic amines (acetylornithine and hydroxyproline) were significantly altered in plasma. In addition, 16 acylcarnitines were significantly increased in plasma and five were significantly decreased in cardiac tissue compared to saline-treated controls. Plasma lactate and succinate, involved in the Krebs cycle, were significantly altered after a cumulative dose of 6mgkg(-1). A few metabolites remained altered at higher cumulative DOX doses, which could partly indicate a transition from injury processes at 2weeks to repair processes with additional injury happening concurrently before myocardial injury at 8weeks. These altered metabolic profiles in mouse heart and plasma during the initial stages of injury progression due to DOX treatment may suggest these metabolites as candidate early biomarkers of cardiotoxicity. Published 2016. This article is a U.S. Government work and is in the public domain in the USA Metabolomics analyses of plasma and heart tissue from male B6C3F(1) mice dosed weekly with 3mgkg(-1) doxorubicin or saline for 2, 3, 4, 6 or 8weeks (cumulative doses of 6, 9, 12, 18 and 24mgkg(-1), respectively) identified potential early stage injury biomarkers of doxorubicin-induced cardiotoxicity. Select metabolites were altered after the 6mgkg(-1) cumulative dose whereas myocardial injury and cardiac pathology were not noted until after the 18 and 24mgkg(-1) cumulative doses, respectively. C1 [Schnackenberg, Laura K.; Pence, Lisa; Vijay, Vikrant; Moland, Carrie L.; Cao, Zhijun; Yu, Li-Rong; Fuscoe, James C.; Beger, Richard D.; Desai, Varsha G.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. [George, Nysia] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Schnackenberg, LK (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM laura.schnackenberg@fda.hhs.gov RI Vijay, Vikrant/E-7651-2010 OI Vijay, Vikrant/0000-0001-8425-1285 NR 43 TC 1 Z9 1 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0260-437X EI 1099-1263 J9 J APPL TOXICOL JI J. Appl. Toxicol. PD NOV PY 2016 VL 36 IS 11 BP 1486 EP 1495 DI 10.1002/jat.3307 PG 10 WC Toxicology SC Toxicology GA DY0WW UT WOS:000384817900012 PM 26934058 ER PT J AU Guo, XQ Li, Y Yan, J Ingle, T Jones, MY Mei, N Boudreau, MD Cunningham, CK Abbas, M Paredes, AM Zhou, T Moore, MM Howard, PC Chen, T AF Guo, Xiaoqing Li, Yan Yan, Jian Ingle, Taylor Jones, Margie Yvonne Mei, Nan Boudreau, Mary D. Cunningham, Candice K. Abbas, Mazhar Paredes, Angel M. Zhou, Tong Moore, Martha M. Howard, Paul C. Chen, Tao TI Size- and coating-dependent cytotoxicity and genotoxicity of silver nanoparticles evaluated using in vitro standard assays SO NANOTOXICOLOGY LA English DT Article DE Ames test; genotoxicity; in vitro micronucleus assay; mouse lymphoma assay; silver nanoparticles ID MOUSE LYMPHOMA-CELLS; THYMIDINE KINASE GENE; ETHYL-N-NITROSOUREA; OXIDATIVE STRESS; CELLULAR UPTAKE; AMES TEST; INTERNATIONAL WORKSHOP; TOXICITY MECHANISM; CHEMICAL MUTAGENS; MUTATION ASSAY AB The physicochemical characteristics of silver nanoparticles (AgNPs) may greatly alter their toxicological potential. To explore the effects of size and coating on the cytotoxicity and genotoxicity of AgNPs, six different types of AgNPs, having three different sizes and two different coatings, were investigated using the Ames test, mouse lymphoma assay (MLA) and in vitro micronucleus assay. The genotoxicities of silver acetate and silver nitrate were evaluated to compare the genotoxicity of nanosilver to that of ionic silver. The Ames test produced inconclusive results for all types of the silver materials due to the high toxicity of silver to the test bacteria and the lack of entry of the nanoparticles into the cells. Treatment of L5718Y cells with AgNPs and ionic silver resulted in concentration-dependent cytotoxicity, mutagenicity in the Tk gene and the induction of micronuclei from exposure to nearly every type of the silver materials. Treatment of TK6 cells with these silver materials also resulted in concentration-dependent cytotoxicity and significantly increased micronucleus frequency. With both the MLA and micronucleus assays, the smaller the AgNPs, the greater the cytotoxicity and genotoxicity. The coatings had less effect on the relative genotoxicity of AgNPs than the particle size. Loss of heterozygosity analysis of the induced Tk mutants indicated that the types of mutations induced by AgNPs were different from those of ionic silver. These results suggest that AgNPs induce cytotoxicity and genotoxicity in a size- and coating-dependent manner. Furthermore, while the MLA and in vitro micronucleus assay (in both types of cells) are useful to quantitatively measure the genotoxic potencies of AgNPs, the Ames test cannot. C1 [Guo, Xiaoqing; Li, Yan; Yan, Jian; Mei, Nan; Abbas, Mazhar; Moore, Martha M.; Chen, Tao] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Ingle, Taylor; Jones, Margie Yvonne; Cunningham, Candice K.; Paredes, Angel M.; Howard, Paul C.] US FDA, Nanotechnol Core Facil, Natl Ctr Toxicol Res, Jefferson, AR USA. [Boudreau, Mary D.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Abbas, Mazhar] Univ Lahore, Inst Mol Biol & Biotechnol, Lahore, Pakistan. [Zhou, Tong] US FDA, Ctr Vet Med, Rockville, MD 20857 USA. RP Chen, T (reprint author), US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM tao.chen@fda.hhs.gov FU Postgraduate Research Program at the NCTR; Collaborative Opportunities for Research Excellence in Science (CORES) program from the U.S. FDA FX This research was partially supported by appointments (YL, TI and MA) to the Postgraduate Research Program at the NCTR administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration (FDA). This project also was partially funded by the Collaborative Opportunities for Research Excellence in Science (CORES) program from the U.S. FDA. The views presented in this paper do not necessarily reflect those of the U.S. FDA. NR 68 TC 1 Z9 1 U1 23 U2 23 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 PD NOV PY 2016 VL 10 IS 9 BP 1373 EP 1384 DI 10.1080/17435390.2016.1214764 PG 12 WC Nanoscience & Nanotechnology; Toxicology SC Science & Technology - Other Topics; Toxicology GA DW1ZH UT WOS:000383442200016 PM 27441588 ER PT J AU Eischeid, AC Stadig, SR Handy, SM Fry, FS Deeds, J AF Eischeid, Anne C. Stadig, Sarah R. Handy, Sara M. Fry, Frederick S. Deeds, Jonathan TI Optimization and evaluation of a method for the generation of DNA barcodes for the identification of crustaceans SO LWT-FOOD SCIENCE AND TECHNOLOGY LA English DT Article DE Seafood Cytochrome oxidase I; COI; PCR; Sequencing; Mitochondrial ID BIOLOGICAL IDENTIFICATIONS; FISH; DECAPODA; PUFFER AB Efficient methods for the species identification of seafood are important for ensuring food safety and detecting fraud. DNA barcoding, a technique based on PCR amplification and capillary sequencing of a short, standardized segment of a gene, is a reliable method for species identification of processed and packaged seafood when the species cannot be determined visually. Here we report the optimization and evaluation of a DNA barcoding method for identifying representative commercial decapod crustacean species, including select shrimp, crab, crayfish, and lobster. Two different segments of the mitochondria(cytochrome c oxidase 1 (COI) gene were evaluated-a 655 base pair fragment beginning near the 5' end, representing the "standard" DNA barcode fragment, and a non-overlapping 475 base pair fragment beginning near the 3' end, representing an alternative DNA barcode marker for shrimp. The standard 5' fragment was successfully amplified and sufficient to identify most crustacean species tested, but amplification of both the 5' and 3' barcodes were often required to efficiently identify shrimp. Published by Elsevier Ltd. C1 [Eischeid, Anne C.; Stadig, Sarah R.; Handy, Sara M.; Fry, Frederick S.; Deeds, Jonathan] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. RP Eischeid, AC (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. EM Anne.Eischeid@fda.hhs.gov FU U.S. Food and Drug Administration FX The authors would like to acknowledge Amy Beaven at the University of Maryland Genomics Core (College Park, MD) for technical assistance with DNA sequencing. We would also like to thank Kenneth Powell and Calvin Walker at the NOAA National Seafood Inspection Laboratory (Pascagoula, MS) and Darryl Felder at the University of Louisiana at Lafayette (Lafayette, LA) for providing several of the crustacean tissue samples used in this study. This work was funded by the U.S. Food and Drug Administration. NR 21 TC 0 Z9 0 U1 38 U2 38 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0023-6438 EI 1096-1127 J9 LWT-FOOD SCI TECHNOL JI LWT-Food Sci. Technol. PD NOV PY 2016 VL 73 BP 357 EP 367 DI 10.1016/j.lwt.2016.06.033 PG 11 WC Food Science & Technology SC Food Science & Technology GA DT2OU UT WOS:000381321100051 ER PT J AU Alymova, IV York, IA Air, GM Cipollo, JF Gulati, S Baranovich, T Kumar, A Zeng, H Gansebom, S McCullers, JA AF Alymova, Irina V. York, Ian A. Air, Gillian M. Cipollo, John F. Gulati, Shelly Baranovich, Tatiana Kumar, Amrita Zeng, Hui Gansebom, Shane McCullers, Jonathan A. TI Glycosylation changes in the globular head of H3N2 influenza hemagglutinin modulate receptor binding without affecting virus virulence Irina SO SCIENTIFIC REPORTS LA English DT Article ID A VIRUS; UNITED-STATES; CELLS; EVOLUTION; SITES; HOST; SPECIFICITY; GLYCANS; ENTRY; GENE AB Since the emergence of human H3N2 influenza A viruses in the pandemic of 1968, these viruses have become established as strains of moderate severity. A decline in virulence has been accompanied by glycan accumulation on the hemagglutinin globular head, and hemagglutinin receptor binding has changed from recognition of a broad spectrum of glycan receptors to a narrower spectrum. The relationship between increased glycosylation, binding changes, and reduction in H3N2 virulence is not clear. We evaluated the effect of hemagglutinin glycosylation on receptor binding and virulence of engineered H3N2 viruses. We demonstrate that low-binding virus is as virulent as higher binding counterparts, suggesting that H3N2 infection does not require either recognition of a wide variety of, or high avidity binding to, receptors. Among the few glycans recognized with low-binding virus, there were two structures that were bound by the vast majority of H3N2 viruses isolated between 1968 and 2012. We suggest that these two structures support physiologically relevant binding of H3N2 hemagglutinin and that this physiologically relevant binding has not changed since the 1968 pandemic. Therefore binding changes did not contribute to reduced severity of seasonal H3N2 viruses. This work will help direct the search for factors enhancing influenza virulence. C1 [Alymova, Irina V.; York, Ian A.; Kumar, Amrita; Zeng, Hui; Gansebom, Shane] Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. [Air, Gillian M.; Gulati, Shelly] Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73190 USA. [Cipollo, John F.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Baranovich, Tatiana; McCullers, Jonathan A.] St Jude Childrens Res Hosp, Dept Infect Dis, 332 N Lauderdale St, Memphis, TN 38105 USA. [Kumar, Amrita] Battelle Mem Inst, Atlanta, GA USA. [McCullers, Jonathan A.] Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Memphis, TN 38163 USA. RP Alymova, IV (reprint author), Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. EM xeq3@cdc.gov FU American Lebanese Syrian Associated Charities (ALSAC); NIH [A1050933]; NIGMS [GM98791]; National Center for Functional Glycomics - Glycan Array Synthesis Core (The Scripps Research Institute, La Jolla, CA) [P41GM103694] FX This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) and NIH (A1050933). The authors would like to acknowledge The Consortium for Functional Glycomics funded by the NIGMS GM98791 and the National Center for Functional Glycomics funded by P41GM103694 for services provided by the Glycan Array Synthesis Core (The Scripps Research Institute, La Jolla, CA) that produced the mammalian glycan microarray and Drs. Dave Smith and Jamie Heimburg-Molinaro of the Protein-Glycan Interaction Core (Emory University School of Medicine, Atlanta, GA), who assisted with analysis of samples on the array. We also thank Dr. John Nicholls of University of Hong Kong for providing information on the structures of glycans of human RT and helpful discussion, and Drs. James Stevens and Terry Tumpey of Influenza Division of National Center for Immunization & Respiratory Diseases, Centers for Disease Control & Prevention for helpful discussions. 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 or funding agency. NR 50 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 31 PY 2016 VL 6 AR 36216 DI 10.1038/srep36216 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA3MA UT WOS:000386505500001 PM 27796371 ER PT J AU Schotland, P Bojunga, N Zien, A Trame, MN Lesko, LJ AF Schotland, Peter Bojunga, Niels Zien, Alexander Trame, Mirjam Nadine Lesko, Lawrence J. TI Improving drug safety with a systems pharmacology approach SO EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE Stevens-Johnson Syndrome; Drug safety; Systems pharmacology; Informatics ID TOXIC EPIDERMAL NECROLYSIS; STEVENS-JOHNSON-SYNDROME; SIGNAL-DETECTION; MARKETED DRUGS; EVENTS; HYPERSENSITIVITY; PREDICTION; RISK; ALGORITHMS; DATABASES AB Systems pharmacology is used to mechanistically analyze drug-adverse drug reaction (ADRs) pairs and is a promising solution to the complex problem of understanding mechanisms of toxicity. In this research, we have explored the feasibility of retrospectively mapping population-level adverse events from the FDA Adverse Event Reporting System (FAERS) to chemical and biological databases to identify drug safety signals and the underlying molecular mechanisms. We used an analytic platform - Molecular Analysis of Side Effects (MASETm). For this purpose, we selected the adverse event of severe and potentially fatal cutaneous reactions (SCARs) that are associated with acetaminophen (APAP). SCARs encompass the continuum between Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). We found a statistically significant association between APAP and TEN, the most severe form of SCARs. We also explored the influence of APAP on other classes of drugs commonly associated with SCARs. We found that APAP significantly reduced the risk of SCARs commonly associated with carbamazepine (CBZ). We used molecular docking simulations to propose a mechanism for APAP's reduction in CBZ-induced SCARs which is competitive inhibition of the binding of CBZ to HLA-B*15:02. We conclude that systems pharmacology can complement established surveillance methodologies by providing a means to undertake an independent investigation and review of the mechanisms by which drugs cause adverse events. (C) 2016 Published by Elsevier B.V. C1 [Schotland, Peter; Trame, Mirjam Nadine; Lesko, Lawrence J.] Univ Florida, Ctr Pharmacometr & Syst Pharmacol, 6550 Sanger Rd, Orlando, FL 32816 USA. [Bojunga, Niels; Zien, Alexander] Mol Hlth, Heidelberg, Germany. [Schotland, Peter] US FDA, Off Clin Pharmacol, Off Translat Sci, Rockville, MD 20857 USA. RP Lesko, LJ (reprint author), Univ Florida, Ctr Pharmacometr & Syst Pharmacol, 6550 Sanger Rd, Orlando, FL 32816 USA. EM llesko@cop.ufl.edu NR 33 TC 2 Z9 2 U1 13 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0928-0987 EI 1879-0720 J9 EUR J PHARM SCI JI Eur. J. Pharm. Sci. PD OCT 30 PY 2016 VL 94 SI SI BP 84 EP 92 DI 10.1016/j.ejps.2016.06.009 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EA6LD UT WOS:000386739800009 PM 27287422 ER PT J AU Kawamura, Y Miura, H Matsumoto, Y Uchida, H Kudo, K Hata, T Ito, Y Kimura, H Yoshikawa, T AF Kawamura, Yoshiki Miura, Hiroki Matsumoto, Yuji Uchida, Hidetoshi Kudo, Kazuko Hata, Tadayoshi Ito, Yoshinori Kimura, Hiroshi Yoshikawa, Tetsushi TI A case of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis with severe cardiac complications SO BMC PEDIATRICS LA English DT Article DE Epstein-Barr virus; Hemophagocytic lymphohistiocytosis; Coronary artery lesion; Myocarditis; Rituximab ID KAWASAKI-DISEASE; INFECTION; CHILDREN AB Background: Hemophagocytic lymphohistiocytosis (HLH) is a life threatening hematological disorder associated with severe systemic inflammation caused by an uncontrolled and ineffective immune response resulting in cytokine storm. Epstein-Barr virus (EBV) is the most common infectious agent in patients with the viral-associated HLH. Limited numbers of cases with cardiac complication have been demonstrated in other viral-associated HLH patients. Herein, we report a pediatric case of severe EBV-associated HLH with cardiac complications. Case presentation: A previously healthy 4-year-old Japanese female was admitted to a local hospital with a four day history of fever. Despite antibiotic treatment, her fever persisted to day 7 of the illness. Finally, the diagnosis of HLH was confirmed by fulfilling diagnostic criteria for HLH and pathological analysis of bone marrow aspiration. Real-time PCR detected a high copy number of EBV DNA in the peripheral blood mononuclear cells (PBMCs) at the time of hospital admission. During treatment according to HLH-2004 protocol, sudden cardiopulmonary arrest (CPA) occurred on day 30 of the illness and immediate resuscitation was successful. Acute myocarditis was considered the cause of the CPA. Although the treatment regimen was completed on day 88 of the illness, a remarkably high copy number of EBV DNA was still detected in her PBMCs. Based on our flow cytometric in situ hybridization analysis that revealed EBV infection of only B lymphocytes, we decided to administer rituximab to control the abnormal EBV infection. Afterwards the amount of EBV DNA decreased gradually to undetectable level on day 130 of the illness. Unfortunately, a coronary artery aneurysm was discovered at the left main coronary artery on day 180 of the illness. Finally, the patient was discharged from the hospital on day 203 of the illness without sequelae except for a coronary aneurysm. Conclusions: In this case report, EBV-HLH was complicated with cardiac symptoms such as myocarditis and coronary artery aneurysm. Although remarkably high copy number of EBV DNA was detected in PBMCs after completion of the HLH-2004 protocol, rituximab treatment resulted in a dramatic decrease of EBV DNA to undetectable levels. Rituximab treatment might have been beneficial for the patient's survival. C1 [Kawamura, Yoshiki; Miura, Hiroki; Matsumoto, Yuji; Uchida, Hidetoshi; Kudo, Kazuko; Yoshikawa, Tetsushi] Fujita Hlth Univ, Sch Med, Dept Pediat, 1-98 Dengakugakubo,Kutsukake Cho, Toyoake, Aichi 4701192, Japan. [Hata, Tadayoshi] Fujita Hlth Univ, Sch Hlth Sci, Fac Med Technol, 1-98 Dengakugakubo,Kutsukake Cho, Toyoake, Aichi 4701192, Japan. [Ito, Yoshinori] Nagoya Univ, Grad Sch Med, Dept Pediat, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan. [Kimura, Hiroshi] Nagoya Univ, Grad Sch Med, Dept Virol, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan. [Kawamura, Yoshiki] US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Kawamura, Y (reprint author), Fujita Hlth Univ, Sch Med, Dept Pediat, 1-98 Dengakugakubo,Kutsukake Cho, Toyoake, Aichi 4701192, Japan.; Kawamura, Y (reprint author), US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM kyoshiki3@hotmail.com RI Kimura, Hiroshi/I-2246-2012; OI Kawamura, Yoshiki/0000-0003-3942-7098 NR 15 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2431 J9 BMC PEDIATR JI BMC Pediatr. PD OCT 28 PY 2016 VL 16 AR 172 DI 10.1186/s12887-016-0718-3 PG 5 WC Pediatrics SC Pediatrics GA EB3PX UT WOS:000387279000001 PM 27793118 ER PT J AU Holmes, DR Califf, R Farb, A Abel, D Mack, M Jensen, TS Zuckerman, B Leon, M Shuren, J AF Holmes, David R., Jr. Califf, Robert Farb, Andrew Abel, Dorothy Mack, Michael Jensen, Tamara Syrek Zuckerman, Bram Leon, Martin Shuren, Jeff TI Overcoming the Challenges of Conducting Early Feasibility Studies of Medical Devices in the United States SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE equipment design; new device development strategies; research design; research ethics committees; United States Food and Drug Administration AB Initial clinical studies of new medical technologies involve a complex balance of research participant benefits versus risks and costs of uncertainty when novel concepts are tested. The Food and Drug Administration Center for Devices and Radiological Health has recently introduced the Early Feasibility Study (EFS) Program for facilitating the conduct of these studies under the Investigational Device Exemption regulations. However, a systematic approach is needed to successfully implement this program while affording appropriate preservation of the rights and interests of patients. For this to succeed, a holistic reform of the clinical studies ecosystem for performing early-stage clinical research in the United States is necessary. The authors review the current landscape of the U.S. EFS and make recommendations for developing an efficient EFS process to meet the goal of improving access to early-stage, potentially beneficial medical devices in the United States. (C) 2016 by the American College of Cardiology Foundation. All rights reserved. C1 [Holmes, David R., Jr.] Mayo Clin, Dept Cardiol, Rochester, MN USA. [Califf, Robert; Farb, Andrew; Abel, Dorothy; Zuckerman, Bram; Shuren, Jeff] Food & Drug Adm, Silver Spring, MD USA. [Mack, Michael] Baylor Scott & White Hlth, Plano, TX USA. [Jensen, Tamara Syrek] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. [Leon, Martin] Columbia Univ, Med Ctr, Ctr Intervent Vasc Therapy, New York, NY USA. RP Holmes, DR (reprint author), Mayo Clin, Dept Cardiovasc Dis & Internal Med, 200 First St SW, Rochester, MN 55905 USA. EM holmes.david@mayo.edu FU Patient-Centered Outcomes Research Institute; National Institutes of Health; U.S. Food and Drug Administration; Amylin; Eli Lilly and Company; Bristol-Myers Squibb; Janssen Research and Development; Merck; Novartis; Amgen; Bayer Healthcare; BMEB Services; Genentech; GlaxoSmithKline; Heart.org/Daiichi-Sankyo; Kowa; Les Laboratoires Servier; Medscape/Heart.org; Regado; Roche FX Dr. Califf currently holds the post of Commissioner of Food and Drugs, U.S. Food and Drug Administration; prior to his appointment to the FDA, Dr. Califf received research grant funding from the Patient-Centered Outcomes Research Institute, the National Institutes of Health, the U.S. Food and Drug Administration, Amylin, and Eli Lilly and Company; research grants and consulting payments from Bristol-Myers Squibb, Janssen Research and Development, Merck, and Novartis; received consulting payments from Amgen, Bayer Healthcare, BMEB Services, Genentech, GlaxoSmithKline, Heart.org/Daiichi-Sankyo, Kowa, Les Laboratoires Servier, Medscape/Heart.org, Regado, and Roche; and held equity in N30 Pharma and Portola. Dr. Mack has served as an uncompensated coprimary investigator of the Partner 3 and COAPT trials. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Robert Harrington, MD, served as Guest Editor for this paper. NR 12 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 25 PY 2016 VL 68 IS 17 BP 1908 EP 1915 DI 10.1016/j.jacc.2016.07.769 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA7QN UT WOS:000386826700012 PM 27765194 ER PT J AU Tang, S Patel, A Krause, PR AF Tang, Shuang Patel, Amita Krause, Philip R. TI Herpes simplex virus ICP27 regulates alternative pre-mRNA polyadenylation and splicing in a sequence-dependent manner SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE polyadenylation; alternative splicing; DNA viruses; host-pathogen interactions; RNA 3 ' polyadenylation signals ID HOST SHUTOFF RNASE; C-TERMINAL DOMAIN; GC-RICH SEQUENCES; NF-KAPPA-B; POLYMERASE-II; PROTEIN ICP27; TYPE-1 ICP27; U1 SNRNP; RGG BOX; GENE-EXPRESSION AB The herpes simplex virus (HSV) infected cell culture polypeptide 27 (ICP27) protein is essential for virus infection of cells. Recent studies suggested that ICP27 inhibits splicing in a gene-specific manner via an unknown mechanism. Here, RNA-sequencing revealed that ICP27 not only inhibits splicing of certain introns in < 1% of cellular genes, but also can promote use of alternative 5' splice sites. In addition, ICP27 induced expression of pre-mRNAs prematurely cleaved and polyadenylated from cryptic polyadenylation signals (PAS) located in intron 1 or 2 of similar to 1% of cellular genes. These previously undescribed prematurely cleaved and polyadenylated pre-mRNAs, some of which contain novel ORFs, were typically intronless, < 2 Kb in length, expressed early during viral infection, and efficiently exported to cytoplasm. Sequence analysis revealed that ICP27-targeted genes are GC-rich (as are HSV genes), contain cytosine-rich sequences near the 5' splice site, and have suboptimal splice sites in the impacted intron, suggesting that a common mechanism is shared between ICP27-mediated alternative polyadenylation and splicing. Optimization of splice site sequences or mutation of nearby cytosines eliminated ICP27-mediated splicing inhibition, and introduction of C-rich sequences to an ICP27-insensitive splicing reporter conferred this phenotype, supporting the inference that specific gene sequences confer susceptibility to ICP27. Although HSV is the first virus and ICP27 is the first viral protein shown to activate cryptic PASs in introns, we suspect that other viruses and cellular genes also encode this function. C1 [Tang, Shuang; Patel, Amita; Krause, Philip R.] US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Tang, S; Krause, PR (reprint author), US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM shuang.tang@fda.hhs.gov; philip.krause@fda.hhs.gov NR 51 TC 0 Z9 0 U1 3 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 25 PY 2016 VL 113 IS 43 BP 12256 EP 12261 DI 10.1073/pnas.1609695113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ7ZI UT WOS:000386087100075 PM 27791013 ER PT J AU Rossignol, P Pitt, B Thompson, A Zannad, F AF Rossignol, Patrick Pitt, Bertram Thompson, Aliza Zannad, Faiez TI Roadmap for cardiovascular prevention trials in chronic kidney disease SO LANCET LA English DT Editorial Material ID HEMODIALYSIS-PATIENTS; CLINICAL-TRIALS; EVENTS; EPIDEMIOLOGY; RISK C1 [Rossignol, Patrick; Zannad, Faiez] Univ Lorraine, CHU Nancy, Ctr Invest Clin Plurithemat, Inserm 1433, F-54500 Vandoeuvre Les Nancy, France. [Rossignol, Patrick; Zannad, Faiez] F CRIN INI CRCT Cardiovasc & Renal Clin Trialists, Nancy, France. [Rossignol, Patrick] Assoc Lorraine Traitement Insuffisance Renale, Nancy, France. [Pitt, Bertram] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Thompson, Aliza] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Rossignol, P (reprint author), Univ Lorraine, CHU Nancy, Ctr Invest Clin Plurithemat, Inserm 1433, F-54500 Vandoeuvre Les Nancy, France.; Rossignol, P (reprint author), F CRIN INI CRCT Cardiovasc & Renal Clin Trialists, Nancy, France.; Rossignol, P (reprint author), Assoc Lorraine Traitement Insuffisance Renale, Nancy, France. EM p.rossignol@chru-nancy.fr NR 12 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD OCT 22 PY 2016 VL 388 IS 10055 BP 1964 EP 1966 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DZ6EQ UT WOS:000385954800008 PM 27789005 ER PT J AU Budnitz, DS Lovegrove, MC Sapiano, MRP Mathew, J Kegler, SR Geller, AI Hampp, C AF Budnitz, Daniel S. Lovegrove, Maribeth C. Sapiano, Mathew R. P. Mathew, Justin Kegler, Scott R. Geller, Andrew I. Hampp, Christian TI Pediatric Emergency Department Visits for Buprenorphine/Naloxone Ingestion - United States, 2008-2015 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID YOUNG-CHILDREN; EXPOSURES C1 [Budnitz, Daniel S.; Lovegrove, Maribeth C.; Sapiano, Mathew R. P.; Geller, Andrew I.] CDC, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Mathew, Justin; Hampp, Christian] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Kegler, Scott R.] CDC, Div Res Anal & Practice Integrat, Natl Ctr Injury Prevent & Control, Atlanta, GA 30333 USA. RP Budnitz, DS (reprint author), CDC, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. EM dbudnitz@cdc.gov NR 6 TC 0 Z9 0 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 OCT 21 PY 2016 VL 65 IS 41 BP 1148 EP 1149 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EA5EX UT WOS:000386643300006 PM 27764078 ER PT J AU Zineh, I Christl, LA AF Zineh, Issam Christl, Leah A. TI The Biosimilarity Concept: Toward an Integrated Framework for Evidence Assessment SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Zineh, Issam; Christl, Leah A.] US FDA, Silver Spring, MD 20993 USA. [Zineh, Issam] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, White Oak Bldg 51,Room 3177, Silver Spring, MD 20993 USA. [Christl, Leah A.] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, White Oak Bldg 22,Room 6426,New Hampshire Ave, Silver Spring, MD 20993 USA. RP Zineh, I (reprint author), US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, White Oak Bldg 51,Room 3177, Silver Spring, MD 20993 USA. EM issam.zineh@fda.hhs.gov NR 5 TC 0 Z9 0 U1 1 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 18 PY 2016 VL 165 IS 8 BP 595 EP + DI 10.7326/M16-1559 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DZ6BM UT WOS:000385946600023 PM 27478907 ER PT J AU Hsiao, PY Kalin, JH Sun, IH Amin, MN Lo, YC Chiang, MJ Giddens, J Sysa-Shah, P Gabrielson, K Wang, LX Powell, JD Cole, PA AF Hsiao, Po-Yuan Kalin, Jay H. Sun, Im-Hong Amin, Mohammed N. Lo, Ying-Chun Chiang, Meng-Jung Giddens, John Sysa-Shah, Polina Gabrielson, Kathleen Wang, Lai-Xi Powell, Jonathan D. Cole, Philip A. TI An Fc-Small Molecule Conjugate for Targeted Inhibition of the Adenosine2A Receptor SO CHEMBIOCHEM LA English DT Article DE adenosine receptors; drug design; Fc domain; inhibitors; small molecules ID T-CELLS; ANTAGONIST; PROTEIN; PHARMACOLOGY; BLOCKADE; FUSION; POTENT; RATS AB The adenosine A(2A) receptor (A(2A)R) is expressed in immune cells, as well as brain and heart tissue, and has been intensively studied as a therapeutic target for multiple disease indications. Inhibitors of the A(2A)R have the potential for stimulating immune response, which could be valuable for cancer immune surveillance and mounting a response against pathogens. One well-established potent and selective small molecule A(2A)R antagonist, ZM-241385 (ZM), has a short pharmacokinetic half-life and the potential for systemic toxicity due to A(2A)R effects in the brain and the heart. In this study, we designed an analogue of ZM and tethered it to the Fc domain of the immunoglobulin IgG3 by using expressed protein ligation. The resulting protein-small molecule conjugate, Fc-ZM, retained high affinity for two Fc receptors: FcRI and the neonatal Fc receptor, FcRn. In addition, Fc-ZM was a potent A(2A)R antagonist, as measured by a cell-based cAMP assay. Cell-based assays also revealed that Fc-ZM could stimulate interferon production in splenocytes in a fashion that was dependent on the presence of A(2A)R. We found that Fc-ZM, compared with the small molecule ZM, was a superior A(2A)R antagonist in mice, consistent with the possibility that Fc attachment can improve pharmacokinetic and/or pharmacodynamic properties of the small molecule. C1 [Hsiao, Po-Yuan; Kalin, Jay H.; Chiang, Meng-Jung; Cole, Philip A.] Johns Hopkins Univ, Dept Pharmacol & Mol Sci, Sch Med, 302 Wood Basic Sci Bldg,725 N Wolfe St, Baltimore, MD 21205 USA. [Sun, Im-Hong; Lo, Ying-Chun; Powell, Jonathan D.] Johns Hopkins Sch Med, Sidney Kimmel Comprehens Canc Res Ctr, Dept Oncol, Harry & Jeanette Weinberg Bldg,Ste 1100, Baltimore, MD 21205 USA. [Amin, Mohammed N.; Giddens, John; Wang, Lai-Xi] Univ Maryland, Dept Chem & Biochem, 8051 Regents Dr, College Pk, MD 20742 USA. [Amin, Mohammed N.] Univ Maryland, Ctr Vaccine Dev, Sch Med, 685 West Baltimore St, Baltimore, MD 21201 USA. [Lo, Ying-Chun] Yale Sch Med, Dept Pathol, 310 Cedar St,LH 108, New Haven, CT 06520 USA. [Chiang, Meng-Jung] US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Sysa-Shah, Polina] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, 601 N Caroline St, Baltimore, MD 21287 USA. [Gabrielson, Kathleen] Johns Hopkins Sch Med, Dept Mol & Comparat Pathobiol, 733 North Broadway,Miller Res Bldg,Room 807, Baltimore, MD 21205 USA. RP Cole, PA (reprint author), Johns Hopkins Univ, Dept Pharmacol & Mol Sci, Sch Med, 302 Wood Basic Sci Bldg,725 N Wolfe St, Baltimore, MD 21205 USA. EM pcole1@jhmi.edu FU National Institutes of Health; FAMRI Foundation FX This work was supported by the National Institutes of Health and the FAMRI Foundation. We thank Dr. Yana Li (the Eukaryotic Tissue Culture Facility at Johns Hopkins) for her help and support with insect cell culture. We thank Safiat Ayinde (Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine) for her help with peptide synthesis and protein expression. We also thank Dr. Robert Leone, Chirag Patel, Min-Hee Oh and Jiayu Wen (Department of Oncology, Johns Hopkins School of Medicine) for their guidance and training in immunology research and animal care. NR 25 TC 0 Z9 0 U1 3 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1439-4227 EI 1439-7633 J9 CHEMBIOCHEM JI ChemBioChem PD OCT 17 PY 2016 VL 17 IS 20 BP 1951 EP 1960 DI 10.1002/cbic.201600337 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA EA6XK UT WOS:000386772300011 PM 27432157 ER PT J AU Petrie, JG Ohmit, SE Truscon, R Johnson, E Braun, TM Levine, MZ Eichelberger, MC Monto, AS AF Petrie, Joshua G. Ohmit, Suzanne E. Truscon, Rachel Johnson, Emileigh Braun, Thomas M. Levine, Min Z. Eichelberger, Maryna C. Monto, Arnold S. TI Modest Waning of Influenza Vaccine Efficacy and Antibody Titers During the 2007-2008 Influenza Season SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE influenza; influenza vaccine; efficacy; waning; hemagglutinin; neuraminidase; antibody persistence; longevity of antibody; serologic assays; immune correlates ID IMMUNIZATION PRACTICES ACIP; TEST-NEGATIVE DESIGN; ADVISORY-COMMITTEE; VIRUS NEURAMINIDASE; UNITED-STATES; PROTECTION; CHILDREN; RECOMMENDATIONS; PREVENTION; CORRELATE AB Background. Antibody titers decrease with time following influenza vaccination, raising concerns that vaccine efficacy might wane. However, the relationship between time since vaccination and protection is unclear. Methods. Time-varying vaccine efficacy (VE[t]) was examined in healthy adult participants (age range, 18-49 years) in a placebo-controlled trial of inactivated influenza vaccine (IIV) and live-attenuated influenza vaccine (LAIV) performed during the 2007-2008 influenza season. Symptomatic respiratory illnesses were laboratory-confirmed as influenza. VE(t) was estimated by fitting a smooth function based on residuals from Cox proportional hazards models. Subjects had blood samples collected immediately prior to vaccination, 30 days after vaccination, and at the end of the influenza season for testing by hemagglutination inhibition and neuraminidase inhibition assays. Results. Overall efficacy was 70% (95% confidence interval [CI], 50%-82%) for IIV and 38% (95% CI, 5%-59%) for LAIV. Statistically significant waning was detected for IIV (P = .03) but not LAIV (P = .37); however, IIV remained significantly efficacious until data became sparse at the end of the season. Similarly, antibody titers against influenza virus hemagglutinin and neuraminidase significantly decreased over the season among IIV recipients. Conclusions. Both vaccines were efficacious but LAIV less so. IIV efficacy decreased slowly over time, but the vaccine remained significantly efficacious for the majority of the season. C1 [Petrie, Joshua G.; Ohmit, Suzanne E.; Truscon, Rachel; Johnson, Emileigh; Monto, Arnold S.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Braun, Thomas M.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Levine, Min Z.] Ctr Dis Control & Prevent, Influenza Div, Atlanta, GA USA. [Eichelberger, Maryna C.] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Silver Spring, MD USA. RP Petrie, JG (reprint author), Univ Michigan, Sch Publ Hlth, 1415 Washington Hts, Ann Arbor, MI 48109 USA. EM jpetrie@umich.edu FU Sanofi Pasteur; Center for Biologics Evaluation and Research (PanFlu funds) FX This work was supported by Sanofi Pasteur (unrestricted grant) and the Center for Biologics Evaluation and Research (PanFlu funds). NR 36 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 IS 8 BP 1142 EP 1149 DI 10.1093/infdis/jiw105 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8UL UT WOS:000386147200006 PM 27095420 ER PT J AU Walker, AJ Wedam, S Amiri-Kordestani, L Bloomquist, E Tang, SG Sridhara, R Chen, W Palmby, TR Zirkelbach, JF Fu, WT Liu, Q Tilley, A Kim, G Kluetz, PG McKee, AE Pazdur, R AF Walker, Amanda J. Wedam, Suparna Amiri-Kordestani, Laleh Bloomquist, Erik Tang, Shengui Sridhara, Rajeshwari Chen, Wei Palmby, Todd R. Zirkelbach, Jeanne Fourie Fu, Wentao Liu, Qi Tilley, Amy Kim, Geoffrey Kluetz, Paul G. McKee, Amy E. Pazdur, Richard TI FDA Approval of Palbociclib in Combination with Fulvestrant for the Treatment of Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID PATIENT-REPORTED OUTCOMES AB On February 19, 2016, the FDA approved palbociclib (Ibrance, Pfizer) for use in combination with fulvestrant (Faslodex, Astra-Zeneca) for the treatment of women with hormone receptor (HR)positive, HER2-negative advanced or metastatic breast cancer (MBC) with disease progression following endocrine therapy. The approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 521 pre- and postmenopausal women with HR-positive, HER2-negative advanced or MBC. Patients were randomized (2: 1) to receive palbociclib plus fulvestrant (n = 347) or placebo plus fulvestrant (n = 174). The primary endpoint was investigator-assessed progression-free survival (PFS). A statistically significant and clinically meaningful improvement in PFS (9.5 months vs. 4.6 months) was observed in patients receiving palbociclib plus fulvestrant [HR 0.46; 95% confidence interval (CI), 0.36-0.59; P < 0.0001]. Safety data confirmed the known adverse reaction profile of palbociclib. The most common adverse reactions (> 20%) in patients treated with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, and thrombocytopenia. This approval was granted in the context of a prior accelerated approval for palbociclib in combination with letrozole in patients with HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy. (C) 2016 AACR. C1 [Walker, Amanda J.; Wedam, Suparna; Amiri-Kordestani, Laleh; Bloomquist, Erik; Tang, Shengui; Sridhara, Rajeshwari; Chen, Wei; Palmby, Todd R.; Zirkelbach, Jeanne Fourie; Fu, Wentao; Liu, Qi; Tilley, Amy; Kim, Geoffrey; Kluetz, Paul G.; McKee, Amy E.; Pazdur, Richard] US FDA, Ctr Drug Evaluat & Res, White Oak, MD USA. RP Walker, AJ; Wedam, S (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 22,Room 2103, Silver Spring, MD 20993 USA. EM amanda.walker@fda.hhs.gov; suparna.wedam@fda.hhs.gov NR 14 TC 3 Z9 3 U1 9 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2016 VL 22 IS 20 BP 4968 EP 4972 DI 10.1158/1078-0432.CCR-16-0493 PG 5 WC Oncology SC Oncology GA DZ1WP UT WOS:000385632700003 PM 27407089 ER PT J AU Payabyab, EC Balasubramaniam, S Edgerly, M Velarde, M Merino, MJ Venkatesan, AM Leuva, H Litman, T Bates, SE Fojo, T AF Payabyab, Eden C. Balasubramaniam, Sanjeeve Edgerly, Maureen Velarde, Margarita Merino, Maria J. Venkatesan, Aradhana M. Leuva, Harshraj Litman, Thomas Bates, Susan E. Fojo, Tito TI Adrenocortical Cancer: A Molecularly Complex Disease Where Surgery Matters SO CLINICAL CANCER RESEARCH LA English DT Article ID ADRENAL-CORTICAL CARCINOMA; LONG-TERM SURVIVAL; LAPAROSCOPIC ADRENALECTOMY; GENOMIC CHARACTERIZATION; ONCOLOGIC OUTCOMES; ADJUVANT MITOTANE; PHASE-II; STAGE-I; THERAPY; TUMORS AB The development of new therapies has lagged behind for rare cancers without defined therapeutic targets. Adrenocortical cancer is no exception. Mitotane, an older agent considered "adrenolytic," is used both to control symptoms in advanced disease and as adjuvant therapy after surgical resection. Molecular characterization of adrenocortical cancer has deepened our understanding of this genetically complex disease while identifying subgroups whose importance remains to be determined. Unfortunately, such studies have yet to demonstrate a therapeutic target for drug development, and to date, no targeted therapy has achieved meaningful outcomes. Consequently, first-line therapy for metastatic disease remains a combination regimen of etoposide, doxorubicin, and cisplatinum established in a randomized clinical trial. In addition to evaluating recent studies in adrenocortical cancer, we raise one critical clinical issue-the risk of peritoneal dissemination following laparoscopic resection of adrenocortical cancer. In a retrospective case series of 267 patients referred to the NCI for the treatment of recurrent or advanced adrenocortical cancer, we found extensive peritoneal dissemination in 25 of the 45 patients (55.6%) who had undergone laparoscopic resection, compared with only 7 of the 222 patients (3%) who had undergone an open resection (P < 0.0001). Although this has been debated in the literature, our data argue for an end to laparoscopic resection of adrenocortical cancers to avoid peritoneal dissemination, a complication of laparoscopy that is uniformly fatal. (C) 2016 AACR. C1 [Payabyab, Eden C.] NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Payabyab, Eden C.] NCI, Thorac & GI Oncol Branch, NIH, Bethesda, MD 20892 USA. [Balasubramaniam, Sanjeeve] USDA, Div Oncol Prod 1, OHOP, CDER, Silver Spring, MD USA. [Edgerly, Maureen; Velarde, Margarita] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Venkatesan, Aradhana M.] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Div Diagnost Imaging, Houston, TX 77030 USA. [Leuva, Harshraj; Bates, Susan E.; Fojo, Tito] James J Peters Vet Adm Med Ctr, Bronx, NY USA. [Litman, Thomas] Univ Copenhagen, Med Biostat, Copenhagen, Denmark. [Bates, Susan E.; Fojo, Tito] Columbia Univ, Dept Med, Med Ctr, Div Med Oncol, New York, NY 10032 USA. RP Fojo, T (reprint author), Columbia Univ, Dept Med, Med Ctr, Div Med Oncol, New York, NY 10032 USA.; Fojo, T (reprint author), James J Peters VA Med Ctr, Bronx, NY 10468 USA. EM atf2116@cumc.columbia.edu OI Balasubramaniam, Sanjeeve/0000-0002-0643-2117 NR 57 TC 2 Z9 2 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2016 VL 22 IS 20 BP 4989 EP 5000 DI 10.1158/1078-0432.CCR-16-1570 PG 12 WC Oncology SC Oncology GA DZ1WP UT WOS:000385632700007 PM 27742785 ER PT J AU Bhatia, H Read, E Agarabi, C Brorson, K Lute, S Yoon, S AF Bhatia, Hemlata Read, Erik Agarabi, Cyrus Brorson, Kurt Lute, Scott Yoon, Seongkyu TI A design space exploration for control of Critical Quality Attributes of mAb SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Design space; Critical quality attribute; Critical process parameter ID MONOCLONAL-ANTIBODY; PHARMACEUTICAL QUALITY; GLYCOSYLATION; STABILITY; FC AB A unique "design space (DSp) exploration strategy," defined as a function of four key scenarios, was successfully integrated and validated to enhance the DSp building exercise, by increasing the accuracy of analyses and interpretation of processed data. The four key scenarios, defining the strategy, were based on cumulative analyses of individual models developed for the Critical Quality Attributes (23 Glycan Profiles) considered for the study. The analyses of the CQA estimates and model performances were interpreted as (1) Inside Specification/Significant Model (2) Inside Specification/Non-significant Model (3) Outside Specification/Significant Model (4) Outside Specification/Non-significant Model. Each scenario was defined and illustrated through individual models of CQA aligning the description. The R-2, Q(2), Model Validity and Model Reproducibility estimates of G2, G2FaGbGN, GO and G2FaG2, respectively, signified the four scenarios stated above. Through further optimizations, including the estimation of Edge of Failure and Set Point Analysis, wider and accurate DSps were created for each scenario, establishing critical functional relationship between Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs). A DSp provides the optimal region for systematic evaluation, mechanistic understanding and refining of a QbD approach. DSp exploration strategy will aid the critical process of consistently and reproducibly achieving predefined quality of a product throughout its lifecycle. (C) 2016 Elsevier B.V. All rights reserved. C1 [Bhatia, Hemlata; Yoon, Seongkyu] Univ Massachusetts Lowell, Dept Chem Engn, 1 Univ Ave, Lowell, MA 01854 USA. [Read, Erik; Agarabi, Cyrus; Brorson, Kurt; Lute, Scott] US FDA, Div 2, Off Biotechnol Prod, Off Pharmaceut Qual,CDER, Silver Spring, MD USA. RP Yoon, S (reprint author), Univ Massachusetts Lowell, Dept Chem Engn, 1 Univ Ave, Lowell, MA 01854 USA. EM seongkyu_yoon@uml.edu OI yoon, seongkyu/0000-0002-5330-8784 FU Biopharmaceutical Product and Quality Consortium, University of Massachusetts Lowell; FDA/CDER Critical Path Project [1500]; Pfizer FX The authors gratefully acknowledge scholarship support for this research from the Biopharmaceutical Product and Quality Consortium, University of Massachusetts Lowell. The bioreactor runs were funded by FDA/CDER Critical Path Project 1500. The authors thank Pfizer for the partial funding of this research. This project was also 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 30 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD OCT 15 PY 2016 VL 512 IS 1 BP 242 EP 252 DI 10.1016/j.ijpharm.2016.08.046 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DY1OG UT WOS:000384863700026 PM 27575657 ER PT J AU Hao, HH Fien, N Han, J Foley, SL Iqbal, Z Cheng, GY Kuang, XH Liu, J Liu, ZL Dai, MH Wang, YL Yuan, ZH AF Hao, Haihong Ren, Ni Han, Jing Foley, Steven L. Iqbal, Zahid Cheng, Guyue Kuang, Xiuhua Liu, Jie Liu, Zhenli Dai, Menghong Wang, Yulian Yuan, Zonghui TI Virulence and Genomic Feature of Multidrug Resistant Campylobacter jejuni Isolated from Broiler Chicken SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE Campylobacter jejuni; broiler chicken; multidrug resistance; virulence; de novo genome sequencing ID BIOFILM FORMATION; MACROLIDE RESISTANCE; ANTIMICROBIAL RESISTANCE; ANTIBIOTIC-RESISTANCE; BACTERIOPHAGE DEFENSE; IDENTIFICATION; GENES; INFECTION; STRAINS; PROTEIN AB The aim of this study was to reveal the molecular mechanism involved in multidrug resistance and virulence of Campylobacter jejuni isolated from broiler chickens. The virulence of six multidrug resistant C. jejuni was determined by in vitro and in vivo methods. The de novo whole genome sequencing technology and molecular biology methods were used to analyze the genomic features associated with the multidrug resistance and virulence of a selected isolate (C. jejuni 1655). The comparative genomic analyses revealed a large number of single nucleotide polymorphisms, deletions, rearrangements, and inversions in C. jejuni 1655 compared to reference C. jejuni genomes. The co-emergence of Thr-86-1Ie mutation in gyrA gene, A2075G mutation in 23S rRNA gene, tetO, aphA and aadE genes and pTet plasmid in C. jejuni 1655 contributed its multidrug resistance to fluoroquinolones, macrolides, tetracycline, and aminoglycosides. The combination of multiple virulence genes may work together to confer the relative higher virulence in C. jejuni 1655. The co-existence of mobile gene elements (e.g., pTet) and CRISPR-Cas system in C. jejuni 1655 may play an important role in the gene transfer and immune defense. The present study provides basic information of phenotypic and genomic features of C. jejuni 1655, a strain recently isolated from a chicken displaying multidrug resistance and relatively high level of virulence. C1 [Hao, Haihong; Cheng, Guyue; Wang, Yulian; Yuan, Zonghui] Natl Reference Lab Vet Drug Residues HZAU, Wuhan, Peoples R China. [Hao, Haihong; Cheng, Guyue; Wang, Yulian; Yuan, Zonghui] MOA Key Lab Detect Vet Drug Residues, Wuhan, Peoples R China. [Hao, Haihong; Ren, Ni; Iqbal, Zahid; Kuang, Xiuhua; Liu, Jie; Liu, Zhenli; Dai, Menghong; Yuan, Zonghui] MOA Lab Risk Assessment Qual & Safety Livestock &, Wuhan, Peoples R China. [Hao, Haihong; Ren, Ni; Yuan, Zonghui] Huazhong Agr Univ, Hubei Collaborat Innovat Ctr Anim Nutr & Feed Saf, Wuhan, Peoples R China. [Han, Jing; Foley, Steven L.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Wang, YL; Yuan, ZH (reprint author), Natl Reference Lab Vet Drug Residues HZAU, Wuhan, Peoples R China.; Wang, YL; Yuan, ZH (reprint author), MOA Key Lab Detect Vet Drug Residues, Wuhan, Peoples R China.; Dai, MH; Yuan, ZH (reprint author), MOA Lab Risk Assessment Qual & Safety Livestock &, Wuhan, Peoples R China.; Yuan, ZH (reprint author), Huazhong Agr Univ, Hubei Collaborat Innovat Ctr Anim Nutr & Feed Saf, Wuhan, Peoples R China. EM daimenghong@mail.hzau.edu.cn; wangyullan@mail.hzau.edu.cn; yuan5802@mail.hzau.edu.cn RI yuan, zonghui/A-1158-2017 FU National Basic Research Program of China [2013CB127200]; National Key research and development program [2016YFD0501302]; National Natural Science Foundation of China [31101856]; National Key Technology RD Program [2012BAK01B00]; Morning program of Wuhan in China [2015070404010191]; Fundamental Research Funds for the Central Universities [2662015PY035]; National Program for Risk Assessment of Quality and Safety of Livestock and Poultry Products [GJFP2016008] FX This work was supported by National Basic Research Program of China (2013CB127200), National Key research and development program (2016YFD0501302), National Natural Science Foundation of China (31101856), National Key Technology R&D Program (2012BAK01B00), Morning program of Wuhan in China (2015070404010191), Fundamental Research Funds for the Central Universities (2662015PY035), and National Program for Risk Assessment of Quality and Safety of Livestock and Poultry Products (GJFP2016008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The opinions expressed in this manuscript are solely the responsibility of the authors and do not necessarily represent the official views and policy of the US Food and Drug Administration or National Institutes of Health. Reference to any commercial materials, equipment, or process does not in any way constitute approval, endorsement, or recommendation by the Food and Drug Administration. NR 66 TC 0 Z9 0 U1 3 U2 3 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 OCT 14 PY 2016 VL 7 AR 1605 DI 10.3389/fmicb.2016.01605 PG 14 WC Microbiology SC Microbiology GA ED0HC UT WOS:000388522600001 PM 27790202 ER PT J AU Plank-Bazinet, JL Sampson, A Miller, LR Fadiran, EO Kallgren, D Agarwal, RK Barfield, W Brooks, CE Begg, L Mistretta, AC Scott, PE Clayton, JA Cornelison, TL AF Plank-Bazinet, Jennifer L. Sampson, Annie Miller, Leah R. Fadiran, Emmanuel O. Kallgren, Deborah Agarwal, Rajeev K. Barfield, Whitney Brooks, Claudette E. Begg, Lisa Mistretta, Amy C. Scott, Pamela E. Clayton, Janine Austin Cornelison, Terri L. TI The science of sex and gender in human health: online courses to create a foundation for sex and gender accountability in biomedical research and treatment SO BIOLOGY OF SEX DIFFERENCES LA English DT Article DE Sex; Gender; Continuing medical education; Continuing nursing education; Continuing pharmacy education; Disease-specific sex and gender differences; Disease manifestation and outcomes ID PRIMARY PREVENTION; ASPIRIN; WOMEN AB Background: Sex and gender differences play a significant role in the course and outcome of conditions that affect specific organ systems in the human body. Research on differences in the effects of medical intervention has helped scientists develop a number of sex- and gender-specific guidelines on the treatment and management of these conditions. An online series of courses, "The Science of Sex and Gender in Human Health," developed by the National Institutes of Health Office of Research on Women's Health and the U.S. Food and Drug Administration Office of Women's Health, examines sex and gender differences and their implications. Thus far, three online courses have been generated. The first course offers an overview of the scientific and biological basis for sex- and gender-related differences. The second course is focused on disease-specific sex and gender differences in health and behavior and their implications. Finally, the third course covers the influence of sex and gender on disease manifestation, treatment, and outcome. Methods: Data were obtained using website analytics and post-course surveys. Results: To date, over 1000 individuals have completed at least one course. Additionally, 600 users have received continuing education credit for completing a course in the series. Finally, the majority of respondents to the online course survey have indicated that the courses considerably enhanced their professional effectiveness. Conclusions: "The Science of Sex and Gender in Human Health" online courses are freely available sources of information that provide healthcare providers and researchers with the resources to successfully account for sex and gender in their medical practice and research programs. C1 [Plank-Bazinet, Jennifer L.; Sampson, Annie; Miller, Leah R.; Agarwal, Rajeev K.; Barfield, Whitney; Brooks, Claudette E.; Begg, Lisa; Mistretta, Amy C.; Clayton, Janine Austin; Cornelison, Terri L.] Natl Inst Hlth Off Res Womens Hlth, 6707 Democracy Blvd,Suite 400, Bethesda, MD 20817 USA. [Fadiran, Emmanuel O.; Kallgren, Deborah; Scott, Pamela E.] US FDA, Off Womens Hlth, 10903 New Hampshire Ave,W032-2333, Silver Spring, MD 20993 USA. RP Cornelison, TL (reprint author), Natl Inst Hlth Off Res Womens Hlth, 6707 Democracy Blvd,Suite 400, Bethesda, MD 20817 USA. EM cornelit@od.nih.gov FU NIH Office of Research on Women's Health; FDA Office of Women's Health FX Publication of this work was funded by the NIH Office of Research on Women's Health and the FDA Office of Women's Health. NR 13 TC 0 Z9 0 U1 3 U2 3 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 OCT 14 PY 2016 VL 7 AR 47 DI 10.1186/s13293-016-0100-z PG 9 WC Endocrinology & Metabolism; Genetics & Heredity SC Endocrinology & Metabolism; Genetics & Heredity GA EA2BZ UT WOS:000386398300005 PM 27785349 ER PT J AU Perkins, KM Lawsin, A Hasan, NA Strong, M Halpin, AL Rodger, RR Moulton-Meissner, H Crist, MB Schwartz, S Marders, J Daley, CL Salfinger, M Perz, JE AF Perkins, Kiran M. Lawsin, Adrian Hasan, Nabeeh A. Strong, Michael Halpin, Alison L. Rodger, Rachael R. Moulton-Meissner, Heather Crist, Matthew B. Schwartz, Suzanne Marders, Julia Daley, Charles L. Salfinger, Max Perz, Joseph E. TI Mycobacterium chimaera Contamination of Heater-Cooler Devices Used in Cardiac Surgery - United States SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Perkins, Kiran M.; Lawsin, Adrian; Halpin, Alison L.; Moulton-Meissner, Heather; Crist, Matthew B.; Perz, Joseph E.] CDC, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Hasan, Nabeeh A.; Strong, Michael; Rodger, Rachael R.; Daley, Charles L.; Salfinger, Max] Natl Jewish Hlth, Denver, CO 80206 USA. [Schwartz, Suzanne; Marders, Julia] US FDA, Rockville, MD 20857 USA. RP Perkins, KM (reprint author), CDC, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. EM kperkins@cdc.gov NR 6 TC 13 Z9 13 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 OCT 14 PY 2016 VL 65 IS 40 BP 1117 EP 1118 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EA1AM UT WOS:000386320700006 PM 27740609 ER PT J AU Huang, YZ Li, W Lu, WG Xiong, CR Yang, Y Yan, HJ Liu, KC Cao, P AF Huang, Yuzheng Li, Wei Lu, Wuguang Xiong, Chunrong Yang, Yang Yan, Huaijiang Liu, Kun Connie Cao, Peng TI Cloning and in vitro characterization of a Schistosoma japonicum aquaglyceroporin that functions in osmoregulation SO SCIENTIFIC REPORTS LA English DT Article ID AQUAPORIN WATER CHANNELS; OPISTHORCHIS-VIVERRINI; ANOPHELES-GAMBIAE; GLYCEROL; KINASE; PERMEABILITY; ADAPTATION; PATHWAY; LIVER; MECHANISMS AB As one of the three major human pathogens that cause schistosomiasis, Schistosoma japonicum is the only one that is endemic in China. Despite great progress on schistosomiasis control over the past 50 years in China, S. japonicum transmission still occurs in certain endemic regions, which causes significant public health problems and enormous economic losses. During different life stages, parasites are able to survive dramatic osmolality changes between its vector, fresh water, and mammal host. However, the molecular mechanism of parasite osmoregulation remains unknown. To address this challenging question, we report the first cloning of an S. japonicum aquaglyceroporin (SjAQP) from an isolate from Jiangsu province, China. Expressing SjAQP in Xenopus oocytes facilitated the permeation of water, glycerol, and urea. The water permeability of SjAQP was inhibited by 1 mM HgCl2, 3 mM tetraethylammonium, 1 mM ZnCl2, and 1 mM CuSO4. SjAQP was constitutively expressed throughout the S. japonicum life cycle, including in the egg, miracidia, cercaria, and adult stages. The highest expression was detected during the infective cercaria stage. Our results suggest that SjAQP plays a role in osmoregulation throughout the S. japonicum life cycle, especially during cercariae transformation, which enables parasites to survive osmotic challenges. C1 [Huang, Yuzheng; Lu, Wuguang; Yang, Yang; Yan, Huaijiang; Cao, Peng] Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing 210028, Jiangsu, Peoples R China. [Huang, Yuzheng; Lu, Wuguang; Yang, Yang; Yan, Huaijiang; Cao, Peng] Jiangsu Prov Acad Tradit Chinese Med, Nanjing 210028, Jiangsu, Peoples R China. [Li, Wei; Xiong, Chunrong] Minist Hlth, Key Lab Technol Parasit Dis Prevent & Control, Jiangsu Inst Parasit Dis, Wuxi 214064, Jiangsu, Peoples R China. [Liu, Kun Connie] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Johns Hopkins Malaria Res Inst, Baltimore, MD 21205 USA. [Liu, Kun Connie] US FDA, Pacific Reg Lab Northwest, Bothell, WA 98021 USA. RP Huang, YZ; Cao, P (reprint author), Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing 210028, Jiangsu, Peoples R China.; Huang, YZ; Cao, P (reprint author), Jiangsu Prov Acad Tradit Chinese Med, Nanjing 210028, Jiangsu, Peoples R China.; Liu, KC (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Johns Hopkins Malaria Res Inst, Baltimore, MD 21205 USA.; Liu, KC (reprint author), US FDA, Pacific Reg Lab Northwest, Bothell, WA 98021 USA. EM yzhyz01@163.com; kunliuphd@gmail.com; pcao79@yahoo.com FU NIH [R01 HL48268, U19 AI089680]; JHMRI; Bloomberg Philanthropies; Natural Science Foundation of China [31201893, 81673673]; Natural Science Foundation of Jiangsu Province [BK2011164]; Jiangsu Province's Key Medical Center [201108]; Jiangsu branch of CACMS [H1604]; Jiangsu Health Science Project [X201110, X201416, X201505]; Preventive Medicine Association of Jiangsu Province [Y2015071]; Jiangsu Health International Exchange Program; Key Laboratory of Jiangsu Preventive Veterinary Medicine [K13045]; Jiangsu Provincial Key Laboratory on Biological Pharmacy of Veterinary Medicine [GCZXKF1404]; Jiangsu Provincial Science and Technology Project of Traditional Chinese Medicine [Z2011189] FX We are grateful to the Gene Array Core Facilities at the Johns Hopkins Malaria Research Institute (JHMRI) for help with the qPCRs. We also thank the animal facility at the Jiangsu Parasitic Diseases Institute for aiding in the mouse experiment. This study was supported by grants R01 HL48268 and U19 AI089680 from the NIH, two pilot grants from the JHMRI and the Bloomberg Philanthropies to P Agre and K Liu, and grants to Y Huang, including those from the Natural Science Foundation of China (no. 31201893, no. 81673673), the Natural Science Foundation of Jiangsu Province (no. BK2011164), Jiangsu Province's Key Medical Center (no. 201108), Open project of Jiangsu branch of CACMS (H1604), the Jiangsu Health Science Project (nos. X201110, X201416 and X201505), Project of Preventive Medicine Association of Jiangsu Province(grant No. Y2015071), the Jiangsu Health International Exchange Program, the Open Project of Key Laboratory of Jiangsu Preventive Veterinary Medicine (no. K13045), the Open Project of Jiangsu Provincial Key Laboratory on Biological Pharmacy of Veterinary Medicine (no. GCZXKF1404), and Jiangsu Provincial Science and Technology Project of Traditional Chinese Medicine (Z2011189). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 13 PY 2016 VL 6 AR 35030 DI 10.1038/srep35030 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0NB UT WOS:000385535900001 PM 27733755 ER PT J AU Choi, JE Hong, SH Won, JH Park, HS Cho, YS Chung, WH Cho, YS Moon, IJ AF Choi, Ji Eun Hong, Sung Hwa Won, Jong Ho Park, Hee-Sung Cho, Young Sang Chung, Won-Ho Cho, Yang-Sun Moon, Il Joon TI Evaluation of Cochlear Implant Candidates using a Non-linguistic Spectrotemporal Modulation Detection Test SO SCIENTIFIC REPORTS LA English DT Article ID HEARING-IMPAIRED LISTENERS; SPEECH-INTELLIGIBILITY; USERS; DISCRIMINATION; SENSITIVITY; VOWEL AB Adults who score 50% correct or less in open-set sentence recognition test under the best aided listening condition may be considered as candidates for cochlear implant (CI). However, the requirement for 'the best aided listening condition' needs significant time and clinical resources to ensure such condition. As speech signals are composed of dynamic spectral and temporal modulations, psychoacoustic sensitivity to the combinations of spectral and temporal modulation cues may be a strong predictor for aided speech recognition. In this study, we tested 27 adults with moderately severe to profound hearing loss to explore the possibility that a non-linguistic unaided spectrotemporal modulation (STM) detection test might be a viable option as a surrogate measure to evaluate CI candidacy. Our results showed that STM detection thresholds were significantly correlated with aided sentence recognition scores for the 27 hearing impaired listeners. The receiver operator characteristic (ROC) curve analysis demonstrated that the CI candidacy evaluation by both unaided STM detection test and the traditional best-aided sentence recognition test was fairly consistent. More specifically, our results demonstrated that the STM detection test using a low spectral and temporal modulation rate might provide an efficient process for CI candidacy evaluation. C1 [Choi, Ji Eun; Park, Hee-Sung; Cho, Young Sang; Chung, Won-Ho; Cho, Yang-Sun; Moon, Il Joon] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Otorhinolaryngol Head & Neck Surg, Seoul, South Korea. [Hong, Sung Hwa] Sungkyunkwan Univ, Sch Med, Samsung Changwon Hosp, Dept Otorhinolaryngol Head & Neck Surg, Seoul, South Korea. [Won, Jong Ho] US FDA, Div Ophthalm & Ear Nose & Throat Devices, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Moon, IJ (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Otorhinolaryngol Head & Neck Surg, Seoul, South Korea. EM moonij@skku.edu NR 14 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 12 PY 2016 VL 6 AR 35235 DI 10.1038/srep35235 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY3OK UT WOS:000385003300001 PM 27731425 ER PT J AU Santiago-Frangos, A Kavita, K Schu, DJ Gottesman, S Woodson, SA AF Santiago-Frangos, Andrew Kavita, Kumari Schu, Daniel J. Gottesman, Susan Woodson, Sarah A. TI C-terminal domain of the RNA chaperone Hfq drives sRNA competition and release of target RNA SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE small noncoding RNA; RNA chaperone; intrinsically disordered protein; posttranscriptional regulation; ChiX ID ESCHERICHIA-COLI-HFQ; SM-LIKE PROTEIN; SMALL REGULATORY RNA; RYHB SMALL RNA; MESSENGER-RNA; INTERACTION SURFACES; STRAND DISPLACEMENT; SECONDARY STRUCTURE; STRESS-RESPONSE; OUTER-MEMBRANE AB The bacterial Sm protein and RNA chaperone Hfq stabilizes small noncoding RNAs (sRNAs) and facilitates their annealing to mRNA targets involved in stress tolerance and virulence. Although an arginine patch on the Sm core is needed for Hfq's RNA chaperone activity, the function of Hfq's intrinsically disordered C-terminal domain (CTD) has remained unclear. Here, we use stopped flow spectroscopy to show that the CTD of Escherichia coli Hfq is not needed to accelerate RNA base pairing but is required for the release of dsRNA. The Hfq CTD also mediates competition between sRNAs, offering a kinetic advantage to sRNAs that contact both the proximal and distal faces of the Hfq hexamer. The change in sRNA hierarchy caused by deletion of the Hfq CTD in E. coli alters the sRNA accumulation and the kinetics of sRNA regulation in vivo. We propose that the Hfq CTD displaces sRNAs and annealed sRNA.mRNA complexes from the Sm core, enabling Hfq to chaperone sRNA-mRNA interactions and rapidly cycle between competing targets in the cell. C1 [Santiago-Frangos, Andrew] Johns Hopkins Univ, Cell Mol Dev Biol & Biophys Program, Baltimore, MD 21218 USA. [Kavita, Kumari; Schu, Daniel J.; Gottesman, Susan] NCI, Lab Mol Biol, Bethesda, MD 20892 USA. [Woodson, Sarah A.] Johns Hopkins Univ, Thomas C Jenkins Dept Biophys, Baltimore, MD 21218 USA. [Schu, Daniel J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Gottesman, S (reprint author), NCI, Lab Mol Biol, Bethesda, MD 20892 USA.; Woodson, SA (reprint author), Johns Hopkins Univ, Thomas C Jenkins Dept Biophys, Baltimore, MD 21218 USA. EM gottesms@helix.nih.gov; swoodson@jhu.edu OI Woodson, Sarah/0000-0003-0170-1987; Santiago-Frangos, Andrew/0000-0001-9615-065X FU National Institute of General Medicine [R01GM46686, R01GM120425]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The authors thank Nadim Majdalani (NIH) for the hfq- E. coli strain NM694 used for the expression of the Hfq variants, Ricardo Francis for construction of RAF1042, and Subrata Panja for the Hfq Cy3-labeling strategy and protocol. This work was supported by National Institute of General Medicine Grants R01GM46686 and R01GM120425 (to S.A.W.) and, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (S.G.). NR 81 TC 2 Z9 2 U1 7 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 OCT 11 PY 2016 VL 113 IS 41 BP E6089 EP E6096 DI 10.1073/pnas.1613053113 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY1XE UT WOS:000384886900013 PM 27681631 ER PT J AU Yang, XX Duan, J Fisher, J AF Yang, Xiaoxia Duan, John Fisher, Jeffrey TI Application of Physiologically Based Absorption Modeling to Characterize the Pharmacokinetic Profiles of Oral Extended Release Methylphenidate Products in Adults SO PLOS ONE LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT-HYPERACTIVITY DISORDER; SINGLE-DOSE PHARMACOKINETICS; DL-THREO-METHYLPHENIDATE; HEALTHY-VOLUNTEERS; INTACT CAPSULE; DELIVERY-SYSTEMS; FORMULATIONS; DRUGS; BIOAVAILABILITY AB A previously presented physiologically-based pharmacokinetic model for immediate release (IR) methylphenidate (MPH) was extended to characterize the pharmacokinetic behaviors of oral extended release (ER) MPH formulations in adults for the first time. Information on the anatomy and physiology of the gastrointestinal (GI) tract, together with the biopharmaceutical properties of MPH, was integrated into the original model, with model parameters representing hepatic metabolism and intestinal non-specific loss recalibrated against in vitro and in vivo kinetic data sets with IR MPH. A Weibull function was implemented to describe the dissolution of different ER formulations. A variety of mathematical functions can be utilized to account for the engineered release/dissolution technologies to achieve better model performance. The physiological absorption model tracked well the plasma concentration profiles in adults receiving a multilayer-release MPH formulation or Metadate CD, while some degree of discrepancy was observed between predicted and observed plasma concentration profiles for Ritalin LA and Medikinet Retard. A local sensitivity analysis demonstrated that model parameters associated with the GI tract significantly influenced model predicted plasma MPH concentrations, albeit to varying degrees, suggesting the importance of better understanding the GI tract physiology, along with the intestinal non-specific loss of MPH. The model provides a quantitative tool to predict the biphasic plasma time course data for ER MPH, helping elucidate factors responsible for the diverse plasma MPH concentration profiles following oral dosing of different ER formulations. C1 [Yang, Xiaoxia; Fisher, Jeffrey] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Duan, John] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Yang, XX (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM xiaoxia.yang@fda.hhs.gov FU U.S. Food and Drug Administration; National Center for the Toxicological Research FX This study was supported by U.S. Food and Drug Administration/National Center for the Toxicological Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views presented in the current paper do not necessarily represent the views of the FDA. NR 77 TC 0 Z9 0 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 10 PY 2016 VL 11 IS 10 AR e0164641 DI 10.1371/journal.pone.0164641 PG 28 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0CF UT WOS:000385504100077 PM 27723791 ER PT J AU Haley, BJ Kim, SW Pettengill, J Luo, Y Karns, JS Van Kessel, JAS AF Haley, Bradd J. Kim, Seon Woo Pettengill, James Luo, Yan Karns, Jeffrey S. Van Kessel, Jo Ann S. TI Genomic and Evolutionary Analysis of Two Salmonella enterica Serovar Kentucky Sequence Types Isolated from Bovine and Poultry Sources in North America SO PLOS ONE LA English DT Article ID FIELD GEL-ELECTROPHORESIS; ANTIMICROBIAL RESISTANCE; POPULATION-STRUCTURE; EFFECTOR PROTEINS; VIBRIO-CHOLERAE; HEMOLYSIN-III; DAIRY FARM; SEROTYPES; TYPHIMURIUM; PREVALENCE AB Salmonella enterica subsp. enterica serovar Kentucky is frequently isolated from healthy poultry and dairy cows and is occasionally isolated from people with clinical disease. A genomic analysis of 119 isolates collected in the United States from dairy cows, ground beef, poultry and poultry products, and human clinical cases was conducted. Results of the analysis demonstrated that the majority of poultry and bovine-associated S. Kentucky were sequence type (ST) 152. Several bovine-associated (n = 3) and food product isolates (n = 3) collected from the United States and the majority of human clinical isolates were ST198, a sequence type that is frequently isolated from poultry and occasionally from human clinical cases in Northern Africa, Europe and Southeast Asia. A phylogenetic analysis indicated that both STs are more closely related to other Salmonella serovars than they are to each other. Additionally, there was strong evidence of an evolutionary divergence between the poultry-associated and bovine-associated ST152 isolates that was due to polymorphisms in four core genome genes. The ST198 isolates recovered from dairy farms in the United States were phylogenetically distinct from those collected from human clinical cases with 66 core genome SNPs differentiating the two groups, but more isolates are needed to determine the significance of this distinction. Identification of S. Kentucky ST198 from dairy animals in the United States suggests that the presence of this pathogen should be monitored in food-producing animals. C1 [Haley, Bradd J.; Kim, Seon Woo; Karns, Jeffrey S.; Van Kessel, Jo Ann S.] ARS, Environm Microbial & Food Safety Lab, Beltsville Area Res Ctr, USDA, Beltsville, MD 20705 USA. [Pettengill, James; Luo, Yan] US FDA, Off Analyt & Outreach, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Van Kessel, JAS (reprint author), ARS, Environm Microbial & Food Safety Lab, Beltsville Area Res Ctr, USDA, Beltsville, MD 20705 USA. EM joann.vankessel@ars.usda.gov FU internal USDA/ARS research funding FX This project was supported by internal USDA/ARS research funding.; We gratefully acknowledge Jakeitha Sonnier for laboratory assistance. This project was supported by internal USDA/ARS research funding. The mention of a trade name, proprietary product, or specific equipment does not constitute guarantee or warranty by the USDA and does not imply approval to the exclusion of other products that might be suitable. NR 62 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 3 PY 2016 VL 11 IS 10 AR e0161225 DI 10.1371/journal.pone.0161225 PG 36 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0TR UT WOS:000385553100008 PM 27695032 ER PT J AU Muralidharan, S Dirda, NDA Katz, EJ Tang, CM Bandyopadhyay, S Kanold, PO Kao, JPY AF Muralidharan, Sukumaran Dirda, Nathaniel D. A. Katz, Elizabeth J. Tang, Cha-Min Bandyopadhyay, Sharba Kanold, Patrick O. Kao, Joseph P. Y. TI Ncm, a Photolabile Group for Preparation of Caged Molecules: Synthesis and Biological Application SO PLOS ONE LA English DT Article ID ACID ESTER PRODRUGS; ORTHO-NITROBENZYL ESTERS; IN-VITRO; ARYLNITROSO COMPOUNDS; REDUCED GLUTATHIONE; CHEMICAL-STABILITY; PROTECTING GROUP; AUDITORY-CORTEX; DRUG-DELIVERY; THIOLS AB Ncm, 6-nitrocoumarin-7-ylmethyl, is a photolabile protective group useful for making "caged" molecules. Ncm marries the reliable photochemistry of 2-nitrobenzyl systems with the excellent stability and spectroscopic properties of the coumarin chromophore. From simple, commercially available starting materials, preparation of Ncm and its caged derivatives is both quick and easy. Photorelease of Ncm-caged molecules occurs on the microsecond time scale, with quantum efficiencies of 0.05-0.08. We report the synthesis and physical properties of Ncm and its caged derivatives. The utility of Ncm-caged glutamate for neuronal photostimulation is demonstrated in cultured hippocampal neurons and in brain slice preparations. C1 [Muralidharan, Sukumaran; Dirda, Nathaniel D. A.; Kao, Joseph P. Y.] Univ Maryland, Sch Med, Ctr Biomed Engn & Technol, Baltimore, MD 21201 USA. [Muralidharan, Sukumaran; Dirda, Nathaniel D. A.; Kao, Joseph P. Y.] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. [Katz, Elizabeth J.; Tang, Cha-Min; Kao, Joseph P. Y.] Univ Maryland, Program Neurosci, Baltimore, MD 21201 USA. [Katz, Elizabeth J.; Tang, Cha-Min] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Bandyopadhyay, Sharba; Kanold, Patrick O.] Univ Maryland, Dept Biol, College Pk, MD 20742 USA. [Katz, Elizabeth J.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Kao, JPY (reprint author), Univ Maryland, Sch Med, Ctr Biomed Engn & Technol, Baltimore, MD 21201 USA.; Kao, JPY (reprint author), Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA.; Kao, JPY (reprint author), Univ Maryland, Program Neurosci, Baltimore, MD 21201 USA. EM jkao@umaryland.edu OI Kanold, Patrick/0000-0002-7529-5435 FU U.S. National Institutes of Health [DC009607, GM056481] FX This work was supported by Research grants DC009607 (POK) and GM056481 (JPYK) from the U.S. National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 1 Z9 1 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 3 PY 2016 VL 11 IS 10 AR e0163937 DI 10.1371/journal.pone.0163937 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0TR UT WOS:000385553100066 PM 27695074 ER PT J AU Qu, HO Quevedo, IR Linder, SW Fong, A Mudalige, TK AF Qu, Haiou Quevedo, Ivan R. Linder, Sean W. Fong, Andrew Mudalige, Thilak K. TI Importance of material matching in the calibration of asymmetric flow field-flow fractionation: material specificity and nanoparticle surface coating effects on retention time SO JOURNAL OF NANOPARTICLE RESEARCH LA English DT Article DE Physicochemical characterization; Asymmetric flow field-flow fractionation; Multiangle light scattering; Nanoparticle standards ID SILVER NANOPARTICLES; DIETARY-SUPPLEMENTS; MASS-SPECTROMETRY; SIZE; FUNCTIONALIZATION; QUANTIFICATION; NANOMATERIALS; OPTIMIZATION; AGGREGATION; SEPARATION AB Asymmetric flow field-flow fractionation (AF4) coupled with dynamic light scattering or multiangle light scattering detectors is a promising technique for the size-based separation of colloidal particles (nano-and submicron scale) and the online determination of the particle size of the separated fractions in aqueous suspensions. In most cases, the applications of these detectors are problematic due to the material-specific properties of the analyte that results in erroneous calculations, and as an alternative, different nanoparticle size standards are required to properly calibrate the size-based retention in AF4. The availability of nanoparticle size standards in different materials is limited, and this deviation from ideal conditions of retention is mainly due to material-specific and particle coating-specific membrane-particle interactions. Here, we present an experimental method on the applicability of polystyrene nanoparticles (PS NP) as standard for AF4 calibration and compare with gold nanoparticle (Au NP) standards having different nominal sizes and surface functionalities. C1 [Qu, Haiou; Linder, Sean W.; Fong, Andrew; Mudalige, Thilak K.] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Quevedo, Ivan R.] Univ Iberoamer, Dept Ingn Ciencias & Quim, Prolongac Paseo Reforma 880, Mexico City 01210, DF, Mexico. 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 NR 26 TC 1 Z9 1 U1 12 U2 12 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1388-0764 EI 1572-896X J9 J NANOPART RES JI J. Nanopart. Res. PD OCT 3 PY 2016 VL 18 IS 10 AR 292 DI 10.1007/s11051-016-3601-0 PG 10 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA DY5XP UT WOS:000385178200004 ER PT J AU Ragupathy, V Xue, W Tan, J Devadas, K Gao, YM Hewlett, I AF Ragupathy, Viswanath Xue, Wang Tan, Ji Devadas, Krishnakumar Gao, Yamei Hewlett, Indira TI Progesterone augments cell susceptibility to HIV-1 and HIV-1/HSV-2 co-infections SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Article DE HIV/HSV-2; infectivity; apoptosis; progesterone; hormonal contraception ID HERPES-SIMPLEX-VIRUS; HORMONAL CONTRACEPTIVE USE; CD4(+) T-CELLS; TYPE-2 INFECTION; STEROID-HORMONES; GENE-EXPRESSION; SOUTH-AFRICA; ACQUISITION; WOMEN; RISK AB In human immunodeficiency virus type 1 (HIV-1)-infected women, oral or injectable progesterone containing contraceptive pills may enhance HIV-1 acquisition in vivo, and the mechanism by which this occurs is not fully understood. In developing countries, Herpes simplex virus type-2 (HSV-2) co-infection has been shown to be a risk for increase of HIV-1 acquisition and, if co- infected women use progesterone pills, infections may increase several fold. In this study, we used an in vitro cell culture system to study the effects of progesterone on HIV-1 replication and to explore the molecular mechanism of progesterone effects on infected cells. In our in vitro model, CEMss cells (lymphoblastoid cell line) were infected with either HIV-1 alone or co- infected with HSV-2. HIV-1 viral load was measured with and without sex hormone treatment. Progesterone-treated cells showed an increase in HIV-1 viral load (1411.2pg/mL) compared with cells without progesterone treatment (993.1 pg/mL). Increased cell death was noted with HSV-2 co-infection and in progesterone-treated cells. Similar observations were noted in peripheral blood mononuclear cells (PBMC) cells derived from three female donors. Progesterone-treated cells also showed reduced antiviral efficacy. Inflammatory cytokines and associations with biomarkers of disease progression were explored. Progesterone upregulated inflammatory cytokines and chemokines conversely and downregulated anti- apoptotic Bcl-2 expression. Nuclear protein analysis by electrophoretic mobility shift assay showed the association of progesterone with progesterone response element (PRE), which may lead to downregulation of Bcl-2. These data indicate that progesterone treatment enhances HIV-1 replication in infected cells and co- infection with HSV-2 may further fuel this process. C1 [Ragupathy, Viswanath; Xue, Wang; Tan, Ji; Devadas, Krishnakumar; Hewlett, Indira] US FDA, Lab Mol Virol, Div Emerging Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20903 USA. [Gao, Yamei] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Hewlett, I (reprint author), US FDA, Lab Mol Virol, Div Emerging Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20903 USA. EM Viswanath.Ragupathy@fda.hhs.gov; Indira.hewlett@fda.hhs.gov FU FDA's Office of Women's Health FX This work was funded by an intramural grant from the FDA's Office of Women's Health. NR 47 TC 1 Z9 1 U1 0 U2 0 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0952-5041 EI 1479-6813 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD OCT PY 2016 VL 57 IS 3 BP 185 EP 199 DI 10.1530/JME-16-0138 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EL0TP UT WOS:000394335000007 PM 27538988 ER PT J AU Bi, YW Paterniti, MO Karimi-Shah, BA Chowdhury, BA Wang, YN Rekic, D AF Bi, Youwei Paterniti, Miya O. Karimi-Shah, Banu A. Chowdhury, Badrul A. Wang, Yaning Rekic, Dinko TI A Disease Progression Model of Longitudinal Lung Function Decline in Idiopathic Pulmonary Lung Fibrosis Patients SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract ID PIRFENIDONE; TRIALS C1 [Bi, Youwei; Wang, Yaning; Rekic, Dinko] US FDA, Off Clin Pharmacol, OTS, CDER, Silver Spring, MD USA. [Paterniti, Miya O.; Karimi-Shah, Banu A.; Chowdhury, Badrul A.] US FDA, Div Pulm Allergy & Rheumatol Prod, OND, CDER, Silver Spring, MD USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2016 VL 43 SU 1 MA M-81 BP S47 EP S48 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK4JU UT WOS:000393893700083 ER PT J AU Chen, J Fang, L Pu, X Wang, YN Pan, YZ Lu, DM Jiang, XJ Stier, E Li, B Zhao, L AF Chen, Jia Fang, Lanyan (Lucy) Pu, Xia Wang, Yaning Pan, Yuzhuo Lu, Dongmei Jiang, Xiaojian Stier, Ethan Li, Bing Zhao, Liang TI Methodology Advancement on Dose-Scale Analysis to Assess Pharmacodynamic Equivalence SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Chen, Jia; Fang, Lanyan (Lucy); Pu, Xia; Zhao, Liang] US FDA, Off Res & Stand, Off Gener Drugs, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2016 VL 43 SU 1 MA M-27 BP S24 EP S24 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK4JU UT WOS:000393893700029 ER PT J AU Gaitonde, P Huh, Y Heimann, G Li, JG Lu, KF Benson, C Darpo, B Ferber, G Keirns, J Sebastien, B Tsai, K Wang, YN Zhou, MJ Riley, S AF Gaitonde, Puneet Huh, Yeamin Heimann, Guenter Li, Jianguo Lu, Kaifeng Benson, Charles Darpo, Borje Ferber, Georg Keirns, Jim Sebastien, Bernard Tsai, Kuenhi Wang, Yaning Zhou, Meijian Riley, Steve TI Predictive Performance of Early Phase 1 Studies in Assessing Thorough QT Outcome Across 12 Compounds - Application of a Novel Analysis Method SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Gaitonde, Puneet; Huh, Yeamin; Riley, Steve] Pfizer Inc, New York, NY USA. [Huh, Yeamin] A2PG, Ann Arbor, MI USA. [Heimann, Guenter] Novartis, Basel, Switzerland. [Li, Jianguo] AstraZeneca, London, England. [Lu, Kaifeng] Allergan Plc, Parsippany, NJ USA. [Benson, Charles] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Darpo, Borje; Zhou, Meijian] ICardiac Technol, Brighton, NY USA. [Ferber, Georg] Stat Georg Ferber GmbH, Riehen, Switzerland. [Keirns, Jim] Astellas Pharma Inc, Chuo, Tokyo, Japan. [Sebastien, Bernard] Sanofi, Paris, France. [Tsai, Kuenhi] Merck & Co Inc, Kenilworth, NJ USA. [Wang, Yaning] US FDA, Rockville, MD 20857 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2016 VL 43 SU 1 MA T-61 BP S76 EP S76 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK4JU UT WOS:000393893700145 ER PT J AU He, H Wu, Y Zhang, XY Cao, YG AF He, Hua Wu, Yun Zhang, Xinyuan Cao, Yanguang TI A Multiscale Physiologically Based Pharmacokinetic Model for Doxorubicin: Scale-up from Mouse to Human SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [He, Hua; Cao, Yanguang] Univ N Carolina, Sch Pharm, DPET, Chapel Hill, NC USA. [He, Hua] China Pharmaceut Univ, Nanjing, Jiangsu, Peoples R China. [Wu, Yun] SUNY Buffalo, Dept Biomed Engn, Buffalo, NY USA. [Zhang, Xinyuan] US FDA, Div Quantitat Methods & Modeling, Off Res & Stand, OGD, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2016 VL 43 SU 1 MA T-01 BP S48 EP S49 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK4JU UT WOS:000393893700085 ER PT J AU Li, L Ji, P Kalaria, S He, L Chen, JM Marathe, A Doddapaneni, S Wang, YN Sahajwalla, C AF Li, Liang Ji, Ping Kalaria, Shamir He, Lei Chen, Jianmeng Marathe, Anshu Doddapaneni, Suresh Wang, Yaning Sahajwalla, Chandrahas TI Dose sensitivity of pharmacokinetic difference between similar biologics with target-mediated drug disposition SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Li, Liang; Ji, Ping; Kalaria, Shamir; He, Lei; Chen, Jianmeng; Marathe, Anshu; Doddapaneni, Suresh; Wang, Yaning; Sahajwalla, Chandrahas] US FDA, Div Clin Pharmacol 2, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2016 VL 43 SU 1 MA W-50 BP S108 EP S108 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK4JU UT WOS:000393893700215 ER PT J AU Ma, L Zhuang, LN Williams, G Chow, A Harrold, J Melhem, M Yang, BB Marathe, D Wang, YN Bergman, K Ouyang, YL Dickerson, W Huang, L Lutterodt, F Laniyonu, A Zalkikar, J Gorovets, A Marzella, L Mehrotra, N AF Ma, Lian Zhuang, Luning Williams, Gene Chow, Andrew Harrold, John Melhem, Murad Yang, Bing-Bing Marathe, Dhananjay Wang, Yaning Bergman, Kimberly Ouyang, Yanli Dickerson, William Huang, Lan Lutterodt, Frank Laniyonu, Adebayo Zalkikar, Jyoti Gorovets, Alex Marzella, Libero Mehrotra, Nitin TI Dosing Regimen Selection under the Animal Rule for Pegfilgrastim to Treat Patients with Hematopoietic Syndrome of Acute Radiation Syndrome (HS-ARS) SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Ma, Lian; Zhuang, Luning; Williams, Gene; Marathe, Dhananjay; Wang, Yaning; Bergman, Kimberly; Ouyang, Yanli; Dickerson, William; Huang, Lan; Lutterodt, Frank; Laniyonu, Adebayo; Zalkikar, Jyoti; Gorovets, Alex; Marzella, Libero; Mehrotra, Nitin] US FDA, Silver Spring, MD USA. [Chow, Andrew; Harrold, John; Melhem, Murad; Yang, Bing-Bing] Amgen Inc, Thousand Oaks, CA 91320 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2016 VL 43 SU 1 MA W-49 BP S107 EP S108 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK4JU UT WOS:000393893700214 ER PT J AU Rhee, SJ Chung, H Yi, S Yu, KS Chung, JY AF Rhee, Su-jin Chung, Hyewon Yi, SoJeong Yu, Kyung-Sang Chung, Jae-Yong TI Physiologically Based Pharmacokinetic Modeling of Metformin and Prediction of Pharmacokinetics in Geriatric Population SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Rhee, Su-jin; Chung, Hyewon; Yu, Kyung-Sang] Seoul Natl Univ, Coll Med & Hosp, Dept Clin Pharmacol & Therapeut, Seoul, South Korea. [Yi, SoJeong] US FDA, Div Clin Pharmacol 3, OCP, CDER, Silver Spring, MD USA. [Chung, Jae-Yong] Seoul Natl Univ, Coll Med, Dept Clin Pharmacol & Therapeut, Seongnam, South Korea. [Chung, Jae-Yong] Bundang Hosp, Seongnam, South Korea. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2016 VL 43 SU 1 MA T-67 BP S78 EP S79 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK4JU UT WOS:000393893700151 ER PT J AU Shivva, V Fang, LY Yang, XY Zheng, N Zhu, H Raney, SG Zhao, L AF Shivva, Vittal Fang, Lanyan Yang, Xiaoyan Zheng, Nan Zhu, Hao Raney, Sam G. Zhao, Liang TI Use of a Model Based Approach for Evaluation of partial Area Under the Curve for Bioequivalence Assessment of Methylphenidate Transdermal products SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Shivva, Vittal; Fang, Lanyan; Yang, Xiaoyan; Raney, Sam G.; Zhao, Liang] US FDA, Off Res & Stand, OGD, CDER, Rockville, MD 20857 USA. [Zheng, Nan; Zhu, Hao] US FDA, Off Clin Pharmacol, OTS, CDER, Rockville, MD 20857 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2016 VL 43 SU 1 MA T-74 BP S81 EP S81 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK4JU UT WOS:000393893700158 ER PT J AU Sweeney, MM Rass, O Johnson, PS Strain, EC Berry, MS Vo, HT Fishman, MJ Munro, CA Rebok, GW Mintzer, MZ Johnson, MW AF Sweeney, Mary M. Rass, Olga Johnson, Patrick S. Strain, Eric C. Berry, Meredith S. Vo, Hoa T. Fishman, Marc J. Munro, Cynthia A. Rebok, George W. Mintzer, Miriam Z. Johnson, Matthew W. TI Initial Feasibility and Validity of a Prospective Memory Training Program in a Substance Use Treatment Population SO EXPERIMENTAL AND CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE prospective memory; working memory; cognitive training; substance use disorder; addiction ID METHADONE-MAINTENANCE PATIENTS; WORKING-MEMORY; EXECUTIVE FUNCTION; FORMER USERS; OLDER-ADULTS; CANNABIS USE; DEFICITS; IMPAIRMENT; PERFORMANCE; ECSTASY AB Individuals with substance use disorders have shown deficits in the ability to implement future intentions, called prospective memory. Deficits in prospective memory and working memory, a critical underlying component of prospective memory, likely contribute to substance use treatment failures. Thus, improvement of prospective memory and working memory in substance use patients is an innovative target for intervention. We sought to develop a feasible and valid prospective memory training program that incorporates working memory training and may serve as a useful adjunct to substance use disorder treatment. We administered a single session of the novel prospective memory and working memory training program to participants (n = 22; 13 men, 9 women) enrolled in outpatient substance use disorder treatment and correlated performance to existing measures of prospective memory and working memory. Generally accurate prospective memory performance in a single session suggests feasibility in a substance use treatment population. However, training difficulty should be increased to avoid ceiling effects across repeated sessions. Consistent with existing literature, we observed superior performance on event-based relative to time-based prospective memory tasks. Performance on the prospective memory and working memory training components correlated with validated assessments of prospective memory and working memory, respectively. Correlations between novel memory training program performance and established measures suggest that our training engages appropriate cognitive processes. Further, differential event-and time-based prospective memory task performance suggests internal validity of our training. These data support the development of this intervention as an adjunctive therapy for substance use disorders. C1 [Sweeney, Mary M.; Rass, Olga; Johnson, Patrick S.; Strain, Eric C.; Berry, Meredith S.; Fishman, Marc J.; Munro, Cynthia A.; Mintzer, Miriam Z.; Johnson, Matthew W.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Vo, Hoa T.; Fishman, Marc J.] Mt Manor Treatment Ctr, Baltimore, MD USA. [Rebok, George W.] Johns Hopkins Univ, Dept Mental Hlth, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Rass, Olga] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. [Johnson, Patrick S.] Calif State Univ Chico, Chico, CA 95929 USA. [Mintzer, Miriam Z.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Johnson, MW (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Behav Pharmacol Res Unit, 5510 Nathan Shock Dr, Baltimore, MD 21224 USA. EM marymsweeney@jhmi.edu OI Sweeney, Mary Margaret/0000-0001-6931-4321 FU National Institute on Drug Abuse [R01DA035277, K24DA023186, T32DA07209] FX This research was supported by National Institute on Drug Abuse Grants R01DA035277 and K24DA023186 to Matthew W. Johnson and Eric C. Strain, respectively. Support for Mary M. Sweeney, Olga Rass, Patrick S. Johnson, and Meredith S. Berry was provided by National Institute on Drug Abuse Grant T32DA07209. The funding source had no role other than financial support. We acknowledge Peter Rendell for developing Virtual Week and providing access. We thank Len Onyiah for computer programming. We thank Lisa Mitchell for her assistance in conducting this research. This work was presented in part at the Third Annual Collaborative Perspectives on Addiction Conference of the American Psychological Association and at the 77th Annual Meeting of the College on Problems of Drug Dependence. Initial findings were described in an abstract published in Drug and Alcohol Dependence (i.e., Sweeney, Rass, Johnson, & Johnson, 2015). NR 64 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1064-1297 EI 1936-2293 J9 EXP CLIN PSYCHOPHARM JI Exp. Clin. Psychopharmacol. PD OCT PY 2016 VL 24 IS 5 BP 390 EP 399 DI 10.1037/pha0000091 PG 10 WC Psychology, Biological; Psychology, Clinical; Pharmacology & Pharmacy; Psychiatry SC Psychology; Pharmacology & Pharmacy; Psychiatry GA EL2ZA UT WOS:000394488200009 PM 27690506 ER PT J AU Hategan, AP Bianchet, M Karnaukhova, E Steiner, J Dimitriadis, E Nath, A AF Hategan, Alina Popescu Bianchet, Mario Karnaukhova, Elena Steiner, Joseph Dimitriadis, Emilios Nath, Avindra TI HIV-Tat protein: molecular structure, aggregation and interaction with amyloid beta SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 14th International Symposium on NeuroVirology CY OCT 25-28, 2016 CL Toronto, CANADA C1 [Hategan, Alina Popescu; Steiner, Joseph; Nath, Avindra] NINDS, Sect Infect Nervous Syst, Bethesda, MD 20892 USA. [Bianchet, Mario] Johns Hopkins Sch Med, Dept Neurog, Baltimore, MD USA. [Karnaukhova, Elena] FDA, CBER, Silver Spring, MD USA. [Dimitriadis, Emilios] NIBIB, Scanning Probe Microscopy Unit, Bethesda, MD USA. EM alina.popescu@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2016 VL 22 SU 1 MA P127 BP S62 EP S62 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA EK7GH UT WOS:000394093700128 ER PT J AU Fales, AM Crawford, BM Vo-Dinh, T AF Fales, Andrew M. Crawford, Bridget M. Tuan Vo-Dinh TI Folate Receptor-Targeted Theranostic Nanoconstruct for Surface-Enhanced Raman Scattering Imaging and Photodynamic Therapy SO ACS Omega LA English DT Article ID SINGLET-OXYGEN GENERATION; COATED GOLD NANOSTARS; SERS; NANOPARTICLES; PHOTOSENSITIZERS; NANOPROBES; CANCER; AGENTS; CELLS; TAGS AB We report the synthesis of a folate receptor (FR)-targeted theranostic nanocomposite for surface-enhanced Raman scattering (SERS) imaging and photodynamic therapy (PDT). FR-specific SERS detection and PDT are demonstrated in vitro using two FR-positive cancer cell lines and one FR-negative cancer cell lines. C1 [Fales, Andrew M.; Crawford, Bridget M.; Tuan Vo-Dinh] Duke Univ, Fitzpatrick Inst Photon, 101 Sci Dr,Box 90281, Durham, NC 27708 USA. [Fales, Andrew M.; Crawford, Bridget M.; Tuan Vo-Dinh] Duke Univ, Dept Biomed Engn, 101 Sci Dr,Box 90281, Durham, NC 27708 USA. [Tuan Vo-Dinh] Duke Univ, Dept Chem, 101 Sci Dr,Box 90281, Durham, NC 27708 USA. [Fales, Andrew M.] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 62,Room G205C, Silver Spring, MD 20993 USA. RP Vo-Dinh, T (reprint author), Duke Univ, Fitzpatrick Inst Photon, 101 Sci Dr,Box 90281, Durham, NC 27708 USA.; Vo-Dinh, T (reprint author), Duke Univ, Dept Biomed Engn, 101 Sci Dr,Box 90281, Durham, NC 27708 USA.; Vo-Dinh, T (reprint author), Duke Univ, Dept Chem, 101 Sci Dr,Box 90281, Durham, NC 27708 USA. EM tuan.vodinh@duke.edu FU Defense Advanced Research Projects Agency [HR0011-13-2-0003]; Duke University Exploratory Research Funds FX This work was sponsored by the Defense Advanced Research Projects Agency (HR0011-13-2-0003) and the Duke University Exploratory Research Funds. The content of this article does not necessarily reflect the position or the policy of the U.S. Government, and no official endorsement should be inferred. NR 26 TC 0 Z9 0 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2470-1343 J9 ACS OMEGA JI ACS Omega PD OCT PY 2016 VL 1 IS 4 BP 730 EP 735 DI 10.1021/acsomega.6b00176 PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA EI7XH UT WOS:000392717300025 ER PT J AU Kumsa, DW Bhadra, N Hudak, EM Kelley, SC Untereker, DF Mortimer, JT AF Kumsa, Doe W. Bhadra, Narendra Hudak, Eric M. Kelley, Shawn C. Untereker, Darrel F. Mortimer, J. Thomas TI Electron transfer processes occurring on platinum neural stimulating electrodes: a tutorial on the i(V-e) profile SO JOURNAL OF NEURAL ENGINEERING LA English DT Article DE electrochemistry; platinum; neural stimulation; neural prostheses; electron transfer processes; oxidation; reduction; cyclic voltammetry ID ADSORPTION AB The aim of this tutorial is to encourage members of the neuroprosthesis community to incorporate electron transfer processes into their thinking and provide them with the tools to do so when they design and work with neurostimulating devices. The focus of this article is on platinum because it is the most used electrode metal for devices in commercial use. The i(V-e) profile or cyclic voltammogram contains information about electron transfer processes that can occur when the electrode-electrolyte interface, V-e, is at a specific potential, and assumed to be near steady-state conditions. For the engineer/designer this means that if the potential is not in the range of a specific electron transfer process, that process cannot occur. An i(V-e) profile, recorded at sweep rates greater than 0.1 mVs(-1), approximates steady-state conditions. Rapid transient potential excursions, like that seen with neural stimulation pulses, may be too fast for the reaction to occur, however, this means that if the potential is in the range of a specific electron transfer process it may occur and should be considered. The approach described here can be used to describe the thermodynamic electron transfer processes on other candidate electrode metals, e.g. stainless steel, iridium, carbon-based, etc. C1 [Kumsa, Doe W.; Bhadra, Narendra; Mortimer, J. Thomas] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Hudak, Eric M.] Adv Bion LLC, Dept Res & Technol, Valencia, CA USA. [Kelley, Shawn C.; Untereker, Darrel F.] Medtronic Plc, Fridley, MN USA. [Kumsa, Doe W.] US FDA, Med Device Innovat Consortium, Rockville, MD 20857 USA. RP Mortimer, JT (reprint author), Case Western Reserve Univ, Cleveland, OH 44106 USA. EM jtm3@case.edu FU Advanced Bionics LLC Westinghouse Place, Valencia, CA; Boston Scientific (Neuromodulation) Rye Canyon Loop, Valencia, CA; Boston Scientific (CRM) Hamline Ave, North MS St. Paul, MN; Medtronic, Inc. Medtronic Parkway, Minneapolis, MN; St. Jude Medical, Inc. (IES), Sylmar, CA; Case Western Reserve University, Cleveland, OH FX Participation of the following individuals is gratefully acknowledged: Doe W Kumsa (Case Western Reserve University, presently at Food and Drug Administration), Fred W Montague (Case Western Reserve University), Martin Cholette (formerly at St. Jude Medical), Narendra Bhadra (Case Western Reserve University), Michael Colvin (previously with Boston Scientific Neuromodulation currently Syntilla Medical), Benjamin Hahn (Boston Scientific, Neuromodulation), Juan G Hincapie (Boston Scientific Neuromodulation), Eric M Hudak (Advanced Bionics), Shawn Kelley (Medtronicplc). Kurt J Koester (Advanced Bionics), Hyowon (Hugh) Lee (formerly at St. Jude now at Purdue University), Brian Soltis (Boston Scientific CRM), Karl Steinke (Boston Scientific, Neuromodulation), Darrel F Untereker (Medtronicplc). In 2013, the above list of individuals came together at first in quarterly meetings and then into weekly teleconference meetings. Their purpose was to develop a better understanding of the electron transfer processes taking place on platinum neural stimulating electrodes with the specific goal of finding a way or ways to inject more charge than was currently possible while adhering to the criterion developed by Robert Shannon [8]. Experiments were designed, carried out, and the results studied in 2013 and 2014. The group functioned as a sounding board for ideas that related to the design of experiments, interpretation of results, and framing of the presentation. Each individual's input left a mark on the way the group performed, and for that they are recognized. Funding to support the postdoctoral fellowship for Dr Doe Kumsa was provided by: Advanced Bionics LLC 28515 Westinghouse Place, Valencia, CA; Boston Scientific (Neuromodulation) 25155 Rye Canyon Loop, Valencia, CA; Boston Scientific (CRM) 4100 Hamline Ave, North MS 5-395 St. Paul, MN; Medtronic, Inc. 710 Medtronic Parkway, Minneapolis, MN; St. Jude Medical, Inc. (IES), Sylmar, CA. The David and Jane Watterson Endowment Fund at Case Western Reserve University, Cleveland, OH, also provided project funding. Funding support does not imply or suggest a sponsor's endorsement of the work presented in this document. I (JTM) am deeply indebted to Professor Daniel Scherson of Case Western Reserve University, for his patience and guiding my understanding of electrochemistry. Many of the cartoons used here, I attribute to his tutelage. We acknowledge and appreciate the editorial changes made by Dr Kristine Kelley. Ms. Michele Krantz provided important wording changes. NR 10 TC 0 Z9 0 U1 1 U2 1 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 OCT PY 2016 VL 13 IS 5 AR 052001 DI 10.1088/1741-2560/13/5/052001 PG 15 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA EI7WG UT WOS:000392714500001 PM 27518125 ER PT J AU Torrence, ME AF Torrence, Mary E. TI Introduction to Preharvest Food Safety SO MICROBIOLOGY SPECTRUM LA English DT Article ID ESCHERICHIA-COLI O157H7; RESISTANT STAPHYLOCOCCUS-AUREUS; DEVELOPING RESEARCH PROTOCOLS; RANDOMIZED CONTROLLED-TRIALS; HEMOLYTIC-UREMIC-SYNDROME; FEEDLOT CATTLE; UNITED-STATES; SALMONELLA-ENTERITIDIS; REPORTING GUIDELINES; MICROBIAL HAZARDS AB This introductory article provides an overview of preharvest food safety activities and initiatives for the past 15 years. The section on traditional areas of preharvest food safety focuses on significant scientific advancements that are a culmination of collaborative efforts (both public health and agriculture) and significant research results. The highlighted advancements provide the foundation for exploring future preharvest areas and for improving and focusing on more specific intervention/control/prevention strategies. Examples include Escherichia coli and cattle, Salmonella and Campylobacter in poultry, and interventions and prevention and control programs. The section on "nontraditional" preharvest food safety areas brings attention to potential emerging food safety issues and to future food safety research directions. These include organic production, the FDA's Produce Rule (water and manure), genomic sequencing, antimicrobial resistance, and performance metrics. The concluding section emphasizes important themes such as strategic planning, coordination, epidemiology, and the need for understanding food safety production as a continuum. Food safety research, whether at the pre- or postharvest level, will continue to be a fascinating complex web of foodborne pathogens, risk factors, and scientific and policy interactions. Food safety priorities and research must continue to evolve with emerging global issues, emerging technologies, and methods but remain grounded in a multidisciplinary, collaborative, and systematic approach. C1 [Torrence, Mary E.] US FDA, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Torrence, ME (reprint author), US FDA, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. EM mary.torrence@fda.hhs.gov NR 57 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA EI 2165-0497 J9 MICROBIOL SPECTR JI Microbiol. Spectr. PD OCT PY 2016 VL 4 IS 5 AR UNSP PFS-0009-2015 DI 10.1128/microbiolspec.PFS-0009-2015 PG 11 WC Microbiology SC Microbiology GA EG9EQ UT WOS:000391361600017 ER PT J AU Jarow, JP Viviano, C Baxley, JH AF Jarow, Jonathan P. Viviano, Charles Baxley, John H. TI How much clinical evidence is enough: regulation of medical devices? SO ANNALS OF TRANSLATIONAL MEDICINE LA English DT Editorial Material C1 [Jarow, Jonathan P.] US FDA, Ctr Drug Evaluat & Res, WO51 RM6364,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Viviano, Charles; Baxley, John H.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Jarow, JP (reprint author), US FDA, Ctr Drug Evaluat & Res, WO51 RM6364,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jonathan.jarow@fda.hhs.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2305-5839 EI 2305-5847 J9 ANN TRANSL MED JI ANN. TRANSL. MED. PD OCT PY 2016 VL 4 IS 20 AR 414 DI 10.21037/atm.2016.08.44 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EF0TD UT WOS:000390038000025 PM 27867966 ER PT J AU Hong, HX Rua, D Sakkiah, S Selvaraj, C Ge, WG Tong, WD AF Hong, Huixiao Rua, Diego Sakkiah, Sugunadevi Selvaraj, Chandrabose Ge, Weigong Tong, Weida TI Consensus Modeling for Prediction of Estrogenic Activity of Ingredients Commonly Used in Sunscreen Products SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE sunscreen; ingredient; estrogenic activity; prediction; model ID STRUCTURE ELUCIDATION; EXPERT-SYSTEM; RECEPTOR BINDING; DECISION FOREST; KNOWLEDGE-BASE; CHEMICALS; SPECTRA; ESSESA; REPRESENTATION; BENZOPHENONE-2 AB Sunscreen products are predominantly regulated as over-the-counter (OTC) drugs by the US FDA. The "active" ingredients function as ultraviolet filters. Once a sunscreen product is generally recognized as safe and effective (GRASE) via an OTC drug review process, new formulations using these ingredients do not require FDA review and approval, however, the majority of ingredients have never been tested to uncover any potential endocrine activity and their ability to interact with the estrogen receptor (ER) is unknown, despite the fact that this is a very extensively studied target related to endocrine activity. Consequently, we have developed an in silico model to prioritize single ingredient estrogen receptor activity for use when actual animal data are inadequate, equivocal, or absent. It relies on consensus modeling to qualitatively and quantitatively predict ER binding activity. As proof of concept, the model was applied to ingredients commonly used in sunscreen products worldwide and a few reference chemicals. Of the 32 chemicals with unknown ER binding activity that were evaluated, seven were predicted to be active estrogenic compounds. Five of the seven were confirmed by the published data. Further experimental data is needed to confirm the other two predictions. C1 [Hong, Huixiao; Sakkiah, Sugunadevi; Selvaraj, Chandrabose; Ge, Weigong; Tong, Weida] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Rua, Diego] US FDA, Ctr Drug Evaluat & Res, Div Nonprescript Drug Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Hong, HX (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, 3900 NCTR Rd, Jefferson, AR 72079 USA.; Rua, D (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Nonprescript Drug Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Huixiao.Hong@fda.hhs.gov; Diego.Rua@fda.hhs.gov; Suguna.Sakkiah@fda.hhs.gov; Selvaraj.Chandrabose@fda.hhs.gov; Weigong.Ge@fda.hhs.gov; Weida.Tong@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration FX This research was supported in part by an appointment to the Research Participation Program at the National Center for Toxicological Research (Sugunadevi Sakkiah, Sevaraji Chandrabose) 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 authors thank Charles Ganley and Jian Wang for critical review of the manuscript. NR 36 TC 0 Z9 0 U1 1 U2 1 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD OCT PY 2016 VL 13 IS 10 AR 958 DI 10.3390/ijerph13100958 PG 17 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA EE4KF UT WOS:000389570100025 ER PT J AU Meehan, RA Mon, DT Kelly, KM Rocca, M Dickinson, G Ritter, J Johnson, CM AF Meehan, Rebecca A. Mon, Donald T. Kelly, Kandace M. Rocca, Mitra Dickinson, Gary Ritter, John Johnson, Constance M. TI Increasing EHR system usability through standards: Conformance criteria in the HL7 EHR-system functional model SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Editorial Material DE Electronic health records; Usability; Standards; Health information technology ID DESIGN AB Though substantial work has been done on the usability of health information technology, improvements in electronic health record system (EHR) usability have been slow, creating frustration, distrust of EHRs and the use of potentially unsafe work-arounds. Wability standards could be part of the solution for improving EHR usability. EHR system functional requirements and standards have been used successfully in the past to specify system behavior, the criteria of which have been gradually implemented in EHR systems through certification programs and other national health IT strategies. Similarly, functional requirements and standards for usability can help address the multitude of sequelae associated with poor usability. This paper describes the evidence-based functional requirements for usability contained in the Health Level Seven (HL7) EHR System Functional Model, and the benefits of open and voluntary EHR system usability standards. (C) 2016 Elsevier Inc. All rights reserved. C1 [Meehan, Rebecca A.] Kent State Univ, Kent, OH 44242 USA. [Mon, Donald T.] RTI Int, Chicago, IL USA. [Kelly, Kandace M.] UCLA Hlth, Los Angeles, CA USA. [Rocca, Mitra] Food & Drug Adm, Dip Inform Med, Silver Spring, MD USA. [Dickinson, Gary] CentriHealth, Los Angeles, CA USA. [Ritter, John] Your Data Steward, Monroeville, PA USA. [Johnson, Constance M.] Duke Univ, Durham, NC USA. RP Meehan, RA (reprint author), Kent State Univ, Sch Lib & Informat Sci, 314 Lib,1125 Risman Dr, Kent, OH 44242 USA. EM Rmeehan3@kent.edu NR 23 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 EI 1532-0480 J9 J BIOMED INFORM JI J. Biomed. Inform. PD OCT PY 2016 VL 63 BP 169 EP 173 DI 10.1016/j.jbi.2016.08.015 PG 5 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA EE4FF UT WOS:000389557000019 PM 27523469 ER PT J AU Vogt, WC Jia, CX Wear, KA Garra, BS Pfefer, TJ AF Vogt, William C. Jia, Congxian Wear, Keith A. Garra, Brian S. Pfefer, T. Joshua TI Biologically relevant photoacoustic imaging phantoms with tunable optical and acoustic properties SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE image quality; tissue phantoms; standardization; breast imaging; photoacoustic tomography; optoacoustics ID BREAST-TISSUE; IN-VIVO; LABORATORY PROTOTYPE; MIMICKING PHANTOMS; TOMOGRAPHY; SYSTEM; MAMMOGRAPHY; BLOOD AB Established medical imaging technologies such as magnetic resonance imaging and computed tomography rely on well-validated tissue-simulating phantoms for standardized testing of device image quality. The availability of high-quality phantoms for optical-acoustic diagnostics such as photoacoustic tomography ( PAT) will facilitate standardization and clinical translation of these emerging approaches. Materials used in prior PAT phantoms do not provide a suitable combination of long-term stability and realistic acoustic and optical properties. Therefore, we have investigated the use of custom polyvinyl chloride plastisol (PVCP) formulations for imaging phantoms and identified a dual-plasticizer approach that provides biologically relevant ranges of relevant properties. Speed of sound and acoustic attenuation were determined over a frequency range of 4 to 9 MHz and optical absorption and scattering over a wavelength range of 400 to 1100 nm. We present characterization of several PVCP formulations, including one designed to mimic breast tissue. This material is used to construct a phantom comprised of an array of cylindrical, hemoglobin-filled inclusions for evaluation of penetration depth. Measurements with a custom near-infrared PAT imager provide quantitative and qualitative comparisons of phantom and tissue images. Results indicate that our PVCP material is uniquely suitable for PAT system image quality evaluation and may provide a practical tool for device validation and intercomparison. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. C1 [Vogt, William C.; Jia, Congxian; Wear, Keith A.; Garra, Brian S.; Pfefer, T. Joshua] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Pfefer, TJ (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Joshua.Pfefer@fda.hhs.gov FU FDA Medical Countermeasures Initiative; FDA Office of Women's Health; ORISE fellowship program through Oak Ridge Associated Universities FX The authors gratefully acknowledge funding support from the FDA Medical Countermeasures Initiative and the FDA Office of Women's Health, as well as the ORISE fellowship program through Oak Ridge Associated Universities. The authors also wish to thank Irada Isayeva, Ph.D., and Katherine Vorvolakos, Ph.D., of the Center for Devices and Radiological Health for insightful discussions. NR 54 TC 4 Z9 4 U1 5 U2 5 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 EI 1560-2281 J9 J BIOMED OPT JI J. Biomed. Opt. PD OCT PY 2016 VL 21 IS 10 AR 101405 DI 10.1117/1.JBO.21.10.101405 PG 11 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA EC5YN UT WOS:000388213300007 PM 26886681 ER PT J AU Bai, JPF AF Bai, Jane P. F. TI Pharmacodynamics and Systems Pharmacology Approaches to Repurposing Drugs in the Wake of Global Health Burden SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE global health; big data; pharmacodynamics; systems pharmacology ID FDA-APPROVED DRUGS; MORTALITY; CANCER; METFORMIN; DISEASE; ASSOCIATION; EXPRESSION; THERAPY; RECORDS AB There are emergent needs for cost-effective treatment worldwide, for which repurposing to develop a drug with existing marketing approval of disease(s) for new disease(s) is a valid option. Although strategic mining of electronic health records has produced real-world evidences to inform drug repurposing, using omics data (drug and disease), knowledge base of protein interactions, and database of transcription factors have been explored. Structured integration of all the existing data under the framework of drug repurposing will facilitate decision making. The ability to foresee the need to integrate new data types produced by emergent technologies and to enable data connectivity in the context of human biology and targeted diseases, as well as to use the existing crucial quality data of all approved drugs will catapult the number of drugs being successfully repurposed. However, translational pharmacodynamics databases for modeling information across human biology in the context of host factors are lacking and are critically needed for drug repurposing to improve global public health, especially for the efforts to combat neglected tropic diseases as well as emergent infectious diseases such as Zika or Ebola virus. Published by Elsevier Inc. on behalf of the American Pharmacists Association. C1 [Bai, Jane P. F.] US FDA, Off Clin Pharmacol, Ctr Drug Res & Evaluat, Silver Spring, MD 20993 USA. RP Bai, JPF (reprint author), US FDA, Off Clin Pharmacol, Ctr Drug Res & Evaluat, Silver Spring, MD 20993 USA. EM jane.bai@fda.hhs.gov NR 32 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD OCT PY 2016 VL 105 IS 10 BP 3007 EP 3012 DI 10.1016/j.xphs.2016.07.004 PG 6 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA EC6ST UT WOS:000388267700002 PM 27522921 ER PT J AU Lin, HP Sun, DJ Zhang, XY Wen, H AF Lin, Ho-Pi Sun, Dajun Zhang, Xinyuan Wen, Hong TI Physiologically Based Pharmacokinetic Modeling for Substitutability Analysis of Venlafaxine Hydrochloride Extended-Release Formulations Using Different Release Mechanisms: Osmotic Pump Versus Openable Matrix SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE physiologically based pharmacokinetic modeling; osmotic pumps; controlled-release; oral drug delivery; bioequivalence ID DRUG-DRUG INTERACTIONS; WATER-SOLUBLE DRUGS; SUSTAINED-RELEASE; DELIVERY SYSTEMS; XANTHAN GUM; IN-VITRO; FOOD; ANTIDEPRESSANTS; OPTIMIZATION; PERFORMANCE AB Food and Drug Administrationeapproved generic oral product of venlafaxine hydrochloride (HCl) extended-release (ER) tablets has used a release mechanism based on an openable matrix, which is different from the pushepull osmotic pump system of its reference-listed drug. In an extreme case, a delay in the bursting of the openable matrix may be considered a product failure mode that alters the intended profile of systemic exposure. A physiologically based pharmacokinetic absorption model was established and verified to simulate the pharmacokinetic profiles after a single-dose oral administration of ER venlafaxine HCl tablets based on an osmotic pump or openable matrix design. This model adequately predicted the observed human mean pharmacokinetic metrics with < 20% difference between the predicted and observed data. Based on the modeling and simulation results, Cmax and AUCt of the venlafaxine openable matrix tablets were entirely within the bioequivalence acceptance limits (i.e., 80%-125%) when the lag time varied from 0 to 4 h and using drug-release profiles under most dissolution conditions. The results indicated that a bioinequivalence risk is minimal for a delayed onset of drug release from the approved generic venlafaxine HCl ER tablets with an openable matrix design, supporting its substitutability to the reference product. (C) Published by Elsevier Inc. on behalf of the American Pharmacists Association. C1 [Lin, Ho-Pi; Sun, Dajun; Zhang, Xinyuan; Wen, Hong] US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Zhang, XY; Wen, H (reprint author), US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Xinyuan.Zhang@fda.hhs.gov; Hong.Wen@fda.hhs.gov FU ORISE Research Participation Program at the Center for Drug Evaluation and Research FX The authors would like acknowledge scientific discussions and support of Drs. Robert Lionberger, Wenlei Jiang, Liang Zhao, Sarah Dutcher, and Ming Qin. This was supported in part by an appointment to the ORISE Research Participation Program at the Center for Drug Evaluation and Research, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. Disclaimer: This article reflects the views of the authors and should not be construed to represent the FDA's views or policies. NR 40 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD OCT PY 2016 VL 105 IS 10 BP 3088 EP 3096 DI 10.1016/j.xphs.2016.06.015 PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA EC6ST UT WOS:000388267700012 PM 27449228 ER PT J AU Gray, RA Pathmanathan, P AF Gray, Richard A. Pathmanathan, Pras TI A Parsimonious Model of the Rabbit Action Potential Elucidates the Minimal Physiological Requirements for Alternans and SpiralWave Breakup SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID HUMAN VENTRICULAR CELLS; ION CHANNELS; GUINEA-PIG; CARDIAC ELECTROPHYSIOLOGY; MYOCARDIAL FIBERS; EXCITABLE MEDIA; SLOW RECOVERY; I-KS; HEART; FIBRILLATION AB Elucidating the underlying mechanisms of fatal cardiac arrhythmias requires a tight integration of electrophysiological experiments, models, and theory. Existing models of transmembrane action potential (AP) are complex (resulting in over parameterization) and varied (leading to dissimilar predictions). Thus, simpler models are needed to elucidate the "minimal physiological requirements" to reproduce significant observable phenomena using as few parameters as possible. Moreover, models have been derived from experimental studies from a variety of species under a range of environmental conditions (for example, all existing rabbit AP models incorporate a formulation of the rapid sodium current, I-Na, based on 30 year old data from chick embryo cell aggregates). Here we develop a simple "parsimonious" rabbit AP model that is mathematically identifiable (i.e., not over parameterized) by combining a novel Hodgkin-Huxley formulation of I-Na with a phenomenological model of repolarization similar to the voltage dependent, time-independent rectifying outward potassium current (I-K). The model was calibrated using the following experimental data sets measured from the same species (rabbit) under physiological conditions: dynamic current-voltage (I-V) relationships during the AP upstroke; rapid recovery of AP excitability during the relative refractory period; and steady-state I-Na inactivation via voltage clamp. Simulations reproduced several important "emergent" phenomena including cellular alternans at rates >250 bpm as observed in rabbit myocytes, reentrant spiral waves as observed on the surface of the rabbit heart, and spiral wave breakup. Model variants were studied which elucidated the minimal requirements for alternans and spiral wave break up, namely the kinetics of I-Na inactivation and the non-linear rectification of I-K. The simplicity of the model, and the fact that its parameters have physiological meaning, make it ideal for engendering generalizable mechanistic insight and should provide a solid "building-block" to generate more detailed ionic models to represent complex rabbit electrophysiology. C1 [Gray, Richard A.; Pathmanathan, Pras] US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Gray, RA (reprint author), US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM Richard.Gary@fda.hhs.gov OI GRAY, RICHARD/0000-0003-2798-6378 FU FDA Center of Devices and Radiological Health Critical Path Program FX This work was supported by the FDA Center of Devices and Radiological Health Critical Path Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 1 Z9 1 U1 5 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD OCT PY 2016 VL 12 IS 10 AR e1005087 DI 10.1371/journal.pcbi.1005087 PG 21 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA EB8SC UT WOS:000387660200008 PM 27749895 ER PT J AU He, XB Ma, L Xia, QS Fu, PP AF He, Xiaobo Ma, Liang Xia, Qingsu Fu, Peter P. TI 7-N-Acetylcysteine-pyrrole conjugate-A potent DNA reactive metabolite of pyrrolizidine alkaloids SO JOURNAL OF FOOD AND DRUG ANALYSIS LA English DT Article DE DHP; LC-ES-MS/MS; 7-N-acetylcysteine-DHP; pyrrolizidine alkaloid ID ALCOHOL GLUTATHIONE CONJUGATE; ADDUCT FORMATION; IN-VIVO; MICROSOMAL FORMATION; DIETARY-SUPPLEMENTS; N-OXIDES; ACTIVATION; MONOCROTALINE; LIVER; TUMORIGENICITY AB Plants containing pyrrolizidine alkaloids (PAs) are widespread throughout the world and are the most common poisonous plants affecting livestock, wildlife, and humans. PAs require metabolic activation to form reactive dehydropyrrolizidine alkaloids (dehydro-PAs) that are capable of alkylating cellular DNA and proteins, form (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-DNA and DHP-protein adducts, and lead to cytotoxicity, genotoxicity, and tumorigenicity. In this study, we determined that the metabolism of riddelliine and monocrotaline by human and rat liver microsomes in the presence of N-acetylcysteine both produced 7-N-acetylcysteine-DHP (7-NAC-DHP) and DHP. Reactions of 7-NAC-DHP with 2'-deoxyguanosine (dG), 2'-deoxyadenosine (dA), and calf thymus DNA in aqueous solution followed by enzymatic hydrolysis yielded DHP-dG and/or DHP-dA adducts. These results indicate that 7-NAC-DHP is a reactive metabolite that can lead to DNA adduct formation. Copyright (C) 2016, Food and Drug Administration, Taiwan. Published by Elsevier Taiwan LLC. C1 [He, Xiaobo; Ma, Liang; Xia, Qingsu; Fu, Peter P.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Fu, PP (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM peter.fu@fda.hhs.gov NR 32 TC 1 Z9 1 U1 3 U2 3 PU FOOD & DRUG ADMINSTRATION PI TAIPEI PA 161-2 KUNYANG STREET, NANGANG, TAIPEI, 00000, TAIWAN SN 1021-9498 J9 J FOOD DRUG ANAL JI J. Food Drug Anal. PD OCT PY 2016 VL 24 IS 4 BP 682 EP 694 DI 10.1016/j.jfda.2016.08.001 PG 13 WC Food Science & Technology; Pharmacology & Pharmacy SC Food Science & Technology; Pharmacology & Pharmacy GA EC2JD UT WOS:000387937100002 ER PT J AU Yamini, S Trumbo, PR AF Yamini, Sedigheh Trumbo, Paula R. TI Qualified health claim for whole-grain intake and risk of type 2 diabetes: an evidence-based review by the US Food and Drug Administration SO NUTRITION REVIEWS LA English DT Review DE diabetes; health claim; type 2 diabetes; whole grains ID CROSS-SECTIONAL ASSOCIATION; CARDIOVASCULAR-DISEASE RISK; RANDOMIZED CONTROLLED-TRIAL; LOWER POSTPRANDIAL GLUCOSE; DIETARY FIBER INTAKE; INSULIN RESPONSES; METABOLIC SYNDROME; GLYCEMIC INDEX; BLOOD-GLUCOSE; BROWN RICE AB The objective of this review is to explain how the US Food and Drug Administration (FDA) used its evidence-based review system to evaluate the scientific evidence for a qualified health claim on the role of whole-grain consumption in reducing the risk of type 2 diabetes. The labeling of health claims, including qualified health claims, on conventional foods and dietary supplements requires premarket approval by the FDA. Health claims characterize the relationship between a substance (food or food component) and a disease (eg, diabetes or cardiovascular disease) or a health-related condition (eg, hypertension). This review describes the FDA's evaluation of intervention and observational studies that characterize a relationship between whole grains and type 2 diabetes. This evidence-based review provides very limited evidence to support a health claim of a relationship between intake of whole grains and a reduced risk of type 2 diabetes. C1 [Yamini, Sedigheh; Trumbo, Paula R.] US FDA, Off Nutr & Food Labeling, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Yamini, S (reprint author), 5100 Campus Dr,HFS 830, College Pk, MD 20740 USA. EM essie.yamini@fda.hhs.gov NR 108 TC 0 Z9 0 U1 10 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0029-6643 EI 1753-4887 J9 NUTR REV JI Nutr. Rev. PD OCT 1 PY 2016 VL 74 IS 10 BP 601 EP 611 DI 10.1093/nutrit/nuw027 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EB7TC UT WOS:000387592500001 PM 27566984 ER PT J AU Gabay, O Clouse, KA AF Gabay, Odile Clouse, Kathleen A. TI Epigenetics of cartilage diseases SO JOINT BONE SPINE LA English DT Review DE Epigenetics; DNA methylation; miRNA; Histone deacetylases; Arthritis; Cartilage ID ARTICULAR CHONDROCYTES; DNA METHYLATION; OSTEOARTHRITIC CHONDROCYTES; RHEUMATOID-ARTHRITIS; HISTONE DEACETYLASE; MECHANICAL-STRESS; SIGNALING PATHWAY; CPG SITES; EXPRESSION; SIRT1 AB Osteoarticular diseases, such as arthritis or osteoarthritis, are multifactorial diseases with an underlying genetic etiology that are challenging to study. Genome-Wide Association studies (GWAS) have identified several genetic loci associated with these diseases. Epigenetics is a complex mechanism of chromatin and gene modulation through DNA methylation, histone deacetylation or microRNA, which might contribute to the inheritability of disease. Some of these mechanisms have been studied for decades in other diseases or as part of the aging process, where epigenetic changes seem to play an important role. With the implementation of better technological tools, such as the Illumina next generation sequencing, altered methylation of DNA has been linked to articular diseases and these mechanisms have been shown to regulate metalloprotease (MMP) expression and cartilage matrix integrity. Some miRNA have also been identified and more extensively characterized, such as delineation of the role played by miR-140 in chondrogenesis, followed by the discovery of numerous miRNA potentially involved in the epigenetic regulation of osteoarthritic disease. Histone deacetylases have long been linked to aging, particularly with respect to the Sirtuin family with Sirt1 as the major player. Because aging is the major risk factor for osteoarthritis, the involvement of Sirtuins in the etiology of osteoarthritis has been suggested and investigated. All of these fine regulations together shed new light on cartilage disease pathophysiology. We present in this short review an update of the role of these pathways in articular diseases. (C) 2015 Societe francaise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. C1 [Gabay, Odile; Clouse, Kathleen A.] US FDA, Div Biotechnol Review & Res 1, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,White Oak Fed Campus, Silver Spring, MD 20993 USA. RP Gabay, O (reprint author), US FDA, Div Biotechnol Review & Res 1, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,White Oak Fed Campus, Silver Spring, MD 20993 USA. EM odile.engel@fda.hhs.gov NR 36 TC 2 Z9 2 U1 5 U2 5 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 1297-319X EI 1778-7254 J9 JOINT BONE SPINE JI Joint Bone Spine PD OCT PY 2016 VL 83 IS 5 BP 491 EP 494 DI 10.1016/j.jbspin.2015.10.004 PG 4 WC Rheumatology SC Rheumatology GA EA4ZN UT WOS:000386626000006 PM 26723856 ER PT J AU Selzman, KA Fellman, M Farb, A de del Castillo, S Zuckerman, B AF Selzman, Kimberly A. Fellman, Mark Farb, Andrew de del Castillo, Sergio Zuckerman, Bram TI New technology in electrophysiology: FDA process and perspective SO JOURNAL OF INTERVENTIONAL CARDIAC ELECTROPHYSIOLOGY LA English DT Article DE Regulatory science; Innovation; Post market surveillance; Food and Drug Administration (FDA) AB The Food and Drug Administration (FDA) is a large regulatory agency that monitors everything from food, tobacco, and veterinary medicine to pharmaceutical drugs and medical devices. The Mission statement of the CDRH, one of the Centers of the FDA, in its most succinct form is to protect and promote public health. This is accomplished through timely and continued access to safe, effective, and high quality medical devices. This paper aims to review the overarching principles of the Agency's review process for cardiac devices as well as highlight some of the newer programs that FDA has engaged in to facilitate innovation, device development, research, and timely market approval. C1 [Selzman, Kimberly A.; Fellman, Mark; Farb, Andrew; de del Castillo, Sergio; Zuckerman, Bram] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Implantable Electrophysiol Devices Branch, 10903 New Hampshire Ave,WO66, Silver Spring, MD 20993 USA. RP Selzman, KA (reprint author), US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Implantable Electrophysiol Devices Branch, 10903 New Hampshire Ave,WO66, Silver Spring, MD 20993 USA. EM kimberly.selzman@fda.hhs.gov NR 2 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1383-875X EI 1572-8595 J9 J INTERV CARD ELECTR JI J. Interv. Card. Electrophysiol. PD OCT PY 2016 VL 47 IS 1 SI SI BP 11 EP 18 DI 10.1007/s10840-016-0127-4 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EB1KO UT WOS:000387110400003 PM 27020440 ER PT J AU Huang, J Kang, B Ishida, E Griesman, T Wheatley, AK Khurana, S Narpala, SR McDermott, AB Poole, A Bailer, RT Koup, RA Alexander, J Smith, J Migueles, SA Golding, H Wohlbold, TJ Chromikova, V Krammer, F Gurwith, M Connors, M AF Huang, Jinghe Kang, Byong Ishida, Elise Griesman, Trevor Wheatley, Adam K. Khurana, Surender Narpala, Sandeep R. McDermott, Adrian B. Poole, April Bailer, Robert T. Koup, Richard A. Alexander, Jeffrey Smith, Jonathan Migueles, Stephen A. Golding, Hana Wohlbold, Teddy John Chromikova, Veronika Krammer, Florian Gurwith, Marc Connors, Mark TI Upper Respiratory Tract (URT) Administration of a Replication Competent Ad4-H5-Vtn Vaccine Induces Durable Neutralizing Antibody Responses in Humans SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on HIV Research for Prevention (HIV R4P) CY OCT 17-20, 2016 CL Chicago, IL C1 [Huang, Jinghe; Kang, Byong; Ishida, Elise; Griesman, Trevor; Poole, April; Migueles, Stephen A.; Connors, Mark] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Wheatley, Adam K.; Narpala, Sandeep R.; McDermott, Adrian B.; Bailer, Robert T.; Koup, Richard A.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Khurana, Surender; Golding, Hana] US FDA, Rockville, MD 20857 USA. [Alexander, Jeffrey; Smith, Jonathan; Gurwith, Marc] PaxVax Inc, San Diego, CA USA. [Wohlbold, Teddy John; Chromikova, Veronika; Krammer, Florian] Icahn Sch Med Mt Sinai, New York, NY 10029 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2016 VL 32 SU 1 MA OA22.05 BP 101 EP 101 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EA6YH UT WOS:000386774600180 ER PT J AU Yoon, SS Dillon, CF Illoh, K Carroll, M AF Yoon, Sung Sug (Sarah) Dillon, Charles F. Illoh, Kachi Carroll, Margaret TI Trends in the Prevalence of Coronary Heart Disease in the US National Health and Nutrition Examination Survey, 2001-2012 SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID UNITED-STATES; BLOOD-PRESSURE; SELF-REPORTS; HYPERTENSION; ADULTS; MORTALITY; RISK; LIPOPROTEINS; POPULATION; VALIDITY AB Introduction: This study evaluated recent trends in the prevalence of coronary heart disease in the U.S. population aged >= 40 years. Methods: A total of 21,472 adults aged >= 40 years from the 2001-2012 National Health and Nutrition Examination Survey were included in the analysis. The analysis was conducted in 2015. Coronary heart disease included myocardial infarction, angina, and any other type of coronary heart disease, which were defined as a history of medical diagnosis of these specific conditions. Angina was also defined as currently taking anti-angina medication or having Rose Angina Questionnaire responses that scored with a Grade >= 1. Trends from 2001 to 2012 were analyzed overall, within demographic subgroups, and by major coronary heart disease risk factors. Results: Between 2001 and 2012, the overall prevalence of coronary heart disease significantly decreased from 10.3% to 8.0% (p-trend<0.05). The prevalence of angina significantly decreased from 7.8% to 5.5% and myocardial infarction prevalence decreased from 5.5% to 4.7% (p-trend <0.05 for both groups). Overall coronary heart disease prevalence significantly decreased among women, adults aged >60 years, non-Hispanic whites, non-Hispanic blacks, adults who did not complete high school, adults with more than a high school education, and adults who had health insurance (p-trend <0.05 for all groups). Conclusions: The overall prevalence of coronary heart disease including angina and myocardial infarction decreased significantly over the 12-year survey period. However, this reduction was seen mainly among persons without established coronary heart disease risk factors. There was no change in coronary heart disease prevalence among those with specific coronary heart disease risk factors. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Yoon, Sung Sug (Sarah)] NIH, Healthcare Delivery & Methodol IRG, Div AIDS Behav & Populat Sci, Ctr Sci Review, 6701 Rockledge Dr,Room 3152,MSC 7770, Bethesda, MD 20892 USA. [Dillon, Charles F.] CDC, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Illoh, Kachi] US FDA, Off New Drugs Immediate Off, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Carroll, Margaret] CDC, Div Hlth & Nutr Examinat Surveys, Natl Ctr Hlth Stat, Hyattsville, MD USA. RP Yoon, SS (reprint author), NIH, Healthcare Delivery & Methodol IRG, Div AIDS Behav & Populat Sci, Ctr Sci Review, 6701 Rockledge Dr,Room 3152,MSC 7770, Bethesda, MD 20892 USA. EM sarah.yoon@nih.gov NR 39 TC 2 Z9 2 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2016 VL 51 IS 4 BP 437 EP 445 DI 10.1016/j.amepre.2016.02.023 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EA7BX UT WOS:000386784200008 PM 27113539 ER PT J AU Chien, HC Yang, YHK Bai, JPF AF Chien, Hsu-Chih Yang, Yea-Huei Kao Bai, Jane P. F. TI Trastuzumab-Related Cardiotoxic Effects in Taiwanese Women A Nationwide Cohort Study SO JAMA ONCOLOGY LA English DT Article ID BREAST-CANCER PATIENTS; CARDIAC SAFETY ANALYSIS; HEART-FAILURE; ADJUVANT CHEMOTHERAPY; TIME BIAS; FOLLOW-UP; TRIAL; THERAPY; ASIA; DOXORUBICIN AB IMPORTANCE Trastuzumab is an essential medicine per the World Health Organization Model List, but its cardiac safety information in Asian women is limited. OBJECTIVE To estimate the rate and the risk of heart failure (HF) and/or cardiomyopathy (CM) in Asian women undergoing trastuzumab treatment. DESIGN This cohort study used the Taiwanese National Health Insurance Research Database (NHIRD), a nationwide claim database covering more than 99% of the entire Taiwanese population, to identify 23 006 women with incident breast cancer (BC) who received chemotherapy from 2006 to 2009. We grouped women per their initial treatment regimens and found 1066 new trastuzumab users. We matched trastuzumab users with nonusers by year of BC diagnosis and propensity score (PS) with the caliper widths at 0.25 standard deviation of PS (up to 4 nonusers per trastuzumab user). The study lasted from January 2006 to December 2013 with a median follow-up of 5.29 years and a landmark design to avoid immortal time bias. EXPOSURE Trastuzumab. MAIN OUTCOMES AND MEASURES To estimate HF and/or CM rates and time to HF and/or CM, we employed a cause-specific hazard model. Trastuzumab exposure was a time-dependent variable, while cumulative courses of chemotherapy agents with known cardiotoxic effects (including anthracyclines, taxanes, and cyclophosphamide) were defined as time-dependent covariates in the analysis model. We also performed 6 sensitivity analyses. RESULTS In this cohort of 23 006 women (mean age, 50.99 years), the crude incidence of HF and/or CM was 4.03% in trastuzumab users and 2.88% in nonusers. The median time to HF and/or CM was 456 days in trastuzumab users and 966 days in nonusers. The 1-year cumulative hazard ratio was 1.86 (95% CI, 1.08-3.19). The sensitivity analyses yielded similar results. CONCLUSIONS AND RELEVANCE Compared with the published results, the trastuzumab-related HF and/or CM rate was 5-fold lower in Taiwanese women with breast cancer. Nonetheless, our cohort had a similar trastuzumab-related HF and/or CM risk. Our study provides critical cardiac safety information of trastuzumab for Asian women with BC under current treatment guidelines and label information. C1 [Chien, Hsu-Chih; Bai, Jane P. F.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Chien, Hsu-Chih; Yang, Yea-Huei Kao] Natl Cheng Kung Univ, Coll Med, Inst Clin Pharm & Pharmaceut Sci, 1 Univ Rd, Tainan 70101, Taiwan. [Chien, Hsu-Chih; Yang, Yea-Huei Kao] Natl Cheng Kung Univ, Hlth Outcome Res Ctr, Tainan, Taiwan. RP Yang, YHK (reprint author), Natl Cheng Kung Univ, Coll Med, Inst Clin Pharm & Pharmaceut Sci, 1 Univ Rd, Tainan 70101, Taiwan.; Bai, JPF (reprint author), US EPA, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM yhkao@mail.ncku.edu.tw; jane.bai@fda.hhs.gov FU Taiwan Ministry of Science and Technology [102-2628-B-006-003-MY3]; FDA CDER [12-30] FX This research was supported by the Taiwan Ministry of Science and Technology (grant No. 102-2628-B-006-003-MY3) and a 2012 Critical Path Award (#12-30) from the FDA CDER. NR 35 TC 1 Z9 1 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA EI 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD OCT 1 PY 2016 VL 2 IS 10 BP 1317 EP 1325 DI 10.1001/jamaoncol.2016.1269 PG 9 WC Oncology SC Oncology GA EA3GB UT WOS:000386488600016 PM 27310478 ER PT J AU Karunathilaka, SR Kia, ARF Srigley, C Chung, JK Mossoba, MM AF Karunathilaka, Sanjeewa R. Kia, Ali-Reza Fardin Srigley, Cynthia Chung, Jin Kyu Mossoba, Magdi M. TI Nontargeted, Rapid Screening of Extra Virgin Olive Oil Products for Authenticity Using Near-Infrared Spectroscopy in Combination with Conformity Index and Multivariate Statistical Analyses SO JOURNAL OF FOOD SCIENCE LA English DT Article DE Authentication; olive oil; rapid screening ID HAZELNUT OIL; ADULTERATION; QUANTIFICATION; CHEMOMETRICS; IDENTIFICATION; RAMAN AB A rapid tool for evaluating authenticity was developed and applied to the screening of extra virgin olive oil (EVOO) retail products by using Fourier-transform near infrared (FT-NIR) spectroscopy in combination with univariate and multivariate data analysis methods. Using disposable glass tubes, spectra for 62 reference EVOO, 10 edible oil adulterants, 20 blends consisting of EVOO spiked with adulterants, 88 retail EVOO products and other test samples were rapidly measured in the transmission mode without any sample preparation. The univariate conformity index (CI) and the multivariate supervised soft independent modeling of class analogy (SIMCA) classification tool were used to analyze the various olive oil products which were tested for authenticity against a library of reference EVOO. Better discrimination between the authentic EVOO and some commercial EVOO products was observed with SIMCA than with CI analysis. Approximately 61% of all EVOO commercial products were flagged by SIMCA analysis, suggesting that further analysis be performed to identify quality issues and/or potential adulterants. Due to its simplicity and speed, FT-NIR spectroscopy in combination with multivariate data analysis can be used as a complementary tool to conventional official methods of analysis to rapidly flag EVOO products that may not belong to the class of authentic EVOO. Practical Application This report describes the application of near-infrared spectroscopy to the rapid screening of extra virgin olive oils (EVOO) for authenticity. It provides government regulators and stakeholders a practical tool to rapidly assess EVOO quality and/or purity. The proposed procedure should flag mislabeled and intentionally adulterated products, and meet potential safety concerns should fraudsters adulterate with toxic chemicals. C1 [Karunathilaka, Sanjeewa R.; Kia, Ali-Reza Fardin; Srigley, Cynthia; Chung, Jin Kyu; Mossoba, Magdi M.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. RP Mossoba, MM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. EM magdi.mossoba@fda.hhs.gov NR 28 TC 0 Z9 0 U1 15 U2 15 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 OCT PY 2016 VL 81 IS 10 BP C2390 EP C2397 DI 10.1111/1750-3841.13432 PG 8 WC Food Science & Technology SC Food Science & Technology GA DZ3AN UT WOS:000385715500015 PM 27626761 ER PT J AU Kaul, S Zimmer, J Dehus, O Costanzo, A Daas, A Buchheit, KH Asturias, JA Barber, D Carnes, J Chapman, M Dayan-Kenigsberg, J Doring, S Fuhrer, F Hanschmann, KM Holzhauser, T Ledesma, A Moingeon, P Nony, E Pini, C Plunkett, G Reese, G Sandberg, E Sander, I Strecker, D Valerio, C van Ree, R Vieths, S AF Kaul, S. Zimmer, J. Dehus, O. Costanzo, A. Daas, A. Buchheit, K. H. Asturias, J. A. Barber, D. Carnes, J. Chapman, M. Dayan-Kenigsberg, J. Doering, S. Fuehrer, F. Hanschmann, K. M. Holzhauser, T. Ledesma, A. Moingeon, P. Nony, E. Pini, C. Plunkett, G. Reese, G. Sandberg, E. Sander, I. Strecker, D. Valerio, C. van Ree, R. Vieths, S. TI Standardization of allergen products: 3. Validation of candidate European Pharmacopoeia standard methods for quantification of major birch allergen Bet v 1 SO ALLERGY LA English DT Article DE Bet v 1; biological standardisation; ELISA; European Pharmacopoeia; major allergen ID SUBLINGUAL IMMUNOTHERAPY; CREATE PROJECT; POLLEN; EXPOSURE; UNION; UNITS AB Background: The BSP090 project aims at establishing European Pharmacopoeia Reference Substances in combination with the corresponding ELISA methods for the quantification of major allergens in allergen products. Two sandwich ELISAs proved suitable for quantification of Bet v 1, the major birch pollen allergen, in preceding phases of BSP090. Methods: Two Bet v 1-specific ELISA systems were compared with respect to accuracy and precision in a ring trial including 13 laboratories. Model samples containing recombinant rBet v 1.0101 as well as native birch pollen extracts were measured independently at least three times in each facility. The assessment was completed with a comparative quantification of Bet v 1 in 30 marketed birch allergen products in one laboratory, simulating the future use as reference method. Results: In the collaborative study, both candidate ELISAs confirmed their suitability to quantify recombinant and native Bet v 1. ELISA-A showed higher precision and lower interlaboratory variability, yet ELISA-B exhibited slightly higher accuracy. Subsequent parallel measurement of Bet v 1 in a panel of 'real-life' birch allergen products indicated better repeatability of ELISA-B. Both systems detected substantial differences in Bet v 1 content between allergen products, but the effect was more pronounced using ELISA-B due to persistently higher values compared to ELISA-A. Conclusions: In the collaborative study, no deciding differences were observed between the two candidate ELISAs. Further comparison under conditions simulating the intended use combined with the criterion of long-term availability enabled the selection of one Bet v 1-specific ELISA for proposal as European Pharmacopoeia standard method. C1 [Kaul, S.; Zimmer, J.; Dehus, O.; Doering, S.; Fuehrer, F.; Hanschmann, K. M.; Holzhauser, T.; Strecker, D.; Vieths, S.] Paul Ehrlich Inst, Paul Ehrlich Str 51-59, D-63225 Langen, Germany. [Costanzo, A.; Daas, A.; Buchheit, K. H.] European Directorate Qual Med & HealthCare EDQM, Strasbourg, France. [Asturias, J. A.] BIAL Ind Farmaceut, Zamudio, Spain. [Barber, D.; Ledesma, A.] ALK Abello SA, Madrid, Spain. [Carnes, J.] Lab Leti SL, Tres Cantos, Spain. [Chapman, M.] Indoor Biotechnol, Charlottesville, VA USA. [Dayan-Kenigsberg, J.] ANSM, St Denis, France. [Moingeon, P.; Nony, E.] Stallergenes Greer, Antony, France. [Pini, C.] ISS CRIVIB, Rome, Italy. [Plunkett, G.] ALK Abello Inc, Round Rock, TX USA. [Reese, G.] Allergopharma GmbH & Co KG, Reinbek, Germany. [Sandberg, E.] Danish Med Agcy, Copenhagen S, Denmark. [Sander, I.] Ruhr Univ Bochum IPA, Inst Prevent & Occupat Med, German Social Accid Insurance, Bochum, Germany. [Valerio, C.] US FDA, Silver Spring, MD USA. [van Ree, R.] Acad Med Ctr, Amsterdam, Netherlands. RP Vieths, S (reprint author), Paul Ehrlich Inst, Paul Ehrlich Str 51-59, D-63225 Langen, Germany. EM stefan.vieths@pei.de FU EDQM [BSP090] FX The project BSP090 is supported by a grant from the EDQM. We thank all participating laboratories for their contribution and the technical staff for timely and reliable work at the bench. In particular, we thank Maud Hrabina (Stallergenes Greer), Monika Raulf (IPA), Barbara Brunetto and Patrizia Iacovacci (ISS CRIVIB), Agnes Bertocchi and Gilles Chaudemanche (ANSM), Mayte Gallego and Maria Morales (Laboratorios LETI) for their highly valued contributions. Grateful acknowledgements go to the companies ALK-Abello and Stallergenes Greer for providing materials, SOPs and technical support throughout the project. NR 30 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-4538 EI 1398-9995 J9 ALLERGY JI Allergy PD OCT PY 2016 VL 71 IS 10 BP 1414 EP 1424 DI 10.1111/all.12898 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA DZ7YX UT WOS:000386085800005 PM 27018782 ER PT J AU Liu, K Tsujimoto, H Huang, YZ Rasgon, JL Agre, P AF Liu, Kun Tsujimoto, Hitoshi Huang, Yuzheng Rasgon, Jason L. Agre, Peter TI Aquaglyceroporin function in the malaria mosquito Anopheles gambiae SO BIOLOGY OF THE CELL LA English DT Article DE Anopheles gambiae; Aquaglyceroporin; Gene silencing; Malaria control; Stress adaptation ID AQUAPORIN WATER CHANNEL; AEDES-AEGYPTI; GLYCEROL; ADAPTATION; SUSCEPTIBILITY; PERMEATION; EXPRESSION; INFECTION; TRANSPORT; PROFILES AB Background informationAnopheles gambiae is the major mosquito vector for Plasmodium falciparum malaria in sub-Saharan Africa, where it survives in stressful climates. Aquaporin water channels are expressed in all life forms, where they provide environmental adaptation by conferring rapid trans-cellular movement of water (classical aquaporins) or water plus glycerol (aquaglyceroporins). Here, we report an aquaglyceroporin homolog in A. gambiae, AgAQP3 (A. gambiae aquaglyceroporin 3). ResultsDespite atypical pore-lining amino acids, AgAQP3 is permeated by water, glycerol and urea, and is not significantly inhibited by 1mM HgCl2. AgAQP3 is expressed more heavily in male mosquitoes, yet adult female A. gambiae abundantly express AgAQP3 in Malpighian tubules and gut where large amounts of fluid exchange occur during blood meal digestion, water and nutrient absorption and waste secretion. Reducing expression of AgAQP3 by RNA interference reduces median mosquito survival at 39 degrees C. After an infectious blood meal, mosquitoes with depleted AgAQP3 expression exhibit fewer P. falciparum oocysts in the midgut compared to control mosquitoes. ConclusionsOur studies reveal critical contributions of AgAQP3 to A. gambiae heat tolerance and P. falciparum development in vivo. SignificanceThis study indicates that AgAQP3 may be a major factor explaining why A. gambiae is an important malaria vector mosquito in sub-Saharan Africa, and may be a potential target for novel malaria control strategies. C1 [Liu, Kun; Agre, Peter] Johns Hopkins Univ, Johns Hopkins Malaria Res Inst, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Tsujimoto, Hitoshi; Rasgon, Jason L.] Penn State Univ, Huck Inst Life Sci, Ctr Infect Dis Dynam, Dept Entomol, University Pk, PA 16802 USA. [Huang, Yuzheng] Jiangsu Inst Parasit Dis, Wuxi 214064, Jiangsu, Peoples R China. [Huang, Yuzheng] Jiangsu Prov Acad Tradit Chinese Med, Nanjing 210028, Jiangsu, Peoples R China. [Liu, Kun] US FDA, Pacific Reg Lab Northwest, 22201 23rd DR SE, Bothell, WA 98021 USA. [Tsujimoto, Hitoshi] New Mexico State Univ, Dept Biol, Las Cruces, NM 88003 USA. RP Rasgon, JL (reprint author), Penn State Univ, Huck Inst Life Sci, Ctr Infect Dis Dynam, Dept Entomol, University Pk, PA 16802 USA. EM JLR54@psu.edu FU NIH [R01 HL48268, U19 AI089680, R21 AI111175, R21 AI088311, R01 AI116636, R01 AI067371]; JHMRI; Bloomberg Philanthropies; Jiangsu Health International Exchange Program in China; National Natural Science Foundation of China [31201893]; Natural and Science Foundation of Jiangsu Province [BK2011164]; Jiangsu Health Science Project [X201110, X200736]; Jiangsu Province Key Medical Center [201108]; Foundation of Key Lab of Jiangsu Preventive Veterinary Medicine [K13045] FX This study was supported by NIH grants R01 HL48268 and U19 AI089680 (to PA) and R21 AI111175, R21 AI088311, R01 AI116636 and R01 AI067371 (to JLR); two pilot grants from the JHMRI and Bloomberg Philanthropies (to JLR, PA and KL); funds from Jiangsu Health International Exchange Program in China; National Natural Science Foundation of China no. 31201893; Natural and Science Foundation of Jiangsu Province no. BK2011164; Jiangsu Health Science Project Nos. X201110 and X200736 and Jiangsu Province Key Medical Center no. 201108; Foundation of Key Lab of Jiangsu Preventive Veterinary Medicine no. K13045. The funders have no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 40 TC 1 Z9 1 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0248-4900 EI 1768-322X J9 BIOL CELL JI Biol. Cell PD OCT PY 2016 VL 108 IS 10 BP 294 EP 305 DI 10.1111/boc.201600030 PG 12 WC Cell Biology SC Cell Biology GA DZ3PM UT WOS:000385760900002 PM 27406921 ER PT J AU Fang, H Harris, SC Liu, ZC Zhou, GX Zhang, GP Xu, JS Rosario, L Howard, PC Tong, WD AF Fang, Hong Harris, Stephen C. Liu, Zhichao Zhou, Guangxu Zhang, Guoping Xu, Joshua Rosario, Lilliam Howard, Paul C. Tong, Weida TI FDA drug labeling: rich resources to facilitate precision medicine, drug safety, and regulatory science SO DRUG DISCOVERY TODAY LA English DT Review ID INDUCED LIVER-INJURY; INFORMATION AB Here, we provide a concise overview of US Food and Drug Administration (FDA) drug labeling, which details drug products, drug-drug interactions, adverse drug reactions (ADRs), and more. Labeling data have been collected over several decades by the FDA and are an important resource for regulatory research and decision making. However, navigating through this data is challenging. To aid such navigation, the FDALabel database was developed, which contains a set of approximately 80 000 labeling data. The full-text searching capability of FDALabel and querying based on any combination of specific sections, document types, market categories, market date, and other labeling information makes it a powerful and attractive tool for a variety of applications. Here, we illustrate the utility of FDALabel using case scenarios in pharmacogenomics biomarkers and ADR studies. C1 [Fang, Hong; Harris, Stephen C.; Liu, Zhichao; Zhou, Guangxu; Zhang, Guoping; Xu, Joshua; Howard, Paul C.; Tong, Weida] US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Rosario, Lilliam] US FDA, Off Computat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. RP Tong, WD (reprint author), US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM weida.tong@fda.hhs.gov FU FDA internal funding; National Center for Toxicological Research of the FDA through the Oak Ridge Institute for Science and Education FX The project was supported by FDA internal funding. G.Z. is grateful to the National Center for Toxicological Research of the FDA for postdoctoral support through the Oak Ridge Institute for Science and Education. The authors would like to thank many FDA colleagues for their support and assistance. Particularly, we thank Crystal Allard, Helena Sviglin, and Eileen Navarro Almario for collecting user feedback; Farrokh Sohrabi and Eric Brodsky for comprehensive comments to improve the FDALabel home webpage and tool; and Lonnie Smith for providing valuable information regarding SPL data content. We thank Qiang Shi, Minjun Chen, and Robin Stingley for their constructive review of the manuscript and helpful discussion to improve the FDALabel. We appreciate the support from the NCTR IT Team, FDA IT Scientific Enclave Team, and NCTR Web Development Team. NR 21 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 EI 1878-5832 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD OCT PY 2016 VL 21 IS 10 BP 1566 EP 1570 DI 10.1016/j.drudis.2016.06.006 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EA2CS UT WOS:000386401000002 PM 27319291 ER PT J AU Yang, HT Yang, H Chiang, JH Wang, SJ AF Yang, Hsih-Te Yang, Hong Chiang, Jung-Hsien Wang, Shih-Jon TI Translating genomic sequences into antibody efficacy and safety against influenza toward clinical trial outcomes: a case study SO DRUG DISCOVERY TODAY LA English DT Review ID FIT BACKBONE REFINEMENT; VIRUS HEMAGGLUTININ; A VIRUSES; MONOCLONAL-ANTIBODY; MOLECULAR DOCKING; WEB SERVER; NEUTRALIZATION; RECOGNIZES; PREDICTION; EPITOPE AB Antibodies (Abs) are regarded as a newly emerging form of therapeutics that can provide passive protection against influenza. Although the application of genomics in clinics has increased dramatically, the number of therapeutics available for the treatment of many diseases remains insufficient. To translate genomics into medicines, we established a computational workflow to reconstruct 3D structures of hemagglutinin [HA, antigen (Ag)] and Ab for modeling Ab-HA interactions, based on their protein sequences. This platform was capable of testing the validity of bioinformatics predictions against viral neutralization titers for four Abs: CH65, CR8020, C05, and 5J8. By considering off-target effects, CR8020, the only successful candidate in clinical trials, was prospectively identified. Our approach could facilitate the discovery of Ab drugs against infectious diseases. C1 [Yang, Hsih-Te; Chiang, Jung-Hsien] Natl Cheng Kung Univ, Inst Med Informat, Dept Comp Sci & Informat Engn, Tainan 701, Taiwan. [Yang, Hsih-Te] Natl Cheng Kung Univ, Coll Med, Inst Oral Med, Tainan 701, Taiwan. [Yang, Hong] US FDA, Ctr Biol Evaluat & Res, Office Biostat & Epidemiol, Silver Spring, MD USA. [Wang, Shih-Jon] Chang Jung Christian Univ, Dept Biosci Technol, Tainan, Taiwan. RP Yang, HT (reprint author), Natl Cheng Kung Univ, Inst Med Informat, Dept Comp Sci & Informat Engn, Tainan 701, Taiwan.; Yang, HT (reprint author), Natl Cheng Kung Univ, Coll Med, Inst Oral Med, Tainan 701, Taiwan. EM yanghsi@mail.ncku.edu.tw FU ORISE grant; ZDOCK web server FX A part of this work was done when the 1st author was ORISE fellow in FDA, and was supported by ORISE grant. We thank Brian G. Pierce for the supports of ZDOCK web server; Yi-Jing Ou for the validation of software system; NCKU Bioinformatics Center for high-performance computing. NR 34 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 EI 1878-5832 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD OCT PY 2016 VL 21 IS 10 BP 1664 EP 1671 DI 10.1016/j.drudis.2016.06.008 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EA2CS UT WOS:000386401000011 PM 27319290 ER PT J AU Carlos, KSR de Jager, LS AF Carlos, Katherine S. Robbins de Jager, Lowri S. TI Comparison of multiple methods for the determination of sulphite in Allium and Brassica vegetables SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE LC-MS; MS; sulphites; food additives; false-positive ID LIQUID-CHROMATOGRAPHY; S-METHYLCYSTEINE; SULFOXIDE; FOODS; LYASE AB Sulphites are a family of additives regulated for use worldwide in food products. They must be declared on the label if they are present in concentrations greater than 10mgkg(-1), determined as sulphur dioxide (SO2). The current US regulatory method for sulphites, the optimised Monier-Williams method (OMW), produces false-positive results with vegetables from the Allium (garlic) and Brassica (cabbage) genera due to extraction conditions that are thought to cause endogenous sulphur compounds to release SO2. Recently, modifications to the OMW method (2x MW) were published that reportedly reduced this false-positive in garlic. However, no other vegetables from these genera have been investigated. In addition, an LC-MS/MS method was developed for sulphite analysis, but it has not yet been tested with these problematic matrices. Ten vegetable species were analysed using these sulphite methods (OMW titration, OMW gravimetric, 2x MW and LC-MS/MS) to determine the false-positive rate. Sulphite concentrations >10mgkg(-1) SO2 were observed with the OMW analyses. The 2x MW method reduced the measured concentration in unsulphited samples to 10mgkg(-1) SO2 for all matrices analysed. The LC-MS/MS method showed concentrations <10mgkg(-1) for the Brassica samples, but only displayed a slight reduction in the Allium matrices. Spiked recovery studies were conducted to determine if these methods can detect added sulphite. The 2x MW had recoveries of 17% and 42% for water and fresh garlic, respectively, and the LC-MS/MS had recoveries of 108%, 125%, 116% and 107% for water, fresh garlic, roasted garlic, and hummus, respectively. The low recoveries of the 2x MW may indicate that sulphur compounds cannot be properly quantified with this method. The ability to eliminate false-positives will enable accurate determination of added sulphite to ensure compliance with sulphite labelling requirements. C1 [Carlos, Katherine S. Robbins; de Jager, Lowri S.] US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr,HFS 706, College Pk, MD 20740 USA. RP Carlos, KSR (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr,HFS 706, College Pk, MD 20740 USA. EM katherine.carlos@fda.hhs.gov NR 16 TC 0 Z9 0 U1 3 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PD OCT PY 2016 VL 33 IS 10 BP 1509 EP 1517 DI 10.1080/19440049.2016.1229869 PG 9 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA EA1HE UT WOS:000386342300001 ER PT J AU Hagan, AK Carlson, PE Hanna, PC AF Hagan, A. K. Carlson, P. E., Jr. Hanna, P. C. TI Flying under the radar: The non-canonical biochemistry and molecular biology of petrobactin from Bacillus anthracis SO MOLECULAR MICROBIOLOGY LA English DT Review ID NONRIBOSOMAL PEPTIDE SYNTHETASES; SIDEROPHORE BIOSYNTHESIS; IRON TRANSPORT; ESCHERICHIA-COLI; MARINOBACTER-HYDROCARBONOCLASTICUS; STERNE 34F(2); CITRIC-ACID; DOMAINS; BACTERIA; CONDENSATION AB The dramatic, rapid growth of Bacillus anthracis that occurs during systemic anthrax implies a crucial requirement for the efficient acquisition of iron. While recent advances in our understanding of B. anthracis iron acquisition systems indicate the use of strategies similar to other pathogens, this review focuses on unique features of the major siderophore system, petrobactin. Ways that petrobactin differs from other siderophores include: A. unique ferric iron binding moieties that allow petrobactin to evade host immune proteins; B. a biosynthetic operon that encodes enzymes from both major siderophore biosynthesis classes; C. redundancy in membrane transport systems for acquisition of Fe-petrobactin holo-complexes; and, D. regulation that appears to be controlled predominately by sensing the host-like environmental signals of temperature, CO2 levels and oxidative stress, as opposed to canonical sensing of intracellular iron levels. We argue that these differences contribute in meaningful ways to B. anthracis pathogenesis. This review will also outline current major gaps in our understanding of the petrobactin iron acquisition system, some projected means for exploiting current knowledge, and potential future research directions. C1 [Hagan, A. K.; Hanna, P. C.] Univ Michigan, Sch Med, Dept Microbiol & Immunol, 1150 W Med Ctr Dr,6703 Med Sci Bldg 2, Ann Arbor, MI 48109 USA. [Carlson, P. E., Jr.] US FDA, Lab Mucosal Pathogens & Cellular Immun, Div Bacterial Parasit & Allergen Prod, Off Vaccines Res & Review,Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 52-72,Rm 3306, Silver Spring, MD 20993 USA. RP Hanna, PC (reprint author), Univ Michigan, Sch Med, Dept Microbiol & Immunol, 1150 W Med Ctr Dr,6703 Med Sci Bldg 2, Ann Arbor, MI 48109 USA. EM pchanna@umich.edu NR 73 TC 0 Z9 0 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD OCT PY 2016 VL 102 IS 2 BP 196 EP 206 DI 10.1111/mmi.13465 PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA DZ8ED UT WOS:000386101000002 PM 27425635 ER PT J AU Colin-Gonzalez, A Maya-Lopez, M Pedraza-Chaverri, J Ali, SF Chavarria, A Santamaria, A AF Laura Colin-Gonzalez, Ana Maya-Lopez, Marisol Pedraza-Chaverri, Jose Ali, Syed F. Chavarria, Anahi Santamaria, Abel TI The Janus faces of 3-hydroxykynurenine: Dual redox modulatory activity and lack of neurotoxicity in the rat striatum (vol 1589, pg 1, 2014) SO BRAIN RESEARCH LA English DT Correction C1 [Laura Colin-Gonzalez, Ana; Maya-Lopez, Marisol; Santamaria, Abel] SSA, Inst Nacl Neurol & Neurocirugia, Lab Aminoacidos Excitadores, Mexico City 14269, DF, Mexico. [Pedraza-Chaverri, Jose] Univ Nacl Autonoma Mexico, Fac Quim, Dept Biol, Mexico City, DF, Mexico. [Ali, Syed F.] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Chavarria, Anahi] Univ Nacl Autonoma Mexico, Fac Med, Dept Med Expt, Mexico City, DF, Mexico. RP Santamaria, A (reprint author), SSA, Inst Nacl Neurol & Neurocirugia, Lab Aminoacidos Excitadores, Mexico City 14269, DF, Mexico. EM absada@yahoo.com NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD OCT 1 PY 2016 VL 1648 BP 525 EP 525 DI 10.1016/j.brainres.2016.07.004 PN A PG 1 WC Neurosciences SC Neurosciences & Neurology GA DY7OI UT WOS:000385318400058 ER PT J AU Nagaraju, GP Rajitha, B Aliya, S Kotipatruni, RP Madanraj, AS Hammond, A Park, D Chigurupati, S Alam, A Pattnaik, S AF Nagaraju, Ganji Purnachandra Rajitha, Balney Aliya, Sheik Kotipatruni, Rama P. Madanraj, Appiya Santharam Hammond, Anthea Park, Dongkyoo Chigurupati, Srinivasulu Alam, Afroz Pattnaik, Subasini TI The role of adiponectin in obesity-associated female-specific carcinogenesis SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE Adiponectin; Obesity; Cervical cancer; Ovarian cancer; Endometrial cancer; Breast cancer ID ACTIVATED PROTEIN-KINASE; ENDOMETRIAL CANCER-RISK; SMOOTH-MUSCLE-CELL; BODY-MASS INDEX; MOLECULAR-WEIGHT ADIPONECTIN; HUMAN OVARIAN-CANCER; BREAST-CANCER; PLASMA ADIPONECTIN; CERVICAL-CANCER; PERITONEAL-FLUID AB Adipose tissue is a highly vascularized endocrine organ, and its secretion profiles may vary with obesity. Adiponectin is secreted by adipocytes that make up adipose tissue. Worldwide, obesity has been designated a serious health problem among women and is associated with a variety of metabolic disorders and an increased risk of developing cancer of the cervix, ovaries, uterus (uterine/endometrial), and breast. In this review, the potential link between obesity and female-specific malignancies is comprehensively presented by discussing significant features of the intriguing and complex molecule, adiponectin, with a focus on recent findings highlighting its molecular mechanism of action in female specific carcinogenesis. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Nagaraju, Ganji Purnachandra; Rajitha, Balney; Hammond, Anthea] Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Nagaraju, Ganji Purnachandra; Pattnaik, Subasini] Berhampur Univ, Dept Biotechnol, Berhampur 760007, Odisha, India. [Rajitha, Balney; Alam, Afroz] Banasthali Univ, Dept Microbiol, Banasthali 304022, Rajasthan, India. [Aliya, Sheik] Jawaharlal Nehru Technol Univ, Dept Biotechnol, Hyderabad 500085, Andhra Pradesh, India. [Kotipatruni, Rama P.] Washington Univ, Sch Med, Div Canc Biol, Dept Radiat Oncol, St Louis, MO 63110 USA. [Madanraj, Appiya Santharam] Univ Leicester, Dept Infect Immun & Inflammat, Leicester LE1 9HN, Leics, England. [Park, Dongkyoo] Emory Univ, Winship Canc Inst, Dept Radiat Oncol, Atlanta, GA 30322 USA. [Chigurupati, Srinivasulu] US FDA, Off Regulatory Sci, Rockville, MD 20857 USA. RP Nagaraju, GP (reprint author), 1365 Clifton RD NE, Atlanta, GA 30322 USA. EM pganji@emory.edu; rajitha.balney@wellstar.org; biotechaliya@gmail.com; rkotipatruni@uchicago.edu; madanraj.appiah@gmail.com; alhammo@emory.edu; dpark33@emory.edu; srinivasulu.chigurupati@fda.hhs.gov; aafroj@banasthali.in; sp.zool@buodisha.edu.in OI Nagaraju, Ganji Purnachandra/0000-0002-4989-5234 NR 138 TC 2 Z9 2 U1 7 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 EI 1879-0305 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD OCT PY 2016 VL 31 SI SI BP 37 EP 48 DI 10.1016/j.cytogfr.2016.03.014 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DZ1JU UT WOS:000385595500004 PM 27079372 ER PT J AU Talpos, JC De-Wit, L Olley, J Riordan, J Steckler, T AF Talpos, John C. de-Wit, Lee Olley, Joseph Riordan, Jack Steckler, Thomas TI Do wholes become more than the sum of their parts in the rodent (Rattus Norvegicus) visual system? A test case with the configural superiority effect SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE Gestalt; touch screen; translation; visual perception ID HOMO-SAPIENS; PERCEPTION; CORTEX; SCHIZOPHRENIA; IMPAIRMENT; GESTALTS; AUTISM; SHAPE; TOP AB The rodent has been used to model various aspects of the human visual system, but it is unclear to what extent human visual perception can be modelled in the rodent. Research suggests rodents can perform invariant object recognition tasks in a manner comparable to humans. There is further evidence that rodents also make use of certain grouping cues, but when performing a shape discrimination they have a tendency to rely much more on local image cues than human participants. In the current work, we exploit the fact that humans sometimes discriminate better between whole shapes, rather than the parts from which they are constructed, to ask whether rodents show a classic Configural Superiority Effect. Using touchscreen-equipped operant boxes, rats were trained to discriminate 'part' or 'whole' images based off of those used by J. R. Pomerantz et al. (1977) J Exp Psychol Hum Percept Perform, 3, 422-435. Here, we show that rats show no advantage for wholes and that they perform better when presented with simpler image parts, a pattern of effect opposite to what was seen in humans when highly comparable stimuli were used. These results add to our understanding of the similarities and differences between the human and rodent visual system, and suggest that the rodent visual system may not compute part whole relationships in a way comparable to humans. These results are significant from both a comparative anatomy perspective, and of particular relevance for those wishing to use rodents to model visuo-perceptual deficits associated with human psychiatric disorders. C1 [Talpos, John C.; Olley, Joseph; Riordan, Jack; Steckler, Thomas] Janssen Res & Dev, Dept Neurosci, Turnhoutseweg 30, B-2340 Beerse, Belgium. [Talpos, John C.] Natl Ctr Toxicol Res, 3900 NCTR Dr, Jefferson, AR 72079 USA. [de-Wit, Lee] Univ Cambridge, Inst Continuing Educ, Cambridge, England. [de-Wit, Lee] UCL, Cognit & Language Sci, London, England. RP Talpos, JC (reprint author), Janssen Res & Dev, Dept Neurosci, Turnhoutseweg 30, B-2340 Beerse, Belgium.; Talpos, JC (reprint author), Natl Ctr Toxicol Res, 3900 NCTR Dr, Jefferson, AR 72079 USA. EM johnctalpos@gmail.com NR 20 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD OCT PY 2016 VL 44 IS 8 BP 2593 EP 2599 DI 10.1111/ejn.13350 PG 7 WC Neurosciences SC Neurosciences & Neurology GA DY8QL UT WOS:000385394800004 PM 27471169 ER PT J AU Draganova, EB Adrian, SA Lukat-Rodgers, GS Keutcha, CS Schmitt, MP Rodgers, KR Dixon, DW AF Draganova, Elizabeth B. Adrian, Seth A. Lukat-Rodgers, Gudrun S. Keutcha, Cyrianne S. Schmitt, Michael P. Rodgers, Kenton R. Dixon, Dabney W. TI Corynebacterium diphtheriae HmuT: dissecting the roles of conserved residues in heme pocket stabilization SO JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY LA English DT Article DE Heme uptake; Heme binding; Resonance Raman; Electrospray; Thermal unfolding ID AVIUM SSP PARATUBERCULOSIS; CYTOCHROME-C PEROXIDASE; ALLENE OXIDE SYNTHASE; PROTEIN INTERACTIONS; BINDING PROTEINS; RESONANCE RAMAN; IRON; CATALASE; ACQUISITION; BACTERIA AB The heme-binding protein HmuT is part of the Corynebacterium diphtheriae heme uptake pathway and is responsible for the delivery of heme to the HmuUV ABC transporter. HmuT binds heme with a conserved His/Tyr heme axial ligation motif. Sequence alignment revealed additional conserved residues of potential importance for heme binding: R237, Y272 and M292. In this study, site-directed mutations at these three positions provided insight into the nature of axial heme binding to the protein and its effect on the thermal stability of the heme-loaded protein fold. UV-visible absorbance, resonance Raman (rR) and thermal unfolding experiments, along with collision-induced dissociation electrospray ionization mass spectrometry, were used to probe the contributions of each mutated residue to the stability of I- HmuT. Thermal unfolding and rR experiments revealed that R237 and M292 are important residues for heme binding. Arginine 237 is a hydrogen-bond donor to the phenol side chain of Y235, which serves as an axial heme ligand. Methionine 292 serves a supporting structural role, favoring the R237 hydrogen-bond donation, which elicits a, heretofore, unobserved modulating influence on pi donation by the axial tyrosine ligand in the heme carbonyl complex, HmuT-CO. C1 [Draganova, Elizabeth B.; Keutcha, Cyrianne S.; Dixon, Dabney W.] Georgia State Univ, Dept Chem, Atlanta, GA 30302 USA. [Adrian, Seth A.; Lukat-Rodgers, Gudrun S.; Rodgers, Kenton R.] North Dakota State Univ, Dept Chem & Biochem, Fargo, ND 58108 USA. [Schmitt, Michael P.] US FDA, Lab Resp & Special Pathogens, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Dixon, DW (reprint author), Georgia State Univ, Dept Chem, Atlanta, GA 30302 USA. EM ddixon@gsu.edu FU Georgia State University Molecular Basis of Disease Fellowship Program; Research Corporation (DWD); National Institutes of Health [AI072719, GM114787] FX We would like to thank Siming Wang for technical assistance with the mass spectrometry experiments and insightful discussions. We would also like to thank the Georgia State University Molecular Basis of Disease Fellowship Program for financially supporting E. B. Draganova. Financial support for this project was provided by the Research Corporation (DWD) and National Institutes of Health Grants AI072719 (KRR) and GM114787 (GSLR). NR 61 TC 1 Z9 1 U1 24 U2 24 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0949-8257 EI 1432-1327 J9 J BIOL INORG CHEM JI J. Biol. Inorg. Chem. PD OCT PY 2016 VL 21 IS 7 BP 875 EP 886 DI 10.1007/s00775-016-1386-3 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear SC Biochemistry & Molecular Biology; Chemistry GA DY5OA UT WOS:000385147900006 PM 27561288 ER PT J AU Novatt, H Theisen, TC Massie, T Massie, T Simonyan, V Voskanian-Kordi, A Renn, LA Rabin, RL AF Novatt, Hilary Theisen, Terence C. Massie, Tammy Massie, Tristan Simonyan, Vahan Voskanian-Kordi, Alin Renn, Lynnsey A. Rabin, Ronald L. TI Distinct Patterns of Expression of Transcription Factors in Response to Interferon and Interferon1 SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article DE interferon-beta; interferon-lambda; interferon regulatory factor-1 (IRF1); respiratory epithelial cells; interferon stimulated genes (ISG); transcription factors ID AIRWAY EPITHELIAL-CELLS; REGULATORY FACTOR-I; HEPATITIS-C VIRUS; LARGE GENE LISTS; STIMULATED GENES; KINETIC DIFFERENCES; ANTIVIRAL DEFENSE; CARCINOMA-CELLS; IMMUNE-RESPONSE; HOST-DEFENSE AB After viral infection, type I and III interferons (IFNs) are coexpressed by respiratory epithelial cells (RECs) and activate the ISGF3 transcription factor (TF) complex to induce expression of a cell-specific set of interferon-stimulated genes (ISGs). Type I and III IFNs share a canonical signaling pathway, suggesting that they are redundant. Animal and in vitro models, however, have shown that they are not redundant. Because TFs dictate cellular phenotype and function, we hypothesized that focusing on TF-ISG will reveal critical combinatorial and nonredundant functions of type I or III IFN. We treated BEAS-2B human RECs with increasing doses of IFN or IFN1 and measured expression of TF-ISG. ISGs were expressed in a dose-dependent manner with a nonlinear jump at intermediate doses. At subsaturating combinations of IFN and IFN1, many ISGs were expressed in a pattern that we modeled with a cubic equation that mathematically defines this threshold effect. Uniquely, IFN alone induced early and transient IRF1 transcript and protein expression, while IFN1 alone induced IRF1 protein expression at low levels that were sustained through 24h. In combination, saturating doses of these 2 IFNs together enhanced and sustained IRF1 expression. We conclude that the cubic model quantitates combinatorial effects of IFN and IFN1 and that IRF1 may mediate nonredundancy of type I or III IFN in RECs. C1 [Novatt, Hilary; Theisen, Terence C.; Massie, Tammy; Simonyan, Vahan; Voskanian-Kordi, Alin; Renn, Lynnsey A.; Rabin, Ronald L.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Massie, Tristan] US FDA, Drugs Evaluat & Res, Silver Spring, MD USA. RP Rabin, RL (reprint author), US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM ronald.rabin@fda.hhs.gov FU FDA/CBER intramural funds; FDA Medical Countermeasures Initiative FX This work was supported by FDA/CBER intramural funds and the FDA Medical Countermeasures Initiative. T.C.T and H.A.N were supported by an appointment to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. The authors thank Steeve Boulant and Rachel Gottschalk for critical review of the manuscript. NR 74 TC 0 Z9 0 U1 2 U2 2 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 OCT PY 2016 VL 36 IS 10 BP 589 EP 598 DI 10.1089/jir.2016.0031 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA DZ2EK UT WOS:000385654900003 PM 27447339 ER PT J AU Kumsa, D Hudak, EM Montague, FW Kelley, SC Untereker, DF Hahn, BP Condit, C Cholette, M Lee, H Bardot, D Takmakov, P AF Kumsa, Doe Hudak, Eric M. Montague, Fred W. Kelley, Shawn C. Untereker, Darrel F. Hahn, Benjamin P. Condit, Chris Cholette, Martin Lee, Hyowon Bardot, Dawn Takmakov, Pavel TI Electrical neurostimulation with imbalanced waveform mitigates dissolution of platinum electrodes SO JOURNAL OF NEURAL ENGINEERING LA English DT Article DE neuromodulation; electrical stimulation; neurostimulation safety; charge balance; medical devices ID TISSUE-DAMAGE; NEURAL TISSUE; STIMULATION; DIFFUSION; CORTEX; MODEL AB Objective. Electrical neurostimulation has traditionally been limited to the use of charge-balanced waveforms. Charge-imbalanced and monophasic waveforms are not used to deliver clinical therapy, because it is believed that these stimulation paradigms may generate noxious electrochemical species that cause tissue damage. Approach. In this study, we investigated the dissolution of platinum as one of such irreversible reactions over a range of charge densities up to 160 mu C cm(-2) with current-controlled first phase, capacitive discharge second phase waveforms of both cathodic-first and anodic-first polarity. We monitored the concentration of platinum in solution under different stimulation delivery conditions including charge-balanced, charge-imbalanced, and monophasic pulses. Main results. We observed that platinum dissolution decreased during charge-imbalanced and monophasic stimulation when compared to charge-balanced waveforms. Significance. This observation provides an opportunity to re-evaluate the charge-balanced waveform as the primary option for sustainable neural stimulation. C1 [Kumsa, Doe; Takmakov, Pavel] US FDA, White Oak Fed Res Ctr, Ctr Devices & Radiol Hlth, Div Biol Chem & Mat Sci,Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Kumsa, Doe; Bardot, Dawn] Med Device Innovat Consortium, St Louis Pk, MN USA. [Hudak, Eric M.] Adv Bion LLC, Dept Res & Technol, Westinghouse Pl, Valencia, CA USA. [Montague, Fred W.] Case Western Reserve Univ, Dept Biomed Engn, Wickenden Bldg,10900 Euclid Ave, Cleveland, OH 44106 USA. [Kelley, Shawn C.; Untereker, Darrel F.] Medtron Plc, 710 Medtron Pkwy, Minneapolis, MN USA. [Hahn, Benjamin P.] Boston Sci Corp, Neuromodulat Div, 25155 Rye Canyon Loop, Valencia, CA USA. [Condit, Chris; Cholette, Martin] St Jude Med, Implantable Elect Syst Div, 6901 Preston Rd, Plano, TX USA. [Lee, Hyowon] Purdue Univ, Birck Nanotechnol Ctr, Weldon Sch Biomed Engn, W Lafayette, IN USA. RP Takmakov, P (reprint author), US FDA, White Oak Fed Res Ctr, Ctr Devices & Radiol Hlth, Div Biol Chem & Mat Sci,Off Sci & Engn Labs, Silver Spring, MD 20993 USA. EM Pavel.Takmakov@fda.hhs.gov OI Takmakov, Pavel/0000-0001-6591-0257 NR 25 TC 0 Z9 0 U1 0 U2 0 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 OCT PY 2016 VL 13 IS 5 AR 054001 DI 10.1088/1741-2560/13/5/054001 PG 5 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA DY9YN UT WOS:000385493100001 ER PT J AU Ikejimba, LC Glick, SJ Choudhury, KR Samei, E Lo, JY AF Ikejimba, Lynda C. Glick, Stephen J. Choudhury, Kingshuk Roy Samei, Ehsan Lo, Joseph Y. TI Assessing task performance in FFDM, DBT, and synthetic mammography using uniform and anthropomorphic physical phantoms SO MEDICAL PHYSICS LA English DT Article DE full-field digital mammography; synthetic mammography; digital breast tomosynthesis; observer study; breast phantom; contrast-detail phantom ID DIGITAL BREAST TOMOSYNTHESIS; RECONSTRUCTED PROJECTION IMAGES; OBSERVER-PERFORMANCE; POPULATION AB Purpose: The purpose of this study is to quantify the differences in detectability between full field digital mammography (FFDM), digital breast tomosynthesis (DBT), and synthetic mammography (SM) for challenging, low contrast signals, in the context of both a uniform and an anthropomorphic, textured phantom. Methods: Images of the phantoms were acquired using a Hologic Selenia Dimensions system. Images were taken at 50%, 100%, and 200% of the dose delivered under automatic exposure control (AEC). Low-contrast disks, created using an inkjet printer with iodine-doped ink, were inserted into the phantom. The disks varied in diameter from 210 to 630 mu m, and in local contrast from 1.1% to 2.8% in regular increments. Human observers located the disks in a 4 alternative forced choice experiment. Proportion correct (PC) was computed as the number of correct localizations out of the total number of tries. Results: Overall, scores from FFDM and DBT were consistently greater than scores from SM. At an exposure corresponding to the AEC setting, mean PC scores for the largest disks with the uniform phantom were 0.80 for FFDM, 0.83 for DBT, and 0.66 for SM, with the same rank ordering at other doses. Scores were similar but lower for the nonuniform background. At an exposure twice the AEC setting, however, the difference between uniform and nonuniform scores was most pronounced for DBT alone. Differences between scores for FFDM and SM were statistically significant, while those between FFDM and DBT were not. Scores were used to compute the minimum contrast level needed to reach 62.5% detection rate. The minimum contrast for SM was 36%-81% higher compared to FFDM or DBT, in either background. Conclusions: This study shows that an anthropomorphic phantom and lesions inserts may be used to conduct a reader study. Detectability was significantly lower for synthetic mammography than for FFDM or DBT, for all conditions. Additionally, observer performance was consistently lower for the anthropomorphic phantom, indicating the greater challenge due to anatomical background. Because of this, it may be important to use realistic phantoms in observer studies in order to draw conclusions that are more clinically relevant. (C) 2016 American Association of Physicists in Medicine. C1 [Ikejimba, Lynda C.; Choudhury, Kingshuk Roy; Samei, Ehsan; Lo, Joseph Y.] Duke Univ, Med Phys Grad Program, Carl E Ravin Adv Imaging Labs, Dept Radiol, Durham, NC 27705 USA. [Ikejimba, Lynda C.; Glick, Stephen J.] US FDA, Ctr Diagnost & Radiol Hlth, Off Sci & Engn Labs, Div Imaging Diagnost & Software Reliabil, Silver Spring, MD 20993 USA. [Samei, Ehsan; Lo, Joseph Y.] Duke Univ, Dept Biomed Engn, Dept Elect & Comp Engn, Durham, NC 27705 USA. [Samei, Ehsan] Duke Univ, Dept Phys, Durham, NC 27705 USA. RP Ikejimba, LC (reprint author), Duke Univ, Med Phys Grad Program, Carl E Ravin Adv Imaging Labs, Dept Radiol, Durham, NC 27705 USA.; Ikejimba, LC (reprint author), US FDA, Ctr Diagnost & Radiol Hlth, Off Sci & Engn Labs, Div Imaging Diagnost & Software Reliabil, Silver Spring, MD 20993 USA. EM lynda.ikejimba@fda.hhs.gov FU Charles E. Putman, M.D. Seed Fund of the Department of Radiology; Duke University School of Medicine; Critical Path grant from the Center for Devices and Radiological Health; Oak Ridge Institute for Science and Education through U.S. Department of Energy; Oak Ridge Institute for Science and Education through U.S. Food and Drug Administration FX This work was partly supported by the Charles E. Putman, M.D. Seed Fund of the Department of Radiology, Duke University School of Medicine, and a Critical Path grant from the Center for Devices and Radiological Health, with a fellowship administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. The authors would like to thank Nooshin Kiarashi, Gregory Sturgeon, Adam Nolte, and Dhiraj Sikaria for assisting in developing the Doublet phantom and inkjet lesion procedures; Adam Wunderlich, Aria Pezeshk, and Rongping Zeng at Food and Drug Administration for their scientific input and assistance with software; and the human readers Andreu Badal-Soler, Mina Choi, Ashley Chung, Bahaa Madhev, Andrey Makeev, Aria Pezeshk, Silvina Zabala, and Rongping Zeng at the Food and Drug Administration for their significant time contributions to the study. NR 35 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD OCT PY 2016 VL 43 IS 10 DI 10.1118/1.4962475 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DZ1DA UT WOS:000385577900033 PM 27782687 ER PT J AU Zhang, ZW Liu, W Zhang, B Tang, L Zhang, J AF Zhang, Zhiwei Liu, Wei Zhang, Bo Tang, Li Zhang, Jun TI Causal inference with missing exposure information: Methods and applications to an obstetric study SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE counterfactual; double robustness; inverse probability weighting; missing at random; missing covariate; propensity score; triple robustness ID DOUBLY ROBUST ESTIMATION; PROPENSITY SCORE; PARAMETRIC REGRESSION; MAXIMUM-LIKELIHOOD; INCOMPLETE DATA; MODELS; BIAS AB Causal inference in observational studies is frequently challenged by the occurrence of missing data, in addition to confounding. Motivated by the Consortium on Safe Labor, a large observational study of obstetric labor practice and birth outcomes, this article focuses on the problem of missing exposure information in a causal analysis of observational data. This problem can be approached from different angles (i.e. missing covariates and causal inference), and useful methods can be obtained by drawing upon the available techniques and insights in both areas. In this article, we describe and compare a collection of methods based on different modeling assumptions, under standard assumptions for missing data (i.e. missing-at-random and positivity) and for causal inference with complete data (i.e. no unmeasured confounding and another positivity assumption). These methods involve three models: one for treatment assignment, one for the dependence of outcome on treatment and covariates, and one for the missing data mechanism. In general, consistent estimation of causal quantities requires correct specification of at least two of the three models, although there may be some flexibility as to which two models need to be correct. Such flexibility is afforded by doubly robust estimators adapted from the missing covariates literature and the literature on causal inference with complete data, and by a newly developed triply robust estimator that is consistent if any two of the three models are correct. The methods are applied to the Consortium on Safe Labor data and compared in a simulation study mimicking the Consortium on Safe Labor. C1 [Zhang, Zhiwei] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,WO66,Rm 2266, Silver Spring, MD 20993 USA. [Liu, Wei] Harbin Inst Technol, Dept Math, Harbin, Peoples R China. [Zhang, Bo] Oregon State Univ, Biostat Core, Sch Biol & Populat Hlth Sci, Coll Publ Hlth & Human Sci, Corvallis, OR 97331 USA. [Tang, Li] St Jude Childrens Res Hosp, Dept Biostat, 332 N Lauderdale St, Memphis, TN 38105 USA. [Zhang, Jun] Shanghai Jiao Tong Univ, Sch Med, MOE, Shanghai, Peoples R China. [Zhang, Jun] Shanghai Jiao Tong Univ, Sch Med, Shanghai Key Lab Childrens Environm Hlth, Xinhua Hosp, Shanghai, Peoples R China. RP Zhang, ZW (reprint author), US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,WO66,Rm 2266, Silver Spring, MD 20993 USA. EM zhiwei.zhang@fda.hhs.gov FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported in part by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 27 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD OCT PY 2016 VL 25 IS 5 BP 2053 EP 2066 DI 10.1177/0962280213513758 PG 14 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA DZ0UO UT WOS:000385555400019 PM 24318273 ER PT J AU Zhang, ZW Qu, YP Zhang, B Nie, L Soon, GX AF Zhang, Zhiwei Qu, Yanping Zhang, Bo Nie, Lei Soon, Guoxing TI Use of auxiliary covariates in estimating a biomarker-adjusted treatment effect model with clinical trial data SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE conditional effect; interaction; personalized medicine; predictive biomarker; treatment effect heterogeneity; treatment selection ID CANCER AB A biomarker-adjusted treatment effect (BATE) model describes the effect of one treatment versus another on a subpopulation of patients defined by a biomarker. Such a model can be estimated from clinical trial data without relying on additional modeling assumptions, and the estimator can be made more efficient by incorporating information on the main effect of the biomarker on the outcome of interest. Motivated by an HIV trial known as THRIVE, we consider the use of auxiliary covariates, which are usually available in clinical trials and have been used in overall treatment comparisons, in estimating a BATE model. Such covariates can be incorporated using an existing augmentation technique. For a specific type of estimating functions for difference-based BATE models, the optimal augmentation depends only on the joint main effects of marker and covariates. For a ratio-based BATE model, this result holds in special cases but not in general; however, simulation results suggest that the augmentation based on the joint main effects of marker and covariates is virtually equivalent to the theoretically optimal augmentation, especially when the augmentation terms are estimated from data. Application of these methods and results to the THRIVE data yields new insights on the utility of baseline CD4 cell count and viral load as predictive or treatment selection markers. C1 [Zhang, Zhiwei; Qu, Yanping] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Zhang, Bo] Oregon State Univ, Biostat Core, Sch Biol & Populat Hlth Sci, Coll Publ Hlth & Human Sci, Corvallis, OR 97331 USA. [Nie, Lei; Soon, Guoxing] US FDA, Div Biometr 4, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Zhang, ZW (reprint author), US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM Zhiwei.Zhang@fda.hhs.gov NR 22 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD OCT PY 2016 VL 25 IS 5 BP 2103 EP 2119 DI 10.1177/0962280213515572 PG 17 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA DZ0UO UT WOS:000385555400022 PM 24346166 ER PT J AU Zimmerman, KO Wu, HL Greenberg, R Guptill, JT Hill, K Patel, UD Ku, L Gonzalez, D Hornik, C Jiang, WL Zheng, N Melloni, C Cohen-Wolkowiez, M AF Zimmerman, Kanecia O. Wu, Huali Greenberg, Rachel Guptill, Jeffrey T. Hill, Kevin Patel, Uptal D. Ku, Lawrence Gonzalez, Daniel Hornik, Christoph Jiang, Wenlei Zheng, Nan Melloni, Chiara Cohen-Wolkowiez, Michael TI Therapeutic Drug Monitoring, Electronic Health Records, and Pharmacokinetic Modeling to Evaluate Sirolimus Drug Exposure-Response Relationships in Renal Transplant Patients SO THERAPEUTIC DRUG MONITORING LA English DT Article DE sirolimus; pharmacokinetics; pharmacodynamics; anemia; thrombocytopenia; adverse event; efficacy ID CHRONIC ALLOGRAFT NEPHROPATHY; SINGLE-CENTER EXPERIENCE; POPULATION PHARMACOKINETICS; CALCINEURIN INHIBITORS; ACUTE REJECTION; DE-NOVO; CYCLOSPORINE; RECIPIENTS; RAPAMYCIN; CONVERSION AB Background:Sirolimus, an immunosuppressive agent used in renal transplantation, can prevent allograft rejection. Identification of the therapeutic index (the ratio of minimum toxic concentration to minimum therapeutic concentration) for immunosuppresants is necessary to optimize the care of patients and set standards for bioequivalence evaluation of sirolimus products. However, the therapeutic index for sirolimus has been inconsistently defined, potentially because of inconsistencies in sirolimus exposure-response relationships.Methods:The authors used retrospective therapeutic drug monitoring data from the electronic health records of patients treated in a tertiary health care system from 2008 to 2014 to (1) develop a population pharmacokinetic (PK) model, (2) use the model to simulate sirolimus concentrations, and (3) characterize the exposure-response relationship. Using Wilcoxon rank-sum and Fisher exact tests, the authors determined relationships between sirolimus exposure and adverse events (AEs) (anemia, leukopenia, thrombocytopenia, hyperlipidemia, and decline in renal function) and the composite efficacy end point of graft loss or rejection.Results:The developed 2-compartment population PK model showed appropriate goodness of fit. In a late-phase (>12 months), postrenal transplant population of 27 inpatients, the authors identified statistically significant relationships between 83 simulated peak and trough sirolimus concentrations and outcomes: graft loss or rejection (P = 0.018) and decline in renal function (P = 0.006), respectively.Conclusions:Use of therapeutic drug monitoring results and PK modeling permitted correlation of sirolimus concentrations with graft loss or rejection and decline in renal function. However, the method was limited in its assessment of other AEs. To better evaluate sirolimus exposure-response relationships, the method should be applied to a larger sample of newly transplanted patients with a higher propensity toward AEs or efficacy failure. C1 [Zimmerman, Kanecia O.; Wu, Huali; Greenberg, Rachel; Guptill, Jeffrey T.; Hill, Kevin; Patel, Uptal D.; Ku, Lawrence; Hornik, Christoph; Melloni, Chiara; Cohen-Wolkowiez, Michael] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Zimmerman, Kanecia O.; Greenberg, Rachel; Hill, Kevin; Patel, Uptal D.; Ku, Lawrence; Hornik, Christoph; Cohen-Wolkowiez, Michael] Duke Univ, Dept Pediat, Sch Med, Durham, NC 27706 USA. [Patel, Uptal D.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Gonzalez, Daniel] Univ N Carolina, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. [Jiang, Wenlei; Zheng, Nan] US FDA, Off Gener Drugs, Silver Spring, MD USA. RP Cohen-Wolkowiez, M (reprint author), Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM michael.cohenwolkowiez@duke.edu FU Food and Drug Administration [1U01FD004858-01] FX Funding for this article was made possible, in part, by the Food and Drug Administration through grant 1U01FD004858-01. NR 35 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 0163-4356 EI 1536-3694 J9 THER DRUG MONIT JI Ther. Drug Monit. PD OCT PY 2016 VL 38 IS 5 BP 600 EP 606 DI 10.1097/FTD.0000000000000313 PG 7 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA DY8TQ UT WOS:000385404400007 PM 27259059 ER PT J AU Lacher, DW Gangiredla, J Patel, I Elkins, CA Feng, PCH AF Lacher, David W. Gangiredla, Jayanthi Patel, Isha Elkins, Christopher A. Feng, Peter C. H. TI Use of the Escherichia coli Identification Microarray for Characterizing the Health Risks of Shiga Toxin-Producing Escherichia coli Isolated from Foods SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Foods; Health risk; Shiga toxin-producing Escherichia coli ID HEMOLYTIC-UREMIC SYNDROME; VIRULENCE FACTORS; FRESH PRODUCE; UNITED-STATES; STRAINS; ASSOCIATION; DISEASE; CATTLE; INFECTIONS; VARIANTS AB More than 470 serotypes of Shiga toxin producing Escherichia coli (STEC) have been identified, but not all cause severe illness in humans. Most SiEC that cause severe diseases can adhere to epithelial cells, produce specific stx subtypes, and belong to certain serotypes; therefore, these traits appear to be critical STEC risk factors. However, testing for these traits is labor intensive, and serotyping is inadequate because of extensive variations among E. coli O and H antigen types. In the present study, the E. coli identification microarray, which tests for over 40,000 E. coli gene targets, was examined for its potential to quickly characterize STEC strains. Analysis of 47 E. coli isolates, including 31 STEC isolates, recovered from 39 foods revealed that the microarray effectively determined the presence or absence of adherence genes and identified the specific eae allele in 3 isolates. The array identified most of the stx subtypes carried by all the isolates but had some difficulties in discerning between stx(2a), stx(2c), and stx(2d) because of the genetic similarities of these subtypes. The array determined the O and H types of 68 and 96% of the isolates, respectively, and although most serotypes were unremarkable, a few known pathogenic serotypes were also found. These selected STEC traits provided a scientific basis for assessing the potential health risks of STEC strains and also showed the importance of H typing in determining health risks. However, the diversity of the STEC group, the complexity of virulence mechanisms, and the variation in pathotypes among strains continue to pose challenges to assessing the potential of STEC strains to cause severe illness. C1 [Lacher, David W.; Gangiredla, Jayanthi; Patel, Isha; Elkins, Christopher A.] US FDA, Div Mol Biol, Laurel, MD 20708 USA. [Feng, Peter C. H.] US FDA, Div Microbiol, College Pk, MD 20740 USA. RP Feng, PCH (reprint author), US FDA, Div Microbiol, College Pk, MD 20740 USA. EM peter.feng@fda.hhs.gov NR 37 TC 0 Z9 0 U1 3 U2 3 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD OCT PY 2016 VL 79 IS 10 BP 1656 EP 1662 DI 10.4315/0362-028X.JFP-16-176 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA DY3AS UT WOS:000384963800001 PM 28221838 ER PT J AU Alam, MS Costales, M Cavanaugh, C Pereira, M Gaines, D Williams, K AF Alam, Mohammad S. Costales, Matthew Cavanaugh, Christopher Pereira, Marion Gaines, Dennis Williams, Kristina TI Oral exposure to Listeria monocytogenes in aged IL-17RKO mice: A possible murine model to study listeriosis in susceptible populations SO MICROBIAL PATHOGENESIS LA English DT Article DE Listeria monocytogenes; Aging; IL17RA-KO mice; Immune-dysregulation; T helper-cells ID DELTA-T-CELLS; CD8-T-CELL MEMORY; IMMUNE-RESPONSES; CD4-T-CELL HELP; INNATE IMMUNITY; HOST-DEFENSE; INFECTION; GAMMA; RESISTANCE; SYSTEM AB Foodborne Listeria monocytogenes (LM) is a cause of serious illness and death in the US. The case-fatality rate of invasive LM infection in the elderly population is >50%. The goal of this study is to establish a murine model of oral LM infection that can be used as a surrogate for human foodborne listeriosis in the geriatric population. Adult C57BL/6 (wild-type, WT) and adult or old IL17R-KO (knock-out) mice were gavaged with a murinized LM strain (Lmo-InlA(m)) and monitored for body-weight loss and survivability. Tissues were collected and assayed for bacterial burden, histology, and cytokine responses. When compared to WT mice, adult IL17R-KO mice are more susceptible to LM infection and showed increased LM burden and tissue pathology and a higher mortality rate. Older LM-infected KO-mice lost significantly (p < 0.02, ANOVA) more body-weight and had a higher bacterial burden in the liver (p = 0.03) and spleen as compared to adult mice. Uninfected, aged KO-mice showed a higher baseline pro-inflammatory response when compared to uninfected adult-KO mice. After infection, the pro-inflammatory cytokine, IFN-gamma, mRNA in the liver was higher in the adult mice as compared to the old mice. The anti-inflammatory cytokine, IL-10, mRNA and regulatory T-cells (CD4(+)CD25(+h) or CD4(+)Foxp3(+)) cells in the aged mice increased significantly after infection as compared to adult mice. Expression of the T-cell activation marker, CD25 (IL-2R alpha) in the aged mice did not increase significantly over baseline. These data suggest that aged IL17R-KO mice can be used as an in vivo model to study oral listeriosis and that aged mice are more susceptible to LM infection due to dysregulation of pro- and anti-inflammatory responses compared to adult mice, resulting in a protracted clearance of the infection. Published by Elsevier Ltd. C1 [Alam, Mohammad S.; Costales, Matthew; Cavanaugh, Christopher; Pereira, Marion; Gaines, Dennis; Williams, Kristina] US FDA, Immunobiol Branch, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Costales, Matthew] Scripps Res Inst, Scripps Florida, Dept Chem, 130 Scripps Way, Jupiter, FL 33458 USA. RP Alam, MS (reprint author), US FDA, Immunobiol Branch, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. EM Mohammad.alam@fda.hhs.gov FU intramural research program for the Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration; Oak Ridge Institute of Science and Education (ORISE) FX We are grateful to Dr. Marianna Solomotis for critical review and valuable suggestions in the preparation of. this manuscript. This research was supported by the intramural research program for the Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration. Matthew Costales and Christopher Cavanagh are supported by a Fellowship from Oak Ridge Institute of Science and Education (ORISE). The authors are grateful to Amgen. Inc., for providing us with the IL17RA-deficient mouse breeding pairs and also Drs. Wolf-Dieter Schubert and Thomas Wollert, HZI, Germany, for providing Lmo-InlAm strain. NR 49 TC 1 Z9 1 U1 2 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0882-4010 J9 MICROB PATHOGENESIS JI Microb. Pathog. PD OCT PY 2016 VL 99 BP 236 EP 246 DI 10.1016/j.micpath.2016.08.035 PG 11 WC Immunology; Microbiology SC Immunology; Microbiology GA DY4GJ UT WOS:000385056700034 PM 27574777 ER PT J AU Khozin, S Chuk, M Kim, T Kim, G Pazdur, R De, S Sahoo, S AF Khozin, Sean Chuk, Meredith Kim, Tamy Kim, Geoffrey Pazdur, Richard De, Suranjan Sahoo, Sanjay TI REGULATORY WATCH Evaluating the potential for digital submission of expedited premarket safety reports to the FDA SO NATURE REVIEWS DRUG DISCOVERY LA English DT News Item C1 [Khozin, Sean; Chuk, Meredith; Kim, Tamy; Kim, Geoffrey; Pazdur, Richard] US FDA, Ctr Drug Evaluat & Res, New Hampshire Ave, Silver Spring, MD 20993 USA. [De, Suranjan; Sahoo, Sanjay] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD 20993 USA. RP Khozin, S (reprint author), US FDA, Ctr Drug Evaluat & Res, New Hampshire Ave, Silver Spring, MD 20993 USA. EM sean.khozin@fda.hhs.gov NR 1 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD OCT PY 2016 VL 15 IS 10 BP 670 EP 671 DI 10.1038/nrd.2016.189 PG 2 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA DY3AX UT WOS:000384964300007 PM 27681787 ER PT J AU Sha, S Agarabi, C Brorson, K Lee, DY Yoon, S AF Sha, Sha Agarabi, Cyrus Brorson, Kurt Lee, Dong-Yup Yoon, Seongkyu TI N-Glycosylation Design and Control of Therapeutic Monoclonal Antibodies SO TRENDS IN BIOTECHNOLOGY LA English DT Review ID HAMSTER OVARY CELLS; METABOLIC FLUX ANALYSIS; FED-BATCH CULTURES; CHO-CELLS; LINKED GLYCOSYLATION; GENE-EXPRESSION; PROTEIN GLYCOSYLATION; EFFECTOR FUNCTIONS; MAMMALIAN-CELLS; AMINO-ACID AB The N-linked glycan profiles on recombinant monoclonal antibody therapeutics significantly affect antibody biological functions and are largely determined by host cell genotypes and culture conditions. A key step in bioprocess development for monoclonal antibodies (mAbs) involves optimization and control of N-glycan profiles. With pressure from pricing and biosimilars looming, more efficient and effective approaches are sought in the field of glycoengineering. Metabolic studies and mathematical modeling are two such approaches that optimize bioprocesses by better understanding and predicting glycosylation. In this review, we summarize a group of strategies currently used for glycan profile modulation and control. Metabolic analysis and mathematical modeling are then explored with an emphasis on how these two techniques can be utilized to advance glycoengineering. C1 [Sha, Sha; Yoon, Seongkyu] Univ Massachusetts, Biomed Engn & Biotechnol, Lowell, MA 01850 USA. [Agarabi, Cyrus; Brorson, Kurt] US FDA, Div Biotechnol Review & Res 2, Off Biotechnol Prod, OPQ,CDER, Silver Spring, MD USA. [Lee, Dong-Yup] Natl Univ Singapore, Dept Chem & Biomol Engn, 4 Engn Dr, Singapore 117585, Singapore. RP Yoon, S (reprint author), Univ Massachusetts, Biomed Engn & Biotechnol, Lowell, MA 01850 USA. EM Seongkyu_Yoon@uml.edu NR 87 TC 3 Z9 3 U1 20 U2 20 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0167-7799 J9 TRENDS BIOTECHNOL JI Trends Biotechnol. PD OCT PY 2016 VL 34 IS 10 BP 835 EP 846 DI 10.1016/j.tibtech.2016.02.013 PG 12 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DY1LM UT WOS:000384856500009 PM 27016033 ER PT J AU Heiman, KE Garalde, VB Gronostaj, M Jackson, KA Beam, S Joseph, L Saupe, A Ricotta, E Waechter, H Wellman, A Adams-Cameron, M Ray, G Fields, A Chen, Y Datta, A Burall, L Sabol, A Kucerova, Z Trees, E Metz, M Leblanc, P Lance, S Griffin, PM Tauxe, RV Silk, BJ AF Heiman, K. E. Garalde, V. B. Gronostaj, M. Jackson, K. A. Beam, S. Joseph, L. Saupe, A. Ricotta, E. Waechter, H. Wellman, A. Adams-Cameron, M. Ray, G. Fields, A. Chen, Y. Datta, A. Burall, L. Sabol, A. Kucerova, Z. Trees, E. Metz, M. Leblanc, P. Lance, S. Griffin, P. M. Tauxe, R. V. Silk, B. J. TI Multistate outbreak of listeriosis caused by imported cheese and evidence of cross-contamination of other cheeses, USA, 2012 SO EPIDEMIOLOGY AND INFECTION LA English DT Article DE Cheese; contamination; Listeria; outbreak ID MEXICAN-STYLE CHEESE; UNITED-STATES; MONOCYTOGENES INFECTION; PASTEURIZED MILK; CONSUMPTION; GERMANY; GROWTH; RISK; MEAT AB Listeria monocytogenes is a foodborne pathogen that can cause bacteraemia, meningitis, and complications during pregnancy. In July 2012, molecular subtyping identified indistinguishable L. monocytogenes isolates from six patients and two samples of different cut and repackaged cheeses. A multistate outbreak investigation was initiated. Initial analyses identified an association between eating soft cheese and outbreak-related illness (odds ratio 173, 95% confidence interval 20-8257) but no common brand. Cheese inventory data from locations where patients bought cheese and an additional location where repackaged cheese yielded the outbreak strain were compared to identify cheeses for microbiological sampling. Intact packages of imported ricotta salata yielded the outbreak strain. Fourteen jurisdictions reported 22 cases from March-October 2012, including four deaths and a fetal loss. Six patients ultimately reported eating ricotta salata; another reported eating cheese likely cut with equipment also used for contaminated ricotta salata, and nine more reported eating other cheeses that might also have been cross-contaminated. An FDA import alert and US and international recalls followed. Epidemiology-directed microbiological testing of suspect cheeses helped identify the outbreak source. Cross-contamination of cheese highlights the importance of using validated disinfectant protocols and routine cleaning and sanitizing after cutting each block or wheel. C1 [Heiman, K. E.; Jackson, K. A.; Joseph, L.; Sabol, A.; Kucerova, Z.; Trees, E.; Griffin, P. M.; Tauxe, R. V.; Silk, B. J.] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Atlanta, GA USA. [Garalde, V. B.; Fields, A.; Chen, Y.; Datta, A.; Burall, L.; Metz, M.; Leblanc, P.; Lance, S.] US FDA, Silver Spring, MD USA. [Gronostaj, M.] Allegheny Cty Hlth Dept, Pittsburgh, PA USA. [Beam, S.] Calif Dept Food & Agr, Sacramento, CA 95814 USA. [Saupe, A.] Minnesota Dept Hlth, St Paul, MN USA. [Ricotta, E.] Maryland Dept Hlth & Mental Hyg, Baltimore, MD USA. [Waechter, H.] New York City Dept Hlth & Hyg, New York, NY USA. [Wellman, A.] Virginia Dept Hlth, Richmond, VA USA. [Adams-Cameron, M.] New Mexico Dept Hlth, Santa Fe, NM USA. [Ray, G.] Dist Columbia Dept Hlth, Washington, DC USA. RP Heiman, KE (reprint author), 1600 Clifton Rd NE MS A-38, Atlanta, GA 30329 USA. EM uwj0@cdc.gov NR 35 TC 3 Z9 3 U1 17 U2 17 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 EI 1469-4409 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD OCT PY 2016 VL 144 IS 13 BP 2698 EP 2708 DI 10.1017/S095026881500117X PG 11 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DX5RG UT WOS:000384438800002 PM 26122394 ER PT J AU Scully, CG Gomatam, S Forrest, S Strauss, DG AF Scully, Christopher G. Gomatam, Shanti Forrest, Shawn Strauss, David G. TI Importance of re-calibration time on pulse contour analysis agreement with thermodilution measurements of cardiac output: a retrospective analysis of intensive care unit patients SO JOURNAL OF CLINICAL MONITORING AND COMPUTING LA English DT Article DE Cardiac output; Pulse contour analysis; Method comparison; Trend monitoring ID ARTERIAL-PRESSURE; TRANSPULMONARY THERMODILUTION; PRECISION STATISTICS; INVASIVE MEASUREMENT; BLOOD-GLUCOSE; SURGERY; ACCURACY; NEXFIN; RELIABILITY; COMPONENTS AB We assessed the effect of re-calibration time on cardiac output estimation and trending performance in a retrospective analysis of an intensive care unit patient population using error grid analyses. Paired thermodilution and arterial blood pressure waveform measurements (N = 2141) from 222 patient records were extracted from the Multiparameter Intelligent Monitoring in Intensive Care II database. Pulse contour analysis was performed by implementing a previously reported algorithm at calibration times of 1, 2, 8 and 24 h. Cardiac output estimation agreement was assessed using Bland-Altman and error grid analyses. Trending was assessed by concordance and a 4-Quadrant error grid analysis. Error between pulse contour and thermodilution increased with longer calibration times. Limits of agreement were -1.85 to 1.66 L/min for 1 h maximum calibration time compared to -2.70 to 2.41 L/min for 24 h. Error grid analysis resulted in 74.2 % of points bounded by 20 % error limits of thermodilution measurements for 1 h calibration time compared to 65 % for 24 h. 4-Quadrant error grid analysis showed < 75 % of changes in pulse contour estimates to be within +/- 80 % of the change in the thermodilution measurement at any calibration time. Shorter calibration times improved the agreement of cardiac output pulse contour estimates with thermodilution. Use of minimally invasive pulse contour methods in intensive care monitoring could benefit from prospective studies evaluating calibration protocols. The applied pulse contour analysis method and thermodilution showed poor agreement to monitor changes in cardiac output. C1 [Scully, Christopher G.; Strauss, David G.] US FDA, Off Sci & Engn Labs, Div Biomed Phys, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Gomatam, Shanti] US FDA, Off Surveillance & Biometr, Div Biostat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Forrest, Shawn] US FDA, Off Device Evaluat, Div Cardiovasc Devices, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Scully, CG (reprint author), US FDA, Off Sci & Engn Labs, Div Biomed Phys, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM christopher.scully@fda.hhs.gov FU US Food and Drug Administration's Medical Countermeasures Initiative FX This work was supported in part by the US Food and Drug Administration's Medical Countermeasures Initiative. C.G.S., S.G., S.F., and D.G.S. are employed by the US Food and Drug Administration. C.G.S. was supported 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. NR 45 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1387-1307 EI 1573-2614 J9 J CLIN MONIT COMPUT JI J. Clin. Monitor. Comp. PD OCT PY 2016 VL 30 IS 5 BP 577 EP 586 DI 10.1007/s10877-015-9749-9 PG 10 WC Anesthesiology SC Anesthesiology GA DW4GX UT WOS:000383602300011 PM 26285740 ER PT J AU Hinderling, PH AF Hinderling, Peter H. TI The Pharmacokinetics of Potassium in Humans Is Unusual SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Review DE potassium; exogenous; endogenous; humans; pharmacokinetics; renal clearance ID CHLORIDE TABLET; BIOAVAILABILITY; HOMEOSTASIS; EXCRETION; CAPSULE; SHEEP AB Potassium is critical for maintaining cellular tonicity, propagation of nerve impulses, contraction of cardiac, skeletal, and smooth muscles, and normal renal function. The focus of this review is on the pharmacokinetics of potassium, K+, after administration of liquid and solid formulations of potassium chloride, KCl, to healthy subjects. Potassium can be considered an endogenous and exogenous compound. The amounts of endogenous K+ are kept constant by balancing intake and loss of exogenous K+. Food and ingestion of KCl-containing medicines are sources for exogenous K+. In the pharmacokinetic context exogenous K+ from KCl-containing medicines, K-exo,dose(+), is of primary interest. The distinction between the different K+ entities is critical for obtaining unbiased estimates of the kinetic parameters for K-exo,dose(+). A literature search using prespecified acceptance criteria was performed. Publications were selected that reported plasma and urine data of K-exo,dose(+) directly or provided information allowing their determination. Additional criteria applied included that the studies used a randomized design and controlled for the important covariates. Most of the selected publications reported urinary excretion data. Only 2 publications also reported plasma concentrations. The excursions of the plasma concentrations of K-exo,dose(+) were considered too small to be of use by most investigators. The aggregate results indicate that urinary recovery data have the potential for providing reliable estimates for bioavailability and bioequivalence of K-exo,dose(+) with KCl-containing formulations. Absorption efficiency, peak rates, and corresponding times of K-exo,dose(+) with liquid formulations are fairly consistent among studies. The mean absorption efficiency of K-exo,dose(+) with solid and liquid formulations of KCl ranges between 70% and 90%. The absorption rate of liquid formulations is rapid, whereas the solid formulations show extended release characteristics. The time-averaged renal clearance of K-exo,dose(+) is about 200 mL/min during daytime and significantly smaller around midnight. Circadian rhythm and delayed homeostatic control of potassium make the pharmacokinetics of K-exo,dose(+) time dependent. The impact of these endogenous controls makes the pharmacokinetics of K-exo,dose(+) unusual. C1 [Hinderling, Peter H.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Hinderling, Peter H.] Amer Coll Clin Pharmacol, Ashburn, VA USA. RP Hinderling, PH (reprint author), 10903 New Hampshire Ave,Bldg 51, Silver Spring, MD 20993 USA. EM peter.hinderling@fda.hhs.gov NR 24 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD OCT PY 2016 VL 56 IS 10 BP 1212 EP 1220 DI 10.1002/jcph.713 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DX7DD UT WOS:000384545600005 PM 26854277 ER PT J AU Lagishetty, CV Deng, JX Lesko, LJ Rogers, H Pacanowski, M Schmidt, S AF Lagishetty, Chakradhar V. Deng, Jiexin Lesko, Lawrence J. Rogers, Hobart Pacanowski, Michael Schmidt, Stephan TI How Informative Are Drug-Drug Interactions of Gene-Drug Interactions? SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE drug-drug interaction; genetics; CYP; polymorphism and physiologically based pharmacokinetics ID PROTON PUMP INHIBITORS; QUANTITATIVE PREDICTION; CONCOMITANT USE; CLOPIDOGREL; OMEPRAZOLE; EXPOSURE; POLYMORPHISMS; PANTOPRAZOLE AB FDA recommendations to manage polymorphic CYP-mediated drug-drug interactions (DDIs) and gene-drug interactions (GDIs) are typically similar. However, DDIs may not always reliably predict GDIs because the victim drug may have multiple metabolic pathways and the perpetrator drug may affect multiple enzymes or transporters. Consequently, it is of great interest to both the pharmaceutical industry and regulatory agencies to determine if DDI studies can be leveraged to inform GDIs or vice versa for dose adjustment and labeling. The objective of this study was to investigate under what circumstances DDIs can be used to predict GDIs for prototypical CYP2C9, CYP2C19, and CYP2D6 substrates. We investigated model substrates for CYP2D6 (metoprolol, dextromethorphan, atomoxetine, and vortioxetine), CYP2C9 (warfarin, flurbiprofen, and celecoxib), and CYP2C19 (omeprazole and clopidogrel). Data on drug exposure for poor metabolizers (GDI) and for DDIs mediated by strong/moderate inhibitors in extensive metabolizers were collected. The impact of DDIs and GDIs on drug exposure was compared using: (1) a descriptive and (2) a physiologically based pharmacokinetic convergence analysis. Results from both approaches indicate that information on DDIs can be used to reliably predict GDIs for CYP2D6 substrates. The situation is more complex for CYP2C9 and CYP2C19 substrates because dose of the inhibitor (CYP2C9) and potency of the inhibitor (CYP2C19) impact the extent to which perpetrator drugs phenotypically convert extensive metabolizers to poor(er) metabolizers. C1 [Lagishetty, Chakradhar V.; Deng, Jiexin; Lesko, Lawrence J.; Schmidt, Stephan] Univ Florida Lake Nona, Ctr Pharmacometr & Syst Pharmacol, Coll Pharm, Orlando, FL 32827 USA. [Rogers, Hobart; Pacanowski, Michael] US FDA, FDA Genom & Targeted Therapy Grp, Off Clin Pharmacol, Off Translat Sci,CDER, Silver Spring, MD USA. [Lesko, Lawrence J.] Amer Coll Clin Pharmacol FCP, Ashburn, VA USA. RP Schmidt, S (reprint author), Univ Florida Lake Nona, Ctr Pharmacometr & Syst Pharmacol, Coll Pharm, Orlando, FL 32827 USA. EM sschmidt@cop.ufl.edu FU US Department of Energy; US Food and Drug Administration FX C.L. is supported by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research administered by 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 29 TC 1 Z9 1 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD OCT PY 2016 VL 56 IS 10 BP 1221 EP 1231 DI 10.1002/jcph.743 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DX7DD UT WOS:000384545600006 PM 27040602 ER PT J AU Dember, LM Archdeacon, P Krishnan, M Lacson, E Ling, SM Roy-Chaudhury, P Smith, KA Flessner, MF AF Dember, Laura M. Archdeacon, Patrick Krishnan, Mahesh Lacson, Eduardo, Jr. Ling, Shari M. Roy-Chaudhury, Prabir Smith, Kimberly A. Flessner, Michael F. TI Pragmatic Trials in Maintenance Dialysis: Perspectives from the Kidney Health Initiative SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Review ID CLINICAL-TRIALS; QUALITY; CARE; NEPHROLOGY; CLINICALTRIALS.GOV; INCREASE; CONSENT; POLICY; SAFETY; PBRN AB Pragmatic clinical trials are conducted under the real-world conditions of clinical care delivery. As a result, these trials yield findings that are highly generalizable to the nonresearch setting, identify interventions that are readily translatable into clinical practice, and cost less than trials that require extensive research infrastructures. Maintenance dialysis is a setting especially well suited for pragmatic trials because of inherently frequent and predictable patient encounters, highly granular and uniform data collection, use of electronic data systems, and delivery of care by a small number of provider organizations to approximately 90% of patients nationally. Recognizing the potential for pragmatic trials to generate much needed evidence to guide the care of patients receiving maintenance dialysis, the Kidney Health Initiative assembled a group of individuals with relevant expertise from academia, industry, and government to provide the nephrology community with information about the design and conduct of such trials, with a specific focus on the dialysis setting. Here, we review this information, and where applicable, use experience from the ongoing Time to Reduce Mortality in End Stage Renal Disease Trial, a large cluster-randomized, pragmatic trial evaluating hemodialysis session duration, to illustrate challenges and solutions to operational, ethical, and regulatory issues. C1 [Dember, Laura M.] Univ Penn, Renal Electrolyte & Hypertens Div, Perelman Sch Med, Philadelphia, PA 19104 USA. [Dember, Laura M.] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Archdeacon, Patrick] US FDA, Off Med Policy, Silver Spring, MD USA. [Archdeacon, Patrick; Smith, Kimberly A.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Krishnan, Mahesh] DaVita Healthcare Partners, Denver, CO USA. [Lacson, Eduardo, Jr.] Tufts Med Ctr, Div Nephrol, Boston, MA USA. [Lacson, Eduardo, Jr.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Ling, Shari M.] Ctr Medicare Serv, Ctr Clin Stand & Qual, Baltimore, MD USA. [Ling, Shari M.] Ctr Medicaid Serv, Ctr Clin Stand & Qual, Baltimore, MD USA. [Roy-Chaudhury, Prabir] Univ Arizona, Coll Med, Div Nephrol, Tucson, AZ USA. [Roy-Chaudhury, Prabir] Southern Arizona Vet Adm Hlth Care Syst, Tucson, AZ USA. [Flessner, Michael F.] NIDDK, Div Kidney Urol & Hematol, Bethesda, MD 20892 USA. RP Dember, LM (reprint author), Univ Penn, Perelman Sch Med, Blockley Hall,Room 920,423 Guardian Dr, Philadelphia, PA 19104 USA. EM ldember@upenn.edu FU Kidney Health Initiative (KHI); American Society of Nephrology; US Food and Drug Administration; National Institutes of Health Office of the Director; National Institute of Diabetes and Digestive and Kidney Diseases [UH2-AT007797, UH3-DK102384] FX This work was supported by the Kidney Health Initiative (KHI), a public-private partnership between the American Society of Nephrology, the US Food and Drug Administration, and >75 member organizations and companies to enhance patient safety and foster innovation in kidney disease. KHI funds were used to defray costs incurred during the conduct of the project, including project management support which was expertly provided by American Society of Nephrology staff members, Melissa West and Ryan Murray. There was no honorarium or other financial support provided to KHI workgroup members. The authors of this paper had final review authority and are fully responsible for its content.; KHI makes every effort to avoid actual, potential, or perceived conflicts of interest that may arise as a result of industry relationships or personal interests among the members of the workgroup. More information on KHI, the workgroup, or the conflict of interest policy can be found at www.kidneyhealthinitiative.org. The TiME Trial is funded by the National Institutes of Health Office of the Director and the National Institute of Diabetes and Digestive and Kidney Diseases (UH2-AT007797 and UH3-DK102384 to L.M.D.). The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any agency of the US Government, DaVita Healthcare Partners, or Fresenius Medical Care. NR 43 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD OCT PY 2016 VL 27 IS 10 BP 2955 EP 2963 DI 10.1681/ASN.2016030340 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA DX8HK UT WOS:000384628500008 PM 27401689 ER PT J AU Ajiro, M Tang, S Doorbar, J Zheng, ZM AF Ajiro, Masahiko Tang, Shuang Doorbar, John Zheng, Zhi-Ming TI Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements SO JOURNAL OF VIROLOGY LA English DT Article ID SPINAL MUSCULAR-ATROPHY; TRACT BINDING-PROTEIN; MESSENGER-RNA; SR PROTEINS; FACTOR SRP20; MOUSE MODEL; HNRNP A1; CERVICAL-CANCER; DOWN-REGULATION; EXON SEQUENCES AB Human papillomavirus 18 (HPV18) is the second most common oncogenic HPV type associated with cervical, anogenital, and oropharyngeal cancers. Like other oncogenic HPVs, HPV18 encodes two major (one early and one late) polycistronic premRNAs that are regulated by alternative RNA splicing to produce a repertoire of viral transcripts for the expression of individual viral genes. However, RNA cis-regulatory elements and trans-acting factors contributing to HPV18 alternative RNA splicing remain unknown. In this study, an exonic splicing enhancer (ESE) in the nucleotide (nt) 3520 to 3550 region in the HPV18 genome was identified and characterized for promotion of HPV18 929 boolean AND 3434 splicing and E1 boolean AND E4 production through interaction with SRSF3, a host oncogenic splicing factor differentially expressed in epithelial cells and keratinocytes. Introduction of point mutations in the SRSF3-binding site or knockdown of SRSF3 expression in cells reduces 929 boolean AND 3434 splicing and E1 boolean AND E4 production but activates other, minor 929 boolean AND 3465 and 929 boolean AND 3506 splicing. Knockdown of SRSF3 expression also enhances the expression of E2 and L1 mRNAs. An exonic splicing silencer (ESS) in the HPV18 nt 612 to 639 region was identified as being inhibitory to the 233 boolean AND 416 splicing of HPV18 E6E7 pre-mRNAs via binding to hnRNP A1, a well-characterized, abundantly and ubiquitously expressed RNA-binding protein. Introduction of point mutations into the hnRNP A1-binding site or knockdown of hnRNP A1 expression promoted 233 boolean AND 416 splicing and reduced E6 expression. These data provide the first evidence that the alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host trans-acting splicing factors. IMPORTANCE Expression of HPV18 genes is regulated by alternative RNA splicing of viral polycistronic pre-mRNAs to produce a repertoire of viral early and late transcripts. RNA cis elements and trans-acting factors contributing to HPV18 alternative RNA splicing have been discovered in this study for the first time. The identified ESS at the E7 open reading frame (ORF) prevents HPV18 233 boolean AND 416 splicing in the E6 ORF through interaction with a host splicing factor, hnRNP A1, and regulates E6 and E7 expression of the early E6E7 polycistronic pre-mRNA. The identified ESE at the E1 boolean AND E4 ORF promotes HPV18 929 boolean AND 3434 splicing of both viral early and late pre-mRNAs and E1 boolean AND E4 production through interaction with SRSF3. This study provides important observations on how alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host splicing factors and offers potential therapeutic targets to overcome HPV-related cancer. C1 [Ajiro, Masahiko; Tang, Shuang; Zheng, Zhi-Ming] NCI, Tumor Virus RNA Biol Sect, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res,NIH, Frederick, MD 21701 USA. [Doorbar, John] Univ Cambridge, Dept Pathol, Div Virol, Cambridge, England. [Ajiro, Masahiko] Kyoto Univ, Grad Sch Med, Dept Anat & Dev Biol, Dept Drug Discovery Med, Kyoto, Japan. [Tang, Shuang] US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Zheng, ZM (reprint author), NCI, Tumor Virus RNA Biol Sect, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res,NIH, Frederick, MD 21701 USA. EM zhengt@exchange.nih.gov FU HHS \ NIH \ NIH Office of the Director (OD) [1ZIASC010357]; HHS \ NIH \ Intramural Research Program FX This work, including the efforts of Zhi-Ming Zheng, was funded by HHS vertical bar NIH vertical bar NIH Office of the Director (OD) (1ZIASC010357). This work was funded by HHS vertical bar NIH vertical bar Intramural Research Program. NR 87 TC 1 Z9 1 U1 7 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 OCT PY 2016 VL 90 IS 20 BP 9138 EP 9152 DI 10.1128/JVI.00965-16 PG 15 WC Virology SC Virology GA DX7NO UT WOS:000384574900002 PM 27489271 ER PT J AU Manivannan, S Baxter, VK Schultz, KLW Slusher, BS Griffin, DE AF Manivannan, Sivabalan Baxter, Victoria K. Schultz, Kimberly L. W. Slusher, Barbara S. Griffin, Diane E. TI Protective Effects of Glutamine Antagonist 6-Diazo-5-Oxo-L-Norleucine in Mice with Alphavirus Encephalomyelitis SO JOURNAL OF VIROLOGY LA English DT Article ID NEUROADAPTED SINDBIS-VIRUS; T-LYMPHOCYTE ACTIVATION; CANCER-CELL METABOLISM; DON 6-DIAZO-5-OXO-L-NORLEUCINE; RECEPTOR ANTAGONISTS; NONCYTOLYTIC CLEARANCE; GAMMA-INTERFERON; NERVOUS-SYSTEM; NEURONAL DEATH; SPINAL-CORD AB Inflammation is a necessary part of the response to infection but can also cause neuronal injury in both infectious and autoimmune diseases of the central nervous system (CNS). A neurovirulent strain of Sindbis virus (NSV) causes fatal paralysis in adult C57BL/6 mice during clearance of infectious virus from the CNS, and the virus-specific immune response is implicated as a mediator of neuronal damage. Previous studies have shown that survival is improved in T-cell-deficient mice and in mice with pharmacological inhibition of the inflammatory response and glutamate excitotoxicity. Because glutamine metabolism is important in the CNS for the generation of glutamate and in the immune system for lymphocyte proliferation, we tested the effect of the glutamine antagonist DON (6-diazo-5-oxo-L-norleucine) on the outcome of NSV infection in mice. DON treatment for 7 days from the time of infection delayed the onset of paralysis and death. Protection was associated with reduced lymphocyte proliferation in the draining cervical lymph nodes, decreased leukocyte infiltration into the CNS, lower levels of inflammatory cytokines, and delayed viral clearance. In vitro studies showed that DON inhibited stimulus-induced proliferation of lymphocytes. When in vivo treatment with DON was stopped, paralytic disease developed along with the inflammatory response and viral clearance. These studies show that fatal NSV-induced encephalomyelitis is immune mediated and that antagonists of glutamine metabolism can modulate the immune response and protect against virus-induced neuroinflammatory disease. IMPORTANCE Encephalomyelitis due to infection with mosquito-borne alphaviruses is an important cause of death and of long-term neurological disability in those who survive infection. This study demonstrates the role of the virus-induced immune response in the generation of neurological disease. DON, a glutamine antagonist, inhibited the proliferation of lymphocytes in response to infection, prevented the development of brain inflammation, and protected mice from paralysis and death during treatment. However, because DON inhibited the immune response to infection, clearance of the virus from the brain was also prevented. When treatment was stopped, the immune response was generated, brain inflammation occurred, virus was cleared, and mice developed paralysis and died. Therefore, more definitive treatment for alphaviral encephalomyelitis should inhibit virus replication as well as neuroinflammatory damage. C1 [Manivannan, Sivabalan; Baxter, Victoria K.; Schultz, Kimberly L. W.; Griffin, Diane E.] Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Baxter, Victoria K.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD USA. [Slusher, Barbara S.] Johns Hopkins Univ, Brain Sci Inst, Dept Neurol, Sch Med, Baltimore, MD 21205 USA. [Schultz, Kimberly L. W.] US FDA, Silver Spring, MD USA. RP Griffin, DE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. EM dgriffi6@jhu.edu FU Johns Hopkins Brain Science Institute; HHS \ National Institutes of Health (NIH) [R01 NS087539, T32 OD011089, T32 AI007247, T32 AI 07417] FX This work, including the efforts of Barbara S. Slusher, was funded by Johns Hopkins Brain Science Institute (pilot grant). This work, including the efforts of Diane E. Griffin, was funded by HHS vertical bar National Institutes of Health (NIH) (R01 NS087539, T32 OD011089, T32 AI007247, and T32 AI 07417). NR 67 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD OCT PY 2016 VL 90 IS 20 BP 9251 EP 9262 DI 10.1128/JVI.01045-16 PG 12 WC Virology SC Virology GA DX7NO UT WOS:000384574900024 PM 27489275 ER PT J AU Khurana, S Chung, KY Coyle, EM Meijer, A Golding, H AF Khurana, Surender Chung, Ka Yan Coyle, Elizabeth M. Meijer, Adam Golding, Hana TI Antigenic Fingerprinting of Antibody Response in Humans following Exposure to Highly Pathogenic H7N7 Avian Influenza Virus: Evidence for Anti-PA-X Antibodies SO JOURNAL OF VIROLOGY LA English DT Article ID A VIRUS; AFFINITY MATURATION; HUMAN INFECTION; SEGMENT 3; VACCINE; POULTRY; PROTEIN; DIVERSITY; VIRULENCE; OUTBREAK AB Infections with H7 highly pathogenic avian influenza (HPAI) viruses remain a major public health concern. Adaptation of lowpathogenic H7N7 to highly pathogenic H7N7 in Europe in 2015 raised further alarm for a potential pandemic. An in-depth understanding of antibody responses to HPAI H7 virus following infection in humans could provide important insight into virus gene expression as well as define key protective and serodiagnostic targets. Here we used whole-genome gene fragment phage display libraries (GFPDLs) expressing peptides of 15 to 350 amino acids across the complete genome of the HPAI H7N7 A/Netherlands/33/03 virus. The hemagglutinin (HA) antibody epitope repertoires of 15 H7N7-exposed humans identified clear differences between individuals with no hemagglutination inhibition (HI) titers (<1:10) and those with HI titers of >1:40. Several potentially protective H7N7 epitopes close to the HA receptor binding domain (RBD) and neuraminidase (NA) catalytic site were identified. Surface plasmon resonance (SPR) analysis identified a strong correlation between HA1 (but not HA2) binding antibodies and H7N7 HI titers. A proportion of HA1 binding in plasma was contributed by IgA antibodies. Antibodies against the N7 neuraminidase were less frequent but targeted sites close to the sialic acid binding site. Importantly, we identified strong antibody reactivity against PA-X, a putative virulence factor, in most H7N7-exposed individuals, providing the first evidence for in vivo expression of PA-X and its recognition by the immune system during human influenza A virus infection. This knowledge can help inform the development and selection of the most effective countermeasures for prophylactic as well as therapeutic treatments of HPAI H7N7 avian influenza virus. IMPORTANCE An outbreak of pathogenic H7N7 virus occurred in poultry farms in The Netherlands in 2003. Severe outcome included conjunctivitis, influenza-like illness, and one lethal infection. In this study, we investigated convalescent-phase sera from H7N7-exposed individuals by using a whole-genome phage display library (H7N7-GFPDL) to explore the complete repertoire of post-H7N7exposure antibodies. PA-X is a recently identified influenza virus virulence protein generated by ribosomal frameshifting in segment 3 of influenza virus coding for PA. However, PA-X expression during influenza virus infection in humans is unknown. We identified strong antibody reactivity against PA-X in most H7N7-exposed individuals (but not in unexposed adults), providing the first evidence for in vivo expression of PA-X and its recognition by the immune system during human infection with pathogenic H7N7 avian influenza virus. C1 [Khurana, Surender; Chung, Ka Yan; Coyle, Elizabeth M.; Golding, Hana] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Meijer, Adam] Natl Inst Publ Hlth & Environm RIVM, Div Virol, Ctr Infect Dis Res Diagnost & Screening, Bilthoven, Netherlands. RP Khurana, S (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Surender.Khurana@fda.hhs.gov FU HHS \ U.S. Food and Drug Administration (FDA) (MCM) FX This work, including the efforts of Hana Golding, was funded by HHS vertical bar U.S. Food and Drug Administration (FDA) (MCM). NR 28 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD OCT PY 2016 VL 90 IS 20 BP 9383 EP 9393 DI 10.1128/JVI.01408-16 PG 11 WC Virology SC Virology GA DX7NO UT WOS:000384574900009 PM 27512055 ER PT J AU Turner, MA Davis, JM McCune, S Bax, R Portman, RJ Hudson, LD AF Turner, Mark A. Davis, Jonathan M. McCune, Susan Bax, Ralph Portman, Ronald J. Hudson, Lynn D. CA Int Neonatal Consortium TI The International Neonatal Consortium: collaborating to advance regulatory science for neonates SO PEDIATRIC RESEARCH LA English DT Article ID DEVELOP C1 [Turner, Mark A.] Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England. [Davis, Jonathan M.] Tufts Univ, Floating Hosp Children, Tufts Med Ctr, Dept Pediat, Boston, MA USA. [Davis, Jonathan M.] Tufts Univ, Tufts Clin & Translat Sci Inst, Boston, MA USA. [McCune, Susan] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Bax, Ralph] European Med Agcy, Paediat Med Prod Dev & Sci Support Dept, London, England. [Portman, Ronald J.] Novartis Pharmaceut, Pediat Therapeut Area, E Hanover, NJ USA. [Hudson, Lynn D.] Crit Path Inst, Tucson, AZ USA. RP Turner, MA (reprint author), Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England. EM mark.turner@liverpool.ac.uk FU U.S. Food and Drug Administration (FDA) [U18FD005320-01] FX The International Neonatal Consortium (INC) is supported in part by grant number U18FD005320-01 from the U.S. Food and Drug Administration (FDA) to the Critical Path Institute (http://c-path.org) and through annual dues of member companies. NR 9 TC 1 Z9 1 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0031-3998 EI 1530-0447 J9 PEDIATR RES JI Pediatr. Res. PD OCT PY 2016 VL 80 IS 4 BP 462 EP 464 DI 10.1038/pr.2016.119 PG 3 WC Pediatrics SC Pediatrics GA DX9IC UT WOS:000384705800001 PM 27384407 ER PT J AU Liu, ZC Fang, H Slikker, W Tong, WD AF Liu, Zhichao Fang, Hong Slikker, William Tong, Weida TI Potential Reuse of Oncology Drugs in the Treatment of Rare Diseases SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID PLURIPOTENT STEM-CELLS; GENOME-WIDE ASSOCIATION; NEPHROGENIC SYSTEMIC FIBROSIS; IMATINIB MESYLATE TREATMENT; TOLL-LIKE RECEPTORS; LEOPARD-SYNDROME; CANCER PREDISPOSITION; PRECISION MEDICINE; PARKINSONS-DISEASE; GENETIC-VARIANTS AB Cancer research has made remarkable progress with the help of advancing genomics techniques, resulting in more precise clinical application and many new anticancer drugs on the market. By contrast, very few treatment options are available for rare diseases that are often progressive, severe, and life-threatening. In this opinion we elaborate on the possible association between cancers and rare diseases across three different levels including clinical observation, crosstalk between germline mutation and somatic mutation, and shared biological pathways. Consequently, by utilizing systematic drug-repositioning approaches, and taking safety issues into consideration, we suggest that oncology drugs have great potential for reuse in the treatment of rare diseases. C1 [Liu, Zhichao; Fang, Hong; Slikker, William; Tong, Weida] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Liu, ZC; Tong, WD (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Zhichao.liu@fda.hhs.gov; weida.tong@fda.hhs.gov NR 153 TC 0 Z9 0 U1 14 U2 14 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD OCT PY 2016 VL 37 IS 10 BP 843 EP 857 DI 10.1016/j.tips.2016.06.010 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DY1MA UT WOS:000384857900006 PM 27461952 ER PT J AU Toro, M Retamal, P Ayers, S Barreto, M Allard, M Brown, EW Gonzalez-Escalona, N AF Toro, Magaly Retamal, Patricio Ayers, Sherry Barreto, Marlen Allard, Marc Brown, Eric W. Gonzalez-Escalona, Narjol TI Whole-Genome Sequencing Analysis of Salmonella enterica Serovar Enteritidis Isolates in Chile Provides Insights into Possible Transmission between Gulls, Poultry, and Humans SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID HOST ADAPTATION; UNITED-STATES; EVOLUTIONARY; OUTBREAK; SURVEILLANCE; EPIDEMIOLOGY; POPULATION; INFECTIONS; PHENOTYPES; SEROTYPES AB Salmonella enterica subsp. enterica serotype Enteritidis is a major cause of human salmonellosis worldwide; however, little is known about the genetic relationships between S. Enteritidis clinical strains and S. Enteritidis strains from other sources in Chile. We compared the whole genomes of 30 S. Enteritidis strains isolated from gulls, domestic chicken eggs, and humans in Chile, to investigate their phylogenetic relationships and to establish their relatedness to international strains. Core genome multilocus sequence typing (cgMLST) analysis showed that only 246/4,065 shared loci differed among these Chilean strains, separating them into two clusters (I and II), with cluster II being further divided into five subclusters. One subcluster (subcluster 2) contained strains from all surveyed sources that differed at 1 to 18 loci (of 4,065 loci) with 1 to 18 single-nucleotide polymorphisms (SNPs), suggesting interspecies transmission of S. Enteritidis in Chile. Moreover, clusters were formed by strains that were distant geographically, which could imply that gulls might be spreading the pathogen throughout the country. Our cgMLST analysis, using other S. Enteritidis genomes available in the National Center for Biotechnology Information (NCBI) database, showed that S. Enteritidis strains from Chile and the United States belonged to different lineages, which suggests that S. Enteritidis regional markers might exist and could be used for trace-back investigations. IMPORTANCE This study highlights the importance of gulls in the spread of Salmonella Enteritidis in Chile. We revealed a close genetic relationship between some human and gull S. Enteritidis strains (with as few as 2 of 4,065 genes being different), and we also found that gull strains were present in clusters formed by strains isolated from other sources or distant locations. Together with previously published evidence, this suggests that gulls might be spreading this pathogen between different regions in Chile and that some of those strains have been transmitted to humans. Moreover, we discovered that Chilean S. Enteritidis strains clustered separately from most of S. Enteritidis strains isolated throughout the world (in the GenBank database) and thus it might be possible to distinguish the geographical origins of strains based on specific genomic features. This could be useful for trace-back investigations of foodborne illnesses throughout the world. C1 [Toro, Magaly] Univ Chile, Inst Nutr & Tecnol Alimentos, Santiago, Chile. [Retamal, Patricio] Univ Chile, Fac Ciencias Vet & Pecuarias, Santiago, Chile. [Ayers, Sherry] US FDA, Ctr Vet Med, Laurel, MD USA. [Barreto, Marlen] Univ Autonoma Chile, Fac Hlth Sci, Ctr Biomed Res, Santiago, Chile. [Allard, Marc; Brown, Eric W.; Gonzalez-Escalona, Narjol] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Gonzalez-Escalona, N (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM narjol.gonzalez-escalona@fda.hhs.gov RI Retamal, Patricio/G-3054-2013; Toro, Magaly/F-6525-2011 OI Retamal, Patricio/0000-0001-8597-9550; Toro, Magaly/0000-0002-6280-2215 FU Fondecyt [111 50 491]; FDA Foods Program Intramural Funds FX This work, including the efforts of Magaly Toro, was funded by Fondecyt (111 50 491). This work, including the efforts of Sherry Ayers, Marc W. Allard, Eric Brown, and Narjol Gonzalez-Escalona, was funded by FDA Foods Program Intramural Funds. NR 34 TC 0 Z9 0 U1 6 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD OCT PY 2016 VL 82 IS 20 BP 6223 EP 6232 DI 10.1128/AEM.01760-16 PG 10 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DX5RP UT WOS:000384439700015 PM 27520817 ER PT J AU Chen, Y Gonzalez-Escalona, N Hammack, TS Allard, MW Strain, EA Brown, EW AF Chen, Yi Gonzalez-Escalona, Narjol Hammack, Thomas S. Allard, Marc W. Strain, Errol A. Brown, Eric W. TI Core Genome Multilocus Sequence Typing for Identification of Globally Distributed Clonal Groups and Differentiation of Outbreak Strains of Listeria monocytogenes SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; FIELD GEL-ELECTROPHORESIS; EPIDEMIC CLONES; UNITED-STATES; MULTISTATE OUTBREAK; PASTEURIZED MILK; VIRULENCE; GASTROENTERITIS; INFECTION; DISEASE AB Many listeriosis outbreaks are caused by a few globally distributed clonal groups, designated clonal complexes or epidemic clones, of Listeria monocytogenes, several of which have been defined by classic multilocus sequence typing (MLST) schemes targeting 6 to 8 housekeeping or virulence genes. We have developed and evaluated core genome MLST (cgMLST) schemes and applied them to isolates from multiple clonal groups, including those associated with 39 listeriosis outbreaks. The cgMLST clusters were congruent with MLST-defined clonal groups, which had various degrees of diversity at the whole-genome level. Notably, cgMLST could distinguish among outbreak strains and epidemiologically unrelated strains of the same clonal group, which could not be achieved using classic MLST schemes. The precise selection of cgMLST gene targets may not be critical for the general identification of clonal groups and outbreak strains. cgMLST analyses further identified outbreak strains, including those associated with recent outbreaks linked to contaminated French-style cheese, Hispanic-style cheese, stone fruit, caramel apple, ice cream, and packaged leafy green salad, as belonging to major clonal groups. We further developed lineage-specific cgMLST schemes, which can include accessory genes when core genomes do not possess sufficient diversity, and this provided additional resolution over species-specific cgMLST. Analyses of isolates from different common-source listeriosis outbreaks revealed various degrees of diversity, indicating that the numbers of allelic differences should always be combined with cgMLST clustering and epidemiological evidence to define a listeriosis outbreak. IMPORTANCE Classic multilocus sequence typing (MLST) schemes targeting internal fragments of 6 to 8 genes that define clonal complexes or epidemic clones have been widely employed to study L. monocytogenes biodiversity and its relation to pathogenicity potential and epidemiology. We demonstrated that core genome MLST schemes can be used for the simultaneous identification of clonal groups and the differentiation of individual outbreak strains and epidemiologically unrelated strains of the same clonal group. We further developed lineage-specific cgMLST schemes that targeted more genomic regions than the species-specific cgMLST schemes. Our data revealed the genome-level diversity of clonal groups defined by classic MLST schemes. Our identification of U.S. and international outbreaks caused by major clonal groups can contribute to further understanding of the global epidemiology of L. monocytogenes. C1 [Chen, Yi; Gonzalez-Escalona, Narjol; Hammack, Thomas S.; Allard, Marc W.; Strain, Errol A.; Brown, Eric W.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Chen, Y (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM yi.chen@fda.hhs.gov NR 59 TC 4 Z9 4 U1 12 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD OCT PY 2016 VL 82 IS 20 BP 6258 EP 6272 DI 10.1128/AEM.01532-16 PG 15 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DX5RP UT WOS:000384439700018 PM 27520821 ER PT J AU Han, J Sanad, YM Deck, J Sutherland, JB Li, Z Walters, MJ Duran, N Holman, MR Foley, SL AF Han, Jing Sanad, Yasser M. Deck, Joanna Sutherland, John B. Li, Zhong Walters, Matthew J. Duran, Norma Holman, Matthew R. Foley, Steven L. TI Bacterial Populations Associated with Smokeless Tobacco Products SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID GRADIENT GEL-ELECTROPHORESIS; HUMAN ORAL MICROBIOME; 16S RIBOSOMAL-RNA; UNITED-STATES; N-NITROSAMINES; TOTAL NICOTINE; MOIST SNUFF; HEALTH; BACILLUS; DISEASE AB There are an estimated 8 million users of smokeless tobacco products (STPs) in the United States, and yet limited data on microbial populations within these products exist. To better understand the potential microbiological risks associated with STP use, a study was conducted to provide a baseline microbiological profile of STPs. A total of 90 samples, representing 15 common STPs, were purchased in metropolitan areas in Little Rock, AR, and Washington, DC, in November 2012, March 2013, and July 2013. Bacterial populations were evaluated using culture, pyrosequencing, and denaturing gradient gel electrophoresis (DGGE). Moist-snuff products exhibited higher levels of bacteria (average of 1.05 x 10(6) CFU/g STP) and diversity of bacterial populations than snus (average of 8.33 x 10(1) CFU/g STP) and some chewing tobacco products (average of 2.54 x 10(5) CFU/g STP). The most common species identified by culturing were Bacillus pumilus, B. licheniformis, B. safensis, and B. subtilis, followed by members of the genera Oceanobacillus, Staphylococcus, and Tetragenococcus. Pyrosequencing analyses of the 16S rRNA genes identified the genera Tetragenococcus, Carnobacterium, Lactobacillus, Geobacillus, Bacillus, and Staphylococcus as the predominant taxa. Several species identified are of possible concern due to their potential to cause opportunistic infections and reported abilities to reduce nitrates to nitrites, which may be an important step in the formation of carcinogenic tobacco-specific N'-nitrosamines. This report provides a microbiological baseline to help fill knowledge gaps associated with microbiological risks of STPs and to inform potential regulations regarding manufacture and testing of STPs. IMPORTANCE It is estimated that there 8 million users of smokeless tobacco products (STPs) in the United States; however, there are limited data on microbial populations that exist within these products. The current study was undertaken to better understand the potential microbiological risks associated with STP use and provide a baseline microbiological profile of STPs. Several bacterial species were identified that are of possible concern due to their potential to cause opportunistic infections. In addition, some species have abilities to reduce nitrates to nitrites, which may be an important step in the formation of carcinogenic tobaccospecific N'-nitrosamines. Overall, this report provides a microbiological baseline to help fill knowledge gaps related to the microbiological risks of STPs and to inform potential regulations regarding the manufacture and testing of STPs. C1 [Han, Jing; Sanad, Yasser M.; Deck, Joanna; Sutherland, John B.; Foley, Steven L.] Natl Ctr Toxicol Res, FDA, Div Microbiol, Jefferson, AR 72079 USA. [Li, Zhong; Walters, Matthew J.; Duran, Norma; Holman, Matthew R.] Ctr Tobacco Prod, FDA, Div Prod Sci, Silver Spring, MD USA. RP Foley, SL (reprint author), Natl Ctr Toxicol Res, FDA, Div Microbiol, Jefferson, AR 72079 USA. EM steven.foley@fda.hhs.gov FU Center for Tobacco Products, U.S. FDA [E0750501] FX This work, including the efforts of Jing Han, Yasser M. Sanad, Joanna Deck, John B. Sutherland, Zhong Li, Matthew J. Walters, Norma Duran, Matthew R. Holman, and Steven L. Foley, was funded by Center for Tobacco Products, U.S. FDA (E0750501). NR 42 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD OCT PY 2016 VL 82 IS 20 BP 6273 EP 6283 DI 10.1128/AEM.01612-16 PG 11 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DX5RP UT WOS:000384439700019 PM 27565615 ER PT J AU Bashaw, ED AF Bashaw, E. D. TI A clinical pharmacology-regulatory perspective on the approval of drugs for rare diseases SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut AB Orphan drugs or drugs for rare diseases represents a particular regulatory conundrum. There is a desperate need for effective therapies for these patients, who have been historically underserved by the drug development community. However, there is also a need to make sure these therapies are both safe and effective. In response, the US Food and Drug Administration (FDA) has evolved new approaches to facilitate drug development in this area. C1 [Bashaw, E. D.] US FDA, Div Clin Pharmacol 3, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Bashaw, ED (reprint author), US FDA, Div Clin Pharmacol 3, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Edward.Bashaw@fda.hhs.gov NR 3 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 OCT PY 2016 VL 100 IS 4 BP 327 EP 329 DI 10.1002/cpt.427 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DX1CQ UT WOS:000384103500014 PM 27417549 ER PT J AU Sakkiah, S Ng, HW Tong, WD Hong, HX AF Sakkiah, Sugunadevi Ng, Hui Wen Tong, Weida Hong, Huixiao TI Structures of androgen receptor bound with ligands: advancing understanding of biological functions and drug discovery SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Review DE Androgen receptor; dihydrotestosterone; endocrine disruptors; endocrine receptor; testosterone ID AMINO-TERMINAL DOMAIN; ENDOCRINE-DISRUPTING CHEMICALS; RESISTANT PROSTATE-CANCER; DNA-BINDING DOMAIN; 3 BF3 SITE; NUCLEAR RECEPTOR; ESTROGEN-RECEPTOR; GLUCOCORTICOID-RECEPTOR; ALPHA-FETOPROTEIN; STEROID-HORMONES AB Introduction: Androgen receptor (AR) is a ligand-dependent transcription factor and a member of the nuclear receptor superfamily. It plays a vital role in male sexual development and regulates gene expression in various tissues, including prostate. Androgens are compounds that exert their biological effects via interaction with AR. Binding of androgens to AR initiates conformational changes in AR that affect binding of co-regulator proteins and DNA. AR agonists and antagonists are widely used in a variety of clinical applications (i.e. hypogonadism and prostate cancer therapy).Areas covered: This review provides a close look at structures of AR-ligand complexes and mutations in the receptor that have been revealed, discusses current challenges in the field, and sheds light on future directions.Expert opinion: AR is one of the primary targets for the treatment of prostate cancer, as AR antagonists inhibit prostate cancer growth. However, these drugs are not effective for long-term treatment and lead to castration-resistant prostate cancer. The structures of AR-ligand complexes are an invaluable scientific asset that enhances our understanding of biological functions and mechanisms of androgenic and anti-androgenic chemicals as well as promotes the discovery of superior drug candidates. C1 [Sakkiah, Sugunadevi; Ng, Hui Wen; Tong, Weida; Hong, Huixiao] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Hong, HX (reprint author), US FDA, Natl Ctr Toxicol Res, Bldg 5C Room 109,3900 NCTR Rd, Jefferson, AR 72079 USA. EM huixiao.hong@fda.hhs.gov FU Food and Drug Administration [E074501] FX This research was supported, in part, by an appointment to the Research Participation Program at the National Center for Toxicological Research (SD Sakkiah and HW Ng) 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. All authors have been supported by internal funding from the Food and Drug Administration (E074501). The findings and conclusions in this article have not been formally disseminated by the US Food and Drug Administration (FDA) and should not be construed to represent the FDA determination or policy. 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 155 TC 0 Z9 0 U1 9 U2 9 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1472-8222 EI 1744-7631 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD OCT PY 2016 VL 20 IS 10 BP 1267 EP 1282 DI 10.1080/14728222.2016.1192131 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DX4DU UT WOS:000384332100012 PM 27195510 ER PT J AU Agrawal, A Baxi, J Calhoun, W Chen, CL Ishikawa, H Schuman, JS Wollstein, G Hammer, DX AF Agrawal, Anant Baxi, Jigesh Calhoun, William Chen, Chieh-Li Ishikawa, Hiroshi Schuman, Joel S. Wollstein, Gadi Hammer, Daniel X. TI Optic Nerve Head Measurements With Optical Coherence Tomography: A Phantom-Based Study Reveals Differences Among Clinical Devices SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE optical coherence tomography; phantom; optic nerve head ID SPECTRAL-DOMAIN; RETINAL THICKNESS; TIME-DOMAIN; RNFL THICKNESS; OCT DEVICES; MODEL AB PURPOSE. Optical coherence tomography (OCT) can monitor for glaucoma by measuring dimensions of the optic nerve head (ONH) cup and disc. Multiple clinical studies have shown that different OCT devices yield different estimates of retinal dimensions. We developed phantoms mimicking ONH morphology as a new way to compare ONH measurements from different clinical OCT devices. METHODS. Three phantoms were fabricated to model the ONH: One normal and two with glaucomatous anatomies. Phantoms were scanned with Stratus, RTVue, and Cirrus clinical devices, and with a laboratory OCT system as a reference. We analyzed device-reported ONH measurements of cup-to-disc ratio (CDR) and cup volume and compared them with offline measurements done manually and with a custom software algorithm, respectively. RESULTS. The mean absolute difference between clinical devices with device-reported measurements versus offline measurements was 0.082 vs. 0.013 for CDR and 0.044 mm(3) vs. 0.019 mm(3) for cup volume. Statistically significant differences between devices were present for 16 of 18 comparisons of device-reported measurements from the phantoms. Offline Cirrus measurements tended to be significantly different from those from Stratus and RTVue. CONCLUSIONS. The interdevice differences in CDR and cup volume are primarily caused by the devices' proprietary ONH analysis algorithms. The three devices yield more similar ONH measurements when a consistent offline analysis technique is applied. Scan pattern on the ONH also may be a factor in the measurement differences. This phantom-based study has provided unique insights into characteristics of OCT measurements of the ONH. C1 [Agrawal, Anant; Baxi, Jigesh; Calhoun, William; Hammer, Daniel X.] US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Chen, Chieh-Li; Ishikawa, Hiroshi; Schuman, Joel S.; Wollstein, Gadi] Univ Pittsburgh, Sch Med, Dept Ophthalmol, UPMC Eye Ctr,Eye & Ear Inst,Ophthalmol & Visual S, Pittsburgh, PA 15261 USA. [Chen, Chieh-Li; Ishikawa, Hiroshi; Schuman, Joel S.; Wollstein, Gadi] Univ Pittsburgh, Dept Bioengn, Swanson Sch Engn, Pittsburgh, PA USA. RP Agrawal, A (reprint author), 10903 New Hampshire Ave,Bldg 62,Room 1102, Silver Spring, MD 20993 USA. EM anant.agrawal@fda.hhs.gov OI Ishikawa, Hiroshi/0000-0001-6310-5748 FU National Institutes of Health (Bethesda, MD) [R01-EY013178, P30-EY008098]; Eye and Ear Foundation (Pittsburgh, PA); Research to Prevent Blindness (New York, NY); Food and Drug Administration Critical Path Initiative (Silver Spring, MD) FX Supported in part by National Institutes of Health contracts R01-EY013178, P30-EY008098 (Bethesda, MD), Eye and Ear Foundation (Pittsburgh, PA), Research to Prevent Blindness (New York, NY), and Food and Drug Administration Critical Path Initiative (Silver Spring, MD). NR 17 TC 0 Z9 0 U1 1 U2 1 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 JUL PY 2016 VL 57 IS 9 BP OCT413 EP OCT420 DI 10.1167/iovs.15-18738 PG 8 WC Ophthalmology SC Ophthalmology GA DW9MY UT WOS:000383985400042 PM 27409500 ER PT J AU Li, YC Fariss, RN Qian, JW Cohen, ED Qian, HH AF Li, Yichao Fariss, Robert N. Qian, Jennifer W. Cohen, Ethan D. Qian, Haohua TI Light-Induced Thickening of Photoreceptor Outer Segment Layer Detected by Ultra-High Resolution OCT Imaging SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE optical coherence tomography; subretinal space; light/dark adaptation; outer segments; retinal pigment epithelium ID OPTICAL COHERENCE TOMOGRAPHY; SPACE SURROUNDING PHOTORECEPTORS; RAT RETINA; IN-VIVO; INTERPHOTORECEPTOR MATRIX; DEPENDENT HYDRATION; POSTERIOR SEGMENT; PHAGOCYTOSIS; PHOTOSTASIS; BANDS AB PURPOSE. We examined if light induces changes in the retinal structure that can be observed using optical coherence tomography (OCT). METHODS. Normal C57BL/6J mice ( age 3-6 months) adapted to either room light (15 minutes to similar to 5 hours, 50-500 lux) or darkness (overnight) were imaged using a Bioptigen UHR-OCT system. Confocal histologic images were obtained from mice killed under light- or dark-adapted conditions. RESULTS. The OCT image of eyes adapted to room light exhibited significant increases (6.1 +/- 0.8 mu m, n = 13) in total retina thickness compared to the same eyes after overnight dark adaptation. These light- adapted retinal thickness changes occurred mainly in the outer retina, with the development of a hyporeflective band between the RPE and photoreceptor-tip layers. Histologic analysis revealed a light- evoked elongation between the outer limiting membrane and Bruch's membrane from 45.8 +/- 1.7 mu m in the dark (n = 5) to 52.1 +/- 3.7 mu m (n = 5) in the light. Light-adapted retinas showed an increase of actin staining in RPE apical microvilli at the same location as the hyporeflective band observed in OCT images. Elongation of the outer retina could be detected even with brief light exposures, increasing 2.1 +/- 0.3 mu m after 15 minutes (n = 9), and 4.1 +/- 1.0 mu m after 2 hours (n = 6). Conversely, dark-adaptation caused outer retinal shortening of 1.4 +/- 0.4 mu m (n = 7) and 3.0 +/- 0.5 mu m (n = 8) after 15 minutes and 2 hours, respectively. CONCLUSIONS. Light-adaption induces an increase in the thickness of the outer retina and the appearance of a hyporeflective band in the OCT image. This is consistent with previous reports of light-induced fluid accumulation in the subretinal space. C1 [Li, Yichao; Qian, Haohua] NEI, Visual Funct Core, NIH, Bethesda, MD 20892 USA. [Fariss, Robert N.] NEI, Biol Imaging Core, NIH, Bethesda, MD 20892 USA. [Qian, Jennifer W.] Univ Virginia, Coll Arts & Sci, Charlottesville, VA USA. [Cohen, Ethan D.] US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Qian, HH (reprint author), NEI, Visual Funct Core, NIH, Bethesda, MD 20892 USA. EM Haohua.qian@nih.gov FU intramural program of the National Eye Institute (Bethesda, MD, USA) FX Supported by the intramural program of the National Eye Institute (Bethesda, MD, USA). 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 0 Z9 0 U1 3 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 JUL PY 2016 VL 57 IS 9 BP OCT105 EP OCT111 DI 10.1167/iovs.15-18539 PG 7 WC Ophthalmology SC Ophthalmology GA DW9MY UT WOS:000383985400002 PM 27409460 ER PT J AU Nagaraja, S Palepu, V AF Nagaraja, Srinidhi Palepu, Vivek TI Comparisons of Anterior Plate Screw Pullout Strength Between Polyurethane Foams and Thoracolumbar Cadaveric Vertebrae SO JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LA English DT Article DE spine; polyurethane foams; cadaver; biomechanics; screw pullout ID HUMAN CANCELLOUS BONE; TRABECULAR BONE; MECHANICAL-PROPERTIES; OSTEOPOROTIC BONE; SYNTHETIC FOAM; MODEL; COMPRESSION; SPECIMENS; THICKNESS; FIXATION AB Synthetic polyurethane foams are frequently used in biomechanical testing of spinal medical devices. However, it is unclear what types of foam are most representative of human vertebral trabecular bone behavior, particularly for testing the bone-implant interface. Therefore, a study was conducted to compare polyurethane foam microstructure and screw pullout properties to human vertebrae. Cadaveric thoracolumbar vertebrae underwent microcomputed tomography to assess trabecular bone microstructure. Spine plate screws were implanted into the vertebral body and pullout testing was performed. The same procedure was followed for eight different densities (grades 5-30) of commercially available closed cell (CCF) and open cell foams (OCF). The results indicated that foam microstructural parameters such as volume fraction, strut thickness, strut spacing, and material density rarely matched that of trabecular bone. However, certain foams provided mechanical properties that were comparable to the cadavers tested. Pullout force and work to pullout for screws implanted into CCF grade 5 were similar to osteoporotic female cadavers. In addition, screw pullout forces and work to pullout in CCF grade 8, grade 10, and OCF grade 30 were similar to osteopenic male cadavers. All other OCF and CCF foams possessed pullout properties that were either significantly lower or higher than the cadavers tested. This study elucidated the types and densities of polyurethane foams that can represent screw pullout strength in human vertebral bone. Synthetic bone surrogates used for biomechanical testing should be selected based on bone quantity and quality of patients who may undergo device implantation. C1 [Nagaraja, Srinidhi; Palepu, Vivek] US FDA, Off Sci & Engn Labs, Div Appl Mech, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 62,Room 2210, Silver Spring, MD 20993 USA. RP Nagaraja, S (reprint author), US FDA, Off Sci & Engn Labs, Div Appl Mech, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 62,Room 2210, Silver Spring, MD 20993 USA. RI Palepu, Vivek/P-5446-2016 NR 29 TC 0 Z9 0 U1 2 U2 2 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 0148-0731 EI 1528-8951 J9 J BIOMECH ENG-T ASME JI J. Biomech. Eng.-Trans. ASME PD OCT PY 2016 VL 138 IS 10 AR 104505 DI 10.1115/1.4034427 PG 6 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA DW9ML UT WOS:000383984000013 ER PT J AU Wang, J Mehrotra, N Kim, I Lee, SC Sohrabi, F He, R Mulberg, A Sinha, V Ahn, HY Bashaw, D Griebel, D AF Wang, Jian Mehrotra, Nitin Kim, Insook Lee, Sue-Chih Sohrabi, Farrokh He, Ruyi Mulberg, Andrew Sinha, Vikram Ahn, Hae-Young Bashaw, Dennis Griebel, Donna TI Exposure-Response of Palonosetron for Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE dose selection; exposure matching; 5-hydroxytryptamine-3 receptor antagonist; pediatrics ID EMETOGENIC CHEMOTHERAPY; POSTOPERATIVE EMESIS; GRANISETRON; CHILDREN; EFFICACY; CANCER AB Objectives: Extrapolation of efficacy from adult populations to pediatrics may be appropriate if it is reasonable to assume that the 2 populations have similar disease progression and response to intervention. When full extrapolation of efficacy is deemed appropriate, the pediatric dose can be determined by "matching'' exposure to a drug with that observed in adult patients. This approach has been used in certain therapeutic areas to alleviate the burden of pediatric clinical trials. We present here a case in which exposure matching is not appropriate. Methods: Data analyses including pharmacokinetics and exposure-response were performed using data obtained from 2 pediatric chemotherapy-induced nausea and vomiting trials for intravenously administered palonosetron (Aloxi; a 5-HT3 receptor antagonist) injection and the results were compared with adult findings. Results: At the approved doses for adults (0.25 mg) and pediatric patients (20 mg/kg), mean systemic exposure (area under the curve) of palonosetron in pediatric patients was approximately 3-fold higher than that in adults, whereas the response rate was similar between the 2 populations. Across pediatric patients, those younger than 6 years of age appeared to have a higher response than those ages 6 years or older, even though estimated systemic exposure was comparable between these age groups. Conclusions: Overall, these analyses provide an example in which pediatric and adult exposure data alone are insufficient to adequately identify effective pediatric doses and raise questions about the appropriateness of exposure matching for other drugs in the same therapeutic class. In such cases, pediatric dose-ranging and efficacy studies are needed. C1 [Wang, Jian; Mehrotra, Nitin; Kim, Insook; Lee, Sue-Chih; Sinha, Vikram; Ahn, Hae-Young; Bashaw, Dennis] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Sohrabi, Farrokh; He, Ruyi; Mulberg, Andrew; Griebel, Donna] US FDA, Div Gastroenterol & Inborn Error Prod 1, Off Drug Evaluat 3, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Griebel, D (reprint author), US FDA, Div Gastroenterol & Inborn Error Prod 1, Off Drug Evaluat 3, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Donna.Griebel@fda.hhs.gov NR 12 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-2116 EI 1536-4801 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD OCT PY 2016 VL 63 IS 4 BP 412 EP 416 DI 10.1097/MPG.0000000000001173 PG 5 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA DX4NP UT WOS:000384358700012 PM 26913757 ER PT J AU Yang, ZH Leonard, SR Mammel, MK Elkins, CA Kulka, M AF Yang, Zhihui Leonard, Susan R. Mammel, Mark K. Elkins, Christopher A. Kulka, Michael TI Towards next-generation sequencing analytics for foodborne RNA viruses: Examining the effect of RNA input quantity and viral RNA purity SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE Detection; Foodborne viruses; RNA isolation; Next generation sequences ID HEPATITIS-A-VIRUS; DNA MICROARRAYS; CELL-CULTURE; INFECTION; PCR; DEGRADATION; ACTIVATION; EXTRACTION; INDUCTION; NOROVIRUS AB Detection and identification of viruses in food samples are technically challenging due largely to the low viral copy number in contaminated food items, and the lack of effective culture enrichment methods that are amenable to regulatory applications for many of the common foodborne viruses. Using an Illumina MiSeq platform and two hepatitis A virus (HAV) cell-culture adapted strains as a representative enteric virus species, this study examined the limits of single-stranded RNA (ssRNA) viral detection following next-generation sequencing without pre-amplification of the viral genome. Complete viral genome sequences were obtained from HAV samples of varying purities and with an input as low as 2 ng total RNA containing 1.4 x 10(5) copies of viral RNA. In addition, single nucleotide variations were reproducibly detected over the range of concentrations examined, and their identity confirmed by alternate sequencing technology. In summary, next-generation sequencing technology has the potential for sensitive detection/identification of a viral genome at a low copy number. This study provides a benchmark for metagenomic sequencing application as is required for virus detection in complex food matrices using a culture-independent diagnostic approach. Published by Elsevier B.V. C1 [Yang, Zhihui; Leonard, Susan R.; Mammel, Mark K.; Elkins, Christopher A.; Kulka, Michael] US FDA, Div Mol Biol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, 8301 Muirkirk Rd, Laurel, MD 20708 USA. RP Kulka, M (reprint author), US FDA, Div Mol Biol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM michael.kulka@fda.hhs.gov NR 34 TC 0 Z9 0 U1 10 U2 10 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 OCT PY 2016 VL 236 BP 221 EP 230 DI 10.1016/j.jviromet.2016.07.013 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA DW8YR UT WOS:000383941900032 PM 27435336 ER PT J AU Garrard, L Price, LR Bott, MJ Gajewski, BJ AF Garrard, Lili Price, Larry R. Bott, Marjorie J. Gajewski, Byron J. TI A Novel Method for Expediting the Development of Patient-Reported Outcome Measures and an Evaluation Across Several Populations SO APPLIED PSYCHOLOGICAL MEASUREMENT LA English DT Article DE OBID; Bayesian leave-one-out cross-validation; Bayesian IRT; Bayesian model comparison; patient-reported outcome measures; PROMs ID POSTERIOR PREDICTIVE ASSESSMENT; RESPONSE THEORY MODELS; CROSS-VALIDATION; ASYMPTOTIC EQUIVALENCE; INSTRUMENT DEVELOPMENT; INFORMATION CRITERION; LIMITED-INFORMATION; BAYESIAN-ESTIMATION; CONTENT VALIDITY; FIT AB Item response theory (IRT) models provide an appropriate alternative to the classical ordinal confirmatory factor analysis (CFA) during the development of patient-reported outcome measures (PROMs). Current literature has identified the assessment of IRT model fit as both challenging and underdeveloped. This study evaluates the performance of Ordinal Bayesian Instrument Development (OBID), a Bayesian IRT model with a probit link function approach, through applications in two breast cancer-related instrument development studies. The primary focus is to investigate an appropriate method for comparing Bayesian IRT models in PROMs development. An exact Bayesian leave-one-out cross-validation (LOO-CV) approach is implemented to assess prior selection for the item discrimination parameter in the IRT model and subject content experts' bias (in a statistical sense and not to be confused with psychometric bias as in differential item functioning) toward the estimation of item-to-domain correlations. Results support the utilization of content subject experts' information in establishing evidence for construct validity when sample size is small. However, the incorporation of subject experts' content information in the OBID approach can be sensitive to the level of expertise of the recruited experts. More stringent efforts need to be invested in the appropriate selection of subject experts to efficiently use the OBID approach and reduce potential bias during PROMs development. C1 [Garrard, Lili] US FDA, Silver Spring, MD USA. [Price, Larry R.] Texas State Univ, San Marcos, TX USA. [Bott, Marjorie J.; Gajewski, Byron J.] Univ Kansas, Sch Nursing, Kansas City, KS USA. [Gajewski, Byron J.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. RP Garrard, L (reprint author), US FDA, Div Biometr 3, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,White Oak Bldg 21, Silver Spring, MD 20993 USA. EM lili.garrard@fda.hhs.gov FU National Institute of Nursing Research of the National Institutes of Health [R03NR013236] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Research reported in this publication was supported by the National Institute of Nursing Research of the National Institutes of Health under Award R03NR013236. NR 48 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0146-6216 EI 1552-3497 J9 APPL PSYCH MEAS JI Appl. Psychol. Meas. PD OCT PY 2016 VL 40 IS 7 BP 455 EP 468 DI 10.1177/0146621616652634 PG 14 WC Social Sciences, Mathematical Methods; Psychology, Mathematical SC Mathematical Methods In Social Sciences; Psychology GA DW1YS UT WOS:000383440700001 PM 27667878 ER PT J AU Califf, RM AF Califf, Robert M. TI Pragmatic clinical trials: Emerging challenges and new roles for statisticians SO CLINICAL TRIALS LA English DT Article; Proceedings Paper CT 8th Annual Symposium on Statistical Issues in Clinical Trials CY APR, 2015 CL Univ Penn, Philadelphia, PA HO Univ Penn DE Biostatistics; statistics; evidence; quality by design; clinical trial; pragmatic clinical trial; randomization; electronic health record ID BLOOD INSTITUTE; NATIONAL HEART; CLINICALTRIALS.GOV; ASSOCIATION; GUIDELINES; LUNG AB Patients, clinicians, and policymakers alike need access to high-quality scientific evidence in order to make informed choices about health and healthcare, but the current national clinical trials enterprise is not yet optimally configured for the efficient creation and dissemination of such evidence. However, new technologies and methods hold significant potential for accelerating the rate at which we are able to translate raw findings gathered from both patient care and clinical research into actionable knowledge. We are now entering a period in which the quantitative sciences are emerging as the critical disciplines for advancing knowledge about health and healthcare, and statisticians will increasingly serve as critical mediators in transforming data into evidence. In this new, data-centric era, biostatisticians not only need to be expert at analyzing data but should also be involved directly in diverse efforts, including the review and analysis of research portfolios in order to optimize the relevance of research questions, the use of quality by design principles to improve reliability and validity of each individual trial, and the mining of aggregate knowledge derived from the clinical research enterprise as a whole. In order to meet these challenges, it is imperative that we (1) nurture and build the biostatistical workforce, (2) develop a deeper understanding of the biological and clinical context among statisticians, (3) facilitate collaboration among biostatisticians and other members of the clinical trials enterprise, (4) focus on communication skills in training and education programs, and (5) enhance the quantitative capacity of the research and clinical practice worlds. C1 [Califf, Robert M.] US FDA, Silver Spring, MD USA. RP Califf, RM (reprint author), US FDA, Off Commissioner, 10903 New Hampshire Ave,Bldg 1, Silver Spring, MD 20993 USA. EM Robert.Califf@fda.hhs.gov NR 34 TC 1 Z9 1 U1 6 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD OCT PY 2016 VL 13 IS 5 BP 471 EP 477 DI 10.1177/1740774516656944 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DW1GZ UT WOS:000383392600002 PM 27378791 ER PT J AU Drouin, LM Lins, B Janssen, M Bennett, A Chipman, P McKenna, R Chen, WJ Muzyczka, N Cardone, G Baker, TS Agbandje-McKenna, M AF Drouin, Lauren M. Lins, Bridget Janssen, Maria Bennett, Antonette Chipman, Paul McKenna, Robert Chen, Weijun Muzyczka, Nicholas Cardone, Giovanni Baker, Timothy S. Agbandje-McKenna, Mavis TI Cryo-electron Microscopy Reconstruction and Stability Studies of the Wild Type and the R432A Variant of Adeno-associated Virus Type 2 Reveal that Capsid Structural Stability Is a Major Factor in Genome Packaging SO JOURNAL OF VIROLOGY LA English DT Article ID ASSEMBLY-ACTIVATING PROTEIN; GENE-THERAPY; ELECTRON CRYOMICROSCOPY; IMAGE-RECONSTRUCTION; MUTATIONAL ANALYSIS; RECEPTOR-BINDING; SEROTYPE 8; VECTORS; REP68; IDENTIFICATION AB The adeno-associated viruses (AAV) are promising therapeutic gene delivery vectors and better understanding of their capsid assembly and genome packaging mechanism is needed for improved vector production. Empty AAV capsids assemble in the nucleus prior to genome packaging by virally encoded Rep proteins. To elucidate the capsid determinants of this process, structural differences between wild-type (wt) AAV2 and a packaging deficient variant, AAV2-R432A, were examined using cryo-electron microscopy and three-dimensional image reconstruction both at an similar to 5.0-angstrom resolution (medium) and also at 3.8- and resolutions (high), respectively. The high resolution structures showed that removal of the arginine side chain in AAV2-R432A eliminated hydrogen bonding interactions, resulting in altered intramolecular and intermolecular interactions propagated from under the 3-fold axis toward the 5-fold channel. Consistent with these observations, differential scanning calorimetry showed an similar to 10 degrees C decrease in thermal stability for AAV2-R432A compared to wt-AAV2. In addition, the medium resolution structures revealed differences in the juxtaposition of the less ordered, N-terminal region of their capsid proteins, VP1/2/3. A structural rearrangement in AAV2-R432A repositioned the beta A strand region under the icosahedral 2-fold axis rather than antiparallel to the beta B strand, eliminating many intramolecular interactions. Thus, a single amino acid substitution can significantly alter the AAV capsid integrity to the extent of reducing its stability and possibly rendering it unable to tolerate the stress of genome packaging. Furthermore, the data show that the 2-, 3-, and 5-fold regions of the capsid contributed to producing the packaging defect and highlight a tight connection between the entire capsid in maintaining packaging efficiency. IMPORTANCE The mechanism of AAV genome packaging is still poorly understood, particularly with respect to the capsid determinants of the required capsid-Rep interaction. Understanding this mechanism may aid in the improvement of AAV packaging efficiency, which is currently similar to 1:10 (10%) genome packaged to empty capsid in vector preparations. This report identifies regions of the AAV capsid that play roles in genome packaging and that may be important for Rep recognition. It also demonstrates the need to maintain capsid stability for the success of this process. This information is important for efforts to improve AAV genome packaging and will also inform the engineering of AAV capsid variants for improved tropism, specific tissue targeting, and host antibody escape by defining amino acids that cannot be altered without detriment to infectious vector production. C1 [Drouin, Lauren M.; Lins, Bridget; Bennett, Antonette; Chipman, Paul; McKenna, Robert; Agbandje-McKenna, Mavis] Univ Florida, Coll Med, McKnight Brain Inst, Dept Biochem & Mol Biol,Ctr Struct Biol, Gainesville, FL 32611 USA. [Chen, Weijun; Muzyczka, Nicholas] Univ Florida, Coll Med, Genet Inst, Dept Mol Genet & Microbiol, Gainesville, FL USA. [Janssen, Maria; Cardone, Giovanni; Baker, Timothy S.] Univ Calif San Diego, Dept Chem & Biochem, San Diego, CA 92103 USA. [Janssen, Maria; Cardone, Giovanni; Baker, Timothy S.] Univ Calif San Diego, Div Biol Sci, San Diego, CA 92103 USA. [Drouin, Lauren M.] Voyager Therapeut Inc, Cambridge, MA USA. [Lins, Bridget] US FDA, Div Viral Prod, CBER, Silver Spring, MD USA. [Janssen, Maria] Scripps Res Inst, La Jolla, CA 92037 USA. [Cardone, Giovanni] Max Planck Inst Biochem, Facil Opt Imaging, Martinsried, Germany. RP Agbandje-McKenna, M (reprint author), Univ Florida, Coll Med, McKnight Brain Inst, Dept Biochem & Mol Biol,Ctr Struct Biol, Gainesville, FL 32611 USA.; Baker, TS (reprint author), Univ Calif San Diego, Dept Chem & Biochem, San Diego, CA 92103 USA.; Baker, TS (reprint author), Univ Calif San Diego, Div Biol Sci, San Diego, CA 92103 USA. EM tsb@ucsd.edu; mckenna@ufl.edu FU HHS \ National Institutes of Health (NIH) [GM109524, HL59412, GM33050, GM008799] FX This work, including the efforts of Lauren M. Drouin, Bridget Lins, Antonette Bennett, Paul Chipman, Robert McKenna, Weijun Chen, Nicholas Muzyczka, and Mavis Agbandje-McKenna, was funded by HHS vertical bar National Institutes of Health (NIH) (GM109524 and HL59412). This work, including the efforts of Maria Janssen, Giovanni Cardone, and Timothy S. Baker, was funded by HHS vertical bar National Institutes of Health (NIH) (GM33050). This work, including the efforts of Lauren M. Drouin, was funded by HHS vertical bar National Institutes of Health (NIH) (GM008799). NR 61 TC 1 Z9 1 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD OCT PY 2016 VL 90 IS 19 BP 8542 EP 8551 DI 10.1128/JVI.00575-16 PG 10 WC Virology SC Virology GA DW6LH UT WOS:000383761900015 PM 27440903 ER PT J AU Saylor, DM Adidharma, L Fisher, JW Brown, RP AF Saylor, David M. Adidharma, Lingga Fisher, Jeffrey W. Brown, Ronald P. TI A biokinetic model for nickel released from cardiovascular devices SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Nitinol; Nickel release; Diffusion; Compartment model; Biomonitoring ID IN-VIVO CORROSION; AMPLATZER OCCLUDER; SURFACE-TREATMENT; REFERENCE VALUES; STENTS; NITI; BEHAVIOR; URINE; BLOOD; SERUM AB Many alloys used in cardiovascular device applications contain high levels of nickel, which if released in sufficient quantities, can lead to adverse health effects. While nickel release from these devices is typically characterized through the use of in-vitro immersion tests, it is unclear if the rate at which nickel is released from a device during in-vitro testing is representative of the release rate following implantation in the body. To address this uncertainty, we have developed a novel biokinetic model that combines a traditional toxicokinetic compartment model with a physics based model to estimate nickel release from an implanted device. This model links the rate of in-vitro nickel release from a cardiovascular device to serum nickel concentrations, an easily measured endpoint, to estimate the rate and extent of in-vivo nickel release from an implanted device. The model was initially parameterized using data in the literature on in-vitro nickel release from a nickel containing alloy (nitinol) and baseline serum nickel levels in humans. The results of this first step were then used to validate specific components of the model. The remaining unknown quantities were fit using serum values reported in patients following implantation with nitinol atrial occluder devices. The model is not only consistent with levels of nickel in serum and urine of patients following treatment with the atrial occluders, but also the optimized parameters in the model were all physiologically plausible. The congruity of the model with available data suggests that it can provide a framework to interpret nickel biomonitoring data and use data from in-vitro nickel immersion tests to estimate in-vivo nickel release from implanted cardiovascular devices. Published by Elsevier Inc. C1 [Saylor, David M.; Adidharma, Lingga; Brown, Ronald P.] FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Fisher, Jeffrey W.] FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Saylor, DM (reprint author), FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM david.saylor@fda.hhs.gov NR 32 TC 0 Z9 0 U1 5 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD OCT PY 2016 VL 80 BP 1 EP 8 DI 10.1016/j.yrtph.2016.05.019 PG 8 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA DW0EY UT WOS:000383314900001 PM 27208438 ER PT J AU Healy, MJ Tong, W Ostroff, S Eichler, HG Patak, A Neuspiel, M Deluyker, H Slikker, W AF Healy, Marion J. Tong, Weida Ostroff, Stephen Eichler, Hans-Georg Patak, Alex Neuspiel, Margaret Deluyker, Hubert Slikker, William, Jr. TI Regulatory bioinformatics for food and drug safety SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Bioinformatics; Regulatory bioinformatics; Drug safety; Food safety; Regulatory science; GCRSR; GSRS; Next-generation sequencing; Microbiome; Genomics ID PRECISION MEDICINE; GLOBAL-SUMMIT; SCIENCE; TOXICOLOGY AB "Regulatory Bioinformatics" strives to develop and implement a standardized and transparent bioinformatic framework to support the implementation of existing and emerging technologies in regulatory decision-making. It has great potential to improve public health through the development and use of clinically important medical products and tools to manage the safety of the food supply. However, the application of regulatory bioinformatics also poses new challenges and requires new knowledge and skill sets. In the latest Global Coalition on Regulatory Science Research (GCRSR) governed conference, Global Summit on Regulatory Science (GSRS2015), regulatory bioinformatics principles were presented with respect to global trends, initiatives and case studies. The discussion revealed that datasets, analytical tools, skills and expertise are rapidly developing, in many cases via large international collaborative consortia. It also revealed that significant research is still required to realize the potential applications of regulatory bioinformatics. While there is significant excitement in the possibilities offered by precision medicine to enhance treatments of serious and/or complex diseases, there is a clear need for further development of mechanisms to securely store, curate and share data, integrate databases, and standardized quality control and data analysis procedures. A greater understanding of the biological significance of the data is also required to fully exploit vast datasets that are becoming available. The application of bioinformatics in the microbiological risk analysis paradigm is delivering clear benefits both for the investigation of food borne pathogens and for decision making on clinically important treatments. It is recognized that regulatory bioinformatics will have many beneficial applications by ensuring high quality data, validated tools and standardized processes, which will help inform the regulatory science community of the requirements necessary to ensure the safe introduction and effective use of these applications. Published by Elsevier Inc. C1 [Healy, Marion J.] Food Stand Australia New Zealand, Barton, ACT 2905, Australia. [Tong, Weida; Slikker, William, Jr.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Ostroff, Stephen] US FDA, Silver Spring, MD 20993 USA. [Eichler, Hans-Georg] European Med Agcy, London E14 5EU, England. [Patak, Alex] European Comm, Joint Res Ctr, I-21027 Ispra, Varese, Italy. [Neuspiel, Margaret] Canadian Food Inspect Agcy, Ottawa, ON, Canada. [Deluyker, Hubert] European Food Safety Author, I-43126 Parma, Italy. RP Tong, W; Slikker, W (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM marion.healy@foodstandards.gov.au; weida.tong@fda.hhs.gov; stephen.ostroff@fda.hhs.gov; hans-georg.eichler@ema.europa.eu; alex.patak@ec.europa.eu; margaret.neuspiel@inspection.gc.ca; Hubert.deluyker@efsa.europa.eu; william.slikker@fda.hhs.gov RI Patak, Alex/L-2882-2015 OI Patak, Alex/0000-0002-9282-188X NR 18 TC 0 Z9 0 U1 13 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD OCT PY 2016 VL 80 BP 342 EP 347 DI 10.1016/j.yrtph.2016.05.021 PG 6 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA DW0EY UT WOS:000383314900038 PM 27208439 ER PT J AU Sun, JC Jin, JS Beger, RD Cerniglia, CE Yang, MC Chen, HZ AF Sun, Jinchun Jin, Jinshan Beger, Richard D. Cerniglia, Carl E. Yang, Maocheng Chen, Huizhong TI Metabolomics evaluation of the impact of smokeless tobacco exposure on the oral bacterium Capnocytophaga sputigena SO TOXICOLOGY IN VITRO LA English DT Article DE Smokeless tobacco; Toxicology; Oral bacteria; Metabolomics ID CIGARETTE-SMOKING; ENDOTHELIAL DYSFUNCTION; NICOTINE; MICROBIOTA; DISEASE; PERIODONTITIS; METABONOMICS; MICROFLORA; PROFILES; PRESSURE AB The association between exposure to smokeless tobacco products (STP) and oral diseases is partially due to the physiological and pathological changes in the composition of the oral microbiome and its metabolic profile. However, it is not clear how STPs affect the physiology and ecology of oral microbiota. A UPLC/QTof-MS-based metabolomics study was employed to analyze metabolic alterations in oral bacterium, Capnocytophaga sputigena as a result of smokeless tobacco exposure and to assess the capability of the bacterium to metabolize nicotine. Pathway analysis of the metabolome profiles indicated that smokeless tobacco extracts caused oxidative stress in the bacterium. The metabolomics data also showed that the arginine-nitric oxide pathway was perturbed by the smokeless tobacco treatment. Results also showed that LC/MS was useful in identifying SW constituents and additives, including caffeine and many flavoring compounds. No significant changes in levels of nicotine and its major metabolites were found when C. sputigena was cultured in a nutrient rich medium, although hydroxylnicotine and cotinine N-oxide were detected in the bacterial metabolites suggesting that nicotine metabolism might be present as a minor degradation pathway in the bacterium. Study results provide new insights regarding the physiological and toxicological effects of smokeless tobacco on oral bacterium C. sputigena and associated oral health as well as measuring the ability of the oral bacterium to metabolize nicotine. Published by Elsevier Ltd. C1 [Sun, Jinchun; Beger, Richard D.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Jin, Jinshan; Cerniglia, Carl E.; Chen, Huizhong] US FDA, Div Microbiol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Yang, Maocheng] US FDA, Off Sci, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Sun, JC (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA.; Chen, HZ (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA.; Yang, MC (reprint author), US FDA, Off Sci, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Jinchun.Sun@fda.hhs.gov; Maocheng.yang@fda.hhs.gov; Huizhong.Chen@fda.hhs.gov FU Center for Tobacco Products, U.S. Food and Drug Administration [E0747201]; Oak Ridge Institute for Science and Education FX We thank Drs. Steven L Foley, John B. Sutherland and Hans Rosenfeldt for their critical review of this manuscript. We also thank CTP writer Deborah Neveleff for proof reading the manuscript. This study was funded by the Center for Tobacco Products, U.S. Food and Drug Administration (E0747201). Dr. Jinshan Jin was supported through the Oak Ridge Institute for Science and Education. The findings and conclusions in this publication are those of the authors and do not represent FDA positions or policies. NR 41 TC 0 Z9 0 U1 12 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD OCT PY 2016 VL 36 BP 133 EP 141 DI 10.1016/j.tiv.2016.07.020 PG 9 WC Toxicology SC Toxicology GA DW7JC UT WOS:000383826000016 PM 27480511 ER PT J AU Woods, JW Calci, KR Marchant-Tambone, JG Burkhardt, W AF Woods, Jacquelina W. Calci, Kevin R. Marchant-Tambone, Joey G. Burkhardt, William, III TI Detection and molecular characterization of norovirus from oysters implicated in outbreaks in the US SO FOOD MICROBIOLOGY LA English DT Article DE Norovirus; Outbreak; Molecular characterization; Oysters ID NORWALK-LIKE VIRUSES; HEPATITIS-A VIRUS; ENTERIC VIRUSES; UNITED-STATES; GASTROENTERITIS OUTBREAK; ESCHERICHIA-COLI; MURINE NOROVIRUS; VIRAL PATHOGENS; SHELLFISH; PCR AB Human noroviruses are the leading cause of non-bacterial shellfish associated gastroenteritis. Here we report on the detection and characterization of norovirus (NoV) in shellfish associated outbreaks. Requests were received from state and federal officials for technical assistance in the analysis of shellfish for NoV and male specific coliphage (MSC; an enteric virus surrogate) during the years 2009 thru 2014. In outbreaks where NoV was detected, genogroup II (GII) levels ranged from 2.4 to 82.0 RT-qPCR U/g of digestive diverticula (DD) while NoV genogroup I (GI) levels ranged from 1.5 to 29.8 RT-qPCR U/g of DD. Murine norovirus extraction efficiencies ranged between 50 and 85%. MSC levels ranged from <6 to 80 PFU/100 g. Phylogenetic analysis of the outbreak sequences revealed strains clustering with GI.8, GI.4, GII.3, GII.4, GII.7, and GII.21. There was 100% homology between the shellfish and clinical strains occurring in 2 of 8 outbreaks. Known shellfish consumption data demonstrated probable infectious particles ingested as low as 12. These investigations demonstrate effective detection, quantification, and characterization of NoV in shellfish associated with illness. Published by Elsevier Ltd. C1 [Woods, Jacquelina W.; Calci, Kevin R.; Marchant-Tambone, Joey G.; Burkhardt, William, III] FDA, Div Seafood Safety, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. RP Woods, JW (reprint author), FDA, Gulf Coast Seafood Lab, 1 Iberville Dr, Dauphin Isl, AL 36528 USA. EM jacquelina.woods@fda.hhs.gov NR 57 TC 0 Z9 0 U1 9 U2 14 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0740-0020 EI 1095-9998 J9 FOOD MICROBIOL JI Food Microbiol. PD OCT PY 2016 VL 59 BP 76 EP 84 DI 10.1016/j.fm.2016.05.009 PG 9 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA DT7NY UT WOS:000381674700009 PM 27375246 ER PT J AU Garcia-Heredia, A Garcia, S Merino-Mascorro, JA Feng, P Heredia, N AF Garcia-Heredia, Alam Garcia, Santos Angel Merino-Mascorro, Jose Feng, Peter Heredia, Norma TI Natural plant products inhibits growth and alters the swarming motility, biofilm formation, and expression of virulence genes in enteroaggregative and enterohemorrhagic Escherichia coli SO FOOD MICROBIOLOGY LA English DT Article DE Escherichia coli; Natural products; EHEC; EAEC; Virulence factors ID HAEMATOXYLON-BRASILETTO; LIPPIA-GRAVEOLENS; CARVACROL; ANTIBIOTICS; PATHOGEN; O104/H4; STRAIN; SALMONELLA; EXTRACTS; O157-H7 AB The purpose of this study was to determine the effects of plant products on the growth, swarming motility, biofilm formation and virulence gene expression in enterohemorrhagic Escherichia coli O157: H7 and enteroaggregative E. coli strain 042 and a strain of O104: H4 serotype. Extracts of Lippia graveolens and Haematoxylon brassiletto, and carvacrol, brazilin were tested by an antimicrobial microdilution method using citral and rifaximin as controls. All products showed bactericidal activity with minimal bactericidal concentrations ranging from 0.08 to 8.1 mg/ml. Swarming motility was determined in soft LB agar. Most compounds reduced swarming motility by 7%-100%; except carvacrol which promoted motility in two strains. Biofilm formation studies were done in microtiter plates. Rifaximin inhibited growth and reduced biofilm formation, but various concentrations of other compounds actually induced biofilm formation. Real time PCR showed that most compounds decreased stx2 expression. The expression of pic and rpoS in E. coli 042 were suppressed but in E. coli O104: H4 they varied depending on compounds. In conclusion, these extracts affect E. coli growth, swarming motility and virulence gene expression. Although these compounds were bactericidal for pathogenic E. coli, sublethal concentrations had varied effects on phenotypic and genotypic traits, and some increased virulence gene expression. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Garcia-Heredia, Alam; Garcia, Santos; Angel Merino-Mascorro, Jose; Heredia, Norma] Univ Autonoma Nuevo Leon, Fac Ciencias Biol, Apdo Postal 124-F, San Nicolas 66451, NL, Mexico. [Feng, Peter] US FDA, Div Microbiol, College Pk, MD USA. RP Heredia, N (reprint author), Univ Autonoma Nuevo Leon, Fac Ciencias Biol, Apdo Postal 124-F, San Nicolas 66451, NL, Mexico. EM norma@microbiosymas.com FU Consejo Nacional de Ciencia y Tecnologia de Mexico (CONACYT); PAICYT-UANL FX This research was supported in part by the Consejo Nacional de Ciencia y Tecnologia de Mexico (CONACYT) and PAICYT-UANL. NR 46 TC 0 Z9 0 U1 14 U2 21 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0740-0020 EI 1095-9998 J9 FOOD MICROBIOL JI Food Microbiol. PD OCT PY 2016 VL 59 BP 124 EP 132 DI 10.1016/j.fm.2016.06.001 PG 9 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA DT7NY UT WOS:000381674700016 PM 27375253 ER PT J AU Restrepo, BJ AF Restrepo, Brandon J. TI Parental investment responses to a low birth weight outcome: who compensates and who reinforces? SO JOURNAL OF POPULATION ECONOMICS LA English DT Article DE Parental investment; Human capital; Low birth weight; Education; Income ID INTRAHOUSEHOLD RESOURCE-ALLOCATION; NONCOGNITIVE SKILL FORMATION; COGNITIVE-DEVELOPMENT; CHILD-DEVELOPMENT; FETAL ORIGINS; HEALTH SHOCKS; LABOR-MARKET; ENDOWMENTS; TWINS; FAMILY AB This study analyzes how parental investment responds to a low birth weight (LBW) outcome and finds important differences in investment responses by maternal education. High school dropouts reinforce a LBW outcome by providing less investment in the human capital of their LBW children relative to their normal birth weight children whereas higher educated mothers compensate by investing more in their LBW children. In addition, an increase in the number of LBW siblings present in the home raises investment in a child, which is consistent with reinforcement, but this positive effect tends to be concentrated among high school dropouts. These results suggest that studies analyzing the effects of LBW on child outcomes that do not account for heterogeneity in investment responses to a LBW outcome by maternal education may overestimate effects of LBW on child outcomes for those born to low-educated mothers and underestimate such effects for those born to high-educated mothers. C1 [Restrepo, Brandon J.] US FDA, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Restrepo, BJ (reprint author), US FDA, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM brandon.restrepo@eui.eu OI Restrepo, Brandon/0000-0002-8005-4839 NR 56 TC 1 Z9 1 U1 9 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0933-1433 EI 1432-1475 J9 J POPUL ECON JI J. Popul. Econ. PD OCT PY 2016 VL 29 IS 4 BP 969 EP 989 DI 10.1007/s00148-016-0590-3 PG 21 WC Demography; Economics SC Demography; Business & Economics GA DS0FR UT WOS:000380271300001 ER PT J AU Pahlavan, A Sharma, GM Pereira, M Williams, KM AF Pahlavan, Autusa Sharma, Girdhari M. Pereira, Marion Williams, Kristina M. TI Effects of grain species and cultivar, thermal processing, and enzymatic hydrolysis on gluten quantitation SO FOOD CHEMISTRY LA English DT Article DE Gluten; Processing; ELISA; Grain cultivar ID CELIAC PATIENTS; GLIADIN; WHEAT; FOOD; ELISA; R5; IMMUNOASSAYS; FERMENTATION; ANTIBODIES; FRACTIONS AB Gluten from wheat, rye, and barley can trigger IgE-mediated allergy or Celiac disease in sensitive individuals. Gluten-free labeled foods are available as a safe alternative. Immunoassays such as the enzyme-linked immunosorbent assay (ELISA) are commonly used to quantify gluten in foods. However, various non-assay related factors can affect gluten quantitation. The effect of gluten-containing grain cultivars, thermal processing, and enzymatic hydrolysis on gluten quantitation by various ELISA kits was evaluated. The ELISA kits exhibited variations in gluten quantitation depending on the gluten-containing grain and their cultivars. Acceptable gluten recoveries were obtained in 200 mg/kg wheat, rye, and barley-spiked corn flour thermally processed at various conditions. However, depending on the enzyme, gluten grain source, and ELISA kit used, measured gluten content was significantly reduced in corn flour spiked with 200 mg/kg hydrolyzed wheat, rye, and barley flour. Thus, the gluten grain source and processing conditions should be considered for accurate gluten analysis. Published by Elsevier Ltd. C1 [Pahlavan, Autusa] Univ Maryland, Joint Inst Food Safety & Appl Nutr, 5201 Paint Branch Pkwy, College Pk, MD 20742 USA. [Sharma, Girdhari M.; Pereira, Marion; Williams, Kristina M.] US FDA, Immunobiol Branch, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, 8301 Muirkirk Rd, Laurel, MD 20708 USA. RP Sharma, GM (reprint author), 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM Girdhari.Sharma@fda.hhs.gov NR 26 TC 0 Z9 0 U1 14 U2 36 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 OCT 1 PY 2016 VL 208 BP 264 EP 271 DI 10.1016/j.foodchem.2016.03.092 PG 8 WC Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics SC Chemistry; Food Science & Technology; Nutrition & Dietetics GA DL7YP UT WOS:000375856600033 PM 27132849 ER PT J AU Gruber, S Tchetgen, ET AF Gruber, Susan Tchetgen, Eric Tchetgen TI Limitations of empirical calibration of p-values using observational data SO STATISTICS IN MEDICINE LA English DT Article DE p-value calibration; OMOP; safety; pharmacovigilance; p-value ID CONTROL GENES AB Controversy over non-reproducible published research reporting a statistically significant result has produced substantial discussion in the literature. p-value calibration is a recently proposed procedure for adjusting p-values to account for both random and systematic errors that address one aspect of this problem. The method's validity rests on the key assumption that bias in an effect estimate is drawn from a normal distribution whose mean and variance can be correctly estimated. We investigated the method's control of type I and type II error rates using simulated and real-world data. Under mild violations of underlying assumptions, control of the type I error rate can be conservative, while under more extreme departures, it can be anti-conservative. The extent to which the assumption is violated in real-world data analyses is unknown. Barriers to testing the plausibility of the assumption using historical data are discussed. Our studies of the type II error rate using simulated and real-world electronic health care data demonstrated that calibrating p-values can substantially increase the type II error rate. The use of calibrated p-values may reduce the number of false-positive results, but there will be a commensurate drop in the ability to detect a true safety or efficacy signal. While p-value calibration can sometimes offer advantages in controlling the type I error rate, its adoption for routine use in studies of real-world health care datasets is premature. Separate characterizations of random and systematic errors provide a richer context for evaluating uncertainty surrounding effect estimates. Copyright (C) 2016 John Wiley & Sons, Ltd. C1 [Gruber, Susan] US FDA, Reagan Udall Fdn, 1025 Connecticut Ave NW,Suite 1000, Washington, DC 20036 USA. [Tchetgen, Eric Tchetgen] Harvard Sch Publ Hlth Boston, Dept Biostat, Boston, MA USA. [Tchetgen, Eric Tchetgen] Harvard Sch Publ Hlth Boston, Dept Epidemiol, Boston, MA USA. RP Gruber, S (reprint author), US FDA, Reagan Udall Fdn, 1025 Connecticut Ave NW,Suite 1000, Washington, DC 20036 USA. EM sgruber65@yahoo.com OI Gruber, Susan/0000-0003-0127-0099 FU NIH [AI104459] FX Dr. Tchetgen Tchetgen was supported by NIH grant AI104459. The authors would like to thank George Hripcsak, Patrick Ryan, Christian Reich, Sara Dempster, Lisa Kammerman, Adler Perotte, Marc Suchard, and David Madigan for helpful discussions. We also thank anonymous reviewers, whose critiques of an earlier draft motivated important changes to the manuscript. NR 19 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD SEP 30 PY 2016 VL 35 IS 22 BP 3869 EP 3882 DI 10.1002/sim.6936 PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DW5XX UT WOS:000383722100001 PM 26970249 ER PT J AU Yang, SG Santos, MD Tang, CM Kim, JG Yang, S AF Yang, Sunggu Santos, Mariton D. Tang, Cha-Min Kim, Jae Geun Yang, Sungchil TI A Postsynaptic Role for Short-Term Neuronal Facilitation in Dendritic Spines SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Article DE synaptic integration; sensory perception; dendritic spike; NMDA receptor; short-term synaptic plasticity ID CAT AUDITORY-CORTEX; PYRAMIDAL NEURONS; HIPPOCAMPUS; MECHANISMS; TIME; CONNECTIONS; INFORMATION; GENERATION; RECEPTORS; SYSTEM AB Synaptic plasticity is a fundamental component of information processing in the brain. Presynaptic facilitation in response to repetitive stimuli, often referred to as paired pulse facilitation (PPF), is a dominant form of short-term synaptic plasticity. Recently, an additional cellular mechanism for short-term facilitation, short-term postsynaptic plasticity (STPP), has been proposed. While a dendritic mechanism was described in hippocampus, its expression has not yet been demonstrated at the levels of the spine. Furthermore, it is unknown whether the mechanism can be expressed in other brain regions, such as sensory cortex. Here, we demonstrated that a postsynaptic response can be facilitated by prior spine excitation in both hippocampal and cortical neurons, using 3D digital holography and two-photon calcium imaging. The coordinated action of pre- and post synaptic plasticity may provide a more thorough account of information processing in the brain. C1 [Yang, Sunggu] Incheon Natl Univ, Dept Nanobioengn, Inchon, South Korea. [Santos, Mariton D.; Tang, Cha-Min] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Santos, Mariton D.; Tang, Cha-Min] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. [Santos, Mariton D.] US FDA, Off Dietafy Supplement Programs, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Kim, Jae Geun] Incheon Natl Univ, Div Life Sci, Coll Life Sci & Bioengn, Inchon, South Korea. [Yang, Sungchil] City Univ Hong Kong, Dept Biomed Sci, Kowloon, Hong Kong, Peoples R China. RP Yang, SG (reprint author), Incheon Natl Univ, Dept Nanobioengn, Inchon, South Korea.; Yang, S (reprint author), City Univ Hong Kong, Dept Biomed Sci, Kowloon, Hong Kong, Peoples R China. EM sungguyang@inu.ac.kr; sungchilyang@cityu.edu.hk FU Incheon National University (International Cooperative) Research Grant; CityU Research Project [9610347]; center for biosystems, neuroscience and nanotechnology [9360148] FX We thank Ken Burke for his constructive comments of this article. This work was supported by an Incheon National University (International Cooperative) Research Grant for Sunggu Yang, and a CityU Research Project (project No. 9610347) and center for biosystems, neuroscience and nanotechnology (project No. 9360148) for Sungchil Yang. The authors declare no competing financial interests. NR 30 TC 0 Z9 0 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD SEP 30 PY 2016 VL 10 AR 224 DI 10.3389/fncel.2016.00224 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DX6EJ UT WOS:000384475900002 PM 27746721 ER PT J AU Chen, YL Reese, DH AF Chen, Yanling Reese, David H. TI Corexit-EC9527A Disrupts Retinol Signaling and Neuronal Differentiation in P19 Embryonal Pluripotent Cells SO PLOS ONE LA English DT Article ID HORIZON OIL-SPILL; DISPERSANT COREXIT EC9500A; EARLY-LIFE STAGES; CARCINOMA-CELLS; CRUDE-OIL; NEUROPEPTIDE-Y; ACUTE INHALATION; STEM-CELLS; VITAMIN-A; ACID AB Corexit-EC9500A and Corexit-EC9527A are two chemical dispersants that have been used to remediate the impact of the 2010 Deepwater Horizon oil spill. Both dispersants are composed primarily of organic solvents and surfactants and act by emulsifying the crude oil to facilitate biodegradation. The potential adverse effect of the Corexit chemicals on mammalian embryonic development remains largely unknown. Retinol (vitamin A) signaling, mediated by all-trans retinoic acid (RA), is essential for neural tube formation and the development of many organs in the embryo. The physiological levels of RA in cells and tissues are maintained by the retinol signaling pathway (RSP), which controls the biosynthesis of RA from dietary retinol and the catabolism of RA to polar metabolites for removal. RA is a potent activating ligand for the RAR/RXR nuclear receptors. Through RA and the receptors, the RSP modulates the expression of many developmental genes; interference with the RSP is potentially teratogenic. In this study the mouse P19 embryonal pluripotent cell, which contains a functional RSP, was used to evaluate the effects of the Corexit dispersants on retinol signaling and associated neuronal differentiation. The results showed that Corexit-EC9500A was more cytotoxic than Corexit-EC9527A to P19 cells. At non-cytotoxic doses, Corexit-EC9527A inhibited retinol-induced expression of the Hoxa1 gene, which encodes a transcription factor for the regulation of body patterning in the embryo. Such inhibition was seen in the retinol-and retinal-induced, but not RA-induced, Hoxa1 up-regulation, indicating that the Corexit chemicals primarily inhibit RA biosynthesis from retinal. In addition, Corexit-EC9527A suppressed retinol-induced P19 cell differentiation into neuronal cells, indicating potential neurotoxic effect of the chemicals under the tested conditions. The surfactant ingredient, dioctyl sodium sulfosuccinate (DOSS), may be a major contributor to the observed effect of Corexit-EC9527A in the cell. C1 [Chen, Yanling; Reese, David H.] US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Div Mol Biol, Laurel, MD 20708 USA. RP Chen, YL (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Div Mol Biol, Laurel, MD 20708 USA. EM yanling.chen@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration FX We thank Dr. Paddy L. Wiesenfeld's group at the U.S. FDA for providing the Corexit-EC9500A and Corexit-EC9527A for this study. We thank Drs. Keith Lampel, Solomotis Marianna, and Christopher Elkins for reviewing this manuscript and helpful comments. This project was supported in part by the appointment of Yanling Chen to the Research Participation Program at the Center for Food Safety and Applied Nutrition 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. Food and Drug Administration. NR 66 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 29 PY 2016 VL 11 IS 9 AR e0163724 DI 10.1371/journal.pone.0163724 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX4CV UT WOS:000384328500105 PM 27684493 ER PT J AU Kumari, V Dyba, MA Holland, RJ Liang, YH Singh, SV Ji, XH AF Kumari, Vandana Dyba, Marzena A. Holland, Ryan J. Liang, Yu-He Singh, Shivendra V. Ji, Xinhua TI Irreversible Inhibition of Glutathione S-Transferase by Phenethyl Isothiocyanate (PEITC), a Dietary Cancer Chemopreventive Phytochemical SO PLOS ONE LA English DT Article ID CHROMATOGRAPHY; VEGETABLES; P1-1; SITE AB Dietary isothiocyanates abundant as glucosinolate precursors in many edible cruciferous vegetables are effective for prevention of cancer in chemically-induced and transgenic rodent models. Some of these agents, including phenethyl isothiocyanate (PEITC), have already advanced to clinical investigations. The primary route of isothiocyanate metabolism is its conjugation with glutathione (GSH), a reaction catalyzed by glutathione S-transferase (GST). The pi class GST of subunit type 1 (hGSTP1) is much more effective than the alpha class GST of subunit type 1 (hGSTA1) in catalyzing the conjugation. Here, we report the crystal structures of hGSTP1 and hGSTA1 each in complex with the GSH adduct of PEITC. We find that PEITC also covalently modifies the cysteine side chains of GST, which irreversibly inhibits enzymatic activity. C1 [Kumari, Vandana; Dyba, Marzena A.; Holland, Ryan J.; Liang, Yu-He; Ji, Xinhua] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Dyba, Marzena A.] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Singh, Shivendra V.] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA. [Singh, Shivendra V.] Univ Pittsburgh, Sch Med, Inst Canc, Pittsburgh, PA USA. [Holland, Ryan J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Liang, Yu-He] Rutgers State Univ, Ctr Integrat Prote Res, Piscataway, NJ USA. RP Ji, XH (reprint author), NCI, Ctr Canc Res, Frederick, MD 21701 USA. EM jix@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Cancer Institute (NCI); Center for Cancer Research; Frederick National Laboratory for Cancer Research; NCI; NIH [HHSN261200800001E]; USPHS [R01 CA101753] FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research, and in part with Federal funds from the Frederick National Laboratory for Cancer Research, NCI, NIH, under contract HHSN261200800001E to Leidos Biomedical Research, Inc. that provided support in the form of salary for one author [MAD], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The research efforts of SVS were funded by the USPHS grant R01 CA101753 awarded by the NCI. The specific roles of MAD are articulated in the 'author contributions' section. NR 23 TC 0 Z9 0 U1 7 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 29 PY 2016 VL 11 IS 9 AR e0163821 DI 10.1371/journal.pone.0163821 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX4CV UT WOS:000384328500119 PM 27684484 ER PT J AU Marston, HD Lurie, N Borio, LL Fauci, AS AF Marston, Hilary D. Lurie, Nicole Borio, Luciana L. Fauci, Anthony S. TI Considerations for Developing a Zika Virus Vaccine SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID INFECTION C1 [Marston, Hilary D.; Fauci, Anthony S.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Borio, Luciana L.] US FDA, Off Commissioner, Silver Spring, MD USA. [Lurie, Nicole] US Dept HHS, Off Assistant Secretary Preparedness & Response, Washington, DC 20201 USA. RP Marston, HD (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 4 TC 6 Z9 6 U1 25 U2 25 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 29 PY 2016 VL 375 IS 13 BP 1209 EP 1212 DI 10.1056/NEJMp1607762 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DX3HU UT WOS:000384265000001 PM 27682031 ER PT J AU Tesfamariam, B AF Tesfamariam, Belay TI Local arterial wall drug delivery using balloon catheter system SO JOURNAL OF CONTROLLED RELEASE LA English DT Review DE Local drug delivery; Drug-coated balloon; Excipients; Drug transfer; Binding; Retention; Lipophilic drugs ID PACLITAXEL-COATED BALLOON; PORCINE CORONARY-ARTERIES; IN-STENT RESTENOSIS; DINUCLEOTIDE PHOSPHATE OXIDASE; ELUTING BALLOON; RE-ENDOTHELIALIZATION; TISSUE UPTAKE; SWINE MODEL; INHIBITION; TRANSPORT AB Balloon-based drug delivery systems allow localized application of drugs to a vascular segment to reduce neointimal hyperplasia and restenosis. Drugs are coated onto balloons using excipients as drug carriers to facilitate adherence and release of drug during balloon inflation. Drug-coated balloon delivery system is characterized by a rapid drug transfer that achieves high drug concentration along the vessel wall surface, intended to correspond to the balloon dilation-induced vascular injury and healing processes. The balloon catheter system allows homogenous drug delivery to the vessel wall, such that the drug release per unit surface area is kept constant along balloons of different lengths. Optimization of the balloon coating matrix is essential for efficient drug transfer and tissue retention until the artery remodels to a normal set point. Challenges in the development of balloon-based drug delivery to the arterial wall include finding suitable excipients for drug formulation to enable drug release to a targeted lesion site effectively, maintain coating integrity during transit, prolong tissue retention and reduce particulate generation. This review highlights various factors involved in the successful design of balloon-based delivery systems, including drug release kinetics, matrix coating transfer, transmural drug partitioning, dissolution rate and release of unbound active drug. Published by Elsevier B.V. C1 [Tesfamariam, Belay] US FDA, Div Cardiovasc & Renal, CDER, 10903 New Hampshire Ave,Bldg 22,Rm 4176, Silver Spring, MD 20993 USA. RP Tesfamariam, B (reprint author), US FDA, Div Cardiovasc & Renal, CDER, 10903 New Hampshire Ave,Bldg 22,Rm 4176, Silver Spring, MD 20993 USA. EM belay.tesfamariam@fda.hhs.gov NR 47 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 EI 1873-4995 J9 J CONTROL RELEASE JI J. Control. Release PD SEP 28 PY 2016 VL 238 BP 149 EP 156 DI 10.1016/j.jconrel.2016.07.041 PG 8 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DX9FV UT WOS:000384699900014 PM 27473765 ER PT J AU Dharmasena, MN Feuille, CM Starke, CEC Bhagwat, AA Stibitz, S Kopecko, DJ AF Dharmasena, Madushini N. Feuille, Catherine M. Starke, Carly Elizabeth C. Bhagwat, Arvind A. Stibitz, Scott Kopecko, Dennis J. TI Development of an Acid-Resistant Salmonella Typhi Ty21a Attenuated Vector For Improved Oral Vaccine Delivery SO PLOS ONE LA English DT Article ID ESCHERICHIA-COLI; TOLERANCE RESPONSE; STABLE EXPRESSION; SHIGELLA-FLEXNERI; STRESS-RESPONSE; RPOS MUTANT; LIVE; GENES; FEVER; ENTERICA AB The licensed oral, live-attenuated bacterial vaccine for typhoid fever, Salmonella enterica serovar Typhi strain Ty21a, has also been utilized as a vaccine delivery platform for expression of diverse foreign antigens that stimulate protection against shigellosis, anthrax, plague, or human papilloma virus. However, Ty21a is acid-labile and, for effective oral immunization, stomach acidity has to be either neutralized with buffer or by-passed with Ty21a in an enteric-coated capsule (ECC). Several studies have shown that efficacy is reduced when Ty21a is administered in an ECC versus as a buffered liquid formulation, the former limiting exposure to GI tract lymphoid tissues. However, the ECC was selected as a more practical delivery format for both packaging/shipping and vaccine administration ease. We have sought to increase Ty21a acid-resistance to allow for removal from the ECC and immune enhancement. To improve Ty21a acid-resistance, glutamate-dependent acid resistance genes (GAD; responsible for Shigella spp. survival at very low pH) were cloned on a multi-copy plasmid (pGad) under a controllable arabinose-inducible promoter. pGad enhanced acid survival of Ty21a by 5 logs after 3 hours at pH 2.5, when cells were pre-grown in arabinose and under conditions that promote an acid-tolerance response (ATR). For genetically 100% stable expression, we inserted the gad genes into the Ty21a chromosome, using a method that allowed for subsequent removal of a selectable antibiotic resistance marker. Further, both bacterial growth curves and survival assays in cultured human monocytes/macrophages suggest that neither the genetic methods employed nor the resulting acid-resistance conferred by expression of the Gad proteins in Ty21a had any effect on the existing attenuation of this vaccine strain. C1 [Dharmasena, Madushini N.; Feuille, Catherine M.; Starke, Carly Elizabeth C.; Stibitz, Scott; Kopecko, Dennis J.] US FDA, Lab Mucosal Pathogens & Cellular Immunol, Ctr Biol Evaluat & Res, New Hampshire Ave, Silver Spring, MD 20993 USA. [Bhagwat, Arvind A.] ARS, Environm Microbial & Food Safety Lab, USDA, Beltsville, MD USA. [Kopecko, Dennis J.] CombiVax LLC, Silver Spring, MD USA. RP Dharmasena, MN; Kopecko, DJ (reprint author), US FDA, Lab Mucosal Pathogens & Cellular Immunol, Ctr Biol Evaluat & Res, New Hampshire Ave, Silver Spring, MD 20993 USA.; Kopecko, DJ (reprint author), CombiVax LLC, Silver Spring, MD USA. EM Madushint.Dharmasena@fda.hhs.gov; kopecko@netscape.net FU Intramural Research Program of the Center for Biologics Evaluation and Research, Food and Drug Administration FX This work was supported by the Intramural Research Program of the Center for Biologics Evaluation and Research, Food and Drug Administration. NR 50 TC 1 Z9 1 U1 8 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 SEP 27 PY 2016 VL 11 IS 9 AR e0163511 DI 10.1371/journal.pone.0163511 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX2AT UT WOS:000384169900021 PM 27673328 ER PT J AU Ottesen, AR Gorham, S Reed, E Newell, MJ Ramachandra, P Canida, T Allard, M Evans, P Brown, E White, JR AF Ottesen, Andrea R. Gorham, Sasha Reed, Elizabeth Newell, Michael J. Ramachandra, Padmini Canida, Travis Allard, Marc Evans, Peter Brown, Eric White, James Robert TI Using a Control to Better Understand Phyllosphere Microbiota SO PLOS ONE LA English DT Article ID BACTERIAL COMMUNITY; FOOD SAFETY; FARMING SYSTEM; RIBOSOMAL-RNA; DIVERSITY; SEQUENCES; TOMATOES; ECOLOGY; IMPACT; REGION AB An important data gap in our understanding of the phyllosphere surrounds the origin of the many microbes described as phyllosphere communities. Most sampling in phyllosphere research has focused on the collection of microbiota without the use of a control, so the opportunity to determine which taxa are actually driven by the biology and physiology of plants as opposed to introduced by environmental forces has yet to be fully realized. To address this data gap, we used plastic plants as inanimate controls adjacent to live tomato plants (phyllosphere) in the field with the hope of distinguishing between bacterial microbiota that may be endemic to plants as opposed to introduced by environmental forces. Using 16S rRNA gene amplicons to study bacterial membership at four time points, we found that the vast majority of all species-level operational taxonomic units were shared at all time-points. Very few taxa were unique to phyllosphere samples. A higher taxonomic diversity was consistently observed in the control samples. The high level of shared taxonomy suggests that environmental forces likely play a very important role in the introduction of microbes to plant surfaces. The observation that very few taxa were unique to the plants compared to the number that were unique to controls was surprising and further suggests that a subset of environmentally introduced taxa thrive on plants. This finding has important implications for improving our approach to the description of core phytobiomes as well as potentially helping us better understand how foodborne pathogens may become associated with plant surfaces. C1 [Ottesen, Andrea R.; Gorham, Sasha; Reed, Elizabeth; Ramachandra, Padmini; Canida, Travis; Allard, Marc; Brown, Eric; White, James Robert] US FDA, Mol Methods & Subtyping Branch, Div Microbiol, Off Regulatory Sci,Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Newell, Michael J.] Univ Maryland, Wye Res & Educ Ctr, Queenstown, MD USA. [Evans, Peter] USDA, Food Safety & Inspect Serv, Washington, DC 20250 USA. RP Ottesen, AR (reprint author), US FDA, Mol Methods & Subtyping Branch, Div Microbiol, Off Regulatory Sci,Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM andrea.ottesen@fda.hhs.gov FU Center for Food Safety and Applied Nutrition FX The authors received funding from the Center for Food Safety and Applied Nutrition. NR 48 TC 1 Z9 1 U1 12 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 26 PY 2016 VL 11 IS 9 AR e0163482 DI 10.1371/journal.pone.0163482 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX1ZV UT WOS:000384167300050 PM 27669159 ER PT J AU Hoo, LS Banna, CD Radeke, CM Sharma, N Albertolle, ME Low, SH Weimbs, T Vandenberg, CA AF Hoo, Linda Soo Banna, Chris D. Radeke, Carolyn M. Sharma, Nikunj Albertolle, Mary E. Low, Seng Hui Weimbs, Thomas Vandenberg, Carol A. TI The SNARE Protein Syntaxin 3 Confers Specificity for Polarized Axonal Trafficking in Neurons Linda SO PLOS ONE LA English DT Article ID APICAL PLASMA-MEMBRANE; CANINE KIDNEY-CELLS; EPITHELIAL-CELLS; HIPPOCAMPAL-NEURONS; INITIAL SEGMENT; POTASSIUM CHANNELS; NEURITE OUTGROWTH; ION CHANNELS; T-SNARE; FUSION AB Cell polarity and precise subcellular protein localization are pivotal to neuronal function. The SNARE machinery underlies intracellular membrane fusion events, but its role in neuronal polarity and selective protein targeting remain unclear. Here we report that syntaxin 3 is involved in orchestrating polarized trafficking in cultured rat hippocampal neurons. We show that syntaxin 3 localizes to the axonal plasma membrane, particularly to axonal tips, whereas syntaxin 4 localizes to the somatodendritic plasma membrane. Disruption of a conserved N-terminal targeting motif, which causes mislocalization of syntaxin 3, results in coincident mistargeting of the axonal cargos neuron-glia cell adhesion molecule (NgCAM) and neurexin, but not transferrin receptor, a somatodendritic cargo. Similarly, RNAi-mediated knockdown of endogenous syntaxin 3 leads to partial mistargeting of NgCAM, demonstrating that syntaxin 3 plays an important role in its targeting. Additionally, overexpression of syntaxin 3 results in increased axonal growth. Our findings suggest an important role for syntaxin 3 in maintaining neuronal polarity and in the critical task of selective trafficking of membrane protein to axons. C1 [Hoo, Linda Soo; Banna, Chris D.; Radeke, Carolyn M.; Sharma, Nikunj; Albertolle, Mary E.; Low, Seng Hui; Weimbs, Thomas; Vandenberg, Carol A.] Univ Calif Santa Barbara, Dept Mol Cellular & Dev Biol, Santa Barbara, CA 93106 USA. [Hoo, Linda Soo; Banna, Chris D.; Radeke, Carolyn M.; Sharma, Nikunj; Albertolle, Mary E.; Low, Seng Hui; Weimbs, Thomas; Vandenberg, Carol A.] Univ Calif Santa Barbara, Neurosci Res Inst, Santa Barbara, CA 93106 USA. [Hoo, Linda Soo] Gilead Sci, Tech Serv, San Dimas, CA USA. [Sharma, Nikunj] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Vandenberg, CA (reprint author), Univ Calif Santa Barbara, Dept Mol Cellular & Dev Biol, Santa Barbara, CA 93106 USA.; Vandenberg, CA (reprint author), Univ Calif Santa Barbara, Neurosci Res Inst, Santa Barbara, CA 93106 USA. EM carol.vandenberg@lifesci.ucsb.edu FU National Institutes of Health [NS43377, GM66785, DK095248]; Cottage Hospital; American Heart Association Western Affiliate [0655234Y]; Cancer Research Award from the California Cancer Research Coordinating Committee FX This work was supported by National Institutes of Health Grants NS43377 to CAV and GM66785 and DK095248 to TW, Cottage Hospital Research Grant to CAV, an American Heart Association Western Affiliate Grant-in-Aid 0655234Y to CAV, and a Cancer Research Award from the California Cancer Research Coordinating Committee to TW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 0 Z9 0 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 23 PY 2016 VL 11 IS 9 AR e163671 DI 10.1371/journal.pone.0163671 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW8GR UT WOS:000383893500057 ER PT J AU Roberts, JN Graham, BS Karron, RA Munoz, FM Falsey, AR Anderson, LJ Marshall, V Kim, S Beeler, JA AF Roberts, Jeffrey N. Graham, Barney S. Karron, Ruth A. Munoz, Flor M. Falsey, Ann R. Anderson, Larry J. Marshall, V. Kim, Sonnie Beeler, Judy A. TI Challenges and opportunities in RSV vaccine development: Meeting report from FDA/NIH workshop SO VACCINE LA English DT Article DE RSV; Vaccination; Infants; Elderly; Maternal immunization; Vaccine-enhanced illness; Animal models; Subunit vaccine; Vaccine vector; Neutralization; Bronchitis; Wheezing; Human challenge; Clinical trials ID RESPIRATORY SYNCYTIAL VIRUS; IMMUNE GLOBULIN; UNITED-STATES; INFECTION; INFANTS; DISEASE; ADULTS; RISK; PREGNANCY; CHILDREN AB Respiratory syncytial virus (RSV) is the most common cause of serious acute lower respiratory illness in infants and young children and a significant cause of disease burden in the elderly and immunocompromised. There are no licensed RSV vaccines to address this significant public health need. While advances in vaccine technologies have led to a recent resurgence in RSV vaccine development, the immune correlates of protection against RSV and the immunology of vaccine-associated enhanced respiratory disease (ERD) remain poorly understood. FDA's Center for Biologics Evaluation and Research (CBER) and NIH's National Institute of Allergy and Infectious Diseases (NIAID) organized and co-sponsored an RSV Vaccines Workshop in Bethesda, Maryland on June 1 and 2, 2015. The goal of the conference was to convene scientists, regulators, and industry stakeholders to discuss approaches to RSV vaccine development within the context of three target populations - infants and children, pregnant women, and individuals >60 years of age. The agenda included topics related to RSV vaccine development in general, as well as considerations specific to each target population, such as clinical and serological endpoints. The meeting focused on vaccine development for high income countries (HIC), because issues relevant to vaccine development for low and middle income countries (LMIC) have been discussed in other forums. This manuscript summarizes the discussion of clinical, scientific, and regulatory perspectives, research gaps, and lessons learned. C1 [Roberts, Jeffrey N.; Marshall, V.; Beeler, Judy A.] FDA, CBER, OVRR, Silver Spring, MD 20993 USA. [Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Karron, Ruth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Immunizat Res, Baltimore, MD 21205 USA. [Munoz, Flor M.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Munoz, Flor M.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Falsey, Ann R.] Univ Rochester, Rochester Gen Hosp, Dept Med, Div Infect Dis, Rochester, NY USA. [Anderson, Larry J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA. [Anderson, Larry J.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Kim, Sonnie] NIAID, Div Microbiol & Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Roberts, JN (reprint author), FDA, CBER, OVRR, Silver Spring, MD 20993 USA. EM jeff.roberts@fda.hhs.gov FU Division of Microbiology and Infectious Diseases (DMID) at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH); DMID FX The Division of Microbiology and Infectious Diseases (DMID) at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH) is supporting a wide range of basic, preclinical and clinical research activities through grants and several contracts to develop RSV vaccines and therapeutics. In addition, DMID has developed reagent resources in the Biodefense and Emerging Infections (BEI) repository, preclinical contract services to allow researchers to perform gap analysis of their products, process development, cGMP production of compounds, animal model efficacy testing, assay development, and GLP toxicology testing.; DMID has awarded contracts for the Vaccine and Treatment Evaluation Units (VTEUs), the Respiratory Pathogens Research Centers (RPRC), and the Phase 1 Therapeutics Unit. The VTEUs perform phase 1, 2 safety and immunogenicity and phase 4 immunogenicity and efficacy trials as well as epidemiologic studies in a wide range of populations, including healthy adults, pregnant women, pediatric and the elderly. VTEU supports the evaluation of novel vaccines, therapeutics and delivery systems; it is also currently supporting the development of T cell and B cell assays for the detection of active and past RSV infection. NR 39 TC 3 Z9 3 U1 8 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD SEP 22 PY 2016 VL 34 IS 41 BP 4843 EP 4849 DI 10.1016/j.vaccine.2016.07.057 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DY1LY UT WOS:000384857700001 PM 27566900 ER PT J AU Zhao, JQ Liu, JK Vemula, SV Lin, C Tan, JY Ragupathy, V Wang, X Mbondji-Wonje, C Ye, ZP Landry, ML Hewlett, I AF Zhao, Jiangqin Liu, Jikun Vemula, Sai Vikram Lin, Corinna Tan, Jiying Ragupathy, Viswanath Wang, Xue Mbondji-Wonje, Christelle Ye, Zhiping Landry, Marie L. Hewlett, Indira TI Sensitive Detection and Simultaneous Discrimination of Influenza A and B Viruses in Nasopharyngeal Swabs in a Single Assay Using Next-Generation Sequencing-Based Diagnostics SO PLOS ONE LA English DT Article ID UNITED-STATES; H7N9 VIRUS; H1N1 VIRUS; SWINE; IDENTIFICATION; AMPLIFICATION; OSELTAMIVIR; INFECTION; SUSCEPTIBILITY; CHALLENGES AB Reassortment of 2009 (H1N1) pandemic influenza virus (pdH1N1) with other strains may produce more virulent and pathogenic forms, detection and their rapid characterization is critical. In this study, we reported a "one-size-fits-all" approach using a next-generation sequencing (NGS) detection platform to extensively identify influenza viral genomes for diagnosis and determination of novel virulence and drug resistance markers. A de novo module and other bioinformatics tools were used to generate contiguous sequence and identify influenza types/subtypes. Of 162 archived influenza-positive patient specimens, 161(99.4%) were positive for either influenza A or B viruses determined using the NGS assay. Among these, 135(83.3%) were A(H3N2), 14(8.6%) were A(pdH1N1), 2(1.2%) were A(H3N2) and A(pdH1N1) virus co-infections and 10(6.2%) were influenza B viruses. Of the influenza A viruses, 66.7% of A(H3N2) viruses tested had a E627K mutation in the PB2 protein, and 87.8% of the influenza A viruses contained the S31N mutation in the M2 protein. Further studies demonstrated that the NGS assay could achieve a high level of sensitivity and reveal adequate genetic information for final laboratory confirmation. The current diagnostic platform allows for simultaneous identification of a broad range of influenza viruses, monitoring emerging influenza strains with pandemic potential that facilitating diagnostics and antiviral treatment in the clinical setting and protection of the public health. C1 [Zhao, Jiangqin; Liu, Jikun; Vemula, Sai Vikram; Lin, Corinna; Tan, Jiying; Ragupathy, Viswanath; Wang, Xue; Mbondji-Wonje, Christelle; Hewlett, Indira] US FDA, DETTD, OBRR, CBER, Silver Spring, MD 20993 USA. [Ye, Zhiping] US FDA, DVP, OVRR, CBER, Silver Spring, MD 20993 USA. [Landry, Marie L.] Yale Univ, Sch Med, Dept Lab Med, 333 Cedar St, New Haven, CT 06520 USA. RP Zhao, JQ; Hewlett, I (reprint author), US FDA, DETTD, OBRR, CBER, Silver Spring, MD 20993 USA. EM jiangqin.zhao@fda.hhs.gov; indira.hewlett@fda.hhs.gov OI Zhao, Jiangqin/0000-0003-4672-0735 FU Center for Biologics Evaluation and Research (CBER) intramural; US Food and Drug Administration (FDA) Medical Countermeasures Initiative (MCMi) funds; Medical Countermeasures Initiative funds FX The research was supported by Center for Biologics Evaluation and Research (CBER) intramural and US Food and Drug Administration (FDA) Medical Countermeasures Initiative (MCMi) funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This work was funded through FDA Center for Biologics Evaluation and Research (CBER) intramural and Medical Countermeasures Initiative funds. We are thankful to FDA, CBER core facility for help with some NGS assays and oligonucleotide synthesis. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. We would like to thank Drs. Heike Sichtig and Shyh-Ching Lo for their critical reading of our manuscript. NR 49 TC 0 Z9 0 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 22 PY 2016 VL 11 IS 9 AR e0163175 DI 10.1371/journal.pone.0163175 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW8GO UT WOS:000383893200080 PM 27658193 ER PT J AU Khare, S Drake, KL Lawhon, SD Nunes, JES Figueiredo, JF Rossetti, CA Gull, T Everts, RE Lewin, HA Adams, LG AF Khare, Sangeeta Drake, Kenneth L. Lawhon, Sara D. Nunes, Jairo E. S. Figueiredo, Josely F. Rossetti, Carlos A. Gull, Tamara Everts, Robin E. Lewin, Harris. A. Adams, Leslie Garry TI Systems Analysis of Early Host Gene Expression Provides Clues for Transient Mycobacterium avium ssp avium vs. Persistent Mycobacterium avium ssp paratuberculosis Intestinal Infections SO PLOS ONE LA English DT Article ID MONOCYTE-DERIVED MACROPHAGES; SUBSP-PARATUBERCULOSIS; BOVINE MONOCYTES; IMMUNE-RESPONSE; ECONOMIC-IMPACT; NK CELLS; TUBERCULOSIS; DISEASE; KINASE; KEGG AB It has long been a quest in ruminants to understand how two very similar mycobacterial species, Mycobacterium avium ssp. paratuberculosis (MAP) and Mycobacterium avium ssp. avium (MAA) lead to either a chronic persistent infection or a rapid-transient infection, respectively. Here, we hypothesized that when the host immune response is activated by MAP or MAA, the outcome of the infection depends on the early activation of signaling molecules and host temporal gene expression. To test our hypothesis, ligated jejuno-ileal loops including Peyer's patches in neonatal calves were inoculated with PBS, MAP, or MAA. A temporal analysis of the host transcriptome profile was conducted at several times post-infection (0.5, 1, 2, 4, 8 and 12 hours). When comparing the transcriptional responses of calves infected with the MAA versus MAP, discordant patterns of mucosal expression were clearly evident, and the numbers of unique transcripts altered were moderately less for MAA-infected tissue than were mucosal tissues infected with the MAP. To interpret these complex data, changes in the gene expression were further analyzed by dynamic Bayesian analysis. Bayesian network modeling identified mechanistic genes, gene-to-gene relationships, pathways and Gene Ontologies (GO) biological processes that are involved in specific cell activation during infection. MAP and MAA had significant different pathway perturbation at 0.5 and 12 hours post inoculation. Inverse processes were observed between MAP and MAA response for epithelial cell proliferation, negative regulation of chemotaxis, cell-cell adhesion mediated by integrin and regulation of cytokine-mediated signaling. MAP inoculated tissue had significantly lower expression of phagocytosis receptors such as mannose receptor and complement receptors. This study reveals that perturbation of genes and cellular pathways during MAP infection resulted in host evasion by mucosal membrane barrierweakening to access entry in the ileum, inhibition of Ca signaling associated with decreased phagosome-lysosome fusion as well as phagocytosis inhibition, bias toward Th2 cell immune response accompanied by cell recruitment, cell proliferation and cell differentiation; leading to persistent infection. Contrarily, MAA infection was related to cellular responses associated with activation of molecular pathways that release chemicals and cytokines involved with containment of infection and a strong bias toward Th1 immune response, resulting in a transient infection. C1 [Khare, Sangeeta; Lawhon, Sara D.; Nunes, Jairo E. S.; Figueiredo, Josely F.; Rossetti, Carlos A.; Gull, Tamara; Adams, Leslie Garry] Texas A&M Univ, Dept Vet Pathobiol, Coll Vet Med & Biomed Sci, College Stn, TX 77843 USA. [Khare, Sangeeta] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. [Drake, Kenneth L.] Seralogix LLC, Austin, TX 78730 USA. [Everts, Robin E.; Lewin, Harris. A.] Univ Illinois, Dept Anim Sci, Urbana, IL USA. RP Khare, S; Adams, LG (reprint author), Texas A&M Univ, Dept Vet Pathobiol, Coll Vet Med & Biomed Sci, College Stn, TX 77843 USA.; Khare, S (reprint author), US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. EM Sangeeta.khare@fda.hhs.gov; gadams@cvm.tamu.edu FU U.S. Department of Agriculture Cooperative State Research, Education and Extension Service-National Research Initiative-Coordinated Agricultural Project-Johne's Disease Integrated Program [2004-35605-14243, Q6286224133]; USDA [TEX08409] FX This work was funded by a U.S. Department of Agriculture Cooperative State Research, Education and Extension Service-National Research Initiative-Coordinated Agricultural Project-Johne's Disease Integrated Program (2004-35605-14243 sub-award Q6286224133) to SK and USDA Project TEX08409 to LGA. The funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials.; The authors thank Alan Patranella for the assistance with animal care, Roberta Pugh and Doris Hunter for technical support. The study was supported by funds to Sangeeta Khare from the U.S. Department of Agriculture Cooperative State Research, Education and Extension Service-National Research Initiative-Coordinated Agricultural Project-Johne's Disease Integrated Program (2004-35605-14243 sub-award Q6286224133) and funds awarded to L. Garry Adams through USDA Project TEX08409. "Funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials." The views presented in this article do not reflect those of the US Food and Drug Administration. NR 56 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 21 PY 2016 VL 11 IS 9 AR e0161946 DI 10.1371/journal.pone.0161946 PG 33 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW8GK UT WOS:000383892700013 PM 27653506 ER PT J AU Underbayev, C Kasar, S Ruezinsky, W Degheidy, H Schneider, JS Marti, G Bauer, SR Fraidenraich, D Lightfoote, MM Parashar, V Raveche, E Batish, M AF Underbayev, Chingiz Kasar, Siddha Ruezinsky, William Degheidy, Heba Schneider, Joel Solomon Marti, Gerald Bauer, Steven R. Fraidenraich, Diego Lightfoote, Marilyn M. Parashar, Vijay Raveche, Elizabeth Batish, Mona TI Role of mir-15a/16-1 in early B cell development in a mouse model of chronic lymphocytic leukemia SO ONCOTARGET LA English DT Article DE chronic lymphocytic leukemia; microRNAs; B1 progenitors; induced pluripotent stem cells; cancer stem cells ID BONE-MARROW; STEM-CELLS; C-MYB; DIFFERENTIATION; ACTIVATION; LINEAGES; MIR-16-1; LYMPHOMA; PU.1; MICE AB In both human chronic lymphocytic leukemia (CLL) and the New Zealand Black (NZB) murine model of CLL, decreased levels of microRNAs miR-15a/16 play an important role in the disease. Here we investigate the effects of this microRNA on early steps of B cell development and the capacity of miR-15a-deficient hematopoietic stem cells (HSC) and B1 progenitor cells (B1P) to reproduce CLL-like phenotype both in vitro and in vivo. Our results demonstrate that both miR-15a deficient HSC and B1P cells are capable of repopulating irradiated recipients and produce higher numbers of B1 cells than sources with normal miR-15a/16 levels. Furthermore, induced pluripotent stem (iPS) cells derived for the first time from NZB mice, provided insights into the B cell differentiation roadblock inherent in this strain. In addition, exogenously delivered miR-15a into the NZB derived B cell line provided valuable clues into novel targets such as Mmp10 and Mt2. Our data supports the hypothesis that miR-15a/16 deficient stem cells and B1Ps experience a maturation blockage, which contributes to B1 cells bias in development. This work will help understand the role of miR-15a in early events of CLL and points to B1P cells as potential cells of origin for this incurable disease. C1 [Underbayev, Chingiz; Kasar, Siddha; Ruezinsky, William; Fraidenraich, Diego; Raveche, Elizabeth; Batish, Mona] Rutgers State Univ, New Jersey Med Sch, Newark, NJ 08901 USA. [Marti, Gerald] OSEL CDRH FDA, Silver Spring, MD USA. [Degheidy, Heba; Bauer, Steven R.; Lightfoote, Marilyn M.] CBER FDA Silver Spring, Silver Spring, MD USA. [Schneider, Joel Solomon] Solid Biosci LLC, Cambridge, MA USA. [Parashar, Vijay] Rutgers State Univ, Rutgers Sch Dent Med, Newark, NJ USA. [Underbayev, Chingiz] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Degheidy, Heba] Mansoura Univ, Fac Med, Mansoura, Egypt. RP Batish, M (reprint author), Rutgers State Univ, New Jersey Med Sch, Newark, NJ 08901 USA. EM batishmo@njms.rutgers.edu FU NIH [DP5OD012160, R01CA12926]; NSF [1238375] FX This work was supported by NIH Director's Early Independence Award DP5OD012160 (MB) and NIH R01CA12926 and NSF 1238375 grants (ER). NR 41 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 20 PY 2016 VL 7 IS 38 BP 60986 EP 60999 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB2CN UT WOS:000387164700016 PM 27533467 ER PT J AU Shuren, J Califf, RM AF Shuren, Jeffrey Califf, Robert M. TI Need for a National Evaluation System for Health Technology SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Shuren, Jeffrey; Califf, Robert M.] US FDA, Silver Spring, MD USA. RP Shuren, J (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jeff.shuren@fda.hhs.gov NR 2 TC 6 Z9 6 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 20 PY 2016 VL 316 IS 11 BP 1153 EP 1154 DI 10.1001/jama.2016.8708 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DW2PK UT WOS:000383484100012 PM 27398696 ER PT J AU Mishra-Kalyani, PS Johnson, BA Glass, JD Long, Q AF Mishra-Kalyani, Pallavi S. Johnson, Brent A. Glass, Jonathan D. Long, Qi TI Estimating the palliative effect of percutaneous endoscopic gastrostomy in an observational registry using principal stratification and generalized propensity scores SO SCIENTIFIC REPORTS LA English DT Article ID CAUSAL INFERENCE AB Clinical disease registries offer a rich collection of valuable patient information but also pose challenges that require special care and attention in statistical analyses. The goal of this paper is to propose a statistical framework that allows for estimating the effect of surgical insertion of a percutaneous endogastrostomy (PEG) tube for patients living with amyotrophic lateral sclerosis (ALS) using data from a clinical registry. Although all ALS patients are informed about PEG, only some patients agree to the procedure which, leads to the potential for selection bias. Assessing the effect of PEG is further complicated by the aggressively fatal disease, such that time to death competes directly with both the opportunity to receive PEG and clinical outcome measurements. Our proposed methodology handles the "censoring by death" phenomenon through principal stratification and selection bias for PEG treatment through generalized propensity scores. We develop a fully Bayesian modeling approach to estimate the survivor average causal effect (SACE) of PEG on BMI, a surrogate outcome measure of nutrition and quality of life. The use of propensity score methods within the principal stratification framework demonstrates a significant and positive effect of PEG treatment, particularly when time of treatment is included in the treatment definition. C1 [Mishra-Kalyani, Pallavi S.] US FDA, Off Biostat, Silver Spring, MD 20903 USA. [Johnson, Brent A.] Univ Rochester, Dept Biostat & Computat Biol, Rochester, NY 14642 USA. [Glass, Jonathan D.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Long, Qi] Emory Univ, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. RP Long, Q (reprint author), Emory Univ, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. EM qlong@emory.edu FU NIH/NINDS grant [R21-NS091630] FX This work was supported in part by an NIH/NINDS grant (R21-NS091630). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 15 TC 0 Z9 0 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD SEP 19 PY 2016 VL 6 AR 33431 DI 10.1038/srep33431 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW0JC UT WOS:000383325700001 PM 27640365 ER PT J AU Ison, G Beaver, JA McGuinn, WD Palmby, TR Dinin, J Charlab, R Marathe, A Jin, RY Liu, Q Chen, XH Ysern, X Stephens, O Bai, G Wang, YN Dorff, SE Cheng, J Tang, SH Sridhara, R Pierce, W Mckee, AE Ibrahim, A Kim, G Pazdur, R AF Ison, Gwynn Beaver, Julia A. McGuinn, W. David, Jr. Palmby, Todd R. Dinin, Jeannette Charlab, Rosane Marathe, Anshu Jin, Runyan Liu, Qi Chen, Xiao Hong Ysern, Xavier Stephens, Olen Bai, Ge Wang, Yaning Dorff, Sarah E. Cheng, Joyce Tang, Shenghui Sridhara, Rajeshwari Pierce, William Mckee, Amy E. Ibrahim, Amna Kim, Geoffrey Pazdur, Richard TI FDA Approval: Uridine Triacetate for the Treatment of Patients Following Fluorouracil or Capecitabine Overdose or Exhibiting Early-Onset Severe Toxicities Following Administration of These Drugs SO CLINICAL CANCER RESEARCH LA English DT Article ID DIHYDROPYRIMIDINE DEHYDROGENASE-DEFICIENCY; CANCER AB On December 11, 2015, the FDA approved uridine triacetate (VISTOGARD; Wellstat Therapeutics Corporation) for the emergency treatment of adult and pediatric patients following a fluorouracil or capecitabine overdose regardless of the presence of symptoms, and of those who exhibit early-onset, severe, or life-threatening toxicity affecting the cardiac or central nervous system, and/or early onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration. Uridine triacetate is not recommended for the nonemergent treatment of adverse reactions associated with fluorouracil or capecitabine because it may diminish the efficacy of these drugs, and the safety and efficacy of uridine triacetate initiated more than 96 hours following the end of administration of these drugs has not been established. The approval is based on data from two single-arm, open-label, expanded-access trials in 135 patients receiving uridine triacetate (10 g or 6.2 g/m(2) orally every 6 hours for 20 doses) for fluorouracil or capecitabine overdose, or who exhibited severe or life-threatening toxicities within 96 hours following the end of fluorouracil or capecitabine administration. Ninety-six percent of patients met the major efficacy outcome measure, which was survival at 30 days or survival until the resumption of chemotherapy, if prior to 30 days. The most common adverse reactions were vomiting, nausea, and diarrhea. This article summarizes the FDA review of this New Drug Application, the data supporting approval of uridine triacetate, and the unique regulatory situations encountered by this approval. (C)2016 AACR. C1 [Ison, Gwynn; Beaver, Julia A.; McGuinn, W. David, Jr.; Palmby, Todd R.; Dinin, Jeannette; Charlab, Rosane; Marathe, Anshu; Jin, Runyan; Liu, Qi; Chen, Xiao Hong; Ysern, Xavier; Stephens, Olen; Bai, Ge; Wang, Yaning; Dorff, Sarah E.; Cheng, Joyce; Tang, Shenghui; Sridhara, Rajeshwari; Pierce, William; Mckee, Amy E.; Ibrahim, Amna; Kim, Geoffrey; Pazdur, Richard] US FDA, Ctr Drug Evaluat & Res, White Oak, MD USA. RP Ison, G (reprint author), US FDA, 10903 New Hampshire Ave, White Oak, MD 20993 USA. EM Gwynn.Ison@fda.hhs.gov NR 11 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2016 VL 22 IS 18 BP 4545 EP 4549 DI 10.1158/1078-0432.CCR-16-0638 PG 5 WC Oncology SC Oncology GA DW0US UT WOS:000383359000003 PM 27401247 ER PT J AU Kwong, JC Stafford, R Strain, E Stinear, TP Seemann, T Howden, BP AF Kwong, Jason C. Stafford, Russell Strain, Errol Stinear, Timothy P. Seemann, Torsten Howden, Benjamin P. TI Sharing Is Caring: International Sharing of Data Enhances Genomic Surveillance of Listeria monocytogenes SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID TIME C1 [Kwong, Jason C.; Stinear, Timothy P.; Seemann, Torsten; Howden, Benjamin P.] Doherty Inst, Doherty Appl Microbial Genom, Melbourne, Vic, Australia. [Kwong, Jason C.; Stinear, Timothy P.; Howden, Benjamin P.] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic, Australia. [Stafford, Russell] Queensland Hlth, Communicable Dis Branch, OzFoodNet, Brisbane, Qld, Australia. [Strain, Errol] US FDA, College Pk, MD USA. [Seemann, Torsten] Univ Melbourne, Victorian Life Sci Computat Initiat, Carlton, Vic, Australia. [Howden, Benjamin P.] Doherty Inst, Publ Hlth Lab, Microbiol Diagnost Unit, Melbourne, Vic, Australia. RP Howden, BP (reprint author), Doherty Inst Infect & Immun, Publ Hlth Lab, Microbiol Diagnost Unit, 792 Elizabeth St, Melbourne, Vic 3000, Australia. EM bhowden@unimelb.edu.au OI Seemann, Torsten/0000-0001-6046-610X NR 4 TC 1 Z9 1 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2016 VL 63 IS 6 DI 10.1093/cid/ciw359 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DW7UK UT WOS:000383857500025 ER PT J AU Sangster-Guity, N Tu-Sekine, B Raben, DM Denmeade, SR Williams, SA AF Sangster-Guity, Niquiche Tu-Sekine, Becky Raben, Daniel M. Denmeade, Samuel R. Williams, Simon A. TI Mutational Analysis of Prostate-Specific Antigen Defines the Intrinsic Proteolytic Activity of the proPSA Zymogen SO PROSTATE LA English DT Article DE PSA; zymogen; mutational analysis ID HUMAN GLANDULAR KALLIKREIN; HORMONE-RELATED PROTEIN; CRYSTAL-STRUCTURE; SERINE-PROTEASE; IN-VITRO; PLASMINOGEN-ACTIVATOR; SUBSTRATE-SPECIFICITY; RADICAL PROSTATECTOMY; SEMINAL PLASMA; CELL-ADHESION AB BACKGROUND. Prostate-specific antigen (PSA) is an important prostate cancer biomarker. It is also a protease expressed at high concentrations by the normal and malignant prostate. PSA is secreted as a zymogen (proPSA) with an inhibitory prodomain that must be removed for full activity. ProPSA variants, assumed to be inactive, are found in the blood of prostate cancer patients, and are indicative of poor clinical outcome. Despite the abundance of clinical reports, our understanding of PSA's enzymology is limited, in part due to a lack of appropriate experimental systems. We sought to develop a series of PSA-derived mutants that would help to enhance our understanding of the gene. METHODS. Sixteen rPSA variants were generated and characterized by a variety of biochemical methods. RESULTS. The wildtype cDNA (WT) provided the template for generating a panel of recombinants. These included variants that abolished removal of the prodomain (R24A), disabled its enzymatic activity (S213A), and/or facilitated a cell-based conversion to the active conformation (FR). The purified variants' proteolytic activity was examined using a fluorogenic substrate, known PSA-cleavable proteins, and physiologically relevant inhibitors. Upon demonstrating our successful generation and purification of the PSA variants, we characterized proPSA activity, describing cleavage of synthetic and biologic substrates, but not serum protease inhibitors. This finding was exploited in the development of a self-activating mutant (PSA_QY) that exhibited the greatest enzymatic activity of all the variants. CONCLUSIONS. The system described herein will prove useful for varied applications. ProPSA is partially functional with relatively high activity compared to the mature enzyme. In demonstrating the zymogen's intrinsic activity, we suggest that the proPSA in prostate cancer patient serum is not inert. This may have implications for our understanding of the disease. (C) 2016 Wiley Periodicals, Inc. C1 [Sangster-Guity, Niquiche; Denmeade, Samuel R.; Williams, Simon A.] Johns Hopkins Univ, Sch Med, Brady Urol Res Inst, Baltimore, MD USA. [Tu-Sekine, Becky; Raben, Daniel M.] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. [Denmeade, Samuel R.; Williams, Simon A.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Williams, SA (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM simon.williams@fda.hhs.gov NR 70 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD SEP 15 PY 2016 VL 76 IS 13 BP 1203 EP 1217 DI 10.1002/pros.23216 PG 15 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA DW2MO UT WOS:000383476700007 PM 27273171 ER PT J AU Willemin, ME Lumen, A AF Willemin, Marie-Emilie Lumen, Annie TI Development of a PBPK model of thiocyanate in rats with an extrapolation to humans: A computational study to quantify the mechanism of action of thiocyanate kinetics in thyroid SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Thiocyanate; Bayesian; PBPK model; NIS; TPO; Thyroid ID GLOBAL SENSITIVITY-ANALYSIS; PHARMACOKINETIC MODELS; RISK-ASSESSMENT; PREGNANT-WOMEN; PERCHLORATE; METABOLISM; INHIBITION; CYANIDE; IODIDE; EXPOSURE AB Thyroid homeostasis can be disturbed due to thiocyanate exposure from the diet or tobacco smoke. Thiocyanate inhibits both thyroidal uptake of iodide, via the sodium-iodide symporter (NIS), and thyroid hormone (TH) synthesis in the thyroid, via thyroid peroxidase (TPO), but the mode of action of thiocyanate is poorly quantified in the literature. The characterization of the link between intra-thyroidal thiocyanate concentrations and dose of exposure is crucial for assessing the risk of thyroid perturbations due to thiocyanate exposure. We developed a PBPK model for thiocyanate that describes its kinetics in the whole-body up to daily doses of 0.15 mmol/kg, with a mechanistic description of the thyroidal kinetics including NIS, passive diffusion, and TPO. The model was calibrated in a Bayesian framework using published studies in rats. Goodness-of-fit was satisfactory, especially for intra-thyroidal thiocyanate concentrations. Thiocyanate kinetic processes were quantified in vivo, including the metabolic clearance by TPO. The passive diffusion rate was found to be greater than NIS-mediated uptake rate. The model captured the dose-dependent kinetics of thiocyanate after acute and chronic exposures. Model behavior was evaluated using a Morris screening test. The distribution of thiocyanate into the thyroid was found to be determined primarily by the partition coefficient, followed by NIS and passive diffusion; the impact of the latter two mechanisms appears to increase at very low doses. Extrapolation to humans resulted in good predictions of thiocyanate kinetics during chronic exposure. The developed PBPK model can be used in risk assessment to quantify dose-response effects of thiocyanate on TH. Published by Elsevier Inc. C1 [Willemin, Marie-Emilie; Lumen, Annie] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, HFT 110,3900 NCTR Rd, Jefferson, AR 72079 USA. RP Lumen, A (reprint author), US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, HFT 110,3900 NCTR Rd, Jefferson, AR 72079 USA. EM Annie.Lumen@fda.hhs.gov FU FDA Office of Women's Health; National Center for Toxicological Research (NCTR) through Oak Ridge Institute for Science and Education (ORISE) FX This study was funded by the FDA Office of Women's Health and National Center for Toxicological Research (NCTR) through Oak Ridge Institute for Science and Education (ORISE). We appreciate Drs. William Tolleson, Xiaoxia Yang, and Frederick A. Beland for critically reviewing this manuscript. NR 77 TC 1 Z9 1 U1 8 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 15 PY 2016 VL 307 BP 19 EP 34 DI 10.1016/j.taap.2016.07.011 PG 16 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DU7TL UT WOS:000382417400003 PM 27445130 ER PT J AU Avishek, K Kaushal, H Gannavaram, S Dey, R Selvapandiyan, A Ramesh, V Negi, NS Dubey, US Nakhasi, HL Salotra, P AF Avishek, Kumar Kaushal, Himanshu Gannavaram, Sreenivas Dey, Ranadhir Selvapandiyan, Angamuthu Ramesh, V. Negi, Narender Singh Dubey, Uma S. Nakhasi, Hira L. Salotra, Poonam TI Gene deleted live attenuated Leishmania vaccine candidates against visceral leishmaniasis elicit pro-inflammatory cytokines response in human PBMCs SO SCIENTIFIC REPORTS LA English DT Article ID AZAR DERMAL LEISHMANIASIS; ANTIGEN-PRESENTING CELLS; CUTANEOUS LEISHMANIASIS; PROTECTIVE IMMUNITY; DONOVANI INFECTION; KALA-AZAR; INTERFERON-GAMMA; PARASITES; INDIA; SUSCEPTIBILITY AB Currently no effective vaccine is available for human visceral leishmaniasis(VL) caused by Leishmania donovani. Previously, we showed that centrin1 and p27gene deleted live attenuated Leishmania parasites (LdCen1(-/-) and Ldp27(-/-)) are safe, immunogenic and protective in animal models. Here, to assess the correlates of protection, we evaluated immune responses induced by LdCen1(-/-) and Ldp27(-/-) in human blood samples obtained from healthy, healed VL (HVL), post kala-azar dermal leishmaniasis(PKDL) and VL subjects. Both parasites infected human macrophages, as effectively as the wild type parasites. Further, LdCen1(-/-) and Ldp27(-/-) strongly stimulated production of pro-inflammatory cytokines including, IL-12, IFN-gamma, TNF-alpha, IL-2, IL-6 and IL-17 in the PBMCs obtained from individuals with a prior exposure to Leishmania (HVL and PKDL). There was no significant stimulation of anti-inflammatory cytokines (IL-4 and IL-10). Induction of Th1 biased immune responses was supported by a remarkable increase in IFN-gamma secreting CD4(+) and CD8(+) T cells and IL-17 secreting CD4+ cells in PBMCs from HVL cases with no increase in IL- 10 secreting T cells. Hence, LdCen1(-/-) and Ldp27(-/-) are promising as live vaccine candidates against VL since they elicit strong protective immune response in human PBMCs from HVL, similar to the wild type parasite infection, mimicking a naturally acquired protection following cure. C1 [Avishek, Kumar; Kaushal, Himanshu; Salotra, Poonam] Natl Inst Pathol ICMR, Safdarjung Hosp Campus, New Delhi, India. [Gannavaram, Sreenivas; Dey, Ranadhir; Nakhasi, Hira L.] US FDA, CBER, Div Emerging & Transfus Transmitted Dis, Bethesda, MD 20014 USA. [Selvapandiyan, Angamuthu] Jamia Hamdard, JH Inst Mol Med, New Delhi, India. [Ramesh, V.] VMMC, Dept Dermatol, New Delhi, India. [Ramesh, V.; Negi, Narender Singh] Safdarjang Hosp, New Delhi, India. [Negi, Narender Singh] VMMC, Dept Med, New Delhi, India. [Dubey, Uma S.] Birla Inst Technol & Sci Pilani, Dept Biol Sci, Pilani, Rajasthan, India. RP Salotra, P (reprint author), Natl Inst Pathol ICMR, Safdarjung Hosp Campus, New Delhi, India. EM salotra@vsnl.com FU Department of Biotechnology (DBT), Government of India; Council for Scientific and Industrial Research (CSIR); Indian Council of Medical Research (ICMR), India FX This work was funded by grants from Department of Biotechnology (DBT), Government of India. K.A. and H.K. are grateful to the Council for Scientific and Industrial Research (CSIR) and the Indian Council of Medical Research (ICMR), India, for fellowships. We are thankful to T.A. Nagarajuna and Dr. Vinay Gupta of BD Academy, Jamia Hamdard, India for helpful discussions. NR 54 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD SEP 14 PY 2016 VL 6 AR 33059 DI 10.1038/srep33059 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV7MA UT WOS:000383119000001 PM 27624408 ER PT J AU Sturdivant, NM Smith, SG Ali, SF Wolchok, JC Balachandran, K AF Sturdivant, Nasya M. Smith, Sean G. Ali, Syed F. Wolchok, Jeffrey C. Balachandran, Kartik TI Acetazolamide Mitigates Astrocyte Cellular Edema Following Mild Traumatic Brain Injury SO SCIENTIFIC REPORTS LA English DT Article ID IN-VITRO; CEREBRAL EDEMA; VOLUME REGULATION; AQUAPORIN 4; TISSUE; MICE; CULTURES; STRAIN; PATHOPHYSIOLOGY; MECHANISMS AB Non-penetrating or mild traumatic brain injury (mTBI) is commonly experienced in accidents, the battlefield and in full-contact sports. Astrocyte cellular edema is one of the major factors that leads to high morbidity post-mTBI. Various studies have reported an upregulation of aquaporin-4 (AQP4), a water channel protein, following brain injury. AZA is an antiepileptic drug that has been shown to inhibit AQP4 expression and in this study we investigate the drug as a therapeutic to mitigate the extent of mTBI induced cellular edema. We hypothesized that mTBI-mediated astrocyte dysfunction, initiated by increased intracellular volume, could be reduced when treated with AZA. We tested our hypothesis in a three-dimensional in vitro astrocyte model of mTBI. Samples were subject to no stretch (control) or one high-speed stretch (mTBI) injury. AQP4 expression was significantly increased 24 hours after mTBI. mTBI resulted in a significant increase in the cell swelling within 30 min of mTBI, which was significantly reduced in the presence of AZA. Cell death and expression of S100B was significantly reduced when AZA was added shortly before mTBI stretch. Overall, our data point to occurrence of astrocyte swelling immediately following mTBI, and AZA as a promising treatment to mitigate downstream cellular mortality. C1 [Sturdivant, Nasya M.; Smith, Sean G.; Wolchok, Jeffrey C.; Balachandran, Kartik] Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA. [Ali, Syed F.] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Balachandran, K (reprint author), Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA. EM kbalacha@uark.edu FU National Science Foundation [CMMI-1404716]; NSF Graduate Research Fellowship [DGE-1450079] FX This work was supported by the National Science Foundation under grant no. CMMI-1404716 and by the NSF Graduate Research Fellowship Program under grant no. DGE-1450079. We would like to acknowledge Dr. Timothy Muldoon for the use of the multiphoton microscope in his laboratory. We also acknowledge Addison Walker for his assistance with the neonatal rat astrocyte harvest. NR 61 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD SEP 14 PY 2016 VL 6 AR 33330 DI 10.1038/srep33330 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV8QE UT WOS:000383200700001 PM 27623738 ER PT J AU Konduru, K Shurtleff, AC Bradfute, SB Nakamura, S Bavari, S Kaplan, G AF Konduru, Krishnamurthy Shurtleff, Amy C. Bradfute, Steven B. Nakamura, Siham Bavari, Sina Kaplan, Gerardo TI Ebolavirus Glycoprotein Fc Fusion Protein Protects Guinea Pigs against Lethal Challenge SO PLOS ONE LA English DT Article ID RESPIRATORY-TRACT IMMUNIZATION; VESICULAR STOMATITIS-VIRUS; NONHUMAN-PRIMATES; HEMORRHAGIC-FEVER; FAMILY FILOVIRIDAE; VACCINE CANDIDATE; PARTICLES PROTECT; IMMUNE-RESPONSES; INFECTION; ANTIBODY AB Ebola virus (EBOV), a member of the Filoviridae that can cause severe hemorrhagic fever in humans and nonhuman primates, poses a significant threat to the public health. Currently, there are no licensed vaccines or therapeutics to prevent and treat EBOV infection. Several vaccines based on the EBOV glycoprotein (GP) are under development, including vectored, virus-like particles, and protein-based subunit vaccines. We previously demonstrated that a subunit vaccine containing the extracellular domain of the Ebola ebolavirus (EBOV) GP fused to the Fc fragment of human IgG1 (EBOVgp-Fc) protected mice against EBOV lethal challenge. Here, we show that the EBOVgp-Fc vaccine formulated with QS-21, alum, or polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose (poly-ICLC) adjuvants induced strong humoral immune responses in guinea pigs. The vaccinated animals developed anti-GP total antibody titers of approximately 10(5)-10(6) and neutralizing antibody titers of approximately 103 as assessed by a BSL-2 neutralization assay based on vesicular stomatitis virus (VSV) pseudotypes. The poly-ICLC formulated EBOVgp-Fc vaccine protected all the guinea pigs against EBOV lethal challenge performed under BSL-4 conditions whereas the same vaccine formulated with QS-21 or alum only induced partial protection. Vaccination with a mucin-deleted EBOVgp-Fc construct formulated with QS-21 adjuvant did not have a significant effect in anti-GP antibody levels and protection against EBOV lethal challenge compared to the full-length GP construct. The bulk of the humoral response induced by the EBOVgp-Fc vaccine was directed against epitopes outside the EBOV mucin region. Our findings indicate that different adjuvants can eliciting varying levels of protection against lethal EBOV challenge in guinea pigs vaccinated with EBOVgp-Fc, and suggest that levels of total anti-GP antibodies elicit by protein-based GP subunit vaccines do not correlate with protection. Our data further support the development of Fc fusions of GP as a candidate vaccine for human use. C1 [Konduru, Krishnamurthy; Nakamura, Siham; Kaplan, Gerardo] Food & Drug Adm, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Shurtleff, Amy C.; Bradfute, Steven B.; Bavari, Sina] US Army, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Bradfute, Steven B.] Univ New Mexico, Albuquerque, NM 87131 USA. RP Konduru, K (reprint author), Food & Drug Adm, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM krishnamurthy.konduru@fda.hhs.gov FU CBER/FDA from National Institutes of Allergy and Infectious Disease (NIH) [IAA Y1-AI-0664-01]; Defense Threat Reduction Agency (DTRA) [IAA 11005IA-3333-Basic]; FDA; USAMRIID; FDA-U.S. Department of Energy FX This work was supported by Interagency Agreements (IAAs) with CBER/FDA (GK) from the National Institutes of Allergy and Infectious Disease (NIH IAA Y1-AI-0664-01) and the Defense Threat Reduction Agency (DTRA IAA 11005IA-3333-Basic) and intramural funds from FDA (GK) and USAMRIID (SB). SN was supported by an appointment to a Research Participation Program administered by the Oak Ridge Institute for Science and Education through a FDA-U.S. Department of Energy interagency agreement. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 0 Z9 0 U1 5 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 13 PY 2016 VL 11 IS 9 AR e0162446 DI 10.1371/journal.pone.0162446 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DW5JR UT WOS:000383681000032 PM 27622456 ER PT J AU Coutte, L Huot, L Antoine, R Slupek, S Merkel, TJ Chen, Q Stibitz, S Hot, D Locht, C AF Coutte, Loic Huot, Ludovic Antoine, Rudy Slupek, Stephanie Merkel, Tod J. Chen, Qing Stibitz, Scott Hot, David Locht, Camille TI The multifaceted RisA regulon of Bordetella pertussis SO SCIENTIFIC REPORTS LA English DT Article ID BVG-REPRESSED GENES; CYCLIC-DI-GMP; FILAMENTOUS HEMAGGLUTININ; IRON STARVATION; SUICIDE VECTORS; IN-VIVO; BRONCHISEPTICA; EXPRESSION; LOCUS; REPLACEMENT AB The whooping cough agent Bordetella pertussis regulates the production of its virulence factors by the BvgA/S system. Phosphorylated BvgA activates the virulence-activated genes (vags) and represses the expression of the virulence-repressed genes (vrgs) via the activation of the bvgR gene. In modulating conditions, with MgSO4, the BvgA/S system is inactive, and the vrgs are expressed. Here, we show that the expression of almost all vrgs depends on RisA, another transcriptional regulator. We also show that some vags are surprisingly no longer modulated by MgSO4 in the risA-background. RisA also regulates the expression of other genes, including chemotaxis and flagellar operons, iron-regulated genes, and genes of unknown function, which may or may not be controlled by BvgA/S. We identified RisK as the likely cognate RisA kinase and found that it is important for expression of most, but not all RisA-regulated genes. This was confirmed using the phosphoablative RisAD(60)N and the phosphomimetic RisAD(60)E analogues. Thus the RisA regulon adds a new layer of complexity to B. pertussis virulence gene regulation. C1 [Coutte, Loic; Huot, Ludovic; Antoine, Rudy; Slupek, Stephanie; Hot, David; Locht, Camille] Inst Pasteur, Ctr Infect & Immun Lille, Lille, France. [Coutte, Loic; Huot, Ludovic; Antoine, Rudy; Slupek, Stephanie; Hot, David; Locht, Camille] Univ Lille, Lille, France. [Coutte, Loic; Huot, Ludovic; Antoine, Rudy; Slupek, Stephanie; Hot, David; Locht, Camille] CNRS, UMR 8204, Lille, France. [Coutte, Loic; Huot, Ludovic; Antoine, Rudy; Slupek, Stephanie; Locht, Camille] INSERM, U1019, Lille, France. [Merkel, Tod J.; Chen, Qing; Stibitz, Scott] FDA, Ctr Biol Evaluat & Res, Div Bacterial Parasit & Allergen Prod, Silver Spring, MD USA. RP Coutte, L (reprint author), Inst Pasteur, Ctr Infect & Immun Lille, Lille, France.; Coutte, L (reprint author), Univ Lille, Lille, France.; Coutte, L (reprint author), CNRS, UMR 8204, Lille, France.; Coutte, L (reprint author), INSERM, U1019, Lille, France. EM loic.coutte@inserm.fr NR 32 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD SEP 13 PY 2016 VL 6 AR 32774 DI 10.1038/srep32774 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV4WJ UT WOS:000382925800001 PM 27620673 ER PT J AU Teng, J Yuan, F Ye, YW Zheng, L Yao, L Xue, F Chen, W Li, BG AF Teng, Jun Yuan, Fang Ye, Yingwang Zheng, Lei Yao, Li Xue, Feng Chen, Wei Li, Baoguang TI Aptamer-Based Technologies in Foodborne Pathogen Detection SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE aptamers; SELEX; ligands; aptamer-based biosensors; bacterial pathogen detection; dissociation constants; biomolecular screening; high affinity ID IN-VITRO SELECTION; ENHANCED RAMAN-SPECTROSCOPY; ESCHERICHIA-COLI; EXPONENTIAL ENRICHMENT; LISTERIA-MONOCYTOGENES; RAPID DETECTION; DNA APTAMERS; LEGIONELLA-PNEUMOPHILA; STAPHYLOCOCCUS-AUREUS; SYSTEMATIC EVOLUTION AB Aptamers are single stranded DNA or RNA ligands, which can be selected by a method called systematic evolution of ligands by exponential enrichment (SELEX); and they can specifically recognize and bind to their targets. These unique characteristics of aptamers offer great potentials in applications such as pathogen detection and biomolecular screening. Pathogen detection is the critical means in detecting and identifying the problems related to public health and food safety; and only the rapid, sensitive and efficient detection technologies can enable the users to make the accurate assessments on the risks of infections (humans and animals) or contaminations (foods and other commodities) caused by various pathogens. This article reviews the development in the field of the aptamer-based approaches for pathogen detection, including whole-cell SELEX and Genomic SELEX. Nowadays, a variety of aptamer-based biosensors have been developed for pathogen detection. Thus, in this review, we also cover the development in aptamer-based biosensors including optical biosensors for multiple pathogen detection by multiple-labeling or label-free models such as fluorescence detection and surface plasmon resonance, electrochemical biosensors and lateral chromatography test strips, and their applications in pathogen detection and biomolecular screening. While notable progress has been made in the field in the last decade, challenges or drawbacks in their applications such as pathogen detection and biomolecular screening remain to be overcome. C1 [Teng, Jun; Ye, Yingwang; Zheng, Lei; Yao, Li; Chen, Wei] Hefei Univ Technol, Coll Food Sci & Engn, Hefei, Peoples R China. [Yuan, Fang; Xue, Feng] Jiangsu Entry Exit Inspect & Quarantine Bur, Anim Quarantine Lab, Nanjing, Jiangsu, Peoples R China. [Li, Baoguang] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD USA. RP Chen, W (reprint author), Hefei Univ Technol, Coll Food Sci & Engn, Hefei, Peoples R China.; Xue, F (reprint author), Jiangsu Entry Exit Inspect & Quarantine Bur, Anim Quarantine Lab, Nanjing, Jiangsu, Peoples R China. EM fengxue1219@aliyun.com; chenweishnu@163.com RI Chen, Wei /F-4557-2010 OI Chen, Wei /0000-0003-3763-1183 FU NSFC grant [21475030, 31301460]; S&T Research Project of Anhui Province [15czz03109]; National 10000 Talents-Youth Topnotch Talent Program; National and Zhejiang Public Benefit Research Project [201313010, 2014C32051] FX This work is financially supported by the NSFC grant of 21475030, 31301460, the S&T Research Project of Anhui Province 15czz03109, the National 10000 Talents-Youth Topnotch Talent Program, the National and Zhejiang Public Benefit Research Project (201313010, 2014C32051). NR 69 TC 0 Z9 1 U1 72 U2 72 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 SEP 12 PY 2016 VL 7 AR 1426 DI 10.3389/fmicb.2016.01426 PG 11 WC Microbiology SC Microbiology GA DV3LG UT WOS:000382822900001 PM 27672383 ER PT J AU Holbrook, K Subramanian, C Chotewutmontri, P Reddick, LE Wright, S Zhang, HX Moncrief, L Bruce, BD AF Holbrook, Kristen Subramanian, Chitra Chotewutmontri, Prakitchai Reddick, L. Evan Wright, Sarah Zhang, Huixia Moncrief, Lily Bruce, Barry D. TI Functional Analysis of Semi-conserved Transit Peptide Motifs and Mechanistic Implications in Precursor Targeting and Recognition SO MOLECULAR PLANT LA English DT Article DE chloroplast biology; protein translocation; Toc34; transit peptide; cell biology ID MULTIPLE SEQUENCE ALIGNMENT; CHLOROPLAST PROTEIN IMPORT; ENVELOPE CONTACT SITES; ACCUMULATION IN-VIVO; SMALL-SUBUNIT; CHLAMYDOMONAS-REINHARDTII; FERREDOXIN PRECURSOR; OUTER ENVELOPE; RIBULOSE-1,5-BISPHOSPHATE CARBOXYLASE; PHYSCOMITRELLA-PATENS AB Over 95% of plastid proteins are nuclear-encoded as their precursors containing an N-terminal extension known as the transit peptide (TP). Although highly variable, TPs direct the precursors through a conserved, posttranslational mechanism involving translocons in the outer (TOC) and inner envelope (TOC). The organelle import specificity is mediated by one or more components of the Toc complex. However, the high TP diversity creates a paradox on how the sequences can be specifically recognized. An emerging model of TP design is that they contain multiple loosely conserved motifs that are recognized at different steps in the targeting and transport process. Bioinformatics has demonstrated that many TPs contain semi-conserved physicochemical motifs, termed FGLK. In order to characterize FGLK motifs in TP recognition and import, we have analyzed two well-studied TPs from the precursor of RuBisCO small subunit (SStp) and ferredoxin (Fdtp). Both SStp and Fdtp contain two FGLK motifs. Analysis of large set mutations (similar to 85) in these two motifs using in vitro, in organello, and in vivo approaches support a model in which the FGLK domains mediate interaction with TOC34 and possibly other TOC components. In vivo import analysis suggests that multiple FGLK motifs are functionally redundant. Furthermore, we discuss how FGLK motifs are required for efficient precursor protein import and how these elements may permit a convergent function of this highly variable class of targeting sequences. C1 [Holbrook, Kristen; Reddick, L. Evan; Zhang, Huixia; Moncrief, Lily; Bruce, Barry D.] Univ Tennessee, Dept Biochem Cellular & Mol Biol, Knoxville, TN 37996 USA. [Subramanian, Chitra; Bruce, Barry D.] Univ Tennessee, Grad Program Plant Physiol & Genet, Knoxville, TN 37996 USA. [Chotewutmontri, Prakitchai; Bruce, Barry D.] Univ Tennessee, Grad Sch Genome Sci & Technol, Knoxville, TN 37996 USA. [Wright, Sarah] Univ Tennessee, Dept Bot, Knoxville, TN 37996 USA. [Subramanian, Chitra] St Jude Childrens Res Hosp, Dept Infect Dis, 332 N Lauderdale St, Memphis, TN 38105 USA. [Chotewutmontri, Prakitchai] Univ Oregon, Inst Mol Biol, Eugene, OR 97403 USA. [Reddick, L. Evan] Univ Texas Southwestern Med Ctr Dallas, Dept Microbiol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Wright, Sarah] Cornell Univ, Albert R Mann Lib, Ithaca, NY 14850 USA. [Zhang, Huixia] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Bruce, BD (reprint author), Univ Tennessee, Dept Biochem Cellular & Mol Biol, Knoxville, TN 37996 USA.; Bruce, BD (reprint author), Univ Tennessee, Grad Program Plant Physiol & Genet, Knoxville, TN 37996 USA.; Bruce, BD (reprint author), Univ Tennessee, Grad Sch Genome Sci & Technol, Knoxville, TN 37996 USA. EM bbruce@utk.edu OI Holbrook, Kristen/0000-0001-6923-3580 FU National Science Foundation Program in Cell Biology [MCB-0628670, MCB-0344601]; TN-SCORE, a multi-disciplinary research program - NSF-EPSCOR [EPS-100408] FX This work was supported in part by the National Science Foundation Program in Cell Biology (MCB-0628670 and MCB-0344601) to B.D.B. and from TN-SCORE, a multi-disciplinary research program sponsored by NSF-EPSCOR (EPS-100408) to B.D.B. NR 78 TC 1 Z9 1 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1674-2052 EI 1752-9867 J9 MOL PLANT JI Mol. Plant. PD SEP 6 PY 2016 VL 9 IS 9 BP 1286 EP 1301 DI 10.1016/j.molp.2016.06.004 PG 16 WC Biochemistry & Molecular Biology; Plant Sciences SC Biochemistry & Molecular Biology; Plant Sciences GA EA4LZ UT WOS:000386585500005 PM 27378725 ER PT J AU Zenarruzabeitia, O Vitalle, J Garcia-Obregon, S Astigarraga, I Eguizabal, C Santos, S Simhadri, VR Borrego, F AF Zenarruzabeitia, Olatz Vitalle, Joana Garcia-Obregon, Susana Astigarraga, Itziar Eguizabal, Cristina Santos, Silvia Simhadri, Venkateswara R. Borrego, Francisco TI The expression and function of human CD300 receptors on blood circulating mononuclear cells are distinct in neonates and adults SO SCIENTIFIC REPORTS LA English DT Article ID NATURAL-KILLER-CELLS; ACUTE LYMPHOBLASTIC-LEUKEMIA; DENDRITIC CELLS; CORD BLOOD; INHIBITORY RECEPTOR; IMMUNE-RESPONSES; LIGAND RECOGNITION; INNATE IMMUNITY; HUMAN MONOCYTES; PHOSPHATIDYLSERINE AB Neonates are more susceptible to infections than adults. This susceptibility is thought to reflect neonates' qualitative and quantitative defects in the adaptive and innate immune responses. Differential expression of cell surface receptors may result in altered thresholds of neonatal immune cell activation. We determined whether the expression and function of the lipid-binding CD300 family of receptors are different on neonatal immune cells compared to adult immune cells. A multiparametric flow cytometry analysis was performed to determine the expression of CD300 receptors on adult peripheral blood mononuclear cells and neonatal cord blood mononuclear cells. The expression of the CD300a inhibitory receptor was significantly reduced on cells from the newborn adaptive immune system, and neonatal antigen presenting cells exhibited a different CD300 receptors expression pattern. We also found differential LPS-mediated regulation of CD300 receptors expression on adult monocytes compared to cord blood monocytes, and that CD300c and CD300e-mediated activation was quantitatively different in neonatal monocytes. This is the first complete study examining the expression of CD300 receptors on human neonatal immune cells compared with adult immune cells. Significant differences in the expression and function of CD300 receptors may help to explain the peculiarities and distinctness of the neonatal immune responses. C1 [Zenarruzabeitia, Olatz; Vitalle, Joana; Borrego, Francisco] BioCruces Hlth Res Inst, Immunopathol Grp, Baracaldo, Spain. [Garcia-Obregon, Susana; Astigarraga, Itziar] BioCruces Hlth Res Inst, Pediat Oncol Grp, Baracaldo, Spain. [Astigarraga, Itziar] Cruces Univ Hosp, Pediat Serv, Baracaldo, Spain. [Astigarraga, Itziar] Univ Basque Country, Fac Med & Dent, Dept Pediat, Leioa, Spain. [Eguizabal, Cristina; Santos, Silvia] Basque Ctr Transfus & Human Tissues, Cell Therapy & Stem Cell Grp, Galdakao, Spain. [Simhadri, Venkateswara R.] US FDA, Div Biotechnol Review & Res 1, Off Biotechnol Prod Review & Res, CDER, Rockville, MD 20857 USA. [Borrego, Francisco] Basque Fdn Sci, Ikerbasque, Bilbao, Spain. RP Borrego, F (reprint author), BioCruces Hlth Res Inst, Immunopathol Grp, Baracaldo, Spain.; Borrego, F (reprint author), Basque Fdn Sci, Ikerbasque, Bilbao, Spain. EM francisco.borregorabasco@osakidetza.eus FU Plan Estatal de I+D+I, ISCIII-Subdireccion de Evaluacion y Fomento de la Investigacion-Fondo Europeo de Desarrollo Regional (FEDER) [PI13/00889]; Marie Curie Actions, Career Integration Grant, European Commission [CIG 631674]; SAIOTEK, Departamento de Desarrollo Economico y Competitividad, Gobierno Vasco [SAIO13-PE13BF005] FX We thank the Basque Biobank for the samples collection, and the donors and personnel from the Basque Center for Transfusion and Human Tissues and from the Basurto Hospital. This work was supported by grants from "Plan Estatal de I+D+I 2013-2016, ISCIII-Subdireccion de Evaluacion y Fomento de la Investigacion-Fondo Europeo de Desarrollo Regional (FEDER) (PI13/00889); Marie Curie Actions, Career Integration Grant, European Commission (CIG 631674); and SAIOTEK, Departamento de Desarrollo Economico y Competitividad, Gobierno Vasco (SAIO13-PE13BF005)". NR 61 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD SEP 6 PY 2016 VL 6 AR 32693 DI 10.1038/srep32693 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU8QU UT WOS:000382479600001 PM 27595670 ER PT J AU Kern, SE Lorenz, LM Lanzarotta, A Nickum, EA Litzau, JJ AF Kern, Sara E. Lorenz, Lisa M. Lanzarotta, Adam Nickum, Elisa A. Litzau, Jonathan J. TI Isolation and structural characterization of a new tadalafil analog (chloropropanoylpretadalafil) found in a dietary supplement SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Phosphodiesterase type-5 (PDE-5); inhibitors; New tadalafil analog; LC-HRAM-MS; GC/FT-IR/MS ID SYNTHETIC PHOSPHODIESTERASE-5 INHIBITORS; PERFORMANCE LIQUID-CHROMATOGRAPHY; MASS-SPECTROMETRY; PDE-5 INHIBITORS; STRUCTURE ELUCIDATION; COUNTERFEIT PRODUCTS; ERECTILE DYSFUNCTION; IDENTIFICATION; SILDENAFIL; ADULTERANT AB A screen for known PDE-5 inhibitors in a dietary supplement product marketed for "enhanced sexual performance" detected a compound that structurally resembled chloropretadalafil, a known analog of 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 gas chromatography with Fourier Transform infrared detection and mass spectral detection (GC/FT-IR/MS), as well as high resolution mass spectrometry (HRMS). The analog had an accurate mass of m/z 441.1216 (error is 0.8706 ppm) for the protonated species [M+H](+), corresponding to a molecular formula of C23H22ClN2O5. HRAM and GC/FT-IR/MS mass spectral fragmentation data suggested that the modification is a chloropropanoyl moiety extending from the nitrogen on the piperidine ring of chloropretadalafil. The proposed new analog has been named chloropropanoylpretadalafil. Published by Elsevier B.V. C1 [Kern, Sara E.; Lorenz, Lisa M.; Lanzarotta, Adam; Nickum, Elisa A.; Litzau, Jonathan J.] US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. RP Kern, SE (reprint author), US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. EM sara.kern@fda.hhs.gov NR 33 TC 1 Z9 1 U1 4 U2 4 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 SEP 5 PY 2016 VL 128 BP 360 EP 366 DI 10.1016/j.jpba.2016.05.038 PG 7 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DT6KA UT WOS:000381591900043 PM 27337189 ER PT J AU Chen, K Long, DS Lute, SC Levy, MJ Brorson, KA Keire, DA AF Chen, Kang Long, Dianna S. Lute, Scott C. Levy, Michaella J. Brorson, Kurt A. Keire, David A. TI Simple NMR methods for evaluating higher order structures of monoclonal antibody therapeutics with quinary structure SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Dilution-injection; SEC-FPLC; in-situ; Digestion; PCA ID PROTEIN THERAPEUTICS; CIRCULAR-DICHROISM; HETERONUCLEAR NMR; NATURAL-ABUNDANCE; SPECTROSCOPY; PRODUCTS; COMPARABILITY; BIOSIMILARS; MS; INFLIXIMAB AB Monoclonal antibody (mAb) drugs constitute the largest class of protein therapeutics currently on the market. Correctly folded protein higher order structure (HOS), including quinary structure, is crucial for mAb drug quality. The quinary structure is defined as the association of quaternary structures (e.g., oligomerized mAb). Here, several commonly available analytical methods, i.e., size-exclusion chromatography (SEC) FPLC, multi-angle light scattering (MALS), circular dichroism (CD), NMR and multivariate analysis, were combined and modified to yield a complete profile of HOS and comparable metrics. Rituximab and infliximab were chosen for method evaluation because both IgG1 molecules are known to be homologous in sequence, superimposable in Fab crystal structure and identical in Fc structure. However, herein the two are identified to be significantly different in quinary structure in addition to minor secondary structure differences. All data collectively showed rituximab was mostly monomeric while infliximab was in mono-oligomer equilibrium driven by its Fab fragment. The quinary structure differences were qualitatively inferred from the less used but more reproducible dilution-injection-SEC-FPLC curve method. Quantitative principal component analysis (PCA) was performed on NMR spectra of either the intact or the in-situ enzymatic-digested mAb samples. The cleavage reactions happened directly in NMR tubes without further separation, which greatly enhanced NMR spectra quality and resulted in larger inter- and intra-lot variations based on PCA. The new in-situ enzymatic digestion method holds potential in identifying structural differences on larger therapeutic molecules using NMR. Published by Elsevier B.V. C1 [Chen, Kang] US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Qual, Div Pharmaceut Anal,Off Testing & Res, Silver Spring, MD 20993 USA. [Long, Dianna S.; Levy, Michaella J.; Keire, David A.] US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Qual, Div Pharmaceut Anal,Off Testing & Res, St Louis, MO 63110 USA. [Lute, Scott C.; Brorson, Kurt A.] US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Qual, Off Biotechnol Prod,Div 2, Silver Spring, MD 20993 USA. RP Chen, K (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Qual, Div Pharmaceut Anal,Off Testing & Res, Silver Spring, MD 20993 USA. EM kang.chen@fda.hhs.gov FU US FDA Critical Path FX We thank Gregory Petsko for discussing with us the concept of quinary structure, Nico Tjandra for allowing access to the NIH/NHLBI 600 MHz NMR spectrometer and Zhaohua (Joe) Zhou (CDER/OBP) for helpful discussions. Support for this work from the US FDA Critical Path funding is gratefully acknowledged. NR 43 TC 1 Z9 1 U1 10 U2 12 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 SEP 5 PY 2016 VL 128 BP 398 EP 407 DI 10.1016/j.jpba.2016.06.007 PG 10 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DT6KA UT WOS:000381591900048 PM 27344629 ER PT J AU Bryan, W AF Bryan, Wilson TI The state of gene therapies SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Bryan, Wilson] US FDA, Off Cellular Tissue & Gene Therapies, Silver Spring, MD USA. [Bryan, Wilson] CBER, Off Cellular Tissue & Gene Therapies, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2016 VL 57 IS 12 PG 1 WC Ophthalmology SC Ophthalmology GA EK8YM UT WOS:000394210604124 ER PT J AU Cohen, ED Neufeld, E Montanaro, H Iacono, MI Angelone, LM Kainz, W AF Cohen, Ethan D. Neufeld, Esra Montanaro, Hazael Iacono, Maria I. Angelone, Leonardo M. Kainz, Wolfgang TI Development of an alpha retinal ganglion cell model for epiretinal electrode stimulation SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Cohen, Ethan D.; Iacono, Maria I.; Angelone, Leonardo M.; Kainz, Wolfgang] US FDA, Div Biomed Phys, Off Sci & Eng Labs, Ctr Dev & Rad Hlth, Silver Spring, MD USA. [Neufeld, Esra; Montanaro, Hazael] ITIS Res Fdn, Computat Life Sci, Zurich, Switzerland. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2016 VL 57 IS 12 MA 3716 PG 3 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210203100 ER PT J AU Matter, B Ghaffari, A Bourne, D Wang, Y Choi, S Kompella, UB AF Matter, Brock Ghaffari, Alireza Bourne, David Wang, Yan Choi, Stephanie Kompella, Uday B. TI Dexamethasone Degradation During In Vitro Release from an Intravitreal Implant SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 01-05, 2016 CL Seattle, WA SP Assoc Res Vis & Ophthalmol C1 [Matter, Brock; Ghaffari, Alireza; Bourne, David; Kompella, Uday B.] Univ Colorado, Pharmaceut Sci, Aurora, CO USA. [Wang, Yan; Choi, Stephanie] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. FU FDA [1U01FD004929] FX Support FDA Grant 1U01FD004929 NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2016 VL 57 IS 12 MA 4010 PG 2 WC Ophthalmology SC Ophthalmology GA EK8YI UT WOS:000394210203287 ER PT J AU Persoskie, A Donaldson, EA King, BA AF Persoskie, Alexander Donaldson, Elisabeth A. King, Brian A. TI Ever-Use and Curiosity About Cigarettes, Cigars, Smokeless Tobacco, and Electronic Cigarettes Among US Middle and High School Students, 2012-2014 SO PREVENTING CHRONIC DISEASE LA English DT Article ID YOUNG-ADULTS; SMOKING INITIATION; UNITED-STATES; EXPOSURE; YOUTH; EXPERIMENTATION; SUSCEPTIBILITY; DISPARITIES; REASONS; HEALTH AB Introduction Among young people, curiosity about tobacco products is a primary reason for tobacco experimentation and is a risk factor for future use. We examined whether curiosity about and ever-use of tobacco products among US middle and high school students changed from 2012 to 2014. Methods Data came from the 2012 and 2014 National Youth Tobacco Surveys, nationally representative surveys of US students in grades 6 through 12. For cigarettes, cigars, smokeless tobacco, and e-cigarettes (2014 only), students were classified as ever-users or neverusers of each product. Among never-users, curiosity about using each product was assessed by asking participants if they had "definitely," "probably," "probably not," or "definitely not" been curious about using the product. Results From 2012 to 2014, there were declines in ever-use of cigarettes (26% to 22%; P=.005) and cigars (21% to 18%; P =.003) overall and among students who were Hispanic (cigarettes, P=.001; cigars, P=.001) or black (cigarettes, P =.004; cigars, P=.01). The proportion of never-users reporting they were " definitely not" curious increased for cigarettes (51% to 54%; P=.01) and cigars (60% to 63%; P=.03). Ever-use and curiosity about smokeless to bacco did not change significantly from 2012 to 2014. In 2014, the proportion of young people who were "definitely" or "probably" curious never-users of each product was as follows: cigarettes, 11.4%; e-cigarettes, 10.8%; cigars, 10.3%; and smokeless tobacco, 4.4%. Conclusion The proportion of US students who are never users and are not curious about cigarettes and cigars increased. However, many young people remain curious about tobacco products, including ecigarettes. Understanding factors driving curiosity can inform tobacco use prevention for youth. C1 [Persoskie, Alexander] Bldg 71,Room G335,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Donaldson, Elisabeth A.] US FDA, Off Sci, Ctr Tobacco Prod, Silver Spring, MD USA. [King, Brian A.] Ctr Dis Control & Prevent, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. RP Persoskie, A (reprint author), Bldg 71,Room G335,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM alexander.persoskie@fda.hhs.gov FU Food and Drug Administration's Center for Tobacco Products FX Publication of this article was supported by the Food and Drug Administration's Center for Tobacco Products. NR 36 TC 1 Z9 1 U1 2 U2 2 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD SEP PY 2016 VL 13 AR 160151 DI 10.5888/pcd13.160151 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ3JN UT WOS:000393108500018 ER PT J AU Weimer, BC Storey, DB Elkins, CA Baker, RC Markwell, P Chambliss, DD Edlund, SB Kaufman, JH AF Weimer, B. C. Storey, D. B. Elkins, C. A. Baker, R. C. Markwell, P. Chambliss, D. D. Edlund, S. B. Kaufman, J. H. TI Defining the food microbiome for authentication, safety, and process management SO IBM JOURNAL OF RESEARCH AND DEVELOPMENT LA English DT Article ID ESCHERICHIA-COLI O104/H4; GENOMIC EPIDEMIOLOGY; LACTOCOCCUS-LACTIS; BACTERIA; METATRANSCRIPTOME; IDENTIFICATION; FERMENTATIONS; METAGENOMICS; CONSUMPTION; PROBIOTICS AB Under intense scrutiny for safety and authenticity, our food supply encompasses probiotic supplementation, fermentation organisms, pathogenic bacteria, and microbial toxins-in short, the microbiome and metabolome of food. Recent claims regarding probiotic supplements, additives, and cultured foods highlight the need for widely accepted protocols for evidence-based oversight of such products, as well as specific methods to assess their safety and authenticity. Rapid improvements in high-throughput sequencing technologies, curated and annotated reference databases of whole genome sequences, bacterial strain banks, and novel informatics techniques coupled to a scalable computing platform are poised to provide a robust solution extendable to encompass systematic authentication of the microbiome and its variations up and down the supply chain. Members of the Sequence the Food Supply Chain Consortium are working to characterize and quantify the microbiome at a baseline and after processing. They are also working to create reference databases and develop a Metagenomics Computation and Analytics Workbench, capable of verifying the effectiveness of good manufacturing practices and monitoring control measures highlighted in a site's Hazard Analysis Critical Control Point plan. In this paper, we propose how microbial ecology, evolvability, and phylogenetic diversity exhort the application of new molecular techniques to assure safety, authenticity, and traceability for wholesome food. C1 [Weimer, B. C.; Storey, D. B.] Univ Calif Davis, Davis Sch Vet Med, Davis, CA 95616 USA. [Elkins, C. A.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Baker, R. C.] Mars Inc, Mars Global Food Safety Ctr, Mclean, VA 22101 USA. [Markwell, P.] Mars Inc, Food Safety Sci, Mclean, VA 22101 USA. [Chambliss, D. D.; Edlund, S. B.; Kaufman, J. H.] IBM Res, Almaden Res Ctr, San Jose, CA 95120 USA. RP Weimer, BC (reprint author), Univ Calif Davis, Davis Sch Vet Med, Davis, CA 95616 USA. EM bcweimer@ucdavis.edu; dylan.storey@gmail.com; chris.elkins@fda.hhs.gov; robert.c.baker@effem.com; peter.markwell@effem.com; chamb@us.ibm.com; sedlund@us.ibm.com; jhkauf@us.ibm.com NR 55 TC 0 Z9 0 U1 1 U2 1 PU IBM CORP PI ARMONK PA 1 NEW ORCHARD ROAD, ARMONK, NY 10504 USA SN 0018-8646 EI 2151-8556 J9 IBM J RES DEV JI IBM J. Res. Dev. PD SEP-NOV PY 2016 VL 60 IS 5-6 AR 1 DI 10.1147/JRD.2016.2582598 PG 13 WC Computer Science, Hardware & Architecture; Computer Science, Information Systems; Computer Science, Software Engineering; Computer Science, Theory & Methods SC Computer Science GA EJ2KW UT WOS:000393039900002 ER PT J AU Colatsky, T Fermini, B Gintant, G Pierson, JB Sager, P Sekino, Y Strauss, DG Stockbridge, N AF Colatsky, Thomas Fermini, Bernard Gintant, Gary Pierson, Jennifer B. Sager, Philip Sekino, Yuko Strauss, David G. Stockbridge, Norman TI The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative Update on progress SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Article DE CiPA; Proarrhythmia; In silico model; Ion channel; Myocyte ID CELL-DERIVED CARDIOMYOCYTES; CARDIAC RISK-ASSESSMENT; DRUG SAFETY ASSESSMENT; LATE SODIUM CURRENT; MULTIELECTRODE ARRAY; QT PROLONGATION; BLOCK; REPOLARIZATION; INHIBITION; AFTERDEPOLARIZATIONS AB The implementation of the ICH S7B and E14 guidelines has been successful in preventing the introduction of potentially torsadogenic drugs to the market, but it has also unduly constrained drug development by focusing on hERG block and QT prolongation as essential determinants of proarrhythmia risk. The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative was established to develop a new paradigm for assessing proarrhythmic risk, building on the emergence of new technologies and an expanded understanding of torsadogenic mechanisms beyond hERG block. An international multi-disciplinary team of regulatory, industry and academic scientists are working together to develop and validate a set of predominantly nonclinical assays and methods that eliminate the need for the thorough-QT study and enable a more precise prediction of clinical proarrhythmia risk. The CiPA effort is led by a Steering Team that provides guidance, expertise and oversight to the various working groups and includes partners from US FDA, HESI, CSRC, SPS, EMA, Health Canada, Japan NIHS, and PMDA. The working groups address the three pillars of CiPA that evaluate drug effects on: 1) human ventricular ionic channel currents in heterologous expression systems, 2) in silico integration of cellular electrophysiologic effects based on ionic current effects, the ion channel effects, and 3) fully integrated biological systems (stem-cell-derived cardiac myocytes and the human ECG). This article provides an update on the progress of the initiative towards its target date of December 2017 for completing validation. (C) 2016 The Authors. Published by Elsevier Inc. C1 [Colatsky, Thomas; Strauss, David G.; Stockbridge, Norman] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Fermini, Bernard] Pfizer, Eastern Point Rd MS 4083, Groton, CT 06340 USA. [Gintant, Gary] AbbVie, R46R AP 9,1 North Waukegan Rd, N Chicago, IL 60064 USA. [Pierson, Jennifer B.] ILSI Hlth & Environm Sci Inst, 1156 15th St NW,Suite 200, Washington, DC 20005 USA. [Sager, Philip] Stanford Univ, 719 Carolina St, San Francisco, CA 94107 USA. [Sekino, Yuko] NIHS Japan, Setagaya Ku, Kamiyoga 1-18-1, Tokyo 1588501, Japan. RP Pierson, JB (reprint author), ILSI Hlth & Environm Sci Inst, 1156 15th St NW,Suite 200, Washington, DC 20005 USA. EM Thomas.Colatsky@fda.hhs.gov; Bernard.Fermini@pfizer.com; Gary.Gintant@abbvie.com; jpierson@hesiglobal.org; psager@stanford.edu; yukos@nihs.go.jp; David.Strauss@fda.hhs.gov; Norman.Stockbridge@fda.hhs.gov NR 40 TC 8 Z9 8 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD SEP-OCT PY 2016 VL 81 BP 15 EP 20 DI 10.1016/j.vascn.2016.06.002 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE3YB UT WOS:000389537100003 PM 27282641 ER PT J AU Authier, S Arezzo, J Delatte, MS Kallman, MJ Markgraf, C Paquette, D Pugsley, MK Ratcliffe, S Redfern, WS Stevens, J Valentin, JP Vargas, HM Curtis, MJ AF Authier, Simon Arezzo, Joseph Delatte, Marcus S. Kallman, Mary-Jeanne Markgraf, Carrie Paquette, Dominique Pugsley, Michael K. Ratcliffe, Sian Redfern, William S. Stevens, Joanne Valentin, Jean-Pierre Vargas, Hugo M. Curtis, Michael J. TI Safety pharmacology investigations on the nervous system: An industry survey SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Article DE Safety pharmacology; EEG; Seizure; Sleep; Neurological functional observation battery; Abuse ID ABUSE LIABILITY ASSESSMENT; INDUCED PERIPHERAL NEUROPATHY; STATUS EPILEPTICUS; NONHUMAN-PRIMATES; ATTRITION RATES; DRUGS; CHEMOTHERAPY; PACLITAXEL; RISK; HYPERTENSION AB The Safety Pharmacology Society (SPS) conducted an industry survey in 2015 to identify industry practices as they relate to central, peripheral and autonomic nervous system ('CNS') drug safety testing. One hundred fifty-eight (158) participants from Asia (16%), Europe (20%) and North America (56%) responded to the survey. 52% of participants were from pharmaceutical companies (>1000 employees). Oncology (67%) and neurology/psychiatry (66%) were the most frequent target indications pursued by companies followed by inflammation (48%), cardiovascular (43%), metabolic (39%), infectious (37%), orphan (32%) and respiratory (29%) diseases. Seizures (67% of participants), gait abnormalities (67%), tremors (65%), emesis (56%), sedation (52%) and salivation (47%) were themost commonly encountered CNS issues in pre-clinical drug developmentwhile headache (65%), emesis/nausea (60%), fatigue (51%) and dizziness (49%) were the most frequent issues encountered in Phase I clinical trials. 54% of respondents reported that a standard battery of tests applied to screen drug candidates was the approach most commonly used to address non-clinical CNS safety testing. A minority (14% of all participants) reported using electroencephalography (EEG) screening prior to animal inclusion on toxicology studies. Themost frequent group sizewas n=8 for functional observation battery (FOB), polysomnography and seizure liability studies. FOB evaluations were conducted in a dedicated room (78%) by blinded personnel (66%) with control for circadian cycle (55%) effects (e.g., dosing at a standardized time; balancing time of day across treatment groups). The rat was reported as the most common species used for seizure liability, nerve conduction and drug-abuse liability testing. (C) 2016 Elsevier Inc. All rights reserved. C1 [Authier, Simon; Paquette, Dominique] CiToxLAB North Amer, 445 Armand Frappier, Laval, PQ H7V 4B3, Canada. [Arezzo, Joseph] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10467 USA. [Delatte, Marcus S.] US FDA, DAAAP, CDER, Silver Spring, MD USA. [Kallman, Mary-Jeanne] Kallman Preclin Consulting, Greenfield, IN 46140 USA. [Markgraf, Carrie] Merck Res Labs, Discovery Sci Support, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA. [Pugsley, Michael K.] Purdue Pharma LP, Dept Toxicol, Cranbury, NJ 08512 USA. [Ratcliffe, Sian] Pfizer, Safety Pharmacol COE, Groton, CT 06340 USA. [Redfern, William S.] AstraZeneca, Drug Safety & Metab, 310 Cambridge Sci Pk, Cambridge CB4 0WG, England. [Stevens, Joanne] Merck Res Labs, Dept Pharmacol, West Point, PA 19486 USA. [Valentin, Jean-Pierre] UCB Biopharma, Nonclin Dev, Brussels, Belgium. [Vargas, Hugo M.] Amgen Inc, Integrated Discovery & Safety Pharmacol, Thousand Oaks, CA 91320 USA. [Curtis, Michael J.] Kings Coll London, St Thomas Hosp, Rayne Inst, Cardiovasc Div,Fac Life Sci & Med, London SE1 7EH, England. [Arezzo, Joseph] Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10467 USA. RP Authier, S (reprint author), CiToxLAB North Amer, 445 Armand Frappier, Laval, PQ H7V 4B3, Canada. EM authiers@ca.citoxlab.com NR 86 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD SEP-OCT PY 2016 VL 81 BP 37 EP 46 DI 10.1016/j.vascn.2016.06.001 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE3YB UT WOS:000389537100005 PM 27263834 ER PT J AU Li, ZH Dutta, S Sheng, JS Tran, PN Wu, W Colatsky, T AF Li, Zhihua Dutta, Sara Sheng, Jiansong Tran, Phu N. Wu, Wendy Colatsky, Thomas TI A temperature-dependent in silico model of the human ether-a-go-go-related (hERG) gene channel SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Article DE CiPA; hERG; Kv11.1; Markov model; Methods; Temperature ID QT INTERVAL PROLONGATION; DRUG SAFETY ASSESSMENT; POTASSIUM CHANNEL; CARDIAC-ARRHYTHMIA; K+ CHANNEL; INACTIVATION; INHIBITION; DOFETILIDE; CISAPRIDE; MECHANISM AB Introduction: Current regulatory guidelines for assessing the risk of QT prolongation include in vitro assays assessing drug effects on the human ether-a-go-go-related (hERG; also known as Kv11.1) channel expressed in cell lines. These assays are typically conducted at room temperature to promote the ease and stability of recording hERG currents. However, the new Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm proposes to use an in silico model of the human ventricular myocyte to assess risk, requiring as input hERG channel pharmacology data obtained at physiological temperatures. To accommodate current industry safety pharmacology practices for measuring hERG channel activity, an in silico model of hERG channel that allows for the extrapolation of hERG assay data across different temperatures is desired. Because temperature may have an effect on both channel gating and drug binding rate, such models may need to have two components: a base model dealing with temperature-dependent gating changes without drug, and a pharmacodynamic component simulating temperature-dependent drug binding kinetics. As a first step, a base mode that can capture temperature effects on hERG channel gating without drug is needed. Methods and results: To meet this need for a temperature-dependent base model, a Markov model of the hERG channel with state transition rates explicitly dependent on temperature was developed and calibrated using data from a variety of published experiments conducted over a range of temperatures. The model was able to reproduce observed temperature-dependent changes in key channel gating properties and also to predict the results obtained in independent sets of new experiments. Discussion: This new temperature-sensitive model of hERG gating represents an attempt to improve the predictivity of safety pharmacology testing by enabling the translation of room temperature hERG assay data to more physiological conditions. With further development, this model can be incorporated into the CiPA paradigm and also be used as a tool for developing insights into the thermodynamics of hERG channel gating mechanisms and the temperature-dependence of hERG channel block by drugs. Published by Elsevier Inc. C1 [Li, Zhihua; Dutta, Sara; Sheng, Jiansong; Tran, Phu N.; Wu, Wendy; Colatsky, Thomas] US FDA, Div Appl Regulatory Sci, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Li, ZH (reprint author), WO Bldg 64 Rm 2084,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Zhihua.li@fda.hhs.gov OI Li, Zhihua/0000-0002-2772-0839 FU Intramural FDA HHS [FD999999] NR 26 TC 3 Z9 4 U1 9 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD SEP-OCT PY 2016 VL 81 BP 233 EP 239 DI 10.1016/j.vascn.2016.05.005 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE3YB UT WOS:000389537100025 PM 27178106 ER PT J AU Crumb, WJ Vicente, J Johannesen, L Strauss, DG AF Crumb, William J., Jr. Vicente, Jose Johannesen, Lars Strauss, David G. TI An evaluation of 30 clinical drugs against the comprehensive in vitro proarrhythmia assay (CiPA) proposed ion channel panel SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Article DE CiPA; Electrophysiology; Ion channels; Manual patch clamp; Torsade de pointes ID TORSADE-DE-POINTES; CARDIAC REPOLARIZATION; HERG; BLOCK; RANOLAZINE; SAFETY; PROLONGATION; INHIBITION; QUINIDINE; VERAPAMIL AB Introduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is intended to address the misidentification of drug-associated torsade de pointes risk based solely on hERG and QT data. This new paradigm will consist of four interrelated components, one of which is a panel consisting of six ion channels whose currents are important in both depolarization and repolarization of the cardiac action potential. This study examined the effects of 30 clinical drugs on these ion channels. Methods: Ion currents were evaluated in expression systems using the manual whole cell patch clamp technique. Currents were elicited using either a ventricular action potential waveform or step-ramp voltage protocols. Results: Of the seven ion currents studied, hERG was the most often blocked current followed by Nav1.5-late, and Cav1.2. Using a 20% reduction in current amplitude as an arbitrary maker, at a free plasma C-max concentration, no drug tested blocked Nav1.5-peak, KvLQT1/ mink, Kir2.1 and Kv4.3 by that amount. At a 3x free plasma C-max, every current except Kir2.1 had at least one drug reduce current amplitude by at least 20%. Discussion: This is the first study of its kind to examine the effects of 30 clinical drugs against the seven ion currents currently proposed to makeup the CiPA ion channel panel. The results indicate the importance of drug-induced block of hERG, Nav1.5-late and Cav1.2 at clinically relevant concentrations, with low risk torsade drugs having equal or greater Nav1.5-late or Cav1.2 block compared to hERG block. In addition, the results of this study provide data which can be used to test the ability of various in silico models to predict drug-induced arrhythmias. (C) 2016 Elsevier Inc. All rights reserved. C1 [Crumb, William J., Jr.] Cytocentrics Inc, 1441 Canal St, New Orleans, LA 70112 USA. [Vicente, Jose; Johannesen, Lars; Strauss, David G.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Crumb, WJ (reprint author), Cytocentrics Inc, 1441 Canal St, New Orleans, LA 70112 USA. EM w.crumb@cytocentrics.com NR 25 TC 7 Z9 8 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD SEP-OCT PY 2016 VL 81 BP 251 EP 262 DI 10.1016/j.vascn.2016.03.009 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE3YB UT WOS:000389537100027 PM 27060526 ER PT J AU Authier, S Delatte, MS Kallman, MJ Stevens, J Markgraf, C AF Authier, Simon Delatte, Marcus S. Kallman, Mary-Jeanne Stevens, Joanne Markgraf, Carrie TI EEG in non-clinical drug safety assessments: Current and emerging considerations SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Article DE EEG; Seizure; Polysomnography; Safety pharmacology; Convulsion; Neurotoxicity; Sleep; Spike; Telemetry ID HIGH-FREQUENCY OSCILLATIONS; TEMPORAL-LOBE EPILEPSY; SPONTANEOUS CONVULSIONS; CYNOMOLGUS MONKEYS; NERVOUS-SYSTEM; INTERINDIVIDUAL VARIATION; SEIZURE LIABILITY; ANIMAL-MODELS; BEAGLE DOGS; RATS AB Electroencephalogram (EEG) data in nonclinical species can play a critical role in the successful evaluation of a compound during drug development, particularly in the evaluation of seizure potential and for monitoring changes in sleep. Yet, while non-invasive electrocardiogram (ECG) monitoring is commonly included in preclinical safety studies, pre-dose or post-dose EEG assessments are not. Industry practices as they relate to preclinical seizure liability and sleep assessments are not well characterized and the extent of preclinical EEG testing varies between organizations. In the current paper, we discuss the various aspects of preclinical EEG to characterize drug-induced seizure risk and sleep disturbances, as well as describe the use of these data in a regulatory context. An overview of EEG technology-its correct application and its limitations, as well as best practices for setting up the animal models is presented. Sleep and seizure detection are discussed in detail. A regulatory perspective on the use of EEG data is provided and, tying together the previous topics is a discussion of the translational aspects of EEG. (C) 2016 The Authors. Published by Elsevier Inc. C1 [Authier, Simon] CiToxLAB North Amer, 445 Armand Frappier, Laval, PQ H7V 4B3, Canada. [Delatte, Marcus S.] US FDA, DAAAP, CDER, Silver Spring, MD USA. [Kallman, Mary-Jeanne] Kallman Preclin Consulting, Greenfield, IN 46140 USA. [Stevens, Joanne] Merck Res Labs, Dept Pharmacol, West Point, PA 19486 USA. [Markgraf, Carrie] Merck Res Labs, Safety Assessment, Kenilworth, NJ 07033 USA. RP Authier, S (reprint author), CiToxLAB North Amer, 445 Armand Frappier, Laval, PQ H7V 4B3, Canada. EM authiers@ca.citoxlab.com NR 71 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD SEP-OCT PY 2016 VL 81 BP 274 EP 285 DI 10.1016/j.vascn.2016.03.002 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE3YB UT WOS:000389537100029 PM 26992360 ER PT J AU Strauss, D Vicente, J Mason, J Crumb, W Hosseini, M Stockbridge, N Johannesen, L AF Strauss, David Vicente, Jose Mason, Jay Crumb, William Hosseini, Meisam Stockbridge, Norman Johannesen, Lars TI In vitro to clinical translation to improve proarrhythmic risk assessment SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Meeting Abstract C1 [Strauss, David; Vicente, Jose; Hosseini, Meisam; Stockbridge, Norman; Johannesen, Lars] US FDA, Silver Spring, MD USA. [Mason, Jay] Univ Utah, Salt Lake City, UT USA. [Mason, Jay] Spaulding Clin Res, West Bend, WI USA. [Crumb, William] Zenas Technol, New Orleans, LA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD SEP-OCT PY 2016 VL 81 MA 0084 BP 360 EP 360 DI 10.1016/j.vascn.2016.02.083 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE3YB UT WOS:000389537100117 ER PT J AU Blinova, K Stohlman, J Vicente, J Chan, D Hortigon, M Rodriguez, VZ Smith, G Ross, J Brock, M Chvatal, S Millard, D Johannesen, L Galeotti, L Pang, L Lyn-Cook, B Crumb, W Stockbridge, N Strauss, D AF Blinova, Ksenia Stohlman, Jayna Vicente, Jose Chan, Dulciana Hortigon, Maria Rodriguez, Victor Zamora Smith, Godfrey Ross, James Brock, Mathew Chvatal, Stacie Millard, Daniel Johannesen, Lars Galeotti, Loriano Pang, Li Lyn-Cook, Beverly Crumb, William Stockbridge, Norman Strauss, David TI Comprehensive assessment of multiple induced pluripotent stem cell-derived cardiomyocyte cell lines with microelectrode arrays and voltage sensitive dyes SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Meeting Abstract C1 [Blinova, Ksenia; Stohlman, Jayna; Vicente, Jose; Chan, Dulciana; Johannesen, Lars; Galeotti, Loriano; Strauss, David] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD USA. [Hortigon, Maria; Rodriguez, Victor Zamora] Clyde Biosci, Glasgow, Lanark, Scotland. [Ross, James; Brock, Mathew; Chvatal, Stacie; Millard, Daniel] Ax BioSyst, Atlanta, GA USA. [Smith, Godfrey] Univ Glasgow, Glasgow, Lanark, Scotland. [Pang, Li; Lyn-Cook, Beverly] US FDA, Natl Ctr Toxicol Res, Res Off, Jefferson, AR 72079 USA. [Crumb, William] Zenas Technol, New Orleans, LA USA. [Johannesen, Lars] Karolinska Inst, Dept Clin Physiol, Stockholm, Sweden. [Johannesen, Lars] Karolinska Univ Hosp, Stockholm, Sweden. [Vicente, Jose] Univ Zaragoza, BSICoS Grp, Aragon Inst Engn Res I3A, IIS Aragon, Zaragoza, Spain. [Stockbridge, Norman] US FDA, Ctr Drug Evaluat & Res, Off New Drugs, Silver Spring, MD USA. OI Vicente, Jose/0000-0001-9963-1205 NR 0 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD SEP-OCT PY 2016 VL 81 MA 0150 BP 380 EP 380 DI 10.1016/j.vascn.2016.02.147 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE3YB UT WOS:000389537100181 ER PT J AU Pugsley, MK Guth, B Chiang, A Doyle, J Engwall, M Guillon, JM Hoffmann, P Koerner, J Mittelstadt, S Ottinger, S Pierson, J Rossman, E Walisser, J Sarazan, RD AF Pugsley, Michael K. Guth, Brian Chiang, Alan Doyle, Jennifer Engwall, Mike Guillon, Jean-Michel Hoffmann, Peter Koerner, John Mittelstadt, Scott Ottinger, Sean Pierson, Jennifer Rossman, Eric Walisser, Jacqueline Sarazan, R. Dustan TI A HESI consortium update on cardiac contractility endpoints SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Meeting Abstract C1 [Pugsley, Michael K.] CitoxLAB, Laval, PQ, Canada. [Guth, Brian] Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. [Chiang, Alan] Eli Lilly, Indianapolis, IN USA. [Doyle, Jennifer; Sarazan, R. Dustan] Data Sci Int, St Paul, MN USA. [Engwall, Mike] Amgen Inc, Thousand Oaks, CA USA. [Guillon, Jean-Michel] Sanofi, Alfortville, France. [Hoffmann, Peter] Novartis Pharmaceut, E Hanover, NJ USA. [Koerner, John] US FDA, Washington, DC 20204 USA. [Mittelstadt, Scott] AbbVie, Abbott Pk, IL USA. [Ottinger, Sean] Millennium, Cambridge, MA USA. [Pierson, Jennifer] HESI, Washington, DC USA. [Rossman, Eric] GlaxoSmithKline, King Of Prussia, PA USA. [Walisser, Jacqueline] Covance Inc, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD SEP-OCT PY 2016 VL 81 MA 0183 BP 390 EP 391 DI 10.1016/j.vascn.2016.02.180 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE3YB UT WOS:000389537100214 ER PT J AU McDermott, PF Tyson, GH Kabera, C Chen, YS Li, C Folster, JP Ayers, SL Lam, C Tate, HP Zhao, SH AF McDermott, Patrick F. Tyson, Gregory H. Kabera, Claudine Chen, Yuansha Li, Cong Folster, Jason P. Ayers, Sherry L. Lam, Claudia Tate, Heather P. Zhao, Shaohua TI Whole-Genome Sequencing for Detecting Antimicrobial Resistance in Nontyphoidal Salmonella SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ESCHERICHIA-COLI; QUINOLONE RESISTANCE; UNITED-STATES; BETA-LACTAMASE; PARC GENES; ENTERICA; ANIMALS; FOOD; SURVEILLANCE; HUMANS AB Laboratory-based in vitro antimicrobial susceptibility testing is the foundation for guiding anti-infective therapy and monitoring antimicrobial resistance trends. We used whole-genome sequencing (WGS) technology to identify known antimicrobial resistance determinants among strains of nontyphoidal Salmonella and correlated these with susceptibility phenotypes to evaluate the utility of WGS for antimicrobial resistance surveillance. Six hundred forty Salmonella of 43 different serotypes were selected from among retail meat and human clinical isolates that were tested for susceptibility to 14 antimicrobials using broth microdilution. The MIC for each drug was used to categorize isolates as susceptible or resistant based on Clinical and Laboratory Standards Institute clinical breakpoints or National Antimicrobial Resistance Monitoring System (NARMS) consensus interpretive criteria. Each isolate was subjected to whole-genome shotgun sequencing, and resistance genes were identified from assembled sequences. A total of 65 unique resistance genes, plus mutations in two structural resistance loci, were identified. There were more unique resistance genes (n = 59) in the 104 human isolates than in the 536 retail meat isolates (n = 36). Overall, resistance genotypes and phenotypes correlated in 99.0% of cases. Correlations approached 100% for most classes of antibiotics but were lower for aminoglycosides and beta-lactams. We report the first finding of extended-spectrum beta-lactamases (ESBLs) (bla(CTX-M1) and bla(SHV2a)) in retail meat isolates of Salmonella in the United States. Whole-genome sequencing is an effective tool for predicting antibiotic resistance in nontyphoidal Salmonella, although the use of more appropriate surveillance breakpoints and increased knowledge of new resistance alleles will further improve correlations. C1 [McDermott, Patrick F.; Tyson, Gregory H.; Kabera, Claudine; Chen, Yuansha; Li, Cong; Ayers, Sherry L.; Lam, Claudia; Tate, Heather P.; Zhao, Shaohua] US FDA, Ctr Vet Med, Div Anim & Food Microbiol, Res Off, Laurel, MD 20708 USA. [Folster, Jason P.] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Atlanta, GA USA. RP McDermott, PF (reprint author), US FDA, Ctr Vet Med, Div Anim & Food Microbiol, Res Off, Laurel, MD 20708 USA. EM Patrick.McDermott@fda.hhs.gov FU U.S. Food and Drug Administration FX This work was supported by the U.S. Food and Drug Administration with internal funds as part of routine work. NR 34 TC 2 Z9 2 U1 5 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2016 VL 60 IS 9 BP 5515 EP 5520 DI 10.1128/AAC.01030-16 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA ED7OH UT WOS:000389055400048 PM 27381390 ER PT J AU Reimonn, TM Park, SY Agarabi, CD Brorson, KA Yoon, S AF Reimonn, Thomas M. Park, Seo-Young Agarabi, Cyrus D. Brorson, Kurt A. Yoon, Seongkyu TI Effect of amino acid supplementation on titer and glycosylation distribution in hybridoma cell culturesSystems biology-based interpretation using genome-scale metabolic flux balance model and multivariate data analysis SO BIOTECHNOLOGY PROGRESS LA English DT Article DE cell culture; dynamic flux balance analysis; hybridoma; metabolomics; systems biology ID PARTIAL LEAST-SQUARES; HAMSTER OVARY CELLS; FED-BATCH CULTURE; DISCRIMINANT-ANALYSIS; CHO-CELLS; RECOMBINANT PROTEINS; HYDRODYNAMIC STRESS; ANTIBODY-PRODUCTION; ESCHERICHIA-COLI; MAMMALIAN-CELLS AB Genome-scale flux balance analysis (FBA) is a powerful systems biology tool to characterize intracellular reaction fluxes during cell cultures. FBA estimates intracellular reaction rates by optimizing an objective function, subject to the constraints of a metabolic model and media uptake/excretion rates. A dynamic extension to FBA, dynamic flux balance analysis (DFBA), can calculate intracellular reaction fluxes as they change during cell cultures. In a previous study by Read et al. (2013), a series of informed amino acid supplementation experiments were performed on twelve parallel murine hybridoma cell cultures, and this data was leveraged for further analysis (Read et al., Biotechnol Prog. 2013;29:745-753). In order to understand the effects of media changes on the model murine hybridoma cell line, a systems biology approach is applied in the current study. Dynamic flux balance analysis was performed using a genome-scale mouse metabolic model, and multivariate data analysis was used for interpretation. The calculated reaction fluxes were examined using partial least squares and partial least squares discriminant analysis. The results indicate media supplementation increases product yield because it raises nutrient levels extending the growth phase, and the increased cell density allows for greater culture performance. At the same time, the directed supplementation does not change the overall metabolism of the cells. This supports the conclusion that product quality, as measured by glycoform assays, remains unchanged because the metabolism remains in a similar state. Additionally, the DFBA shows that metabolic state varies more at the beginning of the culture but less by the middle of the growth phase, possibly due to stress on the cells during inoculation. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1163-1173, 2016 C1 [Reimonn, Thomas M.; Park, Seo-Young; Yoon, Seongkyu] Univ Massachusetts Lowell, Dept Chem Engn, Lowell, MA 01854 USA. [Agarabi, Cyrus D.; Brorson, Kurt A.] US FDA, CDER, Off Pharmaceut Qual, Off Biotechnol Prod,Div 2, Silver Spring, MD USA. [Reimonn, Thomas M.] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. RP Yoon, S (reprint author), Univ Massachusetts Lowell, Dept Chem Engn, Lowell, MA 01854 USA. EM Seongkyu_yoon@uml.Edu FU Commonwealth Honors College, University of Massachusetts Lowell; FDA/CDER Critical Path Project [1500]; U.S. Department of Energy; U.S. Food and Drug Administration; Pfizer FX The authors gratefully acknowledge scholarship support for this research from the Commonwealth Honors College, University of Massachusetts Lowell. The bioreactor runs were funded by FDA/CDER Critical Path Project 1500. This project was also 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. The authors thank Dr. Dong-Yup Lee for his constructive feedback on the manuscript and Pfizer for the partial funding of this research. NR 86 TC 0 Z9 0 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8756-7938 EI 1520-6033 J9 BIOTECHNOL PROGR JI Biotechnol. Prog. PD SEP-OCT PY 2016 VL 32 IS 5 BP 1163 EP 1173 DI 10.1002/btpr.2335 PG 11 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EC0JT UT WOS:000387787600008 PM 27452371 ER PT J AU Musante, C Abernethy, DR Allerheiligen, SR Lauffenburger, DA Zager, MG AF Musante, C. J. Abernethy, D. R. Allerheiligen, S. R. Lauffenburger, D. A. Zager, M. G. TI GPS for QSP: A Summary of the ACoP6 Symposium on Quantitative Systems Pharmacology and a Stage for Near-Term Efforts in the Field SO CPT-Pharmacometrics & Systems Pharmacology LA English DT Article AB This article provides a summary, conclusions, and actions resulting from the symposium entitled "GPS for QSP: Where We've Been, Where We Are and Where We're Going," which took place during the Sixth Annual American Conference on Pharmacometrics (ACoP6) in Washington, DC on October 6, 2015. The symposium sought to contextualize the current status of QSP based on its multidisciplinary roots and its historical successes and challenges in order to establish its next direction. Like most fields, this area has evolved from independent, innovative efforts rather than from an overarching, strategic plan. While this diversity is largely responsible for the success of QSP today, it essentially represents the beginning of an emerging discipline. The goal of the session was to explore how history has shaped QSP and to use that understanding to set a course for its advancement as a scientific and practical discipline. The symposium included presentations by industrial, academic, and regulatory scientists followed by a panel discussion that produced three main themes as critical for the future success of QSP as a discipline. These themes resulted in new goals within the International Society of Pharmacometrics' (ISoP) Special Interest Group (SIG) on QSP to engage the community to address them. C1 [Musante, C. J.] Pfizer Inc, Cardiovasc & Metab Dis Res Unit, Cambridge, MA USA. [Abernethy, D. R.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Allerheiligen, S. R.] Merck & Co Inc, Merck Res Labs, Quantitat Pharmacol & Pharmacometr, Rahway, NJ USA. [Lauffenburger, D. A.] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Zager, M. G.] Janssen Res & Dev, Quantitat Sci, San Diego, CA 92121 USA. RP Zager, MG (reprint author), Janssen Res & Dev, Quantitat Sci, San Diego, CA 92121 USA. EM mzager1@its.jnj.com NR 1 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2163-8306 J9 CPT-PHARMACOMET SYST JI CPT-PHARMACOMET. SYST. PHARMACOL. PD SEP PY 2016 VL 5 IS 9 BP 449 EP 451 DI 10.1002/psp4.12109 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED8QV UT WOS:000389136900001 PM 27639191 ER PT J AU Garnett, C Johannesen, L AF Garnett, C. Johannesen, L. TI Commentary on: "Levofloxacin-Induced QTc Prolongation Depends on the Time of Drug Administration" SO CPT-Pharmacometrics & Systems Pharmacology LA English DT Editorial Material ID CARDIOMYOCYTE MOLECULAR CLOCK; REPOLARIZATION; EXPRESSION AB Circadian variations in the corrected QT (QTc) interval have been documented in clinical trials. Animal models show circadian variations in expression of the cardiac ion channels that are necessary to maintain the heart's electrophysiological properties. Can these diurnal rhythms in QTc affect the ability of a drug to delay cardiac repolarization? C1 [Garnett, C.] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Johannesen, L.] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Garnett, C (reprint author), US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM christinegarnett@fda.hhs.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2163-8306 J9 CPT-PHARMACOMET SYST JI CPT-PHARMACOMET. SYST. PHARMACOL. PD SEP PY 2016 VL 5 IS 9 BP 452 EP 454 DI 10.1002/psp4.12128 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED8QV UT WOS:000389136900002 PM 27647678 ER PT J AU Weir, JP Gruber, MF AF Weir, Jerry P. Gruber, Marion F. TI An overview of the regulation of influenza vaccines in the United States SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Editorial Material DE influenza vaccines; vaccine regulation; vaccine licensing ID SEASONAL INFLUENZA; VIRUS; HEMAGGLUTININ; SAFETY AB Influenza virus vaccines are unique among currently licensed viral vaccines. The vaccines designed to protect against seasonal influenza illness must be updated periodically in an effort to match the vaccine strain with currently circulating viruses, and the vaccine manufacturing timeline includes multiple, overlapping processes with a very limited amount of flexibility. In the United States (U.S.), over 150 million doses of seasonal trivalent and quadrivalent vaccine are produced annually, a mammoth effort, particularly in the context of a vaccine with components that usually change on a yearly basis. In addition, emergence of an influenza virus containing an HA subtype that has not recently circulated in humans is an ever present possibility. Recently, pandemic influenza vaccines have been licensed, and the pathways for licensure of pandemic vaccines and subsequent strain updating have been defined. Thus, there are formidable challenges for the regulation of currently licensed influenza vaccines, as well as for the regulation of influenza vaccines under development. This review describes the process of licensing influenza vaccines in the U.S., the process and steps involved in the annual updating of seasonal influenza vaccines, and some recent experiences and regulatory challenges faced in development and evaluation of novel influenza vaccines. C1 [Weir, Jerry P.] US FDA, Lab DNA Viruses, Div Viral Prod, Off Vaccines Res & Review,Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Gruber, Marion F.] US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Weir, JP (reprint author), US FDA, Lab DNA Viruses, Div Viral Prod, Off Vaccines Res & Review,Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jerry.weir@fda.hhs.gov NR 25 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 EI 1750-2659 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD SEP PY 2016 VL 10 IS 5 BP 354 EP 360 DI 10.1111/irv.12383 PG 7 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA ED3MV UT WOS:000388754100001 PM 27426005 ER PT J AU Ilyushina, NA Wright, PF AF Ilyushina, Natalia A. Wright, Peter F. TI In vitro modeling of the interaction between human epithelial cells and lymphocytes upon influenza infection SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article DE Cytotoxic T lymphocytes; influenza virus; lysis; nasal human epithelial cells ID PANDEMIC INFLUENZA; AIRWAY EPITHELIUM; CROSS-REACT; VIRUS; PROTECTION; IMMUNITY; CD4(+); H1N1 AB Influenza viruses are a continuous threat to humans because of their ability to cross species barriers and adapt to new hosts. Data from murine studies, along with limited human data, suggest that CD8(+) cytotoxic T lymphocytes (CTL) that recognize conserved epitopes of structural influenza proteins are the main mediators of influenza virus clearance. Additionally, the fact that many CTLs recognize epitopes shared between different influenza strains offers the potential for broad cross-strain immunity. However, the mechanisms of cellular immunity against influenza viruses are poorly defined in humans, where the CTL response has been hard to measure and interpret. We developed a novel CTL assay that utilizes fully differentiated nasal human epithelial cells taken from volunteers as permissive targets for autologous peripheral blood-derived influenza virus-specific cytotoxic T lymphocytes. This in vitro system of human lymphocyte-epithelial cell co-cultures can be considered as the closest approximation to events in vivo and can be employed for studying the interactions between the pathogen and human host. Modeling of the natural interaction process between the primary cell type that supports the productive replication of influenza and immune cells may allow us to put in perspective CTLs as a correlate of immunity to influenza in humans. C1 [Ilyushina, Natalia A.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Wright, Peter F.] Geisel Sch Med Dartmouth, Dept Pediat, Lebanon, NH USA. RP Ilyushina, NA (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Natalia.Ilyushina@fda.hhs.gov FU American Recovery and Reinvestment Act funding [HHSN272200900026C] FX This work was supported by American Recovery and Reinvestment Act funding (contract no. HHSN272200900026C). We are grateful to Dr. Harry Smith for editorial assistance. NR 19 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 EI 1750-2659 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD SEP PY 2016 VL 10 IS 5 BP 438 EP 442 DI 10.1111/irv.12394 PG 5 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA ED3MV UT WOS:000388754100012 PM 27102577 ER PT J AU Murbach, M Neufeld, E Cabot, E Zastrow, E Corcoles, J Kainz, W Kuster, N AF Murbach, Manuel Neufeld, Esra Cabot, Eugenia Zastrow, Earl Corcoles, Juan Kainz, Wolfgang Kuster, Niels TI Virtual Population-Based Assessment of the Impact of 3 Tesla Radiofrequency Shimming and Thermoregulation on Safety and B-1 + Uniformity SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI safety; SAR; RF shimming performance; virtual population; human thermoregulation; impaired thermoregulation ID MR BODY COIL; CUTANEOUS VASODILATION; WHOLE-BODY; ANATOMICAL MODELS; TEMPERATURE RISE; ABSORPTION RATE; THERMAL-DAMAGE; TISSUE-DAMAGE; NITRIC-OXIDE; RF EXPOSURE AB Purpose: To assess the effect of radiofrequency (RF) shimming of a 3 Tesla (T) two-port body coil on B-1+ uniformity, the local specific absorption rate (SAR), and the local temperature increase as a function of the thermoregulatory response. Methods: RF shimming alters induced current distribution, which may result in large changes in the level and location of absorbed RF energy. We investigated this effect with six anatomical human models from the Virtual Population in 10 imaging landmarks and four RF coils. Three thermoregulation models were applied to estimate potential local temperature increases, including a newly proposed model for impaired thermoregulation. Results: Two-port RF shimming, compared to circular polarization mode, can increase the B-1+ uniformity on average by +32%. Worst-case SAR excitations increase the local RF power deposition on average by +39%. In the first level controlled operating mode, induced peak temperatures reach 42.5 degrees C and 45.6 degrees C in patients with normal and impaired thermoregulation, respectively. Conclusion: Image quality with 3T body coils can be significantly increased by RF shimming. Exposure in realistic scan scenarios within guideline limits can be considered safe for a broad patient population with normal thermoregulation. Patients with impaired thermoregulation should not be scanned outside of the normal operating mode. (C) 2015 Wiley Periodicals, Inc. C1 [Murbach, Manuel; Neufeld, Esra; Cabot, Eugenia; Zastrow, Earl; Kuster, Niels] ITIS Fdn, Zeughausstr 43, CH-8004 Zurich, Switzerland. [Zastrow, Earl; Kuster, Niels] Swiss Fed Inst Technol, Zurich, Switzerland. [Corcoles, Juan] UAM, Escuela Politecn Super, Dept Elect & Commun Technol, Madrid, Spain. [Kainz, Wolfgang] US FDA, CDRH, Silver Spring, MD USA. RP Murbach, M (reprint author), ITIS Fdn, Zeughausstr 43, CH-8004 Zurich, Switzerland. EM murbach@itis.ethz.ch FU MRI; CICYT, Spain [TEC2013-417106-C3-2-R]; Banco Santander-UAM [2015/ASIA/03] FX This study was supported in part by the MRI# project. 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 suggested endorsement of such products by the Department of Health and Human Services. The work of J. Corcoles was supported by CICYT, Spain (contract TEC2013-417106-C3-2-R) and Banco Santander-UAM (contract 2015/ASIA/03). NR 50 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD SEP PY 2016 VL 76 IS 3 BP 986 EP 997 DI 10.1002/mrm.25986 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ED1PK UT WOS:000388617200028 PM 26400841 ER PT J AU Ratain, MJ Rahman, NA AF Ratain, Mark J. Rahman, Nam Atiqur TI The Importance of Dose Optimization Prior to Initiation of a Registration Trial SO CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY LA English DT Editorial Material ID EXPOSURE-RESPONSE; BREAST-CANCER; COMBINATION; NIVOLUMAB C1 [Rahman, Nam Atiqur] US FDA, Div Clin Pharmacol 5, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU MILLENNIUM MEDICAL PUBLISHING, INC PI NEW YORK PA 611 BROADWAY, STE 310, NEW YORK, NY 10012 USA SN 1543-0790 J9 CLIN ADV HEMATOL ONC JI Clin. Adv. Hematol. Oncol. PD SEP PY 2016 VL 14 IS 9 BP 654 EP 657 PG 4 WC Oncology SC Oncology GA EB4JZ UT WOS:000387339000003 ER PT J AU Jha, NK Shestopal, SA Gourley, MJ Woodle, SA Liang, Y Sarafanov, AG Weinstein, M Ovanesov, MV AF Jha, N. K. Shestopal, S. A. Gourley, M. J. Woodle, S. A. Liang, Y. Sarafanov, A. G. Weinstein, M. Ovanesov, M. V. TI Optimization of the thrombin generation test components to measure potency of factor VIII concentrates SO HAEMOPHILIA LA English DT Article DE factor VIII; haemophilia; potency; thrombin generation test ID SEVERE HEMOPHILIA-A; FACTOR XIA; FACTOR-IX; IN-VITRO; PLASMA; ASSAY; FVIII; HEMOSTASIS; INHIBITORS; THROMBOELASTOMETRY AB Introduction: The thrombin generation test (TGT) is used both as a global haemostasis assay, and to compare activities of coagulation factor concentrates that have been spiked into patient plasma. However, TGT has not been systematically optimized to evaluate factor VIII (FVIII) product potency. Aims: To improve the sensitivity of TGT to FVIII and allow a comparative analysis of the thrombin generating capacities of FVIII concentrates against reference preparations with known FVIII activity. Methods: Concentrations of TGT components (analytical variables) were assessed to maximize the linearity and range of responses to the concentration of FVIII. Results: We optimized the range and sensitivity of the TGT assay with respect to FVIII through the addition of FXIa to the assay. Other parameters that were adjusted, i.e. tissue factor (TF), procoagulant lipids and plasma concentrations, did not improve the ability of the assay to measure both high and very low levels of FVIII. In the optimized TF/FXIa-activated TGT assay, all thrombin generation curve parameters were suitable for FVIII quantification, but thrombin peak height and maximal velocity demonstrated better linearity in the desired FVIII range. We found that the optimized TF/FXIa-activated TGT has a wider range of sensitivity to FVIII than a commercially available TGT. Additionally, we demonstrated that the TF/FXIa-activated assay performs adequately by comparing potency measurements of five commercially available FVIII products using TGT and traditional chromogenic and one-stage clotting assays. Conclusions: The optimized TGT assay can be used to quantify and compare the thrombin generating capacities of FVIII concentrates. C1 [Jha, N. K.; Shestopal, S. A.; Gourley, M. J.; Woodle, S. A.; Liang, Y.; Sarafanov, A. G.; Weinstein, M.; Ovanesov, M. V.] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Jha, N. K.] George Washington Univ, Dept Phys, Washington, DC 20052 USA. RP Ovanesov, MV (reprint author), US FDA, 10903 New Hampshire Ave,White Oak Bldg 52-72, Silver Spring, MD 20993 USA. EM mikhail.ovanesov@fda.hhs.gov NR 44 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-8216 EI 1365-2516 J9 HAEMOPHILIA JI Haemophilia PD SEP PY 2016 VL 22 IS 5 BP 780 EP 789 DI 10.1111/hae.12943 PG 10 WC Hematology SC Hematology GA EB5CE UT WOS:000387390000051 PM 27038076 ER PT J AU Chen, YC Chen, JJ AF Chen, Yu-Chuan Chen, James J. TI Ensemble survival trees for identifying subpopulations in personalized medicine SO BIOMETRICAL JOURNAL LA English DT Article DE Cox proportional hazards model; Ensemble method; Personalized medicine; Subgroup identification; Survival trees ID CLINICAL-TRIAL DESIGNS; CELL LUNG-CANCER; ADAPTIVE SIGNATURE DESIGN; SUBGROUP IDENTIFICATION; ADJUVANT CHEMOTHERAPY; GENE SIGNATURE; VALIDATION; REGRESSION AB Recently, personalized medicine has received great attention to improve safety and effectiveness in drug development. Personalized medicine aims to provide medical treatment that is tailored to the patient's characteristics such as genomic biomarkers, disease history, etc., so that the benefit of treatment can be optimized. Subpopulations identification is to divide patients into several different subgroups where each subgroup corresponds to an optimal treatment. For two subgroups, traditionally the multivariate Cox proportional hazards model is fitted and used to calculate the risk score when outcome is survival time endpoint. Median is commonly chosen as the cutoff value to separate patients. However, using median as the cutoff value is quite subjective and sometimes may be inappropriate in situations where data are imbalanced. Here, we propose a novel tree-based method that adopts the algorithm of relative risk trees to identify subgroup patients. After growing a relative risk tree, we apply k-means clustering to group the terminal nodes based on the averaged covariates. We adopt an ensemble Bagging method to improve the performance of a single tree since it is well known that the performance of a single tree is quite unstable. A simulation study is conducted to compare the performance between our proposed method and the multivariate Cox model. The applications of our proposed method to two public cancer data sets are also conducted for illustration. C1 [Chen, Yu-Chuan; Chen, James J.] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Chen, JJ (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM jamesJ.chen@fda.hhs.gov FU Oak Ridge Institute for Science and Education (ORISE) FX Yu-Chuan Chen's work was fully funded by Oak Ridge Institute for Science and Education (ORISE). The views presented in this paper are those of the authors and do not necessarily represent those of the U.S. Food and Drug Administration. NR 33 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0323-3847 EI 1521-4036 J9 BIOMETRICAL J JI Biom. J. PD SEP PY 2016 VL 58 IS 5 BP 1151 EP 1163 DI 10.1002/bimj.201500075 PG 13 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA DW5LQ UT WOS:000383687100009 PM 27073016 ER PT J AU Calvo, MS Mehrotra, A Beelman, RB Nadkarni, G Wang, L Cai, W Goh, BC Kalaras, MD Uribarri, J AF Calvo, Mona S. Mehrotra, Anita Beelman, Robert B. Nadkarni, Girish Wang, Lingzhi Cai, Weijing Goh, Boon Cher Kalaras, Michael D. Uribarri, Jaime TI A Retrospective Study in Adults with Metabolic Syndrome: Diabetic Risk Factor Response to Daily Consumption of Agaricus bisporus (White Button Mushrooms) SO PLANT FOODS FOR HUMAN NUTRITION LA English DT Article DE White button mushrooms; Metabolic syndrome; Type 2 diabetes; Antioxidants; Ergothioneine; Advanced glycation end products; Adiponectin; Oxidative stress ID IMPROVES INSULIN-RESISTANCE; OXIDATIVE STRESS; EDIBLE MUSHROOMS; VITAMIN D-2; ERGOTHIONEINE; INFLAMMATION; RATS; BIOAVAILABILITY; QUANTIFICATION; INDIVIDUALS AB Adults with metabolic syndrome from different race/ethnicities are often predisposed to developing type 2 diabetes (T2D); however, growing evidence suggests that healthy diets and lifestyle choices can significantly slow or prevent progression to T2D. This poorly understood relationship to healthy dietary patterns and prevention of T2D motivated us to conduct a retrospective analysis to determine the potential impact of a minor dietary lifestyle change (daily mushroom consumption) on known T2D risk factors in racially diverse adults with confirmed features of the metabolic syndrome. Retrospectively, we studied 37 subjects who had participated in a dietary intervention focused on vitamin D bioavailability from white button mushrooms (WBM). All 37 had previously completed a 16-week study where they consumed 100 g of WBM daily and were then followed-up for one month during which nomushrooms were consumed. We analyzed differences in serum risk factors from baseline to 16-week, and from baseline to one-month follow-up. Measurement of serum diabetic risk factors included inflammatory and oxidative stress markers and the antioxidant component naturally rich in mushrooms, ergothioneine. Significant beneficial health effects were observed at 16-week with the doubling of ergothioneine from baseline, increases in the antioxidant marker ORAC (oxygen radical absorption capacity) and anti-inflammatory hormone, adiponectin and significant decreases in serum oxidative stress inducing factors, carboxymethyllysine (CML) and methylglyoxal (MG), but no change in the lipid oxidative stress marker 8-isoprostane, leptin or measures of insulin resistance or glucose metabolism. We conclude that WBM contain a variety of compounds with potential anti-inflammatory and antioxidant health benefits that can occur with frequent consumption over time in adults predisposed to T2D. Well-controlled studies are needed to confirm these findings and identify the specific mushroom components beneficial to health. C1 [Calvo, Mona S.] US FDA, Ctr Food Safety & Appl Nutr, MOD-1,HFS-025,8301 Muirkirk Rd, Laurel, MD 20708 USA. [Mehrotra, Anita; Nadkarni, Girish; Uribarri, Jaime] Icahn Sch Med Mt Sinai, Dept Med, 1 Gustave L Levy Pl,Box 1147, New York, NY 10029 USA. [Beelman, Robert B.; Kalaras, Michael D.] Penn State Univ, Dept Food Sci, 202 Rodney A Erickson Food Sci Bldg, University Pk, PA 16802 USA. [Wang, Lingzhi; Goh, Boon Cher] Natl Univ Singapore, Canc Sci Inst, 14 Med Dr, Singapore 117599, Singapore. [Cai, Weijing] Icahn Sch Med Mt Sinai, Dept Geriatr, 1 Gustave L Levy Pl, New York, NY 10029 USA. RP Uribarri, J (reprint author), Icahn Sch Med Mt Sinai, Dept Med, 1 Gustave L Levy Pl,Box 1147, New York, NY 10029 USA. EM Jaime.uribarri@mssm.edu FU Mushroom Council; Australian Mushroom Growers Council FX This study was made possible by funding from the Mushroom Council and the Australian Mushroom Growers Council, neither of which participated in the study design, data collection, data analysis or interpretation of results, or manuscript preparation. NR 30 TC 1 Z9 1 U1 11 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0921-9668 EI 1573-9104 J9 PLANT FOOD HUM NUTR JI Plant Food Hum. Nutr. PD SEP PY 2016 VL 71 IS 3 BP 245 EP 251 DI 10.1007/s11130-016-0552-7 PG 7 WC Plant Sciences; Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics SC Plant Sciences; Chemistry; Food Science & Technology; Nutrition & Dietetics GA EA8MA UT WOS:000386887700004 PM 27193019 ER PT J AU Gruber, S Chakravarty, A Heckbert, SR Levenson, M Martin, D Nelson, JC Psaty, BM Pinheiro, S Reich, CG Toh, S Walker, AM AF Gruber, Susan Chakravarty, Aloka Heckbert, Susan R. Levenson, Mark Martin, David Nelson, Jennifer C. Psaty, Bruce M. Pinheiro, Simone Reich, Christian G. Toh, Sengwee Walker, Alexander M. TI Design and analysis choices for safety surveillance evaluations need to be tuned to the specifics of the hypothesized drug-outcome association SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE medical product safety; monitoring; electronic health records; insurance claim data; pharmacoepidemiology ID PARTNERSHIP AB BackgroundWe reviewed the results of the Observational Medical Outcomes Research Partnership (OMOP) 2010 Experiment in hopes of finding examples where apparently well-designed drug studies repeatedly produce anomalous findings. OMOP had applied thousands of designs and design parameters to 53 drug-outcome pairs across 10 electronic data resources. Our intent was to use this repository to elucidate some sources of error in observational studies. MethodFrom the 2010 OMOP Experiment, we sought drug-outcome-method combinations (DOMCs) that met consensus design criteria, yet repeatedly produced results contrary to expectation. We set aside DOMCs for which we could not agree on the suitability of the designs, then selected for an in-depth scrutiny one drug-outcome pair analyzed by a seemingly plausible methodological approach, whose results consistently disagreed with the a priori expectation. ResultsThe OMOP all-by-all assessment of possible DOMCs yielded many combinations that would not be chosen by researchers as actual study options. Among those that passed a first level of scrutiny, two of seven drug-outcome pairs for which there were plausible research designs had anomalous results. The use of benzodiazepines was unexpectedly associated with acute renal failure and upper gastrointestinal bleeding. We chose the latter as an example for in-depth study. The factitious appearance of a bleeding risk may have been partly driven by an excess of procedures on the first day of treatment. A risk window definition that excluded the first day largely removed the spurious association. ConclusionOne cause of reproducible error may be repeated failure to tie design choices closely enough to the research question at hand. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Gruber, Susan] Reagan Udall Fdn FDA, Innovat Med Evidence Dev & Surveillance, Washington, DC USA. [Gruber, Susan; Toh, Sengwee] Harvard Med Sch, Dept Populat Med, Landmark Ctr 401 Pk Dr,Suite 401, Boston, MA 02215 USA. [Gruber, Susan; Toh, Sengwee] Harvard Pilgrim Hlth Care Inst, Landmark Ctr 401 Pk Dr,Suite 401, Boston, MA 02215 USA. [Chakravarty, Aloka; Levenson, Mark] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Heckbert, Susan R.; Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Martin, David] US FDA, Off Ctr Director, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Nelson, Jennifer C.] Univ Washington, Dept Biostat, Grp Hlth Res Inst, Biostat Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Pinheiro, Simone] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Reich, Christian G.] IMS Hlth, RWE Syst, Burlington, MA USA. [Walker, Alexander M.] WHISCON, Newton, MA USA. RP Gruber, S (reprint author), Harvard Med Sch, Dept Populat Med, Landmark Ctr 401 Pk Dr,Suite 401, Boston, MA 02215 USA.; Gruber, S (reprint author), Harvard Pilgrim Hlth Care Inst, Landmark Ctr 401 Pk Dr,Suite 401, Boston, MA 02215 USA. EM sgruber@hsph.harvard.edu RI Toh, Sengwee/D-7567-2017 OI Toh, Sengwee/0000-0002-5160-0810 FU Reagan-Udall Foundation; US Food and Drug Administration FX Research sponsors: The Reagan-Udall Foundation for the FDA provided salary support for SG and funding to WHISCON, AW's employer. The US Food and Drug Administration provided salary support for AC, ML, DM, and SP. NR 5 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2016 VL 25 IS 9 BP 973 EP 981 DI 10.1002/pds.4065 PG 9 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DW4VX UT WOS:000383642200001 PM 27418432 ER PT J AU Eworuke, E Shaya, F Graham, DJ Major, J Levenson, M Chen, CY Leishear, K Pinheiro, S AF Eworuke, Efe Shaya, Fadia Graham, David J. Major, Jacqueline Levenson, Mark Chen, Chih-Ying Leishear, Kira Pinheiro, Simone TI Strategies addressing inadequate information on health factors in pharmacoepidemiology studies relying on healthcare databases: commentary from a public workshop SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Editorial Material ID ANGIOTENSIN RECEPTOR BLOCKERS; LONG-TERM USE; CANCER; RISK; COHORT; DRUGS C1 [Eworuke, Efe; Major, Jacqueline; Chen, Chih-Ying; Leishear, Kira; Pinheiro, Simone] US FDA, Div Epidemiol, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol,Ctr Drug Evaluat & R, Silver Spring, MD USA. [Shaya, Fadia] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. [Graham, David J.] US FDA, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Levenson, Mark] US FDA, Off Biostat, Silver Spring, MD USA. RP Eworuke, E (reprint author), US FDA, Div Epidemiol DEPI 2 2, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol,Ctr Drug Evaluat & R, 10903 New Hampshire Ave,Bldg 22, Silver Spring, MD 20903 USA. EM efe.eworuke@fda.hhs.gov NR 11 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2016 VL 25 IS 9 BP 998 EP 1001 DI 10.1002/pds.4060 PG 4 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DW4VX UT WOS:000383642200004 PM 27385063 ER PT J AU Mott, K Graham, DJ Toh, S Gagne, JJ Levenson, M Ma, Y Reichman, ME AF Mott, Katrina Graham, David J. Toh, Sengwee Gagne, Joshua J. Levenson, Mark Ma, Yong Reichman, Marsha E. TI Uptake of new drugs in the early post-approval period in the Mini-Sentinel distributed database SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE active surveillance; drug safety; distributed databases; new molecular entities; Sentinel; pharmacoepidemiology; pharmacoepidemiology ID ACUTE MYOCARDIAL-INFARCTION; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; RISK; SYSTEM; THIAZOLIDINEDIONES; POPULATION; MORTALITY; STROKE; TRENDS; SAFETY AB PurposeSeveral factors limit the statistical power of drug safety surveillance during the early post-approval period, including uptake of the drug and lag in data availability. This study characterized new drug uptake in the Mini-Sentinel Distributed Database and determined statistical power to detect levels of risk in post-launch safety assessments. MethodsThe cumulative exposure among initiators of 46 new molecular entities approved from 2008 to 2011 was assessed. Using a Poisson estimation method, minimum incidence rate ratios (IRRs) detectable, with 80% power, were calculated under varying background incidence rates. ResultsTwelve products (26.1%) had more than 15000 new users after 2years. With comparator group incidence rate of 1/1000 person-years, 16 (33.3%) products had enough exposure to detect an IRR of 5 with 24months of data collected that would be available for assessment at 33months post-launch. With an incidence rate of 5/1000 person-years, 23 (50%) products had enough exposure to detect an IRR of 3 with 2years of data collected. At 33months post-launch, only two (4.3%) of the drugs examined had enough data availability to detect IRR of <2, and eight (17.4%) of <3, with a background rate of 1/1000 person-years. ConclusionThis study highlights the importance of drug uptake and data availability in early post-approval drug safety surveillance in Mini-Sentinel. There is limited ability to detect rate ratios below three for events with background rates of 1/1000 person-years or lower. This is largely due to low product uptake. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Mott, Katrina; Graham, David J.; Reichman, Marsha E.] US FDA, CDER Off Surveillance & Epidemiol, Silver Spring, MD USA. [Mott, Katrina] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Toh, Sengwee] Harvard Med Sch, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Gagne, Joshua J.] Harvard Med Sch, Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Dept Med, Boston, MA USA. [Levenson, Mark; Ma, Yong] US FDA, CDER Off Biostat, Silver Spring, MD USA. RP Mott, K (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM kam417@mail.harvard.edu RI Toh, Sengwee/D-7567-2017 OI Toh, Sengwee/0000-0002-5160-0810 FU U.S. Food and Drug Administration [HHSF223200910006I, HHSF22301007T] FX This study was supported through funding from contract HHSF223200910006I, Task Order # HHSF22301007T from the U.S. Food and Drug Administration. This project was supported in part by an appointment to the ORISE Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an agreement between the U.S. Department of Energy and CDER. NR 27 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2016 VL 25 IS 9 BP 1023 EP 1032 DI 10.1002/pds.4013 PG 10 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DW4VX UT WOS:000383642200008 PM 27146123 ER PT J AU Siskey, R Peck, J Mehta, H Kosydar, A Kurtz, S Hill, G AF Siskey, Ryan Peck, Jonathan Mehta, Hitesh Kosydar, Allison Kurtz, Steven Hill, Genevieve TI Development of a clinically relevant impingement test method for a mobile bearing lumbar total disc replacement SO SPINE JOURNAL LA English DT Article DE Cobalt chrome; Explant analysis; Impingement; Retrieval analysis; Total disc arthroplasty; Total disc replacement; Ultra-high molecular weight polyethylene; Wear ID RETRIEVAL-ANALYSIS; POLYETHYLENE WEAR; PERFORMANCE; DEVICES; MOTION; SPINE AB BACKGROUND CONTEXT: Total disc arthroplasty is an alternative therapy to spinal fusion for the treatment of neck or low back pain and is hypothesized to reduce the risk of disease progression to the adjacent spinal levels. Radiographic and retrieval analyses of various total disc replacements (TDRs) have shown evidence of impingement damage. Impingement of TDRs can occur when the device reaches the limits of its functional range of motion, causing contact between peripheral regions of the device. PURPOSE: Impingement can be associated with increased wear and mechanical damage; however, impingement conditions are not simulated in current standardized mechanical bench test methods. This study explored the test conditions necessary to apply clinically relevant impingement loading to a lumbar TDR in vitro. STUDY DESIGN: An experimental protocol was developed and evaluated using in vivo retrievals for qualitative and quantitative validation. METHODS: Retrieval analysis was conducted on a set of 11 size 3 retrieved Charite devices using American Society for Testing and Materials F561 as a guide. The impingement range of motion was determined using a combination of modeling and experiments, and was used as an input in vitro testing. A 1-million cycle in vitro test was then conducted, and the in vitro samples were characterized using methods similar to the retreived devices. RESULTS: All in vitro tested samples exhibited impingement regions and damage patterns consistent with retrieved devices. Consistent with the retrievals, the impingement damage on the rim was a combination of abrasive wear and plastic deformation. Micro computed tomography (microCT) was used to quantitatively assess rim damage due to impingement. Rim penetration was statistically lower in the retrievals when compared with both in vitro groups. Rim elongation was comparable among all groups. The simulated-facet group had statistically greater angular rim deformations than the retrieval group and the no-facet group. CONCLUSIONS: Results demonstrate that clinically relevant impingement seen on mobile bearings of lumbar TDRs can be replicated on the bench. (C) 2016 Elsevier Inc. All rights reserved. C1 [Siskey, Ryan; Kosydar, Allison; Kurtz, Steven] Exponent Inc, Philadelphia, PA USA. [Siskey, Ryan; Kosydar, Allison; Kurtz, Steven] Drexel Univ, Philadelphia, PA 19104 USA. [Peck, Jonathan; Mehta, Hitesh; Hill, Genevieve] US FDA, Bldg 66,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Siskey, R (reprint author), 3440 Market St,Suite 600, Philadelphia, PA 19104 USA. EM rsiskey@exponent.com FU FDA's Critical Path Initiative [GS23F0390K-HHSF223200930112G] FX This project is supported by the FDA's Critical Path Initiative (Grant number: GS23F0390K-HHSF223200930112G). We would like to thank Drs. Srinidhi Nagaraja, John Bowsher, and Ross Ormsby for their technical discussions related to the project. NR 27 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1529-9430 EI 1878-1632 J9 SPINE J JI Spine Journal PD SEP PY 2016 VL 16 IS 9 BP 1133 EP 1142 DI 10.1016/j.spinee.2016.05.004 PG 10 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA EA1RD UT WOS:000386368700047 PM 27179625 ER PT J AU Ho, M Saha, A McCleary, KK Levitan, B Christopher, S Zandlo, K Braithwaite, RS Hauber, AB AF Ho, Martin Saha, Anindita McCleary, K. Kimberly Levitan, Bennett Christopher, Stephanie Zandlo, Kristen Braithwaite, R. Scott Hauber, A. Brett CA Med Device Innovation Consortium's TI A Framework for Incorporating Patient Preferences Regarding Benefits and Risks into Regulatory Assessment of Medical Technologies SO VALUE IN HEALTH LA English DT Article DE patient-derived preferences; preference-based measures; preferences; regulatory AB Background: In response to 2012 guidance in which the US Food and Drug Administration's (FDA) Center for Devices and Radiological Health (CDRH) stated the importance of patient-centric measures in regulatory benefit-risk assessments, the Medical Device Innovation Consortium (MDIC) initiated a project. The project was used to develop a framework to help the Food and Drug Administration (FDA) and industry sponsors understand how patient preferences regarding benefit and risk might be integrated into the review of innovative medical devices. Methods: A public-private partnership of experts from medical device industry, government, academia and non-profits collaborated on development of the MDIC patient centered benefit-risk framework. Results: The MDIC Framework examines what patient preference information is and the potential use and value of patient preference information in the regulatory process and across the product development life cycle. The MDIC Framework also includes a catalog of patient preference assessment methods and an agenda for future research to advance the field. Conclusions: This article discusses key concepts in patient preference assessment of particular importance for regulators and researchers that are addressed in the MDIC Framework for patient centered benefit-risk assessment as well as the unique public-private collaboration that led its development. C1 [Ho, Martin; Saha, Anindita] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [McCleary, K. Kimberly] FasterCures, Milken Inst, Washington, DC USA. [Levitan, Bennett] Janssen Res & Dev LLC, Titusville, NJ USA. [Christopher, Stephanie; Zandlo, Kristen] Med Device Innovat Consortium, 100 North Sixth St,Suite 989C, Minneapolis, MN 55403 USA. [Braithwaite, R. Scott] NYU Sch Med, Dept Populat Hlth, New York, NY USA. [Hauber, A. Brett] RTI Hlth Solut, Res Triangle Pk, NC USA. RP Christopher, S (reprint author), Med Device Innovat Consortium, 100 North Sixth St,Suite 989C, Minneapolis, MN 55403 USA. EM schristopher@mdic.org FU Broad Agency Agreement from the Food and Drug Administration [BAA HHSF223201400011C] FX Funding for the Framework and the Catalog came from a Broad Agency Agreement from the Food and Drug Administration (BAA HHSF223201400011C, "Patient-Centeredness: Integrating Patient Preference into Regulatory Submission"). NR 11 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD SEP-OCT PY 2016 VL 19 IS 6 BP 746 EP 750 DI 10.1016/j.jval.2016.02.019 PG 5 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA DZ5VS UT WOS:000385930500010 PM 27712701 ER PT J AU Woodle, S Liang, YD Monteil, D Lee, T Ovanesov, M AF Woodle, Samuel Liang, Yideng Monteil, Dominique Lee, Timothy Ovanesov, Mikhail TI IMPACT OF FLUOROGENIC SUBSTRATE ARTIFACTS AND ARTIFACT CORRECTION ALGORITHMS ON THROMBIN GENERATION TEST PARAMETERS IN NORMAL AND HEMOPHILIA PLASMA SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Meeting Abstract C1 [Woodle, Samuel; Liang, Yideng; Monteil, Dominique; Lee, Timothy; Ovanesov, Mikhail] US FDA, CBER, 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 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD SEP PY 2016 VL 91 IS 9 MA F33 BP E411 EP E411 PG 1 WC Hematology SC Hematology GA DY6LT UT WOS:000385237100111 ER PT J AU Greenberg, RG Melloni, C Wu, H Gonzalez, D Ku, L Hill, KD Hornik, CP Cohen-Wolkowiez, M Guptill, JT AF Greenberg, Rachel G. Melloni, Chiara Wu, Huali Gonzalez, Daniel Ku, Lawrence Hill, Kevin D. Hornik, Christoph P. Cohen-Wolkowiez, Michael Guptill, Jeffrey T. TI Therapeutic Index Estimation of Antiepileptic Drugs: A Systematic Literature Review Approach SO CLINICAL NEUROPHARMACOLOGY LA English DT Review DE antiepileptic drugs; narrow therapeutic index; carbamazepine; lamotrigine; phenobarbital; phenytoin; valproate; valproic acid ID NEWLY-DIAGNOSED EPILEPSY; RANDOMIZED CONTROLLED-TRIAL; TONIC-CLONIC SEIZURES; CONTROLLED-RELEASE CARBAMAZEPINE; DOUBLE-BLIND; SODIUM VALPROATE; PLASMA-LEVELS; SERUM-LEVELS; ANTICONVULSANT DRUGS; LAMOTRIGINE MONOTHERAPY AB Objectives Our study aimed to determine whether data obtained from the medical literature can be used to estimate the therapeutic index of 5 antiepileptic drugs (AEDs): carbamazepine, lamotrigine, phenobarbital, phenytoin, and valproate. Methods We performed a literature search using PubMed and EMBASE to collect published safety, efficacy, and therapeutic monitoring data for 5 AEDs and extracted all relevant information into a drug- and study-specific drug database. For each AED, we summarized (1) type, severity, and incidence of toxicity-related adverse events and toxicity-associated range of drug doses or concentrations; (2) effective versus toxic concentration and dose (therapeutic range); and (3) therapeutic drug monitoring practices. We defined therapeutic index as the ratio of the minimum toxic concentration to the minimum effective concentration. Results We reviewed a total of 810 full-text articles and extracted data from 163. The literature suggests that the therapeutic index of phenytoin is 2. The therapeutic indices of phenobarbital and valproate exceed 2. There were insufficient data to precisely quantify the therapeutic indices of carbamazepine and lamotrigine. Conclusions For some drugs, this approach offers a low-cost method of therapeutic index estimation. Our results can serve as preliminary data for future trials and as guidance for US Food and Drug Administration decision making regarding narrow therapeutic index classification. C1 [Greenberg, Rachel G.; Melloni, Chiara; Wu, Huali; Ku, Lawrence; Hill, Kevin D.; Hornik, Christoph P.; Cohen-Wolkowiez, Michael; Guptill, Jeffrey T.] Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. [Gonzalez, Daniel] Univ N Carolina, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. [Gonzalez, Daniel] US FDA, Off Gener Drugs, Silver Spring, MD USA. RP Greenberg, RG (reprint author), Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM jeffrey.guptill@duke.edu FU US Food and Drug Administration (FDA) [NIH3U01FD00485801]; National Institutes of Health (NIH) [5T32HD043728-10, 5T32HD043029-13]; National Institute for Child Health and Human Development (NICHD) [HHSN275201000003I]; FDA [3U01FD004858-01, 1U01FD004858-01]; NICHD [K23HD083465]; National Center for Advancing Translational Sciences (NCATS) of the NIH [UL1TR001117]; NCATS of the NIH [UL1TR001117]; NIH [1R01-HD076676-01A1]; NIAID [HHSN275201000003I, HHSN272201500006I, HHSN272201300017I]; Biomedical Advanced Research and Development Authority [HHSO100201300009C]; National Institute of Neurological Disorders and Stroke [K23NS085049-01A1]; Myasthenia Gravis Foundation of America FX This study was supported by a grant from the US Food and Drug Administration (FDA): NIH3U01FD00485801. R.G. received funding from the National Institutes of Health (NIH) training grants (5T32HD043728-10 and 5T32HD043029-13). C.M. received funding from industry for drug development in adults (https://dcri.org/about-us/conflict-of-interest), and from the National Institute for Child Health and Human Development (NICHD) (HHSN275201000003I) and the FDA (3U01FD004858-01). D.G. is funded by the nonprofit Thrasher Research Fund (www.thrasherresearch.org), and by the NICHD (K23HD083465). K.H. receives research support from industry for drug development in children (www.dcri.duke.edu/research/coi.jsp), the nonprofit Mend-A-Heart Foundation (www. medaheart. org), and from the National Center for Advancing Translational Sciences (NCATS) of the NIH (UL1TR001117). C.H. receives salary support for research from the NCATS of the NIH (UL1TR001117). M.C.-W. receives research support from industry for drug development in adults and children (www.dcri.duke.edu/research/coi.jsp), the nonprofit Thrasher Research Fund (www.thrasherresearch.org), and from the NIH (1R01-HD076676-01A1), the NCATS of the NIH (UL1TR001117), the NIAID (HHSN272201500006I and HHSN272201300017I), the NICHD (HHSN275201000003I), the FDA (1U01FD004858-01), and the Biomedical Advanced Research and Development Authority (HHSO100201300009C). J.G. receives support from industry for drug development in adults (www. dcri. duke. edu/research/coi. jsp), from National Institute of Neurological Disorders and Stroke (K23NS085049-01A1), the Myasthenia Gravis Foundation of America, and the NICHD (HHSN275201000003I). For the remaining authors none were declared. NR 82 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0362-5664 EI 1537-162X J9 CLIN NEUROPHARMACOL JI Clin. Neuropharmacol. PD SEP-OCT PY 2016 VL 39 IS 5 BP 232 EP 240 DI 10.1097/WNF.0000000000000172 PG 9 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DZ2HT UT WOS:000385663600004 PM 27428884 ER PT J AU Mehdi, SJ Rosas-Hernandez, H Cuevas, E Lantz, SM Barger, SW Sarkar, S Paule, MG Ali, SF Imam, SZ AF Mehdi, Syed Jafar Rosas-Hernandez, Hector Cuevas, Elvis Lantz, Susan M. Barger, Steven W. Sarkar, Sumit Paule, Merle G. Ali, Syed F. Imam, Syed Z. TI Protein Kinases and Parkinson's Disease SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Review DE Parkinson's disease; dopamine; tyrosine kinase; serine/threonine kinase; kinase inhibitors ID CEREBELLAR GRANULE NEURONS; DOPAMINERGIC CELL-DEATH; G2019S LRRK2 MUTATION; JNK ACTIVATION; MOUSE MODEL; IN-VIVO; C-ABL; SIGNALING PATHWAY; INDUCED APOPTOSIS; TYROSINE KINASES AB Currently, the lack of new drug candidates for the treatment of major neurological disorders such as Parkinson's disease has intensified the search for drugs that can be repurposed or repositioned for such treatment. Typically, the search focuses on drugs that have been approved and are used clinically for other indications. Kinase inhibitors represent a family of popular molecules for the treatment and prevention of various cancers, and have emerged as strong candidates for such repurposing because numerous serine/threonine and tyrosine kinases have been implicated in the pathobiology of Parkinson's disease. This review focuses on various kinase-dependent pathways associated with the expression of Parkinson's disease pathology, and evaluates how inhibitors of these pathways might play a major role as effective therapeutic molecules. C1 [Mehdi, Syed Jafar; Barger, Steven W.; Imam, Syed Z.] Univ Arkansas Med Sci, Dept Geriatr, Little Rock, AR 72205 USA. [Rosas-Hernandez, Hector; Cuevas, Elvis; Lantz, Susan M.; Sarkar, Sumit; Paule, Merle G.; Ali, Syed F.; Imam, Syed Z.] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Barger, Steven W.] Cent Arkansas Vet Healthcare Syst, Ctr Geriatr Res Educ & Clin, Little Rock, AR 72205 USA. RP Imam, SZ (reprint author), Univ Arkansas Med Sci, Dept Geriatr, Little Rock, AR 72205 USA.; Imam, SZ (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM SJMehdi@uams.edu; Hector.Rosas-Hernandez@fda.hhs.gov; Elvis-Yane.Cuevas-Martinez@fda.hhs.gov; Susan.Lantz@fda.hhs.gov; BargerStevenW@uams.edu; Sumit.Sarkar@fda.hhs.gov; Merle.Paule@fda.hhs.gov; Syed.Ali@fda.hhs.gov; Syed.Imam@fda.hhs.gov FU National Center for Toxicological Research/USFDA [E0746601] FX This study was supported by protocol E0746601 National Center for Toxicological Research/USFDA. The entire manuscript was reviewed and edited by Mugimane Manjanataha, NCTR/USFDA. NR 92 TC 0 Z9 0 U1 7 U2 7 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD SEP PY 2016 VL 17 IS 9 AR 1585 DI 10.3390/ijms17091585 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA DZ0JU UT WOS:000385525500198 ER PT J AU Pazo, DY Moliere, F Sampson, MM Reese, CM Agnew-Heard, KA Walters, MJ Holman, MR Blount, BC Watson, CH Chambers, DM AF Pazo, Daniel Y. Moliere, Fallon Sampson, Maureen M. Reese, Christopher M. Agnew-Heard, Kimberly A. Walters, Matthew J. Holman, Matthew R. Blount, Benjamin C. Watson, Clifford H. Chambers, David M. TI Mainstream Smoke Levels of Volatile Organic Compounds in 50 US Domestic Cigarette Brands Smoked With the ISO and Canadian Intense Protocols SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID TOBACCO-SPECIFIC NITROSAMINES; COMMERCIAL CIGARETTES; BENZENE; MARKET AB A significant portion of the increased risk of cancer and respiratory disease from exposure to cigarette smoke is attributed to volatile organic compounds (VOCs). In this study, 21 VOCs were quantified in mainstream cigarette smoke from 50U.S. domestic brand varieties that included high market share brands and 2 Kentucky research cigarettes (3R4F and 1R5F). Mainstream smoke was generated under ISO 3308 and Canadian Intense (CI) smoking protocols with linear smoking machines with a gas sampling bag collection followed by solid phase microextraction/gas chromatography/mass spectrometry (SPME/GC/MS) analysis. For both protocols, mainstream smoke VOC amounts among the different brand varieties were strongly correlated between the majority of the analytes. Overall, Pearson correlation (r) ranged from 0.68 to 0.99 for ISO and 0.36 to 0.95 for CI. However, monoaromatic compounds were found to increase disproportionately compared to unsaturated, nitro, and carbonyl compounds under the CI smoking protocol where filter ventilation is blocked. Overall, machine generated "vapor phase" amounts (A mu g/cigarette) are primarily attributed to smoking protocol (e.g., blocking of vent holes, puff volume, and puff duration) and filter ventilation. A possible cause for the disproportionate increase in monoaromatic compounds could be increased pyrolysis under low oxygen conditions associated with the CI protocol. This is the most comprehensive assessment of volatile organic compounds (VOCs) in cigarette smoke to date, encompassing 21 toxic VOCs, 50 different cigarette brand varieties, and 2 different machine smoking protocols (ISO and CI). For most analytes relative proportions remain consistent among U.S. cigarette brand varieties regardless of smoking protocol, however the CI smoking protocol did cause up to a factor of 6 increase in the proportion of monoaromatic compounds. This study serves as a basis to assess VOC exposure as cigarette smoke is a principle source of overall population-level VOC exposure in the United States. C1 [Pazo, Daniel Y.; Moliere, Fallon; Sampson, Maureen M.; Reese, Christopher M.; Blount, Benjamin C.; Watson, Clifford H.; Chambers, David M.] US Ctr Dis Control & Prevent, Div Lab Sci, Natl Ctr Environm Hlth, 4770 Buford Highway,F-47, Atlanta, GA 30341 USA. [Agnew-Heard, Kimberly A.; Walters, Matthew J.; Holman, Matthew R.] US FDA, Off Sci, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Chambers, DM (reprint author), US Ctr Dis Control & Prevent, Div Lab Sci, Natl Ctr Environm Hlth, 4770 Buford Highway,F-47, Atlanta, GA 30341 USA. EM mzz7@cdc.gov FU U.S. Food and Drug Administration Center for Tobacco Products [IAA: 224-10-9022] FX This study was funded by an interagency agreement (IAA) by the U.S. Food and Drug Administration Center for Tobacco Products (IAA: 224-10-9022). NR 27 TC 1 Z9 1 U1 4 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD SEP PY 2016 VL 18 IS 9 BP 1886 EP 1894 DI 10.1093/ntr/ntw118 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA DZ1WE UT WOS:000385631500012 PM 27113015 ER PT J AU Metzger, CE Baek, K Swift, SN De Souza, MJ Bloomfield, SA AF Metzger, C. E. Baek, K. Swift, S. N. De Souza, M. J. Bloomfield, S. A. TI Exercise during energy restriction mitigates bone loss but not alterations in estrogen status or metabolic hormones SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Bone mass; Energy availability; Energy restriction; Exercise ID AIN-93 PURIFIED DIETS; INDUCED WEIGHT-LOSS; CALORIC RESTRICTION; STRESS-FRACTURES; MINERAL DENSITY; FEMALE RATS; POSTMENOPAUSAL WOMEN; PREMENOPAUSAL WOMEN; TURNOVER MARKERS; BODY-COMPOSITION AB The Summary Energy restriction causes bone loss, increasing stress fracture risk. The impact of exercise during energy restriction on bone and endocrine factors is examined. Exercise with energy restriction did not influence endocrine factors, but did mitigate some bone loss seen with energy restriction in sedentary rats. Introduction Chronic dietary energy restriction (ER) leads to bone loss and increased fracture risk. Strictly controlled trials of long-term ER with and without vigorous exercise are required to determine whether exercise loading can counterbalance ER-induced bone loss. The aim of this current project is to elucidate the impact of exercise and ER on bone mass, estrogen status, and metabolic hormones. Methods Twenty-four virgin female Sprague-Dawley rats (n= 8/group) were divided into three groups-ad libitum fed+exercise (Adlib+EX), 40 % energy restricted+exercise (ER+EX), and 40% energy restricted+sedentary (ER+SED). Energy availability between ER groups was equal. Treadmill running was performed 4 days/week at 70 % VO2max for 12 weeks. Results Fat and lean mass and areal bone mineral density (aBMD) were lower after 12 weeks (p<0.05) for ER+EX vs Adlib+EX, but ER+EX aBMD was higher than ER+SED (p<0.0001). Serum leptin and a urinary estrogen metabolite, estrone-1-glucuronide (E1G), were lower at week 12 (p=0.0002) with ER, with no impact of exercise. Serum insulin-like growth factor I (IGF-I) declined (p=0.02) from baseline to week 12 in both ER groups. ER+EX exhibited higher cortical volumetric bone mineral density (vBMD) at the midshaft tibia (p=0.006) vs ER+SED. Conclusion Exercise during ER mitigated some, but not all, of the bone loss observed in sedentary ER rats, but had little impact on changes in urinary E1G and serum IGF-I and leptin. These data highlight the importance of both adequate energy intake and the mechanical loading of exercise in maintaining bone mass. C1 [Metzger, C. E.; Baek, K.; Bloomfield, S. A.] Texas A&M Univ, Dept Hlth & Kinesiol, College Stn, TX 77843 USA. [Baek, K.] Gangneung Wonju Natl Univ, Coll Dent & Res Oral Sci, Dept Pharmacol, Gangwondo, South Korea. [Swift, S. N.] US FDA, Div Dietary Supplement Programs, College Pk, MD USA. [Swift, S. N.] Texas A&M Univ, Dept Nutr & Food Sci, College Stn, TX USA. [De Souza, M. J.; Bloomfield, S. A.] Penn State Univ, Dept Kinesiol, State Coll, PA 16801 USA. [De Souza, M. J.; Bloomfield, S. A.] Penn State Univ, Dept Physiol, State Coll, PA 16801 USA. RP Bloomfield, SA (reprint author), Texas A&M Univ, Dept Hlth & Kinesiol, College Stn, TX 77843 USA.; Bloomfield, SA (reprint author), Penn State Univ, Dept Kinesiol, State Coll, PA 16801 USA.; Bloomfield, SA (reprint author), Penn State Univ, Dept Physiol, State Coll, PA 16801 USA. EM sbloom@tamu.edu FU United States Department of Defense [WSIXWH-06-1-0479Z] FX Support for this study was provided by the United States Department of Defense Grant No. WSIXWH-06-1-0479Z. The authors gratefully acknowledge the animal husbandry assistance of Jan Stallone, Samantha Manning, and Julia Lemmon and performance of endocrine assay by the Pennsylvania State University Women's Health and Exercise Laboratory. NR 42 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD SEP PY 2016 VL 27 IS 9 BP 2755 EP 2764 DI 10.1007/s00198-016-3590-y PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DZ2LD UT WOS:000385672400013 PM 27129456 ER PT J AU Zimmerman, K Putera, M Hornik, CP Smith, PB Benjamin, DK Mulugeta, Y Burckart, GJ Cohen-Wolkowiez, M Gonzalez, D AF Zimmerman, Kanecia Putera, Martin Hornik, Christoph P. Smith, P. Brian Benjamin, Daniel K., Jr. Mulugeta, Yeruk Burckart, Gilbert J. Cohen-Wolkowiez, Michael Gonzalez, Daniel TI Exposure Matching of Pediatric Anti-infective Drugs: Review of Drugs Submitted to the Food and Drug Administration for Pediatric Approval SO CLINICAL THERAPEUTICS LA English DT Review DE anti-infectives; exposure matching; pediatrics; pharmacodynamics; pharmacokinetics ID CHILDREN AB Purpose: Over the last decade, few new antibiotics have been approved by the Food and Drug Administration (FDA) for pediatric use. For most anti-infective agents, including antibiotics, extrapolation of efficacy from adults to children is possible if the disease and therapeutic exposures are similar between the 2 populations. This approach reduces the number of studies required in children, but relies heavily on exposure matching between children and adults. Failures in exposure matching can lead to delays in pediatric approvals of new anti-infective agents. We sought to determine the extent of exposure matching, defined by a comparison of area under the concentration-time curve, between children and adults, for anti-infective drug products submitted to the FDA for approval. Methods: We reviewed anti-infective submissions to the FDA (2002-2014) for pediatric indication. We included drug products administered via oral, intravenous, or intramuscular administration routes, and those with AUC estimates for children in available FDA reports. Our main outcome of interest was the proportion of drugs with median (or mean) pediatric AUC within 20% of the median (or mean) reported adult value. Findings: We identified 29 drug products that met inclusion criteria, 14 (48%) of which had mean (or median) AUCs of all submitted age groups within 20% of that in adults. Only route of administration and drug class were associated with pediatric AUC within 20% of adult AUC. Implications: Future research is needed to define criteria for and predictors of successful exposure matching of anti-infectives between children and adults. C1 [Zimmerman, Kanecia; Putera, Martin; Hornik, Christoph P.; Smith, P. Brian; Benjamin, Daniel K., Jr.; Cohen-Wolkowiez, Michael] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Zimmerman, Kanecia; Hornik, Christoph P.; Smith, P. Brian; Benjamin, Daniel K., Jr.; Cohen-Wolkowiez, Michael] Duke Univ, Dept Pediat, Sch Med, Durham, NC 27706 USA. [Mulugeta, Yeruk; Burckart, Gilbert J.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Gonzalez, Daniel] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. RP Cohen-Wolkowiez, M (reprint author), Duke Univ, Dept Pediat, Campus Box 3499 DUMC, Durham, NC 27710 USA. EM michael.cohenwolkowiez@duke.edu FU Duke Clinical and Translational Science Awards [KL2TR001115-03]; National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) [UL1TR001117]; NIH [2K24HD 058735-06, 1R01-HD076676-01A1]; National Center for Advancing Translational Sciences of the NIH [UL1TR001117]; National Institute for Child Health and Human Development (NICHD) [HHSN275201000003I, 1R01-HD081044-01, HHSN2752010000031, K23HD083465]; Food and Drug Administration [1R18-FD005292-01, 1U01FD004858-01]; NIH (National Center for Advancing Translational Sciences) [UL1TR001117]; NIH (National Institute of Allergy and Infectious Diseases) [HHSN272201500006I, HHSN 2722015000061, HHSN2722013000171]; Biomedical Advanced Research and Development Authority [HHS0100201300009C]; nonprofit organization Thrasher Research Fund; nonprofit Thrasher Research Fund; National Center for Advancing Translational Sciences [UL1TR001117] FX Dr. Zimmerman is funded by grant KL2TR001115-03 from the Duke Clinical and Translational Science Awards. Dr. Hornik receives salary support for research from the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under award number UL1TR001117. Dr. Smith receives salary support for research from the NIH and the National Center for Advancing Translational Sciences of the NIH (award UL1TR001117), the National Institute for Child Health and Human Development (NICHD) (contract HHSN275201000003I and grant 1R01-HD081044-01), and the Food and Drug Administration (grant 1R18-FD005292-01). Dr. Benjamin receives support from the NIH (award 2K24HD 058735-06, National Center for Advancing Translational Sciences award UL1TR001117, NICHD contract HHSN2752010000031, and National Institute of Allergy and Infectious Diseases contract HHSN272201500006I). Dr. Cohen-Wolkowiez receives support for research from the NIH (grant 1R01-HD076676-01A1), the National Center for Advancing Translational Sciences (award UL1TR001117), the National Institute of Allergy and Infectious Diseases (contracts HHSN 2722015000061 and HHSN2722013000171), the NICHD (contract HHSN2752010000031), the Food and Drug Administration (grant 1U01FD004858-01), the Biomedical Advanced Research and Development Authority (contract HHS0100201300009C), and the nonprofit organization Thrasher Research Fund (www.thrasherresearch.org). Dr. Gonzalez is funded by K23HD083465 from the NICHD and by the nonprofit Thrasher Research Fund (www.thrasherresearch.org). NR 17 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER PI BRIDGEWATER PA 685 ROUTE 202-206, BRIDGEWATER, NJ 08807 USA SN 0149-2918 EI 1879-114X J9 CLIN THER JI Clin. Ther. PD SEP PY 2016 VL 38 IS 9 BP 1995 EP 2005 DI 10.1016/j.clinthera.2016.06.003 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DY3AN UT WOS:000384963300007 PM 27364807 ER PT J AU Banda, M Mckim, KL Parsons, BL AF Banda, M. Mckim, K. L. Parsons, B. L. TI Establishing a Model to Identify Mutant Subpopulations That Cause Resistance to Molecularly-Targeted Cancer Therapies. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Banda, M.; Mckim, K. L.; Parsons, B. L.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA EG-49 BP S75 EP S75 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400137 ER PT J AU Dad, A Mittelstaedt, R Cao, X Heflich, RH AF Dad, A. Mittelstaedt, R. Cao, X. Heflich, R. H. TI Effect of Life Stage and Target Tissue on Dose-Response Assessment of EMS Induced Genotoxicity. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Dad, A.; Mittelstaedt, R.; Cao, X.; Heflich, R. H.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA GT-97 BP S83 EP S83 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400167 ER PT J AU Elespuru, RK AF Elespuru, R. K. TI A Revised Genotoxicity Test Battery for Nanomaterials. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Elespuru, R. K.] 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 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA S55 BP S53 EP S53 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400063 ER PT J AU Fuscoe, JC AF Fuscoe, J. C. TI Age- and Sex-Related Changes in Hepatic and Renal miRNA Expression Profiles during the Life Span of Rats. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Fuscoe, J. C.] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA S40 BP S49 EP S49 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400048 ER PT J AU Guo, X Zhang, Z Chen, S Xuan, J Couch, L Guo, L Mei, N AF Guo, X. Zhang, Z. Chen, S. Xuan, J. Couch, L. Guo, L. Mei, N. TI Role of Topoisomerase II in Ginkgo biloba Leaf Extract-Induced DNA Damage in HepG2 Cells. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Guo, X.; Zhang, Z.; Chen, S.; Xuan, J.; Couch, L.; Guo, L.; Mei, N.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA GT-79 BP S65 EP S65 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400102 ER PT J AU Mattes, WB AF Mattes, W. B. TI Biomarkers, Drug Development, and Pathways for FDA Consideration. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Mattes, W. B.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA S61 BP S54 EP S54 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400068 ER PT J AU McKinzie, PB Revollo, JR AF McKinzie, P. B. Revollo, J. R. TI Whole Genome Sequencing of Mouse Lymphoma L5178Y TK+/- Reveals Gene Mutations with Crucial Roles in Cell Physiology. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [McKinzie, P. B.; Revollo, J. R.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA EG-34 BP S64 EP S64 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400097 ER PT J AU Mei, N Zhang, Z Dial, SL Dobrovolsky, VN Guo, X AF Mei, N. Zhang, Z. Dial, S. L. Dobrovolsky, V. N. Guo, X. TI Reactive Oxygen Species and c-Jun N-Terminal Kinases Contribute to TEMPO-Induced Apoptosis in L5178Y Cells. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Mei, N.; Zhang, Z.; Dial, S. L.; Dobrovolsky, V. N.; Guo, X.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA GT-82 BP S66 EP S66 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400105 ER PT J AU Myers, MB Mckim, KL Parsons, BL AF Myers, M. B. Mckim, K. L. Parsons, B. L. TI High-Sensitivity Quantification of PIK3CA and KRAS Hotspot Point Mutations Identifies Frequent Subpopulations in Human Pancreatic and Prostate Cancers. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Myers, M. B.; Mckim, K. L.; Parsons, B. L.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA EG-48 BP S75 EP S75 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400136 ER PT J AU Parsons, BL Myers, MB Mckim, KL Banda, M AF Parsons, B. L. Myers, M. B. Mckim, K. L. Banda, M. TI Cancer Driver Mutations As Biomarkers of Cancer Risk. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Parsons, B. L.; Myers, M. B.; Mckim, K. L.; Banda, M.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA S60 BP S54 EP S54 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400067 ER PT J AU Shelton, S Townsend, T Mei, N Li, HF Manjanatha, M AF Shelton, S. Townsend, T. Mei, N. Li, H-F Manjanatha, M. TI Evaluation of cII Gene Mutation in the Brains of Big Blue Mice Exposed to Acrylamide and Glycidamide in Drinking Water. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Shelton, S.; Townsend, T.; Mei, N.; Manjanatha, M.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Li, H-F] Xinjiang Inst Food & Drug Control, Urumqi, Xinjiang, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA XB-67 BP S77 EP S77 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400145 ER PT J AU Townsend, TA Parrish, MC Bishop, ME Shelton, SD Engelward, BP Manjanatha, MG AF Townsend, T. A. Parrish, M. C. Bishop, M. E. Shelton, S. D. Engelward, B. P. Manjanatha, M. G. TI The Development and Validation of EpiComet-Chip, a Modified High-Throughput Comet Assay for the Assessment of DNA Methylation Status. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 47th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society CY SEP 24-28, 2016 CL Kansas City, MO SP Environm Mutagenesis & Genom Soc C1 [Townsend, T. A.; Bishop, M. E.; Shelton, S. D.; Manjanatha, M. G.] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Townsend, T. A.] US FDA, Silver Spring, MD USA. [Parrish, M. C.; Engelward, B. P.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2016 VL 57 SU 1 MA EG-26 BP S46 EP S46 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DW4BQ UT WOS:000383587400035 ER PT J AU Wunderlich, A Goossens, B Abbey, CK AF Wunderlich, Adam Goossens, Bart Abbey, Craig K. TI Optimal Joint Detection and Estimation That Maximizes ROC-Type Curves SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Ideal observer; receiver operating characteristic; signal detection theory; expected utility theory ID TRAUMATIC BRAIN-INJURY; OF-THE-ART; DETECTION-LOCALIZATION; OBSERVER-PERFORMANCE; IDEAL OBSERVERS; OPTIMIZATION; BIOMARKERS; STENOSIS; SIGNALS; LESIONS AB Combined detection-estimation tasks are frequently encountered in medical imaging. Optimal methods for joint detection and estimation are of interest because they provide upper bounds on observer performance, and can potentially be utilized for imaging system optimization, evaluation of observer efficiency, and development of image formation algorithms. We present a unified Bayesian framework for decision rules that maximize receiver operating characteristic (ROC)-type summary curves, including ROC, localization ROC (LROC), estimation ROC (EROC), free-response ROC (FROC), alternative free-response ROC (AFROC), and exponentially-transformed FROC (EFROC) curves, succinctly summarizing previous results. The approach relies on an interpretation of ROC-type summary curves as plots of an expected utility versus an expected disutility (or penalty) for signal-present decisions. We propose a general utility structure that is flexible enough to encompass many ROC variants and yet sufficiently constrained to allow derivation of a linear expected utility equation that is similar to that for simple binary detection. We illustrate our theory with an example comparing decision strategies for joint detection-estimation of a known signal with unknown amplitude. In addition, building on insights from our utility framework, we propose new ROC-type summary curves and associated optimal decision rules for joint detection-estimation tasks with an unknown, potentially-multiple, number of signals in each observation. C1 [Wunderlich, Adam] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Wunderlich, Adam] NIST, Commun Technol Lab, Boulder, CO 80305 USA. [Goossens, Bart] Univ Ghent, Dept Telecommun & Informat Proc, TELIN IPI iMinds, B-9000 Ghent, Belgium. [Abbey, Craig K.] Univ Calif Santa Barbara, Dept Psychol & Brain Sci, Santa Barbara, CA 93106 USA. RP Wunderlich, A (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA.; Wunderlich, A (reprint author), NIST, Commun Technol Lab, Boulder, CO 80305 USA. EM adam.wunder-lich@nist.gov OI Wunderlich, Adam/0000-0002-8463-9156 FU Research Foundation Flanders (FWO, Belgium); National Institutes of Health [R21-EB018939] FX B. Goossens acknowledges support from a postdoctoral fellowship of the Research Foundation Flanders (FWO, Belgium). C. K. Abbey was supported by the National Institutes of Health under Grant R21-EB018939. Asterisk indicates corresponding author. NR 42 TC 0 Z9 0 U1 4 U2 4 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 SEP PY 2016 VL 35 IS 9 BP 2164 EP 2173 DI 10.1109/TMI.2016.2553001 PG 10 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 DY6VK UT WOS:000385266800016 PM 27093544 ER PT J AU Walters, JL Chelonis, JJ Fogle, CM Orser, BA Paule, MG AF Walters, Jennifer L. Chelonis, John J. Fogle, Charles M. Orser, Beverley A. Paule, Merle G. TI Single and repeated exposures to the volatile anesthetic isoflurane do not impair operant performance in aged rats SO NEUROTOXICOLOGY LA English DT Article DE Anesthesia; Isoflurane; Operant behavior; Fixed consecutive number; Incremental repeated acquisition ID POSTOPERATIVE COGNITIVE DYSFUNCTION; CONSECUTIVE-NUMBER SCHEDULES; MORRIS WATER MAZE; TEST BATTERY; PREFRONTAL CORTEX; SPATIAL MEMORY; ENVIRONMENTAL ENRICHMENT; REPEATED ACQUISITION; RESPONSE-INHIBITION; GENERAL-ANESTHESIA AB Postoperative Cognitive Dysfunction (POCD) is a complication that can occur in the elderly after anesthesia and surgery and is characterized by impairments in information processing, memory, and executive function. Currently, it is unclear whether POCD is due to the effects of surgery, anesthesia, or perhaps some interaction between these or other perioperative variables. Studies in rodents suggest that the development of POCD may be related directly to anesthesia-induced neuroactivity. Volatile anesthetics have been shown to increase cellular inflammation and apoptosis within the hippocampus of aged rodents, while producing corresponding impairments in hippocampal-dependent brain functions. However, it is unclear whether volatile anesthetics can affect additional aspects of cognition that do not primarily depend upon the hippocampus. The purpose of this study was to use established operant tests to examine the effects of isoflurane on aspects of behavioral inhibition, learning, and motivation in aged rats. Twenty-one adult Sprague-Dawley rats (11 male, 10 female) were trained to perform fixed consecutive number (FCN), incremental repeated acquisition (IRA), and progressive ratio (PR) tasks for a minimum of 15 months prior to receiving anesthesia. At 23 months of age, rats were exposed to 1.3% isoflurane or medical grade air for 2 h. Initial results revealed that a 2 h exposure to isoflurane had no effect on IRA, FCN, or PR performance. Thus, rats received 3 additional exposures to 1.3% isoflurane or medical grade air: 2, 4 and 6 h exposures with 2 weeks elapsing before exposure two, 3 weeks elapsing between exposures two and three, and 2 weeks elapsing between exposures three and four. These additional exposures had no observable effects on performance of any operant task. These results suggest that single and repeated exposures to isoflurane do not impair the performance of aged rats in tasks designed to measure behavioral inhibition, learning, and motivation. This lack of significant effect suggests that the impairments associated with isoflurane exposure may not generalize to all aspects of cognition, but may be selective to tasks that primarily measure spatial memory processes. Published by Elsevier B.V. C1 [Walters, Jennifer L.; Chelonis, John J.; Fogle, Charles M.; Paule, Merle G.] US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Orser, Beverley A.] Univ Toronto, Dept Physiol, Med Sci Bldg,Room 3318,1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada. RP Walters, JL (reprint author), US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Jennifer.Walters@fda.hhs.gov FU NCTR [E0756701] FX The authors would like to thank Edward Bearden, Michael Beaudoin, Martin Jackson, and Richard Rasmussen for programming and maintaining the behavioral testing apparatuses. The authors would also like to thank the NCTR Animal Care Staff for their invaluable assistance in conducting the experiment. This project was supported by NCTR protocol E0756701. NR 90 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X EI 1872-9711 J9 NEUROTOXICOLOGY JI Neurotoxicology PD SEP PY 2016 VL 56 BP 159 EP 169 DI 10.1016/j.neuro.2016.07.012 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA DY4GF UT WOS:000385056300016 PM 27498192 ER PT J AU Ramu, J Konak, T Paule, MG Hanig, JP Liachenko, S AF Ramu, Jaivijay Konak, Tetyana Paule, Merle G. Hanig, Joseph P. Liachenko, Serguei TI Longitudinal diffusion tensor imaging of the rat brain after hexachlorophene exposure SO NEUROTOXICOLOGY LA English DT Article DE DTI; Axial diffusivity; Radial diffusivity; Fractional anisotropy; Hexachlorophene ID SPINAL-CORD-INJURY; CENTRAL-NERVOUS-SYSTEM; MAGNETIC-RESONANCE; SPATIAL STATISTICS; POVIDONE-IODINE; IN-VIVO; TOXICITY; NEUROTOXICITY; TRACTOGRAPHY; TRACKING AB Longitudinal MRI employing diffusion tensor imaging and T-2 mapping approaches has been applied to investigate the mechanisms of white matter damage caused by acute hexachlorophene neurotoxicity in rats in vivo. Male Sprague-Dawley rats were administered hexachlorophene orally once a day for five consecutive days at a dose of 30 mg/kg and were monitored in 7T MRI scanner at days 0 (baseline), 3, 6,13, and 20 following the first hexachlorophene dose. Quantitative T-2 maps as well as a number of diffusion tensor parameters (fractional anisotropy, radial and axial diffusivity, apparent diffusion coefficient, and trace) were calculated from corresponding MR images. T-2, as well as all diffusion tensor derived parameters (except fractional anisotropy) showed significant changes during the course of neurotoxicity development. These changes peaked at 6 days after the first dose of hexachlorophene (one day after the last dose) and recovered to practically baseline levels at the end of observation (20 days from the first dose). While such changes in diffusivity and T-2 relaxation clearly demonstrate myelin perturbations consistent with edema, the lack of changes of fractional anisotropy suggests that the structure of the myelin sheath was not disrupted significantly by hexachlorophene in this study. This is also confirmed by the rapid recovery of all observed MRI parameters after cessation of hexachlorophene exposure. Published by Elsevier B.V. C1 [Ramu, Jaivijay; Konak, Tetyana; Paule, Merle G.; Liachenko, Serguei] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Hanig, Joseph P.] US FDA, Ctr Drug Evaluat & Res, White Oak, MD USA. RP Liachenko, S (reprint author), US FDA, NCTR, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Jaivijay.Ramu@fda.hhs.gov; Tetyana.Konak@fda.hhs.gov; Merle.Paule@fda.hhs.gov; Joseph.Hanig@fda.hhs.gov; Serguei.liachenko@fda.hhs.gov FU National Center for Toxicological Research (NCTR); Center for Drug Evaluation and Research (CDER), U.S. FDA [E07418] FX This work was supported by the National Center for Toxicological Research (NCTR) and Center for Drug Evaluation and Research (CDER), U.S. FDA [protocol number E07418]. NR 74 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X EI 1872-9711 J9 NEUROTOXICOLOGY JI Neurotoxicology PD SEP PY 2016 VL 56 BP 225 EP 232 DI 10.1016/j.neuro.2016.08.011 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA DY4GF UT WOS:000385056300023 PM 27555423 ER PT J AU Chong, Y Ge, CC Fang, G Tian, X Ma, XC Wen, T Wamer, WG Chen, CY Chai, ZF Yin, JJ AF Chong, Yu Ge, Cuicui Fang, Ge Tian, Xin Ma, Xiaochuan Wen, Tao Wamer, Wayne G. Chen, Chunying Chai, Zhifang Yin, Jun-Jie TI Crossover between Anti- and Pro-oxidant Activities of Graphene Quantum Dots in the Absence or Presence of Light SO ACS NANO LA English DT Article DE graphene quantum dots; free radicals; anti-oxidants; phototoxicity; lipid peroxidation ID SINGLET OXYGEN GENERATION; OXIDATIVE STRESS; ASCORBIC-ACID; FREE-RADICALS; CARBON DOTS; SUPEROXIDE; CONVERSION; ANTIOXIDANTS; MECHANISMS; CHEMISTRY AB Graphene quantum dots (GQDs), zero dimensional carbon materials displaying excellent luminescence properties, show great promise for medical applications such as imaging, drug delivery, biosensors, and novel therapeutics. A deeper understanding of how the properties of GQDs interact with biological systems is essential for these applications. Our work demonstrates that GQDs can efficiently scavenge a number of free radicals and thereby protect cells against oxidative damage. However, upon exposure to blue light, GQDs exhibit significant phototoxicity through increasing intracellular reactive oxygen species (ROS) levels and reducing cell viability, attributable to the generation of free radicals under light excitation. We confirm that light-induced formation of ROS originates from the electron-hole pair and, more importantly, reveal that singlet oxygen is generated by photoexcited GQDs via both energy-transfer and electron-transfer pathways. Moreover, upon light excitation, GQDs accelerate the oxidation of non-enzymic anti-oxidants and promote lipid peroxidation, contributing to the phototoxicity of GQDs. Our results reveal that GQDs can display both anti- and pro-oxidant activities, depending upon light exposure, which will be useful in guiding the safe application and development of potential anticancer/antibacterial applications for GQDs. C1 [Chong, Yu; Ge, Cuicui; Fang, Ge; Tian, Xin; Ma, Xiaochuan; Chai, Zhifang] Soochow Univ, Collaborat Innovat Ctr Radiat Med, Jiangsu Higher Educ Inst, Sch Radiol & Interdisciplinary Sci RAD X, Suzhou 215123, Peoples R China. [Chong, Yu; Ge, Cuicui; Wen, Tao; Wamer, Wayne G.; Yin, Jun-Jie] US FDA, Div Bioanalyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Chong, Yu; Ge, Cuicui; Wen, Tao; Wamer, Wayne G.; Yin, Jun-Jie] US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Chen, Chunying; Chai, Zhifang] Chinese Acad Sci, Natl Ctr Nanosci & Technol China, Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100190, Peoples R China. [Chen, Chunying; Chai, Zhifang] Chinese Acad Sci, Inst High Energy Phys, Beijing 100190, Peoples R China. RP Ge, CC (reprint author), Soochow Univ, Collaborat Innovat Ctr Radiat Med, Jiangsu Higher Educ Inst, Sch Radiol & Interdisciplinary Sci RAD X, Suzhou 215123, Peoples R China.; Ge, CC; Yin, JJ (reprint author), US FDA, Div Bioanalyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA.; Ge, CC; Yin, JJ (reprint author), US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA.; Chen, CY (reprint author), Chinese Acad Sci, Natl Ctr Nanosci & Technol China, Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100190, Peoples R China.; Chen, CY (reprint author), Chinese Acad Sci, Inst High Energy Phys, Beijing 100190, Peoples R China. EM ccge@suda.edu.cn; chenchy@nanoctr.cn; junjie.yin@fda.hhs.gov RI Yin, Jun Jie /E-5619-2014 FU National Basic Research Program of China (973 Program) [2014CB931900, 2016-YFA0201600]; National Natural Science Foundation of China [21207164, 11575123]; Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection; Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); FDA Nanotechnology CORES Program; China Scholarship Council [1410100007]; NSFC Distinguished Young Scholars [11425520] FX Dedicated to the memory of Wayne G. Wamer. This work is partially supported by the National Basic Research Program of China (973 Program Grant Nos. 2014CB931900 and 2016-YFA0201600), National Natural Science Foundation of China (21207164 and 11575123), Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) and was partially supported by a regulatory science grant under the FDA Nanotechnology CORES Program. Y. Chong appreciates the support from the China Scholarship Council (no. 1410100007). C. Chen appreciates the support from the NSFC Distinguished Young Scholars (11425520). The authors thank Dr. Lili Fox Velez for editorial and scientific writing support. 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 50 TC 1 Z9 1 U1 51 U2 51 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 EI 1936-086X J9 ACS NANO JI ACS Nano PD SEP PY 2016 VL 10 IS 9 BP 8690 EP 8699 DI 10.1021/acsnano.6b04061 PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA DX5DF UT WOS:000384399300062 PM 27584033 ER PT J AU Kassa, T Jana, S Meng, F Alayash, AI AF Kassa, Tigist Jana, Sirsendu Meng, Fantao Alayash, Abdu I. TI Differential heme release from various hemoglobin redox states and the upregulation of cellular heme oxygenase-1 SO FEBS OPEN BIO LA English DT Article DE ferric; ferryl hemoglobin; heme; hemoglobin ID MITOCHONDRIAL DYSFUNCTION; MYOGLOBIN; CELLS; DISSOCIATION; AUTOXIDATION; OXIDATION; CHAINS; INSTABILITY; MECHANISM; EXCHANGE AB Despite advances in our understanding of the oxidative pathways mediated by free hemoglobin (Hb), the precise contribution of its highly reactive redox forms to tissue and organ toxicities remains ambiguous. Heme, a key degradation byproduct of Hb oxidation, has recently been recognized as a damage-associated molecular pattern (DAMP) molecule, able to trigger inflammatory responses. Equally damaging is the interaction of the highly redox active forms of Hb with other biological molecules. We determined the kinetics of heme loss from individual Hb redox states-ferrous (Fe2+), ferric (Fe3+), and ferryl (Fe4+)-using two different heme receptor proteins: hemopexin (Hxp), a naturally occurring heme scavenger in plasma, and a double mutant (H64Y/V86F), apomyoglobin (ApoMb), which avidly binds heme released from Hb. We show for the first time that ferric Hb (Fe3+) loses heme at rates substantially higher than that of ferryl Hb (Fe4+). This was also supported by a higher expression of heme oxygenase-1 (HO-1) when ferric Hb was added to cultured lung alveolar epithelial cells (E10). The reported cytotoxicity of Hb may therefore be attributed to a combination of accelerated heme loss from the ferric form and protein radical formation associated with ferryl Hb. Targeted therapeutic interventions can therefore be designed to curb specific oxidative pathways of Hb in hemolytic anemias and when Hb is used as an oxygen-carrying therapeutic. C1 [Kassa, Tigist; Jana, Sirsendu; Meng, Fantao; Alayash, Abdu I.] US FDA, Ctr Biol Evaluat & Res, Lab Biochem & Vasc Biol, 10903 New Hampshire Ave,Bldg 52-72,Room 4106, Silver Spring, MD 20993 USA. RP Alayash, AI (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Biochem & Vasc Biol, 10903 New Hampshire Ave,Bldg 52-72,Room 4106, Silver Spring, MD 20993 USA. EM abdu.alayash@fda.hhs.gov FU National Institutes of Health (NIH/NHLBI) [P01-HL110900]; U.S. Food and Drug Administration (MODSCI) FX The authors acknowledge the assistance of Francine Wood in the preparation of HbA and other related Hb solutions. We thank Dr. John Olson of Rice University for providing recombinant myoglobin (H64Y/V86F) and for his valuable comments and suggestions. This work was supported by National Institutes of Health (NIH/NHLBI) grant P01-HL110900 (AIA), and grants from the U.S. Food and Drug Administration (MODSCI) (AIA). NR 39 TC 1 Z9 1 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2211-5463 J9 FEBS OPEN BIO JI FEBS Open Bio PD SEP PY 2016 VL 6 IS 9 BP 876 EP 884 DI 10.1002/2211-5463.12103 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DW4MW UT WOS:000383618300001 PM 27642551 ER PT J AU Hobson, DW Schuh, JCL Zurawski, DV Wang, JY Arbabi, S McVean, M Funk, KA AF Hobson, David W. Schuh, JoAnn C. L. Zurawski, Daniel V. Wang, Jianyong Arbabi, Sam McVean, Maralee Funk, Kathleen A. TI The First Cut Is the Deepest: The History and Development of Safe Treatments for Wound Healing and Tissue Repair SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Article DE wound healing; tissue repair; skin injury ID EXTENSIVELY DRUG-RESISTANT; ACINETOBACTER-BAUMANNII; ANIMAL-MODELS; INFLAMMATION AB As the skin is the primary barrier to infection, the importance of wound healing has been understood since ancient times. This article provides a synopsis on the symposium presentations focusing on how wounds were traditionally treated, what models and pathology endpoints exist to study wound healing, special considerations for wound healing studies, an overview of regulatory aspects of new pharmaceutical and medical device development, and the clinical relevance of such models. The clinical treatment of small and large wounds is also considered. C1 [Hobson, David W.] LoneStar PharmTox LLC, Bergheim, TX USA. [Schuh, JoAnn C. L.] JCL Schuh PLLC, Bainbridge Isl, WA USA. [Zurawski, Daniel V.] Walter Reed Army Inst Res, Bacterial Dis Branch, Wound Infect Dept, Silver Spring, MD USA. [Wang, Jianyong] US FDA, DDDP, OND, CDER, Silver Spring, MD USA. [Arbabi, Sam] Univ Washington, Seattle, WA 98195 USA. [McVean, Maralee] PreClin Res Serv Inc, Ft Collins, CO USA. [Funk, Kathleen A.] Expt Pathol Labs Inc, Sterling, VA USA. RP Funk, KA (reprint author), Expt Pathol Labs, 45600 Terminal Dr, Sterling, VA 20166 USA. EM kfunk@epl-inc.com RI Zurawski, Daniel/B-6578-2009 OI Zurawski, Daniel/0000-0002-7920-5601 FU Military Infectious Diseases Research Program (MIDRP); Defense Medical Research and Development Program (DMRDP) FX Daniel V. Zurawski would like to acknowledge his support by the Military Infectious Diseases Research Program (MIDRP) and the Defense Medical Research and Development Program (DMRDP). NR 34 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD SEP-OCT PY 2016 VL 35 IS 5 BP 491 EP 498 DI 10.1177/1091581816656804 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DX5TL UT WOS:000384444900001 PM 27402775 ER PT J AU Henck, JW Elayan, I Vorhees, C Fisher, JE Morford, LL AF Henck, Judith W. Elayan, Ikram Vorhees, Charles Fisher, J. Edward, Jr. Morford, LaRonda L. TI Current Topics in Postnatal Behavioral Testing SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Article DE developmental neurotoxicity; behavior; postnatal; juvenile; animal models ID MORRIS WATER MAZE; FUNCTIONAL OBSERVATIONAL BATTERY; MARGINAL ZINC DEPRIVATION; ACOUSTIC STARTLE REFLEX; OPEN-FIELD BEHAVIOR; DEVELOPMENTAL NEUROTOXICITY; RHESUS-MONKEYS; REPRODUCTIVE TOXICOLOGY; PREPULSE FACILITATION; GUINEA-PIG AB The study of developmental neurotoxicity (DNT) continues to be an important component of safety evaluation of candidate therapeutic agents and of industrial and environmental chemicals. Developmental neurotoxicity is considered to be an adverse change in the central and/or peripheral nervous system during development of an organism and has been primarily evaluated by studying functional outcomes, such as changes in behavior, neuropathology, neurochemistry, and/or neurophysiology. Neurobehavioral evaluations are a component of a wide range of toxicology studies in laboratory animal models, whereas neurochemistry and neurophysiology are less commonly employed. Although the primary focus of this article is on neurobehavioral evaluation in pre- and postnatal development and juvenile toxicology studies used in pharmaceutical development, concepts may also apply to adult nonclinical safety studies and Environmental Protection Agency/chemical assessments. This article summarizes the proceedings of a symposium held during the 2015 American College of Toxicology annual meeting and includes a discussion of the current status of DNT testing as well as potential issues and recommendations. Topics include the regulatory context for DNT testing; study design and interpretation; behavioral test selection, including a comparison of core learning and memory systems; age of testing; repeated testing of the same animals; use of alternative animal models; impact of findings; and extrapolation of animal results to humans. Integration of the regulatory experience and scientific concepts presented during this symposium, as well as from subsequent discussion and input, provides a synopsis of the current state of DNT testing in safety assessment, as well as a potential roadmap for future advancement. C1 [Henck, Judith W.] Toxicol Solut Consulting LLC, Leeds, UT 84746 USA. [Elayan, Ikram; Fisher, J. Edward, Jr.] US FDA, Silver Spring, MD USA. [Vorhees, Charles] Cincinnati Childrens Res Fdn, Cincinnati, OH USA. [Morford, LaRonda L.] Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Henck, JW (reprint author), Toxicol Solut Consulting LLC, Leeds, UT 84746 USA. EM judith.henck@yahoo.com NR 86 TC 0 Z9 0 U1 4 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD SEP-OCT PY 2016 VL 35 IS 5 BP 499 EP 520 DI 10.1177/1091581816657082 PG 22 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DX5TL UT WOS:000384444900002 PM 27381384 ER PT J AU Morgan, MM Johnson, BP Livingston, MK Schuler, LA Alarid, ET Sung, KE Beebe, DJ AF Morgan, Molly M. Johnson, Brian P. Livingston, Megan K. Schuler, Linda A. Alarid, Elaine T. Sung, Kyung E. Beebe, David J. TI Personalized in vitro cancer models to predict therapeutic response: Challenges and a framework for improvement SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Adverse outcome pathway; Chemotherapy sensitivity and resistance assays; Targeted therapy; Microenvironment; Personalized medicine ID ESTROGEN-RECEPTOR-ALPHA; POSITIVE BREAST-CANCER; ENDOTHELIAL GROWTH-FACTOR; 3-DIMENSIONAL 3D CULTURE; EPITHELIAL OVARIAN-CANCER; DRUG-METABOLIZING-ENZYMES; ADVERSE OUTCOME PATHWAYS; MULTIPLE-MYELOMA CELLS; ENDOCRINE RESISTANCE; TUMOR MICROENVIRONMENT AB Personalized cancer therapy focuses on characterizing the relevant phenotypes of the patient, as well as the patient's tumor, to predict the most effective cancer therapy. Historically, these methods have not proven predictive in regards to predicting therapeutic response. Emerging culture platforms are designed to better recapitulate the in vivo environment, thus, there is renewed interest in integrating patient samples into in vitro cancer models to assess therapeutic response. Successful examples of translating in vitro response to clinical relevance are limited due to issues with patient sample acquisition, variability and culture. We will review traditional and emerging in vitro models for personalized medicine, focusing on the technologies, microenvironmental components, and readouts utilized. We will then offer our perspective on how to apply a framework derived from toxicology and ecology towards designing improved personalized in vitro models of cancer. The framework serves as a tool for identifying optimal readouts and culture conditions, thus maximizing the information gained from each patient sample. (C) 2016 Published by Elsevier Inc. C1 [Morgan, Molly M.; Johnson, Brian P.; Livingston, Megan K.; Sung, Kyung E.; Beebe, David J.] Univ Wisconsin, Biomed Engn, Madison, WI USA. [Schuler, Linda A.] Univ Wisconsin, Dept Comparat Biosci, 2015 Linden Dr W, Madison, WI 53706 USA. [Alarid, Elaine T.; Beebe, David J.] Univ Wisconsin, Dept Oncol, Madison, WI USA. RP Sung, KE (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, 10903 New Hampshire Ave,WO 52-72-3206, Silver Spring, MD 20993 USA.; Beebe, DJ (reprint author), 1111 Highland Ave,Room 6009, Madison, WI 53705 USA. EM Kyung.Sung@fda.hhs.gov; djbeebe@wisc.edu FU EPA grant [83573701]; University of Wisconsin Carbone Cancer Center [P30 CA014520]; NIH [T32 CA157322, R01CA186134]; Movember Prostate Cancer Foundation Challenge Award FX This review was supported by EPA grant number 83573701, University of Wisconsin Carbone Cancer Center, grant P30 CA014520, NIH T32 CA157322, NIH R01CA186134 and Movember Prostate Cancer Foundation Challenge Award. NR 224 TC 1 Z9 1 U1 13 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD SEP PY 2016 VL 165 BP 79 EP 92 DI 10.1016/j.pharmthera.2016.05.007 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DW7GH UT WOS:000383818700007 PM 27218886 ER PT J AU Menis, M Forshee, RA Izurieta, HS Kessler, Z McKean, S Warnock, R Verma, S Worrall, CM Kelman, JA Anderson, S AF Menis, M. Forshee, R. A. Izurieta, H. S. Kessler, Z. McKean, S. Warnock, R. Verma, S. Worrall, C. M. Kelman, J. A. Anderson, S. TI Transfusion-Associated Circulatory Overload Among the Inpatient US Elderly Medicare Beneficiaries, as Recorded During 2011-2014 SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Menis, M.; Forshee, R. A.; Izurieta, H. S.; Anderson, S.] US FDA, CBER, Silver Spring, MD USA. [Kessler, Z.; McKean, S.; Warnock, R.; Verma, S.] Acumen LLC, Burlingame, CA USA. [Worrall, C. M.; Kelman, J. A.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA S23-020A BP 14A EP 14A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400030 ER PT J AU Volkova, E Liu, M Liu, Z Mercado, T Illoh, O Rios, M AF Volkova, E. Liu, M. Liu, Z. Mercado, T. Illoh, O. Rios, M. TI Renewable DNA Reference Panels for Blood Group Genotyping SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Volkova, E.; Liu, M.; Liu, Z.; Mercado, T.; Illoh, O.; Rios, M.] 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP311 BP 152A EP 152A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400415 ER PT J AU Menis, M Forshee, RA Izurieta, HS Kessler, Z McKean, S Warnock, R Worrall, CM Kelman, A Anderson, S AF Menis, M. Forshee, R. A. Izurieta, H. S. Kessler, Z. McKean, S. Warnock, R. Worrall, C. M. Kelman, A. Anderson, S. TI Transfusion-related Anaphylaxis among Inpatient US Elderly Medicare Beneficiaries during 2012-2014 SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Menis, M.; Forshee, R. A.; Izurieta, H. S.; Anderson, S.] FDA CBER, Silver Spring, MD USA. [Kessler, Z.; McKean, S.; Warnock, R.] Acumen LLC, Burlingame, CA USA. [Worrall, C. M.; Kelman, A.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP342 BP 161A EP 162A PG 2 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400446 ER PT J AU Menis, M Forshee, RA Izurieta, HS Kessler, Z McKean, S Warnock, R Worrall, CM Kelman, JA Anderson, S AF Menis, M. Forshee, R. A. Izurieta, H. S. Kessler, Z. McKean, S. Warnock, R. Worrall, C. M. Kelman, J. A. Anderson, S. TI Post-transfusion Purpura (PTP) among US Elderly Medicare Beneficiaries, as Recorded during 2011-2014 SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Menis, M.; Forshee, R. A.; Izurieta, H. S.; Anderson, S.] FDA CBER, Silver Spring, MD USA. [Kessler, Z.; McKean, S.; Warnock, R.] Acumen LLC, Burlingame, CA USA. [Worrall, C. M.; Kelman, J. A.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP341 BP 161A EP 161A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400445 ER PT J AU Menis, M Forshee, RA Izurieta, HS Kessler, Z McKean, S Warnock, R Worrall, CM Kelman, A Anderson, S AF Menis, M. Forshee, R. A. Izurieta, H. S. Kessler, Z. McKean, S. Warnock, R. Worrall, C. M. Kelman, A. Anderson, S. TI Febrile Non-hemolytic Transfusion Reaction among Inpatient US Elderly Medicare Beneficiaries, as Recorded during 2011-2014 SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Menis, M.; Forshee, R. A.; Izurieta, H. S.; Anderson, S.] FDA CBER, Silver Spring, MD USA. [Kessler, Z.; McKean, S.; Warnock, R.] Acumen LLC, Burlingame, CA USA. [Worrall, C. M.; Kelman, A.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP340 BP 161A EP 161A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400444 ER PT J AU Menis, M Forshee, RA Izurieta, HS Kessler, Z McKean, S Warnock, R Verma, S Worrall, CM Kelman, JA Anderson, S AF Menis, M. Forshee, R. A. Izurieta, H. S. Kessler, Z. McKean, S. Warnock, R. Verma, S. Worrall, C. M. Kelman, J. A. Anderson, S. TI Transfusion-related Acute Lung Injury among Inpatient US Elderly Medicare Beneficiaries during 2007-2014 SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Menis, M.; Forshee, R. A.; Izurieta, H. S.; Anderson, S.] FDA CBER, Silver Spring, MD USA. [Kessler, Z.; McKean, S.; Warnock, R.; Verma, S.] Acumen LLC, Burlingame, CA USA. [Worrall, C. M.; Kelman, J. A.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP343 BP 162A EP 162A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400447 ER PT J AU Haddad, S Illoh, O Barash, F Espinola, R Paul, W Rogerson, B AF Haddad, S. Illoh, O. Barash, F. Espinola, R. Paul, W. Rogerson, B. TI Food and Drug Administration Updated System for Classifying Reports of Donation and Transfusion-related Fatalities SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Haddad, S.; Illoh, O.; Barash, F.; Espinola, R.; Paul, W.; Rogerson, B.] 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP352 BP 165A EP 166A PG 2 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400456 ER PT J AU Anderson, S Hinkins, S Stern, M Walderhaug, M Whitaker, B AF Anderson, S. Hinkins, S. Stern, M. Walderhaug, M. Whitaker, B. TI Rapid Donor Surveillance Study Develops Tool to Assess Risk in a Statistically Valid Sample of US Blood Donors: Babesia and Hepatitis E Virus Surveys SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Whitaker, B.] AABB, Res, Bethesda, MD USA. [Anderson, S.; Walderhaug, M.] US FDA, Off Biostat & Epidemiol, Silver Spring, MD USA. [Hinkins, S.; Stern, M.] NORC, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP412 BP 187A EP 187A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400516 ER PT J AU Simonetti, A Menis, M Kumar, S McKean, S Kelman, JA Worrall, CM Anderson, S Forshee, RA AF Simonetti, A. Menis, M. Kumar, S. McKean, S. Kelman, J. A. Worrall, C. M. Anderson, S. Forshee, R. A. TI Testing Strategies for Babesia microti in Blood Donors to Reduce Risk of Transfusion-transmitted Babesiosis in the United States SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Simonetti, A.; Menis, M.; Anderson, S.; Forshee, R. A.] US FDA, Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, Silver Spring, MD USA. [Kumar, S.] US FDA, Ctr Biol Evaluat & Res, Off Blood Res & Review, Silver Spring, MD USA. [McKean, S.] Acumen LLC, Burlingame, CA USA. [Kelman, J. A.; Worrall, C. M.] Ctr Medicare Serv, Baltimore, MD USA. [Kelman, J. A.; Worrall, C. M.] Ctr Medicaid Serv, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP420 BP 190A EP 190A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400524 ER PT J AU Menis, M Forshee, RA Izurieta, HS Kessler, Z McKean, S Warnock, R Verma, S Worrall, CM Kelman, JA Anderson, S AF Menis, M. Forshee, R. A. Izurieta, H. S. Kessler, Z. McKean, S. Warnock, R. Verma, S. Worrall, C. M. Kelman, J. A. Anderson, S. TI Acute Infection Following Transfusion among US Elderly Medicare Beneficiaries, as Recorded by Large Administrative Databases during 2012-2014 SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Menis, M.; Forshee, R. A.; Izurieta, H. S.; Anderson, S.] US FDA, CBER, Silver Spring, MD USA. [Kessler, Z.; McKean, S.; Warnock, R.; Verma, S.] Acumen LLC, Burlingame, CA USA. [Worrall, C. M.; Kelman, J. A.] Ctr Medicare Serv, Baltimore, MD USA. [Worrall, C. M.; Kelman, J. A.] Ctr Medicaid Serv, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP437 BP 195A EP 195A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400541 ER PT J AU Chancey, C Fares, RC Grinev, A Volkova, E Rios, M AF Chancey, C. Fares, R. C. Grinev, A. Volkova, E. Rios, M. TI Zika Virus Outbreak in the Americas: Development of Tools to Assist Responses SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 22-25, 2016 CL Orlando, FL SP AABB C1 [Chancey, C.; Fares, R. C.; Grinev, A.; Volkova, E.; Rios, M.] US FDA, CBER, DETTD, 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 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2016 VL 56 SU 4 SI SI MA SP461 BP 203A EP 203A PG 1 WC Hematology SC Hematology GA DX8NS UT WOS:000384646400565 ER PT J AU Bartoshuk, LM Colquhoun, TA Dotson, S Hudson, SD Odabasi, AZ Puentes, L Sims, CA Snyder, DJ Stamps, JJ AF Bartoshuk, Linda M. Colquhoun, Thomas A. Dotson, Shawn Hudson, Sonia D. Odabasi, Asli Z. Puentes, Lorenzo Sims, Charles A. Snyder, Derek J. Stamps, Jennifer J. TI Sweet Modifications by Miracle Fruit and Gymnema sylvestre Affect Flavor SO CHEMICAL SENSES LA English DT Meeting Abstract CT 38th Annual Meeting of the Association-for-Chemoreception-Sciences (AChemS) CY APR 20-23, 2016 CL Bonita Springs, FL SP Assoc Chemorecept Sci C1 [Bartoshuk, Linda M.; Odabasi, Asli Z.] Univ Florida, Food Sci & Human Nutr, Gainesville, FL USA. [Colquhoun, Thomas A.] Univ Florida, Dept Environm Hort, Gainesville, FL 32611 USA. [Dotson, Shawn] Univ Florida, Neurosci, Gainesville, FL USA. [Hudson, Sonia D.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Puentes, Lorenzo] Merieux Nutrisci Co, Gainesville, FL USA. [Sims, Charles A.; Snyder, Derek J.; Stamps, Jennifer J.] UF Food Sci & Human Nutr, Gainesville, FL USA. NR 0 TC 0 Z9 0 U1 7 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0379-864X EI 1464-3553 J9 CHEM SENSES JI Chem. Senses PD SEP PY 2016 VL 41 IS 7 MA 420 BP E84 EP E84 PG 1 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA DW7TH UT WOS:000383854300204 ER PT J AU Ramage, JG Prentice, KW DePalma, L Venkateswaran, KS Chivukula, S Chapman, C Bell, M Datta, S Singh, A Hoffmaster, A Sarwar, J Parameswaran, N Joshi, M Thirunavkkarasu, N Krishnan, V Morse, S Avila, JR Sharma, S Estacio, PL Stanker, L Hodge, DR Pillai, SP AF Ramage, Jason G. Prentice, Kristin W. DePalma, Lindsay Venkateswaran, Kodumudi S. Chivukula, Sruti Chapman, Carol Bell, Melissa Datta, Shomik Singh, Ajay Hoffmaster, Alex Sarwar, Jawad Parameswaran, Nishanth Joshi, Mrinmayi Thirunavkkarasu, Nagarajan Krishnan, Viswanathan Morse, Stephen Avila, Julie R. Sharma, Shashi Estacio, Peter L. Stanker, Larry Hodge, David R. Pillai, Segaran P. TI Comprehensive Laboratory Evaluation of a Highly Specific Lateral Flow Assay for the Presumptive Identification of Bacillus anthracis Spores in Suspicious White Powders and Environmental Samples SO HEALTH SECURITY LA English DT Article ID INHALATIONAL ANTHRAX; INFECTION; IMMUNOASSAY; AGENTS; THURINGIENSIS; PERFORMANCE; ANTIGEN; CEREUS AB We conducted a comprehensive, multiphase laboratory evaluation of the Anthrax BioThreat Alert((R)) test strip, a lateral flow immunoassay (LFA) for the rapid detection of Bacillus anthracis spores. The study, conducted at 2 sites, evaluated this assay for the detection of spores from the Ames and Sterne strains of B. anthracis, as well as those from an additional 22 strains. Phylogenetic near neighbors, environmental background organisms, white powders, and environmental samples were also tested. The Anthrax LFA demonstrated a limit of detection of about 10(6) spores/mL (ca. 1.5x10(5) spores/assay). In this study, overall sensitivity of the LFA was 99.3%, and the specificity was 98.6%. The results indicated that the specificity, sensitivity, limit of detection, dynamic range, and repeatability of the assay support its use in the field for the purpose of qualitatively evaluating suspicious white powders and environmental samples for the presumptive presence of B. anthracis spores. C1 [Ramage, Jason G.] BAI Inc, Washington, DC USA. [Prentice, Kristin W.] Sci Technol Directorate, DHS, Washington, DC USA. [DePalma, Lindsay; Chivukula, Sruti] Booz Allen Hamilton, Mclean, VA USA. [Venkateswaran, Kodumudi S.; Sarwar, Jawad; Parameswaran, Nishanth; Joshi, Mrinmayi] Omni Array Biotechnol, Rockville, MD USA. [Chivukula, Sruti] DHS, Washington, DC USA. [Chapman, Carol] Geneva Fdn, Silver Spring, MD USA. [Chapman, Carol] Naval Med Res Ctr, Silver Spring, MD USA. [Bell, Melissa; Hoffmaster, Alex] Ctr Dis Control & Prevent, CDC, Bacterial Special Pathogens Branch, Atlanta, GA USA. [Datta, Shomik] Vorsight, Washington, DC USA. [Singh, Ajay] Laulima Govt Solut, Aberdeen Proving Ground, MD USA. [Singh, Ajay] USAMRICD Neurobiol Toxicol Branch, Analyt Toxicol Div, Aberdeen Proving Ground, MD USA. [Thirunavkkarasu, Nagarajan] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Sharma, Shashi] US FDA, Select Agents & Environm Pathogens, Mol Methods & Subtyping Branch, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Krishnan, Viswanathan] Calif State Univ Fresno, Phys Chem, Fresno, CA 93740 USA. [Morse, Stephen] CDC, Div Select Agents & Toxins, Atlanta, GA USA. [Avila, Julie R.] Lawrence Livermore Natl Lab, Biosci & Biotechnol Div, Livermore, CA USA. [Estacio, Peter L.] Lawrence Berkeley Natl Lab, Hlth Serv, Berkeley, CA USA. [Stanker, Larry] USDA ARS, Foodborne Toxin Detect & Prevent Unit, Albany, CA USA. [Hodge, David R.] DHS S&T Chem & Biol Def Div, Washington, DC USA. [Pillai, Segaran P.] US FDA, Off Lab Sci & Safety, Silver Spring, MD 20993 USA. RP Pillai, SP (reprint author), US FDA, Off Lab Sci & Safety, Silver Spring, MD 20993 USA. EM Segaran.Pillai@fda.hhs.gov FU Department of Homeland Security (DHS) Science and Technology Directorate (S&T) Homeland Security Research Projects Agency [HSHQDC-12-C-00071] FX The authors wish to acknowledge the important contributions to this manuscript of Dr. Douglas L. Anders, Hazardous Materials Response Unit, Federal Bureau of Investigation Laboratory, Quantico, Virginia, and Dr. Sally Hojvat, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, Maryland, for subject matter expert advice and consultation. We express our thanks and appreciation for their assistance in the preparation and execution of this project. This work was funded by Department of Homeland Security (DHS) Science and Technology Directorate (S&T) Homeland Security Research Projects Agency, Contract #HSHQDC-12-C-00071. The views expressed here are those of the authors and do not necessarily represent the position of DHS. NR 54 TC 0 Z9 0 U1 2 U2 2 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 SEP-OCT PY 2016 VL 14 IS 5 BP 351 EP 365 DI 10.1089/hs.2016.0041 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DX7BU UT WOS:000384541800008 PM 27661796 ER PT J AU Fisher, JAN Huang, S Ye, MJ Nabili, M Wilent, WB Krauthamer, V Myers, MR Welle, CG AF Fisher, Jonathan A. N. Huang, Stanley Ye, Meijun Nabili, Marjan Wilent, W. Bryan Krauthamer, Victor Myers, Matthew R. Welle, Cristin G. TI Real-Time Detection and Monitoring of Acute Brain Injury Utilizing Evoked Electroencephalographic Potentials SO IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING LA English DT Article DE Animal models; biomarkers; focused ultrasound; somatosensory evoked potentials (SSEPs); traumatic brain injury (TBI) ID INTENSITY FOCUSED ULTRASOUND; CLOSED-HEAD-INJURY; TRANSCALLOSAL INHIBITION; APPROXIMATE ENTROPY; SPREADING DEPRESSION; NETWORK ACTIVITY; GOLDEN HOUR; IN-VIVO; EEG; CONCUSSION AB Rapid detection and diagnosis of a traumatic brain injury (TBI) can significantly improve the prognosis for recovery. Helmet-mounted sensors that detect impact severity based on measurements of acceleration or pressure show promise for aiding triage and transport decisions in active, field environments such as professional sports or military combat. The detected signals, however, report on the mechanics of an impact rather than directly indicating the presence and severity of an injury. We explored the use of cortical somatosensory evoked electroencephalographic potentials (SSEPs) to detect and track, in real-time, neural electrophysiological abnormalities within the first hour following head injury in an animal model. To study the immediate electrophysiological effects of injury in vivo, we developed an experimental paradigm involving focused ultrasound that permits continuous, real-time measurements and minimizes mechanical artifact. Injury was associated with a dramatic reduction of amplitude over the damaged hemisphere directly after the injury. The amplitude systematically improved over time but remained significantly decreased at one hour, compared with baseline. In contrast, at one hour there was a concomitant enhancement of the cortical SSEP amplitude evoked from the uninjured hemisphere. Analysis of the inter-trial electroencephalogram (EEG) also revealed significant changes in low-frequency components and an increase in EEG entropy up to 30 minutes after injury, likely reflecting altered EEG reactivity to somatosensory stimuli. Injury-induced alterations in SSEPs were also observed using noninvasive epidermal electrodes, demonstrating viability of practical implementation. These results suggest cortical SSEPs recorded at just a few locations by head-mounted sensors and associated multiparametric analyses could potentially be used to rapidly detect and monitor brain injury in settings that normally present significant levels of mechanical and electrical noise. C1 [Fisher, Jonathan A. N.; Huang, Stanley; Ye, Meijun; Nabili, Marjan; Krauthamer, Victor; Myers, Matthew R.; Welle, Cristin G.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Fisher, Jonathan A. N.] New York Med Coll, Dept Physiol, Valhalla, NY 10595 USA. [Wilent, W. Bryan] Sentient Med Syst, Hunt Halley, MD 20131 USA. RP Welle, CG (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM jonathan_fisher@nymc.edu; Stanley.huang@fda.hhs.gov; meijun.ye@fda.hhs.gov; marjan.nabili@fda.hhs.gov; bwilent@gmail.com; victor.krauthamer@fda.hhs.gov; matthew.myers@fda.hhs.gov; cristin.welle@ucdenver.edu FU FDA Medical Countermeasures Initiative [274]; New York Medical College FX The work of C. G. Welle was supported by FDA Medical Countermeasures Initiative 274. The work of J. A. N. Fisher was supported by the New York Medical College. (Corresponding author: Cristin G. Welle.) NR 76 TC 0 Z9 0 U1 10 U2 10 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1534-4320 EI 1558-0210 J9 IEEE T NEUR SYS REH JI IEEE Trans. Neural Syst. Rehabil. Eng. PD SEP PY 2016 VL 24 IS 9 BP 1003 EP 1012 DI 10.1109/TNSRE.2016.2529663 PG 10 WC Engineering, Biomedical; Rehabilitation SC Engineering; Rehabilitation GA DX2QZ UT WOS:000384217100009 PM 26955039 ER PT J AU Le, JT Viswanathan, S Tarver, ME Eydelman, M Li, TJ AF Le, Jimmy T. Viswanathan, Shilpa Tarver, Michelle E. Eydelman, Malvina Li, Tianjing TI Assessment of the Incorporation of Patient-Centric Outcomes in Studies of Minimally Invasive Glaucoma Surgical Devices SO JAMA OPHTHALMOLOGY LA English DT Article ID FOOD AB IMPORTANCE Minimally invasive glaucoma surgical (MIGS) devices are one option for lowering intraocular pressure in patients with glaucoma. OBJECTIVE To examine how often existing clinical studies of MIGS devices registered on ClinicalTrials.gov measure patient-centric outcomes that patients value directly. DESIGN, SETTING, AND PARTICIPANTS We searched ClinicalTrials.gov, a registry of publicly and privately supported clinical studies, on February 20, 2015, for records of MIGS device studies involving patients with glaucoma. Two investigators independently abstracted study design and outcome details from eligible records. We classified outcomes as patient-centric or not patient-centric using a prespecified definition. MAIN OUTCOMES AND MEASURES Proportion of patient-centric and nonpatient-centric outcomes registered on ClinicalTrials.gov. RESULTS We identified 51 eligible studies specifying 127 outcomes. Reduction in intraocular pressure was the most frequent outcome specified (78/127; 61%) and a primary outcome in 41 studies. Patient-centric outcomes-such as adverse events (n = 19; 15%), topical medication use (n = 16; 13%), visual acuity (n = 4; 3%), and health-related quality of life (n = 1; 1%)-were less frequently specified (n = 40; 32%) and a primary outcome in only 12 studies. CONCLUSION AND RELEVANCE Patient-centric outcomes that provide insight into the relative desirability and acceptability of the benefits and risks of MIGS devices are not well represented in current clinical studies. C1 [Le, Jimmy T.; Li, Tianjing] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St,E6011, Baltimore, MD 21205 USA. [Viswanathan, Shilpa] Quintiles Real World & Late Phase Res, Rockville, MD USA. [Tarver, Michelle E.] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Eydelman, Malvina] US FDA, Div Ophthalm & Ear Nose & Throat Devices, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Li, TJ (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St,E6011, Baltimore, MD 21205 USA. EM tli19@jhu.edu FU US Food and Drug Administration (FDA) [U01 FD004977-01]; training grant from National Institute on Aging [T32AG000247] FX This project was funded by grant U01 FD004977-01 from the US Food and Drug Administration (FDA) to the Johns Hopkins' Center of Excellence in Regulatory Science and Innovation (CERSI). Mr Le is a CERSI scholar, and he received training grant T32AG000247 from the National Institute on Aging. NR 13 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD SEP PY 2016 VL 134 IS 9 BP 1054 EP 1056 DI 10.1001/jamaophthalmol.2016.2101 PG 3 WC Ophthalmology SC Ophthalmology GA DW9NY UT WOS:000383988800024 PM 27389667 ER PT J AU Burgos, JM Schmitt, MP AF Burgos, Jonathan M. Schmitt, Michael P. TI The ChrSA and HrrSA Two-Component Systems Are Required for Transcriptional Regulation of the hemA Promoter in Corynebacterium diphtheriae SO JOURNAL OF BACTERIOLOGY LA English DT Article ID SIGNAL-TRANSDUCTION SYSTEM; HOST IRON SOURCES; RESPONSE REGULATOR; ESCHERICHIA-COLI; PHOSPHATASE-ACTIVITY; STREPTOMYCES-RETICULI; BACTERIAL CHEMOTAXIS; BINDING PROTEINS; TOXIN REPRESSOR; GENE-EXPRESSION AB Corynebacterium diphtheriae utilizes heme and hemoglobin (Hb) as iron sources for growth in low-iron environments. In C. diphtheriae, the two-component signal transduction systems (TCSs) ChrSA and HrrSA are responsive to Hb levels and regulate the transcription of promoters for hmuO, hrtAB, and hemA. ChrSA and HrrSA activate transcription at the hmuO promoter and repress transcription at hemA in an Hb-dependent manner. In this study, we show that HrrSA is the predominant repressor at hemA and that its activity results in transcriptional repression in the presence and absence of Hb, whereas repression of hemA by ChrSA is primarily responsive to Hb. DNA binding studies showed that both ChrA and HrrA bind to the hemA promoter region at virtually identical sequences. ChrA binding was enhanced by phosphorylation, while binding to DNA by HrrA was independent of its phosphorylation state. ChrA and HrrA are phosphorylated in vitro by the sensor kinase ChrS, whereas no kinase activity was observed with HrrS in vitro. Phosphorylated ChrA was not observed in vivo, even in the presence of Hb, which is likely due to the instability of the phosphate moiety on ChrA. However, phosphorylation of HrrA was observed in vivo regardless of the presence of the Hb inducer, and genetic analysis indicates that ChrS is responsible for most of the phosphorylation of HrrA in vivo. Phosphorylation studies strongly suggest that HrrS functions primarily as a phosphatase and has only minimal kinase activity. These findings collectively show a complex mechanism of regulation at the hemA promoter, where both two-component systems act in concert to optimize expression of heme biosynthetic enzymes. IMPORTANCE Understanding the mechanism by which two-component signal transduction systems function to respond to environmental stimuli is critical to the study of bacterial pathogenesis. The current study expands on the previous analyses of the ChrSA and HrrSA TCSs in the human pathogen C. diphtheriae. The findings here underscore the complex interactions between the ChrSA and HrrSA systems in the regulation of the hemA promoter and demonstrate how the two systems complement one another to refine and control transcription in the presence and absence of Hb. C1 [Burgos, Jonathan M.; Schmitt, Michael P.] US FDA, Lab Resp & Special Pathogens, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Burgos, Jonathan M.] US FDA, Div Monoclonal Antibodies, 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 20993 USA. EM michael.schmitt@fda.hhs.gov FU 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 49 TC 1 Z9 1 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD SEP PY 2016 VL 198 IS 18 BP 2419 EP 2430 DI 10.1128/JB.00339-16 PG 12 WC Microbiology SC Microbiology GA DX4IB UT WOS:000384343300007 PM 27381918 ER PT J AU Beger, RD Dunn, W Schmidt, MA Gross, SS Kirwan, JA Cascante, M Brennan, L Wishart, DS Oresic, M Hankemeier, T Broadhurst, DI Lane, AN Suhre, K Kastenmuller, G Sumner, SJ Thiele, I Fiehn, O Kaddurah-Daouk, R AF Beger, Richard D. Dunn, Warwick Schmidt, Michael A. Gross, Steven S. Kirwan, Jennifer A. Cascante, Marta Brennan, Lorraine Wishart, David S. Oresic, Matej Hankemeier, Thomas Broadhurst, David I. Lane, Andrew N. Suhre, Karsten Kastenmueller, Gabi Sumner, Susan J. Thiele, Ines Fiehn, Oliver Kaddurah-Daouk, Rima CA Precision Med Pharmacometabolomics TI Metabolomics enables precision medicine: "A White Paper, Community Perspective" SO METABOLOMICS LA English DT Article DE Metabolomics; Metabonomics; Pharmacometabolomics; Pharmacometabonomics; Precision medicine; Personalized medicine ID GENOME-WIDE ASSOCIATION; PHARMACOMETABOLOMICS-INFORMED PHARMACOGENOMICS; PERSONALIZED HEALTH-CARE; TANDEM MASS-SPECTROMETRY; HUMAN METABOLISM; DRUG-METABOLISM; INBORN-ERRORS; CARDIOVASCULAR-DISEASE; LARGE-SCALE; HUMAN SERUM AB Introduction: Background to metabolomics Metabolomics is the comprehensive study of the metabolome, the repertoire of biochemicals (or small molecules) present in cells, tissues, and body fluids. The study of metabolism at the global or "-omics" level is a rapidly growing field that has the potential to have a profound impact upon medical practice. At the center of metabolomics, is the concept that a person's metabolic state provides a close representation of that individual's overall health status. This metabolic state reflects what has been encoded by the genome, and modified by diet, environmental factors, and the gut microbiome. The metabolic profile provides a quantifiable readout of biochemical state from normal physiology to diverse pathophysiologies in a manner that is often not obvious from gene expression analyses. Today, clinicians capture only a very small part of the information contained in the metabolome, as they routinely measure only a narrow set of blood chemistry analytes to assess health and disease states. Examples include measuring glucose to monitor diabetes, measuring cholesterol and high density lipoprotein/low density lipoprotein ratio to assess cardiovascular health, BUN and creatinine for renal disorders, and measuring a panel of metabolites to diagnose potential inborn errors of metabolism in neonates. Objectives of White Paper-expected treatment outcomes and metabolomics enabling tool for precision medicine We anticipate that the narrow range of chemical analyses in current use by the medical community today will be replaced in the future by analyses that reveal a far more comprehensive metabolic signature. This signature is expected to describe global biochemical aberrations that reflect patterns of variance in states of wellness, more accurately describe specific diseases and their progression, and greatly aid in differential diagnosis. Such future metabolic signatures will: (1) provide predictive, prognostic, diagnostic, and surrogate markers of diverse disease states; (2) inform on underlying molecular mechanisms of diseases; (3) allow for sub-classification of diseases, and stratification of patients based on metabolic pathways impacted; (4) reveal biomarkers for drug response phenotypes, providing an effective means to predict variation in a subject's response to treatment (pharmacometabolomics); (5) define a metabotype for each specific genotype, offering a functional read-out for genetic variants: (6) provide a means to monitor response and recurrence of diseases, such as cancers: (7) describe the molecular landscape in human performance applications and extreme environments. Importantly, sophisticated metabolomic analytical platforms and informatics tools have recently been developed that make it possible to measure thousands of metabolites in blood, other body fluids, and tissues. Such tools also enable more robust analysis of response to treatment. New insights have been gained about mechanisms of diseases, including neuropsychiatric disorders, cardiovascular disease, cancers, diabetes and a range of pathologies. A series of ground breaking studies supported by National Institute of Health (NIH) through the Pharmacometabolomics Research Network and its partnership with the Pharmacogenomics Research Network illustrate how a patient's metabotype at baseline, prior to treatment, during treatment, and post-treatment, can inform about treatment outcomes and variations in responsiveness to drugs (e.g., statins, antidepressants, antihypertensives and antiplatelet therapies). These studies along with several others also exemplify how metabolomics data can complement and inform genetic data in defining ethnic, sex, and gender basis for variation in responses to treatment, which illustrates how pharmacometabolomics and pharmacogenomics are complementary and powerful tools for precision medicine. Conclusions: Key scientific concepts and recommendations for precision medicine Our metabolomics community believes that inclusion of metabolomics data in precision medicine initiatives is timely and will provide an extremely valuable layer of data that compliments and informs other data obtained by these important initiatives. Our Metabolomics Society, through its "Precision Medicine and Pharmacometabolomics Task Group", with input from our metabolomics community at large, has developed this White Paper where we discuss the value and approaches for including metabolomics data in large precision medicine initiatives. This White Paper offers recommendations for the selection of state of-the-art metabolomics platforms and approaches that offer the widest biochemical coverage, considers critical sample collection and preservation, as well as standardization of measurements, among other important topics. We anticipate that our metabolomics community will have representation in large precision medicine initiatives to provide input with regard to sample acquisition/preservation, selection of optimal omics technologies, and key issues regarding data collection, interpretation, and dissemination. We strongly recommend the collection and biobanking of samples for precisionmedicine initiatives that will take into consideration needs for large-scale metabolic phenotyping studies. C1 [Beger, Richard D.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Dunn, Warwick] Univ Birmingham, Phenome Ctr Birmingham, Sch Biosci, Birmingham B15 2TT, W Midlands, England. [Dunn, Warwick] Univ Birmingham, Inst Metab & Syst Res IMSR, Birmingham B15 2TT, W Midlands, England. [Schmidt, Michael A.] Colorado State Univ, Res Innovat Ctr, Adv Pattern Anal & Countermeasures Grp, Ft Collins, CO 80521 USA. [Gross, Steven S.] Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10021 USA. [Kirwan, Jennifer A.] Univ Birmingham, Sch Biosci, Birmingham B15 2TT, W Midlands, England. [Cascante, Marta] Univ Barcelona, Fac Biol, Dept Biochem & Mol Biomed, Av Diagonal 643, E-08028 Barcelona, Spain. [Cascante, Marta] Univ Barcelona, Inst Biomed, Barcelona, Spain. [Cascante, Marta] CSIC, Associated Unit, Barcelona, Spain. [Brennan, Lorraine] UCD, Inst Food & Hlth, Dublin, Ireland. [Wishart, David S.] Univ Alberta, Dept Comp Sci, Edmonton, AB, Canada. [Wishart, David S.] Univ Alberta, Dept Biol Sci, Edmonton, AB, Canada. [Oresic, Matej] Univ Turku, Turku Ctr Biotechnol, Turku, Finland. [Hankemeier, Thomas] Leiden Univ, Div Analyt Biosci & Cluster Syst Pharmacol, Leiden Acad Ctr Drug Res, Leiden, Netherlands. [Hankemeier, Thomas] Netherlands Metabol Ctr, Leiden, Netherlands. [Broadhurst, David I.] Edith Cowan Univ, Sch Sci, Perth, WA, Australia. [Lane, Andrew N.] Markey Canc Ctr, Dept Toxicol & Canc Biol, Ctr Environm Syst Biochem, Lexington, KY USA. [Suhre, Karsten] Weill Cornell Med Coll Qatar, Dept Physiol & Biophys, Doha, Qatar. [Kastenmueller, Gabi] Helmholtz Ctr Munich, Inst Bioinformat & Syst Biol, Oberschleissheim, Germany. [Sumner, Susan J.] RTI Int, Discovery Sci, Durham, NC USA. [Thiele, Ines] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Campus Belval, Esch Sur Alzette, Luxembourg. [Fiehn, Oliver] Univ Calif Davis, West Coast Metabol Ctr, Davis, CA USA. [Fiehn, Oliver] King Abdulaziz Univ, Dept Biochem, Jeddah, Saudi Arabia. [Kaddurah-Daouk, Rima] Duke Univ, Med Ctr, Psychiat & Behav Sci, Duke Internal Med, Box 3903, Durham, NC 27710 USA. [Kaddurah-Daouk, Rima] Duke Univ, Med Ctr, Duke Inst Brain Sci, Box 3903, Durham, NC 27710 USA. [Kaddurah-Daouk, Rima] Duke Univ, Med Ctr, Ctr Appl Genom & Precis Med, Box 3903, Durham, NC 27710 USA. RP Kaddurah-Daouk, R (reprint author), Duke Univ, Med Ctr, Psychiat & Behav Sci, Duke Internal Med, Box 3903, Durham, NC 27710 USA.; Kaddurah-Daouk, R (reprint author), Duke Univ, Med Ctr, Duke Inst Brain Sci, Box 3903, Durham, NC 27710 USA.; Kaddurah-Daouk, R (reprint author), Duke Univ, Med Ctr, Ctr Appl Genom & Precis Med, Box 3903, Durham, NC 27710 USA. EM rima.kaddurahdaouk@duke.edu OI Kirwan, Jennifer/0000-0002-5423-1651; Brennan, Lorraine/0000-0002-7711-7499; Oresic, Matej/0000-0002-2856-9165 FU National Institute of General Medical Sciences (US) [R24 GM078233, RC2GM092729]; National Institute on Aging [1R01AG046171, RF1AG051550]; Medical Research Council in the UK [MR/M009157/1] FX National Institute of General Medical Sciences (US); Award Numbers: R24 GM078233 and RC2GM092729 "The Pharmacometabolomics Research Network"; National Institute on Aging; Award numbers: 1R01AG046171; RF1AG051550 Grant Recipient: Rima Kaddurah-Daouk. In addition, this work was supported by funding to Phenome Centre Birmingham by the Medical Research Council in the UK (MR/M009157/1). NR 102 TC 6 Z9 6 U1 35 U2 35 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 SEP PY 2016 VL 12 IS 9 AR 149 DI 10.1007/s11306-016-1094-6 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DX4FX UT WOS:000384337700007 PM 27642271 ER PT J AU Miller, RA AF Miller, Ron A. TI Antimicrobial susceptibility testing guidelines as a necessary tool to guide chemotherapeutic interventions in aquaculture SO MICROBIOLOGY AUSTRALIA LA English DT Article ID RESISTANT; BACTERIA; WATER AB The selection of chemotherapy in aquatic animal medicine is not as straightforward as one might believe. A multitude of factors can impact effectiveness in situ. Some of these factors include the pathogen(s) present and their antimicrobial susceptibility, site(s) of infection, timing of treatment, host health/disease status, dose and regimen, water salinity, and water temperature. This article will focus on the first of these factors, and how susceptibility testing of target pathogen(s) can be used to both inform therapy decisions and assist in compliance with principles of prudent and judicious use. C1 [Miller, Ron A.] US FDA, Ctr Vet Med, Off New Anim Drug Evaluat, 7500 Standish Pl, Rockville, MD 20855 USA. RP Miller, RA (reprint author), US FDA, Ctr Vet Med, Off New Anim Drug Evaluat, 7500 Standish Pl, Rockville, MD 20855 USA. EM ron.miller@fda.hhs.gov NR 15 TC 0 Z9 0 U1 1 U2 1 PU CSIRO PUBLISHING PI CLAYTON PA UNIPARK, BLDG 1, LEVEL 1, 195 WELLINGTON RD, LOCKED BAG 10, CLAYTON, VIC 3168, AUSTRALIA SN 1324-4272 EI 2201-9189 J9 MICROBIOL AUST JI Microbiol. Aust. PD SEP PY 2016 VL 37 IS 3 BP 104 EP 107 DI 10.1071/MA16036 PG 4 WC Microbiology SC Microbiology GA DW8DS UT WOS:000383884400003 ER PT J AU Kilili, GK Tilton, L Karbiwnyk, CM AF Kilili, Geoffrey K. Tilton, Lianna Karbiwnyk, Christine M. TI NaOH concentration and streptavidin bead type are key factors for optimal DNA aptamer strand separation and isolation SO BIOTECHNIQUES LA English DT Letter DE SELEX; single-stranded DNA (ssDNA); streptavidin magnetic beads; sodium hydroxide ID GENERATION; LISTERIA; SELEX C1 [Kilili, Geoffrey K.; Tilton, Lianna; Karbiwnyk, Christine M.] US FDA, Winchester Engn & Analyt Ctr, Winchester, MA 01890 USA. RP Kilili, GK; Karbiwnyk, CM (reprint author), US FDA, Winchester Engn & Analyt Ctr, Winchester, MA 01890 USA. EM Geoffrey.Kilili@fda.hhs.gov; Christine.Karbiwnyk@fda.hhs.gov NR 14 TC 0 Z9 0 U1 5 U2 5 PU BIOTECHNIQUES OFFICE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0736-6205 EI 1940-9818 J9 BIOTECHNIQUES JI Biotechniques PD SEP PY 2016 VL 61 IS 3 BP 114 EP 116 DI 10.2144/000114449 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DW6UB UT WOS:000383785700003 PM 27625204 ER PT J AU Kirch, R Reaman, G Feudtner, C Wiener, L Schwartz, LA Sung, L Wolfe, J AF Kirch, Rebecca Reaman, Gregory Feudtner, Chris Wiener, Lori Schwartz, Lisa A. Sung, Lillian Wolfe, Joanne TI Advancing a comprehensive cancer care agenda for children and their families: Institute of Medicine Workshop highlights and next steps SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Article DE end of life; oncology; palliative care; patient-reported outcomes; pediatric; psychosocial care; quality of life; supportive care; survivorship ID PEDIATRIC PALLIATIVE CARE; PSYCHOSOCIAL ASSESSMENT-TOOL; PATIENT-REPORTED OUTCOMES; CHRONIC HEALTH CONDITIONS; CHILDHOOD-CANCER; FOLLOW-UP; ADULT SURVIVORS; HIGH-RISK; ONCOLOGY; LIFE AB This article highlights key findings from the Comprehensive Cancer Care for Children and Their Families March 2015 joint workshop by the Institute of Medicine (IOM) and the American Cancer Society. This initiative convened more than 100 family members, clinician investigators, advocates, and members of the public to discuss emerging evidence and care models and to determine the next steps for optimizing quality-of-life outcomes and well-being for children and families during pediatric cancer treatment, after treatment completion, and across the life spectrum. Participants affirmed the triple aim of pediatric oncology that strives for every child with cancer to be cured; provides high-quality palliative and psychosocial supportive, restorative, and rehabilitative care to children and families throughout the illness course and survivorship; and assures receipt of high-quality end-of-life care for patients with advancing disease. Workshop outcomes emphasized the need for new pediatric cancer drug development and identified critical opportunities to prioritize palliative care and psychosocial support as an integral part of pediatric cancer research and treatment, including the necessity for adequately resourcing these supportive services to minimize suffering and distress, effectively address quality-of-life needs for children and families at all stages of illness, and mitigate the long-term health risks associated with childhood cancer and its treatment. Next steps include dismantling existing silos and enhancing collaboration between clinical investigators, disease-directed specialists, and supportive care services; expanding the use of patient-reported and parent-reported outcomes; effectively integrating palliative and psychosocial care; and clinical communication skills development. CA Cancer J Clin 2016;66:398-407. (c) 2016 American Cancer Society. C1 [Kirch, Rebecca] Ctr Adv Palliat Care, New York, NY USA. [Kirch, Rebecca] Cameron & Hayden Lord Fdn, New York, NY USA. [Reaman, Gregory] USDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Feudtner, Chris] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Feudtner, Chris] Univ Penn, Dept Med Eth & Hlth Policy, Perelman Sch Med, Philadelphia, PA 19104 USA. [Wiener, Lori] NCI, Behav Hlth Core, Bethesda, MD 20892 USA. [Wiener, Lori] NCI, Psychosocial Support & Res Program, Bethesda, MD 20892 USA. [Schwartz, Lisa A.] Childrens Hosp Philadelphia, Dept Pediat, Div Oncol, Philadelphia, PA 19104 USA. [Schwartz, Lisa A.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Sung, Lillian] Hosp Sick Children, Hematol Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Wolfe, Joanne] Dana Farber Canc Inst, Pediat Palliat Care Serv, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave, Boston, MA 02115 USA. [Wolfe, Joanne] Boston Childrens Hosp, Pediat Palliat Care, Boston, MA USA. RP Wolfe, J (reprint author), Dana Farber Canc Inst, Pediat Palliat Care Serv, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave, Boston, MA 02115 USA. EM joanne_wolfe@dfci.harvard.edu NR 83 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-9235 EI 1542-4863 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD SEP-OCT PY 2016 VL 66 IS 5 BP 398 EP 407 DI 10.3322/caac.21347 PG 10 WC Oncology SC Oncology GA DX0CQ UT WOS:000384029500007 PM 27145249 ER PT J AU Chen, MJ Borlak, J Tong, WD AF Chen, Minjun Borlak, Juergen Tong, Weida TI A Model to predict severity of drug-induced liver injury in humans SO HEPATOLOGY LA English DT Article ID ORAL MEDICATIONS; INDUSTRY PERSPECTIVE; COVALENT BINDING; ADVERSE EVENTS; TOXICITY; RISK; HEPATOTOXICITY; BIOACTIVATION; METABOLITES; DISCOVERY AB Drug-induced liver injury (DILI) is a major public health concern, and improving its prediction remains an unmet challenge. Recently, we reported the Rule-of-2 (RO2) and found lipophilicity (logP 3) and daily dose 100 mg of oral medications to be associated with significant risk for DILI; however, the RO2 failed to estimate grades of DILI severity. In an effort to develop a quantitative metrics, we analyzed the association of daily dose, logP, and formation of reactive metabolites (RM) in a large set of Food and Drug Administration-approved oral medications and found factoring RM into the RO2 to highly improve DILI prediction. Based on these parameters and by considering n = 354 drugs, an algorithm to assign a DILI score was developed. In univariate and multivariate logistic regression analyses the algorithm (i.e., DILI score model) defined the relative contribution of daily dose, logP, and RM and permitted a quantitative assessment of risk of clinical DILI. Furthermore, a clear relationship between calculated DILI scores and DILI risk was obtained when applied to three independent studies. The DILI score model was also functional with drug pairs defined by similar chemical structure and mode of action but divergent toxicities. Specifically, for drug pairs where the RO2 failed, the DILI score correctly identified toxic drugs. Finally, the model was applied to n = 159 clinical cases collected from the National Institutes of Health's LiverTox database to demonstrate that the DILI score correlated with the severity of clinical outcome. Conclusions: Based on daily dose, lipophilicity, and RM, a DILI score algorithm was developed that provides a scale of assessing the severity of DILI risk in humans associated with oral medications. (Hepatology 2016;64:931-940) C1 [Chen, Minjun; Tong, Weida] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Borlak, Juergen] Hannover Med Sch, Ctr Pharmacol & Toxicol, Hannover, Germany. RP Tong, WD (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA.; Borlak, J (reprint author), Hannover Med Sch, Ctr Pharmacol & Toxicol, Hannover, Germany. EM borlak.juergen@mh-hannover.de; weida.tong@fda.hhs.gov FU German Federal Ministry for Education and Research as part of the Virtual Liver Network initiative [031 6154]; US Food and Drug Administration's National Center for Toxicological Research FX Supported by the German Federal Ministry for Education and Research as part of the Virtual Liver Network initiative (grant 031 6154, to J.B.) and by the US Food and Drug Administration's National Center for Toxicological Research (to J.B.). NR 37 TC 0 Z9 0 U1 7 U2 7 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 SEP PY 2016 VL 64 IS 3 BP 931 EP 940 DI 10.1002/hep.28678 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DV9TU UT WOS:000383285900022 PM 27302180 ER PT J AU Salazar, E Hammerling, D Wang, X Sanso, B Finley, AO Mearns, LO AF Salazar, Esther Hammerling, Dorit Wang, Xia Sanso, Bruno Finley, Andrew O. Mearns, Linda O. TI Observation-based blended projections from ensembles of regional climate models SO CLIMATIC CHANGE LA English DT Article ID JOINT PROJECTIONS; TEMPERATURE; DESIGN AB We consider the problem of projecting future climate from ensembles of regional climate model (RCM) simulations using results from the North American Regional Climate Change Assessment Program (NARCCAP). To this end, we develop a hierarchical Bayesian space-time model that quantifies the discrepancies between different members of an ensemble of RCMs corresponding to present day conditions, and observational records. Discrepancies are then propagated into the future to obtain high resolution blended projections of 21st century climate. In addition to blended projections, the proposed method provides location-dependent comparisons between the different simulations by estimating the different modes of spatial variability, and using the climate model-specific coefficients of the spatial factors for comparisons. The approach has the flexibility to provide projections at customizable scales of potential interest to stakeholders while accounting for the uncertainties associated with projections at these scales based on a comprehensive statistical framework. We demonstrate the methodology with simulations from the Weather Research & Forecasting regional model (WRF) using three different boundary conditions. We use simulations for two time periods: current climate conditions, covering 1971 to 2000, and future climate conditions under the Special Report on Emissions Scenarios (SRES) A2 emissions scenario, covering 2041 to 2070. We investigate and project yearly mean summer and winter temperatures for a domain in the South West of the United States. C1 [Salazar, Esther] US FDA, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. [Hammerling, Dorit; Mearns, Linda O.] Natl Ctr Atmospher Res, Inst Math Appl Geosci, POB 3000, Boulder, CO 80307 USA. [Wang, Xia] Univ Cincinnati, Dept Math Sci, Cincinnati, OH USA. [Sanso, Bruno] Univ Calif Santa Cruz, Dept Appl Math & Stat, Santa Cruz, CA 95064 USA. [Finley, Andrew O.] Michigan State Univ, Dept Forestry, Lansing, MI USA. [Finley, Andrew O.] Michigan State Univ, Dept Geog, Lansing, MI USA. RP Salazar, E (reprint author), US FDA, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. EM Esther.Salazar@fda.hhs.gov; dorith@ucar.edu; xia.wang@uc.edu; bruno@ams.ucsc.edu; finleya@msu.edu; lindam@ucar.edu OI Hammerling, Dorit/0000-0003-3583-3611 FU NSF Research Network on Statistics in the Atmosphere and Ocean Sciences (STATMOS) [DMS-1106862]; National Science Foundation (NSF) [DMS-1513481, EF-1137309, EF-1241874, EF-1253225]; NASA Carbon Monitoring System grants; [DMS-1513076] FX Dorit Hammerling had partial support from the NSF Research Network on Statistics in the Atmosphere and Ocean Sciences (STATMOS) through grant DMS-1106862. Bruno Sanso had partial support from grant DMS-1513076. We thank Anthony Tracy for his help with specifying the small sub regions. All the data used in this work is available upon request. Andrew Finley was supported by National Science Foundation (NSF) DMS-1513481, EF-1137309, EF-1241874, and EF-1253225, as well as NASA Carbon Monitoring System grants. NR 26 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0165-0009 EI 1573-1480 J9 CLIMATIC CHANGE JI Clim. Change PD SEP PY 2016 VL 138 IS 1-2 BP 55 EP 69 DI 10.1007/s10584-016-1722-1 PG 15 WC Environmental Sciences; Meteorology & Atmospheric Sciences SC Environmental Sciences & Ecology; Meteorology & Atmospheric Sciences GA DU3UT UT WOS:000382138400005 ER PT J AU Vesnovsky, O Di Prima, MA Topoleski, LDT Kovacs, P AF Vesnovsky, Oleg Di Prima, Matthew A. Topoleski, L. D. Timmie Kovacs, Paul TI An Investigation of the Geometric and Surface Finish Features of Co-Cr-Mo Hip Taper Junction Designs SO JOURNAL OF MEDICAL DEVICES-TRANSACTIONS OF THE ASME LA English DT Article; Proceedings Paper CT University-of-Minnesota's Design of Medical Devices (DMD) Conference CY APR 11-14, 2016 CL Minneapolis, MN SP Univ Minnesota C1 [Vesnovsky, Oleg; Di Prima, Matthew A.; Topoleski, L. D. Timmie] US FDA, Silver Spring, MD 20993 USA. [Topoleski, L. D. Timmie] Univ Maryland Baltimore Cty, Baltimore, MD 21250 USA. RP Vesnovsky, O (reprint author), US FDA, Silver Spring, MD 20993 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 1932-6181 EI 1932-619X J9 J MED DEVICES JI J. Med. Devices PD SEP PY 2016 VL 10 IS 3 AR 030907 DI 10.1115/1.4033735 PG 3 WC Engineering, Biomedical SC Engineering GA DV8KC UT WOS:000383184900008 ER PT J AU Liu, ST Graffagino, CL Leser, KA Trombetta, AL Pirie, PL AF Liu, Sherry T. Graffagino, Cheryl L. Leser, Kendall A. Trombetta, Autumn L. Pirie, Phyllis L. TI Obesity Prevention Practices and Policies in Child Care Settings Enrolled and Not Enrolled in the Child and Adult Care Food Program SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Child and Adult Care Food Program; Nutrition; Physical activity; Child care; Practices; Policies ID PHYSICAL-ACTIVITY; CENTERS; NUTRITION; RECOMMENDATIONS; PRESCHOOLERS; ENVIRONMENT AB Objectives The United States Department of Agriculture's Child and Adult Care Food Program (CACFP) provides meals and snacks to low-income children in child care. This study compared nutrition and physical activity practices and policies as well as the overall nutrition and physical activity environments in a sample of CACFP and non-CACFP child care settings. Methods A random stratified sample of 350 child care settings in a large Midwestern city and its suburbs, was mailed a survey on obesity prevention practices and policies concerning menu offerings, feeding practices, nutrition and physical activity education, activity levels, training, and screen time. Completed surveys were obtained from 229 of 309 eligible child care settings (74.1 % response rate). Chi square tests were used to compare practices and policies in CACFP and non-CACFP sites. Poisson and negative binomial regression were used to examine associations between CACFP and total number of practices and policies. Results Sixty-nine percent of child care settings reported CACFP participation. A significantly higher proportion of CACFP sites reported offering whole grain foods daily and that providers always eat the same foods that are offered to the children. CACFP sites had 1.1 times as many supportive nutrition practices as non-CACFP sites. CACFP participation was not associated with written policies or physical activity practices. Conclusions for Practice There is room for improvement across nutrition and physical activity practices and policies. In addition to food reimbursement, CACFP participation may help promote child care environments that support healthy nutrition; however, additional training and education outreach activities may be needed. C1 [Liu, Sherry T.; Leser, Kendall A.; Pirie, Phyllis L.] Ohio State Univ, Coll Publ Hlth, Div Hlth Behav & Hlth Promot, Columbus, OH 43210 USA. [Graffagino, Cheryl L.; Trombetta, Autumn L.] Columbus Publ Hlth, Columbus, OH USA. [Liu, Sherry T.] US FDA, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. RP Liu, ST (reprint author), Ohio State Univ, Coll Publ Hlth, Div Hlth Behav & Hlth Promot, Columbus, OH 43210 USA.; Liu, ST (reprint author), US FDA, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM sherry.t.liu@fda.hhs.gov FU Centers for Disease Control and Prevention [U48-DP001912] FX This work was supported by Cooperative Agreement No. U48-DP001912 from the Centers for Disease Control and Prevention. The findings and conclusions in this journal article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. NR 29 TC 0 Z9 0 U1 7 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD SEP PY 2016 VL 20 IS 9 BP 1933 EP 1939 DI 10.1007/s10995-016-2007-z PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DV2MG UT WOS:000382754100020 PM 27112556 ER PT J AU Felix, SE Mack, KA Jones, CM AF Felix, Sausan El Burai Mack, Karin A. Jones, Christopher M. TI Trends in the Distribution of Opioids in Puerto Rico, 1999-2013 SO PUERTO RICO HEALTH SCIENCES JOURNAL LA English DT Article DE Prescription drugs; Overdose ID UNITED-STATES AB Objective: Limited information has been published about opioid prescribing practices in Puerto Rico. The objective of this study was to create baseline trends of opioids distributed over a period of fourteen years in Puerto Rico. Methods: We examined data from the U.S. Drug Enforcement Administration's Automation of Reports and Consolidated Orders System (ARCOS) for the period 1999-2013. ARCOS data reflects the amount of controlled substances legally dispensed. Analyses include the distribution of opioids (in morphine milligram equivalent kg per 10,000 persons) by year and entity (pharmacy, hospital, practitioner). Results: The distribution of four drugs (fentanyl, hydromorphone, methadone, oxycodone) increased over 100% between 1999 and 2013. The distribution of two drugs (hydrocodone and meperidine) declined between 1999 and 2013. Oxycodone distribution grew from 0.13 MME kg grams per 10,000 persons in 1999 to 0.29 MME kg in 2013. Conclusion: ARCOS data showed that the overall amount of opioid pain relievers distributed in Puerto Rico increased by 68% between 1999 and 2013. Currently, prescription opioid pain reliever overdose deaths in Puerto Rico do not appear to be skyrocketing as they are in the mainland U.S. However, the ongoing problem with prescription opioid pain reliever overdoses in certain areas should serve as a warning to monitor consumption of opioid pain relievers, as well as changes in prescription drug abuse, overdoses, and deaths. C1 [Felix, Sausan El Burai] Ctr Dis Control & Prevent, Natl Ctr Injury Prevent & Control, Div Unintent Injury Prevent, Atlanta, GA USA. [Mack, Karin A.] Ctr Dis Control & Prevent, Natl Ctr Injury Prevent & Control, Div Anal Res & Practice Integrat, 4770 Buford Hwy NE F62, Atlanta, GA 30341 USA. [Jones, Christopher M.] Food & Drug Adm, Off Commissioner, Off Publ Hlth Strategy & Anal, Silver Spring, MD USA. RP Mack, KA (reprint author), Ctr Dis Control & Prevent, Natl Ctr Injury Prevent & Control, Div Anal Res & Practice Integrat, 4770 Buford Hwy NE F62, Atlanta, GA 30341 USA. EM kmack@cdc.gov NR 14 TC 0 Z9 0 U1 0 U2 0 PU UNIV PUERTO RICO MEDICAL SCIENCES CAMPUS PI SAN JUAN PA OFFICE DEAN ACADEMIC AFFAIRS BOX 365067, SAN JUAN, PR 00936-5067 USA SN 0738-0658 J9 P R HEALTH SCI J JI P. R. Health Sci. J. PD SEP PY 2016 VL 35 IS 3 BP 165 EP 169 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DV3XV UT WOS:000382859700007 ER PT J AU Mistry, B Patel, N Jamei, M Rostami-Hodjegan, A Martinez, MN AF Mistry, Bipin Patel, Nikunjkumar Jamei, Masoud Rostami-Hodjegan, Amin Martinez, Marilyn N. TI Examining the Use of a Mechanistic Model to Generate an In Vivo/In Vitro Correlation: Journey Through a Thought Process SO AAPS JOURNAL LA English DT Article DE in vivo/in vitro correlation; mechanistic model; metoprolol ID EXTENDED-RELEASE FORMULATION; NUMERICAL DECONVOLUTION; METOPROLOL TARTRATE; LEAST-SQUARES; NONLINEAR-REGRESSION; PHARMACOKINETIC DATA; IVIVC; BIOPHARMACEUTICS; DEXTROMETHORPHAN; PERMEABILITY AB The attention and interest in establishing in vivo/in vitro correlations (IVIVCs) is grounded in its tremendous utility as a prognostic tool. It can be used to support formulation optimization, predict in vivo drug exposure across a potential patient population, select a biologically relevant in vitro dissolution test condition, and support the use of in vitro dissolution data as a surrogate for in vivo bioequivalence trials. The pharmacological and statistical implications of this correlation are linked to the method by which the IVIVC was determined and to the assumptions and optimization approaches integrated into the estimation procedure. Using previously published data generated in normal healthy volunteers, an IVIVC for metoprolol was established using a mechanistic modeling approach. Within that framework, we explored the consequences of (1) our method of fitting a single Weibull function to the in vivo dissolution, (2) our selection of weighting scheme and optimization approaches, (3) the impact of applying a fixed versus fitted gastric emptying time, and 4) the importance of factoring population variability into our IVIVC estimation and profile reconvolution. We identified those factors found to be critical in terms of their influence on the accuracy of our predicted systemic metoprolol concentration-time profiles. We considered the strengths and weaknesses of our approach and discussed how the results of this study may impact efforts to generate IVIVCs with compounds presenting physicochemical characteristics different from that of metoprolol. C1 [Mistry, Bipin; Martinez, Marilyn N.] US FDA, Off New Drug Evaluat, Ctr Vet Med, Rockville, MD 20855 USA. [Patel, Nikunjkumar; Jamei, Masoud; Rostami-Hodjegan, Amin] Simcyp, Blades Enterprise Ctr, Sheffield, S Yorkshire, England. [Rostami-Hodjegan, Amin] Univ Manchester, Manchester Pharm Sch, Ctr Appl Pharmacokinet Res, Stopford Bldg, Manchester, Lancs, England. RP Martinez, MN (reprint author), US FDA, Off New Drug Evaluat, Ctr Vet Med, Rockville, MD 20855 USA. EM marilyn.martinez@fda.hhs.gov NR 33 TC 1 Z9 1 U1 3 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 SEP PY 2016 VL 18 IS 5 BP 1144 EP 1158 DI 10.1208/s12248-016-9930-1 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DU3ES UT WOS:000382094200009 PM 27312260 ER PT J AU Playdon, MC Sampson, JN Cross, AJ Sinha, R Guertin, KA Moy, KA Rothman, N Irwin, ML Mayne, ST Stolzenberg-Solomon, R Moore, SC AF Playdon, Mary C. Sampson, Joshua N. Cross, Amanda J. Sinha, Rashmi Guertin, Kristin A. Moy, Kristin A. Rothman, Nathaniel Irwin, Melinda L. Mayne, Susan T. Stolzenberg-Solomon, Rachael Moore, Steven C. TI Comparing metabolite profiles of habitual diet in serum and urine SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE metabolomics; metabolite; serum; urine; diet; food; nutrition assessment; biomarker ID MASS-SPECTROMETRY; NUTRITIONAL EPIDEMIOLOGY; COLORECTAL-CANCER; FOOD-INTAKE; COFFEE CONSUMPTION; MEASUREMENT ERROR; ALPHA-TOCOPHEROL; PROLINE BETAINE; CITRUS-FRUIT; L-CARNITINE AB Background: Diet plays an important role in chronic disease etiology, but some diet-disease associations remain inconclusive because of methodologic limitations in dietary assessment. Metabolomics is a novel method for identifying objective dietary biomarkers, although it is unclear what dietary information is captured from metabolites found in serum compared with urine. Objective: We compared metabolite profiles of habitual diet measured from serum with those measured from urine. Design: We first estimated correlations between consumption of 56 foods, beverages, and supplements assessed by a food-frequency questionnaire, with 676 serum and 848 urine metabolites identified by untargeted liquid chromatography mass spectrometry, ultra-high performance liquid chromatography tandem mass spectrometry, and gas chromatography mass spectrometry in a colon adenoma case control study (n = 125 cases and 128 controls) while adjusting for age, sex, smoking, fasting, case-control status, body mass index, physical activity, education, and caloric intake. We controlled for multiple comparisons with the use of a false discovery rate of <0.1. Next, we created serum and urine multiple-metabolite models to predict food intake with the use of 10-fold crossvalidation least absolute shrinkage and selection operator regression for 80% of the data; predicted values were created in the remaining 20%. Finally, we compared predicted values with estimates obtained from self-reported intake for metabolites measured in serum and urine. Results: We identified metabolites associated with 46 of 56 dietary items; 417 urine and 105 serum metabolites were correlated with >= 1 food, beverage, or supplement. More metabolites in urine (n = 154) than in serum (n = 39) were associated uniquely with one food. We found previously unreported metabolite associations with leafy green vegetables, sugar-sweetened beverages, citrus, added sugar, red meat, shellfish, desserts, and wine. Prediction of dietary intake from multiple-metabolite profiles was similar between biofluids. Conclusions: Candidate metabolite biomarkers of habitual diet are identifiable in both serum and urine. Urine samples offer a valid alternative or complement to serum for metabolite biomarkers of diet in large-scale clinical or epidemiologic studies. C1 [Playdon, Mary C.; Irwin, Melinda L.; Mayne, Susan T.] Yale Univ, Yale Sch Publ Hlth, New Haven, CT 06520 USA. [Playdon, Mary C.; Sampson, Joshua N.; Sinha, Rashmi; Guertin, Kristin A.; Moy, Kristin A.; Rothman, Nathaniel; Stolzenberg-Solomon, Rachael; Moore, Steven C.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Cross, Amanda J.] Imperial Coll London, Sch Publ Hlth, Fac Med, London, England. [Irwin, Melinda L.] Yale Canc Ctr, New Haven, CT USA. [Mayne, Susan T.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Playdon, MC (reprint author), Yale Univ, Yale Sch Publ Hlth, New Haven, CT 06520 USA.; Playdon, MC (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. EM mary.playdon@nih.gov RI Moore, Steven/D-8760-2016; Playdon, Mary/I-4050-2016 OI Moore, Steven/0000-0002-8169-1661; FU Yale National Cancer Institute [T32 CA105666]; Intramural Research Program of the NIH; National Cancer Institute FX This work was supported in part by Yale National Cancer Institute pre-doctoral training grant no. T32 CA105666 to STM and by the Intramural Research Program of the NIH and National Cancer Institute. NR 69 TC 1 Z9 1 U1 19 U2 19 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 BP 776 EP 789 DI 10.3945/ajcn.116.135301 PG 14 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UU UT WOS:000382420900031 PM 27510537 ER PT J AU Cho, CY Nowatzke, W Oliver, K Garber, EAE AF Cho, Chung Y. Nowatzke, William Oliver, Kerry Garber, Eric A. E. TI Multiplex detection of food allergens and gluten (vol 407, pg 4195, 2015) SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Correction C1 [Cho, Chung Y.; Garber, Eric A. E.] US FDA, Off Regulatory Sci, CFSAN, College Pk, MD 20740 USA. [Nowatzke, William; Oliver, Kerry] Radix BioSolut, Georgetown, TX 78626 USA. RP Garber, EAE (reprint author), US FDA, Off Regulatory Sci, CFSAN, College Pk, MD 20740 USA. EM Eric.Garber@fda.hhs.gov NR 1 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD SEP PY 2016 VL 408 IS 23 BP 6509 EP 6510 DI 10.1007/s00216-016-9745-z PG 2 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DV1LF UT WOS:000382681900027 ER PT J AU Zhang, YH Barocas, VH Berceli, SA Clancy, CE Eckmann, DM Garbey, M Kassab, GS Lochner, DR Mcculloch, AD Tran-Son-Tay, R Trayanova, NA AF Zhang, Yanhang Barocas, Victor H. Berceli, Scott A. Clancy, Colleen E. Eckmann, David M. Garbey, Marc Kassab, Ghassan S. Lochner, Donna R. Mcculloch, Andrew D. Tran-Son-Tay, Roger Trayanova, Natalia A. TI Multi-scale Modeling of the Cardiovascular System: Disease Development, Progression, and Clinical Intervention SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE Cardiac mechanics; Electrophysiological modeling; Cardiovascular fluid mechanics; Vascular mechanics; Extracellular matrix; Mechanical forces; Pathway network analysis; Constitutive model; Multi-scale modeling ID BIAXIAL MECHANICAL-BEHAVIOR; PORCINE CORONARY-ARTERY; SUDDEN CARDIAC DEATH; ATRIAL-FIBRILLATION; CONSTITUTIVE MODEL; SOFT-TISSUES; SHEAR-STRESS; BLOOD-FLOW; INTERCELLULAR COMMUNICATION; VENTRICULAR-ARRHYTHMIAS AB Cardiovascular diseases (CVDs) are the leading cause of death in the western world. With the current development of clinical diagnostics to more accurately measure the extent and specifics of CVDs, a laudable goal is a better understanding of the structure-function relation in the cardiovascular system. Much of this fundamental understanding comes from the development and study of models that integrate biology, medicine, imaging, and biomechanics. Information from these models provides guidance for developing diagnostics, and implementation of these diagnostics to the clinical setting, in turn, provides data for refining the models. In this review, we introduce multi-scale and multi-physical models for understanding disease development, progression, and designing clinical interventions. We begin with multi-scale models of cardiac electrophysiology and mechanics for diagnosis, clinical decision support, personalized and precision medicine in cardiology with examples in arrhythmia and heart failure. We then introduce computational models of vasculature mechanics and associated mechanical forces for understanding vascular disease progression, designing clinical interventions, and elucidating mechanisms that underlie diverse vascular conditions. We conclude with a discussion of barriers that must be overcome to provide enhanced insights, predictions, and decisions in pre-clinical and clinical applications. C1 [Zhang, Yanhang] Boston Univ, Dept Mech Engn, Boston, MA 02215 USA. [Zhang, Yanhang] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Barocas, Victor H.] Univ Minnesota, Dept Biomed Engn, Minneapolis, MN USA. [Berceli, Scott A.] Univ Florida, Dept Surg, Gainesville, FL USA. [Clancy, Colleen E.] Univ Calif Davis, Dept Pharmacol, Davis, CA 95616 USA. [Eckmann, David M.] Univ Penn, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Garbey, Marc] Methodist Hosp, Res Inst, Ctr Computat Surg, 6535 Fannin, Houston, TX 77030 USA. [Kassab, Ghassan S.] Calif Med Innovat Inst, San Diego, CA USA. [Lochner, Donna R.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Mcculloch, Andrew D.] Univ Calif San Diego, Dept Bioengn, San Diego, CA 92103 USA. [Mcculloch, Andrew D.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Tran-Son-Tay, Roger] Univ Florida, Dept Mech & Aerosp Engn, Gainesville, FL USA. [Tran-Son-Tay, Roger] Univ Florida, Dept Biomed Engn, Gainesville, FL USA. [Trayanova, Natalia A.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. [Trayanova, Natalia A.] Johns Hopkins Univ, Inst Computat Med, Baltimore, MD USA. RP Zhang, YH (reprint author), Boston Univ, Dept Mech Engn, Boston, MA 02215 USA.; Zhang, YH (reprint author), Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. EM yanhang@bu.edu FU National Science Foundation IUCRC CYBHOR [106022, CMMI 1463390, CMMI 0954825]; National Institute of Health [U01EB016638, U01 EB016027, R01 EB006818, U01HL119178-01, R01HL117990, U01 HL118738, P50 GM094503, P41 GM103426-19, R01HL105242,, R01HL121754, R01HL098028]; FDA Critical Path Initiative FX The authors acknowledge funding supports from National Science Foundation IUCRC CYBHOR NSF 106022 (Garbey); NSF CMMI 1463390 and CMMI 0954825 (Zhang), National Institute of Health U01EB016638 (Barocas); U01 EB016027 and R01 EB006818 (Eckmann); U01HL119178-01 (Berceli, Garbey, Tran Son Tay); R01HL117990 (Kassab) and U01 HL118738 (Beard and Kassab); P50 GM094503 (Beard), P41 GM103426-19 (Amaro), R01HL105242, and R01HL121754 (McCulloch); and R01HL098028 (Zhang), and FDA Critical Path Initiative (Lochner). NR 179 TC 2 Z9 2 U1 11 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0090-6964 EI 1573-9686 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD SEP PY 2016 VL 44 IS 9 BP 2642 EP 2660 DI 10.1007/s10439-016-1628-0 PG 19 WC Engineering, Biomedical SC Engineering GA DV1IO UT WOS:000382674700005 PM 27138523 ER PT J AU Taylor, JO Good, BC Paterno, AV Hariharan, P Deutsch, S Malinauskas, RA Manning, KB AF Taylor, Joshua O. Good, Bryan C. Paterno, Anthony V. Hariharan, Prasanna Deutsch, Steven Malinauskas, Richard A. Manning, Keefe B. TI Analysis of Transitional and Turbulent Flow Through the FDA Benchmark Nozzle Model Using Laser Doppler Velocimetry SO CARDIOVASCULAR ENGINEERING AND TECHNOLOGY LA English DT Article DE Laser Doppler velocimetry; Particle image velocimetry; Turbulence; Reynolds stress; Hemolysis ID COMPUTATIONAL FLUID-DYNAMICS; VENTRICULAR ASSIST DEVICE; PARTICLE IMAGE VELOCIMETRY; MECHANICAL HEART-VALVES; SHEAR-STRESS; CARDIOPULMONARY BYPASS; MEAN VELOCITY; BLOOD PUMPS; HEMOLYSIS; DESIGN AB Transitional and turbulent flow through a simplified medical device model is analyzed as part of the FDA's Critical Path Initiative, designed to improve the process of bringing medical products to market. Computational predictions are often used in the development of devices and reliable in vitro data is needed to validate computational results, particularly estimations of the Reynolds stresses that could play a role in damaging blood elements. The high spatial resolution of laser Doppler velocimetry (LDV) is used to collect two component velocity data within the FDA benchmark nozzle model. Two flow conditions are used to produce flow encompassing laminar, transitional, and turbulent regimes, and viscous stresses, principal Reynolds stresses, and turbulence intensities are calculated from the measured LDV velocities. Axial velocities and viscous stresses are compared to data from a prior inter-laboratory study conducted with particle image velocimetry. Large velocity gradients are observed near the wall in the nozzle throat and in the jet shear layer located in the expansion downstream of the throat, with axial velocity changing as much as 4.5 m/s over 200 mu m. Additionally, maximum Reynolds shear stresses of 1000-2000 Pa are calculated in the high shear regions, which are an order of magnitude higher than the peak viscous shear stresses (< 100 Pa). It is important to consider the effects of both viscous and turbulent stresses when simulating flow through medical devices. Reynolds stresses above commonly accepted hemolysis thresholds are measured in the nozzle model, indicating that hemolysis may occur under certain flow conditions. As such, the presented turbulence quantities from LDV, are also available for download at https://fdacfd.nci.nih.gov/, provide an ideal validation test for computational simulations that seek to characterize the flow field and to predict hemolysis within the FDA nozzle geometry. C1 [Taylor, Joshua O.; Good, Bryan C.; Paterno, Anthony V.; Deutsch, Steven; Manning, Keefe B.] Penn State Univ, Dept Biomed Engn, 205 Hallowell Bldg, University Pk, PA 16802 USA. [Taylor, Joshua O.; Deutsch, Steven] Penn State Univ, Appl Res Lab, State Coll, PA 16804 USA. [Hariharan, Prasanna; Malinauskas, Richard A.] US FDA, Off Sci & Engn Labs, Silver Spring, MD USA. [Manning, Keefe B.] Penn State Coll Med, Dept Surg, Hershey, PA USA. RP Manning, KB (reprint author), Penn State Univ, Dept Biomed Engn, 205 Hallowell Bldg, University Pk, PA 16802 USA. EM kbm10@psu.edu FU US Food and Drug Administration's Critical Path Initiative FX This study was supported by the US Food and Drug Administration's Critical Path Initiative. We would like to thank Dr. Luke Herbertson for reviewing the manuscript and providing valuable comments. NR 56 TC 1 Z9 1 U1 6 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1869-408X EI 1869-4098 J9 CARDIOVASC ENG TECHN JI Cardiovasc. Eng. Technol. PD SEP PY 2016 VL 7 IS 3 BP 191 EP 209 DI 10.1007/s13239-016-0270-1 PG 19 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA DU3MS UT WOS:000382116000001 PM 27350137 ER PT J AU Ahn, MR Li, L Shon, J Bashaw, ED Kim, MJ AF Ahn, M. R. Li, L. Shon, J. Bashaw, E. D. Kim, M-J TI Teratogenic Drugs and Their Drug Interactions With Hormonal Contraceptives SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB The US Food and Drug Administration (FDA) Guidance for IndustryDrug Interaction Studies, recommends that a potential human teratogen needs to be studied in vivo for effects on contraceptive steroids.(1) This article highlights the need to evaluate the drug-drug interactions (DDIs) between drugs with teratogenic potential and hormonal contraceptives (HCs) during drug development. It also addresses the FDA's effort of communicating DDI findings in product labels to mitigate the risk of unintended pregnancy. C1 [Ahn, M. R.; Li, L.; Shon, J.; Bashaw, E. D.; Kim, M-J] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Kim, MJ (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM MyongJin.Kim@fda.hhs.gov NR 7 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD SEP PY 2016 VL 100 IS 3 BP 217 EP 219 DI 10.1002/cpt.384 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DV2EE UT WOS:000382732800013 PM 27090193 ER PT J AU Elkins, KL Kurtz, SL De Pascalis, R AF Elkins, Karen L. Kurtz, Sherry L. De Pascalis, Roberto TI Progress, challenges, and opportunities in Francisella vaccine development SO EXPERT REVIEW OF VACCINES LA English DT Review DE Francisella tularensis; tularemia; protective immunity; correlates; intracellular bacteria; T cells; vaccines ID LIVE TULAREMIA VACCINE; TULARENSIS SUBSPECIES TULARENSIS; LETHAL INHALATIONAL INFECTION; MARMOSET CALLITHRIX-JACCHUS; HOST-PARASITE RELATIONSHIP; HUMORAL IMMUNE-RESPONSES; CELL-MEDIATED-IMMUNITY; WILD-TYPE BACTERIA; INTRACELLULAR BACTERIUM; IN-VIVO AB Renewed interest in Francisella tularensis has resulted in substantial new information about its pathogenesis and immunology, along with development of useful animal models. While understanding of protective immunity against Francisella remains incomplete, data in both animals and humans suggest that inducing T cell-mediated immunity is crucial for successful vaccination with current candidates such as the Live Vaccine Strain (LVS), with specific antibodies and immune B cells playing supporting roles. Consistent with this idea, recent results indicate that measurements of T cell functions and relative gene expression by immune T cells predict vaccine-induced protection in animal models. Because field trials of new vaccines will be difficult to design, using such measurements to derive potential correlates of protection may be important to bridge between animal efficacy studies and people. C1 [Elkins, Karen L.; Kurtz, Sherry L.; De Pascalis, Roberto] US FDA, Div Bacterial Parasit & Allergen Prod, CBER, Silver Spring, MD 20993 USA. RP Elkins, KL (reprint author), US FDA, CBER, LMPCI, DBPAP,OVRR, 10903 New Hampshire Ave,Bldg 52-72,Room 5328, Silver Spring, MD 20993 USA. EM karen.elkins@fda.hhs.gov NR 110 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1476-0584 EI 1744-8395 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD SEP PY 2016 VL 15 IS 9 SI SI BP 1183 EP 1196 DI 10.1586/14760584.2016.1170601 PG 14 WC Immunology SC Immunology GA DV2TX UT WOS:000382775700012 PM 27010448 ER PT J AU Seidman, JD Krishnan, J Yemelyanova, A Vang, R AF Seidman, Jeffrey D. Krishnan, Jayashree Yemelyanova, Anna Vang, Russell TI Incidental Serous Tubal Intraepithelial Carcinoma and Non-Neoplastic Conditions of the Fallopian Tubes in Grossly Normal Adnexa: A Clinicopathologic Study of 388 Completely Embedded Cases SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Fallopian tube carcinoma; Mucinous metaplasia; Intraepithelial carcinoma; Serous carcinoma; Fimbriae; Ovarian carcinoma; BRCA; Adenofibroma; Salpingolith ID OVARIAN-CANCER; ENDOMETRIUM; CARCINOGENESIS; SALPINGITIS; LESIONS; PRECURSORS; EPITHELIUM; FREQUENCY; ORIGIN; MODEL AB Serous tubal intraepithelial carcinoma (STIC), the putative precursor of the majority of extrauterine high-grade serous carcinomas, has been reported in both high-risk women (those with a germline BRCA mutation, a personal history of breast carcinoma, and/or family history of breast or ovarian carcinoma) and average risk women from the general population. We reviewed grossly normal adnexal specimens from 388 consecutive, unselected women undergoing surgery, including those with germline BRCA mutation (37 patients), personal history of breast cancer or family history of breast/ovarian cancer (74 patients), endometrial cancer (175 patients), and a variety of other conditions (102 patients). Among 111 high-risk cases and 277 non-high-risk cases, 3 STICs were identified (0.8%), all in non-high-risk women (high risk vs. non-high risk: P=not significant). STIC was found in 2 women with nonserous endometrial carcinoma and 1 with complex atypical endometrial hyperplasia. Salpingoliths (mucosal calcifications), found in 9% of high-risk cases, and fimbrial adenofibromas in 9.9% of high-risk cases, were significantly more common in high-risk as compared with non-high-risk women (1.8% and 2.5%, respectively; P<0.007). Mucinous metaplasia was found in 3.1%, salpingitis isthmica nodosa in 3.4%, hemosiderin or pseudoxanthoma cells in 4.9%, and fibrous luminal nodules in 4.1%. None of these latter features differed significantly in the high-risk versus non-high-risk groups. These findings suggest a possible association between STIC and endometrial hyperplasia and carcinoma, and clarify the frequency of non-neoplastic tubal findings in grossly normal fallopian tubes. C1 [Seidman, Jeffrey D.] US FDA, Mol Pathol & Cytol Branch, Ctr Devices & Radiol Hlth, Div Mol Genet & Pathol,Off Vitro Diagnost & Radio, Silver Spring, MD USA. [Vang, Russell] Johns Hopkins Med Inst, Dept Pathol Obstet & Gynecol, Baltimore, MD 21205 USA. [Krishnan, Jayashree] Washington Hosp Ctr, Dept Pathol, Washington, DC 20010 USA. [Yemelyanova, Anna] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Austin, TX USA. RP Seidman, JD (reprint author), Ctr Devices & Radiol Hlth, Mol Pathol & Cytol Branch, Div Mol Genet & Pathol, Off Vitro Diagnost & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jeffrey.seidman@fda.hhs.gov FU NCI NIH HHS [P30 CA008748] NR 30 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-1691 EI 1538-7151 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD SEP PY 2016 VL 35 IS 5 BP 423 EP 429 DI 10.1097/PGP.0000000000000267 PG 7 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA DT2NW UT WOS:000381318000005 PM 26630221 ER PT J AU Pan, H Buenconsejo, M Reineke, KF Shieh, YC AF Pan, Hao Buenconsejo, Matthew Reineke, Karl F. Shieh, Y. Carol TI Effect of Process Temperature on Virus Inactivation during High Hydrostatic Pressure Processing of Contaminated Fruit Puree and Juice SO JOURNAL OF FOOD PROTECTION LA English DT Article DE High hydrostatic pressure process; Juice; Process control; Puree; Virus inactivation ID HEPATITIS-A VIRUS; MURINE NOROVIRUS; UNITED-STATES; FELINE CALICIVIRUS; STRAWBERRY PUREE; FOOD-INDUSTRY; SURVIVAL; OYSTERS; SURROGATES; OUTBREAKS AB High pressure processing (HPP) can inactivate pathogens and retain fruit qualities. Elevated HPP pressure or time increases virus inactivation, but the effect of temperature is not consistently observed for norovirus and hepatitis A virus. In the present study, the effectiveness of HPP holding temperatures (<40 degrees C) and pressures were evaluated for inactivating surrogates (murine norovirus [MNV] and MS2 coliphage) in pomegranate and strawberry juices and strawberry puree using a 24-liter HPP system. The holding temperature was established by setting the HPP initial temperature via pretrials. All trials were able to arrive at the designated holding pressure and holding temperature simultaneously. MNV inactivation in juices was conducted at 300 MPa for 3 min with various holding temperatures (10 to 30 degrees C). A regression equation was derived, Y = -0.08 X X + 2.6 log PFU, R-2 = 0.96, where Y is the log reduction and X is the holding temperature. The equation was used to predict a 2.6-log reduction in juices at 0 degrees C holding temperature and indicated that MNV inactivation was inversely proportional to temperature increase. MNV survival during HPP did not differ significantly in pomegranate and strawberry juices. However, MS2 coliphage inactivation was greater as the holding temperature increased (from 15 to 38 degrees C) at 600 MPa for 3 min. The increased inactivation trend is presumably similar to that for hepatitis A virus, but the holding temperature was not correlated with the reduction of HPP-resistant MS2 in strawberry puree. When the HPP holding pressure was evaluated independently in strawberry puree, a 5-log reduction of MNV was predicted through regression analysis at the holding pressure of 424 MPa for 3 min at 20 degrees C. These parameters should inactivate >5 log PFU of MNV in juices, based upon a greater inactivation in berry juice than in puree (1.16-versus 0.74-log reduction at 300 MPa). This research illustrates use of predictive inactivation and a feasible means for manipulating HPP parameters for effective virus inactivation in fruit juices and puree. C1 [Pan, Hao; Buenconsejo, Matthew] IIT, Dept Food Sci & Nutr, 6502 S Archer Rd, Bedford Pk, IL 60501 USA. [Reineke, Karl F.; Shieh, Y. Carol] US FDA, Ctr Food Safety & Appl Nutr, Div Food Proc Sci & Technol, 6502 S Archer Rd, Bedford Pk, IL 60501 USA. RP Shieh, YC (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Food Proc Sci & Technol, 6502 S Archer Rd, Bedford Pk, IL 60501 USA. EM carol.shieh@fda.hhs.gov FU U.S. Food and Drug Administration FX The authors thank M. L. Tortorello, C. K. Carstens, D. T. Laird, D. G. Black, and R. E. McDonald for their comments on the manuscript. Appreciation also goes to J. Larkin and E. Patazca for their consultations on HPP unit selection, sample packaging, and the process parameter evaluation at the beginning of the study. The technical assistance by student Mingyan Ma is appreciated as well. This research was largely funded by the U.S. Food and Drug Administration. NR 32 TC 0 Z9 0 U1 10 U2 10 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD SEP PY 2016 VL 79 IS 9 BP 1517 EP 1526 DI 10.4315/0362-028X.JFP-16-004 PG 10 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA DV3DP UT WOS:000382801500007 PM 28221934 ER PT J AU Kase, JA Maounounen-Laasri, A Lin, A AF Kase, Julie A. Maounounen-Laasri, Anna Lin, Andrew TI Rapid Identification of Shiga Toxin-Producing Escherichia coli O Serogroups from Fresh Produce and Raw Milk Enrichment Cultures by Luminex Bead-Based Suspension Array SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Bio-Plex 200 instrumentation; Food enrichment; Luminex; O serogroup identification; Shiga toxin-producing Escherichia coli ID EMERGING ISSUES; UNITED-STATES; TRANSMISSION; INFECTIONS; PATHOGENS AB The U.S. Food and Drug Administration's Bacteriological Analytical Manual (BAM) Chapter 4a describes a Luminex microbead-based suspension array used to screen colonies for 11 clinically relevant Shiga toxin-producing Escherichia coli (STEC) serogroups: 026, 045, 091, 0103, 0104, 0111, 0113, 0121, 0128, 0145, and 0157. We evaluated the usefulness of this method to identify STEC-positive enrichment samples before agar plating. Twelve E. coli strains were added to three types of fresh produce (bagged baby spinach, alfalfa sprouts, and cilantro) at levels near the detection limit of the test. A subset of these strains (six O serogroups) was similarly evaluated in raw milk. For comparison, portions of each of the 168 enrichment cultures were analyzed for serogroup by a real-time PCR assay and a Bio-Plex 200 assay with the bead-based suspensions. No false positive results were obtained. Of the 112 samples with a reported cycle threshold (C-T) value, 101 undiluted, diluted, or extracted enrichment cultures also produced ratios above 5.0 in the Bio-Plex assay. When PCR C-T values approached or were greater than 35, Bio-Plex detection became less reliable. Using undiluted or extracted enrichment cultures resulted in a significantly larger number of positive results. With the same enrichment material prepared for real-time PCR analysis as described in the BAM Chapter 4a, the STEC microbead-based suspension array can accurately screen food enrichment cultures. C1 [Kase, Julie A.; Maounounen-Laasri, Anna] US FDA, Ctr Food Safety & Appl Nutr, Div Microbiol, College Pk, MD 20740 USA. [Maounounen-Laasri, Anna] Oak Ridge Res Inst Sci & Educ, Oak Ridge, TN 37830 USA. [Lin, Andrew] US FDA, Off Regulatory Affairs, San Francisco Lab, Alameda, CA 94502 USA. RP Kase, JA (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Microbiol, College Pk, MD 20740 USA. EM julie.kase@fda.hhs.gov NR 16 TC 0 Z9 0 U1 6 U2 6 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD SEP PY 2016 VL 79 IS 9 BP 1623 EP 1629 DI 10.4315/0362-028X.JFP-16-070 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA DV3DP UT WOS:000382801500019 PM 28221928 ER PT J AU Hsueh, CH Yoshida, K Zhao, P Meyer, TW Zhang, L Huang, SM Giacomini, KM AF Hsueh, Chia-Hsiang Yoshida, Kenta Zhao, Ping Meyer, Timothy W. Zhang, Lei Huang, Shiew-Mei Giacomini, Kathleen M. TI Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3 SO MOLECULAR PHARMACEUTICS LA English DT Article DE organic anion transporter; chronic kidney disease; uremic solute; regulatory science ID DRUG-DRUG INTERACTIONS; CATION TRANSPORTER-2; TUBULAR SECRETION; RAT-KIDNEY; HEMODIALYSIS-PATIENTS; HEALTHY-VOLUNTEERS; ION TRANSPORTERS; DOWN-REGULATION; CANCER-PATIENTS; URIC-ACID AB One of the characteristics of chronic kidney disease (CKD) is the accumulation of uremic solutes in the plasma. Less is known about the effects of uremic solutes on transporters that may play critical roles in pharmacokinetics. We evaluated the effect of 72 uremic solutes on organic anion transporter 1 and 3 (OAT1 and OAT3) using a fluorescent probe substrate, 6-carboxyfluorescein. A total of 12 and 13 solutes were identified as inhibitors of OAT1 and OAT3, respectively. Several of them inhibited OAT1 or OAT3 at clinically relevant concentrations and reduced the transport of other OAT1/3 substrates in vitro. Review of clinical studies showed that the active secretion of most drugs that are known substrates of OAT1/3 deteriorated faster than the renal filtration in CKD. Collectively, these data suggest that through inhibition of OAT1 and OAT3, uremic solutes contribute to the decline in renal drug clearance in patients with CKD. C1 [Hsueh, Chia-Hsiang; Giacomini, Kathleen M.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 USA. [Hsueh, Chia-Hsiang; Yoshida, Kenta; Zhao, Ping; Zhang, Lei; Huang, Shiew-Mei] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Meyer, Timothy W.] Stanford Univ, Sch Med, Div Nephrol, Stanford, CA 94305 USA. RP Giacomini, KM (reprint author), Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 USA. EM kathy.giacomini@ucsf.edu FU Food and Drug Administration (FDA) through Medical Countermeasures initiative [U01FD004979]; Research Participation Program at the Center for Drug Evaluation and Research; US Department of Energy; FDA FX Funding for this paper was made possible, in part, by the Food and Drug Administration (FDA) through Medical Countermeasures initiative, and grant U01FD004979, which supports the UCSF-Stanford Center of Excellence in Regulatory Science and Innovation. Dr. Chia-Hsiang Hsueh and Dr. Kenta Yoshida were supported in part by the appointments 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 FDA. Views expressed in this paper are of authors and do not necessarily reflect the official policies of the FDA; nor does any mention of trade names, commercial practices, or organization imply endorsement by the U.S. Government. NR 79 TC 2 Z9 2 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD SEP PY 2016 VL 13 IS 9 BP 3130 EP 3140 DI 10.1021/acs.molpharmaceut.6b00332 PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DV1WV UT WOS:000382713700027 PM 27467266 ER PT J AU Egger, GF Wharton, GT Malli, S Temeck, J Murphy, MD Tomasi, P AF Egger, Gunter F. Wharton, Gerold T. Malli, Suzanne Temeck, Jean Murphy, M. Dianne Tomasi, Paolo TI A Comparative Review of Waivers Granted in Pediatric Drug Development by FDA and EMA From 2007-2013 SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Review DE Pediatric Regulation; Pediatric Research Equity Act; Paediatric Committee (PDCO); Pediatric Review Committee (PeRC); Best Pharmaceuticals for Children Act; drug regulation in children AB Background: The European Union and the United States have different legal frameworks in place for pediatric drug development, which can potentially lead to different pediatric research requirements for the pharmaceutical industry. This manuscript compares pediatric clinical trial waivers granted by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). Methods: This is a retrospective review comparing EMA's Paediatric Committee (PDCO) decisions with FDA's Pediatric Review Committee (PeRC) recommendations for all product-specific pediatric full waiver applications submitted to EMA from January 2007 through December 2013. Using baseline data from EMA, we matched product-specific waivers with their FDA equivalents during the study period. Results: For single active substance products, PDCO and PeRC adopted similar opinions in 42 of 49 indications (86%). For fixed-dose combinations, PDCO and PeRC adopted similar opinions in 24 of 31 indications (77%). Conclusion: Despite the different legal frameworks, criteria, and processes of determination, the waiver decisions of the 2 agencies were similar in the majority of cases. C1 [Egger, Gunter F.; Tomasi, Paolo] European Med Agcy, 30 Churchill Pl, London E14 5EU, England. [Wharton, Gerold T.; Malli, Suzanne; Temeck, Jean; Murphy, M. Dianne] US FDA, Silver Spring, MD USA. RP Egger, GF (reprint author), European Med Agcy, 30 Churchill Pl, London E14 5EU, England. EM gunter.egger@ema.europa.eu FU Intramural FDA HHS [FD999999] NR 6 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD SEP PY 2016 VL 50 IS 5 BP 639 EP 647 DI 10.1177/2168479016646809 PG 9 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA DV1VU UT WOS:000382711000016 PM 27274951 ER PT J AU Trumbo, PR AF Trumbo, Paula R. TI FDA regulations regarding iodine addition to foods and labeling of foods containing added iodine SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Workshop 1 on Assessment of Iodine Intake - Foods and Supplements CY APR 22-23, 2014 CL NIH, Off Dietary Supplements, Rockville, MD HO NIH, Off Dietary Supplements DE dietary supplements; foods; infant formula; iodine; labeling AB The US Food and Drug Administration (FDA) regulates the addition of iodine to infant formulas, the iodization of salt, and the addition of salt and iodine to foods. The required amount of iodine in infant formulas is based on caloric content, and the label must provide the iodine content per 100 kcal. Cuprous iodide and potassium iodide may be added to table salt as a source of dietary iodine at a maximum amount of 0.01%; if added, the label must indicate that the salt is iodized. Table salt to which iodine has not been added must bear the statement, "This salt does not supply iodide, a necessary nutrient." If a nutrient is to be appropriately added to a food for the purpose of correcting a dietary insufficiency, there should be sufficient scientific information available to demonstrate a nutritional deficiency and/or identify a public health problem. Furthermore, the population groups that would benefit from the proposed fortification should be identified. If iodine is added to a food, the percent Daily Value of iodine must be listed. There are no FDA regulations governing ingredient standards for dietary supplements. As a result, some dietary supplements include iodine and others do not. If a supplement contains iodine, the Supplement Facts label must list iodine as a nutrient ingredient. If iodine is not listed on the Supplement Facts label, then it has not been added. There are similarities between the FDA, which establishes US food regulations and policies, and the Codex Alimentarius (Codex), which develops international food standards and guidelines under the aegis of the FAO and the WHO. Both the FDA and Codex call for the labeling of table salt to indicate fortification with iodine, voluntary labeling of iodine on foods, and a Daily Value (called a Nutrient Reference Value by Codex) of 150 tug for iodine. C1 [Trumbo, Paula R.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Trumbo, PR (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM paula.trumbo@fda.hhs.gov NR 2 TC 4 Z9 4 U1 10 U2 11 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 SU S BP 864S EP 867S DI 10.3945/ajcn.115.110338 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UW UT WOS:000382421100002 PM 27534626 ER PT J AU Pehrsson, PR Patterson, KY Spungen, JH Wirtz, MS Andrews, KW Dwyer, JT Swanson, CA AF Pehrsson, Pamela R. Patterson, Kristine Y. Spungen, Judith H. Wirtz, Mark S. Andrews, Karen W. Dwyer, Johanna T. Swanson, Christine A. TI Iodine in food- and dietary supplement-composition databases SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Workshop 1 on Assessment of Iodine Intake - Foods and Supplements CY APR 22-23, 2014 CL NIH, Off Dietary Supplements, Rockville, MD HO NIH, Off Dietary Supplements DE DSID; FDA; NHANES; Total Diet Study; USDA ID NUTRIENT ANALYSIS PROGRAM; UNITED-STATES; AMERICA-NHANES; NATIONAL FOOD; WOMEN; NUTRITION; MILK; SALT; EAT; AGE AB The US Food and Drug Administration (FDA) and the Nutrient Data Laboratory (NDL) of the USDA Agricultural Research Service have worked independently on determining the iodine content of foods and dietary supplements and are now harmonizing their efforts. The objective of the current article is to describe the harmonization plan and the results of initial iodine analyses accomplished under that plan. For many years, the FDA's Total Diet Study (TDS) has measured iodine concentrations in selected foods collected in 4 regions of the country each year. For more than a decade, the NDL has collected and analyzed foods as part of the National Food and Nutrient Analysis Program.; iodine analysis is now being added to the program. The NDL recently qualified a commercial laboratory to conduct iodine analysis of foods by an inductively coupled plasma mass spectrometry (ICP-MS) method. Co-analysis of a set of samples by the commercial laboratory using the ICP-MS method and by the FDA laboratory using its standard colorimetric method yielded comparable results. The FDA recently reviewed historical TDS data for trends in the iodine content of selected foods, and the NDL analyzed samples of a limited subset of those foods for iodine. The FDA and the NDL are working to combine their data on iodine in foods and to produce an online database that can be used for estimating iodine intake from foods in the US population. In addition, the NDL continues to analyze dietary supplements for iodine and, in collaboration with the NIH Office of Dietary Supplements, to publish the data online in the Dietary Supplement Ingredient Database. The goal is to provide, through these 2 harmonized databases and the continuing TDS focus on iodine, improved tools for estimating iodine intake in population studies. C1 [Pehrsson, Pamela R.; Patterson, Kristine Y.; Andrews, Karen W.] ARS, Nutr Data Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. [Spungen, Judith H.; Wirtz, Mark S.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Dwyer, Johanna T.; Swanson, Christine A.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. RP Pehrsson, PR (reprint author), ARS, Nutr Data Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. EM pamela.pehrsson@ars.usda.gov NR 37 TC 5 Z9 5 U1 10 U2 10 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 SU S BP 868S EP 876S DI 10.3945/ajcn.115.110064 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UW UT WOS:000382421100003 PM 27534627 ER PT J AU Carriquiry, AL Spungen, JH Murphy, SP Pehrsson, PR Dwyer, JT Juan, W Wirtz, MS AF Carriquiry, Alicia L. Spungen, Judith H. Murphy, Suzanne P. Pehrsson, Pamela R. Dwyer, Johanna T. Juan, WenYen Wirtz, Mark S. TI Variation in the iodine concentrations of foods: considerations for dietary assessment SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Workshop 1 on Assessment of Iodine Intake - Foods and Supplements CY APR 22-23, 2014 CL NIH, Off Dietary Supplements, Rockville, MD HO NIH, Off Dietary Supplements DE food composition; iodine; nutrient content; statistical distribution; variability AB Background: Food-composition tables typically give measured nutrient concentrations in foods as a single summary value, often the mean, without providing information as to the shape of the distribution. Objective: Our objective was to explore how the statistical approach chosen to describe the iodine concentrations of foods affects the proportion of the population identified as having either insufficient or excessive iodine intakes. Design: We used food intake data reported by the 2009-2010 NHANES and measured iodine concentrations of Total Diet Study (TDS) foods from 4 US regions sampled in 2004-2011. We created 4 data sets, each by using a different summary statistic (median, mean, and 10th and 90th percentiles), to represent the iodine concentration distribution of each TDS food. We estimated the iodine concentration distribution of each food consumed by NHANES participants as the 4 iodine concentration summary statistics of a similar TDS food and used these, along with NHANES food intake data, to develop 4 estimates of each participant's iodine intake on each survey day. Using the 4 estimates in turn, we calculated 4 usual iodine intakes for each sex- and age-specific subgroup. We then compared these to guideline values and developed 4 estimates of the proportions of each subgroup with deficient and excessive usual iodine intakes. Results: In general, the distribution of iodine intakes was poorly characterized when food iodine concentrations were expressed as mean values. In addition, mean values predicted lower prevalences of iodine deficiency than did median values. For example, in women aged 19-50 y, the estimated prevalence of iodine deficiency was 25% when based on median food iodine concentrations but only 5.8% when based on mean values. Conclusion: For nutrients such as iodine with highly variable concentrations in important food sources, we recommend that food composition tables provide useful variability information, including the mean, SD, and median. C1 [Carriquiry, Alicia L.] Iowa State Univ, Dept Stat, Ames, IA 50011 USA. [Spungen, Judith H.; Juan, WenYen; Wirtz, Mark S.] US FDA, College Pk, MD 20740 USA. [Murphy, Suzanne P.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Pehrsson, Pamela R.] ARS, Nutr Data Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. [Dwyer, Johanna T.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. RP Carriquiry, AL (reprint author), Iowa State Univ, Dept Stat, Ames, IA 50011 USA. EM alicia@iastate.edu NR 20 TC 4 Z9 4 U1 6 U2 6 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 SU S BP 877S EP 887S DI 10.3945/ajcn.115.110353 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UW UT WOS:000382421100004 PM 27534633 ER PT J AU Juan, W Trumbo, PR Spungen, JH Dwyer, JT Carriquiry, AL Zimmerman, TP Swanson, CA Murphy, SP AF Juan, WenYen Trumbo, Paula R. Spungen, Judith H. Dwyer, Johanna T. Carriquiry, Alicia L. Zimmerman, Thea P. Swanson, Christine A. Murphy, Suzanne P. TI Comparison of 2 methods for estimating the prevalences of inadequate and excessive iodine intakes SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Workshop 1 on Assessment of Iodine Intake - Foods and Supplements CY APR 22-23, 2014 CL NIH, Off Dietary Supplements, Rockville, MD HO NIH, Off Dietary Supplements DE dietary surveys; food content; iodine; Total Diet Study; urinary iodine; variability ID URINARY IODINE; MASS SPECTROMETRY; NATIONAL-HEALTH; UNITED-STATES; TOTAL DIET; NUTRITION; POPULATION; SODIUM; FOOD; EXCRETION AB Background: Prevalences of iodine inadequacy and excess are usually evaluated by comparing the population distribution of urinary iodine concentration (UIC) in spot samples with established UIC cutoffs. To our knowledge, until now, dietary intake data have not been assessed for this purpose. Objective: Our objective was to compare 2 methods for evaluating the prevalence of iodine inadequacy and excess in sex- and life stage specific subgroups of the US population: one that uses UIC cutoffs, and one that uses iodine intake cutoffs. Design: By using the iodine concentrations of foods measured in the US Food and Drug Administration's Total Diet Study (TDS), dietary intake data from the NHANES 2003-2010, and a file that maps each NHANES food to a TDS food with similar ingredients, we estimated each NHANES participant's iodine intake from each NHANES food as the mean iodine concentration of the corresponding TDS food in samples gathered over the same 2-y period. We calculated prevalences of iodine inadequacy and excess in each sex and life stage specific subgroup by both the UIC cutoff method and the iodine intake cutoff method using the UIC values and dietary intakes reported for NHANES participants who provided both types of data and compared the prevalences across methods. Results: We found lower prevalences of iodine inadequacy across all sex- and life stage specific subgroups with the iodine intake cutoff method than with the UIC cutoff method; for pregnant females, the respective prevalences were 5.0% and 37.9%. For children aged y, the prevalence of excessive iodine intake was high by either method. Conclusions: The consideration of dietary iodine intake from all sources may provide a more complete understanding of population prevalences of iodine inadequacy and excess and thus better inform dietary guidance than consideration of UIC alone. Methods of adjusting UIC for within-person variation are needed to improve the accuracy of prevalence assessments based on UIC. C1 [Juan, WenYen; Trumbo, Paula R.; Spungen, Judith H.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Dwyer, Johanna T.; Swanson, Christine A.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. [Carriquiry, Alicia L.] Iowa State Univ, Dept Stat, Ames, IA 50011 USA. [Zimmerman, Thea P.] Westat Corp, Rockville, MD 20850 USA. [Murphy, Suzanne P.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. RP Juan, W (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM wenyen.juan@fda.hhs.gov NR 38 TC 3 Z9 3 U1 5 U2 5 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 SU S BP 888S EP 897S DI 10.3945/ajcn.115.110346 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UW UT WOS:000382421100005 PM 27534630 ER PT J AU Zeller, M AF Zeller, Mitchell TI The Deeming Rule: Keeping Pace with the Modern Tobacco Marketplace SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material C1 [Zeller, Mitchell] FDA Ctr Tobacco Prod, Silver Spring, MD 20993 USA. RP Zeller, M (reprint author), FDA Ctr Tobacco Prod, Silver Spring, MD 20993 USA. NR 6 TC 0 Z9 0 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD SEP 1 PY 2016 VL 194 IS 5 BP 538 EP 540 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DU7SY UT WOS:000382416100008 PM 27585382 ER PT J AU Fleck, SC Churchwell, MI Doerge, DR Teeguarden, JG AF Fleck, Stefanie C. Churchwell, Mona I. Doerge, Daniel R. Teeguarden, Justin G. TI Urine and serum biomonitoring of exposure to environmental estrogens II: Soy isoflavones and zearalenone in pregnant women SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Soy isoflavones; Zearalenone; Exposure; Pregnancy; Biomonitoring; Endocrine disruptors ID SPRAGUE-DAWLEY RATS; BREAST-CANCER RISK; PHYSIOLOGICAL CONCENTRATIONS; MYCOTOXIN EXPOSURE; PLACENTAL-TRANSFER; RECEPTOR-ALPHA; GENISTEIN; DIETARY; GROWTH; PHARMACOKINETICS AB Urine and serum biomonitoring was used to measure internal exposure to selected dietary estrogens in a cohort of 30 pregnant women. Exposure was measured over a period comprising one-half day in the field (6 h) and one day in a clinic (24 h). Biomonitoring of the dietary phytoestrogens genistein (GEN), daidzein (DDZ) and equol (EQ), as well as the mycoestrogen, zearalenone (ZEN) and its congeners, was conducted using UPLC-MS/MS. Biomonitoring revealed evidence of internal exposure to naturally occurring dietary estrogens during pregnancy. Urinary concentrations of total GEN, DDZ and EQ were similar to levels reported for general adult U.S. population. Measurable concentrations of total (parent and metabolites) GEN, DDZ and EQ were present in 240, 207 and 2 of 270 serum samples, respectively. Six out of 30 subjects had measurable concentrations of unconjugated GEN and/or DDZ in serum between 0.6 and 7.1 nM. Urine to serum total isoflavone ratios for GEN, DDZ and EQ were 13, 47, and 180, respectively. ZEN and its reductive metabolite, alpha-zearalenol (alpha-ZEL), were present in pregnant women (11 out of 30 subjects) as conjugates at levels near the limit of quantification. The average total urinary concentration was 0.10 mu g/L for ZEN and 0.11 mu g/L for alpha-ZEL. (C) 2016 Published by Elsevier Ltd. C1 [Fleck, Stefanie C.; Churchwell, Mona I.; Doerge, Daniel R.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Teeguarden, Justin G.] Pacific Northwest Natl Lab, Hlth Effects & Exposure Sci, Richland, WA 99352 USA. [Teeguarden, Justin G.] Oregon State Univ, Dept Environm & Mol Toxicol, Corvallis, OR 97331 USA. RP Teeguarden, JG (reprint author), 902 Battelle Blvd, Richland, WA 99352 USA. EM stefanie.fleck@fda.hhs.gov; mona.churchwell@fda.hhs.gov; daniel.doerge@fda.hhs.gov; jt@pnnl.gov NR 46 TC 1 Z9 1 U1 13 U2 14 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 SEP PY 2016 VL 95 BP 19 EP 27 DI 10.1016/j.fct.2016.05.021 PG 9 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA DT9PX UT WOS:000381835900003 PM 27255803 ER PT J AU Waciar, SN Bonomi, PD Govindan, R Hirsch, FR Riely, GJ Papadimitrakopoulou, V Kazandjian, D Khozin, S Larkins, E Dickson, DJ Malik, S Horn, L Ferris, A Shaw, AT Janne, PA Mok, TSK Herbst, R Keegan, P Pazdur, R Blumenthal, GM AF Waciar, Saiama N. Bonomi, Philip D. Govindan, Ramaswamy Hirsch, Fred R. Riely, Gregory J. Papadimitrakopoulou, Vassiliki Kazandjian, Dickran Khozin, Sean Larkins, Erin Dickson, Dane J. Malik, Shakun Horn, Leora Ferris, Andrea Shaw, Alice T. Janne, Pasi A. Mok, Tony S. K. Herbst, Roy Keegan, Patricia Pazdur, Richard Blumenthal, Gideon M. TI Clinician Perspectives on Current Issues in Lung Cancer Drug Development SO JOURNAL OF THORACIC ONCOLOGY LA English DT Review DE Lung cancer; Clinical trials; Targeted therapy; Immunotherapy ID TYROSINE KINASE INHIBITORS; RANDOMIZED PHASE-3 TRIAL; 1ST-LINE TREATMENT; ACQUIRED-RESISTANCE; PERFORMANCE STATUS; EGFR MUTATIONS; OPEN-LABEL; CHEMOTHERAPY; THERAPY; ERLOTINIB AB Recent advances in molecularly targeted therapy and immunotherapy offer a glimmer of hope for potentially realizing the dream of personalized therapy for lung cancer. This article highlights current questions in clinical trial design, enrollment strategies and patient focused drug development, with particular emphasis on unique issues in trials of targeted therapy and immunotherapy. Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer. C1 [Waciar, Saiama N.; Govindan, Ramaswamy] Washington Univ, Sch Med, Div Oncol, St Louis, MO USA. [Bonomi, Philip D.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Hirsch, Fred R.] Univ Colorado, Ctr Canc, Denver, CO 80262 USA. [Riely, Gregory J.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Papadimitrakopoulou, Vassiliki] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kazandjian, Dickran; Khozin, Sean; Larkins, Erin; Keegan, Patricia; Pazdur, Richard; Blumenthal, Gideon M.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. [Dickson, Dane J.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Malik, Shakun] NCI, Bethesda, MD 20892 USA. [Horn, Leora] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Ferris, Andrea] LUNGev Fdn, Bethesda, MD USA. [Shaw, Alice T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Janne, Pasi A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Mok, Tony S. K.] Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Herbst, Roy] Yale Sch Med, New Haven, CT USA. RP Blumenthal, GM (reprint author), US FDA, Div Oncol Prod 2, OHOP, OND, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM Gideon.Blumenthal@fda.hhs.gov FU NCI/NIH [K12 CA167540] FX Dr. Waciar reports grant K12 CA167540 from the NCI/NIH during the conduct of the study, and grant PI on the 1 UM1 CA186704-01 from NIH/NCI outside the submitted work. Dr. Bonomi reports serving on advisory boards of Astra Zeneca, Clovis, Merck, Biodesics, Trovagene, and Eli Lilly and on data monitoring committees of Roche Genentech and Pfizer outside the submitted work. Dr. Govindan reports consulting fees from Boehringer Ingelheim, GlaxoSmithKline, Celgene, Roche, Bayer, Genentech, Clovis, Helsinn Healthcare, and honoraria from Baxalta, and Roche outside the submitted work. Dr. Hirsch reports participation in advisory boards of Bristol-Myers Squibb, Merck, Genentech/Roche, AstraZeneca, and Lilly outside the submitted work. Dr. Riely reports personal fees from Novartis and Roche and grants from Novartis, Millennium, GlaxoSmithKline, Pfizer, Infinity. Pharmaceuticals, and Ariad outside the submitted work. Dr. Papadimitrakopoulou is a scientific advisory committee member for Clovis Oncology and Genentech, reports consulting fees from Merck, AstraZeneca, Bristol-Myers Squibb, and ARIAD Pharmaceuticals and grants from the following: AstraZeneca; Bristol-Myers Squibb; the American Association for Cancer Research; the National Cancer Institute, National Institutes of Health; Cancer Prevention and Research Institute of Texas; and Hope Foundation outside the submitted work. Dr. Horn reports participation in paid advisory board for Lilly Genentech, and Merck, serving as an unpaid advisory board member and steering committee member at Bristol-Myers Squibb and an upaid advisory board member at Boehringer Ingelheim, performing unpaid consulting work for Xcovery, and serving as an uncompensated steering committee member at Bayer outside the submitted work. Dr. Shaw is a consulting and scientific advisory board member for Blueprint medicine and reports consulting fees from Novartis, Genentech/Roche, Ariad, Daiich-Sankyo, Ignyta, Taiho, EMD Serono, and Pfizer outside the submitted work. Dr. Janne reports grants and personal fees from AstraZeneca; consulting fees from Boehringer Ingelheim, Pfizer, Merrimack Pharmaceuticals, Chugai, and Roche; grants from Astellas; consulting fees from Ariad; and stock ownership in Gatekeeper Pharmaceuticals during the conduct of the study. In addition, Dr. Janne receives postmarketing royalties from Dana-Farber Cancer Institute-owned intellectual property on epidermal growth factor receptor mutations licensed to Lab Corp. Dr. Mok reports personal fees from AstraZeneca, Roche/Genentech, Pfizer, Lilly, Boeh, ringer Ingelheim, Merck Serono, Merck Sharp and Dohme, Janssen, Clovis Oncology, BioMarin, GlaxoSmithKline, Novartis, SFJ Pharmaceuticals, ACEA Biosciences, Vertex Pharmaceuticals, Bristol-Myers Squibb, AVEO and Biodesix, Prime Oncology, Amgen, Sanomics Ltd., and geneDecode outside the submitted work. Dr. Herbst reports personal fees from Diatech, Kolltan, AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Pfizer and grants and personal fees from Genentech/Roche and Merck outside the submitted work. The remaining authors declare no conflict of interest. NR 54 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2016 VL 11 IS 9 BP 1387 EP 1396 DI 10.1016/j.jtho.2016.05.009 PG 10 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DU7UN UT WOS:000382420200005 ER PT J AU Zhang, T Bae, D Wang, CL AF Zhang, Ting Bae, Dongryeoul Wang, Chinling TI Listeria monocytogenes DNA Glycosylase AdlP Affects Flagellar Motility, Biofilm Formation, Virulence, and Stress Responses SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID GENE-EXPRESSION; REGULATOR-DEGU; THYMINE GLYCOL; SIGMA B; DAMAGE; REPAIR; CASPASE-1; INTERLEUKIN-1-BETA; CONSTRUCTION; ELONGATION AB The temperature-dependent alteration of flagellar motility gene expression is critical for the foodborne pathogen Listeria monocytogenes to respond to a changing environment. In this study, a genetic determinant, L. monocytogenes f2365_0220 (lmof2365_0220), encoding a putative protein that is structurally similar to the Bacillus cereus alkyl base DNA glycosylase (AlkD), was identified. This determinant was involved in the transcriptional repression of flagellar motility genes and was named adlP (encoding an AlkD-like protein [AdlP]). Deletion of adlP activated the expression of flagellar motility genes at 37 degrees C and disrupted the temperature-dependent inhibition of L. monocytogenes motility. The adlP null strains demonstrated decreased survival in murine macrophage-like RAW264.7 cells and less virulence in mice. Furthermore, the deletion of adlP significantly decreased biofilm formation and impaired the survival of bacteria under several stress conditions, including the presence of a DNA alkylation compound (methyl methanesulfonate), an oxidative agent (H2O2), and aminoglycoside antibiotics. Our findings strongly suggest that adlP may encode a bifunctional protein that transcriptionally represses the expression of flagellar motility genes and influences stress responses through its DNA glycosylase activity. IMPORTANCE We discovered a novel protein that we named AlkD-like protein (AdlP). This protein affected flagellar motility, biofilm formation, and virulence. Our data suggest that AdlP may be a bifunctional protein that represses flagellar motility genes and influences stress responses through its DNA glycosylase activity. C1 [Zhang, Ting; Bae, Dongryeoul; Wang, Chinling] Mississippi State Univ, Dept Basic Sci, Coll Vet Med, Starkville, MS USA. [Zhang, Ting] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Bae, Dongryeoul] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Wang, CL (reprint author), Mississippi State Univ, Dept Basic Sci, Coll Vet Med, Starkville, MS USA. EM cw57@msstate.edu FU USDA/ARS [58-6402-7-230]; Food Safety Initiative Institute at Mississippi State University; Mississippi Agriculture and Forestry Experiment Station FX This work was supported by grants from the USDA/ARS (grant 58-6402-7-230), the Food Safety Initiative Institute at Mississippi State University, and the Mississippi Agriculture and Forestry Experiment Station. NR 59 TC 0 Z9 0 U1 13 U2 13 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 SEP PY 2016 VL 82 IS 17 BP 5144 EP 5152 DI 10.1128/AEM.00719-16 PG 9 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DT5DI UT WOS:000381500700009 PM 27316964 ER PT J AU Leffler, D Kupfer, SS Lebwohl, B Bugin, K Griebel, D Lathrop, JT Lee, JJ Mulberg, AE Papadopoulos, E Tomaino, J Crowe, SE AF Leffler, Daniel Kupfer, Sonia S. Lebwohl, Benjamin Bugin, Kevin Griebel, Donna Lathrop, Julia Tait Lee, Jessica J. Mulberg, Andrew E. Papadopoulos, Elektra Tomaino, Juli Crowe, Sheila E. TI Development of Celiac Disease Therapeutics: Report of the Third Gastroenterology Regulatory Endpoints and Advancement of Therapeutics Workshop SO GASTROENTEROLOGY LA English DT Article ID GLUTEN-FREE DIET; MUCOSAL INJURY; FOLLOW-UP; PREDICTORS; ANTIBODIES; DIAGNOSIS; MORTALITY; SYMPTOMS; ADULTS C1 [Leffler, Daniel] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Kupfer, Sonia S.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Lebwohl, Benjamin] Columbia Univ, Dept Med, New York, NY USA. [Bugin, Kevin; Griebel, Donna; Lathrop, Julia Tait; Lee, Jessica J.; Mulberg, Andrew E.; Papadopoulos, Elektra; Tomaino, Juli] US FDA, Silver Spring, MD USA. [Crowe, Sheila E.] Univ Calif San Diego, Dept Med, 9500 Gilman Dr,BRF 2,Off 4A30, La Jolla, CA 92093 USA. RP Crowe, SE (reprint author), Univ Calif San Diego, Dept Med, 9500 Gilman Dr,BRF 2,Off 4A30, La Jolla, CA 92093 USA. EM nclemens@ucsd.edu NR 22 TC 0 Z9 0 U1 6 U2 6 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 SEP PY 2016 VL 151 IS 3 BP 407 EP 411 DI 10.1053/j.gastro.2016.07.025 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DU5CO UT WOS:000382230000018 PM 27456385 ER PT J AU Woo, EJ AF Woo, Emily Jane TI CORR Insights (R): Disparities in TKA Outcomes: Census Tract Data Show Interactions Between Race and Poverty SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Editorial Material C1 [Woo, Emily Jane] US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Woo, EJ (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jane.woo@fda.hhs.gov NR 4 TC 0 Z9 0 U1 1 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 SEP PY 2016 VL 474 IS 9 BP 1996 EP 1998 DI 10.1007/s11999-016-4947-4 PG 3 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DS3FZ UT WOS:000380669800019 PM 27334329 ER PT J AU Gonzalez, YIR Lynch, PJ Thompson, EE Stultz, BG Hursh, DA AF Gonzalez, Yazmin I. Rovira Lynch, Patrick J. Thompson, Elaine E. Stultz, Brian G. Hursh, Deborah A. TI In vitro cytokine licensing induces persistent permissive at the Indoleamine 2,3-dioxygenase promoter SO CYTOTHERAPY LA English DT Article DE chromatin remodeling; cytokine licensing; histone modifications; immunomodulation; indoleamine 2,3-dioxygenase; mesenchymal stromal cells ID MESENCHYMAL STROMAL CELLS; TIME PCR EXPERIMENTS; ACTIVATED T-CELLS; STEM-CELLS; BONE-MARROW; INTERFERON-GAMMA; IFN-GAMMA; MEDIATED IMMUNOSUPPRESSION; HISTONE MODIFICATIONS; CULTURE AB Background. Mesenchymal stromal cells (MSCs) are being investigated as therapies for inflammatory diseases due to their immunosuppressive capacity. Interferon (IFN)-gamma treatment primes MSC immunosuppression partially through induction of Indoleamine 2,3-dioxygenase (IDO1), which depletes tryptophan necessary to support proliferation of activated T cells. We investigated the role of histone modifications in the timing and maintenance of induced IDO1 expression in MSCs under clinical manufacturing conditions, such as cryopreservation. Methods. We used chromatin immunoprecipitation and quantitative polymerase chain reaction (PCR) to assay levels of transcriptionally permissive acetylated H3K9 and repressive trimethylated H3K9 histone modifications surrounding the transcriptional start site for IDO1, and reverse transcriptase PCR and immunoblotting to detect messenger RNA (mRNA) and protein. Results. MSCs derived from three donors approached maximum IDO1 mRNA levels following 24 hours of in vitro cytokine treatment. Induction of IDO1 expression correlated with increased acetylation of H3K9 concomitant with reduction of trimethylated H3K9 modifications at the promoter. Examination of two additional donors confirmed this result. While induced IDO1 levels decreased within 2 days after cytokine removal and freeze thawing, the activated chromatin state was maintained. Upon re-exposure to cytokines, previously primed MSCs accumulated near-maximum IDO1 mRNA levels within 4-8 h. Discussion. Our data indicate that in vitro priming of MSCs causes chromatin remodeling at the IDO1 promoter, that this alteration is maintained during processing commonly used to prepare MSCs for clinical use and that, once primed, MSCs are poised for IDO1 expression even in the absence of cytokines. C1 [Gonzalez, Yazmin I. Rovira; Lynch, Patrick J.; Thompson, Elaine E.; Stultz, Brian G.; Hursh, Deborah A.] US FDA, Cellular & Tissue Therapies Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave Bldg 72,Rm 3216, Silver Spring, MD 20993 USA. RP Hursh, DA (reprint author), US FDA, Cellular & Tissue Therapies Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave Bldg 72,Rm 3216, Silver Spring, MD 20993 USA.; Lynch, PJ (reprint author), Ctr Drug Evaluat & Res, Div Biotechnol Res & Review, Off Biotechnol Prod, 10903 New Hampshire Ave Bldg 71,Rm 2016, Silver Spring, MD 20993 USA. EM Deborah.Hursh@fda.hhs.gov FU U.S. Food and Drug Administration (FDA) Modernizing Science program; FDA Medical Countermeasures Initiative; Division of Cellular and Gene Therapies FX This work was supported by the U.S. Food and Drug Administration (FDA) Modernizing Science program, the FDA Medical Countermeasures Initiative and the Division of Cellular and Gene Therapies.Yazmin Rovira Gonzalez and Elaine Thompson were supported by fellowships administered by the Oak Ridge Institute for Science and Education. We also thank Drs. Cheng Hong Wei, Steven Bauer, Jeanie Prescott, Ross Marklein and Mark Mortin for critically reviewing the manuscript and members of the FDA's MSC Consortium for valuable discussions. NR 56 TC 1 Z9 1 U1 3 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD SEP PY 2016 VL 18 IS 9 BP 1114 EP 1128 DI 10.1016/j.jcyt.2016.05.017 PG 15 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA DT8WV UT WOS:000381777300005 ER PT J AU Melo, DR Miller, DL Chang, L Moroz, B Linet, MS Simon, SL AF Melo, Dunstana R. Miller, Donald L. Chang, Lienard Moroz, Brian Linet, Martha S. Simon, Steven L. TI ORGAN DOSES FROM DIAGNOSTIC MEDICAL RADIOGRAPHY-TRENDS OVER EIGHT DECADES (1930 TO 2010) SO HEALTH PHYSICS LA English DT Article DE diagnostic radiology; dose; absorbed; epidemiology; radiation; medical ID X-RAY EXAMINATIONS; ACTIVE BONE-MARROW; COMPUTED RADIOGRAPHY; CHEST RADIOGRAPHY; NATIONWIDE EVALUATION; PATIENT DOSIMETRY; RADIATION RISKS; UNITED-STATES; RADIOLOGY; POPULATION AB This study provides a retrospective assessment of doses to 13 organs for the most common radiographic examinations conducted between the 1930s and 2010, taking into account typical technical parameters used for radiography during those years. This study is intended to be a resource on changes in medical diagnostic radiation exposure over time with a specific purpose of supporting retrospective epidemiological studies of radiation health risks. The authors derived organ doses to the brain, esophagus, thyroid, red bone marrow, lungs, breast, heart, stomach, liver, colon, urinary bladder, ovaries, and testes based on 14 common radiographic procedures and compared, when possible, with doses reported in the literature. These dose estimates were based on radiographic exposure parameters described in textbooks widely used by radiologic technologists in training from 1939 to 2010. The derived estimated doses presented here are believed to be representative of typical organs for an average-size adult who might be considered to be similar to the reference person. There were large variations in organ doses noted among the different types of radiographic examinations. Doses were highest in organs within the area imaged and next highest in organs in close proximity to the area imaged. Estimated organ doses have declined substantially [overall 22-fold (+/- 38)] over time as a consequence of changes in technology, imaging protocols and protective measures. For some examinations, only slight differences were observed in doses for the decades of the 1960s, 1970s, and 1980s due to minor changes in technical parameters. Substantial dose reductions were observed in the 1990s and 2000s. C1 [Melo, Dunstana R.] NCI, DCEG, NIH, Bethesda, MD 20892 USA. [Melo, Dunstana R.] Melohill Technol, Rockville, MD USA. [Miller, Donald L.] US FDA, Silver Spring, MD USA. [Chang, Lienard; Moroz, Brian; Linet, Martha S.; Simon, Steven L.] NCI, DCEG, Bethesda, MD 20892 USA. RP Melo, DR (reprint author), 1 Res Court,Suite 450, Rockville, MD 20850 USA. EM dunstana.melo@melohilltech.com FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. We express our appreciation to Alice Sigurdson (NCI, retired) for encouragement, insight and support and to Charles Myers of the Division of Radiological Health, Center for Devices and Radiological Health, Food and Drug Administration for his assistance in defining radiography fields for examinations conducted in past decades. NR 75 TC 0 Z9 0 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD SEP PY 2016 VL 111 IS 3 BP 235 EP 255 DI 10.1097/HP.0000000000000524 PG 21 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA DS4PX UT WOS:000380764100001 PM 27472750 ER PT J AU Sun, DJD Wen, H Taylor, LS AF Sun, Dajun D. Wen, Hong Taylor, Lynne S. TI Non-Sink Dissolution Conditions for Predicting Product Quality and In Vivo Performance of Supersaturating Drug Delivery Systems SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE non-sink; dissolution; amorphous solid dispersions; supersaturation; precipitation ID AMORPHOUS SOLID DISPERSIONS; WATER-SOLUBLE DRUGS; NUCLEAR-MAGNETIC-RESONANCE; LIQUID PHASE-SEPARATION; ORAL BIOAVAILABILITY; CRYSTALLIZATION BEHAVIOR; PHARMACEUTICAL SYSTEMS; PRECIPITATION BEHAVIOR; MEMBRANE-TRANSPORT; AQUEOUS-SOLUTIONS AB With recent advances in the development of supersaturating oral dosage forms for poorly water-soluble drugs, pharmaceutical scientists are increasingly applying in vitro dissolution testing under non-sink conditions for a direct evaluation of their ability to generate and maintain supersaturation as a predictive surrogate for ensuring product quality and in vivo performance. However, the scientific rationale for developing the appropriate non-sink dissolution methodologies has not been extensively debated. This calls for a comprehensive discussion of recent research efforts on theoretical and experimental considerations of amorphous solubility, liquideliquid phase separation, and phase transitions of drugs in a supersaturated solution when dissolution testing is performed under supersaturated non-sink conditions. In addition, we outline the concept of "sink index" that quantifies the magnitude of deviations from perfect sink dissolution conditions in the sink/non-sink continuum and some considerations of non-sink dissolution testing for marketed drug products. These factors should be carefully considered in recommending an adequately discriminatory dissolution method in the performance assessment of supersaturating drug delivery systems. C1 [Sun, Dajun D.; Wen, Hong] US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Taylor, Lynne S.] Purdue Univ, Dept Ind & Phys Pharm, 575 Stadium Mall Dr, W Lafayette, IN 47907 USA. RP Taylor, LS (reprint author), Purdue Univ, Dept Ind & Phys Pharm, 575 Stadium Mall Dr, W Lafayette, IN 47907 USA. EM lstaylor@purdue.edu OI Taylor, Lynne /0000-0002-4568-6021 FU Generic Drug Users Fee Amendment regulatory research program by the United States Food and Drug Administration [1U01FD005259-01] FX This work was supported in part by funding of the Generic Drug Users Fee Amendment regulatory research program by the United States Food and Drug Administration under grant award 1U01FD005259-01. Niraj Trasi and Hitesh Purohit are thanked for helpful discussions. NR 93 TC 2 Z9 2 U1 11 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD SEP PY 2016 VL 105 IS 9 BP 2477 EP 2488 DI 10.1016/j.xphs.2016.03.024 PG 12 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA DT8UG UT WOS:000381770600004 PM 27174227 ER PT J AU Grimaldi, C Finco, D Fort, MM Gliddon, D Harper, K Helms, WS Mitchell, JA O'Lone, R Parish, ST Piche, MS Reed, DM Reichmann, G Ryan, PC Stebbings, R Walker, M AF Grimaldi, Christine Finco, Deborah Fort, Madeline M. Gliddon, Daniel Harper, Kirsty Helms, Whitney S. Mitchell, Jane A. O'Lone, Raegan Parish, Stanley T. Piche, Marie-Soleil Reed, Daniel M. Reichmann, Gabriele Ryan, Patricia C. Stebbings, Richard Walker, Mindi TI Cytokine release: A workshop proceedings on the state-of-the-science, current challenges and future directions SO CYTOKINE LA English DT Article DE Cytokine release assay; Cytokine release syndrome; Pro-inflammatory cytokines ID MONOCLONAL-ANTIBODY TGN1412; STORM; ASSAYS; CELLS; TRIAL; SENSITIVITY; INVOLVEMENT; PREDICTION; RESPONSES AB In October 2013, the International Life Sciences Institute - Health and Environmental Sciences Institute Immunotoxicology Technical Committee (ILSI-HESI ITC) held a one-day workshop entitled, "Workshop on Cytokine Release: State-of-the-Science, Current Challenges and Future Directions". The workshop brought together scientists from pharmaceutical, academic, health authority, and contract research organizations to discuss novel approaches and current challenges for the use of in vitro cytokine release assays (CRAs) for the identification of cytokine release syndrome (CRS) potential of novel monoclonal antibody (mAb) therapeutics. Topics presented encompassed a regulatory perspective on cytokine release and assessment, case studies regarding the translatability of preclinical cytokine data to the clinic, and the latest state of the science of CRAs, including comparisons between mAb therapeutics within one platform and across several assay platforms, a novel physiological assay platform, and assay optimization approaches such as determination of FcR expression profiles and use of statistical tests. The data and approaches presented confirmed that multiple CRA platforms are in use for identification of CRS potential and that the choice of a particular CRA platform is highly dependent on the availability of resources for individual laboratories (e.g. positive and negative controls, number of human blood donors), the assay through-put required, and the mechanism-of-action of the therapeutic candidate to be tested. Workshop participants agreed that more data on the predictive performance of CRA platforms is needed, and current efforts to compare in vitro assay results with clinical cytokine assessments were discussed. In summary, many laboratories continue to focus research efforts on the improvement of the translatability of current CRA platforms as well explore novel approaches which may lead to more accurate, and potentially patient-specific, CRS prediction in the future. (C) 2016 The Authors. Published by Elsevier Ltd. C1 [Grimaldi, Christine] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. [Finco, Deborah] Pfizer Inc, 1 Eastern Point Rd, Groton, CT 06340 USA. [Fort, Madeline M.] Amgen Inc, Comparat Biol & Safety Sci, Thousand Oaks, CA USA. [Gliddon, Daniel; Harper, Kirsty] Envigo, Woolley Rd, Huntingdon PE28 4HS, Cambs, England. [Helms, Whitney S.] US FDA, 10903 New Hampshire Ave, Rockville, MD 20857 USA. [Mitchell, Jane A.; Reed, Daniel M.] Imperial Coll London, London SW3 6LY, England. [O'Lone, Raegan; Parish, Stanley T.] ILSI Hlth & Environm Sci Inst, 1156 15th St NW,Suite 200, Washington, DC 20005 USA. [Piche, Marie-Soleil] Charles River Labs, 20222 Transcanadien, Senneville, PQ H9X 3R3, Canada. [Reichmann, Gabriele] Paul Ehrlich Inst, Fed Inst Vaccines & Biomed, Paul Ehrlich Str 51-59, D-63225 Langen, Germany. [Ryan, Patricia C.] Medimmune Inc, One MedImmune Way, Gaithersburg, MD 20878 USA. [Stebbings, Richard] Natl Inst Biol Stand & Controls, Blanche Ln,South Mimms, Potters Bar EN6 3QG, Herts, England. [Walker, Mindi] Johnson & Johnson Inc, 1 Johnson & Johnson Plaza, New Brunswick, NJ 08933 USA. [Gliddon, Daniel] F Star Biotechnol Ltd, Eddeva B920 Babraham Res Campus, Cambridge CB22 3AT, England. [Stebbings, Richard] MedImmune, Aaron Klug Bldg,Granta Pk, Cambridge CB21 6GH, England. RP Parish, ST (reprint author), ILSI Hlth & Environm Sci Inst, 1156 15th St NW,Suite 200, Washington, DC 20005 USA. EM sparish@hesiglobal.org NR 27 TC 2 Z9 2 U1 5 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD SEP PY 2016 VL 85 BP 101 EP 108 DI 10.1016/j.cyto.2016.06.006 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA DS2JO UT WOS:000380596000017 PM 27309676 ER PT J AU Strickland, J Zang, QD Kleinstreuer, N Paris, M Lehmann, DM Choksi, N Matheson, J Jacobs, A Lowit, A Allen, D Casey, W AF Strickland, Judy Zang, Qingda Kleinstreuer, Nicole Paris, Michael Lehmann, David M. Choksi, Neepa Matheson, Joanna Jacobs, Abigail Lowit, Anna Allen, David Casey, Warren TI Integrated decision strategies for skin sensitization hazard SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE skin sensitization; allergic contact dermatitis; integrated decision strategy; machine learning; LLNA; DPRA; KeratinoSens; h-CLAT; support vector machine ID LYMPH-NODE ASSAY; LINE ACTIVATION TEST; TEST H-CLAT; SCREENING CONTACT ALLERGENS; PEPTIDE REACTIVITY ASSAY; NONANIMAL TEST METHODS; PIG MAXIMIZATION TEST; RISK-ASSESSMENT MODEL; IN-VITRO METHODS; PREDICTIVE PERFORMANCE AB One of the top priorities of the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) is the identification and evaluation of non-animal alternatives for skin sensitization testing. Although skin sensitization is a complex process, the key biological events of the process have been well characterized in an adverse outcome pathway (AOP) proposed by the Organisation for Economic Co-operation and Development (OECD). Accordingly, ICCVAM is working to develop integrated decision strategies based on the AOP using in vitro, in chemico and in silico information. Data were compiled for 120 substances tested in the murine local lymph node assay (LLNA), direct peptide reactivity assay (DPRA), human cell line activation test (h-CLAT) and KeratinoSens assay. Data for six physicochemical properties, which may affect skin penetration, were also collected, and skin sensitization read-across predictions were performed using OECD QSAR Toolbox. All data were combined into a variety of potential integrated decision strategies to predict LLNA outcomes using a training set of 94 substances and an external test set of 26 substances. Fifty-four models were built using multiple combinations of machine learning approaches and predictor variables. The seven models with the highest accuracy (89-96% for the test set and 96-99% for the training set) for predicting LLNA outcomes used a support vector machine (SVM) approach with different combinations of predictor variables. The performance statistics of the SVM models were higher than any of the non-animal tests alone and higher than simple test battery approaches using these methods. These data suggest that computational approaches are promising tools to effectively integrate data sources to identify potential skin sensitizers without animal testing. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA. The Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) evaluated a non-animal decision strategies to predict skin sensitization. Machine learning approaches integrated in vitro, in chemico and in silico data and six physicochemical properties for 120 substances to predict murine local lymph node assay (LLNA) outcomes. The seven models with the highest accuracy used a support vector machine with different combinations of predictor variables. The models outperformed individual non-animal methods and test batteries. This suggests that computational approaches are promising tools to effectively integrate data to identify potential skin sensitizers without animal testing. C1 [Strickland, Judy; Zang, Qingda; Kleinstreuer, Nicole; Paris, Michael; Choksi, Neepa; Allen, David] ILS, Res Triangle Pk, NC 27709 USA. [Lehmann, David M.] US EPA, NHEERL, EPHD, CIB, Res Triangle Pk, NC 27709 USA. [Matheson, Joanna] US Consumer Prod Safety Commiss, Bethesda, MD 20814 USA. [Jacobs, Abigail] US FDA, CDER, Silver Spring, MD 20993 USA. [Lowit, Anna] US EPA, OCSPP, OPP, HED, Washington, DC 20460 USA. [Casey, Warren] NIEHS, NIH, DNTP, NICEATM, Res Triangle Pk, NC 27709 USA. RP Casey, W (reprint author), NIEHS, NIH, DNTP, NICEATM, POB 12233, Res Triangle Pk, NC 27709 USA. EM warren.casey@nih.gov OI Kleinstreuer, Nicole/0000-0002-7914-3682 FU federal funds from the NIEHS, NIH of NICEATM [HHSN273201500010C] FX The authors thank Drs D. Germolec, B.A. Merrick, R. Luebke and M. Ward for their thoughtful critical review of this manuscript. This project was funded in whole or in part with federal funds from the NIEHS, NIH under contract HHSN273201500010C to ILS in support of NICEATM. NR 77 TC 8 Z9 8 U1 4 U2 10 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 SEP PY 2016 VL 36 IS 9 BP 1150 EP 1162 DI 10.1002/jat.3281 PG 13 WC Toxicology SC Toxicology GA DR5PD UT WOS:000379954000008 PM 26851134 ER PT J AU Mosier, PD Chiang, MJ Lin, ZS Gao, YM Althufairi, B Zhou, QB Musayev, F Safo, MK Xie, H Desai, UR AF Mosier, Philip D. Chiang, Meng-Jung Lin, Zhengshi Gao, Yamei Althufairi, Bashayer Zhou, Qibing Musayev, Faik Safo, Martin K. Xie, Hang Desai, Umesh R. TI Broad Spectrum Anti-Influenza Agents by Inhibiting Self-Association of Matrix Protein 1 SO SCIENTIFIC REPORTS LA English DT Article ID INFLUENZA-A VIRUSES; EMPIRICAL SCORING FUNCTIONS; M1 PROTEIN; GENETIC ALGORITHM; BINDING-AFFINITY; FLEXIBLE DOCKING; A/WSN/33 VIRUS; LIGAND DOCKING; SMALL-MOLECULE; UNITED-STATES AB The matrix protein 1 (M1) of influenza A virus (IAV) exists as a three-dimensional oligomeric structure in mature virions with high sequence conservation across different IAV subtypes, which makes it a potential broad spectrum antiviral target. We hypothesized that impairing self-association of M1 through a small molecule 'wedge', which avidly binds to an M1-M1 interface, would result in a completely new class of anti-influenza agents. To establish this proof-of-principle, we performed virtual screening on a library of > 70,000 commercially available small molecules that resulted in several plausible 'wedges'. Biophysical studies showed that the best molecule bound the M1 protein potently and weakened M1-M1 self-association. Most importantly, the agent reduced the thickness of the M1 layer in mature virions and inhibited in ovo propagation of multiple IAV strains including H1N1, pandemic H1N1, H3N2 and H5N1, which supports the "wedge" hypothesis. These results demonstrate that M1 is a promising druggable target for the discovery of a completely new line of broad spectrum anti-IAV agents. C1 [Mosier, Philip D.; Althufairi, Bashayer; Zhou, Qibing; Musayev, Faik; Safo, Martin K.; Desai, Umesh R.] Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, Med Coll Virginia Campus, Richmond, VA 23284 USA. [Mosier, Philip D.; Althufairi, Bashayer; Zhou, Qibing; Musayev, Faik; Safo, Martin K.; Desai, Umesh R.] Virginia Commonwealth Univ, Sch Pharm, Inst Struct Biol Drug Discovery & Dev, Med Coll Virginia Campus, Richmond, VA 23284 USA. [Chiang, Meng-Jung; Lin, Zhengshi; Gao, Yamei; Xie, Hang] US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Zhou, Qibing] Huazhong Univ Sci & Technol, Natl Engn Res Ctr Nanomed, Dept Nanomed & Biopharmaceut, Wuhan, Hubei, Peoples R China. RP Desai, UR (reprint author), Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, Med Coll Virginia Campus, Richmond, VA 23284 USA.; Desai, UR (reprint author), Virginia Commonwealth Univ, Sch Pharm, Inst Struct Biol Drug Discovery & Dev, Med Coll Virginia Campus, Richmond, VA 23284 USA.; Xie, H (reprint author), US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Hang.Xie@fda.hhs.gov; urdesai@vcu.edu FU National Institutes of Health [HL090586, HL107152, HL128639]; National Center for Research Resources [S10 RR027411] FX We thank Yingzi Jin of VCU for performing SPR experiments and Dr. Zhiping Ye of CBER/FDA for providing H5N1 vaccine reassortants. This work was supported by grants HL090586, HL107152 and HL128639 from the National Institutes of Health to URD. We also thank the computational facility provided by National Center for Research Resources to Virginia Commonwealth University through grant S10 RR027411. NR 57 TC 0 Z9 0 U1 1 U2 1 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 AUG 30 PY 2016 VL 6 AR 32340 DI 10.1038/srep32340 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH7VU UT WOS:000391981500001 PM 27573445 ER PT J AU Self, JL Conrad, A Stroika, S Jackson, A Burnworth, L Beal, J Wellman, A Jackson, KA Bidol, S Gerhardt, T Hamel, M Franklin, K Kopko, C Kirsch, P Wise, ME Basler, C AF Self, Julie L. Conrad, Amanda Stroika, Steven Jackson, Alikeh Burnworth, Laura Beal, Jennifer Wellman, Allison Jackson, Kelly A. Bidol, Sally Gerhardt, Terri Hamel, Meghan Franklin, Kristyn Kopko, Christine Kirsch, Penelope Wise, Matthew E. Basler, Colin TI Outbreak of Listeriosis Associated with Consumption of Packaged Salad - United States and Canada, 2015-2016 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Self, Julie L.] CDC, Epidem Intelligence Serv, Div Sci Educ & Profess Dev, Ctr Surveillance Epidemiol & Lab Serv, Atlanta, GA 30333 USA. [Self, Julie L.; Conrad, Amanda; Stroika, Steven; Burnworth, Laura; Jackson, Kelly A.; Wise, Matthew E.; Basler, Colin] CDC, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Jackson, Alikeh; Beal, Jennifer; Wellman, Allison] US FDA, Rockville, MD 20857 USA. [Bidol, Sally] Michigan Dept Hlth & Human Serv, Detroit, MI USA. [Gerhardt, Terri] Ohio Dept Agr, Reynoldsburg, OH USA. [Hamel, Meghan; Franklin, Kristyn] Publ Hlth Agcy Canada, Ottawa, ON, Canada. [Kopko, Christine; Kirsch, Penelope] Canadian Food Inspect Agency, Ottawa, ON, Canada. RP Self, JL (reprint author), CDC, Epidem Intelligence Serv, Div Sci Educ & Profess Dev, Ctr Surveillance Epidemiol & Lab Serv, Atlanta, GA 30333 USA.; Self, JL (reprint author), CDC, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. EM yxj9@cdc.gov NR 4 TC 1 Z9 1 U1 8 U2 8 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD AUG 26 PY 2016 VL 65 IS 33 BP 879 EP 881 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DU3TO UT WOS:000382135300008 PM 27559935 ER PT J AU Rosas-Hernandez, H Cuevas, E Lantz, SM Rice, KC Gannon, BM Fantegrossi, WE Gonzalez, C Paule, MG Ali, SF AF Rosas-Hernandez, Hector Cuevas, Elvis Lantz, Susan M. Rice, Kenner C. Gannon, Brenda M. Fantegrossi, William E. Gonzalez, Carmen Paule, Merle G. Ali, Syed F. TI Methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxypyrovalerone (MDPV) induce differential cytotoxic effects in bovine brain microvessel endothelial cells SO NEUROSCIENCE LETTERS LA English DT Article DE Methamphetamine; MDMA; MDPV; Blood-brain barrier; Cytotoxicity ID BARRIER DISRUPTION; OXIDATIVE STRESS; DOPAMINE TRANSPORTER; IN-VITRO; HYPERTHERMIA; ECSTASY; COCAINE; METHYLENEDIOXYPYROVALERONE; NEUROINFLAMMATION; VASOCONSTRICTION AB Designer drugs such as synthetic psychostimulants are indicative of a worldwide problem of drug abuse and addiction. In addition to methamphetamine (METH), these drugs include 3,4-methylenedioxy-methamphetamine (MDMA) and commercial preparations of synthetic cathinones including 3,4-methylenedioxypyrovalerone (MDPV), typically referred to as "bath salts." These psychostimulants exert neurotoxic effects by altering monoamine systems in the brain. Additionally, METH and MDMA adversely affect the integrity of the blood-brain barrier (BBB): there are no current reports on the effects of MDPV on the BBB. The aim of this study was to compare the effects of METH, MDMA and MDPV on bovine brain microvessel endothelial cells (bBMVECs), an accepted in vitro model of the BBB. Confluent bBMVEC monolayers were treated with METH, MDMA and MDPV (0.5 mM-2.5 mM) for 24 h. METH and MDMA increased lactate dehydrogenase release only at the highest concentration (2.5 mM), whereas MDPV induced cytotoxicity at all concentrations. MDMA and METH decreased cellular proliferation only at 2.5 mM, with similar effects observed after MDPV exposures starting at 1 mM. Only MDPV increased reactive oxygen species production at all concentrations tested whereas all 3 drugs increased nitric oxide production. Morphological analysis revealed different patterns of compound-induced cell damage. METH induced vacuole formation at 1 mM and disruption of the monolayer at 2.5 mM. MDMA induced disruption of the endothelial monolayer from 1 mM without vacuolization. On the other hand, MDPV induced monolayer disruption at doses >= 0.5 mM without vacuole formation; at 2.5 mM, the few remaining cells lacked endothelial morphology. These data suggest that even though these synthetic psychostimulants altermonoaminergic systems, they each induce BBB toxicity by different mechanisms with MDPV being the most toxic. Published by Elsevier Ireland Ltd. C1 [Rosas-Hernandez, Hector; Cuevas, Elvis; Lantz, Susan M.; Paule, Merle G.; Ali, Syed F.] US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Rice, Kenner C.] NIAAA, Drug Design & Synth Sect, Mol Targets & Medicat Discovery Branch, NIDA, Bethesda, MD USA. [Gannon, Brenda M.; Fantegrossi, William E.] UAMS, Dept Pharmacol & Toxicol, Little Rock, AR USA. [Gonzalez, Carmen] UASLP, Fac Ciencias Quim, Slp, Mexico. RP Ali, SF (reprint author), US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Syed.Ali@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration; Intramural Research Programs of the National Institute on Drug Abuse; National Institute on Alcoholism and Alcohol Abuse FX This research was supported in part by an appointment (H. R-H.) 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. A portion of this work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcoholism and Alcohol Abuse. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US. Food and Drug Administration, the National Institute on Drug Abuse, the National Institute of Alcohol Abuse and Alcoholism, or the National Institutes of Health. NR 45 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD AUG 26 PY 2016 VL 629 BP 125 EP 130 DI 10.1016/j.neulet.2016.06.029 PG 6 WC Neurosciences SC Neurosciences & Neurology GA DU7QF UT WOS:000382409000023 PM 27320055 ER PT J AU Wang, PG Zhou, WL AF Wang, Perry G. Zhou, Wanlong TI Rapid determination of cocamidopropyl betaine impurities in cosmetic products by core-shell hydrophilic interaction liquid chromatography-tandem mass spectrometry SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE HILIC; MS/MS; Sensitizers; Allergy; Dimethylaminopropylamine; Lauramidopropyldimethylamine; Matrix effects; Cosmetics ID HEXAPEPTIDES; AMIDOAMINE; ALLERGY; MS/MS AB Cocamidopropyl betaine (CAPB) is a common surfactant widely used in personal care products. Dimethylaminopropylamine (DMAPA) and lauramidopropyldimethylamine (LAPDMA) are two chemicals present as impurities in CAPB and have been reported as skin sensitizers. A rapid and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method, using a core shell hydrophilic interaction liquid chromatography (HILIC) column, has been developed to quantify DMAPA and LAPDMA in cosmetic products. Corresponding stable isotopically labeled analogues of the above native compounds were used as internal standards to compensate for matrix effect and for loss of recovery. Each sample was first screened to determine whether the sample needed to be diluted to minimize matrix effects as well as to fit the calibration range. The concept of matrix effect factor (MEF) was introduced to quantitatively evaluate each sample with a unique matrix using the internal standards. Recoveries at three spiking levels of low, medium, and high concentrations ranged from 98.4 to 112% with RSDs less than 5%. This method has been validated and is the first UHPLC-MS/MS method, which uses core shell HILIC column and stable isotopically labeled internal standards to simultaneously determine these two CAPB impurities in cosmetic products. Published by Elsevier B.V. C1 [Wang, Perry G.; Zhou, Wanlong] US FDA, Off Regulatory Sci, CFSAN HFS 717,5001 Campus Dr, College Pk, MD 20740 USA. RP Wang, PG (reprint author), US FDA, Off Regulatory Sci, CFSAN HFS 717,5001 Campus Dr, College Pk, MD 20740 USA. EM wanggperry@gmail.com NR 14 TC 0 Z9 0 U1 3 U2 3 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 AUG 26 PY 2016 VL 1461 BP 78 EP 83 DI 10.1016/j.chroma.2016.07.056 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DT9RO UT WOS:000381840200010 PM 27473511 ER PT J AU Luo, H Ye, H Ng, HW Sakkiah, S Mendrick, DL Hong, HX AF Luo, Heng Ye, Hao Ng, Hui Wen Sakkiah, Sugunadevi Mendrick, Donna L. Hong, Huixiao TI sNebula, a network-based algorithm to predict binding between human leukocyte antigens and peptides SO SCIENTIFIC REPORTS LA English DT Article ID MISSING VALUE IMPUTATION; GENE-EXPRESSION DATA; MAJOR HISTOCOMPATIBILITY COMPLEX; IN-SILICO PREDICTION; STRUCTURE ELUCIDATION; DECISION FOREST; EXPERT-SYSTEM; ALPHA-FETOPROTEIN; ESTROGENIC ACTIVITY; DIVERSE CHEMICALS AB Understanding the binding between human leukocyte antigens (HLAs) and peptides is important to understand the functioning of the immune system. Since it is time-consuming and costly to measure the binding between large numbers of HLAs and peptides, computational methods including machine learning models and network approaches have been developed to predict HLA-peptide binding. However, there are several limitations for the existing methods. We developed a network-based algorithm called sNebula to address these limitations. We curated qualitative Class I HLA-peptide binding data and demonstrated the prediction performance of sNebula on this dataset using leave-one-out cross-validation and five-fold cross-validations. This algorithm can predict not only peptides of different lengths and different types of HLAs, but also the peptides or HLAs that have no existing binding data. We believe sNebula is an effective method to predict HLA-peptide binding and thus improve our understanding of the immune system. C1 [Luo, Heng; Ye, Hao; Ng, Hui Wen; Sakkiah, Sugunadevi; Mendrick, Donna L.; Hong, Huixiao] US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Luo, Heng] Univ Arkansas, Univ Arkansas Med Sci, Bioinformat Grad Program, 2801 S Univ Ave, Little Rock, AR 72204 USA. RP Hong, HX (reprint author), US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Huixiao.Hong@fda.hhs.gov RI Luo, Heng/D-3616-2016 OI Luo, Heng/0000-0001-5192-8878 FU Research Participation Program at the National Center for Toxicological Research; National Institutes of Health (NIH) National Institute of General Medical Sciences (NIGMS) [P20 GM103429, P20RR016460] FX This research was supported in part by an appointment to the Research Participation Program at the National Center for Toxicological Research (Heng Luo, Hao Ye, Hui Wen Ng and Sugunadevi Sakkiah) 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 grant funding from the National Institutes of Health (NIH) National Institute of General Medical Sciences (NIGMS) (P20 GM103429) (formerly P20RR016460). The findings and conclusions in this article have not been formally disseminated by the US Food and Drug Administration (FDA) and should not be construed to represent the FDA determination or policy. NR 89 TC 0 Z9 0 U1 8 U2 8 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 AUG 25 PY 2016 VL 6 AR 32115 DI 10.1038/srep32115 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU0HO UT WOS:000381883600002 PM 27558848 ER PT J AU Horne, HN Chung, CC Zhang, H Yu, K Prokunina-Olsson, L Michailidou, K Bolla, MK Wang, Q Dennis, J Hopper, JL Southey, MC Schmidt, MK Broeks, A Muir, K Lophatananon, A Fasching, PA Beckmann, MW Fletcher, O Johnson, N Sawyer, EJ Tomlinson, I Burwinkel, B Marme, F Guenel, P Truong, T Bojesen, SE Flyger, H Benitez, J Gonzalez-Neira, A Anton-Culver, H Neuhausen, SL Brenner, H Arndt, V Meindl, A Schmutzler, RK Brauch, H Hamann, U Nevanlinna, H Khan, S Matsuo, K Iwata, H Dork, T Bogdanova, NV Lindblom, A Margolin, S Mannermaa, A Kosma, VM Chenevix-Trench, G Wu, AH den Berg, DV Smeets, A Zhao, H Chang-Claude, J Rudolph, A Radice, P Barile, M Couch, FJ Vachon, C Giles, GG Milne, RL Haiman, CA Le Marchand, L Goldberg, MS Teo, SH Taib, NAM Kristensen, V Borresen-Dale, AL Zheng, W Shrubsole, M Winqvist, R Jukkola-Vuorinen, A Andrulis, IL Knight, JA Devilee, P Seynaeve, C Garcia-Closas, M Czene, K Darabi, H Hollestelle, A Martens, JWM Li, JM Lu, W Shu, XO Cox, A Cross, SS Blot, W Cai, QY Shah, M Luccarini, C Baynes, C Harrington, P Kang, D Choi, JY Hartman, M Chia, KS Kabisch, M Torres, D Jakubowska, A Lubinski, J Sangrajrang, S Brennan, P Slager, S Yannoukakos, D Shen, CY Hou, MF Swerdlow, A Orr, N Simard, J Hall, P Pharoah, PDP Easton, DF Chanock, SJ Dunning, AM Figueroa, JD AF Horne, Hisani N. Chung, Charles C. Zhang, Han Yu, Kai Prokunina-Olsson, Ludmila Michailidou, Kyriaki Bolla, Manjeet K. Wang, Qin Dennis, Joe Hopper, John L. Southey, Melissa C. Schmidt, Marjanka K. Broeks, Annegien Muir, Kenneth Lophatananon, Artitaya Fasching, Peter A. Beckmann, Matthias W. Fletcher, Olivia Johnson, Nichola Sawyer, Elinor J. Tomlinson, Ian Burwinkel, Barbara Marme, Frederik Guenel, Pascal Truong, Therese Bojesen, Stig E. Flyger, Henrik Benitez, Javier Gonzalez-Neira, Anna Anton-Culver, Hoda Neuhausen, Susan L. Brenner, Hermann Arndt, Volker Meindl, Alfons Schmutzler, Rita K. Brauch, Hiltrud Hamann, Ute Nevanlinna, Heli Khan, Sofia Matsuo, Keitaro Iwata, Hiroji Dork, Thilo Bogdanova, Natalia V. Lindblom, Annika Margolin, Sara Mannermaa, Arto Kosma, Veli-Matti Chenevix-Trench, Georgia Wu, Anna H. den Berg, David Ven Smeets, Ann Zhao, Hui Chang-Claude, Jenny Rudolph, Anja Radice, Paolo Barile, Monica Couch, Fergus J. Vachon, Celine Giles, Graham G. Milne, Roger L. Haiman, Christopher A. Le Marchand, Loic Goldberg, Mark S. Teo, Soo H. Taib, Nur A. M. Kristensen, Vessela Borresen-Dale, Anne-Lise Zheng, Wei Shrubsole, Martha Winqvist, Robert Jukkola-Vuorinen, Arja Andrulis, Irene L. Knight, Julia A. Devilee, Peter Seynaeve, Caroline Garcia-Closas, Montserrat Czene, Kamila Darabi, Hatef Hollestelle, Antoinette Martens, John W. M. Li, Jingmei Lu, Wei Shu, Xiao-Ou Cox, Angela Cross, Simon S. Blot, William Cai, Qiuyin Shah, Mitul Luccarini, Craig Baynes, Caroline Harrington, Patricia Kang, Daehee Choi, Ji-Yeob Hartman, Mikael Chia, Kee Seng Kabisch, Maria Torres, Diana Jakubowska, Anna Lubinski, Jan Sangrajrang, Suleeporn Brennan, Paul Slager, Susan Yannoukakos, Drakoulis Shen, Chen-Yang Hou, Ming-Feng Swerdlow, Anthony Orr, Nick Simard, Jacques Hall, Per Pharoah, Paul D. P. Easton, Douglas F. Chanock, Stephen J. Dunning, Alison M. Figueroa, Jonine D. CA kConFab AOCS Investigators TI Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; COMMON VARIANTS; CONFER SUSCEPTIBILITY; GENETIC-VARIATION; 14Q24.1 RAD51L1; RISK; HETEROGENEITY; ALLELES; DISEASE AB The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Perallelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10(-21)). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P <= 8.41 x 10(-5)). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive. C1 [Horne, Hisani N.; Chung, Charles C.; Zhang, Han; Yu, Kai; Prokunina-Olsson, Ludmila; Garcia-Closas, Montserrat; Chanock, Stephen J.; Figueroa, Jonine D.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Horne, Hisani N.] US FDA, Silver Spring, MD USA. [Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Hopper, John L.; Giles, Graham G.; Milne, Roger L.] Univ Melbourne, Ctr Epidemiol & Biostat, Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Schmidt, Marjanka K.; Broeks, Annegien] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Muir, Kenneth; Lophatananon, Artitaya] Univ Warwick, Div Hlth Sci, Warwick Med Sch, Coventry, W Midlands, England. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Fasching, Peter A.; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Dept Obstet & Gynaecol, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen EMN, Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Fletcher, Olivia; Johnson, Nichola; Orr, Nick] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London, England. [Fletcher, Olivia; Johnson, Nichola; Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London, England. [Sawyer, Elinor J.] Kings Coll London, Res Oncol, Guys Hosp, London, England. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England. [Burwinkel, Barbara; Marme, Frederik] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Guenel, Pascal; Truong, Therese] INSERM, Environm Epidemiol Canc, Ctr Res Epidemiol & Populat Hlth, Villejuif, France. [Guenel, Pascal; Truong, Therese] Univ Paris 11, Villejuif, France. [Bojesen, Stig E.] Copenhagen Univ Hosp, Copenhagen Gen Populat Study, Herlev Hosp, Herlev, Denmark. [Bojesen, Stig E.] Copenhagen Univ Hosp, Dept Clin Biochem, Herlev Hosp, Herlev, Denmark. [Bojesen, Stig E.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Flyger, Henrik] Copenhagen Univ Hosp, Dept Breast Surg, Herlev Hosp, Herlev, Denmark. [Benitez, Javier; Gonzalez-Neira, Anna] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras, Valencia, Spain. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Duarte, CA USA. [Brenner, Hermann; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann; Brauch, Hiltrud] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol & Obstet, Munich, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Mol Med, Cologne, Germany. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Institute Clin Pharmac, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Hamann, Ute; Kabisch, Maria; Torres, Diana] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Nevanlinna, Heli; Khan, Sofia] Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Matsuo, Keitaro] Kyushu Univ, Dept Prevent Med, Fac Med Sci, Fukuoka, Japan. [Iwata, Hiroji] Aichi Canc Ctr Hosp, Dept Breast Oncol, Nagoya, Aichi, Japan. [Dork, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Bogdanova, Natalia V.] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Mannermaa, Arto; Kosma, Veli-Matti] Kuopio Univ Hosp, Ctr Canc, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti] Kuopio Univ Hosp, Imaging Ctr, Dept Clin Pathol, Kuopio, Finland. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [kConFab AOCS Investigators] Univ Melbourne, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Wu, Anna H.; den Berg, David Ven; Haiman, Christopher A.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Smeets, Ann] Univ Hosp Gashuisberg, Leuven, Belgium. [Zhao, Hui] Vesalius Res Ctr, Leuven, Belgium. [Zhao, Hui] Univ Leuven, Lab Translat Genet, Dept Oncol, Leuven, Belgium. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany. [Radice, Paolo] Ist Nazl Tumori, Unit Mol Bases Genet Risk & Genet Testing, Dept Prevent & Predict Med, Fdn IRCCS Ist Ricovero & Cura Carattere Sci, Milan, Italy. [Barile, Monica] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Vachon, Celine; Slager, Susan] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Goldberg, Mark S.] McGill Univ, Div Clin Epidemiol, Royal Victoria Hosp, Montreal, PQ, Canada. [Teo, Soo H.] Canc Res Initiat Fdn, Subang Jaya, Selangor, Malaysia. [Teo, Soo H.; Taib, Nur A. M.] Univ Malaya, Med Ctr, Breast Canc Res Unit, Canc Res Inst, Kuala Lumpur, Malaysia. [Kristensen, Vessela; Borresen-Dale, Anne-Lise] Oslo Univ Hosp, Dept Genet, Inst Canc Res, Radiumhosp, Oslo, Norway. [Kristensen, Vessela; Borresen-Dale, Anne-Lise] Univ Oslo, Inst Clin Med, Fac Med, Oslo, Norway. [Kristensen, Vessela] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway. [Zheng, Wei; Shrubsole, Martha; Shu, Xiao-Ou; Blot, William; Cai, Qiuyin] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA. [Winqvist, Robert] Univ Oulu, Lab Canc Genet & Tumor Biol, Dept Clin Chem, Oulu, Finland. [Winqvist, Robert] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Winqvist, Robert] Northern Finland Lab Ctr NordLab, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Jukkola-Vuorinen, Arja] Univ Oulu, Dept Oncol, Oulu Univ Hosp, Oulu, Finland. [Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Knight, Julia A.] Mt Sinai Hosp, Prosserman Ctr Hlth Res, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Knight, Julia A.] Univ Toronto, Div Epidemiol, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Seynaeve, Caroline; Hollestelle, Antoinette; Martens, John W. M.] Erasmus MC Canc Inst, Dept Med Oncol, Family Canc Clin, Rotterdam, Netherlands. [Garcia-Closas, Montserrat; Swerdlow, Anthony] Inst Canc Res, Div Genet & Epidemiol, London, England. [Czene, Kamila; Darabi, Hatef; Li, Jingmei; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Lu, Wei] Shanghai Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Cox, Angela] Univ Sheffield, Sheffield Canc Res, Dept Oncol, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield, S Yorkshire, England. [Blot, William] Int Epidemiol Inst, Rockville, MD USA. [Shah, Mitul; Luccarini, Craig; Baynes, Caroline; Harrington, Patricia; Pharoah, Paul D. P.; Easton, Douglas F.; Dunning, Alison M.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England. [Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Kang, Daehee; Choi, Ji-Yeob] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea. [Kang, Daehee; Choi, Ji-Yeob] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea. [Hartman, Mikael; Chia, Kee Seng] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Hartman, Mikael] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia. [Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand. [Brennan, Paul] Int Agcy Res Canc, Lyon, France. [Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, Mol Diagnost Lab, IRRP, Athens, Greece. [Shen, Chen-Yang] China Med Univ, Sch Publ Hlth, Taichung, Taiwan. [Shen, Chen-Yang] Acad Sinica, Taiwan Biobank, Inst Biomed Sci, Taipei, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Ctr Canc, Chung Ho Mem Hosp, Kaohsiung, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Dept Surg, Chung Ho Mem Hosp, Kaohsiung, Taiwan. [Simard, Jacques] Univ Laval, Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ, Canada. [Figueroa, Jonine D.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. [Figueroa, Jonine D.] Univ Edinburgh, Edinburgh Canc Res UK Ctr, Edinburgh, Midlothian, Scotland. RP Figueroa, JD (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD USA.; Figueroa, JD (reprint author), Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland.; Figueroa, JD (reprint author), Univ Edinburgh, Edinburgh Canc Res UK Ctr, Edinburgh, Midlothian, Scotland. EM jonine.figueroa@ed.ac.uk RI Knight, Julia/A-6843-2012; Zheng, Wei/O-3351-2013; Dork, Thilo/J-8620-2012; Zhang, Han/K-2118-2016; Li, Jingmei/I-2904-2012; Brenner, Hermann/B-4627-2017; OI Zheng, Wei/0000-0003-1226-070X; Zhang, Han/0000-0001-7977-9616; Li, Jingmei/0000-0001-8587-7511; Brenner, Hermann/0000-0002-6129-1572; Khan, Sofia/0000-0003-4185-8882; Matsuo, Keitaro/0000-0003-1761-6314; Yannoukakos, Drakoulis/0000-0001-7509-3510; Dunning, Alison Margaret/0000-0001-6651-7166 FU Cancer Research UK [10124]; NCI NIH HHS [R01 CA176785] NR 43 TC 1 Z9 1 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 24 PY 2016 VL 11 IS 8 AR e0160316 DI 10.1371/journal.pone.0160316 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU5NI UT WOS:000382258100011 PM 27556229 ER PT J AU Han, M Park, S Baek, J AF Han, Minah Park, Subok Baek, Jongduk TI Effect of anatomical noise on the detectability of cone beam CT images with different slice direction, slice thickness, and volume glandular fraction SO OPTICS EXPRESS LA English DT Article ID DISTRIBUTED LUMPY BACKGROUNDS; POWER-LAW NOISE; HUMAN-OBSERVER; BREAST TOMOSYNTHESIS; GAUSSIAN SIGNAL; DETECTION TASKS; SPECTRUM; PERFORMANCE; ALGORITHM; LESION AB We investigate the effect of anatomical noise on the detectability of cone beam CT (CBCT) images with different slice directions, slice thicknesses, and volume glandular fractions (VGFs). Anatomical noise is generated using a power law spectrum of breast anatomy, and spherical objects with diameters from 1mm to 11mm are used as breast masses. CBCT projection images are simulated and reconstructed using the FDK algorithm. A channelized Hotelling observer (CHO) with Laguerre-Gauss (LG) channels is used to evaluate detectability for the signal-known-exactly (SKE) binary detection task. Detectability is calculated for various slice thicknesses in the transverse and longitudinal planes for 15%, 30% and 60% VGFs. The optimal slice thicknesses that maximize the detectability of the objects are determined. The results show that the beta value increases as the slice thickness increases, but that thicker slices yield higher detectability in the transverse and longitudinal planes, except for the case of a 1mm diameter spherical object. It is also shown that the longitudinal plane with a 0.1mm slice thickness provides higher detectability than the transverse plane, despite its higher beta value. With optimal slice thicknesses, the longitudinal plane exhibits better detectability for all VGFs and spherical objects. (C) 2016 Optical Society of America C1 [Han, Minah; Baek, Jongduk] Yonsei Univ, Sch Integrated Technol, Inchon 1621, South Korea. [Han, Minah; Baek, Jongduk] Yonsei Univ, Yonsei Inst Convergence Technol, Inchon 1621, South Korea. [Park, Subok] US FDA, Silver Spring, MD USA. RP Baek, J (reprint author), Yonsei Univ, Sch Integrated Technol, Inchon 1621, South Korea.; Baek, J (reprint author), Yonsei Univ, Yonsei Inst Convergence Technol, Inchon 1621, South Korea. EM jongdukbaek@yonsei.ac.kr FU Institute for Information & Communications Technology Promotion (IITP) [2015-R0346-15-1008]; National Research Foundation of Korea (NRF) [2015R1C1A1A01052268, 2015K2A1A2067635] FX Institute for Information & Communications Technology Promotion (IITP) (2015-R0346-15-1008); National Research Foundation of Korea (NRF) (2015R1C1A1A01052268, 2015K2A1A2067635). NR 35 TC 0 Z9 0 U1 0 U2 0 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD AUG 22 PY 2016 VL 24 IS 17 BP 18843 EP 18859 DI 10.1364/OE.24.018843 PG 17 WC Optics SC Optics GA DY6KV UT WOS:000385227100003 PM 27557168 ER PT J AU Rogers, LJ Basnakian, AG Orloff, MS Ning, BT Yao-Borengasser, A Raj, V Kadlubar, S AF Rogers, Lora J. Basnakian, Alexei G. Orloff, Mohammed S. Ning, Baitang Yao-Borengasser, Aiwei Raj, Vinay Kadlubar, Susan TI 2-amino-1-methyl-6-phenylimidazo(4,5-b) pyridine (PhIP) induces gene expression changes in JAK/STAT and MAPK pathways related to inflammation, diabetes and cancer SO NUTRITION & METABOLISM LA English DT Article DE PhIP; Adipocyte; Gene expression; Inflammation; Diabetes; Cancer risk ID HETEROCYCLIC AROMATIC-AMINES; MAMMARY-GLAND CARCINOMAS; HEPATOMA HEPG2 CELLS; BINDING-PROTEIN 5; ADIPOSE-TISSUE; MEAT CONSUMPTION; COOKED-FOOD; METABOLIC-ACTIVATION; HUMAN LIVER; DNA AB Background: 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), a heterocyclic aromatic amine (HCA) formed in meat that is cooked at high temperatures and then ingested, can potentially be retained in human adipose tissues. Methods: To determine if PhIP is bioactive in the adipocyte, we exposed a human adipocyte cell line, HepG2 and Caco-2 cells to low dose PhIP. Uptake and retention of PhIP was determined and cytotoxicity was assessed by the TUNEL assay. Relative expression of PhIP-activating genes (CYP1A1, CYP1A2, SULT1A1 and UGT1A1) was determined by RT-PCR and global expression changes were also examined. Results: The percent retention of 0.1 mu Ci [C-14]-PhIP over a 24 h period was significantly higher in the adipocyte than the HepG2 (p = 0.0001) and Caco-2 (p = 0.0007) cell lines. Cytotoxicity rates were 14.4 and 2.6 % higher compared to controls in Caco-2 and HepG2 cells (p < 0.001 and 0.054, respectively); no significant differences were detected in adipocyte cells (p = 0.18). Caco-2 and HepG2 cells, respectively, had significantly higher basal expression of CYP1A1 (p = 0.001, p = 0.003), SULT1A1 (p = 0.04, p < 0.001) and UGT1A1 (p < 0.001, p = 0.01) compared to the adipocyte. Exposure to 5nM PhIP did not significantly induce expression of these genes in any of the cell lines. Global gene expression analysis of mature adipocytes exposed to 5nM PhIP for 72 h resulted in statistically significant changes in 8 genes (ANGPTL2, CD14, CIDEA, EGR1, FOS, IGFBP5, PALM and PSAT1). Gene-gene interaction and pathway analysis indicates that PhIP modulates genes controlled by the STAT3 transcriptional factor and initiates leptin signaling via the JAK/STAT and MAPK pathway cascades. Early growth response 1 (EGR1) and prostaglandin synthase 2 (COX-2) were down-regulated via c-Fos, while insulin binding protein 5 (IBP5) was up regulated. Expression of transcription factors (ANGPTL2, HP, LEP, SAA1, SAA2), genes related to inflammation (SAA1, LEP), diabetes (IGFBP5) and cancer risk (SAA2) were also elevated upon exposure to 5 nM PhIP.. Conclusions: PhIP mediates gene expression changes within the adipocyte, and the pathways most affected are related to cancer and other chronic diseases. Further studies are needed on the relationship between dietary carcinogens such as PhIP with cancer, obesity and diabetes. C1 [Rogers, Lora J.; Basnakian, Alexei G.; Orloff, Mohammed S.; Raj, Vinay; Kadlubar, Susan] Univ Arkansas Med Sci, 4301 W Markham St 580, Little Rock, AR 72205 USA. [Ning, Baitang] Natl Ctr Toxicol Res, NCTR Rd, Redfield, AR 72132 USA. [Yao-Borengasser, Aiwei] Pulaski Tech Coll, 3000 W Scen Dr, North Little Rock, AR 72118 USA. RP Kadlubar, S (reprint author), Univ Arkansas Med Sci, 4301 W Markham St 580, Little Rock, AR 72205 USA. EM sakadlubar@uams.edu FU Applied Biosciences Institute at the University of Arkansas for Medical Sciences, Little Rock, AR FX This work was supported by the Applied Biosciences Institute at the University of Arkansas for Medical Sciences, Little Rock, AR. NR 49 TC 0 Z9 0 U1 11 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-7075 J9 NUTR METAB JI Nutr. Metab. PD AUG 20 PY 2016 VL 13 AR 54 DI 10.1186/s12986-016-0111-0 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DT9DF UT WOS:000381795000001 PM 27547236 ER PT J AU Delmonte, P AF Delmonte, Pierluigi TI Evaluation of poly(90% biscyanopropyl/10% cyanopropylphenyl siloxane) capillary columns for the gas chromatographic quantification of trans fatty acids in non-hydrogenated vegetable oils SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Fatty acids; Trans fat; Gas chromatography; GC x GC; Hydrogenation; SP2380 ID LIQUID STATIONARY PHASES; FLIGHT MASS-SPECTROMETRY; CP-SIL 88; IONIC LIQUIDS; ONLINE HYDROGENATION; METHYL-ESTERS; GC ANALYSIS; CIS-FATTY; SEPARATION; SP-2560 AB Current gas chromatographic (GC) methods for the analysis of fatty acids (FA) were optimized primarily for the quantification of the trans 18:1 FAs (18:1 tFAs) produced during the partial hydrogenation of fats and oils. Recent regulatory action regarding the application of partial hydrogenation in the processing of edible fats and oils may reshape the FA composition of these products. The higher content in 18:3 tFAs compared to 18:1 tFAs of most refined non-hydrogenated vegetable oils (RNHVO), and the challenge in their quantification applying current methods, suggest the need for new methodologies. This manuscript describes a simple GC method for the analysis of FAs in RNHVOs utilizing a 100 m (0.25 mm I.D.) capillary column coated with poly(90% biscyanopropy1/10% cyanopropylphenyl siloxane) (90% BCS). The optimization of the chromatographic conditions and the detection of co-eluting compounds were carried out by applying comprehensive two dimensional gas chromatography with online reduction (GC-OR x GC). Results showed that 90% BCS capillary columns operated at the elution temperature of 162 degrees C provide the separation of the 18:1, 18:2 and 18:3 tFAs, contained in RNHVOs, from other components. A minor constituent of Canola oil, 16:3n-3, partially co-eluted with trans-18:1 FAMEs. This simple GC method showed the ability to measure trans-fat in RNHVOs at the level of 0.5 g/100 g, providing comparable quantitative results to the more complex GC x GC methodology. Published by Elsevier B.V. C1 [Delmonte, Pierluigi] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. RP Delmonte, P (reprint author), US FDA, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Pierluigi.delmonte@fda.hhs.gov NR 55 TC 0 Z9 0 U1 14 U2 14 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 AUG 19 PY 2016 VL 1460 BP 160 EP 172 DI 10.1016/j.chroma.2016.07.019 PG 13 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DT5PZ UT WOS:000381536400019 PM 27470095 ER PT J AU Hao, Y Updegrove, TB Livingston, NN Storz, G AF Hao, Yue Updegrove, Taylor B. Livingston, Natasha N. Storz, Gisela TI Protection against deleterious nitrogen compounds: role of sigma(S)-dependent small RNAs encoded adjacent to sdiA SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SMALL NONCODING RNA; ESCHERICHIA-COLI; MESSENGER-RNA; SOLUBLE-RNA; OUTER-MEMBRANE; REGULATORY RNAS; GENE-EXPRESSION; E. COLI; HFQ; RPOS AB Here, we report the characterization of a set of small, regulatory RNAs (sRNAs) expressed from an Escherichia coli locus we have denoted sdsN located adjacent to the LuxR-homolog gene sdiA. Two longer sRNAs, SdsN(137) and SdsN(178) are transcribed from two sigma(S)-dependent promoters but share the same terminator. Low temperature, rich nitrogen sources and the Crl and NarP transcription factors differentially affect the levels of the SdsN transcripts. Whole genome expression analysis after pulse overexpression of SdsN(137) and assays of lacZ fusions revealed that the SdsN(137) directly represses the synthesis of the nitroreductase NfsA, which catalyzes the reduction of the nitrogroup (NO2) in nitroaromatic compounds and the flavohemoglobin HmpA, which has aerobic nitric oxide (NO) dioxygenase activity. Consistent with this regulation, SdsN(137) confers resistance to nitrofurans. In addition, SdsN(137) negatively regulates synthesis of NarP. Interestingly, SdsN(178) is defective at regulating the above targets due to unusual binding to the Hfq protein, but cleavage leads to a shorter form, SdsN(124), able to repress nfsA and hmpA. C1 [Hao, Yue; Updegrove, Taylor B.; Livingston, Natasha N.; Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Mol & Cellular Biol, Bethesda, MD 20892 USA. [Hao, Yue] Chinese Acad Agr Sci, Inst Apicultural Res, Beijing 100093, Peoples R China. [Updegrove, Taylor B.] NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. [Livingston, Natasha N.] US FDA, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. RP Storz, G (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Mol & Cellular Biol, Bethesda, MD 20892 USA. EM storz@helix.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ZIA [HD001608] FX Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Funding for open access charge: ZIA [HD001608]. NR 51 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD AUG 19 PY 2016 VL 44 IS 14 BP 6935 EP 6948 DI 10.1093/nar/gkw404 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5VX UT WOS:000382999900038 PM 27166377 ER PT J AU Cope, JR Collier, SA Srinivasan, K Abliz, E Myers, A Millin, CJ Miller, A Tarver, ME AF Cope, Jennifer R. Collier, Sarah A. Srinivasan, Krithika Abliz, Erkinay Myers, Ann Millin, Courtney J. Miller, Andrew Tarver, Michelle E. TI 2005-2015 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID MICROBIAL KERATITIS; UNITED-STATES; RISK-FACTORS C1 [Cope, Jennifer R.; Collier, Sarah A.; Srinivasan, Krithika] CDC, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Abliz, Erkinay; Myers, Ann; Millin, Courtney J.; Miller, Andrew; Tarver, Michelle E.] US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. RP Cope, JR (reprint author), CDC, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. EM jcope@cdc.gov NR 7 TC 1 Z9 2 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 AUG 19 PY 2016 VL 65 IS 32 BP 817 EP 820 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DU3HZ UT WOS:000382102700002 PM 27538244 ER PT J AU Ferre, EMN Rose, SR Rosenzweig, SD Burbelo, PD Romito, KR Niemela, JE Rosen, LB Break, TJ Gu, WJ Hunsberger, S Browne, SK Hsu, AP Rampertaap, S Swamydas, M Collar, AL Kong, HH Lee, CCR Chascsa, D Simcox, T Pham, A Bondici, A Natarajan, M Monsale, J Kleiner, DE Quezado, M Alevizos, I Moutsopoulos, NM Yockey, L Frein, C Soldatos, A Calvo, KR Adjemian, J Similuk, MN Lang, DM Stone, KD Uzel, G Kopp, JB Bishop, RJ Holland, SM Olivier, KN Fleisher, TA Heller, T Winer, KK Lionakis, MS AF Ferre, Elise M. N. Rose, Stacey R. Rosenzweig, Sergio D. Burbelo, Peter D. Romito, Kimberly R. Niemela, Julie E. Rosen, Lindsey B. Break, Timothy J. Gu, Wenjuan Hunsberger, Sally Browne, Sarah K. Hsu, Amy P. Rampertaap, Shakuntala Swamydas, Muthulekha Collar, Amanda L. Kong, Heidi H. Lee, Chyi-Chia Richard Chascsa, David Simcox, Thomas Pham, Angela Bondici, Anamaria Natarajan, Mukil Monsale, Joseph Kleiner, David E. Quezado, Martha Alevizos, Ilias Moutsopoulos, Niki M. Yockey, Lynne Frein, Cathleen Soldatos, Ariane Calvo, Katherine R. Adjemian, Jennifer Similuk, Morgan N. Lang, David M. Stone, Kelly D. Uzel, Gulbu Kopp, Jeffrey B. Bishop, Rachel J. Holland, Steven M. Olivier, Kenneth N. Fleisher, Thomas A. Heller, Theo Winer, Karen K. Lionakis, Michail S. TI Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy SO JCI INSIGHT LA English DT Article ID SYNDROME TYPE-I; CHRONIC MUCOCUTANEOUS CANDIDIASIS; COMMON VARIABLE IMMUNODEFICIENCY; POLYGLANDULAR SYNDROME TYPE-1; B-CELL POPULATION; ADDISONS-DISEASE; REGULATOR GENE; PERIPHERAL-BLOOD; APS-I; AUTOANTIBODIES AB Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous AIRE mutations. It classically presents with chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues; hypoparathyroidism and adrenal insufficiency are most common. Developing any two of these classic triad manifestations establishes the diagnosis. Although widely recognized in Europe, where nonendocrine autoimmune manifestations are uncommon, APECED is less defined in patients from the Western Hemisphere. We enrolled 35 consecutive American APECED patients (33 from the US) in a prospective observational natural history study and systematically examined their genetic, clinical, autoantibody, and immunological characteristics. Most patients were compound heterozygous; the most common AIRE mutation was c.967_979del13. All but one patient had anti-IFN-omega autoantibodies, including 4 of 5 patients without biallelic AIRE mutations. Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjogren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases. Development of a classic diagnostic dyad was delayed at mean 7.38 years. Eighty percent of patients developed a median of 3 non-triad manifestations before a diagnostic dyad. Only 20% of patients had their first two manifestations among the classic triad. Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations. Patients exhibited expanded peripheral CD4(+) T cells and CD21(lo)CD38(lo) B lymphocytes. In summary, American APECED patients develop a diverse syndrome, with dramatic enrichment in organ-specific nonendocrine manifestations starting early in life, compared with European patients. Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications. C1 [Ferre, Elise M. N.; Rose, Stacey R.; Break, Timothy J.; Swamydas, Muthulekha; Collar, Amanda L.; Pham, Angela; Bondici, Anamaria; Natarajan, Mukil; Yockey, Lynne; Lionakis, Michail S.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Rosenzweig, Sergio D.; Romito, Kimberly R.; Niemela, Julie E.; Rampertaap, Shakuntala; Monsale, Joseph; Fleisher, Thomas A.] NIH, Serv Immunol, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Burbelo, Peter D.] Natl Inst Dent & Craniofacial Res, Dent Clin Res Core, Bethesda, MD USA. [Rosen, Lindsey B.; Browne, Sarah K.; Hsu, Amy P.; Yockey, Lynne; Uzel, Gulbu; Holland, Steven M.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gu, Wenjuan; Frein, Cathleen] Natl Canc Inst NCI Campus Frederick, Clin Res Directorate, Clin Monitoring Res Program, Leidos Biomed Res Inc, Frederick, MD USA. [Hunsberger, Sally] NIAID, Biostat Res Branch, Div Clin Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kong, Heidi H.; Kleiner, David E.; Quezado, Martha] NCI, Dermatol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Lee, Chyi-Chia Richard] NCI, Pathol Lab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Chascsa, David; Simcox, Thomas; Heller, Theo] NIDDK, Translat Hepatol Unit, Liver Dis Branch, Bethesda, MD 20892 USA. [Alevizos, Ilias] Natl Inst Dent & Craniofacial Res, Sjogrens Syndrome & Salivary Gland Dysfunct Unit, NIH, Bethesda, MD USA. [Moutsopoulos, Niki M.] Natl Inst Dent & Craniofacial Res, Oral Immun & Inflammat Unit, NIH, Bethesda, MD USA. [Soldatos, Ariane] NIH, Undiag Dis Program, Common Fund, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Soldatos, Ariane] NHGRI, Bethesda, MD 20892 USA. [Calvo, Katherine R.] NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Adjemian, Jennifer] NIAID, Epidemiol Unit, Lab Clin Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Similuk, Morgan N.] NIAID, Immunol Lab, Bldg 10, Bethesda, MD 20892 USA. [Lang, David M.] NIH, Pediat Consult Serv, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Stone, Kelly D.] NIAID, Lab Allerg Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Branch, Bethesda, MD 20892 USA. [Bishop, Rachel J.] NEI, Consult Serv Sect, Bethesda, MD 20892 USA. [Olivier, Kenneth N.] NHLBI, Cardiovasc & Pulm Branch, Bldg 10, Bethesda, MD 20892 USA. [Winer, Karen K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Growth & Nutr Branch, NIH, Bethesda, MD USA. [Rose, Stacey R.] Baylor Coll Med, Div Infect Dis, Houston, TX 77030 USA. [Browne, Sarah K.] US FDA, Div Vaccines & Related Prod Applicat, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Lionakis, MS (reprint author), NIAID, Fungal Pathogenesis Unit, LCID, NIH, 9000 Rockville Pike,Bldg 10,Room 11C102, Bethesda, MD 20892 USA. EM lionakism@mail.nih.gov NR 63 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD AUG 18 PY 2016 VL 1 IS 13 DI 10.1172/jci.insight.88782 PG 18 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1NO UT WOS:000387119700010 ER PT J AU Rostron, BL Schroeder, MJ Ambrose, BK AF Rostron, Brian L. Schroeder, Megan J. Ambrose, Bridget K. TI Dependence symptoms and cessation intentions among US adult daily cigarette, cigar, and e-cigarette users, 2012-2013 SO BMC PUBLIC HEALTH LA English DT Article DE Tobacco; Dependence; Cessation; Cigarettes; Cigars; E-cigarettes ID YOUTH TOBACCO SURVEY; NICOTINE DEPENDENCE; UNITED-STATES; ELECTRONIC CIGARETTES; SMOKING-CESSATION; FAGERSTROM TEST; YOUNG-ADULTS; PRODUCT USE; SMOKERS; PREVALENCE AB Background: Cigar and e-cigarette use is becoming increasingly common among US tobacco users and the Food and Drug Administration recently asserted regulatory jurisdiction over these products, among others, in May 2016. Research on tobacco dependence among users of these products is limited, however. We therefore examined several symptoms of dependence and cessation intentions among adult cigarette, cigar, and/or e-cigarette users in a nationally representative sample. Methods: We used nationally representative data from more than 60,000 participants in the US National Adult Tobacco Survey (NATS) from 2012 to 2013 to analyze dependence symptoms and cessation intentions for users of cigarettes, cigars, and/or e-cigarettes but not other tobacco products. Results: Among daily tobacco users, dual cigarette and cigar users on average smoked more cigarettes per day (17.3, 95 % CI = 16.1, 18.6 vs. 15.8, 95 % CI = 15.4, 16.2), had shorter times to first tobacco use after waking (21.4 min, 95 % CI = 16.6, 24.9 vs. 25.9 min, 95 % CI = 25.3, 26.5), and were more likely to report withdrawal and craving symptoms than exclusive cigarette smokers. Dual cigarette and e-cigarette users were more likely than exclusive cigarette smokers to report withdrawal and craving symptoms and cessation intentions. Exclusive cigar and e-cigarette users were less likely to report withdrawal and craving symptoms than users of other products, but even so, more than a third of exclusive cigar (38.8 %, 95 % CI = 27.4 %, 51.6 %) and e-cigarette (46.1 %, 95 % CI = 35.1 %, 57.4 %) users reported experiencing a strong craving for a tobacco product in the past 30 days. Conclusions: Dual cigarette and cigar users show evidence of greater dependence symptoms and dual cigarette and e-cigarette users show evidence of greater dependence symptoms and cessation intentions compared with exclusive cigarette smokers. A sizeable number of users of all of the tobacco products report dependence symptoms such as craving for tobacco. C1 [Rostron, Brian L.; Schroeder, Megan J.; Ambrose, Bridget K.] US FDA, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Rostron, BL (reprint author), US FDA, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM brian.rostron@fda.hhs.gov NR 33 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD AUG 18 PY 2016 VL 16 AR 814 DI 10.1186/s12889-016-3510-2 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DT5VN UT WOS:000381551300001 PM 27538489 ER PT J AU Chen, YL Reese, DH AF Chen, Yanling Reese, David H. TI Disruption of Retinol (Vitamin A) Signaling by Phthalate Esters: SAR and Mechanism Studies SO PLOS ONE LA English DT Article ID MALE REPRODUCTIVE DEVELOPMENT; HOMOZYGOUS HOXA1 MUTATIONS; MALE-RAT; SEXUAL-DIFFERENTIATION; EXTERNAL GENITALIA; ACID BIOSYNTHESIS; AXIAL SKELETON; IN-UTERO; EXPRESSION; EXPOSURE AB A spectrum of reproductive system anomalies (cryptorchidism, hypospadias, dysgenesis of Wolffian duct-derived tissues and prostate, and reduced sperm production) in male rats exposed in utero to phthalate esters (PEs) are thought to be caused by PE inhibition of fetal testosterone production. Recently, dibutyl and dipentyl phthalate (DBuP, DPnP) were shown to disrupt the retinol signaling pathway (RSP) in mouse pluripotent P19 embryonal carcinoma cells in vitro. The RSP regulates the synthesis and cellular levels of retinoic acid (RA), the active metabolite of retinol (vitamin A). In this new study, a total of 26 di- and mono-esters were screened to identify additional phthalate structures that disrupt the RSP and explore their mechanisms of action. The most potent PEs, those causing >50% inhibition, contained aryl and cycloalkane groups or C4-C6 alkyl ester chains and were the same PEs reported to cause malformations in utero. They shared similar lipid solubility; logP values were between 4 and 6 and, except for PEs with butyl and phenyl groups, were stable for prolonged periods in culture. Mono-and cognate di-esters varied in ability to disrupt the RSP; e.g., DEHP was inactive but its monoester was active while DBuP was active yet its monoester was inactive. DBuP and dibenzyl phthalate both disrupted the synthesis of RA from retinol but not the ability of RA to activate gene transcription. Both PEs also disrupted the RSP in C3H10T1/2 multipotent mesenchymal stem cells. Based on this in vitro study showing that some PEs disrupt retinol signaling and previous in vivo studies that vitamin A/RA deficiency and PEs both cause strikingly similar anomalies in the male rat reproductive system, we propose that PE-mediated inhibition of testosterone and RA synthesis in utero are both causes of malformations in male rat offspring. C1 [Chen, Yanling; Reese, David H.] US FDA, Div Mol Biol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, 8301 Muirkirk Rd, Laurel, MD 20708 USA. RP Reese, DH (reprint author), US FDA, Div Mol Biol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM dhreeseret@gmail.com NR 56 TC 0 Z9 0 U1 11 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 17 PY 2016 VL 11 IS 8 AR e0161167 DI 10.1371/journal.pone.0161167 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT4YN UT WOS:000381487600069 ER PT J AU Wang, J He, PJ Gaida, M Yang, SH Schetter, AJ Gaedcke, J Ghadimi, BM Ried, T Yfantis, H Lee, D Weiss, JM Stauffer, J Hanna, N Alexander, HR Hussain, SP AF Wang, Jian He, Peijun Gaida, Matthias Yang, Shouhui Schetter, Aaron J. Gaedcke, Jochen Ghadimi, B. Michael Ried, Thomas Yfantis, Harris Lee, Dong Weiss, Jonathan M. Stauffer, Jimmy Hanna, Nader Alexander, H. Richard Hussain, S. Perwez TI Inducible nitric oxide synthase enhances disease aggressiveness in pancreatic cancer SO ONCOTARGET LA English DT Article DE NOS2; NO; PDAC; KPC mouse model ID FORKHEAD TRANSCRIPTION FACTOR; DUCTAL ADENOCARCINOMA; BREAST-CANCER; INFLAMMATION; SURVIVAL; TUMORIGENESIS; INVASION; GROWTH; FOXOS; CELLS AB Pancreatic cancer is one of the most lethal malignancies and is refractory to the available treatments. Pancreatic ductal adenocarcinoma (PDAC) expresses high level of inducible nitric oxide synthase (NOS2), which causes sustained production of nitric oxide (NO). We tested the hypothesis that an aberrantly increased NO-release enhances the development and progression of PDAC. Enhanced NOS2 expression in tumors significantly associated with poor survival in PDAC patients (N = 107) with validation in independent cohorts. We then genetically targeted NOS2 in an autochthonous mouse model of PDAC to examine the effect of NOS2-deficiency on disease progression and survival. Genetic ablation of NOS2 significantly prolonged survival and reduced tumor severity in LSL-Kras(G12D/+); LSL-Trp53(R172H/+); Pdx-1-Cre (KPC) mice. Primary tumor cells isolated from NOS2-deficient KPC (NKPC) mice showed decreased proliferation and invasiveness as compared to those from KPC mice. Furthermore, NKPC tumors showed reduced expression of pERK, a diminished inactivation of Forkhead box transcription factor O (FOXO3), a tumor suppressor, and a decrease in the expression of oncomir-21, when compared with tumors in KPC mice. Taken together, these findings showed that NOS2 is a predictor of prognosis in early stage, resected PDAC patients, and provide proof-of-principle that targeting NOS2 may have potential therapeutic value in this lethal malignancy. C1 [Wang, Jian; He, Peijun; Yang, Shouhui; Hussain, S. Perwez] NCI, Pancreat Canc Unit, Human Carcinogenesis Lab, CCR, Bethesda, MD 20892 USA. [Gaida, Matthias] Univ Heidelberg Hosp, Inst Pathol, Heidelberg, Germany. [Schetter, Aaron J.] US FDA, Silver Spring, MD USA. [Gaedcke, Jochen; Ghadimi, B. Michael] Univ Med, Dept Gen Visceral & Pediat Surg, Gottingen, Germany. [Ried, Thomas] NCI, Genet Branch, CCR, Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. [Yfantis, Harris; Lee, Dong] Baltimore Vet Affairs Med Ctr, Pathol & Lab Med, Baltimore, MD USA. [Weiss, Jonathan M.] NCI, Canc & Inflammat Program, CCR, Frederick, MD 21701 USA. [Stauffer, Jimmy] NCI, Lab Cell & Dev Signaling, Frederick, MD 21701 USA. [Hanna, Nader; Alexander, H. Richard] Univ Maryland, Sch Med, Div Surg Oncol, Baltimore, MD 21201 USA. RP Hussain, SP (reprint author), NCI, Pancreat Canc Unit, Human Carcinogenesis Lab, CCR, Bethesda, MD 20892 USA. EM hussainp@mail.nih.gov FU Intramural Research Program of Center for Cancer Research, National Cancer Institute, NIH FX Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 45 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD AUG 16 PY 2016 VL 7 IS 33 BP 52993 EP 53004 DI 10.18632/oncotarget.10323 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY9DG UT WOS:000385433000029 PM 27367029 ER PT J AU Parnell, CM Chhetri, B Brandt, A Watanabe, F Nima, ZA Mudalige, TK Biris, AS Ghosh, A AF Parnell, Charlette M. Chhetri, Bijay Brandt, Andrew Watanabe, Fumiya Nima, Zeid A. Mudalige, Thilak K. Biris, Alexandru S. Ghosh, Anindya TI Polydopamine-Coated Manganese Complex/Graphene Nanocomposite for Enhanced Electrocatalytic Activity Towards Oxygen Reduction SO SCIENTIFIC REPORTS LA English DT Article ID NITROGEN-DOPED GRAPHENE; CYTOCHROME-C-OXIDASE; CARBON NANOTUBES; EFFICIENT ELECTROCATALYST; FUEL-CELLS; IRON; COMPLEXES; CATALYST; NANOPARTICLES; PORPHYRINS AB Platinum electrodes are commonly used electrocatalysts for oxygen reduction reactions (ORR) in fuel cells. However, this material is not economical due to its high cost and scarcity. We prepared an Mn(III) catalyst supported on graphene and further coated with polydopamine, resulting in superior ORR activity compared to the uncoated PDA structures. During ORR, a peak potential at 0.433 V was recorded, which is a significant shift compared to the uncoated material's -0.303 V (both versus SHE). All the materials reduced oxygen in a wide pH range via a four-electron pathway. Rotating disk electrode and rotating ring disk electrode studies of the polydopamine-coated material revealed ORR occurring via 4.14 and 4.00 electrons, respectively. A rate constant of 6.33 x 10(6) mol(-1)s(-1) was observed for the polydopamine-coated material-over 4.5 times greater than the uncoated nanocomposite and superior to those reported for similar carbon-supported metal catalysts. Simply integrating an inexpensive bioinspired polymer coating onto the Mn-graphene nanocomposite increased ORR performance significantly, with a peak potential shift of over + 730 mV. This indicates that the material can reduce oxygen at a higher rate but with lower energy usage, revealing its excellent potential as an ORR electrocatalyst in fuel cells. C1 [Parnell, Charlette M.; Watanabe, Fumiya; Nima, Zeid A.; Biris, Alexandru S.] Univ Arkansas, Ctr Integrat Nanotechnol Sci, 2801 South Univ Ave, Little Rock, AR 72204 USA. [Chhetri, Bijay; Brandt, Andrew; Ghosh, Anindya] Univ Arkansas, Dept Chem, 2801 South Univ Ave, Little Rock, AR 72204 USA. [Mudalige, Thilak K.] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Ghosh, A (reprint author), Univ Arkansas, Dept Chem, 2801 South Univ Ave, Little Rock, AR 72204 USA. EM axghosh@ualr.edu FU National Science Foundation [CHE-1229149]; Center for Advanced Surface Engineering, under the National Science Foundation [IIA-1457888]; Arkansas EPSCoR Program, ASSET III FX A.G. and A.B. would like to thank National Science Foundation (Grant CHE-1229149) major research instrument grant, which provided the necessary equipment to complete this work. Funding for this research was provided by the Center for Advanced Surface Engineering, under the National Science Foundation Grant No. IIA-1457888 and the Arkansas EPSCoR Program, ASSET III. NR 60 TC 0 Z9 0 U1 50 U2 67 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 AUG 16 PY 2016 VL 6 AR 31415 DI 10.1038/srep31415 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5DP UT WOS:000381501400001 PM 27528439 ER PT J AU Califf, RM AF Califf, Robert M. TI The US Food and Drug Administration and Cardiovascular Medicine Reflections and Observations SO CIRCULATION LA English DT Editorial Material DE evidence-based medicine; government regulation; public health; US Food and Drug Administration C1 [Califf, Robert M.] US FDA, Silver Spring, MD 20993 USA. RP Califf, RM (reprint author), US FDA, Silver Spring, MD 20993 USA. EM Robert.califf@fda.hhs.gov NR 4 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD AUG 16 PY 2016 VL 134 IS 7 BP 501 EP 503 DI 10.1161/CIRCULATIONAHA.116.022137 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DU5XC UT WOS:000382286000004 PM 27528644 ER PT J AU Califf, RM AF Califf, Robert M. TI The Future of Cardiovascular Medicine From the Regulatory Perspective SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material ID AMERICAN-COLLEGE; GUIDELINES C1 [Califf, Robert M.] US FDA, Silver Spring, MD USA. [Califf, Robert M.] US FDA, Food & Drugs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Califf, RM (reprint author), US FDA, Food & Drugs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Robert.califf@fda.hhs.gov NR 13 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 16 PY 2016 VL 68 IS 7 BP 766 EP 769 DI 10.1016/j.jacc.2016.07.001 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DT1XQ UT WOS:000381275800014 PM 27515338 ER PT J AU Tian, Y Mollo, SB Harrington, LE Zajac, AJ AF Tian, Yuan Mollo, Sarah B. Harrington, Laurie E. Zajac, Allan J. TI IL-10 Regulates Memory T Cell Development and the Balance between Th1 and Follicular Th Cell Responses during an Acute Viral Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LYMPHOCYTIC CHORIOMENINGITIS VIRUS; GERMINAL CENTER; SECONDARY RESPONSES; PLASMA-CELLS; IN-VITRO; B-CELLS; HELPER; INTERLEUKIN-10; CD8; EFFECTOR AB T cells provide protective immunity against infections by differentiating into effector cells that contribute to rapid pathogen control and by forming memory populations that survive over time and confer long-term protection. Thus, understanding the factors that regulate the development of effective T cell responses is beneficial for the design of vaccines and immune-based therapies against infectious diseases. Cytokines play important roles in shaping T cell responses, and IL-10 has been shown to modulate the differentiation of CD4 and CD8 T cells. In this study, we report that IL-10 functions in a cell-extrinsic manner early following acute lymphocytic choriomeningitis virus infection to suppress the magnitude of effector Th1 responses as well as the generation of memory CD4 and CD8 T cells. We further demonstrate that the blockade of IL-10 signaling during the priming phase refines the functional quality of memory CD4 and CD8 T cells. This inhibition strategy resulted in a lower frequency of virus-specific follicular Th (Tfh) cells and increased the Th1 to Tfh ratio. Nevertheless, neither germinal center B cells nor lymphocytic choriomeningitis virus-specific Ab levels were influenced by the blockade. Thus, our studies show that IL-10 influences the balance between Th1 and Tfh cell differentiation and negatively regulates the development of functionally mature memory T cells. C1 [Tian, Yuan; Zajac, Allan J.] Univ Alabama Birmingham, Dept Microbiol, 845 19th St South,BBRB 446,Box 23, Birmingham, AL 35294 USA. [Mollo, Sarah B.; Harrington, Laurie E.] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL 35294 USA. [Mollo, Sarah B.] US FDA, Silver Spring, MD USA. RP Zajac, AJ (reprint author), Univ Alabama Birmingham, Dept Microbiol, 845 19th St South,BBRB 446,Box 23, Birmingham, AL 35294 USA. EM azajac@uab.edu FU NIAID NIH HHS [T32 AI007051, U19 AI109962, R01 AI113007, R56 AI049360, R01 AI049360]; NIDDK NIH HHS [R01 DK084082] NR 46 TC 1 Z9 2 U1 0 U2 0 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 AUG 15 PY 2016 VL 197 IS 4 BP 1308 EP 1321 DI 10.4049/jimmunol.1502481 PG 14 WC Immunology SC Immunology GA DY3NB UT WOS:000384999100030 PM 27402701 ER PT J AU Cox, E Cavaleri, M Eichler, HG Woodcock, J Borio, L AF Cox, Edward Cavaleri, Marco Eichler, Hans-Georg Woodcock, Janet Borio, Luciana TI Facilitating Antibacterial Drug Development in a Time of Great Need SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE antibacterial drug; development; public health AB The continued development of new antibacterial drugs is critical to meet patient and public health needs. In this editorial, authors from the US Food and Drug Administration and European Medicines Agency reflect on the role of public-private partnerships and the development of clinical trials networks as agents to guide and perform quality studies of antibacterial drugs. C1 [Cox, Edward; Woodcock, Janet; Borio, Luciana] US FDA, Silver Spring, MD USA. [Cavaleri, Marco; Eichler, Hans-Georg] European Med Agcy, London, England. RP Cox, E (reprint author), US FDA, Off Antimicrobial Prod, 10903 New Hampshire Ave,Bldg 22,Rm 6212, Silver Spring, MD 20993 USA. EM edward.cox@fda.hhs.gov FU Clinical Trials Transformation Initiative FX This article appears as part of the supplement "Facilitating Antibacterial Drug Development in a Time of Great Need," sponsored by the Clinical Trials Transformation Initiative. NR 5 TC 2 Z9 2 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2016 VL 63 SU 2 BP S27 EP S28 DI 10.1093/cid/ciw257 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DV8QX UT WOS:000383202700002 PM 27481949 ER PT J AU Donnelly, H Alemayehu, D Botgros, R Comic-Savic, S Eisenstein, B Lorenz, B Merchant, K Pelfrene, E Reith, C Santiago, J Tiernan, R Wunderink, R Tenaerts, P Knirsch, C AF Donnelly, Helen Alemayehu, Demissie Botgros, Radu Comic-Savic, Sabrina Eisenstein, Barry Lorenz, Benjamin Merchant, Kunal Pelfrene, Eric Reith, Christina Santiago, Jonas Tiernan, Rosemary Wunderink, Richard Tenaerts, Pamela Knirsch, Charles TI Streamlining Safety Data Collection in Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia Trials: Recommendations of the Clinical Trials Transformation Initiative Antibacterial Drug Development Project Team SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE hospital-acquired bacterial pneumonia; ventilator-associated bacterial pneumonia; data collection; clinical trials; CTTI ID GRAM-NEGATIVE BACILLI AB Background. Resistant bacteria are one of the leading causes of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). HABP/VABP trials are complex and difficult to conduct due to the large number of medical procedures, adverse events, and concomitant medications involved. Differences in the legislative frameworks between different regions of the world may also lead to excessive data collection. The Clinical Trials Transformation Initiative (CTTI) seeks to advance antibacterial drug development (ABDD) by streamlining clinical trials to improve efficiency and feasibility while maintaining ethical rigor, patient safety, information value, and scientific validity. Methods.aEuro integral In 2013, CTTI engaged a multidisciplinary group of experts to discuss challenges impeding the conduct of HABP/VABP trials. Separate workstreams identified challenges associated with current data collection processes. Experts defined "data collection" as the act of capturing and reporting certain data on the case report form as opposed to recording of data as part of routine clinical care. The ABDD Project Team developed strategies for streamlining safety data collection in HABP/VABP trials using a Quality by Design approach. Results.aEuro integral Current safety data collection processes in HABP/VABP trials often include extraneous information. More targeted strategies for safety data collection in HABP/VABP trials will rely on optimal protocol design and prespecification of which safety data are essential to satisfy regulatory reporting requirements. Conclusions.aEuro integral A consensus and a cultural change in clinical trial design and conduct, which involve recognition of the need for more efficient data collection, are urgently needed to advance ABDD and to improve HABP/VABP trials in particular. C1 [Donnelly, Helen; Wunderink, Richard] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Alemayehu, Demissie] Pfizer Inc, New York, NY USA. [Botgros, Radu; Pelfrene, Eric] European Med Agcy, Off Antiinfect & Vaccines, London, England. [Comic-Savic, Sabrina] Medicines Co, Parsippany, NJ USA. [Eisenstein, Barry] Merck & Co Inc, Kenilworth, NJ USA. [Lorenz, Benjamin; Santiago, Jonas; Tiernan, Rosemary] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Merchant, Kunal] RRD Int LLC, Rockville, MD USA. [Reith, Christina] Univ Oxford, Oxford OX1 2JD, England. [Tenaerts, Pamela] Clin Trials Transformat Initiat, Durham, NC USA. [Knirsch, Charles] Pfizer Inc, Pearl River, NY USA. RP Knirsch, C (reprint author), Pfizer Vaccines Clin Res, 401 N Middletown Rd, Pearl River, NY 10965 USA. EM charles.knirsch@pfizer.com OI Wunderink, Richard/0000-0002-8527-4195 FU US Food and Drug Administration [R18FD005292, U19FD003800]; CTTI's member organizations FX This work was supported by the US Food and Drug Administration (grant number R18FD005292 and cooperative agreement number U19FD003800). Partial funding was also provided by pooled membership fees from CTTI's member organizations. NR 39 TC 2 Z9 2 U1 3 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2016 VL 63 SU 2 BP S39 EP S45 DI 10.1093/cid/ciw316 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DV8QX UT WOS:000383202700005 PM 27481952 ER PT J AU Knirsch, C Alemayehu, D Botgros, R Comic-Savic, S Friedland, D Holland, TL Merchant, K Noel, GJ Pelfrene, E Reith, C Santiago, J Tiernan, R Tenearts, P Goldsack, JC Fowler, VG AF Knirsch, Charles Alemayehu, Demissie Botgros, Radu Comic-Savic, Sabrina Friedland, David Holland, Thomas L. Merchant, Kunal Noel, Gary J. Pelfrene, Eric Reith, Christina Santiago, Jonas Tiernan, Rosemary Tenearts, Pamela Goldsack, Jennifer C. Fowler, Vance G., Jr. TI Improving Conduct and Feasibility of Clinical Trials to Evaluate Antibacterial Drugs to Treat Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Recommendations of the Clinical Trials Transformation Initiative Antibacterial Drug Development Project Team SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE hospital-acquired bacterial pneumonia; ventilator-associated bacterial pneumonia; protocol development; clinical trials; CTTI ID MULTICENTER; FUTURE; DESIGN AB Background. The etiology of hospital-acquired or ventilator-associated bacterial pneumonia ( HABP/VABP) is often multidrugresistant infections. The evaluation of new antibacterial drugs for efficacy in this population is important, as many antibacterial drugs have demonstrated limitations when studied in this population. HABP/VABP trials are expensive and challenging to conduct due to protocol complexity and low patient enrollment, among other factors. The Clinical Trials Transformation Initiative ( CTTI) seeks to advance antibacterial drug development by streamlining HABP/VABP clinical trials to improve efficiency and feasibility while maintaining ethical rigor, patient safety, information value, and scientific validity. Methods.aEuro integral In 2013, CTTI engaged a multidisciplinary group of experts to discuss challenges impeding the conduct of HABP/VABP trials. Separate workstreams identified challenges associated with HABP/VABP protocol complexity. The Project Team developed potential solutions to streamline HABP/VABP trials using a Quality by Design approach. Results.aEuro integral CTTI recommendations focus on 4 key areas to improve HABP/VABP trials: informed consent processes/practices, protocol design, choice of an institutional review board (IRB), and trial outcomes. Informed consent processes should include legally authorized representatives. Protocol design decisions should focus on eligibility criteria, prestudy antibacterial therapy considerations, use of new diagnostics, and sample size. CTTI recommends that sponsors use a central IRB and discuss trial endpoints with regulators, including defining a clinical failure and evaluating the impact of concomitant antibacterial drugs. Conclusions.aEuro integral Streamlining HABP/VABP trials by addressing key protocol elements can improve trial startup and patient recruitment/retention, reduce trial complexity and costs, and ensure patient safety while advancing antibacterial drug development. C1 [Knirsch, Charles; Alemayehu, Demissie] Pfizer Inc, New York, NY USA. [Botgros, Radu; Pelfrene, Eric] European Med Agcy, Off Antiinfect & Vaccines, London, England. [Comic-Savic, Sabrina] Medicines Co, Parsippany, NJ USA. [Friedland, David] Wockhardt USA, Parsippany, NJ USA. [Holland, Thomas L.; Fowler, Vance G., Jr.] Duke Univ, Durham, NC USA. [Merchant, Kunal] RRD Int LLC, Rockville, MD USA. [Noel, Gary J.] Johnson & Johnson, Raritan, NJ USA. [Reith, Christina] Univ Oxford, Oxford OX1 2JD, England. [Santiago, Jonas; Tiernan, Rosemary] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Tenearts, Pamela; Goldsack, Jennifer C.] Clin Trials Transformat Initiat, Durham, NC USA. RP Fowler, VG (reprint author), Duke Univ, Med Ctr, Hanes Bldg Rm 153,POB 102359, Durham, NC 27710 USA. EM vance.fowler@duke.edu FU Food and Drug Administration [R18FD005292, U19FD003800]; CTTI's member organizations FX This work was supported by the Food and Drug Administration (grant number R18FD005292 and cooperative agreement U19FD003800). Partial funding was also provided by pooled membership fees from CTTI's member organizations. NR 39 TC 4 Z9 4 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2016 VL 63 SU 2 BP S29 EP S36 DI 10.1093/cid/ciw258 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DV8QX UT WOS:000383202700003 PM 27481950 ER PT J AU Toerner, JG Rubin, D AF Toerner, Joseph G. Rubin, Daniel TI Advancing New Antibacterial Drug Development for Treatment of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE hospital-acquired pneumonia; ventilator-associated pneumonia; antibacterial drug; clinical trial ID CLINICAL-TRIALS AB The Clinical Trials Transformation Initiative (CTTI), a public-private partnership comprised of representatives from academia, the pharmaceutical industry, and the federal government including the US Food and Drug Administration, formed a group working toward a common goal of intensified research to facilitate the development of new antibacterial drug therapies for treatment of hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP). The summary of the CTTI HABP/VABP project in this supplement of Clinical Infectious Diseases is a first step in this direction. C1 [Toerner, Joseph G.; Rubin, Daniel] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Toerner, JG (reprint author), US FDA, Div Antiinfect Prod, OMPT, CDER,Off New Drugs, White Oak Bldg 22 Rm 6244,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM joseph.toerner@fda.hhs.gov FU Clinical Trials Transformation Initiative FX This article appears as part of the supplement "Facilitating Antibacterial Drug Development in a Time of Great Need," sponsored by the Clinical Trials Transformation Initiative. NR 5 TC 1 Z9 1 U1 3 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2016 VL 63 SU 2 BP S37 EP S38 DI 10.1093/cid/ciw315 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DV8QX UT WOS:000383202700004 PM 27481951 ER PT J AU Xie, YDL Chen, RY Sereti, I Zerbe, CS Holland, SM Browne, SK AF Xie, Yingda L. Chen, Ray Y. Sereti, Irini Zerbe, Christa S. Holland, Steven M. Browne, Sarah K. TI Neutralizing Anti-Interferon-Gamma Autoantibody Levels May Not Correlate With Clinical Course of Disease Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter C1 [Xie, Yingda L.; Chen, Ray Y.; Zerbe, Christa S.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sereti, Irini] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Browne, Sarah K.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Holland, SM (reprint author), CRC B3-4141 MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2016 VL 63 IS 4 BP 573 EP 574 DI 10.1093/cid/ciw352 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DV8QU UT WOS:000383202400026 PM 27225244 ER PT J AU Schmued, LC AF Schmued, Larry C. TI Development and application of novel histochemical tracers for localizing brain connectivity and pathology SO BRAIN RESEARCH LA English DT Review DE Axonal tract tracing; Axonal transport; Neuronal connectivity; Neuronal degeneration; Brain pathology; Neurotoxicants; Fluoro-Gold; Fluoro-Jade C ID NEURONAL DEGENERATION; FLUORO-JADE; RAT FOREBRAIN; LOCALIZATION; EXPOSURE; METHAMPHETAMINE; ANTEROGRADE; PROGRESSION; MYELIN AB The development of novel tracers and associated histochemical methods has always been need driven. One such need was the development of tracers that could be administered to discrete brain regions in vivo to subsequently reveal neuronal connectivity via axonal transport of the tracer. One such compound is Fluoro-Gold (F-G), which can be used to demonstrate retrograde axonal transport. Advantages of this fluorescent tracer include brightness, sensitivity, contrast, stability, permanence and compatibility with multiple labeling studies. It may be applied to resolve either the afferent or efferent connections of brain regions of interest. Another need addressed was for a simple and definitive way to localize degenerating neurons in brain tissue sections. This led to the development of Fluoro-Jade B (FJ-B) and Fluoro-Jade C (FJ-C). Advantages of these fluorescent histochemical tracers include high specificity, resolution, contrast, stability and suitability for use in multiple labeling studies. These methods can be applied to detect both apoptotic and necrotic neuronal degeneration following a variety of insults including physical trauma, neurodegenerative disease and a wide variety of neurotoxicants. This article is part of a Special Issue entitled SI:50th Anniversary Issue. (C) 2016 Published by Elsevier B.V. C1 [Schmued, Larry C.] US FDA, NCTR, Div Neurotoxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Schmued, LC (reprint author), US FDA, NCTR, Div Neurotoxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM larry.schmued@fda.hhs.gov NR 23 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD AUG 15 PY 2016 VL 1645 SI SI BP 31 EP 35 DI 10.1016/j.brainres.2016.03.053 PG 5 WC Neurosciences SC Neurosciences & Neurology GA DT5QJ UT WOS:000381537400011 PM 27155454 ER PT J AU Peer, CJ Strope, JD Beedie, S Ley, AM Holly, A Calis, K Farkas, R Parepally, J Men, A Fadiran, EO Scott, P Jenkins, M Theodore, WH Sissung, TM AF Peer, Cody J. Strope, Jonathan D. Beedie, Shaunna Ley, Ariel M. Holly, Alesia Calis, Karim Farkas, Ronald Parepally, Jagan Men, Angela Fadiran, Emmanuel O. Scott, Pamela Jenkins, Marjorie Theodore, William H. Sissung, Tristan M. TI Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats SO FRONTIERS IN PHARMACOLOGY LA English DT Article DE zolpidem; drug metabolism; pharmacokinetics; testosterone ID ETHANOL-METABOLISM; HUMAN LIVER; PHARMACOKINETICS; EXPRESSION; MECHANISM; GENDER; BRAIN; MUCOSA; ADULTS; AGE AB Objectives: The recommended zolpidem starting dose was lowered in females (5 mg vs. 10 mg) since side effects were more frequent and severe than those of males; the mechanism underlying sex differences in pharmacokinetics (PK) is unknown. We hypothesized that such differences were caused by known sex-related variability in alcohol dehydrogenase (ADH) expression. Methods: Male, female, and castrated male rats were administered 2.6 mg/kg zolpidem, +/- disulfiram (ADH/ALDH pathway inhibitor) to compare PK changes induced by sex and gonadal hormones. PK analyses were conducted in rat plasma and rat brain. Key findings: Sex differences in PK were evident: females had a higher C-MAX (112.4 vs. 68.1 ug/L) and AUG (537.8 vs. 231.8 h*ug/L) than uncastrated males. Castration induced an earlier T-MAX (0.25 vs. 1 h), greater C-MAX (109.1 vs. 68.1 ug/L), and a corresponding AUG increase (339.7 vs. 231.8 h*ug/L). Administration of disulfiram caused more drastic C-MAX and T-MAX changes in male vs. female rats that mirrored the effects of castration on first-pass metabolism, suggesting that the observed PK differences may be caused by ADH/ALDH expression. Brain concentrations paralleled plasma concentrations. Conclusion: These findings indicate that sex differences in zolpidem PK are influenced by variation in the expression of ADH/ALDH due to gonadal androgens. C1 [Peer, Cody J.; Sissung, Tristan M.] NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA. [Strope, Jonathan D.; Beedie, Shaunna; Ley, Ariel M.; Holly, Alesia] NCI, Mol Pharmacol Program, NIH, Bethesda, MD 20892 USA. [Calis, Karim] Food & Drug Adm, Ctr Drug Evaluat & Res, Off Med Policy, Silver Spring, MD USA. [Farkas, Ronald] Food & Drug Adm, Ctr Drug Evaluat & Res, Div Neurol Prod, Off New Drugs, Silver Spring, MD USA. [Parepally, Jagan; Men, Angela] Food & Drug Adm, Ctr Drug Evaluat & Res, Off Translat Sci, Off Clin Pharmacol, Silver Spring, MD USA. [Fadiran, Emmanuel O.; Scott, Pamela; Jenkins, Marjorie] Food & Drug Adm, Off Commissioner, Off Womens Hlth, Silver Spring, MD USA. [Theodore, William H.] NINDS, Clin Epilepsy Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Sissung, TM (reprint author), NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA. EM sissungt@mail.nih.gov FU National Cancer Institute (National Institutes of Health); Intramural Research Program of the NIH, National Cancer Institute; Office of Women's Health, Food, and Drug Administration; Food Drug Administration FX This project has been funded in whole or in part with federal funds from the National Cancer Institute (National Institutes of Health) and the Food Drug Administration. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, and the Office of Women's Health, Food, and Drug Administration. NR 44 TC 1 Z9 1 U1 3 U2 6 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 AUG 15 PY 2016 VL 7 AR 260 DI 10.3380/fphar.2016.00260 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DT2ZU UT WOS:000381351100001 PM 27574509 ER PT J AU Yakes, BJ Buijs, J Elliott, CT Campbell, K AF Yakes, B. J. Buijs, J. Elliott, C. T. Campbell, K. TI Surface plasmon resonance biosensing: Approaches for screening and characterising antibodies for food diagnostics SO TALANTA LA English DT Article DE Surface plasmon resonance; Antibody; Biosensor; Domoic acid; Marine toxin; Shellfish ID DOMOIC ACID; MONOCLONAL-ANTIBODY; OKADAIC ACID; SHELLFISH; CONTAMINATION; SEAFOOD; TOXINS; ASSAY; IMMUNOSENSOR; IMMUNOASSAY AB Research in biosensing approaches as alternative techniques for food diagnostics for the detection of chemical contaminants and foodborne pathogens has increased over the last twenty years. The key component of such tests is the biorecognition element whereby polyclonal or monoclonal antibodies still dominate the market. Traditionally the screening of sera or cell culture media for the selection of polyclonal or monoclonal candidate antibodies respectively has been performed by enzyme immunoassays. For niche toxin compounds, enzyme immunoassays can be expensive and/or prohibitive methodologies for antibody production due to limitations in toxin supply for conjugate production. Automated, self-regenerating, chip-based biosensors proven in food diagnostics may be utilised as rapid screening tools for antibody candidate selection. This work describes the use of both single channel and multi-channel surface plasmon resonance (SPR) biosensors for the selection and characterisation of antibodies, and their evaluation in shellfish tissue as standard techniques for the detection of domoic acid, as a model toxin compound. The key advantages in the use of these biosensor techniques for screening hybridomas in monoclonal antibody production were the real time observation of molecular interaction and rapid turnaround time in analysis compared to enzyme immunoassays. The multichannel prototype instrument was superior with 96 analyses completed in 2 h compared to 12 h for the single channel and over 24 h for the ELISA immunoassay. Antibodies of high sensitivity, IC50's ranging from 4.8 to 6.9 ng/mL for monoclonal and 2.3-6.0 ng/mL for polyclonal, for the detection of domoic acid in a 1 min analysis time were selected. Although there is a progression for biosensor technology towards low cost, multiplexed portable diagnostics for the food industry, there remains a place for laboratory-based SPR instrumentation for antibody development for food diagnostics as shown herein. (C) 2016 Elsevier B.V. All rights reserved. C1 [Yakes, B. J.] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Buijs, J.] GE Healthcare Biosci AB, Bjorkgatan 30, S-75184 Uppsala, Sweden. [Elliott, C. T.; Campbell, K.] Queens Univ Belfast, Sch Biol Sci, Inst Global Food Secur, David Keir Bldg,Stranmillis Rd, Belfast BT9 5AG, Antrim, North Ireland. [Buijs, J.] Uppsala Univ, Dept Radiol Oncol & Radiat Sci, Uppsala, Sweden. RP Campbell, K (reprint author), Queens Univ Belfast, Sch Biol Sci, Inst Global Food Secur, David Keir Bldg,Stranmillis Rd, Belfast BT9 5AG, Antrim, North Ireland. OI Buijs, Jos/0000-0003-3955-1320 FU European Commission [201724, 265409, 1210/101154811/A1]; European Sustainable Programme under the European Regional Development Fund ("ERDF"); InvestNI FX This research was funded in part by the European Commission through the FP7 European projects; MIDTAL, Grant no. 201724, MicroAqua, Grant no. 265409 and the Advanced ASSET Project, Grant no. 1210/101154811/A1, partly funded through InvestNI and from the European Sustainable Programme 2007-2013 under the European Regional Development Fund ("ERDF"). Thank you to Dr. Stacey DeGrasse for fruitful conversations and Stephen Conrad for maintaining the U.S. FDA/CFSAN seafood sample inventory and to Dr Shauna Devlin for assistance in the monoclonal antibody fusion procedure. NR 41 TC 0 Z9 0 U1 26 U2 53 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0039-9140 EI 1873-3573 J9 TALANTA JI Talanta PD AUG 15 PY 2016 VL 156 BP 55 EP 63 DI 10.1016/j.talanta.2016.05.008 PG 9 WC Chemistry, Analytical SC Chemistry GA DP0MC UT WOS:000378182900009 PM 27260435 ER PT J AU Zelmer, A Tanner, R Stylianou, E Damelang, T Morris, S Izzo, A Williams, A Sharpe, S Pepponi, I Walker, B Hokey, DA McShane, H Brennan, M Fletcher, H AF Zelmer, Andrea Tanner, Rachel Stylianou, Elena Damelang, Timon Morris, Sheldon Izzo, Angelo Williams, Ann Sharpe, Sally Pepponi, Ilaria Walker, Barry Hokey, David A. McShane, Helen Brennan, Michael Fletcher, Helen TI A new tool for tuberculosis vaccine screening: Ex vivo Mycobacterial Growth Inhibition Assay indicates BCG-mediated protection in a murine model of tuberculosis SO BMC INFECTIOUS DISEASES LA English DT Article DE Mycobacteria; Tuberculosis; Vaccines; Growth inhibition assay ID BOVIS BCG; INTERFERON-GAMMA; IMMUNE-RESPONSE; TB VACCINE; INFECTION; EFFICACY; CELLS; MICE AB Background: In the absence of a validated animal model and/or an immune correlate which predict vaccine-mediated protection, large-scale clinical trials are currently the only option to prove efficacy of new tuberculosis candidate vaccines. Tools to facilitate testing of new tuberculosis (TB) vaccines are therefore urgently needed. Methods: We present here an optimized ex vivo mycobacterial growth inhibition assay (MGIA) using a murine Mycobacterium tuberculosis infection model. This assay assesses the combined ability of host immune cells to inhibit mycobacterial growth in response to vaccination. C57BL/6 mice were immunized with Bacillus Calmette-Guerin (BCG) and growth inhibition of mycobacteria by splenocytes was assessed. Mice were also challenged with Mycobacterium tuberculosis Erdman, and bacterial burden was assessed in lungs and spleen. Results: Using the growth inhibition assay, we find a reduction in BCG CFU of 0.3-0.8 log10 after co-culture with murine splenocytes from BCG vaccinated versus naive C57BL/6 mice. BCG vaccination in our hands led to a reduction in bacterial burden after challenge with Mycobacterium tuberculosis of approx. 0.7 log10 CFU in lung and approx. 1 log10 CFU in spleen. This effect was also seen when using Mycobacterium smegmatis as the target of growth inhibition. An increase in mycobacterial numbers was found when splenocytes from interferon gamma-deficient mice were used, compared to wild type controls, indicating that immune mechanisms may also be investigated using this assay. Conclusions: We believe that the ex vivo mycobacterial growth inhibition assay could be a useful tool to help assess vaccine efficacy in future, alongside other established methods. It could also be a valuable tool for determination of underlying immune mechanisms. C1 [Zelmer, Andrea; Damelang, Timon; Fletcher, Helen] London Sch Hyg & Trop Med, London, England. [Tanner, Rachel; Stylianou, Elena; Pepponi, Ilaria; McShane, Helen] Univ Oxford, Jenner Inst, Oxford, England. [Morris, Sheldon] Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Izzo, Angelo] Colorado State Univ, Ft Collins, CO 80523 USA. [Williams, Ann; Sharpe, Sally] Publ Hlth England, Porton Down, England. [Sharpe, Sally] Anim & Plant Hlth Agcy, Weybridge, Surrey, England. [Pepponi, Ilaria; Walker, Barry; McShane, Helen] Aeras, Rockville, MD USA. [Pepponi, Ilaria] Natl Inst Infect Dis Lazzaro Spallanzani, Translat Res Unit, Rome, Italy. RP Zelmer, A (reprint author), London Sch Hyg & Trop Med, London, England. EM andrea.zelmer@lshtm.ac.uk RI APHA, Staff publications/E-6082-2010; Izzo, Angelo/F-1229-2017; OI Izzo, Angelo/0000-0003-3208-2330; Fletcher, Helen/0000-0002-0435-1006 FU Aeras; European Union Horizon2020 program [TBVAC2020] FX Funding for this work was provided by Aeras and the European Union Horizon2020 program (TBVAC2020). NR 20 TC 1 Z9 1 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD AUG 12 PY 2016 VL 16 AR 412 DI 10.1186/s12879-016-1751-4 PG 9 WC Infectious Diseases SC Infectious Diseases GA DT2YR UT WOS:000381348200005 PM 27519524 ER PT J AU Wong, JW Wang, J Kowalski, J AF Wong, Jon W. Wang, Jian Kowalski, Julie TI 52nd North American Chemical Residue Workshop SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Editorial Material C1 [Wong, Jon W.] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Wang, Jian] Canadian Food Inspect Agcy, Calgary Lab, 3650 36th St NW, Calgary, AB T2L 2L1, Canada. [Kowalski, Julie] Restek Corp, 110 Benner Circle, Bellefonte, PA 16823 USA. RP Wong, JW (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM jon.wong@fda.hhs.gov NR 1 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD AUG 10 PY 2016 VL 64 IS 31 BP 6059 EP 6060 DI 10.1021/acs.jafc.6b02741 PG 2 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA DT2TC UT WOS:000381332400001 PM 27441704 ER PT J AU Chen, Y Lopez, S Hayward, DG Park, HY Wong, JW Kim, SS Wan, J Reddy, RM Quinn, DJ Steiniger, D AF Chen, Yang Lopez, Salvador Hayward, Douglas G. Park, Hoon Yong Wong, Jon W. Kim, Suyon S. Wan, Jason Reddy, Ravinder M. Quinn, Daniel J. Steiniger, David TI Determination of Multiresidue Pesticides in Botanical Dietary Supplements Using Gas Chromatography-Triple-Quadrupole Mass Spectrometry (GC-MS/MS) SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article; Proceedings Paper CT 52nd North American Chemical Residue Workshop (NACRW) CY JUL 19-22, 2015 CL Flag Works Inc, St Pete Beach, FL HO Flag Works Inc DE multipesticide residue; botanicals; Carbon X/PSA; Carbon X/PSA/C18 SPE; dual-phase SPE; triple-phase SPE GC-MS/MS ID SOLID-PHASE EXTRACTION; LIQUID-CHROMATOGRAPHY; PIPER-NIGRUM; GINSENG ROOT; ORGANOCHLORINE PESTICIDES; QUECHERS; RESIDUES; CLEANUP; SAMPLES; FRUITS AB A simplified sample preparation method in combination with gas chromatography-triple-quadrupole mass spectrometry (GC-MS/MS) analysis was developed and validated for the simultaneous determination of 227 pesticides in green tea, ginseng, gingko leaves, saw palmetto, spearmint, and black pepper samples. The botanical samples were hydrated with water and extracted with acetonitrile, magnesium sulfate, and sodium chloride. The acetonitrile extract was cleaned up using solid phase extraction with carbon-coated alumina/primary secondary amine with or without C18. Recovery studies using matrix blanks fortified with pesticides at concentrations of 10, 25, 100, and 500 mu g/kg resulted in average recoveries of 70-99% and relative standard deviation of 5-13% for all tested botanicals except for black pepper, for which lower recoveries of fortified pesticides were observed. Matrix-matched standard calibration curves revealed good linearity (r(2) > 0.99) across a wide concentration range (1-1000 mu g/L). Nine commercially available tea and 23 ginseng samples were analyzed using this method. Results revealed 36 pesticides were detected in the 9 tea samples at concentrations of 2-3500 mu g/kg and 61 pesticides were detected in the 23 ginseng samples at concentrations of 1-12500 mu g/kg. C1 [Chen, Yang; Reddy, Ravinder M.] US FDA, Ctr Food Safety & Appl Nutr, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. [Lopez, Salvador; Wan, Jason] IIT, Inst Food Safety & Hlth, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. [Hayward, Douglas G.; Park, Hoon Yong; Wong, Jon W.; Kim, Suyon S.] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Quinn, Daniel J.; Steiniger, David] Thermo Fisher Sci, 2215 Grand Ave Pkwy, Austin, TX 78728 USA. RP Chen, Y (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 6502 South Archer Rd, Bedford Pk, IL 60501 USA.; Hayward, DG; Wong, JW (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM yang.chen@fda.hhs.gov; jon.wong@fda.hhs.gov; douglas.hayward@fda.hhs.gov NR 31 TC 0 Z9 0 U1 21 U2 31 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD AUG 10 PY 2016 VL 64 IS 31 BP 6125 EP 6132 DI 10.1021/acs.jafc.6b00746 PG 8 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA DT2TC UT WOS:000381332400008 PM 27101866 ER PT J AU Krutzke, L Prill, JM Engler, T Schmidt, CQ Xu, Z Byrnes, AP Simmet, T Kreppel, F AF Krutzke, L. Prill, J. M. Engler, T. Schmidt, C. Q. Xu, Z. Byrnes, A. P. Simmet, T. Kreppel, F. TI Substitution of blood coagulation factor X-binding to Ad5 by position-specific PEGylation: Preventing vector clearance and preserving infectivity SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Adenovirus; Blood coagulation factor X; PEG; Natural antibodies; Pharmacokinetics ID ADENOVIRUS TYPE 5; POLYMER-COATED ADENOVIRUS; GENE-TRANSFER; SCAVENGER RECEPTORS; KUPFFER CELLS; IN-VIVO; NEUTRALIZING ANTIBODIES; TRANSGENE EXPRESSION; CAPSID MODIFICATIONS; NATURAL ANTIBODIES AB The biodistribution of adenovirus type 5 (Ad5) vector particles is heavily influenced by interaction of the particles with plasma proteins, including coagulation factor X (FX), which binds specifically to the major Ad5 capsid protein hexon. FX mediates hepatocyte transduction by intravenously-injected Ad5 vectors and shields vector particles from neutralization by natural antibodies and complement. In mice, mutant Ad5 vectors that are ablated for FX-binding become detargeted from hepatocytes, which is desirable for certain applications, but unfortunately such FX-nonbinding vectors also become sensitive to neutralization by mouse plasma proteins. To improve the properties of Ad5 vectors for systemic delivery, we developed a strategy to replace the natural FX shield by a site-specific chemical polyethylene glycol shield. Coupling of polyethylene glycol to a specific site in hexon hypervariable region 1 yielded vector particles that were protected from neutralization by natural antibodies and complement although they were unable to bind FX. These vector particles evaded macrophages in vitro and showed significantly improved pharmacokinetics and hepatocyte transduction in vivo. Thus, site-specific shielding of Ad5 vectors with polyethylene glycol rendered vectors FX-independent and greatly improved their properties for systemic gene therapy. (C) 2016 The Authors. Published by Elsevier B.V. C1 [Krutzke, L.; Prill, J. M.; Engler, T.; Kreppel, F.] Univ Ulm, Dept Gene Therapy, Ulm, Germany. [Schmidt, C. Q.; Simmet, T.] Univ Ulm, Inst Pharmacol Nat Prod & Clin Pharmacol, Ulm, Germany. [Xu, Z.; Byrnes, A. P.] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Kreppel, F (reprint author), Univ Ulm, Dept Gene Therapy, Ulm, Germany. EM florian.kreppel@uni-ulm.de FU International Graduate School Ulm (IGradU, Excellence Initiative of the German Federal and State Governments); German Federal Ministry of Education and Research (BMBF, EXIST Forschungstransfer) [03EFEBW084]; German Federal Ministry of Education and Research (BMBF GO-Bio) [0315562] FX This work was supported by the International Graduate School Ulm (IGradU, Excellence Initiative of the German Federal and State Governments) and the German Federal Ministry of Education and Research (BMBF, EXIST Forschungstransfer, 03EFEBW084, BMBF GO-Bio 0315562). We thank Moritz Krutzke for design and realization of the graphical abstract. NR 53 TC 0 Z9 0 U1 14 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 EI 1873-4995 J9 J CONTROL RELEASE JI J. Control. Release PD AUG 10 PY 2016 VL 235 BP 379 EP 392 DI 10.1016/j.jconrel.2016.06.022 PG 14 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DR1ZF UT WOS:000379702700034 PM 27302248 ER PT J AU Mohan, N Shen, Y Dokmanovic, M Endo, Y Hirsch, DS Wu, WJ AF Mohan, Nishant Shen, Yi Dokmanovic, Milos Endo, Yukinori Hirsch, Dianne S. Wu, Wen Jin TI VPS34 regulates TSC1/TSC2 heterodimer to mediate RheB and mTORC1/S6K1 activation and cellular transformation SO ONCOTARGET LA English DT Article DE VPS34; TSC1/TSC2; RheB; mTORC1/S6K1; cellular transformation ID PROTEIN SORTING 34; PIK3CA GENE; PHOSPHATIDYLINOSITOL 3-PHOSPHATE; TRANSLATION INITIATION; INSULIN ACTIVATION; HIGH-FREQUENCY; DIRECT TARGET; S6 KINASE; TSC2; GROWTH AB VPS34 is reported to activate S6K1 and is implicated in regulating cell growth, the mechanisms of which remain elusive. Here, we describe novel mechanisms by which VPS34 upregulates mTOR/S6K1 activity via downregulating TSC2 protein and activating RheB activity. Specifically, upregulation of VPS34 lipid kinase increases local production of ptdins(3) p in the plasma membrane, which recruits PIKFYVE, a FYVE domain containing protein, to ptdins(3) p enriched regions of the plasma membrane, where VPS34 forms a protein complex with PIKFYVE and TSC1. This in turn disengages TSC2 from the TSC1/TSC2 heterodimer, leading to TSC2 ubiquitination and degradation. Downregulation of TSC2 promotes the activation of RheB and mTOR/S6K1. When VPS34 lipid kinase activity is increased by introduction of an H868R mutation, ptdins(3) p production at the plasma membrane is dramatically increased, which recruits more PIKFYVE and TSC1 molecules to the plasma membrane. This results in the enhanced TSC2 ubiquitination and degradation, and subsequent activation of RheB and mTORC1/S6K1, leading to oncogenic transformation. The role played by VPS34 in regulating mTOR/S6K1 activity and cellular transformation is underscored by the fact that the VPS34 kinase dead mutant blocks VPS34-induced recruitment of PIKFYVE and TSC1 to the plasma membrane. This study provides mechanistic insight into the cellular function of VPS34 in regulating oncogenic transformation and important indications for identifying VPS34 specific mutations in human cancers. C1 [Mohan, Nishant; Shen, Yi; Dokmanovic, Milos; Endo, Yukinori; Hirsch, Dianne S.; Wu, Wen Jin] US FDA, Div Biotechnol Review & Res 1, Off Biotechnol Prod, Off Pharmaceut Qual,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Wu, WJ (reprint author), US FDA, Div Biotechnol Review & Res 1, Off Biotechnol Prod, Off Pharmaceut Qual,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Wu@fda.hhs.gov NR 42 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD AUG 9 PY 2016 VL 7 IS 32 BP 52239 EP 52254 DI 10.18632/oncotarget.10469 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY9CC UT WOS:000385429100115 PM 27409169 ER PT J AU Huang, LY Stuart, C Takeda, K D'Agnillo, F Golding, B AF Huang, Li-Yun Stuart, Christine Takeda, Kazuyo D'Agnillo, Felice Golding, Basil TI Poly(I:C) Induces Human Lung Endothelial Barrier Dysfunction by Disrupting Tight Junction Expression of Claudin-5 SO PLOS ONE LA English DT Article ID DOUBLE-STRANDED-RNA; TOLL-LIKE RECEPTORS; VASCULAR-PERMEABILITY; VIRUS-INFECTION; ACTIVATION; CELLS; PATHOGENESIS; INNATE; INFLAMMATION; RECOGNITION AB Viral infections are often accompanied by pulmonary microvascular leakage and vascular endothelial dysfunction via mechanisms that are not completely defined. Here, we investigated the effect of the Toll-like receptor 3 (TLR3) ligand polyinosinic-polycytidylic acid [Poly(I:C)], a synthetic analog of viral double-stranded RNA (dsRNA) commonly used to simulate viral infections, on the barrier function and tight junction integrity of primary human lung microvascular endothelial cells. Poly(I: C) stimulated IL-6, IL-8, TNF alpha, and IFN beta production in conjunction with the activation of NF-kappa B and IRF3 confirming the Poly(I:C)-responsiveness of these cells. Poly(I:C) increased endothelial monolayer permeability with a corresponding dose-and time-dependent decrease in the expression of claudin-5, a transmembrane tight junction protein and reduction of CLDN5 mRNA levels. Immunofluorescence experiments revealed disappearance of membrane-associated claudin-5 and co-localization of cytoplasmic claudin-5 with lysosomal-associated membrane protein 1. Chloroquine and Bay11-7082, inhibitors of TLR3 and NF-kappa B signaling, respectively, protected against the loss of claudin-5. Together, these findings provide new insight on how dsRNA-activated signaling pathways may disrupt vascular endothelial function and contribute to vascular leakage pathologies. C1 [Huang, Li-Yun; Stuart, Christine; Golding, Basil] US FDA, Lab Plasma Derivat, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [D'Agnillo, Felice] US FDA, Lab Biochem & Vasc Biol, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Takeda, Kazuyo] US FDA, Microscopy & Imaging Core Facil, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Golding, B (reprint author), US FDA, Lab Plasma Derivat, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA.; D'Agnillo, F (reprint author), US FDA, Lab Biochem & Vasc Biol, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Felice.DAgnillo@fda.hhs.gov; Basil.Golding@fda.hhs.gov FU CBER Targeted Funds for Influenza Research FX This project was supported in part by CBER Targeted Funds for Influenza Research to B. Golding (2014-2015). This fund also supported the Research Fellowship Program appointment of CS at the Center for Biologics Evaluation and Research from 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 funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The findings and conclusions in this article have not been formally disseminated by the FDA and should not be construed to represent any agency determination or policy. NR 31 TC 1 Z9 1 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 9 PY 2016 VL 11 IS 8 AR e0160875 DI 10.1371/journal.pone.0160875 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT3IK UT WOS:000381374200071 PM 27504984 ER PT J AU Grajkowski, A Cieslak, J Beaucage, SL AF Grajkowski, Andrzej Cieslak, Jacek Beaucage, Serge L. TI Solid-Phase Purification of Synthetic DNA Sequences SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID OXIME BOND FORMATION; AFFINITY PURIFICATION; OLIGODEOXYNUCLEOTIDE PURIFICATION; BIOTINYLATION PHOSPHORAMIDITE; CHEMOSELECTIVE OXIME; POLYMER SUPPORT; OLIGONUCLEOTIDES; OLIGODEOXYRIBONUCLEOTIDES; RNA; DERIVATIZATION AB Although high-throughput methods for solid phase synthesis of DNA sequences are currently available for synthetic biology applications and technologies for large-scale production of nucleic acid-based drugs have been exploited for various therapeutic indications, little has been done to develop high-throughput procedures for the purification of synthetic nucleic acid sequences. An efficient process for purification of phosphorothioate and native DNA sequences is described herein. This process consists of functionalizing commercial aminopropylated silica gel with aminooxyalkyl functions to enable capture of DNA sequences carrying a 5'-siloxyl ether linker with a "keto" function through an oximation reaction. Deoxyribonucleoside phosphoramidites functionalized with the 5'-siloxyl ether linker were prepared in yields of 75-83% and incorporated last into the solid-phase assembly of DNA sequences. Capture of nucleobase- and phosphate-deprotected DNA sequences released from the synthesis support is demonstrated to proceed near quantitatively. After shorter than full-length DNA sequences were washed from the capture support, the purified DNA sequences were released from this support upon treatment with tetra-n-butylammonium fluoride in dry DMSO. The purity of released DNA sequences exceeds 98%. The scalability and high-throughput features of the purification profess are demonstrated without sacrificing purity of the DNA sequences. C1 [Grajkowski, Andrzej; Cieslak, Jacek; Beaucage, Serge L.] US FDA, Ctr Drug Evaluat & Res, Div Biotechnol Review & Res 4, Biol Chem Lab, 10903 New Hampshire Ave, Silver Spring, MD 20933 USA. RP Beaucage, SL (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Biotechnol Review & Res 4, Biol Chem Lab, 10903 New Hampshire Ave, Silver Spring, MD 20933 USA. EM serge.beaucage@fda.hhs.gov FU intramural FDA funds FX This work was supported by intramural FDA funds. NR 37 TC 0 Z9 0 U1 8 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD AUG 5 PY 2016 VL 81 IS 15 BP 6165 EP 6175 DI 10.1021/acs.joc.6b01020 PG 11 WC Chemistry, Organic SC Chemistry GA DT1IX UT WOS:000381236000002 PM 27382974 ER PT J AU Li, AP Zhang, J AF Li, Albert P. Zhang, Jie TI Editorial: Promising approaches to identify DILI drugs SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Editorial Material ID INDUCED LIVER-INJURY; RISK C1 [Li, Albert P.] Vitro ADMET Labs Inc, Columbia, MD USA. [Zhang, Jie] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Li, AP (reprint author), Vitro ADMET Labs Inc, Columbia, MD USA.; Zhang, J (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM liabert@invitroadmet.com; Jie.Zhang@fda.hhs.gov NR 14 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 EI 1872-7786 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD AUG 5 PY 2016 VL 255 SI SI BP 1 EP 2 DI 10.1016/j.cbi.2016.06.021 PG 2 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA DR7UN UT WOS:000380105300001 PM 27393768 ER PT J AU Zhang, J Doshi, U Suzuki, A Chang, CW Borlak, J Li, AP Tong, WD AF Zhang, Jie Doshi, Utkarsh Suzuki, Ayako Chang, Ching-Wei Borlak, Juergen Li, Albert P. Tong, Weida TI Evaluation of multiple mechanism-based toxicity endpoints in primary cultured human hepatocytes for the identification of drugs with clinical hepatotoxicity: Results from 152 marketed drugs with known liver injury profiles SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE Drug induced liver injury; Acute liver failure; Oxidative stress; In vitro toxicity testing; Human hepatocytes; Drug development ID REPORTING FREQUENCY; HEPATIC-METABOLISM; ORAL MEDICATIONS; ADVERSE EVENTS; VIGIBASE(TM); DETERMINANT; BIOMARKERS; RISK AB We report here the results of a collaborative research program to develop a robust and reliable in vitro system to allow an accurate definition of the drug-induced liver injury (DILI) potential of new drug entities during drug development. The in vitro hepatotoxic potential of 152 drugs with known DILI profiles were evaluated in primary cultured human hepatocytes with four mechanistically-relevant endpoints: cellular ATP depletion, reactive oxygen species (ROS), glutathione (GSH) depletion, and caspase activation for apoptosis. The drugs, 80 in the testing set and 72 in the validation set, were classified based on serious clinical/regulatory outcomes as defined by reported acute liver failure, black-box warning, and/or withdrawal. The drugs were further sub-categorized for dominant types of liver injury. Logistic regression models were performed to calculate the area under the receiver operating characteristics curve (AUROC) and to evaluate the prediction potential of the selected endpoints for serious clinical/regulatory outcomes. The ROS/ATP ratio was found to yield an excellent AUROC in both the testing (0.8989, P < 0.0001) and validation set (0.8545, P < 0.0001), and was found to distinguish drugs associated with severe from non-severe DILI cases (p < 0.0001). The results suggest that evaluation of drugs in primary human hepatocytes using the ROS/ATP ratio endpoint may aid the definition of their potential to cause severe DILI. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Zhang, Jie; Chang, Ching-Wei; Tong, Weida] NCTR FDA, Div Bioinformat & Biostat, Jefferson, AR USA. [Doshi, Utkarsh; Li, Albert P.] Vitro ADMET Labs LLC, Columbia, MD USA. [Suzuki, Ayako] Univ Arkansas Med Sci, Div Gastroenterol, Little Rock, AR USA. [Suzuki, Ayako] Cent Arkansas Vet Healthcare Syst, Little Rock, AR USA. [Borlak, Juergen] Hannover Med Sch, Ctr Pharmacol & Toxicol, Hannover, Germany. RP Li, AP (reprint author), 9221 Rumsey Rd,Suite 8, Columbia, MD 21045 USA.; Tong, WD (reprint author), 3900 NCTR Rd, Jefferson, AR 72079 USA. EM lialbert@invitroadmet.com; Weida.Tong@fda.hhs.gov FU German Federal Ministry for Education and Research as part of the Virtual Liver Network Initiative [031 6154]; ORISE stipend from the US Food and Drug Administration FX Jurgen Borlak is supported by the German Federal Ministry for Education and Research as part of the Virtual Liver Network Initiative (grant 031 6154). He is also a recipient of an ORISE stipend from the US Food and Drug Administration. We appreciated Ke Yu and Yuri An for collecting data from LiverTox, Minjun Chen and Qiang Shi for providing information on FDA Drug Labeling, Weigong Ge and Zhichao Liu for making the figures, and Mikyung Lee for analysis on Toxicogenomics Project data. We also thank Hong Fang and Reagan Kelly for comments and suggestions, and Yumiko LaForge for technical support on experiments. NR 36 TC 3 Z9 3 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 EI 1872-7786 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD AUG 5 PY 2016 VL 255 SI SI BP 3 EP 11 DI 10.1016/j.cbi.2015.11.008 PG 9 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA DR7UN UT WOS:000380105300002 PM 26581450 ER PT J AU Zhang, J He, K Cai, LN Chen, YC Yang, YF Shi, Q Woolf, TF Ge, WG Guo, L Borlak, J Tong, WD AF Zhang, Jie He, Kan Cai, Lining Chen, Yu-Chuan Yang, Yifan Shi, Qin Woolf, Thomas F. Ge, Weigong Guo, Lei Borlak, Juergen Tong, Weida TI Inhibition of bile salt transport by drugs associated with liver injury in primary hepatocytes from human, monkey, dog, rat, and mouse SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE Bile salt export pump; BSEP; ABCB11; Drug-induced liver injury; DILI; Bile salts; Hepatocytes; Species difference ID EXPORT PUMP; SPECIES-DIFFERENCES; CHOLESTASIS; ACID; EXPRESSION; HEPATOTOXICITY; DISPOSITION; MUTATIONS; BINDING; MRP2 AB Interference of bile salt transport is one of the underlying mechanisms for drug-induced liver injury (DILI). We developed a novel bile salt transport activity assay involving in situ biosynthesis of bile salts from their precursors in primary human, monkey, dog, rat, and mouse hepatocytes in suspension as well as LC-MS/MS determination of extracellular bile salts transported out of hepatocytes. Glycine-and taurine-conjugated bile acids were rapidly formed in hepatocytes and effectively transported into the extracellular medium. The bile salt formation and transport activities were time. and bile-acid-concentration. dependent in primary human hepatocytes. The transport activity was inhibited by the bile salt export pump (BSEP) inhibitors ketoconazole, saquinavir, cyclosporine, and troglitazone. The assay was used to test 86 drugs for their potential to inhibit bile salt transport activity in human hepatocytes, which included 35 drugs associated with severe DILI (sDILI) and 51 with non-severe DILI (non-sDILI). Approximately 60% of the sDILI drugs showed potent inhibition (with IC50 values <50 mu M), but only about 20% of the non-sDILI drugs showed this strength of inhibition in primary human hepatocytes and these drugs are associated only with cholestatic and mixed hepatocellular cholestatic (mixed) injuries. The sDILI drugs, which did not show substantial inhibition of bile salt transport activity, are likely to be associated with immune-mediated liver injury. Twenty-four drugs were also tested in monkey, dog, rat and mouse hepatocytes. Species differences in potency were observed with mouse being less sensitive than other species to inhibition of bile salt transport. In summary, a novel assay has been developed using hepatocytes in suspension from human and animal species that can be used to assess the potential for drugs and/or drug-derived metabolites to inhibit bile salt transport and/or formation activity. Drugs causing sDILI, except those by immune-mediated mechanism, are highly associated with potent inhibition of bile salt transport. Published by Elsevier Ireland Ltd. C1 [Zhang, Jie; Chen, Yu-Chuan; Ge, Weigong; Tong, Weida] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [He, Kan; Cai, Lining; Yang, Yifan; Shi, Qin; Woolf, Thomas F.] Biotranex LLC, Monmouth Jct, NJ 08852 USA. [Guo, Lei] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Borlak, Juergen] Hannover Med Sch, Ctr Pharmacol & Toxicol, Hannover, Germany. RP Zhang, J (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA.; He, K (reprint author), Biotranex LLC, Monmouth Jct, NJ 08852 USA. EM jie.zhang@fda.hhs.gov; khe@biotranex.com NR 38 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 EI 1872-7786 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD AUG 5 PY 2016 VL 255 SI SI BP 45 EP 54 DI 10.1016/j.cbi.2016.03.019 PG 10 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA DR7UN UT WOS:000380105300006 ER PT J AU Luo, Y Yang, X Shi, Q AF Luo, Yong Yang, Xi Shi, Qiang TI The cytochrome P450 inhibitor SKF-525A disrupts autophagy in primary rat hepatocytes SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE Autophagy; Hepatocyte; SKF-525A; Cytochrome P450; Hepatotoxicity ID METABOLISM; HEPATOTOXICITY; CYTOTOXICITY; LIVER; ACID; INVOLVEMENT; MICROSOMES; NECROSIS AB The cytochrome P450 (CYP) inhibitor SKF-525A is commonly used to study drug metabolism and toxicity, particularly hepatotoxicity. By using Western blot and immunofluorescence staining, we unexpectedly found that SKF-525A at 2-20 mu M caused remarkable accumulation of microtubule-associated protein light chain 3 II (LC3-II) in primary rat hepatocytes at 1, 4 and 24 h, indicating that autophagy was disrupted. SKF-525A showed no effects on chloroquine induced LC3-II accumulation, suggesting that autophagic flux was blocked, which is further supported by the increased level of the p62 protein after SKF-525A treatment. SKF-525A did not affect proteasome activities or gene expression of LC3-II or p62. Immunofluorescence of green fluorescent protein fused lysosomal-associated membrane protein 1 (LAMP1, a specific protein marker for lysosomes) and LC3-II showed that co-localization of these two proteins was partially abolished by SKF-525A, indicating that autophagosome-lysosome fusion was blocked. The other five CYP inhibitors, metyrapone, 1-aminobenzotriazole, alpha-naphthoflavone, ticlopidine, and ketoconazole, showed no effects in parallel experiments. These findings provide novel insights into the mechanisms by which various CYP inhibitors differentially affect a same drug's toxicity in hepatocytes. The data also indicate that SKF-525A is not an ideal chemical inhibitor for probing the relation between CYP mediated metabolism and toxicity in primary hepatocytes. Published by Elsevier Ireland Ltd. C1 [Luo, Yong; Yang, Xi; Shi, Qiang] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 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 FX This project was supported by the US FDA's Office of Women's Health. NR 27 TC 1 Z9 1 U1 6 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 EI 1872-7786 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD AUG 5 PY 2016 VL 255 SI SI BP 55 EP 62 DI 10.1016/j.cbi.2016.03.007 PG 8 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA DR7UN UT WOS:000380105300007 PM 26964495 ER PT J AU Xuan, JK Chen, S Ning, BT Tolleson, WH Guo, L AF Xuan, Jiekun Chen, Si Ning, Baitang Tolleson, William H. Guo, Lei TI Development of HepG2-derived cells expressing cytochrome P450s for assessing metabolism-associated drug-induced liver toxicity SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE Drug-induced liver toxicity; HepG2; Drug metabolizing enzyme; Cytochrome P450s ID INDUCED HEMOLYTIC-ANEMIA; HEPG2 CELLS; HUMAN HEPATOCYTES; INDUCED HEPATOTOXICITY; CHLORPROMAZINE METABOLITES; AMIODARONE HEPATOTOXICITY; ABSOLUTE BIOAVAILABILITY; PRIMAQUINE METABOLITES; REACTIVE METABOLITES; PLASMODIUM-VIVAX AB The generation of reactive metabolites from therapeutic agents is one of the major mechanisms of drug-induced liver injury (DILI). In order to evaluate metabolism-related toxicity and improve drug efficacy and safety, we generated a battery of HepG2-derived cell lines that express 14 cytochrome P450s (CYPs) (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5 and 3A7) individually using a lentiviral expression system. The expression/production of a specific CYP in each cell line was confirmed by an increased abundance of the CYP at both mRNA and protein levels. Moreover, the enzymatic activities of representative CYPs in the corresponding cell lines were also measured. Using our CYP-expressed HepG2 cells, the toxicity of three drugs that could induce DILI (amiodarone, chlorpromazine and primaquine) was assessed, and all of them showed altered (increased or decreased) toxicity compared to the toxicity in drug-treated wild-type HepG2 cells. CYP-mediated drug toxicity examined in our cell system is consistent with previous reports, demonstrating the potential of these cells for assessing metabolism-related drug toxicity. This cell system provides a practical in vitro approach for drug metabolism screening and for early detection of drug toxicity. It is also a surrogate enzyme source for the enzymatic characterization of a particular CYP that contributes to drug-induced liver toxicity. Published by Elsevier Ireland Ltd. C1 [Xuan, Jiekun; Chen, Si; Tolleson, William H.; Guo, Lei] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Ning, Baitang] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. RP Guo, L (reprint author), US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM Lei.Guo@fda.hhs.gov NR 94 TC 3 Z9 3 U1 10 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 EI 1872-7786 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD AUG 5 PY 2016 VL 255 SI SI BP 63 EP 73 DI 10.1016/j.cbi.2015.10.009 PG 11 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA DR7UN UT WOS:000380105300008 PM 26477383 ER PT J AU Yang, XY Yu, DK Ren, YL Wei, JY Pan, WT Zhou, CC Zhou, LQ Liu, Y Yang, M AF Yang, Xinyu Yu, Dianke Ren, Yanli Wei, Jinyu Pan, Wenting Zhou, Changchun Zhou, Liqing Liu, Yu Yang, Ming TI Integrative Functional Genomics Implicates EPB41 Dysregulation in Hepatocellular Carcinoma Risk SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID LONG-RANGE INTERACTION; CANCER-RISK; COLORECTAL-CANCER; MENINGIOMA PATHOGENESIS; MISSING HERITABILITY; TUMOR-SUPPRESSOR; LUNG-CANCER; MYC; EXPRESSION; SUSCEPTIBILITY AB Genome-wide association studies (GWASs) have provided many insights into cancer genetics. However, the molecular mechanisms of many susceptibility SNPs defined by GWASs in cancer heritability and in promoting cancer risk remain elusive. New research strategies, including functional evaluations, are warranted to systematically explore truly causal genetic variants. In this study, we developed an integrative functional genomics methodology to identify cancer susceptibility SNPs in transcription factor-binding sites across the whole genome. Employing integration of functional genomic data from c-Myc cistromics, 1000 Genomes, and the TRANSFAC matrix, we successfully annotated 12 SNPs present in the c-Myc cistrome with properties consistent with modulating c-Myc binding affinity in hepatocellular carcinoma (HCC). After genotyping these 12 SNPs in 1,806 HBV-related HCC case subjects and 1,708 control subjects, we identified a HCC susceptibility SNP, rs157224G>T, in Chinese populations (T allele: odds ratio = 1.64, 95% confidence interval = 1.322.02; p = 5.2 3 10(-6)). This polymorphism leads to HCC predisposition through modifying c-Myc-mediated transcriptional regulation of EPB41, with the risk rs157224T allele showing significantly decreased gene expression. Based on cell proliferation, wound healing, and transwell assays as well as the mouse xenograft model, we identify EPB41 as a HCC susceptibility gene in vitro and in vivo. Consistent with this notion, we note that EPB41 expression is significantly decreased in HCC tissue specimens, especially in portal vein metastasis or intrahepatic metastasis, compared to normal tissues. Our results highlight the involvement of regulatory genetic variants in HCC and provide pathogenic insights of this malignancy via a genome-wide approach. C1 [Yang, Xinyu; Yang, Ming] Shandong Univ, Shandong Acad Med Sci, Shandong Canc Hosp, Shandong Prov Key Lab Radiat Oncol,Canc Res Ctr, Jinan 250117, Shandong, Peoples R China. [Yang, Xinyu; Ren, Yanli; Wei, Jinyu; Pan, Wenting] Beijing Univ Chem Technol, Coll Life Sci & Technol, Beijing 100029, Peoples R China. [Yu, Dianke] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Zhou, Changchun] Shandong Acad Med Sci, Shandong Canc Hosp, Clin Lab, Jinan 250117, Shandong, Peoples R China. [Zhou, Liqing] Huaian 2 Hosp, Dept Radiat Oncol, Huaian 223002, Jiangsu, Peoples R China. [Liu, Yu] Chinese Acad Med Sci, Canc Hosp, Dept Etiol & Carcinogenesis, Beijing 100021, Peoples R China. RP Yang, M (reprint author), Shandong Univ, Shandong Acad Med Sci, Shandong Canc Hosp, Shandong Prov Key Lab Radiat Oncol,Canc Res Ctr, Jinan 250117, Shandong, Peoples R China. EM aaryoung@yeah.net RI Yang, Ming/G-4705-2012 OI Yang, Ming/0000-0002-7722-7487 FU National Natural Science Foundation of China [81201586, 31271382]; National High-Tech Research and Development Program of China [2015AA020950]; State Key Laboratory of Molecular Oncology [SKL-KF-2015-05] FX This work was supported by National Natural Science Foundation of China (81201586 and 31271382), the National High-Tech Research and Development Program of China (2015AA020950), and the open project of State Key Laboratory of Molecular Oncology (SKL-KF-2015-05). The authors would like to thank the many individuals who participated in the study. We thank Dr. Gwo-Shu Mary Lee of Dana-Farber Cancer Institute, Harvard Medical School for comments and for critically reading and English editing the manuscript. We also thank Dr. Yi-Ran Cai of the Department of Pathology, Beijing Chest Hospital, Capital Medical University for his assistance in tissue IHC analyses and Huaijin Zhang, Honglei Pu, Huijiuan Su, Jing Zhang, and Ling-chen Xiao for excellent technical support. NR 41 TC 0 Z9 0 U1 8 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG 4 PY 2016 VL 99 IS 2 BP 275 EP 286 DI 10.1016/j.ajhg.2016.05.029 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA DT6TO UT WOS:000381617200002 PM 27453575 ER PT J AU Zhao, WZ Chen, JJ Perkins, R Wang, YP Liu, ZC Hong, HX Tong, WD Zou, W AF Zhao, Weizhong Chen, James J. Perkins, Roger Wang, Yuping Liu, Zhichao Hong, Huixiao Tong, Weida Zou, Wen TI A novel procedure on next generation sequencing data analysis using text mining algorithm (vol 17, 213, 2016) SO BMC BIOINFORMATICS LA English DT Correction C1 [Zhao, Weizhong; Chen, James J.; Perkins, Roger; Wang, Yuping; Liu, Zhichao; Hong, Huixiao; Tong, Weida; Zou, Wen] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 20, Jefferson, AR 72079 USA. [Zhao, Weizhong] Xiangtan Univ, Coll Informat Engn, Xiangtan, Hunan, Peoples R China. RP Zou, W (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 20, Jefferson, AR 72079 USA. EM wen.zou@fda.hhs.gov NR 2 TC 0 Z9 0 U1 8 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD AUG 3 PY 2016 VL 17 AR 301 DI 10.1186/s12859-016-1156-9 PG 1 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DT0TX UT WOS:000381197000001 PM 27489012 ER PT J AU Sampson, UKA Kaplan, RM Cooper, RS Roux, AVD Marks, JS Engelgau, MM Peprah, E Mishoe, H Boulware, LE Felix, KL Califf, RM Flack, JM Cooper, LA Gracia, JN Henderson, JA Davidson, KW Krishnan, JA Lewis, TT Sanchez, E Luban, NL Vaccarino, V Wong, WF Wright, JT Meyers, D Ogedegbe, OG Presley-Cantrell, L Chambers, DA Belis, D Bennett, GC Boyington, JE Creazzo, TL de Jesus, JM Krishnamurti, C Lowden, MR Punturieri, A Shero, ST Young, NS Zou, S Mensah, GA AF Sampson, Uchechukwu K. A. Kaplan, Robert M. Cooper, Richard S. Roux, Ana V. Diez Marks, James S. Engelgau, Michael M. Peprah, Emmanuel Mishoe, Helena Boulware, L. Ebony Felix, Kaytura L. Califf, Robert M. Flack, John M. Cooper, Lisa A. Gracia, J. Nadine Henderson, Jeffrey A. Davidson, Karina W. Krishnan, Jerry A. Lewis, Tene T. Sanchez, Eduardo Luban, Naomi L. Vaccarino, Viola Wong, Winston F. Wright, Jackson T., Jr. Meyers, David Ogedegbe, Olugbenga G. Presley-Cantrell, Letitia Chambers, David A. Belis, Deshiree Bennett, Glen C. Boyington, Josephine E. Creazzo, Tony L. de Jesus, Janet M. Krishnamurti, Chitra Lowden, Mia R. Punturieri, Antonello Shero, Susan T. Young, Neal S. Zou, Shimian Mensah, George A. TI Reducing Health Inequities in the US Recommendations From the NHLBI's Health Inequities Think Tank Meeting SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE health information exchange; health policy; health services accessibility; social determinants of health; T4 research; translation research ID CHILDHOOD; DISPARITIES; DESIGN; ATHEROSCLEROSIS; IMPLEMENTATION; EXPERIENCES; PREVENTION; OBJECTIVES; ENGLAND; DISEASE AB The National, Heart, Lung, and Blood Institute convened a Think Tank meeting to obtain insight and recommendations regarding the objectives and design of the next generation of research aimed at reducing health inequities in the United States. The panel recommended several specific actions, including: 1) embrace broad and inclusive research themes; 2) develop research platforms that optimize the ability to conduct informative and innovative research, and promote systems science approaches; 3) develop networks of collaborators and stakeholders, and launch transformative studies that can serve as benchmarks; 4) optimize the use of new data sources, platforms, and natural experiments; and 5) develop unique transdisciplinary training programs to build research capacity. Confronting health inequities will require engaging multiple disciplines and sectors (including communities), using systems science, and intervening through combinations of individual, family, provider, health system, and community-targeted approaches. Details of the panel's remarks and recommendations are provided in this report. (C) 2016 by the American College of Cardiology Foundation. C1 [Sampson, Uchechukwu K. A.; Engelgau, Michael M.; Peprah, Emmanuel; Mishoe, Helena; Belis, Deshiree; Bennett, Glen C.; de Jesus, Janet M.; Krishnamurti, Chitra; Shero, Susan T.; Mensah, George A.] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Kaplan, Robert M.; Meyers, David] US Agcy Healthcare Res & Qual, Rockville, MD USA. [Cooper, Richard S.] Loyola Univ, Dept Publ Hlth, Chicago, IL 60611 USA. [Roux, Ana V. Diez] Drexel Univ, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Marks, James S.] Robert Wood Johnson Fdn, Princeton, NJ 08540 USA. [Boulware, L. Ebony] Duke Univ, Div Gen Internal Med, Durham, NC USA. [Felix, Kaytura L.] US Hlth Resources & Serv Adm, Rockville, MD 20857 USA. [Califf, Robert M.] US FDA, Off Med Prod & Tobacco, Silver Spring, MD USA. [Flack, John M.] Southern Illinois Univ, Dept Internal Med, Springfield, IL USA. [Cooper, Lisa A.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Gracia, J. Nadine] US Dept Hlth & Human Serv, Off Minor Hlth, Rockville, MD USA. [Henderson, Jeffrey A.] Black Hills Ctr Amer Indian Hlth, Rapid City, SD USA. [Davidson, Karina W.] Columbia Univ, Dept Med, Ctr Behav Cardiovasc Hlth, New York, NY USA. [Davidson, Karina W.] New York Presbyterian Hosp, Value Inst, New York, NY USA. [Krishnan, Jerry A.] Univ Illinois Hosp & Hlth Sci Syst, Chicago, IL USA. [Lewis, Tene T.; Vaccarino, Viola] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Sanchez, Eduardo] Amer Hlth Assoc, Dallas, TX USA. [Luban, Naomi L.] George Washington Univ, Sch Med, Dept Pediat, Washington, DC 20052 USA. [Wong, Winston F.] Kaiser Permanente, Los Angeles, CA USA. [Wright, Jackson T., Jr.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Ogedegbe, Olugbenga G.] NYU, Div Hlth Behav, New York, NY USA. [Presley-Cantrell, Letitia] Ctr Dis Control & Prevent, Div Heart Dis & Stroke Prevent, Atlanta, GA USA. [Chambers, David A.] NCI, NIH, Div Canc Control & Populat Sci, Rockville, MD USA. [Boyington, Josephine E.] NHLBI, NIH, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Creazzo, Tony L.] NHLBI, NIH, Div Extramural Res Activ, Bldg 10, Bethesda, MD 20892 USA. [Lowden, Mia R.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Punturieri, Antonello] NHLBI, NIH, Div Lung Dis, Bldg 10, Bethesda, MD 20892 USA. [Young, Neal S.] NHLBI, NIH, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Zou, Shimian] NHLBI, NIH, Div Blood Dis & Resources, Bldg 10, Bethesda, MD 20892 USA. RP Sampson, UKA (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. EM uchechukwu.sampson@nih.gov FU Medtronic; Bayer; GlaxoSmithKline FX The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, National Institutes of Health, or the U.S. Department of Health and Human Services. Dr. Flack has been a consultant for Medtronic, Back Beat Medical, Lundbeck, Forrest, Bayer, Sanofi, and Regeneron; and has received research grants from Medtronic, Bayer, and GlaxoSmithKline. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 25 TC 3 Z9 3 U1 7 U2 12 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 AUG 2 PY 2016 VL 68 IS 5 BP 517 EP 524 DI 10.1016/j.jacc.2016.04.059 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DR7VO UT WOS:000380108000012 PM 27470459 ER PT J AU Sharma, A Stevens, S Lucas, J Fiuzat, M Adams, KF Whellan, DJ Donahue, MP Kitzman, DW Pina, IL Zannad, F Kraus, WE O'Connor, CM Felker, GM AF Sharma, A. Stevens, S. Lucas, J. Fiuzat, M. Adams, K. F. Whellan, D. J. Donahue, M. P. Kitzman, D. W. Pina, I. L. Zannad, F. Kraus, W. E. O'Connor, C. M. Felker, G. M. TI Prognostic Utility of GDF-15 in Chronic Heart Failure: Insights From the HF-ACTION Study SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 27-31, 2016 CL Rome, ITALY SP European Soc Cardiol C1 [Sharma, A.; Stevens, S.; Lucas, J.; Felker, G. M.] Duke Clin Res Inst, Durham, NC USA. [Fiuzat, M.] US FDA, Washington, DC 20204 USA. [Adams, K. F.] Univ N Carolina, Chapel Hill, NC USA. [Whellan, D. J.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Donahue, M. P.; Kraus, W. E.] Duke Univ, Med Ctr, Durham, NC USA. [Kitzman, D. W.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Pina, I. L.] Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA. [Zannad, F.] Univ Lorraine, Nancy, France. [O'Connor, C. M.] Inova Heart & Vasc Inst, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG 1 PY 2016 VL 37 SU 1 MA 2365 BP 441 EP 441 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DW7YL UT WOS:000383869502141 ER PT J AU Sobel, RE Bate, A Marshall, J Daniel, G McCall, T Brown, J Reynolds, RF AF Sobel, Rachel E. Bate, Andrew Marshall, James Daniel, Gregory McCall, Troy Brown, Jeffery Reynolds, Robert F. TI Risk Minimization Evaluation in a Distributed Data Network - An IMEDS Evaluation Pilot Assessment of the 2010 Class Label Change for Proton Pump Inhibitors SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Sobel, Rachel E.; Bate, Andrew; Reynolds, Robert F.] Pfizer Inc, Epidemiol Worldwide Res & Dev, New York, NY USA. [Marshall, James; Brown, Jeffery] Harvard Med & Sch, Populat Med, Boston, MA USA. [Marshall, James; Brown, Jeffery] Sch Harvard Pilgrim Hlth Care, Boston, MA USA. [Daniel, Gregory] Duke Univ, Ctr Healthcare Policy, Washington, DC USA. [McCall, Troy] US FDA, Reagan Udall Fdn, Washington, DC 20204 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 7 BP 6 EP 7 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483501007 ER PT J AU Taylor, LG Greene, P Bird, ST Reichman, ME Sahin, L Tassinari, MS Andrade, SE Haffenreffer, K Toh, D AF Taylor, Lockwood G. Greene, Patty Bird, Steven T. Reichman, Marsha E. Sahin, Leyla Tassinari, Melissa S. Andrade, Susan E. Haffenreffer, Katherine Toh, Darren TI Ondansetron Use Among Pregnancies Identified In The Sentinel Distributed Database SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Taylor, Lockwood G.; Greene, Patty; Bird, Steven T.; Reichman, Marsha E.; Sahin, Leyla; Tassinari, Melissa S.] US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Andrade, Susan E.] Meyers Primary Care Inst, Worcester, MA USA. [Haffenreffer, Katherine; Toh, Darren] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Haffenreffer, Katherine; Toh, Darren] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 19 BP 14 EP 14 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483501019 ER PT J AU Arlett, P De Bruin, M Reynolds, R Dal Pan, G Shakir, S Spooner, A Kurz, X Raine, JM AF Arlett, Peter De Bruin, Marieke Reynolds, Robert Dal Pan, Gerald Shakir, Saad Spooner, Almath Kurz, Xavier Raine, June M. TI Impact of Pharmacovigilance: From PRAC Strategy to Demonstrable Better Health Protection SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Arlett, Peter; Kurz, Xavier] EMA, London, England. [De Bruin, Marieke] CBG MEB, Utrecht, Netherlands. [Reynolds, Robert] Pfizer Ltd, New York, NY USA. [Dal Pan, Gerald] US FDA, Rockville, MD 20857 USA. [Shakir, Saad] DSRU, Southampton, Hants, England. [Spooner, Almath] HPRA, Dublin, Ireland. [Spooner, Almath] PRAC, Dublin, Ireland. [Raine, June M.] MHRA, London, England. [Raine, June M.] PRAC, London, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 75 BP 47 EP 48 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483501075 ER PT J AU Maro, JC Dal Pan, GJ Dashevsky, I Brown, JS Kulldorff, M AF Maro, Judith C. Dal Pan, Gerald J. Dashevsky, Inna Brown, Jeffrey S. Kulldorff, Martin TI Monitoring All Drugs for a Specific Outcome in the Sentinel System SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Maro, Judith C.; Dashevsky, Inna; Brown, Jeffrey S.] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Maro, Judith C.; Dashevsky, Inna; Brown, Jeffrey S.] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Dal Pan, Gerald J.] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Kulldorff, Martin] Harvard Med Sch, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA USA. [Kulldorff, Martin] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 88 BP 56 EP 56 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483501088 ER PT J AU Zhou, M Wang, SV Leonard, CE Gagne, JJ Fuller, C Hampp, C Archdeacon, P Toh, S Iyer, A Woodworth, TS Cavagnaro, E Panozzo, C Axtman, S Carnahan, RM Chrischilles, EA Hennessy, S AF Zhou, Meijia Wang, Shirley V. Leonard, Charles E. Gagne, Joshua J. Fuller, Candace Hampp, Christian Archdeacon, Patrick Toh, Sengwee Iyer, Aarthi Woodworth, Tiffany Siu Cavagnaro, Elizabeth Panozzo, Catherine Axtman, Sophia Carnahan, Ryan M. Chrischilles, Elizabeth A. Hennessy, Sean TI Pilot Test of the Sentinel Modular Program for Propensity-Score Matched Cohort Analyses: Application to Glyburide, Glipizide, and Severe Hypoglycemia SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Zhou, Meijia; Leonard, Charles E.; Hennessy, Sean] Univ Penn, Perelman Sch Med, Ctr Pharmacoepidemiol Res & Training, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Zhou, Meijia; Leonard, Charles E.; Hennessy, Sean] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Wang, Shirley V.; Gagne, Joshua J.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. [Wang, Shirley V.; Gagne, Joshua J.] Harvard Med Sch, Boston, MA USA. [Fuller, Candace; Toh, Sengwee; Iyer, Aarthi; Woodworth, Tiffany Siu; Cavagnaro, Elizabeth; Panozzo, Catherine; Axtman, Sophia] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Fuller, Candace; Toh, Sengwee; Iyer, Aarthi; Woodworth, Tiffany Siu; Cavagnaro, Elizabeth; Panozzo, Catherine; Axtman, Sophia] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Hampp, Christian; Archdeacon, Patrick] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Carnahan, Ryan M.; Chrischilles, Elizabeth A.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 89 BP 56 EP 57 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483501089 ER PT J AU Cheng, H Hu, Y Mishra, N Anderson-Smits, C AF Cheng, Hong Hu, Yuzhi Mishra, Nishant Anderson-Smits, Colin TI Cement Leakage and New Vertebral Fractures after Kyphoplasty and Vertebroplasty: A Meta-Analysis SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Cheng, Hong; Hu, Yuzhi; Mishra, Nishant; Anderson-Smits, Colin] US FDA, Div Epidemiol, Off Surveillance & Biometr, CDRH, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 97 BP 61 EP 61 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483501096 ER PT J AU Cheng, H Hu, Y Zhou, J Anderson-Smits, C AF Cheng, Hong Hu, Yuzhi Zhou, Jie Anderson-Smits, Colin TI Comparison of New Vertebral Fractures After Kyphoplasty and Vertebroplasty Usinig Medicare Data SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Cheng, Hong; Hu, Yuzhi; Zhou, Jie; Anderson-Smits, Colin] US FDA, Div Epidemiol, Off Surveillance & Biometr, CDRH, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 99 BP 62 EP 62 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483501098 ER PT J AU Anderson-Smits, C Sing, D Dmitriev, A Cheng, H AF Anderson-Smits, Colin Sing, Davic Dmitriev, Anton Cheng, Hong TI A Comparative Analysis of Secondary Surgeries of Six Total Cervical Disc Arthroplasty Devices to Cervical Arthrodesis at 5-Years SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Anderson-Smits, Colin; Cheng, Hong] US FDA, Ctr Devices & Radiol Hlth, Div Epidemiol, Silver Spring, MD USA. [Sing, Davic; Dmitriev, Anton] US FDA, Off Sci Engn Labs, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 102 BP 64 EP 64 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483501101 ER PT J AU Tavris, D Ing, F Ghambaryan, A Hagler, D Ringel, RE Deegan, L Forbes, T Magdi, J Eloff, BC AF Tavris, Dale Ing, Frank Ghambaryan, Anna Hagler, Donald Ringel, Richard E. Deegan, Lauren Forbes, Thomas Magdi, Jamie Eloff, Benjamin C. TI Use of FDA Approved Stents Intended for Adults for the Treatment of Pulmonary Artery Stenosis in Children SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Tavris, Dale; Ghambaryan, Anna; Deegan, Lauren; Magdi, Jamie; Eloff, Benjamin C.] US FDA, Ctr Devices & Radiol Hlth, Div Epidemiol, Silver Spring, MD USA. [Ing, Frank] Childrens Hosp, Cardiol, Los Angeles, CA 90027 USA. [Hagler, Donald] Mayo Clin, Coll Med, Pediat Cardiol & Cardiovasc Dis, Rochester, MN USA. [Ringel, Richard E.] Johns Hopkins Sch Med, Div Pediat Cardiol, Baltimore, MD USA. [Forbes, Thomas] Childrens Hosp Michigan, Cardiac Catheterizat Lab, Detroit, MI 48201 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 206 BP 124 EP 125 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483501205 ER PT J AU Anderson-Smits, C Apfel, A Hu, Y Cheng, H Loyo-Berrieros, N AF Anderson-Smits, Colin Apfel, Ariella Hu, Yuzhi Cheng, Hong Loyo-Berrieros, Nilsa TI Spinal Degenerative Disc Disease Procedure Trends in the United States Using the National Inpatient Sample (2008-2012) SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Anderson-Smits, Colin; Apfel, Ariella; Hu, Yuzhi; Cheng, Hong; Loyo-Berrieros, Nilsa] US FDA, Ctr Devices & Radiol Hlth, Div Epidemiol, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 208 BP 126 EP 126 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483501207 ER PT J AU Swain, RS Taylor, LG Mosholder, AD AF Swain, Richard S. Taylor, Lockwood G. Mosholder, Andrew D. TI Detecting Suicidal Outcomes: A Power Analysis SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Swain, Richard S.; Taylor, Lockwood G.; Mosholder, Andrew D.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 232 BP 139 EP 139 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483501230 ER PT J AU Williams, R Gallagher, AM van Staa, T Hammad, T Leufkens, B de Vries, F AF Williams, Rachael Gallagher, Arlene M. van Staa, Tjeerd Hammad, Tarek Leufkens, Bert de Vries, Frank TI Cancer Recording In Patients With Type 2 Diabetes In Primary Care And Hospital Admission Data SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Williams, Rachael; Gallagher, Arlene M.] Clin Practice Res Datalink, London, England. [Williams, Rachael; Gallagher, Arlene M.; van Staa, Tjeerd; Leufkens, Bert; de Vries, Frank] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Utrecht, Netherlands. [Hammad, Tarek] US FDA, Off Surveillance & Epidemiol, Washington, DC 20204 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 263 BP 157 EP 158 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483501261 ER PT J AU Li, J Izem, R AF Li, Jie Izem, Rima TI Interim Analyses in Prospective Observational Studies of Medical Product Safety SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Li, Jie] US FDA, Off Surveillance & Epidemiol, Div Epidemiol 2, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Izem, Rima] US FDA, Off Biostat, Div Biostat 7, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 290 BP 172 EP 173 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483501287 ER PT J AU McMahon, AW Sheridan, PH Yao, L AF McMahon, Ann W. Sheridan, Philip H. Yao, Lynne TI Proceedings of a Workshop from the USFDA: Evaluation of Long-Term Neurocognitive Development in Pediatrics SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [McMahon, Ann W.] US FDA, Off Pediat Therapeut, Silver Spring, MD USA. [Sheridan, Philip H.] US FDA, Div Neurol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Yao, Lynne] US FDA, Div Maternal & Child Hlth, Ctr Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 301 BP 177 EP 177 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483501294 ER PT J AU Nordstrom, BL Weiss, S Lanes, S Wang, CL AF Nordstrom, Beth L. Weiss, Sheila Lanes, Stephan Wang, Cunlin TI What's in a Code? Algorithm Validation in Drug Safety Studies SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Nordstrom, Beth L.] Evidera, Lexington, MA USA. [Weiss, Sheila] Univ Maryland, Catonsville, MD 21228 USA. [Lanes, Stephan] HealthCore Inc, Wilmington, DE USA. [Wang, Cunlin] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 478 BP 280 EP 280 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483502111 ER PT J AU Pinheiro, S Liu, W Nguyen, M Poitras, M Uyama, Y Arlett, P AF Pinheiro, Simone Liu, Wei Nguyen, Michael Poitras, Marc Uyama, Yoshiaki Arlett, Peter TI The Role of Evidence Synthesis in Drug Safety Evaluation and Regulation SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Pinheiro, Simone; Liu, Wei; Nguyen, Michael] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Poitras, Marc] Hlth Canada, Marketed Pharmaceut & Med Devices Bur, Ottawa, ON, Canada. [Uyama, Yoshiaki] Pharmaceut & Med Devices Agcy, Chiyoda Ku, Tokyo, Japan. [Arlett, Peter] European Med Agcy, Pharmacovigilance Dept, London, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 480 BP 281 EP 281 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483502113 ER PT J AU Chien, HC Yang, YHK Bai, JPF AF Chien, Hsu-Chih Yang, Yea-Huei Kao Bai, Jane P. F. TI Risk Factors of Trastuzumab Related Cardiotoxicity in Taiwanese Breast Cancer Women SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Chien, Hsu-Chih; Yang, Yea-Huei Kao] Natl Cheng Kung Univ, Res Ctr, Coll Med & Hlth Outcome, Inst Clin Pharm & Pharmaceut Sci, Tainan, Taiwan. [Yang, Yea-Huei Kao] Natl Cheng Kung Univ, Sch Pharm, Coll Med, Tainan, Taiwan. [Bai, Jane P. F.] 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 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 485 BP 283 EP 284 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483502118 ER PT J AU Kang, E Pinheiro, S Zhou, E Ding, Y Seymour, S Major, JM AF Kang, Elizabeth Pinheiro, Simone Zhou, Esther Ding, Yulan Seymour, Sally Major, Jacqueline M. TI Patterns of Tiotropium Dispensing in the United States and Impact of FDA Drug Safety Communications SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Kang, Elizabeth; Pinheiro, Simone; Zhou, Esther; Ding, Yulan; Major, Jacqueline M.] FDA CDER, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Seymour, Sally] FDA CDER, Off New Drugs, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 502 BP 294 EP 294 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483502135 ER PT J AU Bird, ST Hampp, C Taylor, L Gelperin, K Reichman, M Sahin, L AF Bird, Steven T. Hampp, Christian Taylor, Lockwood Gelperin, Kate Reichman, Marsha Sahin, Leyla TI A Systematic Review of Enrollment and Retention in US Pregnancy Exposure Registries and Corresponding Pharmacovigilance Systems SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Bird, Steven T.; Hampp, Christian; Taylor, Lockwood; Gelperin, Kate; Reichman, Marsha] US FDA, Div Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Sahin, Leyla] US FDA, Div Pediat & Maternal Hlth, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 510 BP 298 EP 299 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483502143 ER PT J AU Qiang, YD Chillarige, Y Said, M Liu, T Dekmezian, C Winiecki, S Nguyen, MD Worrall, CM Kelman, JA Wernecke, M Hua, W AF Qiang, Yandong Chillarige, Yoganand Said, Maria Liu, Tina Dekmezian, Carmen Winiecki, Scott Nguyen, Michael D. Worrall, Chris M. Kelman, Jeffrey A. Wernecke, Michael Hua, Wei TI Feasibility of Using the Medicaid Statistical Information System (MSIS) to Assess Safety and Effectiveness of 3rd Trimester Vaccination: A Case Study with Tetanus Toxoid, Reduced Diphtheria Toxoid And Acellular Pertussis (Tdap) SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Qiang, Yandong; Said, Maria; Winiecki, Scott; Nguyen, Michael D.; Hua, Wei] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Chillarige, Yoganand; Liu, Tina; Dekmezian, Carmen; Wernecke, Michael] Acumen LLC, Burlingame, CA USA. [Worrall, Chris M.; Kelman, Jeffrey A.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 571 BP 333 EP 333 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483502203 ER PT J AU Haynes, K Sterrett, A Shetterly, S Selvan, M Gange, J Lu, C Shoaibi, A Raebel, MA AF Haynes, Kevin Sterrett, Andrew Shetterly, Susan Selvan, Mano Gange, Josh Lu, Christine Shoaibi, Azadeh Raebel, Marsha A. TI Utilization of Laboratory Results Data to Enhance Pregnancy Cohort Identification SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Haynes, Kevin] HealthCore Inc, Govt & Acad Res, Wilmington, DE USA. [Sterrett, Andrew; Shetterly, Susan; Raebel, Marsha A.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. [Selvan, Mano] Humana, Comprehens Heath Insights, Louisville, KY USA. [Gange, Josh] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. [Gange, Josh] Harvard Med Sch, Boston, MA USA. [Lu, Christine] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Lu, Christine] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Shoaibi, Azadeh] US FDA, CBER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 580 BP 338 EP 338 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483502212 ER PT J AU Chien, HC Cheng, CL Lee, CH Bai, JPF Yang, YHK AF Chien, Hsu-Chih Cheng, Ching-Lan Lee, Cheng-Han Bai, Jane P. F. Yang, Yea-Huei Kao TI Detection of Trastuzumab Related Cardiotoxicity in Taiwanese Breast Cancer Women SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Chien, Hsu-Chih; Cheng, Ching-Lan; Yang, Yea-Huei Kao] Natl Cheng Kung Univ, Coll Med, Inst Clin Pharm & Pharmaceut Sci, Tainan, Taiwan. [Chien, Hsu-Chih; Cheng, Ching-Lan; Yang, Yea-Huei Kao] Natl Cheng Kung Univ, Hlth Outcome Res Ctr, Tainan, Taiwan. [Cheng, Ching-Lan; Yang, Yea-Huei Kao] Natl Cheng Kung Univ, Sch Pharm, Coll Med, Tainan, Taiwan. [Lee, Cheng-Han] Natl Cheng Kung Univ Hosp, Div Cardiol, Tainan, Taiwan. [Bai, Jane P. F.] 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 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 607 BP 354 EP 354 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483502239 ER PT J AU Hansen, RA Qian, J Berg, R Linneman, J Seoane-Vazquez, E Dutcher, S Raofi, S Peissig, P AF Hansen, Richard A. Qian, Jingjing Berg, Richard Linneman, James Seoane-Vazquez, Enrique Dutcher, Sarah Raofi, Saeid Peissig, Peggy TI Comparison Of Generic-To-Brand Switchback Patterns For Authorized Generic Vs. Independent Generic Drugs SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Hansen, Richard A.; Qian, Jingjing] Auburn Univ, Dept Hlth Outcomes Res & Policy, Harrison Sch Pharm, Auburn, AL 36849 USA. [Berg, Richard; Linneman, James; Peissig, Peggy] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI USA. [Seoane-Vazquez, Enrique] Massachusetts Coll Pharm & Hlth Sci, Int Ctr Pharmaceut Econ & Policy, Boston, MA USA. [Dutcher, Sarah; Raofi, Saeid] US FDA, Off Gener Drugs, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 610 BP 355 EP 356 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483502242 ER PT J AU Segal, JB Daubresse, M Onasanya, O Dutcher, S Jiang, W Romanelli, R AF Segal, Jodi B. Daubresse, Matthew Onasanya, Oluwadamilola Dutcher, Sarah Jiang, Wenlei Romanelli, Robert TI Determinants of Generic Drug Utilization in the United States SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Segal, Jodi B.] Johns Hopkins Univ, Sch Med, Med, Baltimore, MD USA. [Segal, Jodi B.; Daubresse, Matthew; Onasanya, Oluwadamilola] Johns Hopkins Univ, Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Dutcher, Sarah; Jiang, Wenlei] US FDA, Off Gener Drugs, Silver Spring, MD USA. [Romanelli, Robert] Palo Alto Med Fdn, Res Inst, Palo Alto, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 612 BP 357 EP 357 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483502244 ER PT J AU Torosyan, Y Loyo-Berrios, N Karapetyan, T Kitchner, T Brilliant, M Marinac-Dabic, D AF Torosyan, Yelizaveta Loyo-Berrios, Nilsa Karapetyan, Tigran Kitchner, Terrie Brilliant, Murray Marinac-Dabic, Danica TI In Silico Integration of Epidemiologic and Genetic Evidence on Sex/Race-Related Modifying Effects on Hip Arthroplasty Outcomes SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Torosyan, Yelizaveta; Loyo-Berrios, Nilsa; Karapetyan, Tigran; Marinac-Dabic, Danica] US FDA, Div Epidemiol, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Kitchner, Terrie; Brilliant, Murray] MCRF, Marshfield, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 657 BP 384 EP 384 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483502289 ER PT J AU Dasgupta, N Pierce, CE Bouri, K Pamer, C Proestel, S Rodriguez, HW Van Le, H Freifeld, CC Brownstein, JS Walderhaug, M Edwards, IR AF Dasgupta, Nabarun Pierce, Carrie E. Bouri, Khaled Pamer, Carol Proestel, Scott Rodriguez, Harold W. Van Le, Hoa Freifeld, Clark C. Brownstein, John S. Walderhaug, Mark Edwards, I. Ralph TI Can Facebook and Twitter Monitoring Yield Earlier Detection of Safety Signals for Medical Products? SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Dasgupta, Nabarun; Pierce, Carrie E.; Rodriguez, Harold W.; Van Le, Hoa; Freifeld, Clark C.; Brownstein, John S.] Epidemico Inc, Boston, MA USA. [Bouri, Khaled; Pamer, Carol; Proestel, Scott; Walderhaug, Mark] US FDA, Silver Spring, MD USA. [Edwards, I. Ralph] WHO Collaborating Ctr Int Drug Monitoring, Uppsala Monitoring Ctr, Uppsala, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 699 BP 408 EP 408 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483502330 ER PT J AU Ammann, EM Haskins, CB Fillman, KM Ritter, RL Gu, X Winiecki, SK Carnahan, RM Torner, JC Fireman, BH Jones, MP Chrischilles, EA AF Ammann, Eric M. Haskins, Cole B. Fillman, Kelsey M. Ritter, Rebecca L. Gu, Xiaomei Winiecki, Scott K. Carnahan, Ryan M. Torner, James C. Fireman, Bruce H. Jones, Michael P. Chrischilles, Elizabeth A. TI Intravenous Immune Globulin and Thromboembolic Adverse Events: A Systematic Review and Meta-Analysis of Randomized Controlled Trials SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Ammann, Eric M.; Haskins, Cole B.; Fillman, Kelsey M.; Ritter, Rebecca L.; Gu, Xiaomei; Carnahan, Ryan M.; Torner, James C.; Jones, Michael P.; Chrischilles, Elizabeth A.] Univ Iowa, Iowa City, IA USA. [Winiecki, Scott K.] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Fireman, Bruce H.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 756 BP 440 EP 440 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483503022 ER PT J AU Yih, WK Maro, JC Nguyen, MD Mba-Jonas, A Baker, MA Balsbaugh, C Cole, DV Dashevsky, I Kulldorff, M AF Yih, W. Katherine Maro, Judith C. Nguyen, Michael D. Mba-Jonas, Adamma Baker, Meghan A. Balsbaugh, Carolyn Cole, David V. Dashevsky, Inna Kulldorff, Martin TI Assessing Quadrivalent HPV Vaccine Safety Using the Self-Controlled Tree-Temporal Scan Statistic SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Yih, W. Katherine; Maro, Judith C.; Baker, Meghan A.; Balsbaugh, Carolyn; Cole, David V.; Dashevsky, Inna] Harvard Med Sch, Populat Med, Boston, MA USA. [Yih, W. Katherine; Maro, Judith C.; Baker, Meghan A.; Balsbaugh, Carolyn; Cole, David V.; Dashevsky, Inna] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Nguyen, Michael D.; Mba-Jonas, Adamma] US FDA, Silver Spring, MD USA. [Kulldorff, Martin] Brigham & Womens Hosp, Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 816 BP 473 EP 474 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483503079 ER PT J AU Noren, GN Ball, R Kulldorff, M Walker, AM AF Noren, G. Niklas Ball, Robert Kulldorff, Martin Walker, Alexander M. TI Pattern Discovery in Observational Health Data - What We Did Not Know to Look For SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Noren, G. Niklas] WHO Collaborating Ctr Int Drug Monitoring, Uppsala Monitoring Ctr, Uppsala, Sweden. [Ball, Robert] US FDA, Silver Spring, MD USA. [Kulldorff, Martin] Harvard Med Sch, Boston, MA USA. [Kulldorff, Martin] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Walker, Alexander M.] World Hlth Informat Sci Consultants, Newton, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 827 BP 480 EP 480 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483503090 ER PT J AU Bird, ST Taylor, L Hampp, C Sachin, L Toh, D Andrade, S Haffenreffer, K Reichman, M Gelperin, K AF Bird, Steven T. Taylor, Lockwood Hampp, Christian Sachin, Leyla Toh, Darren Andrade, Susan Haffenreffer, Katie Reichman, Marsha Gelperin, Kate TI Utilization Patterns of Drugs or Biologics with Pregnancy Exposure Registries in Pregnant and Matched Non-Pregnant Women in the Sentinel Database SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Bird, Steven T.; Taylor, Lockwood; Hampp, Christian; Reichman, Marsha; Gelperin, Kate] US FDA, Div Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Sachin, Leyla] US FDA, Div Pediat & Maternal Hlth, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Toh, Darren; Haffenreffer, Katie] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Toh, Darren; Haffenreffer, Katie] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Andrade, Susan] Fallon Community Hlth Plan, Meyers Primary Care Inst, Reliant Med Grp, Worcester, MA USA. [Andrade, Susan] Univ Massachusetts, Sch Med, Worcester, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 837 BP 485 EP 486 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483503100 ER PT J AU Graham, DJ Reichman, ME Wernecke, M Hsueh, YH Izem, R Southworth, MR Wei, YQ Liao, JM Goulding, MR Mott, K Chillarige, Y MaCurdy, TE Worrall, C Kelman, JA AF Graham, David J. Reichman, Marsha E. Wernecke, Michael Hsueh, Ya-Hui Izem, Rima Southworth, Mary Ross Wei, Yuqin Liao, Jiemin Goulding, Margie R. Mott, Katrina Chillarige, Yoganand MaCurdy, Thomas E. Worrall, Chris Kelman, Jeffrey A. TI Stroke, Bleeding, and Mortality Risks in Older Patients Treated with Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Graham, David J.; Reichman, Marsha E.; Hsueh, Ya-Hui; Izem, Rima; Southworth, Mary Ross; Goulding, Margie R.; Mott, Katrina] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Wernecke, Michael; Wei, Yuqin; Liao, Jiemin; Chillarige, Yoganand; MaCurdy, Thomas E.] Acumen LLC, Burlingame, CA USA. [Worrall, Chris; Kelman, Jeffrey A.] Ctr Medicare & Medicaid Serv, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 862 BP 500 EP 501 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483503125 ER PT J AU Gagne, JJ Han, X Hennessy, S Leonard, CE Chrischilles, EA Carnahan, RM Wang, SV Fuller, C Iyer, A Katcoff, H Woodworth, TS Archdeacon, P Meyer, TE Schneeweiss, S Toh, S AF Gagne, Joshua J. Han, Xu Hennessy, Sean Leonard, Charles E. Chrischilles, Elizabeth A. Carnahan, Ryan M. Wang, Shirley V. Fuller, Candace Iyer, Aarthi Katcoff, Hannah Woodworth, Tiffany S. Archdeacon, Patrick Meyer, Tamra E. Schneeweiss, Sebastian Toh, Sengwee TI Assessment of the US Food and Drug Administration's Sentinel Analysis Tools: Angiotensin-Converting Enzyme Inhibitors And Angioedema SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Gagne, Joshua J.; Wang, Shirley V.; Schneeweiss, Sebastian] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. [Gagne, Joshua J.; Wang, Shirley V.; Schneeweiss, Sebastian] Harvard Med Sch, Boston, MA USA. [Han, Xu; Hennessy, Sean; Leonard, Charles E.] Univ Penn, Ctr Pharmacoepidemiol Res & Training, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Han, Xu; Hennessy, Sean; Leonard, Charles E.] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Chrischilles, Elizabeth A.; Carnahan, Ryan M.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Fuller, Candace; Iyer, Aarthi; Katcoff, Hannah; Woodworth, Tiffany S.; Toh, Sengwee] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Fuller, Candace; Iyer, Aarthi; Katcoff, Hannah; Woodworth, Tiffany S.; Toh, Sengwee] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Archdeacon, Patrick] US FDA, Off Med Policy, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Meyer, Tamra E.] US FDA, Div Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 866 BP 503 EP 503 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483503129 ER PT J AU Bate, A Sobel, RE Marshall, J Daniel, G McCall, T Reynolds, RF Brown, J AF Bate, Andrew Sobel, Rachel E. Marshall, Jim Daniel, Greg McCall, Troy Reynolds, Robert F. Brown, Jeff TI Oral Contraceptives and VTE Across the Sentinel Data Network - An IMEDS Evaluation Pilot Assessment SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Bate, Andrew; Sobel, Rachel E.; Reynolds, Robert F.] Pfizer, Epidemiol, New York, NY USA. [Marshall, Jim; Brown, Jeff] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Marshall, Jim; Brown, Jeff] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Daniel, Greg] Duke Univ, Duke Margolis Ctr Hlth Policy, Durham, NC 27706 USA. [McCall, Troy] US FDA, Reagan Udall Fdn, Washington, DC 20204 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 915 BP 532 EP 533 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483503178 ER PT J AU Hansen, RA Qian, JJ Berg, R Linneman, J Seoane-Vazquez, E Dutcher, S Raofi, S Peissig, P AF Hansen, Richard A. Qian, Jingjing Berg, Richard Linneman, James Seoane-Vazquez, Enrique Dutcher, Sarah Raofi, Saeid Peissig, Peggy TI Comparison of Outcomes Following a Switch from a Brand to an Authorized vs. Independent Generic Drug SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Hansen, Richard A.; Qian, Jingjing] Auburn Univ, Dept Hlth Outcomes Res & Policy, Harrison Sch Pharm, Auburn, AL 36849 USA. [Berg, Richard; Linneman, James; Peissig, Peggy] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI USA. [Seoane-Vazquez, Enrique] Massachusetts Coll Pharm & Hlth Sci, Int Ctr Pharmaceut Econ & Policy, Boston, MA USA. [Dutcher, Sarah; Raofi, Saeid] US FDA, Off Gener Drugs, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 SU S3 MA 1036 BP 602 EP 603 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DY9VP UT WOS:000385483503296 ER PT J AU Margolis, KA Nguyen, AB Slavit, WI King, BA AF Margolis, Katherine A. Nguyen, Anh B. Slavit, Wendy I. King, Brian A. TI E-cigarette curiosity among US middle and high school students: Findings from the 2014 national youth tobacco survey SO PREVENTIVE MEDICINE LA English DT Article DE Smoking; Tobacco; Adolescent ID ELECTRONIC CIGARETTES; SMOKING; SUSCEPTIBILITY; ADOLESCENCE; INITIATION; BELIEFS AB Curiosity is a potential risk factor for electronic cigarette (e-cigarette) use, which has increased considerably among US youth in recent years. We examined the relationship between curiosity about e-cigarettes and perceived harm, comparative addictiveness, and e-cigarette advertisement exposure. Data came from the 2014 National Youth Tobacco Survey, a nationally representative survey of U.S. middle and high school students. In 2014, 2.5% of middle school and 9.2% of high school students currently used cigarettes, while 3.9% of middle school and 13.4% of high school students reported current e-cigarette use. Among never e-cigarette users (n=17,286), descriptive statistics assessed curiosity about e-cigarettes by combustible tobacco use, sex, race/ethnicity, and school level. Associations between curiosity and perceived harm (absolute and comparative to cigarettes), comparative addictiveness, and e-cigarette advertising exposure were explored using multivariate models in 2015. Among youth who never used e-cigarettes, 25.8% reported curiosity about e-cigarettes. Higher levels of perceived absolute harm and comparative harm were associated with lower levels of curiosity, while no association was observed between comparative addictiveness and curiosity. Among never combustible tobacco users, the odds of high curiosity were greater among non-Hispanic blacks (odds ratio (OR): 1.39; 95% confidence interval (CI): 1.02-1.88), Hispanics (OR = 1.79; 95% CI: 1.48-2.16), and non-Hispanic 'Other' (OR = 1.47; 95% CI: 1.15-1.89) race/ethnicities than non-Hispanic whites. One-quarter of middle and high school students who have never used e-cigarettes are curious about the products, with greater curiosity among those with lower perceptions of harm from these products. These findings may help inform future strategies aimed at reducing curiosity about e-cigarettes among youth. Published by Elsevier Inc. C1 [Margolis, Katherine A.; Nguyen, Anh B.; Slavit, Wendy I.] US FDA, Ctr Tobacco Prod, Off Sci, 10903 New Hampshire Ave Bldg 75 Room 4444, Silver Spring, MD 20993 USA. [King, Brian A.] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Off Smoking & Hlth, Atlanta, GA USA. RP Margolis, KA (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, 10903 New Hampshire Ave Bldg 75 Room 4444, Silver Spring, MD 20993 USA. EM Katherine.Margolis@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Tobacco Products; Centers for Disease Control and Prevention, Office on Smoking and Health FX Publication of this article was supported by the U.S. Food and Drug Administration, Center for Tobacco Products and The Centers for Disease Control and Prevention, Office on Smoking and Health. NR 38 TC 1 Z9 1 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD AUG PY 2016 VL 89 BP 1 EP 6 DI 10.1016/j.ypmed.2016.05.001 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EC7KJ UT WOS:000388316700001 PM 27155440 ER PT J AU Keadle, SK McKinnon, R Graubard, BI Troiano, RP AF Keadle, Sarah Kozey McKinnon, Robin Graubard, Barry I. Troiano, Richard P. TI Prevalence and trends in physical activity among older adults in the United States: A comparison across three national surveys SO PREVENTIVE MEDICINE LA English DT Article ID SEDENTARY BEHAVIORS; TIME SPENT; US ADULTS; ACCELEROMETER AB This paper examined how many older adults (65 + years) are meeting physical activity (PA) Guidelines (PAG; 150 min/week of moderate-to-vigorous PA) using data from three leading national surveys (NHANES, BRFSS and NHIS). The proportion of individuals meeting aerobic PAG was determined for the most recent cycle available for each survey (NHANES 2011-12, NHIS and BRFSS 2013). We also assessed whether PAG adherence has changed over time. Predicted margins from multinomial logistic regression were computed after adjusting for age, race/ethnicity and gender and sample weights. The proportion of older adults meeting PAG was 27.3% for NHANES, 35.8% for NHIS and 44.3% for BRFSS. Across all surveys, men reported higher levels of activity than women, Non-Hispanic whites reported higher levels than Non-Hispanic blacks and Hispanics, activity declined with age and was lower in those with functional limitations, all P < 0.05. The proportion of older adults meeting PAG in the NHIS survey, the only survey where PA questions remained the same over time, increased from 25.7% in 1998 to 35.8% in 2013 (P < 0.01). Point-estimates for activity levels are different between surveys but they consistently identify sub-groups who are less active. Although older adults are reporting more activity over time, adherence to aerobic and strength training PAG remains low in this population and there is a need for effective interventions to prevent age-related declines in PA and address health disparities among older adults. Published by Elsevier Inc. C1 [Keadle, Sarah Kozey] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Keadle, Sarah Kozey] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [McKinnon, Robin; Troiano, Richard P.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [McKinnon, Robin] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Graubard, Barry I.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Keadle, SK (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.; Keadle, SK (reprint author), NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. EM Sarah.keadle@nih.gov FU Intramural Research Program at National Cancer Institute FX The authors would like to thank Lisa Kahle for her programming assistance. This work is funded in part by the Intramural Research Program at the National Cancer Institute. NR 28 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD AUG PY 2016 VL 89 BP 37 EP 43 DI 10.1016/j.ypmed.2016.05.009 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EC7KJ UT WOS:000388316700006 PM 27196146 ER PT J AU Gagne, JJ Polinski, JM Jiang, WL Dutcher, SK Xie, J Lii, J Fulchino, LA Kesselheim, AS AF Gagne, Joshua J. Polinski, Jennifer M. Jiang, Wenlei Dutcher, Sarah K. Xie, Jing Lii, Joyce Fulchino, Lisa A. Kesselheim, Aaron S. TI Switch-backs associated with generic drugs approved using product-specific determinations of therapeutic equivalence SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE generics; switch-backs; safety; effectiveness; approval; equivalence; pharmacoepidemiology ID ANTIEPILEPTIC DRUGS; CONSEQUENCES; PERCEPTIONS; OUTCOMES AB Purpose US Food and Drug Administration approval for generic drugs relies on demonstrating pharmaceutical equivalence and bioequivalence; however, some drug products have unique attributes that necessitate product-specific approval pathways. We evaluated rates of patients' switching back to brand-name versions from generic versions of four drugs approved via such approaches. Methods We used data from Optum LifeSciences Research Database to identify patients using a brand-name version of a study drug (acarbose tablets, salmon calcitonin nasal spray, enoxaparin sodium injection, and venlafaxine extended release tablets) or a control drug. We followed patients to identify switching to generic versions and then followed those who switched to identify whether they switched back to brand-name versions. We calculated switch and switch-back rates and used Kaplan-Meier and log-rank tests to compare rates between study and control drugs. Results Our cohort included 201 959 eligible patients. Brand-to-generic switch rates ranged from 66 to 106 switches per 100 person-years for study drugs and 80 to 110 for control drugs. Rates of switch-back to brand-name versions ranged from 5 to 37 among study drugs and 3 to 53 among control drugs. Switch-back rates were higher for venlafaxine vs. sertraline (p < 0.01) and calcitonin vs. alendronate (p = 0.01). Switch-back rates were lower for venlafaxine vs. paroxetine (p < 0.01) and acarbose vs. nateglinide (p < 0.01). Rates were similar for acarbose vs. glimepiride (p = 0.97) and for enoxaparin vs. fondiparinux (p = 0.11). Conclusion As compared to control drugs, patients were not more likely to systematically switch back from generic to brand-name versions of the four study drugs. Copyright (C) 2016 John Wiley & Sons, Ltd. C1 [Gagne, Joshua J.; Polinski, Jennifer M.; Xie, Jing; Lii, Joyce; Fulchino, Lisa A.; Kesselheim, Aaron S.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Program Regulat Therapeut & Law PORTAL, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. [Gagne, Joshua J.; Polinski, Jennifer M.; Xie, Jing; Lii, Joyce; Fulchino, Lisa A.; Kesselheim, Aaron S.] Harvard Med Sch, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. [Jiang, Wenlei; Dutcher, Sarah K.] US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Gagne, JJ (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Program Regulat Therapeut & Law PORTAL, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA.; Gagne, JJ (reprint author), Harvard Med Sch, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. EM jgagne1@partners.org FU US Food and Drug Administration Office of Generic Drugs [1U01FD004856-01] FX This study was funded by the US Food and Drug Administration Office of Generic Drugs (1U01FD004856-01). NR 14 TC 2 Z9 2 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2016 VL 25 IS 8 BP 944 EP 952 DI 10.1002/pds.4009 PG 9 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DW4VW UT WOS:000383642100010 PM 27102378 ER PT J AU Plaut, RD Scanlon, KM Taylor, M Teter, K Carbonetti, NH AF Plaut, Roger D. Scanlon, Karen M. Taylor, Michael Teter, Ken Carbonetti, Nicholas H. TI Intracellular disassembly and activity of pertussis toxin require interaction with ATP SO PATHOGENS AND DISEASE LA English DT Article DE pertussis toxin; intracellular transport; retrograde transport; Bordetella pertussis; bacterial toxin; holotoxin dissociation ID ISLET-ACTIVATING PROTEIN; BORDETELLA-PERTUSSIS; ENDOPLASMIC-RETICULUM; ADENINE-NUCLEOTIDES; ADP-RIBOSYLATION; RETROGRADE TRANSPORT; NAD GLYCOHYDROLASE; RESPIRATORY-TRACT; CRYSTAL-STRUCTURE; MAMMALIAN-CELLS AB The active subunit (S1) of pertussis toxin (PT), a major virulence factor of Bordetella pertussis, ADP-ribosylates G(i) proteins in the mammalian cell cytosol to inhibit GPCR signaling. The intracellular pathway of PT includes endocytosis and retrograde transport to the trans-Golgi network (TGN) and endoplasmic reticulum (ER). Subsequent translocation of S1 to the cytosol is presumably preceded by dissociation from the holotoxin. In vitro, such dissociation is stimulated by interaction of PT with ATP. To investigate the role of this interaction in cellular events, we engineered a form of PT (PTDM) with changes to two amino acids involved in the interaction with ATP. PTDM was reduced in (1) binding to ATP, (2) dissociability by interaction with ATP, (3) in vitro enzymatic activity and (4) cellular ADP-ribosylation activity. In cells treated with PTDM carrying target sequences for organelle-specific modifications, normal transport to the TGN and ER occurred, but N-glycosylation patterns of the S1 and S4 subunits were consistent with an inability of PTDM to dissociate in the ER. These results indicate a requirement for interaction with ATP for PT dissociation in the ER and cellular activity. They also indicate that the retrograde transport route is the cellular intoxication pathway for PT. C1 [Plaut, Roger D.; Scanlon, Karen M.; Carbonetti, Nicholas H.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, 685 W Baltimore St,HSF I 380, Baltimore, MD 21201 USA. [Taylor, Michael; Teter, Ken] Univ Cent Florida, Coll Med, Burnett Sch Biomed Sci, Orlando, FL 32826 USA. [Plaut, Roger D.] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Carbonetti, NH (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, 685 W Baltimore St,HSF I 380, Baltimore, MD 21201 USA. EM ncarbonetti@som.umaryland.edu FU National Institute of Allergy and Infectious Diseases [AI50022, AI063080, AI099493] FX This work was supported by the National Institute of Allergy and Infectious Diseases [grant numbers AI50022 and AI063080 to NHC and grant number AI099493 to KT]. NR 37 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2049-632X J9 PATHOG DIS JI Pathog. Dis. PD AUG PY 2016 VL 74 IS 6 AR ftw065 DI 10.1093/femspd/ftw065 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DY3UG UT WOS:000385019700013 ER PT J AU Ahmadi, E Katnani, HA Besheli, LD Gu, Q Atefi, R Villeneuve, MY Eskandar, E Lev, MH Golby, AJ Gupta, R Bonmassar, G AF Ahmadi, Emad Katnani, Husam A. Besheli, Laleh Daftari Gu, Qiang Atefi, Reza Villeneuve, Martin Y. Eskandar, Emad Lev, Michael H. Golby, Alexandra J. Gupta, Rajiv Bonmassar, Giorgio TI An Electrocorticography Grid with Conductive Nanoparticles in a Polymer Thick Film on an Organic Substrate Improves CT and MR Imaging SO RADIOLOGY LA English DT Article ID EPILEPSY; ARRAYS; STATE AB Purpose: To develop an electrocorticography (ECoG) grid by using deposition of conductive nanoparticles in a polymer thick film on an organic substrate (PTFOS) that induces minimal, if any, artifacts on computed tomographic (CT) and magnetic resonance (MR) images and is safe in terms of tissue reactivity and MR heating. Materials and Methods: All procedures were approved by the Animal Care and Use Committee and complied with the Public Health Services Guide for the Care and Use of Animals. Electrical functioning of PTFOS for cortical recording and stimulation was tested in two mice. PTFOS disks were implanted in two mice; after 30 days, the tissues surrounding the implants were harvested, and tissue injury was studied by using immunostaining. Five neurosurgeons rated mechanical properties of PTFOS compared with conventional grids by using a three-level Likert scale. Temperature increases during 30 minutes of 3-T MR imaging were measured in a head phantom with no grid, a conventional grid, and a PTFOS grid. Two neuroradiologists rated artifacts on CT and MR images of a cadaveric head specimen with no grid, a conventional grid, and a PTFOS grid by using a four-level Likert scale, and the mean ratings were compared between grids. Results: Oscillatory local field potentials were captured with cortical recordings. Cortical stimulations in motor cortex elicited muscle contractions. PTFOS implants caused no adverse tissue reaction. Mechanical properties were rated superior to conventional grids (x(2) test, P<.05). The temperature increase during MR imaging for the three cases of no grid, PTFOS grid, and conventional grid was 3.84 degrees C, 4.05 degrees C, and 10.13 degrees C, respectively. PTFOS induced no appreciable artifacts on CT and MR images, and PTFOS image quality was rated significantly higher than that with conventional grids (two-tailed t test, P<.05). Conclusion: PTFOS grids may be an attractive alternative to conventional ECoG grids with regard to mechanical properties, 3-T MR heating profile, and CT and MR imaging artifacts. (C) RSNA, 2016 C1 [Ahmadi, Emad; Atefi, Reza; Villeneuve, Martin Y.; Bonmassar, Giorgio] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, 75 Third Ave,Room 1-402, Charlestown, MA 02129 USA. [Ahmadi, Emad; Besheli, Laleh Daftari; Lev, Michael H.; Gupta, Rajiv] Harvard Med Sch, Massachusetts Gen Hosp, Adv X Ray Imaging Sci Ctr, Dept Radiol, Boston, MA USA. [Katnani, Husam A.; Eskandar, Emad] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA USA. [Gu, Qiang] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Golby, Alexandra J.] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA USA. RP Bonmassar, G (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, 75 Third Ave,Room 1-402, Charlestown, MA 02129 USA. EM giorgio@nmr.mgh.harvard.edu FU National Institutes of Health [5R43NS071988-02, U01-NS075026, 1R21EB016449-01A1]; National Center for Research Resources [P41-RR14075]; National Center for Image Guided Therapy [P41EB015898]; MIND Institute FX Supported by the National Center for Research Resources (grant P41-RR14075), National Center for Image Guided Therapy (grant P41EB015898), and the MIND Institute.; This research was supported by the National Institutes of Health (grants 5R43NS071988-02, U01-NS075026, and 1R21EB016449-01A1) NR 20 TC 0 Z9 0 U1 2 U2 2 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2016 VL 280 IS 2 BP 595 EP 601 DI 10.1148/radiol.2016142529 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DY6UW UT WOS:000385265200028 PM 26844363 ER PT J AU Wang, W Kreimeyer, K Woo, EJ Ball, R Foster, M Pandey, A Scott, J Botsis, T AF Wang, Wei Kreimeyer, Kory Woo, Emily Jane Ball, Robert Foster, Matthew Pandey, Abhishek Scott, John Botsis, Taxiarchis TI A new algorithmic approach for the extraction of temporal associations from clinical narratives with an application to medical product safety surveillance reports SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Natural language processing; Post-marketing surveillance; Temporal information ID INFORMATION EXTRACTION; TEXT; SYSTEM; EVENTS AB The sheer volume of textual information that needs to be reviewed and analyzed in many clinical settings requires the automated retrieval of key clinical and temporal information. The existing natural language processing systems are often challenged by the low quality of clinical texts and do not demonstrate the required performance. In this study, we focus on medical product safety report narratives and investigate the association of the clinical events with appropriate time information. We developed a novel algorithm for tagging and extracting temporal information from the narratives, and associating it with related events. The proposed algorithm minimizes the performance dependency on text quality by relying only on shallow syntactic information and primitive properties of the extracted event and time entities. We demonstrated the effectiveness of the proposed algorithm by evaluating its tagging and time assignment capabilities on 140 randomly selected reports from the US Vaccine Adverse Event Reporting System (VAERS) and the FDA (Food and Drug Administration) Adverse Event Reporting System (FAERS). We compared the performance of our tagger with the SUTime and HeidelTime taggers, and our algorithm's event time associations with the Temporal Awareness and Reasoning Systems for Question Interpretation (TARSQI). We further evaluated the ability of our algorithm to correctly identify the time information for the events in the 2012 Informatics for Integrating Biology and the Bedside (i2b2) Challenge corpus. For the time tagging task, our algorithm performed better than the SUTime and the HeidelTime taggers (F-measure in VAERS and FAERS: Our algorithm: 0.86 and 0.88, SUTime: 0.77 and 0.74, and HeidelTime 0.75 and 0.42, respectively). In the event-time association task, our algorithm assigned an inappropriate timestamp for 25% of the events, while the TARSQI toolkit demonstrated a considerably lower performance, assigning inappropriate timestamps in 61.5% of the same events. Our algorithm also supported the correct calculation of 69% of the event relations to the section time in the i2b2 testing set. Published by Elsevier Inc. C1 [Wang, Wei] Engility Corp, Chantilly, VA USA. [Kreimeyer, Kory; Woo, Emily Jane; Foster, Matthew; Pandey, Abhishek; Scott, John; Botsis, Taxiarchis] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,WO71-1233, Silver Spring, MD 20993 USA. [Ball, Robert] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Botsis, T (reprint author), US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,WO71-1233, Silver Spring, MD 20993 USA. EM Taxiarchis.Botsis@fda.hhs.gov FU US Department of Energy; US FDA; [U54LM008748] FX This work was supported in part by the appointments of Matthew Foster, Kory Kreimeyer, and Abhishek Pandey to the Research Participation Program administered by ORISE through an interagency agreement between the US Department of Energy and the US FDA.; Deidentified clinical records used in this research were provided by the i2b2 National Center for Biomedical Computing funded by U54LM008748 and were originally prepared for the Shared Tasks for Challenges in NLP for Clinical Data organized by Dr. Ozlem Uzuner, i2b2 and SUNY. NR 34 TC 0 Z9 0 U1 3 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 EI 1532-0480 J9 J BIOMED INFORM JI J. Biomed. Inform. PD AUG PY 2016 VL 62 BP 78 EP 89 DI 10.10161/j.jbi.2016.06.006 PG 12 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA DX9HI UT WOS:000384703800008 PM 27327528 ER PT J AU Hyland, KA Greiner, MA Qualls, LG Califf, RM Hernandez, AF Curtis, LH AF Hyland, Kristen A. Greiner, Melissa A. Qualls, Laura G. Califf, Robert M. Hernandez, Adrian F. Curtis, Lesley H. TI TRENDS IN THE CARE AND OUTCOMES OF MEDICARE BENEFICIARIES WITH TYPE 2 DIABETES, 2002-2011 SO ENDOCRINE PRACTICE LA English DT Article ID CARDIOVASCULAR-DISEASE; GLUCOSE CONTROL; UNITED-STATES; RISK-FACTORS; FOLLOW-UP; COMPLICATIONS; MELLITUS; ASSOCIATION; MANAGEMENT; ICD-9-CM AB Objective: To summarize characteristics of Medicare beneficiaries with type 2 diabetes and to describe changing trends in care and outcomes. Methods: We conducted a retrospective cohort study of a nationally representative 5% sample of fee-for-service Medicare beneficiaries 65 years and older with prevalent type 2 diabetes, between January 1, 2002, and December 31, 2011. The main outcome measures were diabetes-related screening tests, mortality, hospital admissions, dialysis, and lower extremity amputation. Results: The average age of Medicare beneficiaries with diabetes was 76.5 years, 56% were women, and 83% were white. Screening practices in beneficiaries with diabetes improved from 2002 to 2011, with rising rates of foot exams, renal screening, hemoglobin A1c tests, and lipid profile tests. The prevalence of nephropathy and neuropathy increased. Although inpatient admissions declined from 2002 to 2011, diabetes-related emergency department visits increased. Amputation and end-stage renal disease remained static, while 1-year mortality declined over the study period. Conclusion: In this medically complex group of patients with high comorbidity, we observed improvements in screening practices and room for further improvement. Although the mortality rate decreased, other outcomes did not improve consistently. Health care resource has changed over time, with decreased hospital admissions and increased emergency department visits. C1 [Hyland, Kristen A.; Greiner, Melissa A.; Qualls, Laura G.; Califf, Robert M.; Hernandez, Adrian F.; Curtis, Lesley H.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Hyland, Kristen A.; Califf, Robert M.; Hernandez, Adrian F.; Curtis, Lesley H.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Hyland, Kristen A.] Wilmington VA Hosp, Div Endocrinol Metab & Nutr, 1601 Kirkwood Highway, Wilmington, DE 19805 USA. [Califf, Robert M.] US FDA, Silver Spring, MD USA. RP Hyland, KA (reprint author), Wilmington VA Hosp, Div Endocrinol Metab & Nutr, 1601 Kirkwood Highway, Wilmington, DE 19805 USA. EM Kristenhylandmd@gmail.com FU Department of Health and Human Services, Centers for Medicare & Medicaid Services [1C1CMS331018-01-00] FX Funding/support: This publication was made possible by Cooperative Agreement Number 1C1CMS331018-01-00 from the Department of Health and Human Services, Centers for Medicare & Medicaid Services. NR 39 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD AUG PY 2016 VL 22 IS 8 BP 920 EP 934 DI 10.4158/EP15807.OR PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DX3NK UT WOS:000384279600002 PM 27042746 ER PT J AU Myers, M Smith, E Messenheimer, J Lewandowski, A Groesbeck, C Zhang, W Swain, T Chiesa, OA Deaver, CM AF Myers, M. Smith, E. Messenheimer, J. Lewandowski, A. Groesbeck, C. Zhang, W. Swain, T. Chiesa, O. A. Deaver, C. M. TI Impact of a nonsteroidal anti-inflammatory drug (NSAID) on serum MCP1 & clinical observations during lipopolysaccharide (LPS) induced inflammation in swine SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT International Congress of Immunology (ICI) CY AUG 21-26, 2016 CL Melbourne, AUSTRALIA C1 [Myers, M.] US FDA, Ctr Vet Med, Laurel, MD USA. [Smith, E.; Messenheimer, J.; Lewandowski, A.; Groesbeck, C.; Zhang, W.; Swain, T.; Chiesa, O. A.; Deaver, C. M.] US FDA, CVM Off Res, Laurel, 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 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD AUG PY 2016 VL 46 SU 1 SI SI MA 318 BP 390 EP 390 PG 1 WC Immunology SC Immunology GA DW4KA UT WOS:000383610400784 ER PT J AU Ippolito, GC Lavinder, JJ Lee, J Boutz, DR Kouiavskaia, DV Chromikova, V Krammer, F Chumakov, K Georgiou, G AF Ippolito, G. C. Lavinder, J. J. Lee, J. Boutz, D. R. Kouiavskaia, D., V Chromikova, V Krammer, F. Chumakov, K. Georgiou, G. TI Emerging technologies for the study of humoral mechanisms underlying human antibody responses SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT International Congress of Immunology (ICI) CY AUG 21-26, 2016 CL Melbourne, AUSTRALIA C1 [Ippolito, G. C.; Lavinder, J. J.; Lee, J.; Boutz, D. R.; Georgiou, G.] Univ Texas Austin, Austin, TX 78712 USA. [Kouiavskaia, D., V; Chumakov, K.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Chromikova, V; Krammer, F.] Icahn Sch Med Mt Sinai, City, New York, NY 10029 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 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD AUG PY 2016 VL 46 SU 1 SI SI MA 1222 BP 1172 EP 1172 PG 1 WC Immunology SC Immunology GA DW4KA UT WOS:000383610402756 ER PT J AU Kawamura, Y Gotoh, K Takeuchi, N Miura, H Nishimura, N Ozaki, T Yoshikawa, T AF Kawamura, Yoshiki Gotoh, Kensei Takeuchi, Nao Miura, Hiroki Nishimura, Naoko Ozaki, Takao Yoshikawa, Tetsushi TI Role of Matrix Metalloproteinases in the Pathogenesis of Childhood Gastroenteritis SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE viral gastroenteritis; bacterial enteritis; matrix metalloproteinase; tissue inhibitors of metalloproteinases ID INFLAMMATORY-BOWEL-DISEASE; ROTAVIRUS ANTIGENEMIA; INFECTION; CHILDREN; COLITIS; RNA AB Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been implicated in the pathogenesis of gastrointestinal diseases, such as rotavirus gastroenteritis (GE). Kinetics of these biomarkers were examined in paired serum samples collected from bacterial enteritis patients with Campylobacter (n = 2) and Salmonella (n = 4) and viral GE patients with rotavirus (n = 27), norovirus (n = 25), and adenovirus (n = 11). At the time of hospital admission, all viral GE patients demonstrated increased MMP-9 and decreased MMP-2 and TIMP-2 serum levels. In contrast to viral GE patients, serum MMP-9 levels were not elevated at the time of hospital admission but elevated at the time of discharge; serum MMP-2 and TIMP-2 levels were decreased both at the time of admission and discharge in bacterial enteritis patients. Interestingly, the kinetics of serum MMP-2, MMP-9, and TIMP-2 levels were similar among the viral GE patients but distinct from bacterial enteritis patients. Thus, the involvement of MMPs and TIMPs in the pathophysiology of gastrointestinal symptoms likely varies depending on the etiological agent. Further studies are required to verify whether the extent of the bacterial enteritis or age of the patients influences these serum biomarkers. (C) 2016 Wiley Periodicals, Inc. C1 [Kawamura, Yoshiki; Takeuchi, Nao; Miura, Hiroki; Yoshikawa, Tetsushi] Fujita Hlth Univ, Sch Med, Dept Pediat, Toyoake, Aichi, Japan. [Gotoh, Kensei; Nishimura, Naoko; Ozaki, Takao] Konan Kosei Hosp, Dept Pediat, Konan, Aichi, Japan. [Kawamura, Yoshiki] US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Kawamura, Y (reprint author), Fujita Hlth Univ, Sch Med, Dept Pediat, Toyoake, Aichi, Japan.; Kawamura, Y (reprint author), US FDA, Div Viral Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM kyoshiki3@hotmail.com NR 29 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0146-6615 EI 1096-9071 J9 J MED VIROL JI J. Med. Virol. PD AUG PY 2016 VL 88 IS 8 BP 1341 EP 1346 DI 10.1002/jmv.24473 PG 6 WC Virology SC Virology GA DW5FU UT WOS:000383669500010 PM 26765397 ER PT J AU Kazandjian, D Blumenthal, GM Luo, L He, K Fran, I Lemery, S Pazdur, R AF Kazandjian, Dickran Blumenthal, Gideon M. Luo, Lola He, Kun Fran, Ingrid Lemery, Steven Pazdur, Richard TI Benefit-Risk Summary of Crizotinib for the Treatment of Patients With ROS1 Alteration-Positive, Metastatic Non-Small Cell Lung Cancer SO ONCOLOGIST LA English DT Article ID TYROSINE KINASE ROS; REARRANGEMENTS; CHEMOTHERAPY; DOCETAXEL; TRIAL; ADENOCARCINOMA; GLIOBLASTOMA; NIVOLUMAB; FUSION; GENE AB On March 11, 2016, after an expedited 5-month review, the U.S. Food and Drug Administration expanded the crizotinib metastatic non-small cell lung cancer (mNSCLC) indication to include the treatment of patients whose tumors harbor a ROS1 rearrangement. The approval was based on a clinically meaningful, durable objective response rate (ORR) in a multicenter, single-arm clinical trial (ROS1 cohort of Trial PROFILE 1001) in patients with ROS1-positive mNSCLC. The trial enrolled 50 patients (age range: 25-77 years) whose tumors were prospectively determined to have a ROS1 gene rearrangement by break-apart fluorescence in situhybridization(96%) or reversetranscriptase polymerase chain reaction (4%) clinical trial assays. Crizotinib demonstrated an ORR of 66% (95% confidence interval [CI]: 51%-79%) with a median duration of response of 18.3 months by independent radiology review and 72% (95% CI: 58%-84%) by investigator review. Patients receivedcrizotinib250mg twice daily and had a median duration of exposure of 34.4 months. The toxicity profile in ROS1-positive patients was generally consistent with the randomized safety data in the U.S. Product Insert from two ALK-positive mNSCLC trials. The most common (>= 25%) adverse reactions and laboratory test abnormalities included vision disorders, elevation of alanine transaminase and aspartate transaminase levels, nausea, hypophosphatemia, diarrhea, edema, vomiting, constipation, neutropenia, and fatigue. There were no treatment-related deaths. A favorable benefit-to-risk evaluation led to the traditional approval of crizotinib for this new supplemental indication. C1 US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Kazandjian, D (reprint author), US FDA, White Oak Campus,10903 New Hampshire Ave,Bldg 22, Silver Spring, MD 20993 USA. EM Dickran.kazandjian@fda.hhs.gov NR 56 TC 5 Z9 5 U1 0 U2 0 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD AUG PY 2016 VL 21 IS 8 BP 974 EP 980 DI 10.1634/theoncologist.2016-0101 PG 7 WC Oncology SC Oncology GA DW1HC UT WOS:000383392900010 PM 27328934 ER PT J AU Prickett, TD Crystal, JS Cohen, CJ Pasetto, A Parkhurst, MR Gartner, JJ Yao, X Wang, R Gros, A Li, YF El-Gamil, M Trebska-McGowan, K Rosenberg, SA Robbins, PF AF Prickett, Todd D. Crystal, Jessica S. Cohen, Cyrille J. Pasetto, Anna Parkhurst, Maria R. Gartner, Jared J. Yao, Xin Wang, Rong Gros, Alena Li, Yong F. El-Gamil, Mona Trebska-McGowan, Kasia Rosenberg, Steven A. Robbins, Paul F. TI Durable Complete Response from Metastatic Melanoma after Transfer of Autologous T Cells Recognizing 10 Mutated Tumor Antigens SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID TRANSFER THERAPY; CANCER REGRESSION; CTLA-4 BLOCKADE; CUTTING EDGE; GENE-THERAPY; LUNG-CANCER; LYMPHOCYTES; IMMUNOTHERAPY; PATIENT; PERSISTENCE AB Immunotherapy treatment of patients with metastatic cancer has assumed a prominent role in the clinic. Durable complete response rates of 20% to 25% are achieved in patients with metastatic melanoma following adoptive cell transfer of T cells derived from metastatic lesions, responses that appear in some patients to be mediated by T cells that predominantly recognize mutated antigens. Here, we provide a detailed analysis of the reactivity of T cells administered to a patient with metastatic melanoma who exhibited a complete response for over 3 years after treatment. Over 4,000 nonsynonymous somatic mutations were identified by whole-exome sequence analysis of the patient's autologous normal and tumor cell DNA. Autologous B cells transfected with 720 mutated minigenes corresponding to the most highly expressed tumor cell transcripts were then analyzed for their ability to stimulate the administered T cells. Autologous tumor-infiltrating lymphocytes recognized 10 distinct mutated gene products, but not the corresponding wild-type products, each of which was recognized in the context of one of three different MHC class I restriction elements expressed by the patient. Detailed clonal analysis revealed that 9 of the top 20 most prevalent clones present in the infused T cells, comprising approximately 24% of the total cells, recognized mutated antigens. Thus, we have identified and enriched mutation-reactive T cells and suggest that such analyses may lead to the development of more effective therapies for the treatment of patients with metastatic cancer. (C) 2016 AACR. C1 [Prickett, Todd D.; Crystal, Jessica S.; Pasetto, Anna; Parkhurst, Maria R.; Gartner, Jared J.; Yao, Xin; Gros, Alena; Li, Yong F.; El-Gamil, Mona; Trebska-McGowan, Kasia; Rosenberg, Steven A.; Robbins, Paul F.] NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. [Cohen, Cyrille J.] Bar Ilan Univ, Lab Tumor Immunol & Immunotherapy, Ramat Gan, Israel. [Wang, Rong] US FDA, Bethesda, MD 20014 USA. RP Prickett, TD (reprint author), NCI, Ctr Canc Res, 10 Ctr Dr,Bldg 10,Room 3W-3864, Bethesda, MD 20892 USA. EM prickettt@mail.nih.gov OI Gros, Alena/0000-0002-1207-1880 FU Intramural NIH HHS [Z01 BC010984-01, Z99 CA999999] NR 38 TC 4 Z9 4 U1 4 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD AUG PY 2016 VL 4 IS 8 BP 669 EP 678 DI 10.1158/2326-6066.CIR-15-0215 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA DV6NE UT WOS:000383052800005 PM 27312342 ER PT J AU Jackson, BR Tarr, C Strain, E Jackson, KA Conrad, A Carleton, H Katz, LS Stroika, S Gould, LH Mody, RK Silk, BJ Beal, J Chen, Y Timme, R Doyle, M Fields, A Wise, M Tillman, G Defibaugh-Chavez, S Kucerova, Z Sabol, A Roache, K Trees, E Simmons, M Wasilenko, J Kubota, K Pouseele, H Klimke, W Besser, J Brown, E Allard, M Gerner-Smidt, P AF Jackson, Brendan R. Tarr, Cheryl Strain, Errol Jackson, Kelly A. Conrad, Amanda Carleton, Heather Katz, Lee S. Stroika, Steven Gould, L. Hannah Mody, Rajal K. Silk, Benjamin J. Beal, Jennifer Chen, Yi Timme, Ruth Doyle, Matthew Fields, Angela Wise, Matthew Tillman, Glenn Defibaugh-Chavez, Stephanie Kucerova, Zuzana Sabol, Ashley Roache, Katie Trees, Eija Simmons, Mustafa Wasilenko, Jamie Kubota, Kristy Pouseele, Hannes Klimke, William Besser, John Brown, Eric Allard, Marc Gerner-Smidt, Peter TI Implementation of Nationwide Real-time Whole-genome Sequencing to Enhance Listeriosis Outbreak Detection and Investigation SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE Listeria monocytogenes; DNA sequencing; outbreaks; foodborne diseases ID UNITED-STATES; FOODBORNE LISTERIOSIS; MONOCYTOGENES; SURVEILLANCE; PATHOGENS; STRAINS; CLONES; FOOD AB Listeria monocytogenes (Lm) causes severe foodborne illness (listeriosis). Previous molecular subtyping methods, such as pulsed-field gel electrophoresis (PFGE), were critical in detecting outbreaks that led to food safety improvements and declining incidence, but PFGE provides limited genetic resolution. A multiagency collaboration began performing real-time, whole-genome sequencing (WGS) on all US Lm isolates from patients, food, and the environment in September 2013, posting sequencing data into a public repository. Compared with the year before the project began, WGS, combined with epidemiologic and product trace-back data, detected more listeriosis clusters and solved more outbreaks (2 outbreaks in pre-WGS year, 5 in WGS year 1, and 9 in year 2). Whole-genome multilocus sequence typing and single nucleotide polymorphism analyses provided equivalent phylogenetic relationships relevant to investigations; results were most useful when interpreted in context of epidemiological data. WGS has transformed listeriosis outbreak surveillance and is being implemented for other foodborne pathogens. C1 [Jackson, Brendan R.; Tarr, Cheryl; Jackson, Kelly A.; Conrad, Amanda; Carleton, Heather; Katz, Lee S.; Stroika, Steven; Gould, L. Hannah; Mody, Rajal K.; Silk, Benjamin J.; Wise, Matthew; Kucerova, Zuzana; Sabol, Ashley; Roache, Katie; Trees, Eija; Besser, John; Gerner-Smidt, Peter] Ctr Dis Control & Prevent, 1600 Clifton Rd NE,MS C-09, Atlanta, GA 30329 USA. [Strain, Errol; Beal, Jennifer; Chen, Yi; Timme, Ruth; Doyle, Matthew; Fields, Angela; Brown, Eric; Allard, Marc] US FDA, College Pk, MD USA. [Tillman, Glenn; Simmons, Mustafa; Wasilenko, Jamie] US Food Safety & Inspect Serv, USDA, Athens, GA USA. [Defibaugh-Chavez, Stephanie] US Food Safety & Inspect Serv, USDA, Washington, DC 20250 USA. [Kubota, Kristy] Assoc Publ Hlth Labs, Silver Spring, MD USA. [Pouseele, Hannes] Appl Maths, Sint Martens Latem, Belgium. [Klimke, William] Natl Inst Biotechnol Informat, NIH, Bethesda, MD USA. RP Jackson, BR (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd NE,MS C-09, Atlanta, GA 30329 USA. EM brjackson1@cdc.gov FU CDC's Advanced Molecular Detection Initiative; CDC [U60HM000803]; FDA; USDA-FSIS; National Institute for Biotechnology Information; NIH, National Library of Medicine FX This work was supported by CDC, including CDC's Advanced Molecular Detection Initiative and Cooperative Agreement number U60HM000803; FDA; USDA-FSIS; National Institute for Biotechnology Information; and the Intramural Research Program of the NIH, National Library of Medicine. H. P. is an employee of Applied Maths. NR 30 TC 17 Z9 17 U1 17 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 1 PY 2016 VL 63 IS 3 BP 380 EP 386 DI 10.1093/cid/ciw242 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DV8QP UT WOS:000383201900014 PM 27090985 ER PT J AU Choi, D Chon, JW Kim, DH Kim, HS Yim, JH Song, KY Seo, KH AF Choi, Dasom Chon, Jung-Whan Kim, Dong-Hyeon Kim, Hong-Seok Yim, Jin-Hyeok Song, Kwang-Young Seo, Kun-Ho TI Improvement of Enterobacteriaceae enrichment broth by supplementation with sodium citrate for detection of Cronobacter sakazakii using real-time PCR SO FOOD SCIENCE AND BIOTECHNOLOGY LA English DT Article DE Cronobacter sakazakii; PCR inhibitor; sodium citrate; EE broth; real-time PCR ID FOODS; ASSAY; CULTURE AB Enterobacteriaceae enrichment (EE) broth, a selective enrichment medium for Cronobacter sakazakii detection, has been shown to contain polymerase chain reaction (PCR) inhibitors. Therefore, a modified enrichment broth was developed, wherein possible PCR inhibitors, brilliant green and bile salts, were substituted with sodium citrate. Investigations were conducted to determine whether realtime PCR detection of C. sakazakii in powdered infant formula and dried vegetables with this modified medium improved compared with conventional culture methods. The detection rate of the modified EE broth was significantly higher (p < 0.05) than that of the conventional EE broth for both types of food. For dried pumpkin samples, real-time PCR after culturing in modified EE broth yielded significantly higher detection rates and selectivity than those achieved using conventional culture in Druggan-Forsythe-Iversen agar. These results show that real-time PCR after enrichment in the modified EE broth may be an effective screening method for detection of C. sakazakii. C1 [Choi, Dasom; Kim, Dong-Hyeon; Kim, Hong-Seok; Yim, Jin-Hyeok; Song, Kwang-Young; Seo, Kun-Ho] Konkuk Univ, Coll Vet Med, KU Ctr Food Safety, Seoul 05029, South Korea. [Chon, Jung-Whan] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Seo, KH (reprint author), Konkuk Univ, Coll Vet Med, KU Ctr Food Safety, Seoul 05029, South Korea. EM bracstu3@konkuk.ac.kr FU National Research Foundation of Korea (NRF) grant - Korea government (MSIP) [2015R1A2A2A05001288] FX This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2015R1A2A2A05001288). NR 13 TC 0 Z9 0 U1 3 U2 3 PU KOREAN SOCIETY FOOD SCIENCE & TECHNOLOGY-KOSFOST PI SEOUL PA #605, KOREA SCI TECHNOL CENT, 635-4 YEOKSAM-DONG, KANGNAM-GU, SEOUL, 135-703, SOUTH KOREA SN 1226-7708 EI 2092-6456 J9 FOOD SCI BIOTECHNOL JI Food Sci. Biotechnol. PD AUG PY 2016 VL 25 IS 4 BP 1205 EP 1209 DI 10.1007/s10068-016-0191-7 PG 5 WC Food Science & Technology SC Food Science & Technology GA DV5DW UT WOS:000382947400037 ER PT J AU Kang, L Liu, AY Tian, LL AF Kang, Le Liu, Aiyi Tian, Lili TI Linear combination methods to improve diagnostic/prognostic accuracy on future observations SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE Multiple biomarkers; receiver operating characteristic curve; area under the receiver operating characteristic curve; linear combination; diagnostic; prognostic accuracy ID OPERATING CHARACTERISTIC CURVE; LOGISTIC-REGRESSION; DISCRIMINANT-ANALYSIS; BIOMARKERS; CLASSIFICATION; PROBABILITY; EFFICIENCY; INFERENCE; SUBJECT; MARKERS AB Multiple diagnostic tests or biomarkers can be combined to improve diagnostic accuracy. The problem of finding the optimal linear combinations of biomarkers to maximise the area under the receiver operating characteristic curve has been extensively addressed in the literature. The purpose of this article is threefold: (1) to provide an extensive review of the existing methods for biomarker combination; (2) to propose a new combination method, namely, the nonparametric stepwise approach; (3) to use leave-one-pair-out cross-validation method, instead of re-substitution method, which is overoptimistic and hence might lead to wrong conclusion, to empirically evaluate and compare the performance of different linear combination methods in yielding the largest area under receiver operating characteristic curve. A data set of Duchenne muscular dystrophy was analysed to illustrate the applications of the discussed combination methods. C1 [Kang, Le] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Bethesda, MD USA. [Tian, Lili] SUNY Buffalo, Dept Biostat, 706 Kimball Tower,3435 Main St, Buffalo, NY 14214 USA. RP Tian, LL (reprint author), SUNY Buffalo, Dept Biostat, 706 Kimball Tower,3435 Main St, Buffalo, NY 14214 USA. EM ltian@buffalo.edu OI Liu, Aiyi/0000-0002-6618-5082 FU US Department of Energy; US Food and Drug Administration; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX Le Kang 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. Aiyi Liu was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. The opinions expressed are solely those of the authors and not necessarily those of the Editors. The authors thank the referees for helpful discussion and comments. A supplementary R code to implement the methods described in this article is in the Appendix. NR 32 TC 4 Z9 4 U1 8 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 AUG PY 2016 VL 25 IS 4 SI SI BP 1359 EP 1380 DI 10.1177/0962280213481053 PG 22 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA DV4CA UT WOS:000382871200018 PM 23592714 ER PT J AU Ma, XY Nie, L Cole, SR Chu, HT AF Ma, Xiaoye Nie, Lei Cole, Stephen R. Chu, Haitao TI Statistical methods for multivariate meta-analysis of diagnostic tests: An overview and tutorial SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE Meta-analysis; diagnostic test; gold standard; generalized linear mixed models ID SYSTEMATIC REVIEWS; GOLD STANDARD; TEST ACCURACY; ROC CURVE; DISEASE PREVALENCE; LIKELIHOOD RATIOS; SPARSE DATA; SPECIFICITY; SENSITIVITY; MODEL AB In this article, we present an overview and tutorial of statistical methods for meta-analysis of diagnostic tests under two scenarios: (1) when the reference test can be considered a gold standard and (2) when the reference test cannot be considered a gold standard. In the first scenario, we first review the conventional summary receiver operating characteristics approach and a bivariate approach using linear mixed models. Both approaches require direct calculations of study-specific sensitivities and specificities. We next discuss the hierarchical summary receiver operating characteristics curve approach for jointly modeling positivity criteria and accuracy parameters, and the bivariate generalized linear mixed models for jointly modeling sensitivities and specificities. We further discuss the trivariate generalized linear mixed models for jointly modeling prevalence, sensitivities and specificities, which allows us to assess the correlations among the three parameters. These approaches are based on the exact binomial distribution and thus do not require an ad hoc continuity correction. Lastly, we discuss a latent class random effects model for meta-analysis of diagnostic tests when the reference test itself is imperfect for the second scenario. A number of case studies with detailed annotated SAS code in MIXED and NLMIXED procedures are presented to facilitate the implementation of these approaches. C1 [Ma, Xiaoye; Chu, Haitao] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Nie, Lei] Off Biometr OTS CDER FDA, Div Biometr 4, Silver Spring, MD USA. [Cole, Stephen R.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP Chu, HT (reprint author), Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. EM chux0051@umn.edu FU US Department of Health and Human Services Agency for Healthcare Research and Quality from the US National Cancer Institute [R03HS020666, P01CA142538, P30CA77598]; US National Institute of Allergy and Infectious Diseases [R21AI103012] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported in part by the US Department of Health and Human Services Agency for Healthcare Research and Quality Grant R03HS020666, P01CA142538 and P30CA77598 from the US National Cancer Institute, and R21AI103012 from the US National Institute of Allergy and Infectious Diseases. NR 41 TC 5 Z9 5 U1 6 U2 6 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 AUG PY 2016 VL 25 IS 4 SI SI BP 1596 EP 1619 DI 10.1177/0962280213492588 PG 24 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA DV4CA UT WOS:000382871200031 PM 23804970 ER PT J AU Cervenakoya, L Saa, P Yakoyleva, O Vasilyeva, I de Castro, J Brown, P Dodd, R AF Cervenakoya, Larisa Saa, Paula Yakoyleva, Oksana Vasilyeva, Irina de Castro, Jorge Brown, Paul Dodd, Roger TI Are prions transported by plasma exosomes? SO TRANSFUSION AND APHERESIS SCIENCE LA English DT Review DE Prion protein; Blood; Plasma; Extracellular vesicles; Prion infectivity ID CREUTZFELDT-JAKOB-DISEASE; TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY; MISFOLDING CYCLIC AMPLIFICATION; CHRONIC WASTING DISEASE; INFECTIOUS PRIONS; EXTRACELLULAR VESICLES; BLOOD INFECTIVITY; PROTEIN; VARIANT; SCRAPIE AB Blood has been shown to contain disease-associated misfolded prion protein (PrPTsE) in animals naturally and experimentally infected with various transmissible spongiform encephalopathy (TSE) agents, and in humans infected with variant Creutzfeldt-Jakob disease (vCJD). Recently, we have demonstrated PrPTsE in extracellular vesicle preparations (EVs) containing exosomes from plasma of mice infected with mouse-adapted vCJD by Protein Misfolding Cyclic Amplification (PMCA). Here we report the detection of PrPTsE by PMCA in EVs from plasma of mice infected with Fukuoka-1 (FU), an isolate from a Gerstmann-Straussler-Scheinker disease patient. We used Tga20 transgenic mice that over-express mouse cellular prion protein, to assay by intracranial injections the level of infectivity in a FU infected brain homogenate from wild-type mice (FU-BH), and in blood cellular components (BCC), consisting of red blood cells, white blood cells and platelets, plasma EVs, and plasma EVs subjected to multiple rounds of PMCA. Only FU-BH and plasma EVs from FU-infected mice subjected to PMCA that contained PrPTsE transmitted disease to Tga20 mice. Plasma EVs not subjected to PMCA and BCC from FU-infected mice failed to transmit disease. These findings confirm the high sensitivity of PMCA for PrPTsE detection in plasma EVs and the efficiency of this in vitro method to produce highly infectious prions. The results of our study encourage further research to define the role of EVs and, more specifically exosomes, as blood-borne carriers of PrPTsE. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Cervenakoya, Larisa; Saa, Paula; Yakoyleva, Oksana; Vasilyeva, Irina; de Castro, Jorge; Dodd, Roger] Amer Natl Red Cross, Sci Affairs, Rockville, MD USA. [Yakoyleva, Oksana] US FDA, Lab Bacterial & Transmissible Spongiforrn Encepha, DETTD, OBRR,CBER, Silver Spring, MD USA. [de Castro, Jorge] Meso Scale Diagnost LLC, Rockville, MD USA. [Brown, Paul] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Cervenakoya, L (reprint author), Amer Natl Red Cross, Sci Affairs, JH Holland Lab, 15601 Crabbs Branch Way, Rockville, MD 20855 USA. EM larisa.cervenakova@redcross.org FU Fondation pour la Recherche Medicale/Foundation Alliance BioSecure, France; American National Red Cross FX We are grateful to Professor Charles Weissmann for permission to use Tga20 mice and Prnp0/0 mice, Dr. Ragy Ragheb (Malvern Instruments) for NTA analysis of mouse plasma EV samples, Mr. Carroll McKenzie and Mr. Anton Cervenak for excellent technical assistance, and Mr. Craig Mayer and Mr. Ward B. Cunningham for daily animal care. This study was funded by the Fondation pour la Recherche Medicale/Foundation Alliance BioSecure, France and by the American National Red Cross. NR 87 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1473-0502 J9 TRANSFUS APHER SCI JI Transfus. Apher. Sci. PD AUG PY 2016 VL 55 IS 1 BP 70 EP 83 DI 10.1016/j.transci.2016.07.013 PG 14 WC Hematology SC Hematology GA DV5YW UT WOS:000383007600010 PM 27499183 ER PT J AU Kirsch, GE Fedorov, NB Kuryshev, YA Liu, ZQ Armstrong, LC Orr, MS AF Kirsch, Glenn E. Fedorov, Nikolai B. Kuryshev, Yuri A. Liu, Zhiqi Armstrong, Lucas C. Orr, Michael S. TI Electrophysiology-Based Assays to Detect Subtype-Selective Modulation of Human Nicotinic Acetylcholine Receptors SO ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES LA English DT Article ID FUNCTIONAL-CHARACTERIZATION; PATCH-CLAMP; IN-VITRO; BRAIN; DEPENDENCE; AGONISTS; IDENTIFICATION; DIPYRIDAMOLE; ASSOCIATION; ANTAGONISTS AB The Family Smoking Prevention and Tobacco Control Act of 2009 (Public Law 111-31) gave the US Food and Drug Administration (FDA) the responsibility for regulating tobacco products. Nicotine is the primary addictive component of tobacco and its effects can be modulated by additional ingredients in manufactured products. Nicotine acts by mimicking the neurotransmitter acetylcholine on neuronal nicotinic acetylcholine receptors (nAChRs), which function as ion channels in cholinergic modulation of neurotransmission. Subtypes within the family of neuronal nAChRs are defined by their alpha- and beta-subunit composition. The subtype-selective profiles of tobacco constituents are largely unknown, but could be essential for understanding the physiological effects of tobacco products. In this report, we report the development and validation of electrophysiology-based high-throughput screens (e-HTS) for human nicotinic subtypes, alpha 3 beta 4, alpha 3 beta 4 alpha 5, alpha 4 beta 2, and alpha 7 stably expressed in Chinese Hamster Ovary cells. Assessment of agonist sensitivity and acute desensitization gave results comparable to those obtained by conventional manual patch clamp electrophysiology assays. The potency of reference antagonists for inhibition of the receptor channels and selectivity of positive allosteric modulators also were very similar between e-HTS and conventional manual patch voltage clamp data. Further validation was obtained in pilot screening of a library of FDA-approved drugs that identified a7 subtype-selective positive allosteric modulation by novel compounds. These assays provide new tools for profiling of nicotinic receptor selectivity. C1 [Kirsch, Glenn E.; Fedorov, Nikolai B.; Kuryshev, Yuri A.; Liu, Zhiqi; Armstrong, Lucas C.] Charles River Discovery, 14656 Neo Pkwy, Cleveland, OH 44128 USA. [Orr, Michael S.] US FDA, Ctr Tobacco Prod, Silver Spring, MD USA. RP Armstrong, LC (reprint author), Charles River Discovery, 14656 Neo Pkwy, Cleveland, OH 44128 USA. EM luke.armstrong@crl.com NR 48 TC 0 Z9 0 U1 2 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-658X EI 1557-8127 J9 ASSAY DRUG DEV TECHN JI ASSAY DRUG DEV. TECHNOL. PD AUG PY 2016 VL 14 IS 6 BP 333 EP 344 DI 10.1089/adt.2015.688 PG 12 WC Biochemical Research Methods; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA DT0YE UT WOS:000381208100003 PM 27505073 ER PT J AU Khuda, SE Sharma, GM Gaines, D Do, AB Pereira, M Chang, M Ferguson, M Williams, KM AF Khuda, Sefat E. Sharma, Girdhari M. Gaines, Dennis Do, Andrew B. Pereira, Marion Chang, Michael Ferguson, Martine Williams, Kristina M. TI Survey of undeclared egg allergen levels in the most frequently recalled food types (including products bearing precautionary labelling) SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE Food allergy; egg allergen; allergen labelling; precautionary labelling; ELISA ID IMMUNOCHEMICAL ANALYTICAL METHODS; MULTIPLE ALLERGENS; RISK-ASSESSMENT; PEANUT; RECOVERY; COOKIES; MILK AB Since the number of recalls involving undeclared allergens is commonly associated with bakery and snack foods, we aimed to determine the frequency of egg allergens in a large number of these products using two commercial enzyme-linked immunosorbent assay (ELISA) methods. Samples were chosen that either had no egg identified on the product label or which had an egg precautionary statement. Among all samples, egg protein was detected in 5% of products using a Morinaga (MO) kit and 1% of products using a R-Biopharm (RB) kit. For bakery samples, egg protein was detected in 6% of 363 samples with no precautionary labelling (6% by MO and 1% by RB kit) and 12% of 80 samples which had precautionary labelling. For snack samples, egg protein was detected in 2% of 371 samples with no precautionary labelling (2% by MO and <1% by RB kit) and 5% of 21 samples which had precautionary labelling. The disagreement rates between two methods were 5.2% for bakery products and 2.6% for snack products. The sample repeatability was at an acceptable level for bakery (<12.5%) and snack foods (<7.5%) for each method. The relative standard deviation between test kits was high (103.1%) for bakery foods. Four bakery products without precautionary labelling had a higher level of egg protein per serving compared with the eliciting dose (ED10 of 3.7mg protein) for egg allergic patients. These results highlight the fact that detection methodology plays a vital role for accurate labelling control and mitigation of risk for egg allergic consumers. C1 [Khuda, Sefat E.; Sharma, Girdhari M.; Gaines, Dennis; Do, Andrew B.; Pereira, Marion; Williams, Kristina M.] US FDA, Ctr Food Safety & Appl Nutr, 8301 Muirkirk Rd, Laurel, MD 20708 USA. [Ferguson, Martine] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Chang, Michael] Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 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 27 TC 0 Z9 0 U1 7 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PD AUG PY 2016 VL 33 IS 8 BP 1265 EP 1273 DI 10.1080/19440049.2016.1198051 PG 9 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA DV0DW UT WOS:000382589200001 PM 27269052 ER PT J AU Khuda, SE Sharma, GM Gaines, D Do, AB Pereira, M Chang, M Ferguson, M Williams, KM AF Khuda, Sefat E. Sharma, Girdhari M. Gaines, Dennis Do, Andrew B. Pereira, Marion Chang, Michael Ferguson, Martine Williams, Kristina M. TI Survey of undeclared soy allergen levels in the most frequently recalled food categories with or without precautionary labelling SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE Food allergy; soy allergen; allergen labelling; precautionary labelling; ELISA ID RISK-ASSESSMENT; PEANUT; CHALLENGES; PRODUCTS; ELISA; WHEAT AB A comprehensive study was designed to determine the frequency and levels of soy allergen in packaged bakery and snack food products. A representative sample of products with no soy allergen disclosed on the label was analysed using two widely used enzyme-linked immunosorbent assay (ELISA) methods. Samples were chosen that either had no soy identified on the product label or which had a soy precautionary statement. Among 558 bakery and snack products, soy protein was detected in 17% of the products using the Neogen (NE) kit and 11% of the products using the Elisa Systems (ES) kit. The disagreement rates between kits were 8.8% for bakery products and 3.3% for snack products. Overall soy protein was detected at higher frequency in bakery products than in snack foods. Among 284 bakery samples, soy protein was detected in 25% of the samples with no precautionary statement and 19% of the samples which had a precautionary statement. Among 274 snack samples, soy protein was detected in 11% of the samples with no precautionary statement and 9% of the samples which had a precautionary statement. The sample repeatability was at an acceptable level (<9%) for each method and food commodity. The reproducibility between kits was 23% for bakery foods and 36% for snack foods. None of the bakery (21) and snack (6) products without precautionary labelling (measured level > 5 ppm) had a higher level of soy protein per serving compared with the eliciting dose(10) (ED10) of 10.6mg for soy allergic patients. But the level of soy protein per serving may be clinically relevant to a subpopulation of soy allergic patients if a more stringent eliciting dose is applied. These findings emphasise that suitable detection methodologies and references doses are crucial for labelling accuracy and the safety of soy allergic consumers. C1 [Khuda, Sefat E.; Sharma, Girdhari M.; Gaines, Dennis; Do, Andrew B.; Pereira, Marion; Williams, Kristina M.] US FDA, Ctr Food Safety & Appl Nutr, 8301 Muirkirk Rd, Laurel, MD 20708 USA. [Ferguson, Martine] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Chang, Michael] Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 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 27 TC 0 Z9 0 U1 6 U2 7 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PD AUG PY 2016 VL 33 IS 8 BP 1274 EP 1282 DI 10.1080/19440049.2016.1207809 PG 9 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA DV0DW UT WOS:000382589200002 PM 27470934 ER PT J AU Viana, SD Valero, J Rodrigues-Santos, P Couceiro, P Silva, AM Carvalho, F Ali, SF Fontes-Ribeiro, CA Pereira, FC AF Viana, Sofia D. Valero, Jorge Rodrigues-Santos, Paulo Couceiro, Patricia Silva, Andrea M. Carvalho, Felix Ali, Syed F. Fontes-Ribeiro, Carlos A. Pereira, Frederico C. TI Regulation of striatal astrocytic receptor for advanced glycation end-products variants in an early stage of experimental Parkinson's disease SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE astrocytes; MPTP; RAGE isoforms; S100B; striatum ID TOLL-LIKE RECEPTOR; MPTP-TREATED MICE; OXIDATIVE STRESS; KAPPA-B; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE MODEL; MOUSE ASTROCYTES; SPLICE VARIANTS; RAGE; EXPRESSION; NEUROTOXICITY AB Convincing evidence indicates that advanced glycation end-products and danger-associated protein S100B play a role in Parkinson's disease (PD). These agents operate through the receptor for advanced glycation end-products (RAGE), which displays distinct isoforms playing protective/deleterious effects. However, the nature of RAGE variants has been overlooked in PD studies. Hence, we attempted to characterize RAGE regulation in early stages of PD striatal pathology. A neurotoxin-based rodent model of PD was used in this study, through administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57BL/6 mice. Animals were killed 6h post-MPTP to assess S100B/RAGE contents (RT-qPCR, ELISA) and RAGE isoform density (WB) and cellular distribution (immunohistochemistry). Dopaminergic and gliotic status were also mapped (HPLC-ED, WB, immunohistochemistry). At this preliminary stage of MPTP-induced PD in mice, RAGE inhibitory isoforms were increased whereas full-length RAGE was not affected. This putative cytoprotective RAGE phenotype paired an inflammatory and pro-oxidant setting fueling DAergic denervation. Increased RAGE inhibitory variants occur in astrocytes showing higher S100B density but no overt signs of hypertrophy or NF-B activation, a canonical effector of RAGE. These findings expand our understanding of the toxic effect of MPTP on striatum and offer first invivo evidence of RAGE being a responder in early stages of astrogliosis dynamics, supporting a protective rather tissue-destructive phenotype of RAGE in the initial phase of PD degeneration. These data lay the groundwork for future studies on the relevance of astrocytic RAGE in DAergic neuroprotection strategies. C1 [Viana, Sofia D.; Silva, Andrea M.; Fontes-Ribeiro, Carlos A.; Pereira, Frederico C.] Univ Coimbra, Lab Pharmacol & Expt Therapeut, Fac Med, IBILI, Subunit 1 Polo 3, P-3000548 Coimbra, Portugal. [Viana, Sofia D.; Valero, Jorge; Silva, Andrea M.; Fontes-Ribeiro, Carlos A.; Pereira, Frederico C.] Univ Coimbra, CNC IBILI, Coimbra, Portugal. [Viana, Sofia D.] ESTESC Coimbra Hlth Sch, Polytech Inst Coimbra, Pharm, Coimbra, Portugal. [Valero, Jorge] Achucarro Basque Ctr Neurosci, Zamudio, Bizkaia, Spain. [Valero, Jorge] Ikerbasque Fdn, Bilbao, Bizkaia, Spain. [Rodrigues-Santos, Paulo] Univ Coimbra, Inst Immunol, Fac Med, Coimbra, Portugal. [Rodrigues-Santos, Paulo; Couceiro, Patricia] Univ Coimbra, Immunol & Oncol Lab, Ctr Neurosci & Cell Biol CNC, Coimbra, Portugal. [Rodrigues-Santos, Paulo] Univ Coimbra, Fac Med, Ctr Invest Environm Genet & Oncobiol CIMAGO, Coimbra, Portugal. [Carvalho, Felix] Univ Porto, Fac Pharm, Dept Biol Sci, UCIBIO REQUIMTE,Lab Toxicol, Oporto, Portugal. [Ali, Syed F.] US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Pereira, FC (reprint author), Univ Coimbra, Lab Pharmacol & Expt Therapeut, Fac Med, IBILI, Subunit 1 Polo 3, P-3000548 Coimbra, Portugal. EM fredcp@ci.uc.pt RI Carvalho, Felix/D-4914-2013; OI Carvalho, Felix/0000-0003-3858-3494; Viana, Sofia/0000-0002-1316-1319; Valero, Jorge/0000-0001-6072-3313 FU Fundacao para a Ciencia e Tecnologia (FCT, Portugal) [PEst-C/SAU/UI3282/2013, UID/NEU/04539/2013]; COMPETE-FEDER; 'Programa Operacional Tematico Fatores de Competitividade (COMPETE/QREN)' [EXPL/DTP-DES/0104/2013]; 'Fundo Comunitario Europeu (FEDER)'; FCT, Portugal [SFRH/BD/78166/2011] FX This research was supported by Fundacao para a Ciencia e Tecnologia (FCT, Portugal), Strategic Project PEst-C/SAU/UI3282/2013, UID/NEU/04539/2013, COMPETE-FEDER and by EXPL/DTP-DES/0104/2013 under the frame of 'Programa Operacional Tematico Fatores de Competitividade (COMPETE/QREN)' and 'Fundo Comunitario Europeu (FEDER)'. SDV is a recipient of a PhD grant from FCT, Portugal (SFRH/BD/78166/2011). The experiments comply with the current laws of Portugal. We also acknowledge Dr. Cristina Rego for gifting antibodies and allowing us to use her laboratory space including the equipment for immunohistochemistry experiments. Authors have no conflict of interest to declare. NR 62 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 IS 4 BP 598 EP 609 DI 10.1111/jnc.13682 PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DU8ZZ UT WOS:000382507300010 PM 27221633 ER PT J AU Bhattacharya, P Dey, R Dagur, PK Joshi, AB Ismail, N Gannavaram, S Debrabant, A Akue, AD KuKuruga, MA Selvapandiyan, A McCoy, JP Nakhasi, HL AF Bhattacharya, Parna Dey, Ranadhir Dagur, Pradeep K. Joshi, Amritanshu B. Ismail, Nevien Gannavaram, Sreenivas Debrabant, Alain Akue, Adovi D. KuKuruga, Mark A. Selvapandiyan, Angamuthu McCoy, John Philip, Jr. Nakhasi, Hira L. TI Live Attenuated Leishmania donovani Centrin Knock Out Parasites Generate Non-inferior Protective Immune Response in Aged Mice against Visceral Leishmaniasis SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID CD8(+) T-CELLS; DENDRITIC CELLS; NITRIC-OXIDE; ELDERLY INDIVIDUALS; DELETED PARASITES; VARICELLA VACCINE; PERIPHERAL-BLOOD; INNATE IMMUNITY; TH1 RESPONSE; IN-VIVO AB Background Visceral leishmaniasis (VL) caused by the protozoan parasite Leishmania donovani causes severe disease. Age appears to be critical in determining the clinical outcome of VL and at present there is no effective vaccine available against VL for any age group. Previously, we showed that genetically modified live attenuated L. donovani parasites (LdCen-/-) induced a strong protective innate and adaptive immune response in young mice. In this study we analyzed LdCen-/- parasite mediated modulation of innate and adaptive immune response in aged mice (18 months) and compared to young (2 months) mice. Methodology Analysis of innate immune response in bone marrow derived dendritic cells (BMDCs) from both young and aged mice upon infection with LdCen-/- parasites, showed significant enhancement of innate effector responses, which consequently augmented CD4(+) Th1 cell effector function compared to LdWT infected BMDCs in vitro. Similarly, parasitized splenic dendritic cells from LdCen-/- infected young and aged mice also revealed induction of proinflammatory cytokines (IL-12, IL-6, IFN-gamma and TNF) and subsequent down regulation of anti- inflammatory cytokine (IL-10) genes compared to LdWT infected mice. We also evaluated in vivo protection of the LdCen-/- immunized young and aged mice against virulent L. donovani challenge. Immunization with LdCen-/- induced higher IgG2a antibodies, lympho-proliferative response, pro- and anti-inflammatory cytokine responses and stimulated splenocytes for heightened leishmanicidal activity associated with nitric oxide production in young and aged mice. Furthermore, upon virulent L. donovani challenge, LdCen-/- immunized mice from both age groups displayed multifunctional Th1-type CD4 and cytotoxic CD8 T cells correlating to a significantly reduced parasite burden in the spleen and liver compared to naive mice. It is interesting to note that even though there was no difference in the LdCen-/-induced innate response in dendritic cells between aged and young mice; the adaptive response specifically in terms of T cell and B cell activation in aged animals was reduced compared to young mice which correlated with less protection in old mice compared to young mice. Conclusions Taken together, LdCen-/-immunization induced a significant but diminished host protective response in aged mice after challenge with virulent L. donovani parasites compared to young mice. C1 [Bhattacharya, Parna; Dey, Ranadhir; Joshi, Amritanshu B.; Ismail, Nevien; Gannavaram, Sreenivas; Debrabant, Alain; Nakhasi, Hira L.] US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Dagur, Pradeep K.; McCoy, John Philip, Jr.] NHLBI, Flow Cytometry Core, NIH, Bldg 10, Bethesda, MD 20892 USA. [Akue, Adovi D.; KuKuruga, Mark A.] Ctr Biol Evaluat & Res, Off Vaccines Res & Review, Silver Spring, MD USA. [Selvapandiyan, Angamuthu] Inst Mol Med, New Delhi, India. RP Bhattacharya, P; Nakhasi, HL (reprint author), US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Parna.Bhattacharya@fda.hhs.gov; Hira.Nakhasi@fda.hhs.gov FU Intramural Research Program at the Center for Biologics Evaluation and Research, FDA FX This research was supported in part by the Intramural Research Program at the Center for Biologics Evaluation and Research, FDA (PB, RD, NI, ABJ, SG, AD, HLN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 82 TC 0 Z9 0 U1 5 U2 5 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 AUG PY 2016 VL 10 IS 8 AR e0004963 DI 10.1371/journal.pntd.0004963 PG 28 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DU7JR UT WOS:000382390800079 PM 27580076 ER PT J AU Palazzi, X Burkhardt, JE Caplain, H Dellarco, V Fant, P Foster, JR Francke, S Germann, P Groters, S Harada, T Harleman, J Inui, K Kaufmann, W Lenz, B Nagai, H Pohlmeyer-Esch, G Schulte, A Skydsgaard, M Tomlinson, L Wood, CE Yoshida, M AF Palazzi, Xavier Burkhardt, John E. Caplain, Henri Dellarco, Vicki Fant, Pierluigi Foster, John R. Francke, Sabine Germann, Paul Groeters, Sibylle Harada, Takanori Harleman, Johannes Inui, Kosei Kaufmann, Wolfgang Lenz, Barbara Nagai, Hirofumi Pohlmeyer-Esch, Gabriele Schulte, Agnes Skydsgaard, Mikala Tomlinson, Lindsay Wood, Charles E. Yoshida, Midori TI Characterizing "Adversity" of Pathology Findings in Nonclinical Toxicity Studies: Results from the 4th ESTP International Expert Workshop SO TOXICOLOGIC PATHOLOGY LA English DT Review DE adversity; adverse effect; toxicologic pathology; LOAEL; NOAEL; hazard identification ID RISK-ASSESSMENT; TOXICOLOGIC PATHOLOGY; OUTCOME PATHWAYS; IPCS FRAMEWORK; POSITION PAPER; LESIONS; MODE; RATS; NEPHROPATHY; ADAPTATION AB The identification of adverse health effects has a central role in the development and risk/safety assessment of chemical entities and pharmaceuticals. There is currently a need for better alignment regarding how nonclinical adversity is determined and characterized. The European Society of Toxicologic Pathology (ESTP) therefore coordinated a workshop to review available definitions of adversity, weigh determining and qualifying factors of adversity based on case examples, and recommend a practical approach to define and characterize adversity in toxicology reports, to serve as a valuable prerequisite for future organ- or lesion-specific workshops planned by the ESTP. C1 [Palazzi, Xavier; Caplain, Henri] Sanofi, Vitry Sur Seine, France. [Burkhardt, John E.; Tomlinson, Lindsay] Pfizer Inc, Groton, CT 06340 USA. [Fant, Pierluigi] WIL Res, Lyon, France. [Foster, John R.] Tox Path Sci, Congleton, Cheshire, England. [Francke, Sabine] US FDA, College Pk, MD USA. [Germann, Paul] AbbVie, Ludwigshafen, Germany. [Groeters, Sibylle] BASF, Ludwigshafen, Germany. [Harada, Takanori] Inst Environm Toxicol, Ibaraki, Japan. [Harleman, Johannes] Fresenius Kabi, Bad Homburg, Germany. [Inui, Kosei] Ishihara Sangyo Kaisha Ltd, Osaka, Japan. [Kaufmann, Wolfgang] Merck, Darmstadt, Germany. [Lenz, Barbara] Roche Pharmaceut Res & Early Dev, Basel, Switzerland. [Nagai, Hirofumi] Takeda Pharmaceut Co Ltd, Fujisawa, Kanagawa, Japan. [Pohlmeyer-Esch, Gabriele] Kaleidis Consultancy, St Louis, France. [Schulte, Agnes] Fed Inst Risk Assessment, Berlin, Germany. [Skydsgaard, Mikala] Novo Nordisk AS, Malov, Denmark. [Wood, Charles E.] US EPA, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Yoshida, Midori] Food Safety Commiss, Cabinet Off, Tokyo, Japan. RP Palazzi, X (reprint author), Sanofi R&D, 13 Quai Jules Guesde, F-94400 Vitry Sur Seine, France. EM xavier.palazzi@sanofi.com FU ESTP FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This workshop was coordinated and supported by ESTP and hosted by Sanofi (Centre de Recherche de Vitry-Alfortville, France). NR 46 TC 3 Z9 3 U1 3 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD AUG PY 2016 VL 44 IS 6 BP 810 EP 824 DI 10.1177/0192623316642527 PG 15 WC Pathology; Toxicology SC Pathology; Toxicology GA DS7ZE UT WOS:000381001300002 PM 27102650 ER PT J AU Richard, AM Judson, RS Houck, KA Grulke, CM Volarath, P Thillainadarajah, I Yang, CH Rathman, J Martin, MT Wambaugh, JF Knudsen, TB Kancherla, J Mansouri, K Patlewicz, G Williams, AJ Little, SB Crofton, KM Thomas, RS AF Richard, Ann M. Judson, Richard S. Houck, Keith A. Grulke, Christopher M. Volarath, Patra Thillainadarajah, Inthirany Yang, Chihae Rathman, James Martin, Matthew T. Wambaugh, John F. Knudsen, Thomas B. Kancherla, Jayaram Mansouri, Kamel Patlewicz, Grace Williams, Antony J. Little, Stephen B. Crofton, Kevin M. Thomas, Russell S. TI ToxCast Chemical Landscape: Paving the Road to 21st Century Toxicology SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID IN-VITRO ASSAYS; ENVIRONMENTAL CHEMICALS; CHEMISTRY DATABASES; DRUG DISCOVERY; TOXICITY; CARCINOGENICITY; PROTECTION; KNOWLEDGE; RESOURCE; RECEPTOR AB The U.S. Environmental Protection Agency's (EPA) ToxCast program is testing a large library of Agency-relevant chemicals using in vitro high-throughput screening (HTS) approaches to support the development of improved toxicity prediction models. Launched in 2007, Phase I of the program screened 310 chemicals, mostly pesticides, across hundreds of ToxCast assay end points. In Phase II, the ToxCast library was expanded to 1878 chemicals, culminating in the public release of screening data at the end of 2013. Subsequent expansion in Phase III has resulted in more than 3800 chemicals actively undergoing ToxCast screening, 96% of which are also being screened in the multi-Agency Tox21 project. The chemical library unpinning these efforts plays a central role in defining the scope and potential application of ToxCast HTS results. The history of the phased construction of EPA's ToxCast library is reviewed,, followed by a survey of the library contents from several different vantage points. CAS Registry Numbers are used to assess ToxCast library coverage of important toxicity, regulatory, and exposure inventories. Structure-based representations of ToxCast chemicals are then used to compute physicochemical properties, substructural features, and structural alerts for toxicity and biotransformation. Cheminformatics approaches using these varied representations are applied to defining the boundaries of HTS testability, evaluating chemical diversity, and comparing the ToxCast library to potential target application inventories, such as used in EPA's Endocrine Disruption Screening Program (EDSP). Through several examples, the ToxCast chemical library is demonstrated to provide comprehensive coverage of the knowledge domains and target inventories of potential interest to EPA. Furthermore, the varied representations and approaches presented here define local chemistry domains potentially worthy of further investigation (e.g., not currently covered in the testing library or defined by toxicity "alerts") to strategically support data mining and predictive toxicology modeling moving forward. C1 [Richard, Ann M.; Judson, Richard S.; Houck, Keith A.; Grulke, Christopher M.; Martin, Matthew T.; Wambaugh, John F.; Knudsen, Thomas B.; Patlewicz, Grace; Williams, Antony J.; Little, Stephen B.; Crofton, Kevin M.; Thomas, Russell S.] US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Mail Code B205-01, Durham, NC 27711 USA. [Volarath, Patra] US FDA, Ctr Food Safety & Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Thillainadarajah, Inthirany] US EPA, Senior Environm Employment Program, Res Triangle Pk, NC 27711 USA. [Yang, Chihae] Mol Networks GmbH, Henkestr 91, D-91052 Erlangen, Germany. [Yang, Chihae; Rathman, James] Altamira LLC, 1455 Candlewood Dr, Columbus, OH 43235 USA. [Rathman, James] Ohio State Univ, Dept Chem & Biomol Engn, 151 W Woodruff Ave, Columbus, OH 43210 USA. [Kancherla, Jayaram; Mansouri, Kamel] US EPA, Durham, NC 27711 USA. [Richard, Ann M.] US EPA, Mail Drop D143-02, Res Triangle Pk, NC 27711 USA. RP Richard, AM (reprint author), US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Mail Code B205-01, Durham, NC 27711 USA.; Richard, AM (reprint author), US EPA, Mail Drop D143-02, Res Triangle Pk, NC 27711 USA. EM richard.ann@epa.gov OI Wambaugh, John/0000-0002-4024-534X; Mansouri, Kamel/0000-0002-6426-8036 FU U.S. Environmental Protection Agency FX The work presented in this manuscript was solely supported by the U.S. Environmental Protection Agency appropriated funds. NR 55 TC 3 Z9 3 U1 20 U2 27 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X EI 1520-5010 J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD AUG PY 2016 VL 29 IS 8 BP 1225 EP 1251 DI 10.1021/acs.chemrestox.6b00135 PG 27 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA DT6KQ UT WOS:000381593500001 PM 27367298 ER PT J AU Xia, QS Zhao, YW Lin, G Beland, FA Cai, LN Fu, PP AF Xia, Qingsu Zhao, Yuewei Lin, Ge Beland, Frederick A. Cai, Lining Fu, Peter P. TI Pyrrolizidine Alkaloid-Protein Adducts: Potential Non-invasive Biomarkers of Pyrrolizidine Alkaloid-Induced Liver Toxicity and Exposure SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID DNA CROSS-LINKING; BIG BLUE RATS; METABOLIC-ACTIVATION; DEHYDROPYRROLIZIDINE ALKALOIDS; DIETARY-SUPPLEMENTS; MASS-SPECTROMETRY; MEDICINAL-PLANTS; IN-VIVO; RIDDELLIINE; HEMOGLOBIN AB Pyrrolizidine alkaloids (PAs) are phytochemicals present in hundreds of plant species from different families widely distributed in many geographical regions around the world. PA-containing plants are probably the most common type of poisonous plants affecting livestock, wildlife, and humans. There have been many large-scale human poisonings caused by the consumption of food contaminated with toxic PAs. PAs require metabolic activation to generate pyrrolic metabolites to exert their toxicity. In this study, we developed a novel method to quantify pyrrole-protein adducts present in the blood. This method involves the use of AgNO3 in acidic ethanol to cleave the thiol linkage of pyrrole-protein (DHP-protein) adducts, and the resulting 7,9-di-C2H5O-DHP is quantified by HPLC-ES-MS/MS multiple reaction monitoring analysis in the presence of a known quantity of isotopically labeled 7,9-di-C2D5O-DHP internal standard. Using this method, we determined that diester-type PAs administered to rats produced higher levels of DHP-protein adducts than other types of PAs. The results suggest that DHP-protein adducts can potentially serve as minimally invasive biomarkers of PA exposure. C1 [Xia, Qingsu; Zhao, Yuewei; Beland, Frederick A.; Fu, Peter P.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Lin, Ge] Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Hong Kong, Hong Kong, Peoples R China. [Cai, Lining] Biotranex LLC, Monmouth Jct, NJ 08852 USA. RP Fu, PP (reprint author), Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM peter.fu@fda.hhs.gov NR 62 TC 1 Z9 1 U1 14 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X EI 1520-5010 J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD AUG PY 2016 VL 29 IS 8 BP 1282 EP 1292 DI 10.1021/acs.chemrestox.6b00120 PG 11 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA DT6KQ UT WOS:000381593500005 PM 27388689 ER PT J AU Hazen, TH Leonard, SR Lampel, KA Lacher, DW Maurelli, AT Rasko, DA AF Hazen, Tracy H. Leonard, Susan R. Lampel, Keith A. Lacher, David W. Maurelli, Anthony T. Rasko, David A. TI Investigating the Relatedness of Enteroinvasive Escherichia coli to Other E. coli and Shigella Isolates by Using Comparative Genomics SO INFECTION AND IMMUNITY LA English DT Article ID SHI-2 PATHOGENICITY ISLAND; LARGE VIRULENCE PLASMID; II SECRETION SYSTEM; BLAST SCORE RATIO; VI SECRETION; FLEXNERI 2A; HEP-2 CELLS; PATHOADAPTIVE MUTATIONS; CONVERGENT EVOLUTION; BACTERIAL GENOMES AB Enteroinvasive Escherichia coli (EIEC) is a unique pathovar that has a pathogenic mechanism nearly indistinguishable from that of Shigella species. In contrast to isolates of the four Shigella species, which are widespread and can be frequent causes of human illness, EIEC causes far fewer reported illnesses each year. In this study, we analyzed the genome sequences of 20 EIEC isolates, including 14 first described in this study. Phylogenomic analysis of the EIEC genomes demonstrated that 17 of the isolates are present in three distinct lineages that contained only EIEC genomes, compared to reference genomes from each of the E. coli pathovars and Shigella species. Comparative genomic analysis identified genes that were unique to each of the three identified EIEC lineages. While many of the EIEC lineage-specific genes have unknown functions, those with predicted functions included a colicin and putative proteins involved in transcriptional regulation or carbohydrate metabolism. In silico detection of the Shigella virulence plasmid (pINV), which is essential for the invasion of host cells, demonstrated that a form of pINV was present in nearly all EIEC genomes, but the Mxi-Spa-Ipa region of the plasmid that encodes the invasion-associated proteins was absent from several of the EIEC isolates. The comparative genomic findings in this study support the hypothesis that multiple EIEC lineages have evolved independently from multiple distinct lineages of E. coli via the acquisition of the Shigella virulence plasmid and, in some cases, the Shigella pathogenicity islands. C1 [Hazen, Tracy H.; Rasko, David A.] Univ Maryland, Inst Genome Sci, Sch Med, Baltimore, MD 21201 USA. [Hazen, Tracy H.; Rasko, David A.] Univ Maryland, Dept Microbiol & Immunol, Sch Med, Baltimore, MD 21201 USA. [Leonard, Susan R.; Lampel, Keith A.; Lacher, David W.] Food & Drug Adm, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Div Mol Biol, Laurel, MD USA. [Maurelli, Anthony T.] Univ Florida, Emerging Pathogens Inst, Coll Publ Hlth & Hlth Profess, Gainesville, FL USA. [Maurelli, Anthony T.] Univ Florida, Dept Environm & Global Hlth, Coll Publ Hlth & Hlth Profess, Gainesville, FL USA. RP Rasko, DA (reprint author), Univ Maryland, Inst Genome Sci, Sch Med, Baltimore, MD 21201 USA.; Rasko, DA (reprint author), Univ Maryland, Dept Microbiol & Immunol, Sch Med, Baltimore, MD 21201 USA. EM drasko@som.umaryland.edu OI Maurelli, Anthony/0000-0002-4788-6166 FU federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900009C, U19AI090873, U19AI110820]; State of Maryland FX This project was funded in part by federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under contract HHSN272200900009C, grants U19AI090873 and U19AI110820, and startup funds from the State of Maryland. S.R.L. was supported by a fellowship appointment administered by the Oak Ridge Institute for Science and Education. NR 83 TC 2 Z9 2 U1 3 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2016 VL 84 IS 8 BP 2362 EP 2371 DI 10.1128/IAI.00350-16 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DS4JC UT WOS:000380746400020 PM 27271741 ER PT J AU Allard, MW AF Allard, Marc W. TI The Future of Whole-Genome Sequencing for Public Health and the Clinic SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Editorial Material AB An American Society for Microbiology (ASM) conference titled the Conference on Rapid Next-Generation Sequencing and Bioinformatic Pipelines for Enhanced Molecular Epidemiological Investigation of Pathogens provided a venue for discussing how technologies surrounding whole-genome sequencing (WGS) are advancing microbiology. Several applications in microbial taxonomy, microbial forensics, and genomics for public health pathogen surveillance were presented at the meeting and are reviewed. All of these studies document that WGS is revolutionizing applications in microbiology and that the impact of these technologies will be profound. ASM is providing support mechanisms to promote discussions of WGS techniques to foster applications and interpretations. C1 [Allard, Marc W.] US FDA, College Pk, MD 20740 USA. RP Allard, MW (reprint author), US FDA, College Pk, MD 20740 USA. EM marc.allard@fda.hhs.gov NR 7 TC 1 Z9 1 U1 4 U2 4 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 AUG PY 2016 VL 54 IS 8 BP 1946 EP 1948 DI 10.1128/JCM.01082-16 PG 3 WC Microbiology SC Microbiology GA DT1YO UT WOS:000381278200004 PM 27307454 ER PT J AU Allard, MW Strain, E Melka, D Bunning, K Musser, SM Brown, EW Timme, R AF Allard, Marc W. Strain, Errol Melka, David Bunning, Kelly Musser, Steven M. Brown, Eric W. Timme, Ruth TI Practical Value of Food Pathogen Traceability through Building a Whole-Genome Sequencing Network and Database SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Review ID ENTERICA SEROVAR ENTERITIDIS; ANTIMICROBIAL RESISTANCE; KLEBSIELLA-PNEUMONIAE; RETAIL MEATS; SURVEILLANCE; PREDICTION; OUTBREAK; ANIMALS; COLI AB The FDA has created a United States-based open-source whole-genome sequencing network of state, federal, international, and commercial partners. The GenomeTrakr network represents a first-of-its-kind distributed genomic food shield for characterizing and tracing foodborne outbreak pathogens back to their sources. The GenomeTrakr network is leading investigations of outbreaks of foodborne illnesses and compliance actions with more accurate and rapid recalls of contaminated foods as well as more effective monitoring of preventive controls for food manufacturing environments. An expanded network would serve to provide an international rapid surveillance system for pathogen traceback, which is critical to support an effective public health response to bacterial outbreaks. C1 [Allard, Marc W.; Strain, Errol; Melka, David; Bunning, Kelly; Musser, Steven M.; Brown, Eric W.; Timme, Ruth] US FDA, College Pk, MD 20740 USA. RP Allard, MW (reprint author), US FDA, College Pk, MD 20740 USA. EM marc.allard@fda.hhs.gov FU U.S. FDA Center for Food Safety and Applied Nutrition FX This work, including the efforts of Marc W. Allard, was funded by U.S. FDA Center for Food Safety and Applied Nutrition. NR 21 TC 11 Z9 11 U1 4 U2 4 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 AUG PY 2016 VL 54 IS 8 BP 1975 EP 1983 DI 10.1128/JCM.00081-16 PG 9 WC Microbiology SC Microbiology GA DT1YO UT WOS:000381278200008 PM 27008877 ER PT J AU Bae, D Kweon, O Khan, AA AF Bae, Dongryeoul Kweon, Ohgew Khan, Ashraf A. TI Isolation and Characterization of Antimicrobial-Resistant Nontyphoidal Salmonella enterica Serovars from Imported Food Products SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Antimicrobial resistance; Food; Plasmid; Salmonella enterica; Type IIA topoisomerase ID CLASS 1 INTEGRON; UNITED-STATES; MOLECULAR CHARACTERIZATION; QUINOLONE-RESISTANCE; ANTIBIOTIC-RESISTANCE; MULTIDRUG-RESISTANCE; DETERMINING REGION; ESCHERICHIA-COLI; CLINICAL-SAMPLES; GENE CASSETTES AB The objective of this study was to determine antimicrobial resistance and elucidate the resistance mechanism in nontyphoidal Salmonella enterica serovars isolated from food products imported into the United States from 2011 to 2013. Food products contaminated with antimicrobial-resistant nontyphoidal S. enterica were mainly imported from Taiwan, Indonesia, Vietnam, and China. PCR, DNA sequencing, and plasmid analyses were used to characterize antimicrobial resistance determinants. Twentythree of 110 S. enterica isolates were resistant to various antimicrobial classes, including P-lactam, aminoglycoside, phenicol, glycopeptide, sulfonamide, trimethoprim, and/or fluoroquinolone antimicrobial agents. Twelve of the isolates were multidrug resistant strains. Antimicrobial resistance determinants bla(TEM-1')., bla(OXA-1), tetA, tetB, tetD, dfrAl, dhfrXII, chf17, aadA1, aadA2, aadA5, olfC, qnrS, and mutations of gyrA and parC were detected in one or more antimicrobial-resistant nontyphoidal S. enterica strains. Plasmid profiles revealed that 12 of the 23 antimicrobial-resistant strains harbored plasmids with incompatibility groups Inc14113, IncHIl, IncIl, IncN, IncW, and IncX. Epidemiologic and antimicrobial resistance monitoring data combined with molecular characterization of antimicrobial resistance determinants in Salmonella strains isolated from imported food products may provide information that can be used to establish or implement food safety programs to improve public health. C1 [Bae, Dongryeoul; Kweon, Ohgew; Khan, Ashraf A.] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. RP Khan, AA (reprint author), US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. EM ashraf.khan@fda.hhs.gov FU National Center for Toxicological Research FX We thank Drs. Carl E. Cerniglia, John B. Sutherland, and M. S. Nawaz for critical review of the manuscript, Christine Summage-West for technical help, and Gwendolyn Anderson and Stephanie Horton for the Salmonella isolates. 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. The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration. NR 38 TC 0 Z9 0 U1 15 U2 16 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD AUG PY 2016 VL 79 IS 8 BP 1348 EP 1354 DI 10.4315/0362-028X.ThP-15-564 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA DT7GR UT WOS:000381655600007 PM 27497122 ER PT J AU Chen, Y Evans, P Hammack, TS Brown, EW Macarisin, D AF Chen, Yi Evans, Peter Hammack, Thomas S. Brown, Eric W. Macarisin, Dumitru TI Internalization of Listeria monocytogenes in Whole Avocado SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Avocado; Internalization; Listeria monocytogenes ID ESCHERICHIA-COLI O157-H7; UNITED-STATES; MULTISTATE OUTBREAK; VIRULENCE; SALMONELLA; CANTALOUPE; TOMATOES; FRUIT AB In recent years, tree fruits have emerged as a new concern for Listeria monocytogenes contamination. The objective of the current study was to evaluate the potential internalization of L. monocytogenes from the surface of avocados into the edible portions of the fruit during certain postharvest practices simulated in a laboratory setting. One set of intact avocados was spot inoculated with L. monocytogenes on the stem scar, and the second set was hydrocooled in water contaminated with L. monocytogenes. Under these experimental conditions, L. monocytogenes internalized into the avocado pulp through the stem or stem scar after both spot inoculation and hydrocooling. In avocados spot inoculated with 50, 130, 500, and 1,300 CFU per fruit, bacteria were detected in the edible portion adjacent to the stem scar within 15 days postinoculation during storage at 4 degrees C. In avocados hydrocooled in water containing L. monocytogenes at 10(6) and 10(8) CFU/ml, bacteria reached the bottom end of the fruit, and the populations in the edible portion adjacent to the stem scar reached up to 5.90 to 7.19 log CFU/g within 10 to 15 days during storage at 4 degrees C. Dye mixed with inoculum was useful for guiding subsequent sampling, but dye penetration patterns were not always consistent with bacterial penetration. C1 [Chen, Yi; Evans, Peter; Hammack, Thomas S.; Brown, Eric W.; Macarisin, Dumitru] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. RP Chen, Y; Macarisin, D (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM yi.chen@fda.hhs.gov; dumitru.macarisin@fda.hhs.gov NR 33 TC 0 Z9 0 U1 9 U2 9 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD AUG PY 2016 VL 79 IS 8 BP 1440 EP 1445 DI 10.4315/0362-028X.J1-P-16-075 PG 6 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA DT7GR UT WOS:000381655600019 PM 27497134 ER PT J AU Woo, EJ Winiecki, SK Arya, D Beeler, J AF Woo, Emily Jane Winiecki, Scott K. Arya, Deepa Beeler, Judy TI Adverse Events After MMR or MMRV Vaccine in Infants Under Nine Months Old SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE measles; mumps and rubella vaccine; infant; adverse events ID MUMPS-RUBELLA VACCINE; REPORTING SYSTEM; MEASLES-VACCINE; IMMUNIZATION; AUTISM; IMMUNOGENICITY; 6-MONTH-OLD; DISORDERS; MOTHERS; SAFETY AB Background: In the United States, measles is resurging, with more than 700 confirmed cases since January 2014. During measles outbreaks, vaccination as early as at 6 months of age is sometimes recommended for infants who are at risk for exposure. Methods: We searched the Vaccine Adverse Event Reporting System for reports of measles, mumps and rubella vaccine combined or measles, mumps, rubella and varicella vaccine combined vaccination in children less than 9 months of age. We performed a clinical assessment of each report and summarized the frequency, range, onset time and severity of adverse events. Results: After excluding 346 reports because they were duplicates or because they contained insufficient information about the child's age or vaccine(s), we retained 204 reports in the analysis, including 35 (17%) that were serious. Among the 169 nonserious reports, more than half (88; 52%) described a vaccination error without any adverse event per se. Other nonserious reports described fever, injection reactions and gastrointestinal symptoms. Serious adverse events included developmental disorders, fever and fussiness. There were 44 reports of fever, but only 4 cases began 5-12 days after immunization, the peak risk window. The vast majority of fever reports listed concomitant vaccines, such as diphtheria and tetanus toxoids, acellular or whole-cell pertussis vaccine. Conclusions: This review did not identify any major safety concerns. These findings may facilitate discussions about the risks and benefits of vaccinating infants who are potentially exposed to this life-threatening disease. C1 [Woo, Emily Jane; Winiecki, Scott K.; Arya, Deepa] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Beeler, Judy] US FDA, Ctr Biol Evaluat & Res, Off Vaccines Res & Review, Silver Spring, MD USA. RP Woo, EJ (reprint author), US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jane.woo@fda.hhs.gov NR 38 TC 0 Z9 0 U1 30 U2 38 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD AUG PY 2016 VL 35 IS 8 BP E253 EP E257 DI 10.1097/INF.0000000000001201 PG 5 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA DS4MK UT WOS:000380755000003 PM 27167117 ER PT J AU Daluwatte, C Johannesen, L Galeotti, L Vicente, J Strauss, DG Scully, CG AF Daluwatte, C. Johannesen, L. Galeotti, L. Vicente, J. Strauss, D. G. Scully, C. G. TI Assessing ECG signal quality indices to discriminate ECGs with artefacts from pathologically different arrhythmic ECGs SO PHYSIOLOGICAL MEASUREMENT LA English DT Article DE signal quality; ECG; arrhythmia ID ALARMS; ELECTROCARDIOGRAM; ALGORITHM AB False and non-actionable alarms in critical care can be reduced by developing algorithms which assess the trueness of an arrhythmia alarm from a bedside monitor. Computational approaches that automatically identify artefacts in ECG signals are an important branch of physiological signal processing which tries to address this issue. Signal quality indices (SQIs) derived considering differences between artefacts which occur in ECG signals and normal QRS morphology have the potential to discriminate pathologically different arrhythmic ECG segments as artefacts. Using ECG signals from the PhysioNet/Computing in Cardiology Challenge 2015 training set, we studied previously reported ECG SQIs in the scientific literature to differentiate ECG segments with artefacts from arrhythmic ECG segments. We found that the ability of SQIs to discriminate between ECG artefacts and arrhythmic ECG varies based on arrhythmia type since the pathology of each arrhythmic ECG waveform is different. Therefore, to reduce the risk of SQIs classifying arrhythmic events as noise it is important to validate and test SQIs with databases that include arrhythmias. Arrhythmia specific SQIs may also minimize the risk of misclassifying arrhythmic events as noise. C1 [Daluwatte, C.; Johannesen, L.; Galeotti, L.; Vicente, J.; Strauss, D. G.; Scully, C. G.] US FDA, Off Sci & Engn Labs, CDRH, Silver Spring, MD USA. [Galeotti, L.] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Vicente, J.] Univ Zaragoza, BSICoS Grp, Aragon Inst Engn Res I3A, IIS Aragon, Zaragoza, Spain. RP Daluwatte, C (reprint author), US FDA, Off Sci & Engn Labs, CDRH, Silver Spring, MD USA. EM Chathuri.Daluwatte@fda.hhs.gov OI Vicente, Jose/0000-0001-9963-1205 FU U.S. Food and Drug Administration Medical Countermeasures Initiative; U.S. Food and Drug Administration Critical Path Initiative; Office of Women's Health; Department of Energy; FDA FX This project was supported in part by U.S. Food and Drug Administration's Medical Countermeasures Initiative, Critical Path Initiative, Office of Women's Health and appointments to the Research Participation Programs at the Oak Ridge Institute for Science and Education through an interagency agreement between the Department of Energy and FDA. NR 22 TC 1 Z9 1 U1 3 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0967-3334 EI 1361-6579 J9 PHYSIOL MEAS JI Physiol. Meas. PD AUG PY 2016 VL 37 IS 8 BP 1370 EP 1382 DI 10.1088/0967-3334/37/8/1370 PG 13 WC Biophysics; Engineering, Biomedical; Physiology SC Biophysics; Engineering; Physiology GA DS5IP UT WOS:000380815200013 PM 27454007 ER PT J AU Athelogou, M Kim, HJ Dima, A Obuchowski, N Peskin, A Gavrielides, MA Petrick, N Saiprasad, G Colditz, DC Beaumont, H Oubel, E Tan, YQ Zhao, BS Kuhnigk, JM Moltz, JH Orieux, G Gillies, RJ Gu, YH Mantri, N Goldmacher, G Zhang, LD Vega, E Bloom, M Jarecha, R Soza, G Tietjen, C Takeguchi, T Yamagata, H Peterson, S Masoud, O Buckler, AJ AF Athelogou, Maria Kim, Hyun J. Dima, Alden Obuchowski, Nancy Peskin, Adele Gavrielides, Marios A. Petrick, Nicholas Saiprasad, Ganesh Colditz, Dirk Colditz Beaumont, Hubert Oubel, Estanislao Tan, Yongqiang Zhao, Binsheng Kuhnigk, Jan-Martin Moltz, Jan Hendrik Orieux, Guillaume Gillies, Robert J. Gu, Yuhua Mantri, Ninad Goldmacher, Gregory Zhang, Luduan Vega, Emilio Bloom, Michael Jarecha, Rudresh Soza, Grzegorz Tietjen, Christian Takeguchi, Tomoyuki Yamagata, Hitoshi Peterson, Sam Masoud, Osama Buckler, Andrew J. TI Algorithm Variability in the Estimation of Lung Nodule Volume From Phantom CT Scans: Results of the QIBA 3A Public Challenge SO ACADEMIC RADIOLOGY LA English DT Article DE CT volumetry; anthropomorphic phantoms; lung tumor; challenge; algorithms; QIBA ID INTRAOBSERVER VARIABILITY; TUMOR RESPONSE; SOLID TUMORS; THORACIC CT; INTEROBSERVER; BIOMARKER; EXAMPLE; CANCER; RECIST; SIZE AB Rationale and Objectives: Quantifying changes in lung tumor volume is important for diagnosis, therapy planning, and evaluation of response to therapy. The aim of this study was to assess the performance of multiple algorithms on a reference data set. The study was organized by the Quantitative Imaging Biomarker Alliance (QIBA). Materials and Methods: The study was organized as a public challenge. Computed tomography scans of synthetic lung tumors in an anthropomorphic phantom were acquired by the Food and Drug Administration. Tumors varied in size, shape, and radiodensity. Participants applied their own semi-automated volume estimation algorithms that either did not allow or allowed post-segmentation correction (type 1 or 2, respectively). Statistical analysis of accuracy (percent bias) and precision (repeatability and reproducibility) was conducted across algorithms, as well as across nodule characteristics, slice thickness, and algorithm type. Results: Eighty-four percent of volume measurements of QIBA-compliant tumors were within 15% of the true volume, ranging from 66% to 93% across algorithms, compared to 61% of volume measurements for all tumors (ranging from 37% to 84%). Algorithm type did not affect bias substantially; however, it was an important factor in measurement precision. Algorithm precision was notably better as tumor size increased, worse for irregularly shaped tumors, and on the average better for type 1 algorithms. Over all nodules meeting the QIBA Profile, precision, as measured by the repeatability coefficient, was 9.0% compared to 18.4% overall. Conclusion: The results achieved in this study, using a heterogeneous set of measurement algorithms, support QIBA quantitative performance claims in terms of volume measurement repeatability for nodules meeting the QIBA Profile criteria. C1 [Athelogou, Maria] Definiens AG, Bernhard Wicki Str 5, D-80636 Munich, Germany. [Kim, Hyun J.] Univ Calif Los Angeles, Ctr Comp Vis & Imaging Biomarkers, Dept Radiol Sci, David Geffen Sch Med,Dept Biostat Fielding,Sch Pu, Los Angeles, CA USA. [Obuchowski, Nancy] Cleveland Clin Fdn, Quantitat Hlth Sci JJN3, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Dima, Alden; Peskin, Adele; Saiprasad, Ganesh] Natl Inst Stand & Technol, Gaithersburg, MD 20899 USA. [Gavrielides, Marios A.; Petrick, Nicholas] US FDA, Silver Spring, MD USA. [Colditz, Dirk Colditz] Consultant QM RA, Jena, Germany. [Beaumont, Hubert; Oubel, Estanislao] MEDIAN Technol, Valbonne Sophia Antipoli, France. [Tan, Yongqiang; Zhao, Binsheng] Columbia Univ, Med Ctr, Dept Radiol, New York, NY USA. [Kuhnigk, Jan-Martin; Moltz, Jan Hendrik] Fraunhofer MEVIS, Inst Med Image Comp, Bremen, Germany. [Orieux, Guillaume] GE Healthcare, Buc, France. [Gillies, Robert J.; Gu, Yuhua] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Gillies, Robert J.; Gu, Yuhua] Res Inst, Tampa, FL USA. [Mantri, Ninad; Goldmacher, Gregory] ICON Med Imaging, Warrington, PA USA. [Zhang, Luduan] INTIO Inc, Broomfield, CO USA. [Vega, Emilio; Bloom, Michael] NYU, Langone Med Ctr, Fac Practice Radiol, New York, NY USA. [Jarecha, Rudresh] Percept Informat, Hyderabad, Andhra Pradesh, India. [Soza, Grzegorz; Tietjen, Christian] Siemens AG, Healthcare Sect, Computed Tomog, Forchheim, Germany. [Takeguchi, Tomoyuki] Corp R&D Ctr, Toshiba Corp, Kawasaki, Kanagawa, Japan. [Yamagata, Hitoshi] Toshiba Med Syst Corp, Toshiba Corp, Otawara, Japan. [Peterson, Sam; Masoud, Osama] Vital Images Inc, Toshiba Med Syst Grp, Minnetonka, MN USA. [Buckler, Andrew J.] Buckler Biomed Associates LLC, Bethesda, MA USA. RP Athelogou, M (reprint author), Definiens AG, Bernhard Wicki Str 5, D-80636 Munich, Germany. EM mathelogou@definiens.com OI Buckler, Andrew/0000-0002-0786-4835 FU Federal funds from the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Department of Health and Human Services [HHSN268201000050C] FX The research reported in this manuscript has been funded in whole or in part with Federal funds from the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN268201000050C (Radiological Society of North America). Certain commercial entities, equipment, instruments, or materials are identified in this paper to specify the experimental procedure adequately. Such identification is not to be construed as either an actual or implied endorsement of such entities or products by the National Institute of Standards and Technology, the Department of Health and Human Services, or the U.S. Food and Drug Administration. Likewise, it is not intended to imply that the materials or equipment identified are necessarily the best available for this purpose. NR 23 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD AUG PY 2016 VL 23 IS 8 BP 940 EP 952 DI 10.1016/j.acra.2016.02.018 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DS4EM UT WOS:000380734200003 PM 27215408 ER PT J AU Chintagari, NR Jana, S Alayash, AI AF Chintagari, Narendranath Reddy Jana, Sirsendu Alayash, Abdu I. TI Oxidized Ferric and Ferryl Forms of Hemoglobin Trigger Mitochondrial Dysfunction and Injury in Alveolar Type I Cells SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE hemoglobin; lung epithelium; mitochondria; heme oxygenase; hemolysis ID MEDIATED OXIDATIVE STRESS; HEME OXYGENASE-1; GUINEA-PIGS; SCAVENGER RECEPTOR; BLOOD SUBSTITUTES; EPITHELIAL-CELLS; HAPTOGLOBIN; DISEASE; ACTIVATION; COMPLEX AB Lung alveoli are lined by alveolar type (AT) 1 cells and cuboidal AT2 cells. The AT1 cells are likely to be exposed to cell-free hemoglobin (Hb) in multiple lung diseases; however, the role of Hb redox (reduction-oxidation) reactions and their precise contributions to AT1 cell injury are not well understood. Using mouse lung epithelial cells (E10) as an AT1 cell model, we demonstrate here that higher Hb oxidation states, ferric Hb (HbFe(3+)) and ferryl Hb (HbFe(4+)) and subsequent heme loss play a central role in the genesis of injury. Exposures to HbFe(2+) and HbFe(3+) for 24 hours induced expression of heme oxygenase (HO)-1 protein in E10 cells and HO-1 translocation in the purified mitochondrial fractions. Both of these effects were intensified with increasing oxidation states of Hb. Next, we examined the effects of Hb oxidation and free heme on mitochondrial bioenergetic function by measuring changes in the mitochondrial transmembrane potential and oxygen consumption rate. In contrast to HbFe(2+), HbFe(3+) reduced basal oxygen consumption rate, indicating compromised mitochondrial activity. However, HbFe(4+) exposure not only induced early expression of HO-1 but also caused mitochondrial dysfunction within 12 hours when compared with HbFe(2+) and HbFe(3+). Exposure to HbFe(4+) for 24 hours also caused mitochondrial depolarization in E10 cells. The deleterious effects of HbFe(3+) and HbFe(4+) were reversed by the addition of scavenger proteins, haptoglobin and hemopexin. Collectively, these data establish, for the first time, a central role for cell-free Hb in lung epithelial injury, and that these effects are mediated through the redox transition of Hb to higher oxidation states. C1 [Chintagari, Narendranath Reddy; Jana, Sirsendu; Alayash, Abdu I.] US FDA, Lab Biochem & Vasc Biol, Div Hematol Review & Res, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Alayash, AI (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Biochem & Vasc Biol, Bldg 52-72,Room 4106,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM abdu.alayash@fda.hhs.gov FU National Institutes of Health grant from the National Heart, Lung, and Blood Institute [P01-HL110900]; Food and Drug Administration Modernizing Science grant FX This work was supported by National Institutes of Health grant P01-HL110900 from the National Heart, Lung, and Blood Institute (A.I.A.) and the Food and Drug Administration Modernizing Science grant (A.I.A.). NR 48 TC 3 Z9 3 U1 2 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD AUG 1 PY 2016 VL 55 IS 2 BP 288 EP 298 DI 10.1165/rcmb.2015-0197OC PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA DT7XT UT WOS:000381702300014 PM 26974230 ER PT J AU Gokulan, K Khare, S Williams, K Foley, SL AF Gokulan, Kuppan Khare, Sangeeta Williams, Katherine Foley, Steven L. TI Transmissible Plasmid Containing Salmonella enterica Heidelberg Isolates Modulate Cytokine Production During Early Stage of Interaction with Intestinal Epithelial Cells SO DNA AND CELL BIOLOGY LA English DT Article ID FROZEN CHICKEN NUGGETS; ULCERATIVE-COLITIS; PANETH CELLS; NEMATODE INFECTION; IMMUNE-RESPONSES; MOUSE INTESTINE; MICE DEVELOP; RISK-FACTOR; GM-CSF; INFLAMMATION AB The variation in cytokine production during bacterial invasion of human intestinal epithelial cells (IECs) is a contributing factor for progression of the infection. A few Salmonella enterica Heidelberg strains isolated from poultry products harbor transmissible plasmids (TPs), including those that encode a type-IV secretion system. Earlier, we showed that these TPs are responsible for increased virulence during infection. This study examines the potential role of these TPs in cytokine production in IECs. This study showed that S. Heidelberg strains containing TPs (we refer as virulent strains) caused decreased interleukin (IL)-10 production in IECs after 1 h infection. The virulent strains induced a high level of tumor necrosis factor-alpha production under identical conditions. The virulent strains of S. Heidelberg also altered the production of IL-2, IL-17, and granulocyte macrophage colony-stimulating factor compared to an avirulent strain. As a part of infection, bacteria cross the epithelial barrier and encounter intestinal macrophages. Hence, we examined the cytotoxic mechanism of strains of S. Heidelberg in macrophages. Scanning electron microscopy showed cell necrosis occurs during the early stage of infection. In conclusion, virulent S. Heidelberg strains were able to modify the host cytokine profile during the early stages of infection and also caused necrosis in macrophages. C1 [Gokulan, Kuppan; Khare, Sangeeta; Williams, Katherine; Foley, Steven L.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Gokulan, K (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM kuppan.gokulan@fda.hhs.gov NR 63 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 1044-5498 EI 1557-7430 J9 DNA CELL BIOL JI DNA Cell Biol. PD AUG PY 2016 VL 35 IS 8 BP 443 EP 453 DI 10.1089/dna.2015.3142 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity GA DS5JH UT WOS:000380817500010 PM 27082282 ER PT J AU Camacho, L Lewis, SM Vanlandingham, MM Juliar, BE Olson, GR Patton, RE da Costa, GG Woodling, K Sepehr, E Bryant, MS Doerge, DR Basavarajappa, MS Felton, RR Delclos, KB AF Camacho, Luisa Lewis, Sherry M. Vanlandingham, Michelle M. Juliar, Beth E. Olson, Greg R. Patton, Ralph E. da Costa, Goncalo Gamboa Woodling, Kellie Sepehr, Estatira Bryant, Matthew S. Doerge, Daniel R. Basavarajappa, Mallikarjuna S. Felton, Robert R. Delclos, K. Barry TI Comparison of endpoints relevant to toxicity assessments in 3 generations of CD-1 mice fed irradiated natural and purified ingredient diets with varying soy protein and isoflavone contents SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Soy; Isoflavones; Natural ingredient diet; Purified ingredient diet; Thiamine; CD-1 mouse ID ANOGENITAL DISTANCE INDEX; LABORATORY-ANIMAL DIETS; SPRAGUE-DAWLEY RATS; B6C3F1 FEMALE MICE; BISPHENOL-A; RODENT DIETS; VITAMIN-A; METABOLIC ABNORMALITIES; PHYTOESTROGEN CONTENT; TRIGLYCERIDE LEVELS AB Diet is an important variable in toxicology. There are mixed reports on the impact of soy components on energy utilization, fat deposition, and reproductive parameters. Three generations of CD-1 mice were fed irradiated natural ingredient diets with varying levels of soy (NIH-41, 5K96, or 5008/5001), purified irradiated AIN-93 diet, or the AIN-93 formulation modified with ethanol-washed soy protein concentrate (SPC) or SPC with isoflavones (SPC-IF). NIH-41 was the control for pairwise comparisons. Minimal differences were observed among natural ingredient diet groups. F-0 males fed AIN-93, SPC, and SPC-IF diets had elevated glucose levels and lower insulin levels compared with the NIH-41 group. In both sexes of the F-1 and F-2 generations, the SPC and SPC-IF groups had lower body weight gains than the NIH-41 controls and the AIN-93 group had an increased percent body fat at postnatal day 21. AIN-93 F-1 pups had higher baseline glucose than NIH-41 controls, but diet did not significantly affect breeding performance or responses to glucose or uterotrophic challenges. Reduced testes weight and sperm in the AIN-93 group may be related to low thiamine levels. Our observations underline the importance of careful selection, manufacturing procedures, and nutritional characterization of diets used in toxicological studies. Published by Elsevier Ltd. C1 [Camacho, Luisa; Vanlandingham, Michelle M.; da Costa, Goncalo Gamboa; Woodling, Kellie; Sepehr, Estatira; Bryant, Matthew S.; Doerge, Daniel R.; Basavarajappa, Mallikarjuna S.; Delclos, K. Barry] Div Biochem Toxicol, Jefferson, AR 72079 USA. [Lewis, Sherry M.] Off Sci Coordinat, Jefferson, AR 72079 USA. [Olson, Greg R.; Patton, Ralph E.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Olson, Greg R.; Patton, Ralph E.] Toxicol Pathol Associates, Jefferson, AR 72079 USA. RP Delclos, KB (reprint author), 3900 NCTR Rd,HFT 110, Jefferson, AR 72079 USA. EM barry.delclos@fda.hhs.gov FU FDA [224-12-0003, AES12013]; NIEHS [224-12-0003, AES12013] FX We are grateful for the outstanding efforts of the NCTR Animal Care, Microbiology, Pathology, and Veterinary Services staffs, as well as Ms. Kathy Carroll of the Office of Scientific Coordination, in the planning, conduct, and reporting of this study. We also thank Ms. Susan Berry of the chemistry group in the Division of Biochemical Toxicology for assistance in the preparation of the manuscript, Dr. Kelly Davis of TPA for assistance in the histological examination of ovaries, and Ms. Kristie Voris-Acuff of TPA for assistance in the clinical chemistry analyses. This study was funded by the NTP under an Interagency Agreement between FDA and NIEHS (FDA IAG # 224-12-0003/NIEHS IAG # AES12013). The opinions expressed in this paper do not necessarily reflect those of the U.S. Food and Drug Administration. NR 72 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD AUG PY 2016 VL 94 BP 39 EP 56 DI 10.1016/j.fct.2016.05.014 PG 18 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA DS1WF UT WOS:000380414900006 PM 27234134 ER PT J AU Kothary, MH Franco, AA Tall, BD Gopinath, GR Datta, AR AF Kothary, Mahendra H. Franco, Augusto A. Tall, Ben D. Gopinath, Gopal R. Datta, Atin R. TI Purification and Characterization of a Rabbit Serum Factor That Kills Listeria Species and Other Foodborne Bacterial Pathogens SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article ID PEPTIDE C3A; MONOCYTOGENES; COMPLEMENT; ANAPHYLATOXIN; SYSTEM AB In an in-vitro assay, rabbit serum, but not human serum, killed Listeria monocytogenes, a foodborne pathogen. The aim of our study was to purify and partially characterize this killing factor. Listericidin was purified from rabbit serum by a single-step ion-exchange chromatography with DEAE-Sephadex A-50 and its antimicrobial activity was assessed by a microdilution method. Listericidin is a protein with a molecular weight of 9 kDa and an isoelectric point of 8.1. It kills L. monocytogenes at 4 degrees C, 25 degrees C, and 37 degrees C, and its activity is resistant to heat (boiling) and acidic conditions (pH < 2). Listericidin's activity is inhibited by sodium chloride and various growth media, is sensitive to proteolytic enzymes and is enhanced by calcium chloride, and is neutralized by monoclonal antibodies to human complement C3a. However, the listericidin reacts weakly with these antibodies in an ELISA. The first 33 N-terminal residues of listericidin (SVQLTEKRMDKVGQYTNKELRKX-XEDGMRDNPM) have homology to various complement C3a components. Listericidin also kills other Listeria spp., Vibrio spp., Salmonella spp., Escherichia spp., Cronobacter spp., and Bacillus spp. The listericidin peptide purified in a single-step chromatography is pH and heat stable, and has a broad antimicrobial spectrum against major foodborne pathogens in addition to L. monocytogenes. C1 [Kothary, Mahendra H.; Franco, Augusto A.; Tall, Ben D.; Gopinath, Gopal R.; Datta, Atin R.] US FDA, Div Virulence Assessment, 8301 Muirkirk Rd, Laurel, MD 20708 USA. RP Kothary, MH; Datta, AR (reprint author), US FDA, Div Virulence Assessment, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM mahendra.kothary@fda.hhs.gov; atin.datta@fda.hhs.gov NR 17 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 1535-3141 EI 1556-7125 J9 FOODBORNE PATHOG DIS JI Foodborne Pathog. Dis. PD AUG PY 2016 VL 13 IS 8 BP 441 EP 447 DI 10.1089/fpd.2015.2109 PG 7 WC Food Science & Technology SC Food Science & Technology GA DS5JC UT WOS:000380816800006 PM 27455064 ER PT J AU Belgrave, FZ Abrams, JA Hood, KB Moore, MP Nguyen, AB AF Belgrave, Faye Z. Abrams, Jasmine A. Hood, Kristina B. Moore, Melanie P. Nguyen, Anh B. TI Development and Validation of a Preliminary Measure of African American Women's Gender Role Beliefs SO JOURNAL OF BLACK PSYCHOLOGY LA English DT Article DE gender roles; sex roles; African American women ID SEX-ROLE INVENTORY; EUROPEAN AMERICANS; ROLE ORIENTATION; ROLE IDENTITY; COGNITION; STRENGTH; STRESS; HEALTH; HYPOTHESIS; HARDINESS AB Gender role beliefs of African American women differ from those of women in other ethnic/racial groups and a culturally valid measure of their gender role beliefs is needed. Three studies were conducted to develop a preliminary measure. In Study 1, focus groups were conducted with a community and college sample of 44 African American women. Transcripts reviewed resulted in an initial pool of 40 items. These items were reviewed by an expert panel and 18 items were retained. In Study 2, an exploratory factor analysis was computed with data from 94 African American female college students. The 18 items were included along with measures to assess convergent and discriminant validity. Nine items were retained. These nine items comprised two subscales labeled Agency and Caretaking. The scales demonstrated good internal consistency and convergent and discriminant validity. In Study 3, a confirmatory factor analysis was computed with a different sample of 184 African American female college students. The confirmatory factor analysis showed acceptable fit for the two-factor structure of Agency and Caretaking. C1 [Belgrave, Faye Z.; Abrams, Jasmine A.; Moore, Melanie P.] Virginia Commonwealth Univ, Richmond, VA USA. [Hood, Kristina B.] Mississippi State Univ, Mississippi State, MS 39762 USA. [Nguyen, Anh B.] US FDA, Silver Spring, MD USA. RP Belgrave, FZ (reprint author), Virginia Commonwealth Univ, Dept Psychol, 806 West Franklin St, Richmond, VA 23284 USA. EM fzbelgra@vcu.edu NR 74 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0095-7984 EI 1552-4558 J9 J BLACK PSYCHOL JI J. Black Psychol. PD AUG PY 2016 VL 42 IS 4 BP 320 EP 342 DI 10.1177/0095798415576614 PG 23 WC Psychology, Multidisciplinary SC Psychology GA DS7DQ UT WOS:000380943400003 ER PT J AU Handley, SC Steinhorn, RH Hopper, AO Govindaswami, B Bhatt, DR Van Meurs, KP Ariagno, RL Gould, JB Lee, HC AF Handley, S. C. Steinhorn, R. H. Hopper, A. O. Govindaswami, B. Bhatt, D. R. Van Meurs, K. P. Ariagno, R. L. Gould, J. B. Lee, H. C. TI Inhaled nitric oxide use in preterm infants in California neonatal intensive care units SO JOURNAL OF PERINATOLOGY LA English DT Article ID PREMATURE-INFANTS; RESPIRATORY-FAILURE; STATEMENT AB OBJECTIVE: To describe inhaled nitric oxide (iNO) exposure in preterm infants and variation in neonatal intensive care unit (NICU) use. STUDY DESIGN: This was a retrospective cohort study of infants, 22 to 33+ 6/7 weeks of gestational age (GA), during 2005 to 2013. Analyses were stratified by GA and included population characteristics, iNO use over time and hospital variation. RESULTS: Of the 65 824 infants, 1718 (2.61%) received iNO. Infants, 22 to 24+ 6/7 weeks of GA, had the highest incidence of iNO exposure (6.54%). Community NICUs (n=77, median hospital use rate 0.7%) used less iNO than regional NICUs (n=23, median hospital use rate 5.8%). In 22 to 24+ 6/7 weeks of GA infants, the median rate in regional centers was 10.6% (hospital interquartile range 3.8% to 22.6%). CONCLUSION: iNO exposure varied with GA and hospital level, with the most use in extremely premature infants and regional centers. Variation reflects a lack of consensus regarding the appropriate use of iNO for preterm infants. C1 [Handley, S. C.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Steinhorn, R. H.] Univ Calif Davis, Dept Pediat, Davis, CA 95616 USA. [Hopper, A. O.] Loma Linda Univ, Dept Pediat, Loma Linda, CA 92350 USA. [Govindaswami, B.] Santa Clara Valley Med Ctr, Dept Pediat, San Jose, CA 95128 USA. [Bhatt, D. R.] Kaiser Permanente, Dept Pediat, Fontana, CA USA. [Van Meurs, K. P.; Ariagno, R. L.; Gould, J. B.; Lee, H. C.] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA. [Ariagno, R. L.] Oak Ridge Inst Res & Educ ORISE, Oak Ridge, TN USA. [Ariagno, R. L.] US FDA, Silver Spring, MD USA. [Gould, J. B.; Lee, H. C.] CPQCC, Stanford, CA USA. RP Lee, HC (reprint author), Stanford Univ, Div Neonatal & Dev Med, 750 Welch Rd,Suite 315, Palo Alto, CA 94304 USA. EM hclee@stanford.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [K23HD068400] FX This study was supported by Grant Number K23HD068400, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). NR 22 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0743-8346 EI 1476-5543 J9 J PERINATOL JI J. Perinatol. PD AUG PY 2016 VL 36 IS 8 BP 635 EP 639 DI 10.1038/jp.2016.49 PG 5 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA DS5UU UT WOS:000380849100012 PM 27031320 ER PT J AU Spelic, D AF Spelic, David TI The Nationwide Evaluation of X-Ray Trends, Part 2: US Trends for CT SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material ID COMPUTED-TOMOGRAPHY C1 [Spelic, David] US FDA, Ctr Devices & Radiol Hlth, WO OIR DRH 66 4534, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Spelic, D (reprint author), US FDA, Ctr Devices & Radiol Hlth, WO OIR DRH 66 4534, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM david.spelic@fda.hhs.gov NR 9 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD AUG PY 2016 VL 13 IS 8 BP 992 EP 994 DI 10.1016/j.jacr.2016.04.029 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DS7NQ UT WOS:000380970600025 PM 27374372 ER PT J AU Lloret, E Fernandez, A Trbojevich, R Arnau, J Picouet, PA AF Lloret, Elsa Fernandez, Avelina Trbojevich, Raul Arnau, Jacint Picouet, Pierre A. TI Relevance of nanocomposite packaging on the stability of vacuum-packed dry cured ham SO MEAT SCIENCE LA English DT Article DE Clay; Nanocomposite; Polyamide; Skin; TBARS; Vacuum; Meat; Ham ID IBERIAN HAM; REFRIGERATED STORAGE; MODIFIED ATMOSPHERES; TRANSPORT-PROPERTIES; OXIDATIVE STABILITY; LIPID OXIDATION; COLOR STABILITY; HIGH-PRESSURE; QUALITY; NITRATE AB In this study effects of a novel high barrier multilayer polyamide film containing dispersed nanoclays (PAN) on the stability of vacuum packed dry-cured ham were investigated during 90 days refrigerated storage in comparison with non-modified multilayer polyamide (PA) and a commercial high barrier film. Characteristic bands of the mineral in FT-IR spectra confirmed the presence of nanoclays in PAN, enhancing oxygen transmission barrier properties and UV protection. Packaging in PAN films did not originate significant changes on colour or lipid oxidation during prolonged storage of vacuum-packed dry-cured ham. Larger oxygen transmission rates in PA films caused changes in CIE b* during refrigerated storage. Ham quality was not affected by light exposition during 90 days and only curing had a significant benefit on colour and TBARS, being cured samples more stable during storage in all the packages used. Packaging of dry-cured ham in PAN was equivalent to commercial high barrier films. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Lloret, Elsa; Arnau, Jacint; Picouet, Pierre A.] IRTA, Dept Tecnol Aliments, Monells, Girona, Spain. [Fernandez, Avelina] Inst Fis Corpuscular CSIC UVEC, Parc Cient, Valencia, Spain. [Trbojevich, Raul] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Picouet, PA (reprint author), IRTA, Dept Tecnol Aliments, Monells, Girona, Spain. EM pierre.picouet@irta.cat FU Spanish Comision Interministerial de Ciencia y Tecnologia (Ministerio de Ciencia e Innovacion) [AGL07-65936-C02]; National Center for Toxicological Research [E0736801]; U.S. Food and Drug Administration FX This study has been carried out with the financial support from the Spanish Comision Interministerial de Ciencia y Tecnologia (Ministerio de Ciencia e Innovacion) under contract AGL07-65936-C02. R. Trbojevich acknowledges support through the project # E0736801 from National Center for Toxicological Research and U.S. Food and Drug Administration and gratefully acknowledges assistance from FDA NCTR/ORA Nanotechnology Core Facility, Jefferson, Arkansas (USA) in which part of this study was conducted. Authors are grateful to Christina Canals and Mauro Vitale (IRTA) for technical assistance and also thank to Dr. Frederick Beland and Dr. Paul Howard for assistance in the review of this manuscript. NR 25 TC 0 Z9 0 U1 10 U2 16 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0309-1740 EI 1873-4138 J9 MEAT SCI JI Meat Sci. PD AUG PY 2016 VL 118 BP 8 EP 14 DI 10.1016/j.meatsci.2016.03.007 PG 7 WC Food Science & Technology SC Food Science & Technology GA DS2GR UT WOS:000380581100002 PM 26998947 ER PT J AU Movassaghian, S Xie, YR Hildebrandt, C Rosati, R Li, Y Kim, NH Conti, DS da Rocha, SRP Yang, ZQ Merkel, OM AF Movassaghian, Sara Xie, Yuran Hildebrandt, Claudia Rosati, Rayna Li, Ying Kim, Na Hyung Conti, Denise S. da Rocha, Sandro R. P. Yang, Zeng-Quan Merkel, Olivia M. TI Post-Transcriptional Regulation of the GASC1 Oncogene with Active Tumor-Targeted siRNA-Nanoparticles SO MOLECULAR PHARMACEUTICS LA English DT Article DE nanoparticle; siRNA; polyethylenimine (PEI); transferrin; transferrin receptor; GASC1; artificial virus; targeting; breast cancer; oncogene; targeted therapy ID NEGATIVE BREAST-CANCER; GENE DELIVERY; IN-VIVO; TRANSFECTION EFFICIENCY; NONVIRAL VECTOR; THERAPY; CELLS; POLYETHYLENIMINE; RECEPTOR; EPIGENETICS AB Basal-like breast cancer (BLBC) accounts for the most aggressive types of breast cancer, marked by high rates of relapse and poor prognoses and with no effective clinical therapy yet. Therefore, investigation of new targets and treatment strategies is more than necessary. Here, we identified a receptor that can be targeted in BLBC for efficient and specific siRNA mediated gene knockdown of therapeutically relevant genes such as the histone demethylase GASC1, which is involved in multiple signaling pathways leading to tumorigenesis. Breast cancer and healthy breast cell lines were compared regarding transferrin receptor (TfR) expression via flow cytometry and transferrin binding assays. Nanobioconjugates made of low molecular weight polyethylenimine (LMW-PEI) and transferrin (Tf) were synthesized to contain a bioreducible disulfide bond. siRNA complexation was characterized by condensation assays and dynamic light scattering. Cytotoxicity, transfection efficiency, and the targeting specificity of the conjugates were investigated in TfR positive and negative healthy breast and breast cancer cell lines by flow cytometry, confocal microscopy, RT-PCR, and Western blot. Breast cancer cell lines revealed a significantly higher TfR expression than healthy breast cells. The conjugates efficiently condensed siRNA into particles with 45 nm size at low polymer concentrations, showed no apparent toxicity on different breast cancer cell lines, and had significantly greater transfection and gene knockdown activity on mRNA and protein levels than PEI/siRNA leading to targeted and therapeutic growth inhibition post GASC1 knockdown. The synthesized nanobioconjugates improved the efficiency of gene transfer and targeting specificity in transferrin receptor positive cells but not in cells with basal receptor expression. Therefore, these materials in combination with our newly identified siRNA sequences are promising candidates for therapeutic targeting of hard-to-treat BLBC and are currently further investigated regarding in vivo targeting efficacy and biocompatibility. C1 [Movassaghian, Sara; Xie, Yuran; Hildebrandt, Claudia; Rosati, Rayna; Li, Ying; Kim, Na Hyung; Merkel, Olivia M.] Wayne State Univ, Eugene Applebaum Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, 259 Mack Ave, Detroit, MI 48201 USA. [Movassaghian, Sara; Rosati, Rayna; Yang, Zeng-Quan; Merkel, Olivia M.] Wayne State Univ, Karmanos Canc Inst, Dept Oncol, Detroit, MI 48201 USA. [Hildebrandt, Claudia] Univ Kiel, Dept Pharmaceut & Biopharmaceut, D-24118 Kiel, Germany. [Conti, Denise S.] Wayne State Univ, Coll Engn, Dept Chem Engn & Mat Sci, Detroit, MI 48202 USA. [da Rocha, Sandro R. P.] Virginia Commonwealth Univ, Coll Pharm, Dept Pharmaceut, Richmond, VA 23298 USA. [da Rocha, Sandro R. P.] Virginia Commonwealth Univ, Dept Chem & Life Sci Engn, Richmond, VA 23284 USA. [Merkel, Olivia M.] Univ Munich, Dept Pharm Pharmaceut Technol & Biopharmaceut, D-80539 Munich, Germany. [Conti, Denise S.] FDA, CDER, Off Gener Drugs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Merkel, OM (reprint author), Wayne State Univ, Eugene Applebaum Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, 259 Mack Ave, Detroit, MI 48201 USA. EM olivia.merkel@wayne.edu FU Karmanos Cancer Institute-SRIG grant; Angelika Burger Fellowship grant; National Institutes of Health [R21CA175244-01A1]; Department of Defense (DoD) Prostate Cancer Program [PC121737, PC130259]; NIH Center Grant [P30CA22453] FX This work was supported by the Karmanos Cancer Institute-SRIG grant and Angelika Burger Fellowship grant awarded to O.M.M. and Z.-Q.Y. and partially supported by grants from the National Institutes of Health R21CA175244-01A1 (to Z.-Q.Y.) and the Department of Defense (DoD) Prostate Cancer Program PC121737 and PC130259 (to Z.-Q.Y.). The NIH Center Grant P30CA22453 supporting the Wayne State Microscopy, Imaging and Cytometry Resources (MICR) is gratefully acknowledged. We thank Dr. Stephen P. Ethier for providing human SUM breast cancer cell lines and acknowledge Barani Govindarajan and Dr. Yuanyuan Jiang for technical support. NR 54 TC 1 Z9 1 U1 7 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD AUG PY 2016 VL 13 IS 8 BP 2605 EP 2621 DI 10.1021/acs.molpharmaceut.5b00948 PG 17 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DS6AT UT WOS:000380864800002 PM 27223606 ER PT J AU Mayne, ST Playdon, MC Rock, CL AF Mayne, Susan T. Playdon, Mary C. Rock, Cheryl L. TI Diet, nutrition, and cancer: past, present and future SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID SQUAMOUS-CELL CARCINOMA; SPECTROMETRY-BASED METABOLOMICS; FOOD-FREQUENCY QUESTIONNAIRE; BREAST-CANCER; RECOVERY BIOMARKERS; PANCREATIC-CANCER; COLORECTAL-CANCER; VEGETABLE INTAKE; RISK-FACTORS; MEASUREMENT ERROR AB Despite the potentially important roles of diet and nutrition in cancer prevention, the evidence to support these roles is widely perceived by the public and health professionals as being inconsistent. In this Review, we present the issues and challenges in conducting and interpreting diet-cancer research, including those relating to the design of epidemiological studies, dietary data collection methods, and factors that affect the outcome of intervention trials. Approaches to improve effect estimates, such as the use of biomarkers to improve the accuracy of characterizing dietary exposures, are also discussed. Nutritional and dietary patterns are complex; therefore, the use of a reductionist approach to investigations, by focusing on specific nutrients, can produce misleading information. The effects of tumour heterogeneity and the failure to appreciate the nonlinear, U-shaped relationship between micronutrients and cancer in both observational studies and clinical trials are discussed. New technologies and investigational approaches are enabling the exploration of complex interactions between genetic, epigenetic, metabolic, and gut-microbial processes that will inform our knowledge of the diet-cancer relationship. Communicating the status of the evolving science in the context of the overall scientific evidence base, and evidence-based dietary recommendations for cancer prevention, should be emphasized in guidance for the public and for individual patients. C1 [Mayne, Susan T.; Playdon, Mary C.] Yale Univ, Yale Sch Publ Hlth, 60 Coll St,POB 208034, New Haven, CT 06520 USA. [Mayne, Susan T.] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Rock, Cheryl L.] Univ Calif San Diego, Sch Med, 3855 Hlth Sci Dr, La Jolla, CA 92093 USA. RP Rock, CL (reprint author), Univ Calif San Diego, Sch Med, 3855 Hlth Sci Dr, La Jolla, CA 92093 USA. EM clrock@ucsd.edu RI Playdon, Mary/I-4050-2016 NR 144 TC 3 Z9 3 U1 27 U2 43 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD AUG PY 2016 VL 13 IS 8 BP 504 EP 515 DI 10.1038/nrclinonc.2016.24 PG 12 WC Oncology SC Oncology GA DS4MU UT WOS:000380756000007 PM 26951041 ER PT J AU Vaithianathan, S Ting, TY Jiang, WL Polli, JE AF Vaithianathan, Soundarya Ting, Tricia Y. Jiang, Wenlei Polli, James E. TI Release of levetiracetam from extended-release tablets that appear intact in patient stool SO SEIZURE-EUROPEAN JOURNAL OF EPILEPSY LA English DT Editorial Material DE Levetiracetam; Extended-release; Generic; Stool; Tablet Remnant C1 [Vaithianathan, Soundarya; Polli, James E.] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Ting, Tricia Y.] Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. [Jiang, Wenlei] US FDA, White Oak, MD USA. RP Polli, JE (reprint author), Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA.; Ting, TY (reprint author), Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. EM tting@som.umaryland.edu; jpolli@rx.umaryland.edu NR 4 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1059-1311 EI 1532-2688 J9 SEIZURE-EUR J EPILEP JI Seizure PD AUG PY 2016 VL 40 BP 7 EP 9 DI 10.1016/j.seizure.2016.05.011 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DT7FY UT WOS:000381653700002 PM 27269879 ER PT J AU Jin, YQ Yu, DK Tolleson, WH Knox, B Deng, HL Guo, YL Ning, BT AF Jin, Yaqiong Yu, Dianke Tolleson, William H. Knox, Bridgett Deng, Helen Guo, Yongli Ning, Baitang TI MicroRNA hsa-miR-25-3p suppresses the expression and drug induction of CYP2B6 in human hepatocytes SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE hsa-miR-25-3p; CYP2B6; Drug metabolizing enzymes; Pharmacogenomics; Inter-individual variability ID HUMAN LIVER-CELLS; IN-VITRO; ANDROSTANE-RECEPTOR; GENE; CARBAMAZEPINE; METABOLISM; PHARMACOKINETICS; PHARMACOGENOMICS; POLYMORPHISMS; ASSOCIATION AB Cytochrome P450 2B6 (CYP2B6), mainly expressed in the liver and brain, is important for processing a number of widely used drugs. Variations in CYP2B6 expression are associated with decreased drug efficacy or adverse effects in some patients. Although CYP2B6 genetic variants are associated with its differential expression, epigenetic mechanisms affecting CYP2B6 gene regulation have not been established. Sequence analysis identified 29 domains in the CYP2B6 mRNA transcript that could be subject to regulation by microRNAs. Inverse correlations were found in human hepatocytes for the levels of the microRNAs hsa-miR-504-5p and hsa-miR-25-3p compared with CYP2B6 mRNA. Reporter gene assays showed that hsa-miR-25-3p suppresses CYP2B6 expression by targeting a specific sequence in the 3'-untranslated region of the mRNA transcript. Electrophoretic mobility shift assays confirmed that hsa-miR-25-3p forms stable complexes with its cognate mRNA sequence and that it recruits cellular factors, including Ago-4. Transfection of HepaRG cells with hsa-miR-25-3p mimics inhibited expression of the endogenous CYP2B6 gene and it also decreased rifampicin-dependent induction of CYP2B6 at the mRNA and protein levels. In summary, in silico and in vitro analyses show that hsa-miR-25-3p suppresses CYP2B6 expression in human liver cells via an epigenetic mechanism. Published by Elsevier Inc. C1 [Jin, Yaqiong; Guo, Yongli] Univ Capital Med, Beijing Childrens Hosp, Beijing Pediat Res Inst, Beijing Key Lab Pediat Dis Otolaryngol Head & Nec, Beijing 100045, Peoples R China. [Yu, Dianke; Tolleson, William H.; Knox, Bridgett; Ning, Baitang] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Deng, Helen] Arkansas Dept Hlth, Little Rock, AR 72205 USA. RP Yu, DK; Ning, BT (reprint author), Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT100, Jefferson, AR 72079 USA.; Guo, YL (reprint author), Capital Med Univ, Beijing Childrens Hosp, Beijing Pediat Res Inst, 56 Nanlishi Rd, Beijing 100045, Peoples R China. EM dianke.yu@fda.hhs.gov; guoyongli@bch.com.cn; baitang.ning@fda.hhs.gov OI Jin, Ya-Qiong/0000-0002-9318-6531 FU National Center for Toxicological Research [E0752601]; U.S. Food and Drug Administration FX This study was supported and funded by the National Center for Toxicological Research (Project E0752601) and U.S. Food and Drug Administration. NR 34 TC 0 Z9 0 U1 3 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD AUG 1 PY 2016 VL 113 BP 88 EP 96 DI 10.1016/j.bcp.2016.06.007 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DS7OH UT WOS:000380972300008 PM 27311985 ER PT J AU Lucano, E Liberti, M Mendoza, GG Lloyd, T Iacono, MI Apollonio, F Wedan, S Kainz, W Angelone, LM AF Lucano, Elena Liberti, Micaela Mendoza, Gonzalo G. Lloyd, Tom Iacono, Maria Ida Apollonio, Francesca Wedan, Steve Kainz, Wolfgang Angelone, Leonardo M. TI Assessing the Electromagnetic Fields Generated By a Radiofrequency MRI Body Coil at 64 MHz: Defeaturing Versus Accuracy SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Field probes; finite-difference time domain (FDTD); safety; symmetric mean absolute percentage error (SMAPE); validation ID TO-NOISE RATIO; INDUCED CURRENT DENSITIES; BIRDCAGE COIL; NUMERICAL ASSESSMENT; INTERVENTIONAL MRI; ABSORPTION RATES; MAGNETIC-FIELDS; HUMAN HEAD; SAR; SIMULATION AB Goal: This study aims at a systematic assessment of five computational models of a birdcage coil formagnetic resonance imaging (MRI) with respect to accuracy and computational cost. Methods: The models were implemented using the same geometrical model and numerical algorithm, but different driving methods (i.e., coil "defeaturing"). The defeatured models were labeled as: specific (S2), generic (G32, G16), and hybrid (H16, H16(fr-forced)). The accuracy of the models was evaluated using the "symmetric mean absolute percentage error" ("SMAPE"), by comparison with measurements in terms of frequency response, as well as electric (parallel to(E) over right arrow parallel to) and magnetic (parallel to(B) over right arrow parallel to) field magnitude. Results: All the models computed the parallel to B parallel to within 35% of the measurements, only the S2, G32, and H16 were able to accurately model the parallel to(E) over right arrow parallel to inside the phantom with a maximum SMAPE of 16%. Outside the phantom, only the S2 showed a SMAPE lower than 11%. Conclusions: Results showed that assessing the accuracy of parallel to(B) over right arrow parallel to based only on comparison along the central longitudinal line of the coil can be misleading. Generic or hybrid coils - when properly modeling the currents along the rings/rungs-were sufficient to accurately reproduce the fields inside a phantom while a specific model was needed to accurately model parallel to(E) over right arrow parallel to in the space between coil and phantom. Significance: Computational modeling of birdcage body coils is extensively used in the evaluation of radiofrequency-induced heating during MRI. Experimental validation of numerical models is needed to determine if a model is an accurate representation of a physical coil. C1 [Lucano, Elena] Sapienza Univ Rome, Rome, Italy. [Lucano, Elena] US FDA, Off Sci & Engn Labs, Div Biomed Phys, CDRH, Silver Spring, MD 20901 USA. [Liberti, Micaela; Apollonio, Francesca] Sapienza Univ Rome, Dept Elect Engn, Rome, Italy. [Lloyd, Tom; Wedan, Steve] Imricor Med Syst, Burnsville, MN USA. [Mendoza, Gonzalo G.; Iacono, Maria Ida; Kainz, Wolfgang; Angelone, Leonardo M.] US FDA, Off Sci & Engn Labs, CDRH, Silver Spring, MD 20901 USA. RP Angelone, LM (reprint author), US FDA, Off Sci & Engn Labs, CDRH, Silver Spring, MD 20901 USA. EM Leonardo.angelone@fda.hhs.gov OI Liberti, Micaela/0000-0002-7494-2696 FU Research Participation Program at the Center for Devices and Radiological Health; Imricor Medical Systems; Center for Devices and Radiological Health, FDA; Office of Women's Health, U.S. FDA FX This work was supported in part by the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration (FDA), in part by a Cooperative Research and Development Agreement between Imricor Medical Systems and the Center for Devices and Radiological Health, FDA, and in part by the Office of Women's Health, U.S. FDA. Asterisk indicates corresponding author. NR 60 TC 0 Z9 0 U1 3 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 EI 1558-2531 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD AUG PY 2016 VL 63 IS 8 BP 1591 EP 1601 DI 10.1109/TBME.2015.2506680 PG 11 WC Engineering, Biomedical SC Engineering GA DS0ZH UT WOS:000380325000004 PM 26685220 ER PT J AU Attaluri, A Seshadri, M Mirpour, S Wabler, M Marinho, T Furqan, M Zhou, H De Paoli, S Gruettner, C Gilson, W DeWeese, T Garcia, M Ivkov, R Liapi, E AF Attaluri, Anilchandra Seshadri, Madhav Mirpour, Sahar Wabler, Michele Marinho, Thomas Furqan, Muhammad Zhou, Haoming De Paoli, Silvia Gruettner, Cordula Gilson, Wesley DeWeese, Theodore Garcia, Monica Ivkov, Robert Liapi, Eleni TI Image-guided thermal therapy with a dual-contrast magnetic nanoparticle formulation: A feasibility study SO INTERNATIONAL JOURNAL OF HYPERTHERMIA LA English DT Article DE Computed tomography; embolisation therapy; hyperthermia; image-guided delivery; Lipiodol; magnetic nanoparticles; magnetic resonance imaging ID TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION; LIVER-TUMOR MODEL; RABBIT LIVER; HEPATOCELLULAR-CARCINOMA; FERROMAGNETIC EMBOLIZATION; INTRAARTERIAL THERAPIES; INTERVENTIONAL ONCOLOGY; TARGETED HYPERTHERMIA; DRUG-DELIVERY; CANCER AB Purpose/objective: The aim of this study was to develop and investigate the properties of a magnetic iron oxide nanoparticle-ethiodised oil formulation for image-guided thermal therapy of liver cancer.Materials and methods: The formulation comprises bionised nano-ferrite (BNF) nanoparticles suspended in ethiodised oil, emulsified with polysorbate 20 (BNF-lip). Nanoparticle size was measured via photon correlation spectroscopy and transmission electron microscopy. In vivo thermal therapy capability was tested in two groups of male Foxn1(nu) mice bearing subcutaneous HepG2 xenograft tumours. Group I (n=12) was used to screen conditions for group II (n=48). In group II, mice received one of BNF-lip (n=18), BNF alone (n=16), or PBS (n=14), followed by alternating magnetic field (AMF) hyperthermia, with either varied duration (15 or 20min) or amplitude (0, 16, 20, or 24kA/m). Image-guided fluoroscopic intra-arterial injection of BNF-lip was tested in New Zealand white rabbits (n=10), bearing liver VX2 tumours. The animals were subsequently imaged with CT and 3 T MRI, up to 7 days post-injection. The tumours were histopathologically evaluated for distribution of BNF-lip.Results: The BNF showed larger aggregate diameters when suspended in BNF-lip, compared to clear solution. The BNF-lip formulation produced maximum tumour temperatures with AMF >20kA/m and showed positive X-ray visibility and substantial shortening of T1 and T2 relaxation time, with sustained intratumoural retention up to 7 days post-injection. On pathology, intratumoural BNF-lip distribution correlated well with CT imaging of intratumoural BNF-lip distribution.Conclusion: The BNF-lip formulation has favourable thermal and dual imaging capabilities for image-guided thermal therapy of liver cancer, suggesting further exploration for clinical applications. C1 [Attaluri, Anilchandra; Seshadri, Madhav; Wabler, Michele; Marinho, Thomas; Furqan, Muhammad; Zhou, Haoming; DeWeese, Theodore; Garcia, Monica; Ivkov, Robert] Johns Hopkins Univ, Dept Radiat Oncol & Mol Radiat Sci, Sch Med, David H Koch Canc Res Bldg,Rm 442,1550 Orleans St, Baltimore, MD 21231 USA. [Mirpour, Sahar; Liapi, Eleni] Johns Hopkins Univ Hosp, Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [De Paoli, Silvia] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Gruettner, Cordula] Micromod Partikeltechnol GmbH, Rostock, Germany. [Gilson, Wesley] Siemens Healthcare Solut Inc, Baltimore, MD USA. [Garcia, Monica] Univ Brasilia, Inst Biol Sci, Dept Genet & Morphol, BR-70910900 Brasilia, DF, Brazil. [Ivkov, Robert] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Ivkov, Robert] Johns Hopkins Univ, Inst NanoBioTechnol, Baltimore, MD USA. [Ivkov, Robert] Johns Hopkins Univ, Dept Mat Sci & Engn, Baltimore, MD 21218 USA. [Attaluri, Anilchandra] Rowan Univ, Dept Mech Engn, Glassboro, NJ USA. RP Ivkov, R (reprint author), Johns Hopkins Univ, Dept Radiat Oncol & Mol Radiat Sci, Sch Med, David H Koch Canc Res Bldg,Rm 442,1550 Orleans St, Baltimore, MD 21231 USA. EM rivkov1@jhmi.edu FU National Cancer Institute [U54CA151838, P50CA062924, R21CA161626, 5R01CA194574-02, P30CA006973] FX C.G. is an employee of micromod Partikeltechnologie, GmbH, manufacturer of the BNF nanoparticles used in this study. R.I. and E.L. are inventors of nanoparticle patents. All patents are assigned to either the Johns Hopkins University or Aduro Biosciences, Inc. All other authors report no conflicts of interest. This work was funded by the National Cancer Institute (grant numbers U54CA151838, P50CA062924, R21CA161626, 5R01CA194574-02 and P30CA006973). The authors alone are responsible for the content and writing of the paper. NR 53 TC 0 Z9 0 U1 5 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0265-6736 EI 1464-5157 J9 INT J HYPERTHER JI Int. J. Hyperthermia PD AUG PY 2016 VL 32 IS 5 BP 543 EP 557 DI 10.3109/02656736.2016.1159737 PG 15 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DR8FF UT WOS:000380133100012 PM 27151045 ER PT J AU Mahmood, LA Casey, D Dolan, JG Dozier, AM Korones, DN AF Mahmood, Laila A. Casey, Denise Dolan, James G. Dozier, Ann M. Korones, David N. TI Feasibility of Early Palliative Care Consultation for Children With High-Risk Malignancies SO PEDIATRIC BLOOD & CANCER LA English DT Article DE consultation; early integration; feasibility; high risk; palliative care; pediatric cancer ID PEDIATRIC ONCOLOGY; EARLY INTEGRATION; HOME-CARE; CANCER; PROFESSIONALS; PERCEPTIONS; BARRIERS; TEAM AB Background. Children with cancer suffer significant morbidity throughout therapy and often face an uncertain prognosis. Because palliative care teams can provide an additional layer of support with symptom management and communication, we conducted a prospective study assessing the feasibility of early palliative care consultation for children with high-risk malignancies. Procedure. This study was part of a larger prospective study examining the impact of early palliative care consultation. Children were eligible if they were <22 years old and had a high-risk malignancy, recurrence, or required hematopoietic stem cell transplantation (HSCT). Data were collected from the medical record on diagnosis, days to consultation, acceptability of consultation to family/staff, and overall survival. Feasibility was defined as enrollment of >75% of eligible patients, palliative care consultation within 1 month of eligibility, and patient/family satisfaction. Results. Twenty of 25 (80%) eligible patients were approached and received a palliative care consultation at initial diagnosis (7), recurrence (12), or time of HSCT (1). Median age of the children was 5 years (0.1-20 years). Median time from new diagnosis/recurrence to consultation was 12 days (2-180 days); 17 (85%) received the consultation within 30 days. Eleven (55%) of the 20 children died. Median time of consultation prior to death was 128 days (10-648 days). Ten of the 11 (91%) received their consultation >30 days prior to death. No families or oncologists declined an early consultation. Conclusions. Early palliative care consultation is feasible for children with high-risk cancer and is acceptable to children, families, and pediatric oncologists. (C) 2016 Wiley Periodicals, Inc. C1 [Mahmood, Laila A.; Korones, David N.] Univ Rochester, Med Ctr, Dept Pediat, Div Pediat Hematol Oncol, Rochester, NY 14642 USA. [Casey, Denise] US FDA, Off Hematol & Oncol Prod, Rochester, NY USA. [Dolan, James G.; Dozier, Ann M.] Univ Rochester, Med Ctr, Dept Publ Hlth Sci, Rochester, NY 14642 USA. RP Mahmood, LA (reprint author), Childrens Natl Med Ctr, Div Pediat Hematol & Pediat Palliat Care, Washington, DC 20010 USA. EM Laila_a_mahmood@hotmail.com NR 22 TC 1 Z9 1 U1 2 U2 4 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 AUG PY 2016 VL 63 IS 8 BP 1419 EP 1422 DI 10.1002/pbc.26024 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DR7VU UT WOS:000380108600015 PM 27148856 ER PT J AU Hwang, CS Kang, EM Kornegay, CJ Staffa, JA Jones, CM McAninch, JK AF Hwang, Catherine S. Kang, Elizabeth M. Kornegay, Cynthia J. Staffa, Judy A. Jones, Christopher M. McAninch, Jana K. TI Trends in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014 SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID CHRONIC NONCANCER PAIN; EMERGENCY-DEPARTMENT VISITS; DRUG-ABUSE DEATHS; UNITED-STATES; OVERDOSE DEATHS; OXYCODONE INVOLVEMENT; MONITORING PROGRAMS; PRESCRIPTION DRUGS; NONMALIGNANT PAIN; CONSENSUS PANEL AB Introduction: Although many clinical guidelines caution against the combined use of opioids and benzodiazepines, overdose deaths and emergency department visits involving the co-ingestion of these drugs are increasing. Methods: In this ecologic time series study, the IMS Health Total Patient Tracker was used to describe nationally projected trends of patients receiving opioids and benzodiazepines in the U.S. outpatient retail setting between January 2002 and December 2014. The IMS Health Data Extract Tool was used to examine trends in the concomitant prescribing of these two medication classes among 177 million individuals receiving opioids during this period. The annual proportion of opioid recipients who were prescribed benzodiazepines concomitantly was calculated and stratified by gender, age, duration of opioid use, immediate-release versus extended-release/long-acting opioids, and benzodiazepine molecule. The proportion of patients with concomitancy receiving opioids and benzodiazepines from the same prescriber was also analyzed. Analyses were conducted from April to June 2015. Results: The nationally projected number of patients receiving opioids and benzodiazepines increased by 8% and 31%, respectively, from 2002 to 2014. During this period, the annual proportion of opioid recipients dispensed a benzodiazepine concomitantly increased from 6.8% to 9.6%, which corresponded to a relative increase of 41%. Approximately half of these patients received both prescriptions from the same prescriber on the same day. Concomitancy was more common in patients receiving opioids for >= 90 days, women, and the elderly. Conclusions: Concomitant prescribing of opioids and benzodiazepines is increasing and may play a growing role in adverse patient outcomes related to these medications. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Hwang, Catherine S.; Kang, Elizabeth M.; Kornegay, Cynthia J.; Staffa, Judy A.; McAninch, Jana K.] US FDA, Ctr Drug Evaluat & Res, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Jones, Christopher M.] US Dept Hlth & Human Serv, Off Assistant Secretary Planning & Evaluat, Div Sci Policy, Washington, DC USA. RP McAninch, JK (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jana.mcaninch@fda.hhs.gov FU U.S. Food and Drug Administration FX The research presented in this paper is that of the authors and does not reflect the official policy or opinion of the U.S. Food and Drug Administration. Support for this study came from the U.S. Food and Drug Administration. 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 (ORISE) through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. ORISE had no role in the study design, review, or decision to publish. NR 59 TC 7 Z9 7 U1 7 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2016 VL 51 IS 2 BP 151 EP 160 DI 10.1016/j.amepre.2016.02.014 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DS0AB UT WOS:000380256400004 PM 27079639 ER PT J AU Meeker-O'Connell, A Glessner, C Behm, M Mulinde, J Roach, N Sweeney, F Tenaerts, P Landray, MJ AF Meeker-O'Connell, Ann Glessner, Coleen Behm, Mark Mulinde, Jean Roach, Nancy Sweeney, Fergus Tenaerts, Pamela Landray, Martin J. TI Enhancing clinical evidence by proactively building quality into clinical trials SO CLINICAL TRIALS LA English DT Article DE quality-by-design; clinical trial; good clinical practice; quality assurance ID CONDUCT; DRUGS AB Background: Stakeholders across the clinical trial enterprise have expressed concern that the current clinical trial enterprise is unsustainable. The cost and complexity of trials have continued to increase, threatening our ability to generate reliable evidence essential for making appropriate decisions concerning the benefits and harms associated with clinical interventions. Overcoming this inefficiency rests on improving protocol design, trial planning, and quality oversight. Methods: The Clinical Trials Transformation Initiative convened a project to evaluate methods to prospectively build quality into the scientific and operational design of clinical trials ("quality-by-design"), such that trials are feasible to conduct and important errors are prevented rather than remediated. A working group evaluated aspects of trial design and oversight and developed the Clinical Trials Transformation Initiative quality-by-design principles document, outlining a series of factors generally relevant to the reliability of trial conclusions and to patient safety. These principles were then applied and further refined during a series of hands-on workshops to evaluate their utility in facilitating proactive, cross-functional dialogue, and decision-making about trial design and planning. Following these workshops, independent qualitative interviews were conducted with 19 workshop attendees to explore the potential challenges for implementing a quality-by-design approach to clinical trials. The Clinical Trials Transformation Initiative project team subsequently developed recommendations and an online resource guide to support implementation of this approach. Conclusion: The Clinical Trials Transformation Initiative quality-by-design principles provide a framework for assuring that clinical trials adequately safeguard participants and provide reliable information on which to make decisions on the effects of treatments. The quality-by-design workshops highlighted the value of active discussions incorporating the different perspectives within and external to an organization (e.g. clinical investigators, research site staff, and trial participants) in improving trial design. Workshop participants also recognized the value of focusing oversight on those aspects of the trial where errors would have a major impact on participant safety and reliability of results. Applying the Clinical Trials Transformation Initiative quality-by-design recommendations and principles should enable organizations to prioritize the most critical determinants of a trial's quality, identify non-essential activities that can be eliminated to streamline trial conduct and oversight, and formulate appropriate plans to define, avoid, mitigate, monitor, and address important errors. C1 [Meeker-O'Connell, Ann] Johnson & Johnson, New Brunswick, NJ USA. [Glessner, Coleen] Alexion, New Haven, CT USA. [Behm, Mark] AstraZeneca, Wilmington, DE USA. [Mulinde, Jean] US FDA, Silver Spring, MD USA. [Roach, Nancy] Fight Colorectal Canc, Alexandria, VA USA. [Sweeney, Fergus] European Med Agcy, London, England. [Tenaerts, Pamela] Duke Univ, Clin Trials Transformat Initiat, 300 W Morgan St,Suite 800, Durham, NC 27701 USA. [Landray, Martin J.] Univ Oxford, Oxford, England. RP Tenaerts, P (reprint author), Duke Univ, Clin Trials Transformat Initiat, 300 W Morgan St,Suite 800, Durham, NC 27701 USA. EM pamela.tenaerts@duke.edu FU United States Food and Drug Administration [R18FD005292, U19FD003800]; CTTI's member organizations FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for this manuscript was made possible, in part, by the United States Food and Drug Administration through grant R18FD005292 and cooperative agreement U19FD003800. Views expressed in this publication does not necessarily reflect the official policies of the United States Department of Health and Human Services or of the European Medicines Agency; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government or European Medicines Agency. Partial funding was also provided by pooled membership fees from CTTI's member organizations. NR 21 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD AUG PY 2016 VL 13 IS 4 BP 439 EP 444 DI 10.1177/1740774516643491 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DR8DV UT WOS:000380129500011 PM 27098014 ER PT J AU Mehrotra, DV Hemmings, RJ Russek-Cohen, E AF Mehrotra, Devan V. Hemmings, Robert J. Russek-Cohen, Estelle CA ICH E9R1 Expert Working Grp TI Seeking harmony: estimands and sensitivity analyses for confirmatory clinical trials SO CLINICAL TRIALS LA English DT Article DE Dropouts; estimand; International Conference on Harmonization E9; missing data; sensitivity analysis; trial planning ID MISSING DATA AB In October 2014, the Steering Committee of the International Conference on Harmonization endorsed the formation of an expert working group to develop an addendum to the International Conference on Harmonization E9 guideline ("Statistical Principles for Clinical Trials"). The addendum will focus on two topics involving randomized confirmatory clinical trials: estimands and sensitivity analyses. Both topics are motivated, in part, by the need to improve the precision with which scientific questions of interest are formulated and addressed by clinical trialists and regulators, specifically in the context of post-randomization events such as use of rescue medication or missing data resulting from dropouts. Given the importance of these topics for the statistical and medical community, we articulate the reasons for the planned addendum. The resulting "ICH E9/R1" guideline will include a framework for improved trial planning, conduct, analysis, and interpretation; a draft is expected to be ready for public comment in the second half of 2016. C1 [Mehrotra, Devan V.] Merck Res Labs, 351 N Sumneytown Pike, N Wales, PA USA. [Hemmings, Robert J.] Med & Healthcare Prod Regulatory Agcy, London, England. [Russek-Cohen, Estelle] US FDA, Silver Spring, MD USA. RP Mehrotra, DV (reprint author), Merck Res Labs, 351 N Sumneytown Pike, N Wales, PA USA. EM devan_mehrotra@merck.com NR 6 TC 2 Z9 2 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD AUG PY 2016 VL 13 IS 4 BP 456 EP 458 DI 10.1177/1740774516633115 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DR8DV UT WOS:000380129500016 PM 26908545 ER PT J AU Miller, V Harrington, P Howe, A Kieffer, T Lennerstrand, J Lenz, O Lontok, E McPhee, F Mo, HM Parkin, N Pilot-Matias, T AF Miller, Veronica Harrington, Patrick Howe, Anita Kieffer, Tara Lennerstrand, Johan Lenz, Oliver Lontok, Erik McPhee, Fiona Mo, Hongmei Parkin, Neil Pilot-Matias, Tami TI Hepatitis C Genotype 4R Resistance-Associated Polymorphisms: The Achilles Heel of the Nonstructural 5A Inhibitors? Reply SO HEPATOLOGY LA English DT Letter ID NS5A; DACLATASVIR; VARIANTS C1 [Miller, Veronica] Univ Calif Berkeley, Forum Collaborat HIV Res, Washington, DC USA. [Harrington, Patrick] US FDA, Ctr Drug Evaluat & Res, Off Antimicrobial Prod, Div Antiviral Prod, Silver Spring, MD USA. [Howe, Anita] BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Kieffer, Tara] Vertex Pharmaceut Inc, Boston, MA USA. [Lennerstrand, Johan] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Lenz, Oliver] Janssen Infect Dis, Beerse, Belgium. [Lontok, Erik] Ctr Strateg Philanthropy, Washington, DC USA. [McPhee, Fiona] Bristol Myers Squibb Res & Dev, Wallingford, CT USA. [Mo, Hongmei] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA. [Parkin, Neil] Data First Consulting Inc, Belmont, CA USA. [Pilot-Matias, Tami] AbbVie Inc, Chicago, IL USA. RP Miller, V (reprint author), Univ Calif Berkeley, Forum Collaborat HIV Res, Washington, DC USA. NR 5 TC 0 Z9 0 U1 1 U2 1 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 AUG PY 2016 VL 64 IS 2 BP 698 EP 699 DI 10.1002/hep.28615 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DR6TP UT WOS:000380034500055 PM 27113118 ER PT J AU Yu, JY Chung, S Zadezensky, I Hu, K Darstein, C Nedelman, J Mehrotra, N AF Yu, Jingyu Chung, Sang Zadezensky, Immo Hu, Ke Darstein, Christelle Nedelman, Jerry Mehrotra, Nitin TI Utility of Exposure-Response Analysis in Regulatory Decision on the Selection of Starting Dose of Pasireotide for Cushing Disease SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE Pharmacometrics; Endocrinology (END); Clinical Pharmacology (CPH); Clinical Trials (CTR); Regulatory/Scientific Affairs (REG) ID LABELING DECISIONS; DRUG APPROVAL; IMPACT C1 [Yu, Jingyu; Mehrotra, Nitin] US FDA, Div Pharmacometr, Off Clin Pharmacol, Silver Spring, MD USA. [Chung, Sang; Zadezensky, Immo] US FDA, Div Clin Pharmacol 2, Off Clin Pharmacol, Silver Spring, MD USA. [Hu, Ke; Nedelman, Jerry] Novartis Pharmaceut, E Hanover, NJ USA. [Darstein, Christelle] Novartis Pharma AG, Basel, Switzerland. RP Mehrotra, N (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Nitin.Mehrotra@fda.hhs.gov NR 7 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD AUG PY 2016 VL 56 IS 8 BP 1035 EP 1038 DI 10.1002/jcph.694 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DR7AE UT WOS:000380051600013 PM 26686944 ER PT J AU Jones, JL Kinsey, TP Johnson, LW Porso, R Friedman, B Curtis, M Wesighan, P Schuster, R Bowers, JC AF Jones, J. L. Kinsey, T. P. Johnson, L. W. Porso, R. Friedman, B. Curtis, M. Wesighan, P. Schuster, R. Bowers, J. C. TI Effects of Intertidal Harvest Practices on Levels of Vibrio parahaemolyticus and Vibrio vulnificus Bacteria in Oysters SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID POSTHARVEST SHELLSTOCK OYSTERS; THERMOSTABLE DIRECT HEMOLYSIN; UNITED-STATES; PREDICTIVE MODEL; PCR ANALYSIS; INFECTIONS; GROWTH; GASTROENTERITIS; VALIDATION; VIRULENCE AB Vibrio parahaemolyticus and Vibrio vulnificus can grow rapidly in shellfish subjected to ambient air conditions, such as during intertidal exposure. In this study, levels of total and pathogenic (tdh(+) and/or trh(+)) V. parahaemolyticus and total V. vulnificus were determined in oysters collected from two study locations where intertidal harvest practices are common. Samples were collected directly off intertidal flats, after exposure (ambient air [Washington State] or refrigerated [New Jersey]), and after reimmersion by natural tidal cycles. Samples were processed using a most-probable-number (MPN) real-time PCR method for total and pathogenic V. parahaemolyticus or V. vulnificus. In Washington State, the mean levels of V. parahaemolyticus increased 1.38 log MPN/g following intertidal exposure and dropped 1.41 log MPN/g after reimmersion for 1 day, but the levels were dependent upon the container type utilized. Pathogenic V. parahaemolyticus levels followed a similar trend. However, V. vulnificus levels increased 0.10 log MPN/g during intertidal exposure in Washington but decreased by >1 log MPN/g after reimmersion. In New Jersey, initial levels of all vibrios studied were not significantly altered during the refrigerated sorting and containerizing process. However, there was an increase in levels after the first day of reimmersion by 0.79, 0.72, 0.92, and 0.71 log MPN/g for total, tdh(+) and trh(+) V. parahaemolyticus, and V. vulnificus, respectively. The levels of all targets decreased to those similar to background after a second day of reimmersion. These data indicate that the intertidal harvest and handling practices for oysters that were studied in Washington and New Jersey do not increase the risk of illness from V. parahaemolyticus or V. vulnificus. IMPORTANCE Vibrio parahaemolyticus and Vibrio vulnificus are the leading causes of seafood-associated infectious morbidity and mortality in the United States. Vibrio spp. can grow rapidly in shellfish subjected to ambient air conditions, such as during periods of intertidal exposure. When oysters are submersed with the incoming tide, the vibrios can be purged. However, data on the rates of increase and purging during intertidal harvest are scarce, which limits the accuracy of risk assessments. The objective of this study was to help fill these data gaps by determining the levels of total and pathogenic (tdh(+) and/or trh(+)) V. parahaemolyticus and V. vulnificus in oysters from two locations where intertidal harvest practices are common, using the current industry practices. The data generated provide insight into the responses of Vibrio spp. to relevant practices of the industry and public health, which can be incorporated into risk management decisions. C1 [Jones, J. L.; Kinsey, T. P.] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. [Johnson, L. W.; Porso, R.] Washington Dept Hlth, Off Environm Hlth & Safety, Tumwater, WA USA. [Friedman, B.; Curtis, M.; Wesighan, P.; Schuster, R.] Bur Marine Water Monitoring, New Jersey Dept Environm Protect, Leeds Point, NJ USA. [Bowers, J. C.] US FDA, Biostat & Bioinformat Staff, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Kinsey, T. P.] Univ Tennessee, Chem & Biomol Engn Dept, Knoxville, TN USA. RP Jones, JL (reprint author), US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. EM Jessica.Jones@fda.hhs.gov FU Interstate Shellfish Sanitation Conference FX Additional thanks to the Interstate Shellfish Sanitation Conference for financial support of T.P.K. NR 30 TC 1 Z9 1 U1 6 U2 15 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD AUG PY 2016 VL 82 IS 15 BP 4517 EP 4522 DI 10.1128/AEM.00721-16 PG 6 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DR2ZK UT WOS:000379772200006 PM 27208133 ER PT J AU Garnett, C Needleman, K Liu, J Brundage, R Wang, Y AF Garnett, C. Needleman, K. Liu, J. Brundage, R. Wang, Y. TI Operational Characteristics of Linear Concentration-QT Models for Assessing QTc Interval in the Thorough QT and Phase I Clinical Studies SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID EXPOSURE-RESPONSE ANALYSIS; TRIALS AB Concentration-QTc (C-QTc) analysis can be used as an alternative to the standard statistical methods in clinical QT studies. Pharmacokinetic/pharmacodynamics (PK/PD) simulations were performed to assess the operating characteristics of four C-QTcmodels. False negatives were 2-6% for crossover and 2-9% for parallel studies, with 12 to 60 subjects per treatment for a dose with 10-ms mean effect. All C-QTc models tested gave less than +1 ms mean bias in the Delta Delta QTc(max) prediction. The power to exclude 10 ms was >80% across all study designs and sizes, for a dose with 3-ms mean effect. The study demonstrates that linear C-QTcmodels have adequate sensitivity and specificity when the simulation and data analytical models are the same. C-QTc models that incorporate time-and treatment-specific terms give the least biased Delta Delta QTc(max) predictions under scenarios of model-misspecifications and offer an advantage when applying to real clinical data where the underlying relationship is not known. C1 [Garnett, C.] FDA, Div Cardiovasc & Renal Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Needleman, K.] FDA, Off Commissioner, Silver Spring, MD USA. [Liu, J.; Wang, Y.] FDA, Div Pharmacometr, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Brundage, R.] Univ Minnesota, Coll Pharm, Dept Expt & Clin Pharmacol, Minneapolis, MN USA. RP Garnett, C (reprint author), FDA, Div Cardiovasc & Renal Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM christine.garnett@fda.hhs.gov NR 14 TC 1 Z9 1 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 AUG PY 2016 VL 100 IS 2 BP 170 EP 178 DI 10.1002/cpt.361 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ6TA UT WOS:000379336900019 PM 26946218 ER PT J AU Sulaiman, IM Jacobs, E Segars, K Simpson, S Kerdahi, K AF Sulaiman, Irshad M. Jacobs, Emily Segars, Katharine Simpson, Steven Kerdahi, Khalil TI Genetic Characterization of Cronobacter sakazakii Recovered from the Environmental Surveillance Samples During a Sporadic Case Investigation of Foodborne Illness SO CURRENT MICROBIOLOGY LA English DT Article ID POWDERED INFANT FORMULA; DUBLINENSIS SP-NOV; ENTEROBACTER-SAKAZAKII; SEQUENCE-ANALYSIS; COMB. NOV; GEN. NOV; IDENTIFICATION; INFECTIONS; TURICENSIS; DIVERSITY AB Cronobacter sakazakii is an opportunistic human-pathogenic bacterium known to cause acute meningitis and necrotizing enterocolitis in neonates and immunocompromised individuals. This human-pathogenic microorganism has been isolated from a variety of food and environmental samples, and has been also linked to foodborne outbreaks associated with powdered infant formula (PIF). The U.S. Food and Drug Administration have a policy of zero tolerance of these organisms in PIF. Thus, this agency utilizes the presence of these microorganisms as one of the criteria in implementing regulatory actions and assessing adulteration of food products of public health importance. In this study, we recovered two isolates of Cronobacter from the 91 environmental swab samples during an investigation of sporadic case of foodborne illness following conventional microbiological protocols. The isolated typical colonies were identified using VITEK2 and real-time PCR protocols. The recovered Cronobacter isolates were then characterized for species identification by sequencing the 16S rRNA locus. Further, multilocus sequence typing (MLST) was accomplished characterizing seven known C. sakazakii-specific MLST loci (atpD, fusA, glnS, gltB, gyrB, infB, and pps). Results of this study confirmed all of the recovered Cronobacter isolates from the environmental swab samples to be C. sakazakii. The MLST profile matched with the published profile of the complex 31 of C. sakazakii. Thus, rRNA and 7-loci MLST-based sequencing protocols are robust techniques for rapid detection and differentiation of Cronobacter species, and these molecular diagnostic tools can be used in implementing successful surveillance program and in the control and prevention of foodborne illness. C1 [Sulaiman, Irshad M.; Jacobs, Emily; Segars, Katharine; Simpson, Steven; Kerdahi, Khalil] US FDA, Southeast Reg Lab, 60 Eighth St, Atlanta, GA 30309 USA. RP Sulaiman, IM (reprint author), US FDA, Southeast Reg Lab, 60 Eighth St, Atlanta, GA 30309 USA. EM Irshad.Sulaiman@fda.hhs.gov FU Division of Field Sciences of FDA FX The findings and conclusions made in this manuscript are those of the authors and do not necessarily represent the views or official position of the U.S. Food and Drug Administration (FDA). The names of vendors or manufacturers are provided as examples of available product sources; inclusion does not imply endorsement of the vendors, manufacturers, or products by the FDA or the U.S. Department of Health and Human Services. This study was supported in part by funding from the Division of Field Sciences of FDA. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. We also thank Ms. Nicky Sulaiman of CDC for her help for the completion of this work. NR 41 TC 0 Z9 0 U1 9 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0343-8651 EI 1432-0991 J9 CURR MICROBIOL JI Curr. Microbiol. PD AUG PY 2016 VL 73 IS 2 BP 273 EP 279 DI 10.1007/s00284-016-1059-z PG 7 WC Microbiology SC Microbiology GA DQ4NQ UT WOS:000379181000018 PM 27155844 ER PT J AU Coss, CC Jones, A Dalton, JT AF Coss, Christopher C. Jones, Amanda Dalton, James T. TI Pharmacokinetic drug interactions of the selective androgen receptor modulator GTx-024(Enobosarm) with itraconazole, rifampin, probenecid, celecoxib and rosuvastatin SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Enobosarm; Selective androgen receptor modulator; SARM; GTx-024; DDI; Drug drug interaction ID BREAST-CANCER; PLASMA-CONCENTRATIONS; HEALTHY-VOLUNTEERS; PHYSICAL FUNCTION; DOUBLE-BLIND; INHIBITOR; ENOBOSARM; INCREASES; VERAPAMIL; EXPOSURE AB GTx-024 (also known as enobosarm) is a first in class selective androgen receptor modulator being developed for diverse indications in oncology. Preclinical studies of GTx-024 supported the evaluation of several potential drug-drug interactions in a clinical setting. A series of open-label Phase I GTx-024 drug-drug interaction studies were designed to interrogate potential interactions with CYP3A4 inhibitor (itraconazole), a CYP3A4 inducer (rifampin), a pan-UGT inhibitor (probenecid), a CYP2C9 substrate (celecoxib) and a BCRP substrate (rosuvastatin). The plasma pharmacokinetics of GTx-024, its major metabolite (GTx-024 glucuronide), and each substrate were characterized in detail. Itraconazole administration had no effect on GTx-024 pharmacokinetics. Likewise, GTx-024 administration did not significantly change the pharmacokinetics of celecoxib or rosuvastatin. Rifampin administration had the largest impact on GTx-024 pharmacokinetics of any co-administered agent and reduced the maximal plasma concentration (C-max) by 23 % and the area under the curve (AUC(a)) by 43 %. Probenecid had a complex interaction with GTx-024 whereby both GTx-024 plasma levels and GTx-024 glucuronide plasma levels (AUC(a)) were increased by co-administration of the UGT inhibitor (50 and 112 %, respectively). Overall, GTx-024 was well tolerated and poses very little risk of generating clinically relevant drug-drug interactions. C1 [Coss, Christopher C.] Ohio State Univ, Coll Pharm, Div Pharmacol, Columbus, OH 43210 USA. [Jones, Amanda] US FDA, Div Bioequivalence, Off Gener Drugs, Silver Spring, MD USA. [Dalton, James T.] Univ Michigan, Pharmaceut Sci, Coll Pharm, 428 Church St, Ann Arbor, MI 48109 USA. RP Dalton, JT (reprint author), Univ Michigan, Pharmaceut Sci, Coll Pharm, 428 Church St, Ann Arbor, MI 48109 USA. EM daltonjt@umich.edu OI dalton, James T/0000-0002-3915-7326 FU GTx, Inc. FX These studies were funded by GTx, Inc. NR 33 TC 1 Z9 1 U1 12 U2 13 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD AUG PY 2016 VL 34 IS 4 BP 458 EP 467 DI 10.1007/s10637-016-0353-8 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA DQ2EP UT WOS:000379015000007 PM 27105861 ER PT J AU Yu, C Wales, SQ Mammel, MK Hida, K Kulka, M AF Yu, Christine Wales, Samantha Q. Mammel, Mark K. Hida, Kaoru Kulka, Michael TI Optimizing a custom tiling microarray for low input detection and identification of unamplified virus targets SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE Detection; Foodborne viruses; Microarray; Genotyping; Low-input target ID HEPATITIS-A-VIRUS; REVERSE TRANSCRIPTION-PCR; ENTERIC VIRUSES; MICROBIAL DETECTION; PATHOGEN DETECTION; DNA MICROARRAYS; RAPID DETECTION; CELL-CULTURE; HYBRIDIZATION; RNA AB Viruses are major pathogens causing foodborne illnesses and are often present at low levels in foods, thus requiring sensitive techniques for their detection in contaminated foods. The lack of efficient culture methods for many foodborne viruses and the potential for multi-species viral contamination have driven investigation toward non-amplification based methods for virus detection and identification. A custom DNA microarray (FDA_EVIR) was assessed for its sensitivity in the detection and identification of low-input virus targets, human hepatitis A virus, norovirus, and coxsackievirus, individually and in combination. Modifications to sample processing were made to accommodate low input levels of unamplified virus targets, which included addition of carrier cDNA, RNase treatment, and optimization of DNase I mediated target fragmentation. Amplification-free detection and identification of foodborne viruses were achieved in the range of 250-500 copies of virus RNA. Alternative data analysis methods were employed to distinguish the genotypes of the viruses particularly at lower levels of target input and the single probe-based analysis approach made it possible to identify a minority species in a multi-virus complex. The oligonucleotide array is shown to be a promising platform to detect foodborne viruses at low levels close to what are anticipated in food or environmental samples. Published by Elsevier B.V. C1 [Yu, Christine; Wales, Samantha Q.; Mammel, Mark K.; Hida, Kaoru; Kulka, Michael] US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Div Mol Biol, 8301 Muirkirk Rd, Laurel, MD 20708 USA. RP Kulka, M (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Div Mol Biol, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM michael.kulka@fda.hhs.gov NR 42 TC 0 Z9 0 U1 5 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 AUG PY 2016 VL 234 BP 54 EP 64 DI 10.1016/j.jviromet.2016.03.013 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA DQ1MC UT WOS:000378964100009 PM 27033182 ER PT J AU Leighton, JK Saber, H Reaman, G Pazdur, R AF Leighton, John K. Saber, Haleh Reaman, Gregory Pazdur, Richard TI An FDA oncology view of juvenile animal studies in support of initial pediatric trials for anticancer drugs SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Editorial Material DE First in pediatric trials; Juvenile animal studies ID PHASE-I TRIALS; OSTEOPROTEGERIN; PHYSIOLOGY; TOXICITY; CHILDREN C1 [Leighton, John K.; Saber, Haleh; Reaman, Gregory; Pazdur, Richard] US FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. RP Leighton, JK (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM john.leighton@fda.hhs.gov NR 14 TC 1 Z9 2 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 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD AUG PY 2016 VL 79 BP 142 EP 143 DI 10.1016/j.yrtph.2016.03.001 PG 2 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA DO5TB UT WOS:000377844600019 PM 26952647 ER PT J AU Strader, MB Kassa, T Meng, F Wood, FB Hirsch, RE Friedman, JM Alayash, AI AF Strader, Michael Brad Kassa, Tigist Meng, Fantao Wood, Francine B. Hirsch, Rhoda Elison Friedman, Joel M. Alayash, Abdu I. TI Oxidative instability of hemoglobin E (beta 26 Glu -> Lys) is increased in the presence of free alpha subunits and reversed by alpha-hemoglobin stabilizing protein (AHSP): Relevance to HbE/beta-thalassemia SO REDOX BIOLOGY LA English DT Article DE Hemoglobin E; Thalassemia; Oxidation; Alpha-hemoglobin stabilizing protein ID DRUG-INDUCED OXIDATION; HYDROGEN-PEROXIDE; BLOOD SUBSTITUTES; HEME LOSS; MASS-SPECTROMETRY; REDOX PROPERTIES; MODEL; HAPTOGLOBIN; MECHANISMS; RATES AB When adding peroxide (H2O2), beta subunits of hemoglobin (Hb) bear the burden of oxidative changes due in part to the direct oxidation of its Cys93. The presence of unpaired alpha subunits within red cells and/or co-inheritance of another beta subunit mutant, HbE (beta 26 Glu -> Lys) have been implicated in the pathogenesis and severity of beta thalassemia. We have found that although both HbA and HbE autoxidize at initially comparable rates, HbE loses heme at a rate almost 2 fold higher than HbA due to unfolding of the protein. Using mass spectrometry and the spin trap, DMPO, we were able to quantify irreversible oxidization of beta Cys93 to reflect oxidative instability of beta subunits. In the presence of free alpha subunits and H2O2, both HbA and HbE showed beta Cys93 oxidation which increased with higher H2O2 concentrations. In the presence of Alph -hemoglobin stabilizing protein (AHSP), which stabilizes the alpha-subunit in a redox inactive hexacoordinate conformation (thus unable to undergo the redox ferric/ferryl transition), Cys93 oxidation was substantially reduced in both proteins. These experiments establish two important features that may have relevance to the mechanistic understanding of these two inherited hemoglobinopathies, i.e. HbE/beta thalassemia: First, a persistent ferryl/ferryl radical in HbE is more damaging to its own beta subunit (i.e., beta Cys93) than HbA. Secondly, in the presence of excess free oc-subunit and under the same oxidative conditions, these events are substantially increased for HbE compared to HbA, and may therefore create an oxidative milieu affecting the already unstable HbE. Published by Elsevier B.V. C1 [Strader, Michael Brad; Kassa, Tigist; Meng, Fantao; Wood, Francine B.; Alayash, Abdu I.] US FDA, Lab Biochem & Vasc Biol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Hirsch, Rhoda Elison] Albert Einstein Coll Med, Dept Med Anat & Struct Biol, Bronx, NY 10461 USA. [Friedman, Joel M.] Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10461 USA. RP Alayash, AI (reprint author), US FDA, CBER, Bldg 52-72,Room 4106,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM abdu.alayash@fda.hhs.gov FU National Institutes of Health (NIH/NHLBI) [P01-HL110900]; U.S. Food and Drug Administration (MODSCI); Einstein Global Health Microgrant; NIH [R21 HL106421] FX This work was supported by National Institutes of Health (NIH/NHLBI) grant P01-HL110900 (MBS, TK, FM, FBW, AIA and JMF), and grants from the U.S. Food and Drug Administration (MODSCI) ((MBS, TK, FM, FBW, AIA) and Einstein Global Health Microgrant and NIH R21 HL106421 (REH and JMF). NR 57 TC 2 Z9 2 U1 5 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2317 J9 REDOX BIOL JI Redox Biol. PD AUG PY 2016 VL 8 BP 363 EP 374 DI 10.1016/j.redox.2016.03.004 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DN9UU UT WOS:000377427000040 PM 26995402 ER PT J AU Zannad, F Rossignol, P Stough, WG Epstein, M Garcia, MDA Bakris, GL Butler, J Kosiborod, M Berman, L Mebazaa, A Rasmussen, HS Ruilope, LM Stockbridge, N Thompson, A Wittes, J Pitt, B AF Zannad, Faiez Rossignol, Patrick Stough, Wendy Gattis Epstein, Murray Garcia, Maria de los Angeles Alonso Bakris, George L. Butler, Javed Kosiborod, Mikhail Berman, Lance Mebazaa, Alexandre Rasmussen, Henrik S. Ruilope, Luis M. Stockbridge, Norman Thompson, Aliza Wittes, Janet Pitt, Bertram TI New approaches to hyperkalemia in patients with indications for renin angiotensin aldosterone inhibitors: Considerations for trial design and regulatory approval SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Review DE Hyperkalemia; Renin-angiotensin system; Clinical trials as topic; Renal insufficiency; Chronic; Heart failure; Polymers ID SODIUM ZIRCONIUM CYCLOSILICATE; CHRONIC KIDNEY-DISEASE; RANDOMIZED CLINICAL-TRIAL; WORSENING RENAL-FUNCTION; HEART-FAILURE PATIENTS; SERUM POTASSIUM; EUROPEAN-SOCIETY; TASK-FORCE; MANAGEMENT; HF AB Hyperkalemia is a common clinical problem, especially in patients with chronic kidney disease, diabetes mellitus, or heart failure. Treatment with renin angiotensin aldosterone system inhibitors exacerbates the risk of hyperkalemia in these patients. Concern about hyperkalemia can result in the failure to initiate, suboptimal dosing, or discontinuation of renin angiotensin aldosterone system inhibitor therapy in patients; effective treatments for hyperkalemia might mitigate such undertreatment. New treatments for hyperkalemia in development may offer better efficacy, tolerability and safety profiles than do existing approved treatments. These compounds might enable more eligible patients to receive renin angiotensin aldosterone system inhibitor therapy or to receive renin angiotensin aldosterone system inhibitors at target doses. The evidence needed to support a treatment claim (reduction in serum potassium) differs from that needed to support a prevention claim (preventing hyperkalemia to allow renin angiotensin aldosterone system inhibitor treatment). Thus, several issues related to clinical trial design and drug development need to be considered. This paper summarizes and expands upon a discussion at the Global Cardiovascular Clinical Trialists 2014 Forum and examines methodologic considerations for trials of new potassium binders for the prevention and management of hyperkalemia in patients with renin angiotensin aldosterone system inhibitor indications. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Zannad, Faiez; Rossignol, Patrick] Univ Lorraine, CHU Nancy, Ctr Invest Clin 1433, INSERM, Nancy, France. [Zannad, Faiez; Rossignol, Patrick] Univ Lorraine, CHU Nancy, U1116, Nancy, France. [Zannad, Faiez; Rossignol, Patrick] F CRIN INI CRCT, Nancy, France. [Stough, Wendy Gattis] Campbell Univ, Coll Pharm & Hlth Sci, Buies Creek, NC 27506 USA. [Epstein, Murray] Univ Miami, Miller Sch Med, Div Nephrol & Hypertens, Miami, FL 33136 USA. [Garcia, Maria de los Angeles Alonso] NHS Trust, Imperial Coll Healthcare, Cardiol,Sci Advice Working Party European Med Agc, Med & Healthcare Prod Regulatory Agcy MHRA, London, England. [Bakris, George L.] Univ Chicago Med, Dept Med, Chicago, IL USA. [Butler, Javed] SUNY Stony Brook, Sch Med, Stony Brook Heart Inst, Stony Brook, NY 11794 USA. [Kosiborod, Mikhail] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Kosiborod, Mikhail] Univ Missouri, Kansas City, MO 64110 USA. [Berman, Lance] Relypsa, Redwood City, CA USA. [Mebazaa, Alexandre] Univ Paris Diderot, Sorbonne Paris Cite, U942, INSERM, Paris, France. [Mebazaa, Alexandre] Hop Univ St Louis Lariboisiere, AP HP, Dept Anesthesia & Crit Care, Paris, France. [Rasmussen, Henrik S.] ZS Pharma, Coppell, TX USA. [Ruilope, Luis M.] Hosp 12 Octubre, Inst Invest, E-28041 Madrid, Spain. [Ruilope, Luis M.] Hosp 12 Octubre, Hypertens Unit, E-28041 Madrid, Spain. [Stockbridge, Norman; Thompson, Aliza] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Wittes, Janet] Stat Collaborat Inc, Washington, DC USA. [Pitt, Bertram] Univ Michigan, Sch Med, Ann Arbor, MI USA. RP Zannad, F (reprint author), Univ Lorraine, F-54500 Vandoeuvre Les Nancy, France.; Zannad, F (reprint author), Inst Lorrain Coeur & Vaisseaux, INI CRCT F CRIN, F-54500 Vandoeuvre Les Nancy, France. EM f.zannad@chu-nancy.fr RI Stough, Wendy/R-4287-2016 OI Stough, Wendy/0000-0001-8290-1205 FU Association de Recherche et d'Information en Cardiologie (ARISC) a non-profit educational organization, in Nancy, France FX This work was generated from discussions during the Eleventh Global Cardiovascular Clinical Trialists (CVCT) Forum held in Washington D.C. in December 2014. CVCT was organized by the Clinical Investigation Center (CIC) Inserm, CHU, and University of Lorraine, France, and INI-CRCT (F-CRIN), Nancy, France, and funded by an unrestricted educational grant from Association de Recherche et d'Information en Cardiologie (ARISC) a non-profit educational organization, in Nancy, France. ARISC had no involvement in preparation, review, or approval of the manuscript for publication. NR 42 TC 2 Z9 2 U1 1 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD AUG 1 PY 2016 VL 216 BP 46 EP 51 DI 10.1016/j.ijcard.2016.04.127 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DN1IY UT WOS:000376820700008 PM 27140336 ER PT J AU Hassan, M Gonzalez, E Hitchins, V Ilev, I AF Hassan, Moinuddin Gonzalez, Elizabeth Hitchins, Victoria Ilev, Ilko TI Detecting bacteria contamination on medical device surfaces using an integrated fiber-optic mid-infrared spectroscopy sensing method SO SENSORS AND ACTUATORS B-CHEMICAL LA English DT Article DE Bacteria contamination; Fourier transform infrared (FTIR) spectroscopy; Fiber-optics sensors; Medical devices; Principal component analysis ID TRANSFORM INFRARED-SPECTROSCOPY; FT-IR SPECTROSCOPY; STAPHYLOCOCCUS-AUREUS; RAPID IDENTIFICATION; LISTERIA-MONOCYTOGENES; DISCRIMINATION; DIFFERENTIATION; MICROORGANISMS; SPECTRA AB Bacterial contamination on medical device surfaces is a critical public health concern. In order to detect bacteria on medical device surface, alternative methods for quantitative, accurate, easy-to-use, and real-time detection and identification of microorganism contamination are needed. We have recently presented a novel proof-of-concept platform for non-contact, label-free and real-time detection of surface contamination employing a fiber-optic Fourier transform infrared (FO-FTIR) spectroscopy sensing methodology in the mid-infrared (mid-IR) spectral range of 1.6-12 mu m. In the present study, we demonstrate the detection capability and sensitivity of the integrated FO-FTIR approach using four species of commonly encountered bacteria: Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pneumoniae. FO-FTIR combined with multivariate approaches such as hierarchical clustering and principal component analysis provided specific mid-IR spectral differentiation of the four microorganisms including when the sample contained mixtures of bacteria types. To assess the sensitivity of the FO-FTIR platform, bacteria samples were prepared at 10(9) colony forming unit (CFU)/ L and then serially diluted 1:10 eight times. The salient findings of this investigation showed that the integrated FO-FTIR based sensor can detect the presence of the bacteria at concentrations between 10(3) and 10(4) CFU/2 mu L, producing unique bacteria signatures with high reproducibility. The advanced features of this sensing method in terms of sensitivity, specificity and repeatability employing non-contact, label free, and real-time approaches, demonstrate its potential use as an alternative effective screening tool for routine monitoring of bacterial contaminated surfaces. Published by Elsevier B.V. C1 [Hassan, Moinuddin; Ilev, Ilko] US FDA, Opt Therapeut & Med Nanophoton Lab, Div Biomed Phys, Off Sci & Engn Labs,Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Gonzalez, Elizabeth; Hitchins, Victoria] US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Hassan, M (reprint author), Bldg 62,Rm 1115,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM moinuddin.hassan@fda.hhs.gov FU Medical Counter Measure initiative (MCMi) of Center for Devices and Radiological Health (CDRH), U.S. Food and Drug Administration (FDA) FX This study is supported by the intramural research program of Medical Counter Measure initiative (MCMi) of Center for Devices and Radiological Health (CDRH), U.S. Food and Drug Administration (FDA). The authors have no conflicts of interest or financial ties to disclose. NR 37 TC 0 Z9 0 U1 7 U2 23 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0925-4005 J9 SENSOR ACTUAT B-CHEM JI Sens. Actuator B-Chem. PD AUG PY 2016 VL 231 BP 646 EP 654 DI 10.1016/j.snb.2016.03.044 PG 9 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation SC Chemistry; Electrochemistry; Instruments & Instrumentation GA DJ6NT UT WOS:000374330900074 ER PT J AU Beaubrun, JJG Flamer, ML Addy, N Ewing, L Gopinath, G Jarvis, K Grim, C Hanes, DE AF Beaubrun, Junia Jean-Gilles Flamer, Marie-Laure Addy, Nicole Ewing, Laura Gopinath, Gopal Jarvis, Karen Grim, Chris Hanes, Darcy E. TI Evaluation of corn oil as an additive in the pre-enrichment step to increase recovery of Salmonella enterica from oregano SO FOOD MICROBIOLOGY LA English DT Article DE Salmonella spp.; Montevideo; Oregano; Additives; Corn oil; Molecular serotyping; Shot-gun metagenomics ID PATHOGEN BACILLUS-CEREUS; CARVACROL; MECHANISMS; ORIGANUM AB Phenolic compounds associated with essential oils of spices and herbs possess a variety of antioxidant and antimicrobial properties that interfere with Salmonella detection from fresh and dried products. Finding a compound to neutralize the effect of these antimicrobial compounds, while allowing Salmonella growth during pre-enrichment, is a crucial step in both traditional pathogen isolation and molecular detection from these foods. This study evaluated the effectiveness of corn oil as a component of the pre-enrichment broth to counteract antimicrobial compounds properties and increase the recovery of Salmonella from spices. Oregano samples artificially contaminated with Salmonella enterica were pre-enriched in modified Buffered Peptone Water (mBPW) supplemented with and without 2% (vol/vol) corn oil respectively. Samples were incubated overnight at 37 degrees C. The results showed that recovery of Salmonella from oregano samples was increased by >= 50% when pre-enriched with corn oil. Serovars were confirmed using a PCR serotyping method. In addition, shot-gun metagenomics analyses demonstrated bacterial diversity and the effect of corn oil on the relative prevalence of Salmonella in the oregano samples. Modifying pre-enrichment broths with corn oil improved the detection and isolation of Salmonella from oregano, and may provide an alternative method for pathogen detection in dried food matrices such as spices. Published by Elsevier Ltd. C1 [Beaubrun, Junia Jean-Gilles; Flamer, Marie-Laure; Addy, Nicole; Ewing, Laura; Gopinath, Gopal; Jarvis, Karen; Grim, Chris; Hanes, Darcy E.] US FDA, Laurel, MD 20708 USA. [Flamer, Marie-Laure] Univ Maryland, UMCP JIFSAN Program, 5201 Paint Branch Pkwy Patapsco Bldg Suite 2134, College Pk, MD 20742 USA. [Addy, Nicole; Grim, Chris] Oak Ridge Inst Sci & Technol, Oak Ridge, TN USA. RP Beaubrun, JJG (reprint author), US FDA, MOD Facil 1, Virulence Mech Branch,Ctr Food Safety & Appl Nutr, Div Virulence Assessment,Off Appl Res & Safety As, HFS-025,8301 Muirkirk Rd, Laurel, MD 20708 USA. EM junia.jean-gillesbeaubrun@fda.hhs.gov RI Fiori, Alex/H-6065-2016 NR 31 TC 1 Z9 1 U1 4 U2 26 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 AUG PY 2016 VL 57 BP 195 EP 203 DI 10.1016/j.fm.2016.03.005 PG 9 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA DI5XF UT WOS:000373573100025 ER PT J AU LaVange, LM Permutt, T AF LaVange, Lisa M. Permutt, Thomas TI A regulatory perspective on missing data in the aftermath of the NRC report SO STATISTICS IN MEDICINE LA English DT Article DE missing data; drug regulation; clinical trials: design; conduct ID CLINICAL-TRIALS; SCHIZOPHRENIA; PREVENTION; CONDUCT AB The issuance of a report in 2010 by the National Research Council (NRC) of the National Academy of Sciences entitled The Prevention and Treatment of Missing Data in Clinical Trials,' commissioned by the US Food and Drug Administration, had an immediate impact on the way that statisticians and clinical researchers in both industry and regulatory agencies think about the missing data problem. We believe that there is currently great potential to improve study quality and interpretabilityby reducing the amount of missing data through changes in trial design and conduct and by planning and conducting analyses that better account for the missing information. Here, we describe our view on some of the recommendations in the report and suggest ways in which these recommendations can be incorporated into new or ongoing clinical trials in order to improve their chance of success. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [LaVange, Lisa M.; Permutt, Thomas] US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Permutt, T (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM thomas.permutt@fda.hhs.gov NR 26 TC 3 Z9 3 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUL 30 PY 2016 VL 35 IS 17 BP 2853 EP 2864 DI 10.1002/sim.6840 PG 12 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 DR6AH UT WOS:000379983000001 PM 26677837 ER PT J AU Permutt, T AF Permutt, Thomas TI A taxonomy of estimands for regulatory clinical trials with discontinuations SO STATISTICS IN MEDICINE LA English DT Article DE missing data; causal inference; benefit and risk AB The National Research Council Panel on Handling Missing Data in Clinical Trials recommended that protocols for clinical trials explicitly define... causal estimands of primary interest'. In discussions with sponsors of clinical trials since the publication of the National Research Council report, the expression causal estimands has been the subject of confusion. It may not be entirely clear what the National Research Council panel meant, and in any case, it has not been clear how this recommendation might be put in practice. This paper's purpose is to say how the working group understands it and how we think it should be put in practice. We classify possible choices of estimand according to their usefulness for regulatory purposes in various clinical settings. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Permutt, Thomas] Ctr Drug Evaluat & Res, Off Biostat, Off Translat Sci, Silver Spring, MD 20993 USA. RP Permutt, T (reprint author), Ctr Drug Evaluat & Res, Off Biostat, Off Translat Sci, Silver Spring, MD 20993 USA. EM thomas.permutt@fda.hhs.gov NR 15 TC 7 Z9 7 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUL 30 PY 2016 VL 35 IS 17 BP 2865 EP 2875 DI 10.1002/sim.6841 PG 11 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 DR6AH UT WOS:000379983000002 PM 26678026 ER PT J AU Permutt, T AF Permutt, Thomas TI Sensitivity analysis for missing data in regulatory submissions SO STATISTICS IN MEDICINE LA English DT Article DE missing data; sensitivity analysis; tipping point AB The National Research Council Panel on Handling Missing Data in Clinical Trials recommended that sensitivity analyses have to be part of the primary reporting of findings from clinical trials. Their specific recommendations, however, seem not to have been taken up rapidly by sponsors of regulatory submissions. The NRC report's detailed suggestions are along rather different lines than what has been called sensitivity analysis in the regulatory setting up to now. Furthermore, the role of sensitivity analysis in regulatory decision-making, although discussed briefly in the NRC report, remains unclear. This paper will examine previous ideas of sensitivity analysis with a view to explaining how the NRC panel's recommendations are different and possibly better suited to coping with present problems of missing data in the regulatory setting. It will also discuss, in more detail than the NRC report, the relevance of sensitivity analysis to decision-making, both for applicants and for regulators. Published 2015. This article is a U.S. Government work and is in the public domain in the USA C1 [Permutt, Thomas] Ctr Drug Evaluat & Res, Div Biometr 2, Offie Biostat, Offie Translat Sci, Silver Spring, MD USA. RP Permutt, T (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM thomas.permutt@fda.hhs.gov NR 3 TC 4 Z9 4 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUL 30 PY 2016 VL 35 IS 17 BP 2876 EP 2879 DI 10.1002/sim.6753 PG 4 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 DR6AH UT WOS:000379983000003 PM 26567763 ER PT J AU Amador-Molina, JC Valerdi-Madrigal, ED Dominguez-Castillo, RI Sirota, LA Arciniega, JL AF Amador-Molina, Juan C. Valerdi-Madrigal, Esther D. Dominguez-Castillo, Rocio I. Sirota, Lev A. Arciniega, Juan L. TI Temperature-mediated recombinant anthrax protective antigen aggregate development: Implications for toxin formation and immunogenicity SO VACCINE LA English DT Article DE Anthrax; Vaccine; Stability; Protective antigen; Aggregation ID BACILLUS-ANTHRACIS; LETHAL TOXIN; ALUMINUM-HYDROXIDE; THERMAL INACTIVATION; NEUTRALIZATION ASSAY; GUINEA-PIGS; VACCINE; DEAMIDATION; PROTEIN; INFECTION AB Anthrax vaccines containing recombinant PA (rPA) as the only antigen face a stability issue: rPA forms aggregates in solution after exposure to temperatures >= 40 degrees C, thus losing its ability to form lethal toxin (LeTx) with Lethal Factor. To study rPA aggregation's impact on immune response, we subjected rPA to several time and temperature combinations. rPA treated at 50 degrees C for 30 min formed high mass aggregates when analyzed by gel electrophoresis and failed to form LeTx as measured by a macrophage lysis assay (MLA). Aggregated rPA-formed LeTx was about 30 times less active than LeTx containing native rPA. Mice immunized with heat-treated rPA combined with Al(OH)(3) developed antibody titers about 49 times lower than mice immunized with native rPA, as measured by a Toxicity Neutralization Assay (TNA). Enzyme Linked Immunosorbent Assay (ELISA) of the same immune sera showed anti-rPA titers only 2-7 times lower than titers elicited by native rPA. Thus, rPA's ability to form LeTx correlates with its production of neutralizing antibodies, and aggregation significantly impairs the protein's antibody response. However, while these findings suggest MLA has some value as an in-process quality test for rPA in new anthrax vaccines, they also confirm the superiority of TNA for use in vaccine potency. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Amador-Molina, Juan C.; Valerdi-Madrigal, Esther D.; Dominguez-Castillo, Rocio I.; Sirota, Lev A.; Arciniega, Juan L.] US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. Tecnol Monterrey, Campus Estado Mexico,Carretera Lago Guadalupe Km, Atizapan De Zaragoza 52926, Estado De Mexic, Mexico. [Dominguez-Castillo, Rocio I.] IPN, Ctr Invest & Estudios Avanzados, Av Inst Politecn Nacl 2508, Mexico City 07360, DF, Mexico. [Sirota, Lev A.] NCI, 9609 Med Ctr Dr, Rockville, MD 20850 USA. RP Amador-Molina, JC (reprint author), Tecnol Monterrey, Campus Estado Mexico,Carretera Lago Guadalupe Km, Atizapan De Zaragoza 52926, Estado De Mexic, Mexico. EM jc.amador@itesm.mx FU Biomedical Advanced Research and Development Authority; Research Participation Program at the Center for Biologics Evaluation and Research FX This project was supported in part by the Biomedical Advanced Research and Development Authority and by an appointment to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 65 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUL 29 PY 2016 VL 34 IS 35 BP 4188 EP 4195 DI 10.1016/j.vaccine.2016.06.057 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DT0JR UT WOS:000381170300015 PM 27364097 ER PT J AU Williams, KM Gokulan, K Cerniglia, CE Khare, S AF Williams, Katherine M. Gokulan, Kuppan Cerniglia, Carl E. Khare, Sangeeta TI Size and dose dependent effects of silver nanoparticle exposure on intestinal permeability in an in vitro model of the human gut epithelium SO JOURNAL OF NANOBIOTECHNOLOGY LA English DT Article DE Silver nanoparticles; Intestinal permeability; Cell junctions; Barrier function ID BARRIER FUNCTION; CELL-LINE; ORAL-EXPOSURE; T84 CELLS; TOXICITY; CYTOTOXICITY; APOPTOSIS; INFLAMMATION; MECHANISMS; RESPONSES AB Background: The antimicrobial activity of silver nanoparticles (AgNP) has led to interest in their use in consumer products such as food contact materials, utensils, and storage containers. Incorporation of these materials into items intended for food processing and storage suggests that consumer use of these products could result in gastrointestinal exposure to AgNP, should the nanoparticles migrate from the product. The health impact of AgNP exposure is unknown, especially effects related to intestinal epithelial permeability and barrier function. This study examined the effects of AgNP exposure of different sizes (10, 20, 75 and 110 nm) and doses (20 and 100 mu g/mL) on the permeability of T84 human colonic epithelial cells, which serve as an in vitro model of the human gut epithelium. Results: Results showed that effects of AgNP on the T84 epithelial cells were size-and dose-dependent, with the 10 nm AgNP causing the most significant changes. Changes in permeability of the epithelial cell monolayer, as measured by transepithelial electrical resistance, after exposure to 10 nm AgNP were most dramatic at the highest dose (100 mu g/mL), but also observed at the lower dose (20 mu g/mL). AgNP could be visualized inside cells using transmission electron microscopy and silver was detected in basal wells using inductively coupled plasma-mass spectrometry. Exposure to AgNP significantly affected the expression of genes involved in anchoring tight junctions, cellular proliferation and signaling, endocytosis, and cell-cell adhesion, with the 10 nm AgNP having the greatest effect. Conclusions: The results of this study show that small-size AgNP have significant effects on intestinal permeability in an in vitro model of the human gastrointestinal epithelium. Such effects have the potential to compromise the integrity of the intestinal epithelium and this disruption of barrier function could have health consequences for the gastrointestinal tract. C1 [Williams, Katherine M.; Gokulan, Kuppan; Cerniglia, Carl E.; Khare, Sangeeta] US FDA, Div Microbiol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Khare, S (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM sangeeta.khare@fda.hhs.gov FU US-FDA/NCTR [E750601]; Oak Ridge Institute for Science and Education FX The study was supported by funds to Dr. Sangeeta Khare from US-FDA/NCTR protocol number E750601. The authors would like to thank Dr. Paul Howard, Dr. Mary Boudreau, Dr. Anil Patri, Dr. Angel Paredes, Ms. Yvonne Jones, Dr. Taylor Ingle, and FDA NanoCore for their assistance with nanoparticle procurement and characterization. Ms. Williams and Dr. Gokulan were supported by research appointments administered by the Oak Ridge Institute for Science and Education. Thanks also to Dr. Bruce Erickson and Dr. Jyotshnabala Kanungo for their critical review of this manuscript. NR 53 TC 2 Z9 2 U1 11 U2 14 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 JUL 28 PY 2016 VL 14 AR 62 DI 10.1186/s12951-016-0214-9 PG 13 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA DT7NV UT WOS:000381674400001 PM 27465730 ER PT J AU O'Connor, TF Yu, LX Lee, SL AF O'Connor, Thomas F. Yu, Lawrence X. Lee, Sau L. TI Emerging technology: A key enabler for modernizing pharmaceutical manufacturing and advancing product quality SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Review DE Pharmaceutical manufacturing; Product quality; Emerging technologies; Innovation; Regulatory science AB Issues in product quality have produced recalls and caused drug shortages in United States (U.S.) in the past few years. These quality issues were often due to outdated manufacturing technologies and equipment as well as lack of an effective quality management system. To ensure consistent supply of safe, effective and high-quality drug products available to the patients, the U.S. Food and Drug Administration (FDA) supports modernizing pharmaceutical manufacturing for improvements in product quality. Specifically, five new initiatives are proposed here to achieve this goal. They include: (i) advancing regulatory science for pharmaceutical manufacturing; (ii) establishing a public-private institute for pharmaceutical manufacturing innovation; (iii) creating incentives for investment in the technological upgrade of manufacturing processes and facilities; (iv) leveraging external expertise for regulatory quality assessment of emerging technologies; and (v) promoting the international harmonization of approaches for expediting the global adoption of emerging technologies. Published by Elsevier B.V. C1 [O'Connor, Thomas F.; Yu, Lawrence X.; Lee, Sau L.] US FDA, Off Pharmaceut Qual, CDER, Silver Spring, MD USA. RP Lee, SL (reprint author), White Oak Bldg 51,Room 4144, Silver Spring, MD 20993 USA. EM Sau.Lee@fda.hhs.gov NR 22 TC 2 Z9 2 U1 6 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 JUL 25 PY 2016 VL 509 IS 1-2 BP 492 EP 498 DI 10.1016/j.ijpharm.2016.05.058 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ1GP UT WOS:000378949800051 PM 27260134 ER PT J AU Zhang, JM Cao, GJ Xu, XB Allard, M Li, P Brown, E Yang, XW Pan, HJ Meng, JH AF Zhang, Jianmin Cao, Guojie Xu, Xuebin Allard, Marc Li, Peng Brown, Eric Yang, Xiaowei Pan, Haijian Meng, Jianghong TI Evolution and Diversity of Listeria monocytogenes from Clinical and Food Samples in Shanghai, China SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE L. monocytogenes; evolution; whole genome analysis; plasmid; China ID VIRULENCE; INTERNALIN; OUTBREAK; SEARCH; CHEESE; GROWTH; MEAT; MICE; TOOL AB Listeria monocytogenes is a significant foodborne pathogen causing severe systemic infections in humans with high mortality rates. The objectives of this work were to establish a phylogenetic framework of L. monocytogenes from China and to investigate sequence diversity among different serotypes. We selected 17 L. monocytogenes strains recovered from patients and foods in China representing serotypes 1/2a, 1/2b, and 1/2c. Draft genome sequences were determined using Illumina MiSeq technique and associated protocols. Open reading frames were assigned using prokaryotic genome annotation pipeline by NCBI. Twenty-four published genomes were included for comparative genomic and phylogenetic analysis. More than 154,000 single nucleotide polymorphisms (SNPs) were identified from multiple genome alignment and used to reconstruct maximum likelihood phylogenetic tree. The 41 genomes were differentiated into lineages I and II, which consisted of 4 and 11 subgroups, respectively. A clinical strain from China (SHL009) contained significant SNP differences compared to the rest genomes, whereas clinical strain SHL001 shared most recent common ancestor with strain SHL017 from food. Moreover, clinical strains SHL004 and SHL015 clustered together with two strains (08-5578 and 08-5923) recovered from an outbreak in Canada. Partial sequences of a plasmid found in the Canadian strain were also present in SHL004. We investigated the presence of various genes and gene clusters associated with virulence and subgroup-specific genes, including internalins, L. monocytogenes pathogenicity islands (LIPIs), L. monocytogenes genomic islands (LGIs), stress survival islet 1 (SSI-1), and clustered regularly interspaced short palindromic repeats (CRISPR)/cas system. A novel genomic island, denoted as LGI-2 was identified. Comparative sequence analysis revealed differences among the L. monocytogenes strains related to virulence, survival abilities, and attributes against foreign genetic elements. L. monocytogenes from China were genetically diverse. Strains from clinical specimens and food related closely suggesting foodborne transmission of human listeriosis. C1 [Zhang, Jianmin] South China Agr Univ, Coll Vet Med, Key Lab Zoonosis Prevent & Control Guangdong Prov, Natl Reg Joint Engn Lab Medicament Zoonosis, Guangzhou, Guangdong, Peoples R China. [Cao, Guojie; Meng, Jianghong] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD USA. [Cao, Guojie; Meng, Jianghong] Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD USA. [Xu, Xuebin] Shanghai Municipal Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Allard, Marc; Brown, Eric] US FDA, Ctr Food Safety & Appl Nutr, Div Microbiol, Off Regulatory Sci, College Pk, MD USA. [Li, Peng] Acad Mil Med Sci, Inst Dis Control & Prevent, Beijing, Peoples R China. [Yang, Xiaowei; Pan, Haijian] Shanghai Jiao Tong Univ, Sch Agr & Biol, Dept Food Sci & Technol, Shanghai, Peoples R China. RP Meng, JH (reprint author), Univ Maryland, Dept Nutr & Food Sci, College Pk, MD USA.; Meng, JH (reprint author), Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD USA. EM jmeng@umd.edu FU National Science and Technology Key Project [2012ZX10004215-003]; China-U.S. Collaborative Program on Emerging and Re-emerging Infectious Diseases [1U2GGH000961-01, 5U2GGH000961-02]; Joint Institute for Food Safety & Applied Nutrition, University of Maryland FX This study was supported in part by the National Science and Technology Key Project (No. 2012ZX10004215-003), China-U.S. Collaborative Program on Emerging and Re-emerging Infectious Diseases (1U2GGH000961-01&5U2GGH000961-02) and the Joint Institute for Food Safety & Applied Nutrition, University of Maryland. NR 44 TC 0 Z9 0 U1 14 U2 18 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 JUL 22 PY 2016 VL 7 AR 1138 DI 10.3389/fmicb.2016.01138 PG 9 WC Microbiology SC Microbiology GA DR7VM UT WOS:000380107800001 PM 27499751 ER PT J AU Kazi, ZB Prater, SN Kobori, JA Viskochil, D Bailey, C Gera, R Stockton, DW McIntosh, P Rosenberg, AS Kishnani, PS AF Kazi, Zoheb B. Prater, Sean N. Kobori, Joyce A. Viskochil, David Bailey, Carrie Gera, Renuka Stockton, David W. McIntosh, Paul Rosenberg, Amy S. Kishnani, Priya S. TI Durable and sustained immune tolerance to ERT in Pompe disease with entrenched immune responses SO JCI INSIGHT LA English DT Article ID ENZYME REPLACEMENT THERAPY; ACID ALPHA-GLUCOSIDASE; ALGLUCOSIDASE ALPHA; CLINICAL-OUTCOMES; INFANTS; BORTEZOMIB; ANTIBODIES; CHILDREN AB BACKGROUND. Enzyme replacement therapy (ERT) has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD), a rapidly progressive neuromuscular disorder. Yet marked interindividual variability in response to ERT, primarily attributable to the development of antibodies to ERT, remains an ongoing challenge. Immune tolerance to ongoing ERT has yet to be described in the setting of an entrenched immune response. METHODS. Three infantile Pompe patients who developed high and sustained rhGAA IgG antibody titers (HSAT) and received a bortezomib-based immune tolerance induction (ITI) regimen were included in the study and were followed longitudinally to monitor the long-term safety and efficacy. A trial to taper the ITI protocol was attempted to monitor if true immune tolerance was achieved. RESULTS. Bortezomib-based ITI protocol was safely tolerated and led to a significant decline in rhGAA antibody titers with concomitant sustained clinical improvement. Two of the 3 IPD patients were successfully weaned off all ITI protocol medications and continue to maintain low/no antibody titers. ITI protocol was significantly tapered in the third IPD patient. B cell recovery was observed in all 3 IPD patients. CONCLUSION. This is the first report to our knowledge on successful induction of long-term immune tolerance in patients with IPD and HSAT refractory to agents such as cyclophosphamide, rituximab, and methotrexate, based on an approach using the proteasome inhibitor bortezomib. As immune responses limit the efficacy and cost-effectiveness of therapy for many conditions, proteasome inhibitors may have new therapeutic applications. C1 [Kazi, Zoheb B.; Prater, Sean N.; Kishnani, Priya S.] Duke Univ, Med Ctr, Dept Pediat, Div Med Genet, Durham, NC 27710 USA. [Kobori, Joyce A.] Kaiser Permanente, Dept Genet, San Jose, CA USA. [Viskochil, David; Bailey, Carrie] Univ Utah, Dept Pediat, Div Med Genet, Salt Lake City, UT USA. [Gera, Renuka] Michigan State Univ, Dept Pediat Human Dev, E Lansing, MI 48824 USA. [Stockton, David W.] Wayne State Univ, Dept Pediat, Div Genet Genom & Metab Disorders, Detroit, MI 48202 USA. [Stockton, David W.] Wayne State Univ, Dept Internal Med, Div Genet Genom & Metab Disorders, Detroit, MI 48202 USA. [Stockton, David W.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [McIntosh, Paul] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Rosenberg, Amy S.] US FDA, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. RP Kishnani, PS (reprint author), Duke Univ, Med Ctr, 905 South LaSalle St,GSRB1, Durham, NC 27710 USA. EM priya.kishnani@duke.edu OI Kazi, Zoheb/0000-0002-0447-2764 NR 24 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD JUL 21 PY 2016 VL 1 IS 11 AR e86821 DI 10.1172/jci.insight.86821 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1MH UT WOS:000387115900005 ER PT J AU Saylor, DM Jawahery, S Silverstein, JS Forrey, C AF Saylor, David M. Jawahery, Sudi Silverstein, Joshua S. Forrey, Christopher TI Communication: Relationship between solute localization and diffusion in a dynamically constrained polymer system SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID GLASS-FORMING LIQUIDS; MOLECULAR-DYNAMICS; RELAXATION; MODELS AB We investigate the link between dynamic localization, characterized by the Debye-Waller factor, < u(2)>, and solute self-diffusivity, D, in a polymer system using atomistic molecular dynamics simulations and vapor sorption experiments. We find a linear relationship between ln D and 1/< u(2)>. over more than four decades of D, encompassing most of the glass formation regime. The observed linearity is consistent with the Langevin dynamics in a periodically varying potential field and may offer a means to rapidly assess diffusion based on the characterization of dynamic localization. C1 [Saylor, David M.; Jawahery, Sudi; Silverstein, Joshua S.; Forrey, Christopher] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Saylor, DM (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. OI Jawahery, Sudi/0000-0001-9950-6199 NR 19 TC 0 Z9 0 U1 6 U2 6 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD JUL 21 PY 2016 VL 145 IS 3 AR 031106 DI 10.1063/1.4959285 PG 4 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA DT3MC UT WOS:000381384300006 PM 27448867 ER PT J AU Aryal, B Rao, VA AF Aryal, Baikuntha Rao, V. Ashutosh TI Deficiency in Cardiolipin Reduces Doxorubicin-Induced Oxidative Stress and Mitochondrial Damage in Human B-Lymphocytes SO PLOS ONE LA English DT Article ID BARTH-SYNDROME; CELL-DEATH; SUPEROXIDE-PRODUCTION; LIPID-PEROXIDATION; SKELETAL-MUSCLE; CANCER-CELLS; LIVE CELLS; ADRIAMYCIN; APOPTOSIS; CARDIOTOXICITY AB Cardiolipin (CL) is an inner mitochondrial membrane phospholipid which plays an important role in mitochondrial function. Perturbation in CL biosynthesis alters mitochondrial bioenergetics causing a severe genetic disorder commonly known as Barth syndrome. Barth syndrome patients are known to have a reduced concentration and altered composition of CL. Cardiolipin is also known to have a high affinity for the chemotherapeutic agent doxorubicin (Dox), resulting in an extensive mitochondrial accumulation of the drug. Our results indicate that B-lymphocytes from healthy individuals are more sensitive to Dox-induced oxidative stress and cellular toxicity compared to the B-lymphocytes from Barth syndrome as indicated by greater cell death and greater level of cleaved caspase-3 following Dox treatment. Barth lymphocytes, when compared to healthy lymphocytes, showed a greater basal level of mitochondrial reactive oxygen species (mito-ROS), yet exhibited a lower level of induced mito-ROS production in response to Dox. Significantly less ATP content and slightly greater OXPHOS protein levels were detected in healthy cells compared to Barth cells after Dox treatment. Consistent with greater mitochondrial ROS, treatment with Dox induced a higher level of lipid peroxidation and protein carbonylation in healthy lymphocytes compared to Barth lymphocytes. The final remodeling of CL during CL synthesis is catalyzed by the tafazzin protein. Knockdown of tafazzin gene in H9c2 cardiomyocytes using siRNA showed decreased oxidant-induced damage, as observed in Barth lymphocytes. Our findings demonstrate that a deficiency in CL might provide a therapeutic advantage in favor of oxidant-induced anticancer activities. C1 [Aryal, Baikuntha; Rao, V. Ashutosh] US FDA, Lab Appl Biochem, Div Biotechnol Review & Res 3, Off Biotechnol Prod,Off Pharmaceut Qual,Ctr Drug, Silver Spring, MD 20993 USA. RP Rao, VA (reprint author), US FDA, Lab Appl Biochem, Div Biotechnol Review & Res 3, Off Biotechnol Prod,Off Pharmaceut Qual,Ctr Drug, Silver Spring, MD 20993 USA. EM ashutosh.rao@fda.hhs.gov FU Center for Drug Evaluation and Research Critical Path Initiative FX This research was supported by the Center for Drug Evaluation and Research Critical Path Initiative. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the United States Food and Drug Administration and the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government.; We would like to thank Dr. Shen Luo (FDA) for help with MS analysis. We would like to thank Elliot Rosen (FDA) for critical reading of the manuscript. This research was supported by the Center for Drug Evaluation and Research Critical Path Initiative. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the United States Food and Drug Administration and the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. NR 50 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 19 PY 2016 VL 11 IS 7 AR e0158376 DI 10.1371/journal.pone.0158376 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR8TG UT WOS:000380169600008 PM 27434059 ER PT J AU Komatsu, E Buist, M Roy, R de Oliveira, AGG Bodnar, E Salama, A Soulillou, JP Perreault, H AF Komatsu, Emy Buist, Marjorie Roy, Rini de Oliveira, Andrey Giovanni Gomes Bodnar, Edward Salama, Apolline Soulillou, Jean-Paul Perreault, Helene TI Characterization of immunoglobulins through analysis of N-glycopeptides by MALDI-TOF MS SO METHODS LA English DT Article DE MALDI-TOF MS; Glycopeptide; Antibody; Immunoglobulin; Glycoform; Glycan; MS/MS ID MASS-SPECTROMETRY; PROTEIN GLYCOSYLATION; QUANTITATIVE-PROTEOMICS; MAGNETIC NANOPARTICLES; MONOCLONAL-ANTIBODY; ENRICHMENT; GLYCOPROTEOME; OLIGOSACCHARIDES; ESTERIFICATION; COMBINATION AB The aim of this report is to emphasize the role, usefulness and power of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) in the analysis of glycoforms of antibodies (Abs) through their proteolytic glycopeptides. Abs are complex biomolecules in which glycans hold determinant properties and thus need to be thoroughly characterized following Ab production by recombinant methods or Ab collection from human/animal serum or tissue. In spite of the great robustness of MALDI-TOF MS in terms of tolerance to impurities, the analysis of Abs and Ab components using this technique requires extensive sample preparation involving all or some of chromatography, solid phase extraction, enzymatic modification, and chemical derivatization. This report focuses on a monoclonal Ab produced in cell culture, as well as on a polyclonal human immunoglobulin (Ig) G obtained commercially and a poly clonal porcine IgG obtained from serum. A method is first provided to separate Ab protein chain components (light chains, heavy chains) by gel electrophoresis, which is useful for instance for protein-A eluates of Igs either from cell culture or biological samples. This allows for in-gel proteolytic digestion of the protein gel band(s) of choice for further MS characterization. Also discussed is the more conventional in solution overnight digestion method used here with each of two proteolytic enzymes, i.e. trypsin and chymotrypsin. The overnight method is in turn compared with a much faster approach, that of digesting Abs with trypsin or chymotrypsin through the action of microwave heating. For method comparison, glycopeptides are fractionated from digestion mixtures using mostly C-18 cartridges for simplicity, although this enrichment procedure is also compared with other published procedures. The advantages of MALDI tandem mass spectrometry are highlighted for glycopeptide analysis, and lastly an esterification method applied to glycopeptides is discussed for retention of sialic acid residues on peptide acidic glycoforms. (C) 2016 Elsevier Inc. All rights reserved. C1 [Komatsu, Emy; Buist, Marjorie; Roy, Rini; de Oliveira, Andrey Giovanni Gomes; Bodnar, Edward; Perreault, Helene] Univ Manitoba, Dept Chem, 144 Dysart Rd, Winnipeg, MB R2T 2N2, Canada. [Salama, Apolline; Soulillou, Jean-Paul] Univ Nantes, ITUN, INSERM, UMR 10 64, F-44035 Nantes, France. [Bodnar, Edward] US FDA, Ctr Biol Evaluat Res, Div Bacterial Parasit & Allergen Prod, Lab Bacterial Polysaccharides, 10903 New Hampshire Ave,Bldg 52-72,Off G430, Silver Spring, MD 20993 USA. RP Perreault, H (reprint author), Univ Manitoba, Dept Chem, 144 Dysart Rd, Winnipeg, MB R2T 2N2, Canada. EM Helene.Perreault@umanitoba.ca FU Natural Sciences and Engineering Council of Canada (NSERC); Canadian Foundation for Innovation (CFI); MabNet FX The authors would like to thank researchers of the Monoclonal Antibody NSERC Strategic Network (MabNet) (www.mabnet.ca) for provision of EG2-hFc mAb. Ms. Jennifer Bestland is thanked for help with SDS-PAGE gels. Funding of this research was provided by the Natural Sciences and Engineering Council of Canada (NSERC), the Canadian Foundation for Innovation (CFI), and MabNet. NR 47 TC 3 Z9 3 U1 18 U2 37 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD JUL 15 PY 2016 VL 104 BP 170 EP 181 DI 10.1016/j.ymeth.2016.01.005 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DS0PN UT WOS:000380299300021 PM 26773578 ER PT J AU Hu, SS Neff, L Agaku, IT Cox, S Day, HR Holder-Hayes, E King, BA AF Hu, S. Sean Neff, Linda Agaku, Israel T. Cox, Shanna Day, Hannah R. Holder-Hayes, Enver King, Brian A. TI Tobacco Product Use Among Adults - United States, 2013-2014 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID ELECTRONIC CIGARETTES; SMOKER C1 [Hu, S. Sean; Neff, Linda; Agaku, Israel T.; Cox, Shanna; King, Brian A.] CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Day, Hannah R.; Holder-Hayes, Enver] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Hu, SS (reprint author), CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. EM shu@cdc.gov NR 10 TC 8 Z9 8 U1 2 U2 3 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD JUL 15 PY 2016 VL 65 IS 27 BP 685 EP 691 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DR7AC UT WOS:000380051400001 PM 27416365 ER PT J AU Collard, MJ Fifer, MS Benz, HL McMullen, DP Wang, YJ Milsap, GW Korzeniewska, A Crone, NE AF Collard, Maxwell J. Fifer, Matthew S. Benz, Heather L. McMullen, David P. Wang, Yujing Milsap, Griffin W. Korzeniewska, Anna Crone, Nathan E. TI Cortical subnetwork dynamics during human language tasks SO NEUROIMAGE LA English DT Article DE Electrocorticography (ECoG); Language networks; Speech processing; Functional connectivity; High gamma; Subnetworks ID NONNEGATIVE MATRIX FACTORIZATION; UNDERLYING FEEDBACK-CONTROL; WORD PRODUCTION COMPONENTS; SUPERIOR TEMPORAL GYRUS; EVENT-RELATED CAUSALITY; AUDITORY-CORTEX; GAMMA ACTIVITY; ELECTROCORTICAL STIMULATION; ELECTRICAL-STIMULATION; MOTOR INTERACTION AB Language tasks require the coordinated activation of multiple subnetworks-groups of related cortical interactions involved in specific components of task processing. Although electrocorticography (ECoG) has sufficient temporal and spatial resolution to capture the dynamics of event-related interactions between cortical sites, it is difficult to decompose these complex spatiotemporal patterns into functionally discrete subnetworks without explicit knowledge of each subnetwork's timing. We hypothesized that subnetworks corresponding to distinct components of task-related processing could be identified as groups of interactions with co-varying strengths. In this study, five subjects implanted with ECoG grids over language areas performed word repetition and picture naming. We estimated the interaction strength between each pair of electrodes during each task using a time varying dynamic Bayesian network (tvDBN) model constructed from the power of high gamma (70-110 Hz) activity, a surrogate for population firing rates. We then reduced the dimensionality of this model using principal component analysis (PCA) to identify groups of interactions with co-varying strengths, which we term functional network components (FNCs). This data-driven technique estimates both the weight of each interaction's contribution to a particular subnetwork, and the temporal profile of each subnetwork's activation during the task. We found FNCs with temporal and anatomical features consistent with articulatory preparation in both tasks, and with auditory and visual processing in the word repetition and picture naming tasks, respectively. These FNCs were highly consistent between subjects with similar electrode placement, and were robust enough to be characterized in single trials. Furthermore, the interaction patterns uncovered by FNC analysis correlated well with recent literature suggesting important functional-anatomical distinctions between processing external and self-produced speech. Our results demonstrate that subnetwork decomposition of event-related cortical interactions is a powerful paradigm for interpreting the rich dynamics of large-scale, distributed cortical networks during human cognitive tasks. (C) 2016 Elsevier Inc. All rights reserved. C1 [Collard, Maxwell J.; Korzeniewska, Anna; Crone, Nathan E.] Johns Hopkins Univ, Dept Neurol, 600 N Wolfe St,Meyer 2-161, Baltimore, MD 21287 USA. [Collard, Maxwell J.; Fifer, Matthew S.; Benz, Heather L.; Wang, Yujing; Milsap, Griffin W.] Johns Hopkins Univ, Dept Biomed Engn, 720 Rutland Ave, Baltimore, MD 21205 USA. [McMullen, David P.] Johns Hopkins Univ, Dept Neurosurg, 600 N Wolfe St, Baltimore, MD 21287 USA. [Benz, Heather L.] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Wang, Yujing] Univ Maryland, Fischell Dept Bioengn, Room 2330 Jeong H Kim Engn Bldg,Bldg 225, College Pk, MD 20742 USA. [Fifer, Matthew S.] Johns Hopkins Univ, Appl Phys Lab, 11100 Johns Hopkins Rd, Laurel, MD 20723 USA. RP Collard, MJ (reprint author), Johns Hopkins Univ, Dept Neurol, 600 N Wolfe St,Meyer 2-161, Baltimore, MD 21287 USA. EM collard@jhu.edu FU National Institute of Neurological Disorders and Stroke [R01 NS40596, R01 NS091139] FX This study was supported by the National Institute of Neurological Disorders and Stroke (R01 NS40596, R01 NS091139). NR 77 TC 1 Z9 1 U1 5 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUL 15 PY 2016 VL 135 BP 261 EP 272 DI 10.1016/j.neuroimage.2016.03.072 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DO8QF UT WOS:000378047600024 PM 27046113 ER PT J AU Serebruany, VL Kim, MH Golukhova, E Pya, Y Bekbossynova, M Cattaneo, M Marciniak, TA AF Serebruany, Victor L. Kim, Moo Hyun Golukhova, Elena Pya, Yury Bekbossynova, Makhabbat Cattaneo, Marco Marciniak, Thomas A. TI Continued vorapaxar versus withdrawed clopidogrel both on top of low dose aspirin in patients undergoing heart surgery: A call for randomized trial SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Editorial Material DE Vorapaxar; Heart surgery; Clinical outcomes; Mortality; Efficacy; Bleeding; Clinical trials ID BYPASS GRAFT-SURGERY; PERCUTANEOUS CORONARY INTERVENTION; DUAL ANTIPLATELET THERAPY; METAANALYSIS; OUTCOMES; DISEASE; SAFETY; PUMP AB Despite advanced techniques and improved clinical outcomes, the optimal antiplatelet strategy following coronary artery bypass grafting (CABG) is an unsolved mystery. Vorapaxar, a novel platelet thrombin receptor (PAR-1/4) blocker, is currently approved for post-myocardial infarction and peripheral artery disease indications on top of clopidogrel or/and aspirin. We here summarize the outcomes in patients after CABG for justification of a future vorapaxar trial. We comprehended the CABG outcomes after vorapaxar yielded from TRACER, TRA2P trials, and affiliated FDA reviews. The verified evidence suggests that composite of death, myocardial infarction and stroke occurred in 2.2% of vorapaxar vs. 8.1% placebo in TRA2P. These data were similar to the endpoint differences (5.9% after vorapaxar vs. 8.3% for placebo) in TRACER. The mortality reduction also consistently suggests vorapaxar advantage (1.7% vs. 2.5% in TRA2P, and 1.7% vs. 3.9% in TRACER). Notably, the post-CABG bleeding risks after vorapaxar were only slightly, but not significantly higher. Moreover, the bleeding disadvantage in the experimental arm was most likely related to overtreatment since majority of patients in both TRACER and TRA2P received triple antiplatelet therapy with aspirin, clopidogrel on top of vorapaxar. Overall, the FDA-confirmed evidence advocate for the future vorapaxar post-CABG outcome-driven trial. The head-to-head trial testing dual therapy with continued over CABG vorapaxar versus withdrawed clopidogrel, both on top of low dose aspirin is warranted. We conclude that the primary outcomes including mortality were consistently better for heart surgery patients after vorapaxar, while the excess of bleeding was mild. Continuing vorapaxar during CABG may be superior to currently recommended withdrawal antiplatelet strategies, and should be tested in an adequately powered randomized outcome-driven trial. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Serebruany, Victor L.] Johns Hopkins Univ, Baltimore, MD USA. [Kim, Moo Hyun] Dong A Univ, Clin Trials Unit, Busan, South Korea. [Golukhova, Elena] Bakoulev Ctr Cardiovasc Surg, Moscow, Russia. [Pya, Yury; Bekbossynova, Makhabbat] Natl Res Cardiac Surg Ctr, Astana, Kazakhstan. [Cattaneo, Marco] Univ Milan, Milan, Italy. [Marciniak, Thomas A.] US FDA, Bethesda, MD 20014 USA. RP Serebruany, VL (reprint author), Johns Hopkins Univ, HeartDrug Res Labs, Osler Med Bldg,7600 Osler Dr,Suite 307, Towson, MD 21204 USA. EM vserebr1@jhmi.edu RI Golukhova, Elena/Q-1768-2015 OI Golukhova, Elena/0000-0002-6252-0322 NR 24 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUL 15 PY 2016 VL 215 BP 273 EP 276 DI 10.1016/j.ijcard.2016.04.124 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DM4DX UT WOS:000376297100062 PM 27128545 ER PT J AU Janes, DW Bin Kim, C Maher, MJ Ellison, CJ AF Janes, Dustin W. Bin Kim, Chae Maher, Michael J. Ellison, Christopher J. TI Orthogonally Spin-Coated Bilayer Films for Photochemical Immobilization and Patterning of Sub-10-Nanometer Polymer Monolayers SO LANGMUIR LA English DT Article ID BLOCK-COPOLYMER LITHOGRAPHY; SELF-ASSEMBLED MONOLAYERS; THIN-FILMS; POLY(METHYL METHACRYLATE); BRUSHES; SURFACES; CONFORMATION; ORIENTATION; FABRICATION; ADSORPTION AB Versatile and spatiotemporally controlled methods for decorating surfaces with monolayers of attached polymers are broadly impactful to many technological applications. However, current materials are usually designed for very specific polymer/surface chemistries and, as a consequence, are not very broadly applicable and/or do not rapidly respond to high-resolution stimuli such as light. We describe here the use of a polymeric adhesion layer, poly(styrene sulfonyl azide-alt-maleic anhydride) (PSSMA), which is capable of immobilizing a 1-7 nm thick monolayer of preformed, inert polymers via photochemical grafting reactions. Solubility of PSSMA in very polar solvents enables processing alongside hydrophobic polymers or solutions and by extension orthogonal spin-coating deposition strategies. Therefore, these materials and processes are fully compatible with photolithographic tools and can take advantage of the immense manufacturing scalability they afford. For example, the thicknesses of covalently grafted poly(styrene) obtained after seconds of exposure are quantitatively equivalent to those obtained by physical adsorption after hours of thermal equilibration. Sequential polymer grafting steps using photomasks were used to pattern different regions of surface energy on the same substrate. These patterns spatially controlled the self-assembled domain orientation of a block copolymer possessing 21 nm half periodicity, demonstrating hierarchical synergy with leading-edge nanopatterning approaches. C1 [Janes, Dustin W.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Bin Kim, Chae; Ellison, Christopher J.] Univ Texas Austin, McKetta Dept Chem Engn, Austin, TX 78712 USA. [Maher, Michael J.] Univ Texas Austin, Dept Chem, Austin, TX 78712 USA. RP Janes, DW (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA.; Ellison, CJ (reprint author), Univ Texas Austin, McKetta Dept Chem Engn, Austin, TX 78712 USA. EM dustin.janes@fda.hhs.gov; ellison@che.utexas.edu FU Robert A. Welch Foundation [F-1709]; National Science Foundation Graduate Research Fellowship [DGE-1110007] FX 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. 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 Department of Health and Human Services. The authors thank the Robert A. Welch Foundation (Grant No. F-1709) for generous financial support and Julie Cushen for providing one of the PS samples. M.J.M. thanks the National Science Foundation Graduate Research Fellowship (Grant DGE-1110007) for financial support. SEM was performed at the Microscopy and Imaging Facility of the Institute for Cellular and Molecular Biology at The University of Texas at Austin. NR 64 TC 0 Z9 0 U1 23 U2 24 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD JUL 12 PY 2016 VL 32 IS 27 BP 6940 EP 6947 DI 10.1021/acs.langmuir.6b01560 PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA DR1ZH UT WOS:000379703900018 PM 27351974 ER PT J AU Strasinger, C Raney, SG Tran, DC Ghosh, P Newman, B Bashaw, ED Ghosh, T Shukla, CG AF Strasinger, Caroline Raney, Sam G. Tran, Doanh C. Ghosh, Priyanka Newman, Bryan Bashaw, Edward D. Ghosh, Tapash Shukla, Chinmay G. TI Navigating sticky areas in transdermal product development SO JOURNAL OF CONTROLLED RELEASE LA English DT Review DE Transdermal; Quality and performance; Adhesives; In-vitro permeation; In-vitro release; Quality by design; Biowaiver; Residual drug analysis; Skin irritation and sensitization ID INVITRO PERCUTANEOUS-ABSORPTION; REGIONAL-VARIATION; DRUG-DELIVERY; DIFFUSION CELL; ANATOMIC SITE; PENETRATION; HEAT; FENTANYL; SYSTEM; PHARMACOKINETICS AB The benefits of transdermal delivery over the oral route to combat such issues of low bioavailability and limited controlled release opportunities are well known and have been previously discussed by many in the field (Prausnitz et al. (2004) [1]; Hadgraft and Lane (2006) [2]). However, significant challenges faced by developers as a product moves from the purely theoretical to commercial production have hampered full capitalization of the dosage forms vast benefits. While different technical aspects of transdermal system development have been discussed at various industry meetings and scientific workshops, uncertainties have persisted regarding the pharmaceutical industry's conventionally accepted approach for the development and manufacturing of transdermal systems. This review provides an overview of the challenges frequently faced and the industry's best practices for assuring the quality and performance of transdermal delivery systems and topical patches (collectively, TDS). The topics discussed are broadly divided into the evaluation of product quality and the evaluation of product performance; with the overall goal of the discussion to improve, advance and accelerate commercial development in the area of this complex controlled release dosage form. Published by Elsevier B.V. C1 [Strasinger, Caroline; Ghosh, Tapash] US FDA, CDER, Off Pharmaceut Qual, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Raney, Sam G.; Ghosh, Priyanka; Newman, Bryan] US FDA, CDER, Off Res & Stand, Off Gener Drugs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Tran, Doanh C.; Bashaw, Edward D.; Shukla, Chinmay G.] US FDA, CDER, Off Clin Pharmacol, Off Translat Sci, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Shukla, CG (reprint author), US FDA, CDER, Off Clin Pharmacol, Off Translat Sci, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Chinmay.Shukla@fda.hhs.gov NR 72 TC 1 Z9 1 U1 17 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 EI 1873-4995 J9 J CONTROL RELEASE JI J. Control. Release PD JUL 10 PY 2016 VL 233 BP 1 EP 9 DI 10.1016/j.jconrel.2016.04.032 PG 9 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DO8TJ UT WOS:000378056400001 PM 27117457 ER PT J AU Elsheikha, HM Schnyder, M Traversa, D Di Cesare, A Wright, I Lacher, DW AF Elsheikha, Hany M. Schnyder, Manuela Traversa, Donato Di Cesare, Angela Wright, Ian Lacher, David W. TI Updates on feline aelurostrongylosis and research priorities for the next decade SO PARASITES & VECTORS LA English DT Review DE Aelurostrongylus abstrusus; Aelurostrongylosis; Cat; Lungworm ID NATURALLY INFECTED CATS; THIRD-STAGE LARVAE; ABSTRUSUS INFECTION; TROGLOSTRONGYLUS-BREVIOR; LUNGWORM DISEASE; DOMESTIC CATS; RISK-FACTORS; SPOT-ON; NEMATODA-METASTRONGYLOIDEA; BRONCHOALVEOLAR LAVAGE AB Feline aelurostrongylosis, caused by the metastrongyloid nematode Aelurostrongylus abstrusus, is an important gastropod-borne parasitic lung disease in cats. Infection with A. abstrusus is widespread globally, but the increasing awareness of this parasite and the advent of more sensitive diagnostics have contributed to the apparent increase in its prevalence and geographic expansion. Clinical features may range in severity from subclinical to life-threatening respiratory disease. Parasitological standard techniques, such as visualization of the nematode first larval stage in faecal and respiratory (bronchial mucus or pleural fluid) samples, remain the mainstays of diagnosis. However, diagnosis is evolving with recent advances in serological and molecular testing, which can improve the time to initiation of effective anthelmintic therapy. Despite numerous anthelmintics that are now available as treatment options, the role of host immunity and lifestyle factors in selecting cats that may benefit from more targeted anthelmintic prophylaxis or treatment practice remains unclear and is likely to guide therapeutic choices as newer data become available. This review summarizes the biology, epidemiology, pathophysiology, diagnosis and treatment options currently available for feline aelurostrongylosis. C1 [Elsheikha, Hany M.] Univ Nottingham, Sch Vet Med & Sci, Sutton Bonington Campus, Loughborough LE12 5RD, Leics, England. [Schnyder, Manuela] Univ Zurich, Inst Parasitol, Vetsuisse Fac, Winterthurerstr 266a, CH-8057 Zurich, Switzerland. [Traversa, Donato; Di Cesare, Angela] Univ Teramo, Fac Vet Med, Teramo, Italy. [Wright, Ian] Withy Grove Vet Surg, 39 Stn Rd, Preston PR5 6QR, Lancs, England. [Lacher, David W.] US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD USA. RP Elsheikha, HM (reprint author), Univ Nottingham, Sch Vet Med & Sci, Sutton Bonington Campus, Loughborough LE12 5RD, Leics, England. EM hany.elsheikha@nottingham.ac.uk NR 107 TC 3 Z9 3 U1 6 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD JUL 7 PY 2016 VL 9 AR 389 DI 10.1186/s13071-016-1671-6 PG 15 WC Parasitology SC Parasitology GA DQ7KH UT WOS:000379385700001 PM 27387914 ER PT J AU Nassiri, I Lombardo, R Lauria, M Morine, MJ Moyseos, P Varma, V Nolen, GT Knox, B Sloper, D Kaput, J Priami, C AF Nassiri, Isar Lombardo, Rosario Lauria, Mario Morine, Melissa J. Moyseos, Petros Varma, Vijayalakshmi Nolen, Greg T. Knox, Bridgett Sloper, Daniel Kaput, Jim Priami, Corrado TI Systems view of adipogenesis via novel omics-driven and tissue-specific activity scoring of network functional modules SO SCIENTIFIC REPORTS LA English DT Article ID GENE SET ENRICHMENT; MESENCHYMAL STEM-CELLS; DE-NOVO LIPOGENESIS; ADIPOCYTE DIFFERENTIATION; PPAR-GAMMA; ADIPOSE DIFFERENTIATION; REGULATES ADIPOGENESIS; PROMOTES ADIPOGENESIS; LIPID-ACCUMULATION; ENERGY-METABOLISM AB The investigation of the complex processes involved in cellular differentiation must be based on unbiased, high throughput data processing methods to identify relevant biological pathways. A number of bioinformatics tools are available that can generate lists of pathways ranked by statistical significance (i.e. by p-value), while ideally it would be desirable to functionally score the pathways relative to each other or to other interacting parts of the system or process. We describe a new computational method (Network Activity Score Finder - NASFinder) to identify tissue-specific, omicsdetermined sub-networks and the connections with their upstream regulator receptors to obtain a systems view of the differentiation of human adipocytes. Adipogenesis of human SBGS pre-adipocyte cells in vitro was monitored with a transcriptomic data set comprising six time points (0, 6, 48, 96, 192, 384 hours). To elucidate the mechanisms of adipogenesis, NASFinder was used to perform time-point analysis by comparing each time point against the control (0 h) and time-lapse analysis by comparing each time point with the previous one. NASFinder identified the coordinated activity of seemingly unrelated processes between each comparison, providing the first systems view of adipogenesis in culture. NASFinder has been implemented into a web-based, freely available resource associated with novel, easy to read visualization of omics data sets and network modules. C1 [Nassiri, Isar; Lombardo, Rosario; Lauria, Mario; Morine, Melissa J.; Moyseos, Petros; Priami, Corrado] Univ Trento, Microsoft Res, Ctr Computat & Syst Biol, Piazza Manifattura 1, I-38068 Rovereto, Italy. [Varma, Vijayalakshmi; Nolen, Greg T.; Knox, Bridgett; Sloper, Daniel] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Kaput, Jim] Nestle Inst Hlth Sci, Lausanne, Switzerland. [Priami, Corrado] Univ Trento, Dept Math, Via Sommar 14, I-38050 Povo, Italy. RP Priami, C (reprint author), Univ Trento, Microsoft Res, Ctr Computat & Syst Biol, Piazza Manifattura 1, I-38068 Rovereto, Italy.; Priami, C (reprint author), Univ Trento, Dept Math, Via Sommar 14, I-38050 Povo, Italy. EM priami@cosbi.eu OI Lauria, Mario/0000-0001-5983-7292 FU National Center for Toxicological Research [E0740401]; Food and Drug Administration; Nestle Institute of Health Sciences FX We thank Alice Matone, Marie-Pier Scott-Boyer and the whole COSBI team for helpful comments on the pipeline during its development and on the manuscript. This study was supported by the National Center for Toxicological Research (Protocol E0740401 (VV)), Food and Drug Administration, and funding from the Nestle Institute of Health Sciences (JK). The results and conclusions presented in this paper are solely the opinion of the authors and do not necessarily reflect the opinion of the Food and Drug Administration. NR 113 TC 1 Z9 1 U1 3 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 7 PY 2016 VL 6 AR 28851 DI 10.1038/srep28851 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ3VM UT WOS:000379131700001 PM 27385551 ER PT J AU Agnihothram, SS Vermudez, SA Mullis, L Townsend, TA Manjanatha, MG Azevedo, MP AF Agnihothram, Sudhakar S. Vermudez, Sheryl Anne Mullis, Lisa Townsend, Todd A. Manjanatha, Mugimane G. Azevedo, Marli P. TI Silicon Dioxide Impedes Antiviral Response and Causes Genotoxic Insult During Calicivirus Replication SO JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY LA English DT Article DE Murine Norovirus; Silica; Proinflammatory Response; Genotoxicity; Feline Calicivirus ID MURINE NOROVIRUS; FELINE CALICIVIRUS; VIRAL-INFECTIONS; GNOTOBIOTIC PIGS; DOWN-REGULATION; FOOD-INDUSTRY; UNITED-STATES; COMET ASSAY; CELL-LINE; TGF-BETA AB Noroviruses (NoV) are the leading cause of nonbacterial gastroenteritis in humans, and replicate extensively in the human gastrointestinal (GI) tract. Silica (also known as silicon dioxide, SiO2) nanoparticles (NPs) used in processed foods, dairy products, and beverages also accumulate in the GI tract. We investigated the effect of silica NPs on NoV replication and host cell response during virus infection, using murine norovirus (MNV-1) infection of RAW 264.7 murine macrophages. Pretreatment with 10 mu g/ml silica significantly reduced the viability of macrophages, but no cumulative effects on viability of macrophages were observed with MNV-1 infection. No difference was observed between exposure to control or silica NPs on either the quantity of viral genome copies or the production of infectious virus in macrophages infected with MNV-1. Silica NPs reduced the ability of macrophages to upregulate genes encoding bone morphogenic proteins (BMPs), chemokine ligands and cytokines for which expression levels were otherwise found to be upregulated in response to MNV-1 infection. Furthermore, silica NPs reduced the levels of proinflammatory cytokines secreted by macrophages in response to MNV infection. Finally, silica NPs with MNV-1 infection produced a genotoxic insult to macrophages. Strikingly, this genotoxic insult was also found to occur as a synergistic effect of silica NPs and feline calicivirus infection in feline kidney epithelial cells. Taken together, our study suggests important safety considerations related to reducing exposure to silica NPs affecting the GI tract in individuals infected with NoVs and possibly other foodborne viruses. C1 [Agnihothram, Sudhakar S.; Vermudez, Sheryl Anne; Mullis, Lisa; Azevedo, Marli P.] US FDA, NCTR, Div Microbiol, Honolulu, HI 96816 USA. [Townsend, Todd A.; Manjanatha, Mugimane G.] US FDA, NCTR, Div Genet & Mol Toxicol, Honolulu, HI 96816 USA. [Vermudez, Sheryl Anne] Chaminade Univ Honolulu, Honolulu, HI 96816 USA. RP Azevedo, MP (reprint author), US FDA, NCTR, Div Microbiol, Honolulu, HI 96816 USA. FU Office of the Commissioner, Office of the Chief Scientist, U.S. Food and Drug Administration FX We thank Dr. John Sutherland and Dr. Kidon Sung for critical review and editing of the manuscript. This project was funded in part by the Commissioner's Fellowship Program (SSA and TAT), Office of the Commissioner, Office of the Chief Scientist, U.S. Food and Drug Administration. NR 64 TC 0 Z9 0 U1 3 U2 3 PU AMER SCIENTIFIC PUBLISHERS PI VALENCIA PA 26650 THE OLD RD, STE 208, VALENCIA, CA 91381-0751 USA SN 1533-4880 EI 1533-4899 J9 J NANOSCI NANOTECHNO JI J. Nanosci. Nanotechnol. PD JUL PY 2016 VL 16 IS 7 BP 7720 EP 7730 DI 10.1166/jnn.2016.12828 PG 11 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EB1HM UT WOS:000387100400158 PM 27547159 ER PT J AU Zhang, X Liu, SL Newport, GD Paule, MG Callicott, R Thompson, J Liu, F Patterson, TA Berridge, MS Apana, SM Brown, CC Maisha, MP Hanig, JP Slikker, W Wang, C AF Zhang, Xuan Liu, Shuliang Newport, Glenn D. Paule, Merle G. Callicott, Ralph Thompson, James Liu, Fang Patterson, Tucker A. Berridge, Marc S. Apana, Scott M. Brown, Christina C. Maisha, Mackean P. Hanig, Joseph P. Slikker, William, Jr. Wang, Cheng TI In Vivo Monitoring of Sevoflurane-induced Adverse Effects in Neonatal Nonhuman Primates Using Small-animal Positron Emission Tomography SO ANESTHESIOLOGY LA English DT Article ID ACETYL-L-CARNITINE; PERIPHERAL BENZODIAZEPINE-RECEPTORS; INDUCED NEURONAL DAMAGE; D-ASPARTATE RECEPTOR; NEURAL STEM-CELLS; ALPHA-LIPOIC ACID; CORTICAL-NEURONS; OXIDATIVE STRESS; RAT-BRAIN; RHESUS-MONKEY AB Background: Animals exposed to sevoflurane during development sustain neuronal cell death in their developing brains. In vivo micro-positron emission tomography (PET)/computed tomography imaging has been utilized as a minimally invasive method to detect anesthetic-induced neuronal adverse effects in animal studies. Methods: Neonatal rhesus monkeys (postnatal day 5 or 6, 3 to 6 per group) were exposed for 8 h to 2.5% sevoflurane with or without acetyl-l-carnitine (ALC). Control monkeys were exposed to room air with or without ALC. Physiologic status was monitored throughout exposures. Depth of anesthesia was monitored using quantitative electroencephalography. After the exposure, microPET/computed tomography scans using F-18-labeled fluoroethoxybenzyl-N-(4-phenoxypyridin-3-yl) acetamide (FEPPA) were performed repeatedly on day 1, 1 and 3 weeks, and 2 and 6 months after exposure. Results: Critical physiologic metrics in neonatal monkeys remained within the normal range during anesthetic exposures. The uptake of [F-18]-FEPPA in the frontal and temporal lobes was increased significantly 1 day or 1 week after exposure, respectively. Analyses of microPET images recorded 1 day after exposure showed that sevoflurane exposure increased [F-18]-FEPPA uptake in the frontal lobe from 0.927 +/- 0.04 to 1.146 +/- 0.04, and in the temporal lobe from 0.859 +/- 0.05 to 1.046 +/- 0.04 (mean +/- SE, P < 0.05). Coadministration of ALC effectively blocked the increase in FEPPA uptake. Sevoflurane-induced adverse effects were confirmed by histopathologic evidence as well. Conclusions: Sevoflurane-induced general anesthesia during development increases glial activation, which may serve as a surrogate for neurotoxicity in the nonhuman primate brain. ALC is a potential protective agent against some of the adverse effects associated with such exposures. C1 [Zhang, Xuan; Liu, Shuliang; Newport, Glenn D.; Paule, Merle G.; Liu, Fang; Patterson, Tucker A.; Wang, Cheng] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Maisha, Mackean P.] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Callicott, Ralph; Thompson, James] US FDA, Div Prior Serv 1, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Berridge, Marc S.; Apana, Scott M.; Brown, Christina C.] 3D Imaging LLC, Little Rock, AR USA. [Hanig, Joseph P.; Slikker, William, Jr.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Zhang, X (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM xuan.zhang@fda.hhs.gov FU National Center for Toxicological Research, Jefferson, Arkansas; Center for Drug Evaluation and Research/U.S. Food and Drug Administration (FDA), Silver Spring, Maryland FX This work was supported by the National Center for Toxicological Research, Jefferson, Arkansas, and the Center for Drug Evaluation and Research/U.S. Food and Drug Administration (FDA), Silver Spring, Maryland. This document has been reviewed in accordance with U.S. FDA policy and approved for publication. Approval does not signify that the contents necessarily reflect the position or opinions of the FDA nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the FDA. NR 100 TC 2 Z9 2 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD JUL PY 2016 VL 125 IS 1 BP 133 EP 146 DI 10.1097/ALN.0000000000001154 PG 14 WC Anesthesiology SC Anesthesiology GA DY2JO UT WOS:000384919100025 PM 27183169 ER PT J AU Friedlaender, J AF Friedlaender, Jonathan TI Beating A Cancer Death Sentence SO HEALTH AFFAIRS LA English DT Editorial Material C1 [Friedlaender, Jonathan] Temple Univ, Biol Anthropol, Philadelphia, PA 19122 USA. [Friedlaender, Jonathan] US FDA, Silver Spring, MD 20993 USA. [Friedlaender, Jonathan] Harvard Univ, Cambridge, MA 02138 USA. [Friedlaender, Jonathan] Univ Wisconsin, Madison, WI 53706 USA. [Friedlaender, Jonathan] Natl Sci Fdn, 4201 Wilson Blvd, Arlington, VA 22230 USA. RP Friedlaender, J (reprint author), Temple Univ, Biol Anthropol, Philadelphia, PA 19122 USA.; Friedlaender, J (reprint author), US FDA, Silver Spring, MD 20993 USA. EM jfriedla@temple.edu NR 0 TC 1 Z9 1 U1 0 U2 0 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 JUL PY 2016 VL 35 IS 7 BP 1333 EP 1337 DI 10.1377/HLTHAFF.2015.1085 PG 5 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DY0QN UT WOS:000384801400026 PM 27385250 ER PT J AU Marques, SDF Tibonati, RMF Sabaa-Srur, AUO Luo, RS Shejwalkar, P Hara, K Dobbs, T Smith, RE AF Fernandes Marques, Simone do Socorro Feio Tibonati, Rosana Maria Oliveira Sabaa-Srur, Armando Ubirajara Luo, Rensheng Shejwalkar, Pushkar Hara, Kenji Dobbs, Thomas Smith, Robert E. TI Evaluation of the effects of passion fruit peel flour (Passilfora edulis fo. flavicarpa) on metabolic changes in HIV patients with lipodystrophy syndrome secondary to antiretroviral therapy SO REVISTA BRASILEIRA DE FARMACOGNOSIA-BRAZILIAN JOURNAL OF PHARMACOGNOSY LA English DT Article DE Passion fruit peel flour; HIV patients; Lipodystrophy syndrothe; Dyslipidemia ID HIGH-DENSITY-LIPOPROTEIN; AMERICAN-HEART-ASSOCIATION; CARDIOVASCULAR-DISEASE; F-FLAVICARPA; CHOLESTEROL; FIBER; MEN; ATHEROSCLEROSIS; RISK; CONSUMPTION AB This study evaluated the effects of using passion fruit peel flour together with diet therapy and counseling in 36 patients with HIV lipodystrophy who were in an ambulatory clinic in a university hospital. The patients were divided into two groups. One received 30 g of passion fruit peel flour daily for 90 days and diet therapy counseling. The other group received only diet therapy counseling. The metabolic changes were analyzed before and after the intervention, with a significance level predetermined at p = 0.05. The use of passion fruit peel flour was effective in reducing total cholesterol and triacylglycerides after 30 days. The concentrations of LDL-C decreased, while HDL-C increased in the blood of lipodystrophy patients after 90 days passion fruit peel flour treatment. No significant differences in food consumption were seen between groups. The use of 30 g of passion fruit peel flour for 90 days together with diet therapy counseling was effective in improving plasma concentrations of total cholesterol, LDL-C, HDL-C and triacylglycerides. Published by Elsevier Editora Ltda. on behalf of Sociedade Brasileira de Farmacognosia. C1 [Fernandes Marques, Simone do Socorro] Ctr Univ Para, Belem, PA, Brazil. [Feio Tibonati, Rosana Maria] Fed Univ Para, Nucl Med Trop, Belem, PA, Brazil. [Oliveira Sabaa-Srur, Armando Ubirajara] Univ Fed Rio de Janeiro, Ctr Ciencias Saude, Inst Nutr, Rio De Janeiro, RJ, Brazil. [Luo, Rensheng] Univ Missouri, Dept Chem & Biochem, St Louis, MO 63121 USA. [Shejwalkar, Pushkar; Hara, Kenji] Tokyo Univ Technol, Sch Engn, Hachioji, Tokyo, Japan. [Dobbs, Thomas; Smith, Robert E.] US FDA, Lenexa, KS USA. [Smith, Robert E.] Park Univ, Parkville, MO USA. RP Smith, RE (reprint author), US FDA, Lenexa, KS USA.; Smith, RE (reprint author), Park Univ, Parkville, MO USA. EM robert.smith@fda.hhs.gov OI Shejwalkar, Pushkar/0000-0002-6342-9299 NR 41 TC 1 Z9 1 U1 2 U2 2 PU SOC BRASILEIRA FARMACOGNOSIA PI CURITIBA-PR PA C/O PROF CID AIMBIRE DE MORAES SANTOS, UFPR-LAB FARM, RUA PREF LOTHARIO MEISSNER, 632-JD BOTANICO, CURITIBA-PR, 80210-170, BRAZIL SN 0102-695X J9 REV BRAS FARMACOGN JI Rev. Bras. Farmacogn.-Braz. J. Pharmacogn. PD JUL-AUG PY 2016 VL 26 IS 4 BP 420 EP 426 DI 10.1016/j.bjp.2016.03.002 PG 7 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DW6CB UT WOS:000383732900003 ER PT J AU LaCasse, D Lute, S Fiadeiro, M Basha, J Stork, M Brorson, K Godavarti, R Gallo, C AF LaCasse, Daniel Lute, Scott Fiadeiro, Marcus Basha, Jonida Stork, Matthew Brorson, Kurt Godavarti, Ranga Gallo, Chris TI Mechanistic failure mode investigation and resolution of parvovirus retentive filters SO BIOTECHNOLOGY PROGRESS LA English DT Article DE monoclonal antibody; purification; virus retentive filtration; depth filtration; viral clearance; parvovirus; bacteriophage; convective flow; in membrane diffusion ID MEMBRANE-FILTER; VIRUS RETENTION; FILTRATION AB Virus retentive filters are a key product safety measure for biopharmaceuticals. A simplistic perception is that they function solely based on a size-based particle removal mechanism of mechanical sieving and retention of particles based on their hydrodynamic size. Recent observations have revealed a more nuanced picture, indicating that changes in viral particle retention can result from process pressure and/or flow interruptions. In this study, a mechanistic investigation was performed to help identify a potential mechanism leading to the reported reduced particle retention in small virus filters. Permeate flow rate or permeate driving force were varied and analyzed for their impact on particle retention in three commercially available small virus retentive filters. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:959-970, 2016 C1 [LaCasse, Daniel; Fiadeiro, Marcus; Basha, Jonida; Stork, Matthew; Godavarti, Ranga; Gallo, Chris] Pfizer Biopharmaceut, 1 Burtt Rd, Andover, MA 01810 USA. [Lute, Scott; Brorson, Kurt] US FDA, CDER, OPS, DMA, 10903 New Hampshire Ave,Bldg 72 RM 2220, Silver Spring, MD 20903 USA. RP LaCasse, D (reprint author), Pfizer Biopharmaceut, 1 Burtt Rd, Andover, MA 01810 USA. EM daniel.lacasse@pfizer.com FU CDER's Office of Biotechnology Products [1041]; Pfizer's BioTherapeutical Pharmaceutical Sciences Organization FX Funding for this study was provided in part by CDER's Office of Biotechnology Products, project number 1041. The authors thank Rashmi Rawat and Cecilia Tami from CDER/FDA for careful review of this manuscript."; Funding for this study was provided in part by Pfizer's BioTherapeutical Pharmaceutical Sciences Organization. The authors thank Aaron Noyes and Thomas L. Emmons from Pfizer for careful review of this manuscript. NR 19 TC 2 Z9 2 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8756-7938 EI 1520-6033 J9 BIOTECHNOL PROGR JI Biotechnol. Prog. PD JUL-AUG PY 2016 VL 32 IS 4 BP 959 EP 970 DI 10.1002/btpr.2298 PG 12 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA DW1IN UT WOS:000383396800015 PM 27160325 ER PT J AU Torosyan, Y Hu, YZ Hoffman, S Luo, QL Carleton, B Marinac-Dabic, D AF Torosyan, Yelizaveta Hu, Yuzhi Hoffman, Sarah Luo, Qianlai Carleton, Bruce Marinac-Dabic, Danica TI An in silico framework for integrating epidemiologic and genetic evidence with health care applications: ventilation-related pneumothorax as a case illustration SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE In silico evidence integration using big data approaches; Translational Epidemiology; Repurposing and re-utilization of pre-existing genetic data; Medical device safety biomarkers ID RESPIRATORY-DISTRESS-SYNDROME; PATIENT SAFETY INDICATORS; MECHANICAL VENTILATION; CYSTIC-FIBROSIS; IATROGENIC PNEUMOTHORAX; RISK-FACTORS; RECURRENCE; PHENOTYPE; LUNGS AB Objective To illustrate an in silico integration of epidemiologic and genetic evidence that is being developed at the Center for Devices and Radiological Health/US Food and Drug Administration as part of regulatory research on postmarket device performance. In addition to using conventional epidemiologic evidence from registries, this innovative approach explores the vast potential of open-access omics databases for identifying genetic evidence pertaining to devices. Material and methods A retrospective analysis of Agency for Healthcare Research and Quality (AHRQ)/Healthcare Cost and Utilization Project (HCUPNet) data (2002-2011) was focused on the ventilation-related iatrogenic pneumothorax (Vent-IP) outcome in discharges with mechanical ventilation (MV) and continuous positive airway pressure (CPAP). The derived epidemiologic evidence was analyzed in conjunction with pre-existing genomic data from Gene Expression Omnibus/National Center for Biotechnology Information and other databases. Results AHRQ/HCUPNet epidemiologic evidence showed that annual occurrence of Vent-IP did not decrease over a decade. While the Vent-IP risk associated with noninvasive CPAP comprised about 0.5%, the Vent-IP risk due to longer-term MV reached 2%. Along with MV posing an independent risk for Vent-IP, female sex and white race were found to be effect modifiers, resulting in the highest Vent-IP risk among mechanically ventilated white females. The Vent-IP risk was also potentiated by comorbidities associated with spontaneous pneumothorax (SP) and fibrosis. Consistent with the epidemiologic evidence, expression profiling in a number of animal models showed that the expression of several collagens and other SP/fibrosis-related genes was modified by ventilation settings. Conclusion Integration of complementary genetic evidence into epidemiologic analysis can lead to a cost- and time-efficient discovery of the risk predictors and markers and thus can facilitate more efficient marker-based evaluation of medical product performance. C1 [Torosyan, Yelizaveta; Hu, Yuzhi; Hoffman, Sarah; Luo, Qianlai; Marinac-Dabic, Danica] US FDA, Div Epidemiol, Ctr Devices & Radiol Hlth, CDRH, Silver Spring, MD 20993 USA. [Hu, Yuzhi] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Hoffman, Sarah; Luo, Qianlai] Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA. [Carleton, Bruce] BC Childrens Hosp, Pharmaceut Outcomes Programme, Vancouver, BC, Canada. [Carleton, Bruce] Univ British Columbia, Div Translat Therapeut, Dept Pediat, Child & Family Res Inst, Vancouver, BC, Canada. RP Torosyan, Y (reprint author), US FDA, DEPI, OSB, CDRH, Bldg 66,Rm 4102, Silver Spring, MD 20993 USA. EM yeliza-veta.torosyan@fda.hhs.gov OI /0000-0002-4485-4054 FU US Department of Energy; FDA FX This work was supported in part by an appointment to the Research Participation Program at the Center for Devices and Radiological Health Office of Surveillance and Biometrics, the US Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA. NR 30 TC 1 Z9 1 U1 5 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL PY 2016 VL 23 IS 4 BP 711 EP 720 DI 10.1093/jamia/ocw031 PG 10 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DW6SS UT WOS:000383782100007 PM 27107435 ER PT J AU MacQueen, KM Eley, NT Frick, M Mingote, LR Chou, A Seidel, SS Hannah, S Hamilton, C AF MacQueen, Kathleen M. Eley, Natalie T. Frick, Mike Mingote, Laia Ruiz Chou, Alicia Seidel, Stephanie S. Hannah, Stacey Hamilton, Carol TI Developing a Framework for Evaluating Ethical Outcomes of Good Participatory Practices in TB Clinical Drug Trials SO JOURNAL OF EMPIRICAL RESEARCH ON HUMAN RESEARCH ETHICS LA English DT Article DE community engagement; stakeholder engagement; good participatory practices; evaluation; theory of change; tuberculosis; clinical trials; global research; research networks ID COMMUNITY ENGAGEMENT; DEVELOPING-COUNTRIES; HIV AB Good Participatory Practice Guidelines for TB Drug Trials (GPP-TB) were issued in 2012, based on similar guidelines for HIV prevention and reflecting growing acceptance of the importance of community engagement and participatory strategies in clinical research. Though the need for such strategies is clear, evaluation of the benefits and burdens are needed. Working with a diverse group of global TB stakeholders including advocates, scientists, and ethicists, we used a Theory of Change approach to develop an evaluation framework for GPP-TB that includes a clearly defined ethical goal, a set of powerful strategies derived from GPP-TB practices for achieving the goal, and outcomes connecting strategies to goal. The framework is a first step in systematically evaluating participatory research in clinical trials. C1 [MacQueen, Kathleen M.; Eley, Natalie T.; Hamilton, Carol] IFHI 360, Durham, NC USA. [Frick, Mike] Treatment Act Grp, New York, NY USA. [Mingote, Laia Ruiz] TB Trials Consortium, Community Res Advisors Grp, Barcelona, Spain. [Chou, Alicia] US FDA, Reagan Udall Fdn, Washington, DC USA. [Seidel, Stephanie S.] TB Alliance, Community Engagement & Stakeholder Relat, New York, NY USA. [Hannah, Stacey] AVAC, New York, NY USA. [Hannah, Stacey] AVAC, Good Participatory Practices Program, New York, NY USA. RP MacQueen, KM (reprint author), FHI 360, Social & Behav Hlth Sci, 359 Blackwell St,Suite 200, Durham, NC 27701 USA. EM kmacqueen@fhi360.org FU National Institute of Allergy And Infectious Diseases of the National Institutes of Health [R21AI108519] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Support for this research was received from the National Institute of Allergy And Infectious Diseases of the National Institutes of Health under Award Number R21AI108519. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 28 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1556-2646 EI 1556-2654 J9 J EMPIR RES HUM RES JI J. Empir. Res. Hum. Res. Ethics PD JUL PY 2016 VL 11 IS 3 BP 203 EP 213 DI 10.1177/1556264616657452 PG 11 WC Ethics; Medical Ethics SC Social Sciences - Other Topics; Medical Ethics GA DV8SS UT WOS:000383207600001 PM 27368311 ER PT J AU Tsetsarkin, KA Kenney, H Chen, RB Liu, GP Manukyan, H Whitehead, SS Laassri, M Chumakov, K Pletnev, AG AF Tsetsarkin, Konstantin A. Kenney, Heather Chen, Rubing Liu, Guangping Manukyan, Hasmik Whitehead, Stephen S. Laassri, Majid Chumakov, Konstantin Pletnev, Alexander G. TI A Full-Length Infectious cDNA Clone of Zika Virus from the 2015 Epidemic in Brazil as a Genetic Platform for Studies of Virus-Host Interactions and Vaccine Development SO MBIO LA English DT Article ID JAPANESE-ENCEPHALITIS-VIRUS; COOPERATIVE INTERACTIONS; RT-PCR; RNA; DNA; ROBUSTNESS; EVOLUTION; AMERICA; AMPLIFICATION; TRANSMISSION AB An arthropod-borne virus, Zika virus (ZIKV), has recently emerged as a major human pathogen. Associated with complications during perinatal development and Guillain-Barr syndrome in adults, ZIKV raises new challenges for understanding the molecular determinants of flavivirus pathogenesis. This underscores the necessity for the development of a reverse genetic system based on an epidemic ZIKV strain. Here, we describe the generation and characterization in cell cultures of an infectious cDNA clone of ZIKV isolated from the 2015 epidemic in Brazil. The cDNA-derived ZIKV replicated efficiently in a variety of cell lines, including those of both neuronal and placental origin. We observed that the growth of cDNA-derived virus was attenuated compared to the growth of the parental isolate in most cell lines, which correlates with substantial differences in sequence heterogeneity between these viruses that were determined by deep-sequencing analysis. Our findings support the role of genetic diversity in maintaining the replicative fitness of viral populations under changing conditions. Moreover, these results indicate that caution should be exercised when interpreting the results of reverse-genetics experiments in attempts to accurately predict the biology of natural viruses. Finally, a Vero cell-adapted cDNA clone of ZIKV was generated that can be used as a convenient platform for studies aimed at the development of ZIKV vaccines and therapeutics. IMPORTANCE The availability of genetic tools and laboratory models determines the progress in understanding mechanisms of virus emergence and pathogenesis. Recent large-scale outbreaks of Zika virus (ZIKV) that were linked to complications during perinatal development and Guillain-Barre syndrome in adults emphasize the urgency for the development of a reverse-genetics system based on an epidemic ZIKV strain. Here, we report a stable infectious cDNA clone for ZIKV isolated during the 2015 epidemic in Brazil, as well as a Vero cell-adapted version of it, which will be used for virus-host interaction studies and vaccine development. C1 [Tsetsarkin, Konstantin A.; Kenney, Heather; Liu, Guangping; Whitehead, Stephen S.; Pletnev, Alexander G.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Chen, Rubing] Univ Texas Med Branch, Dept Pathol, Inst Human Infect & Immun, Galveston, TX 77555 USA. [Manukyan, Hasmik; Laassri, Majid; Chumakov, Konstantin] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Pletnev, AG (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM apletnev@niaid.nih.gov FU Division of Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health NR 44 TC 10 Z9 10 U1 49 U2 49 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2016 VL 7 IS 4 AR e01114 DI 10.1128/mBio.01114-16 PG 8 WC Microbiology SC Microbiology GA DW1YQ UT WOS:000383440500060 ER PT J AU Durmowicz, AG AF Durmowicz, Anthony G. TI CF end point commentary SO JOURNAL OF CYSTIC FIBROSIS LA English DT Editorial Material C1 [Durmowicz, Anthony G.] US FDA, Div Pulm Allergy & Rheumatol Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Durmowicz, AG (reprint author), US FDA, Div Pulm Allergy & Rheumatol Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM Anthony.Durmowicz@fda.hhs.gov NR 2 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-1993 EI 1873-5010 J9 J CYST FIBROS JI J. Cyst. Fibros PD JUL PY 2016 VL 15 IS 4 BP 424 EP 424 DI 10.1016/j.jcf.2016.06.003 PG 1 WC Respiratory System SC Respiratory System GA DU6US UT WOS:000382350700006 PM 27324552 ER PT J AU Stephens, ML Betts, K Beck, NB Cogliano, V Dickersin, K Fitzpatrick, S Freeman, J Gray, G Hartung, T McPartland, J Rooney, AA Scherer, RW Verloo, D Hoffmann, S AF Stephens, Martin L. Betts, Kellyn Beck, Nancy B. Cogliano, Vincent Dickersin, Kay Fitzpatrick, Suzanne Freeman, James Gray, George Hartung, Thomas McPartland, Jennifer Rooney, Andrew A. Scherer, Roberta W. Verloo, Didier Hoffmann, Sebastian TI The Emergence of Systematic Review in Toxicology SO TOXICOLOGICAL SCIENCES LA English DT Review DE systematic review; risk of bias; data integration ID EVIDENCE-BASED MEDICINE; ENVIRONMENTAL-HEALTH SCIENCE; FETAL-GROWTH; EPIDEMIOLOGIC EVIDENCE; ARSENIC EXPOSURE; QUALITY; INTEGRATION; VALIDATION AB The Evidence-based Toxicology Collaboration hosted a workshop on "The Emergence of Systematic Review and Related Evidence-based Approaches in Toxicology," on November 21, 2014 in Baltimore, Maryland. The workshop featured speakers from agencies and organizations applying systematic review approaches to questions in toxicology, speakers with experience in conducting systematic reviews in medicine and healthcare, and stakeholders in industry, government, academia, and non-governmental organizations. Based on the workshop presentations and discussion, here we address the state of systematic review methods in toxicology, historical antecedents in both medicine and toxicology, challenges to the translation of systematic review from medicine to toxicology, and thoughts on the way forward. We conclude with a recommendation that as various agencies and organizations adapt systematic review methods, they continue to work together to ensure that there is a harmonized process for how the basic elements of systematic review methods are applied in toxicology. C1 [Stephens, Martin L.; Hartung, Thomas] Johns Hopkins Ctr Alternat Anim Testing, Baltimore, MD USA. [Beck, Nancy B.] Amer Chem Council, Washington, DC USA. [Cogliano, Vincent] US EPA, Arlington, VA USA. [Dickersin, Kay; Scherer, Roberta W.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Fitzpatrick, Suzanne] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Freeman, James] ExxonMobil Biomed Sci, Annandale, NJ USA. [Gray, George] George Washington Univ, Milken Inst Sch Publ Hlth, Washington, DC USA. [Hartung, Thomas] Univ Konstanz, CAAT Europe, Constance, Germany. [McPartland, Jennifer] Environm Def Fund, Washington, DC USA. [Rooney, Andrew A.] NIEHS, Off Hlth Assessment & Translat, Div Natl Toxicol Program, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Verloo, Didier] European Food Safety Author, I-43126 Parma, Italy. [Hoffmann, Sebastian] Seh Consulting Serv, D-33098 Paderborn, Germany. RP Stephens, ML (reprint author), Johns Hopkins Ctr Alternat Anim Testing, Baltimore, MD USA. EM msteph14@jhu.edu FU ExxonMobil Foundation FX This work was supported by funding from an anonymous private charitable foundation and the ExxonMobil Foundation to the Johns Hopkins Center for Alternatives to Animal Testing (CAAT). CAAT serves as the secretariat for the Evidence-based Toxicology Collaboration, which hosted the workshop on which this article is based. Only those authors working at or for CAAT (K.B., T.H., S.H., and M.L.S.) received compensation from these sources via CAAT for their participation in the workshop or their preparation of this article. NR 44 TC 4 Z9 4 U1 5 U2 6 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 JUL PY 2016 VL 152 IS 1 BP 10 EP 16 DI 10.1093/toxsci/kfw059 PG 7 WC Toxicology SC Toxicology GA DT2AA UT WOS:000381282000002 PM 27208075 ER PT J AU Moro, PL Woo, EJ Paul, W Lewis, P Petersen, BW Cano, M AF Moro, Pedro L. Woo, Emily Jane Paul, Wendy Lewis, Paige Petersen, Brett W. Cano, Maria TI Post-Marketing Surveillance of Human Rabies Diploid Cell Vaccine (Imovax) in the Vaccine Adverse Event Reporting System (VAERS) in the United States, 1990. 2015 SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID ACUTE DISSEMINATED ENCEPHALOMYELITIS; IMMUNIZATION SAFETY DATA; GUILLAIN-BARRE-SYNDROME; ADVISORY-COMMITTEE; RECOMMENDATIONS; VACCINATIONS; GUIDELINES; COLLECTION; RISK AB Background In 1980, human diploid cell vaccine (HDCV, Imovax Rabies, Sanofi Pasteur), was licensed for use in the United States. Objective To assess adverse events (AEs) after HDCV reported to the US Vaccine Adverse Event Reporting System (VAERS), a spontaneous reporting surveillance system. Methods We searched VAERS for US reports after HDCV among persons vaccinated from January 1, 1990-July 31, 2015. Medical records were requested for reports classified as serious ( death, hospitalization, prolonged hospitalization, disability, life-threatening-illness), and those suggesting anaphylaxis and Guillain-Barre syndrome (GBS). Physicians reviewed available information and assigned a primary clinical category to each report using MedDRA system organ classes. Empirical Bayesian (EB) data mining was used to identify disproportional AE reporting after HDCV. Results VAERS received 1,611 reports after HDCV; 93 (5.8%) were serious. Among all reports, the three most common AEs included pyrexia (18.2%), headache (17.9%), and nausea (16.5%). Among serious reports, four deaths appeared to be unrelated to vaccination. Conclusions This 25-year review of VAERS did not identify new or unexpected AEs after HDCV. The vast majority of AEs were non-serious. Injection site reactions, hypersensitivity reactions, and non-specific constitutional symptoms were most frequently reported, similar to findings in pre-licensure studies. C1 [Moro, Pedro L.; Lewis, Paige; Cano, Maria] Ctr Dis Control & Prevent CDC, Immunizat Safety Off, Div Healthcare Qual Promot DHQP, Natl Ctr Zoonot & Emerging Infect Dis NCZEID, Atlanta, GA USA. [Woo, Emily Jane; Paul, Wendy] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Petersen, Brett W.] CDC, Poxvirus & Rabies Branch, Div High Consequence Pathogens & Pathol, NCZEID, Atlanta, GA 30333 USA. RP Moro, PL (reprint author), Ctr Dis Control & Prevent CDC, Immunizat Safety Off, Div Healthcare Qual Promot DHQP, Natl Ctr Zoonot & Emerging Infect Dis NCZEID, Atlanta, GA USA. EM pmoro@cdc.gov NR 22 TC 0 Z9 0 U1 3 U2 3 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 JUL PY 2016 VL 10 IS 7 AR e0004846 DI 10.1371/journal.pntd.0004846 PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DS8FC UT WOS:000381017800050 PM 27410239 ER PT J AU Shah, I Setzer, RW Jack, J Houck, KA Judson, RS Knudsen, TB Liu, J Martin, MT Reif, DM Richard, AM Thomas, RS Crofton, KM Dix, DJ Kavlock, RJ AF Shah, Imran Setzer, R. Woodrow Jack, John Houck, Keith A. Judson, Richard S. Knudsen, Thomas B. Liu, Jie Martin, Matthew T. Reif, David M. Richard, Ann M. Thomas, Russell S. Crofton, Kevin M. Dix, David J. Kavlock, Robert J. TI Using ToxCast (TM) Data to Reconstruct Dynamic Cell State Trajectories and Estimate Toxicological Points of Departure SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID TOXICITY; 21ST-CENTURY; ADVERSE; SYSTEMS; VISION AB BACKGROUND: High-content imaging (HCI) allows simultaneous measurement of multiple cellular phenotypic changes and is an important tool for evaluating the biological activity of chemicals. OBJECTIVES: Our goal was to analyze dynamic cellular changes using HCI to identify the "tipping point" at which the cells did not show recovery towards a normal phenotypic state. METHODS: HCI was used to evaluate the effects of 967 chemicals (in concentrations ranging from 0.4 to 200 mu M) on HepG2 cells over a 72-hr exposure period. The HCI end points included p53, c-Jun, histone H2A. x, alpha-tubulin, histone H3, alpha tubulin, mitochondrial membrane potential, mitochondrial mass, cell cycle arrest, nuclear size, and cell number. A computational model was developed to interpret HCI responses as cell-state trajectories. RESULTS: Analysis of cell-state trajectories showed that 336 chemicals produced tipping points and that HepG2 cells were resilient to the effects of 334 chemicals up to the highest concentration (200 mu M) and duration (72 hr) tested. Tipping points were identified as concentration-dependent transitions in system recovery, and the corresponding critical concentrations were generally between 5 and 15 times (25th and 75th percentiles, respectively) lower than the concentration that produced any significant effect on HepG2 cells. The remaining 297 chemicals require more data before they can be placed in either of these categories. CONCLUSIONS: These findings show the utility of HCI data for reconstructing cell state trajectories and provide insight into the adaptation and resilience of in vitro cellular systems based on tipping points. Cellular tipping points could be used to define a point of departure for risk-based prioritization of environmental chemicals. C1 [Shah, Imran; Setzer, R. Woodrow; Houck, Keith A.; Judson, Richard S.; Knudsen, Thomas B.; Martin, Matthew T.; Richard, Ann M.; Thomas, Russell S.; Crofton, Kevin M.; Dix, David J.; Kavlock, Robert J.] US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Jack, John] North Carolina State Univ, Dept Stat, Raleigh, NC USA. [Liu, Jie] US DOE, ORISE, Oak Ridge, TN USA. [Reif, David M.] North Carolina State Univ, Dept Biol Sci, Raleigh, NC USA. [Dix, David J.] US EPA, Off Sci Coordinat & Policy, Washington, DC 20460 USA. [Kavlock, Robert J.] US EPA, Off Res & Dev, Washington, DC 20460 USA. [Liu, Jie] US FDA, Ctr Food Safety & Appl Nutr, Off Food Addit Safety, College Pk, MD USA. RP Shah, I (reprint author), US EPA, 109 TW Alexander Dr B205-01, Res Triangle Pk, NC 27711 USA. EM Shah.Imran@epa.gov FU U.S. Environmental Protection Agency (EPA) [EP-D-13-013] FX Cell culture, chemical exposure, and HCI imaging were conducted by Apredica, Watertown, Massachusetts, under U.S. Environmental Protection Agency (EPA) contract EP-D-13-013. NR 28 TC 3 Z9 3 U1 3 U2 4 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2016 VL 124 IS 7 BP 910 EP 919 DI 10.1289/ehp.1409029 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DS4KF UT WOS:000380749300011 PM 26473631 ER PT J AU Mansouri, K Abdelaziz, A Rybacka, A Roncaglioni, A Tropsha, A Varnek, A Zakharov, A Worth, A Richard, AM Grulke, CM Trisciuzzi, D Fourches, D Horvath, D Benfenati, E Muratov, E Wedebye, EB Grisoni, F Mangiatordi, GF Incisivo, GM Hong, HX Ng, HW Tetko, IV Balabin, I Kancherla, J Shen, J Burton, J Nicklaus, M Cassotti, M Nikolov, NG Nicolotti, O Andersson, PL Zang, QD Politi, R Beger, RD Todeschini, R Huang, RL Farag, S Rosenberg, SA Slavov, S Hu, X Judson, RS AF Mansouri, Kamel Abdelaziz, Ahmed Rybacka, Aleksandra Roncaglioni, Alessandra Tropsha, Alexander Varnek, Alexandre Zakharov, Alexey Worth, Andrew Richard, Ann M. Grulke, Christopher M. Trisciuzzi, Daniela Fourches, Denis Horvath, Dragos Benfenati, Emilio Muratov, Eugene Wedebye, Eva Bay Grisoni, Francesca Mangiatordi, Giuseppe F. Incisivo, Giuseppina M. Hong, Huixiao Ng, Hui W. Tetko, Igor V. Balabin, Ilya Kancherla, Jayaram Shen, Jie Burton, Julien Nicklaus, Marc Cassotti, Matteo Nikolov, Nikolai G. Nicolotti, Orazio Andersson, Patrik L. Zang, Qingda Politi, Regina Beger, Richard D. Todeschini, Roberto Huang, Ruili Farag, Sherif Rosenberg, Sine A. Slavov, Svetoslav Hu, Xin Judson, Richard S. TI CERAPP: Collaborative Estrogen Receptor Activity Prediction Project SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID ENDOCRINE-DISRUPTING CHEMICALS; COMPUTATIONAL TOXICOLOGY RESOURCE; QUANTITATIVE STRUCTURE-ACTIVITY; THROUGHPUT SCREENING ASSAYS; RELATIONSHIP QSDAR MODELS; ENVIRONMENTAL CHEMICALS; DECISION FOREST; PARTITION-COEFFICIENTS; BINARY CLASSIFICATION; BIOLOGICAL-ACTIVITY AB BACKGROUND: Humans are exposed to thousands of man-made chemicals in the environment. Some chemicals mimic natural endocrine hormones and, thus, have the potential to be endocrine disruptors. Most of these chemicals have never been tested for their ability to interact with the estrogen receptor (ER). Risk assessors need tools to prioritize chemicals for evaluation in costly in vivo tests, for instance, within the U.S. EPA Endocrine Disruptor Screening Program. OBJECTIVES: We describe a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity Prediction Project) and demonstrate the efficacy of using predictive computational models trained on high-throughput screening data to evaluate thousands of chemicals for ER-related activity and prioritize them for further testing. METHODS: CERAPP combined multiple models developed in collaboration with 17 groups in the United States and Europe to predict ER activity of a common set of 32,464 chemical structures. Quantitative structure-activity relationship models and docking approaches were employed, mostly using a common training set of 1,677 chemical structures provided by the U.S. EPA, to build a total of 40 categorical and 8 continuous models for binding, agonist, and antagonist ER activity. All predictions were evaluated on a set of 7,522 chemicals curated from the literature. To overcome the limitations of single models, a consensus was built by weighting models on scores based on their evaluated accuracies. RESULTS: Individual model scores ranged from 0.69 to 0.85, showing high prediction reliabilities. Out of the 32,464 chemicals, the consensus model predicted 4,001 chemicals (12.3%) as high priority actives and 6,742 potential actives (20.8%) to be considered for further testing. CONCLUSION: This project demonstrated the possibility to screen large libraries of chemicals using a consensus of different in silico approaches. This concept will be applied in future projects related to other end points. C1 [Mansouri, Kamel; Richard, Ann M.; Grulke, Christopher M.; Kancherla, Jayaram; Judson, Richard S.] US EPA, Natl Ctr Computat Toxicol, 109 TW Alexander Dr, Res Triangle Pk, NC 27711 USA. [Mansouri, Kamel] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. [Abdelaziz, Ahmed; Tetko, Igor V.] German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Muenchen, Inst Struct Biol, Neuherberg, Germany. [Rybacka, Aleksandra; Andersson, Patrik L.] Umea Univ, Dept Chem, Umea, Sweden. [Roncaglioni, Alessandra; Benfenati, Emilio; Incisivo, Giuseppina M.] Ist Ric Farmacol Mario Negri, IRCCS, Environm Chem & Toxicol Lab, Milan, Italy. [Tropsha, Alexander; Fourches, Denis; Muratov, Eugene; Politi, Regina; Farag, Sherif] Univ North Carolina Chapel Hill, Lab Mol Modeling, Chapel Hill, NC USA. [Varnek, Alexandre; Horvath, Dragos] Univ Strasbourg, Lab Chemoinformat, Strasbourg, France. [Zakharov, Alexey; Nicklaus, Marc] NCI, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Worth, Andrew; Burton, Julien] European Commiss Ispra, Joint Res Ctr, IHCP, Ispra, Italy. [Trisciuzzi, Daniela; Mangiatordi, Giuseppe F.; Nicolotti, Orazio] Univ Bari, Dept Pharmacy Drug Sci, Bari, Italy. [Wedebye, Eva Bay; Nikolov, Nikolai G.; Rosenberg, Sine A.] Tech Univ Denmark, Natl Food Inst, Div Toxicol & Risk Assessment, Copenhagen, Denmark. [Grisoni, Francesca; Cassotti, Matteo; Todeschini, Roberto] Univ Milano Bicocca, Milano Chemometr & QSAR Res Grp, Milan, Italy. [Hong, Huixiao; Ng, Hui W.] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, USDA, Jefferson, AZ USA. [Tetko, Igor V.] BigChem GmbH, Neuherberg, Germany. [Balabin, Ilya] Lockheed Martin, High Performance Comp, Res Triangle Pk, NC USA. [Shen, Jie] Res Inst Fragrance Mat Inc, Woodcliff Lake, NJ USA. [Zang, Qingda; Slavov, Svetoslav] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Beger, Richard D.] USDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AZ USA. [Huang, Ruili; Hu, Xin] NIH, Natl Ctr Adv Translat Sci, DHHS, Bldg 10, Bethesda, MD 20892 USA. RP Judson, RS (reprint author), US EPA, Natl Ctr Computat Toxicol, 109 TW Alexander Dr, Res Triangle Pk, NC 27711 USA. EM judson.richard@epa.gov RI Tetko, Igor/B-1540-2010; Varnek, Alexandre/E-7076-2017; Kancherla, Jayaram/P-7756-2015; OI Tetko, Igor/0000-0002-6855-0012; Varnek, Alexandre/0000-0003-1886-925X; Kancherla, Jayaram/0000-0001-5855-5031; Mansouri, Kamel/0000-0002-6426-8036 FU NIGMS NIH HHS [T32 GM067553] NR 101 TC 17 Z9 17 U1 14 U2 15 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2016 VL 124 IS 7 BP 1023 EP 1033 DI 10.1289/ehp.1510267 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DS4KF UT WOS:000380749300025 PM 26908244 ER PT J AU Hong, HX Harvey, BG Palmese, GR Stanzione, JF Ng, HW Sakkiah, S Tong, WD Sadler, JM AF Hong, Huixiao Harvey, Benjamin G. Palmese, Giuseppe R. Stanzione, Joseph F., III Ng, Hui Wen Sakkiah, Sugunadevi Tong, Weida Sadler, Joshua M. TI Experimental Data Extraction and in Silico Prediction of the Estrogenic Activity of Renewable Replacements for Bisphenol A SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE bio-based; BPA replacement; endocrine disruption ER ID ACTIVITY-RELATIONSHIP MODELS; STRUCTURE ELUCIDATION; EXPERT-SYSTEM; RECEPTOR BINDING; DECISION FOREST; THERMOSETTING RESINS; SUBSTRUCTURE CONSTRAINTS; CYTOCHROME-P450 CYP3A4; KNOWLEDGE-BASE; CHEMICALS AB Bisphenol A (BPA) is a ubiquitous compound used in polymer manufacturing for a wide array of applications; however, increasing evidence has shown that BPA causes significant endocrine disruption and this has raised public concerns over safety and exposure limits. The use of renewable materials as polymer feedstocks provides an opportunity to develop replacement compounds for BPA that are sustainable and exhibit unique properties due to their diverse structures. As new bio-based materials are developed and tested, it is important to consider the impacts of both monomers and polymers on human health. Molecular docking simulations using the Estrogenic Activity Database in conjunction with the decision forest were performed as part of a two-tier in silico model to predict the activity of 29 bio-based platform chemicals in the estrogen receptor-alpha (ER alpha). Fifteen of the candidates were predicted as ER binders and fifteen as non-binders. Gaining insight into the estrogenic activity of the bio-based BPA replacements aids in the sustainable development of new polymeric materials. C1 [Hong, Huixiao; Ng, Hui Wen; Sakkiah, Sugunadevi; Tong, Weida] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Harvey, Benjamin G.] Naval Air Warfare Ctr Weap Div, Res Dept, Div Chem, Ridgecrest, CA 93555 USA. [Palmese, Giuseppe R.] Drexel Univ, Dept Chem & Biol Engn, 3141 Chestnut St, Philadelphia, PA 19104 USA. [Stanzione, Joseph F., III] Rowan Univ, Dept Chem Engn, Glassboro, NJ 08028 USA. [Sadler, Joshua M.] RDRL WMM C, Army Res Lab, 4600 Deer Creek Loop, Aberdeen, MD 21005 USA. RP Hong, HX (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA.; Sadler, JM (reprint author), RDRL WMM C, Army Res Lab, 4600 Deer Creek Loop, Aberdeen, MD 21005 USA. EM huixiao.hong@fda.hhs.gov; benjamin.g.harvey@navy.mil; grp27@drexel.edu; stanzione@rowan.edu; ng.huiwen@yahoo.com; Suguna.Sakkiah@fda.hhs.gov; Weida.Tong@fda.hhs.gov; joshua.m.sadler4@mail.mil FU U.S. Department of Energy; U.S. Food and Drug Administration; U.S. Department of Defense [SERDP WP-2402, SERDP WP-2214]; Office of Naval Research; Army Research Laboratory [W911NF-14-2-0086]; Rowan University FX This research was supported in part by an appointment to the Research Participation Program at the National Center for Toxicological Research (Hui Wen Ng, Sugunadevi Sakkiah) 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. This research was supported by the U.S. Department of Defense, through the Strategic Environmental Research and Development Program (SERDP WP-2402, SERDP WP-2214), and the Office of Naval Research. Additionally, this research was support by the Army Research Laboratory through the Cooperative Agreement W911NF-14-2-0086 with Rowan University. NR 65 TC 3 Z9 3 U1 4 U2 6 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD JUL PY 2016 VL 13 IS 7 AR 705 DI 10.3390/ijerph13070705 PG 16 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DS4OG UT WOS:000380759800081 ER PT J AU Gallagher, D Pouillot, R Hoelzer, K Tang, J Dennis, SB Kause, JR AF Gallagher, Daniel Pouillot, Regis Hoelzer, Karin Tang, Jia Dennis, Sherri B. Kause, Janell R. TI Listeria monocytogenes in Retail Delicatessens: An Interagency Risk Assessment-Risk Mitigations SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Listeria monocytogenes; Retail; Risk assessment; Scenario analysis; Virtual retail deli ID COLD-SMOKED SALMON; TO-EAT FOODS; CROSS-CONTAMINATION; ASSESSMENT-MODEL; DELI MEATS; ESTABLISHMENTS; QUANTIFICATION; ENVIRONMENT; PREVALENCE; DIVERSITY AB Cross-contamination, improper holding temperatures, and insufficient sanitary practices are known retail practices that may lead to product contamination and growth of Listeria monocytogenes. However, the relative importance of control options to mitigate the risk of invasive listeriosis from ready-to-eat (RTE) products sliced or prepared at retail is not well understood. This study illustrates the utility of a quantitative risk assessment model described in a first article of this series (Pouillot, R., D. Gallagher, J. Tang, K. Hoelzer, J. Kause, and S. B. Dennis, J. Food Prot. 78: 134-145, 2015) to evaluate the public health impact associated with changes in retail deli practices and interventions. Twenty-two mitigation scenarios were modeled and evaluated under six different baseline conditions. These scenarios were related to sanitation, worker behavior, use of growth inhibitors, cross-contamination, storage temperature control, and reduction of the level of L. monocytogenes on incoming RTE food products. The mean risk per serving of RTE products obtained under these scenarios was then compared with the risk estimated in the baseline condition. Some risk mitigations had a consistent impact on the predicted listeriosis risk in all baseline conditions (e.g. presence or absence of growth inhibitor), whereas others were greatly dependent on the initial baseline conditions or practices in the deli (e.g. preslicing of products). Overall, the control of the bacterial growth and the control of contamination at its source were major factors of listeriosis risk in these settings. Although control of cross-contamination and continued sanitation were also important, the decrease in the predicted risk was not amenable to a simple solution. Findings from these predictive scenario analyses are intended to encourage improvements to retail food safety practices and mitigation strategies to control L. monocytogenes in RTE foods more effectively and to demonstrate the utility of quantitative risk assessment models to inform risk management decisions. C1 [Gallagher, Daniel; Tang, Jia] Virginia Polytech Inst & State Univ, Dept Civil & Environm Engn, 409 Durham Hall, Blacksburg, VA 24061 USA. [Pouillot, Regis; Hoelzer, Karin; Dennis, Sherri B.] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Kause, Janell R.] US Food Safety & Inspect Serv, Off Publ Hlth Sci, USDA, 1400 Independence Ave SW, Washington, DC 20250 USA. [Hoelzer, Karin] Pew Charitable Trusts, 901 E St NW, Washington, DC 20004 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; USDA-FSIS [AG-3A94-P-08-0166] FX Support for this work was provided by Virginia Tech in collaboration with the USDA-FSIS (contract AG-3A94-P-08-0166). This work was also supported 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 USDA. NR 35 TC 1 Z9 1 U1 6 U2 7 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD JUL PY 2016 VL 79 IS 7 BP 1076 EP 1088 DI 10.4315/0362-028X.JFP-15-336 PG 13 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA DU0PU UT WOS:000381907800001 PM 27357026 ER PT J AU Trucksess, MW Zhang, K AF Trucksess, Mary W. Zhang, Kai TI Cutting-Edge Techniques for Mycotoxin Analysis SO JOURNAL OF AOAC INTERNATIONAL LA English DT Editorial Material C1 [Trucksess, Mary W.] Univ Maryland, Int Food Safety Training Lab, College Pk, MD 20742 USA. [Zhang, Kai] US FDA, College Pk, MD USA. RP Trucksess, MW (reprint author), Univ Maryland, Int Food Safety Training Lab, College Pk, MD 20742 USA. NR 1 TC 0 Z9 0 U1 1 U2 1 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 JUL-AUG PY 2016 VL 99 IS 4 BP 835 EP 836 DI 10.5740/jaoacint.16-0109 PG 2 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA DS1TZ UT WOS:000380384900001 PM 27197094 ER PT J AU Zhang, K Wong, JW Krynitsky, AJ Trucksess, MW AF Zhang, Kai Wong, Jon W. Krynitsky, Alexander J. Trucksess, Mary W. TI Perspective on Advancing FDA Regulatory Monitoring for Mycotoxins in Foods using Liquid Chromatography and Mass Spectrometry (Review) SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID FINISHED GRAIN; AFLATOXINS; PRODUCTS; DEOXYNIVALENOL; METABOLITES; SUPPLEMENTS; OCHRATOXIN; ANALYTES; CLEANUP; PATULIN AB The presence of mycotoxins (such as aflatoxins, deoxynivalenol, fumonisins, and patulin) is routinely monitored by the U.S. Food and Drug Administration (FDA) to ensure that their concentrations in food are below the levels requiring regulatory action or advisories. To improve the efficiency of mycotoxin analysis, the researchers at the FDA's Center for Food Safety and Applied Nutrition have been evaluating modern LC-MS technologies. Consequently, a variety of LC tandem MS and LC high-resolution MS methods have been developed, which simultaneously identify and quantitate multiple mycotoxins in foods and feeds. Although matrix effects (matrix-induced ion suppression or enhancement) associated with LC-MS-based mycotoxin analysis remain, this review discusses methods for managing these effects and proposes practical solutions for the future implementation of LC-MS-based multimycotoxin analysis. C1 [Zhang, Kai; Wong, Jon W.; Krynitsky, Alexander J.; Trucksess, Mary W.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. RP Zhang, K (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM kai.zhang@fda.hhs.gov NR 39 TC 1 Z9 1 U1 8 U2 11 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 JUL-AUG PY 2016 VL 99 IS 4 BP 890 EP 894 DI 10.5740/jaoacint.16-0116 PG 5 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA DS1TZ UT WOS:000380384900008 PM 27330044 ER PT J AU Wilson, P Masse, C AF Wilson, Phyllis Masse, Claude TI Detection of Synthetic rugs as Adulterants in Natural and Herbal Slimming Products by LC-ESI-MS/MS with Polarity Switching SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID WEIGHT-LOSS PRODUCTS; DIETARY-SUPPLEMENTS; MS; HPLC; IDENTIFICATION; SIBUTRAMINE AB The purpose of this study was to develop an LC-tandem MS method for the simultaneous detection of common synthetic drugs as adulterants in natural and herbal slimming products. Sixteen drugs belonging to a wide range of pharmaceutical classes were studied. Included in the list of drugs were anorexics, anxiolytics, antidepressants, diuretics, laxatives, and stimulants. The method used a C18 column (4.6 x 50 mm and 1.8 pm particle size). Separation of the drugs was achieved by gradient elution using 4 mM ammonium formate in water + 0.1% formic acid as the aqueous component and 4 mM ammonium formate in methanol + 0.1% formic as the organic component of the mobile phase. As not all of the analytes ionized in the positive mode, the mass spectrometer was operated in the electrospray ionization mode with polarity switching. The samples were extracted with methanol and the use of 50% acetonitrile in water and 50% methanol in water were investigated as diluents for injection into the LC-MS system. Utilizing both diluents, the validation parameters including accuracy, precision, LOD, and LOQ were assessed. The validation results and utilization of the method to analyze a variety of weight-loss supplements indicate that the two diluents give similar results and can be used interchangeably. This knowledge provides the user with the option of selecting either diluent for sample preparation depending on the sample matrix without having to revalidate the method. The method was applied to the analysis of weight-loss supplements available in local pharmacies, herbal pharmacies, and over the Internet. C1 [Wilson, Phyllis; Masse, Claude] US Dept HHS, US FDA, Northeast Reg Lab, Jamaica, NY 11433 USA. RP Wilson, P (reprint author), US Dept HHS, US FDA, Northeast Reg Lab, Jamaica, NY 11433 USA. EM phyllis.wilson@fda.hhs.gov FU FDA's Office of Women's Health; Oak Ridge Institute for Science and Education (ORISE) Research Participation Program at the Center for Drug Evaluation and Research (CDER), FDA FX This work was supported by the FDA's Office of Women's Health. The project was supported in part by an appointment to the Oak Ridge Institute for Science and Education (ORISE) Research Participation Program at the Center for Drug Evaluation and Research (CDER), FDA, administered by ORISE through an interagency agreement between the U.S. Department of Energy and the FDA/CDER. NR 27 TC 0 Z9 0 U1 4 U2 4 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 JUL-AUG PY 2016 VL 99 IS 4 BP 929 EP 940 DI 10.5740/jaoacint.15-0295 PG 12 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA DS1TZ UT WOS:000380384900014 PM 27143234 ER PT J AU Korchinski, KL Land, AD Craft, DL Brzezinski, JL AF Korchinski, Katie L. Land, Adrian D. Craft, David L. Brzezinski, Jennifer L. TI Detection of Nicotiana DNA in Tobacco Products Using a Novel Multiplex Real-Time PCR Assay SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID POLYMERASE; SOLANACEAE AB Establishing that a product contains tobacco is a requirement for the U.S. Food and Drug Administration's regulation and/or prosecution of tobacco products. Therefore, a multiplex real-time PCR method was designed to determine if Nicotiana (tobacco) DNA is present in tobacco products. The PCR method simultaneously amplifies a 73 bp fragment of the cytochrome P450 monoxygenase CYP82E4 gene and 66 bp fragment in the nia-1 gene for nitrate reductase, which are detected using dual-labeled TaqMan probes. The assay is capable of detecting approximately 7.8 pg purified tobacco DNA, with a similar sensitivity for either gene target while incorporating an internal positive control (IPC). DNA was extracted from prepared tobacco products including chewing tobacco, pipe tobacco, and snuff or from the cut fill (no wrapper) of cigarettes and cigars. Of the 13 products analyzed, 12 were positive for both tobacco-specific markers and the IPC. DNA was also extracted from the fill of five varieties of herbal cigarettes, which were negative for both tobacco-specific gene targets and positive for the IPC. Our method expands on current assays by introducing a multiplex reaction, targeting two sequences in two different genes of interest, incorporating an IPC into the reaction, and lowering the LOD and LOQ while increasing the efficiency of the PCR. C1 [Korchinski, Katie L.; Land, Adrian D.; Craft, David L.; Brzezinski, Jennifer L.] US FDA, Forens Chem Ctr, 6751 Steger Dr, Cincinnati, OH 45237 USA. RP Korchinski, KL (reprint author), US FDA, Forens Chem Ctr, 6751 Steger Dr, Cincinnati, OH 45237 USA.; Korchinski, KL (reprint author), US FDA, Denver Lab, 6th & Kipling St,Bldg 20,POB 25087, Denver, CO 80025 USA. EM katie.korchinski@fda.hhs.gov NR 17 TC 0 Z9 0 U1 3 U2 3 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 EI 1944-7922 J9 J AOAC INT JI J. AOAC Int. PD JUL-AUG PY 2016 VL 99 IS 4 BP 1038 EP 1042 DI 10.5740/jaoacint.16-0008 PG 5 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA DS1TZ UT WOS:000380384900025 PM 27143320 ER PT J AU Dugard, CK Mertz, RA Rayon, C Mercadante, D Hart, C Benatti, MR Olek, AT SanMiguel, PJ Cooper, BR Reiter, WD McCann, MC Carpita, NC AF Dugard, Christopher K. Mertz, Rachel A. Rayon, Catherine Mercadante, Davide Hart, Christopher Benatti, Matheus R. Olek, Anna T. SanMiguel, Phillip J. Cooper, Bruce R. Reiter, Wolf-Dieter McCann, Maureen C. Carpita, Nicholas C. TI The Cell Wall Arabinose-Deficient Arabidopsis thaliana Mutant murus5 Encodes a Defective Allele of REVERSIBLY GLYCOSYLATED POLYPEPTIDE2 SO PLANT PHYSIOLOGY LA English DT Article ID REVERSIBLY GLYCOSYLATED POLYPEPTIDE; HYDROPHOBIC CLUSTER-ANALYSIS; UDP-GALACTOPYRANOSE MUTASE; MUTATION IDENTIFICATION; PLANT DEVELOPMENT; COMPLEX-FORMATION; PROTEIN; GENE; ARABINOFURANOSE; ARABINOPYRANOSE AB Traditional marker-based mapping and next-generation sequencing was used to determine that the Arabidopsis (Arabidopsis thaliana) low cell wall arabinose mutant murus5 (mur5) encodes a defective allele of REVERSIBLY GLYCOSYLATED POLYPEPTIDE2 (RGP2). Marker analysis of 13 F2 confirmed mutant progeny from a recombinant mapping population gave a rough map position on the upper arm of chromosome 5, and deep sequencing of DNA from these 13 lines gave five candidate genes with G -> A (C -> T) transitions predicted to result in amino acid changes. Of these five, only insertional mutant alleles of RGP2, a gene that encodes a UDP-arabinose mutase that interconverts UDP-arabinopyranose and UDP-arabinofuranose, exhibited the low cell wall arabinose phenotype. The identities of mur5 and two SALK insertional alleles were confirmed by allelism tests and overexpression of wild-type RGP2 complementary DNA placed under the control of the 35S promoter in the three alleles. The mur5 mutation results in the conversion of cysteine-257 to tyrosine-257 within a conserved hydrophobic cluster predicted to be distal to the active site and essential for protein stability and possible heterodimerization with other isoforms of RGP. C1 [Dugard, Christopher K.; Mertz, Rachel A.; Olek, Anna T.; Carpita, Nicholas C.] Purdue Univ, Dept Bot & Plant Pathol, W Lafayette, IN 47907 USA. [Benatti, Matheus R.; McCann, Maureen C.; Carpita, Nicholas C.] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Cooper, Bruce R.; McCann, Maureen C.; Carpita, Nicholas C.] Purdue Univ, Bindley Biosci Ctr, W Lafayette, IN 47907 USA. [SanMiguel, Phillip J.] Purdue Univ, Dept Hort & Landscape Architecture, W Lafayette, IN 47907 USA. [Rayon, Catherine] Univ Picardie Jules Verne, EA BIOPI 3900, F-80039 Amiens, France. [Mercadante, Davide] Heidelberg Inst Theoret Studien, Mol Biomech, D-69118 Heidelberg, Germany. [Hart, Christopher; Reiter, Wolf-Dieter] Univ Connecticut, Dept Mol & Cell Biol, Storrs, CT 06269 USA. [Dugard, Christopher K.] US FDA, White Oak Campus,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Mertz, Rachel A.] Univ Missouri, Div Biol Sci, 308 Tucker Hall, Columbia, MO 65211 USA. [Hart, Christopher] CRISPR Therapeut, 200 Sidney St,Suite 340, Cambridge, MA 02139 USA. RP Carpita, NC (reprint author), Purdue Univ, Dept Bot & Plant Pathol, W Lafayette, IN 47907 USA.; Carpita, NC (reprint author), Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA.; Carpita, NC (reprint author), Purdue Univ, Bindley Biosci Ctr, W Lafayette, IN 47907 USA. EM carpita@purdue.edu FU National Science Foundation Emerging Frontiers in Research and Innovation HyBi program [0938033]; Center for Direct Catalytic Conversion of Bio-mass to Biofuels, an Energy Frontier Research Center - U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-SC0000997]; Division of Chemical Sciences, Geosciences, and Biosciences, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-FG02-08ER20203] FX This work was supported by the National Science Foundation Emerging Frontiers in Research and Innovation HyBi program (grant no. 0938033), by the Center for Direct Catalytic Conversion of Bio-mass to Biofuels, an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences (grant no. DE-SC0000997), and by the Division of Chemical Sciences, Geosciences, and Biosciences, Office of Basic Energy Sciences, of the U.S. Department of Energy (grant no. DE-FG02-08ER20203 to W.-D.R.). NR 56 TC 0 Z9 0 U1 5 U2 5 PU AMER SOC PLANT BIOLOGISTS PI ROCKVILLE PA 15501 MONONA DRIVE, ROCKVILLE, MD 20855 USA SN 0032-0889 EI 1532-2548 J9 PLANT PHYSIOL JI Plant Physiol. PD JUL PY 2016 VL 171 IS 3 BP 1905 EP 1920 DI 10.1104/pp.15.01922 PG 16 WC Plant Sciences SC Plant Sciences GA DT2IF UT WOS:000381303300033 PM 27217494 ER EF