FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Jacobson, AP Wang, H Gill, VS Duvall, R Arce, G Chirtel, S Hammack, TS AF Jacobson, Andrew P. Wang, Hua Gill, Vikas S. Duvall, Robert Arce, Gabriela Chirtel, Stuart Hammack, Thomas S. TI Relative effectiveness of selected preenrichment media for the detection of Salmonella from leafy green produce and herbs SO FOOD MICROBIOLOGY LA English DT Article ID ESCHERICHIA-COLI O157-H7; FRESH PRODUCE; UNITED-STATES; FOODBORNE OUTBREAKS; MICROBIOLOGICAL QUALITY; MICROBIAL SAFETY; VEGETABLES; ENRICHMENT; RECOVERY; PROTEIN AB Four buffered preenrichment media (BAX (R) System MP Media (BAX)), Universal Preenrichment Broth (UPB), modified Buffered Peptone Water (mBPW), and Buffered Peptone Water (BPW)) were compared with lactose broth (LB) in the Bacteriological Analytical Manual's (BAM) Salmonella culture method for the analysis of 9 leafy green produce and herb types. Artificially contaminated test portions were pre-enriched in each medium and the results were analyzed statistically using Fisher's Exact 2-tailed F test (p < 0.05) with pairwise comparisons. There was no difference in recovery of Salmonella from curly parsley and basil among the five media (p > 0.05). UPB was consistently among the most effective media for recovery of Salmonella from the nine produce types; however, S. Typhimurium and S. Newport were isolated from cabbage more frequently with mBPW than with UPB (p < 0.05). Comparisons of the results among the preenrichment media from all experimental trials, with leafy green produce and herbs, demonstrate that Salmonella is more effectively detected and isolated using buffered enrichments than with the currently recommended LB (p < 0.05). There were no significant differences among the buffered preenrichments for the detection of Salmonella-positive test portions of the produce tested (BAX (160 Salmonella-positive test portions/480 test portions), UPB (176/480), mBPW (184/480), BPW (169/480), LB (128/480))(p > 0.05). Published by Elsevier Ltd. C1 [Jacobson, Andrew P.; Wang, Hua; Gill, Vikas S.; Duvall, Robert; Arce, Gabriela; Chirtel, Stuart; Hammack, Thomas S.] US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr, College Pk, MD 20740 USA. [Gill, Vikas S.] Touro Univ Calif, Coll Educ & Hlth Sci, Publ Hlth Program, Vallejo, CA USA. [Arce, Gabriela] Duke Univ, Durham, NC USA. RP Hammack, TS (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr, College Pk, MD 20740 USA.; Jacobson, AP (reprint author), US FDA, Microbial Methods Dev Branch, Div Microbiol, Off Regulatory Sci,Ctr Food Safety & Appl Nutr, 5001 Campus Dr,HFS 711, College Pk, MD 20740 USA. EM Andrew.Jacobson@fda.hhs.gov; VikasGill@gmail.com; gca6@dulce.ed NR 51 TC 0 Z9 0 U1 22 U2 22 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 MAY PY 2017 VL 63 BP 123 EP 128 DI 10.1016/j.fm.2016.11.006 PG 6 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA EI2YH UT WOS:000392355500015 PM 28040159 ER PT J AU Persoskie, A Nguyen, AB Kaufman, AR Tworek, C AF Persoskie, Alexander Nguyen, Anh B. Kaufman, Annette R. Tworek, Cindy TI Criterion validity of measures of perceived relative harm of e-cigarettes and smokeless tobacco compared to cigarettes SO ADDICTIVE BEHAVIORS LA English DT Article DE Perceived harm; Measures; Validity; Tobacco; Electronic cigarettes; Smokeless tobacco ID RISK PERCEPTIONS; CONSTRUCT-VALIDITY; LIGHT CIGARETTES; UNITED-STATES; HEALTH-RISKS; SMOKING; SMOKERS; AWARENESS; ADULTS; HARMFULNESS AB Beliefs about the relative harmfulness of one product compared to another (perceived relative harm) are central to research and regulation concerning tobacco and nicotine-containing products, but techniques for measuring such beliefs vary widely. We compared the validity of direct and indirect measures of perceived harm of e-cigarettes and smokeless tobacco (SLT) compared to cigarettes. On direct measures, participants explicitly compare the harmfulness of each product. On indirect measures, participants rate the harmfulness of each product separately, and ratings are compared. The U.S. Health Information National Trehds Survey (HINTS-FDA-2015; N = 3738) included direct measures of perceived harm of e-cigarettes and SLT compared to cigarettes. Indirect measures were created by comparing ratings of harm from e-cigarettes, SLT, and cigarettes on 3-point scales. Logistic regressions tested validity by assessing whether direct and indirect measures were associated with criterion variables including: ever-trying e-cigarettes, ever-trying snus, and SLT use status. Compared to the indirect measures, the direct measures of harm were more consistently associated with criterion variables. On direct measures, 26% of adults rated e -cigarettes as less harmful than cigarettes, and 11% rated SLT as less harmful than cigarettes. Direct measures appear to provide valid information about individuals' harm beliefs, which may be used to inform research and tobacco control policy. Further validation research is encouraged. Published by Elsevier Ltd. C1 [Persoskie, Alexander; Nguyen, Anh B.; Tworek, Cindy] US FDA, Off Sci, Ctr Tobacco Prod, Silver Spring, MD USA. [Kaufman, Annette R.] NCI, Tobacco Control Res Branch, Rockville, MD 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 U.S. Food and Drug Administration; Center for Tobacco Products; U.S. National Cancer Institute, National Institutes of Health FX Publication of this article was supported by the U.S. Food and Drug Administration, Center for Tobacco Products, and the U.S. National Cancer Institute, National Institutes of Health. No funding was provided specifically for conducting the analysis, drafting the manuscript, or submitting this paper for publication. NR 41 TC 0 Z9 0 U1 4 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD APR PY 2017 VL 67 BP 100 EP 105 DI 10.1016/j.addbeh.2017.01.001 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA EJ1XP UT WOS:000393004200017 PM 28073035 ER PT J AU Ge, BL Mukherjee, S Hsu, CH Davis, JA Tran, TTT Yang, Q Abbott, JW Ayers, SL Young, SR Crarey, ET Womack, NA Zhao, SH McDermott, PF AF Ge, Beilei Mukherjee, Sampa Hsu, Chih-Hao Davis, Johnnie A. Tran, Thu Thuy T. Yang, Qianru Abbott, Jason W. Ayers, Sherry L. Young, Shenia R. Crarey, Emily T. Womack, Niketta A. Zhao, Shaohua McDermott, Patrick F. TI MRSA and multidrug-resistant Staphylococcus aureus in US retail meats, 2010-2011 SO FOOD MICROBIOLOGY LA English DT Article DE MRSA; LA-MRSA; ST398; USA300; MDRSA; Retail meat ID ANTIMICROBIAL SUSCEPTIBILITY; MOLECULAR CHARACTERIZATION; ANTIBIOTIC-RESISTANCE; PREVALENCE; STRAINS; CHICKEN; ORIGIN; ST398; PORK; WORKERS AB Methicillin-resistant Staphylococcus aureus (MRSA) has been detected in retail meats, although large-scale studies are scarce. We conducted a one-year survey in 2010-2011 within the framework of the National Antimicrobial Resistance Monitoring System. Among 3520 retail meats collected from eight U.S. states, 982 (27.9%) contained S. aureus and 66 (1.9%) were positive for MRSA. Approximately 10.4% (107/1032) of S. aureus isolates, including 37.2% (29/78) of MRSA, were multidrug-resistant (MDRSA). Turkey had the highest MRSA prevalence (3.5%), followed by pork (1.9%), beef (1.7%), and chicken (0.3%). Whole-genome sequencing was performed for all 66 non-redundant MRSA. Among five multilocus sequence types identified, ST8 (72.7%) and ST5 (22.7%) were most common and livestock-associated MRSA ST398 was assigned to one pork isolate. Eleven spa types were represented, predominately t008 (43.9%) and t2031 (22.7%). All four types of meats harbored t008, whereas t2031 was recovered from turkey only. The majority of MRSA (84.8%) possessed SCCmec IV and 62.1% harbored Panton-Valentine leukocidin. Pulsed field gel electrophoresis showed that all ST8 MRSA belonged to the predominant human epidemic clone USA300, and others included USA100 and USA200. We conclude that a diverse MRSA population was present in U.S. retail meats, albeit at low prevalence. Published by Elsevier Ltd. C1 [Ge, Beilei; Mukherjee, Sampa; Hsu, Chih-Hao; Davis, Johnnie A.; Tran, Thu Thuy T.; Yang, Qianru; Abbott, Jason W.; Ayers, Sherry L.; Young, Shenia R.; Crarey, Emily T.; Womack, Niketta A.; Zhao, Shaohua; McDermott, Patrick F.] US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, 8401 Muirkirk Rd, Laurel, MD 20708 USA. [Davis, Johnnie A.] Procter & Gamble Co, Mason, OH 45040 USA. [Womack, Niketta A.] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. RP Ge, BL (reprint author), US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM beilei.ge@fda.hhs.gov NR 44 TC 0 Z9 0 U1 68 U2 68 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 APR PY 2017 VL 62 BP 289 EP 297 DI 10.1016/j.fm.2016.10.029 PG 9 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA EF7HE UT WOS:000390499900039 PM 27889161 ER PT J AU Miranda, S Reid, DK John, CS AF Miranda, Sabina Reid, Derrece K. John, Christy S. TI Myasthenia Gravis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID MUSK; AUTOANTIBODIES C1 [Miranda, Sabina] El Paso Vet Affairs Hlth Care Syst, El Paso, TX 79930 USA. [Reid, Derrece K.] Albany Med Ctr, Albany, NY USA. [John, Christy S.] US FDA, Silver Spring, MD USA. RP Miranda, S (reprint author), El Paso Vet Affairs Hlth Care Syst, El Paso, TX 79930 USA. EM sabina.miranda@va.gov NR 3 TC 0 Z9 0 U1 0 U2 0 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 MAR 30 PY 2017 VL 376 IS 13 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EP8KS UT WOS:000397624900030 ER PT J AU Bertagnolli, MM Sartor, O Chabner, BA Rothenberg, ML Khozin, S Hugh-Jones, C Reese, DM Murphy, MJ AF Bertagnolli, Monica M. Sartor, Oliver Chabner, Bruce A. Rothenberg, Mace L. Khozin, Sean Hugh-Jones, Charles Reese, David M. Murphy, Martin J. TI Advantages of a Truly Open-Access Data-Sharing Model SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID PROSTATE-CANCER C1 [Bertagnolli, Monica M.] Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. [Chabner, Bruce A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Sartor, Oliver] Tulane Med Sch, New Orleans, LA USA. [Rothenberg, Mace L.] Pfizer, New York, NY USA. [Hugh-Jones, Charles] Carmine Res, New York, NY USA. [Khozin, Sean] US FDA, Silver Spring, MD USA. [Reese, David M.] Amgen Inc, Thousand Oaks, CA USA. [Murphy, Martin J.] Project Data Sphere, Cary, NC USA. RP Bertagnolli, MM (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 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 MAR 23 PY 2017 VL 376 IS 12 BP 1178 EP 1181 DI 10.1056/NEJMsb1702054 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA EO9NB UT WOS:000397014300018 PM 28328337 ER PT J AU Gulley, JL Berzofsky, JA Butler, MO Cesano, A Fox, BA Gnjatic, S Janetzki, S Kalavar, S Karanikas, V Khleif, SN Kirsch, I Lee, PP Maccalli, C Maecker, H Schlom, J Seliger, B Siebert, J Stroncek, DF Thurin, M Yuan, JD Butterfield, LH AF Gulley, James L. Berzofsky, Jay A. Butler, Marcus O. Cesano, Alessandra Fox, Bernard A. Gnjatic, Sacha Janetzki, Sylvia Kalavar, Shyam Karanikas, Vaios Khleif, Samir N. Kirsch, Ilan Lee, Peter P. Maccalli, Cristina Maecker, Holden Schlom, Jeffrey Seliger, Barbara Siebert, Janet Stroncek, David F. Thurin, Magdalena Yuan, Jianda Butterfield, Lisa H. TI Immunotherapy biomarkers 2016: overcoming the barriers SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE Biomarkers; Immunotherapy; Immune monitoring; High throughput; Baseline measures; Tumor microenvironment ID MONITORING TECHNOLOGY PRIMER; T-CELL RESPONSES; ADVANCED MELANOMA PATIENTS; CHIMERIC ANTIGEN RECEPTOR; PD-1 BLOCKADE; LUNG-CANCER; IMMUNE CONTEXTURE; PERIPHERAL-BLOOD; PREDICT RESPONSE; DRUG DEVELOPMENT AB This report summarizes the symposium, 'Immunotherapy Biomarkers 2016: Overcoming the Barriers', which was held on April 1, 2016 at the National Institutes of Health in Bethesda, Maryland. The symposium, cosponsored by the Society for Immunotherapy of Cancer (SITC) and the National Cancer Institute (NCI), focused on emerging immunotherapy biomarkers, new technologies, current hurdles to further progress, and recommendations for advancing the field of biomarker development. C1 [Gulley, James L.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, 10 Ctr Dr,13 N240, Bethesda, MD 20892 USA. [Berzofsky, Jay A.] Ctr Canc Res, Vaccine Branch, 41 Medlars Dr,Bldg 41 Rm D702D, Bethesda, MD 20892 USA. [Butler, Marcus O.] Princess Margaret Canc Ctr, Ontario Canc Inst, RM 9-622,610 Univ Ave, Toronto, ON, Canada. [Cesano, Alessandra] NanoString Inc, 500 Fairview Ave North, Seattle, WA 98109 USA. [Fox, Bernard A.] Providence Canc Ctr, Earle A Chiles Res Inst, 4805 NE Glisan St, Portland, OR 97213 USA. [Gnjatic, Sacha] Icahn Sch Med Mt Sinai, Dept Hematol Oncol, Tisch Canc Inst, S5-105,1470 Madison Ave,Box 1128, New York, NY 10029 USA. [Janetzki, Sylvia] ZellNet Consulting Inc, 555 North Ave, Ft Lee, NJ 07024 USA. [Kalavar, Shyam] US FDA, Ctr Devices & Radiol Hlth, 1401 Rockville Pike, Rockville, MD 20852 USA. [Karanikas, Vaios] Roche Innovat Ctr Zurich, Wagistr 18, Schlieren, Switzerland. [Khleif, Samir N.] Augusta Univ, Georgia Canc Ctr, 1120 15th St,CN-2101A, Augusta, GA 30912 USA. [Kirsch, Ilan] Adapt Biotechnol Inc, 1551 Eastlake Ave E, Seattle, WA 98102 USA. [Lee, Peter P.] City Hope Natl Med Ctr, Dept Immunooncol, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Maccalli, Cristina] Sidra Med & Res Ctr, Dept Translat Med, Doha, Qatar. [Maecker, Holden] Stanford Univ, Med Ctr, 299 Campus Dr, Stanford, CA 94303 USA. [Schlom, Jeffrey] NCI, NIH, 10 Ctr Dr,Bldg 10,Room 8B09, Bethesda, MD 20892 USA. [Seliger, Barbara] Martin Luther Univ Halle Wittenberg, Inst Med Immunol, Magdeburger Str 2, Halle, Germany. [Siebert, Janet] CytoAnalytics, 3500 South Alb St, Cherry Hills Village, CO 80113 USA. [Stroncek, David F.] NIH, Dept Transfus Med, 10 Ctr Dr,Bldg 10,Room 3C720, Bethesda, MD 20892 USA. [Thurin, Magdalena] NCI, Canc Diag Program, DCTD, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Yuan, Jianda] Merck Res Labs, Early Clin Oncol Dev, Rahway, NJ 07065 USA. [Butterfield, Lisa H.] Univ Pittsburgh, Inst Canc, Dept Med Surg & Immunol, 5117 Ctr Ave, Pittsburgh, PA 15213 USA. RP Butterfield, LH (reprint author), Univ Pittsburgh, Inst Canc, Dept Med Surg & Immunol, 5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM butterfieldl@upmc.edu NR 75 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD MAR 21 PY 2017 VL 5 AR 29 DI 10.1186/s40425-017-0225-6 PG 10 WC Oncology SC Oncology GA EO8CT UT WOS:000396917300002 ER PT J AU Thomas, JT Dollins, DE Andrykovich, KR Chu, T Stultz, BG Hursh, DA Moos, M AF Thomas, J. Terrig Dollins, D. Eric Andrykovich, Kristin R. Chu, Tehyen Stultz, Brian G. Hursh, Deborah A. Moos, Malcolm TI SMOC can act as both an antagonist and an expander of BMP signaling SO ELIFE LA English DT Article ID HEPARAN-SULFATE PROTEOGLYCANS; DPP MORPHOGEN GRADIENT; EMBRYONIC-DEVELOPMENT; SPEMANN ORGANIZER; XENOPUS EMBRYOS; PROTEIN; DROSOPHILA; DIFFERENTIATION; SUPERFAMILY; BINDING AB The matricellular protein SMOC (Secreted Modular Calcium binding protein) is conserved phylogenetically from vertebrates to arthropods. We showed previously that SMOC inhibits bone morphogenetic protein (BMP) signaling downstream of its receptor via activation of mitogen-activated protein kinase (MAPK) signaling. In contrast, the most prominent effect of the Drosophila orthologue, pentagone (pent), is expanding the range of BMP signaling during wing patterning. Using SMOC deletion constructs we found that SMOC-Delta EC, lacking the extracellular calcium binding (EC) domain, inhibited BMP2 signaling, whereas SMOC-EC (EC domain only) enhanced BMP2 signaling. The SMOC-EC domain bound HSPGs with a similar affinity to BMP2 and could expand the range of BMP signaling in an in vitro assay by competition for HSPG-binding. Together with data from studies in vivo we propose a model to explain how these two activities contribute to the function of Pent in Drosophila wing development and SMOC in mammalian joint formation. C1 [Thomas, J. Terrig; Dollins, D. Eric; Andrykovich, Kristin R.; Chu, Tehyen; Stultz, Brian G.; Hursh, Deborah A.; Moos, Malcolm] US FDA, Off Tissues & Adv Therapies, Div Cellular & Gene Therapies, Silver Spring, MD 20993 USA. RP Thomas, JT (reprint author), US FDA, Off Tissues & Adv Therapies, Div Cellular & Gene Therapies, Silver Spring, MD 20993 USA. EM thomas@fda.hhs.gov FU U.S. Department of Health and Human Services FX U.S. Department of Health and Human Services J Terrig Thomas Brian G Stultz Deborah A Hursh Malcolm Moos; FDA Commissioner's Fellowship Program Tehyen Chu NR 66 TC 0 Z9 0 U1 0 U2 0 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 21 PY 2017 VL 6 AR e17935 DI 10.7554/eLife.17935 PG 22 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EP8OT UT WOS:000397635400001 ER PT J AU Mauri, L Boccardi, G Torri, G Karfunkle, M Macchi, E Muzi, L Keire, D Guerrini, M AF Mauri, Lucio Boccardi, Giovanni Torri, Giangiacomo Karfunkle, Michael Macchi, Eleonora Muzi, Laura Keire, David Guerrini, Marco TI Qualification of HSQC methods for quantitative composition of heparin and low molecular weight heparins SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Heparin; Low molecular weight heparins; Quantitative NMR; Heteronuclear Single Quantum Correlation (HSQC); Robustness; Method qualification ID MAGNETIC-RESONANCE-SPECTROSCOPY; NMR-SPECTROSCOPY; DIFFERENTIATION; PRODUCTS; PATTERNS AB An NMR HSQC method has recently been proposed for the quantitative determination of the mono- and disaccharide subunits of heparin and low molecular weight heparins (LMWH). The focus of the current study was the validation of this procedure to make the 2D-NMR method suitable for pharmaceutical quality control applications. Pre-validation work investigated the effects of several experimental parameters to assess robustness and to optimize critical factors. Important experimental parameters were pulse sequence selection, equilibration interval between pulse trains and temperature. These observations were needed so that the NMR method was sufficiently understood to enable continuous improvement. A standard validation study on heparin then examined linearity, repeatability, intermediate precision and limits of detection and quantitation; selected validation parameters were also determined for LMWH. (C) 2017 Elsevier B.V. All rights reserved. C1 [Mauri, Lucio; Boccardi, Giovanni; Torri, Giangiacomo; Macchi, Eleonora; Muzi, Laura; Guerrini, Marco] Inst Chem & Biochem Res G Ronzoni, Via G Colombo 81, I-20133 Milan, Italy. [Karfunkle, Michael; Keire, David] US FDA, Div Pharmaceut Anal, Off Testing & Res, Ctr Drug Evaluat & Res, 645 S Newstead Ave, St Louis, MO 63110 USA. RP Guerrini, M (reprint author), Inst Chem & Biochem Res G Ronzoni, Via G Colombo 81, I-20133 Milan, Italy.; Keire, D (reprint author), US FDA, Div Pharmaceut Anal, Off Testing & Res, Ctr Drug Evaluat & Res, 645 S Newstead Ave, St Louis, MO 63110 USA. EM David.Keire@fda.hhs.gov; guerrini@ronzoni.it NR 41 TC 0 Z9 0 U1 5 U2 5 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 MAR 20 PY 2017 VL 136 BP 92 EP 105 DI 10.1016/j.jpba.2016.12.031 PG 14 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA EJ9IR UT WOS:000393540300011 PM 28068519 ER PT J AU Navin, CV Tondepu, C Toth, R Lawson, LS Rodriguez, JD AF Navin, Chelliah V. Tondepu, Chaitanya Toth, Roxana Lawson, Latevi S. Rodriguez, Jason D. TI Quantitative determinations using portable Raman spectroscopy SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article ID CHEMOMETRICS AB A portable Raman spectrometer was used to develop chemometric models to determine percent (%) drug release and potency for 500 mg ciprofloxacin HCl tablets. Parallel dissolution and chromatographic experiments were conducted alongside Raman experiments to assess and compare the performance and capabilities of portable Raman instruments in determining critical drug attributes. All batches tested passed the 30 min dissolution specification and the Raman model for drug release was able to essentially reproduce the dissolution profiles obtained by ultraviolet spectroscopy at 276 nm for all five batches of the 500 mg ciprofloxacin tablets. The five batches of 500 mg ciprofloxacin tablets also passed the potency (assay) specification and the % label claim for the entire set of tablets run were nearly identical, 99.4 +/- 5.1 for the portable Raman method and 99.2 +/- 1.2 for the chromatographic method. The results indicate that portable Raman spectrometers can be used to perform quantitative analysis of critical product attributes of finished drug products. The findings of this study indicate that portable Raman may have applications in the areas of process analytical technology and rapid pharmaceutical surveillance. Published by Elsevier B.V. C1 [Navin, Chelliah V.; Tondepu, Chaitanya; Toth, Roxana; Lawson, Latevi S.; Rodriguez, Jason D.] US FDA, Div Pharmaceut Anal, Ctr Drug Evaluat & Res, 645 S Newstead Ave, St Louis, MO 63110 USA. RP Rodriguez, JD (reprint author), US FDA, Div Pharmaceut Anal, Ctr Drug Evaluat & Res, 645 S Newstead Ave, St Louis, MO 63110 USA. EM Jason.Rodriguez@fda.hhs.gov FU CDER Medical Counter-Measures initiative (MCMi) FX This project was supported, in part, by an appointment (C.V.N, C.T., R.T., L.S.L) 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. Support for this project was received through the CDER Medical Counter-Measures initiative (MCMi). NR 26 TC 0 Z9 0 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 MAR 20 PY 2017 VL 136 BP 156 EP 161 DI 10.1016/j.jpba.2016.12.020 PG 6 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA EJ9IR UT WOS:000393540300019 PM 28081502 ER PT J AU Zhao, LQ Zhang, BL AF Zhao, Liqun Zhang, Baolin TI Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes SO SCIENTIFIC REPORTS LA English DT Article ID CELL-DERIVED-CARDIOMYOCYTES; HIGH-DOSE CHEMOTHERAPY; ST-SEGMENT ELEVATION; SOFT-TISSUE SARCOMA; CARCINOMA-CELLS; IN-VIVO; DILATED CARDIOMYOPATHY; MYOCARDIAL INJURY; FAS EXPRESSION; CANCER-THERAPY AB Doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. The mechanisms of doxorubicin-induced cardiotoxicity remain incompletely understood. Here we investigated doxorubicin-induced cytotoxicity in human induced pluripotent stem cells-derived cardiomyocytes (iPS-CMs). We found that doxorubicin and related anthracycline agents (e.g., daunorubicin, idarubicin, and epirubicin) significantly upregulated the expression of death receptors (DRs) (TNFR1, Fas, DR4 and DR5) in iPS-derived cardiomyocytes at both protein and mRNA levels. The resulting iPS-CMs cells underwent spontaneous apoptosis which was further enhanced by physiologically relevant death ligands including TNF-related apoptosis inducing ligand (TRAIL). Furthermore, TRAIL potentiated doxorubicin-induced decrease in beating rate and amplitude of iPS-derived cardiomyocytes. These data demonstrate that the induction of death receptors in cardiomyocytes is likely a critical mechanism by which doxorubicin causes cardiotoxicity. C1 [Zhao, Liqun; Zhang, Baolin] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Zhang, BL (reprint author), US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Baolin.zhang@fda.hhs.gov FU US Food and Drug Administration FX This study was supported by intramural funding of the US Food and Drug Administration. We thank Julianne Twomey for assistance with drawing the artwork in Figure 6. NR 58 TC 0 Z9 0 U1 0 U2 0 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 MAR 16 PY 2017 VL 7 AR 44735 DI 10.1038/srep44735 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO2NI UT WOS:000396532800001 PM 28300219 ER PT J AU Marks, PW Witten, CM Califf, RM AF Marks, Peter W. Witten, Celia M. Califf, Robert M. TI Clarifying Stem-Cell Therapy's Benefits and Risks SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Marks, Peter W.; Witten, Celia M.; Califf, Robert M.] US FDA, Silver Spring, MD 20993 USA. RP Marks, PW (reprint author), US FDA, Silver Spring, MD 20993 USA. NR 5 TC 0 Z9 0 U1 2 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 16 PY 2017 VL 376 IS 11 BP 1007 EP 1009 DI 10.1056/NEJMp1613723 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA EO0QT UT WOS:000396403700003 PM 27959704 ER PT J AU Beaver, JA Tzou, A Blumenthal, GM Mckee, AE Kim, G Pazdur, R Philip, R AF Beaver, Julia A. Tzou, Abraham Blumenthal, Gideon M. Mckee, Amy E. Kim, Geoffrey Pazdur, Richard Philip, Reena TI An FDA Perspective on the Regulatory Implications of Complex Signatures to Predict Response to Targeted Therapies SO CLINICAL CANCER RESEARCH LA English DT Article AB As technologies evolve, and diagnostics move from detection of single biomarkers toward complex signatures, an increase in the clinical use and regulatory submission of complex signatures is anticipated. However, to date, no complex signatures have been approved as companion diagnostics. In this article, we will describe the potential benefit of complex signatures and their unique regulatory challenges, including analytic performance validation, complex signature simulation, and clinical performance evaluation. We also will review the potential regulatory pathways for clearance, approval, or acceptance of complex signatures by the FDA. These regulatory pathways include regulations applicable to in vitro diagnostic devices, including companion diagnostic devices, the potential for labeling as a complementary diagnostic, and the biomarker qualification program. (C) 2016 AACR. C1 [Beaver, Julia A.; Tzou, Abraham; Blumenthal, Gideon M.; Mckee, Amy E.; Kim, Geoffrey; Pazdur, Richard; Philip, Reena] US FDA, White Oak, MD USA. RP Philip, R (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Reena.Philip@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 21 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 MAR 15 PY 2017 VL 23 IS 6 BP 1368 EP 1372 DI 10.1158/1078-0432.CCR-16-1098 PG 5 WC Oncology SC Oncology GA EP4IS UT WOS:000397344800002 PM 27993967 ER PT J AU Izurieta, HS Wernecke, M Kelman, J Wong, S Forshee, R Pratt, D Lu, Y Sun, Q Jankosky, C Krause, P Worrall, C MaCurdy, T Harpaz, R AF Izurieta, Hector S. Wernecke, Michael Kelman, Jeffrey Wong, Sarah Forshee, Richard Pratt, Douglas Lu, Yun Sun, Qin Jankosky, Christopher Krause, Philip Worrall, Chris MaCurdy, Tom Harpaz, Rafael TI Effectiveness and Duration of Protection Provided by the Live-attenuated Herpes Zoster Vaccine in the Medicare Population Ages 65 Years and Older SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE Herpes Zoster vaccine; vaccine effectiveness; post-herpetic neuralgia; opthalmic zoster; elderly ID POSTHERPETIC NEURALGIA; VARICELLA-VACCINATION; PROPENSITY SCORE; ADULTS; RISK; ASSOCIATION; EFFICACY; RATES; PAIN; BIAS AB Background. Tens of millions of seniors are at risk of herpes zoster (HZ) and its complications. Live attenuated herpes zoster vaccine (HZV) reduces that risk, although questions regarding effectiveness and durability of protection in routine clinical practice remain. We used Medicare data to investigate HZV effectiveness (VE) and its durability. Methods. This retrospective cohort study included beneficiaries ages >= 65 years during January 2007 through July 2014. Multiple adjustments to account for potential bias were made. HZV-vaccinated beneficiaries were matched to unvaccinated beneficiaries (primary analysis) and to HZV-unvaccinated beneficiaries who had received pneumococcal vaccination (secondary analysis). HZ outcomes in community and hospital settings were analyzed, including ophthalmic zoster (OZ) and postherpetic neuralgia (PHN). Results. Among eligible beneficiaries (average age 77 years), the primary analysis found VE for community HZ of 33% (95% CI: 32%-35%) and 19% (95% CI: 17%-22%), for the first 3, and subsequent 4+ years postvaccination, respectively. In the secondary analysis, VE was, respectively, 37% (95% CI: 36%-39%) and 22% (95% CI: 20%-25%). In the primary analysis, VE for PHN was 57% (95% CI: 52%-61%) and 45% (95% CI: 36%-53%) in the first 3 and subsequent 4+ years, respectively; VE for hospitalized HZ was, respectively, 74% (95% CI: 67%-79%) and 55% (95% CI: 39%-67%). Differences in VE by age group were not significant. Conclusions. In both the primary and secondary analyses, HZV provided protection against HZ across all ages, but effectiveness declined over time. VE was higher and better preserved over time for PHN and HZ-associated hospitalizations than for community HZ. C1 [Izurieta, Hector S.; Forshee, Richard; Pratt, Douglas; Lu, Yun; Jankosky, Christopher; Krause, Philip] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Wernecke, Michael; Wong, Sarah; Sun, Qin; MaCurdy, Tom] Acumen LLC, Burlingame, CA USA. [Kelman, Jeffrey; Worrall, Chris] Ctr Medicare & Medicaid Serv, Washington, DC USA. [Harpaz, Rafael] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. [Izurieta, Hector S.] Univ Rey Juan Carlos, Madrid, Spain. RP Izurieta, HS (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Hector.izurieta@fda.hhs.gov FU Food and Drug Administration; office of the Assistant Secretary of Planning and Evaluation FX This work was funded by the Food and Drug Administration. Additional funding was provided by the office of the Assistant Secretary of Planning and Evaluation. NR 34 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 MAR 15 PY 2017 VL 64 IS 6 BP 785 EP 793 DI 10.1093/cid/ciw854 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP3TI UT WOS:000397304200014 PM 28362955 ER PT J AU Meng, FT Alayash, AI AF Meng, Fantao Alayash, Abdu I. TI Determination of extinction coefficients of human hemoglobin in various redox states SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Hemoglobin; Extinction coefficients; Spectrometric; HPLC measurements ID SICKLE-CELL-DISEASE; SPECTROPHOTOMETRIC ANALYSIS; MITOCHONDRIAL DYSFUNCTION; HYDROGEN-PEROXIDE; HEME OXYGENASE-1; ALPHA-SUBUNITS; FERRYL IRON; OXYGENATION; HAPTOGLOBIN; SULFHEMOGLOBIN AB The role of hemoglobin (Hb) redox forms in tissue and organ toxicities remain ambiguous despite the well-documented contribution of Hb redox reactivity to cellular and subcellular oxidative changes. Moreover, several recent studies, in which Hb toxicity were investigated, have shown conflicting out-comes. Uncertainties over the potential role of these species may in part be due to the protein preparation method of choice, the use of published extinction coefficients and the lack of suitable controls for Hb oxidation and heme loss. Highly purified and well characterized redox forms of human Hb were used in this study and the extinction coefficients of each Hb species (ferrous/oxy, ferric/met and ferry]) were determined. A new set of equations were established to improve' accuracy in determining the transient ferryl Hb species. Additionally, heme concentrations in solutions and in human plasma were determined using a novel reversed phase HPLC method in conjugation with our photometric measurements. The use of more accurate redox-specific extinction coefficients and method calculations will be an invaluable tool for both in vitro and in vivo experiments aimed at determining the role of Hb-mediated vascular pathology in hemolytic anemias and when Hb is used as oxygen therapeutics. Published by Elsevier Inc. C1 [Meng, Fantao; Alayash, Abdu I.] US FDA, Lab Biochem & Vasc Biol, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 52-72,Room 4106, Silver Spring, MD 20993 USA. RP Alayash, AI (reprint author), US FDA, Lab Biochem & Vasc Biol, Ctr Biol Evaluat & Res, 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) grant [P01-HL110900]; U.S. Food and Drug Administration (MODSCI) FX 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 46 TC 0 Z9 0 U1 7 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAR 15 PY 2017 VL 521 BP 11 EP 19 DI 10.1016/j.ab.2017.01.002 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA EK4YN UT WOS:000393934000003 PM 28069451 ER PT J AU Jiang, XM Wang, LM Ji, YL Tang, JL Tian, X Cao, MJ Li, JX Bi, SY Wu, XC Chen, CY Yin, JJ AF Jiang, Xiumei Wang, Liming Ji, Yinglu Tang, Jinglong Tian, Xin Cao, Mingjing Li, Jingxuan Bi, Shuying Wu, Xiaochun Chen, Chunying Yin, Jun-Jie TI Interference of Steroidogenesis by Gold Nanorod Core/Silver Shell Nanostructures: Implications for Reproductive Toxicity of Silver Nanomaterials SO SMALL LA English DT Article ID FOLLICLE-STIMULATING-HORMONE; OXIDATIVE STRESS; IN-VITRO; GRANULOSA-CELLS; CELLULAR UPTAKE; ALLOY NANOPARTICLES; EMBRYO DEVELOPMENT; APOPTOSIS; CYTOTOXICITY; MECHANISM AB As a widely used nanomaterial in daily life, silver nanomaterials may cause great concern to female reproductive system as they are found to penetrate the bloodplacental barrier and gain access to the ovary. However, it is largely unknown about how silver nanomaterials influence ovarian physiology and functions such as hormone production. This study performs in vitro toxicology study of silver nanomaterials, focusing especially on cytotoxicity and steroidogenesis and explores their underlying mechanisms. This study exposes primary rat granulosa cells to gold nanorod core/silver shell nanostructures (Au@Ag NRs), and compares outcomes with cells exposed to gold nanorods. The Au@Ag NRs generate more reactive oxygen species and reduce mitochondrial membrane potential and less production of adenosine triphosphate. Au@Ag NRs promote steroidogenesis, including progesterone and estradiol, in a time-and dose-dependent manner. Chemical reactivity and transformation of Au@Ag NRs are then studied by electron spin resonance spectroscopy and X-ray absorption near edge structure, which analyze the generation of free radical and intracellular silver species. Results suggest that both particle-specific activity and intracellular silver ion release of Au@Ag NR contribute to the toxic response of granulosa cells. C1 [Jiang, Xiumei; Wang, Liming; Tang, Jinglong; Cao, Mingjing; Chen, Chunying] Natl Ctr Nanosci & Technol, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100190, Peoples R China. [Jiang, Xiumei; Wang, Liming; Tang, Jinglong; Cao, Mingjing; Chen, Chunying] Natl Ctr Nanosci & Technol, CAS Ctr Excellence Nanosci, Beijing Key Lab Ambient Particles Hlth Effects &, Beijing 100190, Peoples R China. [Jiang, Xiumei; Wang, Liming; Tang, Jinglong; Cao, Mingjing; Chen, Chunying] Inst High Energy Phys, Beijing 100190, Peoples R China. [Ji, Yinglu; Wu, Xiaochun] Natl Ctr Nanosci & Technol, CAS Key Lab Standardizat & Measurement Nanotechno, Beijing 100190, Peoples R China. [Ji, Yinglu; Wu, Xiaochun] Natl Ctr Nanosci & Technol, CAS Ctr Excellence Nanosci, Beijing 100190, Peoples R China. [Tian, Xin; Yin, Jun-Jie] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Li, Jingxuan; Bi, Shuying] Air Force PLA, Gen Hosp, Beijing 100142, Peoples R China. RP Chen, CY (reprint author), Natl Ctr Nanosci & Technol, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100190, Peoples R China.; Chen, CY (reprint author), Natl Ctr Nanosci & Technol, CAS Ctr Excellence Nanosci, Beijing Key Lab Ambient Particles Hlth Effects &, Beijing 100190, Peoples R China.; Chen, CY (reprint author), Inst High Energy Phys, Beijing 100190, Peoples R China.; Wu, XC (reprint author), Natl Ctr Nanosci & Technol, CAS Key Lab Standardizat & Measurement Nanotechno, Beijing 100190, Peoples R China.; Wu, XC (reprint author), Natl Ctr Nanosci & Technol, CAS Ctr Excellence Nanosci, Beijing 100190, Peoples R China. EM wuxc@nanoctr.cn; chenchy@nanoctr.cn FU Ministry of Science and Technology of China [2016YFA0201600, 2016YFA0203200]; National Natural Science Foundation of China [21320102003, 21403043, 91543206, 11435002]; Strategic Priority Research Program of the Chinese Academy of Sciences [XDA09040400]; Science Fund for Creative Research Groups of the National Natural Science Foundation of China [11621505]; CAS Key Research Program for Frontier Sciences [QYZDJ-SSW-SLH022]; Beijing Natural Science Foundation [2152037]; National Science Fund for Distinguished Young Scholars [11425520]; regulatory science grant under FDA Nanotechnology CORES Program FX X.J. and L.W. contributed equally to this work. This work was supported by the Ministry of Science and Technology of China (2016YFA0201600, 2016YFA0203200), the National Natural Science Foundation of China (21320102003, 21403043, 91543206, 11435002), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA09040400), Science Fund for Creative Research Groups of the National Natural Science Foundation of China (11621505), CAS Key Research Program for Frontier Sciences (QYZDJ-SSW-SLH022), Beijing Natural Science Foundation (2152037), the National Science Fund for Distinguished Young Scholars (11425520), and was partially supported by a regulatory science grant under the FDA Nanotechnology CORES Program. The authors thank Dr. Lili Fox Velez for her scientific editing 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 62 TC 0 Z9 0 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1613-6810 EI 1613-6829 J9 SMALL JI Small PD MAR 14 PY 2017 VL 13 IS 10 AR UNSP 1602855 DI 10.1002/smll.201602855 PG 13 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EP8HJ UT WOS:000397616200014 ER PT J AU Sousa, GR Gomes, JAS Damasio, MPS Nunes, MCP Costa, HS Medeiros, NI Fares, RCG Chaves, AT Correa-Oliveira, R Rocha, MOC AF Sousa, Giovane R. Gomes, Juliana A. S. Damasio, Marcos Paulo S. Nunes, Maria Carmo P. Costa, Henrique S. Medeiros, Nayara I. Fares, Rafaelle C. G. Chaves, Ana Thereza Correa-Oliveira, Rodrigo Rocha, Manoel Otavio C. TI The role of interleukin 17-mediated immune response in Chagas disease: High level is correlated with better left ventricular function SO PLOS ONE LA English DT Article ID HEART-DISEASE; T-CELLS; B-CELLS; CARDIOMYOPATHY; IL-17; ECHOCARDIOGRAPHY; ASSOCIATION; MANAGEMENT; CAPACITY; FAMILY AB Interleukin 17A (IL-17A) has been associated with protective rather than pathogenic response in Chagas disease (ChD). However, it is not established whether or not IL-17Amediated immune response is correlated with patient's left ventricular (LV) function in ChD. To address this question we have gathered cardiac functional parameters from ChD patients and analysed the possible relationship between their plasma IL-17A levels and LV function. Plasma IL-17A levels were measured by BD Cytometric Bead Array (CBA) in 240 patients with positive specific serology for Trypanosoma cruzi (T. cruzi) grouped as indeterminate (IND) and Chagas cardiomyopathy (CARD) forms. The levels of IL-17A in ChD patients were compared with 32 healthy individuals, mean age of 39 years, 50% male, that were also included as a control group (non-infected [NI]). The overall mean age of ChD patients was 46 years and 52% were male. The IND group included 95 asymptomatic patients, with ages ranging from 27 to 69 years (mean of 43 years), and 42.1% of them were male. The CARD group included 145 patients, which 58.6% were male, with ages ranging from 23 to 67 years (mean of 49). The IND group presented substantially higher levels of IL17A, median of 26.16 (3.66-48.33) as compared to both the CARD group, median of 13.89 (3.87-34.54) (P < 0.0001), and the NI group, median of 10.78 (6.23-22.26) (P < 0.0001). The data analysis demonstrated that the IND group comprises a significantly greater proportion (P < 0.001) of high IL-17A producers (52.6%, 50 of 95 subjects) than do the other groups. A significant direct correlation was verified between IL-17A levels and cardiac function expressed by LV ejection fraction (LVEF), LV diastolic diameter (LVDd), and body surface area (BSA)-indexed LVDd as well as ratio of the early diastolic transmitral flow velocity to early diastolic mitral annular velocity (E/e') in both groups. We demonstrated that plasma IL17A levels has an accurate sensitivity and specificity to predict heart failure in serology-positive patients and might be a useful parameter to distinguish patients with or without cardiac impairment. This study indicates a consistent relationship between high expression of IL17A and better LV in human chronic ChD. Our data raise the possibility that IL-17A plays an important immunomodulatory role in the chronic phase of ChD and might be involved in protection against myocardial damage. C1 [Sousa, Giovane R.; Gomes, Juliana A. S.; Nunes, Maria Carmo P.; Costa, Henrique S.; Chaves, Ana Thereza; Rocha, Manoel Otavio C.] Univ Fed Minas Gerais, Sch Med, Postgrad Course Infect Dis & Trop Med, Belo Horizonte, MG, Brazil. [Gomes, Juliana A. S.; Damasio, Marcos Paulo S.] Univ Fed Minas Gerais, Inst Biol Sci, Dept Morphol, Lab Cell Cell Interact, Belo Horizonte, MG, Brazil. [Medeiros, Nayara I.; Fares, Rafaelle C. G.; Correa-Oliveira, Rodrigo] Fiocruz MS, Ctr Pesquisas Rene Rachou, Lab Cellular & Mol Immunol, Belo Horizonte, MG, Brazil. [Correa-Oliveira, Rodrigo] Natl Inst Sci & Technol Trop Dis INCT DT, Belo Horizonte, MG, Brazil. [Sousa, Giovane R.] Harvard Med Sch, Joslin Diabet Ctr, Immunobiol Sect, Boston, MA 02115 USA. [Damasio, Marcos Paulo S.] Univ Dundee, Sch Life Sci, Div Cell Signalling & Immunol, Dundee, Scotland. [Fares, Rafaelle C. G.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Sousa, GR (reprint author), Univ Fed Minas Gerais, Sch Med, Postgrad Course Infect Dis & Trop Med, Belo Horizonte, MG, Brazil.; Sousa, GR (reprint author), Harvard Med Sch, Joslin Diabet Ctr, Immunobiol Sect, Boston, MA 02115 USA. EM giovane.sousa@gmail.com FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [407692/2012-6, 478846/2009-6, 404151/2012-4, 475497/2007-4, 403592/2008-9, 308219/2012-0]; Fundacao de Amparo a Pesquisa do Estado de Minas Gerais [APQ-02601-10, APQ-04129-10, PPM-00501-13]; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Fundacao de Amparo Pesquisa do Estado de Minas Gerais (FAPEMIG), Brazil FX This work was funded by the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, http//www.cripq.br, [407692/2012-6, 478846/2009-6, 404151/2012-4 (RCO), 475497/2007-4, 403592/2008-9, 308219/2012-0 (JASG)] and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais, http://www.fapermg.br, [APQ-02601-10, APQ-04129-10, PPM-00501-13 (JASG)]. JASG, MCPN, RCO and MOCR are CNPq Research Fellows. GRS was supported by a Ph.D. Studentship from the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank the colleagues of the Division of Echocardiography and of the Referral Outpatient Center for Chagas Disease at the Clinical Hospital, UFMG as well as of the Laboratory of Cellular and Molecular Immunology and of the Flow Cytometry facility at the Centro de Pesquisas Rene Rachou, FIOCRUZ for their technical assistance. The authors also thank the Program for Technological Development in Tools for Health PDTIS FIOCRUZ for the use of its facilities. We acknowledge Professor Paul Crocker at the Division of Cell Signalling and Immunology, University of Dundee, UK for helpful discussions. We are very grateful to all patients and control volunteers who participated in this study. This work was supported by the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and Fundacao de Amparo Pesquisa do Estado de Minas Gerais (FAPEMIG), Brazil. JASG, MCPN, RCO and MOCR are CNPq Research Fellows. GRS was supported by a Ph.D. Studentship from the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES). NR 38 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 MAR 9 PY 2017 VL 12 IS 3 AR e0172833 DI 10.1371/journal.pone.0172833 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6AW UT WOS:000396087900130 PM 28278264 ER PT J AU Aguilar-Calvo, P Xiao, X Bett, C Erana, H Soldau, K Castilla, J Nilsson, KPR Surewicz, WK Sigurdson, CJ AF Aguilar-Calvo, Patricia Xiao, Xiangzhu Bett, Cyrus Erana, Hasier Soldau, Katrin Castilla, Joaquin Nilsson, K. Peter R. Surewicz, Witold K. Sigurdson, Christina J. TI Post-translational modifications in PrP expand the conformational diversity of prions in vivo SO SCIENTIFIC REPORTS LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; ALPHA-SYNUCLEIN STRAINS; PROTEIN AMYLOID FIBRILS; MASS-SPECTROMETRY DATA; PHOSPHOLIPASE-C; HYDROGEN/DEUTERIUM EXCHANGE; ALZHEIMERS-DISEASE; TRANSGENIC MICE; SCRAPIE; BRAIN AB Misfolded prion protein aggregates (PrPSc) show remarkable structural diversity and are associated with highly variable disease phenotypes. Similarly, other proteins, including amyloid-beta, tau, alpha-synuclein, and serum amyloid A, misfold into distinct conformers linked to different clinical diseases through poorly understood mechanisms. Here we use mice expressing glycophosphatidylinositol (GPI)anchorless prion protein, PrPC, together with hydrogen-deuterium exchange coupled with mass spectrometry (HXMS) and a battery of biochemical and biophysical tools to investigate how posttranslational modifications impact the aggregated prion protein properties and disease phenotype. Four GPI-anchorless prion strains caused a nearly identical clinical and pathological disease phenotype, yet maintained their structural diversity in the anchorless state. HXMS studies revealed that GPIanchorless PrPSc is characterized by substantially higher protection against hydrogen/deuterium exchange in the C-terminal region near the N-glycan sites, suggesting this region had become more ordered in the anchorless state. For one strain, passage of GPI-anchorless prions into wild type mice led to the emergence of a novel strain with a unique biochemical and phenotypic signature. For the new strain, histidine hydrogen-deuterium mass spectrometry revealed altered packing arrangements of beta-sheets that encompass residues 139 and 186 of PrPSc. These findings show how variation in posttranslational modifications may explain the emergence of new protein conformations in vivo and also provide a basis for understanding how the misfolded protein structure impacts the disease. C1 [Aguilar-Calvo, Patricia; Bett, Cyrus; Castilla, Joaquin; Sigurdson, Christina J.] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Aguilar-Calvo, Patricia; Bett, Cyrus; Soldau, Katrin; Sigurdson, Christina J.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Xiao, Xiangzhu; Surewicz, Witold K.] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44116 USA. [Erana, Hasier; Castilla, Joaquin] CIC bioGUNE, Parque Tecnol Bizkaia,Ed 800, Derio 48160, Spain. [Castilla, Joaquin] Ikerbasque, Basque Fdn Sci, Bilbao 48013, Spain. [Nilsson, K. Peter R.] Linkoping Univ, Dept Phys Chem & Biol, S-58183 Linkoping, Sweden. [Sigurdson, Christina J.] Univ Calif Davis, Dept Pathol Immunol & Microbiol, Davis, CA 95616 USA. [Bett, Cyrus] US FDA, Div Emerging & Transfus Transmitted Dis, Off Blood Res & Review, Silver Spring, MD USA. RP Sigurdson, CJ (reprint author), Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA.; Sigurdson, CJ (reprint author), Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA.; Sigurdson, CJ (reprint author), Univ Calif Davis, Dept Pathol Immunol & Microbiol, Davis, CA 95616 USA. EM csigurdson@ucsd.edu FU National Institutes of Health [NS069566, NS076896, AI106705, NS083687]; Swedish Foundation for Strategic Research (KPRN) FX We thank Nazilla Alderson, Jun Liu, Carlitos Chen, and Don Pizzo for providing excellent technical support. We are grateful for the excellent care provided by the animal caretakers at UC San Diego. We thank Dr. Michael Oldstone for providing the Tg(GPI-PrP) mice, and Dr. Adriano Aguzzi for generously providing the anti-PrP antibodies (POM series). This study was supported by the National Institutes of Health grants NS069566 (to CJS), NS076896 (to CJS), AI106705 (to WKS) and NS083687 (to WKS), and the Swedish Foundation for Strategic Research (KPRN). NR 73 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 MAR 8 PY 2017 VL 7 AR 43295 DI 10.1038/srep43295 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN1DC UT WOS:000395749700001 PM 28272426 ER PT J AU Jia, W Chu, XG Chang, J Wang, PG Chen, Y Zhang, F AF Jia, Wei Chu, Xiaogang Chang, James Wang, Perry G. Chen, Ying Zhang, Feng TI High-throughput untargeted screening of veterinary drug residues and metabolites in tilapia using high resolution orbitrap mass spectrometry SO ANALYTICA CHIMICA ACTA LA English DT Article DE UHPLC/ESI Q-Orbitrap; Aquaculture; Veterinary drug residues; Multi-residue ID PERFORMANCE LIQUID-CHROMATOGRAPHY; BIOLOGICAL SAMPLES; AQUACULTURE; FISH; FOOD; PHARMACEUTICALS; IDENTIFICATION; METABOLOMICS; CONFIRMATION; ANTIBIOTICS AB An analytical method was developed and validated for simultaneous analysis of one hundred and thirty-seven veterinary drug residues and metabolites from sixteen different classes in tilapia utilizing an improved fully non-targeted way of data acquisition with fragmentation. The automated on-line extraction procedure was achieved in a simple disposable pipet extraction. Ultrahigh-performance liquid chromatography and electrospray ionization quadrupole Orbitrap high-resolution mass spectrometry (UHPLC Q-Orbitrap) was used for the separation and detection of all the analytes. The methodology was validated by taking into consideration the guidelines specified in European SANCO/12571/2013 Guideline 2013 and Commission Decision 2002/657/EC. The extraction recoveries ranged from 81% to 111%. The limits of decision ranged from 0.01 to 2.73 mu g kg(-1) and the detection capabilities ranged from 0.01 to 4.73 mu g kg(-1). The one hundred and thirty-seven compounds behave dynamic 0.1-500 mu g kg(-1), with correlation coefficient >0.99. The fully non-targeted data acquisition way improves both sensitivity and selectivity for the fragments, which is beneficial for screening performance and identification capability. This validated method has been successfully applied on screening of veterinary drug residues and metabolites in muscle of tilapia, an important and intensively produced fish in aquaculture. (C) 2017 Elsevier B.V. All rights reserved. C1 [Jia, Wei; Chu, Xiaogang] Shaanxi Univ Sci & Technol, Sch Food & Biol Engn, Xian 710021, Peoples R China. [Jia, Wei; Chu, Xiaogang; Chen, Ying; Zhang, Feng] Chinese Acad Inspect & Quarantine, Inst Food Safety, Beijing 100123, Peoples R China. [Chang, James] Thermo Fisher Sci, 355 River Oaks Pkwy, San Jose, CA 95134 USA. [Wang, Perry G.] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy,HFS 717, College Pk, MD 20740 USA. RP Jia, W (reprint author), Shaanxi Univ Sci & Technol, Sch Food & Biol Engn, Xian 710021, Peoples R China. EM foodjiawei@aliyun.com FU General Administration of Quality Supervision, Inspection and Quarantine of the People's Republic of China [2012104002]; Natural Science Foundation of Shaanxi University of Science and Technology [126021665] FX The authors gratefully acknowledge the General Administration of Quality Supervision, Inspection and Quarantine of the People's Republic of China (Project number: 2012104002), and the Natural Science Foundation of Shaanxi University of Science and Technology (Project number: 126021665). NR 36 TC 0 Z9 0 U1 15 U2 15 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 MAR 8 PY 2017 VL 957 BP 29 EP 39 DI 10.1016/j.aca.2016.12.038 PG 11 WC Chemistry, Analytical SC Chemistry GA EJ5IZ UT WOS:000393252900004 PM 28107831 ER PT J AU Tiwari, N Kumar, V Gedda, MR Singh, AK Singh, VK Gannavaram, S Singh, SP Singh, RK AF Tiwari, Neeraj Kumar, Vinod Gedda, Mallikarjuna Rao Singh, Ashish K. Singh, Vijay K. Gannavaram, Sreenivas Singh, Surya P. Singh, Rakesh K. TI Identification and Characterization of miRNAs in Response to Leishmania donovani Infection: Delineation of Their Roles in Macrophage Dysfunction SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE L.donovani; miRNA; biomarkers; macrophages; dysfunction ID HOST IMMUNE-RESPONSE; KALA-AZAR; VISCERAL LEISHMANIASIS; MICRORNA; MECHANISMS; AMPHOTERICIN; MILTEFOSINE; PENTAMIDINE; RESISTANCE; PARASITES AB The outcome of Leishmania infection depends on parasite abilities to evade host immune response and its survival in hostile environment of host macrophages. Despite a wealth of gained crucial information, parasite strategies by which it dampens host macrophage functions remain poorly understood. Micro RNAs (miRNAs) are evolutionarily conserved class of endogenous 22-nucleotide small non-coding RNA gene products, described to participate in the regulation of almost every cellular process investigated so far. In this study, we identified 940 miRNAs in Leishmania donovani infected macrophages by de novo sequencing out of which levels of 85 miRNAs were found to be consistently modified by parasite infection. Herein, we report the functional characteristics of 10 miRNAs i.e., mir-3620, mir-6385, mir-6973a, mir-6996, mir-328, mir-8113, mir-3473f, mir-763, mir-6540, and mir-1264 that were differentially but constantly regulated in infected macrophages for their role in regulation of macrophage effector functions. The target gene prediction and biological interaction analysis revealed involvement of these miRNAs in various biological processes such as apoptosis inhibition, phagocytosis, drug response, and T cell phenotypic transitions. These findings could contribute for the better understanding of macrophages dysfunction and leishmanial pathogenesis. Further, the identified miRNAs could also be used as biomarker/s in diagnosis, prognosis, and therapeutics of Leishmania infection. C1 [Tiwari, Neeraj; Gedda, Mallikarjuna Rao; Singh, Ashish K.; Singh, Surya P.; Singh, Rakesh K.] Banaras Hindu Univ, Inst Sci, Dept Biochem, Mol Immunol Grp, Varanasi, Uttar Pradesh, India. [Kumar, Vinod] Rajendra Mem Res Inst, Dept Parasitol & Mol Biol, Patna, Bihar, India. [Singh, Vijay K.] Cent Univ South Bihar, Bioinformat Programme, Ctr Biol Sci, Patna, Bihar, India. [Gannavaram, Sreenivas] US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Singh, RK (reprint author), Banaras Hindu Univ, Inst Sci, Dept Biochem, Mol Immunol Grp, Varanasi, Uttar Pradesh, India. EM rakesh_bc@bhu.ac.in FU Department of Science and Technology, New Delhi [SB/SO/HS/0091/2013]; University Grants Commission (UGC); BHU; DST [YSS/2015/000687] FX Financial support from Department of Science and Technology, New Delhi (SB/SO/HS/0091/2013) is greatly acknowledged. NT and MG are thankful to University Grants Commission (UGC) and BHU for their research fellowships and VK is thankful to DST (YSS/2015/000687) for providing fellowship. The technical support received from VK Singh, Bioinformatics Centre, School of Biotechnology, Banaras Hindu University is greatly acknowledged. NR 41 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 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD MAR 2 PY 2017 VL 8 AR 314 DI 10.3389/fmicb.2017.00314 PG 11 WC Microbiology SC Microbiology GA EL9ZS UT WOS:000394979200001 PM 28303124 ER PT J AU Kim, Y Nabili, M Acharya, P Lopez, A Myers, MR AF Kim, Yeonho Nabili, Marjan Acharya, Priyanka Lopez, Asis Myers, Matthew R. TI Microvessel rupture induced by high-intensity therapeutic ultrasound-a study of parameter sensitivity in a simple in vivo model SO JOURNAL OF THERAPEUTIC ULTRASOUND LA English DT Article DE Vessel rupture; Therapeutic ultrasound; Transcranial ultrasound; High-intensity focused ultrasound; Transcranial ultrasound ID FOCUSED ULTRASOUND AB Background: Safety analyses of transcranial therapeutic ultrasound procedures require knowledge of the dependence of the rupture probability and rupture time upon sonication parameters. As previous vessel-rupture studies have concentrated on a specific set of exposure conditions, there is a need for more comprehensive parametric studies. Methods: Probability of rupture and rupture times were measured by exposing the large blood vessel of a live earthworm to high-intensity focused ultrasound pulse trains of various characteristics. Pressures generated by the ultrasound transducers were estimated through numerical solutions to the KZK ( Khokhlov-Zabolotskaya-Kuznetsov) equation. Three ultrasound frequencies ( 1.1, 2.5, and 3.3 MHz) were considered, as were three pulse repetition frequencies ( 1, 3, and 10 Hz), and two duty factors ( 0.0001, 0.001). The pressures produced ranged from 4 to 18 MPa. Exposures of up to 10 min in duration were employed. Trials were repeated an average of 11 times. Results: No trends as a function of pulse repetition rate were identifiable, for either probability of rupture or rupture time. Rupture time was found to be a strong function of duty factor at the lower pressures; at 1.1 MHz the rupture time was an order of magnitude lower for the 0.001 duty factor than the 0.0001. At moderate pressures, the difference between the duty factors was less, and there was essentially no difference between duty factors at the highest pressure. Probability of rupture was not found to be a strong function of duty factor. Rupture thresholds were about 4 MPa for the 1.1 MHz frequency, 7 MPa at 3.3 MHz, and 11 MPa for the 2.5 MHz, though the pressure value at 2.5 MHz frequency will likely be reduced when steep-angle corrections are accounted for in the KZK model used to estimate pressures. Mechanical index provided a better collapse of the data ( less separation of the curves pertaining to the different frequencies) than peak negative pressure, for both probability of rupture and rupture time. Conclusion: The results provide a database with which investigations in more complex animal models can be compared, potentially establishing trends by which bioeffects in human vessels can be estimated. C1 [Kim, Yeonho] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Preclin Studies Core, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Nabili, Marjan] US FDA, Ctr Devices & Radiol Hlth, Off In Vitro Diagnost & Radiol Hlth, Div Radiol Hlth, 10903 New Hampshire Ave,Bldg 62,Room 4311, Silver Spring, MD 20993 USA. [Acharya, Priyanka] Univ Maryland, Dept Chem & Biomol Engn, 4418 Stadium Dr, College Pk, MD 20742 USA. [Lopez, Asis] Tulane Univ, Sch Sci & Engn, Bioinnovat PhD Program, 6823 St Charles Ave,Lindy Boggs Ctr,Room 440, New Orleans, LA 70118 USA. [Myers, Matthew R.] US FDA, Ctr Devices & Radiol Hlth, Div Appl Mech, Off Sci & Engn Labs, 10903 New Hampshire Ave,Bldg 62,Room 2231, Silver Spring, MD 20993 USA. RP Myers, MR (reprint author), US FDA, Ctr Devices & Radiol Hlth, Div Appl Mech, Off Sci & Engn Labs, 10903 New Hampshire Ave,Bldg 62,Room 2231, Silver Spring, MD 20993 USA. EM Matthew.myers@fda.hhs.gov NR 9 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2050-5736 J9 J THER ULTRASOUND JI J. Ther. Ultrasound PD MAR 2 PY 2017 VL 5 BP 1 EP 9 AR 5 DI 10.1186/s40349-017-0082-2 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EM4ZC UT WOS:000395320700001 PM 28265413 ER PT J AU Moran, MB Walker, MW Alexander, TN Jordan, JW Wagner, DE AF Moran, Meghan B. Walker, Matthew W. Alexander, Tesfa N. Jordan, Jeffrey W. Wagner, Dana E. TI Why Peer Crowds Matter: Incorporating Youth Subcultures and Values in Health Education Campaigns SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material ID WEIGHT CONTROL BEHAVIORS; GROUP IDENTIFICATION; AFFILIATION; IDENTITY; SMOKING; NORMS; CIGARETTES; STRATEGIES C1 [Moran, Meghan B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, 624 N Broadway,Hampton House 7th Fl, Baltimore, MD 21205 USA. [Walker, Matthew W.; Alexander, Tesfa N.] US FDA, Ctr Tobacco Prod, Silver Spring, MD USA. [Jordan, Jeffrey W.; Wagner, Dana E.] Rescue, San Diego, CA USA. RP Moran, MB (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, 624 N Broadway,Hampton House 7th Fl, Baltimore, MD 21205 USA. EM mmoran@jhu.edu FU National Institutes of Health, National Institute for Drug Abuse [K01DA037903]; US Food and Drug Administration (FDA) Center for Tobacco Products; FDA [HHSF223201210006I] FX M. B. Moran's effort was focused solely on the theoretical aspects of tobacco prevention campaigns and is supported by the National Institutes of Health, National Institute for Drug Abuse (K01 award K01DA037903) and the US Food and Drug Administration (FDA) Center for Tobacco Products. Fresh Empire is supported by the FDA (contract HHSF223201210006I). NR 45 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAR PY 2017 VL 107 IS 3 BP 389 EP 395 DI 10.2105/AJPH.2016.303595 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO9YV UT WOS:000397044900020 PM 28103067 ER PT J AU Fu, PP Xia, QS He, XB Barel, S Edery, N Beland, FA Shimshoni, JA AF Fu, Peter P. Xia, Qingsu He, Xiaobo Barel, Shimon Edery, Nir Beland, Frederick A. Shimshoni, Jakob A. TI Detection of Pyrrolizidine Alkaloid DNA Adducts in Livers of Cattle Poisoned with Heliotropium europaeum SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID METABOLIC-ACTIVATION; MEDICINAL-PLANTS; SENECIO-JACOBAEA; IN-VIVO; TUMORIGENICITY; MECHANISMS; CALVES; RIDDELLIINE AB Pyrrolizidine alkaloids are among the most common poisonous plants affecting livestock, wildlife, and humans. Exposure of humans and livestock to toxic pyrrolizidine alkaloids through the intake of contaminated food and feed may result in poisoning, leading to devastating epidemics. During February 2014, 73 mixed breed female beef cows from the Galilee region of Israel were accidently fed pyrrolizidine alkaloid contaminated hay for 42 days, resulting in the sudden death of 24 cows over a period of 63 days. The remaining cows were slaughtered 2.5 months after the last ingestion of the contaminated hay. In this study, we report the histopathological analysis of the livers from five of the slaughtered cows and quantitation of pyrrolizidine alkaloid-derived DNA adducts from their livers and three livers of control cows fed with feed free of weeds producing pyrrolizidine alkaloids. Histopathological examination revealed that the five cows suffered from varying degrees of bile duct proliferation, fibrosis, and megalocytosis. Selected reaction monitoring HPLC ES-MS/MS analysis indicated that (+/-)-6,7dihydro-7-hydroxy-1-hydroxymethyl-SH-pyrrolizine (DHP)-derived DNA adducts were formed in all five livers. The livers from the three control cows did not have any liver damage nor any indication of DHP DNA adduct formed. These results confirm that the toxicity observed in these cattle was caused by pyrrolizidine alkaloid poisoning and that pyrrolizidine alkaloid-derived DNA adducts could still be detected and quantified in the livers of the chronically poisoned cows 2.5 months after their last exposure to the contaminated feed, suggesting that DHP-derived DNA adducts can serve as biomarkers for pyrrolizidine alkaloid exposure and poisoning. C1 [Fu, Peter P.; Xia, Qingsu; He, Xiaobo; Beland, Frederick A.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Barel, Shimon; Shimshoni, Jakob A.] Kimron Vet Inst, Dept Toxicol, IL-50250 Bet Dagan, Israel. [Edery, Nir] Kimron Vet Inst, Dept Pathol, IL-50250 Bet Dagan, Israel. RP Beland, FA (reprint author), Kimron Vet Inst, Dept Toxicol, IL-50250 Bet Dagan, Israel.; Fu, PP (reprint author), HFT 110, 3900 NCTR Dr, Jefferson, AR 72079 USA. EM peter.fu@fda.hhs.gov; jakobshimshoni@gmail.com FU internal FDA fund FX Funding was provided by an internal FDA fund. NR 31 TC 0 Z9 0 U1 1 U2 1 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 MAR PY 2017 VL 30 IS 3 BP 851 EP 858 DI 10.1021/acs.chemrestox.6b00456 PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA EP1VB UT WOS:000397171300010 PM 28125883 ER PT J AU Slavov, SH Beger, RD AF Slavov, Svetoslav H. Beger, Richard D. TI RIGOROUS 3-DIMENSIONAL SPECTRAL DATA ACTIVITY RELATIONSHIP APPROACH MODELING STRATEGY FOR TOXCAST ESTROGEN RECEPTOR DATA CLASSIFICATION, VALIDATION, AND FEATURE EXTRACTION SO ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY LA English DT Article DE 3D-Spectral Data-Activity Relationship; Estrogen receptor; Classification model; ToxCast database; Validation ID ENDOCRINE-DISRUPTING CHEMICALS; BINDING-AFFINITY; BINARY CLASSIFICATION; QSAR; TOXICITY; PREDICTION; ALPHA; DOCKING; PROJECT; BETA AB The estrogenic potential (expressed as a score composite of 18 high throughput screening bioassays) of 1528 compounds from the ToxCast database was modeled by a 3-dimensional spectral data activity relationship approach (3D-SDAR). Due to a lack of O-17 nuclear magnetic resonance (NMR) simulation software, the most informative carbon-carbon 3D-SDAR fingerprints were augmented with indicator variables representing oxygen atoms from carbonyl and carboxamide, ester, sulfonyl, nitro, aliphatic hydroxyl, and phenolic hydroxyl groups. To evaluate the true predictive performance of the authors' model the United States Environmental Protection Agency provided them with a blind test set consisting of 2008 compounds. Of these, 543 had available literature data-their binding affinity served to estimate the external classification accuracy of the developed model: predictive accuracy of 0.62, sensitivity of 0.71, and specificity of 0.53 were obtained. Compared with alternative modeling techniques, the authors' model displayed very little reduction in performance between the modeling and the prediction set. A 3D-SDAR mapping technique allowed identification of structural features essential for estrogenicity: 1) the presence of a phenolic OH group or cyclohexenone, 2) a second aromatic or phenolic ring at a distance of 6 angstrom to 8 angstrom from the oxygen of the first phenol ring, 3) the presence of a methyl group approximately 6 angstrom away from the centroid of a phenol ring, and 4) a carbonyl group in close proximity (similar to 4 angstrom measured to the centroid) to 1 of the phenol rings. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. C1 [Slavov, Svetoslav H.; Beger, Richard D.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Beger, RD (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Richard.Beger@fda.hhs.gov NR 40 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-7268 EI 1552-8618 J9 ENVIRON TOXICOL CHEM JI Environ. Toxicol. Chem. PD MAR PY 2017 VL 36 IS 3 BP 823 EP 830 DI 10.1002/etc.3578 PG 8 WC Environmental Sciences; Toxicology SC Environmental Sciences & Ecology; Toxicology GA EL5YX UT WOS:000394698700020 PM 27509091 ER PT J AU Sulaiman, IM Jacobs, E Simpson, S Kerdahi, K AF Sulaiman, Irshad M. Jacobs, Emily Simpson, Steven Kerdahi, Khalil TI Identification of 18 vector species belonging to Group I, Group II, and Group III "Dirty 22' species known to contaminate food and spread foodborne pathogens: DNA barcoding study of public health importance SO INTERNATIONAL JOURNAL OF TROPICAL INSECT SCIENCE LA English DT Article DE "Dirty 22' vector species; DNA barcoding; foodborne disease; public health ID REGULATORY ACTION CRITERIA; OXIDASE SUBUNIT-I; PHYLOGENETIC ANALYSIS; ELONGATION FACTOR-1-ALPHA; MOLECULAR SYSTEMATICS; NUCLEOTIDE-SEQUENCES; DIPTERA-SIMULIIDAE; FLIES DIPTERA; FILTH; GENE AB The US Food and Drug Administration (US-FDA) uses the presence of filth and extraneous materials as one of the criteria in implementing regulatory actions and assessing food adulteration of public health importance. So far, 22 common pest species ('Dirty 22' species) have been considered by this agency for the spreading of foodborne illness, and their presence is an indicator of unsanitary conditions in food processing and storage facilities. Recently, we classified the 'Dirty 22' species into four groups: Group I (four cockroach species), Group II (two ant species), Group III (12 fly species), and Group IV (four rodent species), and described two molecular diagnostic methods for group-specific identification. We developed a PCR-RFLP assay based on rRNA gene for the detection and differentiation of Group I 'Dirty 22' species. Later, we designed three Group II 'Dirty 22' species-specific nested PCR primer sets and sequence characterized the rRNA, elongation factor 1-alpha (EF-1a), and wingless (WNT-1) loci. In this follow-up study, we have evaluated the robustness of five unique sets of published primers targeting the mitochondrial cytochrome oxidase I (COI) gene for insect barcoding. With modified PCR conditions, we successfully used COI barcoding for 18 members of Group I, Group II, and Group III 'Dirty 22' species. Results of this study reveal that COI barcoding is an effective tool for rapid identification of insects of Groups I, II, and III 'Dirty 22' species known to contaminate food and spread foodborne pathogens. C1 [Sulaiman, Irshad M.; Jacobs, Emily; Simpson, Steven; Kerdahi, Khalil] US FDA, Microbiol Sci Branch, South Reg Lab, 60 Eight St, Atlanta, GA 30309 USA. RP Sulaiman, IM (reprint author), US FDA, Microbiol Sci Branch, South Reg Lab, 60 Eight St, Atlanta, GA 30309 USA. EM irshad.sulaiman@fda.hhs.gov NR 55 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1742-7584 EI 1742-7592 J9 INT J TROP INSECT SC JI Int. J. Trop. Insect Sci. PD MAR PY 2017 VL 37 IS 1 BP 1 EP 10 DI 10.1017/S1742758416000217 PG 10 WC Entomology SC Entomology GA EM6RJ UT WOS:000395439500001 ER PT J AU Fiuzat, M Mayne, ST Hillebrenner, M Stockbridge, N Zuckerman, B Califf, RM AF Fiuzat, Mona Mayne, Susan T. Hillebrenner, Matt Stockbridge, Norman Zuckerman, Bram Califf, Robert M. TI JACC: Heart Failure Series: FDA in the 21st Century Focus on Nutrition and Heart Failure Prevention SO JACC-HEART FAILURE LA English DT Editorial Material DE FDA; heart failure; nutrition; sodium reduction; trans fat C1 [Fiuzat, Mona; Mayne, Susan T.; Hillebrenner, Matt; Stockbridge, Norman; Zuckerman, Bram; Califf, Robert M.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Fiuzat, M (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Mona.fiuzat@fda.hhs.gov NR 6 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD MAR PY 2017 VL 5 IS 3 BP 229 EP 231 DI 10.1016/i.jchf.2016.12.012 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EN4IV UT WOS:000395972100013 PM 28254130 ER PT J AU Tang, LY Heller, M Meng, Z Yu, LR Tang, Y Zhou, M Zhang, YE AF Tang, Liu-Ya Heller, Mary Meng, Zhaojing Yu, Li-Rong Tang, Yi Zhou, Ming Zhang, Ying E. TI Transforming Growth Factor-beta (TGF-beta) Directly Activates the JAK1-STAT3 Axis to Induce Hepatic Fibrosis in Coordination with the SMAD Pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STAT3 SIGNALING ACTIVATION; STELLATE CELLS; JUNB PROMOTER; LIVER; EXPRESSION; APOPTOSIS; IL-6; PHOSPHORYLATION; TRANSCRIPTION-3; TRANSDUCTION AB Transforming growth factor-beta (TGF-beta) signals through both SMAD and non-SMAD pathways to elicit a wide array of biological effects. Existing data have shown the association and coordination between STATs and SMAD sin mediating TGF-beta functions in hepatic cells, but it is not clear how STATs are activated under these circumstances. Here, we report that JAK1 is a constitutive TGF beta RI binding protein and is absolutely required for phosphorylation of STATs in a SMAD-independent manner within minutes of TGF-beta stimulation. Following the activation of SMADs, TGF-beta also induces a second phase of STAT phosphorylation that requires SMADs, de novo protein synthesis, and contribution from JAK1. Our global gene expression profiling indicates that the non-SMAD JAK1/STAT pathway is essential for the expression of a subset of TGF-beta target genes in hepatic stellate cells, and the cooperation between the JAK1STAT3 and SMAD pathways is critical to the roles of TGF-beta in liver fibrosis. C1 [Tang, Liu-Ya; Heller, Mary; Tang, Yi; Zhang, Ying E.] Natl Inst Hlth, NCI, Ctr Canc Res, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. [Meng, Zhaojing; Yu, Li-Rong; Zhou, Ming] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Prot Characterizat Lab, Frederick, MD 21702 USA. [Yu, Li-Rong] Div System Biol, Biomarkers & Alternat Models Branch, Food & Drug Adm, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Zhang, Ying E.] Natl Inst Hlth, NCI, Ctr Canc Res, Lab Cellular & Mol Biol, Bldg 37, Bethesda, MD 20892 USA. RP Zhang, YE (reprint author), Natl Inst Hlth, NCI, Ctr Canc Res, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. EM zhangyin@mail.nih.gov FU National Institutes of Health; NCI, Center for Cancer Research FX This work was supported by the intramural research program of the National Institutes of Health, NCI, Center for Cancer Research (to Y.E.Z.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 36 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR PY 2017 VL 292 IS 10 BP 4302 EP 4312 DI 10.1074/jbc.M116.773085 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN2JZ UT WOS:000395837100027 PM 28154170 ER PT J AU Meng, XF Zhang, ZF Li, KT Wang, Y Xia, XD Wang, X Xi, ML Meng, JH Cui, SH Yang, BW AF Meng, Xiaofeng Zhang, Zengfeng Li, Keting Wang, Yin Xia, Xiaodong Wang, Xin Xi, Meili Meng, Jianghong Cui, Shenghui Yang, Baowei TI Antibiotic Susceptibility and Molecular Screening of Class I Integron in Salmonella Isolates Recovered from Retail Raw Chicken Carcasses in China SO MICROBIAL DRUG RESISTANCE LA English DT Article DE Salmonella; antibiotic resistance; class I integrons ID ANTIMICROBIAL RESISTANCE GENES; SITE-SPECIFIC RECOMBINATION; GRAM-NEGATIVE BACTERIA; UNITED-STATES; ESCHERICHIA-COLI; DNA ELEMENTS; GROUND-BEEF; ENTERICA; SEROVARS; CASSETTES AB Salmonella is one of the leading causes for foodborne diseases. Foods, particularly those of animal origin, act as an important role for Salmonella transmission. In this study, the antibiotic susceptibility of 743 Salmonella isolates recovered from retail raw chicken carcasses in eight provinces was tested, and the isolates were also screened for the presence of class I integron and drug-resistant gene cassettes. One hundred thirteen (15.21%) isolates were harboring class I integron. A higher percentage of integron-positive Salmonella isolates were found in retail chicken in Sichuan Province (29.33%), followed by Beijing (22.14%), Shaanxi (19.15%), Guangxi (14.13%), Henan (12.50%), Shanghai (7.25%), Fujian (8.22%), and Guangdong (6.25%) Provinces. The respective prevalence of class I integron in Salmonella isolates recovered from retail chickens in large, free, and small markets was 16.31%, 14.04%, and 15.27%. Moreover, 20.13%, 14.02%, and 13.74% of Salmonella isolates recovered from retail chickens stored in frozen, chilled, and ambient conditions, respectively, were positive for class I integron. Subsequent sequencing of class I integron revealed the presence of 10 gene cassettes harboring resistance genes (dfrA17-aadA5, dfrA17-aadA5, dfrA1-aadA1, dfrA12-aadA2, dfrA17-aadA5-aadA4, dfrA1-aadA1-aadA2, dfrA1, dfrA5, aadA2, aacA4-catB8-aadA1-dfrA1-(aac6-II)-(bla(CARB)-8), bla(PSE-1)-bla(P1)). The most prevalent gene cassette was dfrA17-aadA5 (59.62%). Class I integron-positive isolates were significantly more resistant to multiple antibiotics, and they commonly exhibited corresponding antibiotic resistance profiles to the antibiotic resistance gene cassettes harbored in their class I integron. The results indicated that class I integron with different antibiotic resistance gene cassettes that were prevalent in Salmonella isolates differed from provinces, marketplaces, and chicken storage conditions. C1 [Meng, Xiaofeng; Zhang, Zengfeng; Li, Keting; Wang, Yin; Xia, Xiaodong; Wang, Xin; Xi, Meili; Meng, Jianghong; Yang, Baowei] Northwest A&F Univ, Coll Food Sci & Engn, Yangling 712100, Peoples R China. [Meng, Jianghong] Univ Maryland, Joint Inst Food Safety & Appl Nutr, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Cui, Shenghui] Natl Inst Food & Drug Control, Beijing, Peoples R China. RP Yang, BW (reprint author), Northwest A&F Univ, Coll Food Sci & Engn, Yangling 712100, Peoples R China. EM ybwsheng@163.com FU National Natural Science Foundation of China [31171682] FX The research work was supported by the National Natural Science Foundation of China (No. 31171682). NR 44 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1076-6294 EI 1931-8448 J9 MICROB DRUG RESIST JI Microb. Drug Resist. PD MAR PY 2017 VL 23 IS 2 BP 230 EP 235 DI 10.1089/mdr.2015.0359 PG 6 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA EN1IA UT WOS:000395762500013 PM 27309257 ER PT J AU Liu, MM Huang, KM Yeung, S Chang, A Zhang, SH Mei, N Parsa, C Orlando, R Huang, Y AF Liu, Mandy M. Huang, Kevin M. Yeung, Steven Chang, Andy Zhang, Suhui Mei, Nan Parsa, Cyrus Orlando, Robert Huang, Ying TI Inhibition of Neoplastic Transformation and Chemically-Induced Skin Hyperplasia in Mice by Traditional Chinese Medicinal Formula Si-Wu-Tang SO NUTRIENTS LA English DT Article DE cancer prevention; DMBA; skin cancer; AP-1; NF-kappa B; SWT; SENCAR mice; EGF; JB6; Ames test ID JUZEN-TAIHO-TO; ENDOMETRIAL CARCINOGENESIS; KAPPA-B; PREVENTION; CONSTITUENTS; CANCER; GENES; ALPHA; PCR AB Exploring traditional medicines may lead to the development of low-cost and non-toxic cancer preventive agents. Si-Wu-Tang (SWT), comprising the combination of four herbs, Rehmanniae, Angelica, Chuanxiong, and Paeoniae, is one of the most popular traditional Chinese medicines for women's diseases. In our previous studies, the antioxidant Nrf2 pathways were strongly induced by SWT in vitro and in vivo. Since Nrf2 activation has been associated with anticarcinogenic effects, the purpose of this study is to evaluate SWT's activity of cancer prevention. In the Ames test, SWT demonstrated an antimutagenic activity against mutagenicity induced by the chemical carcinogen 7,12-dimethylbenz(a) anthracene (DMBA). In JB6 P+ cells, a non-cancerous murine epidermal model for studying tumor promotion, SWT inhibited epidermal growth factor (EGF)-induced neoplastic transformation. The luciferase reporter gene assays demonstrated that SWT suppressed EGF-induced AP-1 and TNF-alpha -induced NF-kappa B activation, which are essential factors involved in skin carcinogenesis. In a DMBA-induced skin hyperplasia assay in 'Sensitivity to Carcinogenesis' (SENCAR) mice, both topical and oral SWT inhibited DMBA-induced epidermal hyperplasia, expression of the proliferation marker Proliferating cell nuclear antigen (PCNA), and H-ras mutations. These findings demonstrate, for the first time, that SWT prevents tumor promoter and chemical-induced carcinogenesis in vitro and in vivo, partly by inhibiting DNA damage and blocking the activation of AP-1 and NF-kappa B. C1 [Liu, Mandy M.; Huang, Kevin M.; Yeung, Steven; Chang, Andy; Huang, Ying] Western Univ Hlth Sci, Coll Pharm, Dept Pharmaceut Sci, Pomona, CA 91766 USA. [Zhang, Suhui] Shanghai Inst Food & Drug Control, Dept Pharmacol & Toxicol, Shanghai 201203, Peoples R China. [Zhang, Suhui; Mei, Nan] Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Parsa, Cyrus; Orlando, Robert] Western Univ Hlth Sci, Coll Osteopath Med, Dept Clin Sci, Pomona, CA 91766 USA. RP Huang, Y (reprint author), Western Univ Hlth Sci, Coll Pharm, Dept Pharmaceut Sci, Pomona, CA 91766 USA. EM mmliu@westernu.edu; huang.2834@buckeyemail.osu.edu; skyeung@westernu.edu; chang.andy.y@gmail.com; suhuizhangbc@gmail.com; nan.mei@fda.hhs.gov; cparsa@westernu.edu; rorlando@beverly.org; yhuang@westernu.edu FU Innovation and Technology Commission of the Hong Kong Special Administrative Region of the People's Republic of China [ITS/112/07, ITS/446/09]; Western University of Health Sciences; Office of International Programs, the U.S., Food and Drug Administration (FDA) FX We thank David Sanchez at Western University of Health Sciences for kindly providing the luciferase reporter construct pGL4.22-AP1. SWT and its herbal components were provided by Zhong Zuo at Chinese University of Hong Kong. The manufacturing of Si-Wu-Tang was supported by the Innovation and Technology Fund (ITS/112/07, PI: Zhong Zuo) from the Innovation and Technology Commission of the Hong Kong Special Administrative Region of the People's Republic of China. This work was partly supported by the Innovation and Technology Grants (ITS/112/07 and ITS/446/09) from the Innovation and Technology Commission of the Hong Kong Special Administrative Region of the People's Republic of China and by Western University of Health Sciences. Suhui Zhang from Shanghai Institute for Food and Drug Control (Shanghai, China) participated in the International Scientist Exchange Program (ISEP) at the National Center for Toxicological Research (NCTR) receiving funding from the Office of International Programs, the U.S., Food and Drug Administration (FDA). Funds for covering the costs to publish in open access are provided by Western University of Health Sciences. NR 29 TC 0 Z9 0 U1 0 U2 0 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2072-6643 J9 NUTRIENTS JI Nutrients PD MAR PY 2017 VL 9 IS 3 AR 300 DI 10.3390/nu9030300 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EO9QQ UT WOS:000397023600119 ER PT J AU Su, JR Leroy, Z Lewis, PW Haber, P Marin, M Leung, J Woo, EJ Shimabukuro, TT AF Su, John R. Leroy, Zanie Lewis, Paige W. Haber, Penina Marin, Mona Leung, Jessica Woo, Emily Jane Shimabukuro, Tom T. TI Safety of Second-Dose Single-Antigen Varicella Vaccine SO PEDIATRICS LA English DT Article ID EVENT REPORTING SYSTEM; UNITED-STATES; HEALTHY-CHILDREN; SURVEILLANCE; MEASLES; IMMUNOGENICITY; EPIDEMIOLOGY; IMMUNIZATION; PREVENTION; MORTALITY AB BACKGROUND AND OBJECTIVE: In 2006, routine 2-dose varicella vaccination for children was recommended to improve control of varicella. We assessed the safety of second-dose varicella vaccination. METHODS: We identified second-dose single-antigen varicella vaccine reports in the Vaccine Adverse Event Reporting System during 2006 to 2014 among children aged 4 to 18 years. We analyzed reports by age group (4-6 and 7-18 years), sex, serious or nonserious status, most common adverse events (AEs), and whether other vaccines were administered concomitantly with varicella vaccine. We reviewed serious reports of selected AEs and conducted empirical Bayesian data mining to detect disproportional reporting of AEs. RESULTS: We identified 14 641 Vaccine Adverse Event Reporting System reports after second-dose varicella vaccination, with 494 (3%) classified as serious. Among nonserious reports, injection site reactions were most common (48% of children aged 4-6 years, 38% of children aged 7-18 years). The most common AEs among serious reports were pyrexia (31%) for children aged 4 to 6 years and headache (28%) and vomiting (27%) for children aged 7 to 18 years. Serious reports of selected AEs included anaphylaxis (83), meningitis (5), encephalitis (16), cellulitis (52), varicella (6), herpes zoster (6), and deaths (7). One immunosuppressed adolescent was reported with vaccine-strain herpes zoster. Only previously known AEs were reported more frequently after second-dose varicella vaccination compared with other vaccines. CONCLUSIONS: We identified no new or unexpected safety concerns for second-dose varicella vaccination. Robust safety monitoring remains an important component of the national varicella vaccination program. C1 [Su, John R.; Lewis, Paige W.; Haber, Penina; Shimabukuro, Tom T.] Ctr Dis Control & Prevent, Immunizat Safety Off, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA USA. [Leroy, Zanie] Ctr Dis Control & Prevent, Sch Hlth Branch, Div Populat Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Marin, Mona; Leung, Jessica] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Div Viral Dis, Epidemiol Branch, Atlanta, GA USA. [Woo, Emily Jane] US FDA, Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, Silver Spring, MD USA. RP Su, JR (reprint author), Ctr Dis Control & Prevent, Immunizat Safety Off, 1600 Clifton Rd,MS D-26, Atlanta, GA 30333 USA. EM ezu2@cdc.gov NR 37 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD MAR PY 2017 VL 139 IS 3 AR e20162536 DI 10.1542/peds.2016-2536 PG 8 WC Pediatrics SC Pediatrics GA EM0IY UT WOS:000395003200029 ER PT J AU Aikin, KJ Southwell, BG Paquin, RS Rupert, DJ O'Donoghue, AC Betts, KR Lee, PK AF Aikin, Kathryn J. Southwell, Brian G. Paquin, Ryan S. Rupert, Douglas J. O'Donoghue, Amie C. Betts, Kevin R. Lee, Philip K. TI Correction of misleading information in prescription drug television advertising: The roles of advertisement similarity and time delay SO RESEARCH IN SOCIAL & ADMINISTRATIVE PHARMACY LA English DT Article DE Corrective advertising; Direct-to-consumer prescription drug advertising; Misinformation; Risk communication ID CONSUMER; MISINFORMATION; STATEMENTS; MEMORY AB Background: Prescription drug television advertisements containing potentially consequential misinformation sometimes appear in the United States. When that happens, the U.S. Food and Drug Administration can request that companies distribute corrective advertisements to address misinformation and inaccurate claims. Previous research has demonstrated effectiveness in corrective advertising for various products. Objectives: The present article builds on that work with a randomized experimental study (n = 6454) of corrective advertising investigating the extent to which visual similarity matters between violative and corrective ads and the extent to which time delay matters between violative and corrective advertisement exposure. Methods: Our study sample included overweight or obese U.S. adults recruited from an existing online consumer panel representative of the U.S. adult population. We created a brand for a fictitious prescription weight-loss drug and produced corresponding direct-to-consumer (DTC) television ads. All participants viewed the same violative ad, but were randomly assigned to view corrective ads with different levels of visual similarity and exposure time delay using a 4 x 4 between-subjects factorial design. Results: Results suggest corrective ad exposure can influence consumer perceptions of drug efficacy, risks, and benefits previously established by violative ads that overstated drug efficacy, broadened drug indication, and omitted important risk information. Corrective ads also can weaken consumer intentions to consider and investigate a drug. However, ad similarity does not appear to affect consumer perceptions and preferences. Although we found that the effects of violative ad exposure tend to diminish over time, the length of the delay between violative and corrective ad exposure has limited influence. An exception to this was observed with regard to recall of drug benefits and risks, where the impact of corrective ad exposure increases with greater time delay. Conclusions: These results extend previous research to a new health condition and hold implications for regulatory policy. Published by Elsevier Inc. C1 [Aikin, Kathryn J.; O'Donoghue, Amie C.; Betts, Kevin R.] US FDA, Off Prescript Drug Promot, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Southwell, Brian G.; Paquin, Ryan S.; Rupert, Douglas J.; Lee, Philip K.] RTI Int, 3040 E Cornwallis Rd,POB 12194, Res Triangle Pk, NC 27709 USA. RP Aikin, KJ (reprint author), US FDA, Off Prescript Drug Promot, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Kathryn.Aikin@fda.hhs.gov NR 25 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 1551-7411 EI 1934-8150 J9 RES SOC ADMIN PHARM JI Res. Soc. Adm. Pharm. PD MAR-APR PY 2017 VL 13 IS 2 BP 378 EP 388 DI 10.1016/j.sapharm.2016.04.004 PG 11 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA EP0JA UT WOS:000397072400018 PM 27178746 ER PT J AU Cao, XF Muskhelishvili, L Latendresse, J Richter, P Heflich, RH AF Cao, Xuefei Muskhelishvili, Levan Latendresse, John Richter, Patricia Heflich, Robert H. TI Evaluating the Toxicity of Cigarette Whole Smoke Solutions in an Air-Liquid-Interface Human In Vitro Airway Tissue Model SO TOXICOLOGICAL SCIENCES LA English DT Article DE cigarette whole smoke solution (WSS); human air-liquid-interface (ALI) airway tissue model; oxidative stress; mucin; matrix metalloproteinase (MMP) ID OBSTRUCTIVE PULMONARY-DISEASE; MUC5B GENE; EXPRESSION; COPD AB Exposure to cigarette smoke causes a multitude of pathological changes leading to tissue damage and disease. Quantifying such changes in highly differentiated in vitro human tissue models may assist in evaluating the toxicity of tobacco products. In this methods development study, well-differentiated human air-liquid-interface (ALI) in vitro airway tissue models were used to assess toxicological endpoints relevant to tobacco smoke exposure. Whole mainstream smoke solutions (WSSs) were prepared from 2 commercial cigarettes (R60 and S60) that differ in smoke constituents when machine-smoked under International Organization for Standardization conditions. The airway tissue models were exposed apically to WSSs 4-h per day for 1-5 days. Cytotoxicity, tissue barrier integrity, oxidative stress, mucin secretion, and matrix metalloproteinase (MMP) excretion were measured. The treatments were not cytotoxic and had marginal effects on tissue barrier properties; however, other endpoints responded in time-and dose-dependent manners, with the R60 resulting in higher levels of response than the S60 for many endpoints. Based on the lowest effect dose, differences in response to the WSSs were observed for mucin induction and MMP secretion. Mitigation of mucin induction by cotreatment of cultures with Nacetylcysteine suggests that oxidative stress contributes to mucus hypersecretion. Overall, these preliminary results suggest that quantifying disease-relevant endpoints using ALI airway models is a potential tool for tobacco product toxicity evaluation. Additional research using tobacco samples generated under smoking machine conditions that more closely approximate human smoking patterns will inform further methods development. C1 [Cao, Xuefei; Heflich, Robert H.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Muskhelishvili, Levan; Latendresse, John] Toxicol Pathol Associates, Jefferson, AR 72079 USA. [Richter, Patricia] US FDA, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. RP Cao, XF (reprint author), US FDA, NCTR, Div Genet & Mol Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM xuefei.cao@fda.hhs.gov FU U.S. Food and Drug Administration Center for Tobacco Products FX This work is supported by the U.S. Food and Drug Administration Center for Tobacco Products. This work was conducted between February and August of 2014. NR 27 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD MAR PY 2017 VL 156 IS 1 BP 14 EP 24 DI 10.1093/toxsci/kfw239 PG 11 WC Toxicology SC Toxicology GA EO9ZR UT WOS:000397047100004 PM 28115645 ER PT J AU Huo, JH Kamalakar, A Yang, X Word, B Stockbridge, N Lyn-Cook, B Pang, L AF Huo, Jianhua Kamalakar, Archana Yang, Xi Word, Beverly Stockbridge, Norman Lyn-Cook, Beverly Pang, Li TI Evaluation of Batch Variations in Induced Pluripotent Stem Cell-Derived Human Cardiomyocytes from 2 Major Suppliers SO TOXICOLOGICAL SCIENCES LA English DT Article DE drug-induced proarrhythmia; iPSC-CMs; batch variations ID TORSADES-DE-POINTES; LONG-QT SYNDROME; VENTRICULAR MYOCYTES; RISK-ASSESSMENT; DOFETILIDE; MATURATION; CONTRACTILITY; PROLONGATION; IMPEDANCE; MODELS AB Drug-induced proarrhythmia is a major safety issue in drug development. Developing sensitive in vitro assays that can predict drug-induced cardiotoxicity in humans has been a challenge of toxicology research for decades. Recently, induced pluripotent stem cell-derived human cardiomyocytes (iPSC-hCMs) have become a promising model because they largely replicate the electrophysiological behavior of human ventricular cardiomyocytes. Patient-specific iPSC-hCMs have been proposed for personalized cardiac drug selection and adverse drug response prediction; however, many procedures are involved in cardiomyocytes differentiation and purification process, which may result in large line-to-line and batch-tobatch variations. Here, we examined the purity, cardiac ion channel gene expression profile, and electrophysiological response of 3 batches of iPSC-hCMs from each of 2 major cell suppliers. We found that iPSC-hCMs from both vendors had similar purities. Most of the cardiac ion channel genes were expressed uniformly among different batches of iCells, while larger variations were found in Cor. 4U cells, particularly in the expression of CACNA1C, KCND2, and KCNA5 genes, which could underlie the differences in baseline beating rate (BR) and field potential duration (FPD) measurements. Although, in general, the electrophysiological responses of different batches of cells to Na+, Ca2(+), I-kr, and I-ks channel blockers were similar, with Ikr blocker-induced proarrhythmia, the sensitivities were depended on baseline BR and FPD values: cells that beat slower had longer FPD and greater sensitivity to drug-induced proarrhythmia. Careful evaluation of the performance of iPSC-hCMs and methods of data analysis is warranted for shaping regulatory standards in qualifying iPSC-hCMs for drug safety testing. C1 [Huo, Jianhua; Kamalakar, Archana; Word, Beverly; Lyn-Cook, Beverly; Pang, Li] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Huo, Jianhua] Xi An Jiao Tong Univ, Hosp 1, Dept Cardiovasc Med, 277 Yanta West Rd, Xian 710061, Shaanxi, Peoples R China. [Yang, Xi] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Stockbridge, Norman] US FDA, Div Cardiovasc & Renal Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Pang, L (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Bldg 12-120,3900 NCTR Rd, Jefferson, AR 72079 USA. EM li.pang@fda.hhs.gov FU FDA Center for Drug Evaluation and Research, Office of Women's Health; National Center for Toxicological Research (NCTR) FX This study was supported by the FDA Center for Drug Evaluation and Research, Office of Women's Health, and National Center for Toxicological Research (NCTR). The project was supported in part by an appointment to the ORISE Research Participation Program at the NCTR, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA/Center. NR 38 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD MAR PY 2017 VL 156 IS 1 BP 25 EP 38 DI 10.1093/toxsci/kfw235 PG 14 WC Toxicology SC Toxicology GA EO9ZR UT WOS:000397047100005 PM 28031415 ER PT J AU Shpyleva, S Dreval, K de Conti, A Kindrat, I Melnyk, S Yan, J Chen, T Beland, FA Pogribny, IP AF Shpyleva, Svitlana Dreval, Kostiantyn de Conti, Aline Kindrat, Iryna Melnyk, Stepan Yan, Jian Chen, Tao Beland, Frederick A. Pogribny, Igor P. TI Organ-Specific Epigenetic Changes Induced by the Nongenotoxic Liver Carcinogen Methapyrilene in Fischer 344 Rats SO TOXICOLOGICAL SCIENCES LA English DT Article DE nongenotoxic carcinogens; liver; methapyrilene; epigenetics ID DNA-DAMAGE; OXIDATIVE STRESS; HEPATOCELLULAR-CARCINOMA; GENE-EXPRESSION; F344 RATS; METHYLATION; CANCER; HEPATOCARCINOGENESIS; NEPHROTOXICITY; TUMORIGENESIS AB Continuous lifetime exposure to certain natural and man-made chemicals is a major cause of cancers in humans; therefore, evaluating the carcinogenic risks of chemicals remains important. Currently, substantial progress has been made in identification of genotoxic carcinogens; in contrast, predicting the carcinogenic potential of nongenotoxic compounds is a challenge due to many different modes of action that may lead to tumorigenesis. In the present study, we investigated the effects of the nongenotoxic liver carcinogen methapyrilene and the nongenotoxic noncarcinogen usnic acid, at doses that do not exhibit organ cytotoxicity, on epigenomic alterations in the livers and kidneys of Fischer 344 (F344) rats. We demonstrate that a repeat-dose oral treatment of male F344 rats with methapyrilene for 6 weeks caused target organspecific epigenetic alterations in the livers. In contrast, only very slight epigenetic changes were found in the livers of F344 rats treated with hepatotoxicant, but noncarcinogen, usnic acid. The methapyrilene-induced epigenetic changes consisted of changes in histone lysine acetylation and methylation, with the greatest increase occurring in global and gene-specific histone H3 lysine 9 (H3K9) deacetylation. Importantly, the results of the present study show an association between genespecific histone H3K9 deacetylation and a reduced expression of critical cancer-related genes, including prospero homeobox 1 (Prox1), HNF1 homebox A (Hnf1a), and peroxisome proliferator activated receptor alpha (Ppara), which provides a mechanistic link between methapyrilene-induced epigenetic aberrations and liver carcinogenesis. C1 [Shpyleva, Svitlana; Dreval, Kostiantyn; de Conti, Aline; Kindrat, Iryna; Beland, Frederick A.; Pogribny, Igor P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd,Off 14C-101, Jefferson, AR 72079 USA. [Melnyk, Stepan] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72202 USA. [Yan, Jian; Chen, Tao] Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd,Off 14C-101, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov NR 48 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD MAR PY 2017 VL 156 IS 1 BP 190 EP 198 DI 10.1093/toxsci/kfw242 PG 9 WC Toxicology SC Toxicology GA EO9ZR UT WOS:000397047100017 PM 28013212 ER PT J AU Avonto, C Rua, D Lasonkar, PB Chittiboyina, AG Khan, IA AF Avonto, Cristina Rua, Diego Lasonkar, Pradeep B. Chittiboyina, Amar G. Khan, Ikhlas A. TI Identification of a compound isolated from German chamomile (Matricaria chamomilla) with dermal sensitization potential SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE German chamomile; Skin sensitization; in chemico methods; DCYA; LLNA ID ALLERGIC CONTACT-DERMATITIS; SESQUITERPENE LACTONE MIX; LYMPH-NODE ASSAY; SKIN SENSITIZERS; CLASSIFICATION; URTICARIA; FLOWERS; REACTIVITY; EXTRACTS; PLANTS AB German chamomile is one of the most popular herbal ingredients used in cosmetics and personal care products. Allergic skin reactions following topical application of German chamomile have been occasionally reported, although it is not fully understood which of the chemical constituents is responsible for this adverse effect. In the present work, three candidate sensitizers were isolated from German chamomile based on activity-guided fractionation of chamomile extracts tested using the in vitro KeratinoSens(Tm) assay. The compounds were identified as the polyacetylene tonghaosu (1), and both trans-and cis-glucomethoxycinnamic acids (2 and 3). These three compounds were classified as non-to weakly reactive using in chemico methods; however, aged tonghaosu was found to be more reactive when compared to freshly isolated tonghaosu. The polyacetylene (1) constituent was determined to be chemically unstable, generating a small electrophilic spirolactone, 1,6-dioxaspiro[4.4]non-3-en-2-one (4), upon aging. This small lactone (4) was strongly reactive in both in chemico HIS-and NMR-DCYA methods and further confirmed as a potential skin sensitizer by Local Lymph Node Assay (LLNA). (C) 2017 Elsevier Inc. All rights reserved. C1 [Avonto, Cristina; Lasonkar, Pradeep B.; Chittiboyina, Amar G.; Khan, Ikhlas A.] Univ Mississippi, Sch Pharm, Pharmaceut Sci Res Inst, Natl Ctr Nat Prod Res, University, MS 38677 USA. [Rua, Diego] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Khan, Ikhlas A.] Univ Mississippi, Sch Pharm, Dept BioMol Sci, Div Phamacognosy, University, MS 38677 USA. RP Khan, IA (reprint author), Univ Mississippi, Natl Ctr Nat Prod Res, University, MS 38677 USA. EM ikhan@olemiss.edu FU Food and Drug Administration [1U01FD004246-04] FX This work was supported by the Food and Drug Administration "Science Based Authentication of Dietary Supplements" [grant number 1U01FD004246-04]. NR 30 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 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAR 1 PY 2017 VL 318 BP 16 EP 22 DI 10.1016/j.taap.2017.01.009 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EL3ZE UT WOS:000394558400003 PM 28109818 ER PT J AU Tobon-Velasco, JC Vazquez-Victorio, G Macias-Silva, M Cuevas, E Ali, SF Maldonado, PD Gonzalez-Trujano, ME Cuadrado, A Pedraza-Chaverri, J Santamaria, A AF Cesar Tobon-Velasco, Julio Vazquez-Victorio, Genaro Macias-Silva, Marina Cuevas, Elvis Ali, Syed F. Maldonado, Perla D. Eva Gonzalez-Trujano, Maria Cuadrado, Antonio Pedraza-Chaverri, Jose Santamaria, Abel TI S-Allyl cysteine protects against 6-hydroxydopamineinduced neurotoxicity in the rat striatum: involvement of Nrf2 transcription factor activation and modulation of signaling kinase cascades (Retraction of Vol 53, Pg 1024, 2012) SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Retraction C1 [Cesar Tobon-Velasco, Julio; Santamaria, Abel] Inst Nacl Neurol & Neurocirugia SSA, Lab Aminoacidos Excitadores, Mexico City, DF, Mexico. [Cesar Tobon-Velasco, Julio; Pedraza-Chaverri, Jose; Santamaria, Abel] Univ Nacl Autonoma Mexico, Fac Quim, Dept Biol, Mexico City, DF, Mexico. [Vazquez-Victorio, Genaro; Macias-Silva, Marina] Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Biol Celular & Desarrollo, Mexico City, DF, Mexico. [Cuevas, Elvis; Ali, Syed F.] Natl Ctr Toxicol Res FDA, Div Neurotoxicol, Jefferson, AR USA. [Maldonado, Perla D.] Inst Nacl Neurol & Neurocirugia SSA, Lab Patol Vasc, Mexico City, DF, Mexico. [Eva Gonzalez-Trujano, Maria] Inst Nacl Psiquiatria SSA, Dept Invest Neurociencias, Mexico City, DF, Mexico. [Cuadrado, Antonio] Ctr Invest Red Enfermedades Neurodegenerat CIBERN, Dept Bioquim, Madrid, Spain. [Cuadrado, Antonio] Ctr Invest Red Enfermedades Neurodegenerat CIBERN, Inst Invest Biomed Alberto Sols UAM CSIC, Madrid, Spain. RP Tobon-Velasco, JC (reprint author), Inst Nacl Neurol & Neurocirugia SSA, Lab Aminoacidos Excitadores, Mexico City, DF, Mexico.; Tobon-Velasco, JC (reprint author), Univ Nacl Autonoma Mexico, Fac Quim, Dept Biol, Mexico City, DF, Mexico. NR 1 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 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD MAR PY 2017 VL 104 BP 382 EP 382 DI 10.1016/j.freeradbiomed.2016.12.044 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA EN4HJ UT WOS:000395968300032 PM 28237391 ER PT J AU Williams, A Read, EK Agarabi, CD Lute, S Brorson, KA AF Williams, Abasha Read, Erik K. Agarabi, Cyrus D. Lute, Scott Brorson, Kurt A. TI Automated 2D-HPLC method for characterization of protein aggregation with in-line fraction collection device SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE 2D-HPLC; Protein aggregation; PAT; QBD; Heart-cutting; Monoclonal antibody purification ID 2-DIMENSIONAL LIQUID-CHROMATOGRAPHY; MONOCLONAL-ANTIBODY PRODUCTION; SIZE-EXCLUSION CHROMATOGRAPHY; HOST-CELL PROTEINS; MASS-SPECTROMETRY; IDENTIFICATION; VARIANTS; PRODUCTS; QUALITY AB Monoclonal antibodies are mainly produced by mammalian cell culture, which due to its complexity, results in a wide range of product variants/isoforms. With the growing implementation of Quality by Design (QbD) and Process Analytical Technology (PAT) in drug manufacturing, monitoring and controlling quality attributes within a predefined range during manufacturing may provide added consistency to product quality. To implement these concepts, more robust analytical tools could reduce the time needed for monitoring quality attributes during upstream processing. The formation of protein aggregates is one such quality attribute that can lead to safety and efficacy issues in the final drug product. Described in this study is a fully automated two-dimensional high performance liquid chromatography (2D-HPLC) method for characterizing protein aggregation of crude in-process bioreactor samples. It combines protein A purification and separation by size exclusion into a single analytical module that has the potential to be employed at-line within a bioprocessing system. This method utilizes a novel in-line fraction collection device allowing for the collection of up to twelve fractions from a single sample or peak which facilitates the subsequent linked analysis of multiple protein peaks of interest in one chromatography module. Published by Elsevier B.V. C1 [Williams, Abasha; Read, Erik K.; Agarabi, Cyrus D.; Lute, Scott] Food & Drug Adm, Ctr Drug Evaluat & Res Off Prod Qual, Off Biotechnol Prod, Div Biotechnol Review & Res II, Silver Spring, MD 20815 USA. [Brorson, Kurt A.] FDA CDER OPQ OBP DBRRII, White Oak, Building 72, Room 2220, 10903, Silver Spring, MD 20993 USA. [Williams, Abasha] VPPL VRC NIAID NIH, Gaithersburg, MD 20697 USA. [Read, Erik K.] AstraZeneca, Manufacturing Sci & Technol, Frederick, MD 21701 USA. RP Brorson, KA (reprint author), FDA CDER OPQ OBP DBRRII, White Oak, Building 72, Room 2220, 10903, Silver Spring, MD 20993 USA. EM kurt.brorson@fda.hhs.gov FU Research Participation Program at the Center for Drug Evaluation; CDER Critical Path project [15-01] FX This project was supported, in part, by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. It was also supported by CDER Critical Path project 15-01. NR 32 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 EI 1873-376X J9 J CHROMATOGR B JI J. Chromatogr. B PD MAR 1 PY 2017 VL 1046 BP 122 EP 130 DI 10.1016/j.jchromb.2017.01.021 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA EM9AB UT WOS:000395602100015 PM 28178596 ER PT J AU Herath, K Girard, L Reimschuessel, R Jayasuriya, H AF Herath, Kithsiri Girard, Lauren Reimschuessel, Renate Jayasuriya, Hiranthi TI Application of time-of-flight mass spectrometry for screening of crude glycerins for toxic phorbol ester contaminants SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Jatropha factors; Glycerin; Jatropha curcas; UHPLC/Q-TOF ID JATROPHA-CURCAS; RESINIFERATOXIN; DITERPENE; CAPSAICIN; OIL AB Since 2007, the U.S. Food and Drug Administration (FDA) has received numerous complaints of pet illnesses that may be related to the consumption of jerky pet treats. Many of those treats include glycerin as an ingredient. Glycerin can be made directly from oils such as palm seed oil, but can also be derived from the seed oil of toxicJatropha plant during biodiesel production. If crude glycerin from biodiesel production from Jatropha curcas is used in the manufacture of animal feed, toxic tigliane diterpene phorbol esters (PEs), namely Jatropha factors (JFs), maybe present and could lead to animal illnesses. Considering the numerous uses of glycerin in consumer products there is a need for a rapid method to screen crude glycerin for JF toxins and other PE contaminants. We describe the development of an ultra-high pressure liquid chromatography/quadrupole time of flight (UHPLC/Q-TOF) method for screening crude glycerin for PEs. An exact mass database, developed in-house, of previously identified PEs from Jatropha curcas as well as putative compounds was used to identify possible contaminants. C1 [Herath, Kithsiri; Girard, Lauren; Jayasuriya, Hiranthi] US FDA, Div Residue Chem, Ctr Vet Med, Res Off, 8401 Muirkirk Rd, Laurel, MD 20708 USA. [Reimschuessel, Renate] US FDA, Vet Lab Invest & Response Network, Ctr Vet Med, Res Off, 8401 Muirkirk Rd, Laurel, MD 20708 USA. RP Jayasuriya, H (reprint author), US FDA, Div Residue Chem, Ctr Vet Med, Res Off, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM hiranthi.jayasuriya@fda.hhs.gov FU Research Participation Program at the Center for Veterinary Medicine; U.S. Food and Drug Administration FX This project was supported in part by an appointment to the Research Participation Program at the Center for Veterinary Medicine and the U.S. Food and Drug Administration NR 14 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 EI 1873-376X J9 J CHROMATOGR B JI J. Chromatogr. B PD MAR 1 PY 2017 VL 1046 BP 226 EP 234 DI 10.1016/j.jchromb.2017.01.005 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA EM9AB UT WOS:000395602100028 PM 28202317 ER PT J AU Li, F Howard, KD Myers, MJ AF Li, Fei Howard, Karyn D. Myers, Michael J. TI Influence of P-glycoprotein on the disposition of fexofenadine and its enantiomers SO JOURNAL OF PHARMACY AND PHARMACOLOGY LA English DT Article DE ABCB1-1 Delta; Collies; enantiomer; fexofenadine; fluorescence ID PERFORMANCE LIQUID-CHROMATOGRAPHY; TANDEM MASS-SPECTROMETRY; DRUG-INTERACTIONS; HUMAN PLASMA; QUANTITATIVE-DETERMINATION; FLUORESCENCE DETECTION; SHORT-TERM; PHARMACOKINETICS; ABCB1; HPLC AB Objectives P-glycoprotein (P-gp) is responsible for the efflux of a broad variety of human and veterinary drugs. Canine P-gp polymorphisms alter drug disposition and toxicity, but their impact on the disposition of enantiomeric drugs is unknown. Using fexofenadine as a model compound, we developed and validated HPLC-fluorescence methods to determine the effect of P-gp on the disposition of fexofenadine and its enantiomers. Methods A chiral CD-Ph column was used for the separation of (R) and (S)-fexofenadine. Determination of racemic fexofenadine was achieved on an XDB-CN column. Fexofenadine and its enantiomers were detected by fluorescence at the excitation wavelength of 220 nm and emission wavelength of 300 nm. These methods were used to measure concentrations of fexofenadine and its enantiomers in Collie plasma after oral administration. Key findings This study demonstrates that P-gp prefers to transport (S)-fexofenadine, and P-gp deficiency causes the increase in both (R)-fexofenadine and (S)-fexofenadine in plasma. Racemic fexofenadine, (R)-fexofenadine and (S)-fexofenadine were increased in ABCB1-1 Collies (118.7, 72.0 and 48.3 ng/ml) compared to wild-type Collies (25.0, 16.5 and 7.7 ng/ml) at 1 h postadministration. The results demonstrate that the stereoselectivity of P-gp plays a key role in the disposition of fexofenadine enantiomers. Conclusions The information derived from this drug model will be used to determine whether additional safety or efficacy requirements are necessary for enantiomeric drugs that would be used in dogs or humans. C1 [Li, Fei; Howard, Karyn D.; Myers, Michael J.] US FDA, Div Appl Vet Res, Res Off, Ctr Vet Med, Laurel, MD USA. [Li, Fei] Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650204, Peoples R China. RP Myers, MJ (reprint author), US FDA, Laurel, MD 20708 USA. EM michael.myers@fda.hhs.gov FU Intramural Research Program of the Center for Veterinary Medicine, Food and Drug Administration FX The authors thank Dr. Pak S. Chu and Dr. Hui Li from U.S. Food and Drug Administration for suggestions on the development and validation of methods. This work was supported by the Intramural Research Program of the Center for Veterinary Medicine, Food and Drug Administration. The views expressed in this study are those of the author(s) and may not reflect the official policy of the Department of Health and Human Services, the U.S. Food and Drug Administration, or the U.S. Government. NR 35 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3573 EI 2042-7158 J9 J PHARM PHARMACOL JI J. Pharm. Pharmacol. PD MAR PY 2017 VL 69 IS 3 BP 274 EP 284 DI 10.1111/jphp.12687 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EM3BJ UT WOS:000395189200006 PM 28090646 ER PT J AU Wang, R Conner, DP Li, BV AF Wang, Rong Conner, Dale P. Li, Bing V. TI Bioavailability and Bioequivalence Aspects of Oral Modified-Release Drug Products SO AAPS JOURNAL LA English DT Review DE bioavailability; bioequivalence; modified release; oral dosage form ID MONTE-CARLO SIMULATIONS; FORMULATIONS; SINGLE AB Oral modified-release (MR) products are dosage forms administered through the mouth and designed to release drug in a controlled manner to achieve maximum efficacy, minimal side effects, and better patient compliance. With significant progress in pharmaceutical technologies and favored therapeutic benefit, more and more oral MR products including the generic versions of these products are being developed, marketed, and used in the USA. Because different types of MR products may exhibit unique drug release modes and specific pharmacokinetic profiles, a better understanding of the regulation and evaluation of these generic MR products can help development and marketing of generic MR products that are therapeutically equivalent to the corresponding reference product. This review summarizes the general regulatory requirements for establishing bioequivalence between generic and reference oral MR products. In addition, some special regulatory considerations for bioequivalence evaluation are highlighted with examples of specific oral MR drug products. C1 [Wang, Rong; Li, Bing V.] US FDA, Div Bioequivalence 1, Off Bioequivalence, Off Gener Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Conner, Dale P.] US FDA, Off Bioequivalence, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Li, BV (reprint author), US FDA, Div Bioequivalence 1, Off Bioequivalence, Off Gener Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM bing.li@fda.hhs.gov NR 19 TC 1 Z9 1 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 MAR PY 2017 VL 19 IS 2 BP 360 EP 366 DI 10.1208/s12248-016-0025-9 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EM0KA UT WOS:000395006000004 PM 28004346 ER PT J AU Tyson, GH Zhao, SH Li, C Ayers, S Sabo, JL Lam, C Miller, RA McDermott, PF AF Tyson, Gregory H. Zhao, Shaohua Li, Cong Ayers, Sherry Sabo, Jonathan L. Lam, Claudia Miller, Ron A. McDermott, Patrick F. TI Establishing Genotypic Cutoff Values To Measure Antimicrobial Resistance in Salmonella SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article DE Salmonella; antibiotic resistance; breakpoints; whole-genome; sequencing ID NONTYPHOIDAL SALMONELLA; ESCHERICHIA-COLI; BREAKPOINTS; PLASMID AB Whole-genome sequencing (WGS) has transformed our understanding of antimicrobial resistance, helping us to better identify and track the genetic mechanisms underlying phenotypic resistance. Previous studies have demonstrated high correlations between phenotypic resistance and the presence of known resistance determinants. However, there has never been a large-scale assessment of how well resistance genotypes correspond to specific MICs. We performed antimicrobial susceptibility testing and WGS of 1,738 nontyphoidal Salmonella strains to correlate over 20,000 MICs with resistance determinants. Using these data, we established what we term genotypic cutoff values (GCVs) for 13 antimicrobials against Salmonella. For the drugs we tested, we define a GCV as the highest MIC of isolates in a population devoid of known acquired resistance mechanisms. This definition of GCV is distinct from epidemiological cutoff values (ECVs or ECOFFs), which currently differentiate wild-type from non-wild-type strains based on MIC distributions alone without regard to genetic information. Due to the large number of isolates involved, we observed distinct MIC distributions for isolates with different resistance gene alleles, including for ciprofloxacin and tetracycline, suggesting the potential to predict MICs based on WGS data alone. C1 [Tyson, Gregory H.; Zhao, Shaohua; Li, Cong; Ayers, Sherry; Sabo, Jonathan L.; Lam, Claudia; McDermott, Patrick F.] US FDA, Ctr Vet Med, Res Off, Laurel, MD 20708 USA. [Miller, Ron A.] US FDA, Ctr Vet Med, Off New Anim Drug Evaluat, Rockville, MD 20857 USA. RP Tyson, GH (reprint author), US FDA, Ctr Vet Med, Res Off, Laurel, MD 20708 USA. EM Gregory.Tyson@fda.hhs.gov NR 26 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 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAR PY 2017 VL 61 IS 3 AR e02140-16 DI 10.1128/AAC.02140-16 PG 12 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA EL4QM UT WOS:000394605900061 ER PT J AU Davis, JM Ekman, DR Skelton, DM LaLone, CA Ankley, GT Cavallin, JE Villeneuve, DL Collette, TW AF Davis, J. M. Ekman, D. R. Skelton, D. M. LaLone, C. A. Ankley, G. T. Cavallin, J. E. Villeneuve, D. L. Collette, T. W. TI Metabolomics for informing adverse outcome pathways: Androgen receptor activation and the pharmaceutical spironolactone SO AQUATIC TOXICOLOGY LA English DT Article DE Metabolomics; Fathead minnow; Mineralocorticoid; Reproduction ID MINNOW PIMEPHALES-PROMELAS; L-CARNITINE SUPPLEMENTATION; MINERALOCORTICOID RECEPTOR; FATHEAD MINNOW; POECILIA-RETICULATA; FISH; EXPOSURE; METABOLISM; 17-BETA-TRENBOLONE; CORTICOSTERONE AB One objective in developing adverse outcome pathways (AOPs) is to connect biological changes that are relevant to risk assessors (i.e., fecundity) to molecular and cellular-level alterations that might be detectable at earlier stages of a chemical exposure. Here, we examined biochemical responses of fathead minnows (Pimephales promelas) to inform an AOP relevant to spironolactone's activation of the androgen receptor, as well as explore other biological impacts possibly unrelated to this receptor. Liquid chromatography with high resolution mass spectrometry (LC-MS) was used to measure changes in endogenous polar metabolites in livers of male and female fish that were exposed to five water concentrations of spironolactone (0, 0.05, 0.5. 5, or 50 mu g L-1) for 21 days. Metabolite profiles were affected at the two highest concentrations (5 and 50 mu g L-1), but not in the lower-level exposures, which agreed with earlier reported results of reduced female fecundity and plasma vitellogenin (VTG) levels. We then applied partial least squares regression to assess whether metabolite alterations covaried with changes in fecundity, VTG gene expression and protein concentrations, and plasma 17 beta-estradiol and testosterone concentrations. Metabolite profiles significantly covaried with all measured endpoints in females, but only with plasma testosterone in males. Fecundity reductions occurred in parallel with changes in metabolites important in osmoregulation (e.g., betaine), membrane transport (e.g., L-carnitine), and biosynthesis of carnitine (e.g., methionine) and VTG (e.g., glutamate). Based on a network analysis program (i.e., mummichog), spironolactone also affected amino acid, tryptophan, and fatty acid metabolism. Thus, by identifying possible key events related to changes in biochemical pathways, this approach built upon an established AOP describing spirono-lactone's androgenic properties and highlighted broader implications potentially unrelated to androgen receptor activation, which could form a basis for the development of an AOP network. Published by Elsevier B.V. C1 [Davis, J. M.; Ekman, D. R.; Skelton, D. M.; Collette, T. W.] US EPA, Natl Exposure Res Lab, 960 Coll Stn Rd, Athens, GA 30605 USA. [LaLone, C. A.; Ankley, G. T.; Cavallin, J. E.; Villeneuve, D. L.] US EPA, Natl Hlth & Environm Effects Res Lab, 6201 Congdon Blvd, Duluth, MN 55804 USA. [Davis, J. M.] US EPA, Water Protect Div, Reg 4,61 Forsyth St SW, Atlanta, GA 30303 USA. [Skelton, D. M.] US FDA, 6751 Steger Dr, Cincinnati, OH 45237 USA. RP Davis, JM; Ekman, DR (reprint author), US EPA, Natl Exposure Res Lab, 960 Coll Stn Rd, Athens, GA 30605 USA.; Davis, JM (reprint author), US EPA, Water Protect Div, Reg 4,61 Forsyth St SW, Atlanta, GA 30303 USA. EM davis.john@epa.gov; ekman.drew@epa.gov FU Great Lakes National Program Office; ORISE Fellowship FX We thank E. Durhan, M. Hughes, K. Jensen, M. Kahl, E. Makynen, S. Skolness, and K. Stevens for technical assistance, and T. Smith for research support. J. Mosley provided advice on processing of LC-MS/MS data. J. Davis was supported by the Great Lakes National Program Office and an appointment to the Postdoctoral Research Program at the National Exposure Research Laboratory, administered by Oak Ridge Institute for Science and Education (ORISE) through interagency agreement between US Department of Energy and Environmental Protection Agency (EPA). J. Cavallin was also supported by an ORISE Fellowship. Views expressed in this article are those of the authors and do not necessarily represent views or policies of the US EPA. Mention of products or trade names does not indicate endorsement of by US EPA. NR 59 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-445X EI 1879-1514 J9 AQUAT TOXICOL JI Aquat. Toxicol. PD MAR PY 2017 VL 184 BP 103 EP 115 DI 10.1016/j.aquatox.2017.01.001 PG 13 WC Marine & Freshwater Biology; Toxicology SC Marine & Freshwater Biology; Toxicology GA EM9CO UT WOS:000395608900009 PM 28129603 ER PT J AU Tryndyak, V de Conti, A Doerge, DR Olson, GR Beland, FA Pogribny, IP AF Tryndyak, Volodymyr de Conti, Aline Doerge, Daniel R. Olson, Greg R. Beland, Frederick A. Pogribny, Igor P. TI Furan-induced transcriptomic and gene-specific DNA methylation changes in the livers of Fischer 344 rats in a 2-year carcinogenicity study SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Furan; Carcinogenicity; Liver; Gene expression; DNA methylation ID HUMAN HEPATOCELLULAR-CARCINOMA; HIPPO PATHWAY; GROWTH-FACTOR; MOUSE-LIVER; F344 RATS; IN-VIVO; EXPRESSION PROFILES; DUCTULAR REACTION; AMPHIREGULIN; CANCER AB Furan is a significant food contaminant and a potent hepatotoxicant and rodent liver carcinogen. The carcinogenic effect of furan has been attributed to genotoxic and non-genotoxic, including epigenetic, changes in the liver; however, the mechanisms of the furan-induced liver tumorigenicity are still unclear. The goal of the present study was to investigate the role of transcriptomic and epigenetic events in the development of hepatic lesions in Fischer (F344) rats induced by furan treatment in a classic 2-year rodent tumorigenicity bioassay. High-throughput whole-genome transcriptomic analysis demonstrated distinct alterations in gene expression in liver lesions induced in male F344 rats treated with 0.92 or 2.0 mg furan/kg body weight (bw)/day for 104 weeks. Compared to normal liver tissue, 1336 and 1541 genes were found to be differentially expressed in liver lesions in rats treated with 0.92 and 2.0 mg furan/kg bw/day, respectively, among which 1001 transcripts were differentially expressed at both doses. Pairing transcriptomic and next-generation bisulfite sequencing analyses of the common differentially expressed genes identified 42 CpG island-containing genes in which the methylation level was correlated inversely with gene expression. Forty-eight percent of these genes (20 genes, including Areg, Jag1, and Foxe1) that exhibited the most significant methylation and gene expression changes were involved in key pathways associated with different aspects of liver pathology. Our findings illustrate that gene-specific DNA methylation changes have functional consequences and may be an important component of furan hepatotoxicity and hepatocarcinogenicity. C1 [Tryndyak, Volodymyr; de Conti, Aline; Doerge, Daniel R.; Beland, Frederick A.; Pogribny, Igor P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Olson, Greg R.] Natl Ctr Toxicol Res, Toxicol Pathol Associates, Jefferson, AR 72079 USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov NR 49 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD MAR PY 2017 VL 91 IS 3 BP 1233 EP 1243 DI 10.1007/s00204-016-1786-8 PG 11 WC Toxicology SC Toxicology GA EM0BC UT WOS:000394982800012 PM 27387713 ER PT J AU Chen, S Zhang, ZH Qing, T Ren, Z Yu, DK Couch, L Ning, BT Mei, N Shi, LM Tolleson, WH Guo, L AF Chen, Si Zhang, Zhuhong Qing, Tao Ren, Zhen Yu, Dianke Couch, Letha Ning, Baitang Mei, Nan Shi, Leming Tolleson, William H. Guo, Lei TI Activation of the Nrf2 signaling pathway in usnic acid-induced toxicity in HepG2 cells SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Usnic acid; Liver toxicity; Oxidative stress; Nrf2 pathway ID ENDOPLASMIC-RETICULUM STRESS; INDUCED LIVER-INJURY; S-PHASE ARREST; OXIDATIVE STRESS; (+)-USNIC ACID; HEPATIC CELLS; DNA-DAMAGE; TRANSCRIPTION FACTOR; WEIGHT-LOSS; GENE AB Many usnic acid-containing dietary supplements have been marketed as weight loss agents, although severe hepatotoxicity and acute liver failure have been associated with their overuse. Our previous mechanistic studies revealed that autophagy, disturbance of calcium homeostasis, and ER stress are involved in usnic acid-induced toxicity. In this study, we investigated the role of oxidative stress and the Nrf2 signaling pathway in usnic acid-induced toxicity in HepG2 cells. We found that a 24-h treatment with usnic acid caused DNA damage and S-phase cell cycle arrest in a concentration-dependent manner. Usnic acid also triggered oxidative stress as demonstrated by increased reactive oxygen species generation and glutathione depletion. Short-term treatment (6 h) with usnic acid significantly increased the protein level for Nrf2 (nuclear factor erythroid 2-related factor 2), promoted Nrf2 translocation to the nucleus, up-regulated antioxidant response element (ARE)-luciferase reporter activity, and induced the expression of Nrf2-regulated targets, including glutathione reductase, glutathione S-transferase, and NAD(P)H quinone oxidoreductase-1 (NQO1). Furthermore, knockdown of Nrf2 with shRNA potentiated usnic acid-induced DNA damage and cytotoxicity. Taken together, our results show that usnic acid causes cell cycle dysregulation, DNA damage, and oxidative stress and that the Nrf2 signaling pathway is activated in usnic acid-induced cytotoxicity. C1 [Chen, Si; Ren, Zhen; Couch, Letha; Tolleson, William H.; Guo, Lei] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, HFT 110,3900 NCTR Rd, Jefferson, AR 72079 USA. [Zhang, Zhuhong; Mei, Nan] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Zhang, Zhuhong] Tianjin Med Univ, Gen Hosp, Tianjin 300052, Peoples R China. [Qing, Tao; Shi, Leming] Fudan Univ, Sch Pharm, Sch Life Sci, Fudan Zhangjiang Ctr Clin Genom, Shanghai 200438, Peoples R China. [Qing, Tao; Shi, Leming] Fudan Univ, Zhanjiang Ctr Translat Med, Shanghai 200438, Peoples R China. [Yu, Dianke; Ning, Baitang] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Guo, L (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, HFT 110,3900 NCTR Rd, Jefferson, AR 72079 USA. EM lei.guo@fda.hhs.gov FU U.S. FDA's intramural grant; National High Technology Research and Development Program of China [2015AA020104]; National Natural Science Foundation of China [31471239]; 111 Project [B13016]; National Super-computer Center in Guangzhou, China FX ZH. Z., DK. Y., and Z. R. were supported by appointments to the Postgraduate Research Program at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science Education through an interagency agreement between the US Department of Energy and the U.S. FDA. This work was supported by U.S. FDA's intramural grant. L.S. was supported by the National High Technology Research and Development Program of China (2015AA020104), the National Natural Science Foundation of China (31471239), the 111 Project (B13016), and the National Super-computer Center in Guangzhou, China NR 62 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD MAR PY 2017 VL 91 IS 3 BP 1293 EP 1307 DI 10.1007/s00204-016-1775-y PG 15 WC Toxicology SC Toxicology GA EM0BC UT WOS:000394982800016 PM 27369375 ER PT J AU Van Epps, P Tumpey, T Pearce, MB Golding, H Higgins, P Hornick, T Burant, C Wilson, BM Banks, R Gravenstein, S Canaday, DH AF Van Epps, Puja Tumpey, Terrence Pearce, Melissa B. Golding, Hana Higgins, Patricia Hornick, Thomas Burant, Christopher Wilson, Brigid M. Banks, Richard Gravenstein, Stefan Canaday, David H. TI Preexisting Immunity, Not Frailty Phenotype, Predicts Influenza Postvaccination Titers among Older Veterans SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article DE Frailty; influenza vaccines ID HEMAGGLUTINATION INHIBITION ASSAY; HEALTH-CARE PERSONNEL; ANTIBODY-RESPONSE; UNITED-STATES; VACCINE EFFICACY; VIRUS; HOSPITALIZATIONS; PROTECTION; INFECTION; COMMUNITY AB Both preexisting immunity to influenza and age have been shown to be correlates of influenza vaccine responses. Frailty, an indicator of functional impairment in older adults, was also shown in one study to predict lower influenza vaccine responses among nonveterans. In the current study, we aimed to determine the associations between frailty, preexisting immunity, and immune responses to influenza vaccine among older veterans. We studied 117 subjects (age range, 62 to 95 years [median age, 81 years]), divided into three cohorts based on the Fried frailty test, i.e., nonfrail (NF) (n = 23 [median age, 68 years]), prefrail (n = 50 [median age, 80 years]), and frail (n = 44 [median age, 82 years]), during the 2010-2011 and 20112012 influenza seasons. Subjects received the seasonal trivalent inactivated influenza vaccine, and baseline and postvaccination samples were obtained. Anti-influenza humoral immunity, as measured by hemagglutination inhibition (HI) and microneutralization assays, was measured for influenza B, A(H1N1) pdm09, and A(H3N2) viruses. Postvaccination titers were not different between frail and NF subjects overall in this older subset of veterans. However, preexisting HI titers were strongly correlated with postvaccination titers among all functional status groups. When microneutralization titers were compared, the association between preexisting immunity and vaccine responses varied by frailty status, with the strongest correlation being observed for the NF group. In conclusion, preexisting immunity rather than frailty appeared to predict postvaccination titers in this older veteran cohort. C1 [Van Epps, Puja; Higgins, Patricia; Hornick, Thomas; Burant, Christopher; Wilson, Brigid M.; Banks, Richard; Canaday, David H.] Louis Stokes Cleveland VA Med Ctr, Geriatr Res Educ & Clin Ctr, Cleveland, OH 44106 USA. [Van Epps, Puja; Hornick, Thomas; Canaday, David H.] Case Western Reserve Univ, Dept Internal Med, Cleveland, OH 44106 USA. [Tumpey, Terrence; Pearce, Melissa B.] Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. [Golding, Hana] US FDA, Div Viral Prod, CBER, Silver Spring, MD USA. [Higgins, Patricia; Burant, Christopher] Case Western Reserve Univ, Sch Nursing, Cleveland, OH 44106 USA. [Gravenstein, Stefan] Case Western Reserve Univ, Dept Med, Div Geriatr, Cleveland, OH 44106 USA. RP Van Epps, P (reprint author), Louis Stokes Cleveland VA Med Ctr, Geriatr Res Educ & Clin Ctr, Cleveland, OH 44106 USA.; Van Epps, P (reprint author), Case Western Reserve Univ, Dept Internal Med, Cleveland, OH 44106 USA. EM puja.vanepps@va.gov FU VA Merit Review funds; NIH [AI108972] FX The work was supported by VA Merit Review funds and NIH grant AI108972. NR 41 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 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD MAR PY 2017 VL 24 IS 3 AR UNSP e00498 DI 10.1128/CVI.00498-16 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EN1US UT WOS:000395796300001 ER PT J AU Ahn, J Albusaysi, S Alfonsi, J Ande, A Bank, P Barr, E Bezencon, J Bhagwat, S Borden, B Bos, J Brewer, J Bruckm, H Chanu, P Chen, XY Chen, H Chen, MQ Chowdhury, S Chu, LH Cooper, J Dhapare, S Freimuth, R Freise, K Hashida, T Hassan, O He, J Hoefman, S Hutchaleelaha, A Imai, S Jackson, I Job, K Kaspera, R Kleiber, N Klopp-Schulze, L Kramers, C Kumar, S Lai, E Lam, J Leibrand, C Lemmen, J Li, J Lo, A Lon, HK Maas, H Maass, C Marcath, L Marroum, P Morse, B Mostafa, N Mueck, W Mukherjee, D Ning, MR Oishi, M Pak, Y Park, WS Pasternak, A Piao, Z Poi, M Prasad, TN Prem, K Ramaiya, A Raut, A Rotter, C Salem, F Schmidt, K Seligson, N Shibata, K Shivva, V Suleiman, A Tanner, JA Tariq, B Trueman, S Wind, S Xia, C Xiong, H Yamada, T Yang, UO Yu, JJ Zhang, S Zhao, WH Zhou, JW AF Ahn, Jihye Albusaysi, Salwa Alfonsi, Jeffrey Ande, Anusha Bank, Paul Barr, Erin Bezencon, Jacqueline Bhagwat, Sharvari Borden, Brittany Bos, Jacqueline Brewer, Jamie Bruckm, Henrike Chanu, Pascal Chen, Xiaoying Chen, Heller Chen, Mingqing Chowdhury, Swapan Chu, Liang-Hui Cooper, Jennifer Dhapare, Sneha Freimuth, Robert Freise, Kevin Hashida, Tohru Hassan, Omar He, Jimmy Hoefman, Sven Hutchaleelaha, Athiwat Imai, Satoki Jackson, Isabel Job, Kathleen Kaspera, Rudiger Kleiber, Niina Klopp-Schulze, Lena Kramers, Cornelis Kumar, Shaun Lai, Eseng Lam, Justine Leibrand, Crystal Lemmen, Julia Li, Jerry Lo, Arthur Lon, Hoi Kei Maas, Hugo Maass, Christian Marcath, Lauren Marroum, Patrick Morse, Bridget Mostafa, Nael Mueck, Wolfgang Mukherjee, Dwaipavan Ning, Miaoran Oishi, Masayo Pak, Youngeen Park, Wan-Su Pasternak, Amy Piao, Zhenji Poi, Ming Prasad, Nagendra T. Prem, Komal Ramaiya, Atulkumar Raut, Anuja Rotter, Charles Salem, Farzaneh Schmidt, Keith Seligson, Nathan Shibata, Kaito Shivva, Vittal Suleiman, Ahmed Tanner, Julie-Anne Tariq, Bilal Trueman, Sheryl Wind, Sven Xia, Cindy Xiong, Hao Yamada, Takahiro Yang, Uan-Ou Yu, Jingjing Zhang, Steven Zhao, Weihan Zhou, Jiawei CA ASCPT Members TI 2017 Annual Meeting - What you need to know before you arrive SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material C1 [Ahn, Jihye] US FDA, Washington, DC 20204 USA. [Albusaysi, Salwa] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Alfonsi, Jeffrey] Univ Western Ontario, London, ON N6A 3K7, Canada. [Ande, Anusha] Univ Florida, Gainesville, FL 32611 USA. [Bank, Paul] Leiden Univ, Med Ctr, NL-2300 RA Leiden, Netherlands. [Barr, Erin; Borden, Brittany] Univ Chicago, Chicago, IL 60637 USA. [Bezencon, Jacqueline] Univ N Carolina, Chapel Hill, NC USA. [Bhagwat, Sharvari] Amgen Inc, Thousand Oaks, CA USA. [Bos, Jacqueline] Canisius Wilhelmina Hosp, Nijmegen, Netherlands. [Brewer, Jamie] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Bruckm, Henrike] Univ Hosp Schleswig Holstein, Kiel, Germany. [Chanu, Pascal] F Hoffmann La Roche Ltd, Basel, Switzerland. [Chen, Xiaoying] Pfizer Global Res & Dev, New London, CT USA. [Chen, Heller] Novartis Oncol, Basel, Switzerland. [Chen, Mingqing; Poi, Ming; Seligson, Nathan] Ohio State Univ, Columbus, OH 43210 USA. [Chowdhury, Swapan] Takeda Pharmaceut Co, Osaka, Japan. [Chu, Liang-Hui] Biogen, Cambridge, MA USA. [Cooper, Jennifer] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Dhapare, Sneha; Hassan, Omar; Leibrand, Crystal; Raut, Anuja] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Freimuth, Robert; Prem, Komal] Mayo Clin, Rochester, MN USA. [Freise, Kevin; Lon, Hoi Kei; Marroum, Patrick; Mostafa, Nael; Ning, Miaoran; Suleiman, Ahmed; Tariq, Bilal; Trueman, Sheryl; Xiong, Hao; Zhao, Weihan] AbbVie, N Chicago, IL USA. [Hashida, Tohru] Kobe City Med Ctr Gen Hosp, Kobe, Hyogo, Japan. [He, Jimmy] INC Res, Raleigh, NC USA. [Hoefman, Sven] Ablynx NV, Ghent, Belgium. [Hutchaleelaha, Athiwat] Global Blood Therapeut, San Francisco, CA USA. [Imai, Satoki] Sumitomo Dainippon Pharm, Osaka, Japan. [Jackson, Isabel] Univ Maryland, College Pk, MD 20742 USA. [Job, Kathleen; Kumar, Shaun] Univ Utah, Salt Lake City, UT 84112 USA. [Kaspera, Rudiger] Astellas Pharma Europe BV, Leiden, Netherlands. [Kleiber, Niina] Eramus MC Rotterdam, Rotterdam, Netherlands. [Klopp-Schulze, Lena] Free Univ Berlin, Berlin, Germany. [Kramers, Cornelis] Radboud Univ Nijmegen, Med Ctr, Nijmegen, Netherlands. [Lai, Eseng] Merck & Co Inc, Kenilworth, NJ USA. [Lam, Justine; Ramaiya, Atulkumar] Pfizer Inc, New York, NY USA. [Lemmen, Julia; Mueck, Wolfgang] Bayer AG, Leverkusen, Germany. [Li, Jerry; Marcath, Lauren; Pasternak, Amy] Univ Michigan, Ann Arbor, MI 48109 USA. [Lo, Arthur] Theravance Inc, San Francisco, CA USA. [Maas, Hugo] Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany. [Maass, Christian] MIT, Cambridge, MA 02139 USA. [Morse, Bridget] Eli Lilly, Indianapolis, IN USA. [Ning, Miaoran] Univ Illinois, Chicago, IL USA. [Oishi, Masayo] Pfizer Japan Inc, Tokyo, Japan. [Pak, Youngeen] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Park, Wan-Su] Catholic Univ Korea, Seoul, South Korea. [Piao, Zhenji] Seoul Natl Univ Hosp, Seoul, South Korea. [Prasad, Nagendra T.] Prestige Shantiniketan, Bangalore, Karnataka, India. [Rotter, Charles] Sekisui XenoTech LLC, Kansas City, KS USA. [Salem, Farzaneh] Simcyp Certara, Princeton, NJ USA. [Schmidt, Keith] NCI, Bethesda, MD 20892 USA. [Shibata, Kaito; Yamada, Takahiro] Hamamatsu Univ Sch Med, Hamamatsu, Shizuoka, Japan. [Shivva, Vittal] ORISE, Oak Ridge, TN USA. [Tanner, Julie-Anne] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Wind, Sven] Boehringer Ingelheim Pharm GmbH & Co Kg, Ingelheim, Germany. [Xia, Cindy] Takeda Pharmaceut Int Co, Osaka, Japan. [Yang, Uan-Ou] Incyte, Wilmington, DE USA. [Yu, Jingjing] Univ Washington, Seattle, WA 98195 USA. [Zhang, Steven] Takeda Pharmaceut, Osaka, Japan. [Zhou, Jiawei] Tsinghua Univ, Beijing, Peoples R China. RP Ahn, J (reprint author), US FDA, Washington, DC 20204 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY 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 MAR PY 2017 VL 101 IS 3 BP 310 EP 316 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EO6ZJ UT WOS:000396840700004 ER PT J AU Irwin, JJ Pottel, J Zou, L Wen, H Zuk, S Zhang, X Sterling, T Shoichet, BK Lionberger, R Giacomini, KM AF Irwin, J. J. Pottel, J. Zou, L. Wen, H. Zuk, S. Zhang, X. Sterling, T. Shoichet, B. K. Lionberger, R. Giacomini, K. M. TI A Molecular Basis for Innovation in Drug Excipients SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB Excipients are ubiquitous in drug formulation, ensuring that active ingredient drugs are properly released on dosing, retain their properties over time, and are palatable, among other roles. Despite their crucial roles, surprisingly little is known about their systemic availability and activities on molecular targets. Here we review key excipient properties, introduce a public-accessible database that enumerates and categorizes them, and sketch a strategy for exploring their possible direct actions on molecular targets. C1 [Irwin, J. J.; Pottel, J.; Sterling, T.; Shoichet, B. K.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. [Irwin, J. J.; Pottel, J.; Sterling, T.; Shoichet, B. K.] Univ Calif San Francisco, Inst QB3, San Francisco, CA 94143 USA. [Zou, L.; Giacomini, K. M.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Wen, H.; Zuk, S.; Zhang, X.; Lionberger, R.] US FDA, Silver Spring, MD USA. RP Shoichet, BK (reprint author), Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA.; Shoichet, BK (reprint author), Univ Calif San Francisco, Inst QB3, San Francisco, CA 94143 USA.; Giacomini, KM (reprint author), Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA.; Lionberger, R (reprint author), US FDA, Silver Spring, MD USA. EM bshoichet@gmail.com; Robert.Lionberger@fda.hhs.gov; kathy.giacomini@ucsf.edu FU US Food & Drug Administration [U01FD004979] FX The work of the UCSF investigators was supported by a grant from the US Food & Drug Administration U01FD004979 (PI KM Giacomini and R Altman). NR 7 TC 0 Z9 0 U1 0 U2 0 PU WILEY 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 MAR PY 2017 VL 101 IS 3 BP 320 EP 323 DI 10.1002/cpt.458 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EO6ZJ UT WOS:000396840700006 PM 27557422 ER PT J AU Gould, LH Kline, J Monahan, C Vierk, K AF Gould, L. Hannah Kline, Jennifer Monahan, Caitlin Vierk, Katherine TI Outbreaks of Disease Associated with Food Imported into the United States, 1996-2014(1) SO EMERGING INFECTIOUS DISEASES LA English DT Article AB The proportion of US food that is imported is increasing; most seafood and half of fruits are imported. We identified a small but increasing number of foodborne disease out-breaks associated with imported foods, most commonly fish and produce. New outbreak investigation tools and federal regulatory authority are key to maintaining food safety. C1 [Gould, L. Hannah; Kline, Jennifer] Ctr Dis Control & Prevent, Atlanta, GA USA. [Monahan, Caitlin; Vierk, Katherine] US FDA, College Pk, MD USA. RP Gould, LH (reprint author), NYC Dept Mental Hlth & Hyg, 42-09 28th St,7th Fl, Queens, NY 11101 USA. EM hgould@health.nyc.gov NR 11 TC 0 Z9 0 U1 1 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD MAR PY 2017 VL 23 IS 3 BP 525 EP 528 DI 10.3201/eid2303.161462 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EL7WB UT WOS:000394830900025 PM 28221117 ER PT J AU Zhang, GD Ali, L Gill, V Tatavarthy, A Deng, XH Hu, LJ Brown, EW Hammack, TS AF Zhang, Guodong Ali, Laila Gill, Vikas Tatavarthy, Aparna Deng, Xiaohong Hu, Lijun Brown, Eric W. Hammack, Thomas S. TI Development and Validation of a Cultural Method for the Detection and Isolation of Salmonella in Cloves SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Clove; Microbial detection; Preenrichment; Salmonella; Spice; US Food and Drug Administration Bacteriological Analytical Manual ID SPICES; CONTAMINATION; PREVALENCE; OUTBREAK; SPP. AB Detection of Salmonella in some spices, such as cloves, remains a challenge due to their inherent antimicrobial properties. The purpose of this study was to develop an effective detection method for Salmonella from spices using cloves as a model. Two clove varieties, Ceylon and Madagascar, were used in the study. Cloves were inoculated with Salmonella enterica subsp. enterica serotypes Montevideo, Typhimurium, or Weltevreden at about 1, 3, or 6 log CFU/25 g. Two test portion sizes, 10 and 25 g, were compared. After adding Trypticase soy broth (TSB) to the weighed cloves for preenrichment, three preenrichment methods were compared: cloves were left in the TSB for 24 h during preenrichment (PreEl), or the cloves-TSB mixture was shaken vigorously for 30s (PreE2) or 60s (PreE3), and the decanted material was transferred to a new bag for 24 h of preenrichment. The rest of the procedures were carried out according to the U.S. Food and Drug Administration Bacteriological Analytical Manual (BAM). At the low inoculation level (<1 log CFU/25 g), the detection rate was low across the three preenrichment methods, with the highest for PreE3 and lowest for PreEl. At the medium and high inoculation levels (3 and 6 log CFU/25 g), all samples from PreE2 and PreE3 were positive for Salmonella, whereas PreEl produced only 12 positive samples from the 48 samples at the medium inoculation level and 38 positive samples from the 48 samples at the high inoculation level. Therefore, PreE3 with 25 g of cloves per sample was more effective than the other two tested methods. This newly designed method was then validated by comparing with the BAM method in six trials, with each trial consisting of 40 test samples. The results showed that PreE3 detected Salmonella from 88 of 120 inoculated test samples compared with only 31 positive from 120 test samples with the BAM method. Thus, our newly designed method PreE3 was more sensitive and easier to operate than the current BAM method for detection of Salmonella in cloves. C1 [Zhang, Guodong; Ali, Laila; Gill, Vikas; Tatavarthy, Aparna; Deng, Xiaohong; Hu, Lijun; Brown, Eric W.; Hammack, Thomas S.] US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr, College Pk, MD 20740 USA. RP Zhang, GD (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr, College Pk, MD 20740 USA. EM guodong.zhang@fda.hhs.gov NR 25 TC 0 Z9 0 U1 1 U2 1 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD MAR PY 2017 VL 80 IS 3 BP 376 EP 382 DI 10.4315/0362-028X.ThP-16-376 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EM7ML UT WOS:000395495800002 PM 28199150 ER PT J AU Feng, P Delannoy, S Lacher, DW Bosilevac, JM Fach, P AF Feng, Peter Delannoy, Sabine Lacher, David W. Bosilevac, Joseph M. Fach, Patrick TI Characterization and Virulence Potential of Serogroup 0113 Shiga Toxin Producing Escherichia coli Strains Isolated from Beef and Cattle in the United States SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Diversity; Shiga toxin-producing Escherichia coli; 0113; Virulence ID HEMOLYTIC-UREMIC SYNDROME; REAL-TIME PCR; ENTEROCYTE EFFACEMENT; GENETIC DIVERSITY; 5'-NUCLEASE PCR; FRESH PRODUCE; LOCUS; SEROTYPES; FOOD; EHEC AB Shiga toxin producing Escherichia coli (STEC) of serotype O113:H21 have caused severe diseases but are unusual in that they do not produce the intimin protein required for adherence to intestinal epithelial cells. Strains of serogroup O113 are one of the most common STEC found in ground beef and beef products in the United States, but their virulence potential is unknown. We used a microarray to characterize 65 O113 strains isolated in the United States from ground beef, beef trim, cattle feces, and fresh spinach. Most were O113:H21 strains, but there were also nine strains of O113:H4 serotype. Although strains within the same serotype had similar profiles for the genes that were tested on the array, the profiles were distinct between the two serotypes, and the strains belonged to different clonal groups. Analysis by clustered regularly interspaced short palindromic repeat analysis showed that O113:H4 strains are conserved genetically, but the O113:H21 strains showed considerable polymorphism and genetic diversity. In comparison to the O113:H21 strains from Australia that were implicated in severe disease, the U.S. isolates showed similar genetic profiles to the known pathogens from Australia, suggesting that these may also have the potential to cause infections. C1 [Feng, Peter] US FDA, Div Microbiol, 5001 Campus Dr, College Pk, MD 20740 USA. [Delannoy, Sabine; Fach, Patrick] French Agcy Food Environm & Occupat Hlth & Safety, 27-31 Ave Gen Leclerc, F-94701 Maisons Alfort, France. [Lacher, David W.] US FDA, Div Mol Biol, 8401 Muirkirk Rd, Laurel, MD 20708 USA. [Bosilevac, Joseph M.] ARS, US Meat Anim Res Ctr, USDA, POB 166,State Spur 18D, Clay Ctr, NE 68933 USA. RP Feng, P (reprint author), US FDA, Div Microbiol, 5001 Campus Dr, College Pk, MD 20740 USA. EM peter.feng@fda.hhs.gov NR 43 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 80 IS 3 BP 383 EP 391 DI 10.4315/0362-028X.JFP-16-325 PG 9 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EM7ML UT WOS:000395495800003 PM 28199145 ER PT J AU Zhang, GD Hu, LJ Melka, D Wang, H Laasri, A Brown, EW Strain, E Allard, M Bunning, VK Musser, SM Johnson, R Farakos, SMS Scott, VN Pouillot, R van Doren, JM Hammack, TS AF Zhang, Guodong Hu, Lijun Melka, David Wang, Hua Laasri, Anna Brown, Eric W. Strain, Errol Allard, Marc Bunning, Vincent K. Musser, Steven M. Johnson, Rhoma Farakos, Sofia M. Santillana Scott, Virginia N. Pouillot, Regis van Doren, Jane M. Hammack, Thomas S. TI Prevalence of Salmonella in Cashews, Hazelnuts, Macadamia Nuts, Pecans, Pine Nuts, and Walnuts in the United States SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Low moisture; Low water activity; Nutmeat; Serotype; Tree nuts ID ESCHERICHIA-COLI O157H7; BACTERIOLOGICAL QUALITY; MICROBIOLOGICAL SAFETY; PROCESSING FACILITIES; RAW; KERNELS; PEANUTS; INFORMATION; PISTACHIOS; SURVIVAL AB Nuts have been identified as a vector for salmonellosis. The objective of this project was to estimate the prevalence and contamination level of Salmonella in raw tree nuts (cashews, pecans, hazelnuts, macadamia nuts, pine nuts, and walnuts) at retail markets in the United States. A total of 3,656 samples of six types of tree nuts were collected from different types of retail stores and markets nationwide between October 2014 and October 2015. These samples were analyzed using a modified version of the Salmonella culture method from the U.S. Food and Drug Administration's Bacteriological Analytical Manual. Of the 3,656 samples collected and tested, 32 were culturally confirmed as containing Salmonella. These isolates represented 25 serotypes. Salmonella was not detected in pecans and in-shell hazelnuts. Salmonella prevalence estimates (and 95% confidence intervals) in cashews, shelled hazelnuts, pine nuts, walnuts, and macadamia nuts were 0.55% [0.15, 1.40], 0.35% [0.04, 1.20], 0.48% [0.10, 1.40], 1.20% [0.53, 2.40], and 4.20% [2.40, 6.90], respectively. The rates of Salmonella isolation from major or big chain supermarkets, small chain supermarkets, discount, variety, or drug stores, and online were 0.64% [0.38, 1.00], 1.60% [0.80, 2.90], 0.00% [0.00, 2.40], and 13.64% [2.90, 35.00], respectively (Cochran-Mantel-Haenszel test: P = 0.02). The rates of Salmonella isolation for conventional and organic nuts were not significantly different. Of the samples containing Salmonella, 60.7% had levels less than 0.003 most probable number (MPN)/g. The highest contamination level observed was 0.092 MPN/g. The prevalence and levels of Salmonella in these tree nut samples were comparable to those previously reported for similar foods. C1 [Zhang, Guodong; Hu, Lijun; Melka, David; Wang, Hua; Laasri, Anna; Brown, Eric W.; Strain, Errol; Allard, Marc; Bunning, Vincent K.; Musser, Steven M.; Johnson, Rhoma; Farakos, Sofia M. Santillana; Scott, Virginia N.; Pouillot, Regis; van Doren, Jane M.; Hammack, Thomas S.] US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr, College Pk, MD 20740 USA. RP Zhang, GD (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr, College Pk, MD 20740 USA. EM guodong.zhang@fda.hhs.gov NR 30 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 80 IS 3 BP 459 EP 466 DI 10.4315/0362-028X.JFP-16-396 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EM7ML UT WOS:000395495800013 PM 28207311 ER PT J AU Swanson, S Fu, TJ AF Swanson, Sara Fu, Tong-Jen TI Effect of Water Hardness on Efficacy of Sodium Hypochlorite Inactivation of Escherichia coli O157:H7 in Water SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Chlorine inactivation; Escherichia coli O157:H7; Water hardness ID CHLORINE INACTIVATION; CROSS-CONTAMINATION; PRODUCE WASH; ORGANIC LOAD; DISINFECTION; SURVIVAL; O157-H7; LETTUCE AB This study examined how the hardness of water affected the efficacy of sodium hypochlorite in inactivating Escherichia coli 0157:H7 in water. Water was prepared at different degrees of total hardness (0, 50, 100, 200, 500, 1,000, 2,000, and 5,000 mg/ liter CaCO3). Inactivation was assessed at different levels of free chlorine (0, 0.2, 0.5, and 1.0 ppm) at 2 to 4 degrees C and pH 6.5. Thirty milliliters of chlorinated water was inoculated with 6 log CFU/ml of E. coli O157:H7 and allowed to mix for 3, 10, 20, or 30 s. In the absence of sodium hypochlorite, no reduction in counts of E. coli O157:H7 was observed regardless of the degree of water hardness. However, in the presence of hard water, under certain chlorine concentrations and exposure times, the reduction of E. coli O157:H7 in chlorinated hard water was significantly less than the reduction observed in chlorinated deionized water. For example, after exposure to 0.5 ppm of free chlorine for 10 s, E. coli O157:H7 counts were reduced by 4.8 +/- 1.4, 2.0 +/- 1.3, 1.6 +/- 0.7, 0.5 +/- 0.7, and 0.0 +/- 0.1 log CFU/m1 in water containing 0, 100, 1,000, 2,000, and 5,000 mg/liter CaCO3, respectively. With the exception of 5,000 mg/liter CaCO3, the effect of water hardness was no longer visible after 20 s of exposure to 0.5 ppm of free chlorine. Also, hard water significantly lowered the efficacy of sodium hypochlorite at 3 s of exposure to 1.0 ppm of free chlorine. But after 20 s of exposure to 1.0 ppm of free chlorine, the impact of water hardness was no longer observed. This study demonstrated that water hardness can affect the germicidal efficacy of sodium hypochlorite, and such an impact may or may not be apparent depending on the condition of the solution and the treatment time at which the observation is made. Under the conditions typically seen in commercial produce washing operations, the impact of water hardness on chlorine efficacy is likely to be insignificant compared with that of organic load. C1 [Swanson, Sara] Illinois Inst Technol, Inst Food Safety & Hlth, 6502 S Archer Rd,Pk, Bedford, IL 60501 USA. [Fu, Tong-Jen] US FDA, Div Food Proc Sci & Technol, 6502 South Archer Rd,Pk, Bedford, IL 60501 USA. RP Fu, TJ (reprint author), US FDA, Div Food Proc Sci & Technol, 6502 South Archer Rd,Pk, Bedford, IL 60501 USA. EM tongjen.fu@fda.hhs.gov FU U.S. Food and Drug Administration [U19FD005322]; Institute for Food Safety and Health FX This work was supported by cooperative agreement U19FD005322 between the U.S. Food and Drug Administration and the Institute for Food Safety and Health. We thank Dr. Kaiping Deng at the Illinois Institute of Technology for providing the E. coli O157:H7 strain used in this study. NR 24 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 80 IS 3 BP 497 EP 501 DI 10.4315/0362-028X-JFP-16-112 PG 5 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EM7ML UT WOS:000395495800018 PM 28207312 ER PT J AU Kang, IB Chon, JW Kim, DH Jeong, D Kim, HS Kem, H Seo, KH AF Kang, Il-Byeong Chon, Jung-Whan Kim, Dong-Hyeon Jeong, Dana Kim, Hong-Seok Kem, Hyunsook Seo, Kun-Ho TI Improvement of Polymyxin-Egg Yolk-Mannitol-Bromothymol Blue Agar for the Enumeration and Isolation of Bacillus cereus in Various Foods SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Bacillus cereus; Competing microflora; Modified polymyxin-egg yolk-mannitol-bromothymol blue agar; Selective media; Trimethoprim ID LISTERIA-MONOCYTOGENES; QUANTITATIVE DETECTION; TRIMETHOPRIM; IDENTIFICATION; STANDARD AB A modified polymyxin egg-yolk mannitol-bromothymol blue agar (mPEMBA) was developed by supplementing polymyxin egg yolk mannitol bromothymol blue agar (PEMBA) with trimethoprim to improve the selectivity for and recoverability of Bacillus cereus from naturally and artificially contaminated food samples. The number of B. cereus in mPEMBA was significantly higher than in PEMBA, indicating better recoverability (P < 0.05) in red pepper powder (PEMBA 0.80 +/- 0.22 log CFU/g versus mPEMBA 1.95 +/- 0.17 log CFU/g) and soybean paste (PEMBA 2.19 +/- 0.18 log CFU/g versus mPEMBA 3.09 +/- 0.13 log CFU/g). In addition, mPEMBA provided better visual differentiation of B. cereus colonies than PEMBA, which is attributable to the reduced number of competing microfiora. We conclude that the addition of trimethoprim to PEMBA could generate a synergistic effect to improve selectivity for B. cereus. C1 [Kang, Il-Byeong; Chon, Jung-Whan; Kim, Dong-Hyeon; Jeong, Dana; Kim, Hong-Seok; Seo, Kun-Ho] Konkuk Univ, Ctr One Hlth, Coll Veterinaty Med, 1 Hwayang dong, Seoul 05029, South Korea. [Kem, Hyunsook] Hanyang Univ, Coll Human Ecol, Dept Food & Nutr, Seoul 04763, South Korea. [Chon, Jung-Whan] Natl Ctr Toxicol Res, US Food & Drug Adm, Div Microbiol, Jefferson, AR 72079 USA. RP Seo, KH (reprint author), Konkuk Univ, Ctr One Hlth, Coll Veterinaty Med, 1 Hwayang dong, Seoul 05029, South Korea. EM bracstu3@konkuk.ac.kr FU National Research Foundation of Korea (NRF) - Korea government (Ministry of Science, Information and Communications Technology, and Future Planning) [2015R1A2A2A05001288] FX This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science, Information and Communications Technology, and Future Planning; No. 2015R1A2A2A05001288). NR 18 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 80 IS 3 BP 502 EP 505 DI 10.4315/0362-028X-JFP-16-206 PG 4 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EM7ML UT WOS:000395495800019 PM 28207304 ER PT J AU Liachenko, S Ramu, J AF Liachenko, Serguei Ramu, Jaivijay TI Quantification and Reproducibility Assessment of the Regional Brain T-2 Relaxation in Naive Rats at 7T SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article ID INDUCED STATUS EPILEPTICUS; MULTIPLE-SCLEROSIS; KAINIC ACID; NEURONAL DAMAGE; IN-VIVO; MRI; DIFFUSION; NEUROTOXICITY; ATLAS; MECHANISMS AB Purpose: To measure the reproducibility of T-2 relaxation and to determine the statistical power of T-2 mapping in the rat brain as a characteristic of the baseline performance of the T-2 relaxation as a potential biomarker of neurotoxicity. Materials and Methods: Multislice multiecho spin-echo imaging was utilized to obtain the quantitative T-2 maps in 138 naive rats at 7T. Images were skull-stripped and coregistered to the common anatomical reference. A full anatomical segmentation mask, which included all major brain structures, was created using the same reference T-2 map. The overall variability map was also calculated from all T-2 maps and the areas with arbitrarily high variability (coefficient of variation >25%) were excluded from the full segmentation mask to produce a trimmed mask. T-2 maps were segmented using both these masks and statistical power analysis was conducted in all segmented areas. Results: The coefficient of variation of T-2 relaxation in different brain areas varied from 5.4% (cerebrospinal fluid) to 1.2% (cortex) when using a full segmentation mask. The use of a trimmed segmentation mask decreased the coefficient of variation in many areas, which ranged between 3.2% (inferior colliculi) and 1.2% (cortex) in this case. As revealed by statistical power analysis to detect 5% change with power of 0.8, the minimum number of observations needed for different areas ranged from 3 (cortex) to 8 (inferior colliculi) in the case of use of a trimmed segmentation mask. Conclusion: T-2 relaxation is a very reproducible MRI parameter of the rat brain with high statistical power, which allows detecting very small changes in groups consisting of a minimal number of experimental animals. C1 [Liachenko, Serguei; Ramu, Jaivijay] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Liachenko, S (reprint author), 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Serguei.Liachenko@fda.hhs.gov FU National Center for Toxicological Research (NCTR); Center for Drug Evaluation and Research (CDER); U. S. Food and Drug Administration (FDA) [E07418] FX Contract grant sponsor: National Center for Toxicological Research (NCTR); Contract grant sponsor: Center for Drug Evaluation and Research (CDER); Contract grant sponsor: U.S. Food and Drug Administration (FDA) (protocol number E07418). NR 43 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD MAR PY 2017 VL 45 IS 3 BP 700 EP 709 DI 10.1002/jmri.25378 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EL4QF UT WOS:000394605200007 PM 27384412 ER PT J AU Stoyanova-Slavova, IB Slavov, SH Buzatu, DA Beger, RD Wilkes, JG AF Stoyanova-Slavova, Iva B. Slavov, Svetoslav H. Buzatu, Dan A. Beger, Richard D. Wilkes, Jon G. TI 3D-SDAR modeling of hERG potassium channel affinity: A case study in model design and toxicophore identification SO JOURNAL OF MOLECULAR GRAPHICS & MODELLING LA English DT Article DE 3D-QSDAR; hERG; Toxicophore; Modeling; Potassium channel ID VECTOR MACHINE METHOD; LONG-QT-SYNDROME; K+ CHANNELS; IN-SILICO; BIOLOGICAL EVALUATION; CLASSIFICATION MODEL; ACUTE TOXICITY; QSAR MODELS; BLOCKERS; INHIBITION AB A dataset of 237 human Ether-a-go-go Related Gene (hERG) potassium channel inhibitors (180 of which were used for model building and validation, whereas 57 constituted the "true" external prediction set) collected from 22 literature sources was modeled by 3D-SDAR. To produce reliable and reproducible classification models for hERG blocking, the initial set of 180 chemicals was split into two subsets: a balanced modeling set consisting of 118 compounds and an unbalanced validation set comprised of 62 compounds. A PLS bagging-like algorithm written in Matlab was used to process the data and assign each compound to one of the two (hERG+ or hERG-) activity classes. The best predictive model evaluated on the basis of a fully randomized hold-out test set (comprising 20% of the modeling set) used 4 latent variables and a grid of 6 ppm x 6 ppm x 1 angstrom in the C-C region, 6 ppm x 30 ppm x 1 angstrom in the C-N region, and 30 ppm x 30 ppm x 1 angstrom in the N-N region. An overall accuracy of 0.84 was obtained for both the hold-out test set and the validation set. Further, an external prediction set consisting of 57 drugs and drug derivatives was used to estimate the true predictive power of the reported 3D-SDAR model - a slight reduction of the overall accuracy down to 0.77 was observed. 3 D-SDAR map of the most frequently occurring bins and their projection on the standard coordinate space of the chemical structures allowed identification of a three-center toxicophore composed of two aromatic rings and an amino group. A U test along the distance axis of the most frequently occurring 3D-SDAR bins was used to set the distance limits of the toxicophore. This toxicophore was found to be similar to an earlier reported phospholipidosis (PLD) toxicophore. Published by Elsevier Inc. C1 [Stoyanova-Slavova, Iva B.; Slavov, Svetoslav H.; Buzatu, Dan A.; Beger, Richard D.; Wilkes, Jon G.] Natl Ctr Toxicol Res, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Stoyanova-Slavova, IB (reprint author), Natl Ctr Toxicol Res, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Iva.StoyanovaSlavova@fda.hhs.gov NR 65 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 1093-3263 EI 1873-4243 J9 J MOL GRAPH MODEL JI J. Mol. Graph. PD MAR PY 2017 VL 72 BP 246 EP 255 DI 10.1016/j.jmgm.2017.01.012 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Computer Science, Interdisciplinary Applications; Crystallography; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology GA EN2LM UT WOS:000395841700027 PM 28129595 ER PT J AU Verrill, L Wood, D Cates, S Lando, A Zhang, YT AF Verrill, Linda Wood, Dallas Cates, Sheryl Lando, Amy Zhang, Yuanting TI Vitamin-Fortified Snack Food May Lead Consumers to Make Poor Dietary Decisions SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Nutrient content claims; Vitamin-fortified; Fortification; Snack foods; Food label ID NUTRITION LABELS; HEALTH CLAIMS; INFORMATION; OBESITY; PERCEPTIONS; PREVALENCE; PRODUCTS; DISEASE AB Background The US Food and Drug Administration's (FDA's) fortification policy discourages the fortification of certain foods, including sugars and snack foods such as cookies, candies, cakes, chips, and carbonated beverages, yet manufacturers sometimes add vitamins and minerals to snack foods. Objective To assess whether vitamin-fortified snack foods affect consumers' information-seeking, purchase decisions, and product-related health perceptions. Design For this experimental study, participants were randomly assigned to study conditions to compare products that varied in product type, nutrition profile, and fortification and nutrient claim status. Data were collected via an online consumer panel. Participants/setting US adults aged 18 years and older were randomly selected from Research Now's e-panel online household panel. Data were collected during fall 2014 (N=5,076). Intervention Participants were randomly assigned to one of 24 conditions: two products (vegetable chip/potato chip), two nutrition profiles (healthier/less healthy), two fortification scenarios (not fortified/fortified), and three nutrient claim conditions (two no claim/one with claim). The design was not balanced; claims were not shown on products that were not vitamin fortified. Main outcome measures Outcome measures were information-seeking (viewed the Nutrition Facts label), purchase decisions, perception of product health-fulness, and correct selection of product with the healthier nutrient profile. Statistical analysis performed Logistic regression was used to test all models. Analyses was adjusted for general label use, consumes product, health status, age, sex, level of education, presence of children in the household, and race/ethnicity. Results When the snack food carried a nutrient claim for vitamin fortification, participants were 1) less likely to look for nutrition information on the Nutrition Facts label, 2) more likely to select the product for purchase, 3) more likely to perceive the product as healthier, and 4) less likely to correctly choose the healthier product. Conclusions Snack foods that have been vitamin-fortified may cause consumers to make poor dietary decisions. J Acad Nutr Diet. 2017;117:376-385. C1 [Verrill, Linda; Lando, Amy; Zhang, Yuanting] US FDA, 5100 Paint Branch Pkwy,HFS-013,Room 2C-095, College Pk, MD 20740 USA. [Wood, Dallas] RTI Int, Res Triangle Pk, NC USA. [Zhang, Yuanting] Colorado Dept Human Serv, Denver, CO USA. RP Verrill, L (reprint author), US FDA, 5100 Paint Branch Pkwy,HFS-013,Room 2C-095, College Pk, MD 20740 USA. EM linda.verrill@fda.hhs.gov FU US Food and Drug Administration FX All financial and material support for the research was funded through the US Food and Drug Administration. NR 24 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 2212-2672 EI 2212-2680 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD MAR PY 2017 VL 117 IS 3 BP 376 EP 385 DI 10.1016/j.jand.2016.10.008 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EM7MH UT WOS:000395495400006 PM 27914913 ER PT J AU Pham, T Major, JM Chai, G Moeny, D Wang, CL Blum, MD AF Tracy Pham Major, Jacqueline M. Chai, Grace Moeny, David Wang, Cunlin Blum, Michael D. TI Response to Consumer Healthcare Products Association letter to "Trend in rates of acetaminophen-related adverse events in the United States" SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Letter C1 [Tracy Pham; Major, Jacqueline M.; Chai, Grace; Moeny, David; Wang, Cunlin; Blum, Michael D.] US FDA, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Tracy Pham] US FDA, Div Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 22, Silver Spring, MD 20993 USA. RP Pham, T (reprint author), US FDA, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA.; Pham, T (reprint author), US FDA, Div Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 22, Silver Spring, MD 20993 USA. EM tracy.pham@fda.hhs.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU WILEY 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 MAR PY 2017 VL 26 IS 3 BP 355 EP 355 DI 10.1002/pds.4172 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA EP3SE UT WOS:000397301200016 PM 28247546 ER PT J AU Mounts, P AF Mounts, Phoebe TI Regulatory strategies to facilitate surgical innovation SO SURGERY LA English DT Article AB Phoebe Mounts, PhD, Esq, is a partner in the Food and Drug Administration Practice Group in the Washington, DC, office of Morgan Lewis & Bockius LLP. She counsels clients on regulatory issues for medical devices, drugs, and biologics. Prior to joining Morgan Lewis, she was on the faculty of the Johns Hopkins University School of Public Health in the Department of Molecular Microbiology, Immunology, and Infectious Diseases. Although she is a partner in the FDA Practice Group at Morgan Lewis, the views expressed in this article are hers and should not be attributed to the Firm. C1 [Mounts, Phoebe] US FDA, Practice Grp, Washington, DC 20204 USA. [Mounts, Phoebe] Off Morgan Lewis & Bockius LLP, Washington, DC USA. [Mounts, Phoebe] Johns Hopkins Univ, Sch Publ Hlth, Dept Mol Microbiol Immunol & Infect Diseases, Baltimore, MD 21218 USA. RP Mounts, P (reprint author), Morgan Lewis & Bockius LLP, 1111 Penn Ave NW, Washington, DC 20004 USA. EM Phoebe.Mounts@morganlewis.com NR 5 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD MAR PY 2017 VL 161 IS 3 BP 567 EP 570 DI 10.1016/j.surg.2016.08.019 PG 4 WC Surgery SC Surgery GA EL6JT UT WOS:000394729100001 PM 28190506 ER PT J AU Huang, HX Falgout, B Takeda, K Yamada, KM Dhawan, S AF Huang, Hanxia Falgout, Barry Takeda, Kazuyo Yamada, Kenneth M. Dhawan, Subhash TI Nrf2-dependent induction of innate host defense via heme oxygenase-1 inhibits Zika virus replication SO VIROLOGY LA English DT Article DE Zika; Monocytes; Macrophages; Heme oxygenase-1; Nuclear factor erythroid-related factor 2 ID INFECTION; MALARIA; HCV AB We identified primary human monocyte-derived macrophages (MDM) as vulnerable target cells for Zika virus (ZIKV) infection. We demonstrate dramatic effects of hemin, the natural inducer of the heme catabolic enzyme heme oxygenase-1 (HO-1), in the reduction of ZIKV replication in vitro. Both LLC-MK2 monkey kidney cells and primary MDM exhibited hemin-induced HO-1 expression with major reductions of > 90% in ZIKV replication, with little toxicity to infected cells. Silencing expression of HO-1 or its upstream regulatory gene, nuclear factor erythroid-related factor 2 (Nrf2), attenuated hemin-induced suppression of ZIKV infection, suggesting an important role for induction of these intracellular mediators in retarding ZIKV replication. The inverse correlation between hemin-induced HO-1 levels and ZIKV replication provides a potentially useful therapeutic modality based on stimulation of an innate cellular response against Zika virus infection. C1 [Huang, Hanxia; Falgout, Barry; Takeda, Kazuyo; Dhawan, Subhash] US FDA, Silver Spring, MD 20993 USA. [Yamada, Kenneth M.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Dhawan, S (reprint author), US FDA, Silver Spring, MD 20993 USA. EM subhash.dhawan@fda.hhs.gov FU NIDCR Intramural Research Program; FDA Intramural Research Program FX We thank Dr. Rana Nagarkatti and Dr. Sreenivas Gannavaram for critical review of the manuscript. The findings and conclusions in this paper have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any agency determination or policy. This work was supported by FDA and NIDCR Intramural Research Programs. NR 25 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 0042-6822 J9 VIROLOGY JI Virology PD MAR PY 2017 VL 503 BP 1 EP 5 DI 10.1016/j.virol.2016.12.019 PG 5 WC Virology SC Virology GA EM5MR UT WOS:000395356200001 PM 28068513 ER PT J AU Malinauskas, RA Hariharan, P Day, SW Herbertson, LH Buesen, M Steinseifer, U Aycock, KI Good, BC Deutsch, S Manning, KB Craven, BA AF Malinauskas, Richard A. Hariharan, Prasanna Day, Steven W. Herbertson, Luke H. Buesen, Martin Steinseifer, Ulrich Aycock, Kenneth I. Good, Bryan C. Deutsch, Steven Manning, Keefe B. Craven, Brent A. TI FDA Benchmark Medical Device Flow Models for CFD Validation SO ASAIO JOURNAL LA English DT Article DE computational fluid dynamics; validation; medical devices; particle image velocimetry; in vitro hemolysis testing ID ROTARY BLOOD PUMPS; NOZZLE MODEL; SIMULATION; VELOCIMETRY; DAMAGE AB Computational fluid dynamics (CFD) is increasingly being used to develop blood-contacting medical devices. However, the lack of standardized methods for validating CFD simulations and blood damage predictions limits its use in the safety evaluation of devices. Through a U.S. Food and Drug Administration (FDA) initiative, two benchmark models of typical device flow geometries (nozzle and centrifugal blood pump) were tested in multiple laboratories to provide experimental velocities, pressures, and hemolysis data to support CFD validation. In addition, computational simulations were performed by more than 20 independent groups to assess current CFD techniques. The primary goal of this article is to summarize the FDA initiative and to report recent findings from the benchmark blood pump model study. Discrepancies between CFD predicted velocities and those measured using particle image velocimetry most often occurred in regions of flow separation (e.g., downstream of the nozzle throat, and in the pump exit diffuser). For the six pump test conditions, 57% of the CFD predictions of pressure head were within one standard deviation of the mean measured values. Notably, only 37% of all CFD submissions contained hemolysis predictions. This project aided in the development of an FDA Guidance Document on factors to consider when reporting computational studies in medical device regulatory submissions. There is an accompanying podcast available for this article. C1 [Malinauskas, Richard A.; Hariharan, Prasanna; Herbertson, Luke H.; Craven, Brent A.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD USA. [Day, Steven W.] Rochester Inst Technol, Dept Biomed Engn, Rochester, NY 14623 USA. [Buesen, Martin; Steinseifer, Ulrich] Rhein Westfal TH Aachen, Dept Cardiovasc Engn, Aachen, Germany. [Aycock, Kenneth I.; Good, Bryan C.; Deutsch, Steven; Manning, Keefe B.] Penn State Univ, Dept Biomed Engn, University Pk, PA 16802 USA. RP Malinauskas, RA (reprint author), US FDA, Ctr Devices & Radiol Hlth, Bldg 62,Room 2108,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Richard.Malinauskas@fda.hhs.gov FU FDA's Critical Path Initiative program FX Funding for this project was provided through the FDA's Critical Path Initiative program. NR 40 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 1058-2916 EI 1538-943X J9 ASAIO J JI Asaio J. PD MAR-APR PY 2017 VL 63 IS 2 BP 150 EP 160 DI 10.1097/MAT.0000000000000499 PG 11 WC Engineering, Biomedical; Transplantation SC Engineering; Transplantation GA EO1EF UT WOS:000396440500013 PM 28114192 ER PT J AU McEachran, AD Sobus, JR Williams, AJ AF McEachran, Andrew D. Sobus, Jon R. Williams, Antony J. TI Identifying known unknowns using the US EPA's CompTox Chemistry Dashboard SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Non-targeted analysis; Suspect screening; DSSTox; High-resolution mass spectrometry ID RESOLUTION MASS-SPECTROMETRY; WASTE-WATER; SURFACE WATERS; IDENTIFICATION; STRATEGIES; CHEMSPIDER; PRODUCTS; DATABASE; TOOLS AB Chemical features observed using high-resolution mass spectrometry can be tentatively identified using online chemical reference databases by searching molecular formulae and monoisotopic masses and then rank-ordering of the hits using appropriate relevance criteria. The most likely candidate "known unknowns," which are those chemicals unknown to an investigator but contained within a reference database or literature source, rise to the top of a chemical list when rank-ordered by the number of associated data sources. The U.S. EPA's CompTox Chemistry Dashboard is a curated and freely available resource for chemistry and computational toxicology research, containing more than 720,000 chemicals of relevance to environmental health science. In this research, the performance of the Dashboard for identifying known unknowns was evaluated against that of the online ChemSpider database, one of the primary resources used by mass spectrometrists, using multiple previously studied datasets reported in the peer-reviewed literature totaling 162 chemicals. These chemicals were examined using both applications via molecular formula and monoisotopic mass searches followed by rank-ordering of candidate compounds by associated references or data sources. A greater percentage of chemicals ranked in the top position when using the Dashboard, indicating an advantage of this application over ChemSpider for identifying known unknowns using data source ranking. Additional approaches are being developed for inclusion into a non-targeted analysis workflow as part of the CompTox Chemistry Dashboard. This work shows the potential for use of the Dashboard in exposure assessment and risk decision-making through significant improvements in non-targeted chemical identification. C1 [McEachran, Andrew D.] US FDA, Oak Ridge Inst Sci & Educ, Res Participat Program, 109 TW Alexander Dr, Durham, NC 27711 USA. [Sobus, Jon R.] US FDA, Natl Exposure Res Lab, Off Res & Dev, 109 TW Alexander Dr, Durham, NC 27711 USA. [Williams, Antony J.] US FDA, Natl Ctr Computat Toxicol, Off Res & Dev, 109 TW Alexander Dr, Durham, NC 27711 USA. RP McEachran, AD (reprint author), US FDA, Oak Ridge Inst Sci & Educ, Res Participat Program, 109 TW Alexander Dr, Durham, NC 27711 USA.; Williams, AJ (reprint author), US FDA, Natl Ctr Computat Toxicol, Off Res & Dev, 109 TW Alexander Dr, Durham, NC 27711 USA. EM mceachran.andrew@epa.gov; williams.antony@epa.gov OI McEachran, Andrew/0000-0003-1423-330X FU US EPA; DOE FX The authors would like to thank Jim Little for graciously providing the dataset used in Little et al. (2012). This work was supported in part by an appointment to the ORISE participant research program supported by an interagency agreement between the US EPA and DOE. This work has been internally reviewed at the US EPA and has been approved for publication. The views expressed in this paper are those of the authors and do not necessarily represent the views or policies of the U.S. Environmental Protection Agency. NR 24 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 MAR PY 2017 VL 409 IS 7 BP 1729 EP 1735 DI 10.1007/s00216-016-0139-z PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA EL1JS UT WOS:000394377200002 PM 27987027 ER PT J AU Chang, CM Edwards, SH Arab, A Del Valle-Pinero, AY Yang, L Hatsukami, DK AF Chang, Cindy M. Edwards, Selvin H. Arab, Aarthi Del Valle-Pinero, Arseima Y. Yang, Ling Hatsukami, Dorothy K. TI Biomarkers of Tobacco Exposure: Summary of an FDA-Sponsored Public Workshop SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Review ID NUTRITION EXAMINATION SURVEY; LUNG-CANCER DEVELOPMENT; POLYCYCLIC AROMATIC-HYDROCARBON; EXAMINATION SURVEY NHANES; VOLATILE ORGANIC-COMPOUNDS; CIGARETTE SMOKERS; SMOKELESS TOBACCO; URINARY LEVELS; NATIONAL-HEALTH; CADMIUM EXPOSURE AB Since 2009, the FDA Center for Tobacco Products (CTP) has had the authority to regulate the manufacturing, distribution, and marketing of tobacco products in order to reduce the death and disease caused by tobacco use. Biomarkers of exposure pertain to actual human exposure to chemicals arising from tobacco use and could play an important role across a number of FDA regulatory activities, including assessing new and modified-risk tobacco products and identifying and evaluating potential product standards. On August 3-4, 2015, FDA/CTP hosted a public workshop focused on biomarkers of exposure with participants from government, industry, academia, and other organizations. The workshop was divided into four sessions focused on: (i) approaches to evaluating and selecting biomarkers; (ii) biomarkers of exposure and relationship to disease risk; (iii) currently used biomarkers of exposure and biomarkers in development; and (iv) biomarkers of exposure and the assessment of smokeless tobacco and electronic nicotine delivery systems. This article synthesizes the main findings from the workshop and highlights research areas that could further strengthen the science around biomarkers of exposure and help determine their application in tobacco product regulation. (C)2016 AACR. C1 [Chang, Cindy M.; Edwards, Selvin H.; Arab, Aarthi; Del Valle-Pinero, Arseima Y.; Yang, Ling] US FDA, Off Sci, Ctr Tobacco Prod, Silver Spring, MD USA. [Hatsukami, Dorothy K.] Univ Minnesota, Dept Psychiat, Tobacco Res Programs, Minneapolis, MN 55455 USA. RP Chang, CM (reprint author), US FDA, Bldg 71,Room G335,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Cindy.Chang@fda.hhs.gov FU FDA FX For this work, all authors were supported by funds from the FDA. NR 113 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 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2017 VL 26 IS 3 BP 291 EP 302 DI 10.1158/1055-9965.EPI-16-0675 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EN5BI UT WOS:000396020200002 PM 28151705 ER PT J AU Strickland, J Zang, QD Paris, M Lehmann, DM Allen, D Choksi, N Matheson, J Jacobs, A Casey, W Kleinstreuer, N AF Strickland, Judy Zang, Qingda Paris, Michael Lehmann, David M. Allen, David Choksi, Neepa Matheson, Joanna Jacobs, Abigail Casey, Warren Kleinstreuer, Nicole TI Multivariate models for prediction of human skin sensitization hazard SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE Skin sensitization; allergic contact dermatitis (ACD); integrated decision strategy; machine learning; LLNA; DPRA; KeratinoSens; h-CLAT ID LYMPH-NODE ASSAY; LINE ACTIVATION TEST; TEST H-CLAT; IN-VITRO METHODS; SCREENING CONTACT ALLERGENS; INTEGRATED TESTING STRATEGY; PEPTIDE REACTIVITY ASSAY; RISK-ASSESSMENT MODEL; ICCVAM EVALUATION; RANDOM FOREST AB One of the Interagency Coordinating Committee on the Validation of Alternative Method's (ICCVAM) top priorities is the development and evaluation of non-animal approaches to identify potential skin sensitizers. The complexity of biological events necessary to produce skin sensitization suggests that no single alternative method will replace the currently accepted animal tests. ICCVAM is evaluating an integrated approach to testing and assessment based on the adverse outcome pathway for skin sensitization that uses machine learning approaches to predict human skin sensitization hazard. We combined data from three in chemico or in vitro assays - the direct peptide reactivity assay (DPRA), human cell line activation test (h-CLAT) and KeratinoSens assay - six physicochemical properties and an in silico read-across prediction of skin sensitization hazard into 12 variable groups. The variable groups were evaluated using two machine learning approaches, logistic regression and support vector machine, to predict human skin sensitization hazard. Models were trained on 72 substances and tested on an external set of 24 substances. The six models (three logistic regression and three support vector machine) with the highest accuracy (92%) used: (1) DPRA, h-CLAT and read-across; (2) DPRA, h-CLAT, read-across and KeratinoSens; or (3) DPRA, h-CLAT, read-across, KeratinoSens and log P. The models performed better at predicting human skin sensitization hazard than the murine local lymph node assay (accuracy 88%), any of the alternative methods alone (accuracy 63-79%) or test batteries combining data from the individual methods (accuracy 75%). These results suggest that computational methods are promising tools to identify effectively the potential human 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 on the Validation of Alternative Methods evaluated a non-animal decision strategy using machine learning approaches to integrate in vitro, in chemico and in silico data and physicochemical properties to predict human skin sensitization hazard for 96 substances. The six most accurate models used different combinations of variables and outperformed the local lymph node assay and individual non-animal methods. Results of this evaluation suggest that computational approaches are promising tools to integrate data effectively to identify potential sensitizers without animal testing. C1 [Strickland, Judy; Zang, Qingda; Paris, Michael; Allen, David; Choksi, Neepa] ILS, POB 13501, Res Triangle Pk, NC 27709 USA. [Lehmann, David M.] US FDA, Res Triangle Pk, NC 27709 USA. [Casey, Warren; Kleinstreuer, Nicole] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. [Matheson, Joanna] US Consumer Prod Safety Commiss, Rockville, MD 20850 USA. [Jacobs, Abigail] US FDA, Silver Spring, MD USA. RP Strickland, J (reprint author), ILS, POB 13501, Res Triangle Pk, NC 27709 USA. EM strickl2@niehs.nih.gov FU NIEHS, NIH of the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods [HHSN273201500010C] FX The authors thank Drs. R. Luebke, M. Ward, D. Germolec and B.A. Merrick 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 the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods. NR 69 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0260-437X EI 1099-1263 J9 J APPL TOXICOL JI J. Appl. Toxicol. PD MAR PY 2017 VL 37 IS 3 BP 347 EP 360 DI 10.1002/jat.3366 PG 14 WC Toxicology SC Toxicology GA EL2BR UT WOS:000394425600011 PM 27480324 ER PT J AU Scully, CG Mitrou, N Braam, B Cupples, WA Chon, KH AF Scully, Christopher G. Mitrou, Nicholas Braam, Branko Cupples, Willliam A. Chon, Ki H. TI Detecting Interactions between the Renal Autoregulation Mechanisms in Time and Space SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Bispectrum; laser speckle contrast imaging (LSCI); quadratic phase coupling (QPC); renal autoregulation ID BLOOD-FLOW REGULATION; NONLINEAR-INTERACTIONS; MYOGENIC OSCILLATIONS; WAVELET BICOHERENCE; TUBULAR PRESSURE; LOW-FREQUENCY; KIDNEY; SYNCHRONIZATION; STATISTICS; QUANTIFY AB Objective: Our objective is to identify localized interactions between the renal autoregulation mechanisms over time. Methods: A time-varying phase-randomized wavelet bicoherence detector for quadratic phase coupling between tubuloglomerular feedback and the myogenic response is presented. Through simulations we show its ability to interrogate quadratic phase coupling. The method is applied to kidney blood flow and laser speckle imaging sequences of cortical perfusion from anesthetized rats before and after nonselective inhibition of nitric-oxide synthase. Results: Quadratic phase coupling in kidney blood flow data was present in four out of nine animals during the control period for 13.0 +/- 5.6% (mean +/- SD) of time and in five out of nine animals during inhibition of nitric-oxide synthase for 15.8 +/- 8.2% of time. Approximately 60% of time-series extracted from laser speckle imaging pixels of the renal cortex showed significant quadratic phase coupling. Pixels with significant coupling had a median coupling length of 10.8 +/- 2.2% and 12.1 +/- 3.1% of time with the 95th percentile of pixels being coupled for 25.5 +/- 4.4% and 30.9 +/- 6.4% of time during control and inhibition of nitric-oxide synthase, respectively. Conclusion: These results indicate quadratic phase coupling exists in short time intervals between tubuloglomerular feedback and the myogenic response and is detected more often in local renal perfusion signals than whole kidney blood flow in anesthetized rats. Significance: Combining the detector and laser speckle imaging provides identification of coordination between renal autoregulation mechanisms that is localized in time and space. C1 [Scully, Christopher G.] Worcester Polytech Inst, Dept Biomed Engn, Worcester, MA 01609 USA. [Scully, Christopher G.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Mitrou, Nicholas; Cupples, Willliam A.] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Braam, Branko] Univ Alberta, Dept Physiol & Med, Edmonton, AB T6G 2M7, Canada. [Chon, Ki H.] Univ Connecticut, Dept Biomed Engn, Storrs, CT USA. RP Scully, CG (reprint author), Worcester Polytech Inst, Dept Biomed Engn, Worcester, MA 01609 USA. EM christopher.scully@fda.hhs.gov FU American Heart Association; Canadian Institutes of Health Research [MOP-102694] FX This work was supported by the Canadian Institutes of Health Research under Grant MOP-102694. The work of C. G. Scully was supported by an American Heart Association predoctoral fellowship. NR 32 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 64 IS 3 BP 690 EP 698 DI 10.1109/TBME.2016.2569453 PG 9 WC Engineering, Biomedical SC Engineering GA EN2VM UT WOS:000395868400021 PM 27244712 ER PT J AU Tejada-Strop, A Costafreda, MI Dimitrova, Z Kaplan, GG Teo, CG AF Tejada-Strop, Alexandra Costafreda, Maria Isabel Dimitrova, Zoya Kaplan, Gerardo G. Teo, Chong-Gee TI Evaluation of Potencies of Immune Globulin Products Against Hepatitis A SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Tejada-Strop, Alexandra; Dimitrova, Zoya; Teo, Chong-Gee] Ctr Dis Control & Prevent, Div Viral Hepatitis, 1600 Clifton Rd NE,Mailstop A33, Atlanta, GA 30329 USA. [Costafreda, Maria Isabel; Kaplan, Gerardo G.] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Tejada-Strop, A (reprint author), Ctr Dis Control & Prevent, Div Viral Hepatitis, 1600 Clifton Rd NE,Mailstop A33, Atlanta, GA 30329 USA. EM atejadastrop@cdc.gov FU US Food and Drug Administration (FDA) FX This study was supported by US Food and Drug Administration (FDA) intramural funds to Dr Kaplan; also, the appointment to the Research Participation Program at the Center for Biologics Evaluation and Research (CBER) administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the US Department of Energy with the Centers for Disease Control and Prevention (Ms Tejada-Strop) and the FDA (Dr Costafreda). NR 6 TC 2 Z9 2 U1 0 U2 0 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 MAR 1 PY 2017 VL 177 IS 3 BP 430 EP 432 DI 10.1001/jamainternmed.2016.9057 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA EN7RX UT WOS:000396201000032 PM 28097299 ER PT J AU Tyndall, A Du, W Breder, CD AF Tyndall, Adria Du, Wenny Breder, Christopher D. TI The target product profile as a tool for regulatory communication: advantageous but underused SO NATURE REVIEWS DRUG DISCOVERY LA English DT News Item C1 [Tyndall, Adria] Catalent Pharma Solut, 2210 Lakeshore Dr, Woodstock, IL 60098 USA. [Du, Wenny] Bayer, 100 Bayer Blvd, Whippany, NJ 07981 USA. [Breder, Christopher D.] Johns Hopkins Univ, Adv Acad Programs Regulatory Sci JHUAAP, 9601 Med Ctr Dr, Rockville, MD 20850 USA. [Breder, Christopher D.] US FDA, Rockville, MD 20857 USA. RP Breder, CD (reprint author), Johns Hopkins Univ, Adv Acad Programs Regulatory Sci JHUAAP, 9601 Med Ctr Dr, Rockville, MD 20850 USA.; Breder, CD (reprint author), US FDA, Rockville, MD 20857 USA. EM cbreder1@jhu.edu NR 0 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 16 IS 3 BP 156 EP 156 PG 1 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA EM7MN UT WOS:000395496000008 PM 28209989 ER PT J AU Nan, XL Verrill, L Kim, J AF Nan, Xiaoli Verrill, Linda Kim, Jarim TI Mapping Sources of Food Safety Information for US Consumers: Findings From a National Survey SO HEALTH COMMUNICATION LA English DT Article ID HEALTH INFORMATION; LABEL USE; NUTRITION KNOWLEDGE; TRENDS SURVEY; CANCER; PERCEPTIONS; RISKS; BEHAVIORS; SELECTION; INTERNET AB This research examines the sources from which U.S. consumers obtain their food safety information. It seeks to determine differences in the types of information sources used by U.S. consumers of different sociodemographic background, as well as the relationships between the types of information sources used and food safety risk perceptions. Analyzing the 2010 Food Safety Survey (N = 4,568) conducted by the U.S. Food and Drug Administration, we found that age, gender, education, and race predicted the use of different sources for food safety information. Additionally, use of several information sources predicted perceived susceptibility to foodborne illnesses and severity of food contamination. Implications of the findings for food safety risk communication are discussed. C1 [Nan, Xiaoli; Kim, Jarim] Univ Maryland, Dept Commun, 2105A Skinner Bldg, College Pk, MD 20742 USA. [Verrill, Linda] US FDA, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. RP Nan, XL (reprint author), Univ Maryland, Dept Commun, 2105A Skinner Bldg, College Pk, MD 20742 USA. EM nan@umd.edu FU U.S. Food and Drug Administration through Joint Institute for Food Safety and Applied Nutrition FX Research reported in this publication was supported by the U.S. Food and Drug Administration through the Joint Institute for Food Safety and Applied Nutrition. NR 55 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1041-0236 EI 1532-7027 J9 HEALTH COMMUN JI Health Commun. PD MAR PY 2017 VL 32 IS 3 BP 356 EP 365 DI 10.1080/10410236.2016.1138385 PG 10 WC Communication; Health Policy & Services SC Communication; Health Care Sciences & Services GA EI9PE UT WOS:000392839800011 PM 27268120 ER PT J AU Li, ZY Srigley, CT AF Li, Ziyi Srigley, Cynthia T. TI A novel method for the quantification of long-chain omega-3 polyunsaturated fatty acids (PUFA) in gummy dietary supplements SO JOURNAL OF FOOD COMPOSITION AND ANALYSIS LA English DT Article DE Gummy; Dietary supplement; Food analysis; Food composition; Gas chromatography; Omega-3 polyunsaturated fatty acid; Validation; Standard reference material (SRM) 3275 ID METABOLIC SYNDROME; MASS-SPECTROMETRY; LIPID EXTRACTION; FLAVOR RELEASE; RAPID METHOD; OMEGA-3-FATTY-ACIDS; PREGNANCY; ESTERS; OIL; CRAVINGS AB Dietary supplements containing long-chain omega-3 polyunsaturated fatty acids (PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are frequently consumed in the United States (US) to support health and reduce the risk of chronic disease. Gummy supplements which are formulated to contain marine oils are perceived as more palatable alternatives to conventional marine oil soft gels or liquids. However, despite the increasing popularity of these products, a validated method for analyzing their contents of fatty acids has yet to be reported. The objective of this study was to develop and validate a novel analytical method for the quantification of long-chain omega-3 PUFA and other lipids in gummy supplements. This method involves mild digestion of cryogenically homogenized gummy samples followed by liquid-liquid extraction with low toxicity solvents. Extracted lipids are then derivatized to fatty acid methyl esters and analyzed by gas chromatography with flame ionization detection. This method shows excellent performance in validation studies for accuracy, repeatability, linearity, robustness, and absence of interferences or contaminant carryover. This novel Gummy Method is appropriate for the quantification of long-chain omega-3 PUFA in a variety of gummy supplements which are currently available in the US market. Published by Elsevier Inc. C1 [Li, Ziyi] Univ Maryland, Joint Inst Food Safety & Appl Nutr, 5145 Campus Dr,Patapsco Bldg Suite 2134, College Pk, MD 20742 USA. [Srigley, Cynthia T.] US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr, College Pk, MD 20740 USA. RP Srigley, CT (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr, College Pk, MD 20740 USA. EM cynthia.srigley@fda.hhs.gov FU JIFSAN; FDA [FDU001418] FX The authors acknowledge the technical assistance of Ms. Carolyn J. Oles from the Center for Food Safety and Applied Nutrition/FDA and Mr. Ermias A. Haile from the Joint Institute of Food Safety and Applied Nutrition (JIFSAN), University of Maryland in College Park, MD. This work was funded in part by the JIFSAN through a cooperative agreement with the FDA (#FDU001418). NR 56 TC 0 Z9 0 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 0889-1575 EI 1096-0481 J9 J FOOD COMPOS ANAL JI J. Food Compos. Anal. PD MAR PY 2017 VL 56 BP 1 EP 10 DI 10.1016/j.jfca.2016.11.006 PG 10 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA EJ9DK UT WOS:000393526600001 ER PT J AU Handy, SM Mueller, S Jacob, SM Paul, SZ Garrett, SD Deeds, JR AF Handy, Sara M. Mueller, Steffen Jacob, Salena M. Paul, Stephen Z. Garrett, Stephen D. Deeds, Jonathan R. TI Evaluation of the Agilent Technologies Bioanalyzer-based DNA Fish Identification Solution SO FOOD CONTROL LA English DT Article DE Species identification; Fish; PCR-RFLP; Bioanalyzer; CO1 ID SPECIES IDENTIFICATION AB A wide variety of DNA based methods have been developed to identify fish species, including those that employ a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. One such method developed by Dooley, Sage, Clarke, Brown, and Garrett (2005) used amplification of a portion of the mitochondrial cytochrome B (cytB) gene, with a three enzyme digestion, visualized and identified using the Agilent 2100 Bioanalyzer System. More recently this method was modified by Agilent Technologies to target a section of the cytochrome c oxidase 1 (CO1) gene, within the 655 base pair (bp) "barcoding" fragment, using a two enzyme digestion to increase sample throughput and to exploit publically available CO1 data generated through the Barcode of Life initiative (Mueller et al. 2015). Here we evaluate this method on fifteen different commercial fish species with five replicate specimens of each. DNA barcoding of the CO1 gene was used as an orthogonal confirmatory method and also to further understand the results found using the modified Agilent PCR-RFLP method. Published by Elsevier Ltd. C1 [Handy, Sara M.; Jacob, Salena M.; Paul, Stephen Z.; Deeds, Jonathan R.] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, 5001 Campus Dr, College Pk, MD 20740 USA. [Mueller, Steffen] Agilent Technol, Hewlett Packard Str 8, D-76337 Waldbronn, Germany. [Garrett, Stephen D.] Campden BRI, Stn Rd, Chipping Campden GL55 6LD, Glos, England. RP Handy, SM (reprint author), HFS-706,5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Sara.Handy@fda.hhs.gov FU Agilent Technologies [171-11]; US Food and Drug Administration Center for Food Safety and Applied Nutrition [171-11] FX This work was supported under Cooperative Research and Development Agreement (CRADA) #171-11 between Agilent Technologies and the US Food and Drug Administration Center for Food Safety and Applied Nutrition. NR 12 TC 0 Z9 0 U1 21 U2 21 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-7135 EI 1873-7129 J9 FOOD CONTROL JI Food Control PD MAR PY 2017 VL 73 BP 627 EP 633 DI 10.1016/j.foodcont.2016.09.013 PN B PG 7 WC Food Science & Technology SC Food Science & Technology GA EG3SU UT WOS:000390965800067 ER PT J AU Kubachka, KM Hanley, T Mantha, M Wilson, RA Falconer, TM Kassa, Z Oliveira, A Landero, J Caruso, J AF Kubachka, Kevin M. Hanley, Traci Mantha, Madhavi Wilson, Robert A. Falconer, Travis M. Kassa, Zena Oliveira, Aline Landero, Julio Caruso, Joseph TI Evaluation of selenium in dietary supplements using elemental speciation SO FOOD CHEMISTRY LA English DT Article DE Selenium; Dietary supplement; Speciation; LC-ICP-MS ID ICP-MS; MASS-SPECTROMETRY; RICH YEAST; HPLC; SELENOMETHIONINE; BIOAVAILABILITY; IDENTIFICATION; SELENOCYSTEINE; REQUIREMENTS; EXTRACTION AB Selenium-enriched dietary supplements containing various selenium compounds are readily available to consumers. To ensure proper selenium intake and consumer confidence, these dietary supplements must be safe and have accurate label claims. Varying properties among selenium species requires information beyond total selenium concentration to fully evaluate health risk/benefits. A LC-ICP-MS method was developed and multiple extraction methods were implemented for targeted analysis of common "seleno-amino acids" and related oxidation products, selenate, selenite, and other species relatable to the quality and/or accuracy of the labeled selenium ingredients. Ultimately, a heated water extraction was applied to recover selenium species from non-selenized yeast supplements in capsule, tablet, and liquid forms. For selenized yeast supplements, inorganic selenium was monitored as a means of assessing selenium yeast quality. A variety of commercially available selenium supplements were evaluated and discrepancies between labeled ingredients and detected species were noted. Published by Elsevier Ltd. C1 [Kubachka, Kevin M.; Hanley, Traci; Mantha, Madhavi; Wilson, Robert A.; Falconer, Travis M.] US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. [Kassa, Zena] Minnesota Dept Agr, St Paul, MN 55155 USA. [Oliveira, Aline; Landero, Julio; Caruso, Joseph] Univ Cincinnati, Dept Chem, Cincinnati, OH USA. [Oliveira, Aline] Univ Sao Carlos, Dept Chem, Grp Appl Instrumental Anal, BR-13565905 Sao Carlos, SP, Brazil. RP Kubachka, KM (reprint author), US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. EM kevin.kubachka@fda.hhs.gov; traci.hanley@fda.hhs.gov; madhavi.mantha@fda.hhs.gov; robert.wilson@fda.hhs.gov; travis.falconer@fda.hhs.gov; zena.kassa@state.mn.us; alinefo@gmail.com; julio_landero80@yahoo.com OI Fernandes de Oliveira, Aline/0000-0002-4327-7064 NR 38 TC 0 Z9 0 U1 116 U2 116 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 MAR 1 PY 2017 VL 218 BP 313 EP 320 DI 10.1016/j.foodchem.2016.08.086 PG 8 WC Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics SC Chemistry; Food Science & Technology; Nutrition & Dietetics GA EA2GB UT WOS:000386409700041 PM 27719915 ER PT J AU Hassan, M Tan, X Hitchins, VM Calogero, D Ilev, IK AF Hassan, Moinuddin Tan, Xin Hitchins, Victoria M. Calogero, Don Ilev, Ilko K. TI Noninvasive and Label-Free Sensing of Endotoxin Contamination in Ophthalmic Viscosurgical Devices Using a Fiber-Optic Fourier-Transform Infrared Spectroscopy Based Method SO IEEE JOURNAL OF SELECTED TOPICS IN QUANTUM ELECTRONICS LA English DT Article DE Toxic anterior segment syndrome (TASS); ophthalmic viscosurgical devices (OVDs); endotoxin; FTIR spectroscopy; multivariate analysis ID PRINCIPAL COMPONENT ANALYSIS; ANTERIOR SEGMENT SYNDROME; FT-IR MICROSPECTROSCOPY; BACTERIAL LIPOPOLYSACCHARIDES; LISTERIA-MONOCYTOGENES; STAPHYLOCOCCUS-AUREUS; RAPID IDENTIFICATION; DISCRIMINATION; DIFFERENTIATION; CLASSIFICATION AB Ophthalmic viscosurgical devices (OVDs) are essential medical tools for ophthalmic surgeons to use routinely in cataract surgery. OVD endotoxin contamination has been implicated in toxic anterior segment syndrome, a severe inflammatory condition after surgery. Current standard methods for endotoxin detection in medical devices rely on dwindling Horseshoe Crab resources for Limulus amoebocyte lysate assay or rabbit intracameral and intravitreal assays. Endotoxin recovery from OVDs poses particular challenge due to the nature and composition of the device. In the present proof-of-concept study, we demonstrate real-time detection capability of endotoxin by employing a noncontact and label-free fiber-optic Fourier transform infrared transmission spectroscopy based sensing method in the midinfrared spectral range of 1.6-12 mu m. We performed testing on OVD samples spiked with a series of different concentrations of endotoxin. The study suggested that endotoxin contamination in OVD might be associated with fingerprint spectral peak shift in the wavenumber ranges of 2925-2890 cm(-1) and 1125-1100 cm(-1), and the distance of shifting is dependent upon endotoxin concentration in OVD. FO-FTIR integrated with multivariate approaches such as hierarchical clustering and principal component analysis provides significant differentiation of OVD, endotoxin, and contaminated OVD at different concentrations. C1 [Hassan, Moinuddin; Tan, Xin; Ilev, Ilko K.] US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Hitchins, Victoria M.] US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Calogero, Don] US FDA, Div Ophthalm & Ear Nose & Throat Devices, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Hassan, M (reprint author), US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM moinuddin.hassan@fda.hhs.gov; xin.tan@fda.hhs.gov; victoria.hitchins@fda.hhs.gov; don.calogero@fda.hhs.gov; don.calogero@fda.hhs.gov FU FDA Medical Countermeasure Initiatives FX This work was supported by the FDA Medical Countermeasure Initiatives by funding the infrastructure of this research project. NR 45 TC 0 Z9 0 U1 74 U2 74 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1077-260X EI 1558-4542 J9 IEEE J SEL TOP QUANT JI IEEE J. Sel. Top. Quantum Electron. PD MAR-APR PY 2017 VL 23 IS 2 AR 6900207 DI 10.1109/JSTQE.2016.2599405 PG 7 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA DZ9XH UT WOS:000386234300001 ER PT J AU Sen, P Luo, J Hada, A Hailu, SG Dechassa, ML Persinger, J Brahma, S Paul, S Ranish, J Bartholomew, B AF Sen, Payel Luo, Jie Hada, Arjan Hailu, Solomon G. Dechassa, Mekonnen Lemma Persinger, Jim Brahma, Sandipan Paul, Somnath Ranish, Jeff Bartholomew, Blaine TI Loss of Snf5 Induces Formation of an Aberrant SWI/SNF Complex SO CELL REPORTS LA English DT Article ID CHROMATIN REMODELING COMPLEX; MALIGNANT RHABDOID TUMORS; TAF14 YEATS DOMAIN; SACCHAROMYCES-CEREVISIAE; IN-VIVO; NUCLEOSOME; CANCER; TRANSCRIPTION; ACETYLATION; RECRUITMENT AB The SWI/SNF chromatin remodeling complex is highly conserved from yeast to human, and aberrant SWI/SNF complexes contribute to human disease. The Snf5/SMARCB1/INI1 subunit of SWI/SNF is a tumor suppressor frequently lost in pediatric rhabdoid cancers. We examined the effects of Snf5 loss on the composition, nucleosome binding, recruitment, and remodeling activities of yeast SWI/SNF. The Snf5 subunit is shown by crosslinking-mass spectrometry (CX-MS) and subunit deletion analysis to interact with the ATPase domain of Snf2 and to form a submodule consisting of Snf5, Swp82, and Taf14. Snf5 promotes binding of the Snf2 ATPase domain to nucleosomal DNA and enhances the catalytic and nucleosome remodeling activities of SWI/SNF. Snf5 is also required for SWI/SNF recruitment by acidic transcription factors. RNA-seq analysis suggests that both the recruitment and remodeling functions of Snf5 are required in vivo for SWI/SNF regulation of gene expression. Thus, loss of SNF5 alters the structure and function of SWI/SNF. C1 [Hada, Arjan; Hailu, Solomon G.; Persinger, Jim; Brahma, Sandipan; Paul, Somnath; Bartholomew, Blaine] UT MD Anderson Canc Ctr, Smithville, TX 78597 USA. [Hada, Arjan; Hailu, Solomon G.; Persinger, Jim; Bartholomew, Blaine] UT MD Anderson Ctr Canc Epigenet, Smithville, TX 78597 USA. [Luo, Jie; Ranish, Jeff] Inst Syst Biol, Seattle, WA 98109 USA. [Sen, Payel; Dechassa, Mekonnen Lemma] Southern Illinois Univ, Dept Biochem & Mol Biol, Carbondale, IL 62901 USA. [Sen, Payel] Univ Penn, Smilow Ctr Translat Res, 3400 Civ Ctr Blvd,9th Floor, Philadelphia, PA 19104 USA. [Dechassa, Mekonnen Lemma] US FDA, NCTR Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Bartholomew, B (reprint author), UT MD Anderson Canc Ctr, Smithville, TX 78597 USA.; Bartholomew, B (reprint author), UT MD Anderson Ctr Canc Epigenet, Smithville, TX 78597 USA. EM bbartholomew@mdanderson.org FU NIH [R01 GM048413, P50 GM076547, R21 CA175849]; CPRIT [RP120348] FX We want to acknowledge the support provided by NIH R01 GM048413 (to B.B.), P50 GM076547 (to J.R.), and R21 CA175849 (to J.R.). This study also made use of the Science Park NGS Core, supported by CPRIT Core Facility Support Grant RP120348. NR 48 TC 1 Z9 1 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD FEB 28 PY 2017 VL 18 IS 9 BP 2135 EP 2147 DI 10.1016/j.celrep.2017.02.017 PG 13 WC Cell Biology SC Cell Biology GA EP4CO UT WOS:000397328400008 PM 28249160 ER PT J AU Dusane, DH Diamond, SM Knecht, CS Farrar, NR Peters, C Howlin, RP Swearingen, MC Calhoun, JH Plaut, RD Nocera, TM Granger, JF Stoodley, P AF Dusane, Devendra H. Diamond, Scott M. Knecht, Cory S. Farrar, Nicholas R. Peters, CaseyW. Howlin, Robert P. Swearingen, Matthew C. Calhoun, Jason H. Plaut, Roger D. Nocera, Tanya M. Granger, Jeffrey F. Stoodley, Paul TI Effects of loading concentration, blood and synovial fluid on antibiotic release and anti-biofilm activity of bone cement beads SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Periprosthetic infection; Biofilm; Bone cement; Antibiotic release; Zone of inhibition ID PERIPROSTHETIC JOINT INFECTION; CALCIUM-SULFATE BEADS; IN-VITRO; PSEUDOMONAS-AERUGINOSA; GENTAMICIN SULFATE; UNITED-STATES; DELIVERY; ELUTION; VANCOMYCIN; DIFFUSION AB Antibiotic loaded cement beads are commonly used for the treatment of biofilm related orthopaedic periprosthetic infections; however the effects of antibiotic loading and exposure of beads to body fluids on release kinetics are unclear. The purpose of this study was to determine the effects of (i) antibiotic loading density (ii) loading amount (iii) material type and (iv) exposure to body fluids (blood or synovial fluid) on release kinetics and efficacy of antibiotics against planktonic and lawn biofilm bacteria. Short-termrelease into an agar gelwas evaluated using a fluorescent tracer (fluorescein) incorporated in the carrier materials calcium sulfate (CaSO4) and polymethylmethacrylate (PMMA). Different fluorescein concentrations in CaSO4 beads were evaluated. Mechanical properties of fluorescein-incorporated beads were analyzed. Efficacy of the antibiotics vancomycin (VAN) or tobramycin (TOB) alone and in combination was evaluated against lawn biofilms of bioluminescent strains of Staphylococcus aureus and Pseudomonas aeruginosa. Zones of inhibition of cultures (ZOI) were measured visually and using an in-vivo imaging system (IVIS). The influence of body fluids on release was assessed using CaSO4 beads that contained fluorescein or antibiotics and were pre-coated with human blood or synovial fluid. The spread fromthe beads followed a square root of time relationship in all cases. The loading concentration had no influence on short-termfluorescein release and pre-coating of beads with body fluids did not affect shortterm release or antibacterial activity. Compared to PMMA, CaSO4 had a more rapid short term rate of elution and activity against planktonic and lawn biofilms. This study highlights the importance of considering antibiotic loading and packing density when investigating the clinical application of bone cements for infection management. (C) 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license. C1 [Dusane, Devendra H.] Ohio State Univ, Dept Microbial Infect & Immun, Columbus, OH 43210 USA. [Diamond, Scott M.; Knecht, Cory S.] Ohio State Univ, Dept Med, Columbus, OH 43210 USA. [Farrar, Nicholas R.; Howlin, Robert P.; Nocera, Tanya M.] Ohio State Univ, Dept Biomed Engn, Columbus, OH 43210 USA. [Peters, CaseyW.] Ohio State Univ, Dept Biochem, Columbus, OH 43210 USA. [Howlin, Robert P.] Univ Southampton, Fac Nat Environm Sci Inst Life Sci, Ctr Biol Sci, Southampton, Hants, England. [Calhoun, Jason H.] Dept Muscoskeletal Sci, Spectrum Hlth Med Grp, Grand Rapids, MI USA. [Plaut, Roger D.] Div Bacterial Parasit, Food & Drug Adm, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Granger, Jeffrey F.; Stoodley, Paul] Ohio State Univ, Dept Orthopaed, Columbus, OH 43210 USA. [Stoodley, Paul] Natl Ctr Adv Tribol, Southampton, Hants, England. RP Dusane, DH (reprint author), Ohio State Univ, Dept Microbial Infect & Immun, Columbus, OH 43210 USA. EM Devendra.Dusane@osumc.edu NR 46 TC 0 Z9 0 U1 2 U2 2 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 FEB 28 PY 2017 VL 248 BP 24 EP 32 DI 10.1016/j.jconrel.2017.01.005 PG 9 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA EP2JW UT WOS:000397210300003 PM 28087408 ER PT J AU Wenninger, EJ Emmert, SY Tindall, K Ding, HJ Boetel, MA Rajabaskar, D Eigenbrode, SD AF Wenninger, Erik J. Emmert, Susan Y. Tindall, Kelly Ding, Hongjian Boetel, Mark A. Rajabaskar, D. Eigenbrode, Sanford D. TI Aggregation Behavior and a Putative Aggregation Pheromone in Sugar Beet Root Maggot Flies (Diptera: Ulidiidae) SO JOURNAL OF INSECT SCIENCE LA English DT Article DE Tetanops myopaeformis; sex pheromone; sugar beet root maggot fly; lekking; Beta vulgaris ID ANASTREPHA-FRATERCULUS DIPTERA; FRUIT-FLY DIPTERA; CAGED HOST TREE; MATING-BEHAVIOR; RHAGOLETIS-POMONELLA; MAJOR COMPONENTS; LEKKING BEHAVIOR; TEPHRITIDAE; SELECTION; ECOLOGY AB Male-biased aggregations of sugar beet root maggot, Tetanops myopaeformis (Roder) (Diptera: Ulidiidae), flies were observed on utility poles near sugar beet (Beta vulgaris L. [Chenopodiaceae]) fields in southern Idaho; this contrasts with the approximately equal sex ratio typically observed within fields. Peak observation of mating pairs coincided with peak diurnal abundance of flies. Volatiles released by individual male and female flies were sampled from 08:00 to 24:00 hours in the laboratory using solid-phase microextraction and analyzed using gas chromatography/mass spectrometry (GC/MS). Eleven compounds were uniquely detected from males. Three of these compounds (2-undecanol, 2-decanol, and sec-nonyl acetate) were detected in greater quantities during 12:00-24:00hours than during 08:00-12:00 hours. The remaining eight compounds uniquely detected from males did not exhibit temporal trends in release. Both sexes produced 2-nonanol, but males produced substantially higher (ca. 80-fold) concentrations of this compound than females, again peaking after 12:00hours. The temporal synchrony among male aggregation behavior, peak mating rates, and release of certain volatile compounds by males suggest that T. myopaeformis flies exhibit lekking behavior and produce an associated pheromone. Field assays using synthetic blends of the putative aggregation pheromone showed evidence of attraction in both females and males. C1 [Wenninger, Erik J.] Univ Idaho, Kimberly Res & Extens Ctr, Dept Plant Soil & Entomol Sci, Kimberly, ID 83341 USA. [Emmert, Susan Y.; Ding, Hongjian; Rajabaskar, D.; Eigenbrode, Sanford D.] Univ Idaho, Dept Plant Soil & Entomol Sci, Moscow, ID 83844 USA. [Tindall, Kelly] Twin Falls Cty Cooperat Extens, 246 3rd Ave East, Twin Falls, ID 83301 USA. [Ding, Hongjian] US FDA, Jefferson, AR 72079 USA. [Boetel, Mark A.] North Dakota State Univ, NDSU Dept 7650, Dept Entomol, POB 6050, Fargo, ND 58108 USA. [Rajabaskar, D.] Tamil Nadu Agr Univ, Dept Agr Entomol, Coimbatore 641003, Tamil Nadu, India. RP Wenninger, EJ (reprint author), Univ Idaho, Kimberly Res & Extens Ctr, Dept Plant Soil & Entomol Sci, Kimberly, ID 83341 USA. EM erikw@uidaho.edu FU CSREES-CAR program [00-51100-9605]; Idaho Sugar Industry FX For assistance with field studies, we gratefully acknowledge T. Daley, J. Neufeld, R. Srinivasan, N. Payton, R. Dregseth, A. Schroeder, and J. Rikhus. R. Stoltz and E. Bechinski helped with collection of flies for laboratory experiments. E. Bechinski and J. McCaffrey provided helpful comments on earlier drafts of this manuscript. This research was supported by grants from the CSREES-CAR program to SDE (award #00-51100-9605) and from the Idaho Sugar Industry to E.J.W. NR 43 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 1536-2442 EI 2250-2645 J9 J INSECT SCI JI J Insect Sci. PD FEB 28 PY 2017 VL 17 AR 29 DI 10.1093/jisesa/ew123 PG 9 WC Entomology SC Entomology GA EO4WU UT WOS:000396695800006 ER PT J AU Wu, LC Chen, F Lee, SL Raw, A Yu, LX AF Wu, Larisa C. Chen, Fu Lee, Sau L. Raw, Andre Yu, Lawrence X. TI Building parity between brand and generic peptide products.: Regulatory and scientific considerations for quality of synthetic peptides SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Peptide; Regulatory; Risk assessment; Quality control; Peptide structure; Solid phase peptide synthesis ID METAL-CATALYZED OXIDATION; SOLID-PHASE SYNTHESIS; BETA-AMYLOID PEPTIDE; AMINO-ACID RESIDUES; LIQUID-CHROMATOGRAPHY; AQUEOUS-SOLUTION; PROTEIN PHARMACEUTICALS; ASPARTIMIDE FORMATION; METHIONINE OXIDATION; MASS-SPECTROMETRY AB Peptides are a fast growing segment in the pharmaceutical industry. Consequently, the industry and regulatory agencies are increasing their focus on the regulatory path and quality considerations for peptide development and manufacturing. Although most peptides are synthetic, manufactured by solid phase synthesis, nevertheless they are complex molecules with challenging quality and regulatory aspects. This paper provides a structured overview of relevant quality issues for chemically synthesized peptides used as active pharmaceutical ingredients (API) in drug products. It addresses the unique characteristics of peptides pertaining to structural and physicochemical characterization, manufacturing and in process controls, impurities and aggregates arising from manufacturing and storage, along with their potential impact on safety (including immunogenicity) and efficacy of the peptide drug products. Published by Elsevier B.V. C1 [Wu, Larisa C.; Chen, Fu; Lee, Sau L.; Raw, Andre; Yu, Lawrence X.] US FDA, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Wu, LC (reprint author), US FDA, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Larisa.Wu@fda.hhs.gov FU Office of Pharmaceutical Quality/Center for Drug Evaluation and Research, U.S. Food and Drug Administration FX This project was supported in part by an appointment to the Research Participation Program at the Office of Pharmaceutical Quality/Center for Drug Evaluation and Research, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA. NR 150 TC 0 Z9 0 U1 3 U2 3 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 FEB 25 PY 2017 VL 518 IS 1-2 BP 320 EP 334 DI 10.1016/j.ijpharm.2016.12.051 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EL1SU UT WOS:000394402100033 PM 28027918 ER PT J AU Chawla, B Hedman, AC Sayedyahossein, S Erdemir, HH Li, ZG Sacks, DB AF Chawla, Bhavna Hedman, Andrew C. Sayedyahossein, Samar Erdemir, Huseyin H. Li, Zhigang Sacks, David B. TI Absence of IQGAP1 Protein Leads to Insulin Resistance SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Akt PKB; insulin; insulin receptor; insulin receptor substrate 1 (IRS-1); insulin resistance; mitogen-activated protein kinase (MAPK); phosphatidylinositide 3-kinase (PI 3-kinase); IQGAP1 ID PLECKSTRIN-HOMOLOGY DOMAIN; HEPATOCELLULAR-CARCINOMA; MICE LACKING; PTB DOMAIN; IQ MOTIFS; RECEPTOR; IRS-1; SCAFFOLD; BINDING; ACTIVATION AB Insulin binds to the insulin receptor (IR) and induces tyrosine phosphorylation of the receptor and insulin receptor substrate-1 (IRS-1), leading to activation of the PKB/Akt and MAPK/ERK pathways. IQGAP1 is a scaffold protein that interacts with multiple binding partners and integrates diverse signaling cascades. Here we show that IQGAP1 associates with both IR and IRS-1 and influences insulin action. In vitro analysis with pure proteins revealed that the IQ region of IQGAP1 binds directly to the intracellular domain of IR. Similarly, the phosphotyrosine-binding domain of IRS-1 mediates a direct interaction with the C-terminal tail of IQGAP1. Consistent with these observations, both IR and IRS-1 co-immunoprecipitated with IQGAP1 from cells. Investigation of the functional effects of the interactions revealed that in the absence of IQGAP1, insulin-stimulated phosphorylation of Akt and ERK, as well as the association of phosphatidylinositol 3-kinase with IRS-1, were significantly decreased. Importantly, loss of IQGAP1 results in impaired insulin signaling and glucose homeostasis in vivo. Collectively, these data reveal that IQGAP1 is a scaffold for IR and IRS-1 and implicate IQGAP1 as a participant in insulin signaling. C1 [Chawla, Bhavna; Hedman, Andrew C.; Sayedyahossein, Samar; Erdemir, Huseyin H.; Li, Zhigang; Sacks, David B.] NIH, Dept Lab Med, 10 Ctr Dr,10-2C306, Bethesda, MD 20892 USA. [Chawla, Bhavna] US FDA, Ctr Biol Evaluat & Res, Div Emerging & Transfus Transmitted Dis, Silver Spring, MD 20993 USA. [Erdemir, Huseyin H.] Cleveland Clin, Dept Pediat Hematol Oncol, Cleveland, OH 44195 USA. [Erdemir, Huseyin H.] Cleveland Clin, BMT, Cleveland, OH 44195 USA. RP Sacks, DB (reprint author), NIH, Dept Lab Med, 10 Ctr Dr,10-2C306, Bethesda, MD 20892 USA. EM david.sacks2@nih.gov OI Sacks, David/0000-0003-3100-0735 FU National Institutes of Health Intramural Research Program FX This work was supported by the National Institutes of Health Intramural Research Program. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 53 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 24 PY 2017 VL 292 IS 8 BP 3273 EP 3289 DI 10.1074/jbc.M116.752642 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EM8CM UT WOS:000395538800019 PM 28082684 ER PT J AU Wen, GZ Markey, MK Park, S AF Wen, Gezheng Markey, Mia K. Park, Subok TI Model observer design for multi-signal detection in the presence of anatomical noise SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE model observer; multiple signal detection; partial least squares; channelized Hotelling observer; medical image quality; multifocal multicentric cancer ID POWER-LAW NOISE; DIGITAL BREAST TOMOSYNTHESIS; CLUSTERED LUMPY BACKGROUNDS; PARTIAL LEAST-SQUARES; TEXTURE SYNTHESIS; GAZE-TRACKING; MAMMOGRAPHY; ACQUISITION; PERFORMANCE; CANCERS AB As psychophysical studies are resource-intensive to conduct, model observers are commonly used to assess and optimize medical imaging quality. Model observers are typically designed to detect at most one signal. However, in clinical practice, there may be multiple abnormalities in a single image set (e.g. multifocal multicentric (MFMC) breast cancer), which can impact treatment planning. Prevalence of signals can be different across anatomical regions, and human observers do not know the number or location of signals a priori. As new imaging techniques have the potential to improve multiple-signal detection (e.g. digital breast tomosynthesis may be more effective for diagnosis of MFMC than mammography), image quality assessment approaches addressing such tasks are needed. In this study, we present a model observer to detect multiple signals in an image dataset. A novel implementation of partial least squares (PLS) was developed to estimate different sets of efficient channels directly from the images. The PLS channels are adaptive to the characteristics of signals and the background, and they capture the interactions among signal locations. Corresponding linear decision templates are employed to generate both image-level and location-specific scores on the presence of signals. Our results show that: (1) the model observer can achieve high performance with a reasonably small number of channels; (2) the model observer with PLS channels outperforms that with benchmark modified Laguerre-Gauss channels, especially when realistic signal shapes and complex background statistics are involved; (3) the tasks of clinical interest, and other constraints such as sample size would alter the optimal design of the model observer. C1 [Wen, Gezheng] Univ Texas Austin, Dept Elect & Comp Engn, Austin, TX 78712 USA. [Wen, Gezheng] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX 77030 USA. [Markey, Mia K.] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Markey, Mia K.] Univ Texas MD Anderson Canc Ctr, Dept Imaging Phys, Houston, TX 77030 USA. [Park, Subok] Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. RP Wen, GZ (reprint author), Univ Texas Austin, Dept Elect & Comp Engn, Austin, TX 78712 USA.; Wen, GZ (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX 77030 USA. EM wen.gezheng@utexas.edu; mia.markey@utexas.edu; subok.park@fda.hhs.gov FU NSF/FDA Scholar-in-Residence at the FDA [CBET-1445713] FX We would like to thank scientists and staff in the Division of Imaging, Diagnostics, and Software Reliability in the Center for Devices and Radiological Health of the U.S. Food and Drug Administration (FDA) for their support on this work. This work was partially supported by NSF/FDA Scholar-in-Residence at the FDA grant number CBET-1445713. NR 57 TC 0 Z9 0 U1 1 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD FEB 21 PY 2017 VL 62 IS 4 BP 1396 EP 1416 DI 10.1088/1361-6560/aa51e9 PG 21 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA EL4KM UT WOS:000394590100011 PM 28114105 ER PT J AU Galappaththige, SK Gray, RA Roth, BJ AF Galappaththige, Suran K. Gray, Richard A. Roth, Bradley J. TI Cardiac strength-interval curves calculated using a bidomain tissue with a parsimonious ionic current SO PLOS ONE LA English DT Article ID ELEVATED EXTRACELLULAR POTASSIUM; ANODE-BREAK STIMULATION; ELECTRICAL-STIMULATION; INTRACELLULAR CALCIUM; MECHANISM; MODEL; SIMULATIONS; ELECTRODES; HEART AB The strength-interval curve plays a major role in understanding how cardiac tissue responds to an electrical stimulus. This complex behavior has been studied previously using the bidomain formulation incorporating the Beeler-Reuter and Luo-Rudy dynamic ionic current models. The complexity of these models renders the interpretation and extrapolation of simulation results problematic. Here we utilize a recently developed parsimonious ionic current model with only two currents-a sodium current that activates rapidly upon depolarization I-Na and a time-independent inwardly rectifying repolarization current I-K-which reproduces many experimentally measured action potential waveforms. Bidomain tissue simulations with this ionic current model reproduce the distinctive dip in the anodal (but not cathodal) strength-interval curve. Studying model variants elucidates the necessary and sufficient physiological conditions to predict the polarity dependent dip: a voltage and time dependent I-Na, a nonlinear rectifying repolarization current, and bidomain tissue with unequal anisotropy ratios. C1 [Galappaththige, Suran K.; Roth, Bradley J.] Oakland Univ, Dept Phys, Rochester, MI 48309 USA. [Gray, Richard A.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Roth, BJ (reprint author), Oakland Univ, Dept Phys, Rochester, MI 48309 USA. EM roth@oakland.edu RI Roth, Bradley/A-4920-2008 FU National Institutes of Health [R01HL118392] FX Support was provided by the National Institutes of Health, grant R01HL118392. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This research was supported in part by a grant from the National Institutes of Health (R01HL118392). NR 24 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 FEB 21 PY 2017 VL 12 IS 2 AR e0171144 DI 10.1371/journal.pone.0171144 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EL5QV UT WOS:000394676800009 ER PT J AU Bone, MA Wilk, AJ Perault, AI Marlatt, SA Scheller, EV Anthouard, R Chen, Q Stibitz, S Cotter, PA Julio, SM AF Bone, M. Ashley Wilk, Aaron J. Perault, Andrew I. Marlatt, Sara A. Scheller, Erich V. Anthouard, Rebecca Chen, Qing Stibitz, Scott Cotter, Peggy A. Julio, Steven M. TI Bordetella PlrSR regulatory system controls BvgAS activity and virulence in the lower respiratory tract SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Bordetella; two-component system; virulence; respiratory infection; gene regulation ID ACELLULAR PERTUSSIS VACCINES; ADENYLATE-CYCLASE TOXIN; SENSOR-KINASE; FILAMENTOUS HEMAGGLUTININ; SIGNAL-TRANSDUCTION; CONTROLS EXPRESSION; 2-COMPONENT SYSTEM; IMMUNE-RESPONSES; FHA PROMOTER; IN-VIVO AB Bacterial pathogens coordinate virulence using two-component regulatory systems (TCS). The Bordetella virulence gene (BvgAS) phosphorelay-type TCS controls expression of all known protein virulence factor-encoding genes and is considered the "master virulence regulator" in Bordetella pertussis, the causal agent of pertussis, and related organisms, including the broad host range pathogen Bordetella bronchiseptica. We recently discovered an additional sensor kinase, PlrS [for persistence in the lower respiratory tract (LRT) sensor], which is required for B. bronchiseptica persistence in the LRT. Here, we show that PlrS is required for BvgAS to become and remain fully active in mouse lungs but not the nasal cavity, demonstrating that PlrS coordinates virulence specifically in the LRT. PlrS is required for LRT persistence even when BvgAS is rendered constitutively active, suggesting the presence of BvgAS-independent, PlrS-dependent virulence factors that are critical for bacterial survival in the LRT. We show that PlrS is also required for persistence of the human pathogen B. pertussis in the murine LRT and we provide evidence that PlrS most likely functions via the putative cognate response regulator PlrR. These data support a model in which PlrS senses conditions present in the LRT and activates PlrR, which controls expression of genes required for the maintenance of BvgAS activity and for essential BvgAS-independent functions. In addition to providing a major advance in our understanding of virulence regulation in Bordetella, which has served as a paradigm for several decades, these results indicate the existence of previously unknown virulence factors that may serve as new vaccine components and therapeutic or diagnostic targets. C1 [Bone, M. Ashley; Perault, Andrew I.; Marlatt, Sara A.; Scheller, Erich V.; Anthouard, Rebecca; Cotter, Peggy A.] Univ North Carolina Chapel Hill, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Wilk, Aaron J.; Julio, Steven M.] Westmont Coll, Dept Biol, Santa Barbara, CA 93108 USA. [Chen, Qing; Stibitz, Scott] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Wilk, Aaron J.] Stanford Univ, Med Scientist Training Program, Sch Med, Stanford, CA 94305 USA. [Marlatt, Sara A.] Azusa Pacific Univ, Dept Biol & Chem, Azusa, CA 91702 USA. RP Cotter, PA (reprint author), Univ North Carolina Chapel Hill, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA.; Julio, SM (reprint author), Westmont Coll, Dept Biol, Santa Barbara, CA 93108 USA. EM peggy_cotter@med.unc.edu; sjulio@westmont.edu FU NIH [R01 AI AI094991]; Training, Workforce Development & Diversity division of the National Institute of General Medical Sciences, NIH. [K12GM000678] FX We thank members of the P.A.C. and S.M.J. laboratories for critical discussions and technical assistance.This work was supported by NIH Grant R01 AI AI094991(to P.A.C.), and institutional funds (S.M.J.). S.A.M. was supported by Grant K12GM000678 from the Training, Workforce Development & Diversity division of the National Institute of General Medical Sciences, NIH. NR 59 TC 0 Z9 0 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 21 PY 2017 VL 114 IS 8 BP E1519 EP E1527 DI 10.1073/pnas.1609565114 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM1TI UT WOS:000395099500025 PM 28167784 ER PT J AU Califf, RM AF Califf, Robert M. TI Benefit-Risk Assessments at the US Food and Drug Administration Finding the Balance SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material 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@duke.edu FU Patient-Centered Outcomes Research Institute; National Institutes of Health; US 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 The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Califf was the Commissioner of Food and Drugs of the FDA from February 2016 through January 20,2017. 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 US 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; consulting payments from Amgen, Bayer Healthcare, BMEB Services, Genentech, GlaxoSmithKline, Heart. org-Daiichi Sankyo, Kowa, Les Laboratoires Servier, Medscape/Heart.org, Regado, and Roche; he also held equity in N30 Pharma and Portola. NR 3 TC 1 Z9 1 U1 0 U2 0 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 FEB 21 PY 2017 VL 317 IS 7 BP 693 EP 694 DI 10.1001/jama.2017.0410 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EL8WR UT WOS:000394901600012 PM 28114599 ER PT J AU Hunt, R Yalamanoglu, A Tumlin, J Schiller, T Baek, JH Wu, A Fogo, AB Yang, HC Wong, E Miller, P Buehler, PW Kimchi-Sarfaty, C AF Hunt, Ryan Yalamanoglu, Ayla Tumlin, James Schiller, Tal Baek, Jin Hyen Wu, Andrew Fogo, Agnes B. Yang, Haichun Wong, Edward Miller, Peter Buehler, Paul W. Kimchi-Sarfaty, Chava TI A mechanistic investigation of thrombotic microangiopathy associated with IV abuse of Opana ER SO BLOOD LA English DT Article ID VON-WILLEBRAND-FACTOR; ACUTE KIDNEY INJURY; DRAG-REDUCING POLYMERS; INDUCED PLATELET-AGGREGATION; PLASMA VONWILLEBRAND-FACTOR; HEMOLYTIC-UREMIC SYNDROME; FACTOR-CLEAVING PROTEASE; THROMBOCYTOPENIC PURPURA; GUINEA-PIGS; INTRAVENOUS ABUSE AB Since 2012, a number of case reports have described the occurrence of thrombotic microangiopathy (TMA) following IV abuse of extended-release oxymorphone hydrochloride (Opana ER), an oral opioid for long- term treatment of chronic pain. Here, we present unique clinical features of 3 patients and investigate IV exposure to the tablet's inert ingredients as a possible causal mechanism. Guinea pigs were used as an animal model to understand the hematopathologic and nephrotoxic potential of the inert ingredient mixture (termed here as PEO+) which primarily contains high-molecularweight polyethylene oxide (HMW PEO). Microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury were found in a group of 3 patients following recent injection of adulterated extended-release oxymorphone tablets. Varying degrees of cardiac involvement and retinal ischemia occurred, with TMA evident on kidney biopsy. A TMA-like state also developed in guinea pigs IV administered PEO+. Acute tubular and glomerular renal injury was accompanied by nonheme iron deposition and hypoxia-inducible factor-1 alpha upregulation in the renal cortex. Similar outcomes were observed following dosing with HMW PEO alone. IV exposure to the inert ingredients in reformulated extended-release oxymorphone can elicit TMA. Although prescription opioid abuse shows geographic variation, all physicians should be highly inquisitive of IV drug abuse when presented with cases of TMA. C1 [Hunt, Ryan; Schiller, Tal; Wu, Andrew; Kimchi-Sarfaty, Chava] US FDA, Div Plasma Prot Therapeut, Off Tissues & Adv Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Yalamanoglu, Ayla; Baek, Jin Hyen; Buehler, Paul W.] US FDA, Div Blood Components & Devices, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Tumlin, James] Univ Tennessee, Dept Internal Med, Coll Med Chattanooga, Chattanooga, TN USA. [Fogo, Agnes B.; Yang, Haichun] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN USA. [Wong, Edward] George Washington Sch Med & Hlth Sci, Dept Pediat, Washington, DC USA. [Wong, Edward] George Washington Sch Med & Hlth Sci, Dept Pathol, Washington, DC USA. [Wong, Edward] Quest Diagnost Nichols Inst, Dept Coagulat, Chantilly, VA USA. [Miller, Peter] Wake Forest Sch Med, Dept Internal Med, Sect Hematol & Oncol, Winston Salem, NC USA. [Miller, Peter] Wake Forest Sch Med, Dept Anesthesiol, Sect Pulm Crit Care Allergy & Immunol, Winston Salem, NC USA. [Miller, Peter] Wake Forest Sch Med, Dept Anesthesiol, Sect Crit Care Med, Winston Salem, NC USA. RP Buehler, PW (reprint author), US FDA, Lab Biochem & Vasc Biol, DBCD OBRR CBER, 10903 New Hampshire Ave,Bldg 52-72,Room 4108, Silver Spring, MD 20993 USA.; Kimchi-Sarfaty, C (reprint author), US FDA, Hemostasis Branch, DPPT OTAT CBER, 10903 New Hampshire Ave,Bldg 52-72,Room 4118, Silver Spring, MD 20993 USA. EM paul.buehler@fda.hhs.gov; chava.kimchi-sarfaty@fda.hhs.gov NR 56 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 16 PY 2017 VL 129 IS 7 BP 896 EP 905 DI 10.1182/blood-2016-08-736579 PG 10 WC Hematology SC Hematology GA EO9OW UT WOS:000397019000014 PM 27864296 ER PT J AU Gassman, AL Nguyen, CP Joffe, HV AF Gassman, Audrey L. Nguyen, Christine P. Joffe, Hylton V. TI FDA Regulation of Prescription Drugs SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID APPROVAL; RISK C1 [Gassman, Audrey L.; Nguyen, Christine P.; Joffe, Hylton V.] US FDA, Div Bone Reprod & Urol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Joffe, HV (reprint author), US FDA, Div Bone Reprod & Urol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM hylton.joffe@fda.hhs.gov NR 38 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 16 PY 2017 VL 376 IS 7 BP 674 EP 682 DI 10.1056/NEJMra1602972 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EO0QJ UT WOS:000396402700018 PM 28199811 ER PT J AU Kim, JJ Sabatelli, N Tutak, W Giuseppetti, A Frukhtbeyn, S Shaffer, I Wilhide, J Routkevitch, D Ondov, JM AF Kim, Jeffrey J. Sabatelli, Nicole Tutak, Wojtek Giuseppetti, Anthony Frukhtbeyn, Stanislav Shaffer, Ian Wilhide, Joshua Routkevitch, Denis Ondov, John M. TI Universal electronic-cigarette test: physiochemical characterization of reference e-liquid SO TOBACCO INDUCED DISEASES LA English DT Article DE Electronic-cigarette; e-cig; Reference material; e-liquid; Universal testing method ID NICOTINE DELIVERY-SYSTEMS; UNITED-STATES; US ADULTS; HEALTH; AWARENESS; PRODUCTS AB Background: Despite the rising health and safety concerns of e-cigarettes, a universal e-cigarette testing method is still in its early developmental stage. The aim of this study was to develop an e-liquid Reference Material that can be used to improve accuracy and reproducibility of research results, and advance health risk assessment of e-cigarette products. Methods: E-liquid Reference Material was developed by purity assessment, gravimetric measurement, homogeneity testing, and stability testing with material and instrument traceability (adopted from ISO 35: 2006E). Results: Homogeneity tests showed e-liquid Reference Material requires >= 1 h rotation at a speed of 5 rpm to reach complete homogeneity. Stability tests showed homogeneity is intact for at least 2 weeks without secondary separation, and e-liquids are stable in 21 degrees C-50 degrees C thermocycling conditions up to 72 h. A change in the e-liquid color was first observed at day seven, and progressed to 2-and 16-fold increase in absorbance by one and 6 months respectively. We found that e-liquids do not have inherent material instabilities such as immiscibility or secondary separation. However, discrepancies in concentration and composition arose mainly due to viscosity of propylene glycol and glycerin. Aerosol generated from the e-liquid Reference Material had 16 chemical-byproducts and was composed of similar to 634,000 particles of which 38% were Fine Particulate Matters (< 0.5 mu m in diameter). Conclusions: The efforts described here to create a standardized e-liquid Reference Material aim to provide unbiased and robust testing parameters that may be useful for researchers, the industry and government agencies. Additionally, the reference e-liquid could open a channel of conversation among different laboratories by providing the means of independent verification and validation while establishing a system of transparency and reproducibility in materials and methods. C1 [Kim, Jeffrey J.; Tutak, Wojtek; Giuseppetti, Anthony; Frukhtbeyn, Stanislav] ADA Fdn, Volpe Res Ctr, Clin Res, 100 Bur Dr Stop 8546 NIST, Gaithersburg, MD 20899 USA. [Sabatelli, Nicole] Univ Maryland, Sch Engn, College Pk, MD 20742 USA. [Shaffer, Ian; Wilhide, Joshua] Univ Maryland Baltimore Cty, Mol Characterizat & Anal Complex, Baltimore, MD 21228 USA. [Routkevitch, Denis] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. [Ondov, John M.] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Tutak, Wojtek] US FDA, Silver Spring, MD USA. RP Kim, JJ (reprint author), ADA Fdn, Volpe Res Ctr, Clin Res, 100 Bur Dr Stop 8546 NIST, Gaithersburg, MD 20899 USA. EM jeffrey.kim@nist.gov FU ADA Foundation (Intramural - Clinical Research) FX This work was supported by the ADA Foundation (Intramural - Clinical Research). NR 35 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 1617-9625 J9 TOB INDUC DIS JI Tob. Induc. Dis. PD FEB 16 PY 2017 VL 15 AR 14 DI 10.1186/s12971-017-0119-x PG 10 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA EL1QF UT WOS:000394394300001 PM 28239329 ER PT J AU Taylor, V Goodale, B Raab, A Schwerdtle, T Reimer, K Conklin, S Karagas, MR Francesconi, KA AF Taylor, Vivien Goodale, Britton Raab, Andrea Schwerdtle, Tanja Reimer, Ken Conklin, Sean Karagas, Margaret R. Francesconi, Kevin A. TI Human exposure to organic arsenic species from seafood SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Organic arsenic; Seafood; Arsenosugar; Arsenolipid ID HPLC-ICP-MS; PLASMA-MASS SPECTROMETRY; VITRO TOXICOLOGICAL CHARACTERIZATION; PHYTOPLANKTON DUNALIELLA-TERTIOLECTA; THIO-DIMETHYLARSINIC ACID; MUSSELS MYTILUS-EDULIS; CONTAINING FATTY-ACIDS; MICROWAVE-ASSISTED EXTRACTION; NUTRITION EXAMINATION SURVEY; ATLANTIC HYDROTHERMAL VENTS AB Seafood, including finfish, shellfish, and seaweed, is the largest contributor to arsenic (As) exposure in many human populations. In contrast to the predominance of inorganic As in water and many terrestrial foods, As in marine-derived foods is present primarily in the form of organic compounds. To date, human exposure and toxicological assessments have focused on inorganic As, while organic As has generally been considered to be nontoxic. However, the high concentrations of organic As in seafood, as well as the often complex As speciation, can lead to complications in assessing As exposure from diet. In this report, we evaluate the presence and distribution of organic As species in seafood, and combined with consumption data, address the current capabilities and needs for determining human exposure to these compounds. The analytical approaches and shortcomings for assessing these compounds are reviewed, with a focus on the best practices for characterization and quantitation. Metabolic pathways and toxicology of two important classes of organic arsenicals, arsenolipids and arsenosugars, are examined, as well as individual variability in absorption of these compounds. Although determining health outcomes or assessing a need for regulatory policies for organic As exposure is premature, the extensive consumption of seafood globally, along with the preliminary toxicological profiles of these compounds and their confounding effect on assessing exposure to inorganic As, suggests further investigations and process-level studies on organic As are needed to fill the current gaps in knowledge. (C) 2016 Elsevier B.V. All rights reserved. C1 [Taylor, Vivien; Goodale, Britton] Dartmouth Coll, Hanover, NH 03755 USA. [Raab, Andrea] Univ Aberdeen, Aberdeen AB9 1FX, Scotland. [Schwerdtle, Tanja] Univ Potsdam, Potsdam, Germany. [Reimer, Ken] Royal Mil Coll Canada, Kingston, ON, Canada. [Conklin, Sean] Food & Drug Adm, Silver Spring, MD USA. [Karagas, Margaret R.] Geisel Sch Med Dartmouth, Hanover, NH USA. [Francesconi, Kevin A.] Graz Univ, A-8010 Graz, Austria. RP Taylor, V (reprint author), Dartmouth Coll, Hanover, NH 03755 USA. EM vivien.f.taylor@dartmouth.edu FU Dartmouth College Toxic Metals Superfund Research Program through funds from the National Institute of Environmental Health Sciences of the National Institutes of Health [1R13ES026493-01, P42ES007373]; Children's Environmental Health and Disease Prevention Research Center at Dartmouth through funds from the National Institute of Environmental Health Sciences of the National Institutes of Health [P01ES022832]; US EPA Award [RD83544201]; Austrian Science Fund [FWF I2412-B21]; NIEHS [F32ES025082]; DFG (German Research Foundation) [SCHW 903/10-1] FX This paper, a product of the Collaborative on Food with Arsenic and associated Risk and Regulation (C-FARR), is supported by the Dartmouth College Toxic Metals Superfund Research Program through funds from the National Institute of Environmental Health Sciences of the National Institutes of Health under Award Number 1R13ES026493-01 to C. Chen and Award Number P42ES007373 to B. Stanton, and the Children's Environmental Health and Disease Prevention Research Center at Dartmouth through funds from the National Institute of Environmental Health Sciences of the National Institutes of Health under Award Number P01ES022832 and from the US EPA Award Number RD83544201 to M. Karagas. K.A. Francesconi support from Austrian Science Fund (FWF I2412-B21); B.Goodale from NIEHS Award Number F32ES025082 to B.Goodale; and T. Schwerdtle acknowledges DFG (German Research Foundation) grant number SCHW 903/10-1. NR 244 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 EI 1879-1026 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD FEB 15 PY 2017 VL 580 BP 266 EP 282 DI 10.1016/j.scitotenv.2016.12.113 PG 17 WC Environmental Sciences SC Environmental Sciences & Ecology GA EM5LS UT WOS:000395353600027 PM 28024743 ER PT J AU Goblick, GN Ao, YP Anbarchian, JM Calci, KR AF Goblick, Gregory N. Ao, Yaping Anbarchian, Julie M. Calci, Kevin R. TI Determination of buildup and dilution of wastewater effluent in shellfish growing waters through a modified application of super-position SO MARINE POLLUTION BULLETIN LA English DT Article DE Dilution; Wastewater treatment plant; Shellfish growing area; Super-position; Fluorometers; Rhodamine WT dye tracing AB Since 1925, dilution analysis has been used to minimize pathogenic impacts to bivalve molluscan shellfish growing areas from treated wastewater effluent in the National Shellfish Sanitation Program (NSSP). For over twenty five years, the U.S. Food and Drug Administration (FDA) has recommended a minimum of 1000:1 dilution of effluent within prohibited closure zones established around wastewater treatment plant (WWTP) discharges. During May 2010, using recent technologies, a hydrographic dye study was conducted in conjunction with a pathogen bioaccumulation study in shellfish adjacent to a WWTP discharge in Yarmouth, ME. For the first time an improved method of the super-position principle was used to determine the buildup of dye tagged sewage effluent and steady state dilution in tidal waters. Results of the improved method of dilution analysis illustrate an economical, reliable and more accurate and manageable approach for estimating the buildup and steady state pollutant conditions in coastal and estuarine waters. Published by Elsevier Ltd. C1 [Goblick, Gregory N.; Ao, Yaping] US FDA, Off Food Safety, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Anbarchian, Julie M.] US FDA, Cent Reg, Off Regulatory Affairs, 6000 Metro Dr,Suite 101, Baltimore, MD 21215 USA. [Calci, Kevin R.] US FDA, Off Food Safety, Ctr Food Safety & Appl Nutr, Dauphin Isl, AL 36528 USA. RP Goblick, GN (reprint author), US FDA, Off Food Safety, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM Gregory.Goblick@fda.hhs.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0025-326X EI 1879-3363 J9 MAR POLLUT BULL JI Mar. Pollut. Bull. PD FEB 15 PY 2017 VL 115 IS 1-2 BP 164 EP 171 DI 10.1016/j.marpolbul.2016.12.011 PG 8 WC Environmental Sciences; Marine & Freshwater Biology SC Environmental Sciences & Ecology; Marine & Freshwater Biology GA EL1RX UT WOS:000394399800032 PM 27956013 ER PT J AU Golestanirad, L Iacono, MI Keil, B Angelone, LM Bonmassar, G Fox, MD Herrington, T Adalsteinsson, E LaPierre, C Mareyam, A Wald, LL AF Golestanirad, Laleh Iacono, Maria Ida Keil, Boris Angelone, Leonardo M. Bonmassar, Giorgio Fox, Michael D. Herrington, Todd Adalsteinsson, Elfar LaPierre, Cristen Mareyam, Azma Wald, Lawrence L. TI Construction and modeling of a reconfigurable MRI coil for lowering SAR in patients with deep brain stimulation implants SO NEUROIMAGE LA English DT Article DE Deep brain stimulation (DBS); Finite element method (FEM); Magnetic resonance imaging (MRI); Medical implants; Neurostimulation; Parkinson's disease; RF heating; Safety; Specific absorption rate (SAR) ID SUBTHALAMIC NUCLEUS; PARKINSONS-DISEASE; 1.5 T; LEADS; SAFETY; WIRES; ELECTRODES; MANAGEMENT; DEVICES; ISSUES AB Post-operative MRI of patients with deep brain simulation (DBS) implants is useful to assess complications and diagnose comorbidities, however more than one third of medical centers do not perform MRIs on this patient population due to stringent safety restrictions and liability risks. A new system of reconfigurable magnetic resonance imaging head coil composed of a rotatable linearly-polarized birdcage transmitter and a close-fitting 32-channel receive array is presented for low-SAR imaging of patients with DBS implants. The novel system works by generating a region with low electric field magnitude and steering it to coincide with the DBS lead trajectory. We demonstrate that the new coil system substantially reduces the SAR amplification around DBS electrodes compared to commercially available circularly polarized coils in a cohort of 9 patient-derived realistic DBS lead trajectories. We also show that the optimal coil configuration can be reliably identified from the image artifact on B1(+) field maps. Our preliminary results suggest that such a system may provide a viable solution for high-resolution imaging of DBS patients in the future. More data is needed to quantify safety limits and recommend imaging protocols before the novel coil system can be used on patients with DBS implants. C1 [Golestanirad, Laleh; Keil, Boris; Bonmassar, Giorgio; Adalsteinsson, Elfar; LaPierre, Cristen; Mareyam, Azma; Wald, Lawrence L.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Golestanirad, Laleh; Bonmassar, Giorgio; Fox, Michael D.; Wald, Lawrence L.] Harvard Med Sch, Boston, MA USA. [Iacono, Maria Ida; Angelone, Leonardo M.] US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Keil, Boris] THM, Inst Med Phys & Radiat Protect, Life Sci Engn, Giessen, Germany. [Fox, Michael D.] Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA 02215 USA. [Adalsteinsson, Elfar] MIT, Elect Engn & Comp Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Herrington, Todd] Harvard Med Sch, Brigham & Womens Hosp, Massachusetts Gen Hosp, Partners Neurol, Boston, MA USA. RP Golestanirad, L (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. EM lgolestanirad@gmail.com FU NIH [K99EB021320, R01EB006847, P41EB015896] FX This work has been supported by NIH grant K99EB021320, R01EB006847, and P41EB015896. NR 54 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2017 VL 147 BP 577 EP 588 DI 10.1016/j.neuroimage.2016.12.056 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EL3ZW UT WOS:000394560600051 PM 28011252 ER PT J AU Mudalige, TK Qu, HO Linder, SW AF Mudalige, Thilak K. Qu, Haiou Linder, Sean W. TI Rejection of Commonly Used Electrolytes in Asymmetric Flow Field Flow Fractionation: Effects of Membrane Molecular Weight Cutoff Size, Fluid Dynamics, and Valence of Electrolytes SO LANGMUIR LA English DT Article ID NANOFILTRATION MEMBRANES; POTENTIAL MEASUREMENTS; MULTIDETECTOR APPROACH; DLVO INTERACTION; SURFACE; NANOPARTICLES; SEPARATION; CHANNEL; MODEL; SIMULATIONS AB Asymmetric flow field flow fractionation (AF4) is an efficient size-based separation technique for the characterization of submicron size particulates. In AF4, membranes having various molecular weight cutoff sizes are used as a barrier to retain particles while allowing the carrier fluid containing electrolytes to permeate. Here, we have hypothesized that electrolyte rejection by the barrier membrane leads to the accumulation of electrolytes in the membrane channel during operation. Electrolyte accumulation can cause various adverse effects that can lead to membrane fouling. An instrument setup containing a conductivity detector was flow out assembled, and the rejection of commonly used carrier (to waste) electrolytes such as trisodium citrate, ethylenediaminetetraacetic acid, sodium chloride, and ammonium carbonate was evaluated by varying the concentration, cross-flow rate, focusing flow rate, membrane material type, and cutoff sizes. The results showed that electrolyte rejection increased with a decrease in the electrolyte concentration and the molecular weight cutoff size (pore size) or with an increase in the charge state of the anion in the carrier electrolytes. We proposed an electrostatic repulsion-based rejection mechanism and verified it with the measurement of the rejection rate while varying the electrolyte concentration in the running media. C1 [Mudalige, Thilak K.; Qu, Haiou; Linder, Sean W.] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Mudalige, TK (reprint author), US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Thilak.Mudalige@fda.hhs.gov NR 31 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD FEB 14 PY 2017 VL 33 IS 6 BP 1442 EP 1450 DI 10.1021/acs.langmuir.6b03749 PG 9 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA EL1WC UT WOS:000394411100015 PM 28098465 ER PT J AU Shaw, DK Wang, XW Brown, LJ Chavez, ASO Reif, KE Smith, AA Scott, AJ McClure, EE Boradia, VM Hammond, HL Sundberg, EJ Snyder, GA Liu, L DePonte, K Villar, M Ueti, MW de la Fuente, J Ernst, RK Pal, U Fikrig, E Pedra, JHF AF Shaw, Dana K. Wang, Xiaowei Brown, Lindsey J. Chavez, Adela S. Oliva Reif, Kathryn E. Smith, Alexis A. Scott, Alison J. McClure, Erin E. Boradia, Vishant M. Hammond, Holly L. Sundberg, Eric J. Snyder, Greg A. Liu, Lei DePonte, Kathleen Villar, Margarita Ueti, Massaro W. de la Fuente, Jose Ernst, Robert K. Pal, Utpal Fikrig, Erol Pedra, Joao H. F. TI Infection-derived lipids elicit an immune deficiency circuit in arthropods SO NATURE COMMUNICATIONS LA English DT Article ID IXODES-SCAPULARIS; INNATE IMMUNITY; LYME-DISEASE; IMD PATHWAY; TICK VECTOR; PGRP-LC; DROSOPHILA; PEPTIDOGLYCAN; COLONIZATION; ACTIVATION AB The insect immune deficiency (IMD) pathway resembles the tumour necrosis factor receptor network in mammals and senses diaminopimelic-type peptidoglycans present in Gram-negative bacteria. Whether unidentified chemical moieties activate the IMD signalling cascade remains unknown. Here, we show that infection-derived lipids 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) and 1-palmitoyl-2-oleoyl diacylglycerol (PODAG) stimulate the IMD pathway of ticks. The tick IMD network protects against colonization by three distinct bacteria, that is the Lyme disease spirochete Borrelia burgdorferi and the rickettsial agents Anaplasma phagocytophilum and A. marginale. Cell signalling ensues in the absence of transmembrane peptidoglycan recognition proteins and the adaptor molecules Fas-associated protein with a death domain (FADD) and IMD. Conversely, biochemical interactions occur between x-linked inhibitor of apoptosis protein (XIAP), an E3 ubiquitin ligase, and the E2 conjugating enzyme Bendless. We propose the existence of two functionally distinct IMD networks, one in insects and another in ticks. C1 [Shaw, Dana K.; Wang, Xiaowei; Brown, Lindsey J.; Chavez, Adela S. Oliva; McClure, Erin E.; Boradia, Vishant M.; Hammond, Holly L.; Pedra, Joao H. F.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Reif, Kathryn E.; Ueti, Massaro W.] USDA ARS, Anim Dis Res Unit, Pullman, WA 99164 USA. [Smith, Alexis A.; Pal, Utpal] Univ Maryland, Virginia Maryland Reg Coll Vet Med, Dept Vet Med, College Pk, MD 20742 USA. [Scott, Alison J.; Ernst, Robert K.] Univ Maryland, Sch Dent, Dept Microbial Pathogenesis, Baltimore, MD 21201 USA. [Sundberg, Eric J.; Snyder, Greg A.] Univ Maryland, Sch Med, Inst Human Virol, Dept Med, Baltimore, MD 21201 USA. [Sundberg, Eric J.; Snyder, Greg A.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Liu, Lei; DePonte, Kathleen; Fikrig, Erol] Yale Univ, Sch Med, Dept Internal Med, Infect Dis Sect, New Haven, CT 06510 USA. [Villar, Margarita; de la Fuente, Jose] UCLM, JCCM, CSIC, SaBio Inst Invest Recursos Cineget IREC, Ciudad Real 13005, Spain. [de la Fuente, Jose] Oklahoma State Univ, Ctr Vet Hlth Sci, Dept Vet Pathobiol, Stillwater, OK 74078 USA. [Fikrig, Erol] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Brown, Lindsey J.] US FDA, White Oak Campus, Silver Spring, MD 20993 USA. [Reif, Kathryn E.] Kansas State Univ, Ctr Excellence Vector Borne Dis, Dept Diagnost Med & Pathobiol, Manhattan, KS 66506 USA. RP Pedra, JHF (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. EM jpedra@som.umaryland.edu FU National Institutes of Health [R01 AI093653, R01AI116523]; University of Maryland, Baltimore School of Medicine; National Institute of Allergy and Infectious Diseases [T32AI007540] FX We acknowledge Kimberly Stephens, Gregor Blaha (University of California, Riverside) and Sukanya Narasimhan (Yale University) for technical assistance; Ulrike Munderloh (University of Minnesota) for providing tick ISE6 cells; Jon Skare (Texas A&M Health Science Center) for providing the B. burgdorferi B31 strain, clone MSK5; Neal Silverman (University of Massachusetts Medical School) for providing S2star Drosophila cells; the Core facilities at the University of Maryland, Baltimore for services related to circular dichroism and proteomics. This work was supported by the National Institutes of Health (R01 AI093653 and R01AI116523 to J.H.F.P.) and the University of Maryland, Baltimore School of Medicine. E.E.M. was a trainee under the Institutional Training Grant T32AI007540 from the National Institute of Allergy and Infectious Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. NR 58 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 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB 14 PY 2017 VL 8 AR 14401 DI 10.1038/ncomms14401 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK3WB UT WOS:000393858000001 PM 28195158 ER PT J AU Fuentes, S Klenow, L Golding, H Khurana, S AF Fuentes, Sandra Klenow, Laura Golding, Hana Khurana, Surender TI Preclinical evaluation of bacterially produced RSV-G protein vaccine: Strong protection against RSV challenge in cotton rat model SO SCIENTIFIC REPORTS LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; BALB/C MICE; PULMONARY PATHOLOGY; IMMUNE GLOBULIN; G GLYCOPROTEIN; T-CELLS; INFECTION; IMMUNIZATION; DISEASE; INFANTS AB In current study, we evaluated the safety and protective efficacy of recombinant unglycosylated RSVG protein ectodomain produced in E.coli (in presence and absence of oil-in-water adjuvant) in a preclinical RSV susceptible cotton rat challenge model compared to formaldehyde inactivated RSV (FI-RSV) and live RSV experimental infection. The adjuvanted G protein vaccine induced robust neutralization antibody responses comparable to those generated by live RSV infection. Importantly, adjuvanted G protein significantly reduced viral loads in both the lungs and nose at early time points following viral challenge. Antibody kinetics determined by Surface Plasmon Resonance showed that adjuvanted G generated 10-fold higher G-binding antibodies compared to non-adjvuanted G vaccine and live RSV infection, which correlated strongly with both neutralization titers and viral load titers in the nose and lungs post-viral challenge. Antibody diversity analysis revealed immunodominant antigenic sites in the N-and C-termini of the RSV-G protein, that were boosted > 10-fold by adjuvant and inversely correlated with viral load titers. Enhanced lung pathology was observed only in animals vaccinated with FI-RSV, but not in animals vaccinated with unadjuvanted or adjuvanted RSV-G vaccine after viral challenge. The bacterially produced unglycosylated G protein could be developed as a protective vaccine against RSV disease. C1 [Fuentes, Sandra; Klenow, Laura; Golding, Hana; Khurana, Surender] US FDA, Div Viral Prod, CBER, Silver Spring, MD 20903 USA. RP Khurana, S (reprint author), US FDA, Div Viral Prod, CBER, Silver Spring, MD 20903 USA. EM Surender.Khurana@fda.hhs.gov FU DMID, NIAID, NIH under the NIAID Non-Clinical Evaluation Agreement [HHSN272201000006I/HHSN27200011] FX This preclinical testing of RSV-G vaccine in cotton rats was performed with support from DMID, NIAID, NIH under the NIAID Non-Clinical Evaluation Agreement # HHSN272201000006I/HHSN27200011. We thank Drs Judy Beeler and Steven Rubin for a thorough review of the manuscript. NR 48 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 FEB 10 PY 2017 VL 7 AR 2428 DI 10.1038/srep42428 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK3DN UT WOS:000393806300001 PM 28186208 ER PT J AU Kothary, MH Gopinath, GR Gangiredla, J Rallabhandi, PV Harrison, LM Yan, QQ Chase, HR Lee, B Park, E Yoo, Y Chung, T Finkelstein, SB Negrete, FJ Patel, IR Carter, L Sathyamoorthy, V Fanning, S Tall, B AF Kothary, Mahendra H. Gopinath, Gopal R. Gangiredla, Jayanthi Rallabhandi, Prasad V. Harrison, Lisa M. Yan, Qiong Q. Chase, Hannah R. Lee, Boram Park, Eunbi Yoo, YeonJoo Chung, Taejung Finkelstein, Samantha B. Negrete, Flavia J. Patel, Isha R. Carter, Laurenda Sathyamoorthy, Venugopal Fanning, Seamus Tall, Ben D. TI Analysis and Characterization of Proteins Associated with Outer Membrane Vesicles Secreted by Cronobacter spp. SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE outer membrane vesicles; outer membrane proteins; EM; PCR; microarray ID INTESTINAL EPITHELIAL-CELLS; ENTEROBACTER-SAKAZAKII; ESCHERICHIA-COLI; INFANT FORMULA; GENUS CRONOBACTER; ENDOTHELIAL-CELLS; VIRULENCE GENES; VIBRIO-CHOLERAE; INFECTIONS; PCR AB Little is known about secretion of outer membrane vesicles (OMVs) by Cronobacter. In this study, OMVs isolated from Cronobacter sakazakii, Cronobacter turicensis, and Cronobacter malonaticus were examined by electron microscopy (EM) and their associated outer membrane proteins (OMP) and genes were analyzed by SDS-PAGE, protein sequencing, BLAST, PCR, and DNA microarray. EM of stained cells revealed that the OMVs are secreted as pleomorphic micro-vesicles which cascade from the cell's surface. SDS-PAGE analysis identified protein bands with molecular weights of 18 kDa to >100 kDa which had homologies to OMPs such as GroEL; OmpA, C, E, F, and X; MipA proteins; conjugative plasmid transfer protein; and an outer membrane auto-transporter protein (OMATP). PCR analyses showed that most of the OMP genes were present in all seven Cronobacter species while a few genes (OMATP gene, groEL, ompC, mipA, ctp, and ompX) were absent in some phylogenetically-related species. Microarray analysis demonstrated sequence divergence among the OMP genes that was not captured by PCR. These results support previous findings that OmpA and OmpX may be involved in virulence of Cronobacter, and are packaged within secreted OMVs. These results also suggest that other OMV-packaged OMPs may be involved in roles such as stress response, cell wall and plasmid maintenance, and extracellular transport. C1 [Kothary, Mahendra H.; Gopinath, Gopal R.; Gangiredla, Jayanthi; Rallabhandi, Prasad V.; Harrison, Lisa M.; Chase, Hannah R.; Lee, Boram; Park, Eunbi; Yoo, YeonJoo; Chung, Taejung; Finkelstein, Samantha B.; Negrete, Flavia J.; Patel, Isha R.; Carter, Laurenda; Sathyamoorthy, Venugopal; Tall, Ben D.] US FDA, Laurel, MD 20708 USA. [Yan, Qiong Q.; Fanning, Seamus] Univ Coll Dublin, WHO Collaborating Ctr Cronobacter, Sch Publ Hlth Physiotherapy & Sports Sci, Ctr Food Safety, Dublin, Ireland. RP Tall, B (reprint author), US FDA, Laurel, MD 20708 USA. EM ben.tall@fda.hhs.gov FU International Offices of Kyungpook National University (KNU), Daegu; Gachon University, Gyeonggi, Republic of Korea; Joint Institute for Food Safety and Applied Nutrition; FDA [FDU001418]; Oak Ridge Institute for Science and Education of Oak Ridge, Tennessee; Undergraduate Research and Internship Programs, Joint Institute of Food Safety and Applied Nutrition, University of Maryland, College Park, MD; U.S. FDA FX We thank the student internship programs of the International Offices of Kyungpook National University (KNU), Daegu, and Gachon University, Gyeonggi, Republic of Korea for sponsoring student interns: BL, EP, YY, and TC. We thank the office of Undergraduate Research and Internship Programs, Joint Institute of Food Safety and Applied Nutrition, University of Maryland, College Park, MD for sponsoring student interns SBF and FN. We also thank Michael Kulka, FDA for critically reading the manuscript and offerring valuable suggestions. This research was funded (in part) by the Joint Institute for Food Safety and Applied Nutrition through a cooperative agreement with the FDA under contract #FDU001418. We thank the Oak Ridge Institute for Science and Education of Oak Ridge, Tennessee, for sponsoring research fellow HC. Other funds supporting this work were obtained internally through U.S. FDA appropriations. The authors would also like to thank interns Seungeun Jeong and JiHyeon Park, KNU for their help in preparing the figures used in the manuscript. NR 72 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 FEB 9 PY 2017 VL 8 AR 134 DI 10.3389/fmicb.2017.00134 PG 14 WC Microbiology SC Microbiology GA EJ9RQ UT WOS:000393564500001 PM 28232819 ER PT J AU Resnic, FS Majithia, A Marinac-Dabic, D Robbins, S Ssemaganda, H Hewitt, K Ponirakis, A Loyo-Berrios, N Moussa, I Drozda, J Normand, SL Matheny, ME AF Resnic, Frederic S. Majithia, Arjun Marinac-Dabic, Danica Robbins, Susan Ssemaganda, Henry Hewitt, Kathleen Ponirakis, Angelo Loyo-Berrios, Nilsa Moussa, Issam Drozda, Joseph Normand, Sharon-Lise Matheny, Michael E. TI Registry-Based Prospective, Active Surveillance of Medical-Device Safety SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PERCUTANEOUS CORONARY INTERVENTION; RISK; VALIDATION; SYSTEM; SCORE AB BACKGROUND The process of assuring the safety of medical devices is constrained by reliance on voluntary reporting of adverse events. We evaluated a strategy of prospective, active surveillance of a national clinical registry to monitor the safety of an implantable vascular-closure device that had a suspected association with increased adverse events after percutaneous coronary intervention (PCI). METHODS We used an integrated clinical-data surveillance system to conduct a prospective, propensity-matched analysis of the safety of the Mynx vascular-closure device, as compared with alternative approved vascular-closure devices, with data from the CathPCI Registry of the National Cardiovascular Data Registry. The primary outcome was any vascular complication, which was a composite of access-site bleeding, access-site hematoma, retroperitoneal bleeding, or any vascular complication requiring intervention. Secondary safety end points were access-site bleeding requiring treatment and postprocedural blood transfusion. RESULTS We analyzed data from 73,124 patients who had received Mynx devices after PCI procedures with femoral access from January 1, 2011, to September 30, 2013. The Mynx device was associated with a significantly greater risk of any vascular complication than were alternative vascular-closure devices (absolute risk, 1.2% vs. 0.8%; relative risk, 1.59; 95% confidence interval [CI], 1.42 to 1.78; P<0.001); there was also a significantly greater risk of access-site bleeding (absolute risk, 0.4% vs. 0.3%; relative risk, 1.34; 95% CI, 1.10 to 1.62; P = 0.001) and transfusion (absolute risk, 1.8% vs. 1.5%; relative risk, 1.23; 95% CI, 1.13 to 1.34; P<0.001). The initial alerts occurred within the first 12 months of monitoring. Relative risks were greater in three prespecified high-risk subgroups: patients with diabetes, those 70 years of age or older, and women. All safety alerts were confirmed in an independent sample of 48,992 patients from April 1, 2014, to September 30, 2015. CONCLUSIONS A strategy of prospective, active surveillance of a clinical registry rapidly identified potential safety signals among recipients of an implantable vascular-closure device, with initial alerts occurring within the first 12 months of monitoring. C1 [Resnic, Frederic S.; Majithia, Arjun; Robbins, Susan; Ssemaganda, Henry] Lahey Hosp & Med Ctr, Comparat Effectiveness Res Inst, Burlington, MA USA. [Resnic, Frederic S.] Tufts Sch Med, Boston, MA USA. [Normand, Sharon-Lise] Harvard Med Sch, Boston, MA USA. [Normand, Sharon-Lise] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Marinac-Dabic, Danica; Loyo-Berrios, Nilsa] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Hewitt, Kathleen; Ponirakis, Angelo] Amer Coll Cardiol, Natl Cardiovasc Data Registry, Washington, DC USA. [Moussa, Issam] First Coast Cardiovasc Inst, Jacksonville, FL USA. [Moussa, Issam] Univ Cent Florida, Coll Med, Orlando, FL 32816 USA. [Drozda, Joseph] Mercy Hlth, St Louis, MO USA. [Matheny, Michael E.] Vet Affairs Tennessee Valley Healthcare Syst, Nashville, TN USA. [Matheny, Michael E.] Vanderbilt Univ, Med Ctr, Ctr Populat Hlth Informat, Dept Biomed Informat, Nashville, TN USA. [Matheny, Michael E.] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN USA. [Matheny, Michael E.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. RP Resnic, FS (reprint author), Lahey Hosp & Med Ctr, Dept Cardiovasc Med, 41 Mall Rd, Burlington, MA 01805 USA. EM frederic.resnic@lahey.org FU Food and Drug Administration (FDA) [223200830058C, U01 FD004963]; William M. Wood Foundation; FDA [223201110172C, U01 FD004493]; Department of Veterans Affairs [VA HSRD CDA 08-020, VA HSRD IIR 11-292]; St. Jude Medical FX Supported by grants (HHSF contract 223200830058C and U01 FD004963, to Dr. Resnic) from the Food and Drug Administration (FDA) and by the William M. Wood Foundation; a grant (HHSF contract 223201110172C through the MDEpiNet Methodology Center, to Drs. Resnic and Normand) from the FDA; a grant (U01 FD004493 through the MDEpiNet Medical Counter Measures Study, to Dr. Normand) from the FDA; and grants (VA HSR&D CDA 08-020 and VA HSR&D IIR 11-292, to Dr. Matheny) from the Department of Veterans Affairs.; Dr. Resnic reports receiving consulting fees from St. Jude Medical. No other potential conflict of interest relevant to this article was reported. NR 28 TC 1 Z9 1 U1 2 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 9 PY 2017 VL 376 IS 6 BP 526 EP 535 DI 10.1056/NEJMoa1516333 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EJ8XL UT WOS:000393510500007 PM 28121489 ER PT J AU Morgeaux, S Poirier, B Ragan, CI Wilkinson, D Arabin, U Guinet-Morlot, F Levis, R Meyer, H Riou, P Shaid, S Volokhov, D Tordo, N Chapsal, JM AF Morgeaux, Sylvie Poirier, Bertrand Ragan, C. Ian Wilkinson, Dianna Arabin, Ulrich Guinet-Morlot, Francoise Levis, Robin Meyer, Heidi Riou, Patrice Shaid, Shahjahan Volokhov, Dmitriy Tordo, Noel Chapsal, Jean-Michel TI Replacement of in vivo human rabies vaccine potency testing by in vitro glycoprotein quantification using ELISA - Results of an international collaborative study SO VACCINE LA English DT Article DE Vaccine; Human; Rabies; ELISA; In vitro; NIH test ID HUMAN MONOCLONAL-ANTIBODY; VIRUS GLYCOPROTEIN; FUSION ACTIVITY; TRIMERS AB Three different ELISAs quantifying rabies glycoprotein were evaluated as in vitro alternatives to the National Institutes of Health (NIH) in vivo potency test for batch release of human rabies vaccines. The evaluation was carried out as an international collaborative study supported 'by the European Partnership for Alternatives to Animal Testing (EPAA). This pre-validation study, the results of which are presented in this paper, compared three different ELISA designs, assessing their within- and between-laboratory precision. One of the ELISA designs was proposed to the European Directorate for the Quality of Medicines & HealthCare (EDQM) and accepted for an international collaborative study under the umbrella of the Biological Standardisation Programme. (C) 2017 Elsevier Ltd. All rights reserved. C1 [Morgeaux, Sylvie] Agence Natl Secur Medicament & Prod Sante, Batch Release & Mkt Surveillance Biol Prod Dept, Lab Controls Div, 312 Ave Jean Jaures, F-69007 Lyon, France. [Poirier, Bertrand] 207 Love, F-69700 Chassagny, France. [Ragan, C. Ian] European Partnership Alternat Approaches Anim Tes, Brussels, Belgium. [Wilkinson, Dianna] Natl Inst Biol Stand & Controls, Div Virol, Potters Bar EN6 3QG, Herts, England. [Arabin, Ulrich; Shaid, Shahjahan] GSK Vaccines GmbH, Emil von Behring Str 76, D-35041 Marburg, Germany. [Guinet-Morlot, Francoise; Riou, Patrice] Sanofi Pasteur, 1541 Av Marcel Merieux, F-69280 Marcy Letoile, France. [Levis, Robin; Volokhov, Dmitriy] US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Meyer, Heidi] Paul Ehrlich Inst, Fed Inst Vaccines & Biomed, Paul Ehrlich Str 51-59, D-63225 Langen, Germany. [Tordo, Noel] Inst Pasteur, Unite Strategies Antivirales, 25 Rue Dr Roux, F-75724 Paris 15, France. [Tordo, Noel] Inst Pasteur Guinee, Conakry, Guinea. [Chapsal, Jean-Michel] 195 Traverse Verdelieres, F-69380 Charnay, France. RP Ragan, CI (reprint author), European Partnership Alternat Approaches Anim Tes, Brussels, Belgium. EM ian.ragan1@btinternet.com FU European Commission; EPAA; Sanofi-Pasteur; Novartis Vaccines Diagnostics; [CR.IHCP.B441165ST] FX Funding was provided by the European Commission (via EURL ECVAM) and contract CR.IHCP.B441165ST "Statistical support to the interlaboratory evaluation of in vitro ELISA antibody quantification assays for potency testing of human rabies vaccines". In addition, the authors thanks the EPAA for funding the conference organisation and the writing of this publication. Further support for the meeting was provided by Sanofi-Pasteur and Novartis Vaccines & Diagnostics, now acquired by the GSK group of companies. NR 26 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD FEB 7 PY 2017 VL 35 IS 6 BP 966 EP 971 DI 10.1016/j.vaccine.2016.12.039 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EK8SX UT WOS:000394196000018 PM 28081969 ER PT J AU Ghammraoui, B Popescu, LM AF Ghammraoui, Bahaa Popescu, Lucretiu M. TI Non-invasive classification of breast microcalcifications using x-ray coherent scatter computed tomography SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE coherent scatter computed tomography; breast microcalcifications; breast imaging; energy-resolved photon-counting detectors; image reconstruction; x-ray diffraction ID CALCIUM-OXALATE; FORM-FACTORS; MONTE-CARLO; TISSUES; DIFFRACTION; MAMMOGRAPHY; LESIONS; BENIGN; SPECIMENS; DIAGNOSIS AB We investigate the use of energy dispersive x-ray coherent scatter computed tomography (ED-CSCT) as a non-invasive diagnostic method to differentiate between type I and type II breast calcifications. This approach is sensitive to the differences of composition and internal crystal structure of different types of microcalcifications. The study is carried out by simulating a CSCT system with a scanning pencil beam, considering a polychromatic x-ray source and an energy-resolving photon counting detector. In a first step, the multidimensional angle and energy distributed CSCT data is reduced to the projection-space distributions of only a few components, corresponding to the expected target composition: adipose, glandular tissue, weddellite (calcium oxalate) for type I calcifications, and hydroxyapatite for type II calcifications. The maximum-likelihood estimation of scatter components algorithm used, operating in the projection space, takes into account the polychromatic source, the detector response function and the energy dependent attenuation. In the second step, component images are reconstructed from the corresponding estimated component projections using filtered backprojection. In a preliminary step the coherent scatter differential cross sections for hydroxyapatite and weddellite minerals were determined experimentally. The classification of type I or II calcifications is done using the relative contrasts of their components as the criterion. Simulation tests were carried out for different doses and energy resolutions for multiple realizations. The results were analyzed using relative/receiver operating characteristic methodology and show good discrimination ability at medium and higher doses. The noninvasive CSCT technique shows potential to further improve the breast diagnostic accuracy and reduce the number of breast biopsies. C1 [Ghammraoui, Bahaa; Popescu, Lucretiu M.] US FDA, Off Sci & Engn Labs, CDRH, Silver Spring, MD 20993 USA. RP Ghammraoui, B (reprint author), US FDA, Off Sci & Engn Labs, CDRH, Silver Spring, MD 20993 USA. EM bahaa.ghammraoui@fda.hhs.gov; lucretiu.popescu@ieee.org NR 40 TC 0 Z9 0 U1 0 U2 0 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD FEB 7 PY 2017 VL 62 IS 3 BP 1192 EP 1207 DI 10.1088/1361-6560/aa5187 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA EK5EJ UT WOS:000393949400007 PM 28092637 ER PT J AU Chen, Y Luo, Y Curry, P Timme, R Melka, D Doyle, M Parish, M Hammack, TS Allard, MW Brown, EW Strain, EA AF Chen, Yi Luo, Yan Curry, Phillip Timme, Ruth Melka, David Doyle, Matthew Parish, Mickey Hammack, Thomas S. Allard, Marc W. Brown, Eric W. Strain, Errol A. TI Assessing the genome level diversity of Listeria monocytogenes from contaminated ice cream and environmental samples linked to a listeriosis outbreak in the United States SO PLOS ONE LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; MOBILE GENETIC ELEMENTS; PHAGE SEARCH TOOL; PROCESSING PLANTS; EPIDEMIC CLONES; SEQUENCE DATA; STRAINS; PHYLOGENIES; SALMONELLA; PROPHAGES AB A listeriosis outbreak in the United States implicated contaminated ice cream produced by one company, which operated 3 facilities. We performed single nucleotide polymorphism (SNP)-based whole genome sequencing (WGS) analysis on Listeria monocytogenes from food, environmental and clinical sources, identifying two clusters and a single branch, belonging to PCR serogroup IIb and genetic lineage I. WGS Cluster I, representing one outbreak strain, contained 82 food and environmental isolates from Facility I and 4 clinical isolates. These isolates differed by up to 29 SNPs, exhibited 9 pulsed-field gel electrophoresis (PFGE) profiles and multilocus sequence typing (MLST) sequence type (ST) 5 of clonal complex 5 (CC5). WGS Cluster II contained 51 food and environmental isolates from Facility II, 4 food isolates from Facility I and 5 clinical isolates. Among them the isolates from Facility II and clinical isolates formed a clade and represented another outbreak strain. Isolates in this clade differed by up to 29 SNPs, exhibited 3 PFGE profiles and ST5. The only isolate collected from Facility III belonged to singleton ST489, which was in a single branch separate from Clusters I and II, and was not associated with the outbreak. WGS analyses clustered together outbreak-associated isolates exhibiting multiple PFGE profiles, while differentiating them from epidemiologically unrelated isolates that exhibited outbreak PFGE profiles. The complete genome of a Cluster I isolate allowed the identification and analyses of putative prophages, revealing that Cluster I isolates differed by the gain or loss of three putative prophages, causing the banding pattern differences among all 3 AscI-PFGE profiles observed in Cluster I isolates. WGS data suggested that certain ice cream varieties and/or production lines might have contamination sources unique to them. The SNP-based analysis was able to distinguish CC5 as a group from non-CC5 isolates and differentiate among CC5 isolates from different outbreaks/incidents. C1 [Chen, Yi; Luo, Yan; Curry, Phillip; Timme, Ruth; Melka, David; Doyle, Matthew; Parish, Mickey; Hammack, Thomas S.; Allard, Marc W.; Brown, Eric W.; Strain, Errol A.] 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 46 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 FEB 6 PY 2017 VL 12 IS 2 AR e0171389 DI 10.1371/journal.pone.0171389 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK1QH UT WOS:000393700100037 PM 28166293 ER PT J AU Fuenffinger, N Ritchie, M Ruth, A Gryniewicz-Ruzicka, C AF Fuenffinger, Nathan Ritchie, Melissa Ruth, Ashley Gryniewicz-Ruzicka, Connie TI Evaluation of ion mobility spectrometry for the detection of mitragynine in kratom products SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Ion mobility spectrometry; Kratom; Mitragynine; Herbal supplements; Rapid screening ID TRAP MASS-SPECTROMETRY; HUMAN URINE; DIETARY-SUPPLEMENTS; SPECIOSA; DRUGS; RAT AB An ion mobility spectrometry (IMS) method was developed for the rapid detection of mitragynine, the most abundant alkaloid in Mitragyna speciosa also known as kratom. The peak corresponding to the mitragynine protonated ion exhibited a reduced ion mobility of 0.95 +/- 0.00014 cm(2)/(Vs), and the mitragynine limit of detection using IMS was 0.5 ng. The IMS method was applied to the analysis of 15 commercial samples suspected of containing kratom. IMS results were compared to those obtained from liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of the same samples. Mitragynine was conclusively detected in 14 of 15 samples using LC-MS/MS and 13 of 15 samples using IMS. The discrepancy between methods reflected the fact that one sample contained mitragynine at a concentration below the IMS detection limit. This study demonstrates the utility of IMS for the rapid screening of products containing kratom as well as the scientific reliability of the IMS screening method, which was demonstrated by comparing the IMS results to the confirmatory results obtained using LC-MS/MS. Published by Elsevier B.V. C1 [Fuenffinger, Nathan; Ritchie, Melissa; Ruth, Ashley; Gryniewicz-Ruzicka, Connie] US FDA, Div Pharmaceut Anal, 645 S Newstead, St Louis, MO 63110 USA. RP Gryniewicz-Ruzicka, C (reprint author), US FDA, Div Pharmaceut Anal, 645 S Newstead, St Louis, MO 63110 USA. EM connie.ruzicka@fda.hhs.gov NR 31 TC 0 Z9 0 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 FEB 5 PY 2017 VL 134 BP 282 EP 286 DI 10.1016/j.jpba.2016.11.055 PG 5 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA EJ0OT UT WOS:000392909900036 PM 27951469 ER PT J AU Kwekel, JC Vijay, V Han, T Moland, CL Desai, VG Fuscoe, JC AF Kwekel, Joshua C. Vijay, Vikrant Han, Tao Moland, Carrie L. Desai, Varsha G. Fuscoe, James C. TI Sex and age differences in the expression of liver microRNAs during the life span of F344 rats SO BIOLOGY OF SEX DIFFERENCES LA English DT Article DE Sex difference; Age difference; Liver; miRNA expression ID DLK1-DIO3 GENOMIC REGION; NONALCOHOLIC FATTY LIVER; HEPATOCELLULAR-CARCINOMA; CIRCULATING MICRORNAS; CELL-PROLIFERATION; TUMOR-SUPPRESSOR; GENE-EXPRESSION; MESENCHYMAL TRANSITION; POTENTIAL BIOMARKERS; CARBON-TETRACHLORIDE AB Background: Physiological factors such as age and sex have been shown to be risk factors for adverse effects in the liver, including liver diseases and drug-induced liver injury. Previously, we have reported age-and sex-related significant differences in hepatic basal gene expression in rats during the life span that may be related to susceptibility to such adverse effects. However, the underlying mechanisms of the gene expression changes were not fully understood. In recent years, increasing evidence for epigenetic mechanisms of gene regulation has fueled interest in the role of microRNAs (miRNAs) in toxicogenomics and biomarker discovery. We therefore proposed that significant age and sex differences exist in baseline liver miRNA expression, and that comprehensive profiling of miRNAs will provide insights into the epigenetic regulation of gene expression in rat liver. Methods: To address this, liver tissues from male and female F344 rats were examined at 2, 5, 6, 8, 15, 21, 52, 78, and 104 weeks of age for the expression of 677 unique miRNAs. Following data processing, predictive pathway analysis was performed on selected miRNAs that exhibited prominent age and/or sex differences in expression. Results: Of the 314 miRNAs found to be expressed, 214 were differentially expressed; 65 and 212 miRNAs showed significant (false discovery rate (FDR) <5% and >= 1.5-fold change) sex-and age-related differences in expression, respectively. Thirty-eight miRNAs showed 2-week-specific expression, of which 31 miRNAs were found to be encoded within the Dlk1-Dio3 cluster located on chromosome 6. This cluster has been associated with tissue proliferation and differentiation, and liver energy homeostasis in postnatal development. Predictive pathway analysis linked sex-biased miRNA expression with sexually dimorphic molecular functions and toxicological functions that may reflect sex differences in hepatic physiology and disease. The expression of miRNAs (miR-18a, miR-99a, and miR-203, miR-451) was also found to associate with specific sexually dimorphic hepatic histopathology. The expression of miRNAs involved in regulating cell death, cell proliferation, and cell cycle was found to change as the rats matured from adult to old age. Conclusions: Overall, significant age-and sex-related differences in liver miRNA expression were identified and linked to histopathological findings and predicted functional pathways that may underlie susceptibilities to liver toxicity and disease. C1 [Kwekel, Joshua C.; Vijay, Vikrant; Han, Tao; Moland, Carrie L.; Desai, Varsha G.; Fuscoe, James C.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Kwekel, Joshua C.] Cent Baptist Coll, Dept Math & Sci, Conway, AR USA. RP Fuscoe, JC (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM James.Fuscoe@fda.hhs.gov FU U.S. Food and Drug Administration FX Funding for this research was from appropriated funds to the U.S. Food and Drug Administration. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the FDA. NR 86 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 2042-6410 J9 BIOL SEX DIFFER JI Biol. Sex Differ. PD FEB 3 PY 2017 VL 8 AR 6 DI 10.1186/s13293-017-0127-9 PG 21 WC Endocrinology & Metabolism; Genetics & Heredity SC Endocrinology & Metabolism; Genetics & Heredity GA EL0BP UT WOS:000394288100001 PM 28174625 ER PT J AU Iha, MH Mini, CA Okada, IA Briganti, RD Trucksess, MW AF Iha, Maria Helena Mini, Camila Alessandra Okada, Isaura Akemi Briganti, Rita de Cassia Trucksess, Mary W. TI The use of regenerated immunoaffinity columns for aflatoxins B-1, B-2, G(1) and G(2) in peanut confection SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Aflatoxins; Peanut confection "pacoca"; Immunoaffinity column; Regeneration ID LIQUID-CHROMATOGRAPHY; PRODUCTS; CLEANUP; BRAZIL; RISK AB The aim of this study was to investigate the feasibility of using multitime-regenerated immunoaffinity column (IAC) for aflatoxins B-1, B-2, G(1) and G(2) in peanut confection. After each use, the IAC was washed immediately with phosphate-buffered saline and stored for >12 h prior to reuse. The evaluation procedure consisted of using extracts of naturallycontaminated peanut confection (4 replicates), aflatoxin-free peanut confection (duplicates), and aflatoxin-free peanut confection sample spiked with.the 4 aflatoxins (AFT) at 3 levels in 4 replicates. Each day, 18 test extracts were analyzed using 18 designated IACs. After each use, the IACs were regenerated and reused for corresponding test extracts on the following day. This procedure was repeated daily over the course of 9 days. Analytical steps included passing the test extracts through the IACs, washing the columns with water, and eluting AFT with methanol. The eluates were diluted with water and were subjected to reversed phase LC separation, post-column photochemical derivatization and fluorescence detection. After eluting AFT, IACs were immediately regenerated by washing with phosphate buffer solution and storing overnight at 8 degrees C for re-use the following day. Results were analyzed using ANOVA and Tukey tests. The numbers of reuse varied for each AF: For AFB(1) AFB(2), AFG(1) and AFG(2) could be reused for 9, 6, 6 and 0 times, respectively. According to AOAC method performance criteria, recoveries ranging from 70% to 125% are considered acceptable at the spiking levels used in this study. (C) 2017 Elsevier B.V. All rights reserved. C1 [Iha, Maria Helena; Mini, Camila Alessandra; Okada, Isaura Akemi; Briganti, Rita de Cassia] Adolfo Lutz Inst Ribeirao Preto VI, Reg Lab Ctr, Ctr Chem Sci & Bromatol, Rua Minas 877, BR-14085410 Ribeirao Preto, SP, Brazil. [Trucksess, Mary W.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5100 Paint Branch Pkwy, College Pk, MD USA. RP Iha, MH (reprint author), Adolfo Lutz Inst Ribeirao Preto VI, Reg Lab Ctr, Ctr Chem Sci & Bromatol, Rua Minas 877, BR-14085410 Ribeirao Preto, SP, Brazil. EM mhiha@ial.sp.gov.br; camilaamini@gmail.com; lsaura@ial.sp.gov.br; rcbriganti@ial.sp.gov.br; mary.trucksess@fda.hhs.gov FU FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo) FX The authors are grateful to FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo) for financial support. We thank Dr. Thomas B. Whitaker of North Carolina State University for reviewing and editing the paper. NR 15 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD FEB 3 PY 2017 VL 1483 BP 1 EP 7 DI 10.1016/j.chroma.2016.12.040 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA EJ5IB UT WOS:000393249900001 PM 28063641 ER PT J AU Loomis, Z Eigenberger, P Redinius, K Lisk, C Karoor, V Nozik-Grayck, E Ferguson, SK Hassell, K Nuss, R Stenmark, K Buehler, P Irwin, DC AF Loomis, Zoe Eigenberger, Paul Redinius, Katherine Lisk, Christina Karoor, Vijaya Nozik-Grayck, Eva Ferguson, Scott K. Hassell, Kathryn Nuss, Rachelle Stenmark, Kurt Buehler, Paul Irwin, David C. TI Hemoglobin induced cell trauma indirectly influences endothelial TLR9 activity resulting in pulmonary vascular smooth muscle cell activation SO PLOS ONE LA English DT Article ID MITOCHONDRIAL-DNA DAMAGE; HAPTOGLOBIN PRESERVES; RAT LUNGS; HYPERTENSION; INFLAMMATION; PATHOLOGY; DISEASE; INJURY; HEMOPEXIN; HEMOLYSIS AB It is now well established that both inherited and acquired forms of hemolytic disease can promote pulmonary vascular disease consequent of free hemoglobin (Hb) induced NO scavenging, elevations in reactive oxygen species and lipid peroxidation. It has recently been reported that oxidative stress can activate NFkB through a toll-like receptor 9 (TLR9) mediated pathway; further, TLR9 can be activated by either nuclear or mitochondrial DNA liberated by stress induced cellular trauma. We hypothesis that Hb induced lipid peroxidation and subsequent endothelial cell trauma is linked to TLR9 activation, resulting in IL-6 mediated pulmonary smooth muscle cell proliferation. We examined the effects of Hb on rat pulmonary artery endothelial and smooth muscle cells (rPAEC and rPASMC, respectively), and then utilized TLR9 and IL6 inhibitors, as well as the Hb and heme binding proteins (haptoglobin (Hp) and hemopexin (Hpx), respectively) to further elucidate the aforementioned mediators. Further, we explored the effects of Hb in vivo utilizing endothelial cell (EC) specific myeloid differentiation primary response gene-88 (MyD88) and TLR9 null mice. Our data show that oxidized Hb induces lipid peroxidation, cellular toxicity (5.5 +/- 1.7 fold; p <= 0.04), increased TLR9 activation (60%; p = 0.01), and up regulated IL6 expression (1.75 +/- 0.3 fold; p = 0.04) in rPAEC. Rat PASMC exhibited a more proliferative state (13 +/- 1%; p = 0.01) when co-cultured with Hb activated rPAEC. These effects were attenuated with the sequestration of Hb or heme by Hp and Hpx as well as with TLR9 an IL-6 inhibition. Moreover, in both EC-MyD88 and TLR9 null mice Hb-infusion resulted in less lung IL-6 expression compared to WT cohorts. These results demonstrate that Hb-induced lipid peroxidation can initiate a modest TLR9 mediated inflammatory response, subsequently generating an activated SMC phenotype. C1 [Loomis, Zoe; Eigenberger, Paul; Redinius, Katherine; Lisk, Christina; Karoor, Vijaya; Nozik-Grayck, Eva; Ferguson, Scott K.; Stenmark, Kurt; Irwin, David C.] Univ Colorado Denver, Dept Med, Cardiovasc & Pulm Res Lab, Anschutz Med Campus, Aurora, CO 80045 USA. [Hassell, Kathryn; Nuss, Rachelle] Univ Colorado, Denver Sch Med, Div Hematol, Aurora, CO USA. [Hassell, Kathryn; Nuss, Rachelle] Univ Colorado, Denver Sch Med, Colorado Sickle Cell Treatment & Res Ctr, Aurora, CO USA. [Buehler, Paul] US FDA, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Irwin, DC (reprint author), Univ Colorado Denver, Dept Med, Cardiovasc & Pulm Res Lab, Anschutz Med Campus, Aurora, CO 80045 USA. EM David.irwin@ucdenver.edu FU National Heart, Lung and Blood Institute [1R01HL125642-01A1, 1 R01HL086680-07, 5P01HL014985-38, T32HL007171] FX This work was supported by the National Heart, Lung and Blood Institute Grants 1R01HL125642-01A1 (Irwin DC), 1 R01HL086680-07 (Nozik-Grayck E), 5P01HL014985-38(Stenmark KR), and T32HL007171 (Stenmark KR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 1 Z9 1 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 FEB 2 PY 2017 VL 12 IS 2 AR e0171219 DI 10.1371/journal.pone.0171219 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN7DB UT WOS:000396161200106 ER PT J AU Battistel, MD Azurmendi, HF Freedbereg, DI AF Battistel, Marcos D. Azurmendi, Hugo F. Freedbereg, Daron I. TI Glycan OH Exchange Rate Determination in Aqueous Solution: Seeking Evidence for Transient Hydrogen Bonds SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; NMR-SPECTROSCOPY; HYDROXYL PROTONS; COUPLING-CONSTANTS; CHEMICAL-EXCHANGE; C-13 NMR; WATER; OLIGOSACCHARIDES; PROTEINS; SUCROSE AB Hydrogen bonds (Hbonds) are important stabilizing forces in biomolecules. However, for glycans in aqueous solution, direct NMR detection of Hbonds is elusive because of their transient nature. Here, we present Isotope based Natural-abundance TOtal correlation eXchange SpectroscopY (INTOXSY), a new H-1-C-13 heteronuclear single quantum coherence-total correlation spectroscopy based method, to extract OH groups' exchange rate constants (k(ex)) for molecules in natural C-13 abundance and show that OH Hbonds can be inferred from "slower" H/D k(ex). We evaluate k(ex), measured with INTOXSY in light of those extracted with line shape analysis. Subsequently, we use a set of common glycans to establish a k(ex), reference basis set and to infer the existence of transient Hbonds involving OH donor groups. Then, we report k(ex) values for a series of mono- and disaccharides, as well as for oligosaccharides sialyl Lewis X and beta-cyclodextrin, and compare the results with those from the reference set to extract Hbond information. Finally, we utilize NMR experimental data in conjunction with molecular dynamics simulations to establish donor and acceptor Hbond pairs. Our exchange rate measurements indicate that OH/OD exchange rates, k(HD), values <10 s(-1) are consistent with transient Hbond OH groups and potential acceptor groups can be uncovered through MD simulations. C1 [Battistel, Marcos D.; Azurmendi, Hugo F.; Freedbereg, Daron I.] US FDA, Lab Bacterial Polysaccharides, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. RP Freedbereg, DI (reprint author), US FDA, Lab Bacterial Polysaccharides, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM daron.freedberg@fda.hhs.gov FU CBER/FDA FX We gratefully acknowledge Drs. Jim Paulson for the sLex-5 sample and Dennis Torchia for helpful discussions. We are also thankful to Drs. Skrynnikov and Chevelkov for the Matlab scripts provided together with the SOLEXSY pulse sequence. This work was supported by intramural funds from CBER/FDA. NR 71 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD FEB 2 PY 2017 VL 121 IS 4 BP 683 EP 695 DI 10.1021/acs.jpcb.6b10594 PG 13 WC Chemistry, Physical SC Chemistry GA EJ7ZX UT WOS:000393443100003 PM 27995788 ER PT J AU Moscicki, RA Tandon, PK AF Moscicki, Richard A. Tandon, P. K. TI Drug-Development Challenges for Small Biopharmaceutical Companies SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID ONSET POMPE-DISEASE; ACID ALPHA-GLUCOSIDASE; CYSTIC-FIBROSIS; REPLACEMENT THERAPY; PARKINSONS-DISEASE; TRANSPLANTATION; MUTATION C1 [Moscicki, Richard A.] US FDA, Ctr Drug Evaluat & Res, 10001 New Hampshire Ave, Silver Spring, MD 20993 USA. [Tandon, P. K.] Sanofi Genzyme, Cambridge, MA USA. RP Moscicki, RA (reprint author), US FDA, Ctr Drug Evaluat & Res, 10001 New Hampshire Ave, Silver Spring, MD 20993 USA.; Tandon, PK (reprint author), Ultragenyx Pharmaceut, 60 Leveroni Ct, Novato, CA 94949 USA. EM richard.moscicki@fda.hhs.gov; ptandon@ultragenyx.com NR 14 TC 0 Z9 0 U1 3 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 2 PY 2017 VL 376 IS 5 BP 469 EP 474 DI 10.1056/NEJMra1510070 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA EJ8WH UT WOS:000393507200010 PM 28146666 ER PT J AU Zhu, L Xue, JY Xia, QS Fu, PP Lin, G AF Zhu, Lin Xue, Junyi Xia, Qingsu Fu, Peter P. Lin, Ge TI The long persistence of pyrrolizidine alkaloid-derived DNA adducts in vivo: kinetic study following single and multiple exposures in male ICR mice SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Pyrrolizidine alkaloid; DNA adducts; Biomarker; Kinetics ID HERBAL DIETARY-SUPPLEMENTS; BIG BLUE RATS; METABOLIC-ACTIVATION; VENOOCCLUSIVE DISEASE; LIVER; RIDDELLIINE; PLANTS; TUMORIGENICITY; HEPATOTOXICITY; PHOTOTOXICITY AB Pyrrolizidine alkaloid (PA)-containing plants are widespread in the world and the most common poisonous plants affecting livestock, wildlife, and humans. Our previous studies demonstrated that PA-derived DNA adducts can potentially be a common biological biomarker of PA-induced liver tumor formation. In order to validate the use of these PA-derived DNA adducts as a biomarker, it is necessary to understand the basic kinetics of the PA-derived DNA adducts formed in vivo. In this study, we studied the dose-dependent response and kinetics of PA-derived DNA adduct formation and removal in male ICR mice orally administered with a single dose (40 mg/kg) or multiple doses (10 mg/kg/day) of retrorsine, a representative carcinogenic PA. In the single-dose exposure, the PA-derived DNA adducts exhibited dose-dependent linearity and persisted for up to 4 weeks. The removal of the adducts following a single-dose exposure to retrorsine was biphasic with half-lives of 9 h (t (1/2 alpha)) and 301 h (similar to 12.5 days, t (1/2 beta)). In the 8-week multiple exposure study, a marked accumulation of PA-derived DNA adducts without attaining a steady state was observed. The removal of adducts after the multiple exposure also demonstrated a biphasic pattern but with much extended half-lives of 176 h (similar to 7.33 days, t (1/2 alpha)) and 1736 h (similar to 72.3 days, t (1/2 beta)). The lifetime of PA-derived DNA adducts was more than 8 weeks following the multiple-dose treatment. The significant persistence of PA-derived DNA adducts in vivo supports their role in serving as a biomarker of PA exposure. C1 [Zhu, Lin; Xue, Junyi; Lin, Ge] Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Shatin, Hong Kong, Peoples R China. [Zhu, Lin; Xue, Junyi; Lin, Ge] Chinese Acad Sci, Joint Res Lab Promoting Globalizat Tradit Chinese, Shanghai, Peoples R China. [Xia, Qingsu; Fu, Peter P.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Lin, G (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Shatin, Hong Kong, Peoples R China.; Lin, G (reprint author), Chinese Acad Sci, Joint Res Lab Promoting Globalizat Tradit Chinese, Shanghai, Peoples R China.; Fu, PP (reprint author), Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM peter.fu@fda.hhs.gov; linge@cuhk.edu.hk FU Research Grant Council of Hong Kong (GRF Grant) [471310, 469712]; CUHK [4054047, 4054134]; CUHK One-off Funding for Joint Lab/Research Collaboration [3132968]; CUHK School of Biomedical Sciences-Seed Fund for Joint Establishments FX The present study was supported by Research Grant Council of Hong Kong (GRF Grant Nos. 471310 and 469712), CUHK Direct Grants (4054047 and 4054134), CUHK One-off Funding for Joint Lab/Research Collaboration (Project Code: 3132968), and CUHK School of Biomedical Sciences-Seed Fund for Joint Establishments. This article is not an official U.S. Food and Drug Administration (FDA) guidance or policy statement. No official support or endorsement by the U.S. FDA is intended or should be inferred. NR 61 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD FEB PY 2017 VL 91 IS 2 BP 949 EP 965 DI 10.1007/s00204-016-1713-z PG 17 WC Toxicology SC Toxicology GA EK8NL UT WOS:000394180500028 PM 27125825 ER PT J AU Olia, SE Herbertson, LH Malinauskas, RA Kameneva, MV AF Olia, Salim E. Herbertson, Luke H. Malinauskas, Richard A. Kameneva, Marina V. TI A Reusable, Compliant, Small Volume Blood Reservoir for In Vitro Hemolysis Testing SO ARTIFICIAL ORGANS LA English DT Article DE Blood reservoir; In vitro hemolysis testing; Mechanical circulatory support devices; Cardiopulmonary bypass AB Bench-top in vitro hemolysis testing is a fundamental tool during the design and regulatory safety evaluation of blood-contacting medical devices. While multiple published experimental protocols exist, descriptions of the test loop reservoir remain ambiguous. A critical fixture within the circuit, there is no readily available blood reser-voir that ensures thorough mixing and complete air evacuation: two major factors which can affect results. As part of the Food and Drug Administration (FDA) Critical Path Initiative, we developed a three-piece reservoir consisting of a 3D-printed base, a plastic clamp set, and a medicalgrade blood bag. This simple, reusable, and cost-effective design was used successfully in the hemolysis assessment of FDA benchmark nozzles and prototype rotary blood pumps, and may be useful as an integral component to any in vitro blood circulation loop. C1 [Olia, Salim E.; Kameneva, Marina V.] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA USA. [Olia, Salim E.; Kameneva, Marina V.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. [Kameneva, Marina V.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. [Olia, Salim E.] Univ Pittsburgh, Med Ctr, Artificial Heart Program, Pittsburgh, PA USA. [Herbertson, Luke H.; Malinauskas, Richard A.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Kameneva, MV (reprint author), McGowan Inst Regenerat Med, 450 Technol Dr Suite 300, Pittsburgh, PA 15219 USA. EM kamenevamv@upmc.edu FU U.S. Food and Drug Administration's Critical Path Initiative; National Institutes of Health [T32-HL076124] FX This work was supported by the U.S. Food and Drug Administration's Critical Path Initiative and in part by the National Institutes of Health (Training Grant T32-HL076124 Cardiovascular Bioengineering Training Program) for Mr. Olia. The authors would like to thank J. Andrew Holmes from the Swanson Center for Product Innovation at the University of Pittsburgh, Swanson School of Engineering for sharing his technical and fabrication expertise. NR 10 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-564X EI 1525-1594 J9 ARTIF ORGANS JI Artif. Organs PD FEB PY 2017 VL 41 IS 2 BP 175 EP 178 DI 10.1111/aor.12724 PG 5 WC Engineering, Biomedical; Transplantation SC Engineering; Transplantation GA EL1KA UT WOS:000394378000010 PM 27087363 ER PT J AU Agrawal, A Pfefer, TJ Woolliams, PD Tomlins, PH Nehmetallah, G AF Agrawal, Anant Pfefer, T. Joshua Woolliams, Peter D. Tomlins, Peter H. Nehmetallah, George TI Methods to assess sensitivity of optical coherence tomography systems SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID SWEPT-SOURCE; PERFORMANCE; LASER; DEPTH AB Measuring the sensitivity of an optical coherence tomography (OCT) system determines the minimum sample reflectivity it can detect and provides a figure of merit for system optimization and comparison. The published literature lacks a detailed description of OCT sensitivity measurement procedures. Here we describe a commonly-used measurement method and introduce two new phantom-based methods, which also offer a means to directly visualize low reflectivity conditions relevant to biological tissue. We provide quantitative results for the three methods from different OCT system configurations and discuss the methods' advantages and disadvantages. (C) 2017 Optical Society of America C1 [Agrawal, Anant; Pfefer, T. Joshua] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Woolliams, Peter D.] Natl Phys Lab, Funct Mat Grp, Teddington, Middx, England. [Tomlins, Peter H.] Queen Mary Univ London, Barts & London Sch Med & Dent, London E1 1BB, England. [Nehmetallah, George] Catholic Univ Amer, Dept Elect & Comp Sci, Washington, DC 20064 USA. RP Agrawal, A (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. EM anant.agrawal@fda.hhs.gov NR 25 TC 0 Z9 0 U1 0 U2 0 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD FEB 1 PY 2017 VL 8 IS 2 BP 902 EP 917 DI 10.1364/BOE.8.000902 PG 16 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA EK8OA UT WOS:000394182100032 PM 28270992 ER PT J AU Vila, MC Rayavarapu, S Hogarth, MW Van der Meulen, JH Horn, A Defour, A Takeda, S Brown, KJ Hathout, Y Nagaraju, K Jaiswal, JK AF Vila, Maria C. Rayavarapu, Sree Hogarth, Marshall W. Van der Meulen, Jack H. Horn, Adam Defour, Aurelia Takeda, Shin'ichi Brown, Kristy J. Hathout, Yetrib Nagaraju, Kanneboyina Jaiswal, Jyoti K. TI Mitochondria mediate cell membrane repair and contribute to Duchenne muscular dystrophy SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID DEFICIENT MDX MOUSE; SKELETAL-MUSCLE FIBERS; CALCIUM LEAK CHANNELS; SEALANT POLOXAMER; LIVING CELLS; CA2+ INFLUX; DYSFERLIN; MICE; PROTEOMICS; PATHOLOGY AB Dystrophin deficiency is the genetic basis for Duchenne muscular dystrophy (DMD), but the cellular basis of progressive myofiber death in DMD is not fully understood. Using two dystrophin-deficient mdx mouse models, we find that the mitochondrial dysfunction is among the earliest cellular deficits of mdx muscles. Mitochondria in dystrophic myofibers also respond poorly to sarcolemmal injury. These mitochondrial deficits reduce the ability of dystrophic muscle cell membranes to repair and are associated with a compensatory increase in dysferlin-mediated membrane repair proteins. Dysferlin deficit in mdx mice further compromises myofiber cell membrane repair and enhances the muscle pathology at an asymptomatic age for dysferlin-deficient mice. Restoring partial dystrophin expression by exon skipping improves mitochondrial function and offers potential to improve myofiber repair. These findings identify that mitochondrial deficit in muscular dystrophy compromises the repair of injured myofibers and show that this repair mechanism is distinct from and complimentary to the dysferlin-mediated repair of injured myofibers. C1 [Vila, Maria C.; Rayavarapu, Sree; Hogarth, Marshall W.; Van der Meulen, Jack H.; Horn, Adam; Defour, Aurelia; Brown, Kristy J.; Hathout, Yetrib; Nagaraju, Kanneboyina; Jaiswal, Jyoti K.] Childrens Natl Hlth Syst, Ctr Genet Med Res, 111 Michigan Ave NW, Washington, DC 20010 USA. [Vila, Maria C.; Horn, Adam] George Washington Univ, Inst Biomed Sci, 2300 Eye St NW,Ross 605, Washington, DC 20037 USA. [Takeda, Shin'ichi] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Mol Therapy, Tokyo, Japan. [Brown, Kristy J.; Hathout, Yetrib; Nagaraju, Kanneboyina; Jaiswal, Jyoti K.] George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Washington, DC 20037 USA. [Brown, Kristy J.; Hathout, Yetrib; Nagaraju, Kanneboyina; Jaiswal, Jyoti K.] George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20037 USA. [Rayavarapu, Sree] US FDA, Div Clin Review, Off Bioequivalence, Off Gener Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Defour, Aurelia] Univ Mediterranee, Fac Med Timone, Myol Translat, Marseille, France. RP Jaiswal, JK (reprint author), Childrens Natl Med Ctr, Med Genet Res Ctr, 111 Michigan Ave NW, Washington, DC 20010 USA. EM jkjaiswal@cnmc.org FU NIAMS [R01AR055686]; MDA [MDA277389]; NIH [K26OD011171, R24HD050846, P50AR060836, U54HD071601, P30HD040677]; US Department of Defense [W81XWH-05-1-0659, W81XWH-11-1-0782, W81XWH-11-1-0330] FX SR and MCV performed these studies as part of their doctoral studies at the Institute for Biomedical Sciences at the George Washington University and the work here from part of their PhD dissertations. We thank Dr. Isabelle Richard (Genethon, France) for the gift of B6A/J mouse model. Financial support was provided by NIAMS (R01AR055686) and MDA (MDA277389) to JKJ as well as by NIH (K26OD011171; R24HD050846, P50AR060836, U54HD071601) and the US Department of Defense (W81XWH-05-1-0659, W81XWH-11-1-0782, W81XWH-11-1-0330) grants to KN. The microscopy core is supported by NIH core grant IDDRC P30HD040677. NR 59 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD FEB PY 2017 VL 24 IS 2 BP 330 EP 342 DI 10.1038/cdd.2016.127 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EN1SE UT WOS:000395789500014 PM 27834955 ER PT J AU Li, ZH Dutta, S Sheng, JS Tran, PN Wu, WD Chang, K Mdluli, T Strauss, DG Colatsky, T AF Li, Zhihua Dutta, Sara Sheng, Jiansong Tran, Phu N. Wu, Wendy Chang, Kelly Mdluli, Thembi Strauss, David G. Colatsky, Thomas TI Improving the In Silico Assessment of Proarrhythmia Risk by Combining hERG (Human Ether-a-go-go-Related Gene) Channel-Drug Binding Kinetics and Multichannel Pharmacology SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE biomarkers; ion channels; torsade de pointes ID TORSADE-DE-POINTES; CARDIAC ACTION-POTENTIALS; EARLY AFTERDEPOLARIZATIONS; SAFETY ASSESSMENT; POTASSIUM CHANNELS; QT PROLONGATION; K+-CURRENT; BLOCK; REPOLARIZATION; DOFETILIDE AB Background-The current proarrhythmia safety testing paradigm, although highly efficient in preventing new torsadogenic drugs from entering the market, has important limitations that can restrict the development and use of valuable new therapeutics. The CiPA (Comprehensive in vitro Proarrhythmia Assay) proposes to overcome these limitations by evaluating drug effects on multiple cardiac ion channels in vitro and using these data in a predictive in silico model of the adult human ventricular myocyte. A set of drugs with known clinical torsade de pointes risk was selected to develop and calibrate the in silico model. Methods and Results-Manual patch-clamp data assessing drug effects on expressed cardiac ion channels were integrated into the O'Hara-Rudy myocyte model modified to include dynamic drug-hERG channel (human Ether-a-go-go-Related Gene) interactions. Together with multichannel pharmacology data, this model predicts that compounds with high torsadogenic risk are more likely to be trapped within the hERG channel and show stronger reverse use dependency of action potential prolongation. Furthermore, drug-induced changes in the amount of electronic charge carried by the late sodium and L-type calcium currents was evaluated as a potential metric for assigning torsadogenic risk. Conclusions-Modeling dynamic drug-hERG channel interactions and multi-ion channel pharmacology improves the prediction of torsadogenic risk. With further development, these methods have the potential to improve the regulatory assessment of drug safety models under the CiPA paradigm. C1 [Li, Zhihua; Dutta, Sara; Sheng, Jiansong; Tran, Phu N.; Wu, Wendy; Chang, Kelly; Mdluli, Thembi; Strauss, David G.; Colatsky, Thomas] US FDA, Div Appl Regulatory Sci, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, WO Bldg 64 Room 2084,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Li, ZH (reprint author), US FDA, Div Appl Regulatory Sci, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, WO Bldg 64 Room 2084,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM zhihua.li@fda.hhs.gov FU Food and Drug Administration Critical Path Award FX This project was funded by the Food and Drug Administration Critical Path Award. NR 40 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 1941-3149 EI 1941-3084 J9 CIRC-ARRHYTHMIA ELEC JI Circ.-Arrhythmia Electrophysiol. PD FEB PY 2017 VL 10 IS 2 AR e004628 DI 10.1161/CIRCEP.116.004628 PG 70 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EL3NF UT WOS:000394525200009 ER PT J AU Calis, KA Archdeacon, P Bain, RP Forrest, A Perlmutter, J DeMets, DL AF Calis, Karim A. Archdeacon, Patrick Bain, Raymond P. Forrest, Annemarie Perlmutter, Jane DeMets, David L. TI Understanding the functions and operations of data monitoring committees: Survey and focus group findings SO CLINICAL TRIALS LA English DT Article DE Data monitoring committee; clinical trial; interim analysis; statistical data interpretation; safety; benefit; futility AB Background: The use of data monitoring committees in the conduct of clinical trials has increased and evolved, but there is a lack of published information on when data monitoring committees are needed and utilized, the acceptable range of data monitoring committee practices, and appropriate qualifications of data monitoring committee members. Methods: To gain a better understanding of data monitoring committee operations and areas for improvement, the Clinical Trials Transformation Initiative conducted a survey and set of focus groups. A total of 143 respondents completed the online survey: 76 data monitoring committee members, 52 sponsors involved with organization of data monitoring committees, and 15 statistical data analysis center representatives. There were 42 focus group participants, including data monitoring committee members; patients and/or patient advocate data monitoring committee members; institutional review board and US Food and Drug Administration representatives; industry, government, and non-profit sponsors; and statistical data analysis center representatives. Results: Participants indicated that the primary responsibility of a data monitoring committee is to be an independent advisory body representing the interests of trial participants by assessing the risk and benefit ratio in ongoing trials. They noted that data monitoring committees must have access to unmasked data in order to perform this role. No clear consensus emerged regarding specific criteria for requiring a data monitoring committee for a given trial, and some participants felt data monitoring committees may be overused. Respondents offered suggestions for the data monitoring committee charter and communications with sponsors, institutional review boards, and regulators. Overall, data monitoring committee members reported that they are able to function independently and their recommendations are almost always accepted by the sponsor. Participants indicated that there are no standards or guidelines pertaining to qualifications of data monitoring committee members. Furthermore, only 8% (6/72) of data monitoring committee member survey respondents received any formal training, and 94% (68/72) were not aware of any training programs. Conclusion: Findings from the survey and focus groups provide a better understanding of contemporary data monitoring committee operations and insights regarding challenges and best practices. Overall, it was clear that increased training will be needed to prepare the next generation of qualified data monitoring committee members to meet the growing demand. These findings can be used by Clinical Trials Transformation Initiative and others to develop recommendations and tools to improve data monitoring committee operations and the overall quality of trial oversight. C1 [Calis, Karim A.; Archdeacon, Patrick] US FDA, Off Med Policy, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Calis, Karim A.] NICHHD, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Bain, Raymond P.] Merck Res Labs, N Wales, PA USA. [Forrest, Annemarie] Clin Trials Transformat Initiat, 300 W Morgan St,Suite 800, Durham, NC 27701 USA. [Perlmutter, Jane] Gemini Grp, Ann Arbor, MI USA. [DeMets, David L.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. RP Forrest, A (reprint author), Clin Trials Transformat Initiat, 300 W Morgan St,Suite 800, Durham, NC 27701 USA. EM ctti@mc.duke.edu FU Food and Drug Administration [R18FD005292, U19FD003800]; CTTI 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 Food and Drug Administration through grant R18FD005292 and cooperative agreement U19FD003800. Views expressed in publications do not necessarily reflect the official policies of the Department of Health and Human Services, nor does any mention of trade names, commercial practices, or organization imply endorsement by the US Government. Partial funding was also provided by pooled membership fees from CTTI's member organizations. NR 9 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 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD FEB PY 2017 VL 14 IS 1 BP 59 EP 66 DI 10.1177/1740774516679665 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EL5HR UT WOS:000394652700006 PM 27885056 ER PT J AU Zhao, P AF Zhao, P. TI Report from the EMA workshop on qualification and reporting of physiologically based pharmacokinetic (PBPK) modeling and simulation SO CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY LA English DT Editorial Material AB On Nov 21, 2016, the European Medicines Agency (EMA) hosted a workshop to discuss its draft guideline on qualification and reporting of physiologically based pharmacokinetic (PBPK) analysis. 1 Published on July 21, 2016, the draft PBPK guideline is currently under the period of public comments. C1 [Zhao, P.] US FDA, Silver Spring, MD USA. RP Zhao, P (reprint author), US FDA, Silver Spring, MD USA. EM ping.zhao@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2163-8306 J9 CPT-PHARMACOMET SYST JI CPT-PHARMACOMET. SYST. PHARMACOL. PD FEB PY 2017 VL 6 IS 2 BP 71 EP 72 DI 10.1002/psp4.12166 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EL9QK UT WOS:000394954900001 PM 28035755 ER PT J AU Nguyen, THT Mouksassi, MS Holford, N Al-Huniti, N Freedman, I Hooker, AC John, J Karlsson, MO Mould, DR Ruixo, JJP Plan, EL Savic, R van Hasselt, JGC Weber, B Zhou, C Comets, E Mentre, F AF Nguyen, T. H. T. Mouksassi, M-S Holford, N. Al-Huniti, N. Freedman, I. Hooker, A. C. John, J. Karlsson, M. O. Mould, D. R. Ruixo, J. J. Perez Plan, E. L. Savic, R. van Hasselt, J. G. C. Weber, B. Zhou, C. Comets, E. Mentre, F. CA Model Evaluation Grp Int Soc Pharm TI Model Evaluation of Continuous Data Pharmacometric Models: Metrics and Graphics SO CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY LA English DT Article ID MIXED-EFFECTS MODELS; COUMARIN ANTICOAGULANT DRUGS; POPULATION PHARMACOKINETICS; PREDICTIVE CHECK; SIMULATION; WARFARIN; DROPOUT AB This article represents the first in a series of tutorials on model evaluation in nonlinear mixed effect models (NLMEMs), from the International Society of Pharmacometrics (ISoP) Model Evaluation Group. Numerous tools are available for evaluation of NLMEM, with a particular emphasis on visual assessment. This first basic tutorial focuses on presenting graphical evaluation tools of NLMEM for continuous data. It illustrates graphs for correct or misspecified models, discusses their pros and cons, and recalls the definition of metrics used. C1 [Nguyen, T. H. T.; Comets, E.; Mentre, F.] INSERM, IAME, UMR 1137, Paris, France. [Nguyen, T. H. T.; Comets, E.; Mentre, F.; Model Evaluation Grp Int Soc Pharm] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France. [Mouksassi, M-S] Certara Strateg Consulting, Montreal, PQ, Canada. [Holford, N.] Univ Auckland, Dept Pharmacol & Clin Pharmacol, Auckland, New Zealand. [Al-Huniti, N.] AstraZeneca, Quantitat Clin Pharmacol, Waltham, MA USA. [Freedman, I.] Dr Immanuel Freedman Inc, Harleysville, PA USA. [Hooker, A. C.; Karlsson, M. O.] Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden. [John, J.] US FDA, Ctr Drug Evaluat & Res, Washington, DC USA. [Mould, D. R.] Project Res Inc, Phoenixville, PA USA. [Ruixo, J. J. Perez] Janssen Pharmaceut Companies Johnson, Beerse, Belgium. [Plan, E. L.] Pharmetheus, Uppsala, Sweden. [Savic, R.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA USA. [van Hasselt, J. G. C.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands. [Weber, B.] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT USA. [Zhou, C.] Genentech Inc, San Francisco, CA USA. [Comets, E.] Univ Rennes 1, INSERM, CIC 1414, Rennes, France. RP Mentre, F (reprint author), INSERM, IAME, UMR 1137, Paris, France.; Mentre, F (reprint author), Univ Paris Diderot, Sorbonne Paris Cite, Paris, France. EM france.mentre@inserm.fr RI Comets, Emmanuelle/C-9328-2017 NR 36 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2163-8306 J9 CPT-PHARMACOMET SYST JI CPT-PHARMACOMET. SYST. PHARMACOL. PD FEB PY 2017 VL 6 IS 2 BP 87 EP 109 DI 10.1002/psp4.12161 PG 23 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EL9QK UT WOS:000394954900003 PM 27884052 ER PT J AU Tallent, SM Hait, JM Knolhoff, AM Bennett, RW Hammack, TS Croley, TR AF Tallent, Sandra M. Hait, Jennifer M. Knolhoff, Ann M. Bennett, Reginald W. Hammack, Thomas S. Croley, Timothy R. TI Rapid Testing of Food Matrices for Bacillus cereus Enterotoxins SO JOURNAL OF FOOD SAFETY LA English DT Article ID REAL-TIME PCR; EMETIC TOXIN; LIVER-FAILURE; QUANTIFICATION; TOXICITY; STRAINS; ILLNESS; NISIN AB Nine different food products frequently associated with Bacillus cereus outbreaks were chosen as representative matrices to be evaluated with end-point polymerase chain reaction (PCR), enzyme linked immunosorbent assay, lateral flow device and mass spectrometry for detection of enterotoxins associated with human illness. Testing was performed on food portions inoculated with a bacterial strain and incubated at 30 degrees C for either 5 h or 24 h. A screening end-point multiplex PCR targeting enterotoxin genes including the emetic toxin and three diarrheal toxins, hemolytic hemolysin BL (Hbl), nonhemoltyic enterotoxin (Nhe), and cytolysin K. Commercially available kits were used to determine the presence/absence of Nhe and Hbl. Finally; a quantitative analysis using mass spectrometry was performed for the detection of the emetic toxin. Definitive results were available after a five hour pre-enrichment in five food products. The following strategy would allow for more efficient testing of surveillance or environmental samples as well as more rapid response time during a foodborne outbreak. Practical ApplicationsThe application of a strategy for processing and analyzing food products for Bacillus cereus and the enterotoxins associated with foodborne illness was explored. Employment of such a strategy will decrease time spent processing negative samples allowing more time for analysis of potentially positive food products. C1 [Tallent, Sandra M.] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Tallent, Sandra M.; Hait, Jennifer M.; Bennett, Reginald W.; Hammack, Thomas S.] Ctr Food Safety & Appl Nutr, Div Microbiol, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Knolhoff, Ann M.; Croley, Timothy R.] Ctr Food Safety & Appl Nutr, Div Analyt Chem, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. RP Tallent, SM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA.; Tallent, SM (reprint author), Ctr Food Safety & Appl Nutr, Div Microbiol, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM sandra.tallent@fda.hhs.gov NR 35 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0149-6085 EI 1745-4565 J9 J FOOD SAFETY JI J. Food Saf. PD FEB PY 2017 VL 37 IS 1 AR e12292 DI 10.1111/jfs.12292 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EL5OR UT WOS:000394670900014 ER PT J AU Parveen, S Jahncke, M Elmahdi, S Crocker, H Bowers, J White, C Gray, S Morris, AC Brohawn, K AF Parveen, Salina Jahncke, Michael Elmahdi, Sara Crocker, Helen Bowers, John White, Chanelle Gray, Stephanie Morris, Amanda C. Brohawn, Kathy TI High Salinity Relaying to Reduce Vibrio parahaemolyticus and Vibrio vulnificus in Chesapeake Bay Oysters (Crassostrea virginica) SO JOURNAL OF FOOD SCIENCE LA English DT Article DE high salinity; Oyster; relaying; seafood safety; Vibrio ID DEPURATION; TEMPERATURE AB Cases of Vibrio infections in the United States have tripled from 1996 to 2009 and these infections are most often associated with the consumption of seafood, particularly oysters (Crassostrea virginica). Information is needed on how to reduce numbers of Vibrio parahaemolyticus and Vibrio vulnificus in bi-valve molluscan shellfish (for example, oysters). The purpose of this study was to evaluate the effectiveness of high salinity relaying or treatment in recirculating aquaculture systems (RASs) as methods to reduce the abundance of V. parahaemolyticus and V. vulnificus in oysters. For relaying field trials, oysters were collected from approved harvest waters, temperature abused outside under a tarp for 4 h, and then transferred to high (29 to 33 ppt.) and moderate (12 to 19 ppt.) salinities. For RAS treatment trial, oysters were transferred to 32 to 34 ppt. salinity at 15 degrees C. After 7, 14, 21, and in some instances 28 d, oysters were collected and analyzed for V. parahaemolyticus and V. vulnificus levels using multiplex real-time PCR. Initial levels of V. parahaemolyticus and V. vulnificus ranged from 3.70 to 5.64 log(10) MPN/g, and were reduced by 2 to 5 logs after 21 to 28 d in high salinity water (29 to 34 ppt.). Oyster mortalities averaged 4% or less, and did not exceed 7%. Relaying of oysters to high salinity field sites or transfer to high salinity RAS tanks was more effective in reducing V. vulnificus compared with V. parahaemolyticus. These results suggest that high salinity relaying of oysters is more effective in reducing V. vulnificus than V. parahaemolyticus in the oyster species used in this study. Practical Application Relaying of naturally contaminated oysters to high salinity sites in the Atlantic Coastal Bays and the Chesapeake Bay could provide a low cost and practical mitigation strategy to reduce Vibrio spp. in oysters. This could result in decreasing the risk of Vibrio illnesses from oyster consumption during the warmer months when Vibrio is present in high numbers. This study provides important information for risk management decisions for the oyster industry and regulatory agencies. C1 [Parveen, Salina; Elmahdi, Sara; White, Chanelle] Univ Maryland Eastern Shore, Princess Anne, MD 21853 USA. [Jahncke, Michael; Crocker, Helen; Gray, Stephanie; Morris, Amanda C.] Virginia Tech, Virginia Seafood Agr Res & Extens Ctr, Hampton, VA 23669 USA. [Bowers, John] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Brohawn, Kathy] Maryland Dept Environm, Baltimore, MD 21230 USA. RP Parveen, S (reprint author), Univ Maryland Eastern Shore, Princess Anne, MD 21853 USA. EM sparveen@umes.edu FU U.S. Dept. of Agriculture CBG award [2010-02370] FX We are grateful to Maryland Dept. of the Environment, Tom Rippen (Maryland Sea Grant), Dr. Dan Kauffman (Virginia Tech.), and Linda McFarland (Virginia Dept. of Health, Div. of Shellfish Sanitation, Norfolk field office) for technical assistance and helpful suggestions. We thank the U.S. Dept. of Agriculture CBG award # 2010-02370 for funding. NR 28 TC 0 Z9 0 U1 0 U2 0 PU WILEY 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 FEB PY 2017 VL 82 IS 2 BP 484 EP 491 DI 10.1111/1750-3841.13584 PG 8 WC Food Science & Technology SC Food Science & Technology GA EM0BA UT WOS:000394982600031 PM 28099766 ER PT J AU Dang, YH Nice, FJ Truong, HA AF Dang, Yen H. Nice, Frank J. Hoai-An Truong TI Academic-Community Partnership for Medical Missions: Lessons Learned and Practical Guidance for Global Health Service-Learning Experiences SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article AB To facilitate an academic-community partnership for sustainable medical missions, a 12-step process was created for an interprofessional, global health educational, and service-learning experience for students and faculty in a school of pharmacy and health professions. Lessons learned and practical guidance are provided to implement similar global health opportunities. C1 [Dang, Yen H.; Hoai-An Truong] Univ Maryland Eastern Shore, Sch Pharm & Hlth Profess, One Coll Backbone Rd,210 Somerset Hall, Princess Anne, MD 21853 USA. [Nice, Frank J.] US FDA, Derwood, MD USA. [Nice, Frank J.] NIH, Derwood, MD USA. [Nice, Frank J.] Nice Breastfeeding LLC, Derwood, MD USA. RP Dang, YH (reprint author), Univ Maryland Eastern Shore, Sch Pharm & Hlth Profess, One Coll Backbone Rd,210 Somerset Hall, Princess Anne, MD 21853 USA. EM ydang@umes.edu NR 7 TC 0 Z9 0 U1 1 U2 1 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 EI 1548-6869 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD FEB PY 2017 VL 28 IS 1 BP 8 EP 13 PG 6 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EL6JU UT WOS:000394729200003 PM 28238981 ER PT J AU Almeida, F Medeiros, MIC Rodrigues, DD Allard, MW Falcao, JP AF Almeida, Fernanda Medeiros, Marta Ines Cazentini Rodrigues, Dalia dos Prazeres Allard, Marc W. Falcao, Juliana Pfrimer TI Molecular characterization of Salmonella Typhimurium isolated in Brazil by CRISPR-MVLST SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Article DE CRISPR-MVLST; PFGE; Salmonella Typhimurium ID SUBSP ENTERICA SEROVAR; VIRULENCE-ASSOCIATED GENES; FIELD GEL-ELECTROPHORESIS; SAO-PAULO STATE; ANTIMICROBIAL RESISTANCE; ENTERITIDIS STRAINS; HUMANS; FOOD; DIVERSITY; MARKERS AB CRISPR-multi-locus virulence sequence typing (CRISPR-MVLST) was performed to type 92 S. Typhimurium strains isolated from humans and food sources between 1983 and 2013 in Brazil and assess the suitability of this methodology comparing it with PFGE already used for subtyping the same strains. Among the 92 S. Typhimurium strains studied, we identified 25 CRISPR1 alleles, 27 CRISPR2 alleles, 2fimH alleles and 3 sseL alleles showing that the genetic variability is much higher in the CRISPRs loci than in the virulence genes. The CRISPR-MVLST analysis provided similar results to the PFGE previously published used to type the same set of strains, demonstrating that CRISPR-MVLST is a very efficient approach for subtyping S. Typhimurium serovar and can be used to complement and validate results obtained by the PFGE methodology. (C) 2016 Elsevier B.V. All rights reserved. C1 [Almeida, Fernanda; Falcao, Juliana Pfrimer] Univ Sao Paulo, Dept Anal Clin Toxicol & Bromatol, Fac Ciencias Farmaceut Ribeirao Preto, Av Cafe S-N, BR-14040903 Ribeirao Preto, SP, Brazil. [Medeiros, Marta Ines Cazentini] Adolfo Lutz Inst, Ctr Lab Reg Ribeirao Preto, Rua Minas 877, Ribeirao Preto, SP, Brazil. [Rodrigues, Dalia dos Prazeres] FIOCRUZ Fundacao Inst Oswaldo Cruz, Lab Enterobacterias, Ave Brasil,4365,Pavilhao Rocha Lima,3 Andar, BR-21040360 Rio De Janeiro, RJ, Brazil. [Allard, Marc W.] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Falcao, JP (reprint author), Univ Sao Paulo, Dept Anal Clin Toxicol & Bromatol, Fac Ciencias Farmaceut Ribeirao Preto, Av Cafe S-N, BR-14040903 Ribeirao Preto, SP, Brazil. EM jufalcao@fcfrp.usp.br RI Falcao, Juliana/E-9652-2012 FU Sao Paulo Research Foundation (FAPESP) [2012/19132-1]; CAPES Programa de Doutorado Sanduiche no Exterior (PDSE) [9708/14-6]; CNPq [162070/2014-4] FX This study was supported by Sao Paulo Research Foundation (FAPESP) (Proc. 2012/19132-1) for financial support. During the course of this work, Almeida, F. was supported by a scholarship from CAPES Programa de Doutorado Sanduiche no Exterior (PDSE) (Proc. 9708/14-6) and CNPq (Proc. 162070/2014-4). NR 34 TC 0 Z9 0 U1 1 U2 1 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 FEB PY 2017 VL 133 BP 55 EP 61 DI 10.1016/j.mimet.2016.12.020 PG 7 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA EK8TJ UT WOS:000394197200011 PM 28034696 ER PT J AU Ikejimba, LC Graff, CG Rosenthal, S Badal, A Ghammraoui, B Lo, JY Glick, SJ AF Ikejimba, Lynda C. Graff, Christian G. Rosenthal, Shani Badal, Andreu Ghammraoui, Bahaa Lo, Joseph Y. Glick, Stephen J. TI A novel physical anthropomorphic breast phantom for 2D and 3D x-ray imaging SO MEDICAL PHYSICS LA English DT Article DE anthropomorphic; breast phantom; iodine; parchment ID SOFTWARE PHANTOM; MAMMOGRAPHY; TOMOSYNTHESIS; SIMULATION; MODEL; GENERATION AB Purpose: Physical phantoms are central to the evaluation of 2D and 3D breast-imaging systems. Currently, available physical phantoms have limitations including unrealistic uniform background structure, large expense, or excessive fabrication time. The purpose of this work is to outline a method for rapidly creating realistic, inexpensive physical anthropomorphic phantoms for use in fullfield digital mammography (FFDM) and digital breast tomosynthesis (DBT). Methods: The phantom was first modeled using analytical expressions and then discretized into voxels of a specified size. The interior of the breast was divided into glandular and adipose tissue classes using Voronoi segmentation, and additional structures like blood vessels, chest muscle, and ligaments were added. The physical phantom was then fabricated from the virtual model in a slice by slice fashion through inkjet printing, using parchment paper and a radiopaque ink containing 33% (I-33%) or 25% (I-25%) iohexol by volume. Three types of parchment paper (P1, P2, and P3) were examined. The phantom materials were characterized in terms of their effective linear attenuation coefficients (mu(eff)) using full-field digital mammography (FFDM) and their energy-dependent linear attenuation coefficients (mu(E)) using a spectroscopic energy discriminating detector system. The printing method was further validated on the basis of accuracy, print consistency, and the reproducibility of ink batches. Results: The mu(eff) of two types of parchment paper were close to that of adipose tissue, with mu(eff) = 0.61 +/- 0.05 cm(-1) for P1, 0.61 +/- 0.04 cm(-1) for P2, and 0.57 +/- 0.03 cm(-1) for adipose tissue. The addition of the iodinated ink increased the effective attenuation to that of glandular tissue, with mu(eff) = 0.89 +/- 0.06 cm(-1) for P1 + I-25% and 0.94 +/- 0.06 cm(-1) for P1 + I-33% compared to 0.90 +/- 0.03 cm(-1) for glandular tissue. Spectroscopic measurements showed a good match between the parchment paper and reference values for adipose and glandular tissues across photon energies. Good accuracy was found between the model and the printed phantom by comparing a FFDM of the virtual model simulated through Monte Carlo with a real FFDM of the fully printed phantom. High consistency was found over multiple prints, with 3% variability in mean ink signal across various samples. Reproducibility of ink consistency was very high with <1% variation signal from multiple batches of ink. Imaging of the phantom using FFDM and DBT systems showed promising utility for 2D and 3D imaging. Conclusions: A novel, realistic breast phantom can be created using an analytically defined breast model and readily available materials. The work provides a method to fabricate any virtual phantom in a manner that is accurate, inexpensive, easily accessible, and can be made with different materials or breast models. (C) 2016 American Association of Physicists in Medicine C1 [Ikejimba, Lynda C.; Graff, Christian G.; Badal, Andreu; Ghammraoui, Bahaa; Glick, Stephen J.] US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Diagnost & Radiol Hlth, Silver Spring, MD 20993 USA. [Rosenthal, Shani] Carnegie Mellon Univ, Dept Comp Sci, Dept Mech Engn, Pittsburgh, PA 15213 USA. [Lo, Joseph Y.] Duke Univ, Dept Elect & Comp Engn, Dept Biomed Engn,Dept Radiol, Med Phys Grad Program,Carl E Ravin Adv Imaging L, Durham, NC 27705 USA. RP Ikejimba, LC (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Diagnost & Radiol Hlth, Silver Spring, MD 20993 USA. EM lynda.ikejimba@fda.hhs.gov FU Critical Path grant from the Center for Devices and Radiological Healthy; Oak Ridge Institute for Science and Education; U.S. Department of Energy; U.S. Food and Drug Administration FX The authors thank Dr. Robert Jennings for his assistance with MammoFilter, and Dr. Katherine Vorvolakos for her contributions to developing the ink. This work was supported by a Critical Path grant from the Center for Devices and Radiological Healthy, 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 have no relevant conflicts of interest to disclose. NR 28 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0094-2405 EI 2473-4209 J9 MED PHYS JI Med. Phys. PD FEB PY 2017 VL 44 IS 2 BP 407 EP 416 DI 10.1002/mp.12062 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EP5EM UT WOS:000397401800009 PM 27992059 ER PT J AU Chou, AY Kennett, NJ Melillo, AA Elkins, KL AF Chou, Alicia Y. Kennett, Nikki J. Melillo, Amanda A. Elkins, Karen L. TI Murine survival of infection with Francisella novicida and protection against secondary challenge is critically dependent on B lymphocytes SO MICROBES AND INFECTION LA English DT Article DE Francisella tularensis; Francisella novicida; B lymphocytes; T lymphocytes; Protective immunity ID LIVE VACCINE STRAIN; TULARENSIS SUBSP NOVICIDA; INTRACELLULAR BACTERIUM; PULMONARY INFECTION; IMMUNE-RESPONSES; GAMMA-INTERFERON; SEVERE SEPSIS; T-CELLS; MICE; TULAREMIA AB Respiratory infection of mice with Francisella novicida has recently been used as a model for the highly virulent human pathogen Francisella tularensis. Similar to E tularensis, even small doses of E novicida administered by respiratory routes are lethal for inbred laboratory mice. This feature obviously limits study of infection-induced immunity. Parenteral sublethal infections of mice with E novicida are feasible, but the resulting immune responses are incompletely characterized. Here we use parenteral intradermal (i.d.) and intraperitoneal (i.p.) E novicida infections of C57BL/6J mice to determine the role of B cells in controlling primary and secondary E novicida infections. Despite developing comparable levels of F. novicida-primed T cells, B cell knockout mice were much more susceptible to both primary i.d. infection and secondary i.p. challenge than wild type (normal) C57BL/6J mice. Transfer of E novicida-immune sera to either wild type C57BL/6J mice or to B cell knockout mice did not appreciably impact survival of subsequent lethal E novicida challenge. However, E novicida-immune mice that were depleted of T cells after priming but just before challenge survived and cleared secondary i.p. E novicida challenge. Collectively these results indicate that B cells, if not serum antibodies, play a major role in controlling E novicida infections in mice. Published by Elsevier Masson SAS on behalf of Institut Pasteur. C1 [Chou, Alicia Y.; Kennett, Nikki J.; Melillo, Amanda A.; Elkins, Karen L.] US FDA, Ctr Biol Evaluat & Res, Div Bacterial Parasit & Allergen Prod, Lab Mucosal Pathogens & Cellular Immunol, Rockville, MD 20852 USA. [Chou, Alicia Y.] Crit Path Inst, 1730 East River Rd, Tucson, AZ 85718 USA. RP Elkins, KL (reprint author), 10903 New Hampshire Ave,Bldg 52-72,Room 5330, Silver Spring, MD 20993 USA. EM karen.elkins@fda.hhs.gov FU National Institute of Allergy and Infectious Disease, NIH, Bethesda, MD [Y1-AI-6153-01, 224-06-1322] FX We are grateful to our CBER colleagues, Siobhan Cowley, Roberto De Pascalis, and Sherry Kurtz, for thoughtful and careful reviews of the manuscript. This work was supported in part by an Interagency Agreement with the National Institute of Allergy and Infectious Disease (#Y1-AI-6153-01/#224-06-1322), NIH, Bethesda, MD. NR 51 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 EI 1769-714X J9 MICROBES INFECT JI Microbes Infect. PD FEB PY 2017 VL 19 IS 2 BP 91 EP 100 DI 10.1016/j.micinf.2016.12.001 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EK8RM UT WOS:000394191400004 PM 27965147 ER PT J AU Zhang, ZH Chen, QZ Jiang, F Townsend, TA Mao, CJ You, CY Yang, WH Sun, ZY Yu, JG Yan, H AF Zhang, Zhu-Hong Chen, Qing-Zhong Jiang, Feng Townsend, Todd A. Mao, Chun-Jie You, Cai-Yun Yang, Wen-Hui Sun, Zhi-Yong Yu, Jin-Guo Yan, Hua TI Changes in TL1A levels and associated cytokines during pathogenesis of diabetic retinopathy SO MOLECULAR MEDICINE REPORTS LA English DT Article DE diabetic retinopathy; TNF ligand related molecule 1A; vascular endothelial growth factor; tumor necrosis factor alpha; interleukin-1 beta ID ENDOTHELIAL GROWTH-FACTOR; MICROGLIAL ACTIVATION; TUMOR-GROWTH; INHIBITOR; CANCER; VEGI; ANGIOGENESIS; INFLAMMATION; SUPPRESSES; EXPRESSION AB Tumor necrosis factor (TNF) ligand related molecule 1A (TL1A), also termed TNF superfamily member 15 and vascular endothelial growth inhibitor is important for tumorigenicity and autoimmunity. However, the function of TL1A in diabetic retinopathy (DR) remains to be elucidated. The present study established a diabetes mellitus (DM) rat model to investigate TL1A, vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) expression levels in the retina, vitreous and serum of rats with DM at different stages (1 month group, 3 month group and 6 month group). The present study determined that TL1A expression levels in the retina and vitreous from the DM 1 month group were significantly lower compared with the control group. However, TL1A levels in the retina and vitreous were significantly increased in advanced stages of DM compared with the control group. Furthermore, the levels of VEGF in the retina and vitreous were significantly higher in the DM groups compared with the control group. The expression levels of TNF-alpha and IL-1 beta in the retina and vitreous were significantly higher in DM 3 month and 6 month groups compared with the control group. It is of note that the expression levels of TL1A were significantly lower in the DM 1 and 3 month groups compared with the control group; however, they were significantly increased in the DM 6 month group compared with the DM 3 month group. The expression levels of VEGF, TNF-alpha and IL-1 beta in blood serum have been observed to exhibit similar expression change dynamics as those of the retina and vitreous. Therefore, these findings suggest that TL1A may be a protective factor of DR, and may provide a rationale for the development of novel therapeutic strategies to treat DR. C1 [Zhang, Zhu-Hong; Chen, Qing-Zhong; Jiang, Feng; Mao, Chun-Jie; You, Cai-Yun; Yang, Wen-Hui; Sun, Zhi-Yong; Yu, Jin-Guo; Yan, Hua] Tianjin Med Univ Gen Hosp, Dept Ophthalmol, Tianjin 300052, Peoples R China. [Townsend, Todd A.] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. RP Yan, H (reprint author), Tianjin Med Univ Gen Hosp, Dept Ophthalmol, Tianjin 300052, Peoples R China. EM phuayan2000@163.com FU National Natural Science Foundation of China [81371038, 91442124, 81500743]; Tianjin Application Infrastructure and Cutting-edge Technology Research Program of China [10JCZDJC20300] FX The present study was supported by the National Natural Science Foundation of China (grant nos. 81371038 and 91442124) and the Tianjin Application Infrastructure and Cutting-edge Technology Research Program of China (grant no 10JCZDJC20300) to Dr Hua Yan, and the National Natural Science Foundation of China (grant no. 81500743) to Dr Zhu-Hong Zhang. The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration. NR 33 TC 0 Z9 0 U1 1 U2 1 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1791-2997 EI 1791-3004 J9 MOL MED REP JI Mol. Med. Rep. PD FEB PY 2017 VL 15 IS 2 BP 573 EP 580 DI 10.3892/mmr.2016.6048 PG 8 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA EL9GE UT WOS:000394927600007 PM 28000874 ER PT J AU Das, SS Lucas, AD Carlin, AS Zheng, JW Patwardhan, DV Saylor, DM AF Das, Srilekha Sarkar Lucas, Anne D. Carlin, Alan S. Zheng, Jiwen Patwardhan, Dinesh V. Saylor, David M. TI Controlled initial surge despite high drug fraction and high solubility SO PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY LA English DT Article DE Biodegradable; controlled release; PLGA; solvent casting; solvent evaporation; tetracycline ID POLY(LACTIC-CO-GLYCOLIC ACID); CONTROLLED-RELEASE; TETRACYCLINE HYDROCHLORIDE; COPOLYMER COMPOSITION; SOLVENT EVAPORATION; PLGA NANOPARTICLES; MOLECULAR-WEIGHT; DELIVERY; MICROSPHERES; DEGRADATION AB Potential connections between release profiles and solvent evaporation rates alongside polymer chemistry were elucidated for the release of tetracycline hydrochloride from two different poly (d, l-lactide-co-glycolide) (PLGA) film matrices containing high drug fractions (50%, 30%, and 15%), and prepared at two distinct solvent evaporation rates. At highest tetracycline concentrations (50%), (i) the early release rates were 0.5g/min in all cases; (ii) release was linear from systems fabricated with lower lactic content and slower solvent evaporation rate and bimodal from systems fabricated with higher lactic content and faster evaporation rate; (iii) surface fractions covered by the drug were similar at both evaporation rates for 85:15 PLGA but very different for 50:50 PLGA, leading to unexpectedly reduced early release from 50:50 PLGA than from 85:15 PLGA when both the matrices were fabricated using a slower evaporation rate. These features remained unaffected in case of low drug concentration. Results suggested that during the formation of the drug-polymer microstructure, the combined effect of polymer chemistry and solvent evaporation rate sets apart the surface characteristics and the initial release profiles of systems containing high drug fraction, and an appropriate combination of these parameters may be utilized to control the early stage of drug release. C1 [Das, Srilekha Sarkar; Lucas, Anne D.; Zheng, Jiwen; Patwardhan, Dinesh V.; Saylor, David M.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Carlin, Alan S.] US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Off Prod Qual, Silver Spring, MD USA. RP Das, SS (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. EM Srilekha.Das@fda.hhs.gov NR 47 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 1083-7450 EI 1097-9867 J9 PHARM DEV TECHNOL JI Pharm. Dev. Technol. PD FEB PY 2017 VL 22 IS 1 BP 35 EP 44 DI 10.3109/10837450.2015.1135341 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EL5EO UT WOS:000394644600005 ER PT J AU Chen, G Chen, JW Yang, JM Chen, L Qu, XF Shi, CP Ning, BT Shi, LM Tong, WD Zhao, YX Zhang, MX Shi, TL AF Chen, Geng Chen, Jiwei Yang, Jianmin Chen, Long Qu, Xiongfei Shi, Caiping Ning, Baitang Shi, Leming Tong, Weida Zhao, Yongxiang Zhang, Meixia Shi, Tieliu TI Significant variations in alternative splicing patterns and expression profiles between human-mouse orthologs in early embryos SO SCIENCE CHINA-LIFE SCIENCES LA English DT Article DE ortholog; alternative splicing; RNA-seq; early embryo; gene expression ID RNA-SEQ; MASS-SPECTROMETRY; LOW CONSERVATION; EVOLUTION; GENOMICS; GENES; TRANSCRIPTOMICS; DIVERGENCE; ARRAYS; CELLS AB Human and mouse orthologs are expected to have similar biological functions; however, many discrepancies have also been reported. We systematically compared human and mouse orthologs in terms of alternative splicing patterns and expression profiles. Human-mouse orthologs are divergent in alternative splicing, as human orthologs could generally encode more isoforms than their mouse orthologs. In early embryos, exon skipping is far more common with human orthologs, whereas constitutive exons are more prevalent with mouse orthologs. This may correlate with divergence in expression of splicing regulators. Orthologous expression similarities are different in distinct embryonic stages, with the highest in morula. Expression differences for orthologous transcription factor genes could play an important role in orthologous expression discordance. We further detected largely orthologous divergence in differential expression between distinct embryonic stages. Collectively, our study uncovers significant orthologous divergence from multiple aspects, which may result in functional differences and dynamics between human-mouse orthologs during embryonic development. C1 [Chen, Geng; Chen, Jiwei; Yang, Jianmin; Chen, Long; Qu, Xiongfei; Shi, Caiping; Shi, Tieliu] East China Normal Univ, Ctr Bioinformat & Computat Biol, Shanghai Key Lab Regulatory Biol, Inst Biomed Sci, Shanghai 200241, Peoples R China. [Chen, Geng; Chen, Jiwei; Yang, Jianmin; Chen, Long; Qu, Xiongfei; Shi, Caiping; Shi, Tieliu] East China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China. [Chen, Geng; Shi, Leming] Fudan Univ, Sch Pharm, Ctr Pharmacogen, Shanghai 201203, Peoples R China. [Ning, Baitang; Shi, Leming; Tong, Weida] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Zhao, Yongxiang] Guangxi Med Univ, Biol Targeting Diag & Therapy Res Ctr, Nanning 530021, Peoples R China. [Zhang, Meixia] Sichuan Univ, West China Hosp, Dept Ophthalmol, Chengdu 610041, Peoples R China. RP Shi, TL (reprint author), East China Normal Univ, Ctr Bioinformat & Computat Biol, Shanghai Key Lab Regulatory Biol, Inst Biomed Sci, Shanghai 200241, Peoples R China.; Shi, TL (reprint author), East China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China.; Zhao, YX (reprint author), Guangxi Med Univ, Biol Targeting Diag & Therapy Res Ctr, Nanning 530021, Peoples R China.; Zhang, MX (reprint author), Sichuan Univ, West China Hosp, Dept Ophthalmol, Chengdu 610041, Peoples R China. EM yongxiangzhao@126.com; zhangmeixia@medmail.com.cn; tlshi@bio.ecnu.edu.cn FU China Human Proteomics Project [2014DFB30010]; National High Technology Research and Development Program of China [2015AA020104]; National Natural Science Foundation of China [31071162]; Graduate School of East China Normal University FX We would like to thank Li Zhang and Rong Cheng from East China Normal University for their helpful discussions. We are also grateful to the Supercomputer Center of East China Normal University. This work was supported by the China Human Proteomics Project (2014DFB30010), the National High Technology Research and Development Program of China (2015AA020104,), the National Natural Science Foundation of China (31071162), and the Graduate School of East China Normal University. NR 47 TC 1 Z9 1 U1 1 U2 1 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1674-7305 EI 1869-1889 J9 SCI CHINA LIFE SCI JI Sci. China-Life Sci. PD FEB PY 2017 VL 60 IS 2 BP 178 EP 188 DI 10.1007/s11427-015-0348-5 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EO7FF UT WOS:000396855900008 PM 27378339 ER PT J AU Miller, KL Woodcock, J AF Miller, Kathleen L. Woodcock, Janet TI Value Assessment in the Regulatory Context SO VALUE IN HEALTH LA English DT Article DE FDA; pharmaceuticals; regulation; value assessment ID SAFETY AB Value assessments are made on new drugs before they even enter the market. Regulators at the Center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration make a clinical benefit-risk assessment to determine whether to approve a new drug. Benefits of a drug are typically quantified directly, as an assessment of efficacy. CDER defines risk as the intersection of the severity of possible harm and the probability of that harm. For a novel drug to be approved, its benefits and risks must be well understood, and the trade-off between the two must be acceptable. To assist with these benefit-risk value assessments, CDER has two ongoing initiatives: the Patient-Focused Drug Development Initiative that aims to substantially increase the role of patient voice in the regulatory process, and a transparency initiative that focuses on creating a structured framework for benefit-risk assessment. C1 [Miller, Kathleen L.] US FDA, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Miller, Kathleen L.] Univ North Carolina Chapel Hill, Gillings Sch Global Publ Hlth, Dept Hlth Policy & Management, Chapel Hill, NC USA. [Woodcock, Janet] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Miller, KL (reprint author), US FDA, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Kathleen.miller@fda.hhs.gov NR 7 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 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD FEB PY 2017 VL 20 IS 2 BP 296 EP 298 DI 10.1016/j.jval.2016.11.010 PG 3 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA EO1HX UT WOS:000396450400022 PM 28237213 ER PT J AU Kamstrup, D Berthelsen, R Sassene, PJ Selen, A Mullertz, A AF Kamstrup, Danna Berthelsen, Ragna Sassene, Philip Jonas Selen, Arzu Mullertz, Anette TI In Vitro Model Simulating Gastro- Intestinal Digestion in the Pediatric Population (Neonates and Young Infants) SO AAPS PHARMSCITECH LA English DT Review DE digestion; in vitro models; oral drug delivery; pediatric ID LIPID-BASED FORMULATIONS; SALT-STIMULATED LIPASE; HEALTHY PRETERM INFANTS; COLIPASE-DEPENDENT LIPASE; DRUG-DELIVERY SYSTEMS; WATER-SOLUBLE DRUGS; ORAL DOSAGE FORMS; FED HUMAN-MILK; FAT DIGESTION; PANCREATIC LIPASE AB The focus on drug delivery for the pediatric population has been steadily increasing in the last decades. In terms of developing in vitro models simulating characteristics of the targeted pediatric population, with the purpose of predicting drug product performance after oral administration, it is important to simulate the gastro-intestinal conditions and processes the drug will encounter upon oral administration. When a drug is administered in the fed state, which is commonly the case for neonates, as they are typically fed every 3 h, the digestion of the milk will affect the composition of the fluid available for drug dissolution/solubilization. Therefore, in order to predict the solubilized amount of drug available for absorption, an in vitro model simulating digestion in the gastro-intestinal tract should be utilized. In order to simulate the digestion process and the drug solubilization taking place in vivo, the following aspects should be considered; physiologically relevant media, media volume, use of physiological enzymes in proper amounts, as well as correct pH and addition of relevant co-factors, e.g., bile salts and co-enzymes. Furthermore, physiological transit times and appropriate mixing should be considered and mimicked as close as possible. This paper presents a literature review on physiological factors relevant for digestion and drug solubilization in neonates. Based on the available literature data, a novel in vitro digestion model simulating digestion and drug solubilization in the neonate and young infant pediatric population (2 months old and younger) was designed. C1 [Kamstrup, Danna; Berthelsen, Ragna; Sassene, Philip Jonas; Mullertz, Anette] Univ Copenhagen, Dept Pharm, Copenhagen, Denmark. [Selen, Arzu] US FDA, Off Testing & Res, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Mullertz, Anette] Univ Copenhagen, Bioneer FARMA, Dept Pharm, Copenhagen, Denmark. RP Mullertz, A (reprint author), Univ Copenhagen, Dept Pharm, Copenhagen, Denmark.; Mullertz, A (reprint author), Univ Copenhagen, Bioneer FARMA, Dept Pharm, Copenhagen, Denmark. EM anette.mullertz@sund.ku.dk NR 110 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-9932 J9 AAPS PHARMSCITECH JI AAPS PharmSciTech PD FEB PY 2017 VL 18 IS 2 BP 317 EP 329 DI 10.1208/s12249-016-0649-1 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EO8EZ UT WOS:000396923200012 PM 27796909 ER PT J AU Gonzalez, EA Nandy, P Lucas, AD Hitchins, VM AF Gonzalez, Elizabeth A. Nandy, Poulomi Lucas, Anne D. Hitchins, Victoria M. TI Designing for cleanability: The effects of material, surface roughness, and the presence of blood test soil and bacteria on devices SO AMERICAN JOURNAL OF INFECTION CONTROL LA English DT Article DE Reusable medical device; Reprocessing; Synthetic soil; Bacterial adhesion ID ADHESION AB Cleaning reusable medical devices removes organic and inorganic soil, which allows for effective disinfection and sterilization. However, it is not always clear what variables to consider when validating cleaning. This study compared the ability of 3 different cleaning agents (ie, water, alcohol, and bleach) to remove bacteria ( ie, vegetative and spores) and artificial blood test soil from 2 common device materials: polypropylene and ultra-high-molecular-weight polyethylene. Therewas a complex interaction between bacteria, soil, and surface roughness. (C) 2017 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved. C1 [Gonzalez, Elizabeth A.; Nandy, Poulomi; Lucas, Anne D.; Hitchins, Victoria M.] US FDA, Lab Microbiol & Infect Control, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Nandy, P (reprint author), US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 64,Rm 4014, Silver Spring, MD 20993 USA. EM Poulomi.Nandy@fda.hhs.gov FU Research Participation Program at the Center for Device and Radiological Heath; US Food and Drug Administration's Medical Countermeasures Initiative and Critical Path FX This project was supported in part by an appointment to the Research Participation Program at the Center for Device and Radiological Heath 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. Additionally, this project was funded by the US Food and Drug Administration's Medical Countermeasures Initiative and Critical Path. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. The findings and conclusions in this article have not been formally disseminated by the US Food and Drug Administration and should not be construed to represent any Agency determination or policy. NR 10 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-6553 EI 1527-3296 J9 AM J INFECT CONTROL JI Am. J. Infect. Control PD FEB 1 PY 2017 VL 45 IS 2 BP 194 EP 196 DI 10.1016/j.ajic.2016.07.025 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA EO8IW UT WOS:000396933700017 PM 27776820 ER PT J AU Persoskie, A Ferrer, RA AF Persoskie, Alexander Ferrer, Rebecca A. TI A Most Odd Ratio: Interpreting and Describing Odds Ratios SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID RARE DISEASE ASSUMPTION; LOGISTIC-REGRESSION; RISK RATIOS; MISUSE AB Introduction: The OR is one of the most commonly used measures of association in preventive medicine, and yet it is unintuitive and easily misinterpreted by journal authors and readers. Methods: This article describes correct interpretations of ORs, explains how ORs are different from risk ratios (RRs), and notes potential supplements and alternatives to the presentation of ORs that may help readers avoid confusion about the strength of associations. Results: ORs are often interpreted as though they have the same meaning as RRs (i.e., ratios of probabilities rather than ratios of odds), an interpretation that is incorrect in cross-sectional and longitudinal analyses. Without knowing the base rate of the outcome event in such analyses, it is impossible to evaluate the size of the absolute or relative change in risk associated with an OR, and misinterpreting the OR as an RR leads to the overestimation of the effect size when the outcome event is common rather than rare in the study sample. In case-control analyses, whether an OR can be interpreted as an RR depends on how the controls were selected. Conclusions: Education, peer reviewer vigilance, and journal reporting standards concerning ORs may improve the clarity and accuracy with which this common measure of association is described and understood in preventive medicine and public health research. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine. C1 [Persoskie, Alexander] FDA Ctr Tobacco Prod, Off Sci, Silver Spring, MD USA. [Ferrer, Rebecca A.] NCI, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. RP Persoskie, A (reprint author), FDA Ctr Tobacco Prod, Bldg 71,Room G335,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM persoskie@gmail.com FU Intramural NIH HHS [Z99 CA999999] NR 26 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 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD FEB PY 2017 VL 52 IS 2 BP 224 EP 228 DI 10.1016/j.amepre.2016.07.030 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EO9DP UT WOS:000396989700013 PM 27639787 ER PT J AU Zhang, YC Cartmel, B Choy, CC Molinaro, AM Leffell, DJ Bale, AE Mayne, ST Ferrucci, LM AF Zhang, Yanchang Cartmel, Brenda Choy, Courtney C. Molinaro, Annette M. Leffell, David J. Bale, Allen E. Mayne, Susan T. Ferrucci, Leah M. TI LEBody mass index, height and early-onset basal cell carcinoma in a case-control study SO CANCER EPIDEMIOLOGY LA English DT Article DE Basal cell carcinoma; Non-melanoma skin cancer; Height; Body mass index; Epidemiology ID NONMELANOMA SKIN-CANCER; BODY-SURFACE AREA; MALIGNANT-MELANOMA; ANTHROPOMETRIC MEASURES; PROSPECTIVE COHORT; UNITED-STATES; RISK; WOMEN; OBESITY; METAANALYSIS AB Introduction: Basal cell carcinoma (BCC) is the most common malignancy in the US. Body mass index (BMI) and height have been associated with a variety of cancer types, yet the evidence regarding BCC is limited. Therefore, we evaluated BMI and height in relation to early-onset BCC (under age 40) and explored the potential role of ultraviolet (UV) radiation exposure and estrogen-related exposures in the BMI-BCC relationship. Methods: BCC cases (n = 377) were identified through a central dermatopathology facility in Connecticut. Control subjects (n = 389) with benign skin conditions were randomly sampled from the same database and frequency matched to cases on age (median = 36, interquartile range 33-39), gender, and biopsy site. Participants reported weight (usual adult and at age 18), adult height, sociodemographic, phenotypic, and medical characteristics, and prior UV exposures. We calculated multivariate odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models. Results: Adult BMI was inversely associated with early-onset BCC (obese vs. normal OR = 0.43, 95% CI = 0.26-0.71). A similar inverse association was present for BMI at age 18 (OR = 0.54, 95% CI = 0.34-0.85). Excluding UV exposures from the BMI models and including estrogen-related exposures among women only did not alter the association between BMI and BCC, indicating limited mediation or confounding. We did not observe an association between adult height and BCC (OR per cm = 1.00, 95% CI = 0.98-1.02). Conclusions: We found a significant inverse association between BMI and early-onset BCC, but no association between height and BCC. This association was not explained by UV exposures or estrogen-related exposures in women. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Zhang, Yanchang; Cartmel, Brenda; Choy, Courtney C.; Mayne, Susan T.; Ferrucci, Leah M.] Yale Sch Publ Hlth, 55 Coll St,Suite 801, New Haven, CT 06520 USA. [Cartmel, Brenda; Leffell, David J.; Bale, Allen E.; Mayne, Susan T.; Ferrucci, Leah M.] Yale Canc Ctr, New Haven, CT 06520 USA. [Molinaro, Annette M.] UCSF, Dept Neurol Surg, San Francisco, CA 94143 USA. [Molinaro, Annette M.] UCSF, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Leffell, David J.; Bale, Allen E.] Yale Univ, Sch Med, 333 Cedar St, New Haven, CT 06520 USA. [Mayne, Susan T.] US FDA, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. RP Ferrucci, LM (reprint author), Yale Sch Publ Hlth, 55 Coll St,Suite 801, New Haven, CT 06520 USA. EM leah.ferrucci@yale.edu FU National Institutes of Health [P50 CA121974R01 CA163687, UL1 RR024139]; Chronic Disease Epidemiology; Mentored Research Scholar Grant in Applied and Clinical Research; American Cancer Society [MRSG-13-016-01CPPB] FX This work was supported by the National Institutes of Health [P50 CA121974R01 CA163687, UL1 RR024139] and the Nancy Hildreth Memorial Fellowship in Chronic Disease Epidemiology. Leah M. Ferrucci, PhD, MPH was supported by a Mentored Research Scholar Grant in Applied and Clinical Research, MRSG-13-016-01CPPB from the American Cancer Society NR 51 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD FEB PY 2017 VL 46 BP 66 EP 72 DI 10.1016/j.canep.2016.12.007 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EO5BA UT WOS:000396706800011 PM 28039770 ER PT J AU Panackal, AA Komori, M Kosa, P Khan, O Hammoud, DA Rosen, LB Browne, SK Lin, YC Romm, E Ramaprasad, C Fries, BC Bennett, JE Bielekova, B Williamson, PR AF Panackal, Anil A. Komori, Mika Kosa, Peter Khan, Omar Hammoud, Dima A. Rosen, Lindsey B. Browne, Sarah K. Lin, Yen-Chih Romm, Elena Ramaprasad, Charu Fries, Bettina C. Bennett, John E. Bielekova, Bibiana Williamson, Peter R. TI Spinal Arachnoiditis as a Complication of Cryptococcal Meningoencephalitis in Non-HIV Previously Healthy Adults SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE Cryptococcus; cauda equina/conus syndromes; meningoencephalitis; spinal arachnoiditis; pulse corticosteroids ID PROGRESSIVE MULTIPLE-SCLEROSIS; DAMAGE-RESPONSE FRAMEWORK; SURROGATE END-POINTS; ADJUNCTIVE DEXAMETHASONE; MICROBIAL PATHOGENESIS; INFECTIOUS-DISEASES; CLINICAL-TRIALS; MENINGITIS; DETERMINANTS; OUTCOMES AB Background. Cryptococcus can cause meningoencephalitis (CM) among previously healthy non-HIV adults. Spinal arachnoiditis is under-recognized, since diagnosis is difficult with concomitant central nervous system (CNS) pathology. Methods. We describe 6 cases of spinal arachnoiditis among 26 consecutively recruited CM patients with normal CD4 counts who achieved microbiologic control. We performed detailed neurological exams, cerebrospinal fluid (CSF) immunophenotyping and biomarker analysis before and after adjunctive immunomodulatory intervention with high dose pulse corticosteroids, affording causal inference into pathophysiology. Results. All 6 exhibited severe lower motor neuron involvement in addition to cognitive changes and gait disturbances from meningoencephalitis. Spinal involvement was associated with asymmetric weakness and urinary retention. Diagnostic specificity was improved by MRI imaging which demonstrated lumbar spinal nerve root enhancement and clumping or lesions. Despite negative fungal cultures, CSF inflammatory biomarkers, sCD27 and sCD21, as well as the neuronal damage biomarker, neurofilament light chain (NFL), were elevated compared to healthy donor (HD) controls. Elevations in these biomarkers were associated with clinical symptoms and showed improvement with adjunctive high dose pulse corticosteroids. Conclusions. These data suggest that a post-infectious spinal arachnoiditis is an important complication of CM in previously healthy individuals, requiring heightened clinician awareness. Despite microbiological control, this syndrome causes significant pathology likely due to increased inflammation and may be amenable to suppressive therapeutics. C1 [Panackal, Anil A.; Rosen, Lindsey B.; Browne, Sarah K.; Bennett, John E.; Williamson, Peter R.] NIH, NIAID, Lab Clin Infect Dis LCID, Bethesda, MD USA. [Panackal, Anil A.; Bennett, John E.] Uniformed Serv Univ Hlth Sci USUHS, Hebert Sch Med, Dept Med, Div Infect Dis, Bethesda, MD USA. [Komori, Mika; Kosa, Peter; Lin, Yen-Chih; Romm, Elena; Bielekova, Bibiana] NIH, Natl Inst Neurol Dis & Stroke NINDS, Neuroimmunol Branch, Neuroimmunol Dis Unit, Bethesda, MD USA. [Khan, Omar] NIH, NINDS, Neurol Consult Serv, Bethesda, MD USA. [Hammoud, Dima A.] NIH Clin Ctr, Ctr Infect Dis Imaging, Radiol & Imaging Sci, Bethesda, MD USA. [Ramaprasad, Charu] Kaiser San Jose Med Ctr, Infectious Dis Kaiser, San Jose, CA USA. [Fries, Bettina C.] SUNY Stony Brook, Div Infect Dis, Stony Brook, NY USA. [Browne, Sarah K.] Food & Drug Adm, Ctr Biol Evaluat & Res, Div Vaccines & Related Product Applicat, Silver Spring, MD USA. RP Panackal, AA (reprint author), NIH, NIAID, LCID DIR, Staff Clin, Bldg 10,Rm 11N222,MSC 1888, Bethesda, MD 20892 USA. EM anil.panackal@nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID) [AI001123-01, AI001124-01]; National Institute of Neurological Diseases and Stroke at the National Institutes of Health (NIH); Intramural Research Program of the NIAID; [U01 AI109657] FX This research was supported by extramural grants AI001123-01 and AI001124-01 from the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Neurological Diseases and Stroke at the National Institutes of Health (NIH), and by the Intramural Research Program of the NIAID. Funding support was also obtained via U01 AI109657. NR 40 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 FEB 1 PY 2017 VL 64 IS 3 BP 275 EP 283 DI 10.1093/cid/ciw739 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP3RQ UT WOS:000397299800014 PM 28011613 ER PT J AU Eydelman, MB Tarver, ME Ferris, F AF Eydelman, Malvina B. Tarver, Michelle E. Ferris, Frederick, III TI Listening to the Patients-The Laser-Assisted In Situ Keratomileusis Quality of Life Collaboration Project SO JAMA OPHTHALMOLOGY LA English DT Editorial Material C1 [Eydelman, Malvina B.; Tarver, Michelle E.] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Ferris, Frederick, III] NEI, Bethesda, MD 20892 USA. RP Eydelman, MB (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM malvina.eydelman@fda.hhs.gov NR 3 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 FEB 1 PY 2017 VL 135 IS 2 BP 83 EP 84 DI 10.1001/jamaophthalmol.2016.4585 PG 2 WC Ophthalmology SC Ophthalmology GA EM9PE UT WOS:000395642800006 ER PT J AU Finkel, RS Bishop, KM Nelson, RM AF Finkel, Richard S. Bishop, Kathie M. Nelson, Robert M. TI Spinal Muscular Atrophy Type I: Is It Ethical to Standardize Supportive Care Intervention in Clinical Trials? SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE SMA; Werdnig-Hoffmann disease; clinical trial design; standard of care ID NATURAL-HISTORY; CONSENSUS STATEMENT; MANAGEMENT; INFANTS; SMA AB The natural history of spinal muscular atrophy type I (SMA-I) has changed as improved medical support has become available. With investigational drugs for spinal muscular atrophy now in clinical trials, efficient trial design focuses on enrolling recently diagnosed infants, providing best available supportive care, and minimizing subject variation. The quandary has arisen whether it is ethically appropriate to specify a predefined level of nutritional and/or ventilation support for spinal muscular atrophy type I subjects while participating in these studies. We conducted a survey at 2 spinal muscular atrophy investigator meetings involving physician investigators, clinical evaluators, and study coordinators from North America, Europe, and Asia-Pacific. Each group endorsed the concept that having a predefined degree of nutritional and ventilation support was warranted in this context. We discuss how autonomy, beneficence/non-maleficence, noncoercion, social benefit, and equipoise can be maintained when a predefined level of supportive care is proposed, for participation in a clinical trial. C1 [Finkel, Richard S.] Nemours Childrens Hosp, Div Neurol, 13535 Nemours Pkwy, Orlando, FL 32827 USA. [Bishop, Kathie M.] Tioga Pharmaceut, San Diego, CA USA. [Nelson, Robert M.] US FDA, Silver Spring, MD USA. RP Finkel, RS (reprint author), Nemours Childrens Hosp, Div Neurol, 13535 Nemours Pkwy, Orlando, FL 32827 USA. EM rfinkel@nemours.org FU Intramural FDA HHS [FD999999] NR 17 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 0883-0738 EI 1708-8283 J9 J CHILD NEUROL JI J. Child Neurol. PD FEB PY 2017 VL 32 IS 2 BP 155 EP 160 DI 10.1177/0883073816671236 PG 6 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA EP2LC UT WOS:000397213600001 PM 27760875 ER PT J AU Katz, LM AF Katz, Linda M. TI Reporting adverse events related to cosmetic products SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter C1 [Katz, Linda M.] Ctr Food Safety & Appl Nutr, US Food & Drug Adm, College Pk, MD 20740 USA. RP Katz, LM (reprint author), Ctr Food Safety & Appl Nutr, US Food & Drug Adm, College Pk, MD 20740 USA. EM linda.katz@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD FEB PY 2017 VL 76 IS 2 BP E61 EP E61 DI 10.1016/j.jaad.2016.07.062 PG 1 WC Dermatology SC Dermatology GA EO7YC UT WOS:000396905000009 PM 28089016 ER PT J AU Kranz, S Dodd, KW Juan, WY Johnson, LK Jahns, L AF Kranz, Sibylle Dodd, Kevin W. Juan, Wen Yen Johnson, Luann K. Jahns, Lisa TI Whole Grains Contribute Only a Small Proportion of Dietary Fiber to the US Diet SO NUTRIENTS LA English DT Article DE whole grain intake; dietary fiber; nutrition monitoring; Dietary Guidelines for Americans; healthy diet; sources of dietary fiber ID NUTRITION EXAMINATION SURVEY; NATIONAL-HEALTH; CARDIOVASCULAR-DISEASE; FOOD SOURCES; BODY-WEIGHT; ENERGY; CONSUMPTION; BENEFITS; OBESITY; ADULTS AB Dietary fiber (DF), found in whole fruits, vegetables, and whole grains (WG), is considered a nutrient of concern in the US diet and increased consumption is recommended. The present study was designed to highlight this critical importance of the difference between WG, high-fiber WG, and sources of fiber that are not from WG. The study is based on the two-day diets reported consumed by the nationally representative sample of Americans participating in What We Eat In America, the dietary component of the National Health and Nutrition Examination Survey from 2003-2010. Foods consumed were classified into tertiles of DF and WG and the contribution of fiber by differing levels of WG content were examined. Foods containing high amounts of WG and DF only contributed about 7% of total fiber intake. Overall, grain-based foods contributed 54.5% of all DF consumed. Approximately 39% of DF came from grain foods that contained no WG, rather these foods contained refined grains, which contain only small amounts of DF but are consumed in large quantities. All WG-containing foods combined contributed a total of 15.3% of DF in the American diet. Thus, public health messaging needs to be changed to specifically encourage consumption of WG foods with high levels of DF to address both recommendations. C1 [Kranz, Sibylle] Univ Virginia, Dept Kinesiol, Charlottesville, VA 22904 USA. [Dodd, Kevin W.] Natl Canc Inst, Bethesda, MD 20892 USA. [Juan, Wen Yen] US FDA, Nutr Assessment & Evaluat, Off Nutr & Food Labeling, Ctr Food & Appl Nutr, College Pk, MD 20740 USA. [Johnson, Luann K.; Jahns, Lisa] USDA, Agr Res Serv, Grand Forks Human Nutr Res Ctr, Grand Forks, ND 58203 USA. RP Kranz, S (reprint author), Univ Virginia, Dept Kinesiol, Charlottesville, VA 22904 USA. EM sibylle.kranz@virginia.edu; doddk@mail.nih.gov; wenyen.juan@fda.hhs.gov; luann.johnson@ars.usda.gov; lisa.jahns@ars.usda.gov FU USDA/Agricultural Research Service [USDA 3062-51000-051-00D]; Kellogg Citizenship Fund FX Financial support was provided by the USDA/Agricultural Research Service, (USDA 3062-51000-051-00D) and The Kellogg Citizenship Fund. NR 36 TC 0 Z9 0 U1 0 U2 0 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2072-6643 J9 NUTRIENTS JI Nutrients PD FEB PY 2017 VL 9 IS 2 AR 153 DI 10.3390/nu9020153 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EO9QL UT WOS:000397023100066 ER PT J AU Hampp, C Pippins, J AF Hampp, Christian Pippins, Jennifer TI Pioglitazone and bladder cancer: FDA's assessment SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Editorial Material C1 [Hampp, Christian] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Pippins, Jennifer] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Hampp, C (reprint author), US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM christian.hampp@fda.hhs.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY 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 FEB PY 2017 VL 26 IS 2 BP 117 EP 118 DI 10.1002/pds.4154 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA EP3KO UT WOS:000397281400001 PM 28067434 ER PT J AU Secora, A Trinidad, JP Zhang, RM Gill, R Dal Pan, G AF Secora, Alex Trinidad, James Phillip Zhang, Rongmei Gill, Rajdeep Dal Pan, Gerald TI Drug availability adjustments in population-based studies of prescription opioid abuse SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE drug abuse; drug utilization; opioid; epidemiologic study; denominators; pharmacoepidemiology ID EMERGENCY-DEPARTMENT VISITS; NONMEDICAL USE; FORMULATIONS; DETERRENT; TRENDS AB Purpose Population-based prescription opioid abuse studies in which one drug is compared to another, or drugs are compared across time, often account for the availability of those drugs in the community. The objective of this investigation is to assess consistency in the relative abuse ratios (RARs) across different approaches for adjusting for drug availability. Methods For the years 2004 through 2010, RARs for each of four prescription opioids (hydrocodone, oxycodone, hydromorphone, and morphine) were calculated using negative binomial regression. Measures of abuse (outcome) were misuse/abuse-related emergency department visits obtained from the Drug Abuse Warning Network. Measures of drug availability (offsets) were drug utilization estimates obtained from IMS Health. Separate regression models were run using each of five measures of drug utilization: unique patients (URDD), prescriptions dispensed (RX), tablets dispensed (TD), kilograms (KGs) sold, and morphine-equivalents (MEs) of kilograms sold. These results were compared for consistency. Results Aside from oxycodone-combination products, across molecules, RARs adjusted by RXs, TDs, and URDDs were generally similar to each other while RARs adjusted by KGs and MEs were different. For example, compared to hydrocodone, oxycodone had statistically significantly increased RARs of 3.6 (95% CI: 2.0-6.5), 3.5 (95% CI: 1.9-6.4), and 2.7 (95% CI: 1.5-5.0) when adjusted by URDDs, RXs, and TDs, respectively, but not when adjusted by KGs or MEs. Conclusions Different drug utilization adjustment approaches may yield inconsistent RAR estimates in population-based prescription opioid abuse analyses. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Secora, Alex; Trinidad, James Phillip; Gill, Rajdeep; Dal Pan, Gerald] US FDA, Off Surveillance & Epidemiol, Div Epidemiol, CDER, Rockville, MD 20857 USA. [Zhang, Rongmei] US FDA, Off Biostat, Div Biometr 7, CDER, Rockville, MD 20857 USA. RP Secora, A; Trinidad, JP (reprint author), WO22,Room 2465 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM alex.secora@fda.hhs.gov; james.trinidad@fda.hhs.gov FU United States Food and Drug Administration (FDA) FX This study was supported by the United States Food and Drug Administration (FDA), and includes commercial proprietary drug utilization data obtained by FDA under contract. All authors of this manuscript worked for FDA when this study was conducted and do not have any financial conflicts of interest to disclose. The views expressed in this manuscript represent the opinions of the authors and do not necessarily represent the views of FDA. NR 20 TC 0 Z9 0 U1 0 U2 0 PU WILEY 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 FEB PY 2017 VL 26 IS 2 BP 180 EP 191 DI 10.1002/pds.4139 PG 12 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA EP3KO UT WOS:000397281400009 PM 28000295 ER PT J AU Gelperin, K Hammad, H Leishear, K Bird, ST Taylor, L Hampp, C Sahin, L AF Gelperin, Kate Hammad, Hoda Leishear, Kira Bird, Steven T. Taylor, Lockwood Hampp, Christian Sahin, Leyla TI A systematic review of pregnancy exposure registries: examination of protocol-specified pregnancy outcomes, target sample size, and comparator selection SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Review DE pregnancy registry; teratogen; birth defect; congenital malformation; pharmacoepidemiology ID 1ST TRIMESTER; MEDICATIONS; LAMOTRIGINE; TERATOGENICITY; TOPIRAMATE; RISK AB Purpose Our study sought to systematically evaluate protocol-specified study methodology in prospective pregnancy exposure registries including pre-specified pregnancy outcomes, power calculations for sample size, and comparator group selection. Methods U.S. pregnancy exposure registries designed to evaluate safety of drugs or biologics were identified from www.clinicaltrials.gov, the FDA's Office of Women's Health website, and the FDA's list of postmarketing studies. Protocols or similar documentation were obtained. Results We identified 35 U.S. registries for drugs or biologic use during pregnancy. All registries assessed risk for overall major congenital malformations. Pre-specified target enrollment was stated for 18 (51%) registries, and ranged from 150 to 500 exposed pregnancies (median 300). Thirty-two (91%) registries identified at least one comparison group, but only nine (26%) planned to use an internal comparator. The most common external comparator group (n = 24, 69%) was the Metropolitan Atlanta Congenital Defects Program (MACDP). Conclusions No registries were designed to have sufficient power to assess specific malformations, despite the plausibility that most teratogens cause specific defects. Only half of the registries included a power analysis. Despite their common use, external comparators, including MACDP, have important limitations. In the absence of randomized controlled trial data in pregnant women, pregnancy registries remain an important tool as part of a comprehensive pregnancy surveillance program; however, pregnancy registries alone may not be sufficient to obtain adequate data regarding risks of specific malformations. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Gelperin, Kate; Hammad, Hoda; Leishear, Kira; Bird, Steven T.; Taylor, Lockwood; Hampp, Christian] US FDA, CDER, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Sahin, Leyla] US FDA, CDER, Off New Drugs, Silver Spring, MD USA. RP Gelperin, K (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Kate.Gelperin@fda.hhs.gov FU U.S. Food and Drug Administration (FDA); FDA Office of Women's Health FX Funding for this study came from the U.S. Food and Drug Administration (FDA) and was supported in part by the FDA Office of Women's Health through a research fellowship administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the FDA. NR 28 TC 0 Z9 0 U1 0 U2 0 PU WILEY 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 FEB PY 2017 VL 26 IS 2 BP 208 EP 214 DI 10.1002/pds.4150 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA EP3KO UT WOS:000397281400012 PM 28028914 ER PT J AU Jo, CL Ambs, A Dresler, CM Backinger, CL AF Jo, Catherine L. Ambs, Anita Dresler, Carolyn M. Backinger, Cathy L. TI Child-resistant and tamper-resistant packaging: A systematic review to inform tobacco packaging regulation SO PREVENTIVE MEDICINE LA English DT Review DE Child safety; Child-resistant; Product packaging; Special packaging; Tamper-resistant ID ORAL PRESCRIPTION DRUGS; TEXAS POISON CENTERS; ELECTRONIC CIGARETTES; EXPOSURES; EXPERIENCE; MEDICATION; MOUTHWASH; QUALITY; LIQUID; ADULTS AB Objective. We aimed to investigate the effects of special packaging (child-resistant, adult-friendly) and tamper- resistant packaging on health and behavioral outcomes in order to identify research gaps and implications for packaging standards for tobacco products. Methods. We searched seven databases for keywords related to special and tamper-resistant packaging, consulted experts, and reviewed citations of potentially relevant studies. 733 unique papers were identified. Two coders independently screened each title and abstract for eligibility. They then reviewed the full text of the remaining papers for a second round of eligibility screening. Included studies investigated a causal relationship between type of packaging or packaging regulation and behavioral or health outcomes and had a study population composed of consumers. Studies were excluded on the basis of publication type, if they were not peer-reviewed, and if they had low external validity. Two reviewers independently coded each paper for study and methodological characteristics and limitations. Discrepancies were discussed and resolved. Results. The review included eight studies: four assessing people's ability to access the contents of different packaging types and four evaluating the impact of packaging requirements on health-related outcomes. Child-resistant packaging was generally more difficult to open than non-child-resistant packaging. Child-resistant packaging requirements have been associated with reductions in child mortality. Conclusions. Child-resistant packaging holds the expectation to reduce tobacco product poisonings among children under six. Published by Elsevier Inc. C1 [Jo, Catherine L.] Univ N Carolina, Dept Hlth Behav, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Ambs, Anita; Dresler, Carolyn M.; Backinger, Cathy L.] US FDA, Off Sci, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Ambs, A (reprint author), US FDA, Off Sci, Ctr Tobacco Prod, Document Control Ctr, Bldg 71,G335,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM anita.ambs@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 47 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 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD FEB PY 2017 VL 95 IS 1 BP 89 EP 95 DI 10.1016/j.ypmed.2016.11.013 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EP3SY UT WOS:000397303200012 PM 27939602 ER PT J AU King, RL Liu, Y Harris, GR AF King, Randy L. Liu, Yunbo Harris, Gerald R. TI QUANTIFICATION OF TEMPERATURE RISE WITHIN THE LENS OF THE PORCINE EYE CAUSED BY ULTRASOUND INSONATION SO ULTRASOUND IN MEDICINE AND BIOLOGY LA English DT Article DE Ultrasound; Ophthalmic; Safety; Porcine; Temperature rise; Eye; Lens ID ATTENUATION; HYDROPHONE AB The soft tissue thermal index defined in the Output Display Standard is not applicable to eye exposures because of unique eye properties such as high ultrasound absorption in the lens and orbital fat. To address this potential safety issue, the U.S. Food and Drug Administration has recommended a maximum exposure level for ophthalmic exams of 50 mW/cm(2) (derated spatial-peak temporal-average intensity, I-SPTA.3) based on a model of ultrasound propagation in the eye. To gain a better understanding of actual temperature rise as a function of I-SPTA.3, an ex vivo experimental study within the porcine lens was performed. Both temperature and acoustic pressure were measured simultaneously in the lens using a fiberoptic probe. At I-SPTA.3 = 50 mW/cm(2), the maximum and average temperature rises over 133 measurements were 0.23 degrees C and 0.09 degrees C, respectively. A 1.5 degrees C temperature rise was not obtained until ISPTA.3 approximate to 435 mW/cm(2). The data indicate that operating below the Food and Drug Administration guidance level should result in relatively low heating in ophthalmic exposures. (E-mail: rlkingku@gmail.com or Randy.King@fda.hhs.gov or rlkingku@yahoo.com) (C) 2016 World Federation for Ultrasound in Medicine & Biology. C1 [King, Randy L.; Liu, Yunbo; Harris, Gerald R.] Div Appl Mech, US Food & Drug Adm, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD USA. RP King, RL (reprint author), CDRH OSEL DAM, US Food & Drug Adm, Bldg 62,Room 2217,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM rlkingku@gmail.com NR 17 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 0301-5629 EI 1879-291X J9 ULTRASOUND MED BIOL JI Ultrasound Med. Biol. PD FEB PY 2017 VL 43 IS 2 BP 476 EP 481 DI 10.1016/j.ultrasmedbio.2016.09.021 PG 6 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA EP1QB UT WOS:000397158300011 PM 27817969 ER PT J AU Bulik, CC Okusanya, OO Lakota, EA Forrest, A Bhavnani, SM Hoover, JL Andes, DR Ambrose, PG AF Bulik, Catharine C. Okusanya, Olanrewaju O. Lakota, Elizabeth A. Forrest, Alan Bhavnani, Sujata M. Hoover, Jennifer L. Andes, David R. Ambrose, Paul G. TI Pharmacokinetic-Pharmacodynamic Evaluation of Gepotidacin against Gram-Positive Organisms Using Data from Murine Infection Models SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article DE Staphylococcus aureus; Streptococcus pneumoniae; gepotidacin ID ANTIMICROBIAL SURVEILLANCE PROGRAM; COMMUNITY-ACQUIRED PNEUMONIA; UNITED-STATES; THIGH; MICE AB Gepotidacin (formerly called GSK2140944) is a novel triazaacenaphthylene bacterial topoisomerase inhibitor with in vitro activity against conventional and biothreat pathogens, including Staphylococcus aureus and Streptococcus pneumoniae. Using neutropenic murine thigh and lung infection models, the pharmacokinetics-pharmacodynamics (PK-PD) of gepotidacin against S. aureus and S. pneumoniae were characterized. Candidate models were fit to single-dose PK data from uninfected mice (for doses of 16 to 128 mg/kg of body weight given subcutaneously [s.c.]). Dose fractionation studies (1 isolate/organism; 2 to 512 mg/kg/day) and dose-ranging studies (5 isolates/organism; 2 to 2,048 mg/kg/day; MIC ranges of 0.5 to 2 mg/liter for S. aureus and 0.125 to 1 mg/liter for S. pneumoniae) were conducted. The presence of an in vivo postantibiotic effect (PAE) was also evaluated. Relationships between the change from baseline in log(10) CFU at 24 h and the ratio of the free-drug plasma area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio), the ratio of the maximum concentration of drug in plasma (Cmax) to the MIC (Cmax/MIC ratio), and the percentage of a 24-h period that the drug concentration exceeded the MIC (% T>MIC) were evaluated using Hill-type models. Plasma and epithelial lining fluid (ELF) PK data were best fit by a four-compartment model with linear distributional clearances, a capacity-limited clearance, and a first-order absorption rate. The ELF penetration ratio in uninfected mice was 0.65. Since the growth of both organisms was poor in the murine lung infection model, lung efficacy data were not reported. As determined using the murine thigh infection model, the free-drug plasma AUC/MIC ratio was the PK-PD index most closely associated with efficacy (r(2) = 0.936 and 0.897 for S. aureus and S. pneumoniae, respectively). Median free-drug plasma AUC/MIC ratios of 13.4 and 58.9 for S. aureus, and 7.86 and 16.9 for S. pneumoniae, were associated with net bacterial stasis and a 1-log(10) CFU reduction from baseline, respectively. Dose-independent PAE durations of 3.07 to 12.5 h and 5.25 to 8.46 h were demonstrated for S. aureus and S. pneumoniae, respectively. C1 [Bulik, Catharine C.; Okusanya, Olanrewaju O.; Lakota, Elizabeth A.; Forrest, Alan; Bhavnani, Sujata M.; Ambrose, Paul G.] Inst Clin Pharmacodynam, Schenectady, NY 12305 USA. [Hoover, Jennifer L.] GlaxoSmithKline, Collegeville, PA USA. [Andes, David R.] Univ Wisconsin, Madison, WI USA. [Okusanya, Olanrewaju O.] US FDA, Silver Spring, MD USA. RP Ambrose, PG (reprint author), Inst Clin Pharmacodynam, Schenectady, NY 12305 USA. EM PAmbrose@ICPD.com OI Hoover, Jennifer/0000-0001-6769-7541 FU GlaxoSmithKline, Collegeville, PA; Defense Threat Reduction Agency [HDTRA1-07-9-0002] FX This study was undertaken with funds supplied by GlaxoSmithKline, Collegeville, PA. This project has been funded in whole or in part with federal funds awarded by the Defense Threat Reduction Agency under agreement HDTRA1-07-9-0002. NR 26 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 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD FEB PY 2017 VL 61 IS 2 AR e00115-16 DI 10.1128/AAC.00115-16 PG 12 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA EK7JQ UT WOS:000394102500001 ER PT J AU Burton, RL Antonello, J Cooper, D Goldblatt, D Kim, KH Plikaytis, BD Roalfe, L Wauters, D Williams, F Xie, GL Nahm, MH Akkoyunlu, M AF Burton, R. L. Antonello, J. Cooper, D. Goldblatt, D. Kim, K. H. Plikaytis, B. D. Roalfe, L. Wauters, D. Williams, F. Xie, G. L. Nahm, M. H. Akkoyunlu, M. TI Assignment of Opsonic Values to Pneumococcal Reference Serum 007sp for Use in Opsonophagocytic Assays for 13 Serotypes SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article DE 007sp; OPA; opsonic; pneumococcus; standardization ID FUNCTIONAL ANTIBODY-ACTIVITY; LINKED-IMMUNOSORBENT-ASSAY; STREPTOCOCCUS-PNEUMONIAE; CONJUGATE VACCINE; OLDER-ADULTS; CAPACITY; INFANTS AB Opsonophagocytic assays (OPAs) are routinely used for assessing the immunogenicity of pneumococcal vaccines, with OPA data often being utilized for licensure of new vaccine formulations. However, no reference serum for pneumococcal OPAs is available, making evaluation of data among different laboratories difficult. This international collaboration was initiated to (i) assign consensus opsonic indexes (OIs) to FDA pneumococcal reference serum lot 007sp (here referred to as 007sp) and a panel of serum samples used for calibration of the OPA and (ii) determine if the normalization of the OPA results obtained with test samples to those obtained with 007sp decreases the variability in OPA results among laboratories. To meet these goals, six participating laboratories tested a panel of serum samples in five runs for 13 serotypes. For each serum sample, consensus OIs were obtained using a mixed-effects analysis of variance model. For the calibration serum samples, normalized consensus values were also determined on the basis of the results obtained with 007sp. For each serotype, the overall reduction in interlaboratory variability was calculated by comparing the coefficients of variation of the unadjusted and the normalized values. Normalization of the results substantially reduced the interlaboratory variability, ranging from a 15% reduction in variability for serotype 9V to a 64% reduction for serotype 7F. Normalization also increased the proportion of data within 2-fold of the consensus value from approximately 70% (average for all serotypes) to >90%. On the basis of the data obtained in this study, pneumococcal reference standard lot 007sp will likely be a useful reagent for the normalization of pneumococcal OPA results from different laboratories. The data also support the use of the 16 FDA serum samples used for calibration of the OPA as part of the initial evaluation of new assays or periodic assessment of established assays. C1 [Burton, R. L.; Nahm, M. H.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Antonello, J.] Merck & Co Inc, Dept Biometr Res, West Point, PA USA. [Cooper, D.] Pfizer, Pfizer Vaccine Res, Pearl River, NY USA. [Goldblatt, D.; Roalfe, L.] UCL Inst Child Hlth, London, England. [Kim, K. H.] Ewha Womans Univ, Sch Med, Dept Pediat, Seoul, South Korea. [Kim, K. H.] Ewha Womans Univ, Sch Med, Ctr Vaccine Evaluat & Study, Seoul, South Korea. [Wauters, D.] GSK Vaccines, Rixensart, Belgium. [Williams, F.; Akkoyunlu, M.] US FDA, CBER, Silver Spring, MD USA. [Xie, G. L.] Lanzhou Inst Biol Prod, Lanzhou, Peoples R China. [Plikaytis, B. D.] BioStat Consulting LLC, Atlanta, GA USA. RP Nahm, MH (reprint author), Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA.; Akkoyunlu, M (reprint author), US FDA, CBER, Silver Spring, MD USA. EM mnahm@uabmc.edu; Mustafa.Akkoyunlu@fda.hhs.gov FU NIH [HHSN272201200005C, 11172MFDS360]; UK National Institute for Health Research FX This work was funded by NIH contract HHSN272201200005C (to M.H.N.), 11172MFDS360 (to K.H.K.), and the UK National Institute for Health Research (to D.G.). NR 17 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 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD FEB PY 2017 VL 24 IS 2 AR UNSP e00457-16 DI 10.1128/CVI.00457-16 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EK9DO UT WOS:000394224400005 ER PT J AU Moro, P Baumblatt, J Lewis, P Cragan, J Tepper, N Cano, M AF Moro, Pedro Baumblatt, Jane Lewis, Paige Cragan, Janet Tepper, Naomi Cano, Maria TI Surveillance of Adverse Events After Seasonal Influenza Vaccination in Pregnant Women and Their Infants in the Vaccine Adverse Event Reporting System, July 2010-May 2016 SO DRUG SAFETY LA English DT Article ID NEONATAL OUTCOMES; SAFETY; IMMUNIZATION; STILLBIRTH; IMPACT; BIRTH; VAERS AB Introduction Routine immunization of pregnant women with seasonal inactivated influenza vaccines (IIVs) is recommended in all trimesters of pregnancy. A review of the Vaccine Adverse Event Reporting System (VAERS) during 1990-2009 did not find any unexpected patterns of pregnancy complications or fetal outcomes after administration of IIV or live attenuated influenza vaccines (LAIVs). During the 2009-2010 pandemic influenza A (H1N1) vaccination campaign, a study noted that the number of VAERS reports from pregnant women who received the H1N1 2009 inactivated monovalent vaccine (n = 288) increased compared with 1990-2009 seasonal IIV pregnancy reports (n = 148). Objectives The objective of this study was to assess the safety of seasonal influenza vaccines in pregnant women and their infants whose reports were submitted to VAERS during 2010-2016. Methods We searched VAERS for US reports of adverse events (AEs) in pregnant women who received IIV or LAIV from 1 July 2010 through 6 May 2016. Clinicians reviewed reports and available medical records and assigned a primary clinical category for each report. Reports were coded as serious based on the Code of Federal Regulations. Results We identified 671 reports after seasonal influenza vaccines administered to pregnant women: 544 after IIV and 127 after LAIV. Serious events occurred among 61 (11.2%) reports following IIV and one (0.8%) report following LAIV. No deaths were reported. Among reports with trimester information (n = 296), IIV was administered during the first trimester in 116 (39.2%). Among IIV reports, the most frequent pregnancy-specific AE was spontaneous abortion in 62 (11.4%) reports, followed by stillbirth in ten (1.8%) and preterm delivery in six (1.1%). The most common non-pregnancy-specific AEs were injection-site reactions (55 [10.1%]). Neonatal or infant outcomes were reported in 22 (4.0%) reports, seven of which had major birth defects of different types and no neonatal deaths. Conclusion As in 2009-2010, no new or unexpected patterns in maternal or fetal outcomes were observed during 2010-2016. C1 [Moro, Pedro; Lewis, Paige; Cano, Maria] Ctr Dis Control & Prevent CDC, Immunizat Safety Off, Div Healthcare Qual Promot, NCEZID, 1600 Clifton Rd,MS D26, Atlanta, GA 30329 USA. [Baumblatt, Jane] US FDA, Div Epidemiol, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Cragan, Janet] CDC, Birth Defects Branch, Div Congenital & Dev Disabil, NCBDDD, Atlanta, GA 30333 USA. [Tepper, Naomi] CDC, Womens Hlth & Fertil Branch, Div Reprod Hlth, NCCDPHP, Atlanta, GA 30333 USA. RP Moro, P (reprint author), Ctr Dis Control & Prevent CDC, Immunizat Safety Off, Div Healthcare Qual Promot, NCEZID, 1600 Clifton Rd,MS D26, Atlanta, GA 30329 USA. EM pmoro@cdc.gov NR 25 TC 0 Z9 0 U1 0 U2 0 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0114-5916 EI 1179-1942 J9 DRUG SAFETY JI Drug Saf. PD FEB PY 2017 VL 40 IS 2 BP 145 EP 152 DI 10.1007/s40264-016-0482-1 PG 8 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA EL1ZB UT WOS:000394418800007 PM 27988883 ER PT J AU Iwamoto, M Reynolds, J Karp, BE Tate, H Fedorka-Cray, PJ Plumblee, JR Hoekstra, RM Whichard, JM Mahon, BE AF Iwamoto, Martha Reynolds, Jared Karp, Beth E. Tate, Heather Fedorka-Cray, Paula J. Plumblee, Jodie R. Hoekstra, Robert M. Whichard, Jean M. Mahon, Barbara E. TI Ceftriaxone-Resistant Nontyphoidal Salmonella from Humans, Retail Meats, and Food Animals in the United States, 1996-2013 SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article DE Salmonella; antimicrobial resistance; foodborne disease; cephalosporin ID ENTERICA SEROVAR HEIDELBERG; AMPC BETA-LACTAMASE; MULTIDRUG-RESISTANT; NEWPORT INFECTIONS; OUTBREAK; TYPHIMURIUM; EMERGENCE; PLASMIDS AB Background: Ceftriaxone resistance in Salmonella is a serious public health threat. Ceftriaxone is commonly used to treat severe Salmonella infections, especially in children. Identifying the sources and drivers of ceftriaxone resistance among nontyphoidal Salmonella is crucial. Materials and Methods: The National Antimicrobial Resistance Monitoring System (NARMS) tracks antimicrobial resistance in foodborne and other enteric bacteria from humans, retail meats, and food animals. We examined NARMS data reported during 1996-2013 to characterize ceftriaxone-resistant Salmonella infections in humans. We used Spearman rank correlation to examine the relationships between the annual percentage of ceftriaxone resistance among Salmonella isolates from humans with isolates from retail meats and food animals. Results: A total of 978 (2.9%) of 34,100 nontyphoidal Salmonella isolates from humans were resistant to ceftriaxone. Many (40%) ceftriaxone-resistant isolates were from children younger than 18 years. Most ceftriaxone-resistant isolates were one of three serotypes: Newport (40%), Typhimurium (26%), or Heidelberg (12%). All were resistant to other antimicrobials, and resistance varied by serotype. We found statistically significant correlations in ceftriaxone resistance between human and ground beef Newport isolates (r = 0.83), between human and cattle Typhimurium isolates (r = 0.57), between human and chicken Heidelberg isolates (r = 0.65), and between human and turkey Heidelberg isolates (r = 0.67). Conclusions: Ceftriaxone resistance among Salmonella Newport, Typhimurium, and Heidelberg isolates from humans strongly correlates with ceftriaxone resistance in isolates from ground beef, cattle, and poultry, respectively. These findings support other lines of evidence that food animals are important reservoirs of ceftriaxone-resistant Salmonella that cause human illness in the United States. C1 [Iwamoto, Martha; Reynolds, Jared; Karp, Beth E.; Hoekstra, Robert M.; Whichard, Jean M.; Mahon, Barbara E.] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, 1600 Clifton Rd NE,Mailstop C-09, Atlanta, GA 30333 USA. [Tate, Heather] US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, Laurel, MD USA. [Fedorka-Cray, Paula J.; Plumblee, Jodie R.] ARS, Bacterial Epidemiol & Antimicrobial Resistance Re, USDA, Athens, GA USA. [Fedorka-Cray, Paula J.] North Carolina State Univ, Coll Vet Med, Dept Populat Hlth & Pathobiol, Raleigh, NC USA. RP Iwamoto, M; Reynolds, J (reprint author), Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, 1600 Clifton Rd NE,Mailstop C-09, Atlanta, GA 30333 USA. EM miwamoto@cdc.gov; jreynolds3@cdc.gov NR 44 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 FEB PY 2017 VL 14 IS 2 BP 74 EP 83 DI 10.1089/fpd.2016.2180 PG 10 WC Food Science & Technology SC Food Science & Technology GA EL0ST UT WOS:000394332800002 PM 27860517 ER PT J AU Kim, HS Choi, D Kang, IB Kim, DH Yim, JH Kim, YJ Chon, JW Oh, DH Seo, KH AF Kim, Hong-Seok Choi, Dasom Kang, Il-Byeong Kim, Dong-Hyeon Yim, Jin-Hyeok Kim, Young-Ji Chon, Jung-Whan Oh, Deog-Hwan Seo, Kun-Ho TI A Single-Step Enrichment Medium for Nonchromogenic Isolation of Healthy and Cold-Injured Salmonella spp. from Fresh Vegetables SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article DE foodborne disease; vegetables; rapid detection; Salmonella ID VIBRIO-PARAHAEMOLYTICUS; LISTERIA-MONOCYTOGENES; FOODBORNE ILLNESS; RECOVERY; SAMPLES; GROWTH; BROTH; PCR AB Culture-based detection of nontyphoidal Salmonella spp. in foods requires at least four working days; therefore, new detection methods that shorten the test time are needed. In this study, we developed a novel single-step Salmonella enrichment broth, SSE-1, and compared its detection capability with that of commercial single-step ONE broth-Salmonella (OBS) medium and a conventional two-step enrichment method using buffered peptone water and Rappaport-Vassiliadis soy broth (BPW-RVS). Minimally processed lettuce samples were artificially inoculated with low levels of healthy and cold-injured Salmonella Enteritidis (10(0) or 10(1) colony-forming unit/25 g), incubated in OBS, BPW-RVS, and SSE-1 broths, and streaked on xylose lysine deoxycholate (XLD) agar. Salmonella recoverability was significantly higher in BPW-RVS (79.2%) and SSE-1 (83.3%) compared to OBS (39.3%) (p < 0.05). Our data suggest that the SSE-1 single-step enrichment broth could completely replace two-step enrichment with reduced enrichment time from 48 to 24 h, performing better than commercial single-step enrichment medium in the conventional nonchromogenic Salmonella detection, thus saving time, labor, and cost. C1 [Kim, Hong-Seok; Choi, Dasom; Kang, Il-Byeong; Kim, Dong-Hyeon; Yim, Jin-Hyeok; Kim, Young-Ji; Chon, Jung-Whan; Seo, Kun-Ho] Konkuk Univ, Coll Vet Med, Ctr One Hlth, Seoul 143701, South Korea. [Oh, Deog-Hwan] Kangwon Natl Univ, Sch Bioconvergence Sci & Technol, Dept Food Sci & Biotechnol, Chunchon, Gangwon, 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, Ctr One Hlth, Seoul 143701, South Korea. EM bracstu3@konkuk.ac.kr FU 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]; Export Promotion Technology Development Program of IPET - Ministry for Food, Agriculture, Forestry, and Fisheries [313010-3]; National Research Foundation of Korea (NRF) - Korea government (MSIP) [2015R1A2A2A05001288] FX This work was supported by 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, funded by Ministry of Agriculture, Food and Rural Affairs (MAFRA) (716002-7), by the Export Promotion Technology Development Program of IPET (No. 313010-3) funded by the Ministry for Food, Agriculture, Forestry, and Fisheries, and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2015R1A2A2A05001288). NR 20 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1535-3141 EI 1556-7125 J9 FOODBORNE PATHOG DIS JI Foodborne Pathog. Dis. PD FEB PY 2017 VL 14 IS 2 BP 84 EP 88 DI 10.1089/fpd.2016.2198 PG 5 WC Food Science & Technology SC Food Science & Technology GA EL0ST UT WOS:000394332800003 PM 28051328 ER PT J AU Hughes, HK Landa, MM Sharfstein, JM AF Hughes, Helen K. Landa, Michael M. Sharfstein, Joshua M. TI Marketing Claims for Infant Formula The Need for Evidence SO JAMA PEDIATRICS LA English DT Editorial Material C1 [Hughes, Helen K.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Landa, Michael M.] US FDA, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. [Sharfstein, Joshua M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. RP Hughes, HK (reprint author), Bloomberg Childrens Ctr, Div Gen Pediat & Adolescent Med, 1800 Orleans St,Room 8461, Baltimore, MD 21287 USA. EM hkinsma1@jhmi.edu 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 FEB PY 2017 VL 171 IS 2 BP 105 EP 106 DI 10.1001/jamapediatrics.2016.3837 PG 2 WC Pediatrics SC Pediatrics GA EM9QN UT WOS:000395646300005 PM 28027329 ER PT J AU Zlatina, K Galuska, CE Tharmalingam, T Prem, G Vann, WF Vionnet, J Reid, CJ Gallagher, ME Carrington, FA Hassett, SL Carrington, SD Galuska, SP AF Zlatina, K. Galuska, C. E. Tharmalingam, T. Prem, G. Vann, W. F. Vionnet, J. Reid, C. J. Gallagher, M. E. Carrington, F. A. Hassett, S. L. Carrington, S. D. Galuska, S. P. TI In vitro polysialylated cervical mucins counteract the cytotoxicity of extracellular histones SO REPRODUCTION IN DOMESTIC ANIMALS LA English DT Meeting Abstract CT 50th Annual Conference of Physiology and Pathology of Reproduction / 42nd Mutual Conference of Veterinary and Human Reproductive Medicine CY FEB 15-17, 2017 CL Munich, GERMANY C1 [Zlatina, K.; Galuska, C. E.; Galuska, S. P.] Leibniz Inst Farm Anim Biol FBN, Dept Reprod Biol, Dummerstorf, Germany. [Zlatina, K.; Galuska, C. E.; Prem, G.; Galuska, S. P.] Justus Liebig Univ, Inst Biochem, Fac Med, Giessen, Germany. [Tharmalingam, T.; Vionnet, J.; Reid, C. J.; Gallagher, M. E.; Carrington, F. A.; Hassett, S. L.; Carrington, S. D.] Univ Coll Dublin, UCD Vet Sci Ctr, Dublin, Ireland. [Vann, W. F.] US FDA, Silver Spring, MD USA. FU Schaumann Foundation FX The project was supported by Schaumann Foundation. 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 0936-6768 EI 1439-0531 J9 REPROD DOMEST ANIM JI Reprod. Domest. Anim. PD FEB PY 2017 VL 52 SU S1 MA 141 BP 58 EP 58 PG 1 WC Agriculture, Dairy & Animal Science; Reproductive Biology; Veterinary Sciences SC Agriculture; Reproductive Biology; Veterinary Sciences GA EK5MF UT WOS:000393969800142 ER PT J AU Edwards, SH Rossiter, LM Taylor, KM Holman, MR Zhang, LQ Ding, YS Watson, CH AF Edwards, Selvin H. Rossiter, Lana M. Taylor, Kenneth M. Holman, Matthew R. Zhang, Liqin Ding, Yan S. Watson, Clifford H. TI Tobacco-Specific Nitrosamines in the Tobacco and Mainstream Smoke of US Commercial Cigarettes SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID TANDEM MASS-SPECTROMETRY; SURGEON GENERALS REPORT; SYRIAN GOLDEN-HAMSTERS; N-NITROSAMINES; F344 RATS; HEALTH CONSEQUENCES; BRAND CIGARETTES; CARCINOGENESIS; N'-NITROSONORNICOTINE; INDUCTION AB Tobacco-specific nitrosamines (TSNAs) are N-nitroso-derivatives of pyridine-alkaloids (e.g., nicotine) present in tobacco and cigarette smoke. Two TSNAs, N'-nitro-sonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are included on the Food and Drug Administration's list of harmful and potentially harmful constituents (HPHCs) in tobacco products and tobacco. The amounts of four TSNAs (NNK, NNN, N-nitro-soanabasine (NAB), and N'-nitrosoanatabine (NAT)) in the tobacco and mainstream smoke from 50 U.S. commercial cigarette brands were measured from November 15, 2011 to January 4, 2012 using a validated HPLC/MS/MS method. Smoke samples were generated using the International Organization of Standardization (ISO) and Canadian Intense (CI) machine-smoking regimens. NNN and NAT were the most abundant TSNAs in tobacco filler and smoke across all cigarette brands, whereas NNK and NAB were present in lesser amounts. The average ratios for each TSNA in mainstream smoke to filler content is 29% by the CI smoking regimen and 13% for the ISO machine-smoking regimen. The reliability of individual TSNAs to predict total TSNA amounts in the filler and smoke was examined. NNN, NAT, and NAB have a moderate to high correlation (R-2 = 0.61-0.98, p < 0.0001), and all three TSNAs individually predict total TSNAs with minimal difference between measured and predicted total TSNA amounts (error < 7.4%). NNK has weaker correlation (R-2 = 0.56-0.82; p < 0.0001) and is a less reliable predictor of total TSNA quantities. Tobacco weight and levels of TSNAs in filler influence TSNA levels in smoke from the CI machine-smoking regimen. In contrast, filter ventilation is a major determinant of levels of TSNAs in smoke by the ISO machine-smoking regimen. Comparative analysis demonstrates substantial variability in TSNA amounts in tobacco filler and mainstream smoke yields under ISO and CI machine-smoking regimens among U.S. commercial cigarette brands. C1 [Edwards, Selvin H.; Rossiter, Lana M.; Taylor, Kenneth M.; Holman, Matthew R.] Food & Drug Adm, Ctr Tobacco Prod, Silver Spring, MD 20850 USA. [Zhang, Liqin; Ding, Yan S.; Watson, Clifford H.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. RP Taylor, KM (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, 10903 New Hampshire Ave,Bldg 32, Silver Spring, MD 20993 USA. EM Kenneth.Taylor@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Tobacco Products FX This research was funded by the. U.S. Food and Drug Administration, Center for Tobacco Products. NR 51 TC 0 Z9 0 U1 4 U2 4 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 FEB PY 2017 VL 30 IS 2 BP 540 EP 551 DI 10.1021/acs.chemrestox.6b00268 PG 12 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA EL6MK UT WOS:000394736500007 PM 28001416 ER PT J AU Komatsu, TE Boyd, S Sherwat, A Tracy, L Naeger, LK O'Rear, JJ Harrington, PR AF Komatsu, Takashi E. Boyd, Sarita Sherwat, Adam Tracy, LaRee Naeger, Lisa K. O'Rear, Julian J. Harrington, Patrick R. TI Regulatory Analysis of Effects of Hepatitis C Virus NS5A Polymorphisms on Efficacy of Elbasvir and Grazoprevir SO GASTROENTEROLOGY LA English DT Article DE DAA; Replication; FDA; Post-Hoc Analysis ID GENOTYPE 1 INFECTION; NS3/4A PROTEASE INHIBITOR; LABEL PHASE-2 TRIAL; PEGYLATED INTERFERON; TREATMENT-NAIVE; ANTIVIRAL DRUGS; RIBAVIRIN; MK-5172; RESISTANCE; VARIANTS AB BACKGROUND & AIMS: Elbasvir (an NS5A inhibitor) and grazoprevir (an NS3/4A protease inhibitor) are direct-acting antiviral agents recently approved in the United States for treatment of chronic hepatitis C virus (HCV) genotype 1 and 4 infections, as a fixed-dose combination. Trials of elbasvir and grazoprevir, with or without ribavirin, demonstrated high rates of sustained virologic response 12 weeks after treatment ended (SVR12). However, 12 weeks of treatment with elbasvir and grazoprevir failed in a small proportion of patients with HCV genotype 1 infection. We summarize findings from independent US Food and Drug Administration analyses of drug resistance data from trials of elbasvir and grazoprevir, with and without ribavirin. METHODS: We independently analyzed HCV drug resistance and HCV RNA measurement results that were submitted to the US Food and Drug Administration to support the regulatory approval of elbasvir and grazoprevir. These data were reported from selected phase 2 and 3 clinical trials of elbasvir and grazoprevir, with and without ribavirin. Genotypic resistance analyses were conducted using Sanger population nucleotide sequencing data derived from blood samples from study patients. RESULTS: In 56 of 506 (11%) patients with HCV genotype 1a infection who received elbasvir and grazoprevir for 12 weeks, baseline HCV genetic variants encoding amino acid polymorphisms in NS5A (M28, Q30, L31, or Y93) reduced treatment efficacy; rates of SVR12 were 70% and 98% for patients with or without NS5A polymorphisms, respectively (P < .0001). Most patients with treatment failure acquired resistance-associated substitutions in NS3 and/or NS5A. Based on data from a small number of patients (n = 6), an intensified 16-week regimen of elbasvir and grazoprevir plus ribavirin could increase efficacy in patients with HCV genotype 1a infection with NS5A polymorphisms. Among patients with HCV genotype 4a or 4d infections with NS5A polymorphisms, all 26 who received the elbasvir and grazoprevir regimens recommended in prescribing information achieved an SVR12. CONCLUSIONS: The combination of elbasvir and grazoprevir, with or without ribavirin is safe and effective for patients with HCV genotype 1 or 4 infections. In patients with HCV genotype 1a infection, polymorphisms in NS5A at baseline (before treatment) can affect the efficacy of this direct-acting antiviral regimen, and pretreatment resistance analyses can optimize treatment selection. C1 [Komatsu, Takashi E.; Boyd, Sarita; Sherwat, Adam; Naeger, Lisa K.; O'Rear, Julian J.; Harrington, Patrick R.] US FDA, Div Antiviral Prod, Off Antimicrobial Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Tracy, LaRee] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Komatsu, TE; Harrington, PR (reprint author), US FDA, Div Antiviral Prod, Off Antimicrobial Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM takashi.komatsu@fda.hhs.gov; patrick.harrington@fda.hhs.gov FU Merck Co, Inc FX The data analyzed for this report were submitted in the New Drug Application for Zepatier. Most analyses are documented in the US FDA clinical virology review of New Drug Application 208261 (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208261Orig1s000M icroR.pdf). The authors acknowledge the study sponsor (Merck & Co, Inc), investigators, and study volunteers as the source of these data. The authors also thank Dr Jeffrey Murray, Dr Debra Birnkrant, and Dr John Farley, as well as the study sponsor, for helpful discussions and editorial suggestions. NR 24 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2017 VL 152 IS 3 BP 586 EP 597 DI 10.1053/j.gastro.2016.10.017 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EO1BC UT WOS:000396431600027 PM 27773808 ER PT J AU Pettigrew, RI Heetderks, WJ Kelley, CA Peng, GCY Krosnick, SH Jakeman, LB Egan, KD Marge, M AF Pettigrew, Roderic I. Heetderks, William J. Kelley, Christine A. Peng, Grace C. Y. Krosnick, Steven H. Jakeman, Lyn B. Egan, Katharine D. Marge, Michael TI Epidural Spinal Stimulation to Improve Bladder, Bowel, and Sexual Function in Individuals With Spinal Cord Injuries: A Framework for Clinical Research SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Autonomic nervous system dysfunctions; epidural spinal cord stimulation (SCS); interventions for spinal cord injuries; paralysis; spinal cord injury (SCI); spinal mapping for bladder; bowel; sexual functions ID PRESERVED CORTICOSPINAL CONDUCTION; DEEP BRAIN-STIMULATION; QUALITY-OF-LIFE; BASIC DATA SET; ELECTRICAL-STIMULATION; VOLUNTARY MOVEMENT; CONTRACTIONS; RECOVERY; RATS; DYSFUNCTION AB While some recent studies that apply epidural spinal cord stimulation (SCS) have demonstrated a breakthrough in improvement of the health and quality of the life of persons with spinal cord injury (SCI), the numbers of people who have received SCS are small. This is in sharp contrast to the thousands of persons worldwide living with SCI who have no practical recourse or hope of recovery of lost functions. Thus, the vision is to understand the full potential of this new intervention and to determine if it is safe and effective in a larger cohort, and if it is scalable so that it can be made available to all those who might benefit. To achieve this vision, the National Institute of Biomedical Imaging and Bioengineering called for and organized a consortium of multiple stakeholder groups: foundations addressing paralysis, federal and public agencies, industrial partners, academicians, and researchers, all interested in the same goal. Based on input from consortium participants, we have reasoned that a first step is to define a scalable SCS approach that is effective in restoring lost autonomic physiology, specifically bladder, bowel, and sexual function. These functions are most critical for improving the quality of life of persons living with SCI. This report outlines a framework for conducting the research needed to define such an effective SCS procedure that might seek Food and Drug Administration approval and be implemented at the population level. C1 [Pettigrew, Roderic I.; Heetderks, William J.; Kelley, Christine A.; Peng, Grace C. Y.; Krosnick, Steven H.; Egan, Katharine D.; Marge, Michael] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. [Heetderks, William J.] US FDA, Rockville, MD 20857 USA. [Jakeman, Lyn B.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Kelley, CA (reprint author), Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. EM kelleyc@mail.nih.gov FU National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health FX This work was supported by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health. NR 49 TC 0 Z9 0 U1 1 U2 1 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 FEB PY 2017 VL 64 IS 2 BP 253 EP 262 DI 10.1109/TBME.2016.2637301 PG 10 WC Engineering, Biomedical SC Engineering GA EL5UO UT WOS:000394686900001 PM 28113186 ER PT J AU Xu, F Gonzalez-Escalona, N Haendiges, J Myers, RA Ferguson, J Stiles, T Hickey, E Moore, M Hickey, JM Schillaci, C Mank, L DeRosia-Banick, K Matluk, N Robbins, A Sebra, RP Cooper, VS Jones, SH Whistler, CA AF Xu, Feng Gonzalez-Escalona, Narjol Haendiges, Julie Myers, Robert A. Ferguson, Jana Stiles, Tracy Hickey, Eric Moore, Michael Hickey, John Michael Schillaci, Christopher Mank, Laurn DeRosia-Banick, Kristin Matluk, Nicholas Robbins, Amy Sebra, Robert P. Cooper, Vaughn S. Jones, Stephen H. Whistler, Cheryl A. TI Sequence Type 631 Vibrio parahaemolyticus, an Emerging Foodborne Pathogen in North America SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Letter DE Vibrio parahaemolyticus; core genome multilocus sequence type analysis; emerging pathogen; genomics; molecular epidemiology C1 [Xu, Feng; Cooper, Vaughn S.; Jones, Stephen H.; Whistler, Cheryl A.] Univ New Hampshire, Northeast Ctr Vibrio Dis & Ecol, Durham, NH 03824 USA. [Xu, Feng; Cooper, Vaughn S.; Whistler, Cheryl A.] Univ New Hampshire, Dept Mol Cellular & Biomed Sci, Durham, NH 03824 USA. [Xu, Feng] Univ New Hampshire, Grad Program Genet, Durham, NH 03824 USA. [Gonzalez-Escalona, Narjol] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Haendiges, Julie; Myers, Robert A.] Dept Hlth & Mental Hyg, Baltimore, MD USA. [Ferguson, Jana; Stiles, Tracy; Hickey, Eric; Moore, Michael] Massachusetts Dept Publ Hlth, Boston, MA USA. [Hickey, John Michael; Schillaci, Christopher] Massachusetts Div Marine Fisheries, New Bedford, MA USA. [Mank, Laurn] Dept Publ Hlth Lab, Rocky Hill, CT USA. [DeRosia-Banick, Kristin] Bur Aquaculture, Dept Agr, State Connecticut, Milford, CT USA. [Matluk, Nicholas; Robbins, Amy] Dept Hlth & Human Serv, Augusta, ME USA. [Sebra, Robert P.] Icahn Sch Med Mt Sinai, Icahn Inst, New York, NY 10029 USA. [Sebra, Robert P.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Cooper, Vaughn S.] Univ Pittsburgh, Sch Med, Microbiol & Mol Genet, Pittsburgh, PA USA. [Jones, Stephen H.] Univ New Hampshire, Dept Nat Resources & Environm, Durham, NH 03824 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 OI Gonzalez-Escalona, Narjol/0000-0003-4568-0022 FU USDA National Institute of Food and Agriculture [NH00574, NH00609, 233555, NH00625, 1004199]; National Oceanic and Atmospheric Administration College Sea Grant program [R/CE-137, R/SSS-2, R/HCE-3]; National Institutes of Health [1R03AI081102-01]; National Science Foundation [EPSCoR IIA-1330641, DBI 1229361]; FDA Foods Science and Research Intramural Program FX Partial funding for this work was provided by the USDA National Institute of Food and Agriculture (Hatch projects NH00574, NH00609 [accession number 233555], and NH00625 [accession number 1004199]). Additional funding was provided by the National Oceanic and Atmospheric Administration College Sea Grant program and grants R/CE-137, R/SSS-2, and R/HCE-3. Support was also provided through the National Institutes of Health (1R03AI081102-01), the National Science Foundation (EPSCoR IIA-1330641), and the National Science Foundation (DBI 1229361 NSF MRI). N.G.-E. was funded through the FDA Foods Science and Research Intramural Program. NR 10 TC 0 Z9 0 U1 2 U2 2 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 FEB PY 2017 VL 55 IS 2 BP 645 EP 648 DI 10.1128/JCM.02162-16 PG 4 WC Microbiology SC Microbiology GA EK0LF UT WOS:000393617300037 PM 27974540 ER PT J AU Risinger, AL Li, J Du, L Benavides, R Robles, AJ Cichewicz, RH Kuhn, JG Mooberry, SL AF Risinger, April L. Li, Jing Du, Lin Benavides, Raymond Robles, Andrew J. Cichewicz, Robert H. Kuhn, John G. Mooberry, Susan L. TI Pharmacokinetic Analysis and in Vivo Antitumor Efficacy of Taccalonolides AF and AJ SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID MICROTUBULE-STABILIZING AGENT; DRUG CONJUGATE ADC; TACCA-PLANTAGINEA; PENTACYCLIC STEROIDS; BINDING-SITES; PELORUSIDE; TUBULIN; POTENT; ZAMPANOLIDE; PACLITAXEL AB The taccalonolides are microtubule stabilizers that covalently bind tubulin and circumvent clinically relevant forms of resistance to other drugs of this class. Efforts are under way to identify a taccalonolide with optimal properties for clinical development. The structurally similar taccalonolides AF and AJ have comparable microtubule-stabilizing activities in vitro, but taccalonolide AF has excellent in vivo antitumor efficacy when administered systemically, while taccalonolide AJ does not elicit this activity even at maximum tolerated dose. The hypothesis that pharmacokinetic differences underlie the differential efficacies of taccalonolides AF and AJ was tested. The effects of serum on their in vivo potency, metabolism by human liver microsomes and in vivo pharmacokinetic properties were evaluated. Taccalonolides AF and AJ were found to have elimination half-lives of 44 and 8.1 min, respectively. Furthermore, taccalonolide AJ was found to have excellent and highly persistent antitumor efficacy when administered directly to the tumor, suggesting that the lack of antitumor efficacy seen with systemic administration of AJ is likely due to its short half-life in vivo. These results help define why some, but not all, taccalonolides inhibit the growth of tumors at systemically tolerable doses and prompt studies to further improve their pharmacokinetic profile and antitumor efficacy. C1 [Risinger, April L.; Li, Jing; Robles, Andrew J.; Mooberry, Susan L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Risinger, April L.; Mooberry, Susan L.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Du, Lin; Cichewicz, Robert H.] Univ Oklahoma, Dept Chem & Biochem, Stephenson Life Sci Res Ctr, Norman, OK 73019 USA. [Du, Lin; Cichewicz, Robert H.] Univ Oklahoma, Nat Prod Discovery Grp, Norman, OK 73019 USA. [Du, Lin; Cichewicz, Robert H.] Univ Oklahoma, Inst Nat Prod Applicat & Res Technol, Norman, OK 73019 USA. [Benavides, Raymond; Kuhn, John G.] Univ Texas Austin, Coll Pharm, Austin, TX 78712 USA. [Li, Jing] US FDA, Off Pharmaceut Qual, CDER, Silver Spring, MD 20993 USA. RP Mooberry, SL (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA.; Mooberry, SL (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. EM Mooberry@uthscsa.edu FU National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR001120]; National Center for Advancing Translational Sciences, National Institutes of Health, through CTRC pilot grant program; National Cancer Institute [CA121138] FX This work was supported by a National Center for Advancing Translational Sciences, National Institutes of Health, through the grant UL1 TR001120 and CTRC pilot grant program and National Cancer Institute grant CA121138 (S.L.M.) NR 34 TC 0 Z9 0 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 EI 1520-6025 J9 J NAT PROD JI J. Nat. Prod. PD FEB PY 2017 VL 80 IS 2 BP 409 EP 414 DI 10.1021/acs.jnatprod.6b00944 PG 6 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA EM0ZL UT WOS:000395046900022 PM 28112516 ER PT J AU Shaw, JM Miller-Novak, LK Mohanram, V McKinnon, K Demberg, T Vargas-Inchaustegui, DA Venzon, D Robert-Guroff, M AF Shaw, Julia M. Miller-Novak, Leia K. Mohanram, Venkatramanan McKinnon, Katherine Demberg, Thorsten Vargas-Inchaustegui, Diego A. Venzon, David Robert-Guroff, Marjorie TI Influence of Plasma Cell Niche Factors on the Recruitment and Maintenance of IRF4(hi) Plasma Cells and Plasmablasts in Vaccinated, Simian Immunodeficiency Virus-Infected Rhesus Macaques with Low and High Viremia SO JOURNAL OF VIROLOGY LA English DT Article DE SIV rhesus macaque model; plasma cell; plasma cell niche factors; plasmablast ID HUMAN BONE-MARROW; MEMORY B-CELLS; HIV-INFECTION; MONOCLONAL-ANTIBODIES; SIV INFECTION; LYMPH-NODES; ANTIRETROVIRAL THERAPY; SURVIVAL NICHES; GENE-EXPRESSION; IN-VITRO AB In a recent study, we found that protection following simian immunodeficiency virus (SIV) exposure correlated with rectal plasma cell frequency in vaccinated female rhesus macaques. We sought to determine if the same macaques maintained high mucosal plasma cell frequencies postinfection and if this translated to reduced viremia. Although delayed SIV acquisition did not predict subsequent viral control, alterations existed in the distribution of plasma cells and plasmablasts between macaques that exhibited high or low viremia. Flow cytometric analysis of cells from rectal biopsy specimens, bone marrow, and mesenteric lymph nodes of vaccinated infected, unvaccinated infected, and uninfected macaques identified two main IRF4(hi) subsets of interest: CD138(+) plasma cells, and CD138(-) lasmablasts. In rectal tissue, plasma cell frequency positively correlated with plasma viremia and unvaccinated macaques had increased plasma cells and plasmablasts compared to vaccinated animals. Likewise, plasmablast frequency in the mesenteric lymph node correlated with viremia. However, in bone marrow, plasmablast frequency negatively correlated with viremia. Accordingly, low-viremic macaques had a higher frequency of both bone marrow IRF4hi subsets than did animals with high viremia. Significant reciprocal relationships between rectal and bone marrow plasmablasts suggested that efficient trafficking to the bone marrow as opposed to the rectal mucosa was linked to viral control. mRNA expression analysis of proteins involved in establishment of plasma cell niches in sorted bone marrow and rectal cell populations further supported this model and revealed differential mRNA expression patterns in these tissues. IMPORTANCE As key antibody producers, plasma cells and plasmablasts are critical components of vaccine-induced immunity to human immunodeficiency virus type 1 (HIV-1) in humans and SIV in the macaque model; however, few have attempted to examine the role of these cells in viral suppression postinfection. Our results suggest that plasmablast trafficking to and retention in the bone marrow play a previously unappreciated role in viral control and contrast the potential contribution of mucosal plasma cells to mediate protection at sites of infection with that of bone marrow plasmablasts and plasma cells to control viremia during chronic infection. Manipulation of niche factors influencing the distribution and maintenance of these critical antibody-secreting cells may serve as potential therapeutic targets to enhance antiviral responses postvaccination and postinfection. C1 [Shaw, Julia M.; Miller-Novak, Leia K.; Mohanram, Venkatramanan; McKinnon, Katherine; Demberg, Thorsten; Vargas-Inchaustegui, Diego A.; Robert-Guroff, Marjorie] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Data Management & Biostat Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shaw, Julia M.] NIAID, Div Allergy Immunol & Transplantat, NIH, Rockville, MD USA. [Miller-Novak, Leia K.] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Silver Spring, MD USA. [Mohanram, Venkatramanan] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Demberg, Thorsten] Immat US Inc, Houston, TX USA. [Vargas-Inchaustegui, Diego A.] NIAID, Viral Dis Lab, Mol Struct Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Robert-Guroff, M (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 85 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 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2017 VL 91 IS 4 AR UNSP e01727 DI 10.1128/JVI.01727-16 PG 19 WC Virology SC Virology GA EK4FU UT WOS:000393883300012 ER PT J AU McKinzie, PB Revollo, JR AF McKinzie, Page B. Revollo, Javier R. TI Whole genome sequencing of mouse lymphoma L5178Y-3.7.2C (TK+/-) reveals millions of mutations and genetic markers SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE Next generation sequencing; Genetics; SNPs ID TK6 CELLS; TUMOR-SUPPRESSOR; FLOW-CYTOMETRY; P53 STATUS; L5178Y; APOPTOSIS; MICRONUCLEI; FRAMEWORK; LINES AB The mouse lymphoma L5178Y-3.7.2C(TK+/-) cell line is extensively used in genetic toxicology to conduct the mouse lymphoma assay (MLA). The MLA is used to establish the mutagenic and clastogenic effects of chemicals and pharmaceuticals, and is one of the few genetic tests widely accepted by regulatory agencies throughout the world. Despite the extensive use and regulatory impact of L5178Y-3.7.2C (TK+/-) cells, little is known about their genetic composition or how it affects the outcome of the MLA. To determine the genetic background of this cell line, we sequenced and analyzed its entire genome. Our results confirm the existence of previously described mutations in the TK1 and Trp53 genes arid catalog millions of other mutations, many of which impair the function of genes with key roles in cell physiology and genetic toxicology. Published by Elsevier B.V. C1 [McKinzie, Page B.; Revollo, Javier R.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP McKinzie, PB (reprint author), 3900 NCTR Rd,HFT 120, Jefferson, AR 72079 USA. EM Page.McKinzie@fda.hhs.gov; Javier.Revollo@fda.hhs.gov FU U.S. Food and Drug Administration FX All research costs were paid by the U.S. Food and Drug Administration. NR 31 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 EI 1879-3592 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD FEB PY 2017 VL 814 BP 1 EP 6 DI 10.1016/j.mrgentox.2016.12.001 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA EK6ZB UT WOS:000394073700001 PM 28137362 ER PT J AU Villenave, R Wales, SQ Hamkins-Indik, T Papafragkou, E Weaver, JC Ferrante, TC Bahinski, A Elkins, CA Kulka, M Ingber, DE AF Villenave, Remi Wales, Samantha Q. Hamkins-Indik, Tiama Papafragkou, Efstathia Weaver, James C. Ferrante, Thomas C. Bahinski, Anthony Elkins, Christopher A. Kulka, Michael Ingber, Donald E. TI Human Gut-On-A-Chip Supports Polarized Infection of Coxsackie B1 Virus In Vitro SO PLOS ONE LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; HUMAN AIRWAY EPITHELIUM; TIGHT JUNCTIONS; CILIATED CELLS; RELEASE; DISEASE; MODEL; MICE; PATHOGENESIS; REPLICATION AB Analysis of enterovirus infection is difficult in animals because they express different virus receptors than humans, and static cell culture systems do not reproduce the physical complexity of the human intestinal epithelium. Here, using coxsackievirus B1 (CVB1) as a prototype enterovirus strain, we demonstrate that human enterovirus infection, replication and infectious virus production can be analyzed in vitro in a human Gut-on-a-Chip microfluidic device that supports culture of highly differentiated human villus intestinal epithelium under conditions of fluid flow and peristalsis-like motions. When CVB1 was introduced into the epithelium-lined intestinal lumen of the device, virions entered the epithelium, replicated inside the cells producing detectable cytopathic effects (CPEs), and both infectious virions and inflammatory cytokines were released in a polarized manner from the cell apex, as they could be detected in the effluent from the epithelial microchannel. When the virus was introduced via a basal route of infection (by inoculating virus into fluid flowing through a parallel lower 'vascular' channel separated from the epithelial channel by a porous membrane), significantly lower viral titers, decreased CPEs, and delayed caspase-3 activation were observed; however, cytokines continued to be secreted apically. The presence of continuous fluid flow through the epithelial lumen also resulted in production of a gradient of CPEs consistent with the flow direction. Thus, the human Gut-on-a-Chip may provide a suitable in vitro model for enteric virus infection and for investigating mechanisms of enterovirus pathogenesis. C1 [Villenave, Remi; Hamkins-Indik, Tiama; Weaver, James C.; Ferrante, Thomas C.; Bahinski, Anthony; Ingber, Donald E.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Wales, Samantha Q.; Papafragkou, Efstathia; Elkins, Christopher A.; Kulka, Michael] US FDA, Mol Virol Team, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD USA. [Ingber, Donald E.] Harvard John A Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Ingber, Donald E.] Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA. [Ingber, Donald E.] Harvard Med Sch, Boston, MA 02115 USA. [Villenave, Remi] Emulate Inc, Boston, MA USA. [Bahinski, Anthony] GlaxoSmithKline, King Of Prussia, PA USA. RP Ingber, DE (reprint author), Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA.; Ingber, DE (reprint author), Harvard John A Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA.; Ingber, DE (reprint author), Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA.; Ingber, DE (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM don.ingber@wyss.harvard.edu FU FDA [HHSF223201310079C]; DARPA [HR0011-15-C-0094]; Wyss Institute for Biologically Inspired Engineering at Harvard University; Food and Drug Administration [HHSF223201310079C]; Defense Advanced Research Projects Agency [HR0011-15-C-0094] FX This work was supported by grants from the Food and Drug Administration (HHSF223201310079C) and The Defense Advanced Research Projects Agency (HR0011-15-C-0094), and by the Wyss Institute for Biologically Inspired Engineering at Harvard University. NR 38 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 FEB 1 PY 2017 VL 12 IS 2 AR e0169412 DI 10.1371/journal.pone.0169412 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6RS UT WOS:000396131700006 ER PT J AU Bhattarai, N McLinden, JH Xiang, JH Mathahs, MM Schmidt, WN Kaufman, TM Stapleton, JT AF Bhattarai, Nirjal McLinden, James H. Xiang, Jinhua Mathahs, M. Meleah Schmidt, Warren N. Kaufman, Thomas M. Stapleton, Jack T. TI Hepatitis C virus infection inhibits a Src-kinase regulatory phosphatase and reduces T cell activation in vivo SO PLOS PATHOGENS LA English DT Article ID ADAPTIVE IMMUNE-RESPONSES; CYTOPLASMIC RNA VIRUS; MICRORNA TARGETS; GLYCOPROTEIN E2; REPLICATION; PROTEIN; INTERFERENCE; PERSISTENCE; BINDING; INNATE AB Among human RNA viruses, hepatitis C virus (HCV) is unusual in that it causes persistent infection in the majority of infected people. To establish persistence, HCV evades host innate and adaptive immune responses by multiple mechanisms. Recent studies identified virus genome-derived small RNAs (vsRNAs) in HCV-infected cells; however, their biological significance during human HCV infection is unknown. One such vsRNA arising from the hepatitis C virus (HCV) E2 coding region impairs T cell receptor (TCR) signaling by reducing expression of a Src-kinase regulatory phosphatase (PTPRE) in vitro. Since TCR signaling is a critical first step in T cell activation, differentiation, and effector function, its inhibition may contribute towards HCV persistence in vivo. The effect of HCV infection on PTPRE expression in vivo has not been examined. Here, we found that PTPRE levels were significantly reduced in liver tissue and peripheral blood mononuclear cells (PBMCs) obtained from HCV-infected humans compared to uninfected controls. Loss of PTPRE expression impaired antigen-specific TCR signaling, and curative HCV therapy restored PTPRE expression in PBMCs; restoring antigen-specific TCR signaling defects. The extent of PTPRE expression correlated with the amount of sequence complementarity between the HCV E2 vsRNA and the PTPRE 3'UTR target sites. Transfection of a hepatocyte cell line with full-length HCV RNA or with synthetic HCV vsRNA duplexes inhibited PTPRE expression, recapitulating the in vivo observation. Together, these data demonstrate that HCV infection reduces PTPRE expression in the liver and PBMCs of infected humans, and suggest that the HCV E2 vsRNA is a novel viral factor that may contribute towards viral persistence. C1 [Bhattarai, Nirjal; McLinden, James H.; Xiang, Jinhua; Mathahs, M. Meleah; Schmidt, Warren N.; Kaufman, Thomas M.; Stapleton, Jack T.] Iowa City Vet Affairs Med Ctr, Res Serv, Iowa City, IA 52246 USA. [Bhattarai, Nirjal; McLinden, James H.; Xiang, Jinhua; Mathahs, M. Meleah; Schmidt, Warren N.; Kaufman, Thomas M.; Stapleton, Jack T.] Iowa City Vet Affairs Med Ctr, Med Serv, Iowa City, IA 52246 USA. [Bhattarai, Nirjal; McLinden, James H.; Xiang, Jinhua; Mathahs, M. Meleah; Schmidt, Warren N.; Kaufman, Thomas M.; Stapleton, Jack T.] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. [Stapleton, Jack T.] Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. [Bhattarai, Nirjal] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Stapleton, JT (reprint author), Iowa City Vet Affairs Med Ctr, Res Serv, Iowa City, IA 52246 USA.; Stapleton, JT (reprint author), Iowa City Vet Affairs Med Ctr, Med Serv, Iowa City, IA 52246 USA.; Stapleton, JT (reprint author), Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA.; Stapleton, JT (reprint author), Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. EM jack-stapleton@uiowa.edu FU U.S. Department of Veterans Affairs [BX000207, CX000821, BX001241, BX000159]; National Institutes of Health [P30CA0868862] FX U.S. Department of Veterans Affairs (BX000207, CX000821, BX001241, BX000159) and National Institutes of Health P30CA0868862. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 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 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2017 VL 13 IS 2 AR e1006232 DI 10.1371/journal.ppat.1006232 PG 20 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EO0TL UT WOS:000396410800014 PM 28235043 ER PT J AU Zhang, XY Cook, KL Warri, A Cruz, IM Rosim, M Riskin, J Helferich, W Doerge, D Clarke, R Hilakivi-Clarke, L AF Zhang, Xiyuan Cook, Katherine L. Warri, Anni Cruz, Idalia M. Rosim, Mariana Riskin, Jeffrey Helferich, William Doerge, Daniel Clarke, Robert Hilakivi-Clarke, Leena TI Lifetime Genistein Intake Increases the Response of Mammary Tumors to Tamoxifen in Rats SO CLINICAL CANCER RESEARCH LA English DT Article ID SOY FOOD-INTAKE; ENDOPLASMIC-RETICULUM STRESS; BREAST-CANCER SURVIVAL; INDUCED AUTOPHAGY; GENE-EXPRESSION; IMMUNE-SYSTEM; CELLS; RESISTANCE; GROWTH; ALPHA AB Purpose: Whether it is safe for estrogen receptor-positive (ER+) patients with breast cancer to consume soy isoflavone genistein remains controversial. We compared the effects of genistein intake mimicking either Asian (lifetime) or Caucasian (adulthood) intake patterns to that of starting its intake during tamoxifen therapy using a preclinical model. Experimental Design: Female Sprague-Dawley rats were fed an AIN93G diet supplemented with 0 (control diet) or 500 ppm genistein from postnatal day 15 onward (lifetime genistein). Mammary tumors were induced with 7,12-dimethylbenz(a) anthracene (DMBA), after which a group of control diet-fed rats were switched to genistein diet (adult genistein). When the first tumor in a rat reached 1.4cm in diameter, tamoxifen was added to the diet and a subset of previously only control diet-fed rats also started genistein intake (post-diagnosis genistein). Results: Lifetime genistein intake reduced de novo resistance to tamoxifen, compared with post-diagnosis genistein groups. Risk of recurrence was lower both in the lifetime and in the adult genistein groups than in the post-diagnosis genistein group. We observed downregulation of unfolded protein response (UPR) and autophagy-related genes (GRP78, IRE1 alpha, ATF4, and Beclin-1) and genes linked to immunosuppression (TGF beta and Foxp3) and upregulation of cytotoxic T-cell marker CD8a in the tumors of the lifetime genistein group, compared with controls, post-diagnosis, and/or adult genistein groups. Conclusions: Genistein intake mimicking Asian consumption patterns improved response of mammary tumors to tamoxifen therapy, and this effect was linked to reduced activity of UPR and prosurvival autophagy signaling and increased antitumor immunity. (C) 2017 AACR. C1 [Zhang, Xiyuan; Warri, Anni; Cruz, Idalia M.; Riskin, Jeffrey; Clarke, Robert; Hilakivi-Clarke, Leena] Georgetown Univ, Dept Oncol, Washington, DC USA. [Cook, Katherine L.] Wake Forest Univ, Dept Surg Sci, Winston Salem, NC 27109 USA. [Warri, Anni] Univ Turku, Fac Med, Inst Biomed, Turku, Finland. [Rosim, Mariana] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Food & Expt Nutr, Sao Paulo, Brazil. [Helferich, William] Univ Illinois, Dept Food Sci & Human Nutr, Urbana, IL USA. [Doerge, Daniel] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Hilakivi-Clarke, L (reprint author), Georgetown Univ, E407 NRB,3970 Reservoir Rd NW, Washington, DC 20057 USA. EM clarkel@georgetown.edu FU National Cancer Institute (NCI) [U54-CA149147, U01-CA184902]; NCI [R01-CA164384, P30-CA51008]; AICR; National Center for Complementary and Integrative Health (NCCIH) [P50AT006268]; Office of Dietary Supplements (ODS) FX This work was supported by U54-CA149147 and U01-CA184902 from the National Cancer Institute (NCI) to R. Clarke, and R01-CA164384 from NCI and AICR grant to L. Hilakivi-Clarke, P50AT006268 from the National Center for Complementary and Integrative Health (NCCIH), the Office of Dietary Supplements (ODS) and NCI for W. Helferich, and P30-CA51008 to Lombardi Comprehensive Cancer Center (funding for Shared Resources). In addition, X. Zhang received a donation to support her PhD thesis work from Solomon family. NR 48 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB PY 2017 VL 23 IS 3 BP 814 EP 824 DI 10.1158/1078-0432.CCR-16-1735 PG 11 WC Oncology SC Oncology GA EK4GB UT WOS:000393884000021 PM 28148690 ER PT J AU Fiuzat, M Nordenberg, TS Zeller, M Hillebrenner, MG Stockbridge, N Zuckerman, B Califf, RM AF Fiuzat, Mona Nordenberg, Tamar S. Zeller, Mitchell Hillebrenner, Matthew G. Stockbridge, Norman Zuckerman, Bram Califf, Robert M. TI FDA in the 21st Century Focus on Tobacco Policies and Heart Failure Prevention SO JACC-HEART FAILURE LA English DT Editorial Material DE drug evaluation; FDA; stroke C1 [Fiuzat, Mona; Nordenberg, Tamar S.; Zeller, Mitchell; Hillebrenner, Matthew G.; Stockbridge, Norman; Zuckerman, Bram; Califf, Robert M.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Fiuzat, M (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Mona.fiuzat@fda.hhs.gov NR 6 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 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD FEB PY 2017 VL 5 IS 2 BP 152 EP 153 DI 10.1016/j.jchf.2016.11.010 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EK0RO UT WOS:000393635000012 PM 28153199 ER PT J AU Ramponi, G Badano, A AF Ramponi, Giovanni Badano, Aldo TI Method for Adapting the Grayscale Standard Display Function to the Aging Eye SO JOURNAL OF DIGITAL IMAGING LA English DT Article DE Aging models; Human visual system; Contrast sensitivity; Grayscale visualization ID AGE-RELATED-CHANGE; CONTRAST SENSITIVITY; PUPIL SIZE; HUMAN LENS; ADULTS; MODEL; CATARACT; SYSTEM; ACUITY; CT AB Perceptual linearity of grayscale images based on a contrast sensitivity model is a widely recognized and used standard for medical imaging visualization. This approach ensures consistency across devices and provides perception of luminance variations in direct relationship to changes in image values. We analyze the effect of aging of the human eye on the precept of linearity and demonstrate that not only the number of just-noticeable differences diminishes for older subjects but also linearity across the range of luminance values is significantly affected. While loss of JNDs is inevitable for a fixed luminance range, our findings suggest possible corrective approaches for maintaining linearity. C1 [Ramponi, Giovanni] Univ Trieste, Dept Engn & Architecture, Trieste, Italy. [Badano, Aldo] US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Badano, A (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Aldo.badano@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 NR 38 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0897-1889 EI 1618-727X J9 J DIGIT IMAGING JI J. Digit. Imaging PD FEB PY 2017 VL 30 IS 1 BP 17 EP 25 DI 10.1007/s10278-016-9900-2 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EK1MM UT WOS:000393689700004 PM 27561752 ER PT J AU Cappozzo, J Jackson, L Lee, HJ Zhou, W Al-Taher, F Zweigenbaum, J Ryu, D AF Cappozzo, Jack Jackson, Lauren Lee, Hyun Jung Zhou, Wei Al-Taher, Fadwa Zweigenbaum, Jerry Ryu, Dojin TI Occurrence of Ochratoxin A in Infant Foods in the United States SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Food safety; Infant cereal; Infant formula; Mycotoxins ID CEREAL-DERIVED PRODUCTS; ISOTOPE DILUTION ASSAY; HEALTH-RISK ASSESSMENT; BABY FOODS; BREAKFAST CEREALS; TURKEY OCCURRENCE; SAFETY EVALUATION; ITALIAN MARKET; CHILD HEALTH; MYCOTOXINS AB Ochratoxin A (OTA) is a possible human carcinogen and occurs frequently in cereal grain, soy, and other agricultural commodities. Infants and young children may be more susceptible to contaminants than adults because of their lower body weight, higher metabolic rate, reduced ability to detoxify food toxicants, and more restricted diet. The purpose of this study was to investigate the occurrence and levels of OTA in infant formula and infant cereal products available in the U.S. market. In the present study, 98 powdered infant formula (milk- and soy-based) samples and 155 infant cereal (barley-, rice-, oat-, wheat-, and mixed grain based) products were collected from different retail locations in the United States over a 2-year period. OTA levels were determined by liquid chromatography tandem mass spectrometry. Although OTA was not detected in any of the infant formula samples, 47 (30%) of 155 infant cereals were contaminated with OTA in the range of 0.6 to 22.1 ng/g. At present, there is no regulatory limit for OTA in the United States. However, all of the positive samples were above the maximum level set by the European Commission (0.5 ng/g) for OTA in baby foods. OTA was detected in all types of infant cereals, but the highest incidence and concentrations were found in oat-based infant cereals (59%), followed by mixed grain cereals (34%). Increased surveillance and monitoring of OTA levels in grains used in infant foods may be needed to reduce exposure of infants and young children to OTA from cereal products. C1 [Cappozzo, Jack; Zhou, Wei; Al-Taher, Fadwa] IIT, 6502 S Archer Rd, Bedford Pk, IL 60501 USA. [Jackson, Lauren] US FDA, Inst Food Safety & Hlth, 6502 S Archer Rd, Bedford Pk, IL 60501 USA. [Lee, Hyun Jung; Ryu, Dojin] Univ Idaho, Sch Food Sci, 875 Perimeter Dr MS 2312, Moscow, ID 83844 USA. [Zweigenbaum, Jerry] Agilent Technol, 2850 Centerville Rd, Wilmington, DE 19808 USA. RP Jackson, L (reprint author), US FDA, Inst Food Safety & Hlth, 6502 S Archer Rd, Bedford Pk, IL 60501 USA.; Ryu, D (reprint author), Univ Idaho, Sch Food Sci, 875 Perimeter Dr MS 2312, Moscow, ID 83844 USA. EM lauren.jackson@fda.hhs.gov; dryu@uidaho.edu FU Agriculture and Food Research Initiative competitive grant from the U.S. Department of Agriculture (USDA), National Institute of Food and Agriculture [2011-67005-20676]; U.S. Food and Drug Administration (FDA); Institute for Food Safety and Health FX This project was supported by the Agriculture and Food Research Initiative competitive grant 2011-67005-20676 from the U.S. Department of Agriculture (USDA), National Institute of Food and Agriculture; the U.S. Food and Drug Administration (FDA); and the Institute for Food Safety and Health. Sampling was conducted in collaboration with Charlene Wolf-Hall (North Dakota State University), Jayne Stratton and Andreia Bianchini (University of Nebraska-Lincoln), Jeffery Palumbo (USDA, Western Regional Research Laboratory), and Felicia Wu (University of Pittsburgh; currently at Michigan State University). The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the FDA. NR 50 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 FEB PY 2017 VL 80 IS 2 BP 251 EP 256 DI 10.4315/0362-028X.JFP-16-339 PG 6 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EK1YV UT WOS:000393724600008 PM 28218865 ER PT J AU Hildebrandt, IM Hu, CX Grasso-Kelley, EM Ye, PR Anderson, NM Keller, SE AF Hildebrandt, Ian M. Hu, Chuxuan Grasso-Kelley, Elizabeth M. Ye, Peiran Anderson, Nathan M. Keller, Susanne E. TI Dry Transfer Inoculation of Low-Moisture Spices Containing Antimicrobial Compounds SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Dry transfer; Inoculation; Salmonella; Spices ID SALMONELLA-ENTERICA; SURVIVAL; EXTRACTS AB Inoculation of a food product for use in subsequent validation studies typically makes use of a high concentration cocktail of microorganisms suspended in aqueous media. However, this inoculation method may prove difficult particularly when the food product is a low-moisture food containing antimicrobial compounds, such as some dried spices. In this study, a dry transfer method for inoculation of clove powder, oregano leaves, ginger powder, and ground black pepper with a five-serovar cocktail of Salmonella was developed and compared with a traditional aqueous inoculation procedure. Spices were inoculated at three levels, 10, 8, and 6 log CFU/g, by using both an aqueous suspension of Salmonella and a dry transfer of Salmonella from previously inoculated silica beads. At the highest inoculation level, the dry transfer method resulted in a significantly higher microbial load (P < 0.05) for ground cloves and oregano, but not for ginger and ground black pepper. At the intermediate inoculation level, differences were apparent only for ginger and black pepper. Inoculation levels of 6 log CFU/g resulted in recoveries below detection limits for both methods of inoculation. Additional examination on the survival of Salmonella on silica beads after inoculation and in clove powder after dry transfer from silica beads showed linear rates of decline, with a rate of 0.011 log CFU/g/day for beads and 0.015 log CFU/g/day for clove powder. The results suggest that dry transfer of Salmonella via inoculated silica beads is a viable alternative when traditional aqueous inoculation is not feasible. C1 [Hildebrandt, Ian M.; Anderson, Nathan M.; Keller, Susanne E.] US FDA, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. [Hu, Chuxuan; Grasso-Kelley, Elizabeth M.; Ye, Peiran] IIT, Inst Food Safety & Hlth, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. RP Keller, SE (reprint author), US FDA, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM susanne.keller@fda.hhs.gov FU FDA [5U01FD003801] FX This work was supported by FDA collaborative grant 5U01FD003801 and 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 FDA. NR 23 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 FEB PY 2017 VL 80 IS 2 BP 338 EP 344 DI 10.4315/0362-028X.JFP-16-279 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EK1YV UT WOS:000393724600018 PM 28221981 ER PT J AU Parsons, LM An, YM de Vries, RP de Haan, CAM Cipollo, JF AF Parsons, Lisa M. An, Yanming de Vries, Robert P. de Haan, Cornelis A. M. Cipollo, John F. TI Glycosylation Characterization of an Influenza H5N7 Hemagglutinin Series with Engineered Glycosylation Patterns: Implications for Structure-Function Relationships SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE hemagglutinin; influenza; flu; mass spectrometry; GLYMPS; glycosylation; HEK293; S2 ID A VIRUS HEMAGGLUTININ; RECEPTOR-BINDING SPECIFICITY; N-LINKED GLYCOSYLATION; PROTEIN GLYCOSYLATION; MASS-SPECTROMETRY; 3D STRUCTURE; GLYCAN; MICE; GLYCOPROTEIN; VIRULENCE AB The glycosylation patterns of four recombinant H5 hemagglutinins (HAs) derived from A/Mallard/Denmark/64650/03 (H5N7) have been characterized. The proteins were expressed in (i) HEK293T cells to produce complex glycoforms, (ii) HEK293T cells treated with Vibrio cholera ;neuraminidase to provide asialo-complex glycoforms, (iii) HEK293S GnTI(-) cells with predominantly the canonical Man(5)GlcNAc(2) glycoform, and (iv) Drosophila S2 insect cells producing primarily paucimannose glycoforms. Previously, these HAs were used to investigate the effect of different glycosylation states on the immune responses in chicken and mouse systems. Evidence was found that high-mannose glycans diminished antibody response via DC-SIGN interactions. We performed two semiquantitative analyses including MALDI-TOF MS permethylation analysis of released glycans and LC-MSE analysis of glycosylation site microheterogeneity. Glycosylation site occupancy was also determined by LC-MSE. Our major findings include (1) decreasing complexity of glycosylation from the stem to the globular head, (2) absence of glycosylation at N-10 and N-193, (3) complex glycans at N-165 in HEK293T cell HA but high mannose glycans at this site in HEK293S and S2 cells, and (4) differences between the three-dimensional structures of H3 and H5 HAs that may explain glycan type preferences at selected sites. Biological implications of the findings are discussed. C1 [Parsons, Lisa M.; An, Yanming; Cipollo, John F.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [de Vries, Robert P.] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Dept Med Chem & Chem Biol, NL-3584 CG Utrecht, Netherlands. [de Haan, Cornelis A. M.] Univ Utrecht, Fac Vet Med, Dept Infect Dis & Immunol, Div Virol, Yalelaan 1, NL-3584 CL Utrecht, Netherlands. RP Cipollo, JF (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM john.cipollo@fda.hhs.gov FU Netherlands Organization for Scientific Research (NWO); VENI FX RP.d.V. was a recipient of VENI and Rubicon Grants from The Netherlands Organization for Scientific Research (NWO). NR 58 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD FEB PY 2017 VL 16 IS 2 BP 398 EP 412 DI 10.1021/acs.jproteome.6b00175 PG 15 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA EJ9IK UT WOS:000393539600005 PM 28060516 ER PT J AU Dixon, RG Khiatani, V Statler, JD Walser, EM Midia, M Miller, DL Bartal, G Collins, JD Gross, KA Stecker, MS Nikolic, B AF Dixon, Robert G. Khiatani, Vishal Statler, John D. Walser, Eric M. Midia, Mehran Miller, Donald L. Bartal, Gabriel Collins, Jeremy D. Gross, Kathleen A. Stecker, Michael S. Nikolic, Boris CA Soc Interventional Radiology TI Society of Interventional Radiology: Occupational Back and Neck Pain and the Interventional Radiologist SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIALS; HEALTH HAZARDS; MUSCULOSKELETAL INJURIES; WORKERS-COMPENSATION; JOINT GUIDELINE; GLOBAL BURDEN; PREVENTION; PREVALENCE; CARDIOLOGISTS; METAANALYSIS C1 [Dixon, Robert G.; Khiatani, Vishal] Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. [Statler, John D.] Virginia Intervent & Vasc Associates, Fredericksburg, VA USA. [Walser, Eric M.] Univ Texas Med Branch, Dept Radiol, Galveston, TX 77555 USA. [Miller, Donald L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Collins, Jeremy D.] Northwestern Univ, Dept Radiol, Chicago, IL 60611 USA. [Stecker, Michael S.] Brigham & Womens Hosp, Div Angiog Intervent Radiol, 75 Francis St, Boston, MA 02115 USA. [Nikolic, Boris] Stratton Med Ctr, Dept Radiol, Albany, NY USA. [Midia, Mehran] McMaster Univ, Dept Intervent Radiol, Hamilton, ON, Canada. [Bartal, Gabriel] Meir Med Ctr, Dept Radiol, Kefar Sava, Israel. RP Dixon, RG (reprint author), Care Of Katsarelis D, SIR, 3975 Fair Ridge Dr,Suite 400 N, Fairfax, VA 22033 USA. EM bob_dixon@med.unc.edu NR 68 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 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD FEB PY 2017 VL 28 IS 2 BP 195 EP 199 DI 10.1016/j.jvir.2016.10.017 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA EJ9JU UT WOS:000393543200006 PM 27993508 ER PT J AU Yu, A Baker, JR Fioritto, AF Wang, Y Luo, RJ Li, SW Wen, B Bly, M Tsume, Y Koenigsknecht, MJ Zhang, XY Lionberger, R Amidon, GL Hasler, WL Sun, DX AF Yu, Alex Baker, Jason R. Fioritto, Ann F. Wang, Ying Luo, Ruijuan Li, Siwei Wen, Bo Bly, Michael Tsume, Yasuhiro Koenigsknecht, Mark J. Zhang, Xinyuan Lionberger, Robert Amidon, Gordon L. Hasler, William L. Sun, Duxin TI Measurement of in vivo Gastrointestinal Release and Dissolution of Three Locally Acting Mesalamine Formulations in Regions of the Human Gastrointestinal Tract SO MOLECULAR PHARMACEUTICS LA English DT Article DE mesalamine; in vivo dissolution; pharmacokinetics; modified release; local gastrointestinal concentration; clinical study ID MODERATE ULCERATIVE-COLITIS; 5-AMINOSALICYLIC ACID; ORAL MESALAZINE; MMX MESALAMINE; MAINTENANCE; REMISSION; EFFICACY; TRIAL; MILD; SALICYLAZOSULFAPYRIDINE AB As an orally administered, locally acting gastrointestinal drug, mesalamine products are designed to achieve high local drug concentration in the gastrointestinal (GI) tract for the treatment of ulcerative colitis. The aim of this study was to directly measure and compare drug dissolution of three mesalamine formulations in human GI tract and to correlate their GI concentration with drug concentration in plasma. Healthy human subjects were orally administered Pentasa, Apriso, or Lialda. GI fluids were aspirated from stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum regions. Mesalamine (5-ASA) and its primary metabolite acetyl-5-mesalamine (Ac-S-ASA) were measured using LC-MS/MS. GI tract pH was measured from each GI fluid sample, which averaged 1.82, 4.97, 5.67, 6.17, and 6.62 in the stomach, duodenum, proximal jejunum, middle jejunum, and distal jejunum, respectively. For Pentasa, high levels of 5-ASA in solution were observed in the stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum from 1 to 7 h. Apriso had minimal 5-ASA levels in stomach, low to medium levels of 5-ASA in duodenum and proximal jejunum from 4 to 7 h, and high levels of 5-ASA in distal jejunum from 3 to 7 h. In contrast, Lialda had minimal 5-ASA levels from stomach and early small intestine. A composite appearance rate (CAR) was calculated from the deconvolution of individual plasma concentration to reflect drug release, dissolution, transit, and absorption in the GI tract. Individuals dosed with Pentasa had high levels of CAR from 1 to 10 h; individuals dosed with Apriso had low levels of CAR from 1 to 4 h and high levels of CAR from 5 to 10 h; Lialda showed minimal levels of CAR from 0 to 5 h, then increased to medium levels from 5 to 12 h, and then decreased to further lower levels after 12 h. In the colon region, Pentasa and Apriso showed similar levels of accumulated 5-ASA excreted in the feces, while Lialda showed slightly higher 5-ASA accumulation in feces. However, all three formulations showed similar levels of metabolite Ac-S-ASA in the feces. These results provide direct measurement of drug dissolution in the GI tract, which can serve as a basis for investigation of bioequivalence for locally acting drug products. C1 [Yu, Alex; Fioritto, Ann F.; Wang, Ying; Luo, Ruijuan; Li, Siwei; Wen, Bo; Bly, Michael; Tsume, Yasuhiro; Koenigsknecht, Mark J.; Amidon, Gordon L.; Sun, Duxin] Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA. [Baker, Jason R.; Hasler, William L.] Univ Michigan, Coll Pharm, Dept Internal Med, Ann Arbor, MI 48109 USA. [Zhang, Xinyuan; Lionberger, Robert] US FDA, Off Res & Standards, Off Gen Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Hasler, WL (reprint author), Univ Michigan, Coll Pharm, Dept Internal Med, Ann Arbor, MI 48109 USA.; Sun, DX (reprint author), Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Room 3353,Bldg 520 1600 Huron Pkwy, Ann Arbor, MI 48105 USA. EM whasler@med.umich.edu; duxins@med.umich.edu FU FDA [HHSF223201000082C, HHSF223201300460A] FX This research was supported by FDA grants HHSF223201000082C and HHSF223201300460A. NR 31 TC 0 Z9 0 U1 1 U2 1 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 FEB PY 2017 VL 14 IS 2 BP 345 EP 358 DI 10.1021/acs.molpharmaceut.6b00641 PG 14 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA EK0PV UT WOS:000393630100001 PM 28009518 ER PT J AU Nikolov, NP Shapiro, MA AF Nikolov, Nikolay P. Shapiro, Marjorie A. TI An FDA perspective on the assessment of proposed biosimilar therapeutic proteins in rheumatology SO NATURE REVIEWS RHEUMATOLOGY LA English DT Article ID DEPENDENT CELLULAR CYTOTOXICITY; TERMINAL N-ACETYLGLUCOSAMINE; HIGH-AFFINITY BINDING; FC-GAMMA-RIII; EFFECTOR FUNCTIONS; COMPLEX GLYCOPROTEIN; ANTIBODY; GLYCOSYLATION; CARBOHYDRATE; FUCOSE AB Biologic products have revolutionized the management of many rheumatic diseases, but access to these products might be limited by their relatively high costs. The US Biologics Price Competition and Innovation Act of 2009, which is contained within the Patient Protection and Affordable Care Act, established an abbreviated pathway for licensure by the FDA of biologic products that are demonstrated to be biosimilar to or interchangeable with FDA-licensed biologic products, termed reference products. This law allows for the approval of biosimilar biologic products, which are expected to increase access to treatment for patients, and ensuring the implementation of this Act is a high priority for the FDA. In this Perspectives article we describe the considerations for approval of proposed biosimilar products, including those to treat rheumatological conditions, by describing the FDA's rigorous approach to assessment of biosimilarity. C1 [Nikolov, Nikolay P.] US FDA, Div Pulm Allergy & Rheumatol Prod, Off New Drugs, Ctr Drug Evaluat & Res, HFD 570,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Shapiro, Marjorie A.] US FDA, Div Biotechnol Review & Res 1, Off Biotechnol Prod, Ctr Drug Evaluat & Res, HFD 123,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Nikolov, NP (reprint author), US FDA, Div Pulm Allergy & Rheumatol Prod, Off New Drugs, Ctr Drug Evaluat & Res, HFD 570,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Nikolay.Nikolov@fda.hhs.gov NR 31 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 1759-4790 EI 1759-4804 J9 NAT REV RHEUMATOL JI Nat. Rev. Rheumatol. PD FEB PY 2017 VL 13 IS 2 BP 123 EP 128 DI 10.1038/nrrheum.2016.204 PG 6 WC Rheumatology SC Rheumatology GA EK2BC UT WOS:000393731100011 PM 28053335 ER PT J AU Mullin, T Barton, J AF Mullin, Theresa M. Barton, Joshua L. TI US Prescription Drug User Fee Act (PDUFA): An Introduction for the Pharmaceutical Physician SO PHARMACEUTICAL MEDICINE LA English DT Article AB Originally enacted to address the delays in US Food and Drug Administration (FDA) new drug review due to chronic understaffing and outdated systems, the Prescription Drug User Fee Act (PDUFA) of 1992, with its 5-year reauthorization cycle, enabled rapid rigorous review and ushered in a new era of continuing program innovation, evaluation, and improvement. This has resulted in a scientifically and financially strong program with transparent stakeholder engagement as a routine way of doing business. The enhancements to the process of human drug review, conducted in the FDA Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER), originally focused on the FDA review of a new drug application, have evolved and expanded to include extensive communication and consultation between drug sponsors and FDA throughout drug development, advances in regulatory science applied to drug development and regulatory oversight, strengthening and innovating approaches to post-market safety, increasing patient focus and modernizing supporting informatics. These enhancements, identified and supported in successive rounds of user fee negotiation with regulated industry, have enabled the USA to sustain global leadership in drug innovation, and earlier patient access to safe and effective new medicines. C1 [Mullin, Theresa M.; Barton, Joshua L.] US FDA, Ctr Drug Evaluat & Res, Off Strateg Programs, 10903 New Hampshire Ave,Bldg 51,Room 1178, Silver Spring, MD 20993 USA. RP Mullin, T (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Strateg Programs, 10903 New Hampshire Ave,Bldg 51,Room 1178, Silver Spring, MD 20993 USA. EM Theresa.Mullin@fda.hhs.gov NR 14 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1178-2595 EI 1179-1993 J9 PHARM MED JI Pharm. Med. PD FEB PY 2017 VL 31 IS 1 BP 7 EP 12 DI 10.1007/s40290-016-0170-6 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK1KD UT WOS:000393683300002 ER PT J AU Playdon, MC Moore, SC Derkach, A Reedy, J Subar, AF Sampson, JN Albanes, D Gu, FY Kontto, J Lassale, C Liao, LM Mainnisto, S Mondul, AM Weinstein, SJ Irwin, ML Mayne, ST Stolzenberg-Solomon, R AF Playdon, Mary C. Moore, Steven C. Derkach, Andriy Reedy, Jill Subar, Amy F. Sampson, Joshua N. Albanes, Demetrius Gu, Fangyi Kontto, Jukka Lassale, Camille Liao, Linda M. Mainnisto, Satu Mondul, Alison M. Weinstein, Stephanie J. Irwin, Melinda L. Mayne, Susan T. Stolzenberg-Solomon, Rachael TI Identifying biomarkers of dietary patterns by using metabolomics SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE dietary pattern; diet quality; Healthy Eating Index; biomarker; metabolomics; metabolite ID HEALTHY EATING INDEX; RANDOMIZED CONTROLLED-TRIAL; CAROTENE CANCER PREVENTION; BALTIC SEA DIET; MEDITERRANEAN DIET; CARDIOVASCULAR-DISEASE; QUALITY INDEXES; BETA-CAROTENE; ALL-CAUSE; RISK AB Background: Healthy dietary patterns that conform to national dietary guidelines are related to lower chronic disease incidence and longer life span. However, the precise mechanisms involved are unclear. Identifying biomarkers of dietary patterns may provide tools to validate diet quality measurement and determine underlying metabolic pathways influenced by diet quality. Objective: The objective of this study was to examine the correlation of 4 diet quality indexes [the Healthy Eating Index (HEI) 2010, the Alternate Mediterranean Diet Score (aMED), the WHO Healthy Diet Indicator (HDI), and the Baltic Sea Diet (BSD)] with serum metabolites. Design: We evaluated dietary patterns and metabolites in male Finnish smokers (n = 1336) from 5 nested case-control studies within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Participants completed a validated food-frequency questionnaire and provided a fasting serum sample before study randomization (1985-1988). Metabolites were measured with the use of mass spectrometry. We analyzed cross-sectional partial correlations of 1316 metabolites with 4 diet quality indexes, adjusting for age, body mass index, smoking, energy intake, education, and physical activity. We pooled estimates across studies with the use of fixed-effects meta-analysis with Bonferroni correction for multiple comparisons, and conducted metabolic pathway analyses. Results: The HEI-2010, aMED, HDI, and BSD were associated with 23, 46, 23, and 33 metabolites, respectively (17, 21, 11, and 10 metabolites, respectively, were chemically identified; r-range: -0.30 to 0.20; P = 6 X 10(-15) to 8 X 10(-6)). Food-based diet indexes (HEI-2010, aMED, and BSD) were associated with metabolites correlated with most components used to score adherence (e.g., fruit, vegetables, whole grains, fish, and unsaturated fat). HDI correlated with metabolites related to polyunsaturated fat and fiber components, but not other macro- or micronutrients (e.g., percentages of protein and cholesterol). The lysolipid and food and plant xenobiotic pathways were most strongly associated with diet quality. Conclusions: Diet quality, measured by healthy diet indexes, is associated with serum metabolites, with the specific metabolite profile of each diet index related to the diet components used to score adherence. C1 [Playdon, Mary C.; Irwin, Melinda L.; Mayne, Susan T.] Yale Univ, Yale Sch Publ Hlth, New Haven, CT 06520 USA. [Playdon, Mary C.; Moore, Steven C.; Derkach, Andriy; Sampson, Joshua N.; Albanes, Demetrius; Gu, Fangyi; Liao, Linda M.; Weinstein, Stephanie J.; Stolzenberg-Solomon, Rachael] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Reedy, Jill; Subar, Amy F.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Kontto, Jukka; Mainnisto, Satu] Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland. [Lassale, Camille] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Mondul, Alison M.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Irwin, Melinda L.] Yale Canc Ctr, New Haven, CT USA. [Mayne, Susan T.] US FDA, 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 OI Kontto, Jukka/0000-0003-3899-9852; Irwin, Michael/0000-0001-5801-274X FU Yale-National Cancer Institute predoctoral training grant [T32 CA105666]; NIH Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services FX Supported in part by Yale-National Cancer Institute predoctoral training grant T32 CA105666 to STM. This research was also supported by the NIH Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services. NR 80 TC 1 Z9 1 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 FEB PY 2017 VL 105 IS 2 BP 450 EP 465 DI 10.3945/ajcn.116.144501 PG 16 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EJ6SK UT WOS:000393348900021 PM 28031192 ER PT J AU Siegel, JA Sacks, B Pennington, CW Welsh, JS AF Siegel, Jeffry A. Sacks, Bill Pennington, Charles W. Welsh, James S. TI Response to Comments by Drs Hamaoka and Beyea on "The Birth of the Illegitimate Linear No-Threshold Model: An Invalid Paradigm for Estimating Risk Following Low-dose Radiation Exposure" SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Letter C1 [Siegel, Jeffry A.] Nucl Phys Enterprises, Marlton, NJ 08053 USA. [Sacks, Bill] US FDA, Green Valley, AZ USA. [Pennington, Charles W.] NAC Int, Alpharetta, GA USA. [Welsh, James S.] Loyola Univ Chicago, Stritch Sch Med, Dept Radiat Oncol, Maywood, IL USA. RP Siegel, JA (reprint author), Nucl Phys Enterprises, Marlton, NJ 08053 USA. NR 5 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 0277-3732 EI 1537-453X J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD FEB PY 2017 VL 40 IS 1 BP 106 EP 107 DI 10.1097/COC.0000000000000357 PG 2 WC Oncology SC Oncology GA EJ6SC UT WOS:000393348100017 PM 28106686 ER PT J AU Challacombe, JF Petersen, JM Gallegos-Graves, LV Hodge, D Pillai, S Kuske, CR AF Challacombe, Jean F. Petersen, Jeannine M. Gallegos-Graves, La Verne Hodge, David Pillai, Segaran Kuske, Cheryl R. TI Whole-Genome Relationships among Francisella Bacteria of Diverse Origins Define New Species and Provide Specific Regions for Detection SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article DE Francisella species; Francisella tularensis; Francisella novicida; Francisella ID TULARENSIS SUBSP TULARENSIS; FORMERLY YERSINIA-PHILOMIRAGIA; COD GADUS-MORHUA; PATHOGENICITY ISLAND; ATLANTIC COD; SP NOV.; ENVIRONMENTAL-SAMPLES; NOVICIDA BACTEREMIA; GENUS FRANCISELLA; WOLBACHIA-PERSICA AB Francisella tularensis is a highly virulent zoonotic pathogen that causes tularemia and, because of weaponization efforts in past world wars, is considered a tier 1 biothreat agent. Detection and surveillance of F. tularensis may be confounded by the presence of uncharacterized, closely related organisms. Through DNA-based diagnostics and environmental surveys, novel clinical and environmental Francisella isolates have been obtained in recent years. Here we present 7 new Francisella genomes and a comparison of their characteristics to each other and to 24 publicly available genomes as well as a comparative analysis of 16S rRNA and sdhA genes from over 90 Francisella strains. Delineation of new species in bacteria is challenging, especially when isolates having very close genomic characteristics exhibit different physiological features-for example, when some are virulent pathogens in humans and animals while others are nonpathogenic or are opportunistic pathogens. Species resolution within Francisella varies with analyses of single genes, multiple gene or protein sets, or whole-genome comparisons of nucleic acid and amino acid sequences. Analyses focusing on single genes (16S rRNA, sdhA), multiple gene sets (virulence genes, lipopolysaccharide [LPS] biosynthesis genes, pathogenicity island), and whole-genome comparisons (nucleotide and protein) gave congruent results, but with different levels of discrimination confidence. We designate four new species within the genus; Francisella opportunistica sp. nov. (MA06-7296), Francisella salina sp. nov. (TX07-7308), Francisella uliginis sp. nov. (TX07-7310), and Francisella frigiditurris sp. nov. (CA97-1460). This study provides a robust comparative framework to discern species and virulence features of newly detected Francisella bacteria. IMPORTANCE DNA-based detection and sequencing methods have identified thousands of new bacteria in the human body and the environment. In most cases, there are no cultured isolates that correspond to these sequences. While DNA-based approaches are highly sensitive, accurately assigning species is difficult without known near relatives for comparison. This ambiguity poses challenges for clinical cases, disease epidemics, and environmental surveillance, for which response times must be short. Many new Francisella isolates have been identified globally. However, their species designations and potential for causing human disease remain ambiguous. Through detailed genome comparisons, we identified features that differentiate F. tularensis from clinical and environmental Francisella isolates and provide a knowledge base for future comparison of Francisella organisms identified in clinical samples or environmental surveys. C1 [Challacombe, Jean F.; Gallegos-Graves, La Verne; Kuske, Cheryl R.] Los Alamos Natl Lab, Biosci Div, Los Alamos, NM 87544 USA. [Petersen, Jeannine M.] Ctr Dis Control & Prevent, Div Vector Borne Infect Dis, Ft Collins, CO USA. [Hodge, David] Dept Homeland Secur, Sci & Technol Directorate, Chem & Biol Div, Washington, DC USA. [Pillai, Segaran] US FDA, Off Lab Sci & Safety, Silver Spring, MD USA. RP Kuske, CR (reprint author), Los Alamos Natl Lab, Biosci Div, Los Alamos, NM 87544 USA. EM Kuske@lanl.gov FU U.S. Department of Homeland Security, Science and Technology Directorate FX The genomic sequencing for seven of the isolates was funded by the U.S. Department of Homeland Security, Science and Technology Directorate, through multiple grants to C.R.K. and J.F.C. NR 104 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 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD FEB PY 2017 VL 83 IS 3 AR UNSP e02589 DI 10.1128/AEM.02589-16 PG 17 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA EJ8MW UT WOS:000393480900012 ER PT J AU Williams, K Valencia, L Gokulan, K Trbojevich, R Khare, S AF Williams, Katherine Valencia, Luis Gokulan, Kuppan Trbojevich, Raul Khare, Sangeeta TI Assessment of antimicrobial effects of food contact materials containing silver on growth of Salmonella Typhimurium SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Silver; Food contact material; Bacteria; Growth; Salmonella ID NANOPARTICLES; MIGRATION; CONTAINERS; NANOMATERIALS; NANOSILVER; RESISTANCE; BACTERIA; RELEASE AB Food contact materials containing antibacterial properties are progressively appearing in the market. Items intended to provide antimicrobial effects such as increased shelf life and food safety are incorporating silver materials during the manufacture of such products. This study examined the total silver content, release capacity, and antibacterial activity of three different silver-containing food contact materials: plastic food storage containers, a plastic cutting board, and food wrapping paper. Silver content and release were determined by Inductively Coupled Plasma Mass Spectrometry, and the results showed that, although the amount of silver in each product was similar, migration varied considerably with kind of material and simulant choice. Antimicrobial effect was tested by measuring the growth of Salmonella Typhirhurium during or after exposure to the different food contact materials. The results showed that the food storage containers and wrapping paper delayed the growth of S. Typhimurium under certain conditions, but that these effects were short-lived. The strain of S. Typhimurium used in this study was found to be negative for the presence of tested silver resistance genes. The results of this study suggest that a thorough investigation should be required to show/claim the efficacy of silver containing food contact materials for food safety purposes. Published by Elsevier Ltd. C1 [Williams, Katherine; Valencia, Luis; Gokulan, Kuppan; Khare, Sangeeta] US FDA, Div Microbiol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Trbojevich, Raul] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, 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 ORISE FX The authors would like to thank Dr. Anne Summers, (The University of Georgia, Athens, Georgia) for providing the bacterial strains for sit gene controls and Drs. Taylor Ingle and Rajesh Nayak (NUR/US-FDA) for the critical review of this manuscript. Mr. Valencia was a participant in a summer research program administered by the Oak Ridge Institute for Science and Education (ORISE) and Ms. Williams was supported by an ORISE research appointment. NR 30 TC 0 Z9 0 U1 5 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD FEB PY 2017 VL 100 BP 197 EP 206 DI 10.1016/j.fct.2016.12.014 PG 10 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA EJ5LA UT WOS:000393258300019 PM 28007453 ER PT J AU Shappell, NW Shelver, WL Lupton, SJ Fanaselle, W Van Doren, JM Hakk, H AF Shappell, Nancy W. Shelver, Weilin L. Lupton, Sara J. Fanaselle, Wendy Van Doren, Jane M. Hakk, Heldur TI Distribution of Animal Drugs among Curd, Whey, and Milk Protein Fractions in Spiked Skim Milk and Whey SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE drug residues; curd; whey; skim milk; antibiotic; anthelmintic; NSAID; partition; distribution; protein association ID DAIRY-PRODUCTS; BOVINE-MILK; RESIDUES; CHEESE; FATE; PERSISTENCE; EPRINOMECTIN; ANTIBIOTICS; ALBENDAZOLE; IVERMECTIN AB It is important to understand the partitioning of drugs in processed milk and milk products, when drugs are present in raw milk, in order to estimate the potential consumer exposure. Radioisotopically labeled erythromycin, ivermectin, ketoprofen, oxytetracycline, penicillin G, sulfadimethoxine, and thiabendazole were used to evaluate the distribution of animal drugs among rennet curd, whey, and protein fractions from skim cow milk. Our previous work reported the distribution of these same drugs between skim and fat fractions of milk. Drug distribution between curd and whey was significantly correlated (R-2 = 0.70) to the drug's lipophilicity (log P), with improved correlation using log D (R-2 = 0.95). Distribution of drugs was concentration independent over the range tested (20-2000 nM). With the exception of thiabendazole and ivermectin, more drug was associated with whey protein than casein on a nmol/g protein basis (oxytetracycline experiment not performed). These results provide insights into the distribution of animal drug residues, if present in cow milk, among milk fractions, with possible extrapolation to milk products. C1 [Shappell, Nancy W.; Shelver, Weilin L.; Lupton, Sara J.; Hakk, Heldur] ARS, USDA, Biosci Res Lab, 1605 Albrecht Blvd, Fargo, ND 58102 USA. [Fanaselle, Wendy; Van Doren, Jane M.] US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr, College Pk, MD 20740 USA. RP Shappell, NW (reprint author), ARS, USDA, Biosci Res Lab, 1605 Albrecht Blvd, Fargo, ND 58102 USA. EM Nancy.Shappell@ars.usda.gov OI Shappell, Nancy/0000-0003-4080-4372 FU FDA; USDA ARS [224-14-2006] FX This study was collaboratively funded by an interagency agreement with the FDA and USDA ARS (Interagency Agreement no. 224-14-2006). NR 23 TC 0 Z9 0 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD FEB 1 PY 2017 VL 65 IS 4 BP 938 EP 949 DI 10.1021/acs.jafc.6b04258 PG 12 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA EJ6UP UT WOS:000393355200031 PM 28052193 ER PT J AU Genualdi, S Nyman, P DeJager, L AF Genualdi, Susan Nyman, Patricia DeJager, Lowri TI Simultaneous Analysis of 3-MCPD and 1,3-DCP in Asian Style Sauces Using QuEChERS Extraction and Gas Chromatography-Triple Quadrupole Mass Spectrometry SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE soy sauce; 3-MCPD; 1,3-DCP ID SOY-SAUCE; 3-CHLOROPROPANE-1,2-DIOL 3-MCPD; SIMULTANEOUS DERIVATIZATION; CHLOROPROPANOLS; FOOD; PRODUCTS; MICROEXTRACTION; INGREDIENTS AB Acid hydrolyzed vegetable protein (aHVP) is used for flavoring a wide variety of foods and also in the production of nonfermented soy sauce. During the production of aHVP, chloropropanols including 3-monochloropropane-1,2-diol (3-MCPD) and 1,3 dichloropropane-2-ol (1,3-DCP) can be formed through the reaction of the hydrochloric acid catalyst and residual fat and the reaction of 3-MCPD with acetic acid, respectively. 3-MCPD is a carcinogen, and 1,3-DCP has been classified as a genotoxic carcinogen. The European Union (EU) has set a maximum concentration of 0.02 mg/kg of 3-MCPD in aHVP, and the Food and Drug Administration (FDA) set a guidance limit of 1 mg/kg of 3-MCPD in aHVP. 1,3-DCP is not an approved food additive, and the Joint FAO/WHO Expert Committee on Food Additives (JEFCA) has set a limit at 0.005 mg/kg, which is close to the estimated method detection limit. Currently there are few analytical methods for the simultaneous determination of 3-MCPD and 1,3-DCP without derivatization due to differences in their physical chemical properties and reactivity. A new method was developed using QuEChERS (quick, easy, cheap, effective, rugged, and safe) with direct analysis of the extract without derivatization using gas chromatography-triple quadrupole mass spectrometry (GC-QQQ). Additionally, a market sampling of 60 soy sauce samples was performed in 2015 to determine if concentrations have changed since the FDA limit was set in 2008. The sampling results were compared between the new QuEChERS method and a method using phenylboronic acid (PBA) as a derivatizing agent for 3-MCPD analysis. The concentrations of 3-MCPD detected in soy sauce samples collected in 2015 (5 years (range: 28-107). A total of 79 posaconazole trough concentrations were measured in patients receiving posaconazole as prophylaxis (n = 8) or treatment (n = 12). Posaconazole dose referenced to total body weight ranged from 100 to 492 mg/kg/day. Posaconazole trough concentrations ranged from undetectable (<50 ng/mL) up to 3620 ng/mL and were 500, 700 and 1250 ng/mL in 95%, 60% and 25% of patients, respectively. What is new and conclusionsPatients younger than 13 years of age had highly variable trough concentrations, and recommendations for the appropriate dosing of posaconazole oral suspension remain challenging. Until studies are conducted to determine the appropriate dosing of posaconazole in this patient population, therapeutic drug monitoring should be considered to ensure adequate posaconazole exposure. C1 [Jancel, T.] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Shaw, P. A.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Hallahan, C. W.] NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kim, T.] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. [Freeman, A. F.; Holland, S. M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Penzak, S. R.] Univ North Texas Syst, Dept Pharmacotherapy, Coll Pharm, Ft Worth, TX USA. EM timjancel@gmail.com FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This study reflects the views of the authors and should not be construed to represent the views of the US Food and Drug Administration. This research was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. NR 24 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-4727 EI 1365-2710 J9 J CLIN PHARM THER JI J. Clin. Pharm. Ther. PD FEB PY 2017 VL 42 IS 1 BP 75 EP 79 DI 10.1111/jcpt.12483 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI4ZV UT WOS:000392503900011 PM 27982447 ER PT J AU Zhang, ZW Li, MJ Lin, M Soon, GX Greene, T Shen, CY AF Zhang, Zhiwei Li, Meijuan Lin, Min Soon, Guoxing Greene, Tom Shen, Changyu TI Subgroup selection in adaptive signature designs of confirmatory clinical trials SO JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES C-APPLIED STATISTICS LA English DT Article DE Cross-validation; Personalized medicine; Predictive biomarker; Subgroup analysis; Treatment effect heterogeneity ID INDIVIDUALIZED TREATMENT RULES; ENRICHMENT; SUBPOPULATIONS; EFFICIENCY AB The increasing awareness of treatment effect heterogeneity has motivated flexible designs of confirmatory clinical trials that prospectively allow investigators to test for treatment efficacy for a subpopulation of patients in addition to the entire population. If a target subpopulation is not well characterized in the design stage, it can be developed at the end of a broad eligibility trial under an adaptive signature design. The paper proposes new procedures for subgroup selection and treatment effect estimation (for the selected subgroup) under an adaptive signature design. We first provide a simple and general characterization of the optimal subgroup that maximizes the power for demonstrating treatment efficacy or the expected gain based on a specified utility function. This characterization motivates a procedure for subgroup selection that involves prediction modelling, augmented inverse probability weighting and low dimensional maximization. A cross-validation procedure can be used to remove or reduce any resubstitution bias that may result from subgroup selection, and a bootstrap procedure can be used to make inference about the treatment effect in the subgroup selected. The approach proposed is evaluated in simulation studies and illustrated with real examples. C1 [Zhang, Zhiwei] Univ Calif Riverside, Riverside, CA 92521 USA. [Li, Meijuan; Lin, Min; Soon, Guoxing] US FDA, Silver Spring, MD USA. [Greene, Tom] Univ Utah, Sch Med, Salt Lake City, UT USA. [Shen, Changyu] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. RP Zhang, ZW (reprint author), Univ Calif Riverside, Dept Stat, 900 Univ Ave, Riverside, CA 92521 USA. EM zhiwei_zhang@yahoo.com NR 30 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0035-9254 EI 1467-9876 J9 J R STAT SOC C-APPL JI J. R. Stat. Soc. Ser. C-Appl. Stat. PD FEB PY 2017 VL 66 IS 2 BP 345 EP 361 DI 10.1111/rssc.12175 PG 17 WC Statistics & Probability SC Mathematics GA EI9DO UT WOS:000392807800007 ER PT J AU Qu, H Linder, SW Mudalige, TK AF Qu, Haiou Linder, Sean W. Mudalige, Thilak K. TI Surface coating and matrix effect on the electrophoretic mobility of gold nanoparticles: a capillary electrophoresis-inductively coupled plasma mass spectrometry study SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Capillary electrophoresis; Gold nanoparticles; Surface coating; Matrix effect ID FIELD-FLOW FRACTIONATION; COATED SILVER NANOPARTICLES; CLOUD POINT EXTRACTION; SODIUM DODECYL-SULFATE; ENGINEERED NANOMATERIALS; ZONE-ELECTROPHORESIS; DIETARY-SUPPLEMENTS; SIZE DISTRIBUTION; ICP-MS; SPECIATION AB Capillary electrophoresis (CE) is considered as a versatile technique in the size-based separation and speciation of nanomaterials. The electrophoretic mobility is determined by charge and size of an analyte which are affected by the surface composition of nanomaterials. Size-dependent differential electrophoretic mobility is used as a mechanism for size-based separation of nanoparticles. Understanding the effect of surface chemistry on the electrophoretic mobility of nanomaterials in CE is critical in obtaining accurate results in retention-based size calculation. A suite of gold nanoparticles (NPs) varied in sizes with different coatings, including citric acid (CA), lipoic acid (LA), tannic acid (TA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), branched polyethyleneimine (BPEI), and bovine serum albumin (BSA), were selected to evaluate their impact to the migration pattern of gold NPs. Additionally, surface-coated gold NPs dispersed in Suwannee River humic acid (SRHA) solution and fetal bovine serum (FBS) were used to investigate the matrix effect. It was found that the correlation between NP size and relative electrophoretic mobility is highly dependent on the capping agents. The matrix component in the SRHA solution only exhibited limited influence to the migration of NPs while electrophoretic behaviors were drastically altered in the presence of FBS matrix. C1 [Qu, Haiou; Linder, Sean W.; Mudalige, Thilak K.] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Mudalige, TK (reprint author), US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Thilak.Mudalige@fda.hhs.gov NR 37 TC 0 Z9 0 U1 20 U2 20 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 FEB PY 2017 VL 409 IS 4 BP 979 EP 988 DI 10.1007/s00216-016-0012-0 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA EI6QZ UT WOS:000392622200013 PM 27783123 ER PT J AU Dawoud, TM Khatiwara, A Park, SH Davis, ML Baker, CA Ricke, SC Kwon, YM AF Dawoud, Turki M. Khatiwara, Anita Park, Si Hong Davis, Morgan L. Baker, Christopher A. Ricke, Steven C. Kwon, Young Min TI Heat Survival and Phenotype Microarray Profiling of Salmonella Typhimurium Mutants SO CURRENT MICROBIOLOGY LA English DT Article ID ENHANCED THERMAL-RESISTANCE; ESCHERICHIA-COLI; STRAIN VARIABILITY; UNITED-STATES; ENTERICA; RECOMBINATION; ENTERITIDIS; FOOD; INACTIVATION; PATHOGENS AB Contamination of food products by pathogenic microorganisms continues to be a major public health and food industry concern. Non-typhoidal Salmonella species have led to numerous outbreaks associated with various foods. A wide variety of methods have been applied and introduced for treatment of fresh foods to eliminate pathogenic as well as spoilage microorganisms. Salmonella can become exposed to elevated temperatures while associated with hosts such as poultry. In addition, heat treatment is also applied at various stages of processing to retain the shelf life of food products. Despite this, these microorganisms may overcome exposure to such treatments through the efficient expression of stress response mechanisms and result in illness following consumption. Thermal stress induces a range of destructive exposures to bacterial cells such as protein damage and DNA damage caused by reactive oxygen species. In this study, we chose three genes (a dagger recD, a dagger STM14_5307, and a dagger aroD) associated with conditionally essential genes required for different aspects of optimal growth at 42 A degrees C and evaluated the responses of wild type and mutant Salmonella Typhimurium strains to uncover potential mechanisms that may enable survival and resistance under thermal stress. The RecBCD complex that initiates repair of double-stranded DNA breaks through homologous recombination. STM14_5307 is a transcriptional regulator involved in stationary phase growth and inositol metabolism. The gene aroD is involved in metabolism and stationary phase growth. These strains were characterized via high throughput phenotypic profiling in response to two different growth temperatures (37 A degrees C (human host temperature) and 42 A degrees C (poultry host temperature)). The a dagger aroD strain exhibited the highest sensitivity to the various temperatures followed by the a dagger recD and a dagger STM14_5307 strains, respectively. Achieving more understanding of the molecular mechanisms of heat survival may lead to the development of more effective strategies to limit Salmonella in food products through thermal treatment by developing interventions that specifically target the pathways these genes are involved in. C1 [Dawoud, Turki M.; Khatiwara, Anita; Ricke, Steven C.; Kwon, Young Min] Univ Arkansas, Cell & Mol Biol Program, Fayetteville, AR 72701 USA. [Dawoud, Turki M.; Khatiwara, Anita] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Park, Si Hong; Davis, Morgan L.; Baker, Christopher A.; Ricke, Steven C.; Kwon, Young Min] Univ Arkansas, Ctr Food Safety, Fayetteville, AR 72701 USA. [Park, Si Hong; Davis, Morgan L.; Baker, Christopher A.; Ricke, Steven C.] Univ Arkansas, Dept Food Sci, Fayetteville, AR 72701 USA. [Kwon, Young Min] Univ Arkansas, Dept Poultry Sci, Fayetteville, AR 72701 USA. RP Ricke, SC (reprint author), Univ Arkansas, Cell & Mol Biol Program, Fayetteville, AR 72701 USA.; Ricke, SC (reprint author), Univ Arkansas, Ctr Food Safety, Fayetteville, AR 72701 USA.; Ricke, SC (reprint author), Univ Arkansas, Dept Food Sci, Fayetteville, AR 72701 USA. EM sricke@uark.edu FU King Saud University Riyadh, Saudi Arabia; University of Arkansas, Fayetteville, Department of Food Science (FDSC); Food Science Department at the University of Arkansas; U. S. Poultry & Egg Association FX Author Turki Dawoud was supported by a scholarship from King Saud University Riyadh, Saudi Arabia. We thank the University of Arkansas, Fayetteville, Department of Food Science (FDSC) program for supporting a graduate student assistantship as well as the Michael Johnson Scholarship to author C.A.B. Author Morgan L. Davis was also supported by the Food Science Department at the University of Arkansas. The research of author S.C. Ricke was partially supported by a grant from the U. S. Poultry & Egg Association. NR 57 TC 0 Z9 0 U1 1 U2 1 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 FEB PY 2017 VL 74 IS 2 BP 257 EP 267 DI 10.1007/s00284-016-1170-1 PG 11 WC Microbiology SC Microbiology GA EI2FM UT WOS:000392302100014 PM 27999939 ER PT J AU Sam, WJ Roza, O Hon, YY Alfaro, RM Calis, KA Reynolds, JC Yanovski, JA AF Sam, Wai Johnn Roza, Orsolya Hon, Yuen Yi Alfaro, Raul M. Calis, Karim A. Reynolds, James C. Yanovski, Jack A. TI Effects of SLC22A1 Polymorphisms on Metformin-Induced Reductions in Adiposity and Metformin Pharmacokinetics in Obese Children With Insulin Resistance SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE pharmacokinetics; obesity; pediatric; pharmacogenomics; metformin; weight loss ID TYPE-2 DIABETES-MELLITUS; ORGANIC CATION TRANSPORTERS; BODY-MASS INDEX; CLINICAL PHARMACOKINETICS; POPULATION PHARMACOKINETICS; GLUCOSE-TOLERANCE; GENETIC-VARIATION; HEALTHY-SUBJECTS; RENAL CLEARANCE; DOUBLE-BLIND AB Steady-state population pharmacokinetics of a noncommercial immediate-release metformin (hydrochloride) drug product were characterized in 28 severely obese children with insulin resistance. The concentration-time profiles with double peaks were well described by a 1-compartment model with 2 absorption sites. Mean population apparent clearance (CL/F) was 68.1 L/h, and mean apparent volume of distribution (V/F) was 28.8 L. Body weight was a covariate of CL/F and V/F. Estimated glomerular filtration rate was a significant covariate of CL/F (P < .001). SLC22A1 genotype did not significantly affect metformin pharmacokinetics. The response to 6 months of metformin treatment (HbA(1c), homeostasis model assessment for insulin resistance, fasting insulin, and glucose changes) did not differ between SLC22A1 wild-type subjects and carriers of presumably low-activity SLC22A1 alleles. However, SLC22A1 variant carriers had smaller reductions in percentage of total trunk fat after metformin therapy, although the percentage reduction in trunk fat was small. The median % change in trunk fat was -2.20% (-9.00% to 0.900%) and -1.20% (-2.40% to 7.30%) for the SLC22A1 wild-type subjects and variant carriers, respectively. Future study is needed to evaluate the effects of SLC22A1 polymorphisms on metformin-mediated weight reduction in obese children. C1 [Sam, Wai Johnn; Hon, Yuen Yi; Alfaro, Raul M.; Calis, Karim A.] NIH, Clin Pharmacokinet Res Lab, Ctr Clin, Dept Pharm, Bldg 10, Bethesda, MD 20892 USA. [Roza, Orsolya; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Roza, Orsolya] Univ Szeged, Inst Pharmacognosy, Szeged, Hungary. [Hon, Yuen Yi] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Calis, Karim A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Off Clin Director, NIH, Bethesda, MD USA. [Reynolds, James C.] NIH, Div Nucl Med, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,Hatfield Clin Res Ctr, 10 Ctr Div,Bldg 10,Room 1-3330,MSC 1103, Bethesda, MD 20892 USA. EM jy151@nih.gov FU Intramural Research Program of the National Institutes of Health; Clinical Center Pharmacy Department; Eunice Kennedy Shriver National Institute of Child Health and Human Development, Program in Developmental Endocrinology and Genetics grant from the NICHD [1ZIAHD000641]; National Institute forMinority Health and Health Disparities (NIMHD), NIH FX This work was supported by the Intramural Research Program of the National Institutes of Health, Clinical Center Pharmacy Department and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Program in Developmental Endocrinology and Genetics grant 1ZIAHD000641 from the NICHD, with supplemental funding from the National Institute forMinority Health and Health Disparities (NIMHD), NIH (to Dr. Yanovski). There was no commercial sponsorship. The funding organizations played no role in the design or conduct of the study; the collection, management, analysis, or interpretation of data; or the preparation of the article. NR 48 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD FEB PY 2017 VL 57 IS 2 BP 219 EP 229 DI 10.1002/jcph.796 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH8JI UT WOS:000392017700008 PM 27407018 ER PT J AU Lee, CT Chen, J Kindberg, AA Bendriem, RM Spivak, CE Williams, MP Richie, CT Handreck, A Mallon, BS Lupica, CR Lin, DT Harvey, BK Mash, DC Freed, WJ AF Lee, Chun-Ting Chen, Jia Kindberg, Abigail A. Bendriem, Raphael M. Spivak, Charles E. Williams, Melanie P. Richie, Christopher T. Handreck, Annelie Mallon, Barbara S. Lupica, Carl R. Lin, Da-Ting Harvey, Brandon K. Mash, Deborah C. Freed, William J. TI CYP3A5 Mediates Effects of Cocaine on Human Neocorticogenesis: Studies using an In Vitro 3D Self-Organized hPSC Model with a Single Cortex-Like Unit SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID PLURIPOTENT STEM-CELLS; HUMAN BRAIN; DRUG-METABOLISM; CEREBRAL-CORTEX; NEOCORTEX; EXPOSURE; NEURONS; AUTISM; PROLIFERATION; SCHIZOPHRENIA AB Because of unavoidable confounding variables in the direct study of human subjects, it has been difficult to unravel the effects of prenatal cocaine exposure on the human fetal brain, as well as the cellular and biochemical mechanisms involved. Here, we propose a novel approach using a human pluripotent stem cell (hPSC)-based 3D neocortical organoid model. This model retains essential features of human neocortical development by encompassing a single self-organized neocortical structure, without including an animal-derived gelatinous matrix. We reported previously that prenatal cocaine exposure to rats during the most active period of neural progenitor proliferation induces cytoarchitectural changes in the embryonic neocortex. We also identified a role of CYP450 and consequent oxidative ER stress signaling in these effects. However, because of differences between humans and rodents in neocorticogenesis and brain CYP metabolism, translation of the research findings from the rodent model to human brain development is uncertain. Using hPSC 3D neocortical organoids, we demonstrate that the effects of cocaine are mediated through CYP3A5-induced generation of reactive oxygen species, inhibition of neocortical progenitor cell proliferation, induction of premature neuronal differentiation, and interruption of neural tissue development. Furthermore, knockdown of CYP3A5 reversed these cocaine-induced pathological phenotypes, suggesting CYP3A5 as a therapeutic target to mitigate the deleterious neurodevelopmental effects of prenatal cocaine exposure in humans. Moreover, 3D organoid methodology provides an innovative platform for identifying adverse effects of abused psychostimulants and pharmaceutical agents, and can be adapted for use in neurodevelopmental disorders with genetic etiologies. C1 [Lee, Chun-Ting; Chen, Jia; Kindberg, Abigail A.; Bendriem, Raphael M.; Spivak, Charles E.; Williams, Melanie P.; Richie, Christopher T.; Lupica, Carl R.; Lin, Da-Ting; Harvey, Brandon K.; Freed, William J.] Natl Inst Drug Abuse, IRP, NIH, Baltimore, MD USA. [Lee, Chun-Ting; Mash, Deborah C.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Handreck, Annelie] Univ Vet Med, Dept Pharmacol Toxicol & Pharm, Hannover, Germany. [Mallon, Barbara S.] NINDS, NIH Stem Cell Unit, IRP, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Lee, CT (reprint author), US FDA, Ctr Biol Evaluat & Res, Bldg 52,Room 1121,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Chun-Ting.Lee@fda.hhs.gov FU National Institute on Drug Abuse FX A patent application has been filed for the 3D model (WJ Freed and C-T Lee). This work was supported by the Intramural Research Program of the National Institute on Drug Abuse. NR 46 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2017 VL 42 IS 3 BP 774 EP 784 DI 10.1038/npp.2016.156 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EI0LQ UT WOS:000392166400021 PM 27534267 ER PT J AU Arya, V Zhou, T Yang, X Vaidyanathan, J Zhang, L AF Arya, V. Zhou, T. Yang, X. Vaidyanathan, J. Zhang, L. TI STATISTICAL ANALYSIS TO COMPARE VARIOUS IN VITRO CRITERIA FOR PREDICTING P-GLYCOPROTEIN TRANSPORTER MEDIATED DRUG-DRUG INTERACTIONS IN VIVO SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Arya, V.; Yang, X.; Vaidyanathan, J.; Zhang, L.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Zhou, T.] US FDA, Silver Spring, MD USA. NR 1 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PI-007 BP S21 EP S21 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700059 ER PT J AU Arya, V Vaidyanathan, J Yoshida, K Yang, X Zhang, L AF Arya, V. Vaidyanathan, J. Yoshida, K. Yang, X. Zhang, L. TI STATISTICAL ANALYSIS TO COMPARE VARIOUS IN VITRO CRITERIA FOR PREDICTING ORGANIC ANION TRANSPORTING POLYPEPTIDES 1B1 (OATP1B1)-MEDIATED DRUG INTERACTIONS IN VIVO SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Arya, V.; Vaidyanathan, J.; Yang, X.; Zhang, L.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Yoshida, K.] US FDA, Silver Spring, MD USA. 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PI-008 BP S21 EP S22 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700060 ER PT J AU Li, W Nallani, SC Calderon, SN Fields, E Hertz, SH Xu, Y Sahajwalla, CG AF Li, W. Nallani, S. C. Calderon, S. N. Fields, E. Hertz, S. H. Xu, Y. Sahajwalla, C. G. TI A REVIEW OF SIX OPIOID ANALGESICS WITH ABUSE-DETERRENT LABELING. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Li, W.; Nallani, S. C.; Xu, Y.; Sahajwalla, C. G.] US FDA, DCP2, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Calderon, S. N.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Fields, E.; Hertz, S. H.] US FDA, Div Anesthesia Analgesia & Addict Prod, 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PI-064 BP S36 EP S36 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700116 ER PT J AU Shugg, T Xu, J Younis, IR AF Shugg, T. Xu, J. Younis, I. R. TI HOW DRUG-DRUG INTERACTIONS (DDIS) INFORM DRUG LABELING: A SURVEY OF APPROVED NEW MOLECULAR ENTITIES (NMES) FROM 1998 TO 2015. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Shugg, T.; Xu, J.; Younis, I. R.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PI-103 BP S47 EP S47 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700155 ER PT J AU Woo, EJ AF Woo, Emily Jane TI Letter to the Editor: On Patient Safety: Do You Say "I'm Sorry" to Patients? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Letter ID WORDS C1 [Woo, Emily Jane] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 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 5 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD FEB PY 2017 VL 475 IS 2 BP 570 EP 571 DI 10.1007/s11999-016-5168-6 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA EH7CX UT WOS:000391931600050 PM 27858245 ER PT J AU Ahmed, MA Florian, J Madabushi, R Younis, IR AF Ahmed, M. A. Florian, J. Madabushi, R. Younis, I. R. TI COMPARISON OF NON-COMPARTMENTAL ANALYSIS (NCA) ESTIMATION AND POPULATION PHARMACOKINETIC (PPK) PREDICTIONS OF EXPOSURE CHANGES AS A FUNCTION OF RENAL IMPAIRMENT SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Ahmed, M. A.] Univ Minnesota, Minneaplolis, MN USA. [Florian, J.; Madabushi, R.; Younis, I. R.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA OI-002 BP S97 EP S97 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700349 ER PT J AU Ahmed, MA Florian, J Madabushi, R Younis, IR AF Ahmed, M. A. Florian, J. Madabushi, R. Younis, I. R. TI COMPARISON OF NON-COMPARTMENTAL ANALYSIS (NCA) ESTIMATION AND POPULATION PHARMACOKINETIC (PPK) PREDICTIONS OF EXPOSURE CHANGES AS A FUNCTION OF RENAL IMPAIRMENT SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Ahmed, M. A.] Univ Minnesota, Minneapolis, MN USA. [Florian, J.; Madabushi, R.; Younis, I. R.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PT-001 BP S5 EP S5 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700002 ER PT J AU Ahn, J AbuAsal, B Heil, E Pandit, NS Gopalakrishnan, M AF Ahn, J. AbuAsal, B. Heil, E. Pandit, N. S. Gopalakrishnan, M. TI DOES GASTRIC BYPASS SURGERY AFFECT BIOAVAILABILITY OF ORALLY ADMINISTERED DARUNAVIR? A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING APPROACH SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Ahn, J.; Heil, E.; Pandit, N. S.; Gopalakrishnan, M.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. [AbuAsal, B.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PII-048 BP S65 EP S66 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700233 ER PT J AU Akbar, MA Park, SA Kim, MJ Shon, J Lee, L Ahn, M Li, L Yu, C AF Akbar, M. A. Park, S. -A. Kim, M. -J. Shon, J. Lee, L. Ahn, M. Li, L. Yu, C. TI ASSESSMENT OF UNINTENDED INTERPERSONAL TRANSFERABILITY OF TOPICAL TESTOSTERONE PRODUCTS AND MITIGATION STRATEGIES SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Akbar, M. A.; Park, S. -A.; Kim, M. -J.; Shon, J.; Lee, L.; Ahn, M.; Li, L.; Yu, C.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PII-150 BP S93 EP S93 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700335 ER PT J AU Arwood, MJ Deng, J Drozda, K Nutescu, EA Schmidt, S Duarte, JD Cavallari, LH AF Arwood, M. J. Deng, J. Drozda, K. Nutescu, E. A. Schmidt, S. Duarte, J. D. Cavallari, L. H. TI CLINICAL IMPLEMENTATION OF WARFARIN PHARMACOGENETICS IN A REAL-WORLD SETTING: A PROPOSAL FOR A NEW PHARMACOGENETIC DOSING APPROACH FOR DIVERSE PATIENT POPULATIONS SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Arwood, M. J.; Duarte, J. D.; Cavallari, L. H.] Univ Florida, Gainesville, FL USA. [Deng, J.; Schmidt, S.] Univ Florida, Orlando, FL USA. [Drozda, K.] US FDA, Silver Spring, MD USA. [Nutescu, E. A.] Univ Illinois, 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PT-002 BP S5 EP S5 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700003 ER PT J AU Bae, S Kim, I AF Bae, S. Kim, I. TI A SURVEY OF THE EFFECTS OF SOFT FOOD VEHICLES ON PHARMACOKINETICS FOR THE ALTERNATIVE DOSING METHOD. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Bae, S.] Univ Iowa, Iowa City, IA USA. [Kim, I.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PI-054 BP S34 EP S34 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700106 ER PT J AU Basu, S Yang, H Schmidt, S Fang, L Lesko, L AF Basu, S. Yang, H. Schmidt, S. Fang, L. Lesko, L. TI PHYSIOLOGICALLY BASED ABSORPTION MODELING AS A TOOL TO EVALUATE THE BIOEQUIVALENCE OF METOPROLOL ER PRODUCTS SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Basu, S.; Yang, H.; Schmidt, S.; Lesko, L.] Univ Florida, Orlando, FL USA. [Fang, L.] US FDA, Off Gener Drugs, Silver Spring, FL USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PI-010 BP S22 EP S22 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700062 ER PT J AU Dong, Z Wu, F Zhao, P Lee, SC Zhang, L Seo, P Zhang, L AF Dong, Z. Wu, F. Zhao, P. Lee, S. -C. Zhang, L. Seo, P. Zhang, L. TI APPLICATION OF PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL (PBPK) TO PREDICT PH-DEPENDENT DRUG-DRUG INTERACTION (DDI) FORWEAK BASE DRUGS (WBDS) SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Dong, Z.] ORISE, Oak Ridge, TN USA. [Wu, F.; Seo, P.] US FDA, Off New Drug Prod, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Zhao, P.; Lee, S. -C.; Zhang, L.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Zhang, L.] US FDA, Off Policy Pharmaceut Qual, Off Pharmaceut Qual, 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PI-028 BP S27 EP S27 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700080 ER PT J AU Goldman, JL Chung, WH Lee, B Hoetzenecker, W Micheletti, RG Yasuda, SU Margolis, DJ Shear, NH Struewing, JP Pirmohamed, M AF Goldman, J. L. Chung, W-H Lee, B. Hoetzenecker, W. Micheletti, R. G. Yasuda, S. Usdin Margolis, D. J. Shear, N. H. Struewing, J. P. Pirmohamed, M. TI ADVERSE DRUG REACTION CAUSALITY ASSESSMENT TOOLS FOR DRUG-INDUCED STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS: ROOM FOR IMPROVEMENT. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Goldman, J. L.; Lee, B.] Childrens Mercy Hosp, Kansas City, MO 64108 USA. [Chung, W-H] Chang Gung Mem Hosp, Taipei, Taiwan. [Chung, W-H] Chang Gung Mem Hosp, Linkou, Taiwan. [Chung, W-H] Chang Gung Mem Hosp, Keelung, Taiwan. [Hoetzenecker, W.] Univ Zurich, Zurich, Switzerland. [Micheletti, R. G.] Hosp Univ Penn, 3400 Spruce St, Philadelphia, PA 19104 USA. [Yasuda, S. Usdin] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Margolis, D. J.] Univ Penn, Philadelphia, PA 19104 USA. [Shear, N. H.] Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Shear, N. H.] Univ Toronto, Toronto, ON, Canada. [Struewing, J. P.] NHGRI, Bethesda, MD 20892 USA. [Pirmohamed, M.] Univ Liverpool, Liverpool, Merseyside, England. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PI-037 BP S30 EP S30 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700089 ER PT J AU Hsu, V Pan, Y Zhao, P AF Hsu, V. Pan, Y. Zhao, P. TI NEW SUBMISSIONS TO THE US FOOD AND DRUG ADMINISTRATION (2014-2016) CONFIRMED THE PREDICTIVE PERFORMANCE OF PBPK FOR THE EFFECT OF CYP 3A MODULATORS ON SUBSTRATE DRUGS SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Hsu, V.; Pan, Y.; Zhao, P.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PI-132 BP S53 EP S54 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700184 ER PT J AU Hsueh, CH Zhao, P Hsu, W Zhang, L Giacomini, K Huang, S AF Hsueh, C. -H. Zhao, P. Hsu, W. Zhang, L. Giacomini, K. Huang, S. TI INTACT NEPHRON THEORY MAY NOT FULLY EXPLAIN THE EFFECT OF SEVERE RENAL IMPAIRMENT FOR DRUGS ACTIVELY SECRETED VIA RENAL ORGANIC ANION TRANSPORTERS SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Hsueh, C. -H.] Univ Calif San Francisco, US FDA, San Francisco, CA 94143 USA. [Zhao, P.; Hsu, W.; Zhang, L.; Huang, S.] US FDA, Silver Spring, MD USA. [Giacomini, K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PWIII-003 BP S18 EP S19 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700050 ER PT J AU Hsueh, CH Zhao, P Hsu, W Zhang, L Giacomini, K Huang, S AF Hsueh, C-H Zhao, P. Hsu, W. Zhang, L. Giacomini, K. Huang, S. TI INTACT NEPHRON THEORY MAY NOT FULLY EXPLAIN THE EFFECT OF SEVERE RENAL IMPAIRMENT FOR DRUGS ACTIVELY SECRETED VIA RENAL ORGANIC ANION TRANSPORTERS SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Hsueh, C-H] Univ Calif San Francisco, US FDA, San Francisco, CA 94143 USA. [Zhao, P.; Hsu, W.; Zhang, L.; Huang, S.] US FDA, Silver Spring, MD USA. [Giacomini, K.] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PT-027 BP S12 EP S13 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700028 ER PT J AU Li, H Yu, J Liu, C Wang, Y AF Li, H. Yu, J. Liu, C. Wang, Y. TI TIME DEPENDENT PK OF PEMBROLIZUMAB AND IMPLICATION IN EXPOSURE-RESPONSE (E-R) ANALYSIS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Li, H.; Yu, J.; Liu, C.; Wang, Y.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PII-076 BP S73 EP S73 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700261 ER PT J AU Li, M Pan, Y Zhao, P AF Li, M. Pan, Y. Zhao, P. TI APPLICATION OF PBPK MODELING TO PREDICT FOOD EFFECT ON ORAL DRUG ABSORPTION: A REVIEW OF SCIENTIFIC PUBLICATIONS AND REGULATORY SUBMISSIONS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Li, M.; Pan, Y.; Zhao, P.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PI-063 BP S36 EP S36 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700115 ER PT J AU Liu, C AF Liu, C. TI THE TIME DEPENDENT PHARMACOKINETICS OF NIVOLUMAB IN PATIENTS WITH SOLID TUMOR AND THE IMPLICATION IN EXPOSURE-RESPONSE ANALYSIS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Liu, C.] US FDA, Silver Spring, MD USA. NR 0 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 FEB PY 2017 VL 101 IS S1 MA PII-083 BP S75 EP S75 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700268 ER PT J AU Manerikar, AA Nallani, SC Fields, EW Xu, Y Sahajwalla, CG AF Manerikar, A. A. Nallani, S. C. Fields, E. W. Xu, Y. Sahajwalla, C. G. TI PLACEBO-RESPONSE IN ANALGESIC CLINICAL TRIALS SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Manerikar, A. A.; Nallani, S. C.; Fields, E. W.; Xu, Y.; Sahajwalla, C. G.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PI-071 BP S38 EP S38 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700123 ER PT J AU Marathe, D Yang, Y Shang, E Li, S Zhao, P Lee, SC Mehta, R Omokaro, SO Dimicksantos, L Davis-Williams, A Meyer, J Egan, A Roman, D Bashaw, ED Sinha, V Mehrotra, N AF Marathe, D. Yang, Y. Shang, E. Li, S. Zhao, P. Lee, S. -C. Mehta, R. Omokaro, S. O. Dimicksantos, L. Davis-Williams, A. Meyer, J. Egan, A. Roman, D. Bashaw, E. D. Sinha, V. Mehrotra, N. TI DOSING CONSIDERATIONS FOR OBETICHOLIC ACID (OCA) IN THE TREATMENT OF PRIMARY BILIARY CHOLANGITIS (PBC). SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Marathe, D.; Yang, Y.; Shang, E.; Li, S.; Zhao, P.; Lee, S. -C.; Mehta, R.; Omokaro, S. O.; Dimicksantos, L.; Davis-Williams, A.; Meyer, J.; Egan, A.; Roman, D.; Bashaw, E. D.; Sinha, V.; Mehrotra, N.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PII-090 BP S77 EP S77 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700275 ER PT J AU Qosa, H Avaritt, B Volpe, D AF Qosa, H. Avaritt, B. Volpe, D. TI ASSESSMENT OF A BASIC MODEL FOR PREDICTING POTENTIAL CLINICAL DRUG INTERACTIONS MEDIATED BY CYP3A4 INHIBITION. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Qosa, H.; Avaritt, B.; Volpe, D.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PI-089 BP S43 EP S43 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700141 ER PT J AU Racz, R Burkhart, K AF Racz, R. Burkhart, K. TI UTILIZATION OF INFORMATICS TOOLS TO MECHANISTICALLY ANALYZE DRUGS ASSOCIATED WITH SEROTONIN SYNDROME. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Racz, R.; Burkhart, K.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PI-091 BP S43 EP S44 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700143 ER PT J AU Rekic, D Sachar, M Zhao, P Reynolds, KS Zhang, L Huang, SM AF Rekic, D. Sachar, M. Zhao, P. Reynolds, K. S. Zhang, L. Huang, S. -M. TI SYSTEMATIC REVIEWAND META-ANALYSIS OF DRUG-DRUG INTERACTION EFFECT SIZE BETWEEN COMMONLY-USED CYP INDEX SUBSTRATES AND PERPETRATORS SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Rekic, D.; Sachar, M.; Zhao, P.; Reynolds, K. S.; Zhang, L.; Huang, S. -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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PII-118 BP S84 EP S85 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700303 ER PT J AU Sharma, VD Trame, MN Schmidt, S Fang, LL Lesko, LJ AF Sharma, V. D. Trame, M. N. Schmidt, S. Fang, L. L. Lesko, L. J. TI DEVELOPMENT OF A PHARMACOKINETIC (PK)/PHARMACODYNAMIC (PD) MODEL TO EVALUATE THE IMPACT OF PK VARIATION ON PD FOR EXTENDED RELEASE METOPROLOL FORMULATIONS SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Sharma, V. D.; Trame, M. N.; Schmidt, S.; Lesko, L. J.] Univ Florida, Dept Pharmaceut, Ctr Pharmacometr & Syst Pharmacol, Orlando, FL USA. [Fang, L. L.] US FDA, Off Gener Drugs, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PT-018 BP S9 EP S9 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700019 ER PT J AU Tan, ML Yoshida, K Zhao, P Zhang, L Galetin, A Huang, SM AF Tan, M-L Yoshida, K. Zhao, P. Zhang, L. Galetin, A. Huang, S-M TI COMPARISON OF THE EFFECT OF CHRONIC KIDNEY DISEASE (CKD) ON PHARMACOKINETICS OF CYP1A2, CYP2C8, CYP2C9 AND CYP2C19 SUBSTRATES SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Tan, M-L; Yoshida, K.; Zhao, P.; Zhang, L.; Huang, S-M] US FDA, Silver Spring, MD USA. [Galetin, A.] Univ Manchester, Manchester, Lancs, 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PT-020 BP S10 EP S11 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700021 ER PT J AU Wu, YS Bhattaram, A Earp, J Florian, J Grillo, J Krudys, K Lee, J Li, F Li, H Liu, C Liu, J Ma, L Marathe, A Marathe, D Mulugeta, Y Rekic, D Wang, X Wang, Y Xu, Y Yang, Y Younis, I Yu, J Zhao, P Zheng, N Zhuang, L Sinha, V Mehrotra, N AF Wu, Y. S. Bhattaram, A. Earp, J. Florian, J. Grillo, J. Krudys, K. Lee, J. Li, F. Li, H. Liu, C. Liu, J. Ma, L. Marathe, A. Marathe, D. Mulugeta, Y. Rekic, D. Wang, X. Wang, Y. Xu, Y. Yang, Y. Younis, I. Yu, J. Zhao, P. Zheng, N. Zhuang, L. Sinha, V. Mehrotra, N. TI IMPACT OF POPULATION PHARMACOKINETIC ANALYSES ON LABELING: A REVIEW OF NEW MOLECULAR ENTITIES LABELS APPROVED BETWEEN 2011 AND 2015 SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Wu, Y. S.] Univ Pittsburgh, Sch Pharm, Pittsburgh, PA USA. [Bhattaram, A.; Earp, J.; Florian, J.; Grillo, J.; Krudys, K.; Lee, J.; Li, F.; Li, H.; Liu, C.; Liu, J.; Ma, L.; Marathe, A.; Marathe, D.; Mulugeta, Y.; Rekic, D.; Wang, X.; Wang, Y.; Xu, Y.; Yang, Y.; Younis, I.; Yu, J.; Zhao, P.; Zheng, N.; Zhuang, L.; Mehrotra, N.] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. [Sinha, V.] Merck & Co Inc, N Wales, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PII-142 BP S91 EP S91 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700327 ER PT J AU Yang, Y Rekic, D Galetin, A Zhao, P AF Yang, Y. Rekic, D. Galetin, A. Zhao, P. TI IMPACT OF ORGAN SPECIFIC INDUCTION ON PREDICTING THE EFFECT OF EFAVIRENZ AS A MODERATE CYP3A INDUCER USING PBPK: ANALYSIS OF MODELS SUBMITTED TO THE US FOOD AND DRUG ADMINISTRATION SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Yang, Y.; Rekic, D.; Zhao, P.] US FDA, Silver Spring, MD USA. [Galetin, A.] Univ Manchester, Ctr Appl Pharmacokinet Res, Manchester, Lancs, 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PII-147 BP S93 EP S93 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700332 ER PT J AU Zou, L Zhang, X Ni, Z Tsakalozou, E Giacomini, KM AF Zou, L. Zhang, X. Ni, Z. Tsakalozou, E. Giacomini, K. M. TI EXCIPIENTS INHIBIT HUMAN ORGANIC ANION TRANSPORTING PEPTIDE 2B1 (OATP2B1)-MEDIATED INTESTINAL UPTAKE OF LEVOTHYROXINE SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 15-18, 2017 CL Washington, DC SP Amer Soc Clin Pharmacol & Therapeut C1 [Zou, L.; Giacomini, K. M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Zhang, X.; Ni, Z.; Tsakalozou, E.] US FDA, Div Quantitat Methods & Modeling, Off Res & Stand, Off Gener Drugs, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2017 VL 101 IS S1 MA PT-024 BP S12 EP S12 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH7EM UT WOS:000391935700025 ER PT J AU Al-Taher, F Cappozzo, J Zweigenbaum, J Lee, HJ Jackson, L Ryu, D AF Al-Taher, Fadwa Cappozzo, Jack Zweigenbaum, Jerry Lee, Hyun Jung Jackson, Lauren Ryu, Dojin TI Detection and quantitation of mycotoxins in infant cereals in the US market by LC-MS/MS using a stable isotope dilution assay SO FOOD CONTROL LA English DT Article DE Multi-mycotoxin; Infant cereals; Internal standard; LC-MS/MS; Stable isotope dilution analysis ID TANDEM MASS-SPECTROMETRY; BABY FOODS; OCHRATOXIN-A; CHILD HEALTH; AFLATOXIN; PRODUCTS; CONTAMINATION; FORMULAS; B-1 AB The aim of this study was to develop an analytical method for the simultaneous determination of aflatoxins B-1, B-2, G(1), G(2), ochratoxin A, fumonisins B-1 and B-2, zearalenone, deoxynivalenol, T-2 toxin, and HT-2 toxin in infant cereals using rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS). Another goal was to survey infant cereals purchased in the United States for the presence and amounts of 11 mycotoxins. Separation of the mycotoxins was accomplished using ultra-high performance liquid chromatography (UHPLC) with <10 min analysis time. The toxins were then detected by dynamic multiple reaction monitoring (dMRM) in positive electrospray ionization mode. Due to matrix effects, [C-13]-uniformly labeled mycotoxins were added to the sample extracts prior to LC-MS/MS analysis. Overall recoveries of mycotoxins were 81-130% in rice, 70-119% in barley, 87-123% in oat, and 82-127% in mixed-grain cereals with lower recoveries for fumonisins B1 and B2, (33-67%) at three spiking levels (12.5, 25 and 50 ng/g). The relative standard deviation was <20% for all analytes in the infant cereals. When this method was applied to measure mycotoxin concentrations in infant cereals (n = 64) purchased in the U.S. in 2012, 78% of infant cereals were found to be contaminated with at least one of these mycotoxins. None of the infant cereals exceeded the established regulatory limits in the United States for any of the analyzed mycotoxins. However, a total of 21 samples exceeded the European Union maximum limits for three of the mycotoxins including aflatoxin B-1, ochratoxin A and zearalenone. Results of this study suggest that cereals intended for infants should be routinely monitored for mycotoxin content. Published by Elsevier Ltd. C1 [Al-Taher, Fadwa; Cappozzo, Jack] IIT, Inst Food Safety & Hlth, 6502 S Archer Rd, Bedford Pk, IL 60501 USA. [Zweigenbaum, Jerry] Agilent Technol, 2850 Centerville Rd, Wilmington, DE 19808 USA. [Lee, Hyun Jung; Ryu, Dojin] Univ Idaho, Sch Food Sci, 875 Perimeter Dr MS 2312, Moscow, ID 83844 USA. [Jackson, Lauren] US FDA, Inst Food Safety & Hlth, 6502 S Archer Rd, Bedford Pk, IL 60501 USA. RP Ryu, D (reprint author), Univ Idaho, Sch Food Sci, 875 Perimeter Dr MS 2312, Moscow, ID 83844 USA.; Jackson, L (reprint author), US FDA, Inst Food Safety & Hlth, 6502 S Archer Rd, Bedford Pk, IL 60501 USA. EM Lauren.Jackson@fda.hhs.gov; dryu@uidaho.edu FU Agriculture and Food Research Initiative Competitive Grant from the USDA National Institute of Food and Agriculture [2011-67005-20676]; U.S. Food and Drug Administration (FDA); Institute for Food Safety and Health FX This project was supported by Agriculture and Food Research Initiative Competitive Grant No. 2011-67005-20676 from the USDA National Institute of Food and Agriculture and by the U.S. Food and Drug Administration (FDA) and the Institute for Food Safety and Health. We would like to thank Elisabeth Varga and Franz Berthiller of the Christian Doppler Laboratory of the Mycotoxin Metabolism and Center for Analytical Chemistry (Tulin, Austria) for their help in providing training on the stable isotope dilution assay method. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the U.S. FDA. NR 46 TC 2 Z9 2 U1 18 U2 19 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-7135 EI 1873-7129 J9 FOOD CONTROL JI Food Control PD FEB PY 2017 VL 72 BP 27 EP 35 DI 10.1016/j.foodcont.2016.07.027 PN A PG 9 WC Food Science & Technology SC Food Science & Technology GA EF7OD UT WOS:000390518000005 ER PT J AU Ben Mansour, A Bakke, MJ Guerbej, H Berriche, Z Samaali, M Shaikh, B Sasanya, J Horsberg, TE AF Ben Mansour, A. Bakke, M. J. Guerbej, H. Berriche, Z. Samaali, M. Shaikh, B. Sasanya, J. Horsberg, T. E. TI Disposition of C-14-flumequine in sea bream (Sparus auratus) after single intraperitoneal administration SO FOOD CONTROL LA English DT Article; Proceedings Paper CT FAO/IAEA International Symposium on Food Safety and Quality - Applications of Nuclear and Related Techniques CY NOV 10-13, 2014 CL Vienna, AUSTRIA SP Food & Agr Org, Int Atom Energy Agcy, Food & Environm Protect Subprogramme DE Flumequine; Pharmacokinetics; Tissue distribution; Sea bream; Whole body autoradiography; Liquid scintillation counting ID SALMON SALMO-SALAR; HALIBUT HIPPOGLOSSUS-HIPPOGLOSSUS; EEL ANGUILLA-ANGUILLA; TURBOT SCOPHTHALMUS-MAXIMUS; ATLANTIC SALMON; DOSE PHARMACOKINETICS; OXOLINIC ACID; TISSUE DISTRIBUTION; DORSAL AORTA; FRESH-WATER AB This study was conducted to evaluate the pharmacokinetics of flumequine following intraperitoneal administration of C-14-Flumequine (12 mg/kg, 100 mu Ci/kg) in sea bream (Sparus auratus). Three fish (147 +/- 29 g) were collected at various time points ranging from 0.5 h to 144 h post administration. Absorption, distribution and elimination were studied using whole body autoradiography and liquid scintillation counting whereupon the concentration of flumequine equivalent versus time was evaluated in major organs and tissues (liver, bile, heart, brain, blood, kidney, intestine, spleen, red and white muscle). An agreement between the data obtained from whole body autoradiography and liquid scintillation counting was obserired. A rapid and extensive distribution of flumequine to the major organs 0.5 h after dosing was recorded. The main route of elimination appeared to be biliary excretion due to the high concentration of radioactivity in the bile and the prolonged elimination phase compared to others tissues. The elimination of flumequine from the blood followed a two compartmental model with half life of the first phase and second phase being 0.98 h and 21.4 h respectively. The maximum flumequine recorded in blood (C-max) was 9.09 mg/kg at 0.78 h (T-max.). Only traces of drugs were observed in the major tissues of the fish 72 h after administration. Based on the current results and the elimination in edible tissues in particular, flumequine seems to be an excellent treatment candidate for sea bream. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Ben Mansour, A.; Berriche, Z.; Samaali, M.] Natl Ctr Nucl Sci & Technol, Lab Radiochem, Technopk Sidi Thabet, Sidi Thabet 2020, Tunisia. [Bakke, M. J.; Horsberg, T. E.] Norwegian Univ Lifesci, Sect Pharmacol & Toxicol, Dept Food Safety & Infect Biol, POB 8146 Dep, N-0033 Oslo, Norway. [Guerbej, H.] Natl Inst Marine Sci & Technol, Biodivers & Biotechnol Lab, Route Khniss,BP 59, Monastir 5000, Tunisia. [Shaikh, B.] US FDA, Div Residue Chem, Off Res, CVM, 8401 Muirkirk Rd, Laurel, MD 20708 USA. [Sasanya, J.] IAEA, Dept Nucl Sci & Applicat, Food & Environm Protect Sect, Wagramer Str 5, A-1400 Vienna, Austria. RP Ben Mansour, A (reprint author), Natl Ctr Nucl Sci & Technol, Lab Radiochem, Technopk Sidi Thabet, Sidi Thabet 2020, Tunisia. EM benmansour.aida@gmail.com NR 37 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-7135 EI 1873-7129 J9 FOOD CONTROL JI Food Control PD FEB PY 2017 VL 72 BP 198 EP 204 DI 10.1016/j.foodcont.2016.05.023 PN B PG 7 WC Food Science & Technology SC Food Science & Technology GA EF9EM UT WOS:000390633500006 ER PT J AU Vasudevan, S Patel, K Welle, C AF Vasudevan, Srikanth Patel, Kunal Welle, Cristin TI Rodent model for assessing the long term safety and performance of peripheral nerve recording electrodes SO JOURNAL OF NEURAL ENGINEERING LA English DT Article DE peripheral nerve interface; intrafasicular electrodes; neural interface; neuroprosthetic; safety; performance ID UPPER-LIMB AMPUTEES; RAT SCIATIC-NERVE; INTRAFASCICULAR ELECTRODES; MICROELECTRODE ARRAY; CUFF ELECTRODE; INTERFACE; STIMULATION; BIOCOMPATIBILITY; IMPLANTATION; ABANDONMENT AB Objective. In the US alone, there are approximately 185 000 cases of limb amputation annually, which can reduce the quality of life for those individuals. Current prosthesis technology could be improved by access to signals from the nervous system for intuitive prosthesis control. After amputation, residual peripheral nerves continue to convey motor signals and electrical stimulation of these nerves can elicit sensory percepts. However, current technology for extracting information directly from peripheral nerves has limited chronic reliability, and novel approaches must be vetted to ensure safe long-term use. The present study aims to optimize methods to establish a test platform using rodent model to assess the long term safety and performance of electrode interfaces implanted in the peripheral nerves. Approach. Floating Microelectrode Arrays (FMA, Microprobes for Life Sciences) were implanted into the rodent sciatic nerve. Weekly in vivo recordings and impedance measurements were performed in animals to assess performance and physical integrity of electrodes. Motor (walking track analysis) and sensory (Von Frey) function tests were used to assess change in nerve function due to the implant. Following the terminal recording session, the nerve was explanted and the health of axons, myelin and surrounding tissues were assessed using immunohistochemistry (IHC). The explanted electrodes were visualized under high magnification using scanning electrode microscopy (SEM) to observe any physical damage. Main results. Recordings of axonal action potentials demonstrated notable session-to-session variability. Impedance of the electrodes increased upon implantation and displayed relative stability until electrode failure. Initial deficits in motor function recovered by 2 weeks, while sensory deficits persisted through 6 weeks of assessment. The primary cause of failure was identified as lead wire breakage in all of animals. IHC indicated myelinated and unmyelinated axons near the implanted electrode shanks, along with dense cellular accumulations near the implant site. Scanning electron microscopy (SEM) showed alterations of the electrode insulation and deformation of electrode shanks. Significance. We describe a comprehensive testing platform with applicability to electrodes that record from the peripheral nerves. This study assesses the long term safety and performance of electrodes in the peripheral nerves using a rodent model. Under this animal test platform, FMA electrodes record single unit action potentials but have limited chronic reliability due to structural weaknesses. Future work will apply these methods to other commercially-available and novel peripheral electrode technologies. C1 [Vasudevan, Srikanth; Patel, Kunal; Welle, Cristin] US FDA, Div Biomed Phys, Off Sci & Engn Lab, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Patel, Kunal] Univ Maryland, Coll Comp Math & Nat Sci, College Pk, MD 20742 USA. [Welle, Cristin] Univ Colorado, Anschutz Med Ctr, Dept Neurosurg & Bioengn, Aurora, CO USA. RP Welle, C (reprint author), US FDA, Div Biomed Phys, Off Sci & Engn Lab, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM cristin.welle@ucdenver.edu FU Defense Advanced Research Projects Agency (DARPA); Biotechnology Technology Office (BTO); Hand Proprioception and Touch Interfaces (HAPTIX) Program; US Food and Drug Administration [DARPA-FDA IAA 224-14-6009] FX This research project was supported by the Defense Advanced Research Projects Agency (DARPA), Biotechnology Technology Office (BTO), Hand Proprioception and Touch Interfaces (HAPTIX) Program (Program Manager: Douglas J Weber) through an Interagency Agreement with the US Food and Drug Administration (DARPA-FDA IAA 224-14-6009). NR 64 TC 0 Z9 0 U1 10 U2 10 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1741-2560 EI 1741-2552 J9 J NEURAL ENG JI J. Neural Eng. PD FEB PY 2017 VL 14 IS 1 AR 016008 DI 10.1088/1741-2552/14/1/016008 PG 12 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA EG1SF UT WOS:000390811800002 PM 27934777 ER PT J AU Guo, XQ Dumas, M Robinson, BL Ali, SF Paule, MG Gu, Q Kanungo, J AF Guo, Xiaoqing Dumas, Melanie Robinson, Bonnie L. Ali, Syed F. Paule, Merle G. Gu, Qiang Kanungo, Jyotshna TI Acetyl L-carnitine targets adenosine triphosphate synthase in protecting zebrafish embryos from toxicities induced by verapamil and ketamine: An in vivo assessment SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE verapamil; heart rate; ketamine; zebrafish; acetyl l-carnitine; developmental toxicity ID PROTEIN-KINASE-C; 8-(N,N-DIETHYLAMINO)OCTYL 3,4,5-TRIMETHOXYBENZOATE HYDROCHLORIDE; INOSITOL 1,4,5-TRISPHOSPHATE FORMATION; GUINEA-PIG; RAT-HEART; PHARMACOLOGICAL EVALUATION; PAPILLARY-MUSCLE; SKELETAL-MUSCLES; CA2+ ANTAGONIST; CALCIUM AB Verapamil is a Ca2+ channel blocker and is highly prescribed as an anti-anginal, antiarrhythmic and antihypertensive drug. Ketamine, an antagonist of the Ca2+-permeable N-methyl-d-aspartate-type glutamate receptors, is a pediatric anesthetic. Previously we have shown that acetyl l-carnitine (ALCAR) reverses ketamine-induced attenuation of heart rate and neurotoxicity in zebrafish embryos. Here, we used 48h post-fertilization zebrafish embryos that were exposed to relevant drugs for 2 or 4h. Heart beat and overall development were monitored in vivo. In 48h post-fertilization embryos, 2mm ketamine reduced heart rate in a 2 or 4h exposure and 0.5mm ALCAR neutralized this effect. ALCAR could reverse ketamine's effect, possibly through a compensatory mechanism involving extracellular Ca2+ entry through L-type Ca2+ channels that ALCAR is known to activate. Hence, we used verapamil to block the L-type Ca2+ channels. Verapamil was more potent in attenuating heart rate and inducing morphological defects in the embryos compared to ketamine at specific times of exposure. ALCAR reversed cardiotoxicity and developmental toxicity in the embryos exposed to verapamil or verapamil plus ketamine, even in the presence of 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester, an inhibitor of intracellular Ca2+ release suggesting that ALCAR acts via effectors downstream of Ca2+. In fact, ALCAR's protective effect was blunted by oligomycin A, an inhibitor of adenosine triphosphate synthase that acts downstream of Ca2+ during adenosine triphosphate generation. We have identified, for the first time, using in vivo studies, a downstream effector of ALCAR that is critical in abrogating ketamine- and verapamil-induced developmental toxicities. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Acetyl l-carnitine prevents toxicities induced by ketamine and verapamil in the zebrafish embryos. In vivo assessment using various inhibitors of specific signaling pathways indicates that adenosine triphosphate synthase mediates acetyl L-carnitine's effects and potentially acts downstream of Ca2+ as an effector molecule in reversing adverse effects induced by ketamine and verapamil, alone or in combination, on the overall development and heart rate. C1 [Guo, Xiaoqing; Dumas, Melanie; Robinson, Bonnie L.; Ali, Syed F.; Paule, Merle G.; Gu, Qiang; Kanungo, Jyotshna] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Guo, Xiaoqing] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Kanungo, J (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM jyotshnabala.kanungo@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 64 TC 1 Z9 1 U1 7 U2 7 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 FEB PY 2017 VL 37 IS 2 BP 192 EP 200 DI 10.1002/jat.3340 PG 9 WC Toxicology SC Toxicology GA EE9NF UT WOS:000389952700007 PM 27191126 ER PT J AU Kim, HS Kim, YJ Chon, JW Kim, DH Yim, JH Kim, H Seo, KH AF Kim, Hong-Seok Kim, Young-Ji Chon, Jung-Whan Kim, Dong-Hyeon Yim, Jin-Hyeok Kim, Hyunsook Seo, Kun-Ho TI Two-stage label-free aptasensing platform for rapid detection of Cronobacter sakazakii in powdered infant formula SO SENSORS AND ACTUATORS B-CHEMICAL LA English DT Article DE Cronobacter sakazakii; Aptamer; Gold nanoparticles; Powdered infant formula ID UNMODIFIED GOLD NANOPARTICLES; DNA APTAMERS; COLORIMETRIC DETECTION; NONTHIOLATED DNA; SALMONELLA; ADSORPTION; LIGANDS; PROBE; ASSAY AB Cronobacter sakazakii constitutes one of the most life-threatening foodborne pathogens in neonates, and is typically acquired via contaminated powdered infant formula. In this study, we developed a sensitive and convenient two-stage label-free aptasensing platform for colorimetric detection of C. sakazakii in powdered infant formula. In this system, C. sakazakii depletes aptamers from the test solution, and the reduction of aptamers induces aggregation of gold nanoparticles in salt, a process accompanied by a color change from red to purple. Under optimal conditions, C. sakazakii present in PIF at a concentration as low as 7.1 x 10(3) CFU mL(-1) could be visually detected within 30 min, with a linear range between 7.1 x 10(3) and 7.1 x 10(7) CFU mL(-1). This novel assay provides new opportunities to detect bacteria in real-world samples. (C) 2016 Elsevier B.V. All rights reserved. C1 [Kim, Hong-Seok; Kim, Young-Ji; Chon, Jung-Whan; Kim, Dong-Hyeon; Yim, Jin-Hyeok; Seo, Kun-Ho] Konkuk Univ, Coll Vet Med, Ctr Hlth 1, Seoul, South Korea. [Kim, Hyunsook] Hanyang Univ, Coll Human Ecol, Dept Food & Nutr, Seoul, South Korea. [Chon, Jung-Whan] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. RP Seo, KH (reprint author), Konkuk Univ, Coll Vet Med, Ctr Hlth 1, Seoul, South Korea. EM bracstu3@konkuk.ac.kr FU National Research Foundation of Korea grant - Korea 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 The authors are grateful to Dr. Ben D. Tall at the U.S. FDA for providing Cronobacter strains, and thank Jinho Hyon at Hanyang University for his assistance with transmission electron microscopy. This work was supported by the National Research Foundation of Korea grant funded by the Korea government (MSIP) (2015R1A2A2A05001288) and by 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, funded by Ministry of Agriculture, Food and Rural Affairs (MAFRA) (716002-7). NR 34 TC 0 Z9 0 U1 18 U2 18 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 FEB PY 2017 VL 239 BP 94 EP 99 DI 10.1016/j.snb.2016.07.173 PG 6 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation SC Chemistry; Electrochemistry; Instruments & Instrumentation GA ED6FK UT WOS:000388951300012 ER PT J AU Ahmed, KBR Nagy, AM Brown, RP Zhang, Q Malghan, SG Goering, PL AF Ahmed, Kausar B. Riaz Nagy, Amber M. Brown, Ronald P. Zhang, Qin Malghan, Subhas G. Goering, Peter L. TI Silver nanoparticles: Significance of physicochemical properties and assay interference on the interpretation of in vitro cytotoxicity studies SO TOXICOLOGY IN VITRO LA English DT Review DE Silver nanopartides; Cytotoxicity; Physico-chemical characteristics; Assay interference; Nanoparticle biosynthesis ID METAL-OXIDE NANOPARTICLES; SPERMATOGONIAL STEM-CELLS; RAW 264.7 MACROPHAGES; CELLULAR UPTAKE; ANTIBACTERIAL ACTIVITY; OXIDATIVE STRESS; PROTEIN CORONA; GOLD NANOPARTICLES; ESCHERICHIA-COLI; PARTICLE-SIZE AB Silver nanoparticles (AgNPs) have generated a great deal of interest in the research, consumer product, and medical product communities due to their antimicrobial and anti-biofouling properties. However, in addition to their antimicrobial action, concerns have been expressed about the potential adverse human health effects of AgNPs. In vitro cytotoxicity studies often are used to characterize the biological response to AgNPs and the results of these studies may be used to identify hazards associated with exposure to AgNPs. Various factors, such as nanomaterial size (diameter), surface area, surface charge, redox potential, surface functionalization, and composition play a role in the development of toxicity in in vitro test systems. In addition, the interference of AgNPs with in vitro cytotoxicity assays may result in false negative or false positive results in some in vitro biological tests. The goal of this review is to: 1) summarize the impact of physical-chemical parameters, including size, shape, surface chemistry and aggregate formation on the in vitro cytotoxic effects of AgNPs; and 2) explore the nature of AgNPs interference in in vitro cytotoxicity assays. Published by Elsevier Ltd. C1 [Ahmed, Kausar B. Riaz; Nagy, Amber M.; Brown, Ronald P.; Zhang, Qin; Malghan, Subhas G.; Goering, Peter L.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 64,Rm 4064, Silver Spring, MD 20993 USA. RP Goering, PL (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 64,Rm 4064, Silver Spring, MD 20993 USA. EM peter.goering@fda.hhs.gov NR 188 TC 1 Z9 1 U1 68 U2 68 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 FEB PY 2017 VL 38 BP 179 EP 192 DI 10.1016/j.tiv.2016.10.012 PG 14 WC Toxicology SC Toxicology GA ED9CK UT WOS:000389167600021 ER PT J AU Al Kalaa, MO Balid, W Refai, HH LaSorte, NJ Seidman, SJ Bassen, HI Silberberg, JL Witters, D AF Al Kalaa, Mohamad Omar Balid, Walid Refai, Hazem H. LaSorte, Nickolas J. Seidman, Seth J. Bassen, Howard I. Silberberg, Jeffrey L. Witters, Donald TI Characterizing the 2.4 GHz Spectrum in a Hospital Environment: Modeling and Applicability to Coexistence Testing of Medical Devices SO IEEE TRANSACTIONS ON ELECTROMAGNETIC COMPATIBILITY LA English DT Article DE Coexistence; hospital environment; spectrum survey; wireless medical device; WLAN ID WIRELESS COEXISTENCE; INTERFERENCE; NETWORKS AB The increasing use of shared, unlicensed spectrum bands by medical devices and nonmedical products highlights the need to address wireless coexistence to ensure medical device safety and effectiveness. This paper provides the first step to approximate the probability of a device coexisting in its intended environment by providing a generalized framework for modeling the environment. The application of this framework is shown through an 84-day spectrum survey of the 2.4-2.48 GHz industrial, scientific, and medical band in a hospital environment in the United States. A custom platform was used to monitor power flux spectral density and record received power. Channel utilization of three non-overlapping channels of 20 MHz bandwidth-relative to IEEE 802.11 channels 1, 6, and 11-were calculated and fitted to a generalized extreme value distribution. Low channel utilization was observed (<10%) in the surveyed environment with sporadic occurrences of higher channel utilization (>50%). Reported findings can be complementary to wireless coexistence testing. This paper can provide input to the development of a consensus standard for wireless device coexistence test methods and a consensus document focused on wireless medical device coexistence risk management. C1 [Al Kalaa, Mohamad Omar; Balid, Walid; Refai, Hazem H.] Univ Oklahoma, Dept Elect & Comp Engn, Tulsa, OK 74135 USA. [LaSorte, Nickolas J.; Seidman, Seth J.; Bassen, Howard I.; Silberberg, Jeffrey L.; Witters, Donald] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Al Kalaa, MO (reprint author), Univ Oklahoma, Dept Elect & Comp Engn, Tulsa, OK 74135 USA. EM omarqal@ou.edu; walid@ou.edu; hazem@ou.edu; nickolas.lasorte@fda.hhs.gov; seth.seidman@fda.hhs.gov; howard.bassen@fda.hhs.gov; Jeffrey.Silberberg@fda.hhs.gov; donald.witters@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration FX This work 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 U.S. Department of Energy and the U.S. Food and Drug Administration. NR 34 TC 0 Z9 0 U1 23 U2 23 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9375 EI 1558-187X J9 IEEE T ELECTROMAGN C JI IEEE Trans. Electromagn. Compat. PD FEB PY 2017 VL 59 IS 1 BP 58 EP 66 DI 10.1109/TEMC.2016.2602083 PG 9 WC Engineering, Electrical & Electronic; Telecommunications SC Engineering; Telecommunications GA EB4RC UT WOS:000387359700007 ER PT J AU Ferdinand, KC Senatore, FF Clayton-Jeter, H Cryer, DR Lewin, JC Nasser, SA Fiuzat, M Califf, RM AF Ferdinand, Keith C. Senatore, Fortunato Fred Clayton-Jeter, Helene Cryer, Dennis R. Lewin, John C. Nasser, Samar A. Fiuzat, Mona Califf, Robert M. TI Improving Medication Adherence in Cardiometabolic Disease Practical and Regulatory Implications SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE cardiovascular disease; nonadherence; polypill; United States Food and Drug Administration ID CHRONIC HEART-FAILURE; CARDIOVASCULAR-DISEASE; HEALTH-CARE; EMERGENCY-DEPARTMENT; ETHNIC DISPARITIES; RANDOMIZED-TRIAL; CLINICAL-TRIAL; BLOOD-PRESSURE; BLACK-MEN; HIGH-RISK AB Medication nonadherence, a major problem in cardiovascular disease (CVD), contributes yearly to approximately 125,000 preventable deaths, which is partly attributable to only about one-half of CVD patients consistently taking prescribed life-saving medications. Current interest has focused on how labeling and education influence adherence. This paper summarizes the scope of CVD nonadherence, describes key U.S. Food and Drug Administration initiatives, and identifies potential targets for improvement. We describe key adherence factors, methods, and technological applications for simplifying regimens and enhancing adherence, and 4 areas where additional collaborative research and implementation involving the regulatory system and clinical community could substantially reduce nonadherence: 1) identifying monitoring methods; 2) improving the evidence base to better understand adherence; 3) developing patient/health provider team-based engagement strategies; and 4) alleviating health disparities. Alignment of U.S. Food and Drug Administration approaches to dissemination of information about appropriate use with clinical practice could improve adherence, and thereby reduce CVD death and disability. (C) 2017 by the American College of Cardiology Foundation. C1 [Ferdinand, Keith C.] Tulane Univ, Sch Med, Dept Med, Tulane Heart & Vasc Inst, 1430 Tulane Ave, New Orleans, LA 70112 USA. [Senatore, Fortunato Fred; Clayton-Jeter, Helene; Fiuzat, Mona; Califf, Robert M.] US FDA, Silver Spring, MD USA. [Cryer, Dennis R.] CryerHealth, Washington, DC USA. [Lewin, John C.] Cardiovasc Res Fdn, New York, NY USA. [Nasser, Samar A.] George Washington Univ, Sch Med & Hlth Sci, Dept Clin Res & Leadership, Washington, DC 20052 USA. RP Ferdinand, KC (reprint author), Tulane Univ, Sch Med, 1430 Tulane Ave,SL-48, New Orleans, LA 70112 USA. EM kcferdmd@aol.com FU Boehringer Ingelheim; Patient-Centered Outcomes Research Institute; National Institutes of Health; FDA; 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. Ferdinand has received a grant from Boehringer Ingelheim; and serves as consultant for Amgen, Sanofi, Boehringer Ingelheim, and Eli Lilly. Dr. Cryer has served as a consultant for Amgen. Dr. Califf currently holds the post of Commissioner of Food and Drugs, U.S. Food and Drug Administration (FDA); before his appointment to the FDA, he received research grant funding from the Patient-Centered Outcomes Research Institute, National Institutes of Health, FDA, Amylin, and Eli Lilly and Company; received 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. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 76 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 JAN 31 PY 2017 VL 69 IS 4 BP 437 EP 451 DI 10.1016/j.jacc.2016.11.034 PG 15 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ1UA UT WOS:000392994500011 PM 28126162 ER PT J AU Willhoft, O Kerr, R Patel, D Zhang, WJ Al-Jassar, C Daviter, T Millson, SH Thalassinos, K Vaughan, CK AF Willhoft, Oliver Kerr, Richard Patel, Dipali Zhang, Wenjuan Al-Jassar, Caezar Daviter, Tina Millson, Stefan H. Thalassinos, Konstantinos Vaughan, Cara K. TI The crystal structure of the Sgt1-Skp1 complex: the link between Hsp90 and both SCF E3 ubiquitin ligases and kinetochores SO Scientific Reports LA English DT Article ID F-BOX PROTEINS; YEAST KINETOCHORE; SGT1 DIMERIZATION; IMMUNE-RESPONSES; BINDING-SITES; CO-CHAPERONE; PHOSPHORYLATION; TARGET; OVEREXPRESSION; DEGRADATION AB The essential cochaperone Sgt1 recruits Hsp90 chaperone activity to a range of cellular factors including SCF E3 ubiquitin ligases and the kinetochore in eukaryotes. In these pathways Sgt1 interacts with Skp1, a small protein that heterodimerizes with proteins containing the F-box motif. We have determined the crystal structure of the interacting domains of Saccharomyces cerevisiae Sgt1 and Skp1 at 2.8 angstrom resolution and validated the interface in the context of the full-length proteins in solution. The BTB/POZ domain of Skp1 associates with Sgt1 via the concave surface of its TPR domain using residues that are conserved in humans. Dimerization of yeast Sgt1 occurs via an insertion that is absent from monomeric human Sgt1. We identify point mutations that disrupt dimerization and Skp1 binding in vitro and find that the interaction with Skp1 is an essential function of Sgt1 in yeast. Our data provide a structural rationale for understanding the phenotypes of temperature-sensitive Sgt1 mutants and for linking Skp1-associated proteins to Hsp90-dependent pathways. C1 [Willhoft, Oliver; Patel, Dipali; Zhang, Wenjuan; Al-Jassar, Caezar; Daviter, Tina; Vaughan, Cara K.] Univ Coll London & Birkbeck, Biol Sci, Inst Struct & Mol Biol, Malet St, London WC1E 7HX, England. [Kerr, Richard; Thalassinos, Konstantinos] Univ Coll London & Birkbeck, Inst Struct & Mol Biol, Div Biosci, Darwin Bldg,Gower St, London WC1E 6BT, England. [Millson, Stefan H.] Lincoln Univ, Sch Life Sci, Joseph Banks Lab, Lincoln LN6 7TS, England. [Willhoft, Oliver] Imperial Coll, Sect Struct Biol, Dept Med, Sir Alexander Fleming Bldg, London SW7 2AZ, England. [Kerr, Richard] US FDA, Div Pharmaceut Anal, St Louis, MA 63110 USA. [Patel, Dipali] Relay Therapeut Inc, 215 First St, Cambridge, MA 02142 USA. [Al-Jassar, Caezar] MRC Lab Mol Biol, Struct Studies, Francis Crick Ave, Cambridge CB2 0QH, England. RP Vaughan, CK (reprint author), Univ Coll London & Birkbeck, Biol Sci, Inst Struct & Mol Biol, Malet St, London WC1E 7HX, England. EM c.vaughan@mail.cryst.bbk.ac.uk FU BBSRC FX We thank Martin Singleton and Katsumi Kitagawa for plasmids, Jill Johnson for yeast strains and plasmids, Ambrose Cole for computational crystallography expertise, and Mark Williams for critical discussion. AUC experiments were carried out at the ISMB Biophysics Centre, Birkbeck, University of London. OW, CAJ, WZ & CKV were funded by the BBSRC. NR 58 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 JAN 31 PY 2017 VL 7 AR 41626 DI 10.1038/srep41626 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ3DQ UT WOS:000393093200001 PM 28139700 ER PT J AU Rahman, Z Zidan, AS Korang-Yeboah, M Yang, Y Siddiqui, A Shakleya, D Khan, MA Cruz, C Ashraf, M AF Rahman, Ziyaur Zidan, Ahmed S. Korang-Yeboah, Maxwell Yang, Yang Siddiqui, Akhtar Shakleya, Diaa Khan, Mansoor A. Cruz, Celia Ashraf, Muhammad TI Effects of excipients and curing process on the abuse deterrent properties of directly compressed tablets SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Sotalol; Abuse deterrent tablet formulations; Abuse deterrent properties; Crush resistance; Syringeability and injectability ID OVERDOSE DEATHS; DRUG OVERDOSE; UNITED-STATES; IMPACT; FORMULATIONS; ADULTS; MISUSE; POLICY AB The objective of the present investigation was to understand the effects of excipients and curing process on the abuse deterrent properties (ADP) of Polyox (TM) based directly compressible abuse deterrent tablet formulations (ADFs). The excipients investigated were lactose (monohydrate or anhydrous), microcrystalline cellulose and hydroxypropyl methylcellulose. The ADPs studied were tablet crush resistance or hardness, particle size distribution following mechanical manipulation, drug extraction in water and alcohol, syringeability and injectability. Other non-ADPs such as surface morphology and tablet dissolution were also studied. It was found that presence of 50% or more of water soluble or swellable excipient in the ADF tablets significantly affected the tablet hardness, particle size distribution following mechanical manipulation and drug extraction while small amount (5%) of excipients had either minimal or no effect on ADPs of these tablets. Addition of high molecular weight HPMC (K 100 M) affected syringeability and injectability of ADF. Curing process was found to affect ADPs (hardness, particle size distribution, drug extraction and syringeability and injectability) when compared with uncured tablet. In conclusion, addition of large amount of excipients, especially water soluble ones in Polyox (TM) based ADF tablets increase the risk of abuse by various routes of administration. Published by Elsevier B.V. C1 [Rahman, Ziyaur; Zidan, Ahmed S.; Korang-Yeboah, Maxwell; Yang, Yang; Siddiqui, Akhtar; Shakleya, Diaa; Khan, Mansoor A.; Cruz, Celia; Ashraf, Muhammad] US FDA, Div Prod Qual & Res, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Rahman, Ziyaur; Khan, Mansoor A.] Texas A&M Univ, Irma Lerma Rangel Coll Pharm, College Stn, TX 77843 USA. RP Rahman, Z (reprint author), FDA CDER DPQR, LS Bldg 64,Room 1082,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM rahman.ziyaur@gmail.com RI Zidan, Ahmed/I-1147-2012; OI Rahman, Ziyaur/0000-0002-0402-825X NR 23 TC 0 Z9 0 U1 2 U2 2 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 JAN 30 PY 2017 VL 517 IS 1-2 BP 303 EP 311 DI 10.1016/j.ijpharm.2016.12.015 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI8RL UT WOS:000392775100034 PM 27956191 ER PT J AU Gieraltowski, L Schwensohn, C Meyer, S Eikmeier, D Medus, C Sorenson, A Forstner, M Madad, A Blankenship, J Feng, P Williams, I AF Gieraltowski, Laura Schwensohn, Colin Meyer, Stephanie Eikmeier, Dana Medus, Carlota Sorenson, Alida Forstner, Matthew Madad, Asma Blankenship, Joseph Feng, Peter Williams, Ian TI Multistate Outbreak of Escherichia coli O157:H7 Infections Linked to Dough Mix - United States, 2016 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Gieraltowski, Laura; Schwensohn, Colin; Williams, Ian] CDC, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Meyer, Stephanie; Eikmeier, Dana; Medus, Carlota] Minnesota Dept Hlth, Minneapolis, MN 55414 USA. [Sorenson, Alida; Forstner, Matthew] Minnesota Dept Agr, St Paul, MN USA. [Madad, Asma; Blankenship, Joseph; Feng, Peter] US FDA, Rockville, MD 20857 USA. RP Gieraltowski, L (reprint author), CDC, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. EM LGieraltowski@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 JAN 27 PY 2017 VL 66 IS 3 BP 88 EP 89 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ3CH UT WOS:000393088500005 PM 28125572 ER PT J AU Wang, KJ Vijay, V Fuscoe, JC AF Wang, Kejian Vijay, Vikrant Fuscoe, James C. TI Stably Expressed Genes Involved in Basic Cellular Functions SO PLOS ONE LA English DT Article ID UBIQUITIN-PROTEASOME SYSTEM; MOUSE PHENOTYPING CONSORTIUM; CANCER; VARIANTS; DISEASE AB Stably Expressed Genes (SEGs) whose expression varies within a narrow range may be involved in core cellular processes necessary for basic functions. To identify such genes, we re-analyzed existing RNA-Seq gene expression profiles across 11 organs at 4 developmental stages (from immature to old age) in both sexes of F344 rats (n = 4/group; 320 samples). Expression changes (calculated as the maximum expression/minimum expression for each gene) of > 19000 genes across organs, ages, and sexes ranged from 2.35 to > 10(9) fold, with a median of 165-fold. The expression of 278 SEGs was found to vary <= 4-fold and these genes were significantly involved in protein catabolism (proteasome and ubiquitination), RNA transport, protein processing, and the spliceosome. Such stability of expression was further validated in human samples where the expression variability of the homologous human SEGs was significantly lower than that of other genes in the human genome. It was also found that the homologous human SEGs were generally less subject to non-synonymous mutation than other genes, as would be expected of stably expressed genes. We also found that knockout of SEG homologs in mouse models was more likely to cause complete preweaning lethality than non-SEG homologs, corroborating the fundamental roles played by SEGs in biological development. Such stably expressed genes and pathways across life-stages suggest that tight control of these processes is important in basic cellular functions and that perturbation by endogenous (e.g., genetics) or exogenous agents (e.g., drugs, environmental factors) may cause serious adverse effects. C1 [Wang, Kejian; Vijay, Vikrant; Fuscoe, James C.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Fuscoe, JC (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM James.Fuscoe@fda.hhs.gov NR 37 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 JAN 26 PY 2017 VL 12 IS 1 AR e0170813 DI 10.1371/journal.pone.0170813 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN7IT UT WOS:000396176100045 PM 28125669 ER PT J AU Kasza, KA Ambrose, BK Conway, KP Borek, N Taylor, K Goniewicz, ML Cummings, KM Sharma, E Pearson, JL Green, VR Kaufman, AR Bansal-Travers, M Travers, MJ Kwan, J Tworek, C Cheng, YC Yang, L Pharris-Ciurej, N van Bemmel, DM Backinger, CL Compton, WM Hyland, AJ AF Kasza, Karin A. Ambrose, Bridget K. Conway, Kevin P. Borek, Nicolette Taylor, Kristie Goniewicz, Maciej L. Cummings, K. Michael Sharma, Eva Pearson, Jennifer L. Green, Victoria R. Kaufman, Annette R. Bansal-Travers, Maansi Travers, Mark J. Kwan, Jonathan Tworek, Cindy Cheng, Yu-Ching Yang, Ling Pharris-Ciurej, Nikolas van Bemmel, Dana M. Backinger, Cathy L. Compton, Wilson M. Hyland, Andrew J. TI Tobacco-Product Use by Adults and Youths in the United States in 2013 and 2014 SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CIGARETTE SMOKERS; ELECTRONIC CIGARETTES; SMOKELESS TOBACCO; POLYTOBACCO USE; TRENDS; PREVALENCE; CIGARILLO; AWARENESS; SMOKING; SNUS AB BACKGROUND Noncigarette tobacco products are evolving rapidly, with increasing popularity in the United States. METHODS We present prevalence estimates for 12 types of tobacco products, using data from 45,971 adult and youth participants (>= 12 years of age) from Wave 1 (September 2013 through December 2014) of the Population Assessment of Tobacco and Health (PATH) Study, a large, nationally representative, longitudinal study of tobacco use and health in the United States. Participants were asked about their use of cigarettes, e-cigarettes, traditional cigars, cigarillos, filtered cigars, pipe tobacco, hookah, snus pouches, other smokeless tobacco, dissolvable tobacco, bidis, and kreteks. Estimates of the prevalence of use for each product were determined according to use category (e.g., current use or use in the previous 30 days) and demographic subgroup, and the prevalence of multiple-product use was explored. RESULTS More than a quarter (27.6%) of adults were current users of at least one type of tobacco product in 2013 and 2014, although the prevalence varied depending on use category. A total of 8.9% of youths had used a tobacco product in the previous 30 days; 1.6% of youths were daily users. Approximately 40% of tobacco users, adults and youths alike, used multiple tobacco products; cigarettes plus e-cigarettes was the most common combination. Young adults (18 to 24 years of age), male adults and youths, members of racial minorities, and members of sexual minorities generally had higher use of tobacco than their counterparts. CONCLUSIONS During this study, 28% of U.S. adults were current users of tobacco, and 9% of youths had used tobacco in the previous 30 days. Use of multiple products was common among tobacco users. These findings will serve as baseline data to examine between-person differences and within-person changes over time in the use of tobacco products. (Funded by the National Institute on Drug Abuse and the Food and Drug Administration.) C1 [Kasza, Karin A.; Goniewicz, Maciej L.; Bansal-Travers, Maansi; Travers, Mark J.; Hyland, Andrew J.] Roswell Pk Canc Inst, Dept Hlth Behav, Elm & Carlton Sts, Buffalo, NY 14263 USA. [Ambrose, Bridget K.; Borek, Nicolette; Kwan, Jonathan; Tworek, Cindy; Cheng, Yu-Ching; Yang, Ling; Pharris-Ciurej, Nikolas; van Bemmel, Dana M.; Backinger, Cathy L.] US FDA, Off Sci, Ctr Tobacco Prod, Silver Spring, MD USA. [Conway, Kevin P.; Green, Victoria R.; Compton, Wilson M.] NIDA, NIH, Bethesda, MD 20892 USA. [Kaufman, Annette R.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Taylor, Kristie; Sharma, Eva] Westat Corp, Rockville, MD USA. [Green, Victoria R.] Kelly Govt Solut, Rockville, MD USA. [Cummings, K. Michael] Med Univ South Carolina, Dept Psychiat & Behav Sci, Charleston, SC USA. [Pearson, Jennifer L.] Truth Initiat, Schroeder Inst Tobacco Res & Policy Studies, Washington, DC USA. RP Kasza, KA (reprint author), Roswell Pk Canc Inst, Dept Hlth Behav, Elm & Carlton Sts, Buffalo, NY 14263 USA. EM karin.kasza@roswellpark.org FU National Institute on Drug Abuse, National Institutes of Health; Food and Drug Administration, Department of Health and Human Services [HHSN271201100027C]; Pfizer FX Supported by federal funds from the National Institute on Drug Abuse, National Institutes of Health, and the Food and Drug Administration, Department of Health and Human Services, under a contract (Contract No. HHSN271201100027C) to Westat.; Dr. Cummings reports receiving grant support from Pfizer and fees as a paid expert witness in litigation filed against the tobacco industry; Dr. Goniewicz, receiving fees for serving on an advisory board from Johnson & Johnson and grant support from Pfizer; and Dr. Compton, holding stock in General Electric, the 3M Companies, and Pfizer. No other potential conflict of interest relevant to this article was reported. NR 38 TC 0 Z9 0 U1 2 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 26 PY 2017 VL 376 IS 4 BP 342 EP 353 DI 10.1056/NEJMsa1607538 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EJ3KR UT WOS:000393111600009 PM 28121512 ER PT J AU Wei, YC George, NI Chang, CW Hicks, KA AF Wei, Yu-Chung George, Nysia I. Chang, Ching-Wei Hicks, Karen A. TI Assessing Sex Differences in the Risk of Cardiovascular Disease and Mortality per Increment in Systolic Blood Pressure: A Systematic Review and Meta-Analysis of Follow-Up Studies in the United States SO PLOS ONE LA English DT Review ID CORONARY-HEART-DISEASE; ALL-CAUSE MORTALITY; ACUTE MYOCARDIAL-INFARCTION; PULSE PRESSURE; MIDDLE-AGE; MEN; WOMEN; HEALTH; HYPERTENSION; BLACK AB In the United States (US), cardiovascular (CV) disease accounts for nearly 20% of national health care expenses. Since costs are expected to increase with the aging population, informative research is necessary to address the growing burden of CV disease and sex-related differences in diagnosis, treatment, and outcomes. Hypertension is a major risk factor for CV disease and mortality. To evaluate whether there are sex-related differences in the effect of systolic blood pressure (SBP) on the risk of CV disease and mortality, we performed a systematic review and meta-analysis. We conducted a comprehensive search using PubMed and Google Scholar to identify US-based studies published prior to 31 December, 2015. We identified eight publications for CV disease risk, which provided 9 female and 8 male effect size (ES) observations. We also identified twelve publications for CV mortality, which provided 10 female and 18 male ES estimates. Our meta-analysis estimated that the pooled ES for increased risk of CV disease per 10 mmHg increment in SBP was 25% for women (95% Confidence Interval (CI): 1.18, 1.32) and 15% for men (95% CI: 1.11, 1.19). The pooled increase in CV mortality per 10 mm Hg SBP increment was similar for both women and men (Women: 1.16; 95% CI: 1.10, 1.23; Men: 1.17; 95% CI: 1.12, 1.22). After adjusting for age and baseline SBP, the results demonstrated that the risk of CV disease per 10 mm Hg SBP increment for women was 1.1-fold higher than men (P<0.01; 95% CI: 1.04, 1.17). Heterogeneity was moderate but significant. There was no significant sex difference in CV mortality. C1 [Wei, Yu-Chung; George, Nysia I.; Chang, Ching-Wei] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Wei, Yu-Chung] Feng Chia Univ, Dept Stat, Taichung, Taiwan. [Chang, Ching-Wei] Genentech Inc, San Francisco, CA 94080 USA. [Hicks, Karen A.] US FDA, Off Drug Evaluat 1, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP George, NI; Chang, CW (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA.; Chang, CW (reprint author), Genentech Inc, San Francisco, CA 94080 USA. EM wei0917@gmail.com; nysia.george@fda.hhs.gov FU FDA Office of Women's Health [E0754201]; ORISE Research Participation Program at the National Center for Toxicological Research, U.S. Food and Drug Administration FX This work was supported by the FDA Office of Women's Health (Project ID: E0754201). This project was supported in part by an appointment to the ORISE Research Participation Program at the National Center for Toxicological Research, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA/Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 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 JAN 25 PY 2017 VL 12 IS 1 AR e0170218 DI 10.1371/journal.pone.0170218 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN7FK UT WOS:000396167300052 PM 28122035 ER PT J AU St Clair, JB Detanico, T Aviszus, K Kirchenbaum, GA Christie, M Carpenter, JF Wysocki, LJ AF St Clair, J. Benjamin Detanico, Thiago Aviszus, Katja Kirchenbaum, Greg A. Christie, Merry Carpenter, John F. Wysocki, Lawrence J. TI Immunogenicity of Isogenic IgG in Aggregates and Immune Complexes SO PLOS ONE LA English DT Article ID T-CELL EPITOPES; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; COMPLEMENT-DEPENDENT TRANSPORT; IMMUNOGLOBULIN VARIABLE-REGION; ANTIGEN-ANTIBODY COMPLEXES; B-CELLS; MONOCLONAL-ANTIBODY; IN-VIVO; IMMUNOLOGICAL-UNRESPONSIVENESS; THERAPEUTIC ANTIBODIES AB A paradox in monoclonal antibody (mAb) therapy is that despite the well-documented tolerogenic properties of deaggregated IgG, most therapeutic IgG mAb induce anti-mAb responses. To analyze CD4 T cell reactions against IgG in various physical states, we developed an adoptive transfer model using CD4+ T cells specific for a VK region-derived peptide in the hapten-specific IgG mAb 36-71. We found that heat-aggregated or immune complexes (IC) of mAb 36-71 elicited anti-idiotypic (anti-Id) antibodies, while the deaggregated form was tolerogenic. All 3 forms of mAb 36-71 induced proliferation of cognate CD4+ T cells, but the aggregated and immune complex forms drove more division cycles and induced T follicular helper cells (T-FH) development more effectively than did the deaggregated form. These responses occurred despite no adjuvant and no or only trace levels of endotoxin in the preparations. Physical analyses revealed large differences in micron-and nanometer-sized particles between the aggregated and IC forms. These differences may be functionally relevant, as CD4+ T cell proliferation to aggregated, but not IC mAb 36-71, was nearly ablated upon peritoneal injection of B cell-depleting antibody. Our results imply that, in addition to denatured aggregates, immune complexes formed in vivo between therapeutic mAb and their intended targets can be immunogenic. C1 [St Clair, J. Benjamin; Detanico, Thiago; Aviszus, Katja; Wysocki, Lawrence J.] Natl Jewish Hlth, Dept Biomed Res, Denver, CO 80206 USA. [St Clair, J. Benjamin] Univ Colorado, Sch Med, Med Scientist Training Program, Denver, CO USA. [St Clair, J. Benjamin; Detanico, Thiago; Aviszus, Katja; Kirchenbaum, Greg A.] Natl Jewish Hlth, Integrated Dept Immunol, Denver, CO USA. [St Clair, J. Benjamin; Detanico, Thiago; Aviszus, Katja; Kirchenbaum, Greg A.] Univ Colorado, Sch Med, Denver, CO USA. [Christie, Merry; Carpenter, John F.] Univ Colorado Denver, Dept Pharmaceut Sci, Anschutz Med Campus, Aurora, CO USA. [Kirchenbaum, Greg A.] Univ Georgia, Coll Vet Med, Dept Infect Dis, Athens, GA USA. [Christie, Merry] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Wysocki, Lawrence J.] Univ Colorado, Sch Med, Dept Immunol, Denver, CO 80204 USA. RP Wysocki, LJ (reprint author), Natl Jewish Hlth, Dept Biomed Res, Denver, CO 80206 USA. EM wysockil@njhealth.org FU National Institutes of Health/National Institute of Allergy and Infectious Disease [R01AI033613, R21AI121980, R03AI088408]; National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [F30DK091102] FX Funded by National Institutes of Health/National Institute of Allergy and Infectious Disease: R01AI033613 (LJW) R21AI121980 (LJW), R03AI088408 (LJW) and National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases F30DK091102 (JBS). NR 87 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 JAN 23 PY 2017 VL 12 IS 1 AR e0170556 DI 10.1371/journal.pone.0170556 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6QR UT WOS:000396129000067 PM 28114383 ER PT J AU Fuentes, S Arenas, D Moore, MM Golding, H Khurana, S AF Fuentes, Sandra Arenas, Diego Moore, Martin M. Golding, Hana Khurana, Surender TI Development of bioluminescence imaging of respiratory syncytial virus (RSV) in virus-infected live mice and its use for evaluation of therapeutics and vaccines SO VACCINE LA English DT Article DE RSV; Vaccine; Neutralization; Antibody; Palivizumab; Live imaging. Ds-Cav1; F protein; Pre-fusion F; Animal model; Immune complex; Efficacy; Therapeutic; Treatment ID HUMANIZED MONOCLONAL-ANTIBODY; BRONCHOPULMONARY DYSPLASIA; NEUTRALIZING ANTIBODY; PREMATURE-INFANTS; T-CELLS; SAFETY; PHARMACOKINETICS; PROTEIN; CHALLENGE; CHILDREN AB Respiratory Syncytial virus (RSV) is one of the leading causes of pneumonia among infants with no human vaccine or efficient curative treatments. Efforts are underway to develop new RSV vaccines and therapeutics. There is a dire need for animal models for preclinical evaluation and selection of products against RSV. Herein, we developed a whole body bioluminescence imaging to follow replication of RSV A2 virus strain expressing firefly luciferase (RSVA2-linel9-FFL) in live BALB/c mice that can be used as an extremely sensitive readout for studying effects of antiviral and vaccines in living mice. Strong bioluminescence signal was detected in the nasal cavity and in the lungs following intranasal infection of mice with RSVA2-linel9-FFL. The kinetics of viral replication in lungs quantified by daily live imaging strongly correlated with viral titers measured by ex-vivo plaque assay and by assessing viral RNA by qRT-PCR. Vaccination of mice with a pre-fusion F protein elicited high neutralizing antibody titers conferring strong protective immunity against virus replication in the nasal cavity and lungs. In contrast, post challenge treatment of mice with the monoclonal antibody Palivizumab two days after infection reduced viral replication in the nasal cavity at day 4, but only modestly reduced virus loads in the lungs by day 5. In contrast to RSV bioluminescence, plaque assay did not detect viral titers in lungs on day 5 in Palivizumab-treated animals. This difference between viral loads measured by the two assays was found to be due to coating of virions with the Palivizumab that blocked infection of target cells in vitro and shows importance of live imaging in evaluation of RSV therapeutics. This recombinant RSV based live imaging animal model is convenient and valuable tool that can be used to study host dissemination of RSV and evaluation of antiviral compounds and vaccines against RSV. Published by Elsevier Ltd. C1 [Fuentes, Sandra; Arenas, Diego; Golding, Hana; Khurana, Surender] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Moore, Martin M.] Emory Univ, Emory Childrens Ctr Childhood Infect & Vaccines, Sch Med, Emory Childrens Ctr, Atlanta, GA 30322 USA. RP Khurana, S (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Surender.Khurana@fda.hhs.gov FU FDA/CBER Intramural funds FX We thank Judy Beeler and Marina Zaitseva for their insightful review of the manuscript. Members of the Veterinary staff at CBER, FDA are acknowledged for taking care of the animals. This work was funded by FDA/CBER Intramural funds. NR 22 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JAN 23 PY 2017 VL 35 IS 4 BP 694 EP 702 DI 10.1016/j.vaccine.2016.11.044 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EK1XQ UT WOS:000393721500027 PM 27989627 ER PT J AU Farrelly, MC Duke, JC Nonnemaker, J MacMonegle, AJ Alexander, TN Zhao, XQ Delahanty, JC Rao, P Allen, JA AF Farrelly, Matthew C. Duke, Jennifer C. Nonnemaker, James MacMonegle, Anna J. Alexander, Tesfa N. Zhao, Xiaoquan Delahanty, Janine C. Rao, Pamela Allen, Jane A. TI Association Between The Real Cost Media Campaign and Smoking Initiation Among Youths - United States, 2014-2016 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Farrelly, Matthew C.; Duke, Jennifer C.; Nonnemaker, James; MacMonegle, Anna J.; Allen, Jane A.] RTI Int, Res Triangle Pk, NC 27709 USA. [Alexander, Tesfa N.; Zhao, Xiaoquan; Delahanty, Janine C.; Rao, Pamela] US FDA, Ctr Tobacco Prod, Silver Spring, MD USA. [Zhao, Xiaoquan] George Mason Univ, Dept Commun, Fairfax, VA 22030 USA. [Rao, Pamela] Akira Technol, Washington, DC USA. RP Farrelly, MC (reprint author), RTI Int, Res Triangle Pk, NC 27709 USA. EM mcf@rti.org NR 9 TC 0 Z9 0 U1 1 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD JAN 20 PY 2017 VL 66 IS 2 BP 47 EP 50 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ0LR UT WOS:000392900800002 PM 28103214 ER PT J AU Wang, J Chow, W Chang, J Wong, JW AF Wang, Jian Chow, Willis Chang, James Wong, Jon W. TI Development and Validation of a Qualitative Method for Target Screening of 448 Pesticide Residues in Fruits and Vegetables Using UHPLC/ESI Q-Orbitrap Based on Data-Independent Acquisition and Compound Database SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE UHPLC/ESI; Q-Orbitrap; pesticide residues; compound database; target screening fruits and vegetables ID PERFORMANCE LIQUID-CHROMATOGRAPHY; FLIGHT-MASS-SPECTROMETRY; TIME; MYCOTOXINS AB validated using ultrahigh-performance liquid chromatography coupled with electrospray ionization qiiadrupole Orbitrap high-resolution mass spectrometry (UHPLC/ESLQ:Orbitrap). The Q-Orbitrap Full MS/dd-MS2 (data dependent acquisition) was used to acquire product-ion spectra of individual pesticides to build a compound database or an MS library, While its Full MS/DIA (data independent acquisition) was utilized for sample data acquisition from fruit and vegetable matrices fortified with pesticides at 10 and 100 mu g/kg for target screening purpose. Accurate Mass, retention time and response-threshold were three key parameters in a compound database that were used to detect incurred pesticide residues in samples. The concepts and practical aspects of in-spectrum mass correction or solvent background lock mass correction, retention time alignment and response: threshold adjustment are discussed while building a functional and working compound database for target screening. The validated target screening method is capable of screening at least 94% and 99% of 448,pesticides, at 10 and 100 mu g/kg, respectively, in fruits and vegetables without having to evaluate every compound manually during data processing, which significantly reduced the workload in routine practice. C1 [Wang, Jian; Chow, Willis] Canadian Food Inspect Agcy, Calgary Lab, 3650-36th St NW, Calgary, AB T2L 2L1, Canada. [Chang, James] ThermoFisher Sci, 355 River Oaks Pkwy, San Jose, CA 95134 USA. [Wong, Jon W.] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. RP Wang, J (reprint author), Canadian Food Inspect Agcy, Calgary Lab, 3650-36th St NW, Calgary, AB T2L 2L1, Canada. EM jian.wang@inspection.gc.ca NR 14 TC 0 Z9 0 U1 9 U2 9 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 JAN 18 PY 2017 VL 65 IS 2 BP 473 EP 493 DI 10.1021/acs.jafc.6b05034 PG 21 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA EI4JE UT WOS:000392458900026 PM 28002940 ER PT J AU Hao, HH Li, F Han, J Foley, SL Dai, MH Wang, X Wang, YL Huang, LL Sun, YW Liu, ZL Yuan, ZH AF Hao, Haihong Li, Fei Han, Jing Foley, Steven L. Dai, Menghong Wang, Xu Wang, Yulian Huang, Lingli Sun, Yawei Liu, Zhenli Yuan, Zonghui TI Cj1199 Affect the Development of Erythromycin Resistance in Campylobacter jejuni through Regulation of Leucine Biosynthesis SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE Cj1199; C. jejuni; biological function; leucine biosynthesis; erythromycin resistance ID 23S RIBOSOMAL-RNA; MACROLIDE RESISTANCE; SHORT PEPTIDES; COLI; TRANSCRIPTION; TRANSLATION; MUTATIONS; CLONING; MUTANT; GENES AB The aim of this study was to reveal the biological function of Cj1199 which was overexpressed in the laboratory induced erythromycin resistant strains. The Cj1199 deletion mutant (Phi Cj1199) was constructed via insertional inactivation from its parent strain Campylobacter jejuni NCTC11168. The Phi Cj1199 and NCTC11168 were then subjected to microarray and real-time PCR to find gene pathway of Cj1199. The antimicrobial susceptibility, antimicrobial resistance development, growth characteristics and leucine metabolism were examined to confirm the biological function of Cj1199. Our result showed that a total of 20 genes were down-regulated in Phi Cj1199. These genes were mainly involved in leucine biosynthesis, amino acid transport and periplasmic/membrane structure. Compared to NCTC11168, Phi Cj1199 was difficult to acquire higher-level erythromycin resistance during the in vitro step-wise selection. The competition growth and leucine-dependent growth assays demonstrated that Phi Cj1199 imposed a growth disadvantage under pressure of erythromycin and in the leucine-free medium. In conclusion, Cj1199 gene may directly regulate the leucine biosynthesis and transport and indirectly affect the development of erythromycin resistance in C. jejuni. C1 [Hao, Haihong; Li, Fei; Dai, Menghong; Wang, Yulian; Huang, Lingli; Liu, Zhenli; Yuan, Zonghui] Huazhong Agr Univ, Natl Reference Lab Vet Drug Residues, Wuhan, Peoples R China. [Hao, Haihong; Li, Fei; Dai, Menghong; Wang, Yulian; Huang, Lingli; Liu, Zhenli; Yuan, Zonghui] Huazhong Agr Univ, MOA Key Lab Detect Vet Drug Residues, Wuhan, Peoples R China. [Hao, Haihong; Li, Fei; Dai, Menghong; Wang, Xu; Sun, Yawei; Liu, Zhenli; Yuan, Zonghui] Huazhong Agr Univ, MOA Lab Risk Assessment Qual & Safety Livestock &, Wuhan, Peoples R China. [Hao, Haihong; Wang, Xu; Wang, Yulian; Huang, Lingli; Sun, Yawei; Liu, Zhenli; 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 Yuan, ZH (reprint author), Huazhong Agr Univ, Natl Reference Lab Vet Drug Residues, Wuhan, Peoples R China.; Yuan, ZH (reprint author), Huazhong Agr Univ, MOA Key Lab Detect Vet Drug Residues, Wuhan, Peoples R China.; Yuan, ZH (reprint author), Huazhong Agr Univ, 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 yuan5802@mail.hzau.edu.cn FU National Basic Research Program of China [2013CB127200]; National Key research and development program of China [2016YFD0501302]; Morning program of Wuhan in China [2015070404010191]; Fundamental Research Funds for the Central Universities [2662015PY035]; National Natural Science Foundation of China [31101856]; National Key Technology RD Program [2012BAK01B00]; 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 of China (2016YFD0501302), Morning program of Wuhan in China (2015070404010191), Fundamental Research Funds for the Central Universities (2662015PY035), National Natural Science Foundation of China (31101856), National Key Technology R&D Program (2012BAK01B00), 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 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. 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 42 TC 0 Z9 0 U1 8 U2 8 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 JAN 17 PY 2017 VL 8 AR 16 DI 10.3389/fmicb.2017.00016 PG 10 WC Microbiology SC Microbiology GA EH8JR UT WOS:000392018600001 PM 28144238 ER PT J AU Chen, Y Pouillot, R Burall, LS Strain, EA Van Doren, JM De Jesus, AJ Laasri, A Wang, H Ali, L Tatavarthy, A Zhang, GD Hu, LJ Day, J Sheth, I Kang, JH Sahu, S Srinivasan, D Brown, EW Parish, M Zink, DL Datta, AR Hammack, TS Macarisin, D AF Chen, Yi Pouillot, Regis Burall, Laurel S. Strain, Errol A. Van Doren, Jane M. De Jesus, Antonio J. Laasri, Anna Wang, Hua Ali, Laila Tatavarthy, Aparna Zhang, Guodong Hu, Lijun Day, James Sheth, Ishani Kang, Jihun Sahu, Surasri Srinivasan, Devayani Brown, Eric W. Parish, Mickey Zink, Donald L. Datta, Atin R. Hammack, Thomas S. Macarisin, Dumitru TI Comparative evaluation of direct plating and most probable number for enumeration of low levels of Listeria monocytogenes in naturally contaminated ice cream products SO INTERNATIONAL JOURNAL OF FOOD MICROBIOLOGY LA English DT Article DE Ice cream; Direct plating; Most probable number ID ESCHERICHIA-COLI O157; ESTIMATING POPULATIONS; UNITED-STATES; GROWTH; RECOVERY; FOOD; TEMPERATURE; INOCULUM; POULTRY; SPP. AB A precise and accurate method for enumeration of low level of Listeria monocytogenes in foods is critical to a variety of studies. In this study, paired comparison of most probable number (MPN) and direct plating enumeration of L. monocytogenes was conducted on a total of 1730 outbreak-associated ice cream samples that were naturally contaminated with low level of L. monocytogenes. MPN was performed on all 1730 samples. Direct plating was performed on all samples using the RAPID'Lmono (RLM) agar (1600 samples) and agar Listeria Ottaviani and Agosti (ALOA; 130 samples). Probabilistic analysis with Bayesian inference model was used to compare paired direct plating and MPN estimates of L monocytogenes in ice cream samples because assumptions implicit in ordinary least squares (OLS) linear regression analyses were not met for such a comparison. The probabilistic analysis revealed good agreement between the MPN and direct plating estimates, and this agreement showed that the MPN schemes and direct plating schemes using ALOA or RLM evaluated in the present study were suitable for enumerating low levels of L. monocytogenes in these ice cream samples. The statistical analysis further revealed that OLS linear regression analyses of direct plating and MPN data did introduce bias that incorrectly characterized systematic differences between estimates from the two methods. Published by Elsevier B.V. C1 [Chen, Yi; De Jesus, Antonio J.; Laasri, Anna; Wang, Hua; Ali, Laila; Tatavarthy, Aparna; Zhang, Guodong; Hu, Lijun; Day, James; Sheth, Ishani; Brown, Eric W.; Hammack, Thomas S.; Macarisin, Dumitru] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Pouillot, Regis; Strain, Errol A.; Van Doren, Jane M.] US FDA, Off Analyt & Outreach, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Burall, Laurel S.; Kang, Jihun; Sahu, Surasri; Srinivasan, Devayani; Datta, Atin R.] US FDA, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Parish, Mickey; Zink, Donald L.] US FDA, Off Ctr Director, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Chen, Y (reprint author), US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM yi.chen@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]; FDA Center for Food Safety and Applied Nutrition 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 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 U.S. FDA. NR 54 TC 0 Z9 0 U1 13 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1605 EI 1879-3460 J9 INT J FOOD MICROBIOL JI Int. J. Food Microbiol. PD JAN 16 PY 2017 VL 241 BP 15 EP 22 DI 10.1016/j.ijfoodmicro.2016.09.021 PG 8 WC Food Science & Technology; Microbiology SC Food Science & Technology; Microbiology GA EF1FV UT WOS:000390071600003 PM 27741432 ER PT J AU Archer, JC Jenkins, RG AF Archer, Jeffrey C. Jenkins, Roy G., Jr. TI Automated milk fat extraction for the analyses of persistent organic pollutants SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE POPs; Dioxins; Extraction; Automated; Acid hydrolysis ID DIBENZO-P-DIOXINS; POLYCHLORINATED-BIPHENYLS; COWS MILK; UNITED-STATES; PCBS; FARM; CONTAMINATION; PCDDS; PCDFS; FOOD AB We have utilized an automated acid hydrolysis technology, followed by an abbreviated Soxhlet extraction technique to obtain fat from whole milk for the determination of persistent organic pollutants, namely polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans and polychlorinated biphenyls. The process simply involves (1) pouring the liquid milk into the hydrolysis beaker with reagents and standards, (2) drying the obtained fat on a filter paper and (3) obtaining pure fat via the modified Soxhlet extraction using 100 mL of hexane per sample. This technique is in contrast to traditional manually intense liquid-liquid extractions and avoids the preparatory step of freeze-drying the samples for pressurized liquid extractions. Along with these extraction improvements, analytical results closely agree between the methods, thus no quality has been compromised. The native spike (n = 12) and internal standard (n = 24) precision and accuracy results are within EPA Methods 1613 and 1668 limits. While the median (n = 6) Toxic Equivalency Quotient (TEQ) for polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans and the concentration of the marker polychlorinated biphenyls show a percent difference of 1% and 12%, respectively, compared to 315 previously analyzed milk samples at the same laboratory using liquid-liquid extraction. During our feasibility studies, both egg and fish tissue show substantial promise using this technique as well. Published by Elsevier B.V. C1 [Archer, Jeffrey C.; Jenkins, Roy G., Jr.] US FDA, Arkansas Reg Lab, 3900 NCTR Rd,Bldg 26, Jefferson, AR 72079 USA. RP Archer, JC (reprint author), US FDA, Arkansas Reg Lab, 3900 NCTR Rd,Bldg 26, Jefferson, AR 72079 USA. EM Jeffrey.archer@fda.hhs.gov NR 33 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 EI 1873-376X J9 J CHROMATOGR B JI J. Chromatogr. B PD JAN 15 PY 2017 VL 1041 BP 70 EP 76 DI 10.1016/j.jchromb.2016.12.005 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA EI8TR UT WOS:000392781500008 PM 28012381 ER PT J AU Permutt, T AF Permutt, Thomas TI Comments on 'Estimands in clinical trials - broadening the perspective' SO STATISTICS IN MEDICINE LA English DT Editorial Material C1 [Permutt, Thomas] US FDA, Div Biometr 2, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Permutt, T (reprint author), US FDA, Div Biometr 2, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. EM thomas.permutt@fda.hhs.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JAN 15 PY 2017 VL 36 IS 1 BP 20 EP 21 DI 10.1002/sim.7160 PG 2 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 EE1GO UT WOS:000389329200005 PM 27917551 ER PT J AU Solomon, G Weissfeld, L AF Solomon, Ghideon Weissfeld, Lisa TI Pseudo maximum likelihood approach for the analysis of multivariate left-censored longitudinal data SO STATISTICS IN MEDICINE LA English DT Article DE Left-censored data; Longitudinal biomarker data; Mixed effects model; Pseudo maximum likelihood ID RNA LEVELS; EFFECTS MODELS AB The linear mixed effects model based on a full likelihood is one of the few methods available to model longitudinal data subject to left censoring. However, a full likelihood approach is complicated algebraically because of the large dimension of the numeric computations, and maximum likelihood estimation can be computationally prohibitive when the data are heavily censored. Moreover, for mixed models, the complexity of the computation increases as the dimension of the random effects in the model increases. We propose a method based on pseudo likelihood that simplifies the computational complexities, allows a wide class of multivariate models, and that can be used for many different data structures including settings where the level of censoring is high. The motivation for this work comes from the need for a joint model to assess the joint effect of pro-inflammatory and anti-inflammatory biomarker data on 30-day mortality status while simultaneously accounting for longitudinal left censoring and correlation between markers in the analysis of Genetic and Inflammatory Markers for Sepsis study conducted at the University of Pittsburgh. Two markers, interleukin-6 and interleukin-10, which naturally are correlated because of a shared similar biological pathways and are left-censored because of the limited sensitivity of the assays, are considered to determine if higher levels of these markers is associated with an increased risk of death after accounting for the left censoring and their assumed correlation. Copyright (C) 2016 John Wiley & Sons, Ltd. C1 [Solomon, Ghideon] US FDA, Div Biostat, Off Biostat & Epidemiol, CBER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Weissfeld, Lisa] Stat Collaborat, 1625 Massachusetts Ave NW,Suite 60, Washington, DC 20036 USA. RP Solomon, G (reprint author), US FDA, Div Biostat, Off Biostat & Epidemiol, CBER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Ghideon.Solomon@fda.hhs.gov FU National Institute of General Medical Sciences [R01 GM61992] FX We thank Dr. Derek Angus and the CRISMA laboratory for access to the GenIMS data. The GenIMS study was funded on the grant R01 GM61992 by the National Institute of General Medical Sciences. NR 17 TC 0 Z9 0 U1 10 U2 10 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 JAN 15 PY 2017 VL 36 IS 1 BP 81 EP 91 DI 10.1002/sim.7080 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 EE1GO UT WOS:000389329200014 PM 27538729 ER PT J AU Brooks, MB Turk, JR Guerrero, A Narayanan, PK Nolan, JP Besteman, EG Wilson, DW Thomas, RA Fishman, CE Thompson, KL Ellinger-Ziegelbauer, H Pierson, JB Paulman, A Chiang, AY Schultze, AE AF Brooks, Marjory B. Turk, James R. Guerrero, Abraham Narayanan, Padma K. Nolan, John P. Besteman, Elizabeth G. Wilson, Dennis W. Thomas, Roberta A. Fishman, Cindy E. Thompson, Karol L. Ellinger-Ziegelbauer, Heidrun Pierson, Jennifer B. Paulman, April Chiang, Alan Y. Schultze, Albert E. TI Non-Lethal Endotoxin Injection: A Rat Model of Hypercoagulability SO PLOS ONE LA English DT Article ID DISSEMINATED INTRAVASCULAR COAGULATION; ORGAN DYSFUNCTION; INNATE IMMUNITY; LIPOPOLYSACCHARIDE; SEPSIS; INFLAMMATION; MICRORNAS; PATHWAY; PATHOPHYSIOLOGY; BIOGENESIS AB Systemic inflammation co-activates coagulation, which unchecked culminates in a lethal syndrome of multi-organ microvascular thrombosis known as disseminated intravascular coagulation (DIC). We studied an endotoxin-induced inflammatory state in rats to identify biomarkers of hemostatic imbalance favoring hypercoagulability. Intraperitoneal injection of LPS at 15 mg/kg body weight resulted in peripheral leukopenia and widespread neutrophilic sequestration characteristic of an acute systemic inflammatory response. Early indicators of hemostatic pathway activation developed within 4 hours, including increased circulating concentrations of procoagulant extracellular vesicles (EVs), EVs expressing endothelial cell and platelet membrane markers, and high concentration of soluble intercellular adhesion molecule-1 (sICAM-1), plasminogen activator inhibitor-1 (PAI-1), and D-dimers. Inflammation persisted throughout the 48-hour observation period; however, increases were found in a subset of serum microRNA (miRNA) that coincided with gradual resolution of hemostatic protein abnormalities and reduction in EV counts. Dose-adjusted LPS treatment in rats provides a time-course model to develop biomarker profiles reflecting procoagulant imbalance and rebalance under inflammatory conditions. C1 [Brooks, Marjory B.] Cornell Univ, Dept Populat Med & Diagnost Sci, Comparat Coagulat Sect, Ithaca, NY USA. [Turk, James R.; Guerrero, Abraham; Narayanan, Padma K.] Amgen Inc, Comparat Biol & Safety Sci, Thousand Oaks, CA 91320 USA. [Nolan, John P.] Scintillon Inst, San Diego, CA USA. [Besteman, Elizabeth G.] Merck Res Labs, Dept Pathol Safety Assessment & Lab Anim Resource, West Point, PA USA. [Wilson, Dennis W.] Univ Calif Davis, Sch Vet Med, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA. [Thomas, Roberta A.; Fishman, Cindy E.] GlaxoSmithKline, Res & Dev, King Of Prussia, PA USA. [Thompson, Karol L.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Ellinger-Ziegelbauer, Heidrun] Bayer Pharma AG, Wuppertal, Germany. [Pierson, Jennifer B.] Hlth & Environm Sci Inst, Washington, DC USA. [Paulman, April] Covance Labs, Dept Pathol, Greenfield, IN USA. [Chiang, Alan Y.] Lilly Res Labs, Global Stat Sci, Indianapolis, IN USA. [Schultze, Albert E.] Lilly Corp Ctr, Lilly Res Labs, Dept Pathol, Indianapolis, IN 46285 USA. RP Schultze, AE (reprint author), Lilly Corp Ctr, Lilly Res Labs, Dept Pathol, Indianapolis, IN 46285 USA. EM aes@lilly.com FU Lilly; HESI's corporate sponsors; HESI for hemostatic protein analyses at Cornell University FX Lilly supported the in-life phase of this study by contracting for laboratories services, animals and reagents at the Covance facility in Greenfield, IN. All other work was provided in-kind by the ILSI HESI Cardiac Safety Committee Cardiac Biomarkers Working Group, which is supported by sponsorships from member companies. HESI's scientific initiatives are primarily supported by the in-kind contributions (from public and private sector participants) of time, expertise, and experimental effort. These contributions are supplemented by direct funding (that primarily supports program infrastructure and management) provided primarily by HESI's corporate sponsors. James R. Turk, Abraham Guerrero and Padma K. Narayanan are employed by Amgen Inc. Elizabeth G. Besteman is employed by Merck Research Laboratories. Roberta A. Thomas and Cindy E. Fishman are employed by GlaxoSmith Kline. Heidrun Ellinger-Ziegelbauer is employed by Bayer Pharma AG. April Paulman is employed by Covance Laboratories. Alan Y. Chiang and Albert E. Schultze are employed by Lilly Research Laboratories. Amgen Inc., Merck Research Laboratories, GlaxoSmith Kline, Bayer Pharma AG, Lilly Research Laboratories and Covance Laboratories provided either direct, in-direct or in-kind resources to this study and had a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors acknowledge Tammy Lambert and Karen Lynch (GSK) for sE-Selectin and sICAM assays, Erika Duggan and Patrick Nolan (Scintillon) for extensive work on VFC and NTA, and support of HESI for hemostatic protein analyses at Cornell University. NR 45 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 JAN 12 PY 2017 VL 12 IS 1 AR e0169976 DI 10.1371/journal.pone.0169976 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH7JQ UT WOS:000391949500112 PM 28081568 ER PT J AU He, Y Sultana, I Takeda, K Reed, JL AF He, Yong Sultana, Ishrat Takeda, Kazuyo Reed, Jennifer L. TI Cutaneous Deficiency of Filaggrin and STAT3 Exacerbates Vaccinia Disease In Vivo SO PLOS ONE LA English DT Article ID MAST-CELLS; ATOPIC-DERMATITIS; ACTIVIN-A; INDUCTION AB Rationale Defects in filaggrin and STAT3 are associated with atopic dermatitis (AD) and susceptibility to severe skin infection. Methods We evaluated skin infection with the current smallpox vaccine, ACAM-2000, in immunosuppressed mice with combined cutaneous deficiency in filaggrin and STAT3. In parallel, early events post-infection with ACAM-2000 were investigated in cultured keratinocytes in which filaggrin expression was knocked down via siRNA. Results Immunosuppressed, filaggrin-deficient mice, treated with the topical STAT3 inhibitor Stattic (R) prior to ACAM-2000 infection, demonstrated rapid weight loss, prolonged vaccinia burden in skin, and dermatitis. The TGF-beta family ligand activin A was upregulated ten-fold in infected skin. Topically-applied ALK5/TG beta R1 signaling inhibitor synergized with vaccinia immune globulin (VIG) to promote vaccinia clearance and limit weight loss. In cultured keratinocytes, filaggrin-directed siRNA inhibited programmed necrosis and inflammatory cytokine release induced by ACAM-2000, while viral growth was increased. Conclusions Our findings may point to a novel role for filaggrin in early antiviral responses in skin. In wounded skin with underlying barrier defects, chronically elevated activin A levels may contribute to skin remodeling and cutaneous pathogen persistence. Inhibition of ALK5/TGF beta R1 signaling may provide a novel co-therapeutic approach, together with VIG, to limit cutaneous spread of vaccinia. C1 [He, Yong; Sultana, Ishrat; Takeda, Kazuyo; Reed, Jennifer L.] US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Reed, JL (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jennifer.reed@fda.hhs.gov FU Medical Countermeasures Initiative; Food and Drug Administration, Center for Biologics Evaluation and Research FX This work was supported by Medical Countermeasures Initiative and Modernization of Science funding awarded by the Food and Drug Administration, Center for Biologics Evaluation and Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 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 JAN 12 PY 2017 VL 12 IS 1 AR e0170070 DI 10.1371/journal.pone.0170070 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH7JQ UT WOS:000391949500126 PM 28081250 ER PT J AU Karunathilaka, SR Mossoba, MM Chung, JK Haile, EA Srigley, CT AF Karunathilaka, Sanjeewa R. Mossoba, Magdi M. Chung, Jin Kyu Haile, Ermias A. Srigley, Cynthia T. TI Rapid Prediction of Fatty Acid Content in Marine Oil Omega-3 Dietary Supplements Using a Portable Fourier Transform Infrared (FTIR) Device and Partial Least-Squares Regression (PLSR) Analysis SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE FTIR spectroscopy; chemometrics; omega-3 polyunsaturated fatty acids; marine oil dietary supplements; EPA; DHA ID VIRGIN OLIVE OIL; EDIBLE OILS; ATOPIC-DERMATITIS; SPECTROSCOPY; FISH; OMEGA-3-FATTY-ACIDS; CHEMOMETRICS; PRODUCTS; ESTERS; PUFA AB Using a portable field device, a Fourier transform infrared spectroscopy (FTIR) and partial least-squares regression (PLSR) method was developed for the rapid (<5 min) prediction of major and minor fatty acid (FA) concentrations in marine oil omega-3 dietary supplements. Calibration models were developed with 174 gravimetrically prepared samples. These models were tested using an independent validation set of dietary supplements. FAs analyzed included eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); the sums of saturated, branched-chain, and monounsaturated FAs; and n-6, n-4, n-3, n1, and trans polyunsaturated FA. The spectral ranges 650-1500 or 650-1500 and 2800-3050 cm(-1) provided reliable predictions for FA components in 34 neat oil products: standard error of prediction, 0.73-1.58%; residual predictive deviation, 6.41-12.6. This simple, nondestructive quantitative method is a rapid screening tool and a time and cost-saving alternative to gas chromatography for verifying label declarations and in quality control. C1 [Karunathilaka, Sanjeewa R.; Mossoba, Magdi M.; Chung, Jin Kyu; Srigley, Cynthia T.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5001 Campus Dr, College Pk, MD 20740 USA. [Haile, Ermias A.] Univ Maryland, Joint Inst Food Safety & Appl Nutr, 5201 Campus Dr,Patapsco Bldg Suite 2134, College Pk, MD 20742 USA. RP Mossoba, MM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5001 Campus Dr, College Pk, MD 20740 USA. EM magdi.mossoba@fda.hhs.gov NR 37 TC 0 Z9 0 U1 3 U2 3 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 JAN 11 PY 2017 VL 65 IS 1 BP 224 EP 233 DI 10.1021/acs.jafc.6b04463 PG 10 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA EH8QJ UT WOS:000392037100028 PM 27997173 ER PT J AU Zhang, CW Garrard, L Keighley, J Carlson, S Gajewski, B AF Zhang, Chuanwu Garrard, Lili Keighley, John Carlson, Susan Gajewski, Byron TI Subgroup identification of early preterm birth (ePTB): informing a future prospective enrichment clinical trial design SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article DE Early preterm birth; Risk factor; Interaction; Classification and regression tree; Logistic regression; Enrichment trial design ID RISK-FACTOR; BURDEN; CLASSIFICATION; EVACUATION; REGRESSION; MORTALITY; PREGNANCY; SINGLETON; WEIGHT AB Background: Despite the widely recognized association between the severity of early preterm birth (ePTB) and its related severe diseases, little is known about the potential risk factors of ePTB and the sub-population with high risk of ePTB. Moreover, motivated by a future confirmatory clinical trial to identify whether supplementing pregnant women with docosahexaenoic acid (DHA) has a different effect on the risk subgroup population or not in terms of ePTB prevalence, this study aims to identify potential risk subgroups and risk factors for ePTB, defined as babies born less than 34 weeks of gestation. Methods: The analysis data (N = 3,994,872) were obtained from CDC and NCHS' 2014 Natality public data file. The sample was split into independent training and validation cohorts for model generation and model assessment, respectively. Logistic regression and CART models were used to examine potential ePTB risk predictors and their interactions, including mothers' age, nativity, race, Hispanic origin, marital status, education, pre-pregnancy smoking status, pre-pregnancy BMI, pre-pregnancy diabetes status, pre-pregnancy hypertension status, previous preterm birth status, infertility treatment usage status, fertility enhancing drug usage status, and delivery payment source. Results: Both logistic regression models with either 14 or 10 ePTB risk factors produced the same C-index (0.646) based on the training cohort. The C-index of the logistic regression model based on 10 predictors was 0.645 for the validation cohort. Both C-indexes indicated a good discrimination and acceptable model fit. The CART model identified preterm birth history and race as the most important risk factors, and revealed that the subgroup with a preterm birth history and a race designation as Black had the highest risk for ePTB. The c-index and misclassification rate were 0.579 and 0.034 for the training cohort, and 0.578 and 0.034 for the validation cohort, respectively. Conclusions: This study revealed 14 maternal characteristic variables that reliably identified risk for ePTB through either logistic regression model and/or a CART model. Moreover, both models efficiently identify risk subgroups for further enrichment clinical trial design. C1 [Zhang, Chuanwu; Keighley, John; Gajewski, Byron] Univ Kansas, Med Ctr, Dept Biostat, Mail Stop 1026,3901 Rainbow Blvd, Kansas City, KS 66160 USA. [Garrard, Lili] US FDA, Div Biometr 3, OB OTS CDER, Silver Spring, MD 20993 USA. [Carlson, Susan] Univ Kansas, Med Ctr, Sch Hlth Profess, Dept Dietet & Nutr, Mail Stop 1026,3901 Rainbow Blvd, Kansas City, KS 66160 USA. RP Zhang, CW (reprint author), Univ Kansas, Med Ctr, Dept Biostat, Mail Stop 1026,3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM czhang4@kumc.edu FU National Institutes of Health (NIH) Clinical and Translational Science [UL1 TR000001] FX This study was supported in part by a National Institutes of Health (NIH) Clinical and Translational Science Award Grant (UL1 TR000001, formerly UL1RR033179), awarded to the University of Kansas Medical Center. NR 32 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD JAN 10 PY 2017 VL 17 AR 18 DI 10.1186/s12884-016-1189-0 PG 13 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EH4WW UT WOS:000391773200003 PM 28068927 ER PT J AU Boucher, HW Cosgrove, SE Cox, E Talbot, GH AF Boucher, Helen W. Cosgrove, Sara E. Cox, Edward Talbot, George H. TI The Fight Against Multidrug-Resistant Bacteria SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID PROGRESS; UPDATE C1 [Boucher, Helen W.] Tufts Med Ctr, Boston, MA 02111 USA. [Boucher, Helen W.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Cosgrove, Sara E.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Cox, Edward] US FDA, Silver Spring, MD USA. [Talbot, George H.] Talbot Advisors, Anna Maria, FL USA. RP Boucher, HW (reprint author), Tufts Med Ctr, Boston, MA 02111 USA.; Boucher, HW (reprint author), Tufts Univ, Sch Med, Boston, MA 02111 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 3 PY 2017 VL 166 IS 1 BP 78 EP 79 DI 10.7326/L16-0584 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EH0QD UT WOS:000391467900019 PM 28030674 ER PT J AU Schinkel, SCB Rubin, S Wright, KE AF Schinkel, Stephanie C. Burke Rubin, Steven Wright, Kathryn E. TI Mechanisms of temperature sensitivity of attenuated Urabe mumps virus SO VIRUS RESEARCH LA English DT Article DE Mumps virus; Attenuation; Temperature sensitivity; Transcription; Replication ID RESPIRATORY SYNCYTIAL VIRUS; RNA-POLYMERASE; HEMAGGLUTININ-NEURAMINIDASE; ANTIGENOMIC PROMOTER; CANDIDATE VACCINE; TYPE-3; MUTATIONS; NEUROVIRULENCE; PROTEIN; LIVE AB Temperature sensitivity is a phenotype often associated with attenuation of viruses. Previously, we purified several mumps variants from an incompletely attenuated Urabe strain live attenuated vaccine. Here we characterize one isolate that is sensitive to growth at high temperature. This virus was attenuated in a small animal model of mumps virulence, and we identified unique coding substitutions in the hemagglutinin-neuraminidase (HN), the viral polymerase (L) gene, and a non-coding substitution close to the anti-genome promoter sequences. At the non-permissive temperature, transcription of viral mRNAs and production of the replication intermediate were reduced compared to events at the permissive temperature and to a non-ts virulent Urabe virus. As well, synthesis of viral proteins was also reduced at the higher temperature. While the actual sequence substitutions in the is virus were unique, the pattern of substitutions in HN, L and genome end sequences is similar to another attenuated Urabe virus previously described by us. (C) 2016 Elsevier B.V. All rights reserved. C1 [Schinkel, Stephanie C. Burke; Wright, Kathryn E.] Univ Ottawa, Dept Biochem Microbiol & Immunol, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada. [Rubin, Steven] US FDA, CBER, OVRR, DVP, 10903 New Hampshire Ave,Bldg 52-72, Silver Spring, MD 20993 USA. RP Wright, KE (reprint author), Univ Ottawa, Dept Biochem Microbiol & Immunol, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada. EM sburk089@uottawa.ca; rubins@ceber.FDA.gov; kwright@uottawa.ca FU National Sciences and Engineering Research Council of Canada (NSERC) FX We acknowledge funding from the National Sciences and Engineering Research Council of Canada (NSERC). We thank Erica Langley and Daniel Ngo for technical support with sequencing and western blots, Dr. M. Laassri for deep sequencing, and Dr. C.J Sauder for his review of the manuscript. NR 32 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 EI 1872-7492 J9 VIRUS RES JI Virus Res. PD JAN 2 PY 2017 VL 227 BP 104 EP 109 DI 10.1016/j.virusres.2016.10.003 PG 6 WC Virology SC Virology GA EE6NO UT WOS:000389729700013 PM 27720824 ER PT J AU Zaman, S Sarntivijai, S Abernethy, DR AF Zaman, Shadia Sarntivijai, Sirarat Abernethy, Darrell R. TI Use of Biomedical Ontologies for Integration of Biological Knowledge for Learning and Prediction of Adverse Drug Reactions SO GENE REGULATION AND SYSTEMS BIOLOGY LA English DT Review DE Biomedical ontologies; data integration; PredicTox; adverse drug reaction ID CELL ONTOLOGY; MECHANISMS; DISEASE; EVENTS; PHENOTYPES; DATABASES; PROJECT; OBO AB Drug-induced toxicity is a major public health concern that leads to patient morbidity and mortality. To address this problem, the Food and Drug Administration is working on the PredicTox initiative, a pilot research program on tyrosine kinase inhibitors, to build mechanistic and predictive models for drug-induced toxicity. This program involves integrating data acquired during preclinical studies and clinical trials within pharmaceutical company development programs that they have agreed to put in the public domain and in publicly available biological, pharmacological, and chemical databases. The integration process is accommodated by biomedical ontologies, a set of standardized vocabularies that define terms and logical relationships between them in each vocabulary. We describe a few programs that have used ontologies to address biomedical questions. The PredicTox effort is leveraging the experience gathered from these early initiatives to develop an infrastructure that allows evaluation of the hypothesis that having a mechanistic understanding underlying adverse drug reactions will improve the capacity to understand drug-induced clinical adverse drug reactions. C1 [Zaman, Shadia; Abernethy, Darrell R.] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Off Translat Sci, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Sarntivijai, Sirarat] European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge, England. RP Zaman, S (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Off Translat Sci, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM shadia.zaman@fda.hhs.gov NR 32 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 1177-6250 J9 GENE REGUL SYST BIO JI Gene Regul. Syst. Biol. PY 2017 VL 11 BP 1 EP 7 DI 10.1177/1177625017696075 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA EP6VC UT WOS:000397516000001 ER PT J AU Peckham, JG Kropp, JD Mroz, TA Haley-Zitlin, V Granberg, EM Hawthorne, N AF Peckham, Janet G. Kropp, Jaclyn D. Mroz, Thomas A. Haley-Zitlin, Vivian Granberg, Ellen M. Hawthorne, Nicole TI SOCIOECONOMIC AND DEMOGRAPHIC DETERMINANTS OF THE NUTRITIONAL CONTENT OF NATIONAL SCHOOL LUNCH PROGRAM ENTREE SELECTIONS SO AMERICAN JOURNAL OF AGRICULTURAL ECONOMICS LA English DT Article DE Child nutrition; childhood obesity; food selection; National School Lunch Program; nutrient selection; mixed logit ID CHILDHOOD OBESITY; BODY-MASS; CHILDREN; PARTICIPATION; ADOLESCENTS; PREVALENCE; STANDARDS; HEALTH; IMPACT AB New National School Lunch Program (NSLP) guidelines aim to reduce sodium and saturated fats, limit calories, and eliminate trans-fat and whole milk. This paper provides a novel approach to understanding how the healthfulness of NSLP participants' entree selections varies across socioeconomic and demographic groups. Unlike previous studies that rely on dietary recalls, we use a mixed logit model to examine students' entree choices in a school cafeteria. We estimate the likelihood that an entree is selected from the available lunch choices as a function of the entree's nutrients (fat, carbohydrate, protein, and sodium) and entree's taste profile characteristics (e. g., Mexican, Pizza-like), as well as the student's socio-economic and demographic characteristics. Using these estimates, we examine how changing the nutritional content of an offering impacts the probability of selecting each of the offerings. Free lunch recipients are more likely to choose entrees higher in fat but lower in sodium than other students. Full-price lunch recipients are the most responsive to changes in nutritional content of the offerings and are most likely to respond to changes in the nutritional content of the offered entrees by substituting a lunch brought from home for the school-purchased lunch. Replacing less healthy menu items with popular but healthier items reduces the selection of total calories, calories from fat, and sodium by approximately 4%, 18%, and 8%, respectively, over the study period. The new guidelines should be effective at improving the nutrition of school-age children, and potentially reducing childhood obesity, provided NSLP participation does not decline appreciably. C1 [Peckham, Janet G.] US FDA, Off Commissioner, Rockville, MD 20857 USA. [Kropp, Jaclyn D.] Univ Florida, Food & Resource Econ Dept, Gainesville, FL 32611 USA. [Mroz, Thomas A.] Georgia State Univ, Dept Econ, Andrew Young Sch Policy Studies, Atlanta, GA 30303 USA. [Mroz, Thomas A.] Fed Reserve Bank Atlanta, Atlanta, GA USA. [Haley-Zitlin, Vivian] Clemson Univ, Food Nutr & Packaging Sci Dept, Clemson, SC 29631 USA. [Granberg, Ellen M.] Clemson Univ, Dept Sociol & Anthropol, Clemson, SC 29631 USA. [Hawthorne, Nicole] Putnam Cty Sch Dist Florida, Sch Food Serv, Palatka, FL USA. RP Peckham, JG (reprint author), US FDA, Off Commissioner, Rockville, MD 20857 USA. FU College of Business and Behavioral Science, Clemson University; Institute of Food and Agricultural Science, University of Florida; USDA Cooperative State Research, Education and Extension Service [5337] FX Janet G. Peckham is an economist in the Office of the Commissioner at the U.S. Food and Drug Administration. Jaclyn D. Kropp is an assistant professor in the Food and Resource Economics Department at the University of Florida. Thomas A. Mroz is a professor and Bernard B. and Eugenia A. Ramsey Chair of Private Enterprise in the Department of Economics, Andrew Young School of Policy Studies at Georgia State University and a research fellow at the Federal Reserve Bank of Atlanta. Vivian Haley-Zitlin is an associate professor in the Food, Nutrition, and Packaging Sciences Department at Clemson University. Ellen M. Granberg is an associate professor in the Department of Sociology and Anthropology at Clemson University. Nicole Hawthorne is the director of School Food Service at Putnam County School District in Florida. The authors are grateful to the College of Business and Behavioral Science, Clemson University, for providing funding to support data compilation and analysis through the Healthcare Research Initiative, and the Institute of Food and Agricultural Science, University of Florida, for providing funding to support the analysis through the Early Career Scientist Seed Funding program. The project was also supported by the USDA Cooperative State Research, Education and Extension Service, Hatch grant #5337. The views expressed here are the authors' and not necessarily those of the U.S. Food and Drug Administration, Federal Reserve Bank of Atlanta, or the Federal Reserve System. NR 29 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 0002-9092 EI 1467-8276 J9 AM J AGR ECON JI Am. J. Agr. Econ. PD JAN PY 2017 VL 99 IS 1 BP 1 EP 17 DI 10.1093/ajae/aaw062 PG 17 WC Agricultural Economics & Policy; Economics SC Agriculture; Business & Economics GA EP0IH UT WOS:000397070000001 ER PT J AU Huang, DT Dee, DL Ko, J Cole, JG Houston, K Sircar, KD Gaines, J AF Huang, David T. Dee, Deborah L. Ko, Jean Cole, Jessica G. Houston, Keisha Sircar, Kanta D. Gaines, Joanna TI Seven Prevention Priorities of USPHS Scientist Officers SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Huang, David T.] Ctr Dis Control & Prevent CDC, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Dee, Deborah L.; Ko, Jean; Houston, Keisha] CDC, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Cole, Jessica G.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Sircar, Kanta D.] CDC, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. [Gaines, Joanna] CDC, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. RP Huang, DT (reprint author), Ctr Dis Control & Prevent, Hlth Promot Stat Branch, Natl Ctr Hlth Stat, 3311 Toledo Rd, Hyattsville, MD 20782 USA. EM dhuang@cdc.gov FU Intramural CDC HHS [CC999999] NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JAN PY 2017 VL 107 IS 1 BP 39 EP 40 DI 10.2105/AJPH.2016.303497 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO2KD UT WOS:000396524500029 PM 27925801 ER PT S AU Myers, MJ Smith, ER Turfle, PG AF Myers, Michael J. Smith, Emily R. Turfle, Phillip G. BE Lewin, HA Roberts, RM TI Biomarkers in Veterinary Medicine SO ANNUAL REVIEW OF ANIMAL BIOSCIENCES, VOL 5 SE Annual Review of Animal Biosciences LA English DT Article; Book Chapter DE biomarker; biological marker; domestic animals; laboratory animals; veterinary ID CARDIAC TROPONIN-I; THYMIDINE KINASE-ACTIVITY; CHRONIC KIDNEY-DISEASE; MITRAL-VALVE DISEASE; ANALYTICAL VALIDATION; NATRIURETIC PEPTIDE; RENAL BIOMARKERS; CYANURIC ACID; HEALTHY DOGS; SYMMETRIC DIMETHYLARGININE AB This article summarizes the relevant definitions related to biomarkers; reviews the general processes related to biomarker discovery and ultimate acceptance and use; and finally summarizes and reviews, to the extent possible, examples of the types of biomarkers used in animal species within veterinary clinical practice and human and veterinary drug development. We highlight opportunities for collaboration and coordination of research within the veterinary community and leveraging of resources from human medicine to support biomarker discovery and validation efforts for veterinary medicine. C1 [Myers, Michael J.; Smith, Emily R.; Turfle, Phillip G.] US FDA, Ctr Vet Med, Rockville, MD 20855 USA. RP Myers, MJ (reprint author), US FDA, Ctr Vet Med, Rockville, MD 20855 USA. EM michael.myers@fda.hhs.gov NR 146 TC 0 Z9 0 U1 0 U2 0 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 2165-8102 J9 ANNU REV ANIM BIOSCI PY 2017 VL 5 BP 65 EP 87 DI 10.1146/annurev-animal-021815-111431 PG 23 WC Agriculture, Dairy & Animal Science; Biotechnology & Applied Microbiology; Veterinary Sciences; Zoology SC Agriculture; Biotechnology & Applied Microbiology; Veterinary Sciences; Zoology GA BH0QQ UT WOS:000396050700004 PM 27860493 ER PT J AU Pan, Y Ji, JS Jin, J Kuo, WP Kang, HJ AF Pan, Ying Ji, John S. Jin, Jason (Gang) Kuo, Winston Patrick Kang, Hongjun TI Cancer Liquid Biopsy SO IEEE PULSE LA English DT Article ID CIRCULATING TUMOR-CELLS; PROSTATE-CANCER AB The management of cancer relies on a combination of imaging and tissue biopsy for diagnosis, monitoring, and molecular classification-based patient stratification to ensure appropriate treatment. Conventional tissue biopsy harvests tumor samples with invasive procedures, which are often difficult for patients with advanced disease. Given the well-recognized intratumor getactic heterogeneity [1], the biopsy of small tumor fragments does not necessarily represent all the genetic aberrations in the tumor, but sampling the entire tumor in each patient is not realistic. Moreover, tumors evolve all the time from local to advanced disease and by adapting to selective pressure from treatment. C1 [Pan, Ying] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Ji, John S.] Harvard Sch Business, Boston, MA USA. [Ji, John S.] Peking Univ, Sch Publ Hlth, Beijing, Peoples R China. [Ji, John S.] China Med Board, Cambridge, MA USA. [Ji, John S.] US FDA, Rockville, MD 20857 USA. [Jin, Jason (Gang)] Natl Thousand Talents Program, Tianjin, Peoples R China. [Jin, Jason (Gang)] Cloud Hlth Genom Ltd, Shanghai, Peoples R China. [Jin, Jason (Gang)] CloudHlth Med Grp Ltd, Shanghai, Peoples R China. [Jin, Jason (Gang)] ShanghaiBio Corp, Plainsboro Township, NJ USA. [Jin, Jason (Gang)] Shanghai Biochip Co Ltd, Natl Engn Ctr Biochip, Shanghai, Peoples R China. [Jin, Jason (Gang)] Shanghai Biotechnol Corp, Shanghai, Peoples R China. [Jin, Jason (Gang)] Shanghai Inst Biol Sci, Shanghai, Peoples R China. [Jin, Jason (Gang)] Chinese Acad Sci, Beijing 100864, Peoples R China. [Jin, Jason (Gang)] Fudan Univ, Shanghai, Peoples R China. [Jin, Jason (Gang)] Shanghai Jiao Tong Univ, Shanghai 200030, Peoples R China. [Kuo, Winston Patrick] CloudHlth Genom Ltd, Business Dev, Shanghai, Peoples R China. [Kuo, Winston Patrick] Predicine Holdings Ltd, Hayward, CA USA. [Kuo, Winston Patrick] IES Diagnost, Wayne, PA USA. [Kuo, Winston Patrick] Harvard Sch Dent Med, Dept Dev Biol, Boston, MA USA. [Kuo, Winston Patrick] Harvard Sch Dent Med, Harvard Clin & Translat Sci Lab Innovat Translat, Boston, MA USA. [Kang, Hongjun] Chinese Peoples Liberat Army Gen Hosp, Beijing 100853, Peoples R China. RP Pan, Y (reprint author), Stanford Univ, Sch Med, Stanford, CA 94305 USA. EM yingpan@stanford.edu; johnji@postharvard.edu; jason.jin@cloudhealth99.com; winston.kuo@cloudhealth99.com; doctorklbd@126.com NR 10 TC 0 Z9 0 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2154-2287 J9 IEEE PULSE JI IEEE Pulse PD JAN-FEB PY 2017 VL 8 IS 1 BP 23 EP 27 DI 10.1109/MPUL.2016.2630838 PG 5 WC Engineering, Biomedical SC Engineering GA EM7RE UT WOS:000395509200005 PM 28129138 ER PT J AU Guo, D Kruhlak, N Stavitskaya, L Cross, K Bower, D AF Guo, D. Kruhlak, N. Stavitskaya, L. Cross, K. Bower, D. TI Characterizing Compound Classes by Rodent Carcinogenicity Tumor Severity and Type SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the American-College-of-Toxicology (ACT) CY NOV 06-09, 2016 CL Baltimore, MD SP Amer Coll Toxicol C1 [Guo, D.; Kruhlak, N.; Stavitskaya, L.] US FDA, Silver Spring, MD USA. [Cross, K.; Bower, D.] Leadscope Inc, Columbus, OH USA. 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 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD JAN-FEB PY 2017 VL 36 IS 1 MA P205 BP 66 EP 66 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EP2PJ UT WOS:000397225300044 ER PT J AU Park, E Gintant, G Bi, D Kozeli, D Pettit, S Pierson, J Skinner, M Willard, J Wisialowski, T Koerner, J Valentin, J AF Park, E. Gintant, G. Bi, D. Kozeli, D. Pettit, S. Pierson, J. Skinner, M. Willard, J. Wisialowski, T. Koerner, J. Valentin, J. TI Can Nonclinical Repolarization Assays Predict the Results of Clinical Thorough QT Studies? A HESI-FDA Retrospective Analysis SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the American-College-of-Toxicology (ACT) CY NOV 06-09, 2016 CL Baltimore, MD SP Amer Coll Toxicol C1 [Park, E.; Bi, D.; Kozeli, D.; Willard, J.; Koerner, J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Gintant, G.] AbbVie, Integrat Pharmacol, N Chicago, IL USA. [Pettit, S.; Pierson, J.] HESI, Washington, DC USA. [Skinner, M.] AstraZeneca, Drug Safety & Metab, Macclesfield, Cheshire, England. [Wisialowski, T.] Pfizer, Drug Safety Res & Dev, Groton, CT USA. [Valentin, J.] UCB Biopharma SPRL, Nonclin Dev, Braine Lalleud, Belgium. 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 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD JAN-FEB PY 2017 VL 36 IS 1 MA P305 BP 70 EP 70 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EP2PJ UT WOS:000397225300057 ER PT J AU Howard, K Zadrozny, L Weaver, J AF Howard, K. Zadrozny, L. Weaver, J. TI Immune Humanized Mouse Model: Autoimmunity Induced by Nivolumab SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the American-College-of-Toxicology (ACT) CY NOV 06-09, 2016 CL Baltimore, MD SP Amer Coll Toxicol C1 [Howard, K.; Zadrozny, L.; Weaver, J.] US FDA, Silver Spring, MD USA. 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 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD JAN-FEB PY 2017 VL 36 IS 1 MA P516 BP 85 EP 86 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EP2PJ UT WOS:000397225300101 ER PT J AU Semple, K Howard, K AF Semple, K. Howard, K. TI Development of Hepatic/Immune Humanized Mice SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the American-College-of-Toxicology (ACT) CY NOV 06-09, 2016 CL Baltimore, MD SP Amer Coll Toxicol C1 [Semple, K.; Howard, K.] US FDA, Silver Spring, MD USA. 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 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD JAN-FEB PY 2017 VL 36 IS 1 MA P530 BP 90 EP 90 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EP2PJ UT WOS:000397225300115 ER PT J AU Yang, X Ren, L White, M Mattes, W AF Yang, X. Ren, L. White, M. Mattes, W. TI Application of Small RNA Sequencing to Identify MicroRNAs in Drug-Induced Cardiac Toxicity Using iPSC Cardiomyocytes SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the American-College-of-Toxicology (ACT) CY NOV 06-09, 2016 CL Baltimore, MD SP Amer Coll Toxicol C1 [Yang, X.; Ren, L.; White, M.; Mattes, W.] Natl Ctr Toxicol Res, FDA, Jefferson, AR 72079 USA. 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 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD JAN-FEB PY 2017 VL 36 IS 1 MA P533 BP 91 EP 91 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EP2PJ UT WOS:000397225300118 ER PT J AU Mei, N Guo, XQ Ren, Z Kobayashi, D Wada, K Guo, L AF Mei, Nan Guo, Xiaoqing Ren, Zhen Kobayashi, Daisuke Wada, Keiji Guo, Lei TI Review of Ginkgo biloba-induced toxicity, from experimental studies to human case reports SO JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH PART C-ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS LA English DT Review DE Case report; clinical trial; Ginkgo biloba leaf extract; genotoxicity; ginkgo seeds; toxicity ID HERB-DRUG INTERACTIONS; LIQUID CHROMATOGRAPHY/MASS SPECTROMETRY; PLACEBO-CONTROLLED TRIAL; CAVITY CANCER-CELLS; LEAF EXTRACT; DIETARY-SUPPLEMENTS; GINGKO-BILOBA; IN-VITRO; MUTAGENIC ACTIVITY; ACTIVE COMPONENTS AB Ginkgo biloba seeds and leaves have been used as a traditional herbal remedy for thousands of years, and its leaf extract has been consumed as a botanical dietary supplement for decades. Ginkgo biloba extract is a complex mixture with numerous components, including flavonol glycosides and terpene lactones, and is one of the most widely sold botanical dietary supplements worldwide. Concerns about potential health risks for the general population have been raised because of the widespread human exposure to Ginkgo biloba and its potential toxic and carcinogenic activities in rodents. The National Toxicology Program conducted 2-year gavage studies on one Ginkgo biloba leaf extract and concluded that there was clear evidence of carcinogenic activity of this extract in mice based on an increased incidence of hepatocellular carcinoma and hepatoblastoma. Recently, Ginkgo biloba leaf extract has been classified as a possible human carcinogen (Group 2B) by the International Agency for Research on Cancer. This review presents updated information on the toxicological effects from experimental studies both in vitro and in vivo to human case reports (caused by ginkgo seeds or leaves), and also summarizes the negative results from relatively large clinical trials. C1 [Mei, Nan; Guo, Xiaoqing] Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Ren, Zhen; Guo, Lei] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Kobayashi, Daisuke; Wada, Keiji] Hlth Sci Univ Hokkaido, Fac Pharmaceut Sci, Dept Food & Chem Toxicol, Tobetsu, Hokkaido, Japan. RP Mei, N (reprint author), Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Nan.Mei@fda.hhs.gov FU Postgraduate Research Program at the National Center for Toxicological Research FX ZR was supported by the appointment to the Postgraduate Research Program at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science Education through an interagency agreement between the US Department of Energy and the US FDA. NR 139 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1059-0501 EI 1532-4095 J9 J ENVIRON SCI HEAL C JI J. Environ. Sci. Health Pt. C-Environ. Carcinog. Ecotoxicol. Rev. PY 2017 VL 35 IS 1 BP 1 EP 28 DI 10.1080/10590501.2016.1278298 PG 28 WC Oncology; Environmental Sciences; Toxicology SC Oncology; Environmental Sciences & Ecology; Toxicology GA EM2TB UT WOS:000395167500001 PM 28055331 ER PT J AU Jones, S Pramanik, A Sweet, C Keyes, A Begum, S Vangra, A Yu, H Fu, PP Ray, PC AF Jones, Stacy Pramanik, Avijit Sweet, Carrie Keyes, Anthony Begum, Salma Vangra, Aruna Yu, Hongtal Fu, Peter P. Ray, Paresh Chandra TI Recent progress on the development of anisotropic gold nanoparticles: Design strategies and growth mechanism SO JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH PART C-ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS LA English DT Review DE Anisotropic nanoparticles; challenges; growth mechanism; prospect; surfactant and reactants ID SILVER UNDERPOTENTIAL DEPOSITION; 2ND-HARMONIC GENERATION; GRAPHENE OXIDE; SURFACE-CHEMISTRY; SHAPE CONTROL; TUMOR-CELLS; CANCER-CELL; IN-VITRO; NANORODS; NANOSTRUCTURES AB This review summarizes recent advances on design strategies for shape-controlled anisotropic gold nanoparticles. Detailed chemical mechanism has been discussed to understand the anisotropic growth. The effect of various chemical parameters and surface facets for the formation of different shaped anisotropic nanoparticles have been addressed. C1 [Jones, Stacy; Pramanik, Avijit; Sweet, Carrie; Keyes, Anthony; Begum, Salma; Vangra, Aruna; Ray, Paresh Chandra] Jackson State Univ, Dept Chem & Biochem, Jackson, MS 39217 USA. [Yu, Hongtal] Morgan State Univ, Dixon Sci Res Ctr, Baltimore, MD 21239 USA. [Fu, Peter P.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Ray, PC (reprint author), Jackson State Univ, Dept Chem & Biochem, Jackson, MS 39217 USA. EM paresh.c.ray@jsums.edu FU NSF-PREM grant [DMR-1205194]; NSF CREST grant [1547754]; NSF RISE grant [1547836]; RCMI NIH grant [G12MD007581] FX Dr. Ray thanks NSF-PREM grant # DMR-1205194, NSF CREST grant # 1547754, NSF RISE grant # 1547836, and RCMI NIH grant # G12MD007581 for their generous funding. The views presented in this paper do not necessarily represent those of the US Food and Drug Administration (FDA). No official support or endorsement by the US FDA is intended or should be inferred. NR 86 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1059-0501 EI 1532-4095 J9 J ENVIRON SCI HEAL C JI J. Environ. Sci. Health Pt. C-Environ. Carcinog. Ecotoxicol. Rev. PY 2017 VL 35 IS 1 BP 47 EP 66 DI 10.1080/10590501.2017.1280264 PG 20 WC Oncology; Environmental Sciences; Toxicology SC Oncology; Environmental Sciences & Ecology; Toxicology GA EM2TB UT WOS:000395167500003 PM 28095116 ER PT J AU Li, Y Yan, J Ding, W Chen, Y Pack, LM Chen, T AF Li, Yan Yan, Jian Ding, Wei Chen, Ying Pack, Lindsay M. Chen, Tao TI Genotoxicity and gene expression analyses of liver and lung tissues of mice treated with titanium dioxide nanoparticles SO MUTAGENESIS LA English DT Article ID HUMAN DERMAL FIBROBLASTS; ACUTE-PHASE PROTEINS; TIO2 NANOPARTICLES; OXIDATIVE STRESS; IN-VITRO; PULMONARY TOXICITY; EPITHELIAL-CELLS; ULTRAFINE PARTICLES; SIGNALING PATHWAY; DAMAGE AB Titanium dioxide nanoparticles (TiO2 NPs) are used in paints, plastics, papers, inks, foods, toothpaste, pharmaceuticals and cosmetics. However, TiO2 NPs cause inflammation, pulmonary damage, fibrosis and lung tumours in animals and are possibly carcinogenic to humans. Although there are a large number of studies on the toxicities of TiO2 NPs, the data are inconclusive and the mechanisms underlying the toxicity are not clear. In this study, we used the Comet assay to evaluate genotoxicity and whole-genome microarray technology to analyse gene expression pattern in vivo to explore the possible mechanisms for toxicity and genotoxicity of TiO2 NPs. Mice were treated with three daily i. p. injections of 50 mg/kg 10 nm anatase TiO2 NPs and sacrificed 4 h after the last treatment. The livers and lungs were then isolated for the Comet assay and whole genome microarray analysis of gene expression. The NPs were heavily accumulated in liver and lung tissues. However, the treatment was positive for DNA strand breaks only in liver measured with the standard Comet assay, but positive for oxidative DNA adducts in both liver and lung as determined with the enzyme-modified Comet assay. The genotoxicity results suggest that DNA damage mainly resulted from oxidised nucleotides. Gene expression profiles and functional analyses revealed that exposure to TiO2 NPs triggered distinct gene expression patterns in both liver and lung tissues. The gene expression results suggest that TiO2 NPs impair DNA and cells by interrupting metabolic homeostasis in liver and by inducing oxidative stress, inflammatory responses and apoptosis in lung. These findings have broad implications when evaluating the safety of TiO2 NPs used in numerous consumer products. C1 [Li, Yan; Yan, Jian; Ding, Wei; Chen, Ying; Chen, Tao] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Li, Yan] Covance Labs Inc, Greenfield, IN 46140 USA. [Pack, Lindsay M.] Natl Ctr Toxicol Res, Nanotechnol Core Facil, Jefferson, AR 72079 USA. [Pack, Lindsay M.] Arkansas Childrens Hosp, Arkansas Childrens Nutr Ctr, Little Rock, AR 72202 USA. RP Chen, T (reprint author), US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM tao.chen@fda.hhs.gov NR 88 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 EI 1464-3804 J9 MUTAGENESIS JI Mutagenesis PD JAN PY 2017 VL 32 IS 1 BP 33 EP 46 DI 10.1093/mutage/gew065 PG 14 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA EP0IM UT WOS:000397070600005 PM 28011748 ER PT J AU Li, Y Doak, SH Yan, J Chen, DH Zhou, M Mittelstaedt, RA Chen, Y Li, C Chen, T AF Li, Yan Doak, Shareen H. Yan, Jian Chen, David H. Zhou, Min Mittelstaedt, Roberta A. Chen, Ying Li, Chun Chen, Tao TI Factors affecting the in vitro micronucleus assay for evaluation of nanomaterials SO MUTAGENESIS LA English DT Article ID IRON-OXIDE NANOPARTICLES; WALLED CARBON NANOTUBES; MOUSE LYMPHOMA-CELLS; SILVER NANOPARTICLES; HUMAN-LYMPHOBLASTS; OXIDATIVE STRESS; P53 PROTEIN; AMES TEST; GENOTOXICITY; TOXICITY AB A number of in vitro methodologies have been used to assess the genotoxicity of different nanomaterials, including titanium dioxide nanoparticles (TiO2 NPs) and silver nanoparticles (AgNPs). The in vitro micronucleus assay is one of the most commonly used test methods for genotoxicity evaluation of nanomaterials. However, due to the novel features of nanomaterials, such as high adsorption capacity and fluorescence properties, there are unexpected interactions with experimental components and detection systems. In this study, we evaluate the interference by two nanoparticles, AgNPs and TiO2 NPs, with the in vitro micronucleus assay system and possible confounding factors affecting cytotoxicity and genotoxicity assessment of the nanomaterials including cell lines with different p53 status, nanoparticle coatings and fluorescence, cytochalasin B, fetal bovine serum in cell treatment medium and different measurement methodologies for detecting micronuclei. Our results showed that micronucleus induction by AgNPs was similar when evaluated using flow cytometry or microscope, whereas the induction by TiO2 NPs was different using the two methods due to TiO2's fluorescence interference with the cytometry equipment. Cells with the mutated p53 gene were more sensitive to micronucleus induction by AgNPs than the p53 wild-type cells. The presence of serum during treatment increased the toxicity of AgNPs. The coatings of nanoparticles played an important role in the genotoxicity of AgNPs. These collective data highlight the importance of considering the unique properties of nanoparticles in assessing their genotoxicity using the in vitro micronucleus assay. C1 [Li, Yan; Yan, Jian; Mittelstaedt, Roberta A.; Chen, Ying; Chen, Tao] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Li, Yan] Covance Labs Inc, 671 S Meridian Rd, Greenfield, IN 46140 USA. [Doak, Shareen H.] Swansea Univ, Sch Med, Inst Life Sci, Singleton Pk, Swansea SA2 8PP, W Glam, Wales. [Chen, David H.] Columbia Univ City New York, Columbia Coll, 2960 Broadway, New York, NY 10027 USA. [Zhou, Min; Li, Chun] Univ Texas MD Anderson Canc Ctr, Dept Canc Syst Imaging, 1881 East Rd, Houston, TX 77054 USA. RP Chen, T (reprint author), US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM tao.chen@fda.hhs.gov FU U.S. Department of Energy; U.S. FDA; FDA Nanotechnology CORES Program FX Y.L. was supported by the appointment to the Postgraduate Research Program at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science Education through an interagency agreement between the U.S. Department of Energy and the U.S. FDA. This research was partially supported by a regulatory science grant from the FDA Nanotechnology CORES Program. This article is not an official U.S. Food and Drug Administration (FDA) guidance or policy statement. No official support or endorsement by the U.S. FDA is intended or should be inferred. NR 52 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 EI 1464-3804 J9 MUTAGENESIS JI Mutagenesis PD JAN PY 2017 VL 32 IS 1 BP 151 EP 159 DI 10.1093/mutage/gew040 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA EP0IM UT WOS:000397070600014 PM 27567283 ER PT J AU Gao, Y Cao, ZJ Yang, X Abdelmegeed, MA Sun, JC Chen, S Beger, RD Davis, K Salminen, WF Song, BJ Mendrick, DL Yu, LR AF Gao, Yuan Cao, Zhijun Yang, Xi Abdelmegeed, Mohamed A. Sun, Jinchun Chen, Si Beger, Richard D. Davis, Kelly Salminen, William F. Song, Byoung-Joon Mendrick, Donna L. Yu, Li-Rong TI Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE Acetaminophen; Heme oxygenase 1 (HMOX1); Hepatotoxicity; MS ID MITOCHONDRIAL PERMEABILITY TRANSITION; UNITED-STATES; IN-VIVO; QUANTITATIVE PROTEOMICS; THERAPEUTIC TARGET; OXIDATIVE STRESS; PROTEIN ADDUCT; MOUSE-LIVER; TOXICITY; RATS AB Purpose: Overdose of acetaminophen (APAP) is a major cause of acute liver failure. This study was aimed to identify pathways related to hepatotoxicity and potential biomarkers of liver injury. Experimental design: Rats were treated with low (100 mg/kg) and high (1250 mg/kg) doses of APAP, and liver tissues at 6 and 24 h post-treatment were analyzed using a proteomic approach of 16O/18O labeling and 2D-LC-MS/MS. Results: Molecular pathways evolved progressively from scattered and less significant perturbations to more focused and significant alterations in a dose-and time-dependent manner upon APAP treatment. Imbalanced expression of hemeoxygenase 1 (HMOX1) and biliverdin reductase A (BLVRA) was associated with hepatotoxicity. Protein abundance changes of a total of 31 proteins were uniquely correlated to liver damage, among which a dramatic increase of HMOX1 levels in plasma was observed. Liver injury-associated significant elevation of plasma HMOX1 was further validated in mice treated with APAP. Conclusions and clinical relevance: This study unveiled molecular changes associated with APAP-induced liver toxicity at the pathway levels and identified HMOX1 as a potential plasma biomarker of liver injury. C1 [Gao, Yuan; Cao, Zhijun; Yang, Xi; Sun, Jinchun; Beger, Richard D.; Salminen, William F.; Mendrick, Donna L.; Yu, Li-Rong] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Abdelmegeed, Mohamed A.; Song, Byoung-Joon] NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD USA. [Chen, Si] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Davis, Kelly] US FDA, Toxicol Pathol Associates, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Yu, LR (reprint author), US FDA, Biomarkers & Alternat Models Branch, Div Syst Biol, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 233, Jefferson, AR 72079 USA. EM Lirong.Yu@fda.hhs.gov FU National Center for Toxicological Research, U.S. Food and Drug Administration (NCTR/FDA), Jefferson, Arkansas; National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland FX This study was supported with funds from the National Center for Toxicological Research, U.S. Food and Drug Administration (NCTR/FDA), Jefferson, Arkansas, and in part with the Intramural funds from National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland. The information in this article is not a formal dissemination of information by FDA and does not represent agency position or policy. NR 72 TC 0 Z9 0 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1862-8346 EI 1862-8354 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD JAN PY 2017 VL 11 IS 1-2 AR UNSP 1600123 DI 10.1002/prca.201600123 PG 17 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO0NM UT WOS:000396394800008 ER PT J AU Rahman, M Tiwari, R AF Rahman, Mohammad Tiwari, Ram TI Multiple contrast type tests for the evaluation of animal carcinogenicity studies SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Animal carcinogenicity study; Cochran-Armitage test; dose-response relationship; multiple contrast test ID PROPORTIONS AB The Cochran-Armitage (CA) test is frequently used for testing the dose-response relationship in tumor incidence. This test is based on aweighted linear regression of proportions. It is well known that the CA test lacks power for nonlinear tumor outcomes. For general shape of outcomes, Hothorn and Bretz (2000) proposed a multiple contrast (MC) test. This test suggests the use of the maximum over several single contrasts, where each of them is chosen appropriately to cover a specific dose-response shape. In this work, two new test procedures are proposed and they are compared to the CA and MC tests using power. C1 [Rahman, Mohammad] US FDA, Div Biometr 6, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Tiwari, Ram] US FDA, Intermediate Off, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Rahman, M (reprint author), US FDA, Div Biometr 6, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM mohammad.rahman@fda.hhs.gov NR 14 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1054-3406 EI 1520-5711 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PY 2017 VL 27 IS 1 BP 175 EP 185 DI 10.1080/10543406.2016.1148708 PG 11 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA EO2VW UT WOS:000396555100014 PM 26892383 ER PT J AU Juberg, DR Knudsen, TB Sander, M Beck, NB Faustman, EM Mendrick, DL Fowle, JR Hartung, T Tice, RR Lemazurier, E Becker, RA Fitzpatrick, SC Daston, GP Harrill, A Hines, RN Keller, DA Lipscomb, JC Watson, D Bahadori, T Crofton, KM AF Juberg, Daland R. Knudsen, Thomas B. Sander, Miriam Beck, Nancy B. Faustman, Elaine M. Mendrick, Donna L. Fowle, John R., III Hartung, Thomas Tice, Raymond R. Lemazurier, Emmanuel Becker, Richard A. Fitzpatrick, Suzanne Compton Daston, George P. Harrill, Alison Hines, Ronald N. Keller, Douglas A. Lipscomb, John C. Watson, David Bahadori, Tina Crofton, Kevin M. TI FutureTox III: Bridges for Translation SO TOXICOLOGICAL SCIENCES LA English DT Article DE predictive toxicology; in vitro and alternatives; regulatory/policy; risk assessment; testing alternatives ID ESTROGEN-RECEPTOR; RISK-ASSESSMENT; TOXICITY; 21ST-CENTURY; TOXICOLOGY; EXPOSURE; CHEMICALS; VISION; MODELS; PRIORITIZATION AB Future Tox III, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2015. Building upon Future Tox I and II, Future Tox III was focused on developing the high throughput risk assessment paradigm and taking the science of in vitro data and in silico models forward to explore the question-what progress is being made to address challenges in implementing the emerging big-data toolbox for risk assessment and regulatory decision-making. This article reports on the outcome of the workshop including 2 examples of where advancements in predictive toxicology approaches are being applied within Federal agencies, where opportunities remain within the exposome and AOP domains, and how collectively the toxicology community across multiple sectors can continue to bridge the translation from historical approaches to Tox21 implementation relative to risk assessment and regulatory decision-making. C1 [Juberg, Daland R.] Dow AgroSci, Indianapolis, IN 46268 USA. [Knudsen, Thomas B.; Hines, Ronald N.; Crofton, Kevin M.] US EPA, Res Triangle Pk, NC 27711 USA. [Sander, Miriam] Page One Editorial Serv, Boulder, CO USA. [Beck, Nancy B.; Becker, Richard A.] Amer Chem Council, Washington, DC USA. [Faustman, Elaine M.] Univ Washington, Seattle, WA 98195 USA. [Mendrick, Donna L.] US FDA, Silver Spring, MD USA. [Fowle, John R., III] Sci Inform LLC, Pittsboro, NC USA. [Hartung, Thomas] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Tice, Raymond R.] NIEHS, Natl Toxicol Program, Durham, NC USA. [Lemazurier, Emmanuel] INERIS Chron Risk Div, Verneeuil En Halatte, France. [Fitzpatrick, Suzanne Compton] US FDA, College Pk, MD USA. [Daston, George P.] Procter & Gamble Co, Cincinnati, OH USA. [Harrill, Alison] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Keller, Douglas A.] Sanofi, Bridgewater, NJ USA. [Lipscomb, John C.] US EPA, Cincinnati, OH 45268 USA. [Watson, David] Lhasa Ltd, Leeds, W Yorkshire, England. [Bahadori, Tina] US EPA, Washington, DC 20460 USA. RP Juberg, DR (reprint author), Dow AgroSci, Indianapolis, IN 46268 USA. EM drjuberg@dow.com FU Society of Toxicology; Scientific Liaison Coalition; American Chemistry Council; Dow AgroSciences, LLC; Hamner Institutes for Health Sciences; Human Toxicology Project Consortium; Humane Society of the United States; National Institute of Environmental Health Sciences; U.S. Food and Drug Administration, Office of the Chief Scientist; National Center for Toxicological Reseach; Bayer Crop Science; NSF International; Syngenta Crop Protection LLC; TERA Center; University of Cincinnati; ToxServices; American Academy of Clinical Toxicology; American College of Toxicology; CAAT; Johns Hopkins Center for Alternatives to Animal Testing (CAAT); In Sphero; Lhasa Limited; Ramboll Environ; Safety Pharmacology Society; Society of Toxicologic Pathology; Teratology Society FX FutureTox III Sponsors included Society of Toxicology, Scientific Liaison Coalition, the American Chemistry Council, Dow AgroSciences, LLC, The Hamner Institutes for Health Sciences, Human Toxicology Project Consortium, The Humane Society of the United States, National Institute of Environmental Health Sciences, U.S. Food and Drug Administration, Office of the Chief Scientist and the National Center for Toxicological Reseach, Bayer Crop Science, NSF International, Syngenta Crop Protection LLC, TERA Center, University of Cincinnati, ToxServices, American Academy of Clinical Toxicology, American College of Toxicology, CAAT, Johns Hopkins Center for Alternatives to Animal Testing (CAAT), In Sphero, Lhasa Limited, Ramboll Environ, Safety Pharmacology Society, Society of Toxicologic Pathology, The Teratology Society. NR 41 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD JAN PY 2017 VL 155 IS 1 BP 22 EP 31 DI 10.1093/toxsci/kfw194 PG 10 WC Toxicology SC Toxicology GA EO9XL UT WOS:000397041300003 PM 27780885 ER PT J AU Blinova, K Stohlman, J Vicente, J Chan, D Johannesen, L Hortigon-Vinagre, MP Zamora, V Smith, G Crumb, WJ Pang, L Lyn-Cook, B Ross, J Brock, M Chvatal, S Millard, D Galeotti, L Stockbridge, N Strauss, DG AF Blinova, Ksenia Stohlman, Jayna Vicente, Jose Chan, Dulciana Johannesen, Lars Hortigon-Vinagre, Maria P. Zamora, Victor Smith, Godfrey Crumb, William J. Pang, Li Lyn-Cook, Beverly Ross, James Brock, Mathew Chvatal, Stacie Millard, Daniel Galeotti, Loriano Stockbridge, Norman Strauss, David G. TI Comprehensive Translational Assessment of Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias SO TOXICOLOGICAL SCIENCES LA English DT Article DE CiPA; iPSC-CM; MEA; VSD; iCell; Cor.4U ID TORSADE-DE-POINTES; QT INTERVAL PROLONGATION; LATE SODIUM CURRENT; ACTION-POTENTIALS; DOFETILIDE; BLOCK; DIFFERENTIATION; PROARRHYTHMIA; RANOLAZINE; MODELS AB Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSCCMs to clinical trial results demonstrated good correlation between drug-induced rate-corrected action potential duration and field potential duration (APDc and FPDc) prolongation and clinical trial QTc prolongation. Of 20 drugs studied that exhibit clinical QTc prolongation, 17 caused APDc prolongation (16 in Cor.4U and 13 in iCell cardiomyocytes) and 16 caused FPDc prolongation (16 in Cor.4U and 10 in iCell cardiomyocytes). Of 14 drugs that cause TdP, arrhythmias occurred with 10 drugs. Lack of arrhythmic beating in iPSC-CMs for the four remaining drugs could be due to differences in relative levels of expression of individual ion channels. iPSC-CMs responded consistently to human ether-a-go-go potassium channel blocking drugs (APD prolongation and arrhythmias) and calcium channel blocking drugs (APD shortening and prevention of arrhythmias), with a more variable response to late sodium current blocking drugs. Current results confirm the potential of iPSC-CMs for proarrhythmia prediction under CiPA, where iPSC-CM results would serve as a check to ion channel and in silico modeling prediction of proarrhythmic risk. A multi-site validation study is warranted. C1 [Blinova, Ksenia; Stohlman, Jayna; Vicente, Jose; Chan, Dulciana; Johannesen, Lars; Galeotti, Loriano; Strauss, David G.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD USA. [Vicente, Jose; Stockbridge, Norman] US FDA, Ctr Drug Evaluat & Res, Off New Drugs, Silver Spring, MD USA. [Vicente, Jose] Univ Zaragoza, BSICoS Grp, Aragon Inst Engn Res I3A, IIS Aragon, Zaragoza, Spain. [Hortigon-Vinagre, Maria P.; Zamora, Victor; Smith, Godfrey] Univ Glasgow, Glasgow, Lanark, Scotland. [Hortigon-Vinagre, Maria P.; Zamora, Victor; Smith, Godfrey] Clyde Biosci, Glasgow, Lanark, Scotland. [Crumb, William J.] Zenas Technol, Metairie, LA USA. [Pang, Li; Lyn-Cook, Beverly] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Ross, James; Brock, Mathew; Chvatal, Stacie; Millard, Daniel] Axion Biosyst, Atlanta, GA USA. [Strauss, David G.] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Silver Spring, MD USA. RP Blinova, K (reprint author), US FDA, Bldg 62,Room 1208,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM ksenia.blinova@fda.hhs.gov OI Vicente, Jose/0000-0001-9963-1205 FU FDA's Chief Scientist's Challenge Grant; Critical Path Initiative; FDA Office of Women's Health Grant; U.S. Department of Energy; U.S. Food and Drug Administration; Fundacion Alfonso Martin Escudero (SPAIN) FX This work was supported by FDA's Chief Scientist's Challenge Grant, Critical Path Initiative, FDA Office of Women's Health Grant, and appointments to the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. M.P.H.V. and V.Z. are recipients of Fundacion Alfonso Martin Escudero (SPAIN) postdoctoral fellowships. NR 48 TC 0 Z9 0 U1 1 U2 1 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 JAN PY 2017 VL 155 IS 1 BP 234 EP 247 DI 10.1093/toxsci/kfw200 PG 14 WC Toxicology SC Toxicology GA EO9XL UT WOS:000397041300020 PM 27701120 ER PT J AU Pamies, D Bal-Price, A Simeonov, A Tagle, D Allen, D Gerhold, D Yin, D Pistollato, F Inutsuka, T Sullivan, K Stacey, G Salem, H Leist, M Daneshian, M Vemuri, MC McFarland, R Coecke, S Fitzpatrick, SC Lakshmipathy, U Mack, A Wang, WB Yamazaki, D Sekino, Y Kanda, Y Smirnova, L Hartung, T AF Pamies, David Bal-Price, Anna Simeonov, Anton Tagle, Danilo Allen, Dave Gerhold, David Yin, Dezhong Pistollato, Francesca Inutsuka, Takashi Sullivan, Kristie Stacey, Glyn Salem, Harry Leist, Marcel Daneshian, Mardas Vemuri, Mohan C. McFarland, Richard Coecke, Sandra Fitzpatrick, Suzanne C. Lakshmipathy, Uma Mack, Amanda Wang, Wen Bo Yamazaki, Daiju Sekino, Yuko Kanda, Yasunari Smirnova, Lena Hartung, Thomas TI Good Cell Culture Practice for Stem Cells and Stem-Cell-Derived Models SO ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION LA English DT Editorial Material DE Good Cell Culture Practices; in vitro methods; alternatives to animals; induced pluripotent stem cells ID LINE CROSS-CONTAMINATION; BANKING INITIATIVE ISCBI; SERUM-FREE CELL; HUMAN IPS CELLS; SOMATIC-CELLS; MYCOPLASMA CONTAMINATION; HUMAN ES; CARDIAC DIFFERENTIATION; HOMING ENDONUCLEASE; EPIGENETIC MEMORY AB The first guidance on Good Cell Culture Practice (GCCP) dates back to 2005. This document expands this to include aspects of quality assurance for in vitro cell culture focusing on the increasingly diverse cell types and culture formats used in research, product development, testing and manufacture of biotechnology products and cell-based medicines. It provides a set of basic principles of best practice that can be used in training new personnel, reviewing and improving local procedures, and helping to assure standard practices and conditions for the comparison of data between laboratories and experimentation performed at different times. This includes recommendations for the documentation and reporting of culture conditions. It is intended as guidance to facilitate the generation of reliable data from cell culture systems, and is not intended to conflict with local or higher level legislation or regulatory requirements. It may not be possible to meet all recommendations in this guidance for practical, legal or other reasons. However, when it is necessary to divert from the principles of GCCP, the risk of decreasing the quality of work and the safety of laboratory staff should be addressed and any conclusions or alternative approaches justified. This workshop report is considered a first step toward a revised GCCP 2.0. C1 [Pamies, David; Smirnova, Lena; Hartung, Thomas] Johns Hopkins Univ, Ctr Alternat Anim Testing, Baltimore, MD 21205 USA. [Bal-Price, Anna; Pistollato, Francesca] Joint Res Ctr, European Commiss, Ispra, VA, Italy. [Simeonov, Anton; Tagle, Danilo; Gerhold, David] Natl Ctr Adv Translat Sci Natl Inst Hlth, Rockville, MD USA. [Allen, Dave] Contractor supporting NTP Interagency Ctr Evaluat, Morrisville, NC USA. [Yin, Dezhong] Amer Type Culture Collect ATCC, ATCC Cell Syst, Gaithersburg, MD USA. [Inutsuka, Takashi] Pharmacol Evaluat Inst Japan PEIJ, Tokyo, Japan. [Sullivan, Kristie] Physicians Comm Responsible Med, Washington, DC USA. [Stacey, Glyn] Natl Inst Biol Standardizat & Control, South Mimms, Hertford, England. [Salem, Harry] US Army Edgewood Chem Biol Ctr, Aberdeen Proving Ground, MD USA. [Leist, Marcel; Daneshian, Mardas; Hartung, Thomas] Univ Konstanz, Ctr Alternat Anim Testing Europe, Constance, Germany. [Vemuri, Mohan C.] Life Sci Solut, Thermo Fisher Sci, Carlsbad, CA USA. [McFarland, Richard; Fitzpatrick, Suzanne C.] Ctr Food Safety & Appl Nutr FDA, College Pk, MD USA. [Mack, Amanda; Wang, Wen Bo] Cellular Dynam Int, Madison, WI USA. [Yamazaki, Daiju; Sekino, Yuko; Kanda, Yasunari] Natl Inst Hlth Sci, Divis Pharmacol, Tokyo, Japan. RP Hartung, T (reprint author), Johns Hopkins Univ, Ctr Alternat Anim Testing, Baltimore, MD 21205 USA. EM thartun1@jhu.edu FU EU-ToxRisk Project [681002]; German BMBF grant NeuriTox; Japan Agency for Medical Research and Development grants [15mk0104053h0101, 16mk0104027j0002] FX The work on this article was supported by the EU-ToxRisk Project (European Union's Horizon 2020 research programme grant agreement No 681002, to Marcel Leist and Thomas Hartung), and the German BMBF grant NeuriTox (to Marcel Leist). The contribution of Yuko Sekino was supported by Japan Agency for Medical Research and Development grants (ID: 15mk0104053h0101 and 16mk0104027j0002). NR 193 TC 2 Z9 2 U1 1 U2 1 PU SPEKTRUM AKADEMISCHER VERLAG-SPRINGER-VERLAG GMBH PI HEILDEBERG PA TIERGARTENSTRASSE 17, HEILDEBERG, 69121, GERMANY SN 1868-596X EI 1868-8551 J9 ALTEX-ALTERN ANIM EX JI ALTEX-Altern. Anim. Exp. PY 2017 VL 34 IS 1 BP 95 EP 132 DI 10.14573/altex.1607121 PG 38 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EO3RU UT WOS:000396612700006 PM 27554434 ER PT J AU Perez, DL Baker, PJ Pintar, AL Sun, JR Lin, NJ Lin-Gibson, S AF Perez, Daneli Lopez Baker, Paula J. Pintar, Adam L. Sun, Jirun Lin, Nancy J. Lin-Gibson, Sheng TI Experimental and statistical methods to evaluate antibacterial activity of a quaternary pyridinium salt on planktonic, biofilm-forming, and biofilm states SO BIOFOULING LA English DT Article DE Antimicrobial; biofilm; interval censored data; minimum inhibitory concentration; minimum bactericidal concentration; quaternary pyridinium salt ID STREPTOCOCCUS-MUTANS; BACTERIAL BIOFILMS; PSEUDOMONAS-AERUGINOSA; STAPHYLOCOCCUS-AUREUS; INFECTIONS; SUSCEPTIBILITY; RESISTANCE; AGENTS; QUANTIFICATION; MECHANISMS AB Robust evaluation and comparison of antimicrobial technologies are critical to improving biofilm prevention and treatment. Herein, a multi-pronged experimental framework and statistical models were applied to determine the effects of quaternary pyridinium salt, 4-acetyl-1-hexadecylpyridin-1-ium iodide (QPS-1), on Streptococcus mutans in the planktonic, biofilm-forming and biofilm cell states. Minimum inhibitory and bactericidal concentrations (MIC and MBC, respectively) were determined via common methods with novel application of statistical approaches combining random effects models and interval censored data to estimate uncertainties. The MICs and MBCs for planktonic and biofilm-forming states ranged from 3.12 to 12.5 mu g ml(-1), with biofilm values only approximate to 8 times higher. Potent anti-biofilm activity and reactive structural features make QPS-1 a promising antibacterial additive for dental and potentially other biomedical devices. Together, the experimental framework and statistical models provide estimates and uncertainties for effective antimicrobial concentrations in multiple cell states, enabling statistical comparisons and improved characterization of antibacterial agents. C1 [Perez, Daneli Lopez; Baker, Paula J.; Lin, Nancy J.; Lin-Gibson, Sheng] NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. [Pintar, Adam L.] NIST, Stat Engn Div, Gaithersburg, MD 20899 USA. [Sun, Jirun] Amer Dent Assoc Fdn, Dr Anthony Volpe Res Ctr, Gaithersburg, MD USA. [Perez, Daneli Lopez] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Lin, NJ (reprint author), NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. EM nancy.lin@nist.gov FU National Research Council FX This work was financially supported in part by a National Research Council Postdoctoral Associateship to DLP. NR 43 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 0892-7014 EI 1029-2454 J9 BIOFOULING JI Biofouling PY 2017 VL 33 IS 3 BP 222 EP 234 DI 10.1080/08927014.2017.1286476 PG 13 WC Biotechnology & Applied Microbiology; Marine & Freshwater Biology SC Biotechnology & Applied Microbiology; Marine & Freshwater Biology GA EM9RK UT WOS:000395648600002 ER PT J AU Agarabi, CD Chavez, BK Lute, SC Read, EK Rogstad, S Awotwe-Otoo, D Brown, MR Boyne, MT Brorson, KA AF Agarabi, Cyrus D. Chavez, Brittany K. Lute, Scott C. Read, Erik K. Rogstad, Sarah Awotwe-Otoo, David Brown, Matthew R. Boyne, Michael T., II Brorson, Kurt A. TI Exploring the linkage between cell culture process parameters and downstream processing utilizing a plackett-burman design for a model monoclonal antibody SO BIOTECHNOLOGY PROGRESS LA English DT Article DE design of experiments (DoE); mammalian cell culture; monoclonal antibody; quality by design (QbD); host cell protein (HCP) ID HAMSTER OVARY CELLS; QUALITY ATTRIBUTES; SHEAR-STRESS; PROTEIN; IMMUNOGENICITY; IDENTIFICATION; CHROMATOGRAPHY; PERSPECTIVE; CLEARANCE; RISK AB Linkage of upstream cell culture with downstream processing and purification is an aspect of Quality by Design crucial for efficient and consistent production of high quality biopharmaceutical proteins. In a previous Plackett-Burman screening study of parallel bioreactor cultures we evaluated main effects of 11 process variables, such as agitation, sparge rate, feeding regimens, dissolved oxygen set point, inoculation density, supplement addition, temperature, and pH shifts. In this follow-up study, we observed linkages between cell culture process parameters and downstream capture chromatography performance and subsequent antibody attributes. In depth analysis of the capture chromatography purification of harvested cell culture fluid yielded significant effects of upstream process parameters on host cell protein abundance and behavior. A variety of methods were used to characterize the antibody both after purification and buffer formulation. This analysis provided insight in to the significant impacts of upstream process parameters on aggregate formation, impurities, and protein structure. This report highlights the utility of linkage studies in identifying how changes in upstream parameters can impact downstream critical quality attributes. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:163-170, 2017 C1 [Agarabi, Cyrus D.; Chavez, Brittany K.; Lute, Scott C.; Read, Erik K.; Brown, Matthew R.; Brorson, Kurt A.] US FDA, Div 2, Off Biotechnol Prod, Off Pharmaceut Qual,CDER, Silver Spring, MD USA. [Rogstad, Sarah; Boyne, Michael T., II] US FDA, Div Pharmaceut Anal, Off Testing & Res, OPQ,CDER, Silver Spring, MD USA. [Awotwe-Otoo, David] US FDA, Div Post Mkt Act 2, OPQ, CDER, Silver Spring, MD USA. RP Brorson, KA (reprint author), US FDA, Div 2, Off Biotechnol Prod, Off Pharmaceut Qual,CDER, Silver Spring, MD USA. EM kurt.brorson@fda.hhs.gov FU CDER Critical Path Program [14-5, 14-4]; Internship/ Research Participation Program at the Office of Biotechnology Products, U.S. Food and Drug Administration FX Partial internal funding and support for this work was provided by the CDER Critical Path Program (KB #14-5 and MTB #14-4). This project was supported in part by an appointment to the Internship/ Research Participation Program at the Office of Biotechnology Products, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA. The authors thank Madison Landreth and Sarah A. Johnson for their careful edits and to Maxwell Korang-Yeboah and Adam Fisher for their careful review of the manuscript. This article reflects the views of the authors and should not be construed to represent official FDA's views or policies. NR 30 TC 0 Z9 0 U1 1 U2 1 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 JAN-FEB PY 2017 VL 33 IS 1 BP 163 EP 170 DI 10.1002/btpr.2402 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EL8SF UT WOS:000394889400019 PM 27813291 ER PT J AU Ireland, DDC Tami, C Pedras-Vasconcelos, J Verthelyi, D AF Ireland, Derek D. C. Tami, Cecilia Pedras-Vasconcelos, Joao Verthelyi, Daniela TI CD4 and CD8 T cells mediate distinct lethal meningoencephalitis in mice challenged with Tacaribe arenavirus SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Article DE Astrocytes; CD4 T cells; CD8 T cells; encephalitis; Purkinje cells; virus ID CENTRAL-NERVOUS-SYSTEM; CHORIOMENINGITIS VIRUS-INFECTION; BRAIN-BARRIER DISRUPTION; LYMPHOCYTIC CHORIOMENINGITIS; JUNIN VIRUS; INTERFERON INDUCTION; VIRAL-INFECTION; SINDBIS VIRUS; DISEASE; ACTIVATION AB Neonates are at increased risk of viral encephalopathies that can result in neurological dysfunction, seizures, permanent disability and even death. The neurological damage results from the combined effect of the virus and the immune response it elicits, thus finding tools to facilitate viral clearance from central nervous system (CNS) while minimizing neuron damage remains a critical challenge. Neonatal mice inoculated intraperitoneally with Tacaribe virus (TCRV) develop seizures, hindlimb paralysis and death within 15 days of inoculation. TCRV localizes to the CNS within days of challenge, primarily infecting astrocytes in the cerebellum and brain stem. We show that infection leads to inflammation, T cell and monocyte infiltration into the cerebellar parenchyma, apoptosis of astrocytes, neuronal degeneration and loss of Purkinje cells. Infiltrating antigen-specific T cells fail to clear the virus but drive the disease, as T-cell-deficient CD3 epsilon KO mice survive TCRV infection with minimal inflammation or clinical manifestations despite no difference in CNS viral loads in comparison with T-cell sufficient mice. CD8+ T cells drive the pathology, which even in the absence of CD4+ T-cell help, infiltrate the parenchyma and mediate the apoptotic loss of cerebellar astrocytes, neurodegeneration and loss of Purkinje cells resulting in loss of balance, paralysis and death. CD4+ T cells are also pathogenic inducing gliosis and inflammation in the cerebellum and cerebrum that are associated with wasting and death several weeks after CD4+ T-cell transfer. These data demonstrate distinct pathogenic effects of CD4+ and CD8+ T cells and identify them as possible therapeutic targets. C1 [Ireland, Derek D. C.; Tami, Cecilia; Pedras-Vasconcelos, Joao; Verthelyi, Daniela] US FDA, Div Biol Review & Res 3, Off Biotechnol, Ctr Drug Evaluat & Res, Bldg 52,Room 2112,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Verthelyi, D (reprint author), US FDA, Div Biol Review & Res 3, Off Biotechnol, Ctr Drug Evaluat & Res, Bldg 52,Room 2112,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM daniela.verthelyi@fda.hhs.gov FU Oak Ridge Institute for Science and Education (ORISE); FDA Medical Countermeasures Initiative program FX We thank Jill Ascher, Mary Belcher and the personnel of the animal facility for care of the mice. We thank Dr Cherie Butts, Dr Gouri Chattopadhyay, John Martucci and Vivian Wang for technical assistance and Dr Mohanraj Manageeswaran for helpful discussions. We also thank Drs Steven Rubin and Christian Sauder for careful review of the manuscript. This study was supported in part by a Senior Postgraduate Research Fellowship Award to DI from the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. This study was also supported by a grant from the FDA Medical Countermeasures Initiative program to DV. NR 68 TC 0 Z9 0 U1 0 U2 0 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 EI 2042-0226 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD JAN PY 2017 VL 14 IS 1 BP 90 EP 106 DI 10.1038/cmi.2016.41 PG 17 WC Immunology SC Immunology GA EL0ZN UT WOS:000394350400009 PM 27569560 ER PT J AU Derrick, SC AF Derrick, Steven C. TI Trained Immunity and Susceptibility to HIV SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Editorial Material DE BCG; HIV; trained immunity; tuberculosis; vaccine ID BCG VACCINATION; REINFECTION; PROTECTION; RESPONSES; MONOCYTES; MUCOSAL; TRIAL; STEP AB In this issue of Clinical and Vaccine Immunology, K. Jensen et al. (Clin Vaccine Immunol 24: e00360-16, 2017, https://doi.org/10.1128/CVI.00360-16) describe a dual-purpose attenuated Mycobacterium tuberculosis-simian immunodeficiency virus vaccine (AMTB-SIV). Interestingly, immunized infant macaques required fewer oral exposures to SIV to become infected relative to nonimmunized animals. The authors hypothesized that augmented susceptibility to SIV was due to activation of CD4(+) T cells through trained immunity. This commentary explores the possible relationship between trained immunity, enhanced CD4 T cell responses, and increased susceptibility to human immunodeficiency virus (HIV). C1 [Derrick, Steven C.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20857 USA. RP Derrick, SC (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20857 USA. EM steven.derrick@fda.hhs.gov NR 24 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 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD JAN PY 2017 VL 24 IS 1 AR UNSP e00509-16 DI 10.1128/CVI.00509-16 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EK9DH UT WOS:000394223700016 ER PT J AU Eby, JC Gray, MC Warfel, JM Merkel, TJ Hewlett, EL AF Eby, Joshua C. Gray, Mary C. Warfel, Jason M. Merkel, Tod J. Hewlett, Erik L. TI Use of a Toxin Neutralization Assay To Characterize the Serologic Response to Adenylate Cyclase Toxin after Infection with Bordetella pertussis SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article DE Bordetella pertussis; nonhuman primate; adenylate cyclase; assay development; bacterial toxin; neutralization ID NONHUMAN PRIMATE MODEL; TARGET-CELLS; SERUM ANTIBODY; CYCLIC-AMP; VACCINES; MICE; EPIDEMIOLOGY; TRANSMISSION; PHAGOCYTOSIS; IMMUNIZATION AB Adenylate cyclase toxin (ACT) is an essential virulence factor of Bordetella pertussis, and antibodies to ACT protect against B. pertussis infection in mice. The toxin is therefore a strong candidate antigen for addition to future acellular pertussis vaccines. In order to characterize the functionality of the immunologic response to ACT after infection, we developed an assay for testing the ability of serum samples from subjects infected with B. pertussis to neutralize ACT-induced cytotoxicity in J774 macrophage cells. Baboons develop neutralizing anti-ACT antibodies following infection with B. pertussis, and all sera from baboons with positive anti-ACT IgG enzyme-linked immunosorbent assay (ELISA) results neutralized ACT cytotoxicity. The toxin neutralization assay (TNA) was positive in some baboon sera in which ELISA remained negative. Of serum samples obtained from humans diagnosed with pertussis by PCR, anti-ACT IgG ELISA was positive in 72%, and TNA was positive in 83%. All samples positive for anti-ACT IgG ELISA were positive by TNA, and none of the samples from humans without pertussis neutralized toxin activity. These findings indicate that antibodies to ACT generated following infection with B. pertussis consistently neutralize toxin-induced cytotoxicity and that TNA can be used to improve understanding of the immunologic response to ACT after infection or vaccination. C1 [Eby, Joshua C.; Gray, Mary C.; Hewlett, Erik L.] Univ Virginia, Div Infect Dis, Charlottesville, VA USA. [Warfel, Jason M.; Merkel, Tod J.] FDA, Ctr Biol Evaluat & Res, Div Bacterial Parasit & Allergen Prod, Silver Spring, MD USA. [Warfel, Jason M.] Bristol Myers Squibb, Syracuse, NY USA. RP Eby, JC (reprint author), Univ Virginia, Div Infect Dis, Charlottesville, VA USA. EM jce4u@virginia.edu NR 46 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 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD JAN PY 2017 VL 24 IS 1 AR UNSP e00370-16 DI 10.1128/CVI.00370-16 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EK9DH UT WOS:000394223700006 ER PT J AU Ljungman, P Boeckh, M Hirsch, HH Josephson, F Lundgren, J Nichols, G Pikis, A Razonable, RR Miller, V Griffiths, PD AF Ljungman, Per Boeckh, Michael Hirsch, Hans H. Josephson, Filip Lundgren, Jens Nichols, Garrett Pikis, Andreas Razonable, Raymund R. Miller, Veronica Griffiths, Paul D. CA Dis Definitions Working Grp Cytome TI Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE CMV; stem cell transplantation; organ transplantation; clinical trials ID HEMATOPOIETIC-CELL TRANSPLANTATION; DRUG DEVELOPMENT; DOUBLE-BLIND; RECIPIENTS; PROPHYLAXIS; VACCINE; DNA AB Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2002. Since then, there have been major developments in its diagnosis and management. Therefore, the CMV Drug Development Forum consisting of scientists, clinicians, regulators, and industry representatives has produced an updated version incorporating recent knowledge with the aimto support clinical research and drug development. The main changes compared to previous definitions are the introduction of a "probable disease" category and to incorporate quantitative nucleic acid testing in some end-organ disease categories. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts between scientists, regulators, and industry can provide a platform for this work. C1 [Ljungman, Per] Karolinska Univ Hosp, Dept Allogene Stem Cell Transplantat, Solna, Sweden. [Ljungman, Per] Karolinska Univ Hosp, Dept Hematol, Solna, Sweden. [Ljungman, Per] Karolinska Inst, Dept Med, Div Hematol, Stockholm, Sweden. [Josephson, Filip] Swedish Med Prod Agcy, Uppsala, Sweden. [Boeckh, Michael] Univ Washington, Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis & Clin Res Div, Seattle, WA 98195 USA. [Boeckh, Michael] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Hirsch, Hans H.] Univ Basel, Dept Biomed, Basel, Switzerland. [Lundgren, Jens] Univ Copenhagen, Ctr Hlth & Infect Dis Res CHIP, Dept Infect Dis Rigshospitalet, Copenhagen, Denmark. [Nichols, Garrett] Chimerix Inc, Durham, NC USA. [Pikis, Andreas] Ctr Drug Evaluat & Res, Food & Drug Adm, Div Antiviral Prod, Silver Spring, MD USA. [Razonable, Raymund R.] William J Von Liebig Ctr Transplantat & Clin Rege, Mayo Clin, Dept Med, Div Infect Dis, Rochester, MN USA. [Miller, Veronica] Univ Calif Berkeley, Forum Collaborat HIV Res, Berkeley, CA 94720 USA. [Griffiths, Paul D.] Univ Coll London Med Sch, Inst Immun & Transplantat, London, England. RP Ljungman, P (reprint author), Karolinska Univ Hosp, Dept Hematol, S-14186 Stockholm, Sweden. EM per.ljungman@ki.se FU Danish National Research Foundation FX J. L. is the recipient of a Danish National Research Foundation grant. NR 15 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 JAN 1 PY 2017 VL 64 IS 1 BP 87 EP 91 DI 10.1093/cid/ciw668 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP1CN UT WOS:000397123100024 PM 27682069 ER PT J AU Yao, H Rayburn, ER Shi, Q Gao, L Hu, WJ Li, HB AF Yao, Hui Rayburn, Elizabeth R. Shi, Qiang Gao, Liang Hu, Wenjie Li, Haibo TI FDA-approved drugs that interfere with laboratory tests: A systematic search of US drug labels SO CRITICAL REVIEWS IN CLINICAL LABORATORY SCIENCES LA English DT Review DE Drug-related laboratory test interference; prescription drugs; FDA labels; DailyMed ID URINE; GLUCOSE; TABLETS; ASSAYS AB Drug-related laboratory test interference or drug/laboratory test interactions (DLTI) are a major source of laboratory errors. DLTI is of concern with regard to both the clinical diagnosis and the monitoring of patients. Although there have been numerous reports about specific drugs that interfere with laboratory tests, there has not been a recent review on the topic. We herein provide a review of the known DLTI of US FDA-approved drugs based on a systematic search of DailyMed, a website containing the labels of US FDA-approved drugs. The labels for all human single-ingredient prescription drugs included in the database (1368) were searched using stemmed keywords and were manually reviewed for their relevance to DLTI. A total of 134 labels were positive, which indicated that the drug interferes with at least one clinical laboratory test. Antibacterial agents, psychotropic drugs and contrast media are the classes of drugs most likely to lead to DLTI. Urine was the clinical sample most frequently affected by DLTI. The FDA drug label is a source of information for studies of DLTI, although information is still lacking for most drugs, and additional improvements are needed for many of the existing records. Medical professionals, clinicians and laboratory staff should keep these possible interactions in mind when interpreting the results of laboratory tests, and should ensure that they obtain a complete and accurate record of all drugs being used by patients in order to anticipate potential DLTI. The development of a reporting system to address potential DLTI is warranted. C1 [Yao, Hui; Gao, Liang; Hu, Wenjie; Li, Haibo] Nantong Matern & Child Hlth Hosp, Dept Clin Lab Med, Nantong, Peoples R China. [Rayburn, Elizabeth R.] Various Labs, Birmingham, AL USA. [Shi, Qiang] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Li, HB (reprint author), Nantong Matern & Child Hlth Hosp, Dept Reprod Med, Nantong, Peoples R China. EM ntlihaibo2015@163.com FU International Cooperation and Exchanges Program of the Department of Health in Jiangsu Province, China; US FDA's Office of Women's Health FX The authors declare that they have no potential conflicts of interest with regard to this manuscript. Dr. Haibo Li was supported in part by the International Cooperation and Exchanges (2012) Program of the Department of Health in Jiangsu Province, China. This project was partially supported by the US FDA's Office of Women's Health. NR 44 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1040-8363 EI 1549-781X J9 CRIT REV CL LAB SCI JI Crit. Rev. Clin. Lab. Sci. PD JAN PY 2017 VL 54 IS 1 BP 1 EP 17 DI 10.1080/10408363.2016.1191425 PG 17 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EM1BY UT WOS:000395054200001 PM 27193822 ER PT J AU Lu, Y Xue, JY Fu, PP Lin, G AF Lu, Yao Xue, Junyi Fu, Peter P. Lin, Ge TI IMPAIRED ATP SYNTHASE CONTRIBUTING TO PYRROLIZIDINE ALKALOIDS-INDUCED HEPATOTOXICITY SO DRUG METABOLISM AND PHARMACOKINETICS LA English DT Meeting Abstract C1 [Lu, Yao; Xue, Junyi; Lin, Ge] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Fu, Peter P.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. FU Research Grants Council of Hong Kong Special Administrative Region (GRF Project) [471013]; Chinese University of Hong Kong [4054215]; CUHK School of Biomedical Sciences - Seed Fund for Joint Establishments FX Supported by Research Grants Council of Hong Kong Special Administrative Region (GRF Project No.: 471013), The Chinese University of Hong Kong (Direct Grant: 4054215), and CUHK School of Biomedical Sciences - Seed Fund for Joint Establishments. NR 0 TC 0 Z9 0 U1 1 U2 1 PU JAPANESE SOC STUDY XENOBIOTICS PI TOKYO PA INT MED INF CENTER SHINANOMACHI RENGAKAN, 35 SHINANO-MACHI SHINJUKU-KU, TOKYO, 160-0016, JAPAN SN 1347-4367 EI 1880-0920 J9 DRUG METAB PHARMACOK JI Drug Metab. Pharmacokinet. PD JAN PY 2017 VL 32 IS 1 SU S MA P164 BP S73 EP S73 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EO9MW UT WOS:000397013800243 ER PT J AU Zhu, L Xue, JY Xia, QS Fu, PP Lin, G AF Zhu, Lin Xue, Junyi Xia, Qingsu Fu, Peter P. Lin, Ge TI TOXICOKINETIC STUDY OF PYRROLIZIDINE ALKALOID-DERIVED DNA ADDUCTS, THE POTENTIAL BIOMARKER OF PYRROLIZIDINE ALKALOID-INDUCED TUMORIGENICITY SO DRUG METABOLISM AND PHARMACOKINETICS LA English DT Meeting Abstract C1 [Zhu, Lin; Xue, Junyi; Lin, Ge] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Xia, Qingsu; Fu, Peter P.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. FU GRF grants from the Research Grants Council of the Hong Kong Special Administrative Region [471013, 14110714]; CUHK School of Biomedical Sciences FX Supported by GRF grants from the Research Grants Council of the Hong Kong Special Administrative Region (Project No.: 471013 and 14110714) and CUHK School of Biomedical Sciences - Seed Fund for Joint Establishments. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JAPANESE SOC STUDY XENOBIOTICS PI TOKYO PA INT MED INF CENTER SHINANOMACHI RENGAKAN, 35 SHINANO-MACHI SHINJUKU-KU, TOKYO, 160-0016, JAPAN SN 1347-4367 EI 1880-0920 J9 DRUG METAB PHARMACOK JI Drug Metab. Pharmacokinet. PD JAN PY 2017 VL 32 IS 1 SU S MA A8 BP S24 EP S25 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EO9MW UT WOS:000397013800085 ER PT J AU Lindblom, EN Berman, ML Thrasher, JF AF Lindblom, Eric N. Berman, Micah L. Thrasher, James F. TI FDA-Required Tobacco Product Inserts & Onserts-and the First Amendment SO FOOD AND DRUG LAW JOURNAL LA English DT Article ID CIGARETTE PACKAGE INSERTS; PERCEPTIONS; DESIGN; US; RISK; DESCRIPTORS; EFFICACY; BELIEFS; SMOKERS; LABELS AB In 2012, a federal court of appeals struck down an FDA rule requiring graphic health warnings on cigarettes as violating First Amendment commercial speech protections. Tobacco product inserts and onserts can more readily avoid First Amendment constraints while delivering more extensive information to tobacco users, and can work effectively to support and encourage smoking cessation. This paper examines FDA's authority to require effective inserts and onserts and shows how FDA could design and support them to avoid First Amendment problems. Through this process, the paper offers helpful insights regarding how key Tobacco Control Act provisions can and should be interpreted and applied to follow and promote the statute's purposes and objectives. The paper's rigorous analysis of existing First Amendment case law relating to compelled commercial speech also provides useful guidance for any government efforts either to compel product disclosures or to require government messaging in or on commercial products or their advertising, whether done for remedial, purely informational, or behavior modification purposes. C1 [Lindblom, Eric N.] Georgetown Univ, Ctr Law, ONeill Inst Natl & Global Hlth, Tobacco Control & Food & Drug Law, Washington, DC 20057 USA. [Lindblom, Eric N.] US FDA, Off Policy, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. [Berman, Micah L.] Ohio State Univ, Coll Publ Hlth, Columbus, OH 43210 USA. [Berman, Micah L.] Ohio State Univ, Moritz Coll Law, Columbus, OH 43210 USA. [Thrasher, James F.] Univ South Carolina, Dept Hlth Promot Educ & Behav, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. RP Lindblom, EN (reprint author), Georgetown Univ, Ctr Law, ONeill Inst Natl & Global Hlth, Tobacco Control & Food & Drug Law, Washington, DC 20057 USA.; Lindblom, EN (reprint author), US FDA, Off Policy, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. EM enl27@Jaw.georgetown.edu FU U.S. National Cancer Institute [R01 CA167067] FX Dr. Thrasher's involvement in the writing of this paper was partly supported by a grant from the U.S. National Cancer Institute (R01 CA167067). The funder had no role in the design, analysis, preparation, or decision to publish the manuscript. The opinions and analysis in the article are the authors' own. NR 33 TC 0 Z9 0 U1 0 U2 0 PU FOOD DRUG LAW INST PI WASHINGTON PA 1000 VERMONT AVE NW, SUITE 1200, WASHINGTON, DC 20005-4903 USA SN 1064-590X J9 FOOD DRUG LAW J JI Food Drug Law J. PY 2017 VL 72 IS 1 BP 1 EP 25 PG 25 WC Food Science & Technology; Law; Nutrition & Dietetics; Pharmacology & Pharmacy SC Food Science & Technology; Government & Law; Nutrition & Dietetics; Pharmacology & Pharmacy GA EN4EX UT WOS:000395961900001 ER PT J AU Junod, S AF Junod, Suzanne TI Commemorating the 40th Anniversary of the 1976 Medical Device Amendments SO FOOD AND DRUG LAW JOURNAL LA English DT Article C1 [Junod, Suzanne] US FDA, Hist Off, 10903 New Hampshire Ave,Bldg 1,Room 1204, Silver Spring, MD 20993 USA. RP Junod, S (reprint author), US FDA, Hist Off, 10903 New Hampshire Ave,Bldg 1,Room 1204, Silver Spring, MD 20993 USA. EM Suzanne.Junod@fda.hhs.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU FOOD DRUG LAW INST PI WASHINGTON PA 1000 VERMONT AVE NW, SUITE 1200, WASHINGTON, DC 20005-4903 USA SN 1064-590X J9 FOOD DRUG LAW J JI Food Drug Law J. PY 2017 VL 72 IS 1 BP 26 EP 31 PG 6 WC Food Science & Technology; Law; Nutrition & Dietetics; Pharmacology & Pharmacy SC Food Science & Technology; Government & Law; Nutrition & Dietetics; Pharmacology & Pharmacy GA EN4EX UT WOS:000395961900002 ER PT J AU Gormley, NJ Farrell, AT Pazdur, R AF Gormley, Nicole J. Farrell, Ann T. Pazdur, Richard TI Minimal Residual Disease as a Potential Surrogate End Point-Lingering Questions SO JAMA ONCOLOGY LA English DT Editorial Material ID MULTIPARAMETER FLOW-CYTOMETRY; ARRHYTHMIA SUPPRESSION TRIAL; STEM-CELL TRANSPLANTATION; MULTIPLE-MYELOMA C1 [Gormley, Nicole J.; Farrell, Ann T.; Pazdur, Richard] US FDA, Off Hematol & Oncol Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Gormley, NJ (reprint author), US FDA, Div Hematol Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM nicole.gormley@fda.hhs.gov NR 17 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 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JAN PY 2017 VL 3 IS 1 BP 18 EP 20 DI 10.1001/jamaoncol.2016.3112 PG 3 WC Oncology SC Oncology GA EK9PV UT WOS:000394257300005 PM 27632052 ER PT J AU Eydelman, M Hilmantel, G Tarver, ME Hofmeister, EM May, J Hammel, K Hays, RD Ferris, F AF Eydelman, Malvina Hilmantel, Gene Tarver, Michelle E. Hofmeister, Elizabeth M. May, Jeanine Hammel, Keri Hays, Ron D. Ferris, Frederick, III TI Symptoms and Satisfaction of Patients in the Patient-Reported Outcomes With Laser In Situ Keratomileusis (PROWL) Studies SO JAMA OPHTHALMOLOGY LA English DT Article ID QUALITY-OF-LIFE; SURFACE DISEASE INDEX; WAVE-FRONT ANALYSIS; DRY EYE; REFRACTIVE SURGERY; FOLLOW-UP; FEMTOSECOND LASER; VISUAL SYMPTOMS; RISK-FACTORS; MECHANICAL MICROKERATOME AB IMPORTANCE Patient-reported outcomes should be collected using validated questionnaires prior to and following laser in situ keratomileusis (LASIK) surgery. OBJECTIVE To report the frequency of patient-reported visual symptoms, dry eye symptoms, satisfaction with vision, and satisfaction with LASIK surgery in the Patient-Reported Outcomes With LASIK (PROWL) studies. DESIGN, SETTING, AND PARTICIPANTS The PROWL-1 and PROWL-2 studieswere prospective, observational studies conducted from September 13, 2011, to June 27, 2014. The PROWL-1 study was a single-military center study of 262 active-duty Navy personnel 21 to 52 years of age. The PROWL-2 study was a study of 312 civilians 21 to 57 years of age conducted at 5 private practice and academic centers. The LASIK surgery and the postoperative care were performed based on the usual practice and clinical judgment at the site. Participants completed a self-administered, web-based questionnaire, preoperatively and postoperatively at 1 and 3 months (the PROWL-1 and -2 studies) and at 6 months (the PROWL-2 study). EXPOSURES Participants underwent LASIK surgery formyopia, hyperopia, and/or astigmatism. MAIN OUTCOMES AND MEASURES Visual symptoms (double images, glare, halos, and/or starbursts), dry eye symptoms, participant satisfaction (with vision and LASIK surgery), and clinical measures (visual acuity, refractive error, and slitlamp and posterior segment eye examination findings) were assessed preoperatively and at 1, 3, and 6 months postoperatively. RESULTS A total of 262 participants were enrolled in the PROWL-1 study (mean [SD] age, 29.1 [6.1] years), and a total of 312 participants were enrolled in the PROWL-2 study (mean [SD] age, 31.5 [7.3] years). Visual symptoms and dissatisfaction with vision were common preoperatively. Overall, the prevalence of visual symptoms and dry eye symptoms decreased, although a substantial percentage of participants reported new visual symptoms after surgery (43%[95% CI, 31%-55%] from the PROWL-1 study and 46%[95% CI, 33%-58%] from the PROWL-2 study at 3 months). The percentages of participants in the PROWL-1 study with normal Ocular Surface Disease Index scores were 55%(95% CI, 48%-61%) at baseline, 66%(95% CI, 59%-72%) at 3 months, and 73%(95% CI, 67%-79%) at 6 months. The percentages of participants in the PROWL-2 study with normal Ocular Surface Disease Index scores were 44%(95% CI, 38%-50%) at baseline and 65%(95% CI, 59%-71%) at 3 months. Of those participants who had normal scores at baseline in both the PROWL-1 and -2 studies, about 28%(95% CI, 19%-37%) had mild, moderate, or severe dry eye symptoms at 3 months. While most participants were satisfied, the rates of dissatisfaction with vision ranged from 1% (95% CI, 0%-4%) to 4%(95% CI, 2%-7%), and the rates of dissatisfaction with surgery ranged from 1% (95% CI, 0%-4%) to 2%(95% CI, 1%-5%). CONCLUSIONS AND RELEVANCE The systematic administration of a questionnaire to patients who have undergone LASIK surgery is a new approach to assess symptoms and satisfaction. Our findings support the need for adequate counseling about the possibility of developing new symptoms after LASIK surgery. C1 [Eydelman, Malvina; Hilmantel, Gene; Tarver, Michelle E.] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 66,Room 2410, Silver Spring, MD 20993 USA. [Hofmeister, Elizabeth M.] Navy Med Ctr San Diego, Navy Refract Surg Ctr, Dept Ophthalmol, San Diego, CA USA. [May, Jeanine; Hammel, Keri] Emmes Corp, Rockville, MD USA. [Hays, Ron D.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Ferris, Frederick, III] NEI, Bethesda, MD 20892 USA. RP Eydelman, M (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 66,Room 2410, Silver Spring, MD 20993 USA. EM malvina.eydelman@fda.hhs.gov NR 47 TC 2 Z9 2 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 JAN PY 2017 VL 135 IS 1 DI 10.1001/jamaophthalmol.2016.4587 PG 10 WC Ophthalmology SC Ophthalmology GA EK9PJ UT WOS:000394256100006 PM 27893066 ER PT J AU Hays, RD Tarver, ME Spritzer, KL Reise, S Hilmantel, G Hofmeister, EM Hammel, K May, J Ferris, F Eydelman, M AF Hays, Ron D. Tarver, Michelle E. Spritzer, Karen L. Reise, Steve Hilmantel, Gene Hofmeister, Elizabeth M. Hammel, Keri May, Jeanine Ferris, Frederick, III Eydelman, Malvina TI Assessment of the Psychometric Properties of a Questionnaire Assessing Patient-Reported Outcomes With Laser In Situ Keratomileusis (PROWL) SO JAMA OPHTHALMOLOGY LA English DT Article ID INSTITUTE-REFRACTIVE ERROR; OF-LIFE INSTRUMENT; RELIABILITY; VALIDITY; ANXIETY; SCALE AB IMPORTANCE Patient-reported outcome (PRO) measures for laser in situ keratomileusis (LASIK) are needed. OBJECTIVE To develop PRO measures to assess satisfaction, eye-related symptoms, and their effect on functioning and well-being following LASIK based on patient and expert input. DESIGN, SETTING, AND PARTICIPANTS The Patient-Reported Outcomes With LASIK (PROWL) studies were prospective observational studies of patients undergoing LASIK surgery for myopia, hyperopia, or astigmatism. PROWL-1 was a single-center study of active-duty US Navy personnel and PROWL-2 was a 5-center study of civilians. PROWL-1 enrolled 262 active-duty service personnel and PROWL-2 enrolled 312 civilians 21 years or older who spoke English; 241 individuals in PROWL-1 and 280 in PROWL-2 completed a baseline questionnaire before surgery. The analytic sample included those also completing 1 or more follow-up questionnaires: 240 (99.6%) of those in PROWL-1 and 271 (94.4%) of those in PROWL-2. Questionnaires were self-administered through the internet preoperatively and at 1 and 3 months postoperatively in both studies and at 6 months postoperatively in PROWL-1. PROWL-1 began in August 2011 and was completed May 30, 2014; PROWL-2 began in July 2012 and was completed June 27, 2014. Data were analyzed from June 28, 2014, to October 24, 2016. MAIN OUTCOMES AND MEASURES Scales assessing visual symptoms (double images, glare, halos, and starbursts), dry eye symptoms, satisfaction with vision, and satisfaction with LASIK surgery. Items from the National Eye Institute (NEI) Refractive Error Quality of Life Instrument (NEI-RQL-42), NEI Visual Function Questionnaire (NEI-VFQ), and the Ocular Surface Disease Index (OSDI) were included. All scales are scored on a 0 to 100possible range. Construct validity and responsiveness to change were evaluated (comparing scores before and after surgery). RESULTS The median age of the 240-person PROWL-1 analytic sample was 27 years (range, 21-52 years); 49 were women (20.4%). The median age of the 271-person PROWL-2 analytic sample was 30 years (range, 21-57 years); 147 were women (54.2%). Internal consistency reliabilities for the 4 visual symptom scales ranged from 0.96 to 0.98 in PROWL-1 and from 0.95 to 0.97 in PROWL-2. The median (interquartile range) test-retest intraclass correlation was 0.69 (0.57-0.79) and 0.76 (0.68-0.84) in PROWL-1 and PROWL-2, respectively. Product-moment correlations of satisfaction with surgery with visual symptom scales at follow-up evaluations ranged from r = 0.24 to r = 0.49. Measures improved from baseline to follow-up, with effect sizes of 0.14 to 1.98, but scores on the NEI-RQL-42 glare scale worsened at the 1-month follow-up. Hours of work did not change significantly from baseline to 1-month follow-up, with the mean number (mean [SD] difference) in PROWL-1 of 41.7 vs 40.9 hours (-0.8[18.7]) and in PROWL-2 of 38.8 vs 38.2 hours (-0.6 [17.1]). CONCLUSIONS AND RELEVANCE The results of these studies support the reliability and validity of visual symptom scales to evaluate the effects of LASIK surgery in future studies. C1 [Hays, Ron D.; Spritzer, Karen L.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Hays, Ron D.; Tarver, Michelle E.; Hilmantel, Gene; Eydelman, Malvina] US FDA, Ctr Devices & Radiol Hlth, 10993 New Hampshire Ave,Bldg 66,Room 2410, Silver Spring, MD 20993 USA. [Reise, Steve] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Hofmeister, Elizabeth M.] Naval Med Ctr San Diego, Navy Refract Surg Ctr, Dept Ophthalmol, San Diego, CA USA. [Hammel, Keri; May, Jeanine] Emmes Corp, Rockville, MD USA. [Ferris, Frederick, III] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Eydelman, M (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10993 New Hampshire Ave,Bldg 66,Room 2410, Silver Spring, MD 20993 USA. EM malvina.eydelman@fda.hhs.gov NR 25 TC 2 Z9 2 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 JAN PY 2017 VL 135 IS 1 DI 10.1001/jamaophthalmol.2016.4597 PG 10 WC Ophthalmology SC Ophthalmology GA EK9PJ UT WOS:000394256100005 PM 27893063 ER PT J AU Zhou, EH Seymour, S Goulding, MR Kang, EM Major, JM Iyasu, S AF Zhou, Esther H. Seymour, Sally Goulding, Margie R. Kang, Elizabeth M. Major, Jacqueline M. Iyasu, Solomon TI The US Food and Drug Administration's drug safety recommendations and long-acting beta2-agonist dispensing pattern changes in adult asthma patients: 2003-2012 SO JOURNAL OF ASTHMA AND ALLERGY LA English DT Article DE LABA; dispensing pattern; US FDA; regulatory activities ID COMMERCIALLY INSURED POPULATION; AGONIST COMBINATION THERAPY; BETA(2)-ADRENERGIC AGONIST; STEP-DOWN; COST; CARE; SAMPLES; IMPACT; TRIAL; RISK AB Background: Emerging safety issues associated with long-acting beta 2 -agonist (LABA) have led to multiple regulatory activities by the US Food and Drug Administration (FDA) since 2003, including Drug Safety Communications (DSCs) in 2010. These DSCs had three specific recommendations for the safe use of LABA products in adult asthma treatment. Methods: We examined the initiation of LABA-containing products for adult asthma treatment using an intermittent time series approach in a claims database from 2003 to 2012. We assessed the alignment of dispensing patterns with the following 2010 FDA recommendations: 1) contraindicated use of single-ingredient (SI)-LABA without an asthma controller medication (ACM); 2) a LABA should only be used when asthma is not adequately controlled on inhaled corticosteroids (ICSs) or ACM; and 3) step-down asthma therapy (e.g., discontinue LABA) when asthma control is achieved. Results: There were 477,922 adults (18-64 years old) dispensed a new LABA during 2003-2012. Among LABA initiators, patients who initiated an SI-LABA and who did "not" have an ACM dispensed on the same date decreased from >9% in 2003 (the initial labeling change) to <2% post 2010 DSCs (p-value <0.0001 in the segmented regression model). The proportion of asthma patients dispensed an ICS in 6 months prior to initiating LABA treatment did not increase. The proportion of patients with longer than 4 months of continuous treatment did not decrease over the study period. Conclusion: Although the decrease in SI-LABA initiation is consistent with FDA's recommendations, low ICS dispensing before initiating a LABA and LABA continuation practices require further efforts to move toward the recommended safe practices. C1 [Zhou, Esther H.; Goulding, Margie R.; Kang, Elizabeth M.; Major, Jacqueline M.; Iyasu, Solomon] US FDA, Div Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 22,Room 2462, Silver Spring, MD 20993 USA. [Seymour, Sally] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Zhou, EH (reprint author), US FDA, Div Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 22,Room 2462, Silver Spring, MD 20993 USA. EM Esther.Zhou@fda.hhs.gov NR 33 TC 0 Z9 0 U1 0 U2 0 PU DOVE MEDICAL PRESS LTD PI ALBANY PA PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND SN 1178-6965 J9 J ASTHMA ALLERGY JI J. ASTHMA ALLERGY PY 2017 VL 10 BP 67 EP 74 DI 10.2147/JAA.S124395 PG 8 WC Respiratory System SC Respiratory System GA EO6OB UT WOS:000396811300001 PM 28356763 ER PT J AU Nan, XL Verrill, L Iles, I AF Nan, Xiaoli Verrill, Linda Iles, Irina TI "As Much Calcium as a Glass of Milk!" Understanding American Consumers' Preferences for Fortified Foods SO JOURNAL OF FOOD PRODUCTS MARKETING LA English DT Article DE Food labels; fortified foods; health consciousness; nutrition ID USE FUNCTIONAL FOODS; HEALTH CONSCIOUSNESS; PERCEIVED HEALTHINESS; NUTRITION LABELS; ATTITUDES; WILLINGNESS; INFORMATION; BEHAVIORS; DETERMINANTS; CONSUMPTION AB This study examines predictors of American consumers' preferences for fortified foods, focusing on sociodemographic as well as psychological correlates. Analysis of a probability-based survey (N=6,728) revealed that females and the more educated tended to have greater preferences for fortified foods. Whites held the least favorable views on fortified foods when compared to Blacks and Hispanics. In terms of psychological predictors, people who were more health-conscious were more likely to prefer fortified foods. Perceived usefulness of nutrition labels and confusion about healthy food choices were both associated with stronger preferences for fortified foods. Both relationships appeared to be moderated by health consciousness. Communication and policy implications of these findings are discussed. C1 [Nan, Xiaoli; Iles, Irina] Univ Maryland, Dept Commun, 2105A Skinner Bldg, College Pk, MD 20742 USA. [Verrill, Linda] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Nan, XL (reprint author), Univ Maryland, Dept Commun, 2105A Skinner Bldg, College Pk, MD 20742 USA. EM nan@umd.edu NR 42 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1045-4446 EI 1540-4102 J9 J FOOD PROD MARK JI J. Food Prod. Mark. PY 2017 VL 23 IS 1 BP 24 EP 41 DI 10.1080/10454446.2017.1244782 PG 18 WC Business SC Business & Economics GA EM0LE UT WOS:000395009000002 ER PT J AU Sullivan, HW O'Donoghue, AC Rupert, DJ Willoughby, JF Aikin, KJ AF Sullivan, Helen W. O'Donoghue, Amie C. Rupert, Douglas J. Willoughby, Jessica Fitts Aikin, Kathryn J. TI Placement and Format of Risk Information on Direct-to-Consumer Prescription Drug Websites SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID FDA WARNING LETTERS; WORLD-WIDE-WEB; ORGANIZATIONAL SIGNALS; DECISION-MAKING; TROUBLE SPOTS; COMMUNICATION; TEXT; COMPREHENSION; PRINCIPLES; PROMOTIONS AB We investigated whether the location and format of risk information on branded prescription drug websites influence consumers' knowledge and perceptions of the drug's risks. Participants (Internet panelists with high cholesterol [n = 2,609] or seasonal allergies [n = 2,637]) were randomly assigned to view a website promoting a fictitious prescription drug for their condition. The website presented risk information at the bottom of the homepage, or at the bottom of the homepage with a signal above indicating that the risk information was located below, or on a linked secondary page. We also varied the format of risk information (paragraph, checklist, bulleted list, highlighted box). Participants then answered questions on risk recall and perceptions. Participants recalled fewer drug risks when the risks were placed on a secondary page. The signal had little effect, and risk information format did not affect outcomes. The location of risk information on prescription drug websites can affect consumer knowledge of drug risks; however, signals and special formatting may not be necessary for websites to adequately inform consumers about drug risks. We recommend that prescription drug websites maintain risk information on their homepages to achieve "fair balance" as required by the U.S. Food and Drug Administration. C1 [Sullivan, Helen W.; O'Donoghue, Amie C.; Aikin, Kathryn J.] US FDA, 10903 New Hampshire Ave,Bldg 51, Silver Spring, MD 20993 USA. [Rupert, Douglas J.; Willoughby, Jessica Fitts] RTI Int, Res Triangle Pk, NC USA. RP Sullivan, HW (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 51, Silver Spring, MD 20993 USA. EM Helen.Sullivan@fda.hhs.gov FU Office of Prescription Drug Promotion, U.S. Food and Drug Administration FX Funding was provided by the Office of Prescription Drug Promotion, U.S. Food and Drug Administration, and data were collected through a contract with RTI International. Jessica Fitts Willoughby was a contractor with RTI International at the time this study was conducted. NR 52 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PY 2017 VL 22 IS 2 BP 171 EP 181 DI 10.1080/10810730.2016.1258745 PG 11 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA EO6BH UT WOS:000396776200009 PM 28129069 ER PT J AU Guha, S McCaffrey, B Hariharan, P Myers, MR AF Guha, Suvajyoti McCaffrey, Brady Hariharan, Prasanna Myers, Matthew R. TI Quantification of leakage of sub-micron aerosols through surgical masks and facemasks for pediatric use SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL HYGIENE LA English DT Article DE Filter; leakage; N95; pediatric facemasks; surgical facemasks ID N95 FILTERING-FACEPIECE; TOTAL INWARD LEAKAGE; HEALTH-CARE WORKERS; ACUTE RESPIRATORY SYNDROME; INFLUENZA-VIRUS; QUANTITATIVE ASSESSMENT; PERFORMANCE; TRANSMISSION; SARS; PROTECTION AB Surgical respirators, surgical masks (SMs), and facemasks for pediatric use (FPUs) are routinely used in the U.S. healthcare industry as personal protective equipment (PPE) against infectious diseases. While N95s including surgical respirators have been routinely studied, SMs and FPUs have not received as much attention, particularly in the context of aerosolized threats. This is because SMs and PFUs are not designed to protect against sub-micron aerosols. However, with the possibility of new or re-emerging airborne diseases or bio-aerosol weapons lingering, combined with the limited availability of respirators and logistical issues associated with fit-testing millions, the general adult and pediatric populations may elect to wear SMs and FPUs, respectively, in the case of a pandemic or a bio-terrorist attack. When a person dons a PPE, gaps are created between the wearer's face and the PPE, and aerosols leaking through these gaps can be an important contributor to the risk of infection compared to filtered aerosols. To understand and quantify the contribution of leakage of aerosols through gaps, with particular emphasis on SMs and FPUs, this study investigated leakage of charge-neutralized, polydispersed, dried sodium-chloride aerosols across different brands of PPE. Different breathing rates, aerosol particle sizes, and gap sizes were considered. A few major findings of this study were: (a) leakage, is not a strong function of sub-micron aerosol size; (b) for the same gap size, leakage of aerosols through surgical respirators can often be higher than in SMs and FPUs; and (c) as the gap size increases, the increase in leakage through surgical respirators is higher compared for SMs and FPUs, implying that some SMs and FPUs that possess electret layers may be preferable to N95s that have not been fit-tested. The results obtained can also be used to explain conflicting findings from clinical studies on the effectiveness of SMs when compared to N95s and can be input into risk-assessment models to determine the increase in infection rate resulting from deployment of PPE under less-than-ideal conditions. C1 [Guha, Suvajyoti; Hariharan, Prasanna; Myers, Matthew R.] US FDA, Div Appl Mech, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [McCaffrey, Brady] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. RP Guha, S (reprint author), US FDA, Div Appl Mech, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Suvajyoti.Guha@fda.hhs.gov FU Office of Counterterrorism and Emerging Threats, Food and Drug Administration, Silver Spring, Maryland [MCM2DXXXXX205, MCM2JXXXXX270HT] FX This study was funded by two Medical Countermeasures Initiative projects MCM2DXXXXX205, MCM2JXXXXX270HT from the Office of Counterterrorism and Emerging Threats, Food and Drug Administration, Silver Spring, Maryland. NR 38 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1545-9624 EI 1545-9632 J9 J OCCUP ENVIRON HYG JI J. Occup. Environ. Hyg. PY 2017 VL 14 IS 3 BP 214 EP 223 DI 10.1080/15459624.2016.1237029 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA EL5GU UT WOS:000394650400008 PM 27754781 ER PT J AU Bhirde, AA Sindiri, S Calco, GN Aronova, MA Beaucage, SL AF Bhirde, Ashwinkumar A. Sindiri, Sivasish Calco, Gina N. Aronova, Maria A. Beaucage, Serge L. TI Algorithm-driven high-throughput screening of colloidal nanoparticles under simulated physiological and therapeutic conditions SO NANOSCALE LA English DT Article ID GOLD NANOPARTICLES; SILVER NANOPARTICLES; PRODUCT QUALITY; DRUG-DELIVERY; CANCER-CELLS; IN-VITRO; NANOMATERIALS; PROTEINS; NANOMEDICINE; CHALLENGES AB Colloidal nanoparticles have shown tremendous potential as cancer drug carriers and as phototherapeutics. However, the stability of nanoparticles under physiological and phototherapeutic conditions is a daunting issue, which needs to be addressed in order to ensure a successful clinical translation. The design, development and implementation of unique algorithms are described herein for high-throughput hydrodynamic size measurements of colloidal nanoparticles. The data obtained from such measurements provide clinically-relevant particle size distribution assessments that are directly related to the stability and aggregation profiles of the nanoparticles under putative physiological and phototherapeutic conditions; those profiles are not only dependent on the size and surface coating of the nanoparticles, but also on their composition. Uncoated nanoparticles showed varying degrees of association with bovine serum albumin, whereas PEGylated nanoparticles did not exhibit significant association with the protein. The algorithm-driven, high-throughput size screening method described in this report provides highly meaningful size measurement patterns stemming from the association of colloidal particles with bovine serum albumin used as a protein model. Noteworthy is that this algorithm-based high-throughput method can accomplish sophisticated hydrodynamic size measurement protocols within days instead of years it would take conventional hydrodynamic size measurement techniques to achieve a similar task. C1 [Bhirde, Ashwinkumar A.; Beaucage, Serge L.] US FDA, Lab Biol Chem, Div Biotechnol Review & Res 4, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Sindiri, Sivasish] NCI, Genet Branch, Oncogen Sect, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Calco, Gina N.; Aronova, Maria A.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. RP Bhirde, AA; Beaucage, SL (reprint author), US FDA, Lab Biol Chem, Div Biotechnol Review & Res 4, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Ashwinkumar.Bhirde@fda.hhs.gov; Serge.Beaucage@fda.hhs.gov FU NCI/FDA IOTF Fellowship FX An NCI/FDA IOTF Fellowship to A. A. B. is gratefully acknowledged. We also thank Mrs Rohini Bhirde for helping with illustrations. NR 50 TC 0 Z9 0 U1 0 U2 0 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PY 2017 VL 9 IS 6 BP 2291 EP 2300 DI 10.1039/c6nr08579b PG 10 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EM9JB UT WOS:000395626600024 PM 28127597 ER PT J AU McMahon, AW Wharton, GT Thornton, P De Leon, DD AF McMahon, Ann W. Wharton, Gerold T. Thornton, Paul De Leon, Diva D. TI Octreotide use and safety in infants with hyperinsulinism SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE hyperinsulinism; octreotide; necrotizing Enterocolitis; infants; safety; pharmacoepidemiology; pharmacoepidemiology ID NECROTIZING ENTEROCOLITIS; CONGENITAL HYPERINSULINISM; TERM AB Background Octreotide is a synthetic peptide analog of naturally occurring somatostatin. Octreotide is used off-label in children < 6 years of age for hyperinsulinism, chylothorax, and gastrointestinal bleeding. There is a lack of controlled data on efficacy or potential adverse events from this off-label use. Methods Three pediatric hospitals participated in this study. Patients were hospitalized January 2007-December 2010 and administered octreotide for congenital hyperinsulinism (CHI) at least 1 day. Variables assessed included octreotide dosage, patient demographics, medical interventions, concomitant medicines, serious adverse events (SAEs) including necrotizing enterocolitis (NEC), and mortality. Results The 103 patient sample had a median gestational age of 38 weeks. During the study period, two patients died: one from NEC and the other from cardiomyopathy/sepsis. There were 11 other SAEs in the 101 surviving patients. Conclusion This study highlights potential risks in administering octreotide off-label. This study, like several other published studies, has highlighted NEC in a full-term infant treated with octreotide. It is important to study the efficacy and the safety of octreotide for hyperinsulinism. In the interim, it might be prudent to prescribe octreotide in CHI neonates only in the absence of other risk factors for NEC. Copyright (C) 2016 John Wiley & Sons, Ltd. C1 [McMahon, Ann W.; Wharton, Gerold T.] US FDA, Off Pediat Therapeut, 10903 New Hampshire Ave,Bldg 32,Room 5158, Silver Spring, MD 20993 USA. [Thornton, Paul] Cook Childrens Med Ctr, Ft Worth, TX USA. [De Leon, Diva D.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP McMahon, AW (reprint author), US FDA, Off Pediat Therapeut, 10903 New Hampshire Ave,Bldg 32,Room 5158, Silver Spring, MD 20993 USA. EM ann.mcmahon@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 13 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JAN PY 2017 VL 26 IS 1 BP 26 EP 31 DI 10.1002/pds.4144 PG 6 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA EO0QS UT WOS:000396403600004 PM 27910218 ER PT J AU Thomas, BJ Harruff-Miller, BA Lewis, WK AF Thomas, Brandon J. Harruff-Miller, Barbara A. Lewis, William K. TI Note: A simple detection method for helium droplet spectroscopy experiments SO REVIEW OF SCIENTIFIC INSTRUMENTS LA English DT Review ID SUPERFLUID-HELIUM; MOLECULES; LIQUID AB Helium droplet methods are currently established as a premier experimental technique for the production and spectroscopic study of novel clusters and complexes. Unfortunately, some of the essential equipment required to perform the experiments, such as the detector used to monitor photon-induced depletion of the helium droplet beam, can be relatively large, complex, and expensive. Most often this detector is a quadrupole mass spectrometer (QMS). In this report, we describe the development and evaluation of an extremely simple, straightforward, small, and inexpensive droplet beam detector for use in helium droplet spectroscopy experiments and compare its performance to that of a QMS by recording the infrared spectra of helium droplets doped with either (CO2)-C-13 or CD4. Published by AIP Publishing. C1 [Thomas, Brandon J.] US FDA, Div Pharmaceut Anal, St Louis, MO 63110 USA. [Harruff-Miller, Barbara A.] Univ Dayton, Res Inst, Energy Technol & Mat Div, Dayton, OH 45469 USA. [Lewis, William K.] US Air Force Res Lab, Aerosp Syst Directorate, Wright Patterson AFB, OH 45433 USA. [Thomas, Brandon J.] Spectral Energies LLC, Dayton, OH 45431 USA. RP Lewis, WK (reprint author), US Air Force Res Lab, Aerosp Syst Directorate, Wright Patterson AFB, OH 45433 USA. EM William.Lewis.49@us.af.mil FU Air Force Research Laboratory (AFRL); Air Force Office of Scientific Research (AFOSR) [LRIR-15RQCOR105] FX We gratefully acknowledge funding from the Air Force Research Laboratory (AFRL), and Air Force Office of Scientific Research (AFOSR) through the support of Dr. Michael Berman under AFOSR Award No. LRIR-15RQCOR105. NR 15 TC 0 Z9 0 U1 0 U2 0 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0034-6748 EI 1089-7623 J9 REV SCI INSTRUM JI Rev. Sci. Instrum. PD JAN PY 2017 VL 88 IS 1 AR 016101 DI 10.1063/1.4973775 PG 3 WC Instruments & Instrumentation; Physics, Applied SC Instruments & Instrumentation; Physics GA EM6BD UT WOS:000395396900066 PM 28147675 ER PT J AU Woo, EJ Kaushal, M AF Woo, Emily Jane Kaushal, Megha TI Rhesus Immunoglobulin Dosage and Administration in Obese Individuals SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Letter C1 [Woo, Emily Jane] US FDA, Off Biostat & Epidemiol, Silver Spring, MD 20993 USA. [Kaushal, Megha] US FDA, Off Blood Res & Review, Silver Spring, MD USA. RP Woo, EJ (reprint author), US FDA, Off Biostat & Epidemiol, Silver Spring, MD 20993 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 EI 1543-2165 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD JAN PY 2017 VL 141 IS 1 BP 17 EP 17 DI 10.5858/arpa.2016-0286-LE PG 1 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA EO0GH UT WOS:000396375800003 PM 28029909 ER PT J AU Singh, H Brave, M Beaver, JA Cheng, J Tang, SH Zahalka, E Palmby, TR Venugopal, R Song, PF Liu, Q Liu, C Yu, JY Chen, XH Wang, X Wang, YN Kluetz, PG Daniels, SR Papadopoulos, EJ Sridhara, R Mckee, AE Ibrahim, A Kim, G Pazdur, R AF Singh, Harpreet Brave, Michael Beaver, Julia A. Cheng, Joyce Tang, Shenghui Zahalka, Eias Palmby, Todd R. Venugopal, Rajesh Song, Pengfei Liu, Qi Liu, Chao Yu, Jingyu Chen, Xiao Hong Wang, Xing Wang, Yaning Kluetz, Paul G. Daniels, Selena R. Papadopoulos, Elektra J. Sridhara, Rajeshwari Mckee, Amy E. Ibrahim, Amna Kim, Geoffrey Pazdur, Richard TI US Food and Drug Administration Approval: Cabozantinib for the Treatment of Advanced Renal Cell Carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID EVEROLIMUS AB On April 25, 2016, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of advanced renal cell carcinoma (RCC) in patients who have received prior antiangiogenic therapy. The approval was based on data from one randomized, open-label, multicenter study in which patients with RCC who had received prior antiangiogenic therapy were treated with either cabozantinib 60 mg orally once daily (n = 330) or everolimus 10 mg orally once daily (n = 328). The major efficacy outcome measure was progression-free survival (PFS) as assessed by a blinded independent radiology review committee in the first 375 randomized patients. A statistically significant improvement in PFS was seen, with a median PFS of 7.4 and 3.8 months in the cabozantinib and everolimus arms, respectively [hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.45-0.74; P < 0.0001]. At a second interim analysis, a statistically significant improvement in overall survival (OS) in the intent-to-treat population was also demonstrated, with a median OS of 21.4 and 16.5 months in the cabozantinib and everolimus arms, respectively (HR, 0.66; 95% CI, 0.53-0.83; P = 0.0003). The most common (greater than or equal to 25%) adverse reactions included diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome, hypertension, vomiting, weight loss, and constipation. (C) 2016 AACR. C1 [Singh, Harpreet; Brave, Michael; Beaver, Julia A.; Cheng, Joyce; Tang, Shenghui; Zahalka, Eias; Palmby, Todd R.; Venugopal, Rajesh; Song, Pengfei; Liu, Qi; Liu, Chao; Yu, Jingyu; Chen, Xiao Hong; Wang, Xing; Wang, Yaning; Kluetz, Paul G.; Daniels, Selena R.; Papadopoulos, Elektra J.; Sridhara, Rajeshwari; Mckee, Amy E.; Ibrahim, Amna; Kim, Geoffrey; Pazdur, Richard] US FDA, CDER, White Oak, 10903 New Hampshire Ave,WO 22 Room 2137, Silver Spring, MD 20993 USA. RP Singh, H (reprint author), US FDA, CDER, White Oak, 10903 New Hampshire Ave,WO 22 Room 2137, Silver Spring, MD 20993 USA. EM Harpreet.Singh@fda.hhs.gov NR 12 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN PY 2017 VL 23 IS 2 BP 330 EP 335 DI 10.1158/1078-0432.CCR-16-1073 PG 6 WC Oncology SC Oncology GA EK4EQ UT WOS:000393880300002 PM 27793960 ER PT J AU Eworuke, E AF Eworuke, Efe TI Can left truncation of the data explain the observed null associations? SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Letter ID PREGNANCY; ASTHMA; BIAS C1 [Eworuke, Efe] US FDA, Div Epidemiol 2, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol,Ctr Drug Evaluat & R, Silver Spring, MD USA. RP Eworuke, E (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM efe.eworuke@fda.hhs.gov NR 5 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD JAN-FEB PY 2017 VL 5 IS 1 BP 213 EP 213 DI 10.1016/j.jaip.2016.08.020 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA EO1YI UT WOS:000396493400042 PM 27815063 ER PT J AU Sosnovtsev, SV Sandoval-Jaime, C Parra, GI Tin, CM Jones, RW Soden, J Barnes, D Freeth, J Smith, AW Green, KY AF Sosnovtsev, Stanislav V. Sandoval-Jaime, Carlos Parra, Gabriel I. Tin, Christine M. Jones, Ronald W. Soden, Jo Barnes, Donna Freeth, Jim Smith, Alvin W. Green, Kim Y. TI Identification of Human Junctional Adhesion Molecule 1 as a Functional Receptor for the Hom-1 Calicivirus on Human Cells SO MBIO LA English DT Article ID X-RAY-STRUCTURE; SEA LION VIRUS; FELINE CALICIVIRUS; NONSTRUCTURAL POLYPROTEIN; STRUCTURAL INSIGHTS; NUCLEOTIDE-SEQUENCE; FUSION PROTEINS; CD300 FAMILY; PAN-PANISCUS; EXPRESSION AB The Hom-1 vesivirus was reported in 1998 following the inadvertent transmission of the animal calicivirus San Miguel sea lion virus to a human host in a laboratory. We characterized the Hom-1 strain and investigated the mechanism by which human cells could be infected. An expression library of 3,559 human plasma membrane proteins was screened for reactivity with Hom-1 virus-like particles, and a single interacting protein, human junctional adhesion molecule 1 (hJAM1), was identified. Transient expression of hJAM1 conferred susceptibility to Hom-1 infection on nonpermissive Chinese hamster ovary (CHO) cells. Virus infection was markedly inhibited when CHO cells stably expressing hJAM were pretreated with anti-hJAM1 monoclonal antibodies. Cell lines of human origin were tested for growth of Hom-1, and efficient replication was observed in HepG2, HuH7, and SK-CO15 cells. The three cell lines (of hepatic or intestinal origin) were confirmed to express hJAM1 on their surface, and clustered regularly interspaced short palindromic repeats/Cas9-mediated knockout of the hJAM1 gene in each line abolished Hom-1 propagation. Taken together, our data indicate that entry of the Hom-1 vesivirus into these permissive human cell lines is mediated by the plasma membrane protein hJAM1 as a functional receptor. IMPORTANCE Vesiviruses, such as San Miguel sea lion virus and feline calicivirus, are typically associated with infection in animal hosts. Following the accidental infection of a laboratory worker with San Miguel sea lion virus, a related virus was isolated in cell culture and named Hom-1. In this study, we found that Hom-1 could be propagated in a number of human cell lines, making it the first calicivirus to replicate efficiently in cultured human cells. Screening of a library of human cell surface membrane proteins showed that the virus could utilize human junctional adhesion molecule 1 as a receptor to enter cells and initiate replication. The Hom-1 virus presents a new system for the study of calicivirus biology and species specificity. C1 [Sosnovtsev, Stanislav V.; Sandoval-Jaime, Carlos; Parra, Gabriel I.; Tin, Christine M.; Jones, Ronald W.; Green, Kim Y.] NIAID, Infect Dis Lab, Caliciviruses Sect, NIH, Bethesda, MD 20892 USA. [Smith, Alvin W.] Oregon State Univ, Lab Calicivirus Studies, Corvallis, OR 97331 USA. [Soden, Jo; Barnes, Donna; Freeth, Jim] Retrogenix Ltd, Whaley Bridge, High Peak, England. [Sandoval-Jaime, Carlos] Univ Nacl Autonoma Mexico Cuernavaca, Inst Biotecnol, Cuernavaca, Morelos, Mexico. [Parra, Gabriel I.] US FDA, Div Viral Prod, OVRR, Silver Spring, MD USA. RP Sosnovtsev, SV (reprint author), NIAID, Infect Dis Lab, Caliciviruses Sect, NIH, Bethesda, MD 20892 USA. EM ss216m@nih.gov FU Division of Intramural Research of the NIAID, NIH FX This work was supported by the Division of Intramural Research of the NIAID, NIH. NR 58 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 JAN-FEB PY 2017 VL 8 IS 1 AR e00031-17 DI 10.1128/mBio.00031-17 PG 19 WC Microbiology SC Microbiology GA EN2JE UT WOS:000395835000065 ER PT J AU Norman, J Madurawe, RD Moore, CMV Khan, MA Khairuzzaman, A AF Norman, James Madurawe, Rapti D. Moore, Christine M. V. Khan, Mansoor A. Khairuzzaman, Akm TI A new chapter in pharmaceutical manufacturing: 3D-printed drug products SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE 3D printing technology; 3D printed drug products; On-demand manufacturing; Personalization ID ORAL DOSAGE FORMS; DEPOSITION MODELING FDM; 3D PRINTED BIOCERAMICS; POORLY SOLUBLE DRUGS; DELIVERY SYSTEMS; 3-DIMENSIONAL PRINTING(TM); CHEMICAL-SYNTHESIS; RELEASE PROFILES; MEDICAL DEVICES; STEM-CELLS AB FDA recently approved a 3D-printed drug product in August 2015, which is indicative of a new chapter for pharmaceutical manufacturing. This review article summarizes progress with 3D printed drug products and discusses process development for solid oral dosage forms. 3D printing is a layer-by-layer process capable of producing 3D drug products from digital designs. Traditional pharmaceutical processes, such as tablet compression, have been used for decades with established regulatory pathways. These processes are well understood, but antiquated in terms of process capability and manufacturing flexibility. 3D printing, as a platform technology, has competitive advantages for complex products, personalized products, and products made on-demand. These advantages create opportunities for improving the safety, efficacy, and accessibility of medicines. Although 3D printing differs from traditional manufacturing processes for solid oral dosage forms, risk-based process development is feasible. This review highlights how product and process understanding can facilitate the development of a control strategy for different 3D printing methods. Overall, the authors believe that the recent approval of a 3D printed drug product will stimulate continual innovation in pharmaceutical manufacturing technology. FDA encourages the development of advanced manufacturing technologies, including 3D-printing, using science- and risk-based approaches. Published by Elsevier B.V. C1 [Norman, James; Madurawe, Rapti D.; Khairuzzaman, Akm] US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Moore, Christine M. V.] Merck Res Labs, 770 Sumneytown Pike, West Point, PA 19486 USA. [Khan, Mansoor A.] Texas A&M Hlth Sci Ctr, Irma Lerma Rangel Coll Pharm, 159 Reynolds Med Bldg, College Stn, TX 77843 USA. RP Khairuzzaman, A (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM akm.khairuzzaman@fda.hhs.gov NR 133 TC 2 Z9 2 U1 10 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X EI 1872-8294 J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD JAN 1 PY 2017 VL 108 BP 39 EP 50 DI 10.1016/j.addr.2016.03.001 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EK8RG UT WOS:000394190700005 PM 27001902 ER PT J AU Spinks, CB Zidan, AS Khan, MA Habib, MJ Faustino, PJ AF Spinks, Crystal B. Zidan, Ahmed S. Khan, Mansoor A. Habib, Muhammad J. Faustino, Patrick J. TI Pharmaceutical characterization of novel tenofovir liposomal formulations for enhanced oral drug delivery: in vitro pharmaceutics and Caco-2 permeability investigations SO CLINICAL PHARMACOLOGY-ADVANCES AND APPLICATIONS LA English DT Article DE liposomes; tenofovir; targeting; chromatography; entrapment; permeation ID PERFORMANCE LIQUID-CHROMATOGRAPHY; HUMAN-IMMUNODEFICIENCY-VIRUS; DISOPROXIL FUMARATE; HUMAN PLASMA; HIV-INFECTION; DOUBLE-BLIND; PHARMACOKINETICS; QUANTIFICATION; EMTRICITABINE; ALAFENAMIDE AB Tenofovir, currently marketed as the prodrug tenofovir disoproxil fumarate, is used clinically to treat patients with HIV/AIDS. The oral bioavailability of tenofovir is relatively low, limiting its clinical effectiveness. Encapsulation of tenofovir within modified long-circulating liposomes would deliver this hydrophilic anti-HIV drug to the reticuloendothelial system for better therapeutic efficacy. The objectives of the current study were to prepare and pharmaceutically characterize model liposomal tenofovir formulations in an attempt to improve their bioavailability. The entrapment process was performed using film hydration method, and the formulations were characterized in terms of encapsulation efficiency and Caco-2 permeability. An efficient reverse-phase high-performance liquid chromatography method was developed and validated for tenofovir quantitation in both in vitro liposomal formulations and Caco-2 permeability samples. Separation was achieved isocratically on a Waters Symmetry C8 column using 10 mM Na2PO4/ acetonitrile pH 7.4 (95: 5 v/v). The flow rate was 1 mL/min with a 12 min elution time. Injection volume was 10 mu L with ultraviolet detection at 270 nm. The method was validated according to United States Pharmacopeial Convention category I requirements. The obtained result showed that tenofovir encapsulation within the prepared liposomes was dependent on the employed amount of the positive charge-imparting agent. The obtained results indicated that calibration curves were linear with r(2) > 0.9995 over the analytical range of 1-10 mu g/mL. Inter-and intraday accuracy and precision values ranged from 95% to 101% and 0.3% to 2.6%, respectively. The method was determined to be specific and robust. Regarding the potential of the prepared vectors to potentiate tenofovir permeability through the Caco-2 model, a 10-fold increase in tenofovir apparent permeability was observed compared to its oral solution. In conclusion, this novel and validated method was successfully applied to characterize both in vitro encapsulation efficiency and Caco-2 permeability transport for the pharmaceutical assessment of novel tenofovir formulations. C1 [Spinks, Crystal B.; Habib, Muhammad J.] Howard Univ, Sch Pharm, Dept Pharmaceut Sci, Washington, DC 20059 USA. [Zidan, Ahmed S.; Faustino, Patrick J.] Food & Drug Adm, Off Pharmaceut Qual, Div Prod Qual Res, Life Sci Bldg 64,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Zidan, Ahmed S.] Zagazig Univ, Fac Pharm, Zagazig, Egypt. [Khan, Mansoor A.] Texas A&M Hlth Sci Ctr, Irma Lerma Rangel Coll Pharm, College Stn, TX USA. RP Faustino, PJ (reprint author), Food & Drug Adm, Off Pharmaceut Qual, Div Prod Qual Res, Life Sci Bldg 64,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM patrick.faustino@fda.hhs.gov NR 38 TC 0 Z9 0 U1 1 U2 1 PU DOVE MEDICAL PRESS LTD PI ALBANY PA PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND SN 1179-1438 J9 CLIN PHARMACOL-ADV A JI CLIN. PHARMACOL.-ADV. APPL. PY 2017 VL 9 BP 29 EP 37 DI 10.2147/CPAA.S119875 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EL7NK UT WOS:000394807400001 PM 28260952 ER PT J AU Narang, AS Breckenridge, L Guo, H Wang, J Wolf, A Desai, D Varia, S Badawy, S AF Narang, Ajit S. Breckenridge, Lydia Guo, Hang Wang, Jennifer Wolf, Abraham (Avi) Desai, Divyakant Varia, Sailesh Badawy, Sherif TI Assessment of Tablet Surface Hardness by Laser Ablation and Its Correlation With the Erosion Tendency of Core Tablets SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE analysis; crushing strength; friability; hardness; LIBS; magnesium stearate; spectroscopy; surface; tablet; tartaric acid ID INDUCED BREAKDOWN SPECTROSCOPY; MAGNESIUM STEARATE; QUANTITATIVE-ANALYSIS; COMPRESSION AB Surface erosion of uncoated tablets results in processing problems such as dusting and defects during coating and is governed by the strength of particle bonding on tablet surface. In this study, the correlation between dusting tendency of tablets in a coating pan with friability and laser ablation surface hardness was assessed using tablets containing different concentrations of magnesium stearate and tartaric acid. Surface erosion propensity of different batches was evaluated by assessing their dusting tendency in the coating pan. In addition, all tablets were analyzed for crushing strength, friability, modified friability test using baffles in the friability apparatus, and weight loss after laser ablation. Tablets with similar crushing strength showed differences in their surface erosion and dusting tendency when rotated in a coating pan. These differences did not correlate well with tablet crushing strength or friability but did show reasonably good correlation with mass loss after laser ablation. These results suggest that tablet surface mass loss by laser ablation can be used as a minipiloting (small-scale) tool to assess tablet surface properties during early stages of drug product development to assess the risk of potential large-scale manufacturing issues. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved. C1 [Narang, Ajit S.; Guo, Hang; Wang, Jennifer; Wolf, Abraham (Avi); Desai, Divyakant; Varia, Sailesh; Badawy, Sherif] Bristol Myers Squibb Co, Drug Prod Sci & Technol, New Brunswick, NJ 08903 USA. [Breckenridge, Lydia] Bristol Myers Squibb Co, Analyt & Bioanalyt Dev, New Brunswick, NJ 08903 USA. [Guo, Hang] US FDA, Off Proc & Facil, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, 10,903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Wang, Jennifer] Teva Pharmaceut USA, 1090 Horsham Dr, N Wales, PA 19454 USA. [Wolf, Abraham (Avi)] Princeton Univ, Dept Chem & Biol Engn, 303 Hoyt Lab,William St, Princeton, NJ 08544 USA. [Narang, Ajit S.] Genentech Inc, One DNA Way, San Francisco, CA 94080 USA. RP Narang, AS (reprint author), Genentech Inc, One DNA Way, San Francisco, CA 94080 USA. EM Narang.Ajit@Gene.com 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 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD JAN PY 2017 VL 106 IS 1 BP 200 EP 207 DI 10.1016/j.xphs.2016.08.008 PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA EK4TU UT WOS:000393920500022 PM 27686683 ER PT J AU Trasi, NS Purohit, HS Wen, H Sun, DD Taylor, LS AF Trasi, Niraj S. Purohit, Hitesh S. Wen, Hong Sun, Dajun D. Taylor, Lynne S. TI Non-Sink Dissolution Behavior and Solubility Limit of Commercial Tacrolimus Amorphous Formulations SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE amorphous; solubility; dissolution; tacrolimus; solid dispersion ID IN-VIVO PERFORMANCE; SOLID DISPERSIONS; DRUG SOLUBILITY; MEMBRANE-TRANSPORT; PHASE-BEHAVIOR; P-GLYCOPROTEIN; SUPERSATURATION; WATER; RATS; SALT AB An increasing number of drugs with low aqueous solubility are being formulated and marketed as amorphous solid dispersions because the amorphous form can generate a higher solubility compared to the crystalline solid. The amorphous solubility of a drug can be determined experimentally using various techniques. Most studies in this area investigate the drug in its pure form and do not evaluate any effects from other formulation ingredients. In this study, we use 6 marketed amorphous oral drug products, capsules containing 5 mg of tacrolimus, and various excipients, consisting of 1 innovator product and 5 generics. The amorphous solubility of tacrolimus was evaluated using different techniques and was compared to the crystalline solubility of the drug. Dissolution of the different products was conducted under non-sink conditions to compare the maximum achieved concentration with the amorphous solubility. Diffusion studies were performed to elucidate the maximum flux across a membrane and to evaluate whether there was any difference in the thermodynamic activity of the drug released from the formulation and the pure drug. The amorphous solubility of tacrolimus was found to be a factor of 35 higher than the crystalline solubility. The maximum concentration obtained after dissolution of the capsule contents in non-sink conditions was found to match the experimentally determined amorphous solubility of the pure drug. Furthermore, the membrane flux of tacrolimus following dissolution of the various formulations was found to be similar and maximized. This study demonstrates a link between key physicochemical properties (amorphous solubility) and in vitro formulation performance. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved. C1 [Trasi, Niraj S.; Purohit, Hitesh S.; Taylor, Lynne S.] Purdue Univ, Coll Pharm, Dept Ind & Phys Pharm, W Lafayette, IN 47907 USA. [Wen, Hong; Sun, Dajun D.] US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Taylor, LS (reprint author), Purdue Univ, Coll Pharm, Dept Ind & Phys Pharm, W Lafayette, IN 47907 USA. EM lstaylor@purdue.edu FU U.S. Food and Drug Administration [1U01FD005259-01] FX The authors acknowledge the U.S. Food and Drug Administration for financial support under grant award 1U01FD005259-01. NR 42 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 JAN PY 2017 VL 106 IS 1 BP 264 EP 272 DI 10.1016/j.xphs.2016.09.016 PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA EK4TU UT WOS:000393920500029 PM 27816263 ER PT J AU Lum, F Holladay, JT Glasser, A MacRae, S Masket, S Stark, W Rorer, E Tarver, ME Calogero, D Hilmantel, G Nguyen, T Eydelman, M AF Lum, Flora Holladay, Jack T. Glasser, Adrian MacRae, Scott Masket, Samuel Stark, Walter Rorer, Eva Tarver, Michelle E. Calogero, Don Hilmantel, Gene Nguyen, Tieuvi Eydelman, Malvina TI Special Report: The American Academy of Ophthalmology Task Force for Developing Novel End Points for Premium Intraocular Lenses Introduction SO OPHTHALMOLOGY LA English DT Editorial Material C1 [Lum, Flora] Amer Acad Ophthalmol, San Francisco, CA USA. [Holladay, Jack T.] Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA. [MacRae, Scott] Univ Rochester, Flaum Eye Inst, Rochester, NY USA. [Masket, Samuel] Univ Calif Los Angeles, Jules Stein Eye Inst, David Geffen Sch Med, Adv Vis Care, Los Angeles, CA 90024 USA. [Stark, Walter] Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. [Rorer, Eva; Tarver, Michelle E.; Calogero, Don; Hilmantel, Gene; Nguyen, Tieuvi; Eydelman, Malvina] Ctr Devices & Radiol Hlth, US FDA, Silver Spring, MD USA. RP Lum, F (reprint author), Amer Acad Ophthalmol, Div Qual & Data Sci, 655 Beach St, San Francisco, CA 94109 USA. EM flum@aao.org NR 1 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 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JAN PY 2017 VL 124 IS 1 BP 133 EP 134 PG 2 WC Ophthalmology SC Ophthalmology GA EK4KZ UT WOS:000393896900032 PM 27743646 ER PT J AU Glasser, A Hilmantel, G Calogero, D MacRae, S Masket, S Stark, W Holladay, JT Rorer, E Tarver, ME Nguyen, T Eydelman, ME AF Glasser, Adrian Hilmantel, Gene Calogero, Don MacRae, Scott Masket, Samuel Stark, Walter Holladay, Jack T. Rorer, Eva Tarver, Michelle E. Nguyen, Tieuvi Eydelman, Malvina E. TI Special Report: American Academy of Ophthalmology Task Force Recommendations for Test Methods to Assess Accommodation Produced by Intraocular Lenses SO OPHTHALMOLOGY LA English DT Editorial Material ID ULTRASOUND BIOMICROSCOPY; AUTOREFRACTOR; ABERROMETER C1 [Glasser, Adrian] Amer Acad Ophthalmol, San Francisco, CA USA. [Hilmantel, Gene] Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA. [MacRae, Scott] Univ Rochester, Flaum Eye Inst, Rochester, NY USA. [Masket, Samuel] UCLA, Jules Stein Eye Inst, David Geffen Sch Med, Adv Vision Care, Los Angeles, CA USA. [Stark, Walter] Johns Hopkins Univ, Wilmer Eye Inst, Ophthalmol, Baltimore, MD USA. [Rorer, Eva; Tarver, Michelle E.; Nguyen, Tieuvi; Eydelman, Malvina E.] Ctr Devices & Radiol Hlth, Food & Drug Adm, Silver Spring, MD USA. RP Glasser, A (reprint author), Care Of Flora Lum, Amer Acad Ophthalmol, Dept Qual Care & Knowledge Base Dev, 655 Beach St, San Francisco, CA 94109 USA. EM flum@aao.org NR 11 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 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JAN PY 2017 VL 124 IS 1 BP 134 EP 139 PG 7 WC Ophthalmology SC Ophthalmology GA EK4KZ UT WOS:000393896900033 PM 27743645 ER PT J AU MacRae, S Holladay, JT Glasser, A Calogero, D Hilmantel, G Masket, S Stark, W Tarver, ME Nguyen, T Eydelman, M AF MacRae, Scott Holladay, Jack T. Glasser, Adrian Calogero, Don Hilmantel, Gene Masket, Samuel Stark, Walter Tarver, Michelle E. Nguyen, Tieuvi Eydelman, Malvina TI Special Report: American Academy of Ophthalmology Task Force Consensus Statement for Extended Depth of Focus Intraocular Lenses SO OPHTHALMOLOGY LA English DT Editorial Material C1 [MacRae, Scott] Univ Rochester, Flaum Eye Inst, Rochester, NY USA. [Holladay, Jack T.] Baylor Coll Med, Dept Ophthalmol, Houston, TX USA. [Calogero, Don; Hilmantel, Gene; Tarver, Michelle E.; Nguyen, Tieuvi; Eydelman, Malvina] Ctr Devices & Radiol Hlth, Food & Drug Adm, Silver Spring, MD USA. [Masket, Samuel] UCLA, Jules Stein Eye Inst, David Geffen Sch Med, Adv Vision Care, Los Angeles, CA USA. [Stark, Walter] Johns Hopkins Univ, Wilmer Eye Inst, Ophthalmol, Baltimore, MD USA. RP MacRae, S (reprint author), Care Of Flora Lum, Amer Acad Ophthalmol, Div Qual & Data Sci, 655 Beach St, San Francisco, CA 94109 USA. EM flum@aao.org NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JAN PY 2017 VL 124 IS 1 BP 139 EP 141 PG 4 WC Ophthalmology SC Ophthalmology GA EK4KZ UT WOS:000393896900034 PM 27743644 ER PT J AU MacRae, S Holladay, JT Hilmantel, G Calogero, D Masket, S Stark, W Glasser, A Rorer, E Tarver, ME Nguyen, T Eydelman, M AF MacRae, Scott Holladay, Jack T. Hilmantel, Gene Calogero, Don Masket, Samuel Stark, Walter Glasser, Adrian Rorer, Eva Tarver, Michelle E. Nguyen, Tieuvi Eydelman, Malvina TI Special Report: American Academy of Ophthalmology Task Force Recommendations for Specular Microscopy for Phakic Intraocular Lenses SO OPHTHALMOLOGY LA English DT Editorial Material ID IMPLANTATION C1 [MacRae, Scott] Univ Rochester, Flaum Eye Inst, Rochester, NY USA. [Holladay, Jack T.] Baylor Coll Med, Dept Ophthalmol, Houston, TX USA. [Hilmantel, Gene; Calogero, Don; Rorer, Eva; Tarver, Michelle E.; Nguyen, Tieuvi; Eydelman, Malvina] Ctr Devices & Radiol Hlth, Food & Drug Adm, Silver Spring, MD USA. [Masket, Samuel] UCLA, David Geffen Sch Med, Jules Stein Eye Inst, Adv Vision Care, Los Angeles, CA USA. [Stark, Walter] Johns Hopkins Univ, Wilmer Eye Inst, Ophthalmol, Baltimore, MD USA. RP MacRae, S (reprint author), Care Of Flora Lum, Amer Acad Ophthalmol, Div Qual & Data Sci, 655 Beach St, San Francisco, CA 94109 USA. EM flum@aao.org NR 3 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 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JAN PY 2017 VL 124 IS 1 BP 141 EP 142 PG 3 WC Ophthalmology SC Ophthalmology GA EK4KZ UT WOS:000393896900035 PM 27726960 ER PT J AU Masket, S Rorer, E Stark, W Holladay, JT MacRae, S Tarver, ME Glasser, A Calogero, D Hilmantel, G Nguyen, T Eydelman, M AF Masket, Samuel Rorer, Eva Stark, Walter Holladay, Jack T. MacRae, Scott Tarver, Michelle E. Glasser, Adrian Calogero, Don Hilmantel, Gene Nguyen, Tieuvi Eydelman, Malvina TI Special Report: The American Academy of Ophthalmology Task Force Consensus Statement on Adverse Events with Intraocular Lenses SO OPHTHALMOLOGY LA English DT Editorial Material C1 [Masket, Samuel] UCLA, Jules Stein Eye Inst, David Geffen Sch Med, Adv Vis Care, Los Angeles, CA USA. [Rorer, Eva; Tarver, Michelle E.; Calogero, Don; Hilmantel, Gene; Nguyen, Tieuvi; Eydelman, Malvina] Ctr Devices & Radiol Hlth, Food & Drug Adm, Silver Spring, MD USA. [Stark, Walter] Johns Hopkins Univ, Wilmer Eye Inst, Ophthalmol, Baltimore, MD USA. [Holladay, Jack T.] Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA. [MacRae, Scott] Univ Rochester, Flaum Eye Inst, Rochester, NY USA. RP Masket, S (reprint author), Care Of Flora Lum, Amer Acad Ophthalmol, Div Qual & Data Sci, 655 Beach St, San Francisco, CA 94109 USA. EM flum@aao.org NR 3 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 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JAN PY 2017 VL 124 IS 1 BP 142 EP 144 PG 4 WC Ophthalmology SC Ophthalmology GA EK4KZ UT WOS:000393896900036 PM 27726961 ER PT J AU Holladay, JT Calogero, D Hilmantel, G Glasser, A MacRae, S Masket, S Stark, W Tarver, ME Nguyen, T Eydelman, M AF Holladay, Jack T. Calogero, Don Hilmantel, Gene Glasser, Adrian MacRae, Scott Masket, Samuel Stark, Walter Tarver, Michelle E. Nguyen, Tieuvi Eydelman, Malvina TI Special Report: American Academy of Ophthalmology Task Force Summary Statement for Measurement of Tilt, Decentration, and Chord Length SO OPHTHALMOLOGY LA English DT Editorial Material ID INTRAOCULAR-LENS DECENTRATION; POSTERIOR CORNEAL ASTIGMATISM; PURKINJE; SURGERY; EYES C1 [Holladay, Jack T.] Baylor Coll Med, Dept Ophthalmol, Houston, TX USA. [Calogero, Don; Hilmantel, Gene; Tarver, Michelle E.; Nguyen, Tieuvi; Eydelman, Malvina] Ctr Devices & Radiol Hlth, Food & Drug Adm, Silver Spring, MD USA. [MacRae, Scott] Univ Rochester, Flaum Eye Inst, Rochester, NY USA. [Masket, Samuel] UCLA, Jules Stein Eye Inst, David Geffen Sch Med, Adv Vision Care, Los Angeles, CA USA. [Stark, Walter] Johns Hopkins Univ, Wilmer Eye Inst, Ophthalmol, Baltimore, MD USA. RP Holladay, JT (reprint author), Care Of Flora Lum, Amer Acad Ophthalmol, Div Qual & Data Sci, 655 Beach St, San Francisco, CA 94109 USA. EM flum@aao.org NR 11 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 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JAN PY 2017 VL 124 IS 1 BP 144 EP 146 PG 4 WC Ophthalmology SC Ophthalmology GA EK4KZ UT WOS:000393896900037 PM 27742457 ER PT J AU Permutt, T Li, F AF Permutt, Thomas Li, Feng TI Trimmed means for symptom trials with dropouts SO PHARMACEUTICAL STATISTICS LA English DT Article DE missing data; trimmed mean; dropout; robust ID CLINICAL-TRIALS; LOCATION AB Dropouts from randomized trials, often for lack of efficacy or toxicity, have usually been handled as 'missing data'. We suggest that they are instead complete observations, just not numeric ones. We propose an exact test of the hypothesis of no drug effect, taking all randomized patients into account, based on a readily interpretable statistic. The method also copes with a drug that is toxic in some patients but beneficial to others, a difficult problem for standard methods. A robust conclusion of efficacy can be drawn with no assumptions other than randomization. Published 2016. This article is a U.S. Government work and is in the public domain in the USA C1 [Permutt, Thomas; Li, Feng] US FDA, Div Biometr 2, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Permutt, T (reprint author), US FDA, Div Biometr 2, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM thomas.permutt@fda.hhs.gov NR 18 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1539-1604 EI 1539-1612 J9 PHARM STAT JI Pharm. Stat. PD JAN-FEB PY 2017 VL 16 IS 1 BP 20 EP 28 DI 10.1002/pst.1768 PG 9 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA EK4BB UT WOS:000393871000004 PM 27523396 ER PT J AU Medeiros, NI Fares, RCG Franco, EP Sousa, GR Mattos, RT Chaves, AT Nunes, MDP Dutra, WO Correa-Oliveira, R Rocha, MOC Gomes, JAS AF Medeiros, Nayara I. Fares, Rafaelle C. G. Franco, Eliza P. Sousa, Giovane R. Mattos, Rafael T. Chaves, Ana T. Nunes, Maria do Carmo P. Dutra, Walderez O. Correa-Oliveira, Rodrigo Rocha, Manoel O. C. Gomes, Juliana A. S. TI Differential Expression of Matrix Metalloproteinases 2, 9 and Cytokines by Neutrophils and Monocytes in the Clinical Forms of Chagas Disease SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID TRYPANOSOMA-CRUZI INFECTION; HEART-DISEASE; TGF-BETA; VENTRICULAR-FUNCTION; ADAPTIVE IMMUNITY; TNF-ALPHA; MATRIX-METALLOPROTEINASE-9; INNATE; CARDIOMYOPATHY; INDETERMINATE AB Dilated cardiomyopathy, the most severe manifestation in chronic phase of Chagas disease, affects about 30% of patients and is characterized by myocardial dysfunction and interstitial fibrosis due to extracellular matrix (ECM) remodeling. ECM remodeling is regulated by proteolytic enzymes such as matrix metalloproteinases (MMPs) and cytokines produced by immune cells, including phagocytes. We evaluated by flow cytometry the expression of MMP-2, MMP-9, IL-1 beta, TNF-alpha, TGF-beta and IL-10 by neutrophils and monocytes from patients with indeterminate (IND) and cardiac (CARD) clinical forms of Chagas disease and non-infected individuals (NI), before and after in vitro stimulation with Trypanosoma cruzi antigens. Our results showed an important contribution of neutrophils for MMPs production, while monocytes seemed to be involved in cytokine production. The results showed that neutrophils and monocytes from IND and CARD patients had higher intracellular levels of MMP-2 and MMP-9 than NI individuals. On the other hand, T. cruzi derived-antigens promote a differential expression of MMP-2 and MMP-9 in patients with Chagas disease and may regulate MMPs expression in neutrophils and monocytes, mainly when a cardiac alteration is not present. Our data also showed that in the presence of T. cruzi derived-antigens the production of cytokines by neutrophils and monocytes, but mainly by monocytes, may be intensified. Correlation analysis demonstrated that MMP-2 had a positive correlation with IL-10 and a negative correlation with IL-1 beta, whereas MMP-9 showed a negative correlation with IL-10. We also observed that IND patients presented a greater percentage of high producer cells of regulatory molecules when compared to CARD patients, indicating a different pattern in the immune response. Our data suggest that MMPs and cytokines produced by neutrophils and monocytes are important contributors for cardiac remodeling and may be an interesting target for new biomarker research. C1 [Medeiros, Nayara I.; Fares, Rafaelle C. G.; Correa-Oliveira, Rodrigo] Fiocruz MS, Ctr Pesquisa Rene Rachou, Lab Imunol Celular & Mol, Belo Horizonte, MG, Brazil. [Medeiros, Nayara I.; Franco, Eliza P.; Mattos, Rafael T.; Dutra, Walderez O.; Gomes, Juliana A. S.] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Morfol, Lab Biol Interacoes Celulares, Belo Horizonte, MG, Brazil. [Sousa, Giovane R.; Chaves, Ana T.; Nunes, Maria do Carmo P.; Rocha, Manoel O. C.; Gomes, Juliana A. S.] Univ Fed Minas Gerais, Programas Posgrad Ciencias Saude Infectol & Med T, Fac Med, Belo Horizonte, MG, Brazil. [Dutra, Walderez O.; Correa-Oliveira, Rodrigo] Inst Nacl Ciencia & Tecnol Doencas Topicais INCT, Belo Horizonte, MG, Brazil. [Correa-Oliveira, Rodrigo] Univ Fed Ouro Preto, NUPEB, Ouro Preto, MG, Brazil. [Fares, Rafaelle C. G.] US FDA, Ctr Biol Evaluat & Res Silver Spring, Silver Spring, MD USA. RP Gomes, JAS (reprint author), Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Morfol, Lab Biol Interacoes Celulares, Belo Horizonte, MG, Brazil.; Gomes, JAS (reprint author), Univ Fed Minas Gerais, Programas Posgrad Ciencias Saude Infectol & Med T, Fac Med, Belo Horizonte, MG, Brazil. EM juliana@icb.ufmg.br FU Conselho Nacional do Desenvolvimento Cientifico e Tecnologico (CNPq) [474796/2012, 404151/2012-4]; Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) [02419-15]; Programa de Apoio a Pesquisa Estrategica em Saude/Fundacao Oswaldo Cruz (PAPES/FIOCRUZ) [407692/2012-6]; FAPEMIG; CNPq FX JASG received sources of support provided by Conselho Nacional do Desenvolvimento Cientifico e Tecnologico (CNPq - #474796/2012) and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG - #02419-15). ROC by Programa de Apoio a Pesquisa Estrategica em Saude/Fundacao Oswaldo Cruz (PAPES/FIOCRUZ - #407692/2012-6) and Conselho Nacional do Desenvolvimento Cientifico e Tecnologico (CNPq #404151/2012-4). NIM, RTM and EPF received financial support from FAPEMIG. MdCPN, WOD, RCO, MOCR and JASG received financial support from CNPq PQ Fellowship program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 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 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JAN PY 2017 VL 11 IS 1 AR e0005284 DI 10.1371/journal.pntd.0005284 PG 16 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA EK8CR UT WOS:000394152000054 PM 28118356 ER PT J AU Parra, GI Squires, RB Karangwa, CK Johnson, JA Lepore, CJ Sosnovtsev, SV Green, KY AF Parra, Gabriel I. Squires, R. Burke Karangwa, Consolee K. Johnson, Jordan A. Lepore, Cara J. Sosnovtsev, Stanislav V. Green, Kim Y. TI Static and Evolving Norovirus Genotypes: Implications for Epidemiology and Immunity SO PLOS PATHOGENS LA English DT Article ID INFECTIOUS NONBACTERIAL GASTROENTERITIS; NORWALK-LIKE VIRUSES; RNA VIRUSES; GII.4 NOROVIRUS; SPORADIC GASTROENTERITIS; MOLECULAR EPIDEMIOLOGY; PHYLOGENETIC ANALYSIS; HERD-IMMUNITY; EVOLUTION; CHILDREN AB Noroviruses are major pathogens associated with acute gastroenteritis worldwide. Their RNA genomes are diverse, with two major genogroups (GI and GII) comprised of at least 28 genotypes associated with human disease. To elucidate mechanisms underlying norovirus diversity and evolution, we used a large-scale genomics approach to analyze human norovirus sequences. Comparison of over 2000 nearly full-length ORF2 sequences representing most of the known GI and GII genotypes infecting humans showed a limited number (<= 5) of distinct intra-genotypic variants within each genotype, with the exception of GII. 4. The non-GII. 4 genotypes were comprised of one or more intra-genotypic variants, with each variant containing strains that differed by only a few residues over several decades (remaining "static") and that have co-circulated with no clear epidemiologic pattern. In contrast, the GII. 4 genotype presented the largest number of variants (>10) that have evolved over time with a clear pattern of periodic variant replacement. To expand our understanding of these two patterns of diversification ("static" versus "evolving"), we analyzed using NGS the nearly full-length norovirus genome in healthy individuals infected with GII. 4, GII. 6 or GII. 17 viruses in different outbreak settings. The GII. 4 viruses accumulated mutations rapidly within and between hosts, while the GII. 6 and GII. 17 viruses remained relatively stable, consistent with their diversification patterns. Further analysis of genetic relationships and natural history patterns identified groupings of certain genotypes into larger related clusters designated here as "immunotypes". We propose that "immunotypes" and their evolutionary patterns influence the prevalence of a particular norovirus genotype in the human population. C1 [Parra, Gabriel I.; Karangwa, Consolee K.; Johnson, Jordan A.; Sosnovtsev, Stanislav V.; Green, Kim Y.] NIAID, Caliciviruses Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Squires, R. Burke] NIAID, Bioinformat & Computat Biosci Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Parra, Gabriel I.; Lepore, Cara J.] US FDA, Div Viral Prod, Silver Spring, MD 20993 USA. RP Parra, GI; Green, KY (reprint author), NIAID, Caliciviruses Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Parra, GI (reprint author), US FDA, Div Viral Prod, Silver Spring, MD 20993 USA. EM gabriel.parra@fda.hhs.gov; kgreen@niaid.nih.gov OI Green, Lisbeth Kim/0000-0002-8189-7352 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, DHHS FX This work was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, DHHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 81 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 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JAN PY 2017 VL 13 IS 1 AR e1006136 DI 10.1371/journal.ppat.1006136 PG 22 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EN1AV UT WOS:000395743500040 ER PT J AU Felton, RP Juliar, BE Olson, GR Delclos, KB AF Felton, R. P. Juliar, B. E. Olson, G. R. Delclos, K. B. TI A comment on the discussion and application of statistical methods in Mandrup etal. Low-dose effects of bisphenol A on mammary gland development in rats (Andrology 4: 673-683, 2016) SO ANDROLOGY LA English DT Letter C1 [Felton, R. P.; Juliar, B. E.] Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Olson, G. R.] Natl Ctr Toxicol Res, Toxicol Pathol Associates, Jefferson, AR 72079 USA. [Delclos, K. B.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Delclos, KB (reprint author), 3900 NCTR Rd,HFT 110, Jefferson, AR 72079 USA. EM barry.delclos@fda.hhs.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-2919 EI 2047-2927 J9 ANDROLOGY-US JI Andrology PD JAN PY 2017 VL 5 IS 1 BP 194 EP 195 DI 10.1111/andr.12298 PG 2 WC Andrology SC Endocrinology & Metabolism GA EK1FS UT WOS:000393671800027 PM 27871129 ER PT J AU Unger, EF Califf, RM AF Unger, Ellis F. Califf, Robert M. TI Regarding "Eteplirsen for the treatment of Duchenne muscular dystrophy" SO ANNALS OF NEUROLOGY LA English DT Letter C1 [Unger, Ellis F.; Califf, Robert M.] US FDA, Silver Spring, MD 20993 USA. RP Unger, EF (reprint author), US FDA, Silver Spring, MD 20993 USA. NR 1 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD JAN PY 2017 VL 81 IS 1 BP 162 EP 164 DI 10.1002/ana.24842 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EJ9QV UT WOS:000393562300023 PM 27997035 ER PT J AU Chuk, MK Mulugeta, Y Roth-Cline, M Mehrotra, N Reaman, GH AF Chuk, Meredith K. Mulugeta, Yeruk Roth-Cline, Michelle Mehrotra, Nitin Reaman, Gregory H. TI Enrolling Adolescents in Disease/Target-Appropriate Adult Oncology Clinical Trials of Investigational Agents SO CLINICAL CANCER RESEARCH LA English DT Article ID YOUNG-ADULTS; THERAPEUTIC PROTEINS; PEDIATRIC-PATIENTS; CANCER; PARTICIPATION; ENROLLMENT; PROGRESS; PHARMACOLOGY; WORKSHOP; CHILDREN AB The enrollment of adolescents with cancer in clinical trials is much lower than that of younger pediatric patients. For adolescents with "adult-type" cancers, lack of access to relevant trials is cited as one of the reasons for this discrepancy. Adolescents are generally not eligible for enrollment in adult oncology trials, and initial pediatric trials for many drugs are conducted years later, often after the drug is approved. As a result, accrual of adolescents to these trials may be slow due to off-label use, prospectively collected safety and efficacy data are lacking at the time of initial approval, and, most importantly, these adolescents have delayed access to effective therapies. To facilitate earlier access to investigational and approved drugs for adolescent patients with cancer, and because drug exposure is most often similar in adolescents and adults, we recommend the inclusion of adolescents (ages 12-17) in disease-and target-appropriate adult oncology trials. This approach requires careful monitoring for any differential safety signals, appropriate pharmacokinetic evaluations, and ensuring that ethical requirements are met. Inclusion of adolescents in adult oncology trials will require the cooperation of investigators, cooperative groups, industry, institutional review boards, and regulatory agencies to overcome real and perceived barriers. (C) 2016 AACR. C1 [Chuk, Meredith K.; Reaman, Gregory H.] US FDA, Off Hematol & Oncol Prod, Silver Spring, MD USA. [Mulugeta, Yeruk; Mehrotra, Nitin] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. [Roth-Cline, Michelle] US FDA, Off Pediat Therapeut, Silver Spring, MD USA. RP Chuk, MK (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Meredith.Chuk@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 27 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 JAN PY 2017 VL 23 IS 1 BP 9 EP 12 DI 10.1158/1078-0432.CCR-16-1367 PG 4 WC Oncology SC Oncology GA EK4DC UT WOS:000393876300003 PM 27780857 ER PT J AU Chatham-Stephens, K Taylor, E Chang, A Peterson, A Daniel, J Martin, C Deuster, P Noe, R Kieszak, S Schier, J Klontz, K Lewis, L AF Chatham-Stephens, Kevin Taylor, Ethel Chang, Arthur Peterson, Amy Daniel, Johnni Martin, Colleen Deuster, Patricia Noe, Rebecca Kieszak, Stephanie Schier, Josh Klontz, Karl Lewis, Lauren TI Hepatotoxicity associated with weight loss or sports dietary supplements, including OxyELITE Pro (TM) - United States, 2013 SO DRUG TESTING AND ANALYSIS LA English DT Article DE Supplement; hepatitis; OxyELITE Pro ID INDUCED LIVER-INJURY; US ADULT-POPULATION; OUTBREAK; FAILURE; HERB; PRO AB In September 2013, the Hawaii Department of Health (HDOH) was notified of seven adults who developed acute hepatitis after taking OxyELITE Pro, a weight loss and sports dietary supplement. CDC assisted HDOH with their investigation, then conducted case-finding outside of Hawaii with FDA and the Department of Defense (DoD). We defined cases as acute hepatitis of unknown etiology that occurred from April 1, 2013, through December 5, 2013, following exposure to a weight loss or muscle-building dietary supplement, such as OxyELITE Pro. We conducted case-finding through multiple sources, including data from poison centers (National Poison Data System [NPDS]) and FDA MedWatch. We identified 40 case-patients in 23 states and two military bases with acute hepatitis of unknown etiology and exposure to a weight loss or muscle building dietary supplement. Of 35 case-patients who reported their race, 15 (42.9%) reported white and 9 (25.7%) reported Asian. Commonly reported symptoms included jaundice, fatigue, and dark urine. Twenty-five (62.5%) case-patients reported taking OxyELITE Pro. Of these 25 patients, 17 of 22 (77.3%) with available data were hospitalized and 1 received a liver transplant. NPDS and FDA MedWatch each captured seven (17.5%) case-patients. Improving the ability to search surveillance systems like NPDS and FDA MedWatch for individual and grouped dietary supplements, as well as coordinating case-finding with DoD, may benefit ongoing surveillance efforts and future outbreak responses involving adverse health effects from dietary supplements. This investigation highlights opportunities and challenges in using multiple sources to identify cases of suspected supplement associated adverse events. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Chatham-Stephens, Kevin] 1600 Clifton Rd NE MS C-09, Atlanta, GA 30329 USA. [Chatham-Stephens, Kevin; Taylor, Ethel; Chang, Arthur; Daniel, Johnni; Martin, Colleen; Noe, Rebecca; Kieszak, Stephanie; Schier, Josh; Lewis, Lauren] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Div Environm Hazards & Hlth Effects, Atlanta, GA USA. [Peterson, Amy] Armed Forces Hlth Surveillance Ctr, Div Integrated Biosurveillance, Silver Spring, MD USA. [Deuster, Patricia] Uniformed Serv Univ Hlth Sci, Dept Mil & Emergency Med, Bethesda, MD USA. [Klontz, Karl] US FDA, Off Analyt & Outreach, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. RP Chatham-Stephens, K (reprint author), 1600 Clifton Rd NE MS C-09, Atlanta, GA 30329 USA. EM xdc4@cdc.gov NR 33 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1942-7603 EI 1942-7611 J9 DRUG TEST ANAL JI Drug Test. Anal. PD JAN PY 2017 VL 9 IS 1 BP 68 EP 74 DI 10.1002/dta.2036 PG 7 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA EK4BV UT WOS:000393873000006 PM 27367536 ER PT J AU Kurczewski, FE Edwards, GB Pitts, JP AF Kurczewski, Frank E. Edwards, Glavis B. Pitts, James P. TI Hosts, Nesting Behavior, and Ecology of Some North American Spider Wasps (Hymenoptera: Pompilidae), II SO SOUTHEASTERN NATURALIST LA English DT Article ID UNITED-STATES; AUPLOPUS-CARBONARIUS; PREY RECORDS; GEOLYCOSA; FLORIDA; ARANEAE AB This monograph is a continuation of a multiyear study of the genera and species of North American spider wasps (Pompilidae) and their spider host families, genera and species, nesting behavior, ecology, and natural communities. The study enlarges and enhances host preference, nesting behavior, and ecological information for 77 North American pompilid taxa. The first North American Pompilidae records for the families Tengellidae and Segestriidae, both from central coastal California, are reported herein. New host spider genera and species are listed for many of the pompilid species, including the first North American host record for Dipogon (Dipogon) g. graenicheri. The first detailed observations of male and female behavior in Arachnospila arcta are described. C1 [Kurczewski, Frank E.] POB 15251, Syracuse, NY 13215 USA. [Edwards, Glavis B.] FDACS, Div Plant Ind, Florida State Collect Arthropods, Curator Arachnida & Myriapoda, Gainesville, FL 32614 USA. [Pitts, James P.] Utah State Univ, Dept Biol, 5305 Old Main Hill, Logan, UT 84322 USA. RP Kurczewski, FE (reprint author), POB 15251, Syracuse, NY 13215 USA. EM fkurczewski@twcny.rr.com FU Utah Agricultural Experiment Station, Utah State University FX We thank Matthias Buck for the identification of some spider wasp species and Robb Bennett, David Bixler, Kelly Kissane, Joe Lapp, Robin Leech, Laura Paxson, Darrell Ubick, Rick West, and Chao Lun Wu for naming a number of spider genera and species. Keith E. Kurczewski, son of the first author, assisted with field collections and observations in central coastal California. David Keil identified the California coastal dune scrub plant community and other California plant species. We are indebted to the following individuals for their field observations, online descriptions, telephone and email information, and photographs used and not used in this monograph: Alice J. Abela, Yurika Alexander, Joshua P. Allen, Ralph Arveson, Peter Assmann, Seth J. Ausubel, John and Jane Balaban, Carl D. Barrentine, Kyron Basu, Andrew Bateman, David Brady, Val Bugh, Carmen C. Champagne, Jesse Christopherson, Linda F. Cooper, M.R. Corder, Patrick Cotinis, Rollin E. Coville, Shelly Cox, Stephen Creswell, D. Crispin, Peter Cristophono, Rob Curtis, Jeanne Dammarell, Dandybiologist, Even Dankowicz, Owen Davids (Hobo Joe A.K.A. Insect Lover), Tony DiTerlizzi, Drakken, Eaglebeach, Jeremy Early, Eric R. Eaton, Charles Eiseman, Noah Elhardt, S. J. Falk, Robert Ganz, G. K. Gerber, Sharon E. Ginsburg, J. Gluth, H. Go, Amy Goodman, Jay Greenberg, Jason Griffin, Joyce Gross, Patricia Hankey, George Val Hart, Ron Hemberger, Sam Houston, Wayne Hughes, Phil Huntley-Franck, Jonas Insinga, Eric Isley, Stoil Ivanov, S. R. Johnson, Gordon Johnston, KC Wildlife, Rich Kelly, Gary Kessler, Tom Klein, Josh D. Kouri, John Lampkin, Greg Lasley, Darrah J. G. Leffler (WanderingMogwai), Paul A. Lenhart, LilWeezyAnna, Miller and Stephanie MacDerment, Arthur Scott Macmillan, Martin-Hall, Mayfly 1963, M. D. McIvor, Stan McKechnie, Natalie McNear, Charles W. Melton, Colette Micallef, Eileen Miller, Philippe Moniotte, Graham Montgomery, Mark Moran, Racquel Morris, Arlon Motsch (Arlon), Patrick Murray, Tom Murray, Naturenut, Nick, Loren and Babs Padelford, Dale and Elva Paulson, Julia Pearson, Shelley Penner, Rob Ransom, Bryan E. Reynolds, Donald R. Riley, Shannon Schade, Paul A. Scharf, Marie L. Schmidt, Ken Schneider, Aaron Schusteff, T. Scrider, Adam Selzer, James Shelton, Charles Sheppard, Judith Lopez Sikora (Taogirl), Sipolandis, John M. Smith, Naomi Smith, Rick Snider, R.J. Speer, Mark Swanson, Adrian Thysse, Edward Trammel, Tim Turner, Royal M. Tyler Jr., John VanDyk, Tracy Palmer Villalobos, Richard K. Walton, Melvin Wei, Sally L. White, James Williamson, Cathy Wilson, Herb Wilson, and Bo Zaremba. John VanDyk, Publisher and Editor of BugGuide, was instrumental in serving as liaison between the first author and persons who submitted photographs and descriptions of spider wasp-spider encounters to BugGuide. Charles W. Melton, Rob Ransom, Bryan E. Reynolds, and Tiffany Yau enlarged photographs of specific wasp body parts that enabled the identifications of Auplopus carbonarius, A. mellipes variitarsatus, Anoplius lepidus atramentarius, and A. fulgidus. Joseph W. Stoll reconfigured the front and back cover photographs. Diane H. Kiernan ran a 2 sample t-test of head measurements for Auplopus carbonarius versus A. mellipes variitarsatus. Tsutomu Nakastugawa translated papers written in Japanese. Keith Goldfarb assisted with manuscript editing, formatting, photograph selection, and cover photograph composition. We thank Joseph S. Wilson (Utah State University) for serving as Guest Editor.; This research was supported by the Utah Agricultural Experiment Station, Utah State University, and approved as journal paper number 8948. NR 198 TC 0 Z9 0 U1 0 U2 0 PU HUMBOLDT FIELD RESEARCH INST PI STEUBEN PA PO BOX 9, STEUBEN, ME 04680-0009 USA SN 1528-7092 EI 1938-5412 J9 SOUTHEAST NAT JI Southeast. Nat. PD JAN PY 2017 VL 16 BP 1 EP 82 PG 82 WC Biodiversity Conservation; Ecology SC Biodiversity & Conservation; Environmental Sciences & Ecology GA EL4FY UT WOS:000394578300001 ER PT J AU Almario, EEN Borlak, J Suzuki, A Chen, MJ AF Almario, Eileen E. N. Borlak, Juergen Suzuki, Ayako Chen, Minjun TI Drug-Induced Liver Injury SO BIOMED RESEARCH INTERNATIONAL LA English DT Editorial Material C1 [Almario, Eileen E. N.] US FDA, Ctr Drug Evaluat & Res, Office Computat Sci, Silver Spring, MD USA. [Borlak, Juergen] Hannover Med Sch, Ctr Pharmacol & Toxicol, Hannover, Germany. [Suzuki, Ayako] Univ Arkansas Med Sci, Dept Med, Little Rock, AR 72205 USA. [Chen, Minjun] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. RP Chen, MJ (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. EM minjun.chen@fda.hhs.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU HINDAWI LTD PI LONDON PA ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, WIT 5HE, ENGLAND SN 2314-6133 EI 2314-6141 J9 BIOMED RES INT JI Biomed Res. Int. PY 2017 AR 2461694 DI 10.1155/2017/2461694 PG 2 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA EK6IW UT WOS:000394029300001 ER PT J AU Von Tungeln, LS Walker, NJ Olson, GR Maria, CBMD Felton, RP Thorn, BT Marques, MM Pogribny, IP Doerge, DR Beland, FA AF Von Tungeln, Linda S. Walker, Nigel J. Olson, Greg R. Mendoza, Maria C. B. Felton, Robert P. Thorn, Brett T. Matilde Marques, M. Pogribny, Igor P. Doerge, Daniel R. Beland, Frederick A. TI Low dose assessment of the carcinogenicity of furan in male F344/N Nctr rats in a 2-year gavage study SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Furan; Tumorigenicity; Cholangiocarcinoma; Cholangiofibrosis; Rats; Bioassay ID GAS CHROMATOGRAPHY/MASS SPECTROMETRY; BIG BLUE RATS; FISCHER-344 RATS; REACTIVE METABOLITE; CELL-PROLIFERATION; GENE-EXPRESSION; DRINKING-WATER; IN-VIVO; ACRYLAMIDE; EXPOSURE AB Furan is a volatile organic chemical that is a contaminant in many common foods. Furan is hepatocarcinogenic in mice and rats; however, the risk to humans from dietary exposure to furan cannot be estimated accurately because the lowest tested dose of furan in a 2-year bioassay in rats gave nearly a 100% incidence of cholangiocarcinoma. To provide bioassay data that can be used in preparing risk assessments, the carcinogenicity of furan was determined in male F344/N Nctr rats administered 0, 0.02, 0.044, 0.092, 0.2, 0.44, 0.92, and 2 mg furan/kg body weight (BW) by gavage 5 days/week for 2 years. Exposure to furan was associated with the development of malignant mesothelioma on membranes surrounding the epididymis and on the testicular tunics, with the increase being significant at 2 mg furan/kg BW. There was also a dose-related increase in the incidence of mononuclear cell leukemia, with the increase in incidence being significant at 0.092, 0.2, 0.92, and 2 mg furan/kg BW. Dose-related nonneoplastic liver lesions included cholangiofibrosis, mixed cell foci, basophilic foci, biliary tract hyperplasia, oval cell hyperplasia, regenerative hyperplasia, and cytoplasmic vacuolization. The most sensitive non-neoplastic lesion was cholangiofibrosis, the frequency of which increased significantly at 0.2 mg furan/kg BW. Published by Elsevier Ltd. C1 [Von Tungeln, Linda S.; Pogribny, Igor P.; Doerge, Daniel R.; Beland, Frederick A.] Natl Ctr Toxicol Res, Div Biochem Toxicol, HFT 110,3900 NCTR Rd, Jefferson, AR 72079 USA. [Walker, Nigel J.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Olson, Greg R.] Toxicol Pathol Associates, Jefferson, AR 72079 USA. [Mendoza, Maria C. B.; Felton, Robert P.; Thorn, Brett T.] Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Matilde Marques, M.] Univ Lisbon, Ctr Quim Estrutural, Inst Super Tecn, P-1049001 Lisbon, Portugal. RP Beland, FA (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, HFT 110,3900 NCTR Rd, Jefferson, AR 72079 USA. EM frederick.beland@fda.hhs.gov OI Marques, M. Matilde/0000-0002-7526-4962 FU Intramural Research Program of the NIH/National Institute of Environmental Health Sciences (NIEHS) [224-12-0003, AES12013]; Fundacao para a Ciencia e a Tecnologia, Portugal [RECI/QEQ-MED/0330/2012, UID/QUI/00100/2013] FX We thank F. Michelle McLellen and Matthew S. Bryant for conducting the chemical analyses and Andy Matson and James Carson for preparing dosing solutions and providing animal care. This study was supported by the Intramural Research Program of the NIH/National Institute of Environmental Health Sciences (NIEHS) via an Interagency Agreement between the NTP/NIEHS and the NCTR/FDA (NCTR/FDA IAG #224-12-0003; NIH/NTP IAG #AES12013). Financial support was also provided by Fundacao para a Ciencia e a Tecnologia, Portugal (Grants RECI/QEQ-MED/0330/2012 and UID/QUI/00100/2013). The opinions expressed in this paper do not necessarily represent those of the U.S. Food and Drug Administration. NR 63 TC 0 Z9 0 U1 4 U2 4 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 JAN PY 2017 VL 99 BP 170 EP 181 DI 10.1016/j.fct.2016.11.015 PG 12 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA EI8WV UT WOS:000392789800016 PM 27871980 ER PT J AU Hamasaki-Katagiri, N Lin, BC Simon, J Hunt, RC Schiller, T Russek-Cohen, E Komar, AA Bar, H Kimchi-Sarfaty, C AF Hamasaki-Katagiri, N. Lin, B. C. Simon, J. Hunt, R. C. Schiller, T. Russek-Cohen, E. Komar, A. A. Bar, H. Kimchi-Sarfaty, C. TI The importance of mRNA structure in determining the pathogenicity of synonymous and non-synonymous mutations in haemophilia SO HAEMOPHILIA LA English DT Article DE F8; haemophilia; MFE; mRNA thermodynamic stability; RNA prediction software; synonymous mutations ID SINGLE-NUCLEOTIDE POLYMORPHISM; SECONDARY STRUCTURE; WEB SERVER; PREDICTION; STABILITY; DISEASE AB Introduction: Mutational analysis is commonly used to support the diagnosis and management of haemophilia. This has allowed for the generation of large mutation databases which provide unparalleled insight into genotype-phenotype relationships. Haemophilia is associated with inversions, deletions, insertions, nonsense and missense mutations. Both synonymous and non-synonymous mutations influence the base pairing of messenger RNA (mRNA), which can alter mRNA structure, cellular half-life and ribosome processivity/elongation. However, the role of mRNA structure in determining the pathogenicity of point mutations in haemophilia has not been evaluated. Aim: To evaluate mRNA thermodynamic stability and associated RNA prediction software as a means to distinguish between neutral and disease-associated mutations in haemophilia. Methods: Five mRNA structure prediction software programs were used to assess the thermodynamic stability of mRNA fragments carrying neutral vs. disease-associated and synonymous vs. non-synonymous point mutations in F8, F9 and a third X-linked gene, DMD (dystrophin). Results: In F8 and DMD, disease-associated mutations tend to occur in more structurally stable mRNA regions, represented by lower MFE (minimum free energy) levels. In comparing multiple software packages for mRNA structure prediction, a 101-151 nucleotide fragment length appears to be a feasible range for structuring future studies. Conclusion: mRNA thermodynamic stability is one predictive characteristic, which when combined with other RNA and protein features, may offer significant insight when screening sequencing data for novel disease-associated mutations. Our results also suggest potential utility in evaluating the mRNA thermodynamic stability profile of a gene when determining the viability of interchanging codons for biological and therapeutic applications. C1 [Hamasaki-Katagiri, N.; Lin, B. C.; Simon, J.; Hunt, R. C.; Schiller, T.; Kimchi-Sarfaty, C.] US FDA, Lab Hemostasis, Div Hematol Res & Review, Silver Spring, MD USA. [Russek-Cohen, E.] US FDA, Div Biostat, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Komar, A. A.] Cleveland State Univ, Ctr Gene Regulat Hlth & Dis, Dept Biol Geol & Environm Sci, Cleveland, OH 44115 USA. [Bar, H.] Univ Connecticut, Dept Stat, Coll Liberal Arts & Sci, Storrs, CT 06268 USA. RP Bar, H (reprint author), Univ Connecticut, Dept Stat, Coll Liberal Arts & Sci, Storrs, CT 06268 USA.; Kimchi-Sarfaty, C (reprint author), US FDA, Div Hematol Res & Review, CBER, OBRR, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Haim.Bar@uconn.edu; Chava.Kimchi-Sarfaty@fda.hhs.gov FU Laboratory of Hemostasis, Center for Biologics Evaluation and Research; American Heart Association [13GRNTI7070025]; National Institutes of Health [1R15HL121779-01A1] FX This work was supported by funds from the Laboratory of Hemostasis, Center for Biologics Evaluation and Research (CK-S), the American Heart Association [13GRNTI7070025 to AAK] and the National Institutes of Health [1R15HL121779-01A1 to AAK]. Our contributions are an informal communication and represent our own best judgment. These comments do not bind or obligate FDA. NR 23 TC 0 Z9 0 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 JAN PY 2017 VL 23 IS 1 BP E8 EP E17 DI 10.1111/hae.13107 PG 10 WC Hematology SC Hematology GA EJ9PH UT WOS:000393557900029 PM 27933712 ER PT J AU Wagner, M Wagner, L Wagner, C Bell, SJ Nicholson, BW Strauss, DG Warren, S Pahlm, O Bacharova, L Lipton, J Eisenstein, E Kudaiberdieva, G Hakacova, N AF Wagner, Marilyn Wagner, Laura Wagner, Chris Bell, Samuel J. Nicholson, Brit W. Strauss, David G. Warren, Stafford Pahlm, Olle Bacharova, Ljuba Lipton, Jonathan Eisenstein, Eric Kudaiberdieva, Gulmira Hakacova, Nina TI In memory of Professor Galen S. Wagner MD, Ph.D. (1939-2016): our mentor, colleague and friend SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Biographical-Item C1 [Bell, Samuel J.] IRIS, Boston, MA 02116 USA. [Nicholson, Brit W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Strauss, David G.] US FDA, Washington, DC 20204 USA. [Warren, Stafford] George Washington Univ, Med Ctr, Washington, DC 20037 USA. [Pahlm, Olle; Hakacova, Nina] Lund Univ, Lund, Sweden. [Bacharova, Ljuba] Ctr Int Laser, Ilkovicova 3, Bratislava 84104, Slovakia. [Lipton, Jonathan] Royal Hobart Hosp, Hobart, Tas, Australia. [Lipton, Jonathan] Royal Melbourne Hosp, Melbourne, Vic, Australia. [Eisenstein, Eric] Duke Univ, Durham, NC USA. RP Bacharova, L (reprint author), Ctr Int Laser, Ilkovicova 3, Bratislava 84104, Slovakia. NR 1 TC 2 Z9 2 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD JAN-FEB PY 2017 VL 50 IS 1 BP 3 EP 4 DI 10.1016/j.jelectrocard.2016.11.001 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ9GL UT WOS:000393534500002 PM 27889056 ER PT J AU Meijs, L Zusterzeel, R Wellens, HJJ Gorgels, APM AF Meijs, Loek Zusterzeel, Robbert Wellens, Hein J. J. Gorgels, Anton P. M. TI The Maastricht-Duke bridge: An era of mentoring in clinical research - A model for mentoring in clinical research - A tribute to Dr. Galen Wagner SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE Research; Mentoring; International; Collaboration; Electrocardiography; University ID ELEVATION MYOCARDIAL-INFARCTION; VENTRICULAR-ARRHYTHMIA BURSTS; ST-SEGMENT ABNORMALITIES; BUNDLE-BRANCH BLOCK; QRS COMPLEX; RISK REGION; PRIMARY ANGIOPLASTY; FLOW RESTORATION; ISCHEMIA INDEX; ACUTE ANTERIOR AB Objective: With the passing of Dr. Galen Wagner, an exceptional collaboration between Maastricht University Medical Center, The Netherlands, and Duke Clinical Research Institute, USA, has come to an end. This article focuses on the background of what Galen coined the Maastricht Duke bridge (MD-bridge), its merits, limitations and development throughout the years, and his special role. Methods: Between 2004 and 2015, 23 Maastricht University medical students and post-graduate students were enrolled in the 4-month research elective, mentored by Galen and the Maastricht co-mentor. They were asked to complete a survey about their MD-bridge experience. Results: Sixteen out of the 23 students responded. None but 1 participant had prior research experience. Following their MD bridge-program most participants published 1 or more manuscripts and/or presented their research in an international setting. They felt they had full responsibility as a leader of their project with all participants developing meaningful skills useful in their current job. Fourteen out of 16 would recommend the MD-bridge experience to others. Participants considered the program of great value for their personal growth and independence, giving a feeling of achievement. In addition, for some participants it led to careers in foreign countries including medical practice and research, or obtaining PhDs. Conclusions: With Galen's impressive career of mentoring students, including the 23 MD-bridge participants, he has left behind an amazing concept of self-development in research and personal life. The successes of the MD-bridge prove that it is possible for students to be young investigators during or just after medical school with the potential to contribute to developing meaningful skills and noteworthy careers. Collaborations between international universities, such as the MD-bridge, are feasible and should be embraced by other institutions. Published by Elsevier Inc. C1 [Meijs, Loek] Catharina Hosp, Dept Cardiol, Eindhoven, Netherlands. [Meijs, Loek] Catharina Hosp, Dept Intens Care, Eindhoven, Netherlands. [Zusterzeel, Robbert] US FDA, Silver Spring, MD USA. [Zusterzeel, Robbert] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Wellens, Hein J. J.; Gorgels, Anton P. M.] Maastricht Univ, Med Ctr, Dept Cardiol, Maastricht, Netherlands. RP Zusterzeel, R (reprint author), 10903 New Hampshire Ave 64-2014, Silver Spring, MD 20993 USA. EM robbert.zusterzeel@fda.hhs.gov NR 24 TC 2 Z9 2 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD JAN-FEB PY 2017 VL 50 IS 1 BP 16 EP 20 DI 10.1016/j.jelectrocard.2016.10.009 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ9GL UT WOS:000393534500005 PM 27866647 ER PT J AU Pahlm, O Swenne, CA Man, S Fakhri, Y Atwater, BD Bacharova, L Bang, L Birnbaum, Y Carlsson, E Clemmensen, P Engblom, H Gettes, LS Grande, P Hakacova, N Holmvang, L Jurlander, B Loring, Z Pahlm, U Pettersson, J Ringborn, M Risum, N Sejersten-Ripa, M Sornmo, L Strauss, DG Zusterzeel, R Warren, SG AF Pahlm, Olle Swenne, Cees A. Man, Sumche Fakhri, Yama Atwater, Brett D. Bacharova, Ljuba Bang, Lia Birnbaum, Yochai Carlsson, Esben Clemmensen, Peter Engblom, Henrik Gettes, Leonard S. Grande, Peer Hakacova, Nina Holmvang, Lene Jurlander, Birgit Loring, Zak Pahlm, Ulrika Pettersson, Jonas Ringborn, Michael Risum, Niels Sejersten-Ripa, Maria Sornmo, Leif Strauss, David G. Zusterzeel, Robbert Warren, Stafford G. TI Dr. Galen Wagner (1939-2016) as an Academic Writer: An Overview of his Peer-reviewed Scientific Publications SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; BUNDLE-BRANCH BLOCK; ST-SEGMENT ELEVATION; QRS SCORING SYSTEM; AMERICAN-HEART-ASSOCIATION; OF-CARDIOLOGY-FOUNDATION; ACUTE-CORONARY-SYNDROMES; CARDIAC MAGNETIC-RESONANCE; FOR-COMPUTERIZED-ELECTROCARDIOLOGY; RIGHT-VENTRICULAR HYPERTROPHY C1 [Pahlm, Olle; Engblom, Henrik; Hakacova, Nina; Pahlm, Ulrika] Lund Univ, Dept Clin Sci, Lund, Sweden. [Swenne, Cees A.; Man, Sumche] Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands. [Fakhri, Yama; Holmvang, Lene; Risum, Niels] Rigshosp, Dept Cardiol, Copenhagen, Denmark. [Fakhri, Yama; Clemmensen, Peter; Grande, Peer] Univ Southern Denmark, Nykobing Hosp F, Dept Med, Odense, Denmark. [Atwater, Brett D.; Engblom, Henrik] Duke Univ, Cardiac Electrophysiol, Durham, NC USA. [Bacharova, Ljuba] Ctr Int Laser, Bratislava, Slovakia. [Birnbaum, Yochai] Baylor Coll Med, Dept Med, Cardiol Sect, Houston, TX 77030 USA. [Carlsson, Esben; Engblom, Henrik] Bispebjerg Hosp, Dept Cardiol, Copenhagen, Denmark. [Clemmensen, Peter] Univ Heart Ctr, Dept Gen & Intervent Cardiol, Hamburg, Germany. [Gettes, Leonard S.] Univ N Carolina, Dept Cardiol, Chapel Hill, NC USA. [Jurlander, Birgit] Nordsjaellands Hosp, Dept Cardiol, Hillerod, Denmark. [Loring, Zak] Duke Univ, Med Ctr, Durham, NC USA. [Pettersson, Jonas] Novo Nordisk AS, Med & Sci, Bagsvaerd, Denmark. [Ringborn, Michael] Blekingesjukhuset, Ctr Thorax, Karlskrona, Sweden. [Sejersten-Ripa, Maria] Herlev Univ Hosp, Dept Cardiol, Herlev, Denmark. [Sornmo, Leif] Lund Univ, Dept Biomed Engn, Lund, Sweden. [Strauss, David G.; Zusterzeel, Robbert] US FDA, Silver Spring, MD USA. [Warren, Stafford G.] Chesapeake Cardiac Care, Annapolis, MD USA. RP Pahlm, O (reprint author), SUS Lund, Klin Fysiol & Nukl Med, SE-22185 Lund, Sweden. EM olle.pahlm@med.lu.se OI Fakhri, Yama/0000-0002-3374-4781 NR 583 TC 2 Z9 2 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD JAN-FEB PY 2017 VL 50 IS 1 BP 47 EP 73 DI 10.1016/j.jelectrocard.2016.11.008 PG 27 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ9GL UT WOS:000393534500007 PM 28010929 ER PT J AU Xu, YQ Mahmood, I Zhong, LL Zhang, P Struble, EB AF Xu, Yanqun Mahmood, Iftekhar Zhong, Lilin Zhang, Pei Struble, Evi B. TI Passive Immunoprophylaxis for the Protection of the Mother and Her Baby: Insights from In Vivo Models of Antibody Transport SO JOURNAL OF IMMUNOLOGY RESEARCH LA English DT Article ID TO-CHILD TRANSMISSION; HEPATITIS-B-VIRUS; INTRAVENOUS IMMUNOGLOBULIN; HYPERIMMUNE GLOBULIN; HUMAN-PREGNANCY; CYTOMEGALOVIRUS; POPULATION; INFECTIONS; PREVENTION; SUBCLASSES AB Pregnant women are at high risk for infection by pathogens. Vertical transmission of infectious agents, such as Zika, hepatitis B, and cytomegalovirus during pregnancy, remains a public health problem, associated with dire outcomes for the neonate. Thus, a safe prophylactic and therapeutic approach for protecting the mother and the neonate from infections remains a high priority. Our work is focused on better understanding the safety and efficacy determinants of IgG antibody preparations when used during pregnancy to benefit the mother and her baby. Using pregnant guinea pigs, we demonstrated that biodistribution of administered IgG to the fetus increases with gestation and results in lower maternal and higher fetal antibody concentrations as pregnancy progresses. Data suggests that partition of antibody immunotherapy to the fetal compartment may contribute to a lower maternal exposure (as measured by the AUC) and a shorter mean residence time of the IgG therapeutic at the end of pregnancy compared to nonpregnant age-matched controls, irrespective of the administered dose. Our studies provide insights on the importance of selecting an efficacious dose in pregnancy that takes into account IgG biodistribution to the fetus. The use of appropriate animal models of placental transfer and infectious disease during pregnancy would facilitate pharmacokinetic modeling to derive a starting dose in clinical trials. C1 [Xu, Yanqun; Zhong, Lilin; Zhang, Pei; Struble, Evi B.] US FDA, Div Plasma Prot Therapeut, Off Tissues & Adv Therapies, CBER,Plasma Derivat Branch, Silver Spring, MD 20993 USA. [Mahmood, Iftekhar] US FDA, Div Clin Evaluat & Pharmacol Toxicol, Off Tissues & Adv Therapies, CBER, Silver Spring, MD USA. RP Struble, EB (reprint author), US FDA, Div Plasma Prot Therapeut, Off Tissues & Adv Therapies, CBER,Plasma Derivat Branch, Silver Spring, MD 20993 USA. EM evi.struble@fda.hhs.gov FU US FDA Office of Women's Health FX The authors acknowledge the US FDA Office of Women's Health for funding this work. The authors thank Yun Lu, mathematical statistician, for helping with statistical analysis. NR 30 TC 0 Z9 0 U1 3 U2 3 PU HINDAWI LTD PI LONDON PA ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, WIT 5HE, ENGLAND SN 2314-8861 EI 2314-7156 J9 J IMMUNOL RES JI J Immunol. Res. PY 2017 AR 7373196 DI 10.1155/2017/7373196 PG 8 WC Immunology SC Immunology GA EK5NY UT WOS:000393974300001 ER PT J AU Hockman, D Dong, M Zheng, H Kumar, S Huff, MD Grigorenko, E Beanan, M Duncan, R AF Hockman, Donna Dong, Ming Zheng, Hong Kumar, Sanjai Huff, Matthew D. Grigorenko, Elena Beanan, Maureen Duncan, Robert TI Comparison of multiplex PCR hybridization-based and singleplex real-time PCR-based assays for detection of low prevalence pathogens in spiked samples SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Article DE Spiked specimens; Blood-borne pathogens; Real-time PCR; Target Enriched Multiplex PCR ID POLYMERASE-CHAIN-REACTION; FRANCISELLA-TULARENSIS; BLOOD AB Molecular diagnostic devices are increasingly finding utility in clinical laboratories. Demonstration of the effectiveness of these devices is dependent upon comparing results from clinical samples tested with the new device to an alternative testing method. The preparation of mock clinical specimens will be necessary for the validation of molecular diagnostic devices when a sufficient number of clinical specimens is unobtainable. Examples include rare pathogens, some of which are pathogens posing a biological weapon threat. Here we describe standardized steps for developers to follow for the culture and quantification of three organisms used to spike human whole blood to create mock specimens. The three organisms chosen for this study were the Live Vaccine Strain (LVS) of Francisella tularensis, surrogate for a potential biothreat pathogen, Escherichia coil, a representative Gram-negative bacterium and Babesia microti (Franca) Reichenow Peabody strain, representing a protozoan parasite. Mock specimens were prepared with blood from both healthy donors and donors with nonspecific symptoms including fever, malaise, and flu-like symptoms. There was no significant difference in detection results between the two groups for any pathogen. Testing of the mock samples was compared on two platforms, Target Enriched Multiplex-PCR (TEM-PCRTm) and singleplex real-time PCR (RT-PCR). Results were reproducible on both platforms. The reproducibility demonstrated by obtaining the same results between two testing methods and between healthy and symptomatic mock specimens, indicates the standardized methods described for creating the mock specimens are valid and effective for evaluating diagnostic devices. Published by Elsevier B.V. C1 [Hockman, Donna; Huff, Matthew D.; Grigorenko, Elena] Diatherix Labs LLC, Huntsville, AL USA. [Dong, Ming; Zheng, Hong; Kumar, Sanjai; Duncan, Robert] US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Beanan, Maureen] NIAID, Off Biodef Res Resources & Translat Res, Div Microbiol & Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Duncan, R (reprint author), US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD USA. EM robert.duncan@fda.hhs.gov RI Hockman, Donna/D-7237-2017 OI Hockman, Donna/0000-0002-1790-0895 FU NIAID [AAI13005-002] FX The Francisella tularensis culture was initiated from a colony gratefully obtained from Dr. Karen Elkin's laboratory (FDA/CBER). We wish to acknowledge that this work was supported by NIAID through an Interagency Agreement AAI13005-002 awarded to CBER/FDA. Thanks to Karen Elkins, PhD and Rene Reese, PhD for reading and commenting on the manuscript. NR 20 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7012 EI 1872-8359 J9 J MICROBIOL METH JI J. Microbiol. Methods PD JAN PY 2017 VL 132 BP 76 EP 82 DI 10.1016/j.mimet.2016.11.005 PG 7 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA EJ2CI UT WOS:000393017100013 PM 27838540 ER PT J AU Wang, XQ Ilyushina, NA Lugovtsev, VY Bovin, NV Couzens, LK Gao, J Donnelly, RP Eichelberger, MC Wan, HQ AF Wang, Xiaoquan Ilyushina, Natalia A. Lugovtsev, Vladimir Y. Bovin, Nicolai V. Couzens, Laura K. Gao, Jin Donnelly, Raymond P. Eichelberger, Maryna C. Wan, Hongquan TI Amino Acids in Hemagglutinin Antigenic Site B Determine Antigenic and Receptor Binding Differences between A(H3N2)v and Ancestral Seasonal H3N2 Influenza Viruses SO JOURNAL OF VIROLOGY LA English DT Article DE A(H3N2)v; influenza virus; hemagglutinin; antigenic phenotype; amino acid ID A VIRUSES; UNITED-STATES; SWINE H3N2; AGRICULTURAL FAIR; EMERGING VARIANTS; EPITHELIAL-CELLS; HUMAN INFECTIONS; US SWINE; PIGS; EVOLUTION AB Influenza A H3N2 variant [A(H3N2)v] viruses, which have caused human infections in the United States in recent years, originated from human seasonal H3N2 viruses that were introduced into North American swine in the mid-1990s, but they are antigenically distinct from both the ancestral and current circulating H3N2 strains. A reference A(H3N2)v virus, A/Minnesota/11/2010 (MN/10), and a seasonal H3N2 strain, A/Beijing/32/1992 (BJ/92), were chosen to determine the molecular basis for the antigenic difference between A(H3N2)v and the ancestral viruses. Viruses containing wild-type and mutant MN/10 or BJ/92 hemagglutinins (HAs) were constructed and probed for reactivity with ferret antisera against MN/10 and BJ/92 in hemagglutination inhibition assays. Among the amino acids that differ between the MN/10 and BJ/92 HAs, those in antigenic site A had little impact on the antigenic phenotype. Within antigenic site B, mutations at residues 156, 158, 189, and 193 of MN/10 HA to those in BJ/92 switched the MN/10 antigenic phenotype to that of BJ/92. Mutations at residues 156, 157, 158, 189, and 193 of BJ/92 HA to amino acids present in MN/10 were necessary for BJ/92 to become antigenically similar to MN/10. The HA amino acid substitutions responsible for switching the antigenic phenotype also impacted HA binding to sialyl receptors that are usually present in the human respiratory tract. Our study demonstrates that antigenic site B residues play a critical role in determining both the unique antigenic phenotype and receptor specificity of A(H3N2) v viruses, a finding that may facilitate future surveillance and risk assessment of novel influenza viruses. IMPORTANCE Influenza A H3N2 variant [A(H3N2)v] viruses have caused hundreds of human infections in multiple states in the United States since 2009. Most cases have been children who had contact with swine in agricultural fairs. These viruses originated from human seasonal H3N2 viruses that were introduced into the U.S. swine population in the mid-1990s, but they are different from both these ancestral viruses and current circulating human seasonal H3N2 strains in terms of their antigenic characteristics as measured by hemagglutination inhibition (HI) assay. In this study, we identified amino acids in antigenic site B of the surface glycoprotein hemagglutinin (HA) that explain the antigenic difference between A(H3N2)v and the ancestral H3N2 strains. These amino acid mutations also alter binding to minor human-type glycans, suggesting that host adaptation may contribute to the selection of antigenically distinct H3N2 variants which pose a threat to public health. C1 [Wang, Xiaoquan; Lugovtsev, Vladimir Y.; Couzens, Laura K.; Gao, Jin; Eichelberger, Maryna C.; Wan, Hongquan] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Ilyushina, Natalia A.; Donnelly, Raymond P.] US FDA, Div Biotechnol Res & Review 2, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Bovin, Nicolai V.] Shemyakin Inst Bioorgan Chem, Moscow, Russia. RP Eichelberger, MC; Wan, HQ (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM maryna.eichelberger@fda.hhs.gov; hongquan.wan@fda.hhs.gov OI Donnelly, Raymond/0000-0002-0695-5276 FU intramural FDA funds; RAS Presidium Grant Molecular and Cell Biology FX This study was supported by intramural FDA funds and by RAS Presidium Grant Molecular and Cell Biology to N.V.B. NR 50 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 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2017 VL 91 IS 2 AR UNSP e01512 DI 10.1128/JVI.01512-16 PG 15 WC Virology SC Virology GA EJ4MX UT WOS:000393192500010 ER PT J AU Dahiya, N Sarachana, T Kulkarni, S Wood, WH Zhang, YQ Becker, KG Wang, BD Atreya, CD AF Dahiya, Neetu Sarachana, Tewarit Kulkarni, Sandhya Wood, William H., III Zhang, Yongqing Becker, Kevin G. Wang, Bi-Dar Atreya, Chintamani D. TI miR-570 interacts with mitochondrial ATPase subunit g (ATP5L) encoding mRNA in stored platelets SO PLATELETS LA English DT Article DE ATP5L; microarray; microRNA; platelets; storage lesion ID STORAGE; MICRORNAS; DYSFUNCTION; CORRELATE AB Loss of platelet quality during ex vivo storage is a major concern in the transfusion medicine field and it has been known that platelet mitochondrial dysfunction is associated with storage time. In the last decade, small noncoding RNAs also known as microRNAs (miRNAs) have been reported to regulate key cellular processes through their target sequence interactions with selected mRNAs. In this study, we focused on understanding the mechanisms of platelet mitochondrial dysfunction during storage through miRNA regulation of mRNAs. RNA was isolated from day 0, day 5, and day 9 of stored human leukocyte-depleted platelets and subjected to differential miRNA and mRNA profiling. The miRNA profiling identified several miRNAs at low levels including a set of 12 different miR-548 family members (miR-548a-3p, miR-548aa, miR-548x, miR-548ac, miR-548c-3p, miR-603, miR-548aj, miR-548ae, miR-548z, miR-548u, miR-548al, and miR-570-3p). The mRNA profiling identified, among many, the mitochondria] ATP synthase subunit g (ATP5L) mRNA at high levels during storage. Target Scan algorithm for potential targets of miR-570-3p also identified ATP5L as one of its targets. We further identified two target sites for miR-570-3p in the 3' untranslated region (3'UTR) of ATP5L mRNA. While ATP5L is a subunit of F(0)ATPase complex, its function is not established yet. Overexpression of miR-570-3p in platelets resulted in reduced levels of ATP5L mRNA and concomitant ATP loss. These experimental results provide first-time insights into the miRNA mRNA interactions underlying mitochondrial dysfunction in ex vivo stored platelets and warrants further investigation. C1 [Dahiya, Neetu; Sarachana, Tewarit; Kulkarni, Sandhya; Atreya, Chintamani D.] US FDA, Sect Cell Biol, Lab Cellular Hematol, Div Hematol,Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Sarachana, Tewarit] Chulalongkorn Univ, Fac Allied Hlth Sci, Dept Clin Chem, Bangkok, Thailand. [Wood, William H., III; Zhang, Yongqing; Becker, Kevin G.] NIA, Lab Genet, Baltimore, MD 21224 USA. [Wang, Bi-Dar] George Washington Sch Med & Hlth Sci, Dept Pharmacol & Physiol, Washington, DC USA. RP Atreya, CD (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 71,Room 4236, Silver Spring, MD 20993 USA. EM chintamani.atreya@fda.hhs.gov FU Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration; Center for Biologics Evaluation and Research FX Chintamani D. Atreya received funding for this study from the Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration. Neetu Dahiya and Tewarit Sarachana are recipients of a postdoctoral fellowship at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. The collaborative work performed by the coauthors Kevin G. Becker, William H. Wood, and Yongqing Zhang at the National Institute on Aging, NIH, was supported by their Intramural Research Program. NR 21 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0953-7104 EI 1369-1635 J9 PLATELETS JI Platelets PD JAN PY 2017 VL 28 IS 1 BP 74 EP 81 DI 10.1080/09537104.2016.1203405 PG 8 WC Cell Biology; Hematology SC Cell Biology; Hematology GA EJ5OZ UT WOS:000393268900013 PM 27561077 ER PT J AU Botana, LM Hess, P Munday, R Nathalie, A DeGrasse, SL Feeley, M Suzuki, T van den Berg, M Fattori, V Gamarro, EG Tritscher, A Nakagawa, R Karunasagar, I AF Botana, Luis M. Hess, Philip Munday, Rex Nathalie, Arnich DeGrasse, Stacey L. Feeley, Mark Suzuki, Toshiyuki van den Berg, Martin Fattori, Vittorio Gamarro, Esther Garrido Tritscher, Angelika Nakagawa, Rei Karunasagar, Iddya TI Derivation of toxicity equivalency factors for marine biotoxins associated with Bivalve Molluscs SO TRENDS IN FOOD SCIENCE & TECHNOLOGY LA English DT Review DE Marine toxins; Toxicity Equivalency Factors; FAO; WHO; Bivalve; Mollusc ID PARALYTIC SHELLFISH TOXINS; HUMAN NEUROBLASTOMA-CELLS; GATED SODIUM-CHANNEL; N-TERMINAL KINASE; OKADAIC ACID; DOMOIC ACID; POISONING TOXINS; CULTURED NEURONS; RAT-BRAIN; IN-VITRO AB Background: Seafood toxins pose an important risk to human health, and maximum levels were imposed by regulatory authorities throughout the world. Several toxin groups are known, each one with many analogues of the major toxin. Regulatory limits are set to ensure that commercially available seafood is not contaminated with unsafe levels. Scope and approach: The mouse bioassay was used to measure the toxicity in seafood extracts to determine if a sample exceeded regulatory limits. The advantage of this approach was to provide an estimation of the total toxicity in the sample. As instrumental methods of analysis advance and serve as replacements to the mouse bioassay, the challenge is translating individual toxin concentrations into toxicity to determine whether regulatory limits have been exceeded. Such analyses provide accurate quantitation of the toxin analogues, by they have widely dissimilar potencies. Thus, knowledge of the relative toxicities is required for risk assessment and determining overall toxicity. The ratios between the toxicity of the analogues and that of a reference compound within the same toxin group are termed "Toxicity Equivalency Factors" (TEFs). Key findings and conclusions: In this document, the requirements for determining TEFs of toxin analogues are described, and recommendations for research to further refine TEFs are identified. The proposed TEFs herein, when applied to toxin analogue concentrations determined using analytical methods, will provide a base to determine overall toxicity, thereby protecting human health. (C) 2016 Published by Elsevier Ltd. C1 [Botana, Luis M.] Univ Santiago, Fac Vet, Dept Farmacol, Lugo 27002, Spain. [Hess, Philip] IFREMER, Lab Phycotoxines DYNECO PHYC, Rue Ile Yeu,BP 21105, F-44311 Nantes 3, France. [Munday, Rex] AgResearch Ltd, Ruakura Res Ctr, Private Bag 3123, Hamilton, New Zealand. [Nathalie, Arnich] French Agcy Food Environm & Occupat Hlth & Safety, Risk Assessment Dept, Maisons Alfort, France. [DeGrasse, Stacey L.] US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr, College Pk, MD 20740 USA. [Feeley, Mark] Hlth Canada, Bur Chem Safety, Food Directorate, Ottawa, ON, Canada. [Suzuki, Toshiyuki] Fisheries Res Agcy, Natl Res Inst Fisheries Sci, Kanazawa Ku, 2-12-4 Fukuura, Yokohama, Kanagawa 2368648, Japan. [van den Berg, Martin] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Fattori, Vittorio] Food & Agr Org United Nations, Agr & Consumer Protect Dept, Rome, Italy. [Gamarro, Esther Garrido; Karunasagar, Iddya] Food & Agr Org United Nations, Dept Fisheries & Aquaculture, Rome, Italy. [Tritscher, Angelika; Nakagawa, Rei] WHO, Dept Food Safety & Zoonoses, Geneva, Switzerland. RP Botana, LM (reprint author), Univ Santiago, Fac Vet, Dept Farmacol, Lugo 27002, Spain. EM luis.botana@usc.es OI Botana, Luis M/0000-0003-2153-6608; Hess, Philipp/0000-0002-9047-1345 NR 128 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0924-2244 J9 TRENDS FOOD SCI TECH JI Trends Food Sci. Technol. PD JAN PY 2017 VL 59 BP 15 EP 24 DI 10.1016/j.tifs.2016.09.015 PG 10 WC Food Science & Technology SC Food Science & Technology GA EJ5NA UT WOS:000393263800002 ER PT J AU Li, Y Qin, TC Ingle, T Yan, J He, WW Yin, JJ Chen, T AF Li, Yan Qin, Taichun Ingle, Taylor Yan, Jian He, Weiwei Yin, Jun-Jie Chen, Tao TI Differential genotoxicity mechanisms of silver nanoparticles and silver ions SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Silver nanoparticles; Cytotoxicity; Genotoxicity; Silver ion; Oxidative stress; In vitro micronucleus assay ID HUMAN HEPATOMA-CELLS; IN-VITRO TOXICITY; OXIDATIVE STRESS; RESPIRATORY-CHAIN; ESCHERICHIA-COLI; DNA-DAMAGE; EXPRESSION; APOPTOSIS; NANOSILVER; ARGYRIA AB In spite of many reports on the toxicity of silver nanoparticles (AgNPs), the mechanisms underlying the toxicity are far from clear. A key question is whether the observed toxicity comes from the silver ions (Ag+) released from the AgNPs or from the nanoparticles themselves. In this study, we explored the genotoxicity and the genotoxicity mechanisms of Ag+ and AgNPs. Human TK6 cells were treated with 5 nM AgNPs or silver nitrate (AgNO3) to evaluate their genotoxicity and induction of oxidative stress. AgNPs and AgNO3 induced cytotoxicity and genotoxicity in a similar range of concentrations (1.00-1.75 A mu g/ml) when evaluated using the micronucleus assay, and both induced oxidative stress by measuring the gene expression and reactive oxygen species in the treated cells. Addition of N-acetylcysteine (NAC, an Ag+ chelator) to the treatments significantly decreased genotoxicity of Ag+, but not AgNPs, while addition of Trolox (a free radical scavenger) to the treatment efficiently decreased the genotoxicity of both agents. In addition, the Ag+ released from the highest concentration of AgNPs used for the treatment was measured. Only 0.5 % of the AgNPs were ionized in the culture medium and the released silver ions were neither cytotoxic nor genotoxic at this concentration. Further analysis using electron spin resonance demonstrated that AgNPs produced hydroxyl radicals directly, while AgNO3 did not. These results indicated that although both AgNPs and Ag+ can cause genotoxicity via oxidative stress, the mechanisms are different, and the nanoparticles, but not the released ions, mainly contribute to the genotoxicity of AgNPs. C1 [Li, Yan; Qin, Taichun; Yan, Jian; Chen, Tao] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Ingle, Taylor] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [He, Weiwei; Yin, Jun-Jie] US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [He, Weiwei] Kuching Univ, Key Lab Micronano Mat Energy Storage & Convers He, Inst Surface Micro & Nano Mat, Kaifeng 461000, Henan, Peoples R China. [Li, Yan] Covance Labs Inc, 671 South Meridian Rd, Greenfield, IN 46140 USA. [Qin, Taichun] Biomed Pharmaceut Mfg Corp, 4311 South Dr, Houston, TX 77053 USA. EM tao.chen@fda.hhs.gov FU US Department of Energy; US FDA; FDA Nanotechnology CORES Program FX We would like to thank Barbara Berman for editorial assistance. Y. L., T. I. and T. Q. were supported by the appointment to the Postgraduate Research Program at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science Education through an interagency agreement between the US Department of Energy and the US FDA. This research was partially supported by a regulatory science grant from the FDA Nanotechnology CORES Program. This article is not an official US Food and Drug Administration (FDA) guidance or policy statement. No official support or endorsement by the US FDA is intended or should be inferred. NR 58 TC 2 Z9 2 U1 6 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD JAN PY 2017 VL 91 IS 1 BP 509 EP 519 DI 10.1007/s00204-016-1730-y PG 11 WC Toxicology SC Toxicology GA EI2MF UT WOS:000392320700034 PM 27180073 ER PT J AU Karunathilaka, SR Farris, S Mossoba, MM Moore, JC Yakes, BJ AF Karunathilaka, Sanjeewa R. Farris, Samantha Mossoba, Magdi M. Moore, Jeffrey C. Yakes, Betsy Jean TI Non-targeted detection of milk powder adulteration using Raman spectroscopy and chemometrics: melamine case study SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE Skim milk powder (SMP); non-fat dry milk powder (NFDM); economic adulteration; Raman spectroscopy; PCA; soft independent modelling of class analogy (SIMCA); non-targeted detection; classification ID ECONOMICALLY MOTIVATED ADULTERATION; NEAR-INFRARED SPECTROSCOPY; INFANT FORMULA; VIBRATIONAL SPECTROSCOPY; LIQUID-CHROMATOGRAPHY; RAPID DETECTION; DAIRY-PRODUCTS; PROTEIN; SENSOR; FOODS AB Raman spectroscopy in combination with chemometrics was explored as a rapid, non-targeted screening method for the detection of milk powder (MP) adulteration using melamine as an example contaminant. Raman spectroscopy and an unsupervised pattern-recognition method, principal component analysis (PCA), allowed for the differentiation of authentic MPs from adulterated ones at concentrations >1.0% for dry-blended (DB) samples and >0.30% for wet-blended (WB) ones. Soft independent modelling of class analogy (SIMCA), a supervised pattern-recognition method, was also used to classify test samples as adulterated or authentic. Combined statistics at a 97% confidence level from the SIMCA models correctly classified adulteration of MP with melamine at concentrations 0.5% for DB samples and 0.30% for WB ones, while no false-positives from authentic MPs were found when the spectra in the 600-700cm(-1) range were pre-processed using standard normal variate (SNV) followed by a gap-segment derivatisation. The combined technique of Raman spectroscopy and chemometrics proved to be a useful tool for the rapid and cost-efficient non-targeted detection of adulteration in MP at per cent spiking levels. C1 [Karunathilaka, Sanjeewa R.; Farris, Samantha; Mossoba, Magdi M.; Yakes, Betsy Jean] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5001 Campus Dr, College Pk, MD 20740 USA. [Moore, Jeffrey C.] US Pharmacopeial Convent Inc, Rockville, MD USA. EM Betsy.Yakes@fda.hhs.gov FU Research Participation Program at the Center for Food Safety and Applied Nutrition FX S. R. K. acknowledges the support provided by an appointment to the Research Participation Program at the Center for Food Safety and Applied Nutrition, administered by the Oak Ridge Institute for Science and Education through an inter-agency agreement between the US Department of Energy and the US Food and Drug Administration (USFDA). NR 38 TC 0 Z9 0 U1 4 U2 4 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. PY 2017 VL 34 IS 2 BP 170 EP 182 DI 10.1080/19440049.2016.1260168 PG 13 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA EI6LE UT WOS:000392606300005 PM 27841972 ER PT J AU Akhtar, A AF Akhtar, Aysha TI Nonhuman Animals, Public Health, and Ethics: A First Step, But... SO JOURNAL OF APPLIED ANIMAL WELFARE SCIENCE LA English DT Article DE Public health; ethics; animal experimentation; animal agriculture; infectious disease AB In December 2015, the Johns Hopkins Bloomberg School of Public Health held the first-ever summit on the intersection between nonhuman animal ethics and human health. The conference covered a variety of issues where animal health intersects with human health, including the wildlife trade, animal agriculture, and animal experimentation. This article provides a brief overview and critique of the summit. C1 [Akhtar, Aysha] Oxford Ctr Anim Eth, Oxford, England. [Akhtar, Aysha] US FDA, Gaithersburg, MD USA. RP Akhtar, A (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM aa@ayshaakhtar.com NR 2 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1088-8705 EI 1532-7604 J9 J APPL ANIM WELF SCI JI J. Appl. Anim. Welf. Sci. PD JAN-MAR PY 2017 VL 20 IS 1 BP 106 EP 107 DI 10.1080/10888705.2016.1213633 PG 2 WC Veterinary Sciences SC Veterinary Sciences GA EJ1SS UT WOS:000392991100011 PM 27494236 ER PT J AU Tsong, Y Xia, Q Weng, YT AF Tsong, Yi Xia, Qi Weng, Yu-Ting TI Commentary on "Statistical Approaches to Assess Biosimilarity from Analytical Data" by Burdick et al ([1]) SO AAPS JOURNAL LA English DT Editorial Material DE biosimilarity; variance component model C1 [Tsong, Yi; Weng, Yu-Ting] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Xia, Qi] Temple Univ, 1801 N Broad St, Philadelphia, PA 19122 USA. RP Tsong, Y (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Yi.Tsong@fda.hhs.gov NR 5 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 JAN PY 2017 VL 19 IS 1 BP 15 EP 17 DI 10.1208/s12248-016-9987-x PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI1BR UT WOS:000392210900003 PM 27709453 ER PT J AU Li, M Zou, P Tyner, K Lee, S AF Li, Min Zou, Peng Tyner, Katherine Lee, Sau TI Physiologically Based Pharmacokinetic (PBPK) Modeling of Pharmaceutical Nanoparticles SO AAPS JOURNAL LA English DT Review DE model extrapolation; MPS uptake; nanoparticle; PBPK modeling ID PEGYLATED LIPOSOMAL DOXORUBICIN; MONONUCLEAR PHAGOCYTE SYSTEM; GOLD NANOPARTICLES; POLYACRYLAMIDE NANOPARTICLES; INTRAVENOUS-INJECTION; SILVER NANOPARTICLES; TISSUE DISTRIBUTION; PLGA NANOPARTICLES; BLOOD CLEARANCE; PLASMA-PROTEINS AB With the great interests in the discovery and development of drug products containing nanoparticles, there is a great demand of quantitative tools for assessing quality, safety, and efficacy of these products. Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches provide excellent tools for describing and predicting in vivo absorption, distribution, metabolism, and excretion (ADME) of nanoparticles administered through various routes. PBPK modeling of nanoparticles is an emerging field, and more than 20 PBPK models of nanoparticles used in pharmaceutical products have been published in the past decade. This review provides an overview of the ADME characteristics of nanoparticles and how these ADME processes are described in PBPK models. Recent advances in PBPK modeling of pharmaceutical nanoparticles are summarized. The major challenges in model development and validation and possible solutions are also discussed. C1 [Li, Min; Tyner, Katherine; Lee, Sau] US FDA, Off Pharmaceut Qual, Silver Spring, MD USA. [Zou, Peng] US FDA, Off Clin Pharmacol, Silver Spring, MD 20993 USA. RP Zou, P (reprint author), US FDA, Off Clin Pharmacol, Silver Spring, MD 20993 USA. EM peng.zou@fda.hhs.gov NR 68 TC 1 Z9 1 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 JAN PY 2017 VL 19 IS 1 BP 26 EP 42 DI 10.1208/s12248-016-0010-3 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI1BR UT WOS:000392210900005 PM 27834047 ER PT J AU Yuan, WM Kuai, R Dai, ZP Yuan, Y Zheng, N Jiang, WL Noble, C Hayes, M Szoka, FC Schwendeman, A AF Yuan, Wenmin Kuai, Rui Dai, Zhipeng Yuan, Yue Zheng, Nan Jiang, Wenlei Noble, Charles Hayes, Mark Szoka, Francis C. Schwendeman, Anna TI Development of a Flow-Through USP-4 Apparatus Drug Release Assay to Evaluate Doxorubicin Liposomes SO AAPS JOURNAL LA English DT Article DE Doxil (R); doxorubicin liposomes; release assay; USP-4 apparatus ID RISPERDAL(R) CONSTA(R); TESTING METHOD; VITRO; MICROSPHERES; SIMILARITY; DOXIL(R) AB DoxilA (R) is a complex parenteral doxorubicin (DOX) liposome formulation approved by the FDA. For generic doxorubicin liposomes, analyzing the release profile of DOX is important for quality control and comparability studies. However, there is no robust standard drug release assay available for doxorubicin liposomes. In this study, we describe a USP-4 apparatus assay capable of discriminating DOX liposomal formulations based on release profile. Establishment of the assay was hindered by limited DOX release from liposomes in physiological conditions at 37A degrees C. The addition of NH4HCO3 to the release media facilitated DOX release proportionally to the salt concentration added but caused precipitation of released drug in USP-4 apparatus. Precipitation of DOX was avoided by adding hydroxypropyl-cyclodextrin (HP-CD) to the release medium. We optimized conditions for DOX release by varying a number of parameters such as: concentration of HP-CD, testing temperature, and concentration of tested samples. The optimized release medium contained: 100 mM NH4HCO3, 75 mM 2-(N-morpholino) ethanesulfonic acid (MES) and 5% w/v HP-CD, 5% w/v sucrose, 0.02% w/v NaN3 (pH 6). The drug release assay was performed at 45A degrees C. The optimized release assay can discriminate between DOX liposomal formulations of different compositions, physicochemical properties, and prepared by different manufacturing methods. This indicates that the assay could be used to compare DOX release from generic DOX formulations to the innovator product DoxilA (R). C1 [Yuan, Wenmin; Kuai, Rui; Yuan, Yue; Schwendeman, Anna] Univ Michigan, Coll Pharm, NCRC, Dept Pharmaceut Sci, 2800 Plymouth Rd, Ann Arbor, MI 48105 USA. [Yuan, Wenmin; Kuai, Rui; Yuan, Yue; Schwendeman, Anna] Univ Michigan, Biointerfaces Inst, NCRC, 2800 Plymouth Rd, Ann Arbor, MI 48105 USA. [Dai, Zhipeng; Noble, Charles; Hayes, Mark; Szoka, Francis C.] ZoneOne Pharma Inc, UCSF Mission Bay,QB3 Garage,Byers Hall, San Francisco, CA 94158 USA. [Yuan, Yue] Shenyang Pharmaceut Univ, Sch Pharm, 103 Wenhua Rd, Shenyang 110016, Peoples R China. [Zheng, Nan; Jiang, Wenlei] US FDA, Off Gener Drugs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Szoka, Francis C.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, 513 Parnassus Ave,Box 0912, San Francisco, CA 94143 USA. RP Schwendeman, A (reprint author), Univ Michigan, Coll Pharm, NCRC, Dept Pharmaceut Sci, 2800 Plymouth Rd, Ann Arbor, MI 48105 USA.; Schwendeman, A (reprint author), Univ Michigan, Biointerfaces Inst, NCRC, 2800 Plymouth Rd, Ann Arbor, MI 48105 USA. EM annaschw@umich.edu OI Dai, Zhipeng/0000-0003-4716-3096 FU FDA [U01 FD004893]; National Natural Science for Youth Foundation of China [81202481]; Scientific Research Foundation for the Returned Overseas Chinese Scholars by Shenyang Pharmaceutical University [GGJJ2014102] FX This project was supported by FDA grant U01 FD004893. Yue Yuan was supported by grant 81202481 of National Natural Science for Youth Foundation of China and grant GGJJ2014102 of Scientific Research Foundation for the Returned Overseas Chinese Scholars by Shenyang Pharmaceutical University. NR 27 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 JAN PY 2017 VL 19 IS 1 BP 150 EP 160 DI 10.1208/s12248-016-9958-2 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI1BR UT WOS:000392210900015 PM 27485642 ER PT J AU Gao, ZM AF Gao, Zongming TI In Vitro Dissolution Testing of Gelatin Capsules with Applied Mechanical Compression-a Technical Note SO AAPS PHARMSCITECH LA English DT Article DE biorelevant condition; dissolution testing; gelatin capsule; in vitro; simulated stomach contractile force ID DYNAMIC GASTRIC MODEL; RELEASE DOSAGE FORMS; CROSS-LINKING; ABSORPTION RELATIONSHIPS; SOLUBLE DRUGS; SYSTEM; VIVO; DISINTEGRATION; BIOEQUIVALENCE; PERFORMANCE C1 [Gao, Zongming] US FDA, Div Pharmaceut Anal, Ctr Drug Evaluat & Res, St Louis, MO 63110 USA. RP Gao, ZM (reprint author), US FDA, Div Pharmaceut Anal, Ctr Drug Evaluat & Res, St Louis, MO 63110 USA. EM zongming.gao@fda.hhs.gov NR 26 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-9932 J9 AAPS PHARMSCITECH JI AAPS PharmSciTech PD JAN PY 2017 VL 18 IS 1 BP 231 EP 237 DI 10.1208/s12249-016-0506-2 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH9PV UT WOS:000392104200025 PM 26912355 ER PT J AU Cox, JM Chu, HD Chelliah, MV Debenham, JS Eagen, K Lan, P Lombardo, M London, C Plotkin, MA Shah, U Sun, ZX Vaccaro, HM Venkatraman, S Suzuki, T Wang, NX Ashley, ER Crespo, A Madeira, M Leung, DH Alleyne, C Ogawa, AM Souza, S Thomas-Fowlkes, B Di Salvo, J Weinglass, A Kirkland, M Pachanski, M Powles, MA Tozzo, E Akiyama, TE Ujjainwalla, F Tata, JR Sinz, CJ AF Cox, Jason M. Chu, Hong D. Chelliah, Mariappan V. Debenham, John S. Eagen, Keith Lan, Ping Lombardo, Matthew London, Clare Plotkin, Michael A. Shah, Unmesh Sun, Zhongxiang Vaccaro, Henry M. Venkatraman, Srikanth Suzuki, Takao Wang, Nengxue Ashley, Eric R. Crespo, Alejandro Madeira, Maria Leung, Dennis H. Alleyne, Candice Ogawa, Aimie M. Souza, Sarah Thomas-Fowlkes, Brande Di Salvo, Jerry Weinglass, Adam Kirkland, Melissa Pachanski, Michele Powles, Mary Ann Tozzo, Effie Akiyama, Taro E. Ujjainwalla, Feroze Tata, James R. Sinz, Christopher J. TI Design, Synthesis, and Evaluation of Novel and Selective G-protein Coupled Receptor 120 (GPR120) Spirocyclic Agonists SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE GPR120; FFAR4; insulin sensitization; type 2 diabetes; spirocyclic ID INSULIN; INHIBITION; THERAPIES; GLUCOSE; BINDING; MICE AB Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects. Herein we describe the design, synthesis, and evaluation of a novel spirocyclic GPR120 agonist series, which culminated in the discovery of potent and selective agonist 14. Furthermore, compound 14 was evaluated in vivo and demonstrated acute glucose lowering in an oral glucose tolerance test (oGTT), as well as improvements in homeostatic measurement assessment of insulin resistance (HOMA-IR; a surrogate marker for insulin sensitization) and an increase in glucose infusion rate (GIR) during a hyperinsulinemic euglycemic clamp in diet-induced obese (DIO) mice. C1 [Cox, Jason M.; Chu, Hong D.; Chelliah, Mariappan V.; Debenham, John S.; Eagen, Keith; Lan, Ping; Lombardo, Matthew; London, Clare; Plotkin, Michael A.; Shah, Unmesh; Sun, Zhongxiang; Vaccaro, Henry M.; Venkatraman, Srikanth; Ashley, Eric R.; Crespo, Alejandro; Madeira, Maria; Leung, Dennis H.; Alleyne, Candice; Ogawa, Aimie M.; Souza, Sarah; Thomas-Fowlkes, Brande; Di Salvo, Jerry; Weinglass, Adam; Kirkland, Melissa; Pachanski, Michele; Powles, Mary Ann; Tozzo, Effie; Akiyama, Taro E.; Ujjainwalla, Feroze; Tata, James R.; Sinz, Christopher J.] Merck & Co Inc, Kenilworth, NJ 07033 USA. [Cox, Jason M.; Chu, Hong D.; Chelliah, Mariappan V.; Debenham, John S.; Eagen, Keith; Lan, Ping; Lombardo, Matthew; London, Clare; Plotkin, Michael A.; Shah, Unmesh; Sun, Zhongxiang; Vaccaro, Henry M.; Venkatraman, Srikanth; Ashley, Eric R.; Crespo, Alejandro; Madeira, Maria; Leung, Dennis H.; Alleyne, Candice; Ogawa, Aimie M.; Souza, Sarah; Thomas-Fowlkes, Brande; Di Salvo, Jerry; Weinglass, Adam; Kirkland, Melissa; Pachanski, Michele; Powles, Mary Ann; Tozzo, Effie; Akiyama, Taro E.; Ujjainwalla, Feroze; Tata, James R.; Sinz, Christopher J.] Merck & Co Inc, Rahway, NJ 07065 USA. [Suzuki, Takao; Wang, Nengxue] Wuxi AppTec, Shanghai 200131, Peoples R China. [Chelliah, Mariappan V.] FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Eagen, Keith] Leidos, 356 Ninth Ave,Suite 106, Picatinny Arsenal, NJ 07806 USA. [London, Clare] Dotmatics, 800 W Cummings Pk,Suite 2950, Woburn, MA 01801 USA. [Plotkin, Michael A.] Merck & Co Inc, West Point, PA 19486 USA. [Shah, Unmesh] Jones Day, 250 Vesey St, New York, NY 10281 USA. [Leung, Dennis H.] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA. [Kirkland, Melissa] Charles River Labs, 334 South St, Shrewsbury, MA 01545 USA. [Tozzo, Effie] Mitobridge Inc, 1030 Massachusetts Ave,Suite 200, Cambridge, MA 02138 USA. RP Cox, JM (reprint author), Merck & Co Inc, Kenilworth, NJ 07033 USA. EM jason_cox@merck.com NR 25 TC 0 Z9 0 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD JAN PY 2017 VL 8 IS 1 BP 49 EP 54 DI 10.1021/acsmedchemlett.6b00360 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EH8UM UT WOS:000392047900008 PM 28105274 ER PT J AU Johnson, SA Brown, MR Lute, SC Brorson, KA AF Johnson, Sarah A. Brown, Matthew R. Lute, Scott C. Brorson, Kurt A. TI Adapting Viral Safety Assurance Strategies to Continuous Processing of Biological Products SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Review DE viral clearance; continuous processing; viral safety ID PROTEIN-A CHROMATOGRAPHY; TIME QUANTITATIVE PCR; MEDIATED ISOTHERMAL AMPLIFICATION; PARVOVIRUS RETENTIVE FILTERS; EXCHANGE MEMBRANE ADSORBERS; MOVING-BED CHROMATOGRAPHY; ULTRAVIOLET-C REACTOR; VIRUS REMOVAL; MONOCLONAL-ANTIBODIES; MINUTE VIRUS AB There has been a recent drive in commercial largescale production of biotechnology products to convert current batch mode processing to continuous processing manufacturing. There have been reports of model systems capable of adapting and linking upstream and downstream technologies into a continuous manufacturing pipeline. However, in many of these proposed continuous processing model systems, viral safety has not been comprehensively addressed. Viral safety and detection is a highly important and often expensive regulatory requirement for any new biological product. To ensure success in the adaption of continuous processing to large-scale production, there is a need to consider the development of approaches that allow for seamless incorporation of viral testing and clearance/inactivation methods. In this review, we outline potential strategies to apply current viral testing and clearance/inactivation technologies to continuous processing, as well as modifications of existing unit operations to ensure the successful integration of viral clearance into the continuous processing of biological products. (C) 2016 Wiley Periodicals, Inc. C1 [Johnson, Sarah A.; Brown, Matthew R.; Lute, Scott C.; Brorson, Kurt A.] US FDA, DBRR2, Off Biotechnol Prod, Off Pharmaceut Qual,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Johnson, SA (reprint author), US FDA, DBRR2, Off Biotechnol Prod, Off Pharmaceut Qual,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM sarah.johnson1@fda.hhs.gov FU FDA/CDER's Research Review Coordinating Committee FX Contract grant sponsor: FDA/CDER's Research Review Coordinating Committee. NR 99 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3592 EI 1097-0290 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD JAN PY 2017 VL 114 IS 1 BP 21 EP 32 DI 10.1002/bit.26060 PG 12 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA EI5MQ UT WOS:000392539400002 PM 27474890 ER PT J AU Fu, PP AF Fu, Peter P. TI Pyrrolizidine Alkaloids: Metabolic Activation Pathways Leading to Liver Tumor Initiation SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID DNA ADDUCT FORMATION; HERBAL DIETARY-SUPPLEMENTS; PROTEIN CROSS-LINKS; FORMATION IN-VIVO; BIG BLUE RATS; CARCINOGENIC ACTIVITY; REACTIVE METABOLITE; MASS-SPECTROMETRY; GLUTATHIONE CONJUGATE; HELIOTROPIUM-EUROPAEUM AB Pyrrolizidine alkaloids (PAs) and PA N-oxides are a class of phytochemical,carcinogens contained in over 6000 plant species spread around the world. It has been estimated that approximately half of the 660 PAs and PA N-oxides that have been: characterized are cytotoxic, genotoxic; and tuniorigenic. It was recently determined that a genotoxic mechanism of liver tumor initiation mediated by PA-derived DNA adducts is a common metabolic activation pathway of a number of PAs. We proposed this set of PA derived DNA adducts, could be a common biological biomarker of PA exposure and a potential biomarker of PA-induced liver tumor formation. WO have also found that several reactive secondary pyrrolic metabolites can dissociate and interconvert to other secondary pyrrolic metabolites, resulting in the formation of the same exogenous DNA adducts. This present perspective reports the current progress on these new findings and proposes future research needed for obtaining a greater understanding of the role of this activation pathway and validating the use of this Set Of PA-derived DNA, adducts as a biological biomarker of PA-induced liver tumor initiation. C1 [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 FU FDA fund FX Funding was provided by an internal FDA fund. NR 137 TC 0 Z9 0 U1 0 U2 0 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 JAN PY 2017 VL 30 IS 1 BP 81 EP 93 DI 10.1021/acs.chemrestox.6b00297 PG 13 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA EI1UF UT WOS:000392262900009 PM 28092947 ER PT J AU Bodenlenz, M Tiffner, KI Raml, R Augustin, T Dragatin, C Birngruber, T Schimek, D Schwagerle, G Pieber, TR Raney, SG Kanfer, I Sinner, F AF Bodenlenz, Manfred Tiffner, Katrin I. Raml, Reingard Augustin, Thomas Dragatin, Christian Birngruber, Thomas Schimek, Denise Schwagerle, Gerd Pieber, Thomas R. Raney, Sam G. Kanfer, Isadore Sinner, Frank TI Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence SO CLINICAL PHARMACOKINETICS LA English DT Article ID DERMATOLOGICAL DRUG PRODUCTS; MICRODIALYSIS; BIOAVAILABILITY; FORMULATIONS; SKIN; PERSPECTIVES; PENETRATION; HUMANS AB Background The availability of generic topical dermatological drug products is constrained by the limited methods established to assess topical bioequivalence (BE). A novel cutaneous pharmacokinetic approach, dermal open-flow microperfusion (dOFM), can continuously assess the rate and extent to which a topical drug becomes available in the dermis, to compare in vivo dermal bioavailability (BA) and support BE evaluations for topical products. Objective To evaluate whether dOFM is an accurate, sensitive, and reproducible in vivo method to characterize the intradermal BA of acyclovir from 5 % acyclovir creams, comparing a reference (R) product either to itself or to a different test (T) product. Methods In a single-center clinical study, R or T products were applied to six randomized treatment sites on the skin of 20 healthy human subjects. Two dOFM probes were inserted in each treatment site to monitor the intradermal acyclovir concentration for 36 h. Comparative BA (of R vs. R and T vs. R) was evaluated based on conventional BE criteria for pharmacokinetic endpoints (area under the curve and maximum plasma concentration) where the 90 % confidence interval of the geometric mean ratio between the T and R falls within 0.80-1.25. Results The positive control products (R vs. R) were accurately and reproducibly confirmed to be bioequivalent, while the negative control products (T vs. R) were sensitively discriminated not to be bioequivalent. Conclusions dOFM accurately, sensitively, and reproducibly characterized the dermal BA in a manner that can support BE evaluations for topical acyclovir 5 % creams in a study with n = 40 (20 subjects in this study). C1 [Bodenlenz, Manfred; Tiffner, Katrin I.; Raml, Reingard; Augustin, Thomas; Dragatin, Christian; Birngruber, Thomas; Schimek, Denise; Pieber, Thomas R.; Sinner, Frank] Joanneum Res Forsch Gesell mbH, HLTH Inst Biomed & Hlth Sci, Neue Stiftingtalstr 2, A-8010 Graz, Austria. [Schwagerle, Gerd; Pieber, Thomas R.; Sinner, Frank] Med Univ Graz, Dept Internal Med, Div Endocrinol & Diabetol, Graz, Austria. [Raney, Sam G.] US FDA, Div Therapeut Performance, Off Res & Stand, Off Gener Drugs, Silver Spring, MD USA. [Kanfer, Isadore] Rhodes Univ, Fac Pharm, Grahamstown, South Africa. [Kanfer, Isadore] Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON, Canada. RP Sinner, F (reprint author), Joanneum Res Forsch Gesell mbH, HLTH Inst Biomed & Hlth Sci, Neue Stiftingtalstr 2, A-8010 Graz, Austria.; Sinner, F (reprint author), Med Univ Graz, Dept Internal Med, Div Endocrinol & Diabetol, Graz, Austria. EM frank.sinner@joanneum.at OI Bodenlenz, Manfred/0000-0001-7246-5120 FU FDA [FD004946] FX Funding for this project was made possible, in part, by the FDA through research award FD004946. The views expressed in this publication do not reflect the official policies of the FDA, or the Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government. NR 27 TC 1 Z9 1 U1 2 U2 2 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0312-5963 EI 1179-1926 J9 CLIN PHARMACOKINET JI Clin. Pharmacokinet. PD JAN PY 2017 VL 56 IS 1 BP 91 EP 98 DI 10.1007/s40262-016-0442-z PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI0UH UT WOS:000392189700008 PM 27539717 ER PT J AU Bodenlenz, M Tiffner, KI Raml, R Augustin, T Dragatin, C Birngruber, T Schimek, D Schwagerle, G Pieber, TR Raney, SG Kanfer, I Sinner, F AF Bodenlenz, Manfred Tiffner, Katrin I. Raml, Reingard Augustin, Thomas Dragatin, Christian Birngruber, Thomas Schimek, Denise Schwagerle, Gerd Pieber, Thomas R. Raney, Sam G. Kanfer, Isadore Sinner, Frank TI Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence (vol 56, pg 91, 2017) SO CLINICAL PHARMACOKINETICS LA English DT Correction C1 [Bodenlenz, Manfred; Tiffner, Katrin I.; Raml, Reingard; Augustin, Thomas; Dragatin, Christian; Birngruber, Thomas; Schimek, Denise; Pieber, Thomas R.; Sinner, Frank] Joanneum Res Forsch Gesell mbH, HLTH Inst Biomed & Hlth Sci, Neue Stiftingtalstr 2, A-8010 Graz, Austria. [Schwagerle, Gerd; Pieber, Thomas R.; Sinner, Frank] Med Univ Graz, Dept Internal Med, Div Endocrinol & Diabetol, Graz, Austria. [Raney, Sam G.] US FDA, Div Therapeut Performance, Off Res & Stand, Off Gener Drugs, Silver Spring, MD USA. [Kanfer, Isadore] Rhodes Univ, Fac Pharm, Grahamstown, South Africa. [Kanfer, Isadore] Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON, Canada. RP Sinner, F (reprint author), Joanneum Res Forsch Gesell mbH, HLTH Inst Biomed & Hlth Sci, Neue Stiftingtalstr 2, A-8010 Graz, Austria.; Sinner, F (reprint author), Med Univ Graz, Dept Internal Med, Div Endocrinol & Diabetol, Graz, Austria. EM frank.sinner@joanneum.at NR 2 TC 0 Z9 0 U1 0 U2 0 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0312-5963 EI 1179-1926 J9 CLIN PHARMACOKINET JI Clin. Pharmacokinet. PD JAN PY 2017 VL 56 IS 1 BP 99 EP 99 DI 10.1007/s40262-016-0487-z PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI0UH UT WOS:000392189700009 PM 27873172 ER PT J AU Cowie, MR Blomster, JI Curtis, LH Duclaux, S Ford, I Fritz, F Goldman, S Janmohamed, S Kreuzer, J Leenay, M Michel, A Ong, S Pell, JP Southworth, MR Stough, WG Thoenes, M Zannad, F Zalewski, A AF Cowie, Martin R. Blomster, Juuso I. Curtis, Lesley H. Duclaux, Sylvie Ford, Ian Fritz, Fleur Goldman, Samantha Janmohamed, Salim Kreuzer, Joerg Leenay, Mark Michel, Alexander Ong, Seleen Pell, Jill P. Southworth, Mary Ross Stough, Wendy Gattis Thoenes, Martin Zannad, Faiez Zalewski, Andrew TI Electronic health records to facilitate clinical research SO CLINICAL RESEARCH IN CARDIOLOGY LA English DT Review DE Electronic health records; Clinical trials as topic; Pragmatic clinical trials as topic; Cardiovascular diseases ID QUALITY-OF-CARE; MYOCARDIAL-INFARCTION; DATA STANDARDS; MEANINGFUL USE; HEART-FAILURE; BIG-DATA; TRIAL; CARDIOLOGY; DISEASE; HOSPITALS AB Electronic health records (EHRs) provide opportunities to enhance patient care, embed performance measures in clinical practice, and facilitate clinical research. Concerns have been raised about the increasing recruitment challenges in trials, burdensome and obtrusive data collection, and uncertain generalizability of the results. Leveraging electronic health records to counterbalance these trends is an area of intense interest. The initial applications of electronic health records, as the primary data source is envisioned for observational studies, embedded pragmatic or post-marketing registry-based randomized studies, or comparative effectiveness studies. Advancing this approach to randomized clinical trials, electronic health records may potentially be used to assess study feasibility, to facilitate patient recruitment, and streamline data collection at baseline and follow-up. Ensuring data security and privacy, overcoming the challenges associated with linking diverse systems and maintaining infrastructure for repeat use of high quality data, are some of the challenges associated with using electronic health records in clinical research. Collaboration between academia, industry, regulatory bodies, policy makers, patients, and electronic health record vendors is critical for the greater use of electronic health records in clinical research. This manuscript identifies the key steps required to advance the role of electronic health records in cardiovascular clinical research. C1 [Cowie, Martin R.] Imperial Coll London, Royal Brompton Hosp, Natl Heart & Lung Inst, Sydney St, London SW3 6HP, England. [Blomster, Juuso I.] AstraZeneca R&D, Molndal, Sweden. [Blomster, Juuso I.] Univ Turku, Turku, Finland. [Curtis, Lesley H.] Duke Clin Res Inst, Durham, NC USA. [Duclaux, Sylvie] Servier, Paris, France. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Fritz, Fleur] Univ Munster, Munster, Germany. [Goldman, Samantha] Daiichi Sankyo, London, England. [Janmohamed, Salim] GlaxoSmithKline, Stockley Pk, England. [Kreuzer, Joerg] Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany. [Leenay, Mark] Optum Int, London, England. [Michel, Alexander] Bayer Pharma, Berlin, Germany. [Ong, Seleen] Pfizer Ltd, Tadworth, Surrey, England. [Pell, Jill P.] Univ Glasgow, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland. [Southworth, Mary Ross] US FDA, Silver Spring, MD USA. [Stough, Wendy Gattis] Campbell Univ, Coll Pharm & Hlth Sci, Campbell, NC USA. [Thoenes, Martin] Edwards LifeSci, Nyon, Switzerland. [Zannad, Faiez] Ctr Hosp Univ, Ctr Invest Clin 9501, INSERM, Nancy, France. [Zannad, Faiez] Ctr Hosp Univ, Unite 961, Nancy, France. [Zannad, Faiez] Univ Lorraine, Nancy Univ, Dept Cardiol, Nancy, France. [Zalewski, Andrew] GlaxoSmithKline, King Of Prussia, PA USA. RP Cowie, MR (reprint author), Imperial Coll London, Royal Brompton Hosp, Natl Heart & Lung Inst, Sydney St, London SW3 6HP, England. EM m.cowie@imperial.ac.uk FU National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital, London, UK FX This paper was generated from discussions during a cardiovascular round table (CRT) Workshop organized on 23-24 April 2015 by the European Society of Cardiology (ESC). The CRT is a strategic forum for high-level dialogues between academia, regulators, industry, and ESC leadership to identify and discuss key strategic issues for the future of cardiovascular health in Europe and other parts of the world. We acknowledge Colin Freer for his participation in the meeting. This article reflects the views of the authors and should not be construed to represent FDA's views or policies. The opinions expressed in this paper are those of the authors and cannot be interpreted as the opinion of any of the organizations that employ the authors. MRC's salary is supported by the National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital, London, UK. NR 53 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1861-0684 EI 1861-0692 J9 CLIN RES CARDIOL JI Clin. Res. Cardiol. PD JAN PY 2017 VL 106 IS 1 BP 1 EP 9 DI 10.1007/s00392-016-1025-6 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI3RR UT WOS:000392409500001 PM 27557678 ER PT J AU Inoue-Choi, M Liao, LM Reyes-Guzman, C Hartge, P Caporaso, N Freedman, ND AF Inoue-Choi, Maki Liao, Linda M. Reyes-Guzman, Carolyn Hartge, Patricia Caporaso, Neil Freedman, Neal D. TI Association of Long-term, Low-Intensity Smoking With All-Cause and Cause-Specific Mortality in the National Institutes of Health-AARP Diet and Health Study SO JAMA INTERNAL MEDICINE LA English DT Article ID CORONARY-HEART-DISEASE; CIGARETTE-SMOKING; LUNG-CANCER; INTERMITTENT SMOKING; NONDAILY SMOKERS; UNITED-STATES; LIGHT; RISK; WOMEN; TIME AB IMPORTANCE A growing proportion of US smokers now smoke fewer than 10 cigarettes per day (CPD), and that proportion will likely rise in the future. The health effects of smoking only a few CPD over one's lifetime are less understood than are the effects of heavier smoking, although many smokers believe that their level is modest. OBJECTIVE To evaluate the associations of long-term smoking of fewer than 1 or 1 to 10 CPD (low intensity) with all-cause and cause-specific mortality compared with never smoking cigarettes. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of 290 215 adults in the National Institutes of Health-AARP (formerly known as the American Association of Retired Persons) Diet and Health Study who were aged 59 to 82 years in calendar years 2004-2005 (baseline). Data were gathered with a questionnaire assessing lifetime cigarette smoking history. Hazard ratios (HRs) and 95% CIs were determined for all-cause mortality and cause-specific mortality through the end of 2011. Hazard ratios and 95% CIs were estimated using Cox proportional hazards regression models using age as the underlying time metric and adjusted for sex, race/ ethnicity, educational level, physical activity, and alcohol intake. Data analysis was conducted from December 15, 2015, to September 30, 2016. EXPOSURES Current and historical smoking intensity during 9 previous age periods (from <15 years to >= 70 years) over the lifetime assessed on the 2004-2005 questionnaire. MAIN OUTCOMES AND MEASURES All-cause and cause-specific mortality among current, former, and never smokers. RESULTS Of the 290 215 cohort participants who completed the 2004-2005 questionnaire, 168 140 were men (57.9%); the mean (SD) age was 71 (5.3) years (range, 59-82 years). Most people who smoked fewer than 1 or 1 to 10 CPD at baseline reported smoking substantially higher numbers of CPD earlier in their lives. Nevertheless, 159 (9.1%) and 1493 (22.5%) of these individuals reported consistently smoking fewer than 1 or 1 to 10 CPD in each age period that they smoked, respectively. Relative to never smokers, consistent smokers of fewer than 1 CPD (HR, 1.64; 95% CI, 1.07-2.51) and 1 to 10 CPD (HR, 1.87; 95% CI, 1.64-2.13) had a higher all-cause mortality risk. Associations were similar in women and men for all-cause mortality and were observed across a range of smoking-related causes of death, with an especially strong association with lung cancer (HR, 9.12; 95% CI, 2.92-28.47, and HR, 11.61; 95% CI, 8.25-16.35 for <1 and 1-10 CPD, respectively). Former smokers who had consistently smoked fewer than 1 or 1 to 10 CPD had progressively lower risks with younger age at cessation. For example, the HRs for consistent smokers of fewer than 1 and 1 to 10 CPD who quit at 50 years or older were 1.44 (95% CI, 1.12-1.85) and 1.42 (95% CI, 1.27-1.59), respectively. CONCLUSIONS AND RELEVANCE This study provides evidence that individuals who smoke fewer than 1 or 1 to 10 CPD over their lifetime have higher mortality risks than never smokers and would benefit from cessation. These results provide further evidence that there is no risk-free level of exposure to tobacco smoke. C1 [Inoue-Choi, Maki; Liao, Linda M.; Hartge, Patricia; Caporaso, Neil; Freedman, Neal D.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Reyes-Guzman, Carolyn] US FDA, Off Sci, Ctr Tobacco Prod, Silver Spring, MD USA. RP Inoue-Choi, M (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,6E346, Rockville, MD 20850 USA. EM maki.inoue-choi@nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology Genetics FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology & Genetics. NR 33 TC 2 Z9 2 U1 3 U2 3 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 JAN PY 2017 VL 177 IS 1 BP 87 EP 95 DI 10.1001/jamainternmed.2016.7511 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EI0WN UT WOS:000392196200021 PM 27918784 ER PT J AU Toufanian, M Peters, JR Uhl, K AF Toufanian, Maryll Peters, John R. Uhl, Kathleen TI Prioritization of Generic Drug Review SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Toufanian, Maryll; Peters, John R.; Uhl, Kathleen] US FDA, Ctr Drug Evaluat & Res, Off Gener Drugs, 10903 New Hampshire Ave,WO Bldg 75,Rm 1692, Silver Spring, MD 20993 USA. RP Uhl, K (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Gener Drugs, 10903 New Hampshire Ave,WO Bldg 75,Rm 1692, Silver Spring, MD 20993 USA. EM kathleen.uhl@fda.hhs.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JAN PY 2017 VL 177 IS 1 BP 140 EP 141 DI 10.1001/jamainternmed.2016.7811 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA EI0WN UT WOS:000392196200037 PM 28030732 ER PT J AU Ferber, G Zhou, MJ Dota, C Garnett, C Keirns, J Malik, M Stockbridge, N Darpo, B AF Ferber, Georg Zhou, Meijian Dota, Corina Garnett, Christine Keirns, James Malik, Marek Stockbridge, Norman Darpo, Borje TI Can Bias Evaluation Provide Protection Against False-Negative Results in QT Studies Without a Positive Control Using Exposure-Response Analysis? SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE QT; exposure response analysis; early phase; first-in-human; positive control; bias ID ELECTROCARDIOGRAPHIC DATA QUALITY; THOROUGH QT; ASSAY SENSITIVITY; CLINICAL-PHASE; ICH E14; QT/QTC; REPLACEMENT; PRECISION AB The revised ICH E14 document allows the use of exposure-response analysis to exclude a small QT effect of a drug. If plasma concentrations exceeding clinically relevant levels is achieved, a positive control is not required. In cases when this cannot be achieved, there may be a need for metrics to protect against false-negative results. The objectives of this study were to create bias in electrocardiogram laboratory QT-interval measurements and define a metric that can be used to detect bias severe enough to cause false-negative results using exposure-response analysis. Data from the IQ-CSRC study, which evaluated the QT effect of 5 QT-prolonging drugs, were used. Negative bias using 3 deterministic and 2 random methods was introduced into the reported QTc values and compared with fully automated data from the underlying electrocardiogram algorithm (COMPAS). The slope estimate of the Bland-Altman plot was used as a bias metric. With the deterministic bias methods, negative bias, measured between electrocardiogram laboratory values and COMPAS, had to be larger than approximately -20 milliseconds over a QTcF range of 100 milliseconds to cause failures to predict the QT effect of ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. With the random methods, the rate of false-negatives was 5% with bias severity < -10 milliseconds for all 5 drugs when plasma levels exceeded those of interest. Severe and therefore detectable bias has to be introduced into reported QTc values to cause false-negative predictions with exposure-response analysis. C1 [Ferber, Georg] Stat Georg Ferber GmbH, Riehen, Switzerland. [Zhou, Meijian; Darpo, Borje] iCardiac Technol Inc, Rochester, NY USA. [Dota, Corina] AstraZeneca R&D, Molndal, Sweden. [Garnett, Christine; Stockbridge, Norman] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Keirns, James] Astellas Pharma Global Dev Inc, Clin Pharmacol & Exploratory Dev, Northbrook, IL USA. [Malik, Marek] Univ London, St Pauls Cardiac Elect, London, England. [Malik, Marek] Imperial Coll, London, England. [Darpo, Borje] Karolinska Inst, Div Cardiovasc Med, Dept Clin Sci, Danderyds Hosp, Stockholm, Sweden. RP Darpo, B (reprint author), Karolinska Inst, Div Cardiovasc Med, Dept Clin Sci, S-18288 Stockholm, Sweden. EM borje.darpo@telia.com FU iCardiac Technologies, Rochester, New York FX The authors acknowledge the IQ-CSRC Steering Committee, which planned and conducted the original study.14 The original IQ-CSRC study was funded by iCardiac Technologies, Rochester, New York. NR 25 TC 1 Z9 1 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 JAN PY 2017 VL 57 IS 1 BP 85 EP 95 DI 10.1002/jcph.779 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH8IB UT WOS:000392014300008 PM 27271102 ER PT J AU Younis, IR Powell, JR Rostami-Hodjegan, A Corrigan, B Stockbridge, N Sinha, V Zhao, P Jadhav, P Flamion, B Cook, J AF Younis, Islam R. Powell, J. Robert Rostami-Hodjegan, Amin Corrigan, Brian Stockbridge, Norman Sinha, Vikram Zhao, Ping Jadhav, Pravin Flamion, Bruno Cook, Jack TI Utility of Model-Based Approaches for Informing Dosing Recommendations in Specific Populations: Report From the Public AAPS Workshop SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE specific population; modeling and simulation; dosing recommendations AB This report summarizes the discussions and recommendations of the workshop titled Specific Population Drug Dosing Recommendations: Shifting from Clinical Studies to Predict and Confirm, which preceded the 2015 American Association of Pharmaceutical Scientists annual meeting. Participants from the pharmaceutical industry, regulatory agencies (FDA and EMA), and academia discussed the current state, challenges, opportunities, and future direction of utilizing model-based approaches to inform dosing recommendations in specific populations. C1 [Younis, Islam R.; Zhao, Ping] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Rostami-Hodjegan, Amin] Univ Manchester, Syst Pharmacol, Manchester, Lancs, England. [Corrigan, Brian; Cook, Jack] Pfizer Inc, Clin Pharmacol, Groton, CT 06340 USA. [Stockbridge, Norman] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Sinha, Vikram] Merck & Co Inc, Quantitat Pharmacol & Pharmacometr, N Wales, PA USA. [Jadhav, Pravin] Otsuka Pharmaceut Co Ltd, Innovat Data Solut, Princeton, NJ USA. [Flamion, Bruno] Univ Namur, Dept Med, Namur, Belgium. [Flamion, Bruno] European Med Agcy, Sci Advice Working Party, London, England. RP Younis, IR (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM islam.younis@fda.hhs.gov NR 1 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JAN PY 2017 VL 57 IS 1 BP 105 EP 109 DI 10.1002/jcph.787 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH8IB UT WOS:000392014300010 PM 27365151 ER PT J AU Tempero, M AF Tempero, Margaret TI New Year's Resolutions SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Tempero, Margaret] UCSF Pancreas Ctr, San Francisco, CA 94143 USA. [Tempero, Margaret] NCI, Clin Oncol Study Sect, Bethesda, MD 20892 USA. [Tempero, Margaret] Canc Prevent & Res Inst Texas, Sci Steering Comm, Austin, TX 78701 USA. [Tempero, Margaret] Canc Prevent & Res Inst Texas, Clin & Translat Study Sect, Austin, TX 78701 USA. [Tempero, Margaret] US FDA, Oncol Drug Advisory Comm, Rockville, MD 20857 USA. [Tempero, Margaret] UNMC Eppley Canc Ctr, Omaha, NE USA. [Tempero, Margaret] UCSF, Div Med Oncol, San Francisco, CA 94143 USA. [Tempero, Margaret] UCSF Helen Diller Family Comprehens Canc Ctr, Res Programs, San Francisco, CA USA. RP Tempero, M (reprint author), UCSF Pancreas Ctr, San Francisco, CA 94143 USA.; Tempero, M (reprint author), Canc Prevent & Res Inst Texas, Sci Steering Comm, Austin, TX 78701 USA.; Tempero, M (reprint author), Canc Prevent & Res Inst Texas, Clin & Translat Study Sect, Austin, TX 78701 USA.; Tempero, M (reprint author), UCSF, Div Med Oncol, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD JAN PY 2017 VL 15 IS 1 BP 1 EP 1 PG 1 WC Oncology SC Oncology GA EH8TT UT WOS:000392045900001 PM 28040714 ER PT J AU Gipson, DS Kirkendall, ES Gumbs-Petty, B Quinn, T Steen, A Hicks, A McMahon, A Nicholas, S Zhao-Wong, A Taylor-Zapata, P Turner, M Herreshoff, E Jones, C Davis, JM Haber, M Hirschfeld, S AF Gipson, Debbie S. Kirkendall, Eric S. Gumbs-Petty, Brenda Quinn, Theresa Steen, A. Hicks, Amanda McMahon, Ann Nicholas, Savian Zhao-Wong, Anna Taylor-Zapata, Perdita Turner, Mark Herreshoff, Emily Jones, Charlotte Davis, Jonathan M. Haber, Margaret Hirschfeld, Steven TI Development of a Pediatric Adverse Events Terminology SO PEDIATRICS LA English DT Article ID ERRORS AB In 2009, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) established the Pediatric Terminology Harmonization Initiative to establish a core library of terms to facilitate the acquisition and sharing of knowledge between pediatric clinical research, practice, and safety reporting. A coalition of partners established a Pediatric Terminology Adverse Event Working Group in 2013 to develop a specific terminology relevant to international pediatric adverse event (AE) reporting. Pediatric specialists with backgrounds in clinical care, research, safety reporting, or informatics, supported by biomedical terminology experts from the National Cancer Institute's Enterprise Vocabulary Services participated. The multinational group developed a working definition of AEs and reviewed concepts (terms, synonyms, and definitions) from 16 pediatric clinical domains. The resulting AE terminology contains >1000 pediatric diseases, disorders, or clinical findings. The terms were tested for proof of concept use in 2 different settings: hospital readmissions and the NICU. The advantages of the AE terminology include ease of adoption due to integration with well-established and internationally accepted biomedical terminologies, a uniquely temporal focus on pediatric health and disease from conception through adolescence, and terms that could be used in both well-and underresourced environments. The AE terminology is available for use without restriction through the National Cancer Institute's Enterprise Vocabulary Services and is fully compatible with, and represented in, the Medical Dictionary for Regulatory Activities. The terminology is intended to mature with use, user feedback, and optimization. C1 [Gipson, Debbie S.; Herreshoff, Emily] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Kirkendall, Eric S.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Gumbs-Petty, Brenda; Quinn, Theresa; Steen, A.; Haber, Margaret] NCI, Enterprise Vocabulary Serv, Bethesda, MD 20892 USA. [Taylor-Zapata, Perdita] NICHHD, NIH, Bethesda, MD 20892 USA. [Hicks, Amanda] Univ Arkansas Med Sci, Div Biomed Informat, Little Rock, AR 72205 USA. [McMahon, Ann] US FDA, Off Pediat Therapeut, Bethesda, MD 20014 USA. [Nicholas, Savian; Zhao-Wong, Anna] Maintenance & Support Serv Org, Med Dictionary Regulatory Act, Mclean, VA USA. [Turner, Mark] Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England. [Jones, Charlotte] Nationwide Childrens Hosp, Neurol, Columbus, OH USA. [Davis, Jonathan M.] Tufts Univ, Tufts Med Ctr, Floating Hosp Children, Dept Pediat, Boston, MA 02111 USA. [Davis, Jonathan M.] Tufts Univ, Tufts Clin & Translat Sci Inst, Boston, MA 02111 USA. [Hirschfeld, Steven] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Quinn, T (reprint author), Enterprise Vocabulary Serv, 11300 Rockville Pike,Suite 1100, Rockville, MD 20852 USA. EM quinnt@mail.nih.gov FU National Children's Study [NC013003-001] FX This work was supported by National Children's Study interagency agreement NC013003-001. NR 14 TC 0 Z9 0 U1 2 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD JAN PY 2017 VL 139 IS 1 AR e20160985 DI 10.1542/peds.2016-0985 PG 7 WC Pediatrics SC Pediatrics GA EH9WI UT WOS:000392122000013 ER PT J AU Kerr, KW Wosinska, ME AF Kerr, Kirk W. Wosinska, Marta E. TI Patient Access in Restrictive Risk Management Programs: The Case of iPLEDGE SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article; Proceedings Paper CT Meeting of the Southeast-Health-Economics-Study-Group CY OCT, 2012 CL Fairfax, VA SP SE Hlth Econ Study Grp DE risk management; REMS; prescription drugs; FDA; access; isotretinoin ID CARE AB Background: The isotretinoin risk management program iPLEDGE places requirements on patients and providers to ensure that the benefits of isotretinoin therapy outweigh the risks. Such burdens have the possibility of limiting patient access through mechanisms such as lowered physician participation. Methods: In this study, we utilized prescription claims data to examine changes in patient and provider participation in isotretinoin therapy with iPLEDGE implementation. We examined the change in utilization among patients not targeted by iPLEDGE (male patients) to assess the program's impact on access. We also examined whether provider participation in isotretinoin therapy varies by specialty and isotretinoin prescribing history. Results: Patient access to isotretinoin decreased in the period immediately following iPLEDGE implementation, but recovered to pre-iPLEDGE levels in the succeeding months. In addition, therapy completion rates increased with iPLEDGE implementation, suggesting that patients less committed to isotretinoin therapy may be self-selecting out of therapy. Lastly, iPLEDGE resulted in decreased participation by low-volume, general practitioners, while high-volume, specialists' participation was largely unchanged. Conclusion: We found that participants responded to iPLEDGE's burdens in predictable ways. Insufficient anticipation of potential iPLEDGE rollout issues initially disrupted patient treatment and resulted in far fewer patients starting therapy. Over a longer term, isotretinoin utilization and therapy completion increased and isotretinoin prescribing shifted toward high-volume, specialist providers. We argue that these changes are predictable based on the burdens iPLEDGE imposes on patients and prescribers and may not be inconsistent with the goals of the risk management program. C1 [Kerr, Kirk W.; Wosinska, Marta E.] US FDA, Off Strateg Programs, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20876 USA. RP Kerr, KW (reprint author), US FDA, Off Strateg Programs, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20876 USA. EM kirk.kerr@fda.hhs.gov NR 9 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD JAN PY 2017 VL 51 IS 1 BP 16 EP 23 DI 10.1177/2168479016663266 PG 8 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA EI3AH UT WOS:000392361300004 ER PT J AU He, WL Gallo, P Miller, E Jemiai, Y Maca, J Koury, K Fan, XF Jiang, Q Wang, CS Lin, M AF He, Weili Gallo, Paul Miller, Eva Jemiai, Yannis Maca, Jeff Koury, Ken Fan, Xiaoyin Frank Jiang, Qi Wang, Cunshan Lin, Min TI Addressing Challenges and Opportunities of "Less Well-Understood" Adaptive Designs SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE adaptive trials; phase II/III seamless trial; sample size reassessment; Type I error; data monitoring committee ID CLINICAL-TRIALS; SAMPLE-SIZE; SELECTION; INTERIM AB The draft adaptive design guidance released by FDA in 2010 included references to adaptive study designs that were described as "less well-understood." At that time, there was relatively little regulatory experience with such designs, and their properties were felt to be insufficiently understood. In order to promote greater use of adaptive designs, especially those categorized as less well-understood, the Best Practice Subteam of the DIA Adaptive Designs Scientific Working Group (ADSWG) has worked on describing and characterizing these designs, identifying challenges associated with them and suggesting improvements to design or study conduct aspects that might make them more acceptable. This paper summarizes the work from the subteam. C1 [He, Weili; Koury, Ken] Merck & Co Inc, Clin Biostat, Rahway, NJ 07065 USA. [Gallo, Paul] Novartis Pharmaceut, Stat Methodol, E Hanover, NJ USA. [Jemiai, Yannis] Cytel, Cambridge, MA USA. [Maca, Jeff] Quintiles Inc, Ctr Stat & Drug Dev, Morrisville, NC USA. [Fan, Xiaoyin Frank] Novartis Inst Biomed Res, Stat Sci, Cambridge, MA USA. [Jiang, Qi] Amgen Inc, Thousand Oaks, CA USA. [Wang, Cunshan] Pfizer, Groton, CT USA. [Lin, Min] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP He, WL (reprint author), Merck & Co Inc, 126 Lincoln Ave,RY34-A316, Rahway, NJ 07065 USA. EM Weili_he@merck.com NR 31 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 JAN PY 2017 VL 51 IS 1 BP 60 EP 68 DI 10.1177/2168479016663265 PG 9 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA EI3AH UT WOS:000392361300011 ER PT J AU Lumen, A George, NI AF Lumen, A. George, N. I. TI Estimation of iodine nutrition and thyroid function status in late-gestation pregnant women in the United States: Development and application of a population-based pregnancy model SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Biologically-base dose-response modeling; Reverse dosimetry; Biomonitoring; Iodine; Thyroid hormones ID LONGITUDINAL REFERENCE INTERVALS; MATERNAL HYPOTHYROXINEMIA; BIOMONITORING DATA; CHINESE WOMEN; THYROXINE; DEFICIENCY; TRIMESTER; TRIIODOTHYRONINE; HORMONES; SUPPLEMENTATION AB Previously, a deterministic biologically-based dose-response (BBDR) pregnancy model was developed to evaluate moderate thyroid axis disturbances with and without thyroid-active chemical exposure in a near-term pregnant woman and fetus. In the current study, the existing BBDR model was adapted to include a wider functional range of iodine nutrition, including more severe iodine deficiency conditions, and to incorporate empirically the effects of homeostatic mechanisms. The extended model was further developed into a population-based model and was constructed using a Monte Carlo-based probabilistic framework. In order to characterize total (T4) and free (fT4) thyroxine levels for a given iodine status at the population-level, the distribution of iodine intake for late-gestation pregnant women in the U.S was reconstructed using various reverse dosimetry methods and available biomonitoring data. The range of median (mean) iodine intake values resulting from three different methods of reverse dosimetry tested was 196.5-219.9 mu g of iodine/day (228.2-392.9 mu g of iodine/day). There was minimal variation in model-predicted maternal serum T4 and ft4 thyroxine levels from use of the three reconstructed distributions of iodine intake; the range of geometric mean for T4 and fT4, was 138-151.7 nmol/L and 7.9-8.7 pmol/L, respectively. The average value of the ratio of the 97.5th percentile to the 2.5th percentile equaled 3.1 and agreed well with similar estimates from recent observations in third-trimester pregnant women in the U.S. In addition, the reconstructed distributions of iodine intake allowed us to estimate nutrient inadequacy for late-gestation pregnant women in the U.S. via the probability approach. The prevalence of iodine inadequacy for third-trimester pregnant women in the U.S. was estimated to be between 21% and 44%. Taken together, the current work provides an improved tool for evaluating iodine nutritional status and the corresponding thyroid function status in pregnant women in the U.S. This model enables future assessments of the relevant risk of thyroid hormone level perturbations due to exposure to thyroid-active chemicals at the population-level. Published by Elsevier Inc. C1 [Lumen, A.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 110, Jefferson, AR 72079 USA. [George, N. I.] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 20, Jefferson, AR 72079 USA. RP Lumen, A (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 110, Jefferson, AR 72079 USA.; George, NI (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 20, Jefferson, AR 72079 USA. EM Annie.Lumen@fda.hhs.gov; Nysia.George@fda.hhs.gov FU FDA Office of Women's Health; National Center for Toxicological Research FX This manuscript does not necessarily reflect the views of the U.S. Food and Drug Administration. We appreciate Drs. Marie-Emilie Willemin, William Tolleson, and Frederick A. Beland, for critically reviewing this manuscript. We are also thankful to Dr. Eric Hack, Dr. Jeffrey Fisher and Dr. Conrad Housand for their valuable inputs and code support during model development. This work was supported by the FDA Office of Women's Health and the National Center for Toxicological Research. NR 73 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 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JAN 1 PY 2017 VL 314 BP 24 EP 38 DI 10.1016/j.taap.2016.10.026 PG 15 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EI5TH UT WOS:000392557200003 PM 27818216 ER PT J AU Baker-Austin, C Trinanes, J Gonzalez-Escalona, N Martinez-Urtaza, J AF Baker-Austin, Craig Trinanes, Joaquin Gonzalez-Escalona, Narjol Martinez-Urtaza, Jaime TI Non-Cholera Vibrios: The Microbial Barometer of Climate Change SO TRENDS IN MICROBIOLOGY LA English DT Review ID THERMOSTABLE DIRECT HEMOLYSIN; UNITED-STATES; PARAHAEMOLYTICUS STRAINS; VULNIFICUS DISEASE; PACIFIC-NORTHWEST; RAW OYSTERS; INFECTIONS; OUTBREAK; MARYLAND; GASTROENTERITIS AB There is a growing interest in the role of climate change in driving the spread of waterborne infectious diseases, such as those caused by bacterial pathogens. One particular group of pathogenic bacteria - vibrios - are a globally important cause of diseases in humans and aquatic animals. These Gram-negative bacteria, including the species Vibrio vulnificus, Vibrio parahaemolyticus and Vibrio cholerae, grow in warm, low-salinity waters, and their abundance in the natural environment mirrors ambient environmental temperatures. In a rapidly warming marine environment, there are greater numbers of human infections, and most notably outbreaks linked to extreme weather events such as heatwaves in temperate regions such as Northern Europe. Because the growth of pathogenic vibrios in the natural environment is largely dictated by temperature, we argue that this group of pathogens represents an important and tangible barometer of climate change in marine systems. We provide a number of specific examples of the impacts of climate change on this group of bacteria and their associated diseases, and discuss advanced strategies to improve our understanding of these emerging waterborne diseases through the integration of microbiological, genomic, epidemiological, climatic, and ocean sciences. C1 [Baker-Austin, Craig] Ctr Environm Fisheries & Aquaculture CEFAS, Weymouth DT4 8UB, Dorset, England. [Trinanes, Joaquin] NOAA, Atlantic Oceanog & Meteorol Lab, 4301 Rickenbacker Causeway, Miami, FL 33149 USA. [Trinanes, Joaquin] Univ Santiago de Compostela, Technol Res Inst, Lab Syst, Campus Univ Sur, Santiago De Compostela 15782, Spain. [Trinanes, Joaquin] Univ Miami, Cooperat Inst Marine & Atmospher Studies, Rosenstiel Sch Marine & Atmospher Sci, 4600 Rickenbacker Causeway, Miami, FL 33149 USA. [Gonzalez-Escalona, Narjol] US FDA, Mol Methods & Subtyping Branch, Div Microbiol, Off Regulatory Sci,Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Martinez-Urtaza, Jaime] Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath BA2 7AY, Avon, England. RP Baker-Austin, C (reprint author), Ctr Environm Fisheries & Aquaculture CEFAS, Weymouth DT4 8UB, Dorset, England. EM craig.baker-austin@cefas.co.uk FU FDA Foods Program Intramural Funds; NOAA/OceanWatch; NOAA/AOML; Cefas Seedcorn funding; NERC project [NE/P004121/1] FX N. Gonzalez-Escalona was funded by the FDA Foods Program Intramural Funds, J. Trinanes was funded by NOAA/OceanWatch and NOAA/AOML, and C. Baker-Austin was funded by Cefas Seedcorn funding. We also acknowledge the NERC project (NE/P004121/1). NR 60 TC 0 Z9 0 U1 21 U2 21 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0966-842X EI 1878-4380 J9 TRENDS MICROBIOL JI Trends Microbiol. PD JAN PY 2017 VL 25 IS 1 BP 76 EP 84 DI 10.1016/j.tim.2016.09.008 PG 9 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA EI2XI UT WOS:000392352500011 PM 27843109 ER PT J AU Strauss, DG Blinova, K AF Strauss, David G. Blinova, Ksenia TI Clinical Trials in a Dish SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Editorial Material ID PLURIPOTENT STEM-CELLS; IN-VITRO; INFECTION C1 [Strauss, David G.] US FDA, Div Appl Regulatory Sci, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Blinova, Ksenia] US FDA, Div Biomed Phys, Off Sci Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Strauss, DG (reprint author), US FDA, Div Appl Regulatory Sci, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM David.Strauss@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 12 TC 0 Z9 0 U1 2 U2 2 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 JAN PY 2017 VL 38 IS 1 BP 4 EP 7 DI 10.1016/j.tips.2016.10.009 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI2XH UT WOS:000392352400003 PM 27876286 ER PT J AU Hampton, D Green, JA Robboy, M Eydelman, M AF Hampton, Denise Green, Joffre Angelo Robboy, Marc Eydelman, Malvina TI Food and Drug Administration Efforts to Mitigate Contact Lens Discomfort SO EYE & CONTACT LENS-SCIENCE AND CLINICAL PRACTICE LA English DT Review DE Contact lens; Contact lens solution; Regulation AB The premarket review of contact lenses and accessories by the FDA involves the assessment of nonclinical and clinical information in support of clearance or approval of marketing applications. The review process for these medical devices, including attributes, which may contribute to comfort for lens wearers, is summarized, as are mechanisms by which FDA continues to assess and improve recommendations through the review process and through collaboration with external entities. C1 [Hampton, Denise; Green, Joffre Angelo; Robboy, Marc; Eydelman, Malvina] US FDA, Div Ear Nose & Throat Devices, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Eydelman, M (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM malvina.eydelman@fda.hhs.gov NR 18 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 1542-2321 EI 1542-233X J9 EYE CONTACT LENS JI Eye Contact Lens-Sci. Clin. Pra. PD JAN PY 2017 VL 43 IS 1 BP 2 EP 4 DI 10.1097/ICL.0000000000000324 PG 3 WC Ophthalmology SC Ophthalmology GA EH5WD UT WOS:000391842800003 PM 27941360 ER PT J AU Falconer, TM Kern, SE Brzezinski, JL Turner, JA Boyd, BL Litzau, JJ AF Falconer, Travis M. Kern, Sara E. Brzezinski, Jennifer L. Turner, James A. Boyd, Brian L. Litzau, Jonathan J. TI Identification of the potent toxin bongkrekic acid in a traditional African beverage linked to a fatal outbreak SO FORENSIC SCIENCE INTERNATIONAL LA English DT Article DE Toxin; Bongkrekic acid; Burkholderia gladioli; Pombe; LC-MS ID ISOBONGKREKIC ACID; TOXOFLAVIN AB In January 2015, 75 people died and 177 were hospitalized in the Mozambique village of Chitima after attending a funeral. The deaths were linked to the consumption of a traditional African beverage called pombe. Samples of the suspect pombe were subjected to myriad analyses and compared to a control sample. Ultimately, non-targeted liquid chromatography-mass spectrometry screening revealed the presence of the potent toxin bongkrekic acid, and its structural isomer, isobongkrekic acid. Quantitative analysis found potentially fatal levels of these toxins in the suspect pombe samples. Bongkrekic acid is known to be produced by the bacterium Burkholderia gladioli pv. cocovenenans. This bacterium could not be isolated from the suspect pombe, but bacteria identified as B. gladioli were isolated from corn flour, a starting ingredient in the production of pombe, obtained from the brewer's home. When the bacteria were co-plated with the fungus Rhizopus oryzae, which was also isolated from the corn flour, synergistic production of bongkrekic acid was observed. The results suggest a mechanism for bongkrekic acid intoxication, a phenomenon previously thought to be restricted to specific regions of Indonesia and China. Published by Elsevier Ireland Ltd. C1 [Falconer, Travis M.; Kern, Sara E.; Brzezinski, Jennifer L.; Turner, James A.; Boyd, Brian L.; Litzau, Jonathan J.] US FDA, Forens Chem Ctr, 6751 Steger Dr, Cincinnati, OH 45237 USA. RP Falconer, TM (reprint author), US FDA, Forens Chem Ctr, 6751 Steger Dr, Cincinnati, OH 45237 USA. EM travis.falconer@fda.hhs.gov NR 18 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0379-0738 EI 1872-6283 J9 FORENSIC SCI INT JI Forensic Sci.Int. PD JAN PY 2017 VL 270 BP E5 EP E11 DI 10.1016/j.forsciint.2016.10.015 PG 7 WC Medicine, Legal SC Legal Medicine GA EH1SG UT WOS:000391546900002 PM 27823840 ER PT J AU Degiuseppe, JI Gomes, KA Hadad, MF Parra, GI Stupka, JA AF Degiuseppe, Juan I. Gomes, Karina A. Hadad, Maria F. Parra, Gabriel I. Stupka, Juan A. TI Detection of novel GII.17 norovirus in Argentina, 2015 SO INFECTION GENETICS AND EVOLUTION LA English DT Article DE Norovirus; GII.17; Gastroenteritis; Argentina ID REVERSE TRANSCRIPTION-PCR; GASTROENTERITIS; OUTBREAKS; VARIANT AB During the winter of 2014-2015 a novel GII.17 norovirus strain emerged as a cause of large gastroenteritis outbreaks in Asia; displacing the long-term predominant strain, GII.4. Although sporadically detected, the emerging GII.17 virus was described in North America and Europe. In this study, we describe the presence of this novel strain in Argentina (South America), and provide new information on the genetic diversity of GII.17 noroviruses. Ten stool samples from individuals (1-88 years old; median: 5 years old) experiencing gastroenteritis symptoms from San Martin de los Andes, Argentina were tested for Norovirus using RT-PCR. Subsequently, Norovirus positive samples were analyzed by sequencing. Norovirus was found in four out of 10 samples received. Partial sequencing of the ORF2 was available for 3/4 samples: two samples belonged to genotype GII.4 and one to genotype GII.17 (Arg13099). Sequence analyses of the VP1 encoding region revealed that the GII.17 Argentinean strain presented characteristics from both, the new (cluster C), and older (cluster A and B) GII.17 strains. Phylogenetic and sequence analyses of the RdRp region showed that this strain was closely related to strains from genotypes GII.P3, GII.P13 and GII.P17; however, did not cluster within any of them. This study represents the first report of this emergent strain in South America, and presents further evidence of the genetic plasticity of the GII.17. (C) 2016 Elsevier B.V. All rights reserved. C1 [Degiuseppe, Juan I.; Gomes, Karina A.; Stupka, Juan A.] Inst Nacl Enfermedades Infecciosas ANLIS Dr Carlo, Ave Velez Sarsfield 563, RA-1281 Buenos Aires, DF, Argentina. [Hadad, Maria F.] Zona Sanitaria 4, Neuquen, Argentina. [Parra, Gabriel I.] US FDA, Div Viral Prod, Silver Spring, MD USA. RP Degiuseppe, JI (reprint author), Inst Nacl Enfermedades Infecciosas ANLIS Dr Carlo, Ave Velez Sarsfield 563, RA-1281 Buenos Aires, DF, Argentina. EM jdegiuseppe@anlis.gov.ar NR 18 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-1348 EI 1567-7257 J9 INFECT GENET EVOL JI Infect. Genet. Evol. PD JAN PY 2017 VL 47 BP 121 EP 124 DI 10.1016/j.meegid.2016.11.026 PG 4 WC Infectious Diseases SC Infectious Diseases GA EH5TM UT WOS:000391835800017 PM 27908796 ER PT J AU Stockbridge, N Miller, K Amur, S Hillebrenner, M Zuckerman, B Fiuzat, M Califf, RM AF Stockbridge, Norman Miller, Kristen Amur, Shashi Hillebrenner, Matthew Zuckerman, Bram Fiuzat, Mona Califf, Robert M. TI The FDA in the 21st Century How Is the FDA Responding to the New World? A Focus on Cardiovascular Drug Development SO JACC-HEART FAILURE LA English DT Editorial Material DE drug evaluation; FDA; stroke ID BIOMARKER QUALIFICATION C1 [Stockbridge, Norman; Miller, Kristen; Amur, Shashi; Hillebrenner, Matthew; Zuckerman, Bram; Fiuzat, Mona; Califf, Robert M.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Stockbridge, N (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Norman.stockbridge@fda.hhs.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD JAN PY 2017 VL 5 IS 1 BP 67 EP 70 DI 10.1016/j.jchf.2016.10.009 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EH1JD UT WOS:000391520500011 PM 28034379 ER PT J AU Yang, HHW AF Yang, H. H. Wendy TI Determination of Organic Impurities in Anthraquinone Color Additives D&C Violet No. 2 and D&C Green No. 6 by Ultra-High Performance Liquid Chromatography SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID NO-2 AB A new practical and time-saving ultra-high performance liquid chromatography (UHPLC) method has been developed for determining the organic impurities in the anthraquinone color additives D&C Violet No. 2 and D&C Green No. 6. The impurities determined are p-toluidine, 1-hydroxyanthraquinone, 1,4-dihydroxyanthraquinone, and two subsidiary colors. The newly developed UHPLC method uses a 1.7-mu particle size C-18 column, 0.1 M ammonium acetate and acetonitrile as eluents, and photodiode array detection. For the quantification of the impurities, six-point calibration curves were used with correlation coefficients that ranged from 0.9974 to 0.9998. Recoveries of impurities ranged from 99 to 104%. Relative standard deviations ranged from 0.81 to 4.29%. The limits of detection for the impurities ranged from 0.0067% to 0.216%. Samples from sixteen batches of each color additive were analyzed, and the results favorably compared with the results obtained by gravity-elution column chromatography, thin-layer chromatography, and isooctane extraction. Unlike with those other methods, use of the UHPLC method permits all of the impurities to be determined in a single analysis, while also reducing the amount of organic waste and saving time and labor. The method is expected to be implemented by the U.S. Food and Drug Administration for analysis of color additive samples submitted for batch certification. C1 [Yang, H. H. Wendy] US FDA, Ctr Food Safety & Appl Nutr, Off Cosmet & Colors, College Pk, MD 20740 USA. RP Yang, HHW (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Cosmet & Colors, College Pk, MD 20740 USA. EM hueihsuan.Yang@fda.hhs.gov NR 12 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 JAN-FEB PY 2017 VL 100 IS 1 BP 230 EP 235 DI 10.5740/jaoacint.16-0067 PG 6 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA EH8RY UT WOS:000392041200030 ER PT J AU Flory, JH Roy, J Gagne, JJ Haynes, K Herrinton, L Lu, C Patorno, E Shoaibi, A Raebel, MA AF Flory, James H. Roy, Jason Gagne, Joshua J. Haynes, Kevin Herrinton, Lisa Lu, Christine Patorno, Elisabetta Shoaibi, Azadeh Raebel, Marsha A. TI Missing laboratory results data in electronic health databases: implications for monitoring diabetes risk SO JOURNAL OF COMPARATIVE EFFECTIVENESS RESEARCH LA English DT Article DE ascertainment bias; cohort studies; endocrinology; metabolism AB Aim: Laboratory test (lab) results may be useful to detect incident diabetes in electronic health record and claims-based studies. Research design & methods: Using the Mini-Sentinel distributed database, we assessed the value of lab results added to diagnosis codes and dispensing claims to identify incident diabetes. Results: Inclusion of lab results increased the number of diabetes outcomes identified by 21%. In settings where capture of lab results was relatively complete, the absence of lab results was associated with implausibly low rates of the outcome. Conclusion: Lab results can increase sensitivity of algorithms for detecting diabetes, and missing lab results are associated with much lower rates of diabetes ascertainment regardless of algorithm. Patterns of missing lab results may identify ascertainment bias. C1 [Flory, James H.] Weill Cornell Med, New York, NY 10065 USA. [Roy, Jason] Univ Penn, Philadelphia, PA 19104 USA. [Gagne, Joshua J.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Haynes, Kevin] HealthCore Inc, Wilmingon, DE 19801 USA. [Herrinton, Lisa; Raebel, Marsha A.] Kaiser Permanente, Oakland, CA 94612 USA. [Lu, Christine] Harvard Pilgrim, Boston, MA 02215 USA. [Patorno, Elisabetta] Partners Healthcare Syst, Boston, MA 02215 USA. [Shoaibi, Azadeh] US FDA, Silver Spring, MD 20993 USA. RP Flory, JH (reprint author), Weill Cornell Med, New York, NY 10065 USA. EM jaf9052@med.cornell.edu FU US FDA through Department of Health and Human Services [HHSF22301012T-0008, HHSF223020091006I] FX The Mini-Sentinel program is funded by the US FDA through contract HHSF22301012T-0008 under Master Agreement HHSF223020091006I from the Department of Health and Human Services. 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 12 TC 0 Z9 0 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 2042-6305 EI 2042-6313 J9 J COMP EFFECT RES JI J. Comp. Eff. Res. PD JAN PY 2017 VL 6 IS 1 BP 25 EP 32 DI 10.2217/cer-2016-0033 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EH6CZ UT WOS:000391861600006 PM 27935320 ER PT J AU Lehman, PA Beatch, K Raney, SG Franz, TJ AF Lehman, Paul A. Beatch, Kacie Raney, Sam G. Franz, Thomas J. TI The Tritiated Water Skin Barrier Integrity Test: Considerations for Acceptance Criteria with and Without C-14-Octanol SO PHARMACEUTICAL RESEARCH LA English DT Article DE IVPT; skin barrier; skin permeation; stratum corneum; tritiated water ID VITRO PERCUTANEOUS-ABSORPTION; IN-VITRO; PENETRATION; BIOEQUIVALENCE; PERMEABILITY; RELEVANCE; WORKSHOP; SINGLE AB A study was designed to assess barrier integrity simultaneously using separate compounds (probes) for polar and non-polar pathways through the skin, (H2O)-H-3 and C-14-octanol, respectively; and to determine whether the two probe approach could better define barrier integrity. A 5-min dose of water containing (H2O)-H-3 and C-14 -octanol was applied to ex vivo human skin mounted in Franz diffusion cells. The receptor solution was sampled at 30 min, analyzed for H-3 and C-14 content, and the correlation between water and octanol absorption was determined by statistical tests suitable for non-normally distributed data. This study was conducted on skin from 37 donors with from 3 to 30 replicate skin sections per donor (a total of 426 sections). The correlation between (H2O)-H-3 and C-14-octanol absorption was low (Pearson correlation coefficient = 0.3485). The (H2O)-H-3 absorption cutoff used in this study to select for a normal skin barrier rejected some sections in which C-14-octanol absorption was within normal limits and accepted others in which C-14-octanol absorption was abnormally high. The converse was true for (H2O)-H-3 absorption when the C-14-octanol-based cutoff was used. The results of the (H2O)-H-3 test or of similar tests that primarily assess the permeability of polar pathways through the skin may not necessarily provide information relevant to the absorption of highly lipophilic compounds. Octanol, or another molecule that more closely matches the physicochemical attributes of the test compound, may characterize properties of the skin barrier that are more relevant to compounds of low water solubility. C1 [Lehman, Paul A.] QPS Holdings LLC, Dermal & Transdermal Res Serv, 3 Innovat Way,Suite 240, Newark, DC 19711 USA. [Beatch, Kacie] Upsher Smith Labs Inc, Translat Med, 6701 Evenstad Dr N, Minneapolis, MN 55369 USA. [Raney, Sam G.] US FDA, Off Gener Drugs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Franz, Thomas J.] 10716 SE Forest View LN, Happy Valley, OR 97086 USA. RP Franz, TJ (reprint author), 10716 SE Forest View LN, Happy Valley, OR 97086 USA. EM franzcell@frontier.com NR 31 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 EI 1573-904X J9 PHARM RES-DORDR JI Pharm. Res. PD JAN PY 2017 VL 34 IS 1 BP 217 EP 228 DI 10.1007/s11095-016-2057-3 PG 12 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA EH0DE UT WOS:000391431900019 PM 27822852 ER PT J AU Rudy, SF Durmowicz, EL AF Rudy, Susan F. Durmowicz, Elizabeth L. TI Electronic nicotine delivery systems: overheating, fires and explosions SO TOBACCO CONTROL LA English DT Article ID CIGARETTES AB Background Electronic nicotine delivery system (ENDS)-associated overheating, fire or explosion (OH/F/EXP) events have occurred since at least 2009. Objective To identify the number and nature of ENDS OH/F/EXP events in the USA. Methods Center for Tobacco Products (CTP) scientists searched for event reports among five US federal agencies, scientific literature and media outlets. Findings 100 reference sources identified 92 OH/F/EXP events in the USA, of which 45 (49%) injured 47 people, and 67 (73%) involved property damage beyond the product. Events were identified in media outlets (n= 50; 54%) and reported to four agencies (n= 42; 46%). The report rate peaked at an average of six reports per month in late 2013 with a smaller peak of three to four reports per month in the second quarter of 2015. All reports were incomplete and events exhibited variability. International events in three countries are mentioned, and international responses to events are summarised. Conclusions The scope, causes and trajectory of ENDS OH/F/EXP events remain incompletely defined. Some events have resulted in life-threatening injury, permanent disfigurement or disability, and major property damage, suggesting the need for ongoing surveillance and risk mitigation. More comprehensive reporting could assist future analyses and may help to identify root causes and contributors to the OH/F/EXP events. C1 [Rudy, Susan F.] US FDA, Off Sci, Div Individual Hlth Sci, Med Branch,Ctr Tobacco Prod, Bldg 75 Rm 5464W,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Durmowicz, Elizabeth L.] US FDA, Off Sci, Div Individual Hlth Sci, Ctr Tobacco Prod, Silver Spring, MD USA. RP Rudy, SF (reprint author), US FDA, Off Sci, Div Individual Hlth Sci, Med Branch,Ctr Tobacco Prod, Bldg 75 Rm 5464W,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Susan.rudy@fda.hhs.gov NR 134 TC 3 Z9 3 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 JAN PY 2017 VL 26 IS 1 BP 10 EP 18 DI 10.1136/tobaccocontrol-2015-052626 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EH0FP UT WOS:000391439000010 ER PT J AU Mangrum, JB Mehta, AY Alabbas, AB Desai, UR Hawkridge, AM AF Mangrum, John B. Mehta, Akul Y. Alabbas, Alhumaidi B. Desai, Umesh R. Hawkridge, Adam M. TI Comparative analysis of INLIGHT (TM)-labeled enzymatically depolymerized heparin by reverse-phase chromatography and high-performance mass spectrometry SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Mass spectrometry/ICP-MS; Glycosaminoglycan; Heparin; Chemical derivatization ID MOLECULAR-WEIGHT HEPARINS; N-LINKED GLYCANS; LIQUID-CHROMATOGRAPHY; ELECTROSPRAY-IONIZATION; RELATIVE QUANTIFICATION; STRUCTURAL-ANALYSIS; SULFATE; OLIGOSACCHARIDES; DISACCHARIDES; DERIVATIZATION AB Structural characterization of the microheterogeneity of heparin, heparan sulfate, and other glycosaminoglycans is a major analytical challenge. We present the use of a stable isotope-labeled hydrazide tag (INLIGHT (TM)) with high-resolution/accurate mass (HRAM) reverse-phase LC-MS/MS, which was recently introduced for detailed study of N-glycan heterogeneity, to characterize heparinase-digested heparin (digHep) products without the use of semi-volatile ion pairing reagents. Using both full scan LC-MS and data-dependent LC-MS/MS, we identified 116 unique digHep species, a feat possible because of INLIGHT (TM) labeling. Of these, 83 digHep products were structurally identified, including the 12 standard disaccharides as well as 34 tetra- (DP4), 26 hexa- (DP6), 21 octa- (DP8), and 2 decasaccharides (DP10). Each of the 116 digHep species co-eluted with both light and heavy INLIGHT (TM) tags (L/H-avg = 1.039 +/- 0.163); thus enhancing confidence in their identification via MS and MS/MS. This work sets the foundation for INLIGHT (TM)-based comparative analyses of different forms of heparin, heparan sulfate, and other GAGs with high quantitative precision using mainstay reverse-phase HRAM LC-MS/MS. C1 [Mangrum, John B.] US FDA, College Pk, MD 20740 USA. [Mehta, Akul Y.; Alabbas, Alhumaidi B.; Desai, Umesh R.] Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, 800 E Leigh St,POB 980540, Richmond, VA 23298 USA. [Desai, Umesh R.; Hawkridge, Adam M.] Virginia Commonwealth Univ, Sch Pharm, Inst Struct Biol Drug Discovery & Dev, 800 E Leigh St,Suite 212, Richmond, VA 23219 USA. [Hawkridge, Adam M.] Virginia Commonwealth Univ, Sch Pharm, Dept Pharmaceut, 410 North 12th St,POB 980533, Richmond, VA 23298 USA. [Hawkridge, Adam M.] Virginia Commonwealth Univ, Sch Pharm, Dept Pharmacotherapy & Outcomes Sci, 410 North 12th St,POB 980533, Richmond, VA 23298 USA. RP Hawkridge, AM (reprint author), Virginia Commonwealth Univ, Sch Pharm, Inst Struct Biol Drug Discovery & Dev, 800 E Leigh St,Suite 212, Richmond, VA 23219 USA.; Hawkridge, AM (reprint author), Virginia Commonwealth Univ, Sch Pharm, Dept Pharmaceut, 410 North 12th St,POB 980533, Richmond, VA 23298 USA.; Hawkridge, AM (reprint author), Virginia Commonwealth Univ, Sch Pharm, Dept Pharmacotherapy & Outcomes Sci, 410 North 12th St,POB 980533, Richmond, VA 23298 USA. EM amhawkridge@vcu.edu FU VCU School of Pharmacy; NIH [HL107152] FX The financial support from the VCU School of Pharmacy (AMH) and from NIH grant HL107152 (URD) is gratefully acknowledged. NR 53 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD JAN PY 2017 VL 409 IS 2 BP 499 EP 509 DI 10.1007/s00216-016-0055-2 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA EG9FM UT WOS:000391364200013 PM 27888308 ER PT J AU Selewski, DT Thompson, A Kovacs, S Papadopoulos, EJ Carlozzi, NE Trachtman, H Troost, JP Merkel, PA Gipson, DS AF Selewski, David T. Thompson, Aliza Kovacs, Sarrit Papadopoulos, Elektra J. Carlozzi, Noelle E. Trachtman, Howard Troost, Jonathan P. Merkel, Peter A. Gipson, Debbie S. TI Patient-Reported Outcomes in Glomerular Disease SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID QUALITY-OF-LIFE; CHRONIC KIDNEY-DISEASE; PEDIATRIC NEPHROLOGY CONSORTIUM; ANTIBODY-ASSOCIATED VASCULITIS; ANCA-ASSOCIATED VASCULITIS; NEPHROTIC SYNDROME; CLINICAL-TRIALS; POLYANGIITIS WEGENERS; PROMIS PERSPECTIVE; CHILDREN AB Incorporation of the patient perspective into research and clinical practice will enrich our understanding of the status and management of patients with glomerular disease and may result in therapies that better address patient needs. In recent years, the importance of the patient experience of glomerular disease has become clear, and significant efforts have been undertaken to systematically capture and describe the patient's disease experience. Patient-reported outcome instruments provide a means to assess the patient's experience in a quantitative manner, thus enabling for comparisons within and between patients. Patient-reported outcome assessments are solely on the basis of a patient report about the status of their health without amendment or interpretation by a clinician or others. Patient-reported outcome assessments provide an opportunity to incorporate the patient perspective into clinical care, research, and clinical trials. Our paper provides an overview of terminology and development methods for patient-reported outcomes and reviews (1) currently available patient-reported outcome instruments appropriate for use in glomerular disease, (2) existing patient-reported outcome data in glomerular disease, and (3) opportunities for incorporating patient-reported outcome instruments into clinical care and research. C1 [Selewski, David T.; Troost, Jonathan P.; Gipson, Debbie S.] Univ Michigan, CS Mott Childrens Hosp, Dept Pediat & Communicable Dis, Div Nephrol, 15004 East Hosp Dr, Ann Arbor, MI 48109 USA. [Carlozzi, Noelle E.] Univ Michigan, Dept Phys Med & Rehabil, 15004 East Hosp Dr, Ann Arbor, MI 48109 USA. [Thompson, Aliza] US FDA, Div Cardiovasc & Renal Prod, Silver Spring, MD USA. [Kovacs, Sarrit; Papadopoulos, Elektra J.] US FDA, Immediate Off, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Trachtman, Howard] NYU, Dept Pediat, Div Nephrol, Langone Med Ctr, New York, NY 10016 USA. [Merkel, Peter A.] Univ Penn, Dept Biostat & Epidemiol, Div Rheumatol, Philadelphia, PA 19104 USA. RP Gipson, DS (reprint author), Univ Michigan, CS Mott Childrens Hosp, Pediat Nephrol, 15004 East Hosp Dr, Ann Arbor, MI 48109 USA. EM dgipson@med.umich.edu OI Trachtman, Howard/0000-0001-7447-9489 FU National Institutes of Health; National Center for Research Resources [5U01AR052181-05]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [2U01AR05218106, U54 AR057319, U01 AR5187404, R01 AR064153]; NephCure Kidney International Foundation; Vasculitis Clinical Research Consortium; National Center for Advancing Translational Science; Office of Rare Diseases Research; Outcome Measures in Rheumatology Vasculitis Working Group through a Patient Centered Outcomes Research Institute Pilot Project grant; GlaxoSmithiCine (Brentford, United Kingdom) FX D.T.S., J.P.T., D.S.G., and the work described for pediatric nephrotic syndrome received support from National Institutes of Health, National Center for Research Resources (grant 5U01AR052181-05), National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant 2U01AR05218106), and the NephCure Kidney International Foundation. The Nephrotic Syndrome Patient Reported Outcomes Workshop was supported by the NephCure Kidney International Foundation. P.A.M. and the work described for vasculitis was supported by the Vasculitis Clinical Research Consortium, which has received support from National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants U54 AR057319, U01 AR5187404, and R01 AR064153); the National Center for Advancing Translational Science; and the Office of Rare Diseases Research. Additional support for the work of the Outcome Measures in Rheumatology Vasculitis Working Group was received through a Patient Centered Outcomes Research Institute Pilot Project grant. D.S.G. served as a coinvestigator in the development of the FSGS patient reported outcome sponsored by GlaxoSmithiCine (Brentford, United Kingdom). NR 40 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD JAN PY 2017 VL 12 IS 1 BP 140 EP 148 DI 10.2215/CJN.13231215 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA EG9YD UT WOS:000391416700019 PM 27259977 ER PT J AU Siegel, JA Pennington, CW Sacks, B AF Siegel, Jeffiy A. Pennington, Charles W. Sacks, Bill TI Subjecting Radiologic Imaging to the Linear No-Threshold Hypothesis: A Non Sequitur of Non-Trivial Proportion SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE radiological imaging; linear no-threshold; ALARA; hormesis; adaptive response; radiophobia ID RADIATION-INDUCED CANCER; ATOMIC-BOMB SURVIVORS; IONIZING-RADIATION; NUCLEAR-MEDICINE; PEDIATRIC CT; RISK; PROTECTION; EXPOSURE; COHORT; SCANS AB Radiologic imaging is claimed to carry an iatrogenic risk of cancer, based on an uninformed commitment to the 70-y-old linear no threshold hypothesis (LNTH). Credible evidence of imaging-related low-dose (<100 mGy) carcinogenic risk is nonexistent; it is a hypothetical risk derived from the demonstrably false LNTH. On the contrary, low-dose radiation does not cause, but more likely helps prevent, cancer. The LNTH and its offspring, ALARA (as low as reasonably achievable), are fatally flawed, focusing only on molecular damage while ignoring protective, organismal biologic responses. Although some grant the absence of low-dose harm, they nevertheless advocate the "prudence" of dose optimization (i.e., using ALARA doses); but this is a radiophobia-centered, not scientific, approach. Medical imaging studies achieve a diagnostic purpose and should be governed by the highest science-based principles and policies. The LNTH is an invalidated hypothesis, and its use, in the form of ALARA dosing, is responsible for misguided concerns promoting radiophobia, leading to actual risks far greater than the hypothetical carcinogenic risk purportedly avoided. Further, the myriad benefits of imaging are ignored. The present work calls for ending the radiophobia caused by those asserting the need for dose optimization in imaging: the low-dose radiation of medical imaging has no documented pathway to harm, whereas the LNTH and ALARA most assuredly do. C1 [Siegel, Jeffiy A.] Nucl Phys Enterprises, 4 Wedgewood Dr, Marlton, NJ 08053 USA. [Pennington, Charles W.] NAC Int, Norcross, GA USA. [Sacks, Bill] US FDA, Green Valley, AZ USA. RP Siegel, JA (reprint author), Nucl Phys Enterprises, 4 Wedgewood Dr, Marlton, NJ 08053 USA. EM nukephysics@comcast.net NR 51 TC 7 Z9 7 U1 3 U2 3 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD JAN PY 2017 VL 58 IS 1 BP 1 EP 6 DI 10.2967/jnumed.116.180182 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EG8YM UT WOS:000391343400008 PM 27493264 ER PT J AU Benz, HL Civillico, EF AF Benz, Heather L. Civillico, Eugene F. TI Neuroprosthetics and the science of patient input SO EXPERIMENTAL NEUROLOGY LA English DT Review ID QUALITY-OF-LIFE; LIMB AMPUTATION; DEKA ARM; PROSTHETICS; ABANDONMENT; ORTHOTICS; OUTCOMES; PEOPLE AB Safe and effective neuroprosthetic systems are of great interest to both DARPA and CDRH, due to their innovative nature and their potential to aid severely disabled populations. By expanding what is possible in human-device interaction, these devices introduce new potential benefits and risks. Therefore patient input, which is increasingly important in weighing benefits and risks, is particularly relevant for this class of devices. FDA has been a significant contributor to an ongoing stakeholder conversation about the inclusion of the patient voice, working collaboratively to create a new framework for a patient-centered approach to medical device development. This framework is evolving through open dialogue with researcher and patient communities, investment in the science of patient input, and policymaking that is responsive to patient-centered data throughout the total product life cycle. In this commentary, we will discuss recent developments in patient-centered benefit-risk assessment and their relevance to the development of neural prosthetic systems. Published by Elsevier Inc. C1 [Benz, Heather L.] US FDA, Ctr Devices & Radiol Hlth, Off Ctr Director, 10903 New Hampshire Ave, Silver Spring, MD 20872 USA. [Civillico, Eugene F.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Biomed Phys, 10903 New Hampshire Ave, Silver Spring, MD 20872 USA. RP Benz, HL (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Ctr Director, 10903 New Hampshire Ave, Silver Spring, MD 20872 USA. EM heather.benz@fda.hhs.gov; eugene.civillico@fda.hhs.gov NR 39 TC 0 Z9 0 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 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD JAN PY 2017 VL 287 SI SI BP 486 EP 491 DI 10.1016/j.expneurol.2016.07.017 PN 4 PG 6 WC Neurosciences SC Neurosciences & Neurology GA EG6LU UT WOS:000391158800007 PM 27456271 ER PT J AU Weininger, S Jaffe, MB Rausch, T Goldman, JM AF Weininger, Sandy Jaffe, Michael B. Rausch, Tracy Goldman, Julian M. TI Capturing Essential Information to Achieve Safe Interoperability SO ANESTHESIA AND ANALGESIA LA English DT Article AB In this article, we describe the role of "clinical scenario" information to assure the safety of interoperable systems, as well as the system's ability to deliver the requisite clinical functionality to improve clinical care. Described are methods and rationale for capturing the clinical needs, workflow, hazards, and device interactions in the clinical environment. Key user (clinician and clinical engineer) needs and system requirements can be derived from this information, therefore, improving the communication from clinicians to medical device and information technology system developers. This methodology is intended to assist the health care community, including researchers, standards developers, regulators, and manufacturers, by providing clinical definition to support requirements in the systems engineering process, particularly those focusing on development of Integrated Clinical Environments described in standard ASTM F2761. Our focus is on identifying and documenting relevant interactions and medical device capabilities within the system using a documentation tool called medical device interface data sheets and mitigating hazardous situations related to workflow, product usability, data integration, and the lack of effective medical device-health information technology system integration to achieve safe interoperability. Portions of the analysis of a clinical scenario for a "patient-controlled analgesia safety interlock" are provided to illustrate the method. Collecting better clinical adverse event information and proposed solutions can help identify opportunities to improve current device capabilities and interoperability and support a learning health system to improve health care delivery. Developing and analyzing clinical scenarios are the first steps in creating solutions to address vexing patient safety problems and enable clinical innovation. A Web-based research tool for implementing a means of acquiring and managing this information, the Clinical Scenario Repository (TM) (MD PnP Program), is described. C1 [Weininger, Sandy] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Jaffe, Michael B.] Massachusetts Gen Hosp, MD PnP Program, Boston, MA 02114 USA. [Rausch, Tracy] DocBox, Newton, MA USA. [Goldman, Julian M.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Goldman, Julian M.] Partners HealthCare Syst, Boston, MA USA. RP Weininger, S (reprint author), US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM sandy.weininger@fda.hhs.gov FU Intramural FDA HHS [FD999999]; NIBIB NIH HHS [U01 EB012470] NR 18 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD JAN PY 2017 VL 124 IS 1 BP 83 EP 94 DI 10.1213/ANE.0000000000001351 PG 12 WC Anesthesiology SC Anesthesiology GA EF8WW UT WOS:000390613500013 PM 27387840 ER PT J AU Weininger, S Jaffe, MB Goldman, JM AF Weininger, Sandy Jaffe, Michael B. Goldman, Julian M. TI The Need to Apply Medical Device Informatics in Developing Standards for Safe Interoperable Medical Systems SO ANESTHESIA AND ANALGESIA LA English DT Article ID APNEA AB Medical device and health information technology systems are increasingly interdependent with users demanding increased interoperability. Related safety standards must be developed taking into account these systems' perspective. In this article, we describe the current development of medical device standards and the need for these standards to address medical device informatics. Medical device information should be gathered from a broad range of clinical scenarios to lay the foundation for safe medical device interoperability. Five clinical examples show how medical device informatics principles, if applied in the development of medical device standards, could help facilitate the development of safe interoperable medical device systems. These examples illustrate the clinical implications of the failure to capture important signals and device attributes. We provide recommendations relating to the coordination between historically separate Standards development groups, some of which focus on safety and effectiveness and others focus on health informatics. We identify the need for a shared understanding among stakeholders and describe organizational structures to promote cooperation such that device-to-device interactions and related safety information are considered during standards development. C1 [Weininger, Sandy] US FDA, Off Sci & Engn Labs, CDRH, Silver Spring, MD USA. [Jaffe, Michael B.; Goldman, Julian M.] Massachusetts Gen Hosp, MDPnP Program, Boston, MA 02114 USA. [Goldman, Julian M.] ISO, Geneva, Switzerland. [Goldman, Julian M.] AAMI, Arlington, VA USA. [Goldman, Julian M.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Goldman, Julian M.] Partners HealthCare Syst, Boston, MA USA. RP Weininger, S (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM sandy.weininger@fda.hhs.gov FU Intramural FDA HHS [FD999999]; NIBIB NIH HHS [U01 EB012470] NR 38 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 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD JAN PY 2017 VL 124 IS 1 BP 127 EP 135 DI 10.1213/ANE.0000000000001386 PG 9 WC Anesthesiology SC Anesthesiology GA EF8WW UT WOS:000390613500017 PM 27584685 ER PT J AU Marinho, PES de Oliveira, DB Candiani, TMS Crispim, APC Alvarenga, PPM Castro, FCD Abrahao, JS Rios, M Coimbra, RS Kroon, EG AF Silva Marinho, Paula Eillanny de Oliveira, Danii Bretas Sanchez Candiani, Talitah Michel Correia Crispim, Ana Paula Martins Alvarenga, Pedro Paulb dos Santos Castro, Fabrizia Cristina Abrahao, Jonatas Santos Rios, Maria Coimbra, Roney Santos Kroon, Erna Geessien TI Meningitis Associated with Simultaneous Infection by Multiple Dengue Virus Serotypes in Children, Brazil SO EMERGING INFECTIOUS DISEASES LA English DT Article AB To determine the causes of viral meningitis, we analyzed 22 cerebrospinal fluid samples collected during the 2014-2015 dengue epidemics in Brazil. We identified 3 serotypes of dengue virus (DENV-1, -2, and -3), as well as co-infection with 2 or 3 serotypes. We also detected the Asian II genotype of DENV-2. C1 [Silva Marinho, Paula Eillanny; de Oliveira, Danii Bretas; Correia Crispim, Ana Paula; Abrahao, Jonatas Santos; Kroon, Erna Geessien] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Sanchez Candiani, Talitah Michel; Martins Alvarenga, Pedro Paulb; dos Santos Castro, Fabrizia Cristina] Hosp Infantil Joao Paulo II, Belo Horizonte, MG, Brazil. [Rios, Maria] US FDA, Silver Spring, MD USA. [Coimbra, Roney Santos] Fundacao Oswaldo Cruz, Belo Horizonte, MG, Brazil. [de Oliveira, Danii Bretas] Univ Fed Vales Jequitinhonha & Mucuri, Teofilo Otoni, MG, Brazil. [Silva Marinho, Paula Eillanny; de Oliveira, Danii Bretas] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Microbiol, Lab Virus, Av Antonio Carlos 6627 Caixa Postal 486, BR-31270901 Belo Horizonte, MG, Brazil. RP Kroon, EG (reprint author), Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Microbiol, Lab Virus, Av Antonio Carlos 6627 Caixa Postal 486, BR-31270901 Belo Horizonte, MG, Brazil. EM kroone@icb.ufmg.br FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico; Coordenacdo de Aperfeicoamento de Pessoal de Nivel Superior; Fundacdo de Amparo a Pesquisa do Estado de Minas Gerais FX Financial support was provided by the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (to D.B.O. and E.G.K.), Coordenacdo de Aperfeicoamento de Pessoal de Nivel Superior (to P.E.S.M.), and Fundacdo de Amparo a Pesquisa do Estado de Minas Gerais. NR 14 TC 0 Z9 0 U1 2 U2 2 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD JAN PY 2017 VL 23 IS 1 BP 115 EP 118 DI 10.3201/eid2301.160817 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EG2AV UT WOS:000390836400020 PM 27983492 ER PT J AU Rouse, R Rosenzweig, B Shea, K Knapton, A Stewart, S Xu, L Chockalingam, A Zadrozny, L Thompson, K AF Rouse, Rodney Rosenzweig, Barry Shea, Katie Knapton, Alan Stewart, Sharron Xu, Lin Chockalingam, Ashok Zadrozny, Leah Thompson, Karol TI MicroRNA biomarkers of pancreatic injury in a canine model SO EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY LA English DT Article DE Biomarker; MicroRNA; Pancreas; Pancreatitis; miR-216a; miR-216b; miR-217; miR-375; miR-148a; Droplet digital PCR; Isomirs ID INDUCED LIVER-INJURY; SEQUENCING DATA; MIR-216A; ATLAS; DOG; TOXICITY; PLASMA; RAT AB Pancreas-enriched microRNAs have been experimentally investigated in rodents as candidate serum biomarkers of pancreatic injury with several different acute pancreatic injury models. In the present study, temporal and magnitude responses of exocrine pancreas-enriched miR-216a, miR-216b, and miR-217 and endocrine-enriched miR-375 and miR-148a were measured by droplet digital PCR in serum in a caerulein model of pancreatic injury in the dog. All 5 microRNAs followed a similar time course that mirrored the responses of the conventional serum pancreatic injury biomarkers, amylase and lipase. Detection was improved through the use of assays designed against microRNA isomers (isomirs) identified by sequencing. Serum biomarker increases were concordant with histopathology defined acinar cell injury. Minimal islet cell changes were noted. The pancreas-enriched microRNAs demonstrated similar or greater sensitivity, a larger range of response, and a higher correlation to acinar cell injury compared to amylase and lipase. Our results further support the translational potential of pancreas-enriched microRNAs as sensitive biomarkers of acinar cell injury with evidence from an additional non-clinical model system. Published by Elsevier GmbH. C1 [Rouse, Rodney; Rosenzweig, Barry; Shea, Katie; Knapton, Alan; Stewart, Sharron; Xu, Lin; Chockalingam, Ashok; Zadrozny, Leah; Thompson, Karol] US FDA, Ctr Drug Evaluat & Res, Off Translat Sci, Off Clin Pharmacol,Div Appl Regulatory Sci,White, HFD 910,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Rouse, R (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Translat Sci, Off Clin Pharmacol,Div Appl Regulatory Sci,White, HFD 910,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM rodney.rouse@fda.hhs.gov FU United States Food and Drug Administration FX The authors have no conflicts of interest to identify. All funding for this experimentation was received from the budget of the United States Food and Drug Administration. All of the authors have reviewed and approved this manuscript prior to submission. This manuscript describes the original work of the authors and has not been previously considered for publication. All materials are original. NR 39 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0940-2993 EI 1618-1433 J9 EXP TOXICOL PATHOL JI Exp. Toxicol. Pathol. PD JAN PY 2017 VL 69 IS 1 BP 33 EP 43 DI 10.1016/j.etp.2016.11.001 PG 11 WC Pathology; Toxicology SC Pathology; Toxicology GA EG3TQ UT WOS:000390968000005 PM 27866884 ER PT J AU Chiu, CY Jung, J Wang, YF Weeks, DE Wilson, AF Bailey-Wilson, JE Amos, CI Mills, JL Boehnke, M Xiong, MM Fan, RZ AF Chiu, Chi-Yang Jung, Jeesun Wang, Yifan Weeks, Daniel E. Wilson, Alexander F. Bailey-Wilson, Joan E. Amos, Christopher I. Mills, James L. Boehnke, Michael Xiong, Momiao Fan, Ruzong TI A comparison study of multivariate fixed models and Gene Association with Multiple Traits (GAMuT) for next-generation sequencing SO GENETIC EPIDEMIOLOGY LA English DT Article DE association mapping; common variants; complex traits; functional data analysis; multivariate analysis of variance (MANOVA); multivariate functional linear models (MFLM); quantitative trait loci; rare variants ID FUNCTIONAL LINEAR-MODELS; RARE-VARIANT ASSOCIATION; QUANTITATIVE TRAITS; COMPLEX DISEASES; LEVEL; PLEIOTROPY; METAANALYSIS; PHENOTYPES; NETWORK AB In this paper, extensive simulations are performed to compare two statistical methods to analyze multiple correlated quantitative phenotypes: (1) approximate F-distributed tests of multivariate functional linear models (MFLM) and additive models of multivariate analysis of variance (MANOVA), and (2) Gene Association with Multiple Traits (GAMuT) for association testing of high-dimensional genotype data. It is shown that approximate F-distributed tests of MFLM and MANOVA have higher power and are more appropriate for major gene association analysis (i.e., scenarios in which some genetic variants have relatively large effects on the phenotypes); GAMuT has higher power and is more appropriate for analyzing polygenic effects (i.e., effects from a large number of genetic variants each of which contributes a small amount to the phenotypes). MFLM and MANOVA are very flexible and can be used to perform association analysis for (i) rare variants, (ii) common variants, and (iii) a combination of rare and common variants. Although GAMuT was designed to analyze rare variants, it can be applied to analyze a combination of rare and common variants and it performs well when (1) the number of genetic variants is large and (2) each variant contributes a small amount to the phenotypes (i.e., polygenes). MFLM and MANOVA are fixed effect models that perform well for major gene association analysis. GAMuT can be viewed as an extension of sequence kernel association tests (SKAT). Both GAMuT and SKAT are more appropriate for analyzing polygenic effects and they perform well not only in the rare variant case, but also in the case of a combination of rare and common variants. Data analyses of European cohorts and the Trinity Students Study are presented to compare the performance of the two methods. C1 [Chiu, Chi-Yang; Fan, Ruzong] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, NIH, Bethesda, MD USA. [Jung, Jeesun] NIAAA, Lab Epidemiol & Biometry, NIH, Bethesda, MD USA. [Wang, Yifan] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Weeks, Daniel E.] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Wilson, Alexander F.; Bailey-Wilson, Joan E.] NHGRI, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. [Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, NIH, Bethesda, MD USA. [Amos, Christopher I.] Geisel Sch Med Dartmouth, Dept Biomed Data Sci, Lebanon, NH USA. [Boehnke, Michael] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Xiong, Momiao] Univ Texas Houston, Ctr Human Genet, Houston, TX USA. RP Fan, RZ (reprint author), Georgetown Univ, Dept Biostat Bioinformat & Biomath, Med Ctr, 4000 Reservoir Rd NW,Bldg D-180, Washington, DC 20057 USA. EM rf740@georgetown.edu OI Weeks, Daniel/0000-0001-9410-7228 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; Intramural Research Program of the National Human Genome Research Institute; National Institutes of Health, Bethesda, MD FX Two anonymous reviewers and the editors, Dr. Shete and Dr. Cordell, provided very good and insightful comments for us to improve the manuscript. We greatly thank the European cohorts groups for letting us analyze the data and using them as examples. Dr. Heather M. Stringham and Dr. Tanya M. Teslovich kindly sent us the data of the European cohorts and patiently answered many questions about the cohorts, and we greatly appreciate their help. This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R.F., C.-Y.C., and J.L.M.), by the Intramural Research Program of the National Human Genome Research Institute (A.F.W. and J.E.B.-W.), National Institutes of Health, Bethesda, MD. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 44 TC 0 Z9 0 U1 2 U2 2 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 JAN PY 2017 VL 41 IS 1 BP 18 EP 34 DI 10.1002/gepi.22014 PG 17 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA EG1OE UT WOS:000390801300002 PM 27917525 ER PT J AU Grinev, A Chancey, C Volkova, E Chizhikov, V Rios, M AF Grinev, Andriyan Chancey, Caren Volkova, Evgeniya Chizhikov, Vladimir Rios, Maria TI Development of a microarray-based assay for rapid monitoring of genetic variants of West Nile virus circulating in the United States SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE Flavivirus; West Nile virus; Microarray technology; Viral RNA isolation; Mutations; Genetic variability ID OLIGONUCLEOTIDE MICROARRAY; NORTH-AMERICA; PHYLOGENETIC ANALYSIS; EVOLUTION; GENOTYPE; STRAINS; PCR; RNA; DISCRIMINATION; IDENTIFICATION AB West Nile virus (WNV) has become endemic in the Western Hemisphere since its first introduction in the United States in 1999. An important factor associated with annual reoccurrence of WNV outbreaks in the U.S. is viral adaptation to domestic mosquitoes and birds through accumulation of spontaneous mutations in the WNV genome. Newly emerged mutations in the viral genome can potentially negatively affect the performance of existing diagnostic and screening assays and future vaccines. Therefore, the genetic monitoring of the WNV viral population during annual outbreaks is extremely important for public health and can only be achieved by application of efficient sample preparation methods followed by high throughput genetic analysis. In this study, we developed and evaluated a method for specific isolation of WNV genomic RNA from plasma samples without cultivation of the virus in cells. In combination with the microarray-based genetic analysis of the isolated WNV genomic RNA, this approach is suitable for fast, high throughput genotyping of circulating WNV genetic variants. The methods were evaluated using WNV isolates from the 1999-2012 U.S. epidemics. Published by Elsevier B.V. C1 [Grinev, Andriyan; Chancey, Caren; Volkova, Evgeniya; Rios, Maria] US FDA, LEP, DETTD, OBRR,CBER, Silver Spring, MD 20993 USA. [Chizhikov, Vladimir] US FDA, LMD, DVP, OVRR,CBER, Silver Spring, MD USA. RP Grinev, A; Rios, M (reprint author), US FDA, LEP, DETTD, OBRR,CBER, Silver Spring, MD 20993 USA. EM Andriyan.Grinev@fda.hhs.gov; Maria.Rios@fda.hhs.gov NR 41 TC 0 Z9 0 U1 2 U2 2 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 JAN PY 2017 VL 239 BP 17 EP 25 DI 10.1016/j.jviromet.2016.10.011 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA EF9AY UT WOS:000390624300003 PM 27793647 ER PT J AU Xu, RY Shieh, YC Stewart, DS AF Xu, Ruoyang Shieh, Y. Carol Stewart, Diana S. TI Comparison of RNA extraction kits for the purification and detection of an enteric virus surrogate on green onions via RT-PCR SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE RNA extraction; MS2 coliphage; Enteric virus; Green onions ID HEPATITIS-A VIRUS; REVERSE TRANSCRIPTION-PCR; GASTROENTERITIS OUTBREAK; MULTISTATE OUTBREAK; SENSITIVE DETECTION; SHELLFISH SAMPLES; WATER; NOROVIRUSES; VEGETABLES; ASSAYS AB Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) offers a rapid and sensitive molecular method for detection of enteric viruses. Unfortunately, these assays are often hampered by the low virus titre found in foods and PCR inhibition due to matrix carryover during RNA extraction. Four commercial RNA extraction kits (Qiagen's QIAamp Viral RNA Mini and UltraSens Virus kits, MoBio UltraClean Tissue & Cells RNA Isolation kit, and Ambion MagMAX Viral RNA Isolation kit) were evaluated for their ability to extract and purify MS2 bacteriophage RNA, an enteric virus surrogate, from inoculated green onions, a food which has been associated with viral gastroenteritis outbreaks. Inoculated green onion wash concentrates and green onion pieces with and without Qiagen QIAshredder homogenization were assayed in the kit comparison. MS2 detection and PCR inhibition were evaluated using a duplex real-time RT-PCR for MS2 and an exogenous internal amplification control (IAC) assay. Without homogenization, MS2 inoculated at 40 pfu/g was detected in at least 4 lots of green onion wash concentrates using the silica-membrane spin-column kits. Inhibition was a factor for the magnetic silica-based MagMAX kit, which resulted in detection of MS2 in 1 of 5. Addition of QlAshredder homogenization prior to extraction did not adversely affect the silica-membrane kit results but improved the MS2 detection by MagMAX to 5 of 5 lots. Use of a 1:10 dilution of primary RNA extracts also improved detection. The QIAamp Viral RNA Mini and MagMAX kits were further compared for detection of MS2 from green onion pieces inoculated at 20 and 5 pfu/g. Using homogenization, the MagMAX kit detected 20 pfu/g in only 1 of 2 green onion lots, whereas the QIAamp Viral RNA kit detected 2 of 2 lots at 5 pfu/g without homogenization. Published by Elsevier B.V. C1 [Xu, Ruoyang] Illinois Inst Technol, Inst Food Safety & Hlth, 6502 S Archer Rd, Bedford Pk, IL 60501 USA. [Shieh, Y. Carol; Stewart, Diana S.] US FDA, 6502 S Archer Rd, Bedford Pk, IL 60501 USA. RP Stewart, DS (reprint author), US FDA, 6502 S Archer Rd, Bedford Pk, IL 60501 USA. EM rhona.xry@hotmail.com; carol.shieh@fda.hhs.gov; diana.stewart@fda.hhs.gov FU U. S. Food and Drug Administration [5U01FD003801]; FDA Chief Scientist Challenge grant FX This study was supported in part by grant number 5U01FD003801 from the U. S. Food and Drug Administration to the Institute for Food Safety and Health of the Illinois Institute of Technology and a FDA Chief Scientist Challenge grant. The authors would like to thanks Drs. Mary Tortorello, Richard McDonald and Jason Wan for critical review of this manuscript. NR 38 TC 0 Z9 0 U1 7 U2 7 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 JAN PY 2017 VL 239 BP 61 EP 68 DI 10.1016/j.jviromet.2016.10.016 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA EF9AY UT WOS:000390624300010 PM 27836658 ER PT J AU McDiarmid, MA Gaitens, JM Hines, S Condon, M Roth, T Oliver, M Gucer, P Brown, L Centeno, JA Dux, M Squibb, KS AF McDiarmid, Melissa A. Gaitens, Joanna M. Hines, Stella Condon, Marian Roth, Tracy Oliver, Marc Gucer, Patricia Brown, Lawrence Centeno, Jose A. Dux, Moira Squibb, Katherine S. TI The US Department of Veterans' Affairs depleted uranium exposed cohort at 25 Years: Longitudinal surveillance results SO ENVIRONMENTAL RESEARCH LA English DT Article DE Uranium toxicity; Health surveillance; DU bio-monitoring ID GULF-WAR VETERANS; EMBEDDED FRAGMENTS; KIDNEY INJURY; HEALTH SURVEILLANCE; MASS-SPECTROMETRY; FOLLOW-UP; URINE; TOXICITY; BIOMARKERS; RATS AB Background: A small group of Gulf War I veterans wounded in depleted uranium (DU) friendly-fire incidents have been monitored for health changes in a clinical surveillance program at the Veterans Affairs Medical Center, Baltimore since 1994. Methods: During the spring of 2015, an in-patient clinical surveillance protocol was performed on 36 members of the cohort, including exposure monitoring for total and isotopic uranium concentrations in urine and a comprehensive assessment of health outcomes. Results: On-going mobilization of U from embedded fragments is evidenced by elevated urine U concentrations. The DU isotopic signature is observed principally in participants possessing embedded fragments. Those with only an inhalation exposure have lower urine U concentration and a natural isotopic signature. Conclusions: At 25 years since first exposure to DU, an aging cohort of military veterans continues to show no U-related health effects in known target organs of U toxicity. As U body burden continues to accrue from in-situ mobilization from metal fragment depots, and increases with exposure duration, critical tissue-specific U concentration thresholds may be reached, thus recommending on-going surveillance of this veteran cohort. C1 [McDiarmid, Melissa A.; Gaitens, Joanna M.; Hines, Stella; Condon, Marian; Roth, Tracy; Oliver, Marc; Gucer, Patricia; Brown, Lawrence; Dux, Moira; Squibb, Katherine S.] Dept Vet Affairs Med Ctr Baltimore, 10 N Greene St, Baltimore, MD 21201 USA. [McDiarmid, Melissa A.; Gaitens, Joanna M.; Hines, Stella; Roth, Tracy; Oliver, Marc; Gucer, Patricia; Squibb, Katherine S.] Univ Maryland, Sch Med, Dept Med, 655 W Baltimore S, Baltimore, MD 21201 USA. [Brown, Lawrence] Univ Maryland, Sch Med, Dept Pathol, 655 W Baltimore S, Baltimore, MD 21201 USA. [Centeno, Jose A.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. RP Condon, M (reprint author), Dept Vet Affairs Med Ctr Baltimore, 10 N Greene St, Baltimore, MD 21201 USA. EM mcondon@medicine.umaryland.edu FU U.S. Department of Veterans Affairs, a governmental agency providing medical care for veterans of military service FX This program is funded through the U.S. Department of Veterans Affairs, a governmental agency providing medical care for veterans of military service. We thank the staff and administration of the General Clinical Research Center at the University of Maryland Medical Systems Hospital, the Depleted Uranium Follow-Up Program administrative staff, and the Baltimore Veterans Administration Clinical Laboratories for their invaluable assistance. NR 67 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 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD JAN PY 2017 VL 152 BP 175 EP 184 DI 10.1016/j.envres.2016.10.016 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA EE5YD UT WOS:000389684600022 PM 27792941 ER PT J AU James, RH Landry, RJ Walker, BN Ilev, IK AF James, Robert H. Landry, Robert J. Walker, Bennett N. Ilev, Ilko K. TI EVALUATION OF THE POTENTIAL OPTICAL RADIATION HAZARDS WITH LED LAMPS INTENDED FOR HOME USE SO HEALTH PHYSICS LA English DT Article DE exposure, radiation; radiation, non-ionizing; risk analysis; safety standards ID ENERGY-SAVING LAMPS; INDIVIDUALS AB The authors evaluated the potential for ocular damage from optical radiation emitted by Light Emitting Diode (LED) based lamps used for general illumination. Ten LED lamps were randomly selected off the shelf from a local home improvement store. The LEDs were behind diffusers in half of these lamps, while in the other half, the LEDs were clearly visible. In addition, a battery powered LED lantern having a LED source behind a diffuser was measured. The optical radiation emissions from two common incandescent lamps were also measured to compare the relative hazards of LED and incandescent lamps. All lamp samples were evaluated in accordance with procedures specified in the American National Standards Institute/Illuminating Engineering Society of North America (ANSI/IESNA) Standard RP-27.3. For comparison purposes, the lantern and 100 W incandescent lamps were also evaluated according to ANSI RP-27.1. These measurements indicate that no lamp evaluated poses any photobiological hazard, and therefore, all lamps fall in the RP-27.3 category of Exempt Group. However, when evaluated in accordance with RP-27.1, the 100 W incandescent lamp would be classified in Risk Group 1 (low risk), while the LED lantern would be classified in Risk Group 2 (moderate risk). C1 [James, Robert H.; Landry, Robert J.; Walker, Bennett N.; Ilev, Ilko K.] US FDA, Opt Therapeut & Med Nanophoton Lab, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Walker, Bennett N.] US FDA, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Ilev, IK (reprint author), US FDA, Opt Therapeut & Med Nanophoton Lab, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM ilko.ilev@fda.hhs.gov NR 13 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 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JAN PY 2017 VL 112 IS 1 BP 11 EP 17 DI 10.1097/HP.0000000000000580 PG 7 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 EF6NL UT WOS:000390447700002 PM 27906783 ER PT J AU Cheng, C La Grenade, L Diak, IL Brinker, A Levin, RL AF Cheng, Carmen La Grenade, Lois Diak, Ida-Lina Brinker, Allen Levin, Robert L. TI Chemical Leukoderma Associated with Methylphenidate Transdermal System: Data From the US Food and Drug Administration Adverse Event Reporting System SO JOURNAL OF PEDIATRICS LA English DT Article ID DEPIGMENTATION; CONTACT; SKIN AB Objective To identify and characterize cases of chemical leukoderma, an underrecognized adverse event, associated with the methylphenidate transdermal system (MTS) reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS). Study design We searched the Food and Drug Administration Adverse Event Reporting System for reports of chemical leukoderma associated with MTS, received by the Food and Drug Administration from April 6, 2006 to December 23, 2014. Results We identified 51 cases of chemical leukoderma reported with the use of MTS. The median age was 11 years; 43 cases reported leukoderma at or near the application site only, and 7 reported leukoderma at other parts of the body in addition to the application site; 1 case did not provide enough information to confirm the affected site. The time to onset ranged from 2 months to 4 years after the initiation of MTS. MTS was discontinued in 31 cases. Thirteen patients were prescribed treatment for repigmentation. Three cases reported continued spread of leukoderma after MTS was discontinued. Nineteen cases were diagnosed as vitiligo, including 5 cases reporting histologic features consistent with vitiligo. Leukoderma was persistent in all cases. The median follow-up interval after the discontinuation of MTS in 23 cases was 14 months. Conclusions As outlined in recent changes to the prescribing information for MTS, health care professionals need to be aware of the potential risk of chemical leukoderma caused by MTS, especially given that chemical leukoderma is often misdiagnosed as idiopathic vitiligo. MTS should be discontinued at the earliest sign of pigment loss and other treatment options considered. C1 [Cheng, Carmen; La Grenade, Lois; Diak, Ida-Lina; Brinker, Allen; Levin, Robert L.] US FDA, Ctr Drug Evaluat & Res, Off Surveillance & Epidemiol, Silver Spring, MD USA. RP Cheng, C (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 22,Room 3433, Silver Spring, MD 20993 USA. EM Carmen.Cheng@fda.hhs.gov NR 26 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JAN PY 2017 VL 180 BP 241 EP 246 DI 10.1016/j.jpeds.2016.09.008 PG 6 WC Pediatrics SC Pediatrics GA EF0PL UT WOS:000390028100048 PM 27745746 ER PT J AU Sharma, D Sze, C Bhandari, H Nagarkar, V Badano, A AF Sharma, Diksha Sze, Christina Bhandari, Harish Nagarkar, Vivek Badano, Aldo TI Depth-of-interaction estimates in pixelated scintillator sensors using Monte Carlo techniques SO NUCLEAR INSTRUMENTS & METHODS IN PHYSICS RESEARCH SECTION A-ACCELERATORS SPECTROMETERS DETECTORS AND ASSOCIATED EQUIPMENT LA English DT Article DE Monte Carlo methods; Small-animal SPECT imaging; Depth-of-interaction estimation ID PET SCANNER; PERFORMANCE; DETECTORS; READOUT; SYSTEMS AB Image quality in thick scintillator detectors can be improved by minimizing parallax errors through depth-of interaction (DOI) estimation. A novel sensor for low-energy single photon imaging having a thick, transparent, crystalline pixelated micro-columnar CsI:Tl scintillator structure has been described, with possible future application in small-animal single photon emission computed tomography (SPECT) imaging when using thicker structures under development. In order to understand the fundamental limits of this new structure, we introduce cartesianDETECT2, an open-source optical transport package that uses Monte Carlo methods to obtain estimates of DOI for improving spatial resolution of nuclear imaging applications. Optical photon paths are calculated as a function of varying simulation parameters such as columnar surface roughness, bulk, and top surface absorption. We use scanning electron microscope images to estimate appropriate surface roughness coefficients. Simulation results are analyzed to model and establish patterns between DOI and photon scattering. The effect of varying starting locations of optical photons on the spatial response is studied. Bulk and top-surface absorption fractions were varied to investigate their effect on spatial response as a function of DOI. We investigated the accuracy of our DOI estimation model for a particular screen with various training and testing sets, and for all cases the percent error between the estimated and actual DOI over the majority of the detector thickness was +/- 5% with a maximum error of up to +/- 10% at deeper DOIs. In addition, we found that cartesianDETECT2 is computationally five times more efficient than MANUS. Findings indicate that DOI estimates can be extracted from a double-Gaussian model of the detector response. We observed that our model predicts DOI in pixelated scintillator detectors reasonably well. C1 [Sharma, Diksha; Badano, Aldo] US FDA, Div Imaging Diagnost & Software Reliabil, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Sze, Christina; Bhandari, Harish; Nagarkar, Vivek] Radiat Monitoring Devices Inc, Watertown, MA USA. [Sze, Christina] Drexel Coll Med, 2900 West Queen Lane, Philadelphia, PA 19129 USA. RP Badano, A (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM aldo.badano@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 FU National Institutes of Health (NIH) [1R43CA144078-01] FX This work was supported in part with National Institutes of Health (NIH) grant 1R43CA144078-01. NR 17 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-9002 EI 1872-9576 J9 NUCL INSTRUM METH A JI Nucl. Instrum. Methods Phys. Res. Sect. A-Accel. Spectrom. Dect. Assoc. Equip. PD JAN 1 PY 2017 VL 841 BP 117 EP 123 DI 10.1016/j.nima.2016.10.028 PG 7 WC Instruments & Instrumentation; Nuclear Science & Technology; Physics, Nuclear; Physics, Particles & Fields SC Instruments & Instrumentation; Nuclear Science & Technology; Physics GA EE2DQ UT WOS:000389394300016 ER PT J AU Petibone, DM Majeed, W Casciano, DA AF Petibone, Dayton M. Majeed, Waqar Casciano, Daniel A. TI Autophagy function and its relationship to pathology, clinical applications, drug metabolism and toxicity SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Review DE autophagy; drug toxicity; amphiphilic cationic drugs; phospholipidosis; disease progression; carcinogenesis; clinical applications ID OVARIAN-CANCER CELLS; POTENT HEPATOCARCINOGEN METHAPYRILENE; CELLULAR ACIDIC COMPARTMENTS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; TUMOR-SUPPRESSOR GENE; BECLIN 1 EXPRESSION; GASTRIC-CANCER; INDUCED PHOSPHOLIPIDOSIS; ALPHA-SYNUCLEIN; NEURODEGENERATIVE DISEASE AB Autophagy is a cellular process that facilitates nutrient turnover and removal of expended macromolecules and organelles to maintain homeostasis. The recycling of cytosolic macromolecules and damaged organelles by autophagosomes occurs through the lysosomal degradation pathway. Autophagy can also be upregulated as a prosurvival pathway in response to stress stimuli such as starvation, hypoxia or cell damage. Over the last two decades, there has been a surge in research revealing the basic molecular mechanisms of autophagy in mammalian cells. A corollary of an advanced understanding of autophagy has been a concurrent expansion of research into understanding autophagic function and dysfunction in pathology. Recent studies have revealed a pivotal role for autophagy in drug toxicity, and for utilizing autophagic components as diagnostic markers and therapeutic targets in treating disease and cancer. In this review, advances in understanding the molecular basis of mammalian autophagy, methods used to induce and evaluate autophagy, and the diverse interactions between autophagy and drug toxicity, disease progression and carcinogenesis are discussed. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Petibone, Dayton M.] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Majeed, Waqar; Casciano, Daniel A.] Univ Arkansas, Ctr Integrat Nanotechnol Sci, Little Rock, AR 72204 USA. RP Petibone, DM (reprint author), US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. EM dayton.petibone@fda.hhs.gov NR 212 TC 0 Z9 0 U1 41 U2 41 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 JAN PY 2017 VL 37 IS 1 BP 23 EP 37 DI 10.1002/jat.3393 PG 15 WC Toxicology SC Toxicology GA EC7DF UT WOS:000388295300003 PM 27682190 ER PT J AU Skoog, SA Lu, QJ Malinauskas, RA Sumant, AV Zheng, JW Goering, PL Narayan, RJ Casey, BJ AF Skoog, Shelby A. Lu, Qijin Malinauskas, Richard A. Sumant, Anirudha V. Zheng, Jiwen Goering, Peter L. Narayan, Roger J. Casey, Brendan J. TI Effects of nanotopography on the in vitro hemocompatibility of nanocrystalline diamond coatings SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A LA English DT Article DE nanocrystalline diamond; hemocompatibility; cardiovascular devices; nanostructured topography; blood ID PLATELET-ADHESION; RAMAN-SPECTROSCOPY; HUMAN BLOOD; BIOMEDICAL APPLICATIONS; MEDICAL APPLICATIONS; SURFACE-TOPOGRAPHY; TITANIUM-OXIDE; WEAR BEHAVIOR; ACTIVATION; IMPLANTS AB Nanocrystalline diamond (NCD) coatings have been investigated for improved wear resistance and enhanced hemocompatibility of cardiovascular devices. The goal of this study was to evaluate the effects of NCD surface nanotopography on in vitro hemocompatibility. NCD coatings with small (NCD-S) and large (NCD-L) grain sizes were deposited using microwave plasma chemical vapor deposition and characterized using scanning electron microscopy, atomic force microscopy, contact angle testing, and Raman spectroscopy. NCD-S coatings exhibited average grain sizes of 50-80 nm (RMS 5.8 nm), while NCD-L coatings exhibited average grain sizes of 200-280 nm (RMS 23.1 nm). In vitro hemocompatibility testing using human blood included protein adsorption, hemolysis, nonactivated partial thromboplastin time, platelet adhesion, and platelet activation. Both NCD coatings demonstrated low protein adsorption, a nonhemolytic response, and minimal activation of the plasma coagulation cascade. Furthermore, the NCD coatings exhibited low thrombogenicity with minimal platelet adhesion and aggregation, and similar morphological changes to surface-bound platelets (i.e., activation) in comparison to the HDPE negative control material. For all assays, there were no significant differences in the blood-material interactions of NCD-S versus NCD-L. The two tested NCD coatings, regardless of nanotopography, had similar hemocompatibility profiles compared to the negative control material (HDPE) and should be further evaluated for use in blood-contacting medical devices. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 253-264, 2017. C1 [Skoog, Shelby A.; Narayan, Roger J.] Univ N Carolina, Joint Dept Biomed Engn, Raleigh, NC 27695 USA. [Skoog, Shelby A.; Narayan, Roger J.] North Carolina State Univ, Raleigh, NC 27695 USA. [Skoog, Shelby A.; Lu, Qijin; Malinauskas, Richard A.; Zheng, Jiwen; Goering, Peter L.; Casey, Brendan J.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Sumant, Anirudha V.] Argonne Natl Lab, Ctr Nanoscale Mat, 9700 S Cass Ave, Argonne, IL 60439 USA. RP Skoog, SA (reprint author), Univ N Carolina, Joint Dept Biomed Engn, Raleigh, NC 27695 USA.; Skoog, SA (reprint author), North Carolina State Univ, Raleigh, NC 27695 USA.; Skoog, SA (reprint author), US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM Shelby.Skoog@FDA.HHS.GOV FU NSF/FDA [1136330]; U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; FDA FX Shelby Skoog was supported in part by an NSF/FDA Scholar-in-Residence Award #1136330. Use of the Center for Nanoscale Materials, Argonne National Laboratory, was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. The authors would like to acknowledge FDA intramural research funding and the FDA White Oak Nanotechnology Core Facility for instrument use, scientific, and technical assistance. NR 72 TC 0 Z9 0 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1549-3296 EI 1552-4965 J9 J BIOMED MATER RES A JI J. Biomed. Mater. Res. Part A PD JAN PY 2017 VL 105 IS 1 BP 253 EP 264 DI 10.1002/jbm.a.35872 PG 12 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA ED8UC UT WOS:000389145400026 PM 27543370 ER PT J AU Singh, T Kennedy, S Marynak, K Persoskie, A Melstrom, P King, BA AF Singh, Tushar Kennedy, Sara Marynak, Kristy Persoskie, Alexander Melstrom, Paul King, Brian A. TI Characteristics of Electronic Cigarette Use Among Middle and High School Students - United States, 2015 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Singh, Tushar; Kennedy, Sara; Marynak, Kristy; Melstrom, Paul; King, Brian A.] CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Singh, Tushar] CDC, Epidem Intelligence Serv, Atlanta, GA 30333 USA. [Persoskie, Alexander] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Singh, T (reprint author), CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA.; Singh, T (reprint author), CDC, Epidem Intelligence Serv, Atlanta, GA 30333 USA. EM tsingh@cdc.gov NR 10 TC 1 Z9 1 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 DEC 30 PY 2016 VL 65 IS 50-51 BP 1425 EP 1429 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EH7LJ UT WOS:000391954200002 PM 28033310 ER PT J AU Bottichio, L Medus, C Sorenson, A Donovan, D Sharma, R Dowell, N Williams, I Wellman, A Jackson, A Tolar, B Griswold, T Basler, C AF Bottichio, Lyndsay Medus, Carlota Sorenson, Alida Donovan, Danielle Sharma, Reeti Dowell, Natasha Williams, Ian Wellman, Allison Jackson, Alikeh Tolar, Beth Griswold, Taylor Basler, Colin TI Outbreak of Salmonella Oslo Infections Linked to Persian Cucumbers - United States, 2016 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Bottichio, Lyndsay; Dowell, Natasha; Williams, Ian; Tolar, Beth; Griswold, Taylor; Basler, Colin] CDC, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Medus, Carlota] Minnesota Dept Hlth, Minneapolis, MN 55414 USA. [Sorenson, Alida] Minnesota Dept Agr, St Paul, MN USA. [Donovan, Danielle] Michigan Dept Hlth & Human Serv, Lansing, MI USA. [Sharma, Reeti] Massachusetts Dept Publ Hlth, Boston, MA 02111 USA. [Wellman, Allison; Jackson, Alikeh] US FDA, Coordinated Outbreak Response & Evaluat Network, Silver Spring, MD USA. RP Bottichio, L (reprint author), CDC, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. EM xmm8@cdc.gov NR 4 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 DEC 30 PY 2016 VL 65 IS 50-51 BP 1430 EP 1433 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EH7LJ UT WOS:000391954200003 PM 28033312 ER PT J AU Johannesen, L Vicente, J Hosseini, M Strauss, DG AF Johannesen, Lars Vicente, Jose Hosseini, Meisam Strauss, David G. TI Automated Algorithm for J-T-peak and T-peak-T-end Assessment of Drug-Induced Proarrhythmia Risk SO PLOS ONE LA English DT Article ID LONG QT SYNDROME; CELLULAR-BASIS; REPOLARIZATION; HEART; WAVES; BLOCK; ECG; RANOLAZINE; DOFETILIDE; RECORDINGS AB Background Prolongation of the heart rate corrected QT (QTc) interval is a sensitive marker of torsade de pointes risk; however it is not specific as QTc prolonging drugs that block inward currents are often not associated with torsade. Recent work demonstrated that separate analysis of the heart rate corrected J-T(peak)c (J-T(peak)c) and T-peak-T-end intervals can identify QTc prolonging drugs with inward current block and is being proposed as a part of a new cardiac safety paradigm for new drugs (the "CiPA" initiative). Methods In this work, we describe an automated measurement methodology for assessment of the J-T(peak)c and T-peak-T-end intervals using the vector magnitude lead. The automated measurement methodology was developed using data from one clinical trial and was evaluated using independent data from a second clinical trial. Results Comparison between the automated and the prior semi-automated measurements shows that the automated algorithm reproduces the semi-automated measurements with a mean difference of single-deltas < 1 ms and no difference in intra-time point variability (p for all > 0.39). In addition, the time-profile of the baseline and placebo-adjusted changes are within 1 ms for 63% of the time-points (86% within 2 ms). Importantly, the automated results lead to the same conclusions about the electrophysiological mechanisms of the studied drugs. Conclusions We have developed an automated algorithm for assessment of J-T(peak)c and T-peak-T-end intervals that can be applied in clinical drug trials. Under the CiPA initiative this ECG assessment would determine if there are unexpected ion channel effects in humans compared to preclinical studies. The algorithm is being released as open-source software. C1 [Johannesen, Lars; Vicente, Jose; Hosseini, Meisam; Strauss, David G.] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Vicente, Jose] Univ Zaragoza, BSICoS Grp, Aragon Inst Engn Res I3A, IIS Aragon, Zaragoza, Spain. RP Johannesen, L; Strauss, DG (reprint author), US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Iars.johannesen@fda.hhs.gov; david.strauss@fda.hhs.gov OI Vicente, Jose/0000-0001-9963-1205 FU FDA's Critical Path Initiative, Office of Women's Health FX This project was supported by FDA's 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This project was supported by FDA's 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 39 TC 2 Z9 2 U1 10 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 30 PY 2016 VL 11 IS 12 AR e0166925 DI 10.1371/journal.pone.0166925 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG7LN UT WOS:000391229300004 PM 28036330 ER PT J AU Vicente, J Johannesen, L Hosseini, M Mason', JW Sager, PT Pueyo, E Strauss, DG AF Vicente, Jose Johannesen, Lars Hosseini, Meisam Mason', Jay W. Sager, Philip T. Pueyo, Esther Strauss, David G. TI Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block SO PLOS ONE LA English DT Article ID TORSADE-DE-POINTES; QT INTERVAL; MOXIFLOXACIN; PROLONGATION; REPOLARIZATION; RANOLAZINE AB Background Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the "CiPA" initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans. Methods and Results In this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected J-T-peak interval (J-T(peak)c), followed by QTc and then T-wave flatness. Furthermore, J-T(peak)c is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001). Conclusions Analysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-T(peak)c to detect the presence of late sodium current block. C1 [Vicente, Jose; Johannesen, Lars; Hosseini, Meisam; Strauss, David G.] US FDA, Div Appl Regulatory Sci, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Vicente, Jose; Hosseini, Meisam] US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Vicente, Jose; Pueyo, Esther] Univ Zaragoza, BSICoS Grp, Aragon Inst Engn Res I3A, IIS Aragon, Zaragoza, Spain. [Mason', Jay W.] Univ Utah, Div Cardiol, Salt Lake City, UT 84112 USA. [Mason', Jay W.] Spaulding Clin Res, West Bend, WI USA. [Sager, Philip T.] Stanford Univ, Palo Alto, CA 94304 USA. [Pueyo, Esther] Biomed Res Networking Ctr Bioengn Biomat & Nanome, Zaragoza, Spain. RP Vicente, J; Strauss, DG (reprint author), US FDA, Div Appl Regulatory Sci, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA.; Vicente, J (reprint author), US FDA, Div Biomed Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA.; Vicente, J (reprint author), Univ Zaragoza, BSICoS Grp, Aragon Inst Engn Res I3A, IIS Aragon, Zaragoza, Spain. EM jose.vicente@fda.hhs.gov; david.strauss@fda.hhs.gov OI Vicente, Jose/0000-0001-9963-1205 FU FDA's Critical Path Initiative, Office of Women's Health; Ministerio de Economia y Competitividad (MINECO), Spain [TIN2013-41998-R]; Grupo Consolidado BSICoS from DGA (Aragon); European Social Fund (EU) FX This project was supported by FDA's 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. Pueyo is funded by Ministerio de Economia y Competitividad (MINECO), Spain, under project TIN2013-41998-R and by Grupo Consolidado BSICoS from DGA (Aragon) and European Social Fund (EU). NR 33 TC 1 Z9 1 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 DEC 30 PY 2016 VL 11 IS 12 AR e0163619 DI 10.1371/journal.pone.0163619 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG7LN UT WOS:000391229300002 PM 28036334 ER PT J AU Fisher, AC Lee, SL Harris, DP Buhse, L Kozlowski, S Yu, L Kopcha, M Woodcock, J AF Fisher, Adam C. Lee, Sau L. Harris, Daniel P. Buhse, Lucinda Kozlowski, Steven Yu, Lawrence Kopcha, Michael Woodcock, Janet TI Advancing pharmaceutical quality: An overview of science and research in the US FDA's Office of Pharmaceutical Quality SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Review DE Pharmaceutical quality; Regulatory science; Emerging technology; Quality standards; Policy ID ABUSE DETERRENT FORMULATIONS; METASTATIC BREAST-CANCER; LIFE EXTENSION PROGRAM; IN-VITRO PERFORMANCE; DRUG SUBSTANCES NMR; THERAPEUTIC PROTEINS; WARFARIN SODIUM; MONOCLONAL-ANTIBODIES; GLATIRAMER ACETATE; PRODUCT QUALITY AB Failures surrounding pharmaceutical quality, particularly with respect to product manufacturing issues and facility remediation, account for the majority of drug shortages and product recalls in the United States. Major scientific advancements pressure established regulatory paradigms, especially in the areas of biosimilars, precision medicine, combination products, emerging manufacturing technologies, and the use of real-world data. Pharmaceutical manufacturing is increasingly globalized, prompting the need for more efficient surveillance systems for monitoring product quality. Furthermore, increasing scrutiny and accelerated approval pathways provide a driving force to be even more efficient with limited regulatory resources. To address these regulatory challenges, the Office of Pharmaceutical Quality (OPQ) in the Center for Drug Evaluation and Research (CDER) at the U.S. Food and Drug Administration (FDA) harbors a rigorous science and research program in core areas that support drug quality review, inspection, surveillance, standards, and policy development. Science and research is the foundation of risk-based quality assessment of new drugs, generic drugs, over-the-counter drugs, and biotechnology products including biosimilars. This is an overview of the science and research activities in OPQ that support the mission of ensuring that safe, effective, and high-quality drugs are available to the American public. Published by Elsevier B.V. C1 [Fisher, Adam C.; Lee, Sau L.; Harris, Daniel P.; Buhse, Lucinda; Kozlowski, Steven; Yu, Lawrence; Kopcha, Michael] US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Qual, Silver Spring, MD 20993 USA. [Woodcock, Janet] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Lee, SL (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Qual, Silver Spring, MD 20993 USA. EM sau.lee@fda.hhs.gov NR 102 TC 0 Z9 0 U1 42 U2 42 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD DEC 30 PY 2016 VL 515 IS 1-2 BP 390 EP 402 DI 10.1016/j.ijpharm.2016.10.038 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED8WD UT WOS:000389150700039 PM 27773853 ER PT J AU Dombi, E Baldwin, A Marcus, LJ Fisher, MJ Weiss, B Kim, A Whitcomb, P Martin, S Aschbacher-Smith, LE Rizvi, TA Wu, JQ Ershler, R Wolters, P Therrien, J Glod, J Belasco, JB Schorry, E Brofferio, A Starosta, AJ Gillespie, A Doyle, AL Ratner, N Widemann, BC AF Dombi, Eva Baldwin, Andrea Marcus, Leigh J. Fisher, Michael J. Weiss, Brian Kim, AeRang Whitcomb, Patricia Martin, Staci Aschbacher-Smith, Lindsey E. Rizvi, Tilat A. Wu, Jianqiang Ershler, Rachel Wolters, Pamela Therrien, Janet Glod, John Belasco, Jean B. Schorry, Elizabeth Brofferio, Alessandra Starosta, Amy J. Gillespie, Andrea Doyle, Austin L. Ratner, Nancy Widemann, Brigitte C. TI Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID FARNESYLTRANSFERASE INHIBITOR TIPIFARNIB; CONSORTIUM PHASE-II; CLINICAL-TRIALS; TUMOR-SUPPRESSOR; HYPERACTIVE RAS; MEK INHIBITION; SOLID TUMORS; YOUNG-ADULTS; CHILDREN; CANCER AB BACKGROUND Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling. METHODS We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma. RESULTS A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of >= 20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of >= 20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed. CONCLUSIONS Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.) C1 [Dombi, Eva; Baldwin, Andrea; Marcus, Leigh J.; Whitcomb, Patricia; Martin, Staci; Ershler, Rachel; Wolters, Pamela; Therrien, Janet; Glod, John; Starosta, Amy J.; Gillespie, Andrea; Widemann, Brigitte C.] Ctr Canc Res, Pediatr Oncol Branch, Bethesda, MD USA. [Doyle, Austin L.] Canc Therapy Evaluat Program, Shady Grove, MD USA. [Brofferio, Alessandra] NCI, Bethesda, MD 20892 USA. [Brofferio, Alessandra] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Marcus, Leigh J.; Ershler, Rachel] NIH, Silver Spring, MD USA. [Marcus, Leigh J.; Ershler, Rachel] US FDA, Silver Spring, MD USA. [Fisher, Michael J.; Belasco, Jean B.] Univ Penn, Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Fisher, Michael J.; Belasco, Jean B.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kim, AeRang] Childrens Natl Hlth Syst, Washington, DC USA. [Weiss, Brian; Aschbacher-Smith, Lindsey E.; Rizvi, Tilat A.; Wu, Jianqiang; Schorry, Elizabeth; Ratner, Nancy] Cincinnati Childrens Hosp, Cincinnati, OH USA. RP Widemann, BC (reprint author), NCI, Pediat Oncol Branch, 10 Ctr Dr,Bldg 10 CRC,Rm 1-3752,MSC 1101, Bethesda, MD 20892 USA. EM widemanb@mail.nih.gov FU National Institutes of Health FX Funded by the National Institutes of Health and others NR 43 TC 3 Z9 3 U1 5 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 29 PY 2016 VL 375 IS 26 BP 2550 EP 2560 DI 10.1056/NEJMoa1605943 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EG6SC UT WOS:000391175300008 PM 28029918 ER PT J AU Hirota, K Doty, AC Ackermann, R Zhou, J Olsen, KF Feng, MR Wang, Y Choi, S Qu, W Schwendeman, AS Schwendeman, SP AF Hirota, Keiji Doty, Amy C. Ackermann, Rose Zhou, Jia Olsen, Karl F. Feng, Meihua R. Wang, Yan Choi, Stephanie Qu, Wen Schwendeman, Anna S. Schwendeman, Steven P. TI Characterizing release mechanisms of leuprolide acetate-loaded PLGA microspheres for IVIVC development I: In vitro evaluation SO JOURNAL OF CONTROLLED RELEASE LA English DT Article; Proceedings Paper CT 14th European Symposium on Controlled Drug Delivery (ESCDD) CY APR 13-15, 2016 CL Egmond aan Zee, NETHERLANDS DE PLGA; Leuprolide; Microspheres; Release mechanisms; IVIVC ID BIODEGRADABLE POLY(D,L-LACTIDE); MICROCLIMATE PH; DRUG-RELEASE; VIVO; POLY(LACTIDE-CO-GLYCOLIDE); FILMS; MICROCAPSULES; PROFILES; IMPLANTS; ACID) AB Release testing of parental controlled release microspheres is an essential step in controlling quality and predicting the duration of efficacy. In the first of a two-part study, we examined the effect of various incubation media on release from leuprolide-loaded PLGA microspheres to understand the influence of external pH, plasticization, and buffer type on mechanism of accelerated release. PLGA 50/50 microspheres encapsulating similar to 5% w/w leuprolide were prepared by the double emulsion-solvent evaporation method with or without gelatin or by the self-healing encapsulation method. The microspheres were incubated at 37 degrees C up to 56 days in various media: pH 5.5, 6.5, and 7.4 phosphate buffered-saline (PBS) containing 0.02% Tween 80; pH 7.4 PBS containing 1.0% triethyl citrate (PBStc); and pH 7.4 HEPES buffered-saline containing 0.02% Tween 80 (all media contained 0.02% sodium azide). The recovered release media and microspheres were examined for released drug, polymer molecular weight (Mw), water uptake, mass loss, and BODIPY (green-fluorescent dye) diffusion coefficient in PLGA. After the initial burst release, release of leuprolide from acid-capped PLGA microspheres appeared to be controlled initially by erosion and then by a second mechanism after day 21, which likely consists of a combination of peptide desorption and/or water-mediated breakage of pore connections. PBStc and acidic buffers accelerated degradation of PLGA and pore-network development and increased BODIPY diffusion coefficient, resulting in faster release. Release of leuprolide from the end-capped PLGA showed similar trends as found with acid capped PLGA but with a longer lag time before release. These data provide a baseline mechanistic signature of in vitro release of leuprolide for future comparison with corresponding in vivo performance, and in turn could lead to future development of rational in vitro-in vivo correlations. (C) 2016 Published by Elsevier B.V. C1 [Hirota, Keiji; Doty, Amy C.; Ackermann, Rose; Zhou, Jia; Olsen, Karl F.; Feng, Meihua R.; Schwendeman, Anna S.; Schwendeman, Steven P.] Univ Michigan, Biointerfaces Inst, Dept Pharmaceut Sci, 2800 Plymouth Rd, Ann Arbor, MI 48109 USA. [Wang, Yan; Choi, Stephanie] US FDA, Off Gener Drugs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Qu, Wen] US FDA, Off Pharmaceut Qual, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Schwendeman, Steven P.] Univ Michigan, Dept Biomed Engn, 2800 Plymouth Rd, Ann Arbor, MI 48109 USA. [Hirota, Keiji] Chugai Pharmaceut Co Ltd, Prod Engn Dept, Kita Ku, 5-5-1 Ukima, Tokyo 1158543, Japan. [Doty, Amy C.] Merck Sharp & Dohme Corp, Pharmaceut Sci & Clin Supply, Discovery Pharmaceut Sci, 33 Ave Louis Pasteur, Boston, MA 02460 USA. RP Schwendeman, SP (reprint author), Univ Michigan, Biointerfaces Inst, Dept Pharmaceut Sci, 2800 Plymouth Rd, Ann Arbor, MI 48109 USA.; Schwendeman, SP (reprint author), Univ Michigan, Dept Biomed Engn, 2800 Plymouth Rd, Ann Arbor, MI 48109 USA. EM schwende@med.umich.edu OI Zhou, Jia/0000-0001-7168-5690 FU Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation Research (CDER) at the FDA [1U01FD005014] FX This work was financially supported by the Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation Research (CDER) at the FDA (1U01FD005014). This article reflects the views of the authors and should not be construed to represent FDA's views or policies. NR 40 TC 0 Z9 0 U1 5 U2 5 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 DEC 28 PY 2016 VL 244 BP 302 EP 313 DI 10.1016/j.jconrel.2016.08.023 PN B PG 12 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA EJ3RB UT WOS:000393128200017 PM 27565212 ER PT J AU Chen, C Fan, SH Li, C Chong, Y Tian, X Zheng, JW Fu, PP Jiang, XM Wamer, WG Yin, JJ AF Chen, Chao Fan, Sanhong Li, Chen Chong, Yu Tian, Xin Zheng, Jiwen Fu, Peter P. Jiang, Xiumei Wamer, Wayne G. Yin, Jun-jie TI Platinum nanoparticles inhibit antioxidant effects of vitamin C via ascorbate oxidase-mimetic activity SO JOURNAL OF MATERIALS CHEMISTRY B LA English DT Article ID PEROXIDASE-LIKE ACTIVITY; AT-PT NANOSTRUCTURES; ENZYME-LIKE ACTIVITY; SILVER NANOPARTICLES; GOLD NANOPARTICLES; CATALYTIC-ACTIVITY; CONSUMER PRODUCTS; HYDROGEN-PEROXIDE; SODIUM ASCORBATE; OXYGEN AB The development and application of nanomaterials as consumer products including food, drugs, and cosmetics are rapidly expanding. However, interactions between these novel materials and other chemical components of consumer products have not been thoroughly studied. Here, by using electron spin resonance techniques, we compared the effects of Au, Ag, and Pt nanoparticles (NPs) on the antioxidant activity of vitamin C (sodium L-ascorbate, NaA). Chemical studies showed that Pt NPs exhibit ascorbate oxidase-mimetic activity, thereby oxidizing NaA but Au and Ag NPs do not. This ascorbate oxidase-mimetic activity of Pt NPs results in a dramatic loss of antioxidant activity of NaA for scavenging hydroxyl radicals and superoxide radicals. A further study suggested that the ascorbate oxidase-mimetic activity of Pt NPs is critically dependent on the particle size. Finally, in vitro cell studies demonstrated that Pt NPs with ascorbate oxidase-mimetic activity inhibit the cytoprotective effect of NaA on cells challenged by oxidative stress. Our findings provide a better understanding of enzyme-mimicking NP interactions with naturally-occurring antioxidants and should guide future applications. C1 [Chen, Chao; Fan, Sanhong; Li, Chen] Shanxi Univ, Sch Life Sci, Taiyuan 030006, Peoples R China. [Chen, Chao; Chong, Yu; Tian, Xin] Soochow Univ, Sch Radiol & Interdisciplinary Sci RAD X, Collaborat Innovat Ctr Radiat Med, Jiangsu Higher Educ Inst, Suzhou 215123, Peoples R China. [Tian, Xin; Jiang, Xiumei; Wamer, Wayne G.; Yin, Jun-jie] US FDA, Div Bioanalyt Chem, College Pk, MD 20740 USA. [Tian, Xin; Jiang, Xiumei; Wamer, Wayne G.; Yin, Jun-jie] US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Zheng, Jiwen] US FDA, Div Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20903 USA. [Fu, Peter P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Fan, SH (reprint author), Shanxi Univ, Sch Life Sci, Taiyuan 030006, Peoples R China.; Tian, X (reprint author), Soochow Univ, Sch Radiol & Interdisciplinary Sci RAD X, Collaborat Innovat Ctr Radiat Med, Jiangsu Higher Educ Inst, Suzhou 215123, Peoples R China.; Tian, X; Yin, JJ (reprint author), US FDA, Div Bioanalyt Chem, College Pk, MD 20740 USA.; Tian, X; Yin, JJ (reprint author), US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM fsh729@sxu.edu.cn; xtian@suda.edu.cn; junjie.yin@fda.hhs.gov FU National Natural Science Foundation of China [31400862]; China Postdoctoral Science Foundation [2015M571797]; Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection; Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); FDA Nanotechnology CORES FX The authors acknowledge financial support from National Natural Science Foundation of China (31400862), China Postdoctoral Science Foundation (2015M571797), 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 regulatory science grant under the FDA Nanotechnology CORES. The authors appreciate Lili Fox Velez (Office of Regulatory Science, CFSAN) for her scientific writing support. The views presented in this paper do not necessarily represent those of the U.S. Food and Drug Administration. No official support or endorsement by the U.S. Food and Drug Administration is intended or should be inferred. NR 46 TC 0 Z9 0 U1 12 U2 12 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2050-750X EI 2050-7518 J9 J MATER CHEM B JI J. Mat. Chem. B PD DEC 28 PY 2016 VL 4 IS 48 BP 7895 EP 7901 DI 10.1039/c6tb02382g PG 7 WC Materials Science, Biomaterials SC Materials Science GA EH4XW UT WOS:000391778200013 ER PT J AU Pokrzywinski, KL Biel, TG Kryndushkin, D Rao, VA AF Pokrzywinski, Kaytee L. Biel, Thomas G. Kryndushkin, Dmitry Rao, V. Ashutosh TI Therapeutic Targeting of the Mitochondria Initiates Excessive Superoxide Production and Mitochondrial Depolarization Causing Decreased mtDNA Integrity SO PLOS ONE LA English DT Article ID CANCER CELL-DEATH; DNA COPY NUMBER; OXIDATIVE STRESS; PARKINSONS-DISEASE; ANTIOXIDANT MITOQ; POLYMERASE-GAMMA; 7S DNA; DAMAGE; MAINTENANCE; MITOQUINONE AB Mitochondrial dysregulation is closely associated with excessive reactive oxygen species (ROS) production. Altered redox homeostasis has been implicated in the onset of several diseases including cancer. Mitochondrial DNA (mtDNA) and proteins are particularly sensitive to ROS as they are in close proximity to the respiratory chain (RC). Mitoquinone (MitoQ), a mitochondria-targeted redox agent, selectively damages breast cancer cells possibly through damage induced via enhanced ROS production. However, the effects of MitoQ and other triphenylphosphonium (TPP+) conjugated agents on cancer mitochondrial homeostasis remain unknown. The primary objective of this study was to determine the impact of mitochondria-targeted agent [(MTAs) conjugated to TPP+: mitoTEMPOL, mitoquinone and mitochromanol-acetate] on mitochondrial physiology and mtDNA integrity in breast (MDA-MB-231) and lung (H23) cancer cells. The integrity of the mtDNA was assessed by quantifying the degree of mtDNA fragmentation and copy number, as well as by measuring mitochondrial proteins essential to mtDNA stability and maintenance (TFAM, SSBP1, TWINKLE, POLG and POLRMT). Mitochondrial status was evaluated by measuring superoxide production, mitochondrial membrane depolarization, oxygen consumption, extracellular acidification and mRNA or protein levels of the RC complexes along with TCA cycle activity. In this study, we demonstrated that all investigated MTAs impair mitochondrial health and decrease mtDNA integrity in MDA-MB-231 and H23 cells. However, differences in the degree of mitochondrial damage and mtDNA degradation suggest unique properties among each MTA that may be cell line, dose and time dependent. Collectively, our study indicates the potential for TPP+ conjugated molecules to impair breast and lung cancer cells by targeting mitochondrial homeostasis. C1 [Pokrzywinski, Kaytee L.; Biel, Thomas G.; Kryndushkin, Dmitry; Rao, V. Ashutosh] US FDA, Lab Appl Biochem, Div Biotechnol Res & Review 3, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Rao, VA (reprint author), US FDA, Lab Appl Biochem, Div Biotechnol Res & Review 3, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM ashutosh.rao@fda.hhs.gov NR 55 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 DEC 28 PY 2016 VL 11 IS 12 AR e0168283 DI 10.1371/journal.pone.0168283 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG7JB UT WOS:000391222000042 PM 28030582 ER PT J AU Daiquigan, N Grim, CJ White, JR Hanes, DE Jarvis, KG AF Daiquigan, Ninalynn Grim, Christopher J. White, James R. Hanes, Darcy E. Jarvis, Karen G. TI Early Recovery of Salmonella from Food Using a 6-Hour Non-selective Pre-enrichment and Reformulation of Tetrathionate Broth SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE Salmonella; FDA BAM; metagenomics; 16S rRNA; selective enrichment; tetrathionate broth ID ENRICHMENT CONDITIONS; SELECTIVE ENRICHMENT; RIBOSOMAL-RNA; MEDIA; SENSITIVITY; MICROBIOME; SEQUENCES; ALIGNMENT; PRODUCTS; OUTBREAK AB Culture based methods are commonly employed to detect pathogens in food and environmental samples. These methods are time consuming and complex, requiring multiple non-selective and selective enrichment broths, and usually take at least 1 week to recover and identify pathogens. Improving pathogen detection in foods is a primary goal for regulatory agencies and industry. Salmonella detection in food relies on a series of culture steps in broth formulations optimized to resuscitate Salmonella and reduce the abundance of competitive bacteria. Examples of non-selective pre-enrichment broths used to isolate Salmonella from food include Lactose, Universal Pre-enrichment, BPW, and Trypticase Soy broths. Tetrathionate (TT) and Rappaport-Vassiliadis (RV) broths are employed after a 24-h non-selective enrichment to select for Salmonella and hamper the growth of competitive bacteria. In this study, we tested a new formulation of TT broth that lacks brilliant green dye and has lower levels of TT . We employed this TT broth formulation in conjunction with a 6-h non-selective pre-enrichment period and determined that Salmonella recovery was possible one day earlier than standard food culture methods. We tested the shortened culture method in different non-selective enrichment broths, enumerated Salmonella in the non-selective enrichments, and used 16S rRNA gene sequencing to determine the proportional abundances of Salmonella in the TT and RV selective enrichments. Together these data revealed that a 6-h non-selective pre-enrichment reduces the levels of competitive bacteria inoculated into the selective TT and RV broths, enabling the recovery of Salmonella 1 day earlier than standard culture enrichment methods. C1 [Daiquigan, Ninalynn; Grim, Christopher J.; Hanes, Darcy E.; Jarvis, Karen G.] US FDA, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20740 USA. [Daiquigan, Ninalynn] Oak Ridge Inst Sci & Technol, Oak Ridge, TN USA. [White, James R.] Resphera Biosci, Baltimore, MD USA. RP Jarvis, KG (reprint author), US FDA, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20740 USA. EM karen.jarvis@fda.hhs.gov FU United States Food and Drug Administration; Oak Ridge Institute for Science and Education FX The work was funded by the United States Food and Drug Administration and the Oak Ridge Institute for Science and Education. NR 49 TC 0 Z9 0 U1 9 U2 9 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 DEC 27 PY 2016 VL 7 AR 2103 DI 10.3389/fmicb.2016.02103 PG 12 WC Microbiology SC Microbiology GA EF9QL UT WOS:000390664600001 ER PT J AU Savage, AF Kolev, NG Franklin, JB Vigneron, A Aksoy, S Tschudi, C AF Savage, Amy F. Kolev, Nikolay G. Franklin, Joseph B. Vigneron, Aurelien Aksoy, Serap Tschudi, Christian TI Transcriptome Profiling of Trypanosoma brucei Development in the Tsetse Fly Vector Glossina morsitans SO PLoS One LA English DT Article ID VARIANT SURFACE GLYCOPROTEIN; ADENYLATE CYCLASES; GENE-EXPRESSION; LIFE-CYCLE; AFRICAN TRYPANOSOMES; ANTIGEN REPERTOIRE; STAGE; DIFFERENTIATION; PROTEINS; RHODESIENSE AB African trypanosomes, the causative agents of sleeping sickness in humans and nagana in animals, have a complex digenetic life cycle between a mammalian host and an insect vector, the blood-feeding tsetse fly. Although the importance of the insect vector to transmit the disease was first realized over a century ago, many aspects of trypanosome development in tsetse have not progressed beyond a morphological analysis, mainly due to considerable challenges to obtain sufficient material for molecular studies. Here, we used high-throughput RNA-Sequencing (RNA-Seq) to profile Trypanosoma brucei transcript levels in three distinct tissues of the tsetse fly, namely the midgut, proventriculus and salivary glands. Consistent with current knowledge and providing a proof of principle, transcripts coding for procyclin isoforms and several components of the cytochrome oxidase complex were highly up-regulated in the midgut transcriptome, whereas transcripts encoding metacyclic VSGs (mVSGs) and the surface coat protein brucei alanine rich protein or BARP were extremely up-regulated in the salivary gland transcriptome. Gene ontology analysis also supported the upregulation of biological processes such as DNA metabolism and DNA replication in the proventriculus transcriptome and major changes in signal transduction and cyclic nucleotide metabolism in the salivary gland transcriptome. Our data highlight a small repertoire of expressed mVSGs and potential signaling pathways involving receptor-type adenylate cyclases and members of a surface carboxylate transporter family, called PADs (Proteins Associated with Differentiation), to cope with the changing environment, as well as RNA-binding proteins as a possible global regulators of gene expression. C1 [Savage, Amy F.; Kolev, Nikolay G.; Vigneron, Aurelien; Aksoy, Serap; Tschudi, Christian] Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT USA. [Franklin, Joseph B.] Yale Univ, Sch Med, Dept Cell Biol, New Haven, CT 06510 USA. [Savage, Amy F.] Bard Coll, Dept Biol, Annandale On Hudson, NY USA. [Franklin, Joseph B.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD USA. RP Aksoy, S; Tschudi, C (reprint author), Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT USA. EM serap.aksoy@yale.edu; christian.tschudi@yale.edu FU National Institutes of Health [AI051584, AI076879, AI028798, AI110325]; Ambrose-Monell Foundation FX This work was supported by National Institutes of Health (http://www.nih.gov) grants AI051584 and AI076879 to S.A. and AI028798 and AI110325 to C.T., and by the Ambrose-Monell Foundation (http://www.monellfoundation.org/) to S.A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 0 Z9 0 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 DEC 21 PY 2016 VL 11 IS 12 AR e0168877 DI 10.1371/journal.pone.0168877 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI9TW UT WOS:000392853100074 PM 28002435 ER PT J AU Califf, RM Sherman, RE Slavitt, A AF Califf, Robert M. Sherman, Rachel E. Slavitt, Andrew TI Knowing When and How to Use Medical Products A Shared Responsibility for the FDA and CMS SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Califf, Robert M.; Sherman, Rachel E.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Slavitt, Andrew] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. RP Califf, RM (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM robert.califf@fda.hhs.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 20 PY 2016 VL 316 IS 23 BP 2485 EP 2486 DI 10.1001/jama.2016.16734 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EG3QH UT WOS:000390959300012 PM 27820637 ER PT J AU Cao, LX Weetall, M Bombard, J Qi, HY Arasu, T Lennox, W Hedrick, J Sheedy, J Risher, N Brooks, PC Trifillis, P Trotta, C Moon, YC Babiak, J Almstead, NG Colacino, JM Davis, TW Peltz, SW AF Cao, Liangxian Weetall, Marla Bombard, Jenelle Qi, Hongyan Arasu, Tamil Lennox, William Hedrick, Jean Sheedy, Josephine Risher, Nicole Brooks, Peter C. Trifillis, Panayiota Trotta, Christopher Moon, Young-Choon Babiak, John Almstead, Neil G. Colacino, Joseph M. Davis, Thomas W. Peltz, Stuart W. TI Discovery of Novel Small Molecule Inhibitors of VEGF Expression in Tumor Cells Using a Cell-Based High Throughput Screening Platform SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; INTERNAL RIBOSOME ENTRY; FACTOR MESSENGER-RNA; TRANSLATION INITIATION COMPLEX; URIDINE-RICH ELEMENTS; POSTTRANSCRIPTIONAL REGULATION; GENE-EXPRESSION; CANCER-THERAPY; IN-VIVO; HYPOXIA AB Current anti-VEGF (Vascular Endothelial Growth Factor A) therapies to treat various cancers indiscriminately block VEGF function in the patient resulting in the global loss of VEGF signaling which has been linked to dose-limiting toxicities as well as treatment failures due to acquired resistance. Accumulating evidence suggests that this resistance is at least partially due to increased production of compensatory tumor angiogenic factors/cytokines. VEGF protein production is differentially controlled depending on whether cells are in the normal "homeostatic" state or in a stressed state, such as hypoxia, by post-transcriptional regulation imparted by elements in the 5' and 3' untranslated regions (UTR) of the VEGF mRNA. Using the Gene Expression Modulation by Small molecules (GEMS (TM)) phenotypic assay system, we performed a high throughput screen to identify low molecular weight compounds that target the VEGF mRNA UTR-mediated regulation of stress-induced VEGF production in tumor cells. We identified a number of compounds that potently and selectively reduce endogenous VEGF production under hypoxia in HeLa cells. Medicinal chemistry efforts improved the potency and pharmaceutical properties of one series of compounds resulting in the discovery of PTC-510 which inhibits hypoxia-induced VEGF expression in HeLa cells at low nanomolar concentration. In mouse xenograft studies, oral administration of PTC-510 results in marked reduction of intratumor VEGF production and single agent control of tumor growth without any evident toxicity. Here, we show that selective suppression of stress-induced VEGF production within tumor cells effectively controls tumor growth. Therefore, this approach may minimize the liabilities of current global anti-VEGF therapies. C1 [Cao, Liangxian; Weetall, Marla; Bombard, Jenelle; Qi, Hongyan; Arasu, Tamil; Lennox, William; Hedrick, Jean; Sheedy, Josephine; Risher, Nicole; Trifillis, Panayiota; Trotta, Christopher; Moon, Young-Choon; Babiak, John; Almstead, Neil G.; Colacino, Joseph M.; Davis, Thomas W.; Peltz, Stuart W.] PTC Therapeut Inc, South Plainfield, NJ 07080 USA. [Brooks, Peter C.] Maine Med Ctr, Res Inst, Ctr Mol Med, Scarborough, ME USA. [Arasu, Tamil] US FDA, Parsippany, NJ USA. [Davis, Thomas W.] PMV Pharmaceut Inc, Cedar Brook Corp Ctr, Cranbury Township, NJ USA. RP Cao, LX (reprint author), PTC Therapeut Inc, South Plainfield, NJ 07080 USA. EM lcao@ptcbio.com FU NIH [2 R44 CA108330-02]; PTC Therapeutics, Inc. FX This program was partially supported by funding from NIH to JMC and LXC (2 R44 CA108330-02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors [LC, MW, WL, JH, JS, NR, PT, CT, YM, JBabiak, NA, JMC, TD and SP], have received funding support for the conduct of this study and have also received salary compensation for time, effort, and reimbursed travel expenses related to data discussions and presentations from PTC Therapeutics, Inc. The specific roles of these authors are articulated in the 'author contributions' section. 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 DEC 16 PY 2016 VL 11 IS 12 AR e0168366 DI 10.1371/journal.pone.0168366 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI8LN UT WOS:000392758000042 PM 27992500 ER PT J AU Zhao, ZK Goldin, L Liu, SP Wu, L Zhou, WY Lou, H Yu, QC Tsang, SX Jiang, MM Li, FQ McMaster, M Li, Y Lin, XX Wang, ZF Xu, LQ Marti, G Li, GB Wu, K Yeager, M Yang, HM Xu, X Chanock, SJ Li, B Hou, Y Caporaso, N Dean, M AF Zhao, Zhikun Goldin, Lynn Liu, Shiping Wu, Liang Zhou, Weiyin Lou, Hong Yu, Qichao Tsang, Shirley X. Jiang, Miaomiao Li, Fuqiang McMaster, MaryLou Li, Yang Lin, Xinxin Wang, Zhifeng Xu, Liqin Marti, Gerald Li, Guibo Wu, Kui Yeager, Meredith Yang, Huanming Xu, Xun Chanock, Stephen J. Li, Bo Hou, Yong Caporaso, Neil Dean, Michael TI Evolution of multiple cell clones over a 29-year period of a CLL patient SO NATURE COMMUNICATIONS LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; SINGLE-CELL; EXPRESSION ANALYSIS; BIOLOGIC AGENTS; SEQUENCING DATA; R-PACKAGE; GENOME; CANCER; GENE AB Chronic lymphocytic leukaemia (CLL) is a frequent B-cell malignancy, characterized by recurrent somatic chromosome alterations and a low level of point mutations. Here we present single-nucleotide polymorphism microarray analyses of a single CLL patient over 29 years of observation and treatment, and transcriptome and whole-genome sequencing at selected time points. We identify chromosome alterations 13q14 -, 6q - and 12q+ in early cell clones, elimination of clonal populations following therapy, and subsequent appearance of a clone containing trisomy 12 and chromosome 10 copy-neutral loss of heterogeneity that marks a major population dominant at death. Serial single-cell RNA sequencing reveals an expression pattern with high FOS, JUN and KLF4 at disease acceleration, which resolves following therapy, but reoccurs following relapse and death. Transcriptome evolution indicates complex changes in expression occur over time. In conclusion, CLL can evolve gradually during indolent phases, and undergo rapid changes following therapy. C1 [Zhao, Zhikun; Liu, Shiping; Wu, Liang; Yu, Qichao; Jiang, Miaomiao; Li, Fuqiang; Li, Yang; Lin, Xinxin; Wang, Zhifeng; Xu, Liqin; Li, Guibo; Wu, Kui; Yang, Huanming; Xu, Xun; Li, Bo; Hou, Yong; Dean, Michael] BGI Shenzhen, Shenzhen 518083, Peoples R China. [Zhao, Zhikun] Southeast Univ, State Key Lab Bioelect, Nanjing 210096, Jiangsu, Peoples R China. [Zhao, Zhikun; Jiang, Miaomiao] Southeast Univ, Sch Biol Sci & Med Engn, Nanjing 210096, Jiangsu, Peoples R China. [Goldin, Lynn; McMaster, MaryLou; Chanock, Stephen J.; Caporaso, Neil; Dean, Michael] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Liu, Shiping] Sun Yat Sen Univ, Sch Life Sci, Guangzhou 510006, Guangdong, Peoples R China. [Zhou, Weiyin; Lou, Hong; Yeager, Meredith] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Leidos Biomed Res Inc, Bethesda, MD 20892 USA. [Yu, Qichao] Univ Chinese Acad Sci, BGI Educ Ctr, Shenzhen 518083, Peoples R China. [Tsang, Shirley X.] Biomatrix, Bethesda, MD 20849 USA. [Marti, Gerald] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Li, Guibo; Wu, Kui; Hou, Yong] Univ Copenhagen, Dept Biol, DK-1599 Copenhagen, Denmark. [Yang, Huanming] James D Watson Inst Genome Sci, Hangzhou 310058, Zhejiang, Peoples R China. RP Li, B; Hou, Y; Dean, M (reprint author), BGI Shenzhen, Shenzhen 518083, Peoples R China.; Caporaso, N; Dean, M (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.; Hou, Y (reprint author), Univ Copenhagen, Dept Biol, DK-1599 Copenhagen, Denmark. EM libo@genomics.cn; houyong@genomics.cn; caporasn@mail.nih.gov; deanm@mail.nih.gov FU Shenzhen Science and Technology Program [CXZZ20150330171838997]; Shenzhen Municipal Government of China [ZDSYS20140509153457495]; Science, Technology and Innovation Committee of Shenzhen Municipality [JSGG20140702161347218]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank Rongchang Chen, Weijian Rao, Xiaolong Zhang, Jie Wang, Zhanlong Mei, Xinlan Zhou, Nannan Li, Xulian Shi and Fatima Abbassi for help on data analysis and discussion, Kathleen Noer and the CCR Flow Cytometry Core for cell sorting. This project was supported by grants of the Shenzhen Science and Technology Program (CXZZ20150330171838997), the Shenzhen Municipal Government of China (ZDSYS20140509153457495) and the Science, Technology and Innovation Committee of Shenzhen Municipality (JSGG20140702161347218). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 47 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD DEC 16 PY 2016 VL 7 AR 13765 DI 10.1038/ncomms13765 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF4PX UT WOS:000390315600001 PM 27982015 ER PT J AU Mattos, RT Medeiros, NI Menezes, CA Fares, RCG Franco, EP Dutra, WO Rios-Santos, F Correa-Oliveira, R Gomes, JAS AF Mattos, Rafael T. Medeiros, Nayara I. Menezes, Carlos A. Fares, Rafaelle C. G. Franco, Eliza P. Dutra, Walderez O. Rios-Santos, Fabricio Correa-Oliveira, Rodrigo Gomes, Juliana A. S. TI Chronic Low-Grade Inflammation in Childhood Obesity Is Associated with Decreased IL-10 Expression by Monocyte Subsets SO PLOS ONE LA English DT Article ID HIV-INFECTED INDIVIDUALS; ADIPOSE-TISSUE; INSULIN-RESISTANCE; INNATE IMMUNITY; OXIDIZED LDL; BLOOD; CD36; DIFFERENTIATION; ANGIOGENESIS; MACROPHAGES AB Chronic low-grade inflammation is related to the development of comorbidities and poor prognosis in obesity. Monocytes are main sources of cytokines and play a pivotal role in inflammation. We evaluated monocyte frequency, phenotype and cytokine profile of monocyte subsets, to determine their association with the pathogenesis of childhood obesity. Children with obesity were evaluated for biochemical and anthropometric parameters. Monocyte subsets were characterized by flow cytometry, considering cytokine production and activation/ recognition molecules. Correlation analysis between clinical parameters and immunological data delineated the monocytes contribution for low-grade inflammation. We observed a higher frequency of non-classical monocytes in the childhood obesity group ( CO) than normal-weight group ( NW). All subsets displayed higher TLR4 expression in CO, but their recognition and antigen presentation functions seem to be diminished due to lower expression of CD40, CD80/86 and HLA-DR. All subsets showed a lower expression of IL-10 in CO and correlation analyses showed changes in IL-10 expression profile. The lower expression of IL-10 may be decisive for the maintenance of the low-grade inflammation status in CO, especially for alterations in non-classical monocytes profile. These cells may contribute to supporting inflammation and loss of regulation in the immune response of children with obesity. C1 [Mattos, Rafael T.; Medeiros, Nayara I.; Franco, Eliza P.; Dutra, Walderez O.; Gomes, Juliana A. S.] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Morfol, Lab Biol Interacoes Celulares, Belo Horizonte, MG, Brazil. [Medeiros, Nayara I.; Fares, Rafaelle C. G.; Correa-Oliveira, Rodrigo] Fiocruz MS, Ctr Pesquisa Rene Rachou, Lab Imunol Celular & Mol, Belo Horizonte, MG, Brazil. [Menezes, Carlos A.] Univ Estadual Santa Cruz, Dept Genet, Ilheus, BA, Brazil. [Menezes, Carlos A.] Unimed, Serv Med Prevent, Aracaju, SE, Brazil. [Dutra, Walderez O.; Correa-Oliveira, Rodrigo] Univ Fed Mato Grasso, INCT DT, Cuiaba, MT, Brazil. [Rios-Santos, Fabricio] Univ Fed Mato Grasso, Fac Med, Dept Ciencias Basicas Saude, Cuiaba, MT, Brazil. [Fares, Rafaelle C. G.] US FDA, Ctr Biol Evaluat & Res Silver Spring, Rockville, MD 20857 USA. RP Gomes, JAS (reprint author), Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Morfol, Lab Biol Interacoes Celulares, Belo Horizonte, MG, Brazil. EM juliana@icb.ufmg.br FU FAPEMIG; FAPEMIG/PROBIC; CNPq PQ Fellowship program FX RTM and NIM are received financial support from FAPEMIG. EPF received fellowship from FAPEMIG/PROBIC. WOD, RCO and JASG received financial support from CNPq PQ Fellowship program. NR 39 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 DEC 15 PY 2016 VL 11 IS 12 AR e0168610 DI 10.1371/journal.pone.0168610 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG7HN UT WOS:000391217400122 PM 27977792 ER PT J AU Allard, SM Walsh, CS Wallis, AE Ottesen, AR Brown, EW Micallef, SA AF Allard, Sarah M. Walsh, Christopher S. Wallis, Anna E. Ottesen, Andrea R. Brown, Eric W. Micallef, Shirley A. TI Solanum lycopersicum (tomato) hosts robust phyllosphere and rhizosphere bacterial communities when grown in soil amended with various organic and synthetic fertilizers SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Organic fertilization; Fruit microbiome; Flower microbiome; Vermicompost; Poultry manure; Soil characteristics ID MICROBIAL COMMUNITIES; FOOD SAFETY; CONTAMINATED MANURE; FARMING SYSTEM; DIVERSITY; COMPOST; PLANTS; SUCCESSION; GREENGENES; POPULATION AB Due to the intimate association between plants and their microbial symbionts, an examination of the influence of agricultural practices on phytobiome structure and diversity could foster a more comprehensive understanding of plant health and produce safety. Indeed, the impact of upstream crop producti006Fn practices cannot be overstated in their role in assuring an abundant and safe food supply. To assess whether fertilizer type impacted rhizosphere and phyllosphere bacterial communities associating with tomato plants, the bacterial microbiome of tomato cv. 'BEIN602' grown in soils amended with fresh poultry litter, commercially available sterilized poultry litter pellets, vermicompost or synthetic fertilizer was described. Culture independent DNA was extracted from bulk and rhizosphere soils, and washes of tomato blossoms and ripe fruit. PCR amplicons of hypervariable regions of the 16S rRNA gene were sequenced and profiled using the QIIME pipeline. Bulk and rhizosphere soil, and blossom and fruit surfaces all supported distinct bacterial communities according to principal coordinate analysis and ANOSIM (R = 0.87, p = 0.001 in year 1; R= 0.93,p = 0.001 in year 2). Use of microbiologically diverse organic fertilizers generally did not influence bacterial diversity, community structure or relative abundance of specific taxa on any plant organ surface. However, statistically significant differences in sand and silt contents of soil (p < 0.05) across the field and corresponding shifts in water activity were positively (R-2 = 0.52, p = 0.005) and negatively (R-2 = 0.48, p = 0.009) correlated with changes in bacterial community structure in the rhizosphere, respectively. Over two harvest seasons, this study demonstrated that the application of raw poultry manure, poultry litter pellets and vermicompost had little effect on the tomato microbiome in the rhizosphere and phyllosphere, when compared to synthetically fertilized plants. Plant anatomy, and other factors related to field location, possibly associated with edaphic and air characteristics, were more influential drivers of different tomato organ microbiomes than were diverse soil amendment applications. (C) 2016 Elsevier B.V. All rights reserved. C1 [Allard, Sarah M.; Walsh, Christopher S.; Wallis, Anna E.; Micallef, Shirley A.] Univ Maryland, Dept Plant Sci & Landscape Architecture, College Pk, MD 20742 USA. [Allard, Sarah M.; Ottesen, Andrea R.; Brown, Eric W.] US FDA, Div Microbiol, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Micallef, Shirley A.] Univ Maryland, Ctr Food Safety & Secur Syst, College Pk, MD USA. [Wallis, Anna E.] Cornell Cooperat Extens, Plattsburgh, NY USA. RP Micallef, SA (reprint author), Univ Maryland, Dept Plant Sci & Landscape Architecture, College Pk, MD 20742 USA. EM smicall@umd.edu FU Joint Institute for Food Safety and Applied Nutrition; United States Department of Agriculture, National Institute of Food and Agriculture [2014-68003-21588] FX This project was supported by the Joint Institute for Food Safety and Applied Nutrition and by the United States Department of Agriculture, National Institute of Food and Agriculture, award number 2014-68003-21588 to SAM. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 64 TC 0 Z9 0 U1 29 U2 29 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 EI 1879-1026 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD DEC 15 PY 2016 VL 573 BP 555 EP 563 DI 10.1016/j.scitotenv.2016.08.157 PG 9 WC Environmental Sciences SC Environmental Sciences & Ecology GA EF1FP UT WOS:000390071000051 PM 27580466 ER PT J AU Nunes, J Martins, IL Charneira, C Pogribny, IP de Conti, A Beland, FA Marques, MM Jacob, CC Antunes, AMM AF Nunes, Joao Martins, Ines L. Charneira, Catarina Pogribny, Igor P. de Conti, Aline Beland, Frederick A. Matilde Marques, M. Jacob, Cristina C. Antunes, Alexandra M. M. TI New insights into the molecular mechanisms of chemical carcinogenesis: In vivo adduction of histone H2B by a reactive metabolite of the chemical carcinogen furan SO TOXICOLOGY LETTERS LA English DT Article DE Histone adducts; Chemically induced cancers; Furan; Biomarkers ID COVALENT MODIFICATION; EPIGENETIC CHANGES; F344 RATS; DNA; IDENTIFICATION; HEPATOCARCINOGENESIS; GENOTOXICITY; ACETYLATION; PROTEINS; EXPOSURE AB Furan is a rodent hepatocarcinogen ubiquitously found in the environment and heat-processed foods. Furan undergoes cytochrome P450 2E1-catalyzed bioactivation to cis-2-butene-1,4-dial (BDA), which has been shown to form an electrophilic conjugate (GSH-BDA) with glutathione. Both BDA and GSH-BDA yield covalent adducts with lysine residues in proteins. Dose-and time-dependent epigenetic histone alterations have been observed in furan-treated rats. While the covalent modification of histones by chemical carcinogens has long been proposed, histone-carcinogen adducts have eluded detection in vivo. In this study, we investigated if the covalent modification of histones by furan may occur in vivo prior to epigenetic histone alterations. Using a "bottom-up" methodology, involving the analysis of tryptic peptides by liquid chromatography-high resolution mass spectrometry, we obtained evidence for a cross-link between GSH-BDA and lysine 107 of histone H2B isolated from the livers of male F344 rats treated with tumorigenic doses of furan. This cross-link was detected at the shortest treatment period (90 days) in the lowest dose group (0.92 mg/kg body weight/day), prior to the identification of epigenetic changes, and occurred at a lysine residue that is a target for epigenetic modifications and crucial for nucleosome stability. Our results represent the first unequivocal proof of the occurrence of carcinogen-modified histones in vivo and suggest that such modification happens at the initial stages of furan-induced carcinogenesis. This type of alteration may be general in scope, opening new insights into the mechanisms of chemical carcinogenesis/toxicity and new opportunities for the development of early compound-specific biomarkers of exposure. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Nunes, Joao; Martins, Ines L.; Charneira, Catarina; Matilde Marques, M.; Jacob, Cristina C.; Antunes, Alexandra M. M.] Univ Lisbon, Inst Super Tecn, Ctr Quim Estrutural, P-1049001 Lisbon, Portugal. [Pogribny, Igor P.; de Conti, Aline; Beland, Frederick A.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Antunes, AMM (reprint author), Univ Lisbon, Inst Super Tecn, Ctr Quim Estrutural, P-1049001 Lisbon, Portugal. EM alexandra.antunes@tecnico.ulisboa.pt RI Antunes, Alexandra/B-7871-2009 OI Antunes, Alexandra/0000-0003-1827-7369 FU Cefic-LRI Innovative Science Award; Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) [RECI/QEQ-MED/0330/2012, RECI/QEQ-QIN/0189/2012, IF/01091/2013/CP1163/CT0001, UID/QUI/00100/2013, SFRH/BD/75426/2010, SFRH/BD/102846/2014]; National Center for Toxicological Research/U.S. Food and Drug Administration [Y1ES1027]; U.S. National Institute of Environmental Health Sciences/National Toxicology Program [Y1ES1027]; European Social Fund [IF/01091/2013] FX This work was supported by a Cefic-LRI Innovative Science Award. We also acknowledge Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) (research grants RECI/QEQ-MED/0330/2012, RECI/QEQ-QIN/0189/2012, IF/01091/2013/CP1163/CT0001, and UID/QUI/00100/2013, and fellowships SFRH/BD/75426/2010 (to I.L.M.) and SFRH/BD/102846/2014 (to C.C.)), and Interagency Agreement Y1ES1027 between the National Center for Toxicological Research/U.S. Food and Drug Administration and the U.S. National Institute of Environmental Health Sciences/National Toxicology Program. A.M.M.A. also thanks Programa Operacional Potencial Humano from FCT and the European Social Fund (IF/01091/2013). NR 36 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 0378-4274 EI 1879-3169 J9 TOXICOL LETT JI Toxicol. Lett. PD DEC 15 PY 2016 VL 264 BP 106 EP 113 DI 10.1016/j.toxlet.2016.10.018 PG 8 WC Toxicology SC Toxicology GA EF7DB UT WOS:000390489200012 PM 27825936 ER PT J AU Califf, RM Robb, MA Bindman, AB Briggs, JP Collins, FS Conway, PH Coster, TS Cunningham, FE De Lew, N DeSalvo, KB Dymek, C Dzau, VJ Fleurence, RL Frank, RG Gaziano, M Kaufmann, P Lauer, M Marks, PW McGinnis, JM Richards, C Selby, JV Shulkin, DJ Shuren, J Slavitt, AM Smith, SR Washington, BV White, PJ Woodcock, J Woodson, J Sherman, RE AF Califf, Robert M. Robb, Melissa A. Bindman, Andrew B. Briggs, Josephine P. Collins, Francis S. Conway, Patrick H. Coster, Trinka S. Cunningham, Francesca E. De Lew, Nancy DeSalvo, Karen B. Dymek, Christine Dzau, Victor J. Fleurence, Rachael L. Frank, Richard G. Gaziano, Michael Kaufmann, Petra Lauer, Michael Marks, Peter W. McGinnis, J. Michael Richards, Chesley Selby, Joe V. Shulkin, David J. Shuren, Jeffrey Slavitt, Andrew M. Smith, Scott R. Washington, B. Vindell White, P. Jon Woodcock, Janet Woodson, Jonathan Sherman, Rachel E. TI Transforming Evidence Generation to Support Health and Health Care Decisions SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID TECHNOLOGY; GUIDELINES; SYSTEM C1 [Califf, Robert M.; Sherman, Rachel E.] US FDA, Off Commissioner, Silver Spring, MD USA. [Robb, Melissa A.; Sherman, Rachel E.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Marks, Peter W.] US FDA, Biol Evaluat & Res, Silver Spring, MD USA. [Shuren, Jeffrey] US FDA, Devices & Radiol Hlth, Silver Spring, MD USA. [Bindman, Andrew B.] Agcy Healthcare Res & Qual, Off Director, Rockville, MD USA. [Dymek, Christine] Agcy Healthcare Res & Qual, Ctr Evidence & Practice Improvement, Rockville, MD USA. [Briggs, Josephine P.] NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10, Bethesda, MD 20892 USA. [Collins, Francis S.] NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Kaufmann, Petra] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Lauer, Michael] NIH, Off Extramural Res Act, Bldg 10, Bethesda, MD 20892 USA. [Conway, Patrick H.; Slavitt, Andrew M.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. [Coster, Trinka S.] US Army, Off Surg Gen Pharmacovigilance Ctr, Falls Church, VA USA. [Shulkin, David J.] Dept Vet Affairs, Off Secretary Hlth, Washington, DC USA. [De Lew, Nancy; DeSalvo, Karen B.] Off Assistant Secretary Planning & Evaluat, Off Hlth Policy, Washington, DC USA. [DeSalvo, Karen B.] Off Assistant Secretary Hlth, Washington, DC USA. [Washington, B. Vindell; White, P. Jon] Off Natl Coordinator Hlth Informat Technol, Washington, DC USA. [Dzau, Victor J.; McGinnis, J. Michael] Natl Acad Med, Dept Hlth & Human Serv, Washington, DC USA. [Fleurence, Rachael L.; Selby, Joe V.] Patient Centered Outcomes Res Inst, Washington, DC USA. [Cunningham, Francesca E.] Dept Vet Affairs, Ctr Medicat Safety, Hines, IL USA. [Frank, Richard G.] Harvard Univ, Dept Hlth Care Policy, Boston, MA 02115 USA. [McGinnis, J. Michael] Brigham & Womens Hosp, Div Aging, Mill Veteran Program, Vet Affairs Boston Healthcare Syst, Boston, MA 02115 USA. [McGinnis, J. Michael] Harvard Med Sch, Boston, MA USA. [Woodson, Jonathan] Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA. [Richards, Chesley] Ctr Dis Control & Prevent, Off Publ Hlth Sci Serv, Atlanta, GA USA. RP Califf, RM (reprint author), US FDA, Off Commissioner, Silver Spring, MD USA. NR 13 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 15 PY 2016 VL 375 IS 24 BP 2395 EP 2400 DI 10.1056/NEJMsb1610128 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA EF0SO UT WOS:000390036500014 PM 27974039 ER PT J AU Liu, JK Zhao, JQ Petrochenko, P Zheng, JW Hewlett, I AF Liu, Jikun Zhao, Jiangqin Petrochenko, Peter Zheng, Jiwen Hewlett, Indira TI Sensitive detection of influenza viruses with Europium nanoparticles on an epoxy silica sol-gel functionalized polycarbonate-polydimethylsiloxane hybrid microchip SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE Influenza; Europium nanoparticle; Immunoassay; Sol-gel coating; Surface functionalization; Lab-on-a-chip ID TIME-RESOLVED FLUORESCENCE; MICROFLUIDIC SYSTEM; DISEASE DIAGNOSIS; RAPID DETECTION; UNITED-STATES; MORTALITY; ANTIGEN; AMPLIFICATION; IMMUNOASSAYS; FABRICATION AB In an effort to develop new tools for diagnosing influenza in resource-limited settings, we fabricated a polycarbonate (PC)-polydimethylsiloxane (PDMS) hybrid microchip using a simple epoxy silica sol-gel coating/bonding method and employed it in sensitive detection of influenza virus with Europium nanoparticles (EuNPs). The incorporation of sol-gel material in device fabrication provided functionalized channel surfaces ready for covalent immobilization of primary antibodies and a strong bonding between PDMS substrates and PC supports without increasing background fluorescence. In microchip EuNP immunoassay (mu ENIA) of inactivated influenza viruses, replacing native PDMS microchips with hybrid microchips allowed the achievement of a 6-fold increase in signal-to-background ratio, a 12-fold and a 6-fold decreases in limit-of-detection (LOD) in influenza A and B tests respectively. Using influenza A samples with known titers, the LOD of influenza mu ENIA on hybrid microchips was determined to be similar to 10(4) TCID50 titer/mL and 10(3)-10(4) EID50 titer/mL. A comparison test indicated that the sensitivity of influenza mu ENIA enhanced using the hybrid microchips even surpassed that of a commercial laboratory influenza ELISA test. In addition to the sensitivity improvement, assay variation was clearly reduced when hybrid microchips instead of native PDMS microchips were used in the mu ENIA tests. Finally, infectious reference viruses and nasopharyngeal swab patient specimens were successfully tested using mu ENIA on hybrid microchip platforms, demonstrating the potential of this unique microchip nanoparticle assay in clinical diagnosis of influenza. Meanwhile, the tests showed the necessity of using nucleic acid confirmatory tests to clarify ambiguous test results obtained from prototype or developed point-of-care testing devices for influenza diagnosis. Published by Elsevier B.V. C1 [Liu, Jikun; Zhao, Jiangqin; Hewlett, Indira] US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Petrochenko, Peter; Zheng, Jiwen] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Liu, JK; Hewlett, I (reprint author), US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Jikun.Liu@fdh.hhs.gov; Indira.Hewlett@fda.hhs.gov FU National Heart, Lung and Blood Institute (NHLBI) [Nano IAA-Y1-HB-8027-01]; FDA Medical Countermeasures Initiative (CORES) Nanotechnology Grant; Oak Ridge Institute for Science and Education (ORISE) FX This work was supported financially by the National Heart, Lung and Blood Institute (NHLBI, Nano IAA-Y1-HB-8027-01), FDA Medical Countermeasures Initiative (CORES) FY15 Nanotechnology Grant and Oak Ridge Institute for Science and Education (ORISE). We would like to acknowledge the FDA White Oak Nanotechnology Core Facility for instrument use and technical assistance. We are also grateful to Drs. Yi Wang and Kenneth Phillips at OSEL/CDRH for the help in the operation of plasma cleaner. Finally, we would like to thank Drs. Xue Wang and Krishnakumar Devadas for review of the manuscript. NR 37 TC 1 Z9 1 U1 58 U2 58 PU ELSEVIER ADVANCED TECHNOLOGY PI OXFORD PA OXFORD FULFILLMENT CENTRE THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-5663 EI 1873-4235 J9 BIOSENS BIOELECTRON JI Biosens. Bioelectron. PD DEC 15 PY 2016 VL 86 BP 150 EP 155 DI 10.1016/j.bios.2016.06.044 PG 6 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA DY1KG UT WOS:000384853300023 ER PT J AU Chitranshi, P da Costa, GG AF Chitranshi, Priyanka da Costa, Goncalo Gamboa TI Simple and rapid quantification of brominated vegetable oil in commercial soft drinks by LC-MS SO FOOD CHEMISTRY LA English DT Article DE Brominated vegetable oil; BVO; Soft drinks; LC-MS; Method validation ID LIQUID-CHROMATOGRAPHY AB We report here a simple and rapid method for the quantification of brominated vegetable oil (BVO) in soft drinks based upon liquid chromatography-electrospray ionization mass spectrometry. Unlike previously reported methods, this novel method does not require hydrolysis, extraction or derivatization steps, but rather a simple "dilute and shoot" sample preparation. The quantification is conducted by mass spectrometry in selected ion recording mode and a single point standard addition procedure. The method was validated in the range of 5-25 mu g/mL BVO, encompassing the legal limit of 15 mu g/mL established by the US FDA for fruit-flavored beverages in the US market. The method was characterized by excellent intra-and inter-assay accuracy (97.3-103.4%) and very low imprecision [0.5-3.6% (RSD)]. The direct nature of the quantification, simplicity, and excellent statistical performance of this methodology constitute clear advantages in relation to previously published methods for the analysis of BVO in soft drinks. Published by Elsevier Ltd. C1 [Chitranshi, Priyanka; da Costa, Goncalo Gamboa] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP da Costa, GG (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM goncalo.gamboa@fda.hhs.gov OI Chitranshi, Priyanka/0000-0003-3825-0307 FU Oak Ridge Institute for Science and Education FX PC acknowledges support of a fellowship from the Oak Ridge Institute for Science and Education, administered through an interagency agreement between US Department of Energy and the FDA. NR 12 TC 0 Z9 0 U1 80 U2 80 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 DEC 15 PY 2016 VL 213 BP 567 EP 570 DI 10.1016/j.foodchem.2016.06.110 PG 4 WC Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics SC Chemistry; Food Science & Technology; Nutrition & Dietetics GA DS0MM UT WOS:000380289900072 PM 27451219 ER PT J AU Leigh, JK MacMahon, S AF Leigh, Jessica K. MacMahon, Shaun TI Extraction and Liquid Chromatography-Tandem Mass Spectrometry Detection of 3-Monochloropropanediol Esters and Glycidyl Esters in Infant Formula SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE 3-monochloropropanediol; 3-MCPD; 3-MCPD esters; glycidol; glycidyl esters; processing contaminants; infant formula; fat extraction ID FATTY-ACID ESTERS; ELAEIS-GUINEENSIS OIL; EDIBLE OILS; 3-CHLORO-1,2-PROPANEDIOL 3-MCPD; MCPD ESTERS; 3-CHLOROPROPANE-1,2-DIOL 3-MCPD; PROCESSING CONTAMINANTS; LC-MS/MS; 2-MCPD; MONOCHLOROPROPANEDIOL AB A method was developed for the extraction of fatty acid esters of 3-chloro-1,2-propanediol (3-MCPD) and glycidol from infant formula, followed by quantitative analysis of the extracts using liquid chromatography tandem mass spectrometry (LC-MS/MS). These process-induced chemical contaminants are found in refined vegetable oils, and studies have shown that they are potentially carcinogenic and/or genotoxic, making their presence in edible oils (and processed foods containing these oils) a potential health risk. The extraction procedure involves a liquid liquid extraction, where powdered infant formula is dissolved in water and extracted with ethyl acetate. Following shaking, centrifugation, and drying of the organic phase, the resulting fat extract is cleaned-up using solid-phase extraction and analyzed by LC-MS/MS. Method performance was confirmed by verifying the percent recovery of each 3-MCPD and glycidyl ester in a homemade powdered infant formula reference material. Average ester recoveries in the reference material ranged from 84.9 to 109.0% (0.6-9.5% RSD). The method was also validated by fortifying three varieties of commercial infant formulas with a 3-MCPD and glycidyl ester solution. Average recoveries of the esters across all concentrations and varieties of infant formula ranged from 88.7 to 107.5% (1.0-9.5% RSD). Based on the validation results, this method is suitable for producing 3-MCPD and glycidyl ester occurrence data in all commercially available varieties of infant formula. C1 [Leigh, Jessica K.; MacMahon, Shaun] US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr, College Pk, MD 20740 USA. RP Leigh, JK (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr, College Pk, MD 20740 USA. EM jessica.leigh@fda.hhs.gov NR 43 TC 1 Z9 1 U1 9 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD DEC 14 PY 2016 VL 64 IS 49 BP 9442 EP 9451 DI 10.1021/acs.jafc.6b04361 PG 10 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA EE9RC UT WOS:000389962900022 PM 27960288 ER PT J AU Shah, SN Gelderman, MP Lewis, EMA Farrel, J Wood, F Strader, MB Alayash, AI Vostal, JG AF Shah, Sandeep N. Gelderman, Monique P. Lewis, Emily M. A. Farrel, John Wood, Francine Strader, Michael Brad Alayash, Abdu I. Vostal, Jaroslav G. TI Evaluation of Stem Cell-Derived Red Blood Cells as a Transfusion Product Using a Novel Animal Model SO PLOS ONE LA English DT Article ID HUMAN ERYTHROID PROGENITORS; EX-VIVO GENERATION; HEMATOPOIETIC STEM; FETAL-HEMOGLOBIN; IN-VITRO; HEREDITARY PERSISTENCE; GENE-EXPRESSION; CORD BLOOD; ENUCLEATION; MICE AB Reliance on volunteer blood donors can lead to transfusion product shortages, and current liquid storage of red blood cells (RBCs) is associated with biochemical changes over time, known as 'the storage lesion'. Thus, there is a need for alternative sources of transfusable RBCs to supplement conventional blood donations. Extracorporeal production of stem cellderived RBCs (stemRBCs) is a potential and yet untapped source of fresh, transfusable RBCs. A number of groups have attempted RBC differentiation from CD34(+) cells. However, it is still unclear whether these stemRBCs could eventually be effective substitutes for traditional RBCs due to potential differences in oxygen carrying capacity, viability, deformability, and other critical parameters. We have generated ex vivo stemRBCs from primary human cord blood CD34(+) cells and compared them to donor-derived RBCs based on a number of in vitro parameters. In vivo, we assessed stemRBC circulation kinetics in an animal model of transfusion and oxygen delivery in a mouse model of exercise performance. Our novel, chronically anemic, SCID mouse model can evaluate the potential of stemRBCs to deliver oxygen to tissues (muscle) under resting and exercise-induced hypoxic conditions. Based on our data, stem cell-derived RBCs have a similar biochemical profile compared to donor-derived RBCs. While certain key differences remain between donor-derived RBCs and stemRBCs, the ability of stemRBCs to deliver oxygen in a living organism provides support for further development as a transfusion product. C1 [Shah, Sandeep N.; Gelderman, Monique P.; Lewis, Emily M. A.; Farrel, John; Vostal, Jaroslav G.] US FDA, Lab Cellular Hematol, Div Hematol Res & Review, Off Blood Res & Review,Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Wood, Francine; Strader, Michael Brad; Alayash, Abdu I.] US FDA, Lab Biochem & Vasc Biol, Div Hematol Res & Review, Off Blood Res & Review,Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Vostal, JG (reprint author), US FDA, Lab Cellular Hematol, Div Hematol Res & Review, Off Blood Res & Review,Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Jaroslav.Vostal@fda.hhs.gov FU FDA Critical Path research funding FX Funding for this project came through FDA Critical Path research funding. NR 50 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 DEC 13 PY 2016 VL 11 IS 12 DI 10.1371/journal.pone.0166657 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI8JY UT WOS:000392753900004 ER PT J AU Lewis, RJ Calis, KA DeMets, DL AF Lewis, Roger J. Calis, Karim A. DeMets, David L. TI Enhancing the Scientific Integrity and Safety of Clinical Trials Recommendations for Data Monitoring Committees SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Lewis, Roger J.] Harbor UCLA Med Ctr, Dept Emergency Med, 1000 W Carson St,Bldg D9, Torrance, CA 90509 USA. [Lewis, Roger J.] Berry Consultants LLC, Austin, TX USA. [Calis, Karim A.] US FDA, Ctr Drug Evaluat & Res, Off Med Policy, Silver Spring, MD USA. [Calis, Karim A.] NICHHD, NIH, Bethesda, MD 20892 USA. [DeMets, David L.] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53706 USA. RP Lewis, RJ (reprint author), Harbor UCLA Med Ctr, Dept Emergency Med, 1000 W Carson St,Bldg D9, Torrance, CA 90509 USA. EM roger@emedharbor.edu FU FDA HHS [R18 FD005292, U19 FD003800] NR 1 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 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 13 PY 2016 VL 316 IS 22 BP 2359 EP 2360 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EE8OE UT WOS:000389884600013 PM 27960001 ER PT J AU Leonard, SR Mammel, MK Lacher, DW Elkins, CA AF Leonard, Susan R. Mammel, Mark K. Lacher, David W. Elkins, Christopher A. TI Strain-Level Discrimination of Shiga Toxin-Producing Escherichia coli in Spinach Using Metagenomic Sequencing SO PLOS ONE LA English DT Article ID OUTBREAK DETECTION; FLAGELLIN GENES; INFECTIONS; ALIGNMENT; O157-H7; FOOD AB Consumption of fresh bagged spinach contaminated with Shiga toxin-producing Escherichia coli (STEC) has led to severe illness and death; however current culture-based methods to detect foodborne STEC are time consuming. Since not all STEC strains are considered pathogenic to humans, it is crucial to incorporate virulence characterization of STEC in the detection method. In this study, we assess the comprehensiveness of utilizing a shotgun metagenomics approach for detection and strain-level identification by spiking spinach with a variety of genomically disparate STEC strains at a low contamination level of 0.1 CFU/g. Molecular serotyping, virulence gene characterization, microbial community analysis, and E. coli core gene single nucleotide polymorphism (SNP) analysis were performed on metagenomic sequence data from enriched samples. It was determined from bacterial community analysis that E. coli, which was classified at the phylogroup level, was a major component of the population in most samples. However, in over half the samples, molecular serotyping revealed the presence of indigenous E. coli which also contributed to the percent abundance of E. coli. Despite the presence of additional E. coli strains, the serotype and virulence genes of the spiked STEC, including correct Shiga toxin subtype, were detected in 94% of the samples with a total number of reads per sample averaging 2.4 million. Variation in STEC abundance and/or detection was observed in replicate spiked samples, indicating an effect from the indigenous microbiota during enrichment. SNP analysis of the metagenomic data correctly placed the spiked STEC in a phylogeny of related strains in cases where the indigenous E. coli did not predominate in the enriched sample. Also, for these samples, our analysis demonstrates that strain-level phylogenetic resolution is possible using shotgun metagenomic data for determining the genomic relatedness of a contaminating STEC strain to other closely related E. coli. C1 [Leonard, Susan R.; Mammel, Mark K.; Lacher, David W.; Elkins, Christopher A.] US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Leonard, SR (reprint author), US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. EM Susan.Leonard@fda.hhs.gov FU Oak Ridge Institute for Science and Education FX SRL was supported by a fellowship appointment administered by Oak Ridge Institute for Science and Education. NR 35 TC 0 Z9 0 U1 10 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 8 PY 2016 VL 11 IS 12 AR e0167870 DI 10.1371/journal.pone.0167870 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4OA UT WOS:000389580900053 PM 27930729 ER PT J AU Sherman, RE Anderson, SA Dal Pan, GJ Gray, GW Gross, T Hunter, NL LaVange, L Marinac-Dabic, D Marks, PW Robb, MA Shuren, J Temple, R Woodcock, J Yue, LQ Califf, RM AF Sherman, Rachel E. Anderson, Steven A. Dal Pan, Gerald J. Gray, Gerry W. Gross, Thomas Hunter, Nina L. LaVange, Lisa Marinac-Dabic, Danica Marks, Peter W. Robb, Melissa A. Shuren, Jeffrey Temple, Robert Woodcock, Janet Yue, Lilly Q. Califf, Robert M. TI Real-World Evidence - What Is It and What Can It Tell Us? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID PRAGMATIC CLINICAL-TRIALS; REGULATORY ISSUES; APP C1 [Sherman, Rachel E.; Hunter, Nina L.; Califf, Robert M.] US FDA, Off Commissioner, Silver Spring, MD USA. [Sherman, Rachel E.; Hunter, Nina L.; Califf, Robert M.] US FDA, Off Biostat & Epidemiol, Silver Spring, MD USA. [Marks, Peter W.; Temple, Robert; Woodcock, Janet] US FDA, Off Ctr Director, Silver Spring, MD USA. [Dal Pan, Gerald J.] US FDA, Ctr Biol Evaluat & Res, Off Surveillance & Epidemiol, Silver Spring, MD USA. [LaVange, Lisa] US FDA, Off Biostat, Off Translat Sci, Silver Spring, MD USA. [Robb, Melissa A.] US FDA, Off Med Policy, Silver Spring, MD USA. [Gray, Gerry W.; Yue, Lilly Q.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Gray, Gerry W.; Yue, Lilly Q.] US FDA, Div Biostat, Silver Spring, MD USA. [Marinac-Dabic, Danica] US FDA, Div Epidemiol, Silver Spring, MD USA. [Gross, Thomas] US FDA, Off Surveillance & Biometr, Silver Spring, MD USA. [Shuren, Jeffrey] US FDA, Ctr Devices & Radiol Hlth, Off Ctr Director, Silver Spring, MD USA. RP Robb, MA (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Med Policy, 10903 New Hampshire Ave,Bldg 51,Rm 6346, Silver Spring, MD 20993 USA. EM melissa.robb@fda.hhs.gov NR 33 TC 5 Z9 5 U1 8 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 8 PY 2016 VL 375 IS 23 BP 2293 EP 2297 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA EE0ZQ UT WOS:000389310000016 PM 27959688 ER PT J AU Anderson, L Antkowiak, P Asefa, A Ballard, A Bansal, T Bello, A Berne, B Bowsher, K Blumenkopf, B Broverman, I Bydon, M Chao, K Como, P Cork, K Costello, A De Laurentis, K DeMarco, A Dean, H Doucet, J Dworak, B Epperson, L Franca, E Ghassemian, N Ghosh, C Govindarajan, A Gupta, J Gutowski, S Herrmann, R Hoffmann, M Heetderks, W Hsu, S Kaufman, D Keegan, E Kittlesen, G Khuu, K Lee, H Lo, L Marcus, I Marjenin, T Mathews, B Misra, S Pinto, V Ramos, V Raben, S Russell, A Saha, D Seog, J Shenouda, C Smith, M Tang, XR Wachrathit, K Waterhouse, J Williams, D Zheng, XL Pena, C AF Anderson, Leigh Antkowiak, Patrick Asefa, Aden Ballard, Amber Bansal, Tushar Bello, Ayo Berne, Bernard Bowsher, Kristen Blumenkopf, Bennett Broverman, Ian Bydon, Mohamad Chao, Kuo Como, Peter Cork, Karlene Costello, Ann De laurentis, Kathryn DeMarco, Angela Dean, Heather Doucet, John Dworak, Bradley Epperson, Lisa Franca, Eric Ghassemian, Naz Ghosh, Chandramallika Govindarajan, Anupama Gupta, Jay Gutowski, Stacie Herrmann, Robert Hoffmann, Michael Heetderks, William Hsu, Steven Kaufman, Daryl Keegan, Erin Kittlesen, Gregg Khuu, Kevin Lee, Hyung Lo, Larry Marcus, Ian Marjenin, Timothy Mathews, Binoy Misra, Sanjay Pinto, Vivek Ramos, Vesper Raben, Samuel Russell, Avena Saha, Devjani Seog, Joonil Shenouda, Christian Smith, Myra Tang, Xiaorui Wachrathit, Kelliann Waterhouse, Jaime Williams, Dhanya Zheng, Xiaolin Pena, Carlos TI FDA Regulation of Neurological and Physical Medicine Devices: Access to Safe and Effective Neurotechnologies for All Americans SO NEURON LA English DT Editorial Material AB The United States Food and Drug Administration (FDA) ensures that patients in the U.S. have access to safe and effective medical devices. The Division of Neurological and Physical Medicine Devices reviews medical technologies that interface with the nervous system. This article addresses how to navigate the FDA's regulatory landscape to successfully bring medical devices to patients. C1 [Anderson, Leigh; Antkowiak, Patrick; Asefa, Aden; Ballard, Amber; Bansal, Tushar; Bello, Ayo; Berne, Bernard; Bowsher, Kristen; Blumenkopf, Bennett; Broverman, Ian; Bydon, Mohamad; Chao, Kuo; Como, Peter; Cork, Karlene; Costello, Ann; De laurentis, Kathryn; DeMarco, Angela; Dean, Heather; Doucet, John; Dworak, Bradley; Epperson, Lisa; Franca, Eric; Ghassemian, Naz; Ghosh, Chandramallika; Govindarajan, Anupama; Gupta, Jay; Gutowski, Stacie; Herrmann, Robert; Hoffmann, Michael; Heetderks, William; Hsu, Steven; Kaufman, Daryl; Keegan, Erin; Kittlesen, Gregg; Khuu, Kevin; Lee, Hyung; Lo, Larry; Marcus, Ian; Marjenin, Timothy; Mathews, Binoy; Misra, Sanjay; Pinto, Vivek; Ramos, Vesper; Raben, Samuel; Russell, Avena; Saha, Devjani; Seog, Joonil; Shenouda, Christian; Smith, Myra; Tang, Xiaorui; Wachrathit, Kelliann; Waterhouse, Jaime; Williams, Dhanya; Zheng, Xiaolin; Pena, Carlos] US FDA, Div Neurol & Phys Med Devices, Off Device Evaluat, Ctr Devices & Radiol Hlth, Room 2680,Bldg 66,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Pena, C (reprint author), US FDA, Div Neurol & Phys Med Devices, Off Device Evaluat, Ctr Devices & Radiol Hlth, Room 2680,Bldg 66,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM carlos.pena@fda.hhs.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD DEC 7 PY 2016 VL 92 IS 5 BP 943 EP 948 DI 10.1016/j.neuron.2016.10.036 PG 6 WC Neurosciences SC Neurosciences & Neurology GA EG7VJ UT WOS:000391264200006 PM 27930909 ER PT J AU Wu, XS Lee, SH Sheng, JS Zhang, Z Zhao, WD Wang, DS Jin, YH Charnay, P Ervasti, JM Wu, LG AF Wu, Xin-Sheng Lee, Sung Hoon Sheng, Jiansong Zhang, Zhen Zhao, Wei-Dong Wang, Dongsheng Jin, Yinghui Charnay, Patrick Ervasti, James M. Wu, Ling-Gang TI Actin Is Crucial for All Kinetically Distinguishable Forms of Endocytosis at Synapses SO NEURON LA English DT Article ID CLATHRIN-MEDIATED ENDOCYTOSIS; RETINAL BIPOLAR CELLS; SYNAPTIC VESICLES; PRESYNAPTIC TERMINALS; SLOW ENDOCYTOSIS; NERVE-TERMINALS; HELD SYNAPSE; POLYMERIZATION; CYTOSKELETON; EXPRESSION AB Mechanical force is needed to mediate endocytosis. Whether actin, the most abundant force-generating molecule, is essential for endocytosis is highly controversial in mammalian cells, particularly synapses, likely due to the use of actin blockers, the efficiency and specificity of which are often unclear in the studied cell. Here we addressed this issue using a knockout approach combined with measurements of membrane capacitance and fission pore conductance, imaging of vesicular protein endocytosis, and electron microscopy. We found that two actin isoforms, beta- and gamma-actin, are crucial for slow, rapid, bulk, and overshoot endocytosis at large calyx-type synapses, and for slow endocytosis and bulk endocytosis at small hippocampal synapses. Polymerized actin provides mechanical force to form endocytic pits. Actin also facilitates replenishment of the readily releasable vesicle pool, likely via endocytic clearance of active zones. We conclude that polymerized actin provides mechanical force essential for all kinetically distinguishable forms of endocytosis at synapses. C1 [Wu, Xin-Sheng; Lee, Sung Hoon; Sheng, Jiansong; Zhang, Zhen; Zhao, Wei-Dong; Wang, Dongsheng; Jin, Yinghui; Wu, Ling-Gang] NINDS, 35 Convent Dr, Bethesda, MD 20892 USA. [Charnay, Patrick] PSL Res Univ, Ecole Normale Super, CNRS, Inserm,Inst Biol,Ecole Normale Super, F-75005 Paris, France. [Ervasti, James M.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. [Zhang, Zhen] US FDA, Off Genet Drugs, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Sheng, JS; Zhang, Z; Wu, LG (reprint author), NINDS, 35 Convent Dr, Bethesda, MD 20892 USA.; Zhang, Z (reprint author), US FDA, Off Genet Drugs, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM shengjs@gmail.com; zhen0806@gmail.com; wul@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke; Korea Research Institute of Bioscience and Biotechnology FX This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program, and a fellowship program from Korea Research Institute of Bioscience and Biotechnology. We thank Dr. Yongling Zhu (Northwestern University) for providing synaptophysin-pHluorin2X plasmid, Drs. Zhiping Pang and Thomas C. Sudhof for the gift of the L309 plasmid, and Dr. Ralf Schneggenburger (EPFL) for shipping krox20Cre mice. NR 50 TC 1 Z9 1 U1 4 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD DEC 7 PY 2016 VL 92 IS 5 BP 1020 EP 1035 DI 10.1016/j.neuron.2016.10.014 PG 16 WC Neurosciences SC Neurosciences & Neurology GA EG7VJ UT WOS:000391264200014 PM 27840001 ER PT J AU Song, Y Zemlyanov, D Chen, X Su, ZY Nie, HC Lubach, JW Smith, D Byrn, S Pinal, R AF Song, Yang Zemlyanov, Dmitry Chen, Xin Su, Ziyang Nie, Haichen Lubach, Joseph W. Smith, Daniel Byrn, Stephen Pinal, Rodolfo TI Acid-base interactions in amorphous solid dispersions of lumefantrine prepared by spray-drying and hot-melt extrusion using X-ray photoelectron spectroscopy SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Lumefantrine; Amorphous; Solid dispersion; XPS; Spray-drying; Hot-melt extrusion; Ionic interaction; Salt; Acid-base ID STERIC HINDRANCE; STATE NMR; POLYMERS; DRUG; PERFORMANCE; STORAGE AB This study investigates drug-excipient interactions in amorphous solid dispersions (ASDs) of the model basic compound lumefantrine (LMN), with five acidic polymers. X-ray photoelectron spectroscopy (XPS) was used to measure the extent of the protonation of the tertiary amine in LMN by the five acidic polymers. The extent/efficiency of protonation of the ASDs was assessed a function of polymer type, manufacturing process (hot-melt extrusion vs. spray drying), and drug loading (DL). The most strongly acidic polymer, polystyrene sulfonic acid (PSSA) was found to be the most efficient polymer in protonating LMN, independently of manufacturing method and DL. The rank order for the protonation extent of LMN by each polymer is roughtly the same for both manufacturing processes. However, protonation efficiency of polymers of similar acidic strength ranged from similar to 0% to 75% (HPMCAS and Eudragit L100-55, respectively), suggesting an important role of molecular/mixing effects. For some polymers, including Eudragit L100 55 and HPMCP, spray-drying resulted in higher protonation efficiency compared to hot-melt extrusion. This result is attributable to a more favorable encounter between acid and base groups, when exposed to each other in solution phase. Increasing DL led to decreased protonation efficiency in most cases, particularly for polyacrylic acid, despite having the highest content of acidic groups per unit mass. These results indicate that the combined effects of acid strength and mixing phenomena regulate the efficiency of acid-base interactions in the ASDs. (C) 2016 Published by Elsevier B.V. C1 [Song, Yang; Nie, Haichen; Smith, Daniel; Byrn, Stephen; Pinal, Rodolfo] Purdue Univ, Dept Ind & Phys Pharm, W Lafayette, IN 47907 USA. [Zemlyanov, Dmitry] Purdue Univ, Birck Nanotechnol Ctr, W Lafayette, IN 47907 USA. [Chen, Xin] GlaxoSmithKline, Collegeville, PA 19426 USA. [Su, Ziyang] US FDA, Silver Spring, MD 20993 USA. [Lubach, Joseph W.] Genentech Inc, Small Mol Pharmaceut Sci, San Francisco, CA 94080 USA. RP Pinal, R (reprint author), 575 Stadium Mall Dr, W Lafayette, IN 47907 USA. EM rpinal@purdue.edu NR 24 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD DEC 5 PY 2016 VL 514 IS 2 BP 456 EP 464 DI 10.1016/j.ijpharm.2016.06.126 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EC0HA UT WOS:000387778600014 PM 27370910 ER PT J AU Oakley, MS Verma, N Zheng, H Anantharaman, V Takeda, K Gao, YM Myers, TG Pham, PT Mahajan, B Kumar, N Sangweme, D Tripathi, AK Mlambo, G Aravind, L Kumar, S AF Oakley, Miranda S. Verma, Nitin Zheng, Hong Anantharaman, Vivek Takeda, Kazuyo Gao, Yamei Myers, Timothy G. Phuong Thao Pham Mahajan, Babita Kumar, Nirbhay Sangweme, Davison Tripathi, Abhai K. Mlambo, Godfree Aravind, L. Kumar, Sanjai TI Molecular Markers of Radiation Induced Attenuation in Intrahepatic Plasmodium falciparum Parasites SO PLOS ONE LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; PROTEIN PALMITOYLATION; IRRADIATED SPOROZOITES; MALARIA; IDENTIFICATION; IMMUNIZATION; EXPRESSION; PROTECTION; UBIQUITIN; GENE AB Experimental immunization with radiation attenuated sporozoites (RAS) and genetically attenuated sporozoites has proved to be a promising approach for malaria vaccine development. However, parasite biomarkers of growth attenuation and enhanced immune protection in response to radiation remain poorly understood. Here, we report on the effect of an attenuating dose of.-irradiation (15 krad) on the Plasmodium falciparum sporozoite (PfSPZ) ultrastructure by electron microscopy, growth rate of liver stage P. falciparum in liver cell cultures, and genome-wide transcriptional profile of liver stage parasites by microarray. We find that.-irradiation treated PfSPZ retained a normal cellular structure except that they were vacuous with a partially disrupted plasma membrane and inner membrane complex. A similar infection rate was observed by.-irradiation-treated and untreated PfSPZ in human HCO-4 liver cells (0.47% versus 0.49%, respectively) on day 3 post-infection. In the microarray studies, cumulatively, 180 liver stage parasite genes were significantly transcriptionally altered on day 3 and/or 6 post-infection. Among the transcriptionally altered biomarkers, we identified a signature of seven candidate parasite genes that associated with functionally diverse pathways that may regulate radiation induced cell cycle arrest of the parasite within the hepatocyte. A repertoire of 14 genes associated with protein translation is transcriptionally overexpressed within the parasite by radiation. Additionally, 37 genes encode proteins expressed on the cell surface or exported into the host cell, 4 encode membrane associated transporters, and 10 encode proteins related to misfolding and stress-related protein processing. These results have significantly increased the repertoire of novel targets for 1) biomarkers of safety to define proper attenuation, 2) generating genetically attenuated parasite vaccine candidates, and 3) subunit candidate vaccines against liver stage malaria. C1 [Oakley, Miranda S.; Verma, Nitin] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Zheng, Hong; Phuong Thao Pham; Mahajan, Babita; Kumar, Sanjai] US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Anantharaman, Vivek; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Takeda, Kazuyo; Gao, Yamei] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Myers, Timothy G.] NIAID, Genom Technol Sect, Res Technol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kumar, Nirbhay; Sangweme, Davison; Tripathi, Abhai K.; Mlambo, Godfree] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Kumar, S (reprint author), US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Sanjai.kumar@fda.hhs.gov FU FDA intramural research program; PATH-Malaria Vaccine Initiative FX This research was supported by the FDA intramural research program and a research grant from the PATH-Malaria Vaccine Initiative. NR 58 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 DEC 2 PY 2016 VL 11 IS 12 AR e0166814 DI 10.1371/journal.pone.0166814 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3TF UT WOS:000389520600014 PM 27911910 ER PT J AU Bersoff-Matcha, SJ Cao, KY Jason, M Ajao, A Jones, SC Meyer, T Brinker, AD AF Bersoff-Matcha, Susan J. Cao, Kelly Y. Jason, Mihaela Ajao, Adebola Jones, S. C. Meyer, Tamra Brinker, Allen D. TI Hepatitis B Reactivation Associated with Direct Acting Antiviral Therapy for Hepatitis C: A Review of Spontaneous Post-Marketing Cases SO HEPATOLOGY LA English DT Meeting Abstract CT 67th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 11-15, 2016 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Bersoff-Matcha, Susan J.; Cao, Kelly Y.; Jason, Mihaela; Ajao, Adebola; Jones, S. C.; Meyer, Tamra; Brinker, Allen D.] US FDA, Off Pharmacovigilance & 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 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD DEC PY 2016 VL 64 IS 6 MA LB-17 BP 1129A EP 1130A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4MF UT WOS:000393900200018 ER PT J AU Johnson, SE Coleman, BN Schmitt, CL AF Johnson, Sarah E. Coleman, Blair N. Schmitt, Carol L. TI It's Complicated: Examining Smokers' Relationships With Their Cigarette Brands SO PSYCHOLOGY OF ADDICTIVE BEHAVIORS LA English DT Article DE brand relationship; attitudes; cigarette smoking; marketing; tobacco ID ECOLOGICAL MOMENTARY ASSESSMENT; UNITED-STATES; ADULT SMOKERS; 4 COUNTRIES; SMOKING; CAMPAIGN; BELIEFS; LOYALTY; ASSOCIATIONS; ANTECEDENTS AB Despite increased restrictions and taxes, decreased social acceptability, and widespread awareness of the harms of tobacco use, many in the U.S. continue to smoke cigarettes. Thus, understanding smokers' attitudes and motivations remains an important goal. This study adopts the consumer psychology concept of brand relationship to provide a new lens through which to examine smokers' attitudes about their cigarette use. Twelve focus groups (N = 143) were conducted with adult cigarette smokers from September to November, 2013. Using a semistructured moderator guide and "top of mind" worksheets, the discussion examined participants' attitudes toward (a) their own cigarette brand and (b) tobacco companies in general. Data were coded and analyzed following principles of thematic analysis. Adult smokers reported positive attitudes toward their cigarette brand, as their brand was strongly associated with the positive experience of smoking (e.g., satisfying craving and relief from withdrawal). In contrast, thinking about tobacco companies in general evoked negative reactions, revealing overwhelmingly negative attitudes toward the industry. Findings reveal a complicated relationship between smokers and their cigarette brand: simultaneously embracing their cigarettes and rejecting the industry that makes them. Taken together, these data suggest smokers maintain largely positive brand relationships, diverting negative feelings about smoking toward the tobacco industry. Finally, they highlight the synergy between branding and the subjective smoking experience, whereby positive brand attitudes are reinforced through withdrawal relief. Ultimately, this information could inform a more complete understanding of how smokers interpret and respond to tobacco communications, including marketing from their brand. C1 [Johnson, Sarah E.; Coleman, Blair N.] US FDA, Ctr Tobacco Prod, Silver Spring, MD USA. [Schmitt, Carol L.] RTI Int, Ctr Hlth Policy Sci & Tobacco Res, Washington, DC USA. RP Johnson, SE (reprint author), US FDA, Div Populat Hlth Sci, Off Sci, Ctr Tobacco Prod,Document Control Ctr, Bldg 71 Room G335,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM sarah.johnson@fda.hhs.gov NR 46 TC 0 Z9 0 U1 4 U2 4 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0893-164X EI 1939-1501 J9 PSYCHOL ADDICT BEHAV JI Psychol. Addict. Behav. PD DEC PY 2016 VL 30 IS 8 BP 887 EP 894 DI 10.1037/adb0000225 PG 8 WC Substance Abuse; Psychology, Multidisciplinary SC Substance Abuse; Psychology GA EK1GK UT WOS:000393673600011 PM 27831717 ER PT J AU Monteiro, TSA Brito, JA Vau, SJS Yuan, W LaMondia, JA Dickson, DW AF Monteiro, T. S. A. Brito, J. A. Vau, S. J. S. Yuan, W. LaMondia, J. A. Dickson, D. W. TI FIRST REPORT OF ENDOTOKIA MATRICIDA IN MELOIDOGYNE HAPLA: A STUDY CASE SO JOURNAL OF NEMATOLOGY LA English DT Meeting Abstract C1 [Monteiro, T. S. A.] Univ Vicosa, Plant Path Dept, BR-36570900 Vicosa, MG, Brazil. [Brito, J. A.; Yuan, W.] FDACS, Div Plant Ind, Gainesville, FL 32614 USA. [LaMondia, J. A.] Connecticut Agri Exp Sta, Windsor, CT 06095 USA. [Vau, S. J. S.; Dickson, D. W.] Univ Florida, Dept Entomol & Nematol, Gainesville, FL 32611 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NEMATOLOGISTS PI MARCELINE PA PO BOX 311, MARCELINE, MO 64658 USA SN 0022-300X J9 J NEMATOL JI J. Nematol. PD DEC PY 2016 VL 48 IS 4 BP 354 EP 354 PG 1 WC Zoology SC Zoology GA EJ1FL UT WOS:000392955800156 ER PT J AU Alexander, CS Raveis, V Karus, D Carrero-Tagle, M Wilson, M Brotemarkle, R Pappas, G Wiegand, D Lockman, K Memiah, P Welsh, C Tepper, V Hossain, MB Amoroso, A Selwyn, P AF Alexander, Carla S. Raveis, Victoria Karus, Daniel Carrero-Tagle, Monique Wilson, Monique Brotemarkle, Rebecca Pappas, Gregory Wiegand, Debra Lockman, Kashelle Memiah, Peter Welsh, Christopher Tepper, Vicki Hossain, Mian B. Amoroso, Anthony Selwyn, Peter TI Early Integration of the Palliative Approach in HIV Management: Refining a Curriculum for Non-palliative Specialists SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Meeting Abstract C1 [Alexander, Carla S.; Wilson, Monique; Amoroso, Anthony] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Raveis, Victoria; Karus, Daniel; Carrero-Tagle, Monique] NYU, Psychosocial Res Unit Hlth Aging & Commun, New York, NY USA. [Brotemarkle, Rebecca; Wiegand, Debra] Univ Maryland, Baltimore Sch Nursing, Baltimore, MD 21201 USA. [Pappas, Gregory] US FDA, Rockville, MD 20857 USA. [Lockman, Kashelle] Univ Maryland, Baltimore Sch Pharm, Baltimore, MD 21201 USA. [Welsh, Christopher] Univ Maryland, Sch Med Psychiat, Baltimore, MD 21201 USA. [Memiah, Peter] Univ West Florida, Pensacola, FL 32514 USA. [Tepper, Vicki] Univ Maryland, Sch Med Pediat, Baltimore, MD 21201 USA. [Hossain, Mian B.] Morgan State Univ, Sch Community Hlth & Policy Biostat, Baltimore, MD 21239 USA. [Selwyn, Peter] Montefiore Med Ctr, Family & Social Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD DEC PY 2016 VL 52 IS 6 MA P108 BP E93 EP E93 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA EJ4KE UT WOS:000393184800180 ER PT J AU Alexander, CS Raveis, V Karus, D Carrero-Tagle, M Wilson, M Brotemarkle, R Pappas, G Wiegand, D Lockman, K Memiah, P Welsh, C Tepper, V Hossain, MB Amoroso, A Selwyn, P AF Alexander, Carla S. Raveis, Victoria Karus, Daniel Carrero-Tagle, Monique Wilson, Monique Brotemarkle, Rebecca Pappas, Gregory Wiegand, Debra Lockman, Kashelle Memiah, Peter Welsh, Christopher Tepper, Vicki Hossain, Mian B. Amoroso, Anthony Selwyn, Peter TI Early Integration of the Palliative Approach in HIV Management: Description of HIV plus Young Men Who Have Sex with Men Attending 2 Inner City Clinics Where the Palliative Approach Is Introduced to Improve Retention in Care SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Meeting Abstract C1 [Alexander, Carla S.; Wilson, Monique; Amoroso, Anthony] Univ Maryland, Inst Human Virol, Baltimore Sch Med, Baltimore, MD 21201 USA. [Raveis, Victoria; Karus, Daniel; Carrero-Tagle, Monique] New York Univ, Psychosocial Res Unit Hlth Aging & Commun, New York, NY USA. [Brotemarkle, Rebecca; Wiegand, Debra] Univ Maryland, Baltimore Sch Nursing, Baltimore, MD 21201 USA. [Pappas, Gregory] Food & Drug Adm, Rockville, MD USA. [Lockman, Kashelle] Univ Maryland, Baltimore Sch Pharm, Baltimore, MD 21201 USA. [Welsh, Christopher] Univ Maryland, Baltimore Sch Med Psychiat, Baltimore, MD 21201 USA. [Memiah, Peter] Univ West Florida, Pensacola, FL 32514 USA. [Tepper, Vicki] Univ Maryland, Baltimore Sch Med Pediat, Baltimore, MD 21201 USA. [Hossain, Mian B.] Morgan State Univ, Sch Community Hlth & Policy Biostatist, Baltimore, MD 21239 USA. [Selwyn, Peter] Montefiore Med Ctr, Family & Social Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD DEC PY 2016 VL 52 IS 6 MA F06-C BP E50 EP E50 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA EJ4KE UT WOS:000393184800094 ER PT J AU Ren, Z Chen, S Zhang, J Doshi, U Li, AP Guo, L AF Ren, Zhen Chen, Si Zhang, Jie Doshi, Utkarsh Li, Albert P. Guo, Lei TI Endoplasmic Reticulum Stress Induction and ERK1/2 Activation Contribute to Nefazodone-Induced Toxicity in Hepatic Cells SO TOXICOLOGICAL SCIENCES LA English DT Article DE endoplasmic reticulum stress (ER stress); drug-induced liver toxicity; reporter gene assay; MAPK pathway; nefazodone ID SIGNAL-REGULATED KINASE; CISPLATIN-INDUCED APOPTOSIS; INDUCED LIVER TOXICITY; ACID-INDUCED TOXICITY; N-TERMINAL KINASE; MITOCHONDRIAL DYSFUNCTION; ER STRESS; CLINICAL HEPATOTOXICITY; MEDIATED HEPATOTOXICITY; MAP KINASES AB Nefazodone, an antagonist for the 5-hydroxytryptanine receptor, has been used for the treatment of depression. Acute liver injury has been documented to be associated with the use of nefazodone; however, the mechanisms of nefazodoneinduced liver toxicity are not well defined. In this report, using biochemical and molecular analyses, we characterized the molecular mechanisms underlying the hepatotoxicity of nefazodone. We found that nefazodone induced endoplasmic reticulum (ER) stress in HepG2 cells, as the expression of typical ER stress markers, including CHOP, ATF-4, and p-eIF2 alpha, was significantly increased, and splicing of XBP1 was observed. Nefazodone-suppressed protein secretion was evaluated using a Gaussia luciferase reporter assay that measures ER stress. The ER stress inhibitors (4-phenylbutyrate and salubrinal) and knockdown of ATF-4 gene attenuated nefazodone-induced ER stress and cytotoxicity. Nefazodone activated the MAPK signaling pathway, as indicated by increased phosphorylation of JNK, ERK1/2, and p38. Inhibition of ERK1/2 reduced ER stress caused by nefazodone. Taken together, our findings suggest that ER stress contributes to nefazodone-induced toxicity in HepG2 cells and that the MAPK signaling pathway plays an important role in ER stress. C1 [Ren, Zhen; Chen, Si; Guo, Lei] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Zhang, Jie] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR USA. [Doshi, Utkarsh; Li, Albert P.] Vitro ADMET Labs LLC, Columbia, MD USA. RP Guo, L (reprint author), 3900 NCTR Rd,HFT 110, Jefferson, AR 72079 USA. EM Lei.Guo@fda.hhs.gov FU Postgraduate Research Program at the National Center for Toxicological Research; U.S. FDA's intramural grant FX R.Z. was supported by appointments to the Postgraduate Research Program at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science Education through an interagency agreement between the U.S. Department of Energy and the U.S. FDA. This work was supported by U.S. FDA's intramural grant. NR 49 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 DEC PY 2016 VL 154 IS 2 BP 368 EP 380 DI 10.1093/toxsci/kfw173 PG 13 WC Toxicology SC Toxicology GA EJ5VJ UT WOS:000393286500018 PM 27613715 ER PT J AU Mcculley, L Gelperin, K Bird, S Harris, S Wang, C Waldron, P AF Mcculley, Lynda Gelperin, Kate Bird, Steven Harris, Sarah Wang, Cunlin Waldron, Peter TI Reports to FDA of fatal anaphylaxis associated with intravenous iron products SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter C1 [Mcculley, Lynda; Gelperin, Kate; Bird, Steven; Harris, Sarah; Wang, Cunlin; Waldron, Peter] US FDA, Ctr Drug Evaluat & Res, Off Pharmacovigilance & Epidemiol, Silver Spring, MD USA. RP Waldron, P (reprint author), US FDA, Div Pharmacovigilance 2, Off Pharmacovigilance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM peter.waldron@fda.hhs.gov NR 6 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2016 VL 91 IS 12 BP E496 EP E497 DI 10.1002/ajh.24531 PG 2 WC Hematology SC Hematology GA EI8BY UT WOS:000392730900003 PM 27508336 ER PT J AU Mukherjee, N Sulaiman, IM Banerjee, P AF Mukherjee, Nabanita Sulaiman, Irshad M. Banerjee, Pratik TI Characterization of methicillin-resistant Staphylococcus aureus isolates from fitness centers in the Memphis metropolitan area, Tennessee SO AMERICAN JOURNAL OF INFECTION CONTROL LA English DT Article DE MRSA; Community-acquired infections; Antibiotic resistance; Multiple antibacterial drug resistance; Fomites ID INFECTION; SURFACES AB Indoor skin-contact surfaces of public fitness centers may serve as reservoirs of potential human transmission of methicillin-resistant Staphylococcus aureus (MRSA). We found a high prevalence of multidrug-resistant (MDR) MRSA of clonal complex 59 lineage harboring a variety of extracellular toxin genes from surface swab samples collected from inanimate surfaces of fitness centers in the Memphis metropolitan area, Tennessee. Our findings underscore the role of inanimate surfaces as potential sources of transmission of MDR MRSA strains with considerable genetic diversity. (C) 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved. C1 [Mukherjee, Nabanita; Banerjee, Pratik] Univ Memphis, Div Epidemiol Biostat & Environm Hlth, Sch Publ Hlth, Memphis, TN 38152 USA. [Sulaiman, Irshad M.] US FDA, Southeast Reg Lab, Microbiol Sci Branch, Atlanta, GA USA. EM pbnerjee@memphis.edu OI Banerjee, Pratik/0000-0001-5553-5350 FU University of Memphis; Memphis Research Consortium; U.S. Food & Drug Administration [1U54FD004330-01] FX Partly supported by start-up funds from the University of Memphis, the Memphis Research Consortium, and a grant from the U.S. Food & Drug Administration (1U54FD004330-01) to P.B. NR 10 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-6553 EI 1527-3296 J9 AM J INFECT CONTROL JI Am. J. Infect. Control PD DEC 1 PY 2016 VL 44 IS 12 BP 1681 EP 1683 DI 10.1016/j.ajic.2016.06.031 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA EI6SH UT WOS:000392626300048 PM 27658767 ER PT J AU Stern, ST Martinez, MN Stevens, DM AF Stern, Stephan T. Martinez, Marilyn N. Stevens, David M. TI When Is It Important to Measure Unbound Drug in Evaluating Nanomedicine Pharmacokinetics? SO DRUG METABOLISM AND DISPOSITION LA English DT Editorial Material ID PLASMA-PROTEIN BINDING; ALBUMIN-BOUND PACLITAXEL; IN-VIVO; NONLINEAR PHARMACOKINETICS; ANTICANCER AGENTS; CANCER-PATIENTS; CREMOPHOR-FREE; PHASE-I; DELIVERY; NANOPARTICLE AB Nanoformulations have become important tools for modifying drug disposition, be it from the perspective of enabling prolonged drug release, protecting the drug molecule from metabolism, or achieving targeted delivery. When examining the in vivo pharmacokinetic properties of these formulations, most investigations either focus on systemic concentrations of total (encapsulated plus unencapsulated) drug, or concentrations of encapsulated and unencapsulated drug. However, it is rare to find studies that differentiate between protein-bound and unbound (free) forms of the unencapsulated drug. In light of the unique attributes of these formulations, we cannot simply assume it appropriate to rely upon the protein-binding properties of the traditionally formulated or legacy drug when trying to define the pharmacokinetic or pharmacokinetic/pharmacodynamic characteristics of these nanoformulations. Therefore, this commentary explores reasons why it is important to consider not only unencapsulated drug, but also the portion of unencapsulated drug that is not bound to plasma proteins. Specifically, we highlight those situations when it may be necessary to include measurement of unencapsulated, unbound drug concentrations as part of the nanoformulation pharmacokinetic evaluation. C1 [Stern, Stephan T.; Stevens, David M.] Frederick Natl Lab Canc Res, Leidos Biomed Res, Canc Res Technol Program, Nanotechnol Characterizat Lab, Frederick, MD USA. [Martinez, Marilyn N.] US FDA, Ctr Vet Med, Off New Anim Drug Evaluat, 7500 Standish Pl,HFV-100, Rockville, MD 20855 USA. RP Martinez, MN (reprint author), US FDA, Ctr Vet Med, Off New Anim Drug Evaluat, 7500 Standish Pl,HFV-100, Rockville, MD 20855 USA. EM marilyn.martinez@fda.hhs.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Institutes of Health National Cancer Institute [HHSN261200800e001E] FX This work was supported in whole or in part with federal funds from the National Institutes of Health National Cancer Institute [Grant HHSN261200800e001E]. NR 54 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 EI 1521-009X J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD DEC PY 2016 VL 44 IS 12 BP 1934 EP 1939 DI 10.1124/dmd.116.073148 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI8AN UT WOS:000392726600010 PM 27670412 ER PT J AU Norton, MG Khalenkov, A Kamikawa, TL Kort, T Pushko, P Kennedy, MC Scott, DE AF Norton, Malgorzata G. Khalenkov, Alexey Kamikawa, Tracy L. Kort, Thomas Pushko, Peter Kennedy, Michael C. Scott, Dorothy E. TI Detection of Antibody Inhibition of Influenza H5N1 Binding to a Sialoglycan Receptor Using Surface Plasmon Resonance (SPR) and its Use as a Neutralizing Antibody Screening Assay SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology CY NOV 19-22, 2016 CL New Orleans, LA SP Soc Glycobiol C1 [Norton, Malgorzata G.; Khalenkov, Alexey; Kamikawa, Tracy L.; Kennedy, Michael C.; Scott, Dorothy E.] US FDA, Ctr Biol Evaluat & Res, Off Blood Res & Review, Div Hematol Res & Review,Lab Plasma Derivat, Silver Spring, MD USA. [Kort, Thomas; Pushko, Peter] Medigen Inc, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD DEC PY 2016 VL 26 IS 12 MA 200 BP 1456 EP 1456 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EJ0XX UT WOS:000392935600203 ER PT J AU Lee, C Cheon, G Kim, DH Kang, JU AF Lee, Changho Cheon, Gyeongwoo Kim, Do-Hyun Kang, Jin U. TI Feasibility study: protein denaturation and coagulation monitoring with speckle variance optical coherence tomography SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE denaturation; coagulation; optical coherence tomography; speckle variance ID BOVINE SERUM-ALBUMIN; EGG-WHITE; THERMAL-CONDUCTIVITY; LASER THERAPY; IN-VIVO; STABILITY; PREDICTION; AGENTS; RISE; OCT AB We performed the feasibility study using speckle variance optical coherence tomography (SvOCT) to monitor the thermally induced protein denaturation and coagulation process as a function of temperature and depth. SvOCT provided the depth-resolved image of protein denaturation and coagulation with microscale resolution. This study was conducted using egg white. During the heating process, as the temperature increased, increases in the speckle variance signal was observed as the egg white proteins coagulated. Additionally, by calculating the cross-correlation coefficient in specific areas, denaturized egg white conditions were successfully estimated. These results indicate that SvOCT could be used to monitor the denaturation process of various proteins. (C) 2016 Society of Photo-Optical Instrumentation Engineers (SPIE) C1 [Lee, Changho; Cheon, Gyeongwoo; Kang, Jin U.] Johns Hopkins Univ, Dept Elect & Comp Engn, 3400 North Charles St, Baltimore, MD 21218 USA. [Kim, Do-Hyun] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Lee, C (reprint author), Johns Hopkins Univ, Dept Elect & Comp Engn, 3400 North Charles St, Baltimore, MD 21218 USA. EM ch31037@gmail.com FU World Class 300 Project (Development of Ophthalmic Multipurpose Glaucoma/Retina Diagnosis/Treatment Integral Laser System) of the Small and Medium Business Administration (SMBA), Republic of Korea [S2340708] FX This work was supported by the World Class 300 Project (S2340708, Development of Ophthalmic Multipurpose Glaucoma/Retina Diagnosis/Treatment Integral Laser System) of the Small and Medium Business Administration (SMBA), Republic of Korea. NR 39 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 2016 VL 21 IS 12 AR 125004 DI 10.1117/1.JBO.21.12.125004 PG 8 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA EJ0QG UT WOS:000392914600020 ER PT J AU Srivari, Y Chatterjee, P AF Srivari, Yochana Chatterjee, Parnali TI Factors influencing the fabrication of albumin-bound drug nanoparticles (ABDns): part I. Albumin-bound betulinic acid nanoparticles (ABBns) SO JOURNAL OF MICROENCAPSULATION LA English DT Article DE Betulinic acid; albumin; nanoparticles; solubilisers ID HUMAN SERUM-ALBUMIN; MOLECULAR INTERACTION; DELIVERY SYSTEMS; OLEANOLIC ACID; BREAST-CANCER; TUMOR; CYTOTOXICITY; PERMEABILITY; SURFACTANTS; TRANSPORT AB Though there are many albumin-based drug delivery systems (ABDDS) in the market, it is not known whether ABDDS can be applied across all chemical classes. In this study, we applied ABDDS to a poorly water-soluble drug betulinic acid (BA) to improve its aqueous solubility. Monomeric albumin-bound BA (ABBns) nanoparticles can be fabricated in the range of 10-20 nm. BA self-assembled with HSA at 0.1:1 to 2:1 molar ratio within 0.5 h in phosphate buffer pH 7.4 and 8.4. Approximately, 85-90% BA could be loaded onto HSA in the presence of Tween 20 (T20) and sodium cholate (NaC). The release of BA from ABBns was linear over 5 days. In conclusion, for poorly water-soluble acidic drugs, a suitable solubiliser can release the drug from HSA binding site, depending on the aggregation number and affinity of the solubiliser for the HSA binding site. C1 [Srivari, Yochana; Chatterjee, Parnali] St Johns Univ, Coll Pharm & Hlth Sci, Queens, NY USA. [Chatterjee, Parnali] US FDA, Div Biopharmaceut, Off Pharmaceut Qual, Off New Drug Prod,Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM parnali.chatterjee@fda.hhs.gov FU St. John's University, Venture/SEED grant [FY2012] FX St. John's University, Venture/SEED grant [FY2012] NR 28 TC 0 Z9 0 U1 2 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0265-2048 EI 1464-5246 J9 J MICROENCAPSUL JI J. Microencapsul. PD DEC PY 2016 VL 33 IS 8 BP 689 EP 701 DI 10.1080/02652048.2016.1222005 PG 13 WC Chemistry, Applied; Engineering, Chemical; Pharmacology & Pharmacy SC Chemistry; Engineering; Pharmacology & Pharmacy GA EI6KX UT WOS:000392605600001 PM 27707051 ER PT J AU Maughan, BL Suzman, DL Luber, B Wang, H Glavaris, S Hughes, R Sullivan, R Harb, R Boudadi, K Paller, C Eisenberger, M Demarzo, A Ross, A Antonarakis, ES AF Maughan, Benjamin L. Suzman, Daniel L. Luber, Brandon Wang, Hao Glavaris, Stephanie Hughes, Robert Sullivan, Rana Harb, Rana Boudadi, Karim Paller, Channing Eisenberger, Mario Demarzo, Angelo Ross, Ashely Antonarakis, Emmanuel S. TI Pharmacodynamic study of the oral hedgehog pathway inhibitor, vismodegib, in patients with metastatic castration-resistant prostate cancer SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Vismodegib; Hedgehog; Gli; Metastatic castration-resistant prostate cancer ID SIGNALING PATHWAY; CELL-GROWTH; ITRACONAZOLE AB Purpose Hedgehog (Hh) pathway signaling has been implicated in prostate cancer tumorigenesis and metastatic development and may be upregulated even further in the castration-resistant state. We hypothesized that antagonism of the Hh pathway with vismodegib in men with metastatic castration-resistant prostate cancer (mCRPC) would result in pathway engagement, inhibition and perhaps induce measurable clinical responses in patients. Methods This is a single-arm study of oral daily vismodegib in men with mCRPC. All patients were required to have biopsies of the tumor and skin (a surrogate tissue) at baseline and after 4 weeks of therapy. Ten patients were planned for enrollment. The primary outcome was the pharmacodynamic assessment of Gli1 mRNA suppression with vismodegib in tumor tissue. Secondary outcomes included PSA response rates, progression-free survival (PFS), overall survival (OS) and safety. Results Nine patients were enrolled. Gli1 mRNA was significantly suppressed by vismodegib in both tumor tissue (4/7 evaluable biopsies, 57%) and benign skin biopsies (6/8 evaluable biopsies, 75%). The median number of treatment cycles completed was three, with a median PFS of 1.9 months (95% CI 1.3, NA), and a median OS of 7.04 months (95% CI 3.4, NA). No patient achieved a PSA reduction or a measurable tumor response. Safety data were consistent with the known toxicities of vismodegib. Conclusions Hh signaling, as measured by Gli1 mRNA expression in mCRPC tissues, was suppressed with vismodegib in the majority of patients. Despite this pharmacodynamic response that indicated target inhibition in some patients, there was no apparent signal of clinical activity. Vismodegib will not be developed further as monotherapy in mCRPC. C1 [Maughan, Benjamin L.] Univ Utah, Huntsman Canc Ctr, 2000 Circle Hope Dr, Salt Lake City, UT 84112 USA. [Suzman, Daniel L.] US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Luber, Brandon; Wang, Hao; Glavaris, Stephanie; Hughes, Robert; Sullivan, Rana; Harb, Rana; Boudadi, Karim; Paller, Channing; Eisenberger, Mario; Demarzo, Angelo; Ross, Ashely; Antonarakis, Emmanuel S.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, 1650 Orleans St CRB1 1M45, Baltimore, MD 21287 USA. RP Antonarakis, ES (reprint author), Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, 1650 Orleans St CRB1 1M45, Baltimore, MD 21287 USA. EM eantona1@jhmi.edu FU NIH [P30 CA006973]; ASCO/CCF; Genentech FX This work is partially funded through support by NIH Grant P30 CA006973 and the ASCO/CCF Young Investigator Award, and by Genentech. NR 14 TC 0 Z9 0 U1 7 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD DEC PY 2016 VL 78 IS 6 BP 1297 EP 1304 DI 10.1007/s00280-016-3191-7 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA EI2MU UT WOS:000392322300020 PM 27826729 ER PT J AU Retzky, SS Spring, S AF Retzky, Sandra S. Spring, Silver TI FDA Encourages Reporting of Tobacco Product Adverse Experiences SO CHEST LA English DT Editorial Material ID ACUTE EOSINOPHILIC PNEUMONIA; SMOKING C1 [Retzky, Sandra S.; Spring, Silver] US FDA, Ctr Tobacco Prod, Silver Spring, MD USA. RP Retzky, SS (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM sandra.retzky@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 15 TC 0 Z9 0 U1 2 U2 2 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD DEC PY 2016 VL 150 IS 6 BP 1169 EP 1170 DI 10.1016/j.chest.2016.08.1452 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EI1VQ UT WOS:000392274600009 PM 27938736 ER PT J AU Chunduri, LAA Haleyurgirisetty, MK Patnaik, S Bulagonda, PE Kurdekar, A Liu, J Hewlett, IK Kamisetti, V AF Chunduri, L. A. Avinash Haleyurgirisetty, Mohan Kumar Patnaik, Sandeep Bulagonda, Pradeep Eswarappa Kurdekar, Aditya Liu, Jikun Hewlett, Indira K. Kamisetti, Venkataramaniah TI Development of carbon dot based microplate and microfluidic chip immunoassay for rapid and sensitive detection of HIV-1 p24 antigen SO MICROFLUIDICS AND NANOFLUIDICS LA English DT Article DE Carbon dots; Immunoassay; HIV; p24 antigen; Sensitivity ID GRAPHENE QUANTUM DOTS; FLUORESCENCE IMMUNOASSAY; ONE-STEP; NANOPARTICLES; PHOTOLUMINESCENCE; IMMUNOSENSOR; SURFACES; CYSTEINE; PROBE; ASSAY AB A highly sensitive, precisely specific, environmentally friendly, high-throughput, microwell-plate and microchip-based sandwich assay was developed to detect HIV-1 p24 antigen, a protein biomarker using fluorescent carbon dots. High quantum yield carbon dots were synthesized using citric acid and ethylenediamine as carbon and nitrogen sources by a single-step hydrothermal reaction. The desired amine groups confirmed by FTIR on the carbon dots were coupled to streptavidin by amine-amine coupling reaction using glutaraldehyde. The detection range of the carbon dot based immunoassay (CDIA) was found to be between 20 and 1000 pg/mL in a linear dose-dependent manner. CDIA tested for HIV negative plasma samples showed no false positive results in the detection of HIV-1 p24 antigen. The CDIA was extended to develop a microfluidic carbon dot immunoassay (mu CDIA) which exhibited analytical sensitivity in the range of 30-1000 pg/mL. The CDIA and mu CDIA can easily be adapted to a labon- a-chip platform for use in resource limited settings and can also be multiplexed for the detection of other pathogens like TB and Hepatitis. C1 [Chunduri, L. A. Avinash; Patnaik, Sandeep; Kurdekar, Aditya; Kamisetti, Venkataramaniah] Sri Sathya Sai Inst Higher Learning, Dept Phys, Puttaparthi 515134, Andhra Pradesh, India. [Bulagonda, Pradeep Eswarappa] Sri Sathya Sai Inst Higher Learning, Dept Biosci, Puttaparthi 515134, Andhra Pradesh, India. [Haleyurgirisetty, Mohan Kumar; Liu, Jikun; Hewlett, Indira K.] US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Kamisetti, V (reprint author), Sri Sathya Sai Inst Higher Learning, Dept Phys, Puttaparthi 515134, Andhra Pradesh, India. EM vrkamisetti@gmail.com FU UGC Govt. of India FX All authors are grateful to Bhagawan Sri Sathya Sai Baba for his constant inspiration and guidance. L. A. Avinash Chunduri acknowledges UGC Govt. of India for BSR fellowship. We acknowledge with gratitude Prof. S. Sampath (IPC Department, IISc Bangalore, India) for providing TEM facility. NR 36 TC 0 Z9 0 U1 10 U2 10 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1613-4982 EI 1613-4990 J9 MICROFLUID NANOFLUID JI Microfluid. Nanofluid. PD DEC PY 2016 VL 20 IS 12 AR 167 DI 10.1007/s10404-016-1825-z PG 10 WC Nanoscience & Nanotechnology; Instruments & Instrumentation; Physics, Fluids & Plasmas SC Science & Technology - Other Topics; Instruments & Instrumentation; Physics GA EI2KF UT WOS:000392315200011 ER PT J AU Maxfield, KE Macion, J Vankayalapati, H Whitehurst, AW AF Maxfield, Kimberly E. Macion, Jennifer Vankayalapati, Hariprasad Whitehurst, Angelique W. TI SIK2 Restricts Autophagic Flux To Support Triple-Negative Breast Cancer Survival SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SALT-INDUCIBLE KINASES; COACTIVATOR TORC2; CELL-LINES; INHIBITION; TUMORIGENESIS; SUBTYPES; THERAPY; PROTEIN; PHOSPHORYLATION; IDENTIFICATION AB Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with multiple, distinct molecular subtypes that exhibit unique transcriptional programs and clinical progression trajectories. Despite knowledge of the molecular heterogeneity of the disease, most patients are limited to generic, indiscriminate treatment options: cytotoxic chemotherapy, surgery, and radiation. To identify new intervention targets in TNBC, we used large-scale, loss-of-function screening to identify molecular vulnerabilities among different oncogenomic backgrounds. This strategy returned salt inducible kinase 2 (SIK2) as essential for TNBC survival. Genetic or pharmacological inhibition of SIK2 leads to increased autophagic flux in both normal-immortalized and tumor-derived cell lines. However, this activity causes cell death selectively in breast cancer cells and is biased toward the claudin-low subtype. Depletion of ATG5, which is essential for autophagic vesicle formation, rescued the loss of viability following SIK2 inhibition. Importantly, we find that SIK2 is essential for TNBC tumor growth in vivo. Taken together, these findings indicate that claudin-low tumor cells rely on SIK2 to restrain maladaptive autophagic activation. Inhibition of SIK2 therefore presents itself as an intervention opportunity to reactivate this tumor suppressor mechanism. C1 [Maxfield, Kimberly E.] Univ North Carolina Chapel Hill, Dept Pharmacol, Chapel Hill, NC USA. [Maxfield, Kimberly E.; Macion, Jennifer; Whitehurst, Angelique W.] Univ Texas Southwestern Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA. [Vankayalapati, Hariprasad] Arrien Pharmaceut, Early Discovery & Med Chem, Salt Lake City, UT USA. [Maxfield, Kimberly E.] US FDA, Silver Spring, MD USA. RP Whitehurst, AW (reprint author), Univ Texas Southwestern Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA. EM angelique.whitehurst@utsouthwestern.edu FU NIH [CA154699]; Simmons Cancer Center Support Grant [5P30 CA142543-05]; [T32GM007040-37]; [CA058223] FX K.E.M. was supported by general medicine training grant T32GM007040-37. A.W.W. is supported by NIH grant CA154699. The Simmons Cancer Center Support Grant 5P30 CA142543-05 supported shared resources used in this study at UTSW. This work was also supported by CA058223. NR 44 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 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2016 VL 36 IS 24 BP 3048 EP 3057 DI 10.1128/MCB.00380-16 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EI1DH UT WOS:000392215600004 PM 27697861 ER PT J AU Kim, YJ Kim, HS Kim, KY Chon, JW Kim, DH Seo, KH AF Kim, Young-Ji Kim, Hong-Seok Kim, Kwang-Yeop Chon, Jung-Whan Kim, Dong-Hyeon Seo, Kun-Ho TI High Occurrence Rate and Contamination Level of Bacillus cereus in Organic Vegetables on Sale in Retail Markets SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article DE vegetables; food safety; organic and conventional farming; indicator microorganisms; Bacillus cereus ID MICROBIOLOGICAL QUALITY; SPROUTS; PREVALENCE; GROWTH; FOODS; RESTAURANTS; SALMONELLA; DIVERSITY; PATHOGENS; PRODUCTS AB Organic foods have risen in popularity recently. However, the increased risk of bacterial contamination of organic foods has not been fully evaluated. In this study, 100 samples each of organic and conventional fresh vegetables (55 lettuce samples and 45 sprout samples) sold in South Korea were analyzed for aerobic bacteria, coliforms, Escherichia coli, and Bacillus cereus. Although the aerobic bacteria and coliform counts were not significantly different between the two farming types (p > 0.05), the occurrence rate of B. cereus was higher in organically cultivated vegetables compared with those grown conventionally (70% vs. 30%, respectively). The mean contamination level of B. cereus-positive organic samples was also significantly higher (1.86 log colony-forming unit [CFU]/g vs. 0.69 log CFU/g, respectively) (p < 0.05). In addition, six samples of organic vegetables were found to be contaminated with B. cereus at over 4 log CFU/g categorized as unsatisfactory according to Health Protection Agency guideline. The relatively higher occurrence rate of B. cereus in organic vegetables emphasizes the importance of implementing control measures in organic vegetable production and postharvest processing to reduce the risk of food poisoning. C1 [Kim, Young-Ji; Kim, Hong-Seok; Kim, Kwang-Yeop; Chon, Jung-Whan; Kim, Dong-Hyeon; Seo, Kun-Ho] Konkuk Univ, Coll Vet Med, Ctr Hlth 1, Seoul 143701, 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, Ctr Hlth 1, Seoul 143701, South Korea. EM bracstu3@konkuk.ac.kr FU Export Promotion Technology Development Program of iPET - Ministry for Food, Agriculture, Forestry, and Fisheries [313010-3]; National Research Foundation of Korea (NRF) - Korea government(MSIP) [2015R1A2A2A05001288] FX This research was supported by the Export Promotion Technology Development Program of iPET (No. 313010-3) funded by the Ministry for Food, Agriculture, Forestry, and Fisheries and by the National Research Foundation of Korea (NRF) grant funded by the Korea government(MSIP) (No. 2015R1A2A2A05001288). NR 31 TC 0 Z9 0 U1 4 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1535-3141 EI 1556-7125 J9 FOODBORNE PATHOG DIS JI Foodborne Pathog. Dis. PD DEC PY 2016 VL 13 IS 12 BP 656 EP 660 DI 10.1089/fpd.2016.2163 PG 5 WC Food Science & Technology SC Food Science & Technology GA EH5MY UT WOS:000391818400002 PM 27992273 ER PT J AU Kurtz, SL Bosio, CM De Pascalis, R Elkins, KL AF Kurtz, Sherry L. Bosio, Catharine M. De Pascalis, Roberto Elkins, Karen L. TI GM-CSF has disparate roles during intranasal and intradermal Francisella tularensis infection SO MICROBES AND INFECTION LA English DT Article DE GM-CSF; Alveolar macrophage; Francisella; Immunity ID COLONY-STIMULATING FACTOR; LIVE VACCINE STRAIN; FACTOR-DEFICIENT MICE; ALVEOLAR MACROPHAGES; IMMUNITY; HOST; TUBERCULOSIS; INTERFERON; TULAREMIA; LUNGS AB Our laboratory has employed in vitro and in vivo mouse models based on Francisella tularensis Live Vaccine Strain (LVS)-induced protection to elucidate immune correlates for intracellular bacteria. Among the effectors found was GM-CSF, a pleiotropic cytokine that is integral to the development and proliferation of myeloid cells, including alveolar macrophages. GM-CSF has roles in resistance to primary murine infection with several intracellular pathogens, but its role during Francisella infection is unknown. Francisella is an intracellular pathogen that infects lungs after inhalation, primarily invading alveolar macrophages. Here we show that GM-CSF has route-dependent roles during primary infection of mice with LVS. GM-CSF deficient (GM-CSF KO) mice were slightly more susceptible than wild type to intradermal infection, but had increased resistance to intranasal infection. Similarly, these mice had increased resistance to pulmonary infection with virulent F. tularensis (SchuS4). LVS-vaccinated GM-CSF KO mice had normal adaptive immune responses, as measured by T cell activities after LVS intradermal or intranasal vaccination, and survived lethal secondary LVS challenge. GM-CSF KO mice also had robust humoral responses, producing elevated levels of serum antibodies following LVS vaccination compared to wild type mice. Taken together, our data demonstrates that the absence of GM-CSF improves resistance to pulmonary, but not intradermal, infection with Francisella. Published by Elsevier Masson SAS on behalf of Institut Pasteur. C1 [Kurtz, Sherry L.; De Pascalis, Roberto; Elkins, Karen L.] US FDA, Lab Mucosal Pathogens & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20903 USA. [Bosio, Catharine M.] NIAID, Immun Pulm Pathogens Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT 59480 USA. RP Elkins, KL (reprint author), US FDA, Lab Mucosal Pathogens & Cellular Immunol, Div Bacterial & Allergen Prod, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 52-72,Room 5330 5348, Silver Spring, MD 20993 USA. EM karen.elkins@fda.hhs.gov NR 28 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 EI 1769-714X J9 MICROBES INFECT JI Microbes Infect. PD DEC PY 2016 VL 18 IS 12 BP 758 EP 767 DI 10.1016/j.micinf.2016.07.003 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EH4ZB UT WOS:000391781300005 PM 27475899 ER PT J AU Kazandjian, D Landgren, O AF Kazandjian, Dickran Landgren, Ola TI A look backward and forward in the regulatory and treatment history of multiple myeloma: Approval of novel-novel agents, new drug development, and longer patient survival SO SEMINARS IN ONCOLOGY LA English DT Review DE Myeloma; Smoldering; FDA; EMA; Approvals ID PHASE-3 TRIAL; BONE-MARROW; DEXAMETHASONE; LENALIDOMIDE; BORTEZOMIB; INHIBITOR; THERAPY; MULTICENTER; COMBINATION; DARATUMUMAB AB The past decade has seen significant advances in our understanding and treatment of multiple myeloma (MM) and its precursor diseases. These advances include gains in knowledge of the underlying pathobiology including molecular and cellular prognostic factors for disease progression. In parallel we have witnessed the availability of novel therapeutics. Together these advances have translated into improvements in long-term clinical benefit and survival in MM. Indeed, it has been shown that patients diagnosed in the last decade have experienced almost doubling of median survival time. We aim to review and give further insight into drug development and novel drug approvals that have revolutionized the treatment of MM. Published by Elsevier Inc. C1 [Kazandjian, Dickran] NCI, Myeloma Program, Lymphoid Malignancies Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Kazandjian, Dickran] US FDA, Off Hematol & Oncol Prod, Bethesda, MD USA. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, Myeloma Serv, 1275 York Ave, New York, NY 10021 USA. RP Kazandjian, D (reprint author), NCI, Bldg 10,Room 4N115,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kazandjiandg@mail.nih.gov FU Memorial Sloan Kettering Core Grant [P30 CA008748] FX Memorial Sloan Kettering Core Grant, (P30 CA008748) for grant support. NR 30 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD DEC PY 2016 VL 43 IS 6 BP 682 EP 689 DI 10.1053/j.seminoncol.2016.10.008 PG 8 WC Oncology SC Oncology GA EH6QY UT WOS:000391900200008 PM 28061986 ER PT J AU Kim, DH Jeong, D Kim, H Kang, IB Chon, JW Song, KY Seo, KH AF Kim, Dong-Hyeon Jeong, Dana Kim, Hyunsook Kang, Il-Byeong Chon, Jung-Whan Song, Kwang-Young Seo, Kun-Ho TI Antimicrobial Activity of Kefir against Various Food Pathogens and Spoilage Bacteria SO KOREAN JOURNAL FOR FOOD SCIENCE OF ANIMAL RESOURCES LA English DT Article DE Kefir; probiotics; antimicrobial activity; food-borne pathogen; fermentation time ID LACTIC-ACID BACTERIA; LACTOBACILLUS-ACIDOPHILUS; FERMENTED MILK; STRAINS; YOGURT; GRAINS AB Kefir is a unique fermented dairy product produced by a mixture of lactic acid bacteria, acetic acid bacteria, and yeast. Here, we compared the antimicrobial spectra of four types of kefirs (A, L, M, and S) fermented for 24, 36, 48, or 72 h against eight food-borne pathogens. Bacillus cereus, Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis, Escherichia colt, Salmonella Enteritidis, Pseudomonas aeruginosa, and Cronobacter sakazakii were used as test strains, and antibacterial activity was investigated by the spot on lawn method. The spectra, potencies, and onsets of activity varied according to the type of kefir and the fermentation time. The broadest and strongest antimicrobial spectrum was obtained after at least 36-48 h of fermentation for all kefirs, although the traditional fermentation method of kefir is for 18-24 hat 25 degrees C. For kefir A, B. cereus, E. colt, S. Enteritidis, P aeruginosa, and C. sakazakii were inhibited, while B. cereus, S. aurezis, E. coli, S. Enteritidis, P aeruginosa, and C. sakazakii were inhibited to different extents by kefirs L, M, and S. Remarkably, S. aureus, S. Enteritidis, and C. sakazakii were only inhibited by kefirs L, M, and S, and L. monocytogenes by kefir M after fermentation for specific times, suggesting that the antimicrobial activity is attributable not only to a low pH but also to antimicrobial substances secreted during the fermentation. C1 [Kim, Dong-Hyeon; Jeong, Dana; Kang, Il-Byeong; Chon, Jung-Whan; Song, Kwang-Young; Seo, Kun-Ho] Konkuk Univ, Coll Vet Med, Ctr Hlth 1, Seoul 05029, South Korea. [Kim, Hyunsook] Hanyang Univ, Coll Human Ecol, Dept Food & Nutr, Seoul 04763, South Korea. [Chon, Jung-Whan] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. RP Seo, KH (reprint author), Konkuk Univ, Coll Vet Med, Ctr Hlth 1, Seoul 05029, South Korea. EM bracstu3@konkuk.ac.kr FU Konkuk University FX This paper was supported by Konkuk University in 2016. NR 25 TC 0 Z9 0 U1 14 U2 14 PU KOREAN SOC FOOD SCIENCE ANIMAL RESOURCES PI SEOUL PA 615, COLL ANIMAL BIOSCIENCE & TECHNOLOGY, KONKUK UNIV, SEOUL, 143-701, SOUTH KOREA SN 1225-8563 J9 KOREAN J FOOD SCI AN JI Korean J. Food Sci. Anim. Resour. PD DEC PY 2016 VL 36 IS 6 BP 787 EP 790 DI 10.5851/kosfa.2016.36.6.787 PG 4 WC Food Science & Technology SC Food Science & Technology GA EG7PM UT WOS:000391241300011 PM 28115890 ER PT J AU Balan, KV Bigley, EC Gaines, DW Babu, US AF Balan, Kannan V. Bigley, Elmer C., III Gaines, Dennis W. Babu, Uma S. TI Tissue colonization and circulating T lymphocytes in laying hens upon oral challenge with Salmonella enterica serovars SO POULTRY SCIENCE LA English DT Article DE Laying hens; Salmonella serovars; tissue colonization; T lymphocytes ID EGG CONTAMINATION; REPRODUCTIVE-TRACT; INFECTION; ENTERITIDIS; CHICKENS; SUBPOPULATIONS; TYPHIMURIUM; SEROTYPES; ENVIRONMENT; IMMUNITY AB Evaluating the potential of Salmonella serovars for tissue colonization and egg contamination in laying hens is critical due to widespread consumption of poultry and egg-containing products. The 2009 FDA Egg Rule was implemented to target the eradication of Salmonella enterica Enteritidis (SE) from layers; however, other Salmonella serovars, such as Heidelberg (SH) and Typhimurium (ST), have also been associated with poultry-related outbreaks. We conducted this study to see if serovars other than SE could colonize in laying hens, cause egg contamination, and modulate circulating T-cell populations. Laying hens were orally gavaged with 10(7) colony forming units (CFU) of SE, SH, or ST and assessed for colonization in spleen, ovaries, and oviduct 10 d postchallenge. Splenic colonization was similar for all the serovars; however, colonization of ovaries and oviducts was significantly higher with SH compared to SE and ST. Furthermore, SH challenge resulted in egg contamination, while SE and ST did not result in contaminated eggs. Phenotypic evaluation of peripheral blood lymphocytes showed significant reduction in CD4 cells in SH-challenged birds and lower CD8 alpha and CD8 beta cells in SE-challenged birds compared to controls. Our data showed that non-SE serovars have equal or higher potential to colonize reproductive tissues of laying hens and may be accompanied by altered lymphocyte populations. C1 [Balan, Kannan V.; Bigley, Elmer C., III; Gaines, Dennis W.; Babu, Uma S.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Babu, US (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. EM uma.babu@fda.hhs.gov FU Research Participation Program at the U.S. Food and Drug Administration FX We would like to acknowledge Marion Pereira, Girdhari Sharma, and Lisa Plemons for technical support and CFSAN Animal Husbandry Unit for animal care services. KVB was supported by the Research Participation Program at the U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 33 TC 0 Z9 0 U1 6 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0032-5791 EI 1525-3171 J9 POULTRY SCI JI Poult. Sci. PD DEC PY 2016 VL 95 IS 12 BP 2824 EP 2828 DI 10.3382/ps/pew210 PG 5 WC Agriculture, Dairy & Animal Science SC Agriculture GA EG6CL UT WOS:000391131400011 PM 27418660 ER PT J AU Sunil, M Nigalye, M Somasunderam, A Martinez, ML Yu, XY Arduino, RC Utay, NS Bell, TK AF Sunil, Meena Nigalye, Maitreyee Somasunderam, Anoma Martinez, Maria Laura Yu, Xiaoying Arduino, Roberto C. Utay, Netanya S. Bell, Tanvir K. TI Unchanged Levels of Soluble CD14 and IL-6 Over Time Predict Serious Non-AIDS Events in HIV-1-Infected People SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article DE HIV; sCD14; IL-6; cardiovascular disease; drug abuse ID ACUTE CORONARY SYNDROME; ANTIRETROVIRAL TREATMENT; MICROBIAL TRANSLOCATION; HIV-INFECTION; INFLAMMATION; OUTPATIENT; ACTIVATION; MORTALITY; OUTCOMES; THERAPY AB HIV-1-infected persons have increased risk of serious non-AIDS events (SNAEs) despite suppressive antiretroviral therapy. Increased circulating levels of soluble CD14 (sCD14), soluble CD163 (sCD163), and interleukin-6 (IL-6) at a single time point have been associated with SNAEs. However, whether changes in these biomarker levels predict SNAEs in HIV-1-infected persons is unknown. We hypothesized that greater decreases in inflammatory biomarkers would be associated with fewer SNAEs. We identified 39 patients with SNAEs, including major cardiovascular events, end stage renal disease, decompensated cirrhosis, non-AIDS-defining malignancies, and death of unknown cause, and age- and sex-matched HIV-1-infected controls. sCD14, sCD163, and IL-6 were measured at study enrollment (T1) and proximal to the event (T2) or equivalent duration in matched controls. Over approximate to 34 months, unchanged rather than decreasing levels of sCD14 and IL-6 predicted SNAEs. Older age and current illicit substance abuse, but not HCV coinfection, were associated with SNAEs. In a multivariate analysis, older age, illicit substance use, and unchanged IL-6 levels remained significantly associated with SNAEs. Thus, the trajectories of sCD14 and IL-6 levels predict SNAEs. Interventions to decrease illicit substance use may decrease the risk of SNAEs in HIV-1-infected persons. C1 [Sunil, Meena; Martinez, Maria Laura; Arduino, Roberto C.; Bell, Tanvir K.] Univ Texas Hlth Sci Ctr Houston UTHlth, McGovern Med Sch, Div Infect Dis, Dept Internal Med, Houston, TX USA. [Nigalye, Maitreyee; Somasunderam, Anoma; Utay, Netanya S.] Univ Texas Med Branch, Div Infect Dis, Dept Med, 301 Univ Blvd Route 0435, Galveston, TX 77555 USA. [Yu, Xiaoying] Baylor Coll Med, Ctr AIDS Res, Design & Anal Core, Houston, TX 77030 USA. [Sunil, Meena] Byrd Med Clin, Leesville, LA USA. [Bell, Tanvir K.] US FDA, Div Antiviral Prod, Ctr Drug Evaluat, Silver Spring, MD USA. RP Utay, NS (reprint author), Univ Texas Med Branch, Div Infect Dis, Dept Med, 301 Univ Blvd Route 0435, Galveston, TX 77555 USA. EM neutay@utmb.edu NR 18 TC 1 Z9 1 U1 0 U2 0 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 DEC PY 2016 VL 32 IS 12 BP 1205 EP 1209 DI 10.1089/aid.2016.0007 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EF8PZ UT WOS:000390592600010 PM 27344921 ER PT J AU Liu, M Jin, JS Pan, HM Feng, JH Cerniglia, CE Yang, MC Chen, HZ AF Liu, Min Jin, Jinshan Pan, Hongmiao Feng, Jinhui Cerniglia, Carl E. Yang, Maocheng Chen, Huizhong TI Effect of smokeless tobacco products on human oral bacteria growth and viability SO ANAEROBE LA English DT Article DE Smokeless tobacco; Toxicology; Oral bacteria; Cell viability; Tobacco-specific N-nitrosamines ID DENTAL-CARIES; STREPTOCOCCUS; PERIODONTITIS; EXTRACTS; CANCER; NITROSAMINES; DETERMINANTS; SUBGINGIVAL; NICOTINE; ABSCESS AB To evaluate the toxicity of smokeless tobacco products (STPs) on oral bacteria, seven smokeless tobacco aqueous extracts (STAEs) from major brands of STPs and three tobacco-specific N-nitrosamines (TSNAs) were used in a growth and viability test against 38 oral bacterial species or subspecies. All seven STAEs showed concentration-dependent effects on the growth and viability of tested oral bacteria under anaerobic culture conditions, although there were strain-to-strain variations. In the presence of 1 mg/ml STAEs, the growth of 4 strains decreased over 0.32-2.14 log(10) fold, while 14 strains demonstrated enhanced growth of 0.3-1.76 log(10) fold, and the growth of 21 strains was not significantly affected. In the presence of 10 mg/ml STAE5, the growth of 17 strains was inhibited 0.3-2.11 log(10) fold, 18 strains showed enhanced growth of 0.3-0.97 log(10) fold, and 4 strains were not significantly affected. In the presence of 50 mg/ml STAEs, the growth of 32 strains was inhibited 0.3-2.96 log(10) fold, 8 strains showed enhanced growth of 0.3-1.0 log(10) fold, and 2 strains were not significantly affected. All seven STAEs could promote the growth of 4 bacterial strains, including Eubacterium nodatum, Peptostreptococcus micros, Streptococcus anginosus, and Streptococcus constellatus. Exposure to STAEs modulated the viability of some bacterial strains, with 21.1-66.5% decrease for 4 strains at 1 mg/ml, 20.3-85.7% decrease for 10 strains at 10 mg/ml, 20.0-93.3% decrease for 27 strains at 50 mg/ml, and no significant effect for 11 strains at up to 50 mg/ml. STAE5 from snuffs inhibited more tested bacterial strains than those from snus indicating that the snuffs may be more toxic to the oral bacteria than snus. For TSNAs, cell growth and viability of 34 tested strains were not significantly affected at up to 100 mu g/ml; while the growth of P. micros was enhanced 0.31-0.54 log(10) fold; the growth of Veillonella parvula was repressed 0.33-0.36 log(10) fold; and the cell viabilities of 2 strains decreased 56.6-69.9%. The results demonstrate that STAE5 affected the growth of some types of oral bacteria, which may affect the healthy ecological balance of oral bacteria in humans. On the other hand, TSNAs did not significantly affect the growth of the oral bacteria. Published by Elsevier Ltd. C1 [Liu, Min; Jin, Jinshan; Pan, Hongmiao; Feng, Jinhui; Cerniglia, Carl E.; Chen, Huizhong] USDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Liu, Min] Chinese Acad Trop Agr Sci, Inst Trop Biosci & Biotechnol, Haikou 571101, Peoples R China. [Pan, Hongmiao] Chinese Acad Sci, Inst Oceanol, Key Lab Marine Ecol & Environm Sci, Qingdao 266071, Peoples R China. [Feng, Jinhui] Chinese Acad Sci, Tianjin Inst Ind Biotechnol, Natl Engn Lab Ind Enzymes, Tianjin 300308, Peoples R China. [Yang, Maocheng] USDA, Off Sci, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Chen, HZ (reprint author), USDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA.; Yang, MC (reprint author), USDA, Off Sci, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM 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. John Sutherland, Steven Foley and Hans Rosenfeldt for their critical review of this manuscript. We also thank CTP writer Mrs. Deborah Neveleff for proof reading the manuscript. This study was funded by the Center for Tobacco Products, U.S. Food and Drug Administration (E0747201), and supported in part by appointment (M.L., H.P., J.J., and J.F.) to the Postgraduate Research Fellowship Program by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. The authors thank Mrs. Jinyan Sun for technical assistance with growth of bacterial cultures. The findings and conclusions in this publication are those of the authors and do not represent FDA positions or policies. NR 43 TC 0 Z9 0 U1 8 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1075-9964 EI 1095-8274 J9 ANAEROBE JI Anaerobe PD DEC PY 2016 VL 42 BP 152 EP 161 DI 10.1016/j.anaerobe.2016.10.006 PG 10 WC Microbiology SC Microbiology GA EF9CP UT WOS:000390628600027 PM 27756619 ER PT J AU Fardin-Kia, AR AF Fardin-Kia, Ali Reza TI Preparation, isolation and identification of non-conjugated C18:2 fatty acid isomers SO CHEMISTRY AND PHYSICS OF LIPIDS LA English DT Article DE Fatty acid; Fatty acid/synthesis; Methods/HPLC; Liquid chromatography; Mass spectrometry; Linoleic acid; Picolinyl esters; Fatty acid separation; Hydrazine reduction ID PERFORMANCE LIQUID-CHROMATOGRAPHY; PICOLINYL ESTERS; RETENTION TIMES; METHYL-ESTERS; TRANS FAT; MILK-FAT; CIS; TEMPERATURE; DERIVATIVES; METABOLISM AB Non-conjugated geometric/positional isomers of linoleic acid (c9,c12-18:2) are often present in processed foods and oils. The following work presents a simple addition/elimination reaction for preparation of non-conjugated 18:2 fatty acid isomers. A mixture containing positional and geometric isomers of C18:2 fatty acids was produced by addition of hydrobromic acid to the fatty acid double bonds, followed by its elimination with a strong sterically hindered base. Pure 8,12-, 8,13-, 9,12-, and 9,13-18:2 fatty acid methyl esters were isolated from the synthetic mixture by a combination of sub-ambient RP-HPLC and Ag+-HPLC. The determination of the double bond position was achieved by GC-MS using picolinyl esters derivatives. The determination of the fatty acid double bond geometric configuration was obtained by partial hydrogenation of the isolated isomer with hydrazine, followed by the GC-FID analysis. Published by Elsevier Ireland Ltd. C1 [Fardin-Kia, Ali Reza] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy,HFS 715, College Pk, MD 20740 USA. RP Fardin-Kia, AR (reprint author), US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy,HFS 715, College Pk, MD 20740 USA. EM alireza.fardinkia@fda.hhs.gov NR 27 TC 0 Z9 0 U1 10 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-3084 EI 1873-2941 J9 CHEM PHYS LIPIDS JI Chem. Phys. Lipids PD DEC PY 2016 VL 201 BP 50 EP 58 DI 10.1016/j.chemphyslip.2016.10.003 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA EG0KL UT WOS:000390721600006 PM 27769894 ER PT J AU Cieslak, J Grajkowski, A Ausin, C Beaucage, SL AF Cieslak, Jacek Grajkowski, Andrzej Ausin, Cristina Beaucage, Serge L. TI Protection of the 2-Hydroxy Function of Ribonucleosides as an Iminooxymethyl Propanoate and Its 2-O-Deprotection through an Intramolecular Decarboxylative Elimination Process SO EUROPEAN JOURNAL OF ORGANIC CHEMISTRY LA English DT Article DE Nucleosides; RNA; Protecting groups; 2-O-Cleavage reactions; Elimination ID ALPHA-KETO ACIDS; RNA-SYNTHESIS; CHEMICAL-SYNTHESIS; OLIGORIBONUCLEOTIDES AB The design and implementation of 2-hydroxy protecting groups for ribonucleosides is still a daunting challenge to overcome when assembling RNA (ribonucleic acid) sequences for therapeutic applications. The reaction of 2-O-aminooxymethylribonucleosides with ethyl pyruvate results in the formation of 2-O-iminooxymethyl ethyl propanoates. The cleavage of this type of 2-O-protecting groups is demonstrated through saponification of the esters to 2-O-iminooxymethyl propanoate salts, which, when needed, decarboxylate quantitatively at 55 degrees C in the presence of tetra-n-butylammonium fluoride or chloride in dimethyl sulfoxide (DMSO) to produce all four native ribonucleosides. C1 [Cieslak, Jacek; Grajkowski, Andrzej; Ausin, Cristina; Beaucage, Serge L.] US FDA, Div Biotechnol Review & Res 4, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20933 USA. RP Beaucage, SL (reprint author), US FDA, Div Biotechnol Review & Res 4, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20933 USA. EM serge.beaucage@fda.hhs.gov FU U.S. Food and Drug Administration (FDA) FX This work was supported through the U.S. Food and Drug Administration (FDA) intramural funds. NR 27 TC 0 Z9 0 U1 7 U2 7 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1434-193X EI 1099-0690 J9 EUR J ORG CHEM JI Eur. J. Org. Chem. PD DEC PY 2016 IS 35 BP 5817 EP 5821 DI 10.1002/ejoc.201601308 PG 5 WC Chemistry, Organic SC Chemistry GA EG1GI UT WOS:000390780000006 ER PT J AU Sarrel, PM Sullivan, SD Nelson, LM AF Sarrel, Philip M. Sullivan, Shannon D. Nelson, Lawrence M. TI Hormone replacement therapy in young women with surgical primary ovarian insufficiency SO FERTILITY AND STERILITY LA English DT Review DE Premenopausal oophorectomy; ovarian insufficiency; surgical menopause; estrogen therapy ID BILATERAL SALPINGO-OOPHORECTOMY; RECENTLY POSTMENOPAUSAL WOMEN; TERM HEALTH CONSEQUENCES; LONG-TERM; EARLY MENOPAUSE; CARDIOVASCULAR-DISEASE; VASOMOTOR SYMPTOMS; BREAST-CANCER; HOT FLASHES; PROPHYLACTIC OOPHORECTOMY AB Bilateral oophorectomy performed in women before they are menopausal induces surgical primary ovarian insufficiency, an acute and chronic deficiency of the hormones normally produced by the ovaries. Without hormone replacement therapy (HRT) most of these women develop severe symptoms of estrogen (E) deficiency and are at increased risk for osteoporosis, cardiovascular disease, cognitive decline, dementia, and the associated increases in morbidity and mortality. In cases in which a hysterectomy has been performed at the time of bilateral oophorectomy transdermal or transvaginal E-2 replacement therapy without cyclic progestin replacement is the optimum hormonal management for these women. There is substantial evidence this approach even reduces the risk for breast cancer. Unfortunately, unwarranted fear of all menopausal HRTs has become widespread following the reports of the Women's Health Initiative studies. This fear has led to a steep decline in use of E therapy, even in women in whom HRT is clearly indicated. Discussion of possible ovarian conservation in women who are premenopausal is an integral part of the preoperative planning for any women undergoing hysterectomy. Timely and effective HRT for women who will experience surgical primary ovarian insufficiency is clearly indicated. (C) 2016 by American Society for Reproductive Medicine. C1 [Sarrel, Philip M.] Yale Univ, Dept Obstet Gynecol & Reprod Sci, New Haven, CT USA. [Sarrel, Philip M.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Sullivan, Shannon D.] US FDA, Silver Spring, MD USA. [Nelson, Lawrence M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, CAPT US Publ Hlth Serv, Intramural Res Program, NIH, Bethesda, MD USA. RP Nelson, LM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, CAPT US Publ Hlth Serv, Intramural Res Program, NIH,CRC, Room 1-3330,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM Lawrence_Nelson@nih.gov FU Intramural Research Program, National Institutes of Health, Bethesda, MD FX Supported in part by the Intramural Research Program, National Institutes of Health, Bethesda, MD. NR 76 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD DEC PY 2016 VL 106 IS 7 BP 1580 EP 1587 DI 10.1016/j.fertnstert.2016.09.018 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA EF9RU UT WOS:000390668400007 PM 27793381 ER PT J AU Sullivan, SD Sarrel, PM Nelson, LM AF Sullivan, Shannon D. Sarrel, Philip M. Nelson, Lawrence M. TI Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause SO FERTILITY AND STERILITY LA English DT Review DE Primary ovarian insufficiency; premature ovarian failure; premature menopause; early menopause; estrogen; progestin; androgen; hormone replacement therapy; menopausal hormone therapy; management; morbidity; mortality ID BONE-MINERAL DENSITY; CLINICAL-PRACTICE GUIDELINE; PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; MEIBOMIAN GLAND SECRETIONS; SEX STEROID REPLACEMENT; ISCHEMIC-HEART-DISEASE; POSTMENOPAUSAL WOMEN; ESTROGEN-REPLACEMENT; TURNER-SYNDROME AB Primary ovarian insufficiency (POI) is a rare but important cause of ovarian hormone deficiency and infertility in women. In addition to causing infertility, POI is associated with multiple health risks, including bothersome menopausal symptoms, decreased bone density and increased risk of fractures, early progression of cardiovascular disease, psychologic impact that may include depression, anxiety, and decreased perceived psychosocial support, potential early decline in cognition, and dry eye syndrome. Appropriate hormone replacement therapy (HRT) to replace premenopausal levels of ovarian sex steroids is paramount to increasing quality of life for women with POI and ameliorating associated health risks. In this review, we discuss POI and complications associated with this disorder, as well as safe and effective HRT options. To decrease morbidity associated with POI, we recommend using HRT formulations that most closely mimic normal ovarian hormone production and continuing HRT until the normal age of natural menopause, similar to 50 years. We address special populations of women with POI, including women with Turner syndrome, women with increased risk of breast or ovarian cancer, women approaching the age of natural menopause, and breastfeeding women. (C) 2016 by American Society for Reproductive Medicine. C1 [Sullivan, Shannon D.] US FDA, Silver Spring, MD USA. [Sarrel, Philip M.] Yale Univ, Obstet Gynecol & Reprod Sci & Psychiat, New Haven, CT USA. [Nelson, Lawrence M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program, NIH, Bethesda, MD USA. RP Nelson, LM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, US Publ Hlth Serv, Intramural Res Program, NIH,CRC, Room 1-3330,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM lawrence_nelson@nih.gov FU Intramural Research Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX Supported in part by the Intramural Research Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (L.M.N.). NR 116 TC 1 Z9 1 U1 13 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD DEC PY 2016 VL 106 IS 7 BP 1588 EP 1599 DI 10.1016/j.fertnstert.2016.09.046 PG 12 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA EF9RU UT WOS:000390668400008 PM 27912889 ER PT J AU Babu, US Balan, KV Bigley, E Pereira, M Black, T Olejnik, N Keltner, Z Sprando, RL AF Babu, Uma S. Balan, Kannan V. Bigley, Elmer Pereira, Marion Black, Thomas Olejnik, Nicholas Keltner, Zachary Sprando, Robert L. TI Effects of maternal silver acetate exposure on immune biomarkers in a rodent model SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Silver acetate; Maternal exposure; Immune biomarkers; Rodent model; Natural killer cell activity ID REPEATED-DOSE TOXICITY; NANOPARTICLES; IMMUNOTOXICITY; CELLS; RATS; IONS AB Male and female rats (26-day old) were exposed to 0.0, 0.4, 4 or 40 mg/kg body weight silver acetate (AgAc) in drinking water for 10 weeks prior to and during mating. Sperm positive females remained within their dose groups and were exposed to AgAc during gestation and lactation. Splenic and thymic lymphocyte subsets from Fl generation PD (postnatal day) 4 and 26 pups were assessed by flow cytometry for changes in phenotypic markers. Spleens from PD4 pups had lower percentages of CD8+ lymphocytes in 4 and 40 mg/kg AgAc exposed groups and reduced Concanavalin A (Con A) response at all AgAc exposure groups. Splenic maturation increased in PD26 pups compared to PD4 pups. Con A and lipopolysaccharide (LPS) mediated splenic responses were lower in PD26 pups exposed to 40 mg/kg AgAc. Changes in PD 26 pup splenocyte phenotypic markers included lower TCR + cells at 4 and 40 mg/ kg AgAc exposure and higher B cell population in the 40 mg/kg AgAc. PD26 pup splenic natural killer cell (NK) activity was higher in the 0.4 AgAc group and unchanged in 4 and 40 mg/kg AgAc groups. In conclusion, maternal exposure to AgAc had a significant impact on rat splenic development during the early lactation period. Published by Elsevier Ltd. C1 [Black, Thomas; Olejnik, Nicholas; Keltner, Zachary; Sprando, Robert L.] US FDA, Div Toxicol, Off Appl Res & Safety Assessment, CFSAN, Laurel, MD USA. [Babu, Uma S.; Balan, Kannan V.; Bigley, Elmer; Pereira, Marion] US FDA, Div Virulence Assessment, Off Appl Res & Safety Assessment, CFSAN, Laurel, MD USA. RP Babu, US (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, HFS-275,8301 Muirkirk Rd, Laurel, MD 20708 USA. EM uma.babu@fda.hhs.gov NR 26 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 DEC PY 2016 VL 98 BP 195 EP 200 DI 10.1016/j.fct.2016.10.022 PN B PG 6 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA EF7JH UT WOS:000390505400012 PM 27789322 ER PT J AU Sun, C Gao, J Couzens, L Tian, X Farooqui, MZ Eichelberger, MC Wiestner, A AF Sun, Clare Gao, Jin Couzens, Laura Tian, Xin Farooqui, Mohammed Z. Eichelberger, Maryna C. Wiestner, Adrian TI Seasonal Influenza Vaccination in Patients With Chronic Lymphocytic Leukemia Treated With Ibrutinib SO JAMA ONCOLOGY LA English DT Letter ID INFECTIONS C1 [Sun, Clare; Farooqui, Mohammed Z.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10,CRC Room 3-5140, Bethesda, MD 20892 USA. [Gao, Jin; Couzens, Laura; Eichelberger, Maryna C.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Tian, Xin] NHLBI, Off Biostat Res, NIH, 10 Ctr Dr,Bldg 10,CRC Room 3-5140, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10,CRC Room 3-5140, Bethesda, MD 20892 USA. EM wiestnea@nhlbi.nih.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 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD DEC 1 PY 2016 VL 2 IS 12 BP 1656 EP 1657 DI 10.1001/jamaoncol.2016.2437 PG 2 WC Oncology SC Oncology GA EF8TG UT WOS:000390601900028 PM 27533065 ER PT J AU Blake, KD Portnoy, DB Kaufman, AR Lin, CTJ Lo, SC Backlund, E Cantor, D Hicks, L Lin, A Caporaso, A Davis, T Moser, RP Hesse, BW AF Blake, Kelly D. Portnoy, David B. Kaufman, Annette R. Lin, Chung-Tung Jordan Lo, Serena C. Backlund, Eric Cantor, David Hicks, Lloyd Lin, Amy Caporaso, Andrew Davis, Terisa Moser, Richard P. Hesse, Bradford W. TI Rationale, Procedures, and Response Rates for the 2015 Administration of NCI's Health Information National Trends Survey: HINTS-FDA 2015 SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID TOBACCO PRODUCTS; FOOD AB The National Cancer Institute (NCI) developed the Health Information National Trends Survey (HINTS) to monitor population trends in cancer communication practices, information preferences, health risk behaviors, attitudes, and cancer knowledge. The U.S. Food and Drug Administration (FDA) recognized HINTS as a unique data resource for informing its health communication endeavors and partnered with NCI to field HINTS-FDA 2015. HINTS-FDA 2015 was a self-administered paper instrument sent by mail May 29 to September 8, 2015, using a random probability-based sample of U.S. postal addresses stratified by county-level smoking rates, with an oversampling of high and medium-high smoking strata to increase the yield of current smokers responding to the survey. The response rate for HINTS-FDA 2015 was 33% (N=3,738). The yield of current smokers (n=495) was lower than expected, but the sampling strategy achieved the goal of obtaining more former smokers (n=1,132). Public-use HINTS-FDA 2015 data and supporting documentation have been available for download and secondary data analyses since June 2016 at http://hints.cancer.gov. NCI and FDA encourage the use of HINTS-FDA for health communication research and practice related to tobacco-related communications, public knowledge, and behaviors as well as beliefs and actions related to medical products and dietary supplements. C1 [Blake, Kelly D.; Hesse, Bradford W.] NCI, NIH, Hlth Commun & Informat Res Branch, Behav Res Program,Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E222,MSC 9671, Bethesda, MD 20892 USA. [Portnoy, David B.; Backlund, Eric] US FDA, Off Sci, Ctr Tobacco Prod, Silver Spring, MD USA. [Kaufman, Annette R.] NCI, NIH, Tobacco Control Res Branch, Behav Res Program,Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Lin, Chung-Tung Jordan; Lo, Serena C.] US FDA, Off Analyt & Outreach, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Cantor, David; Hicks, Lloyd; Lin, Amy; Caporaso, Andrew; Davis, Terisa] Westat Corp, Rockville, MD USA. [Moser, Richard P.] NCI, NIH, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Blake, KD (reprint author), NCI, NIH, Hlth Commun & Informat Res Branch, Behav Res Program,Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E222,MSC 9671, Bethesda, MD 20892 USA. EM kelly.blake@nih.gov FU National Cancer Institute (NCI); U.S. Food and Drug Administration's Center for Tobacco Products, Office of the Commissioner; Center for Food Safety and Applied Nutrition; NCI [HHSN261201000064C] FX HINTS-FDA (Health Information National Trends Survey-U.S. Food and Drug Administration) was funded by the National Cancer Institute (NCI) and the U.S. Food and Drug Administration's Center for Tobacco Products, Office of the Commissioner, and Center for Food Safety and Applied Nutrition via interagency agreements with NCI and by contract from NCI to Westat, Inc. (HHSN261201000064C). NR 17 TC 1 Z9 1 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PD DEC PY 2016 VL 21 IS 12 BP 1269 EP 1275 DI 10.1080/10810730.2016.1242672 PG 7 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA EF6BQ UT WOS:000390415100008 PM 27892827 ER PT J AU Shrivastava, D Mishra, SC Gordon, CJ AF Shrivastava, Devashish Mishra, Subhash C. Gordon, Christopher J. TI Modeling bioheat transfer processes and thermoregulatory responses SO JOURNAL OF THERMAL BIOLOGY LA English DT Editorial Material C1 [Shrivastava, Devashish] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Mishra, Subhash C.] Dept Mech Engn, Gauhati 781039, Guwahati, India. [Gordon, Christopher J.] US EPA, Res Triangle Pk, NC 27707 USA. RP Shrivastava, D (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM devashish.shrivastava@gmail.com; scm_iitg@yahoo.com; cjgordon.gordon1@gmail.com NR 0 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 0306-4565 J9 J THERM BIOL JI J. Therm. Biol. PD DEC PY 2016 VL 62 SI SI BP 97 EP 97 DI 10.1016/j.jtherbio.2016.11.011 PN B PG 1 WC Biology; Zoology SC Life Sciences & Biomedicine - Other Topics; Zoology GA EG0KF UT WOS:000390721000001 PM 27888935 ER PT J AU Tournas, V Katsoudas, E AF Tournas, V. Katsoudas, E. TI Inhibition of Penicillium expansum growth on Golden Delicious apples by wild yeasts from various plant materials SO PHYTOPATHOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Phytopathological-Society (APS) CY JUL 30-AUG 03, 2016 CL Tampa, FL SP Amer Phytopathol Soc C1 [Tournas, V.] US FDA, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. [Katsoudas, E.] US FDA, Northeast Reg Lab, ORA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER PHYTOPATHOLOGICAL SOC PI ST PAUL PA 3340 PILOT KNOB ROAD, ST PAUL, MN 55121 USA SN 0031-949X EI 1943-7684 J9 PHYTOPATHOLOGY JI Phytopathology PD DEC PY 2016 VL 106 IS 12 SU S BP 53 EP 53 PG 1 WC Plant Sciences SC Plant Sciences GA EF6WM UT WOS:000390471900273 ER PT J AU Tournas, V Kohn, J Katsoudas, E AF Tournas, V. Kohn, J. Katsoudas, E. TI Fungal profiles in ginger root and cayenne pepper powders from US retail SO PHYTOPATHOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Phytopathological-Society (APS) CY JUL 30-AUG 03, 2016 CL Tampa, FL SP Amer Phytopathol Soc C1 [Tournas, V.] US FDA, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. [Kohn, J.; Katsoudas, E.] US FDA, Northeast Reg Lab, Off Regulatory Affairs, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER PHYTOPATHOLOGICAL SOC PI ST PAUL PA 3340 PILOT KNOB ROAD, ST PAUL, MN 55121 USA SN 0031-949X EI 1943-7684 J9 PHYTOPATHOLOGY JI Phytopathology PD DEC PY 2016 VL 106 IS 12 SU S BP 99 EP 99 PG 1 WC Plant Sciences SC Plant Sciences GA EF6WM UT WOS:000390471900516 ER PT J AU Marklein, RA Klinker, MW Wei, C Bauer, SR AF Marklein, R. A. Klinker, M. W. Wei, C. Bauer, S. R. TI Morphological Features of IFN gamma-Stimulated Mesenchymal Stromal Cells Predict Overall Immunosuppressive Capacity SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS - Americas Conference and Exhibition CY DEC 11-14, 2016 CL San Diego, CA SP TERMIS C1 [Marklein, R. A.; Klinker, M. W.; Wei, C.; Bauer, S. R.] US FDA, Silver Spring, MD USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC PY 2016 VL 22 SU 1 MA 142 BP S39 EP S39 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA EF8HF UT WOS:000390569200139 ER PT J AU Nguyen, AK Jaipan, P Jameson, JR Brittain, S Kaiser, AD Lo, LN Moreno, JL Narayan, RJ Goering, P Kumar, G AF Nguyen, A. K. Jaipan, P. Jameson, J. R. Brittain, S. Kaiser, A. D. Lo, L. N. Moreno, J. L. Narayan, R. J. Goering, P. Kumar, G. TI Effect of Simulated Body Fluid Formulation on Bioactivity SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS - Americas Conference and Exhibition CY DEC 11-14, 2016 CL San Diego, CA SP TERMIS C1 [Nguyen, A. K.; Jaipan, P.; Narayan, R. J.] North Carolina State Univ, Biomed Engn, Raleigh, NC USA. [Nguyen, A. K.; Jameson, J. R.; Brittain, S.; Kaiser, A. D.; Lo, L. N.; Moreno, J. L.; Goering, P.; Kumar, G.] US FDA, Silver Spring, MD USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC PY 2016 VL 22 SU 1 MA 568 BP S148 EP S148 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA EF8HF UT WOS:000390569200554 ER PT J AU Ortega, R AF Ortega, R. TI Enhancing Regulatory Review of Modeling and Simulation for Regenerative Medicine Products SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS - Americas Conference and Exhibition CY DEC 11-14, 2016 CL San Diego, CA SP TERMIS C1 [Ortega, R.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC PY 2016 VL 22 SU 1 MA 281 BP S74 EP S75 PG 2 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA EF8HF UT WOS:000390569200277 ER PT J AU Wang, CL Kane, R Levenson, M Kelman, J Wernecke, M Lee, JY Kozlowski, S Dekmezian, C Zhang, ZW Thompson, A Smith, K Wu, YT Wei, YQ Chillarige, Y Ryan, Q Worrall, C MaCurdy, TE Graham, DJ AF Wang, Cunlin Kane, Robert Levenson, Mark Kelman, Jeffrey Wernecke, Michael Lee, Joo-Yeon Kozlowski, Steven Dekmezian, Carmen Zhang, Zhiwei Thompson, Aliza Smith, Kimberly Wu, Yu-te Wei, Yuqin Chillarige, Yoganand Ryan, Qin Worrall, Chris MaCurdy, Thomas E. Graham, David J. TI Association Between Changes in CMS Reimbursement Policy and Drug Labels for Erythrocyte-Stimulating Agents With Outcomes for Older Patients Undergoing Hemodialysis Covered by Fee-for-Service Medicare SO JAMA INTERNAL MEDICINE LA English DT Article ID CHRONIC KIDNEY-DISEASE; SMALL DIALYSIS ORGANIZATIONS; PROSPECTIVE-PAYMENT SYSTEM; ANEMIA MANAGEMENT; BUNDLED PAYMENT; UNITED-STATES; MORTALITY; EPOETIN; IMPACT; TRENDS AB IMPORTANCE In 2011, the US Centers for Medicare & Medicaid Services (CMS) changed its reimbursement policy for hemodialysis to a bundled comprehensive payment system that included the cost of erythrocyte-stimulating agents (ESAs). Also in 2011, the US Food and Drug Administration revised the drug label for ESAs, recommending more conservative dosing in patients with chronic kidney disease. In response to concerns that these measures could have adverse effects on patient care and outcomes, the CMS and the FDA initiated a collaboration to assess the effect. OBJECTIVE To assess the effects of the changes in reimbursement policy and the ESA drug label on patients who underwent incident hemodialysis. DESIGN, SETTING, AND PARTICIPANTS For this retrospective cohort study, patients 66 years or older who had undergone incident hemodialysis, and were enrolled in Medicare parts A, B, or D for at least 12 months prior to hemodialysis initiation between January 1, 2008, and December 31, 2013, were recruited from hemodialysis centers across the United States. Patients were divided into 2 cohorts based on their date of hemodialysis initiation and followed: January 1, 2008, to December 31, 2009, for the prepolicy cohort and July 1, 2011, to June 30, 2013, for the postpolicy cohort, with the exclusion of January 1, 2010, to June 30, 2011, as a transition period. INTERVENTIONS Changes in CMS reimbursement policy for dialysis and the FDA label for ESAs. MAIN OUTCOMES AND MEASURES Major adverse cardiovascular events (MACEs), including acutemyocardial infarction (AMI), stroke, and all-cause mortality; hospitalized congestive heart failure (H-CHF); venous thromboembolism; and red blood cell transfusions. Secondary outcomes included evaluating effects on black and other patient subgroups. RESULTS Baseline characteristics of the 69 718 incident hemodialysis patients were similar between cohorts. Compared with the prepolicy period, the risk of MACE, death, H-CHF, and venous thromboembolism were similar in the postpolicy period, and the risk of stroke decreased (hazard ratio [HR], 0.77; 95% CI, 0.64-0.93; P = .01); the use of ESAs also decreased, and the rate of blood transfusions increased (HR, 1.09; 95% CI, 1.07-1.12; P < .001). In the post-postpolicy period, black patients had a significant reduction in risk of MACE (HR, 0.82; 95% CI, 0.73-0.92; P < .001) and all-cause mortality (HR, 0.82; 95% CI, 0.73-0.93; P = .002). CONCLUSIONS AND RELEVANCE After the bundling policy and ESA labeling changes in 2011, the risks of MACE and death for patients 66 years or older and covered by fee-for-service Medicare who had undergone incident hemodialysis did not change; the risk of stroke was reduced, and the rate of blood transfusions modestly increased. Black patients had substantial reductions in the risks of MACE and death. C1 [Wang, Cunlin; Graham, David J.] US FDA, Off Surveillance & Epidemiol, CDER, Silver Spring, MD USA. [Kane, Robert; Thompson, Aliza; Smith, Kimberly; Ryan, Qin] US FDA, Off New Drugs, CDER, Silver Spring, MD USA. [Levenson, Mark; Lee, Joo-Yeon; Wu, Yu-te] US FDA, Off Biostat, CDER, Silver Spring, MD USA. [Kelman, Jeffrey; Worrall, Chris] Ctr Medicare & Med Serv, Washington, DC USA. [Wernecke, Michael; Dekmezian, Carmen; Wei, Yuqin; Chillarige, Yoganand; MaCurdy, Thomas E.] Acumen LLC, Burlingame, CA USA. [Kozlowski, Steven] US FDA, Off Pharmaceut Qual, CDER, Silver Spring, MD USA. [Zhang, Zhiwei] US FDA, Ctr Device & Radiol Hlth, Silver Spring, MD USA. RP Wang, CL (reprint author), US FDA, Div Epidemiol 1, Off Surveillance & Epidemiol, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM cunlin.wang@fda.hhs.gov FU Centers for Medicare & Medicaid Services; US Food and Drug Administration FX This study was funded through an intra-agency agreement between the Centers for Medicare & Medicaid Services and the US Food and Drug Administration. NR 23 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD DEC 1 PY 2016 VL 176 IS 12 BP 1818 EP 1825 DI 10.1001/jamainternmed.2016.6520 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA EF3WN UT WOS:000390255700019 PM 27775769 ER PT J AU Yang, AL Schmidt, TE Stibitz, S Derrick, SC Morris, SL Parra, M AF Yang, Amy L. Schmidt, Thomas E. Stibitz, Scott Derrick, Steven C. Morris, Sheldon L. Parra, Marcela TI A simplified mycobacterial growth inhibition assay (MGIA) using direct infection of mouse splenocytes and the MGIT system SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Article DE Tuberculosis; BCG; Vaccine; MGIT; MGIA ID CD4(+) T-CELLS; IN-VITRO; TUBERCULOSIS; SURROGATE; IMMUNITY; VACCINES; BCG AB We describe a simplified Mycobacterial Growth Inhibition Assay (MGIA) for pre-clinical assessment of vaccine mediated protection in mice. The assay is accomplished by directly infecting splenocytes from vaccinated mice with Mycobacterium tuberculosis and quantifying mycobacteria using Mycobacterial Growth Indicator Tubes (MGIT). Vaccine-mediate dimmunogenicity detected by this assay correlated with protection. Published by Elsevier B.V. C1 [Yang, Amy L.; Schmidt, Thomas E.; Stibitz, Scott; Derrick, Steven C.; Morris, Sheldon L.; Parra, Marcela] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Derrick, SC (reprint author), CBER FDA, Bldg 52-72,Room 5322,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM steven.derrick@fda.hhs.gov FU Center for Biologics Evaluation and Research of the Food and Drug Administration FX Support for this work was through internal funding from the Center for Biologics Evaluation and Research of the Food and Drug Administration. NR 19 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 2016 VL 131 BP 7 EP 9 DI 10.1016/j.mimet.2016.09.010 PG 3 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA EF7NT UT WOS:000390517000002 PM 27650198 ER PT J AU Li, Q Liang, YG Huang, Q Zong, M Berman, B Gavrielides, MA Schwartz, LH Zhao, BS Petrick, N AF Li, Qin Liang, Yongguang Huang, Qiao Zong, Min Berman, Benjamin Gavrielides, Marios A. Schwartz, Lawrence H. Zhao, Binsheng Petrick, Nicholas TI Volumetry of low-contrast liver lesions with CT: Investigation of estimation uncertainties in a phantom study SO MEDICAL PHYSICS LA English DT Article DE quantitative imaging biomarker; liver lesion volumetry; computed tomography; phantom study ID LUNG NODULE VOLUME; SOLID TUMORS; RESPONSE EVALUATION; MINIMUM AB Purpose: To evaluate the performance of lesion volumetry in hepatic CT as a function of various imaging acquisition parameters. Methods: An anthropomorphic abdominal phantom with removable liver inserts was designed for this study. Two liver inserts, each containing 19 synthetic lesions with varying diameter (6-40 mm), shape, contrast (10-65 HU), and both homogenous and mixed-density were designed to have background and lesion CT values corresponding to arterial and portal-venous phase imaging, respectively. The two phantoms were scanned using two commercial CT scanners (GE 750 HD and Siemens Biograph mCT) across a set of imaging protocols (four slice thicknesses, three effective mAs, two convolution kernels, two pitches). Two repeated scans were collected for each imaging protocol. All scans were analyzed using a matched- filter estimator for volume estimation, resulting in 6080 volume measurements across all of the synthetic lesions in the two liver phantoms. A subset of portal venous phase scans was also analyzed using a semi-automatic segmentation algorithm, resulting in about 900 additional volume measurements. Lesions associated with large measurement error (quantified by root mean square error) for most imaging protocols were considered not measurable by the volume estimation tools and excluded for the statistical analyses. Imaging protocols were grouped into distinct imaging conditions based on ANOVA analysis of factors for repeatability testing. Statistical analyses, including overall linearity analysis, grouped bias analysis with standard deviation evaluation, and repeatability analysis, were performed to assess the accuracy and precision of the liver lesion volume biomarker. Results: Lesions with lower contrast and size <= 10 mm were associated with higher measurement error and were excluded from further analysis. Lesion size, contrast, imaging slice thickness, dose, and scanner were found to be factors substantially influencing volume estimation. Twenty-four distinct repeatable imaging conditions were determined as protocols for each scanner with a fixed slice thickness and dose. For the matched- filter estimation approach, strong linearity was observed for all imaging data for lesions >= 20 mm. For the Siemens scanner with 50 mAs effective dose at 0.6 mm slice thickness, grouped bias was about -10%. For all other repeatable imaging conditions with both scanners, grouped biases were low (- 3%- 3%). There was a trend of increasing standard deviation with decreasing dose. For each fixed dose, the standard deviations were similar among the three larger slice thicknesses (1.25, 2.5, 5 mm for GE, 1.5, 3, 5 mm for Siemens). Repeatability coefficients ranged from about 8% to 75% and showed similar trend to grouped standard deviation. For the segmentation approach, the results led to similar conclusions for both lesion characteristic factors and imaging factors but with increasing magnitude in all the error metrics assessed. Conclusions: Results showed that liver lesion volumetry was strongly dependent on lesion size, contrast, acquisition dose, and their interactions. The overall performances were similar for images reconstructed with larger slice thicknesses, clinically used pitches, kernels, and doses. Conditions that yielded repeatable measurements were identified and they agreed with the Quantitative Imaging Biomarker Alliance's (QIBA) profile requirements in general. The authors' findings also suggest potential refinements to these guidelines for the tumor volume biomarker, especially for soft-tissue lesions. (C) 2016 American Association of Physicists in Medicine. C1 [Li, Qin; Berman, Benjamin; Gavrielides, Marios A.; Petrick, Nicholas] US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Liang, Yongguang; Huang, Qiao; Zong, Min; Schwartz, Lawrence H.; Zhao, Binsheng] Columbia Univ, Dept Radiol, Med Ctr, New York, NY 10032 USA. [Zong, Min] Nanjing Med Univ, Affiliated Hosp 1, Dept Radiol, Nanjing, Jiangsu, Peoples R China. RP Li, Q (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM qin.li1@fda.hhs.gov FU RSNA QIBA through NIH [HHSN268201300071C]; U.S. Food and Drug Administration; Oak Ridge Institute for Science and Education FX This work was supported in part by a sub-award of RSNA QIBA through NIH Grant No. HHSN268201300071C. This work was also supported, in part, by a Critical Path grant from the U.S. Food and Drug Administration. The authors would also like to thank Mr. Alex Sheldon Herbert for his help in CT data acquisition. Benjamin Berman is 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 U.S. Department of Energy and the U.S. Food and Drug Administration. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. NR 25 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 EI 2473-4209 J9 MED PHYS JI Med. Phys. PD DEC PY 2016 VL 43 IS 12 BP 6608 EP 6620 DI 10.1118/1.4967776 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EF3PR UT WOS:000390237200039 PM 27908157 ER PT J AU Yang, H Won, JH Kang, S Moon, IJ Hong, SH Woo, J AF Yang, Hyejin Won, Jong Ho Kang, Soojin Moon, Il Joon Hong, Sung Hwa Woo, Jihwan TI Prediction of vowel identification for cochlear implant using a computational model SO SPEECH COMMUNICATION LA English DT Article DE Cochlear implant; Computational modeling, Neurogram; Vowel identification ID STIMULATED AUDITORY-NERVE; SPEECH RECOGNITION; USERS; INTELLIGIBILITY; DISCRIMINATION; PSYCHOPHYSICS; PERFORMANCE; PERCEPTION; SIMULATION; FREQUENCY AB A computational biophysical auditory nerve fiber model along with mathematical algorithms are presented that predict vowel identification for cochlear implant (CI) users based on the predicted peripheral neural representations of speech information (i.e., neurogram). Our model simulates the discharge patterns of electrically-stimulated auditory nerve fibers along the length of the cochlea and quantifies the similarity between the neurograms for different speech signals. The effects of background noise (+15, +10, +5, 0, and 5 dB SNR) and stimulation rate (900, 1200, and 1800 pps/ch) on vowel identification were evaluated and compared to CI subject data to demonstrate the performance of our model. Results from both the computational modeling and clinical test showed that vowel identification performance decreased as background noise increased while vowel identification was not significantly influenced by the stimulation rate. The proposed method, both objective and automated, can be used for a wide range of stimulus conditions, signal processing, and different biological conditions in the implanted ears. (C) 2016 Elsevier B.V. All rights reserved. C1 [Yang, Hyejin; Kang, Soojin; Woo, Jihwan] Univ Ulsan, Dept Biomed Engn, Ulsan 680749, 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. [Moon, Il Joon] Sungkyunkwan Univ, Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Samsung Med Ctr, Seoul 330714, South Korea. [Hong, Sung Hwa] Sungkyunkwan Univ, Samsung Changwon Hosp, Dept Otorhinolaryngol Head & Neck Surg, Sch Med, Chang Won 51353, South Korea. RP Woo, J (reprint author), Univ Ulsan, Dept Biomed Engn, Ulsan 680749, South Korea. EM hjyang1990@gmail.com; jhwon15@gmail.com; soojin.kang@daum.net; moon.iljoon@gmail.com; hongsh@skku.edu; jhwoo@ulsan.ac.kr FU University of Ulsan, Republic of Korea FX This work was supported by the 2014 Research Fund of University of Ulsan, Republic of Korea. The authors are grateful to the CI subjects who participated in this study for their dedicated efforts. The views expressed in this paper are those of the authors and do not necessarily reflect the official policy or position of the US Department of Health and Human Services and the US Food and Drug Administration.The authors acknowledge the work of the editor and two anonymous reviewers. NR 44 TC 0 Z9 0 U1 19 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-6393 EI 1872-7182 J9 SPEECH COMMUN JI Speech Commun. PD DEC PY 2016 VL 85 BP 19 EP 28 DI 10.1016/j.specom.2016.10.005 PG 10 WC Acoustics; Computer Science, Interdisciplinary Applications SC Acoustics; Computer Science GA EF7JX UT WOS:000390507000003 ER PT J AU Leiderman, K Chang, WC Ovanesov, M Fogelson, AL AF Leiderman, Karin Chang, William C. Ovanesov, Mikhail Fogelson, Aaron L. TI Synergy Between Tissue Factor and Exogenous Factor XIa in Initiating Coagulation SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE blood coagulation; blood platelets; theoretical models; thrombin; thrombosis ID ACTIVATED FACTOR-XI; THROMBOTIC ADVERSE EVENTS; FACTOR-VIII; FACTOR-IXA; BLOOD-COAGULATION; FACTOR-XA; VONWILLEBRAND-FACTOR; PLATELET DEPOSITION; INTRAVENOUS IMMUNOGLOBULIN; HUMAN-PLASMA AB Objective-Recent evidence suggests involvement of coagulation factor XIa (FXIa) in thrombotic event development. This study was conducted to explore possible synergies between tissue factor (TF) and exogenous FXIa (E-FXIa) in thrombin generation. Approach and Results-In thrombin generation assays, for increasing concentrations of E-FXIa with low, but not with high TF concentrations, peak thrombin significantly increased whereas lag time and time to peak significantly decreased. Similar dependencies of lag times and rates of thrombin generation were found in mathematical model simulations. In both in vitro and in silico experiments that included E-FXIa, thrombin bursts were seen for TF levels much lower than those required without E-FXIa. For in silico thrombin bursts initiated by the synergistic action of TF and E-FXIa, the mechanisms leading to the burst differed substantially from those for bursts initiated by high TF alone. For the synergistic case, sustained activation of platelet-bound FIX by E-FXIa, along with the feedback-enhanced activation of platelet-bound FVIIIa and FXa, was needed to elicit a thrombin burst. Furthermore, the initiation of thrombin bursts by high TF levels relied on different platelet FIX/FIXa binding sites than those involved in bursts initiated by low TF levels with E-FXIa. Conclusions-Low concentrations of TF and exogenous FXIa, each too low to elicit a burst in thrombin production alone, act synergistically when in combination to cause substantial thrombin production. The observation about FIX/ FIXa binding sites may have therapeutic implications. C1 [Leiderman, Karin] Colorado Sch Mines, Dept Appl Math & Stat, Golden, CO 80401 USA. [Chang, William C.; Ovanesov, Mikhail] US FDA, Ctr Biol Evaluat & Res, Off Blood Res & Review, Silver Spring, MD USA. [Fogelson, Aaron L.] Univ Utah, Dept Math, 155 S 1400 E,233 JWB, Salt Lake City, UT 84112 USA. [Fogelson, Aaron L.] Univ Utah, Dept Bioengn, 155 S 1400 E,233 JWB, Salt Lake City, UT 84112 USA. RP Fogelson, AL (reprint author), Univ Utah, Dept Math, 155 S 1400 E,233 JWB, Salt Lake City, UT 84112 USA.; Fogelson, AL (reprint author), Univ Utah, Dept Bioengn, 155 S 1400 E,233 JWB, Salt Lake City, UT 84112 USA. EM fogelson@math.utah.edu FU Oak Ridge Institute for Science and Education (ORISE); National Science Foundation [DMS-1160432, DMS-1521748]; National Heart, Lung, and Blood Institute (NHLBI) [1R01HL126864]; NHLBI [1R01HL120728] FX This study was supported, in part, by a Postgraduate and Postbaccalaureate Research Fellowship Award to W.C. Chang from the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the US Department of Energy and the US Food and Drug Administration (FDA). W.C. Chang and M. Ovanesov are employees of the FDA. This article is an informal communication and represents the authors' best judgment. These comments do not bind or obligate FDA. This work was also supported in part by National Science Foundation grants DMS-1160432 and DMS-1521748 and National Heart, Lung, and Blood Institute (NHLBI) grant 1R01HL126864 to A.L. Fogelson and NHLBI grant 1R01HL120728 to A.L. Fogelson and K. Leiderman. NR 50 TC 1 Z9 1 U1 8 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD DEC PY 2016 VL 36 IS 12 BP 2334 EP 2345 DI 10.1161/ATVBAHA.116.308186 PG 12 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EE1KO UT WOS:000389340500010 PM 27789475 ER PT J AU Regmi, PR Shaw, AL Hungerford, LL Messenheimer, JR Zhou, T Pillai, P Omer, A Gilbert, JM AF Regmi, Prajwal R. Shaw, Ashley L. Hungerford, Laura L. Messenheimer, Janis R. Zhou, Tong Pillai, Padmakumar Omer, Amy Gilbert, Jeffrey M. TI Regulatory Considerations for the Approval of Drugs Against Histomoniasis (Blackhead Disease) in Turkeys, Chickens, and Game Birds in the United States SO AVIAN DISEASES LA English DT Review DE histomoniasis; blackhead disease; Histomonas meleagridis; treatment and control; drug approval; turkey; chicken; game bird; FDA ID MELEAGRIDIS; HETERAKIS; HISTOMONOSIS; GALLINARUM; SURVIVAL; POULTRY AB Histomoniasis, commonly referred to as blackhead disease, is a serious threat to the turkey and game bird industries worldwide, and it is having an increasingly negative impact on the chicken industry as well. The Food and Drug Administration's (FDA) Center for Veterinary Medicine (CVM), charged with the approval and regulation of new animal drugs in the United States, understands the rising need for the availability of therapeutic options against histomoniasis. CVM has actively engaged in discussions with the poultry industry, academic institutions, and animal health companies regarding the current status of histomoniasis in the United States and varied success of past and current management, prophylactic, and therapeutic interventions that have been used against the disease. As effective options against the disease are severely limited, CVM encourages the poultry industry, academic institutions, and animal health companies to work together to research and develop viable management, prophylactic, and therapeutic strategies, such as litter management, deworming programs, vaccines or other biologics, novel technologies, and animal drugs. CVM also recognizes the potential challenges that the poultry industry, academic institutions, and animal health companies may encounter while working towards the approval of safe and effective drug products for the treatment and control of histomoniasis. With that recognition, CVM encourages interested parties to begin discussions with CVM early in order to align research of the drug product against histomoniasis with the drug approval requirements, such that it leads to the approval of a new animal drug in an efficient and expedient manner. This article provides information about the FDA's regulatory process for the approval of new animal drugs in the United States, with especial emphasis on drug products for the treatment and control of histomoniasis in turkeys, chickens, and game birds. C1 [Regmi, Prajwal R.; Shaw, Ashley L.; Hungerford, Laura L.; Messenheimer, Janis R.; Zhou, Tong; Gilbert, Jeffrey M.] US FDA, Off New Anim Drug Evaluat, Ctr Vet Med, Rockville, MD 20855 USA. [Pillai, Padmakumar] US FDA, Off Surveillance & Compliance, Ctr Vet Med, Rockville, MD 20855 USA. [Omer, Amy] US FDA, Off Minor Use & Minor Species, Ctr Vet Med, Rockville, MD 20855 USA. RP Regmi, PR (reprint author), US FDA, Off New Anim Drug Evaluat, Ctr Vet Med, Rockville, MD 20855 USA. EM prajwal.regmi@fda.hhs.gov NR 22 TC 0 Z9 0 U1 7 U2 7 PU AMER ASSOC AVIAN PATHOLOGISTS PI ATHENS PA 953 COLLEGE STATION RD, ATHENS, GA 30602-4875 USA SN 0005-2086 EI 1938-4351 J9 AVIAN DIS JI Avian Dis. PD DEC PY 2016 VL 60 IS 4 BP 725 EP 730 PG 6 WC Veterinary Sciences SC Veterinary Sciences GA EE5QK UT WOS:000389662600002 PM 27902913 ER PT J AU Berry-Bibee, EN Kim, MJ Simmons, KB Tepper, NK Riley, HEM Pagano, HP Curtis, KM AF Berry-Bibee, Erin N. Kim, Myong-Jin Simmons, Katharine B. Tepper, Naomi K. Riley, Halley E. M. Pagano, H. Pamela Curtis, Kathryn M. TI Drug interactions between hormonal contraceptives and psychotropic drugs: a systematic review SO CONTRACEPTION LA English DT Review DE Hormonal contraception; Drug interactions; Psychotropic drugs; Depression; Anxiety ID DOSE ORAL-CONTRACEPTIVES; CIGARETTE-SMOKING; MENTAL-HEALTH; CLOMIPRAMINE; PREGNANCY; WOMEN; AGE; DEPRESSION; CLOZAPINE; PHARMACOKINETICS AB Objective: To examine whether the co-administration of hormonal contraceptives (HC) and psychotropic drugs commonly used to treat anxiety and/or depression results in safety or efficacy concerns for either drug. Methods: We searched PubMed and Cochrane libraries for clinical or pharmacokinetic (PK) studies that examined co-administration of any HC with psychotropic drugs [selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), oral benzodiazepines, bupropion, mirtazapine, trazadone, buspirone, hydroxyzine, monoamine oxidase inhibitors (MAOIs), or atypical antipsychotics] in reproductive aged women. Results: Of 555 articles identified, 22 articles (18 studies) met inclusion criteria. We identified 5 studies on SSRIs, four on TCAs, one on bupropion, three on atypical antipsychotics and five on oral benzodiazepines. No articles met inclusion criteria for SNRIs, mirtazapine, trazadone, buspirone, hydroxyzine or MAOIs. Overall, clinical studies did not demonstrate differences in unintended pregnancy rates when HCs were administered with and without psychotropic drugs or in psychotropic drug treatment outcomes when psychotropic drugs were administered with and without HCs. PK studies did not demonstrate changes in drug exposure related to contraceptive safety, contraceptive effectiveness or psychotropic drug effectiveness for most classes of psychotropic drugs. However, limited PK data raise concern for HCs increasing systemic exposure of amitriptyline and imipramine (both TCAs), theoretically posing safety concerns. Conclusion: Limited quality and quantity evidence on use of psychotropic drugs and HCs suggests low concern for clinically significant interactions, though no data exist specifically for non-oral formulations of HC. Given the high frequency of use for both HCs and psychotropic drugs among reproductive-age women in the US, this review highlights a need for further research in this area. (C) 2016 Elsevier Inc. All rights reserved. C1 [Berry-Bibee, Erin N.; Simmons, Katharine B.; Tepper, Naomi K.; Riley, Halley E. M.; Pagano, H. Pamela; Curtis, Kathryn M.] Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA 30333 USA. [Kim, Myong-Jin] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. RP Berry-Bibee, EN (reprint author), Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA 30333 USA. EM wnw4@cdc.gov NR 41 TC 3 Z9 3 U1 11 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0010-7824 EI 1879-0518 J9 CONTRACEPTION JI Contraception PD DEC PY 2016 VL 94 IS 6 BP 650 EP 667 DI 10.1016/j.contraception.2016.07.011 PG 18 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE2CR UT WOS:000389391800009 PM 27444984 ER PT J AU Berry-Bibee, EN Kim, MJ Tepper, NK Riley, HEM Curtis, KM AF Berry-Bibee, Erin N. Kim, Myong-Jin Tepper, Naomi K. Riley, Halley E. M. Curtis, Kathryn M. TI Co-administration of St. John's wort and hormonal contraceptives: a systematic review SO CONTRACEPTION LA English DT Review DE St. John's wort; Hypericum peiforatum; Hormonal contraception; Drug interactions; Depression ID ALTERNATIVE MEDICINE; PHARMACOKINETICS; COMPLEMENTARY; ADULTS; TRENDS; DRUGS AB Objectives: St. John's wort (SJW) is a known strong inducer of the cytochrome P450 (CYP) 3 A4 enzyme, and both the ethinyl estradiol and progestin components of hormonal contraceptives are substrates of CYP3A4. This systematic review examined whether the co-administration of SJW and hormonal contraceptives leads to significant safety or efficacy concerns. Study design: Systematic review. Methods: PubMed and Cochrane Library databases were searched for articles of any comparative study design (clinical or pharmacokinetic) that examined potential interactions between SJW and hormonal contraceptives in women of reproductive age. Results: Of the 48 identified articles, four studies met inclusion criteria and compared use of combined oral contraceptives (COCs) alone to the use of COCs co-administered with SJW. Two studies demonstrated no change in markers of ovulation, but one study demonstrated increased follicular growth and probable ovulation when COCs were co-administered with SJW. Three studies demonstrated an increased risk of breakthrough bleeding with COCs and SJW. Three studies showed changes in at least one pharmacokinetic parameter that suggested a significantly decreased exposure to hormone concentrations when COCs were co-administered with SJW. The only study that did not demonstrate any significant pharmacokinetic differences examined a SJW product containing a low amount of hypericin. Conclusion: Limited evidence showing increased risk of ovulation and breakthrough bleeding raises concern for decreased contraceptive efficacy when COCs are co-administered with SJW. The pharmacokinetic evidence is mixed but suggests that SJW administration may be associated with weak to moderate induction of the metabolism of COCs. (C) 2016 Elsevier Inc. All rights reserved. C1 [Berry-Bibee, Erin N.; Tepper, Naomi K.; Riley, Halley E. M.; Curtis, Kathryn M.] Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA 30333 USA. [Kim, Myong-Jin] US FDA, Off Clin Pharmacol, Silver Spring, MD USA. RP Berry-Bibee, EN (reprint author), Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA 30333 USA. EM wnw4@cdc.gov NR 24 TC 1 Z9 1 U1 31 U2 31 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0010-7824 EI 1879-0518 J9 CONTRACEPTION JI Contraception PD DEC PY 2016 VL 94 IS 6 BP 668 EP 677 DI 10.1016/j.contraception.2016.07.010 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE2CR UT WOS:000389391800010 PM 27444983 ER PT J AU Hillebrenner, M Zuckerman, B Fiuzat, M Stockbridge, N Califf, R AF Hillebrenner, Matthew Zuckerman, Bram Fiuzat, Mona Stockbridge, Norman Califf, Robert TI The FDA in the 21st Century How Is the FDA Responding to the New World? A Focus on Heart Failure Devices SO JACC-HEART FAILURE LA English DT Article DE heart failure; regulation C1 [Hillebrenner, Matthew; Zuckerman, Bram] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Fiuzat, Mona; Califf, Robert] US FDA, Off Commissioner, Silver Spring, MD USA. [Stockbridge, Norman] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Hillebrenner, M (reprint author), US FDA, 10903 New Hampshire Ave,White Oak 66, Silver Spring, MD 20933 USA. EM matthew.hillebrenner@fda.hhs.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD DEC PY 2016 VL 4 IS 12 BP 974 EP 977 DI 10.1016/j.jchf.2016.09.007 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EE4GY UT WOS:000389561500012 PM 27908396 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 FOOD PROTECTION LA English DT Article ID RANDOMIZED CONTROLLED-TRIALS; MOLECULAR EPIDEMIOLOGY; FOOD SAFETY; QUALITY; GUIDELINES; EXTENSION; ELABORATION; EXPLANATION; LIVESTOCK; DISEASES AB Reporting of observational studies in veterinary research presents challenges that often are not addressed in published reporting guidelines. Our objective was 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. We conducted a consensus meeting with 17 experts in Mississauga, Canada. Experts completed a premeeting 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. 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 and 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). 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, 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, Dept Vet Diagnost & Prod Anim Med, Ames, IA 50011 USA. [Dohoo, I. R.] Univ Prince Edward Isl, Ctr Vet Epidemiol Res, Charlottetown, PE C1A 4P3, Canada. [Erb, H. N.] Cornell Univ, Dept Populat Med & Diagnost Sci, Ithaca, NY 14853 USA. [Cevallos, M.; Egger, M.] Univ Bern, Inst Social & Prevent Med, CH-3012 Bern, Switzerland. [Ersboll, A. K.] Univ Southern Denmark, Natl Inst Publ Hlth, DK-1353 Copenhagen, Denmark. [Nielsen, L. R.] Univ Copenhagen, Sect Anim Welf & Dis Control, DK-1017 Copenhagen, Denmark. [Pfeiffer, D. U.] Univ London, Royal Vet Coll, Dept Prod & Populat Hlth, London NW1 0TU, England. [Sanchez, J.] Univ Prince Edward Isl, Dept Hlth Management, Charlottetown, PE C1A 4P3, Canada. [Torrence, M. E.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Vigre, H.] Tech Univ Denmark, Unit Genom Epidemiol, Natl Food Inst, DK-2800 Lyngby, Denmark. [Waldner, C.] Univ Saskatchewan, Western Coll Vet Med, Dept Large Anim Clin Sci, Saskatoon, SK S7N 5B4, Canada. [Ward, M. P.] Univ Sydney, Fac Vet Sci, Sydney, NSW 2006, Australia. RP Sargeant, JM (reprint author), Univ Guelph, 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 Ward, Michael/C-5758-2009 NR 24 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 DEC PY 2016 VL 79 IS 12 BP 2211 EP 2219 DI 10.4315/0362-028X.JFP-16-016 PG 9 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA EE4JE UT WOS:000389567300023 PM 28221964 ER PT J AU Sun, H Stockbridge, N Ariagno, RL Murphy, D Nelson, RM Rodriguez, W AF Sun, H. Stockbridge, N. Ariagno, R. L. Murphy, D. Nelson, R. M. Rodriguez, W. TI Reliable and developmentally appropriate study end points are needed to achieve drug development for treatment of pediatric pulmonary arterial hypertension SO JOURNAL OF PERINATOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; 6-MINUTE WALK DISTANCE; PHYSICAL-ACTIVITY; CARDIAC-OUTPUT; ELECTRICAL VELOCIMETRY; NONINVASIVE ASSESSMENT; THERMODILUTION; BOSENTAN; HEMODYNAMICS; ACTIGRAPHY AB OBJECTIVE: To identify suitable end points and surrogates for pediatric pulmonary arterial hypertension (PAH) as the lack of developmentally appropriate end point and clinical trials contribute to the unmet medical need. STUDY DESIGN: Reviewed the efficacy end points and surrogates for all trials (1995 to 2013) that were submitted to the Food and Drug Administration (FDA) to support the approval of PAH therapy and conducted literature search. RESULTS: An increase in the 6 min walking distance (6MWD) was used as a primary end point in 8/9 adult PAH trials. This end point is not suitable for infants and young children because of performance limitations and lack of control data. One adult PAH trial used time to the first morbidity or mortality event as a primary end point, which could potentially be used in pediatric PAH trials. In the sildenafil pediatric PAH trial, the change in pulmonary vascular resistance index or mean pulmonary artery pressure was used as a surrogate for the 6MWD to assess exercise capacity. However, two deaths and three severe adverse events during the catheterizations made this an unacceptably high-risk surrogate. The INOmax persistent pulmonary hypertension of the newborn trial used a reduction in initiation of extracorporeal membrane oxygenation treatment as a primary end point, which is not feasible for other pediatric PAH trials. A Literature review revealed none of the existing noninvasive markers are fully validated as surrogates to assess PAH efficacy and long-term safety. CONCLUSIONS: For pediatric PAH trials, clinical end points are acceptable, and novel validated surrogates would be helpful. FDA seeks collaboration with academia, industry and parents to develop other suitable and possibly more efficient efficacy end points to facilitate pediatric PAH drug development. C1 [Sun, H.; Murphy, D.; Nelson, R. M.; Rodriguez, W.] US FDA, Off Pediat Therapeut, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Stockbridge, N.] Food & Drug Adm, Div Cardiovasc & Renal Prod, Silver Spring, MD USA. [Ariagno, R. L.] Stanford Univ, Div Neonatal & Dev Med, Palo Alto, CA 94304 USA. [Ariagno, R. L.] Oak Ridge Inst Sci & Educ, Silver Spring, MD USA. RP Sun, H (reprint author), US FDA, Off Pediat Therapeut, Off Commissioner, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM haihao.sun@fda.hhs.gov FU FDA Chief Scientist Challenge Grant FX This work was in part supported by the FDA Chief Scientist Challenge Grant. NR 40 TC 0 Z9 0 U1 7 U2 7 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 DEC PY 2016 VL 36 IS 12 BP 1029 EP 1033 DI 10.1038/jp.2016.103 PG 5 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA EE6PW UT WOS:000389735700001 PM 27416322 ER PT J AU Betts, KR O'Donoghue, AC Aikin, KJ Kelly, BJ Boudewyns, V AF Betts, Kevin R. O'Donoghue, Amie C. Aikin, Kathryn J. Kelly, Bridget J. Boudewyns, Vanessa TI Professional online community membership and participation among healthcare providers: An extension to nurse practitioners and physician assistants SO JOURNAL OF THE AMERICAN ASSOCIATION OF NURSE PRACTITIONERS LA English DT Article DE Collaborative medicine; information sharing; online communities; social media ID SOCIAL MEDIA; RESPONSE BIAS; INFORMATION; ADOPTION; INTERNET; MEDICINE AB Background and purposeProfessional online communities allow healthcare providers to exchange ideas with their colleagues about best practices for patient care. Research on this topic has focused almost exclusively on primary care physicians and specialists, to the exclusion of advanced practice providers such as nurse practitioners and physician assistants. We expand this literature by examining membership and participation on these websites among each of these provider groups. MethodsParticipants (N = 2008; approximately 500 per provider group) responded to an Internet-based survey in which they were asked if they use professional online communities to dialogue with colleagues and if so, what their motivation is for doing so. ConclusionsNearly half of the participants in our sample reported utilizing professional online communities. Select differences were observed between provider groups, but overall, similar patterns emerged in their membership and participation on these websites. Implications for practiceNurse practitioners and physician assistants utilize professional online communities in similar proportion to primary care physicians and specialists. Providers should be cognizant of the impact this use may have for both themselves and their patients. Researchers are urged to take into account the various professional roles within the healthcare community while developing research on this topic. C1 [Betts, Kevin R.; O'Donoghue, Amie C.; Aikin, Kathryn J.] US FDA, Silver Spring, MD USA. [Kelly, Bridget J.] RTI Int, Res Triangle Pk, NC USA. [Boudewyns, Vanessa] RTI Int, Washington, DC USA. RP Betts, KR (reprint author), US FDA, Off Prescript Drug Promot, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM kevin.betts@fda.hhs.gov NR 22 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2327-6886 EI 2327-6924 J9 J AM ASSOC NURSE PRA JI J. Am. Assoc. Nurs. Pract. PD DEC PY 2016 VL 28 IS 12 BP 639 EP 645 DI 10.1002/2327-6924.12383 PG 7 WC Health Care Sciences & Services; Nursing SC Health Care Sciences & Services; Nursing GA EE2MB UT WOS:000389417300002 PM 27214569 ER PT J AU Tempero, M AF Tempero, Margaret TI An Oncologist's Letter to Santa SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Tempero, Margaret] UCSF, Pancreas Ctr, Med, San Francisco, CA 94143 USA. [Tempero, Margaret] UCSF, Pancreas Ctr, San Francisco, CA 94143 USA. [Tempero, Margaret] ASCO Board, San Francisco, CA USA. [Tempero, Margaret] ASCO, San Francisco, CA USA. [Tempero, Margaret] ASCO, Conquer Canc Fdn Board, San Francisco, CA USA. [Tempero, Margaret] ASCO Methods Clin Canc Res, AACR, San Francisco, CA USA. [Tempero, Margaret] NCI, Clin Oncol Study Sect, Bethesda, MD 20892 USA. [Tempero, Margaret] NCI, Board Sci Counselors Subcomm A, Bethesda, MD 20892 USA. [Tempero, Margaret] Canc Prevent & Res Inst Texas, Sci Steering Comm, Austin, TX USA. [Tempero, Margaret] Canc Prevent & Res Inst Texas, Clin & Translat Study Sect, Austin, TX USA. [Tempero, Margaret] Lustgarten Fdn, Sci Advisory Boards, Bethpage, NY USA. [Tempero, Margaret] V Fdn, Pancreat Canc Act Network, Bethpage, NY USA. [Tempero, Margaret] Alberta Canada Canc Board, Edmonton, AB, Canada. [Tempero, Margaret] EORTC, Copenhagen, Denmark. [Tempero, Margaret] US FDA, Oncol Drug Advisory Comm, Rockville, MD 20857 USA. [Tempero, Margaret] UNMC, Eppley Canc Ctr, Omaha, NE USA. [Tempero, Margaret] UCSF, Div Med Oncol, San Francisco, CA 94143 USA. [Tempero, Margaret] UCSF, Helen Diller Family Comprehens Canc Ctr, Res Programs, San Francisco, CA 94143 USA. RP Tempero, M (reprint author), UCSF, Pancreas Ctr, Med, San Francisco, CA 94143 USA.; Tempero, M (reprint author), UCSF, Pancreas Ctr, San Francisco, CA 94143 USA.; Tempero, M (reprint author), ASCO, Conquer Canc Fdn Board, San Francisco, CA USA.; Tempero, M (reprint author), ASCO Methods Clin Canc Res, AACR, San Francisco, CA USA.; Tempero, M (reprint author), Canc Prevent & Res Inst Texas, Sci Steering Comm, Austin, TX USA.; Tempero, M (reprint author), Canc Prevent & Res Inst Texas, Clin & Translat Study Sect, Austin, TX USA.; Tempero, M (reprint author), Lustgarten Fdn, Sci Advisory Boards, Bethpage, NY USA.; Tempero, M (reprint author), V Fdn, Pancreat Canc Act Network, Bethpage, NY USA.; Tempero, M (reprint author), Alberta Canada Canc Board, Edmonton, AB, Canada.; Tempero, M (reprint author), EORTC, Copenhagen, Denmark.; Tempero, M (reprint author), UCSF, Div Med Oncol, San Francisco, CA 94143 USA.; Tempero, M (reprint author), UCSF, Helen Diller Family Comprehens Canc Ctr, Res Programs, San Francisco, CA 94143 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD DEC PY 2016 VL 14 IS 12 BP 1491 EP 1491 PG 1 WC Oncology SC Oncology GA EE9QU UT WOS:000389962100001 PM 27956532 ER PT J AU Sarkar, S Liachenko, S Paule, MG Bowyer, J Hanig, JP AF Sarkar, Sumit Liachenko, Serguei Paule, Merle G. Bowyer, John Hanig, Joseph P. TI Brain endothelial dysfunction following pyrithiamine induced thiamine deficiency in the rat SO NEUROTOXICOLOGY LA English DT Article DE Pyrithiamine; Endothelial cells; Astrocytes; Microglia; Neurodegeneration ID WERNICKES ENCEPHALOPATHY; PARKINSONS-DISEASE; DIENCEPHALIC LESIONS; DEGENERATION; PATHOGENESIS; ALCOHOLISM; DISORDERS; BARRIER; CELLS; MODEL AB Prolonged vitamin B-1 (thiamine) deficiency can lead to neurological disorders such as Wernicke's encephalopathy and Wernicke-Korsakoff Syndrome (WKS) in humans. These thiamine deficiency disorders have been attributed to vascular leakage, blood-brain barrier breakdown and neuronal loss in the diencephalon and brain stem. However, endothelial dysfunction following thiamine deficiency and its relationship to the phenomenon of neurodegeneration has not been clearly elucidated. The present study sought to begin to address this issue by evaluating vascular morphology and integrity in a pyrithiamine (PT)-induced rat model of thiamine deficiency. Adjacent brain sections were used to either assess vascular integrity through immunohistochemical localization of rat endothelial cell antigen (RECA-1) and endothelial brain barrier antigen (EBA-1) or neurodegeneration using the de Olmos cupric silver method. GFAP and CD11 b immunolabeling was used to evaluate astrocytic and microglial/macrophagic changes. Extensive neurodegeneration occurred concomitant with both vascular damage (thinning and breakage) and microglial activation in the inferior olive, medial thalamic area, and medial geniculate nuclei of pyrithiamine treated rats. Likewise, glucose transporter-1 (Glut-1), which is mostly expressed in endothelial cells, was also severely decreased in this pyrithiamine induced thiamine deficient rat model. MRI scans of these animals prior to sacrifice show that the pyrithiamine induced thiamine deficient animals have abnormal T-2 relaxation values, which are commensurate with, and possibly predictive of, the neurodegeneration and/or endothelial dysfunction subsequently observed histologically in these same animals. Published by Elsevier B.V. C1 [Sarkar, Sumit; Liachenko, Serguei; Paule, Merle G.; Bowyer, John] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Bldg 53D,HFT-32, Jefferson, AR 72079 USA. [Hanig, Joseph P.] US FDA, Off Testing & Res, CDER, White Oak, MD 20993 USA. RP Sarkar, S (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Bldg 53D,HFT-32, Jefferson, AR 72079 USA. EM Sumit.Sarkar@FDA.hhs.gov FU National Center for Toxicological Research/USFDA [E0751201, E0741801] FX This study was supported by protocol E0751201 and E0741801 National Center for Toxicological Research/USFDA. NR 42 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2016 VL 57 BP 298 EP 309 DI 10.1016/j.neuro.2016.10.014 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA EE3NT UT WOS:000389497000034 PM 27984051 ER PT J AU Pogribny, IP Beland, FA Rusyn, I AF Pogribny, Igor P. Beland, Frederick A. Rusyn, Ivan TI The role of microRNAs in the development and progression of chemical-associated cancers SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Chemical carcinogens; Exposure; microRNAs; Cancer ID BRONCHIAL EPITHELIAL-CELLS; INORGANIC ARSENIC EXPOSURE; MALIGNANT-TRANSFORMATION; NEOPLASTIC TRANSFORMATION; EXPRESSION PROFILES; HUMAN KERATINOCYTES; MIR-17-92 CLUSTER; NONCODING RNAS; BLADDER-CANCER; LUNG-CANCER AB Human exposure to certain natural and man-made chemical carcinogens is one of the major risk factors for cancer development. The effect of chemical carcinogens on genetic and epigenetic alterations and their significance in the development of cancer has been well-established. In contrast, the role of microRNAs (miRNAs) in the etiology of chemical-associated cancers remains relatively unexplored despite extensive reports on changes in miRNA expression upon carcinogen exposure. This review summarizes the current knowledge for the role of miRNAs as drivers of chemical-induced carcinogenesis by bridging the gap between carcinogen exposure and cancer development through functional studies. It also emphasizes the potential for miRNA changes as early indicators of the carcinogenic process, markers for carcinogen exposure, and identification of chemical carcinogenic hazards. Published by Elsevier Inc. C1 [Pogribny, Igor P.; Beland, Frederick A.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Rusyn, Ivan] Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. RP Pogribny, IP (reprint author), NCTR, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov NR 119 TC 1 Z9 1 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 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD DEC 1 PY 2016 VL 312 SI SI BP 3 EP 10 DI 10.1016/j.taap.2015.11.013 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE8JA UT WOS:000389870300002 PM 26621330 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 ZOONOSES AND PUBLIC HEALTH LA English DT Article DE Reporting guidelines; veterinary; observational study; animal ID MOLECULAR EPIDEMIOLOGY; QUALITY; EXTENSION; TRIALS; ELABORATION; EXPLANATION; GUIDELINES; DISEASES; TOOLS; BIAS AB The reporting of observational studies in veterinary research presents many challenges that often are not adequately addressed in published reporting guidelines. 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. The consensus meeting was held 11-13 May 2014 in Mississauga, Ontario, Canada. 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. 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 whether 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. The consensus was that six items needed no modifications or additions. Modifications or additions were made to the STROBE items numbered as follows: 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). Published literature was not always available to support modification to, or inclusion of, an item. 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. 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, Unit Genom Epidemiol, 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 Sargeant, JM (reprint author), Univ Guelph, Ctr Publ Hlth & Zoonoses, Guelph, ON, Canada. EM sargeanj@uoguelph.ca RI Ward, Michael/C-5758-2009 NR 23 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1863-1959 EI 1863-2378 J9 ZOONOSES PUBLIC HLTH JI Zoonoses Public Health PD DEC PY 2016 VL 63 IS 8 BP 651 EP 661 DI 10.1111/zph.12314 PG 11 WC Public, Environmental & Occupational Health; Infectious Diseases; Veterinary Sciences SC Public, Environmental & Occupational Health; Infectious Diseases; Veterinary Sciences GA ED8VJ UT WOS:000389148700010 PM 27873478 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 ZOONOSES AND PUBLIC HEALTH LA English DT Article DE Case control study; cohort study; cross-sectional study; observational study; reporting guidelines ID RANDOMIZED CONTROLLED-TRIALS; INFECTIOUS BOVINE KERATOCONJUNCTIVITIS; SOMATIC-CELL COUNT; RISK-FACTORS; SAMPLE-SIZE; DAIRY-COWS; INCREASING VALUE; REDUCING WASTE; MISSING DATA; REPRODUCTIVE-PERFORMANCE 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, 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. EM oconnor@iastate.edu RI Ward, Michael/C-5758-2009 NR 171 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1863-1959 EI 1863-2378 J9 ZOONOSES PUBLIC HLTH JI Zoonoses Public Health PD DEC PY 2016 VL 63 IS 8 BP 662 EP 698 DI 10.1111/zph.12315 PG 37 WC Public, Environmental & Occupational Health; Infectious Diseases; Veterinary Sciences SC Public, Environmental & Occupational Health; Infectious Diseases; Veterinary Sciences GA ED8VJ UT WOS:000389148700011 PM 27873473 ER PT J AU Schuck, RN Marek, E Rogers, H Pacanowski, M AF Schuck, Robert N. Marek, Elizabeth Rogers, Hobart Pacanowski, Michael TI Clinical and regulatory considerations in pharmacogenetic testing SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article DE pharmacogenetics; drug labeling; genetic testing ID THIOPURINE METHYLTRANSFERASE GENOTYPE; IMPLEMENTATION CONSORTIUM GUIDELINES; HYPERSENSITIVITY REACTIONS; AMERICAN-COLLEGE; MEDICINE; ABACAVIR; THERAPY; ASSOCIATION; CLOPIDOGREL; WARFARIN AB Purpose. Both regulatory science and clinical practice rely on best available scientific data to guide decision-making. However, changes in clinical practice may be driven by numerous other factors such as cost. In this review, we reexamine noteworthy examples where pharmacogenetic testing information was added to drug labeling to explore how the available evidence, potential public health impact, and predictive utility of each pharmacogenetic biomarker impacts clinical uptake. Summary. Advances in the field of pharmacogenetics have led to new discoveries about the genetic basis for variability in drug response. The Food and Drug Administration recognizes the value of pharmacogenetic testing strategies and has been proactive about incorporating pharmacogenetic information into the labeling of both new drugs and drugs already on the market. Although some examples have readily translated to routine clinical practice, clinical uptake of genetic testing for many drugs has been limited. Conclusion. Both regulatory science and clinical practice rely on data driven approaches to guide decision making; however, additional factors are also important in clinical practice that do not impact regulatory decision making, and these considerations may result in heterogeneity in clinical uptake of pharmacogenetic testing. C1 [Schuck, Robert N.; Marek, Elizabeth; Rogers, Hobart; Pacanowski, Michael] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Schuck, RN (reprint author), US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM robert.schuck@fda.hhs.gov NR 42 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 EI 1535-2900 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD DEC 1 PY 2016 VL 73 IS 23 BP 1999 EP 2006 DI 10.2146/ajhp160476 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED8ZA UT WOS:000389158200022 PM 27864207 ER PT J AU George, A Zand, DJ Hufnagel, RB Sharma, R Sergeev, YV Legare, JM Rice, GM Schwoerer, JAS Rius, M Tetri, L Gamm, DM Bharti, K Brooks, BP AF George, Aman Zand, Dina J. Hufnagel, Robert B. Sharma, Ruchi Sergeev, Yuri V. Legare, Janet M. Rice, Gregory M. Schwoerer, Jessica A. Scott Rius, Mariana Tetri, Laura Gamm, David M. Bharti, Kapil Brooks, Brian P. TI Biallelic Mutations in MITF Cause Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, and Deafness SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID WAARDENBURG SYNDROME; TFE FAMILY; MOUSE; GENE; MELANOCYTES; HOMOLOG; NETWORK; PROTEIN AB Human MITF is, by convention, called the "microphthalmia-associated transcription factor'' because of previously published seminal mouse genetic studies; however, mutations in MITF have never been associated with microphthalmia in humans. Here, we describe a syndrome that we term COMMAD, characterized by coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness. COMMAD is associated with biallelic MITF mutant alleles and hence suggests a role for MITF in regulating processes such as optic-fissure closure and bone development or homeostasis, which go beyond what is usually seen in individuals carrying monoallelic MITF mutations. C1 [George, Aman; Hufnagel, Robert B.; Sergeev, Yuri V.; Rius, Mariana; Brooks, Brian P.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Zand, Dina J.; Brooks, Brian P.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Sharma, Ruchi; Bharti, Kapil] NEI, Unit Ocular & Stem Cell Translat Res, NIH, Bethesda, MD 20892 USA. [Legare, Janet M.; Rice, Gregory M.; Tetri, Laura; Gamm, David M.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pediat, Madison, WI 53726 USA. [Schwoerer, Jessica A. Scott; Gamm, David M.] Univ Wisconsin, Sch Med & Publ Hlth, McPherson Eye Res Inst, Madison, WI 53726 USA. [Schwoerer, Jessica A. Scott; Gamm, David M.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI 53726 USA. [Zand, Dina J.] US FDA, Off New Drugs, Off Drug Evaluat 3, Div Gastroenterol & Inborn Errors Prod, Silver Spring, MD 20993 USA. [Rius, Mariana] SUNY Stony Brook, Sch Marine & Atmospher Sci, Stony Brook, NY 11790 USA. RP Brooks, BP (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA.; Brooks, BP (reprint author), Childrens Natl Med Ctr, Washington, DC 20010 USA. EM brian.brooks1@nih.gov FU NEI FX We are grateful to the probands and their families. We thank Dr. Heinz Arnheiter for critical comments on the manuscript, Dr. James Lister (Virginia Commonwealth University, Richmond, VA) for the zebrafish mitfa construct, Drs. Noriko Esumi (Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD) and Sridhar Mani (Albert Einstein College of Medicine, Bronx, NY) for luciferase promoter constructs, Drs. Chun Gao and Robert Farris (Biological Imaging Core, National Eye Institute [NEI]) for expert assistance with confocal laser-scanning microscopy experiments, Ramakrishna Alur for technical assistance, Delphine Blain for genetic counseling, the NEI Clinical Photography Section for outstanding technical assistance, and Anna Larson and Tyler Fayard for zebrafish breeding and maintenance. This work was supported by the intramural program of the NEI. NR 23 TC 0 Z9 0 U1 4 U2 4 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 DEC 1 PY 2016 VL 99 IS 6 BP 1388 EP 1394 DI 10.1016/j.ajhg.2016.11.004 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA ED8VI UT WOS:000389148600014 PM 27889061 ER PT J AU Connarn, JN Luo, RJ Windak, J Zhang, XY Babiskin, A Kelly, M Harrington, G Ellingrod, VL Kamali, M McInnis, M Sun, DX AF Connarn, Jamie N. Luo, Ruijuan Windak, Jim Zhang, Xinyuan Babiskin, Andrew Kelly, Marisa Harrington, Gloria Ellingrod, Vicki L. Kamali, Masoud McInnis, Melvin Sun, Duxin TI Identification of non-reported bupropion metabolites in human plasma SO BIOPHARMACEUTICS & DRUG DISPOSITION LA English DT Article DE bupropion; metabolite identification; LC-MS; MS ID HUMAN LIVER; IN-VITRO; INTERINDIVIDUAL VARIABILITY; CYTOCHROME P4502B6; HYDROXYLATION; REDUCTASES; ENZYMES; CYP2B6; PHARMACOKINETICS; GLUCURONIDATION AB Bupropion and its three active metabolites exhibit clinical efficacy in the treatment of major depression, seasonal depression and smoking cessation. The pharmacokinetics of bupropion in humans is highly variable. It is not known if there are any non-reported metabolites formed in humans in addition to the three known active metabolites. This paper reports newly identified and non-reported metabolites of bupropion in human plasma samples. Human subjects were dosed with a single oral dose of 75mg of an immediate release bupropion HCl tablet. Plasma samples were collected and analysed by LC-MS/MS at 0, 6 and 24h. Two non-reported metabolites (M1 and M3) were identified with mass-to-charge (m/z) ratios of 276 (M1, hydration of bupropion) and 258 (M3, hydroxylation of threo/erythrohydrobupropion) from human plasma in addition to the known hydroxybupropion, threo/erythrohydrobupropion and the glucuronidation products of the major metabolites (M2 and M4-M7). These new metabolites may provide new insight and broaden the understanding of bupropion's variability in clinical pharmacokinetics. (c) 2016 The Authors Biopharmaceutics & Drug Disposition Published by John Wiley & Sons Ltd. C1 [Connarn, Jamie N.; Luo, Ruijuan; Sun, Duxin] Univ Michigan, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA. [Windak, Jim] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA. [Zhang, Xinyuan; Babiskin, Andrew] US FDA, Div Quantitat Methods & Modeling, Off Res & Stand, Off Gener Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Kelly, Marisa; Harrington, Gloria; Kamali, Masoud; McInnis, Melvin] Univ Michigan, Dept Psychiat, Sch Med, Ann Arbor, MI 48109 USA. [Ellingrod, Vicki L.] Univ Michigan, Dept Clin Pharm, Ann Arbor, MI 48109 USA. RP Sun, DX (reprint author), Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Room 3353,Bldg 520,1600 Huron Pkwy, Ann Arbor, MI 48105 USA. EM duxins@med.umich.edu FU Food and Drug Administration [HHSF223201310164C, HSF223201310183C] FX We would like to thank the Food and Drug Administration (contract numbers HHSF223201310164C and HSF223201310183C) for funding. NR 33 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0142-2782 EI 1099-081X J9 BIOPHARM DRUG DISPOS JI Biopharm. Drug Dispos. PD DEC PY 2016 VL 37 IS 9 BP 550 EP 560 DI 10.1002/bdd.2046 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EE0ZM UT WOS:000389309600005 PM 27723114 ER PT J AU Mitchell, K Shah, JP Dalgard, CL Tsytsikova, LV Tiption, AC Dmitriev, AE Symes, AJ AF Mitchell, Kendall Shah, Jill P. Dalgard, Clifton L. Tsytsikova, Lyubov V. Tiption, Ashley C. Dmitriev, Anton E. Symes, Aviva J. TI Bone morphogenetic protein-2-mediated pain and inflammation in a rat model of posterolateral arthrodesis SO BMC NEUROSCIENCE LA English DT Article DE Cytokines; Hyperalgesia; Dorsal root ganglia; Inflammation; Macrophages; Bone morphogenetic protein-2 ID DORSAL-ROOT GANGLION; SPINAL-CORD; PERIPHERAL INFLAMMATION; TISSUE INFLAMMATION; GENE-EXPRESSION; NERVE INJURY; RODENT MODEL; RHBMP-2 USE; ACTIVIN; SURGERY AB Background: Bone morphogenetic protein-2 (BMP-2) is a pleiotropic, secreted molecule with diverse effects. The potent ability of BMP-2 to stimulate bone growth prompted its widespread clinical use for arthrodesis (spine fusion). However, elevated post-operative pain in patients treated with BMP-2 has been increasingly reported. Determining whether BMP-2 induces pain directly or whether it induces neuroinflammation, which could lower the threshold for pain, is important for developing therapeutic interventions. We therefore modeled the clinical use of BMP-2 for posterior lumbar fusion by implanting absorbable collagen sponges soaked with either recombinant human BMP-2 (rhBMP-2) or vehicle above the L4-L5 transverse processes of rat spine. Results: Using microarray analysis we found that implantation of rhBMP-2-soaked absorbable collagen sponges resulted in altered expression of numerous pro-inflammatory genes in the adjacent dorsal root ganglia (DRG) showing that implantation of rhBMP-2/ absorbable collagen sponges triggers potent neuroinflammatory responses in the DRG-2. Interestingly, direct BMP-2 treatment of DRG explants resulted in changes in gene expression that were not specifically pro-inflammatory. Rats implanted with rhBMP-2 in absorbable collagen sponges also exhibited a transient change in thermal and mechanical sensitivity indicating that rhBMP-2 applied to the lumbar spine could increase pain sensitivity. Immunohistochemical analysis indicated macrophage infiltration in the DRG and spinal nerve in rats implanted with rhBMP-2/ absorbable collagen sponges or absorbable collagen sponges alone, but not in rats that underwent surgery without implantation of the absorbable collagen sponges suggesting that the sponges contributed to the biological response. Indeed, analysis of DRGs taken from rats implanted with absorbable collagen sponges without rhBMP-2 showed a significant change in gene expression distinct from DRGs from rats undergoing surgery only. Conclusions: Our data indicate that implantation of rhBMP-2/ absorbable collagen sponges on the lumbar spine triggers potent neuroinflammatory responses in the DRG. Importantly, however, these BMP-2 effects may be partially mediated through a response to the absorbable collagen sponges. C1 [Mitchell, Kendall; Shah, Jill P.; Tsytsikova, Lyubov V.; Tiption, Ashley C.; Symes, Aviva J.] Uniformed Service Univ, Dept Pharmacol & Mol Therapeut, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Mitchell, Kendall] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD USA. [Dmitriev, Anton E.] Uniformed Serv Univ Hlth Sci, Dept Surg, Bethesda, MD USA. [Dmitriev, Anton E.] Walter Reed Natl Mil Med Ctr, Dept Orthopaed Surg, Bethesda, MD 20814 USA. [Dmitriev, Anton E.] US FDA, CDRH OSEL, Div Appl Mech, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Symes, AJ (reprint author), Uniformed Service Univ, Dept Pharmacol & Mol Therapeut, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA.; Symes, AJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Pharmacol & Mol Therapeut, 4031 Jones Bridge Rd, Bethesda, MD USA. EM Aviva.symes@usuhs.edu FU Defense Medical Research and Development Program grant FX This work was supported by a Defense Medical Research and Development Program grant to AJS. NR 44 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 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD DEC 1 PY 2016 VL 17 AR 80 DI 10.1186/s12868-016-0314-3 PG 14 WC Neurosciences SC Neurosciences & Neurology GA EE0LK UT WOS:000389266300001 PM 27905881 ER PT J AU George, J Renn, L Verthelyi, D Roederer, M Rabin, RL Mattapallil, JJ AF George, Jeffy Renn, Lynnsey Verthelyi, Daniela Roederer, Mario Rabin, Ronald L. Mattapallil, Joseph J. TI Early treatment with reverse transcriptase inhibitors significantly suppresses peak plasma IFN alpha in vivo during acute simian immunodeficiency virus infection SO CELLULAR IMMUNOLOGY LA English DT Article DE HIV; SIV; IFN alpha; IFN beta; Subtypes; Dendritic cells; Mucosa ID CD4(+) T-CELLS; PATHOGENIC SIV INFECTION; HEPATITIS-C VIRUS; DENDRITIC CELLS; INTERFERON-ALPHA; RHESUS MACAQUES; GASTROINTESTINAL-TRACT; HIV-1 INFECTION; LYMPH-NODES; ANTIRETROVIRAL THERAPY AB Innate interferons (IFN) are comprised of multiple Type I and III subtypes. The in vivo kinetics of subtype responses during human immunodeficiency virus (HIV) infection is not well defined. Using the acute simian immunodeficiency virus (SIV) infection model, we show that plasma IFN alpha levels peak at day 10 post-infection (pi) after which they rapidly declined. The mRNA expression of Type I and III IFN subtypes were significantly elevated in the lymph nodes (LN) at day 10 pi. Though the expression levels of all subtypes declined by day 14-31 pi, numerous subtypes remained elevated suggesting that ongoing viral replication in LN continues to drive induction of these subtypes. Interestingly, treatment with reverse transcriptase (RT) inhibitors at day 7 pi significantly suppressed plasma IFNa responses by day 10 pi that significantly correlated with cell-associated SIV DNA loads suggesting that RT byproducts such as viral DNA likely plays a role in driving IFN responses during acute SIV infection. Quantification of Type I and III subtype transcripts in sorted subsets of LN CD4+ and CD8+ T cells, CD14+/CD14- monocytes/-macrophages, and total CD11c/CD123+ dendritic cells (DC) at day 10 pi showed that DC expressed similar to 3-4 log more subtype transcripts as compared to the other subsets. Taken together, our results provide new insights into the kinetics of innate interferon responses during early stages of infection, and provide evidence that DC's are a major in vivo source of innate IFN during acute SIV infection. Published by Elsevier Inc. C1 [George, Jeffy; Mattapallil, Joseph J.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Renn, Lynnsey; Rabin, Ronald L.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Verthelyi, Daniela] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Roederer, Mario] NIH, Vaccine Res Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Mattapallil, JJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. EM joseph.mattapallil@usuhs.edu FU Uniformed Services University of the Health Sciences FX The described project was supported by funds from the Uniformed Services University of the Health Sciences to JJM. The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense, the Uniformed Services University of the Health Sciences or any other agency of the U.S. Government. NR 84 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 0008-8749 EI 1090-2163 J9 CELL IMMUNOL JI Cell. Immunol. PD DEC PY 2016 VL 310 BP 156 EP 164 DI 10.1016/j.cellimm.2016.09.003 PG 9 WC Cell Biology; Immunology SC Cell Biology; Immunology GA ED4MS UT WOS:000388823700017 PM 27622386 ER PT J AU Rahman, A AF Rahman, A. TI Role of Clinical Pharmacology in the Development and Approval of Immunotherapies Targeting Immune Checkpoints SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB Immune surveillance plays a critical role in preventing the development and progression of cancer. Immune modulators, such as interferon-gamma or interleukin-2, have been a part of the cancer treatment armament over the past few decades. However, new understandings regarding the role of the costimulatory and coinhibitory molecules associated with T-cells and antigen-presenting cells as well as tumor necrosis factor receptors and ligands have ushered the new era of immunotherapy for cancer treatment. We now know that primary cancer cells evade screening by the innate immune system, proliferate, and form metastases by upregulating immune inhibitory pathways referred to as immune checkpoints. The recent development of therapies that target immune checkpoints, such as cytotoxic T lymphocyte antigen 4, programmed cell death 1, programmed cell death ligand 1, indoleamine 2,3-dioxygenase, T-cell immunoglobulin and mucin domain 3, and lymphocyte activation gene 3 precisely target the immune system and give new hope for treating various types of cancer. In select marker-enriched populations, immunotherapies provide high response rates as well as durable responses in terms of progression-free survival and overall survival. Numerous factors, such as patient's immune system, the expression of targets on both immune and cancer cells, maintenance of an effective drug exposure, and tolerability to these agents may play a role in this unique observation. C1 [Rahman, A.] US FDA, NAM Atiqur Rahman, Silver Spring, MD 20993 USA. RP Rahman, A (reprint author), US FDA, NAM Atiqur Rahman, Silver Spring, MD 20993 USA. EM namatiqur.rahman@fda.hhs.gov NR 3 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 DEC PY 2016 VL 100 IS 6 BP 591 EP 593 DI 10.1002/cpt.440 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EC0RY UT WOS:000387809600009 PM 27500894 ER PT J AU Oye, KA Eichler, HG Hoos, A Mori, Y Mullin, TM Pearson, M AF Oye, K. A. Eichler, H. G. Hoos, A. Mori, Y. Mullin, T. M. Pearson, M. TI Pharmaceuticals Licensing and Reimbursement in the European Union, United States, and Japan SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article AB This article describes recent developments in licensing and reimbursement policies in the EU, US, and Japan, examines causes of changes and compares differences and projects trends. With respect to licensing, the European Medicines Agency (EMA), US Food and Drug Administration (FDA), and Japan's Pharmaceuticals and Medical Devices Agency (PMDA) are committed to rigorous evaluation of pharmaceuticals in advance of market access with feedback from postmarket experience. The EMA is exploring integrated adaptive pathways for licensing, with formal pilot tests to provide a practical proof of concept. The FDA is augmenting traditional licensing procedures through reforms including Breakthrough Product Designation. The PMDA is implementing reforms to foster innovation and earlier patient access through its Sakigake strategy and licensing reforms on regenerative medicines. With respect to reimbursement, several generalizations emerge. Relative to US counterparts, EU payers typically set higher standards for evidence of effectiveness as a condition of reimbursement, impose tougher limits on reimbursement by indication, and drive harder deals in negotiations over prices. C1 [Oye, K. A.] MIT, Cambridge, MA 02139 USA. [Eichler, H. G.] European Med Agcy, London, England. [Hoos, A.] Amgen Inc, Zug, Switzerland. [Mori, Y.] Minist Educ Culture Sports Sci & Technol MEXT, Tokyo, Japan. [Mullin, T. M.] US FDA, Silver Spring, MD USA. [Pearson, M.] Org Econ Cooperat & Dev, Paris, France. RP Oye, KA (reprint author), MIT, Cambridge, MA 02139 USA. EM oye@mit.edu FU MIT Center for Biomedical Innovation; Sloan Foundation; Kauffman Foundation; Merck Foundation; Mass Tech Collaborative; Alnylam; Amgen; Biogen-Idec; Biomarin; BMS; Genentech; GSK; Inno; JJ; LFB; Merrimack; Metabolix; Millipore; Novartis; Pfizer; Quintiles; Sanofi FX H.G.E., A.H., Y.M., T.M.M., and M.P. are employed by organizations with interests in the subject of this work. K.A.O. is funded by the MIT Center for Biomedical Innovation; CBI has been funded by Sloan, Kauffman and Merck Foundations, the Mass Tech Collaborative and a consortium including Alnylam, Amgen, Biogen-Idec, Biomarin, BMS, Genentech, GSK, Inno, J&J, LFB, Merrimack, Metabolix, Millipore, Novartis, Pfizer, Quintiles, and Sanofi. NR 1 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD DEC PY 2016 VL 100 IS 6 BP 626 EP 632 DI 10.1002/cpt.505 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EC0RY UT WOS:000387809600016 PM 27618128 ER PT J AU Schneeweiss, S Eichler, HG Garcia-Altes, A Chinn, C Eggimann, AV Garner, S Goettsch, W Lim, R Lobker, W Martin, D Muller, T Park, BJ Platt, R Priddy, S Ruhl, M Spooner, A Vannieuwenhuyse, B Willke, RJ AF Schneeweiss, S. Eichler, H-G Garcia-Altes, A. Chinn, C. Eggimann, A-V Garner, S. Goettsch, W. Lim, R. Loebker, W. Martin, D. Mueller, T. Park, B. J. Platt, R. Priddy, S. Ruhl, M. Spooner, A. Vannieuwenhuyse, B. Willke, R. J. TI Real World Data in Adaptive Biomedical Innovation: A Framework for Generating Evidence Fit for Decision-Making SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID HEALTH-CARE DATA; SAFETY MONITORING-SYSTEM; TASK-FORCE REPORT; MINI-SENTINEL; PROPENSITY SCORE; CLAIMS DATA; DESIGN CONSIDERATIONS; CAUSAL INFERENCE; DRUG DEVELOPMENT; RISK C1 [Schneeweiss, S.] Brigham & Womens Hosp, Div Pharmacoepidemiol DoPE, Dept Med, Boston, MA 02115 USA. [Eichler, H-G] EMA, London, England. [Garcia-Altes, A.] Agencia Qualitat & Avaluacio Sanitaries Catalunya, Barcelona, Spain. [Chinn, C.] Sanofi, Paris, France. [Eggimann, A-V] Bluebird Bio Inc, Cambridge, MA USA. [Garner, S.] Natl Inst Hlth & Care Excellence NICE, London, England. [Goettsch, W.] Utrecht Inst Pharmaceut Sci, Natl Hlth Care Inst, Diemen & Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands. [Lim, R.] Hlth Canada, Hlth Prod & Food Branch, Ottawa, ON, Canada. [Loebker, W.; Mueller, T.] Gemeinsamer Bundesausschuss GBA, Abt Arzneimittel, Berlin, Germany. [Martin, D.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Park, B. J.] Seoul Natl Univ, Dept Prevent Med, Coll Med, Seoul, South Korea. [Platt, R.] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Platt, R.] Harvard Pilgrim Healthcare Inst, Boston, MA USA. [Priddy, S.] CHI, Louisville, KY USA. [Ruhl, M.] Aetion Inc, New York, NY USA. [Spooner, A.] HPRA, Dublin, Ireland. [Vannieuwenhuyse, B.] Janssen Pharmaceut Res & Dev, Innovat Med Initiat European Med Informat Framewo, Beerse, Belgium. [Willke, R. J.] Int Soc Pharmacoecon & Outcomes Res, Lawrenceville, NJ USA. RP Schneeweiss, S (reprint author), Brigham & Womens Hosp, Div Pharmacoepidemiol DoPE, Dept Med, Boston, MA 02115 USA. EM schneeweiss@post.harvard.edu FU Patient Center Outcomes Research Institute; National Institute of Health; US Food and Drug Administration; IMI Get Real; IMI ADAPT SMART; NEWDIGS FX Dr. Schneeweiss' research that contributed to this work is funded by grants and contracts from the Patient Center Outcomes Research Institute, the National Institute of Health, and the US Food and Drug Administration. Parts of this manuscript have been presented earlier at the annual meeting of the International Society for Pharmacoepidemiology, and a workshop funded by IMI Get Real, IMI ADAPT SMART, and NEWDIGS. NR 67 TC 2 Z9 2 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 DEC PY 2016 VL 100 IS 6 BP 633 EP 646 DI 10.1002/cpt.512 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EC0RY UT WOS:000387809600017 PM 27627027 ER PT J AU Raju, GK Gurumurthi, K Domike, R Kazandjian, D Blumenthal, G Pazdur, R Woodcock, J AF Raju, G. K. Gurumurthi, K. Domike, R. Kazandjian, D. Blumenthal, G. Pazdur, R. Woodcock, J. TI A Benefit-Risk Analysis Approach to Capture Regulatory Decision-Making: Non-Small Cell Lung Cancer SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID PHASE-III TRIAL; CLEAR STATISTICAL SIGNIFICANCE; SECONDARY END-POINTS; DOUBLE-BLIND; SURVIVAL; GEFITINIB; PLACEBO; MULTICENTER; BEVACIZUMAB; VANDETANIB AB Drug regulators around the world make decisions about drug approvability based on qualitative benefit-risk analyses. There is much interest in quantifying regulatory approaches to benefit and risk. In this work the use of a quantitative benefit-risk analysis was applied to regulatory decision-making about new drugs to treat advanced non-small cell lung cancer (NSCLC). Benefits and risks associated with 20 US Food and Drug Administration (FDA) decisions associated with a set of candidate treatments submitted between 2003 and 2015 were analyzed. For benefit analysis, the median overall survival (OS) was used where available. When not available, OS was estimated based on overall response rate (ORR) or progression-free survival (PFS). Risks were analyzed based on magnitude (or severity) of harm and likelihood of occurrence. Additionally, a sensitivity analysis was explored to demonstrate analysis of systematic uncertainty. FDA approval decision outcomes considered were found to be consistent with the benefit-risk logic. C1 [Raju, G. K.; Gurumurthi, K.; Domike, R.] Light Pharma Inc, Cambridge, MA 02142 USA. [Kazandjian, D.; Blumenthal, G.; Pazdur, R.; Woodcock, J.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Raju, GK (reprint author), Light Pharma Inc, Cambridge, MA 02142 USA. EM Gk.raju@lightpharma.com FU US FDA FX Some parts of this work were funded by the US FDA. NR 69 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD DEC PY 2016 VL 100 IS 6 BP 672 EP 684 DI 10.1002/cpt.501 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EC0RY UT WOS:000387809600020 PM 27617424 ER PT J AU Mahmood, I Cheng, A Brauer, E Humeniuk, R AF Mahmood, Iftekhar Cheng, Anna Brauer, Edward Humeniuk, Rita TI Prediction of Antimalarial Drug Clearance in Children: A Comparison of Three Different Interspecies Scaling Methods SO EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS LA English DT Article ID UNCOMPLICATED FALCIPARUM-MALARIA; NEW-GUINEAN CHILDREN; POPULATION PHARMACOKINETICS; QUININE PHARMACOKINETICS; PLASMODIUM-FALCIPARUM; PHASE-I; SULFADOXINE-PYRIMETHAMINE; ORAL BIOAVAILABILITY; HEALTHY-VOLUNTEERS; AFRICAN CHILDREN AB Allometric scaling is extensively used for the prediction of pharmacokinetic parameters from animals to humans and is often used for the selection of first-in-human dose. Allometric scaling can also be used to predict a pharmacokinetic parameter in children from adult data including animal species such as rat and dog. The current study was undertaken to evaluate if the clearances of antimalarial drugs in children with malaria can be predicted allometrically (interspecies scaling) from adult rat, dog, and human adult (healthy as well patients with malaria) clearance values. Three methods [simple allometry, maximum lifespan potential (MLP), and MLP with an empirical correction factor] using clearance values from adult rat, dog, and adult humans with and without malaria were used for the prediction of antimalarial drug clearance in children with malaria. The results of this study indicated that the simple allometry would systematically over-predict antimalarial drug clearance in children with malaria whereas the application of MLP would under-predict the clearances of these drugs in children. Therefore, an empirical correction factor was introduced to MLP which substantially improved the antimalarial drug clearances in children. Overall, the results of the study indicated that interspecies scaling using adult rat, dog, and human clearance values of antimalarial drugs could possibly be used to predict drug clearance in children with malaria of different age groups and may be useful during pediatric drug development of antimalarial drugs. C1 [Mahmood, Iftekhar] US FDA, Div Hematol Clin Review, OBRR, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Cheng, Anna; Brauer, Edward] Univ Southern Calif, Sch Pharm, 1985 Zonal Ave, Los Angeles, CA 90089 USA. [Humeniuk, Rita] US FDA, Off Commissioner, Silver Spring, MD 20993 USA. RP Mahmood, I (reprint author), US FDA, Div Hematol Clin Review, OBRR, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Iftekhar.mahmood@fda.hhs.gov NR 75 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER FRANCE PI PARIS PA 22 RUE DE PALESTRO, PARIS, 75002, FRANCE SN 0378-7966 EI 2107-0180 J9 EUR J DRUG METAB PH JI Eur. J. Drug Metabol. Pharmacokinet. PD DEC PY 2016 VL 41 IS 6 BP 767 EP 775 DI 10.1007/s13318-015-0305-2 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED6AD UT WOS:000388934900011 PM 26547922 ER PT J AU Li, HF Shelton, SD Townsend, TA Mei, N Manjanatha, MG AF Li, Hai-fang Shelton, Sharon D. Townsend, Todd A. Mei, Nan Manjanatha, Mugimane G. TI Evaluation of cII gene mutation in the brains of Big Blue mice exposed to acrylamide and glycidamide in drinking water SO JOURNAL OF TOXICOLOGICAL SCIENCES LA English DT Article DE Acrylamide; Glycidamide; Big Blue mice; Brain; Mutation frequency; Mutation spectrum ID MUTAGENIC PROPERTIES; B6C3F(1) MICE; NEUROTOXICITY; RATS; WORKERS; CARCINOGENICITY; GENOTOXICITY; SPECIFICITY; CELLS; DNA AB Potential health risks for humans from dietary exposure to acrylamide (AA) and its reactive epoxide metabolite, glycidamide (GA), exist because substantial amounts of AA are found in a variety of fried and baked starchy foods. AA is tumorigenic in rodents, and a large number of studies indicate that AA is genotoxic in multiple organs of mice and rats. Although AA is neurotoxic, there are no reports on AA-induced gene mutations in the mouse brain. Therefore, to investigate if gene mutation can be induced by AA or its metabolite GA, we screened brains for cli mutant frequency (MF) and scored for mutation types in previously treated male and female Big Blue mice with 0, 1.4 mM, and 7.0 mM AA or GA in drinking water for up to 4 weeks. High doses of AA and GA induced similar cII MFs in males and females but only the induced cII MF in males was significantly higher than the corresponding male control MF (p < 0.05). Molecular analysis of the cli mutants from males showed that AA and GA each induced at least a 2.5-fold increase in the incidence of G:C -> T:A, A:T -> T:A, and A:T -> C:G trans versions compared to the vehicle controls, with similar mutational spectra observed when comparing AA with GA treatment. These results suggest that the MFs and types of mutations induced by AA and GA in the brain are consistent with AA exerting its genotoxicity via metabolism to GA. C1 [Li, Hai-fang; Shelton, Sharon D.; Townsend, Todd A.; Mei, Nan; Manjanatha, Mugimane G.] Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Li, Hai-fang] Xinjiang Inst Food & Drug Control, Urumqi 830004, Xinjiang, Peoples R China. RP Manjanatha, MG (reprint author), Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. EM Mugimane.Manjanatha@fda.hhs.gov FU China Scholarship Council; National Center for Toxicological Research; International Scientist Exchange Program (ISEP) at the U.S. Food and Drug Administration (FDA) FX Hai-fang Li from Xinjiang Institute for Food and Drug Control (Urumqi, China) was supported by the China Scholarship Council and participated in the International Scientist Exchange Program (ISEP) at the U.S. Food and Drug Administration (FDA), National Center for Toxicological Research. We thank Drs. Tao Chen and Xiaoqing Guo for their critical review of this manuscript. The information in this manuscript is not a formal dissemination of information by the U.S. FDA and does not represent agency position or policy. NR 42 TC 0 Z9 0 U1 3 U2 3 PU JAPANESE SOC TOXICOLOGICAL SCIENCES PI TOKYO PA INTERNATIONAL MEDICAL INFORMATION CENTER, SHINANOMACHI RENGAKAN, 35 SHINANO-MACHI, SHINJUKU-KU, TOKYO, 160-0016, JAPAN SN 0388-1350 EI 1880-3989 J9 J TOXICOL SCI JI J. Toxicol. Sci. PD DEC PY 2016 VL 41 IS 6 BP 719 EP 730 PG 12 WC Toxicology SC Toxicology GA EE3NW UT WOS:000389497300002 PM 27853100 ER PT J AU Khurana, S Fuentes, S Coyle, EM Ravichandran, S Davey, RT Beigel, JH AF Khurana, Surender Fuentes, Sandra Coyle, Elizabeth M. Ravichandran, Supriya Davey, Richard T., Jr. Beigel, John H. TI Human antibody repertoire after VSV-Ebola vaccination identifies novel targets and virus-neutralizing IgM antibodies SO NATURE MEDICINE LA English DT Article ID PROTECTS NONHUMAN-PRIMATES; RANDOMIZED CLINICAL-TRIAL; INFLUENZA VACCINE; MEDIATED PROTECTION; AFFINITY MATURATION; B-CELLS; INFECTION; RESPONSES; GLYCOPROTEIN; CHALLENGE AB Development of an effective vaccine against Ebola virus is of high priority. However, knowledge about potential correlates of protection and the durability of immune response after vaccination is limited. Here, we elucidate the human antibody repertoire after administration of vesicular stomatitis virus (VSV)-Ebola vaccine at 3 million, 20 million and 100 million plaque-forming units (PFU) and homologous VSV-Ebola vaccine boost in healthy adult volunteers. Whole genome-fragment phage display libraries, expressing linear and conformational epitopes of Ebola glycoprotein (GP), showed higher diversity of antibody epitopes in individuals vaccinated with 20 million PFU than in those vaccinated with 3 million or 100 million PFU. Surface plasmon resonance kinetics showed higher levels of GP-binding antibodies after a single vaccination with 20 million or 100 million PFU than with 3 million PFU, and these correlated strongly with neutralization titers. A second vaccination did not boost antibody or virus neutralization titers, which declined rapidly, and induced only minimal antibody affinity maturation. Isotype analysis revealed a predominant IgM response even after the second vaccination, which contributed substantially to virus neutralization in vitro. These findings may help identify new vaccine targets and aid development and evaluation of effective countermeasures against Ebola. C1 [Khurana, Surender; Fuentes, Sandra; Coyle, Elizabeth M.; Ravichandran, Supriya] US FDA, Div Viral Prod, CBER, Silver Spring, MD 20993 USA. [Davey, Richard T., Jr.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Beigel, John H.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Frederick, MD USA. RP Khurana, S (reprint author), US FDA, Div Viral Prod, CBER, Silver Spring, MD 20993 USA. EM surender.khurana@fda.hhs.gov FU US National Institute of Allergy and Infectious Diseases; FDA-MCMi-Ebola funds; US National Cancer Institute [HHSN261200800001E]; US Department of Defense (DoD) Medical Countermeasures Systems' Joint Vaccine Acquisition Program at Fort Detrick, Maryland FX We thank S. Rubin and H. Golding for reviewing the manuscript and J. Voell, P. Munoz, R. McConnell, H. Baus, C. Rehm and J. Metcalf for help with clinical studies. We thank J. Crowe (Vanderbilt University) for the gift of MAb 289 and MAb 324. The clinical trial from which the test sera were derived was funded partly by the US National Institute of Allergy and Infectious Diseases. The antibody characterization work described in this manuscript was supported by FDA-MCMi-Ebola funds to S.K. The latter funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This project was funded in whole or in part with federal funds from the US National Cancer Institute under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. We thank the US Army Medical Research Institute of Infectious Diseases team, including S. Kwilas, M. Wisniewski and J. Hooper, for providing the pseudovirion neutralization assay data used in this study. The pseudovirion work was funded by the US Department of Defense (DoD) Medical Countermeasures Systems' Joint Vaccine Acquisition Program at Fort Detrick, Maryland. The opinions, interpretations, conclusions and recommendations contained herein are those of the authors and are not necessarily endorsed by the US DoD. NR 40 TC 1 Z9 1 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD DEC PY 2016 VL 22 IS 12 BP 1439 EP + DI 10.1038/nm.4201 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA EE4CI UT WOS:000389549000021 PM 27798615 ER PT J AU Breckenridge, A Eichler, HG Jarow, JP AF Breckenridge, Alasdair Eichler, Hans-Georg Jarow, Jonathan P. TI Precision medicine and the changing role of regulatory agencies SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material AB The growth of precision medicine presents challenges for the regulators of medicines, related to aspects that include the basis of evidence generation, patient involvement in the regulatory process, cost of new medicines and the need for new regulatory models. It also raises questions about the tolerance of risk, especially with early interventions for life-threatening diseases. C1 [Breckenridge, Alasdair] Univ Liverpool, Dept Pharmacol & Therapeut, Liverpool L69 3BX, Merseyside, England. [Eichler, Hans-Georg] European Med Agcy, London E14 5EU, England. [Jarow, Jonathan P.] US FDA, Silver Spring, MD 20993 USA. RP Breckenridge, A (reprint author), Univ Liverpool, Dept Pharmacol & Therapeut, Liverpool L69 3BX, Merseyside, England. EM ambreck@liv.ac.uk NR 4 TC 0 Z9 0 U1 9 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD DEC PY 2016 VL 15 IS 12 BP 805 EP 806 DI 10.1038/nrd.2016.206 PG 2 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA ED8QE UT WOS:000389135200001 PM 27739512 ER PT J AU Mendoza-Villanueva, D Balamurugan, K Ali, HR Kim, SR Sharan, S Johnson, RC Merchant, AS Caldas, C Landberg, G Sterneck, E AF Mendoza-Villanueva, D. Balamurugan, K. Ali, H. R. Kim, S-R Sharan, S. Johnson, R. C. Merchant, A. S. Caldas, C. Landberg, G. Sterneck, E. TI The C/EBP delta protein is stabilized by estrogen receptor alpha activity, inhibits SNAI2 expression and associates with good prognosis in breast cancer SO ONCOGENE LA English DT Article ID CCAAT/ENHANCER-BINDING PROTEINS; MAMMARY-GLAND INVOLUTION; GENE-EXPRESSION; TUMOR PROGRESSION; CELL-STATE; CYCLIN D1; SLUG; PATHWAY; BETA; IDENTIFICATION AB Hypoxia and inflammatory cytokines like interleukin-6 (IL-6, IL6) are strongly linked to cancer progression, and signal in part through the transcription factor Ccaat/enhancer-binding protein d (C/EBPd, CEBPD), which has been shown to promote mesenchymal features and malignant progression of glioblastoma. Here we report a different role for C/EBPd in breast cancer. We found that the C/EBPd protein is expressed in normal breast epithelial cells and in low-grade cancers. C/EBPd protein (but not mRNA) expression correlates with estrogen receptor (ER+) and progesterone receptor (PGR) expression and longer progression-free survival of breast cancer patients. Specifically in ER+ breast cancers, CEBPD-but not the related CEBPB-mRNA in combination with IL6 correlated with lower risk of progression. Functional studies in cell lines showed that ERa promotes C/EBPd expression at the level of protein stability by inhibition of the FBXW7 pathway. Furthermore, we found that C/EBPd attenuates cell growth, motility and invasiveness by inhibiting expression of the SNAI2 (Slug) transcriptional repressor, which leads to expression of the cyclin-dependent kinase inhibitor CDKN1A (p21(CIP1/WAF1)). These findings identify a molecular mechanism by which ERa signaling reduces the aggressiveness of cancer cells, and demonstrate that C/EBPd can have different functions in different types of cancer. Furthermore, our results support a potentially beneficial role for the IL-6 pathway specifically in ER+ breast cancer and call for further evaluation of the role of intra-tumoral IL-6 expression and of which cancers might benefit from current attempts to target the IL-6 pathway as a therapeutic strategy. C1 [Mendoza-Villanueva, D.; Balamurugan, K.; Kim, S-R; Sharan, S.; Sterneck, E.] NCI, Lab Cell & Dev Signaling, Ctr Canc Res, POB B, Frederick, MD 21702 USA. [Ali, H. R.; Caldas, C.] Univ Cambridge, Cambridge Inst, Dept Oncol, Canc Res UK,Li Ka Shing Ctr, Cambridge, England. [Johnson, R. C.; Merchant, A. S.] Frederick Natl Lab, CCR Collaborat Bioinformat Resource, Adv Biomed Comp Ctr, Leidos Biomed, Frederick, MD USA. [Landberg, G.] Univ Manchester, Breakthrough Breast Canc Unit, Inst Canc Sci, Paterson Inst Canc Res, Manchester, Lancs, England. [Kim, S-R] US FDA, Div Biotechnol Review & Res 4, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Landberg, G.] Gothenburg Univ, Dept Pathol, Sahlgrenska Canc Ctr, Medicinaregatan 1F, S-40530 Gothenburg, Sweden. RP Sterneck, E (reprint author), NCI, Lab Cell & Dev Signaling, Ctr Canc Res, POB B, Frederick, MD 21702 USA. EM sternecg@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute; Frederick National Laboratory (NIH) [HHSN261200800001E]; National Council on Science and Technology (CONACYT), Mexico FX We are thankful to the Laboratory Animal Sciences Program (Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research) for excellent support, especially Donna Butcher and Glenn Summers for superb services, and Bao Tran and Jyoti Shetty (Leidos Biomedical Research, Inc.) for mRNA-Seq data. We also thank Elise Nilsson for excellent technical assistance. We thank student interns Katherine L Zhou and Yasmin Y Lachir for their valuable contributions, Linda Miller for preparation of plasmids, and Allen Kane and Joseph Meyer (Leidos Biomedical Research, Inc.) for preparing the figures for publication. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute and in part with Federal Funds from the Frederick National Laboratory (NIH) under contract no. HHSN261200800001E. DM-V was supported in part by a scholarship from the National Council on Science and Technology (CONACYT), Mexico. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 58 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD DEC 1 PY 2016 VL 35 IS 48 BP 6166 EP 6176 DI 10.1038/onc.2016.156 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ED4YH UT WOS:000388857700002 PM 27181204 ER PT J AU Wyser, Y Adams, M Avella, M Carlander, D Garcia, L Pieper, G Rennen, M Schuermans, J Weiss, J AF Wyser, Yves Adams, Michael Avella, Maurizio Carlander, David Garcia, Leonor Pieper, Gabriele Rennen, Monique Schuermans, Jeroen Weiss, Jochen TI Outlook and Challenges of Nanotechnologies for Food Packaging SO PACKAGING TECHNOLOGY AND SCIENCE LA English DT Review DE benefits; migration; fate; characterization; risk analysis AB Nanotechnology has been considered to have high potential for food packaging applications very early on. The ability to provide additional consumer benefits through the improvement of key properties of packaging materials and the creation of new functionalities means that the increased use of nanomaterials and nanotechnologies is highly likely. It has however up to now failed to reach the widespread use that was initially expected, mainly because of remaining uncertainties on the safety of these materials during the various stages of their life-cycle, which limit legal and consumer acceptance. This paper aims at presenting the latest developments in the field of nanotechnologies for food packaging applications, describing the legal framework linked to their usage and attempts to clarify the current knowledge of the safety of these materials both for the consumer and the environment. It is shown that particulate migration into foodstuff is absent in many applications, which drastically reduces the potential risk during the use phase of packaging materials, i.e. the exposure of the consumer to nanoparticles. Other release routes are also evaluated, showing that, although safe in normal use conditions, prudence should still be used, especially with regard to release after disposal of the materials. Copyright (C) 2016 The Authors Packaging Technology and Science Published by John Wiley & Sons Ltd C1 [Wyser, Yves] Nestle Res Ctr, Lausanne 26, Switzerland. [Adams, Michael] US FDA, College Pk, MD USA. [Avella, Maurizio] CNR, Inst Polymers Composites & Biomat, Pozzuoli, NA, Italy. [Carlander, David] NIA, Woluwe St Pierre, Belgium. [Garcia, Leonor] Coca Cola Co, Brussels, Belgium. [Garcia, Leonor] PlasticsEurope, Brussels, Belgium. [Pieper, Gabriele] Tetra Pak, Stuttgart, Germany. [Rennen, Monique] TNO, Zeist, Netherlands. [Schuermans, Jeroen] ILSI Europe, Ave E Mounier 83,Box 6, B-1200 Brussels, Belgium. [Weiss, Jochen] Univ Hohenheim, Stuttgart, Germany. RP Schuermans, J (reprint author), ILSI Europe, Ave E Mounier 83,Box 6, B-1200 Brussels, Belgium. EM publications@ilsieurope.be FU ILSI Europe Packaging Materials Task Force FX This work was conducted by an expert group of the European branch of the International Life Sciences Institute (ILSI Europe). This publication was coordinated by Massimo Ambrosio and Jeroen Schuermans, Scientific Project Managers at ILSI Europe. The expert group received funding from the ILSI Europe Packaging Materials Task Force. Industry members of this task force are listed on the ILSI Europe website at www.ilsi.eu. For further information about ILSI Europe, please email info@ilsieurope.be or call +32 2 771 00 14. The opinions expressed herein and the conclusions of this publication are those of the authors and do not necessarily represent the views of ILSI Europe nor those of its member companies. NR 0 TC 1 Z9 1 U1 16 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-3214 EI 1099-1522 J9 PACKAG TECHNOL SCI JI Packag. Technol. Sci. PD DEC PY 2016 VL 29 IS 12 SI SI BP 615 EP 648 DI 10.1002/pts.2221 PG 34 WC Engineering, Manufacturing; Food Science & Technology SC Engineering; Food Science & Technology GA ED6PT UT WOS:000388978600009 ER PT J AU Ku, LC Wu, H Greenberg, RG Hill, KD Gonzalez, D Hornik, CP Berezny, A Guptill, JT Jiang, WL Zheng, N Cohen-Wolkowiez, M Melloni, C AF Ku, Lawrence C. Wu, Huali Greenberg, Rachel G. Hill, Kevin D. Gonzalez, Daniel Hornik, Christoph P. Berezny, Alysha Guptill, Jeffrey T. Jiang, Wenlei Zheng, Nan Cohen-Wolkowiez, Michael Melloni, Chiara TI Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine SO THERAPEUTIC DRUG MONITORING LA English DT Article DE phenytoin; lamotrigine; pharmacokinetics; therapeutic index ID ANTIEPILEPTIC DRUGS; ANTICONVULSANT DRUGS; MEGALOBLASTIC-ANEMIA; GENERIC LAMOTRIGINE; EPILEPSY; BIOEQUIVALENCE; THROMBOCYTOPENIA; SUBSTITUTION; STRATEGIES; PARAMETERS AB Background: Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI. Methods: Retrospective EHR data from patients in a tertiary hospital were used to develop phenytoin and lamotrigine population PK models and to identify adverse events (anemia, thrombocytopenia, and leukopenia) and efficacy outcomes (seizure-free). Phenytoin and lamotrigine concentrations were simulated for each day with an adverse event or seizure. Relationships between simulated concentrations and adverse events and efficacy outcomes were used to calculate the TI for phenytoin and lamotrigine. Results: For phenytoin, 93 patients with 270 total and 174 free concentrations were identified. A de novo 1-compartment PK model with Michaelis-Menten kinetics described the data well. Simulated average total and free concentrations of 10-15 and 1.0-1.5 mcg/mL were associated with both adverse events and efficacy in 50% of patients, resulting in a TI of 0.7-1.5. For lamotrigine, 45 patients with 53 concentrations were identified. A published 1-compartment model was adapted to characterize the PK data. No relationships between simulated lamotrigine concentrations and safety or efficacy endpoints were seen; therefore, the TI could not be calculated. Conclusions: This approach correctly determined the TI of phenytoin but was unable to determine the TI of lamotrigine due to a limited sample size. The use of therapeutic drug monitoring and EHR data to aid in narrow TI drug classification is promising, but it requires an adequate sample size and accurate characterization of concentration-response relationships. C1 [Ku, Lawrence C.; Wu, Huali; Greenberg, Rachel G.; Hill, Kevin D.; Hornik, Christoph P.; Berezny, Alysha; Guptill, Jeffrey T.; Cohen-Wolkowiez, Michael; Melloni, Chiara] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Ku, Lawrence C.; Greenberg, Rachel G.; Hill, Kevin D.; Hornik, Christoph P.; Cohen-Wolkowiez, Michael] Duke Univ, Dept Pediat, Sch Med, Durham, NC 27706 USA. [Gonzalez, Daniel] Univ N Carolina, Div Pharmacotherapy & Expt Therapeut, UNC Eshelman Sch Pharm, Chapel Hill, NC USA. [Guptill, Jeffrey T.] Duke Univ, Sch Med, Dept Neurol, Durham, NC USA. [Jiang, Wenlei; Zheng, Nan] US FDA, Off Gener Drugs, Silver Spring, MD USA. RP Melloni, C (reprint author), Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM chiara.melloni@duke.edu FU US Food and Drug Administration [1U01FD004858-01]; National Institutes of Health [T32GM086330-03, 4K12HD043494-14, 5T32HD043728-10, 5T32HD043029-13]; nonprofit Mend-A-Heart Foundation; National Center for Advancing Translational Sciences of the NIH [UL1TR001117]; National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR001117]; NIH [1R01-HD076676-01A1]; National Institute of Allergy and Infectious Disease [HHSN272201500006I, HHSN272201300017I]; National Institute for Child Health and Human Development of the NIH [HHSN275201000003I]; Food and Drug Administration [1U01FD004858-01]; Biomedical Advanced Research and Development Authority (BARDA) [HHSO100201300009C]; nonprofit organization Thrasher Research Fund; industry for drug development in adults and children FX Supported in part by the US Food and Drug Administration through grant 1U01FD004858-01.; L. C. Ku receives salary support for research from the National Institutes of Health training grants (T32GM086330-03, 5T32HD043029-13, and 4K12HD043494-14). R. G. Greenberg receives salary support for research from the National Institutes of Health training grants (5T32HD043728-10 and 5T32HD043029-13). K. D. Hill Receives research support from industry for drug development in children (www.dcri.duke.edu/research/coi.jsp), from the nonprofit Mend-A-Heart Foundation (www.medaheart.org), and from the National Center for Advancing Translational Sciences of the NIH (UL1TR001117). C. P. Hornik receives salary support for research from the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001117). M. Cohen-Wolkowiez receives support for research from the NIH (1R01-HD076676-01A1), the National Center for Advancing Translational Sciences of the NIH (UL1TR001117), the National Institute of Allergy and Infectious Disease (HHSN272201500006I and HHSN272201300017I), the National Institute for Child Health and Human Development of the NIH (HHSN275201000003I), the Food and Drug Administration (1U01FD004858-01), the Biomedical Advanced Research and Development Authority (BARDA) (HHSO100201300009C), the nonprofit organization Thrasher Research Fund (www.thrasherresearch.org), and industry for drug development in adults and children (www.dcri.duke.edu/research/coi.jsp). The remaining authors declare no conflict of interest. NR 58 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 DEC PY 2016 VL 38 IS 6 BP 728 EP 737 DI 10.1097/FTD.0000000000000354 PG 10 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA ED5LY UT WOS:000388894900013 PM 27764025 ER PT J AU Lim, H Linet, MS Van Dyke, ME Miller, DL Simon, SL Sigurdson, AJ Kitahara, CM AF Lim, Hyeyeun Linet, Martha S. Van Dyke, Miriam E. Miller, Donald L. Simon, Steven L. Sigurdson, Alice J. Kitahara, Cari M. TI Changing Patterns in the Performance of Fluoroscopically Guided Interventional Procedures and Adherence to Radiation Safety Practices in a US Cohort of Radiologic Technologists SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE cardiovascular catheterizations; fluoroscopically guided procedures; radiation safety practices; radiologic technologists ID AMERICAN-HEART-ASSOCIATION; IONIZING-RADIATION; CANCER-RISKS; CARDIOLOGISTS; DISEASE; HEALTH; PROTECTION; HAZARDS; WORKING; UPDATE AB OBJECTIVE. Information is limited on changes over time in the types of fluoroscopically guided interventional procedures performed and associated radiation safety practices used by radiologic technologists. MATERIALS AND METHODS. Our study included 12,571 U.S. radiologic technologists who were certified for at least 2 years in 1926-1982 and who reported in a 2012-2013 survey that they ever performed or assisted with fluoroscopically guided interventional procedures. They completed a mailed questionnaire in 2013-2014 describing their detailed work practices for 21 fluoroscopically guided interventional procedures and associated radiation safety practices from the 1950s through 2009. RESULTS. Overall, the proportion of technologists who reported working with therapeutic fluoroscopically guided interventional procedures, including percutaneous coronary interventions, increased over time, whereas the proportion of technologists who worked with diagnostic fluoroscopically guided interventional procedures, including diagnostic cardiovascular catheterization and neuroangiographic procedures, decreased. We also observed substantial increases in the median number of times per month that technologists worked with diagnostic cardiovascular catheterizations and percutaneous coronary interventions. In each time period, most technologists reported consistently (>= 75% of work time) wearing radiation monitoring badges and lead aprons during fluoroscopically guided interventional procedures. However, fewer than 50% of the technologists reported consistent use of thyroid shields, lead glasses, and room shields during fluoroscopically guided interventional procedures, even in more recent time periods. CONCLUSION. This study provides a detailed historical assessment of fluoroscopically guided interventional procedures performed and radiation safety practices used by radiologic technologists from the 1950s through 2009. Results can be used in conjunction with badge dose data to estimate organ radiation dose for studies of radiation-related health risks in radiologic technologists who have worked with fluoroscopically guided interventional procedures. C1 [Lim, Hyeyeun; Linet, Martha S.; Simon, Steven L.; Sigurdson, Alice J.; Kitahara, Cari M.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 9069 Med Ctr Dr, Rockville, MD 20850 USA. [Van Dyke, Miriam E.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Miller, Donald L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Lim, H (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 9069 Med Ctr Dr, Rockville, MD 20850 USA. EM Hyeyeun.lim@nih.gov FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services FX Supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. NR 35 TC 0 Z9 0 U1 7 U2 7 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD DEC PY 2016 VL 207 IS 6 BP 1350 EP 1359 DI 10.2214/AJR.15.15979 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ED2MS UT WOS:000388681400037 PM 27575031 ER PT J AU Pouillot, R Klontz, KC Chen, Y Burall, LS Macarisin, D Doyle, M Bally, KM Strain, E Datta, AR Hammack, TS Van Doren, JM AF Pouillot, Regis Klontz, Karl C. Chen, Yi Burall, Laurel S. Macarisin, Dumitru Doyle, Matthew Bally, Karen M. Strain, Errol Datta, Atin R. Hammack, Thomas S. Van Doren, Jane M. TI Infectious Dose of Listeria monocytogenes in Outbreak Linked to Ice Cream, United States, 2015 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID CUT CANTALOUPE; GROWTH; CHEESE; RISK AB The relationship between the number of ingested Listeria monocytogenes cells in food and the likelihood of developing listeriosis is not well understood. Data from an outbreak of listeriosis linked to milkshakes made from ice cream produced in 1 factory showed that contaminated products were distributed widely to the public without any reported cases, except for 4 cases of severe illness in persons who were highly susceptible. The ingestion of high doses of L. monocytogenes by these patients infected through milkshakes was unlikely if possible additional contamination associated with the preparation of the milkshake is ruled out. This outbreak illustrated that the vast majority of the population did not become ill after ingesting a low level of L. monocytogenes but raises the question of listeriosis cases in highly susceptible persons after distribution of low-level contaminated products that did not support the growth of this pathogen. C1 [Pouillot, Regis; Klontz, Karl C.; Chen, Yi; Macarisin, Dumitru; Doyle, Matthew; Strain, Errol; Hammack, Thomas S.; Van Doren, Jane M.] US FDA, 5001 Campus Dr, College Pk, MD 20740 USA. [Burall, Laurel S.; Datta, Atin R.] US FDA, Laurel, MD USA. [Bally, Karen M.] Via Christi Hosp, Wichita, KS USA. RP Pouillot, R (reprint author), US FDA, 5001 Campus Dr, College Pk, MD 20740 USA. EM Regis.Pouillot@fda.hhs.gov RI Pouillot, Regis/E-8103-2010 OI Pouillot, Regis/0000-0002-6107-5212 NR 21 TC 2 Z9 2 U1 13 U2 13 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD DEC PY 2016 VL 22 IS 12 BP 2113 EP 2119 DI 10.3201/eid2212.160165 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA ED5SP UT WOS:000388912900010 PM 27869595 ER PT J AU Skoog, SA Kumar, G Zheng, JW Sumant, AV Goering, PL Narayan, RJ AF Skoog, Shelby A. Kumar, Girish Zheng, Jiwen Sumant, Anirudha V. Goering, Peter L. Narayan, Roger J. TI Biological evaluation of ultrananocrystalline and nanocrystalline diamond coatings SO JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE LA English DT Article ID HEART-VALVE PROSTHESES; PYROLYTIC CARBON; NANOSTRUCTURED DIAMOND; PROTEIN ADSORPTION; JOINT REPLACEMENT; WEAR BEHAVIOR; CELL-ADHESION; SURFACE; BONE; IMPLANTS AB Nanostructured biomaterials have been investigated for achieving desirable tissue-material interactions in medical implants. Ultrananocrystalline diamond (UNCD) and nanocrystalline diamond (NCD) coatings are the two most studied classes of synthetic diamond coatings; these materials are grown using chemical vapor deposition and are classified based on their nanostructure, grain size, and sp(3) content. UNCD and NCD are mechanically robust, chemically inert, biocompatible, and wear resistant, making them ideal implant coatings. UNCD and NCD have been recently investigated for ophthalmic, cardiovascular, dental, and orthopaedic device applications. The aim of this study was (a) to evaluate the in vitro biocompatibility of UNCD and NCD coatings and (b) to determine if variations in surface topography and sp(3) content affect cellular response. Diamond coatings with various nanoscale topographies (grain sizes 5-400 nm) were deposited on silicon substrates using microwave plasma chemical vapor deposition. Scanning electron microscopy and atomic force microscopy revealed uniform coatings with different scales of surface topography; Raman spectroscopy confirmed the presence of carbon bonding typical of diamond coatings. Cell viability, proliferation, and morphology responses of human bone marrow-derived mesenchymal stem cells (hBMSCs) to UNCD and NCD surfaces were evaluated. The hBMSCs on UNCD and NCD coatings exhibited similar cell viability, proliferation, and morphology as those on the control material, tissue culture polystyrene. No significant differences in cellular response were observed on UNCD and NCD coatings with different nanoscale topographies. Our data shows that both UNCD and NCD coatings demonstrate in vitro biocompatibility irrespective of surface topography. C1 [Skoog, Shelby A.; Narayan, Roger J.] Univ N Carolina, Joint Dept Biomed Engn, Raleigh, NC 27695 USA. [Skoog, Shelby A.; Narayan, Roger J.] North Carolina State Univ, Raleigh, NC 27695 USA. [Skoog, Shelby A.; Kumar, Girish; Zheng, Jiwen; Goering, Peter L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Sumant, Anirudha V.] Argonne Natl Lab, Ctr Nanoscale Mat, 9700 S Cass Ave, Argonne, IL 60439 USA. RP Narayan, RJ (reprint author), Univ N Carolina, Joint Dept Biomed Engn, Raleigh, NC 27695 USA.; Narayan, RJ (reprint author), North Carolina State Univ, Raleigh, NC 27695 USA. EM roger_narayan@unc.edu FU NSF [1136330]; U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; FDA intramural research funding FX Shelby Skoog was supported in part by NSF Award #1136330. Use of the Center for Nanoscale Materials, Argonne National Laboratory was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. The authors would like to acknowledge FDA intramural research funding and the FDA White Oak Nanotechnology Core Facility for instrument use, scientific, and technical assistance. Note: The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. The findings and conclusions in this paper have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any agency determination or policy. NR 47 TC 0 Z9 0 U1 8 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-4530 EI 1573-4838 J9 J MATER SCI-MATER M JI J. Mater. Sci.-Mater. Med. PD DEC PY 2016 VL 27 IS 12 AR 187 DI 10.1007/s10856-016-5798-y PG 13 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA ED1UU UT WOS:000388631200014 PM 27796686 ER PT J AU Mirams, GR Pathmanathan, P Gray, RA Challenor, P Clayton, RH AF Mirams, Gary R. Pathmanathan, Pras Gray, Richard A. Challenor, Peter Clayton, Richard H. TI Uncertainty and variability in computational and mathematical models of cardiac physiology SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID PULSE-WAVE PROPAGATION; FISTULA SURGERY. PART; SENSITIVITY-ANALYSIS; ION CHANNELS; REPOLARIZATION VARIABILITY; CELLULAR ELECTROPHYSIOLOGY; VENTRICULAR-TACHYCARDIA; COMPUTER CODE; MARKOV-MODELS; PREDICTION AB The Cardiac Physiome effort is one of the most mature and successful applications of mathematical and computational modelling for describing and advancing the understanding of physiology. After five decades of development, physiological cardiac models are poised to realise the promise of translational research via clinical applications such as drug development and patient-specific approaches as well as ablation, cardiac resynchronisation and contractility modulation therapies. For models to be included as a vital component of the decision process in safety-critical applications, rigorous assessment of model credibility will be required. This White Paper describes one aspect of this process by identifying and classifying sources of variability and uncertainty in models as well as their implications for the application and development of cardiac models. We stress the need to understand and quantify the sources of variability and uncertainty in model inputs, and the impact of model structure and complexity and their consequences for predictive model outputs. We propose that the future of the Cardiac Physiome should include a probabilistic approach to quantify the relationship of variability and uncertainty of model inputs and outputs. C1 [Mirams, Gary R.] Univ Oxford, Dept Comp Sci, Computat Biol, Oxford OX1 3QD, England. [Pathmanathan, Pras; Gray, Richard A.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Challenor, Peter] Univ Exeter, Coll Engn Math & Phys Sci, Exeter EX4 4QF, Devon, England. [Clayton, Richard H.] Univ Sheffield, Insigneo Inst In Silico Med, Sheffield S1 4DP, S Yorkshire, England. [Clayton, Richard H.] Univ Sheffield, Dept Comp Sci, Sheffield S1 4DP, S Yorkshire, England. RP Clayton, RH (reprint author), Dept Comp Sci, 211 Portobello St, Sheffield S1 4DP, S Yorkshire, England. EM r.h.clayton@sheffield.ac.uk OI Mirams, Gary/0000-0002-4569-4312; Clayton, Richard/0000-0002-8438-7518; GRAY, RICHARD/0000-0003-2798-6378 FU Wellcome Trust [101222/Z/13/Z]; Royal Society [101222/Z/13/Z]; UK Engineering and Physical Sciences Research Council [EP/K037145/1, EP/L001101/1] FX G.R.M. gratefully acknowledges support from a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 101222/Z/13/Z). R.H.C. gratefully acknowledges funding from the UK Engineering and Physical Sciences Research Council (Grant Numbers EP/K037145/1 and EP/L001101/1). The mention of commercial products, their sources, or their use in connection with material reported here is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. NR 83 TC 3 Z9 3 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD DEC 1 PY 2016 VL 594 IS 23 BP 6833 EP 6847 DI 10.1113/JP271671 PG 15 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA ED7GP UT WOS:000389030600009 PM 26990229 ER PT J AU Kawalek, JC Howard, KD Jones, Y Scott, ML Myers, MJ AF Kawalek, J. C. Howard, K. D. Jones, Y. Scott, M. L. Myers, M. J. TI Depletion of florfenicol in lactating dairy cows after intramammary and subcutaneous administration SO JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS LA English DT Article ID ELECTRON-CAPTURE DETECTION; GAS-CHROMATOGRAPHY; VEAL CALVES; PHARMACOKINETICS; CHLORAMPHENICOL; THIAMPHENICOL; RESIDUES; TISSUE; CATTLE; MILK AB Eighteen Holstein dairy cows ranging in body weight from 500-700 kg and with an average milk yield of 37 +/- 6 kg/day were used to investigate the depletion of florfenicol (FFL) in milk and plasma of dairy cows. Three groups of six were administered FFL: Group A, intramammary (IMM) infusion of similar to 2.5 mg FFL/kg BW at three consecutive milking intervals (total amount of similar to 7.5 mg/kg BW); Group B, one IMM infusion (20 mg/kg BW) into one quarter and Group C, one subcutaneous (SC) treatment (40 mg/kg BW). IMM infusions were into the right front quarter. Cows were milked daily at 06: 00 and 18: 00 h. The highest concentrations (C-max) and time to C-max (T-max) were: 1.6 +/- 2.2 mu g.FFL/mL milk at 22 h (Group A), 5.5 +/- 3.6 mu g.FFL/mL milk at 12 h (Group B), and 1.7 +/- 0.4 mu g.FFL/mL milk at 12 h (Group C). The half-lives (t(1/2)) were similar to 19, 5.5, and 60 h, for Groups A, B, and C, respectively. FFL was below the limit of detection (LOD) by 60 h in three Group B cows, but above the LOD at 72, 84, and 120 h in three cows. FFL was above the LOD in milk from Group C's cows for 432-588 h. Plasma values followed the same trends as milk. The results demonstrate that IMM-infused FFL is bioavailable and below the LOD within 72-120 h. The concentration of FFL was detectable in both plasma and milk over the course of 2-3 weeks after SC administration. The absence of residue depletion data presents problems in determining safe levels of FFL residues in milk and edible tissues. The data presented here must not be construed as approval for extra-label use in food animals. C1 [Kawalek, J. C.; Howard, K. D.; Jones, Y.; Scott, M. L.; Myers, M. J.] US FDA, Div Appl Vet Res, Ctr Vet Med, Res Off, Laurel, MD USA. RP Myers, MJ (reprint author), US FDA, Ctr Vet Med, Res Off, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM michael.myers@fda.hhs.gov FU Office of Research's Animal Care Staff FX The authors would like to thank the Office of Research's Animal Care Staff (Sam Howard, Mark McDonald, B.S., Mark Henderson, B.S., and Richard B. Cullison, DVM, M.S.) for their support and diligence during the conduct of the animal phase of this study. In addition, we would like to thank Ms. Jean L. Jackson for her technical assistance in sample collection and for performing the initial HPLC screening analyses during the animal phase of this study. 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 0140-7783 EI 1365-2885 J9 J VET PHARMACOL THER JI J. Vet. Pharmacol. Ther. PD DEC PY 2016 VL 39 IS 6 BP 602 EP 611 DI 10.1111/jvp.12315 PG 10 WC Pharmacology & Pharmacy; Veterinary Sciences SC Pharmacology & Pharmacy; Veterinary Sciences GA ED7RT UT WOS:000389067900010 PM 27189015 ER PT J AU Cleaton, MAM Dent, CL Howard, M Corish, JA Gutteridge, I Sovio, U Gaccioli, F Takahashi, N Bauer, SR Charnock-Jones, DS Powel, TL Smith', GCS Ferguson-Smith, AC Charalambous, M AF Cleaton, Mary A. M. Dent, Claire L. Howard, Mark Corish, Jennifer A. Gutteridge, Isabelle Sovio, Ulla Gaccioli, Francesca Takahashi, Nozomi Bauer, Steven R. Charnock-Jones, D. Steven Powel, Theresa L. Smith', Gordon C. S. Ferguson-Smith, Anne C. Charalambous, Marika TI Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction SO NATURE GENETICS LA English DT Article ID ANTIGEN 1; ADIPOCYTE DIFFERENTIATION; IMPRINTED GENES; BIRTH-WEIGHT; MOUSE; PREF-1; LEPTIN; EXPRESSION; INCREASE; CELLS AB Pregnancy is a state of high metabolic demand. Fasting diverts metabolism to fatty acid oxidation, and the fasted response occurs much more rapidly in pregnant women than in non-pregnant women. The product of the imprinted DLK1 gene (delta-like homolog 1) is an endocrine signaling molecule that reaches a high concentration in the maternal circulation during late pregnancy. By using mouse models with deleted Dlk1, we show that the fetus is the source of maternal circulating DLK1. In the absence of fetally derived DLK1, the maternal fasting response is impaired. Furthermore, we found that maternal circulating DLK1 levels predict embryonic mass in mice and can differentiate healthy small-for-gestational-age (SGA) infants from pathologically small infants in a human cohort. Therefore, measurement of DLK1 concentration in maternal blood may be a valuable method for diagnosing human disorders associated with impaired DLK1 expression and to predict poor intrauterine growth and complications of pregnancy. C1 [Cleaton, Mary A. M.; Ferguson-Smith, Anne C.] Univ Cambridge, Ctr Trophoblast Res, Dept Physiol Dev & Neurosci, Cambridge, England. [Dent, Claire L.; Howard, Mark; Charalambous, Marika] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, Ctr Endocrinol, London, England. [Corish, Jennifer A.; Gutteridge, Isabelle; Takahashi, Nozomi; Ferguson-Smith, Anne C.] Univ Cambridge, Dept Genet, Cambridge, England. [Sovio, Ulla; Gaccioli, Francesca; Charnock-Jones, D. Steven; Smith', Gordon C. S.] Univ Cambridge, Dept Obstet & Gynaecol, Cambridge, England. [Sovio, Ulla; Gaccioli, Francesca; Charnock-Jones, D. Steven; Smith', Gordon C. S.] NIHR Cambridge Comprehens Biomed Res Ctr, Cambridge, England. [Bauer, Steven R.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Powel, Theresa L.] Univ Colorado, Dept Pediat, Sect Neonatol, Anschutz Med Campus, Denver, CO 80202 USA. RP Charalambous, M (reprint author), Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, Ctr Endocrinol, London, England. EM m.charalambous@qmul.ac.uk RI Charnock-Jones, D. Stephen/B-3743-2009; OI Charnock-Jones, D. Stephen/0000-0002-2936-4890; Smith, Gordon/0000-0003-2124-0997 FU Cambridge Centre for Trophoblast Research; MRC [MR/J001597/1, MR/L002345/1, G1100221]; Medical College of Saint Bartholomew's Hospital Trust; Wellcome Trust; EpigeneSys [FP7 Health-257082]; EpiHealth [FP7 Health-278414]; Herchel Smith Fellowship; NIH [RO1 DK89989]; NIHR Cambridge Comprehensive Biomedical Research Centre (Women's Health theme); Sands (Stillbirth and Neonatal Death Charity); GE Healthcare; NIHR Cambridge Clinical Research Facility FX M.A.M.C. was supported by a PhD studentship from the Cambridge Centre for Trophoblast Research. Research was supported by grants from the MRC (MR/J001597/1 and MR/L002345/1), the Medical College of Saint Bartholomew's Hospital Trust, a Wellcome Trust Investigator Award, EpigeneSys (FP7 Health-257082), EpiHealth (FP7 Health-278414), a Herchel Smith Fellowship (N.T.) and NIH grant RO1 DK89989. The contents are the authors' sole responsibility and do not necessarily represent official NIH views. We thank G. Burton for invaluable support, and M. Constancia and I. Sandovici (University of Cambridge) for the Meox2-cre mice. We are extremely grateful to all of the participants in the Pregnancy Outcome Prediction study. This work was supported by the NIHR Cambridge Comprehensive Biomedical Research Centre (Women's Health theme) and project grants from the MRC (G1100221) and Sands (Stillbirth and Neonatal Death Charity). The study was also supported by GE Healthcare (donation of two Voluson i ultrasound systems for this study) and by the NIHR Cambridge Clinical Research Facility, where all research visits took place. NR 33 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD DEC PY 2016 VL 48 IS 12 BP 1473 EP 1480 DI 10.1038/ng.3699 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA ED7BQ UT WOS:000389011100007 PM 27776119 ER PT J AU Staymates, ME MacCrehan, WA Staymates, JL Kunz, RR Mendum, T Ong, TH Geurtsen, G Gillen, GJ Craven, BA AF Staymates, Matthew E. MacCrehan, William A. Staymates, Jessica L. Kunz, Roderick R. Mendum, Thomas Ong, Ta-Hsuan Geurtsen, Geoffrey Gillen, Greg J. Craven, Brent A. TI Biomimetic Sniffing Improves the Detection Performance of a 3D Printed Nose of a Dog and a Commercial Trace Vapor Detector SO SCIENTIFIC REPORTS LA English DT Article ID ODOR PLUMES; AIR-FLOW; MASS-SPECTROMETRY; CANINE OLFACTION; SENSOR ARRAYS; EXPLOSIVES; TRACKING; RATS; DISCRIMINATION; ENVIRONMENT AB Unlike current chemical trace detection technology, dogs actively sniff to acquire an odor sample. Flow visualization experiments with an anatomically-similar 3D printed dog's nose revealed the external aerodynamics during canine sniffing, where ventral-laterally expired air jets entrain odorantladen air toward the nose, thereby extending the "aerodynamic reach" for inspiration of otherwise inaccessible odors. Chemical sampling and detection experiments quantified two modes of operation with the artificial nose-active sniffing and continuous inspiration-and demonstrated an increase in odorant detection by a factor of up to 18 for active sniffing. A 16-fold improvement in detection was demonstrated with a commercially-available explosives detector by applying this bio-inspired design principle and making the device "sniff" like a dog. These lessons learned from the dog may benefit the next-generation of vapor samplers for explosives, narcotics, pathogens, or even cancer, and could inform future bio-inspired designs for optimized sampling of odor plumes. C1 [Staymates, Matthew E.; MacCrehan, William A.; Staymates, Jessica L.; Gillen, Greg J.] NIST, Mat Measurement Lab, Gaithersburg, MD 20899 USA. [Kunz, Roderick R.; Mendum, Thomas; Ong, Ta-Hsuan; Geurtsen, Geoffrey] MIT, Lincoln Lab, Chem Microsyst & Nanoscale Technol, Lexington, MA 02421 USA. [Craven, Brent A.] US FDA, Div Appl Mech, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Staymates, ME (reprint author), NIST, Mat Measurement Lab, Gaithersburg, MD 20899 USA. EM matthew.staymates@nist.gov FU U.S. Department of Homeland Security Science and Technology Directorate through Interagency Agreement [HSHQDC-12-X-00024X]; Department of Homeland Security Science and Technology Directorate, HSARPA, Explosives Division, through Interagency Agreement [HSHQPM-13-X-00107]; Department of Homeland Security Science and Technology Directorate, HSARPA, Explosives Division under Air Force [FA8721-05-C-0002, FA8702-15-D-0001] FX The National Institute of Standards and Technology portion of this work was partially funded by the U.S. Department of Homeland Security Science and Technology Directorate through Interagency Agreement HSHQDC-12-X-00024X. The Lincoln Laboratory portion of this work was funded by the Department of Homeland Security Science and Technology Directorate, HSARPA, Explosives Division, through Interagency Agreement HSHQPM-13-X-00107, and executed under Air Force Contract No. FA8721-05-C-0002 and/or FA8702-15-D-0001. Any opinions, findings, conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the Department of Homeland Security. NR 74 TC 0 Z9 0 U1 19 U2 19 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 DEC 1 PY 2016 VL 6 AR 36876 DI 10.1038/srep36876 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED6TQ UT WOS:000388989700001 PM 27906156 ER PT J AU Li, Q Liu, ST Myers, KJ Gavrielides, MA Zeng, RP Sahiner, B Petrick, N AF Li, Qin Liu, Songtao Myers, Kyle J. Gavrielides, Marios A. Zeng, Rongping Sahiner, Berkman Petrick, Nicholas TI Impact of Reconstruction Algorithms and Gender-Associated Anatomy on Coronary Calcium Scoring with CT: An Anthropomorphic Phantom Study SO ACADEMIC RADIOLOGY LA English DT Article DE Coronary calcium scoring; computed tomography; phantom study; gender differences; quantitative imaging; coronary imaging ID ITERATIVE RECONSTRUCTION; ARTERY CALCIUM; QUANTIFICATION; ANGIOGRAPHY; HEART; SEX; AGE AB Rationale and Objectives: Different computed tomography imaging protocols and patient characteristics can impact the accuracy and precision of the calcium score and may lead to inconsistent patient treatment recommendations. The aim of this work was to determine the impact of reconstruction algorithm and gender characteristics on coronary artery calcium scoring based on a phantom study using computed tomography. Materials and Methods: Four synthetic heart vessels with vessel diameters corresponding to female and male left main and left circumflex arteries containing calcification-mimicking materials (200-1000 HU) were inserted into a thorax phantom and were scanned with and without female breast plates (male and female phantoms, respectively). Ten scans were acquired and were reconstructed at 3-mm slices using filtered back projection (FBP) and iterative reconstruction with medium and strong denoising (IR3 and IR5) algorithms. Agatston and calcium volume scores were estimated for each vessel. Calcium scores for each vessel and the total calcium score (summation of all four vessels) were compared between the two phantoms to quantify the impact of the breast plates and reconstruction parameters. Calcium scores were also compared among vessels of different diameters to investigate the impact of the vessel size. Results: The calcium scores were significantly larger for FBP reconstruction (FBP > IR3>IR5). Agatston scores (calcium volume score) for vessels in the male phantom scans were on average 4.8% (2.9%), 8.2% (7.1%), and 10.5% (9.4%) higher compared to those in the female phantom with FBP, IR3, and IR5, respectively, when exposure was conserved across phantoms. The total calcium scores from the male phantom were significantly larger than those from the female phantom (P < 0.05). In general, calcium volume scores were underestimated (up to about 50%) for smaller vessels, especially when scanned in the female phantom. Conclusions: Calcium scores significantly decreased with iterative reconstruction and tended to be underestimated for female anatomy (smaller vessels and presence of breast plates). C1 [Li, Qin; Myers, Kyle J.; Gavrielides, Marios A.; Zeng, Rongping; Sahiner, Berkman; Petrick, Nicholas] US FDA, CDRH OSEL DIDSR, 10903 New Hampshire Ave,Bldg 62 Rm 4110, Silver Spring, MD 20993 USA. [Liu, Songtao] US FDA, CDRH OIR DRH, Silver Spring, MD USA. RP Li, Q (reprint author), US FDA, CDRH OSEL DIDSR, 10903 New Hampshire Ave,Bldg 62 Rm 4110, Silver Spring, MD 20993 USA. EM qin.li1@fda.hhs.gov FU U.S. Food and Drug Administration Office of Women's Health; an appointment to the Research Participation Program at the Center for Devices and Radiological Health FX This research is supported by funding from the U.S. Food and Drug Administration Office of Women's Health. Qin Li is 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 U.S. Department of Energy and the U.S. Food and Drug Administration. The mention of commercial products, their sources, or their use in connection with materials 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 17 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 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD DEC PY 2016 VL 23 IS 12 BP 1470 EP 1479 DI 10.1016/j.acra.2016.08.014 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EC8ZJ UT WOS:000388431300002 PM 27665673 ER PT J AU Gellin, BG Shen, AK Fish, R Zettle, MA Uscher-Pines, L Ringel, JS AF Gellin, Bruce G. Shen, Angela K. Fish, Rebecca Zettle, Maggie A. Uscher-Pines, Lori Ringel, Jeanne S. TI The National Adult Immunization Plan Strengthening Adult Immunization Through Coordinated Action SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID INFLUENZA C1 [Gellin, Bruce G.; Shen, Angela K.] US Dept HHS, Natl Vaccine Program Off, 200 Independence Ave SW,Room 715H, Washington, DC 20201 USA. [Fish, Rebecca] Emergent BioSolut, Washington, DC USA. [Zettle, Maggie A.] US FDA, Washington, DC 20204 USA. [Uscher-Pines, Lori] RAND Corp, Arlington, VA USA. [Ringel, Jeanne S.] RAND Corp, Santa Monica, CA USA. RP Gellin, BG (reprint author), US Dept HHS, Natl Vaccine Program Off, 200 Independence Ave SW,Room 715H, Washington, DC 20201 USA. EM bruce.gellin@hhs.gov FU National Vaccine Program Office, U.S. DHHS FX This work was funded in part under contract with the National Vaccine Program Office, U.S. DHHS. The funder (U.S. DHHS) collaborated on all aspects of the work, and federal government employees are authors on the manuscript. RAND Corporation offered contract support for the federal government effort described here. NR 20 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 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2016 VL 51 IS 6 BP 1079 EP 1083 DI 10.1016/j.amepre.2016.04.014 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EC7ZD UT WOS:000388358800028 PM 27236479 ER PT J AU Song, A Lee, A Garofolo, F Kaur, S Duggan, J Evans, C Palandra, J Di Donato, L Xu, KY Bauer, R Bustard, M Chen, LZ Cocea, L Croft, S Galliccia, F Haidar, S Hughes, N Ishii-Watabe, A Islam, R Jones, B Kadavil, J Krantz, C Santos, GML Olah, T Pedras-Vasconcelos, J Staelens, L Saito, Y Savoie, N Scheibner, K Spitz, S Tampal, N Thomas, E Vinter, S Wakelin-Smith, J Welink, J Zeng, JN Zhou, SL AF Song, An Lee, Anita Garofolo, Fabio Kaur, Surinder Duggan, Jeff Evans, Christopher Palandra, Joe Di Donato, Lorella Xu, Keyang Bauer, Ronald Bustard, Mark Chen, Linzhi Cocea, Laurent Croft, Stephanie Galliccia, Fabrizio Haidar, Sam Hughes, Nicola Ishii-Watabe, Akiko Islam, Rafiqul Jones, Barry Kadavil, John Krantz, Carsten Lima Santos, Gustavo Mendes Olah, Timothy Pedras-Vasconcelos, Joao Staelens, Ludovicus Saito, Yoshiro Savoie, Natasha Scheibner, Kara Spitz, Susan Tampal, Nilufer Thomas, Eric Vinter, Stephen Wakelin-Smith, Jason Welink, Jan Zeng, Jianing Zhou, Shaolian TI 2016 White Paper on recent issues in bioanalysis: focus on biomarker assay validation (BAV): (Part 2-Hybrid LBA/LCMS and input from regulatory agencies) SO BIOANALYSIS LA English DT Article ID COMMERCIALLY AVAILABLE ASSAYS; TANDEM MASS-SPECTROMETRY; FULL IMMERSION; GLOBAL HARMONIZATION; 1-SMALL MOLECULES; GROUP WORKSHOP; ANTIBODY-DRUG; IMMUNOGENICITY; SPECIFICITY; LCMS 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 is specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecules 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 2) discusses the recommendations for Hybrid LBA/LCMS and regulatory inputs from major global health authorities. Parts 1 (small molecule bioanalysis using LCMS) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) have been published in the Bioanalysis journal, issues 22 and 23, respectively. C1 [Song, An; Kaur, Surinder; Xu, Keyang] Genentech Inc, San Francisco, CA 94080 USA. [Lee, Anita] Merck & Co Inc, Rahway, NJ 07065 USA. [Garofolo, Fabio] Angelini Pharma, Pomezia, RM, Italy. [Duggan, Jeff; Chen, Linzhi] Boehringer Ingelheim GmbH & Co KG, Ridgefield, CT USA. [Evans, Christopher] GlaxoSmithKline, King Of Prussia, PA USA. [Palandra, Joe] Pfizer, Andover, MA USA. [Di Donato, Lorella] Capr Biosci, Montreal, PQ, Canada. [Bauer, Ronald] Austria AGES, Vienna, Austria. [Bustard, Mark; Cocea, Laurent] Hlth Canada, Ottawa, ON, Canada. [Croft, Stephanie] WHO, Geneva, Switzerland. [Galliccia, Fabrizio] Italy AIFA, Rome, Italy. [Haidar, Sam; Kadavil, John; Pedras-Vasconcelos, Joao; Scheibner, Kara; Tampal, Nilufer] US FDA, Silver Spring, MD USA. [Hughes, Nicola] Bioanalyt Lab Serv Div LifeLabs LP, Toronto, ON, Canada. [Ishii-Watabe, Akiko; Saito, Yoshiro] Japan MHLW NIHS, Tokyo, Japan. [Islam, Rafiqul] Celerion, Lincoln, NE USA. [Jones, Barry] Q2 Solut, Ithaca, NY USA. [Krantz, Carsten] Novartis, Basel, Switzerland. [Lima Santos, Gustavo Mendes] Brazil ANVISA, Brasilia, DF, Brazil. [Olah, Timothy; Zeng, Jianing] Bristol Myers Squibb Co, Princeton, NJ USA. [Staelens, Ludovicus] UCB Biopharma, Braine Lalleud, Belgium. [Savoie, Natasha] CFABS, Montreal, PQ, Canada. [Spitz, Susan] MedImmune, Gaithersburg, MD USA. [Spitz, Susan] Incyte Corp, Wilmington, DE USA. [Thomas, Eric] Covance, Indianapolis, IN USA. [Vinter, Stephen; Wakelin-Smith, Jason] UK MHRA, London, England. [Welink, Jan] Dutch MEB, Utrecht, Netherlands. [Zhou, Shaolian] Roche Pharma Res & Early Dev, Roche Innovat Ctr, Basel, Switzerland. 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 43 TC 1 Z9 1 U1 4 U2 4 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 DEC PY 2016 VL 8 IS 23 BP 2457 EP 2474 DI 10.4155/bio-2016-4988 PG 18 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA EC7DQ UT WOS:000388296400009 PM 27855509 ER PT J AU Richards, S Amaravadi, L Pillutla, R Birnboeck, H Torri, A Cowan, KJ Papadimitriou, A Garofolo, F Satterwhite, C Piccoli, S Wu, BN Krinos-Fiorotti, C Allinson, J Berisha, F Cocea, L Croft, S Fraser, S Galliccia, F Gorovits, B Gupta, S Gupta, V Haidar, S Hottenstein, C Ishii-Watabe, A Jani, D Kadavil, J Kamerud, J Kramer, D Litwin, V Santos, GML Santos, L Nelson, R Ni, Y Pedras-Vasconcelos, J Qiu, YC Rhyne, P Safavi, A Saito, Y Savoie, N Scheibner, K Schick, E Siguenza, PY Smeraglia, J Staack, RF Subramanyam, M Sumner, G Thway, T Uhlinger, D Ullmann, M Vitaliti, A Welink, J Whiting, CC Xue, L Zeng, R AF Richards, Susan Amaravadi, Lakshmi Pillutla, Renuka Birnboeck, Herbert Torri, Albert Cowan, Kyra J. Papadimitriou, Apollon Garofolo, Fabio Satterwhite, Christina Piccoli, Steven Wu, Bonnie Krinos-Fiorotti, Corinna Allinson, John Berisha, Flora Cocea, Laurent Croft, Stephanie Fraser, Stephanie Galliccia, Fabrizio Gorovits, Boris Gupta, Swati Gupta, Vinita Haidar, Sam Hottenstein, Charles Ishii-Watabe, Akiko Jani, Darshana Kadavil, John Kamerud, John Kramer, Daniel Litwin, Virginia Lima Santos, Gustavo Mendes Santos, Lima Nelson, Robert Ni, Yan Pedras-Vasconcelos, Joao Qiu, Yongchang Rhyne, Paul Safavi, Afshin Saito, Yoshiro Savoie, Natasha Scheibner, Kara Schick, Eginhard Siguenza, Patricia Y. Smeraglia, John Staack, Roland F. Subramanyam, Meena Sumner, Giane Thway, Theingi Uhlinger, David Ullmann, Martin Vitaliti, Alessandra Welink, Jan Whiting, Chan C. Xue, Li Zeng, Rong TI 2016 White Paper on recent issues in bioanalysis: focus on biomarker assay validation (BAV): (Part 3-LBA, biomarkers and immunogenicity) SO BIOANALYSIS LA English DT Article ID RECEPTOR OCCUPANCY ASSAYS; FLOW-CYTOMETRY; DRUG DEVELOPMENT; PRACTICE GUIDELINES; FULL IMMERSION; REGULATED BIOANALYSIS; BISPECIFIC ANTIBODIES; 1-SMALL MOLECULES; 2-HYBRID LBA/LCMS; GROUP WORKSHOP 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 weeklong event - A Full Immersion Week of Bioanalysis for PK, Biomarkers and Immunogenicity. As usual, it is specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecules involving LCMS, hybrid LBA/LCMS, and LBA approaches, with the focus on PK, 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 3) discusses the recommendations for large molecule bioanalysis using LBA, biomarkers and immunogenicity. Parts 1 (small molecule bioanalysis using LCMS) and Part 2 (Hybrid LBA/LCMS and regulatory inputs from major global health authorities) have been published in the Bioanalysis journal, issues 22 and 23, respectively. C1 [Richards, Susan; Amaravadi, Lakshmi] Sanofi, Framingham, MA USA. [Pillutla, Renuka; Piccoli, Steven; Ni, Yan] Bristol Myers Squibb Co, Princeton, NJ USA. [Birnboeck, Herbert; Schick, Eginhard] Roche Pharma Res & Early Dev, Roche Innovat Ctr, Basel, Switzerland. [Torri, Albert; Sumner, Giane] Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA. [Cowan, Kyra J.; Gupta, Vinita; Siguenza, Patricia Y.] Genentech Inc, San Francisco, CA 94080 USA. [Papadimitriou, Apollon; Staack, Roland F.] Roche Pharma Res & Early Dev, Roche Innovat Ctr, Munich, Germany. [Garofolo, Fabio] Angelini Pharma, Pomezia, RM, Italy. [Satterwhite, Christina] Charles River, Reno, NV USA. [Wu, Bonnie] Janssen R&D, Spring House, PA USA. [Krinos-Fiorotti, Corinna; Safavi, Afshin] Bioagilytix Labs, Durham, NC USA. [Allinson, John] LGC, Cambridge, England. [Berisha, Flora] Daiichi Sankyo, Edison, NJ USA. [Cocea, Laurent] Hlth Canada, Ottawa, ON, Canada. [Croft, Stephanie] WHO, Geneva, Switzerland. [Fraser, Stephanie] Pfizer, Groton, CT USA. [Galliccia, Fabrizio] Italy AIFA, Rome, Italy. [Gorovits, Boris; Jani, Darshana; Xue, Li] Pfizer, Andover, MA USA. [Gupta, Swati] Allergan, Irvine, CA USA. [Haidar, Sam; Kadavil, John; Pedras-Vasconcelos, Joao; Scheibner, Kara] US FDA, Silver Spring, MD USA. [Hottenstein, Charles] GlaxoSmithKline, Paoli, PA USA. [Ishii-Watabe, Akiko; Saito, Yoshiro] Japan MHLW NIHS, Tokyo, Japan. [Kamerud, John] Eurofins Bioanalyt Serv, St Charles, MO USA. [Kramer, Daniel] Sanofi, Frankfurt, Germany. [Litwin, Virginia] Covance, Indianapolis, IN USA. [Lima Santos, Gustavo Mendes; Santos, Lima] Brazil Anvisa, Brasilia, DF, Brazil. [Nelson, Robert] Novimmune, Geneva, Switzerland. [Qiu, Yongchang] Shire, Lexington, MA USA. [Rhyne, Paul] Q2 Solut, Marietta, GA USA. [Savoie, Natasha] CFABS, Laval, PQ, Canada. [Smeraglia, John] UCB Biopharma, Braine Lalleud, Belgium. [Subramanyam, Meena] Biogen, Cambridge, MA USA. [Thway, Theingi] Amgen Inc, Thousand Oaks, CA USA. [Ullmann, Martin] Merck, Aubonne, Switzerland. [Vitaliti, Alessandra] Novartis Pharmaceut, Basel, Switzerland. [Welink, Jan] Dutch MEB, Utrecht, Netherlands. [Whiting, Chan C.] Aduro Biotech, Berkeley, CA USA. [Zeng, Rong] OncoMed Pharmaceut, Redwood City, 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 MHLW; WHO FX The authors would like to acknowledge the US FDA, Europe EMA, UK MHRA, Austria AGES, Italy AIFA, Brazil ANVISA, Health Canada, Japan MHLW 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 71 TC 1 Z9 1 U1 1 U2 1 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1757-6180 EI 1757-6199 J9 BIOANALYSIS JI Bioanalysis PD DEC PY 2016 VL 8 IS 23 BP 2475 EP 2496 DI 10.4155/bio-2016-4989 PG 22 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA EC7DQ UT WOS:000388296400010 PM 27855512 ER PT J AU Munoz, MA Tonning, JM Brinker, AD Delaney, JAC Gatti, JC Avigan, M AF Munoz, Monica A. Tonning, Joseph M. Brinker, Allen D. Delaney, Joseph A. C. Gatti, Jasmine C. Avigan, Mark TI Data Mining of the US FDA's Adverse Events Reporting System Database to Evaluate Drug-Drug Interactions Associated with Statin-Induced Rhabdomyolysis SO PHARMACEUTICAL MEDICINE LA English DT Article ID LIPID-LOWERING DRUGS; SAFETY SIGNALS; RISK-FACTORS; SIMVASTATIN; ITRACONAZOLE; MYOPATHY; PHARMACOKINETICS; THERAPY; ATORVASTATIN; PRAVASTATIN AB With the rise in polypharmacy, it is increasingly important to identify drug-drug interactions (DDIs) that cause serious adverse events in a timely manner. The purpose of the study was to investigate the utility of systematic data mining of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for interactions between statins (HMG-CoA reductase inhibitors) and other drugs that underlie a higher risk for rhabdomyolysis. The strength of association for the reporting of rhabdomyolysis with each statin-drug combination was measured using Bayesian data mining scores, the Interaction Signal Score (INTSS), and simple proportions that were calculated as the reporting odds ratio (ROR). Scores > 1.0 indicate disproportionately higher than expected reporting. A manual case review highlighted strengths and limitations of these measures. As expected, clarithromycin and cyclosporine produced high measures of disproportionate reporting of rhabdomyolysis with lovastatin and simvastatin. Drugs with no known predilection to contribute to statin myopathy produced scores < 1.0 when paired with each statin. In contrast, in some instances INTSS values were < 1.0 when measures of DDI with statin-drug pairs known to interact. This might be due to masking by high numbers of reports linked to the non-statin drug alone. The manual review identified dose as an important risk factor; however, this risk factor could not have been systematically identified without informatics enhancements. While disproportionality methods represent a promising tool for identifying a potential serious DDI, opportunities remain for improvements in both data mining algorithms and the acquisition of adequately informative data. C1 [Munoz, Monica A.; Tonning, Joseph M.; Brinker, Allen D.; Gatti, Jasmine C.; Avigan, Mark] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Munoz, Monica A.; Delaney, Joseph A. C.] Univ Florida, Dept Pharmaceut Outcomes & Policy, Gainesville, FL 32611 USA. [Delaney, Joseph A. C.] Univ Washington, Dept Epidemiol, Seattle, WA USA. RP Munoz, MA (reprint author), US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA.; Munoz, MA (reprint author), Univ Florida, Dept Pharmaceut Outcomes & Policy, Gainesville, FL 32611 USA. EM monica.munoz@fda.hhs.gov NR 38 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1178-2595 EI 1179-1993 J9 PHARM MED JI Pharm. Med. PD DEC PY 2016 VL 30 IS 6 BP 327 EP 337 DI 10.1007/s40290-016-0162-6 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EC5MS UT WOS:000388180300003 ER PT J AU Aycock, KI Campbell, RL Lynch, FC Manning, KB Craven, BA AF Aycock, Kenneth I. Campbell, Robert L. Lynch, Frank C. Manning, Keefe B. Craven, Brent A. TI The Importance of Hemorheology and Patient Anatomy on the Hemodynamics in the Inferior Vena Cava SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE Non-Newtonian blood flow; Patient-specific modeling; Shear-rate histograms; Computational fluid dynamics; Wall shear stress; Blood viscosity; IVC filter ID NEWTONIAN BLOOD-FLOW; DEEP-VEIN THROMBOSIS; NUMERICAL-ANALYSIS; CAROTID-ARTERY; FILTERS; BIFURCATION; SIMULATION; VISCOSITY; RHEOLOGY; MODELS AB Inferior vena cava (IVC) filters have been used for nearly half a century to prevent pulmonary embolism in at-risk patients. However, complications with IVC filters remain common. In this study, we investigate the importance of considering the hemorheological and morphological effects on IVC hemodynamics by simulating Newtonian and non-Newtonian blood flow in three IVC models with varying levels of geometric idealization. Partial occlusion by an IVC filter and a thrombus is also considered. More than 99% of the infrarenal IVC volume is found to contain flow in the nonlinear region of the shear rate-viscosity curve for blood (less than 100 s(-1)) in the unoccluded IVCs. Newtonian simulations performed using the asymptotic viscosity for blood over-predict the non-Newtonian Reynolds numbers by more than a factor of two and under-predict the mean wall shear stress (WSS) by 28-54%. Agreement with the non-Newtonian simulations is better using a characteristic viscosity, but local WSS errors are still large (up to 50%) in the partially occluded cases. Secondary flow patterns in the IVC also depend on the viscosity model and IVC morphological complexity. Non-Newtonian simulations required only a marginal increase in computational expense compared with the Newtonian simulations. We recommend that future studies of IVC hemodynamics consider the effects of hemorheology and IVC morphology when accurate predictions of WSS and secondary flow features are desired. C1 [Aycock, Kenneth I.; Campbell, Robert L.] Penn State Univ, Appl Res Lab, University Pk, PA 16802 USA. [Aycock, Kenneth I.; Manning, Keefe B.] Penn State Univ, Dept Biomed Engn, University Pk, PA 16802 USA. [Campbell, Robert L.] Penn State Univ, Dept Mech & Nucl Engn, University Pk, PA 16802 USA. [Lynch, Frank C.; Manning, Keefe B.] Penn State Hershey Med Ctr, Dept Surg, Hershey, PA USA. [Craven, Brent A.] USDA, Div Appl Mech, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Manning, KB (reprint author), Penn State Univ, Dept Biomed Engn, University Pk, PA 16802 USA. EM kbm10@psu.edu FU Walker Assistantship program at the Penn State Applied Research Laboratory FX The authors thank Elaheh Rahbar, Daisuke Mori, and James E. Moore Jr. for generously providing the geometry for the patient-averaged IVC model. This research was supported by the Walker Assistantship program at the Penn State Applied Research Laboratory. NR 51 TC 0 Z9 0 U1 4 U2 4 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 DEC PY 2016 VL 44 IS 12 BP 3568 EP 3582 DI 10.1007/s10439-016-1663-x PG 15 WC Engineering, Biomedical SC Engineering GA EC4MB UT WOS:000388103900011 PM 27272211 ER PT J AU Morrison, TM Angelone, LM Bestelmeyer, A Bischoff, JE AF Morrison, Tina M. Angelone, Leonardo M. Bestelmeyer, Anita Bischoff, Jeffrey E. TI 2016 BMES/FDA Frontiers in Medical Devices Conference, Washington, DC, USA, May 23-25, 2016 Abstracts SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article C1 [Morrison, Tina M.; Angelone, Leonardo M.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Bestelmeyer, Anita] BD, Res Triangle Pk, NC USA. [Bischoff, Jeffrey E.] Zimmer Biomet Inc, Warsaw, IN USA. RP Morrison, TM (reprint author), US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0090-6964 EI 1573-9686 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD DEC PY 2016 VL 44 IS 12 BP 3719 EP 3749 PG 31 WC Engineering, Biomedical SC Engineering GA EC4MB UT WOS:000388103900023 ER PT J AU Chen, Y Burall, LS Luo, Y Timme, R Melka, D Muruvanda, T Payne, J Wang, C Kastanis, G Maounounen-Laasri, A De Jesus, AJ Curry, PE Stones, R K'Aluoch, O Liu, E Salter, M Hammack, TS Evans, PS Parish, M Allard, MW Datta, A Strain, EA Brown, EW AF Chen, Yi Burall, Laurel S. Luo, Yan Timme, Ruth Melka, David Muruvanda, Tim Payne, Justin Wang, Charles Kastanis, George Maounounen-Laasri, Anna De Jesus, Antonio J. Curry, Phillip E. Stones, Robert K'Aluoch, Okumu Liu, Eileen Salter, Monique Hammack, Thomas S. Evans, Peter S. Parish, Mickey Allard, Marc W. Datta, Atin Strain, Errol A. Brown, Eric W. TI Listeria monocytogenes in Stone Fruits Linked to a Multistate Outbreak: Enumeration of Cells and Whole-Genome Sequencing SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; UNITED-STATES; PROCESSING PLANTS; EPIDEMIC CLONES; DATABASE; TIME; SALMONELLA; ALIGNMENT; STRAINS; SCHEME AB In 2014, the identification of stone fruits contaminated with Listeria monocytogenes led to the subsequent identification of a multistate outbreak. Simultaneous detection and enumeration of L. monocytogenes were performed on 105 fruits, each weighing 127 to 145 g, collected from 7 contaminated lots. The results showed that 53.3% of the fruits yielded L. monocytogenes (lower limit of detection, 5 CFU/fruit), and the levels ranged from 5 to 2,850 CFU/fruit, with a geometric mean of 11.3 CFU/fruit (0.1 CFU/g of fruit). Two serotypes, IVb-v1 and 1/2b, were identified by a combination of PCR- and antiserum-based serotyping among isolates from fruits and their packing environment; certain fruits contained a mixture of both serotypes. Single nucleotide polymorphism (SNP)-based whole-genome sequencing (WGS) analysis clustered isolates from two case-patients with the serotype IVb-v1 isolates and distinguished outbreak-associated isolates from pulsed-field gel electrophoresis (PFGE)-matched, but epidemiologically unrelated, clinical isolates. The outbreak-associated isolates differed by up to 42 SNPs. All but one serotype 1/2b isolate formed another WGS cluster and differed by up to 17 SNPs. Fully closed genomes of isolates from the stone fruits were used as references to maximize the resolution and to increase our confidence in prophage analysis. Putative prophages were conserved among isolates of each WGS cluster. All serotype IVb-v1 isolates belonged to singleton sequence type 382 (ST382); all but one serotype 1/2b isolate belonged to clonal complex 5. IMPORTANCE WGS proved to be an excellent tool to assist in the epidemiologic investigation of listeriosis outbreaks. The comparison at the genome level contributed to our understanding of the genetic diversity and variations among isolates involved in an outbreak or isolates associated with food and environmental samples from one facility. Fully closed genomes increased our confidence in the identification and comparison of accessory genomes. The diversity among the outbreak-associated isolates and the inclusion of PFGE-matched, but epidemiologically unrelated, isolates demonstrate the high resolution of WGS. The prevalence and enumeration data could contribute to our further understanding of the risk associated with Listeria monocytogenes contamination, especially among high-risk populations. C1 [Chen, Yi; Luo, Yan; Timme, Ruth; Melka, David; Muruvanda, Tim; Payne, Justin; Wang, Charles; Kastanis, George; Maounounen-Laasri, Anna; De Jesus, Antonio J.; Curry, Phillip E.; Salter, Monique; Hammack, Thomas S.; Evans, Peter S.; Parish, Mickey; Allard, Marc W.; Strain, Errol A.; Brown, Eric W.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Burall, Laurel S.; Datta, Atin] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD USA. [Stones, Robert] Newcastle Univ, Newcastle Upon Tyne, Tyne & Wear, England. [K'Aluoch, Okumu; Liu, Eileen] US FDA, Off Regulatory Affairs, Alameda, CA USA. [Wang, Charles; Evans, Peter S.] USDA, Washington, DC 20250 USA. RP Chen, Y (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM yi.chen@fda.hhs.gov FU DOE\ LDRD \ Oak Ridge Institute for Science and Education (ORISE) FX This work, including the efforts of Anna Maounounen-Laasri, was funded in part by DOE vertical bar LDRD vertical bar Oak Ridge Institute for Science and Education (ORISE). NR 55 TC 1 Z9 1 U1 11 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD DEC PY 2016 VL 82 IS 24 BP 7030 EP 7040 DI 10.1128/AEM.01486-16 PG 11 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA EC4IH UT WOS:000388090500003 PM 27694232 ER PT J AU Andrade, SE Reichman, ME Mott, K Pitts, M Kieswetter, C Dinatale, M Stone, MB Popovic, J Haffenreffer, K Toh, S AF Andrade, Susan E. Reichman, Marsha E. Mott, Katrina Pitts, Marilyn Kieswetter, Caren Dinatale, Miriam Stone, Marc B. Popovic, Jennifer Haffenreffer, Katherine Toh, Sengwee TI Use of selective serotonin reuptake inhibitors (SSRIs) in women delivering liveborn infants and other women of child-bearing age within the US Food and Drug Administration's Mini-Sentinel program SO ARCHIVES OF WOMENS MENTAL HEALTH LA English DT Article DE Pregnancy; Selective serotonin reuptake inhibitors; Prevalence ID ANTIDEPRESSANT MEDICATION; BIRTH-DEFECTS; UNITED-STATES; PREGNANCY; DEPRESSION; PREVALENCE; RISK AB This study was conducted in order to assess the prevalence of use of selective serotonin reuptake inhibitors (SSRIs) among pregnant women delivering a liveborn infant in the USA. A retrospective study was conducted using the automated databases of 15 health-care systems participating in the Mini-Sentinel program. Diagnosis and procedure codes were used to identify women ages 10 to 54 years delivering a liveborn infant between April 2001 and December 2013. A comparison group of age- and date-matched women without live births was identified. The frequency of use of SSRIs was identified from outpatient dispensing data. Among the 1,895,519 liveborn deliveries, 113,689 women (6.0 %) were exposed to an SSRI during pregnancy during the period 2001-2013; 5.4 % were exposed to an SSRI during 2013. During the corresponding time period, 10.5 % of the age- and date-matched cohort of women without live births was exposed to an SSRI, with 10.1 % exposed to an SSRI during 2013. The most common agents dispensed during pregnancy were sertraline (n = 48,678), fluoxetine (n = 28,983), and citalopram (n = 20,591). Among those women exposed to an SSRI during pregnancy, 53.8 % had a diagnosis of depression and 37.3 % had a diagnosis of an anxiety disorder during pregnancy or within 180 days prior to pregnancy. Our finding that 6 % of women with live births were prescribed SSRIs during pregnancy highlights the importance of understanding the differential effects of these medications and other therapeutic options on the developing fetus and on the pregnant women. C1 [Andrade, Susan E.] Fallon Community Hlth Plan, Meyers Primary Care Inst, Reliant Med Grp, 630 Plantat St, Worcester, MA 01605 USA. [Andrade, Susan E.] Univ Massachusetts, Sch Med, 630 Plantat St, Worcester, MA 01605 USA. [Reichman, Marsha E.; Mott, Katrina; Pitts, Marilyn; Kieswetter, Caren; Dinatale, Miriam; Stone, Marc B.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Popovic, Jennifer; Haffenreffer, Katherine; Toh, Sengwee] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Popovic, Jennifer; Haffenreffer, Katherine; Toh, Sengwee] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. RP Andrade, SE (reprint author), Fallon Community Hlth Plan, Meyers Primary Care Inst, Reliant Med Grp, 630 Plantat St, Worcester, MA 01605 USA.; Andrade, SE (reprint author), Univ Massachusetts, Sch Med, 630 Plantat St, Worcester, MA 01605 USA. EM sandrade@meyersprimary.org RI Toh, Sengwee/D-7567-2017 OI Toh, Sengwee/0000-0002-5160-0810 FU U.S. Food and Drug Administration (FDA) [HHSF223200910006I, HHSF22301007T, HHSF22301016T] FX This study was supported through funding from contract HHSF223200910006I, Task Order # HHSF22301007T and Task Order # HHSF22301016T from the U.S. Food and Drug Administration (FDA). Co-authors from the FDA provided input on the study design and analysis plan, and participated in the interpretation of the results and in the preparation and decision to submit the manuscript for publication. The FDA reviewed and approved this manuscript. The FDA had no role in data collection or management. NR 27 TC 1 Z9 1 U1 5 U2 5 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 1434-1816 EI 1435-1102 J9 ARCH WOMEN MENT HLTH JI Arch. Womens Ment. Health PD DEC PY 2016 VL 19 IS 6 BP 969 EP 977 DI 10.1007/s00737-016-0637-1 PG 9 WC Psychiatry SC Psychiatry GA EB8QT UT WOS:000387656600004 PM 27178125 ER PT J AU Sahu, SC AF Sahu, Saura C. TI MicroRNAs in toxicology and medicine: A special issue of the journal "Food and Chemical Toxicology" SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Editorial Material C1 [Sahu, Saura C.] US FDA, Div Toxicol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Sahu, SC (reprint author), US FDA, Div Toxicol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. EM saura.sahu@fda.hhs.gov NR 0 TC 0 Z9 0 U1 5 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD DEC PY 2016 VL 98 SI SI BP 1 EP 1 DI 10.1016/jfct.2016.08.015 PN A PG 1 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA EC3VD UT WOS:000388054000001 PM 27523293 ER PT J AU de Conti, A Tryndyak, V Doerge, DR Beland, FA Pogribny, IP AF de Conti, Aline Tryndyak, Volodymyr Doerge, Daniel R. Beland, Frederick A. Pogribny, Igor P. TI Irreversible down-regulation of miR-375 in the livers of Fischer 344 rats after chronic furan exposure SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Furan; Liver cancer; Epigenetic; miRNAs; miR-375 ID YES-ASSOCIATED PROTEIN; HUMAN HEPATOCELLULAR-CARCINOMA; HIPPO PATHWAY; EPIGENETIC CHANGES; MICRORNA PROFILES; GENE-EXPRESSION; EFFECTOR YAP; MOUSE-LIVER; B6C3F1 MICE; F344 RATS AB Furan, a rodent liver carcinogen, is a chemical contaminant found in a broad range of cooked foods. Despite a lack of conclusive evidence regarding furan genotoxicity, several reports indicate that furan induces a broad range of non-genotoxic alterations, including aberrant expression microRNAs (miRNAs). In order to clarify the role of miRNA alterations with respect to furan carcinogenicity, we investigated the expression of several cancer-related miRNAs in the livers of Fischer 344 rats treated continuously with furan. The results demonstrate that furan induced marked changes in miRNA expression, characterized by over-expression of hepatic miRNAs, miR-34a, miR-93, miR-200a, miR-200b, and miR-224, and down-regulation of miR-375. Interestingly, a majority of furan-induced miRNA changes diminished after the cessation of the furan treatment. In contrast, the expression of miR-375 steadily decreased in a time-dependent manner following furan treatment. The reduced expression of miR-375 was accompanied by cytosine DNA hypermethylation and increased lysine methylation of histone H3K9 and H3K27 at the MiR-375 gene. The significance of miR-375 inhibition with respect to the pathogenesis of furan-induced liver toxicity and carcinogenicity may be attributed to its role in the up-regulation of Yes-associated protein 1 (YAP1), which is one of the principal events in the liver carcinogenesis. The results of the present study support the hypothesis of the non-genotoxic mode of action of furan and emphasize the importance of epigenetic alterations in the mechanism of furan hepatotoxicity. Published by Elsevier Ltd. C1 [de Conti, Aline; Tryndyak, Volodymyr; Doerge, Daniel R.; Beland, Frederick A.; Pogribny, Igor P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov NR 48 TC 1 Z9 1 U1 11 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD DEC PY 2016 VL 98 SI SI BP 2 EP 10 DI 10.1016/j.fct.2016.06.027 PN A PG 9 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA EC3VD UT WOS:000388054000002 PM 27371368 ER PT J AU Silva, CS Chang, CW Williams, D Porter-Gill, P da Costa, GG Camacho, L AF Silva, Camila S. Chang, Ching-Wei Williams, Denita Porter-Gill, Patricia da Costa, Goncalo Gamboa Camacho, Luisa TI Effects of a 28-day dietary co-exposure to melamine and cyanuric acid on the levels of serum microRNAs in male and female Fisher 344 rats SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Serum miRNA; Kidney; BUN; SCr; Melamine; Cyanuric acid ID DOSE-RESPONSE ASSESSMENT; CHRONIC KIDNEY-DISEASE; F344 RATS; COMBINED-EXPOSURE; INJURY; EXPRESSION; BIOMARKERS; TOXICITY; URINARY; IDENTIFICATION AB We showed previously that a 28-day combined dietary exposure to melamine and cyanuric acid (MEL&CYA) induced kidney lesions in NCTR Fisher 344 (F344) rats. Histopathological changes were significant in females dosed with >= 240 ppm MEL&CYA and in males dosed with >= 180 ppm MEL & CYA; however, the nephrotoxicity biomarkers blood urea nitrogen (BUN) and serum creatinine (SCr) were increased only by >= 240 ppm MEL&CYA. The serum miRNome has been reported to reflect toxicity of several organs, including the kidney. Here, we compared the dose-response of alterations in serum miRNAs to those of BUN, SCr, and kidney histopathology in rats co-exposed to MEL&CYA. The serum miRNome of male F344 rats dosed with 0, 180, or 240 ppm MEL&CYA was screened using quantitative real-time RT-PCR (qRT-PCR) and the levels of selected serum miRNAs were analyzed further in both sexes over the full dose range. The levels of several miRNAs were significantly reduced in rats treated with 240 ppm MEL&CYA versus control. In addition, miR-128-3p and miR-210-3p were decreased in males treated with 180pm MEL&CYA, a dose at which the levels of BUN and SCr were not yet affected by treatment. These data suggest that the serum miRNome is affected by nephrotoxic doses of MEL&CYA in male and female rats. Published by Elsevier Ltd. C1 [Silva, Camila S.; Williams, Denita; Porter-Gill, Patricia; da Costa, Goncalo Gamboa; Camacho, Luisa] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, HFT 110,3900 NCTR Rd, Jefferson, AR 72079 USA. [Chang, Ching-Wei] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Camacho, L (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, HFT 110,3900 NCTR Rd, Jefferson, AR 72079 USA. EM luisa.camacho@fda.hhs.gov FU US National Toxicology Program (NTP) under FDA; US National Toxicology Program (NTP) under National Institute of Environmental Health Sciences (NIEHS) [224-12-0003/NIEHS, AES12013] FX This study was conducted under the auspices of the US National Toxicology Program (NTP) under an interagency agreement (IAG) between the FDA and the National Institute of Environmental Health Sciences (NIEHS) (FDA IAG # 224-12-0003/NIEHS IAG # AES12013). NR 40 TC 0 Z9 0 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD DEC PY 2016 VL 98 SI SI BP 11 EP 16 DI 10.1016/j.fct.2016.09.013 PN A PG 6 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA EC3VD UT WOS:000388054000003 PM 27621052 ER PT J AU White, MC Pang, L Yang, X AF White, Matthew C. Pang, Li Yang, Xi TI MicroRNA-mediated maturation of human pluripotent stem cell-derived cardiomyocytes: Towards a better model for cardiotoxicity? SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE MicroRNA; Human pluripotent stem cells; Cardiomyocytes; Maturation; Cardiotoxicity; Drug screening; Disease modeling ID CALCIUM HANDLING PROPERTIES; HUMAN SOMATIC-CELLS; LONG-QT SYNDROME; IN-VITRO; CARDIAC MYOCYTES; HUMAN MYOCARDIUM; RISK-ASSESSMENT; SODIUM CURRENT; MOUSE; DIFFERENTIATION AB Human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) are a promising human cardiac model system for drug development and toxicity screening, along with cell therapy and mechanistic research. The scalable differentiation of human PSCs into CMs provides a renewable cell source that overcomes species differences present in rodent primary CMs. In addition, induced pluripotent stem cell (iPSC) technology allows for development of patient-specific CMs, representing a valuable tool that may lead to better prediction, prevention, and treatment of cardiovascular diseases in this new era of precision medicine. However, the utility of PSC-CMs as an in vitro model is currently limited by their immature phenotype when compared to adult CMs. Recent work has identified microRNAs (miRNAs) as critical regulators of heart development and function. These studies have shown that miRNAs are essential to key processes that span the life cycle of a cardiomyocyte, including proliferation, hypertrophy, beating rhythm, and apoptosis. Importantly, emerging evidence strongly suggests that modulation of select miRNAs can enhance the maturation of PSC-CMs. Here, we review key miRNAs associated with heart development and function, and discuss strategies to promote PSC-CM maturation, focusing on current knowledge surrounding miRNA-based approaches and the application of PSC-CMs with respect to drug screening and disease models. Ultimately, it is likely that combinations of both miRNA and non-miRNA maturation strategies may collectively provide the best path forward for producing mature cardiomyocytes in vitro. Published by Elsevier Ltd. C1 [White, Matthew C.; Yang, Xi] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Pang, Li] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Yang, X (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Xi.Yang@fda.hhs.gov NR 84 TC 0 Z9 0 U1 6 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD DEC PY 2016 VL 98 SI SI BP 17 EP 24 DI 10.1016/j.fct.2016.05.025 PN A PG 8 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA EC3VD UT WOS:000388054000004 PM 27265266 ER PT J AU Webb, SE Badillo-Vargas, IE Purcifull, DE Hiebert, E Baker, CA Funderburk, JE Adkins, S AF Webb, S. E. Badillo-Vargas, I. E. Purcifull, D. E. Hiebert, E. Baker, C. A. Funderburk, J. E. Adkins, S. TI Zucchini tigre mosaic virus Infection of Cucurbits in Florida SO PLANT DISEASE LA English DT News Item ID PAPAYA RINGSPOT VIRUS C1 [Webb, S. E.] Univ Florida, Dept Entomol & Nematol, Gainesville, FL 32611 USA. [Badillo-Vargas, I. E.] Texas A&M AgriLife Res, Weslaco, TX 78596 USA. [Purcifull, D. E.; Hiebert, E.] Univ Florida, Dept Plant Pathol, Gainesville, FL 32611 USA. [Baker, C. A.] FDACS DPI, Gainesville, FL 32608 USA. [Funderburk, J. E.] Univ Florida, NFREC, Quincy, FL 67891 USA. [Adkins, S.] USDA ARS, Ft Pierce, FL 34945 USA. RP Webb, SE (reprint author), Univ Florida, Dept Entomol & Nematol, Gainesville, FL 32611 USA. NR 5 TC 0 Z9 0 U1 1 U2 1 PU AMER PHYTOPATHOLOGICAL SOC PI ST PAUL PA 3340 PILOT KNOB ROAD, ST PAUL, MN 55121 USA SN 0191-2917 EI 1943-7692 J9 PLANT DIS JI PLANT DIS. PD DEC PY 2016 VL 100 IS 12 BP 2540 EP 2540 DI 10.1094/PDIS-05-16-0660-PDN PG 1 WC Plant Sciences SC Plant Sciences GA EB8IF UT WOS:000387634000074 ER PT J AU Komolprasert, V AF Komolprasert, Vanee TI Packaging food for radiation processing SO RADIATION PHYSICS AND CHEMISTRY LA English DT Article ID PREPACKAGED FOOD; IRRADIATION AB Irradiation can play an important role in reducing pathogens that cause food borne illness. Food processors and food safety experts prefer that food be irradiated after packaging to prevent post-irradiation contamination. Food. irradiation has been studied for the last century. However, the implementation of irradiation on prepackaged food still faces challenges on how to assess the suitability and safety of these packaging materials used during irradiation. Irradiation is known to induce chemical changes to the food packaging materials resulting in the formation of breakdown products, so called radiolysis products (RP), which may migrate into foods and affect the safety of the irradiated foods. Therefore, the safety of the food packaging material (both polymers and adjuvants) must be determined to ensure safety of irradiated packaged food. Evaluating the safety of food packaging materials presents technical challenges because of the range of possible chemicals generated by ionizing radiation. These challenges and the U.S. regulations on food irradiation are discussed in this article. Published by Elsevier Ltd. C1 [Komolprasert, Vanee] US FDA, Div Food Contact Notificat, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. RP Komolprasert, V (reprint author), US FDA, Div Food Contact Notificat, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. EM vanee.komolprasert@fda.hhs.gov NR 7 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 0969-806X J9 RADIAT PHYS CHEM JI Radiat. Phys. Chem. PD DEC PY 2016 VL 129 SI SI BP 35 EP 38 DI 10.1016/j.radphyschem.2016.07.023 PG 4 WC Chemistry, Physical; Nuclear Science & Technology; Physics, Atomic, Molecular & Chemical SC Chemistry; Nuclear Science & Technology; Physics GA EB6UR UT WOS:000387521600007 ER PT J AU Yang, Z Holt, HK Fan, JH Ma, L Liu, Y Chen, W Como, P Zhang, L Qiao, YL AF Yang, Zhao Holt, Hunter K. Fan, Jin-Hu Ma, Li Liu, Ying Chen, Wen Como, Peter Zhang, Lin Qiao, You-Lin TI Optimal Cutoff Scores for Alzheimer's Disease Using the Chinese Version of Mini-Mental State Examination Among Chinese Population Living in Rural Areas SO AMERICAN JOURNAL OF ALZHEIMERS DISEASE AND OTHER DEMENTIAS LA English DT Article DE Alzheimer's disease; Chinese version Mini-Mental State Examination; Chinese population; cutoff scores; rural areas; ROC analysis ID MILD COGNITIVE IMPAIRMENT; GENERAL-POPULATION; CANCER INCIDENCE; DEMENTIA; LINXIAN; DIAGNOSIS; EDUCATION; HEALTH; SUPPLEMENTATION; PREVALENCE AB To explore the optimal cutoff score for initial detection of Alzheimer's Disease (AD) through the Chinese version of Mini-Mental State Examination (CMMSE) in rural areas in China, we conducted a cross-sectional study within the Linxian General Population Nutritional Follow-up study. 16,488 eligible cohort members participated in the survey and 881 completed the CMMSE. Among 881 participants, the median age (Interquartile range) was 69.00 (10.00), 634 (71.92%) were female, 657 (74.57%) were illiterate, 35 (3.97%) had 6 years of education or higher, and 295 (33.48%) were diagnosed with AD. By reducing the CMMSE criteria for illiterate to 16 points, primary school to 19 points, and middle school or higher to 23 points, the efficiency of Chinese version of Mini-Mental State Examination can be significantly improved for initial detection of AD in rural areas in China, especially in those nutrition deficient areas. C1 [Yang, Zhao; Fan, Jin-Hu; Chen, Wen; Qiao, You-Lin] Chinese Acad Med Sci, Canc Hosp Inst, Dept Canc Epidemiol, Beijing, Peoples R China. [Yang, Zhao; Fan, Jin-Hu; Chen, Wen; Qiao, You-Lin] Peking Union Med Coll, Beijing, Peoples R China. [Holt, Hunter K.] Rush Univ, Coll Med, Dept Family Med, Chicago, IL 60612 USA. [Holt, Hunter K.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Ma, Li] Dalian Med Univ, Dept Epidemiol, Dalian, Peoples R China. [Liu, Ying] Second Affiliated Hosp Dalian, Dept Neurol, Dalian, Peoples R China. [Como, Peter] US FDA, Silver Spring, MD USA. [Zhang, Lin] Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA. RP Fan, JH (reprint author), Chinese Acad Med Sci, Canc Hosp Inst, Dept Canc Epidemiol, Beijing, Peoples R China.; Fan, JH (reprint author), Peking Union Med Coll, Beijing, Peoples R China.; Ma, L (reprint author), Dalian Med Univ, Dept Epidemiol, Dalian, Peoples R China. EM fanjh@cicams.ac.cn; mali_lele@sina.com FU NIH [NHHSN261200477001C]; Cancer Institute of the Chinese Academy of Medical Sciences; China National Natural Science Foundation [81200989]; Chinese Academy of Medical Sciences; Intramural Research Program of the US National Cancer Institute, NIH; NIH Fogarty International Center Grant [5R25TW009340] FX This study was supported in part by NIH contract NHHSN261200477001C with the Cancer Institute of the Chinese Academy of Medical Sciences; by funds from the China National Natural Science Foundation No. 81200989; by additional funds from the Chinese Academy of Medical Sciences; by funds from the Intramural Research Program of the US National Cancer Institute, NIH and finally, funds from the NIH Fogarty International Center Grant #5R25TW009340. NR 44 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-3175 EI 1938-2731 J9 AM J ALZHEIMERS DIS JI Am. J. Alzheimers Dis. Other Dement. PD DEC PY 2016 VL 31 IS 8 BP 650 EP 657 DI 10.1177/1533317516662336 PG 8 WC Geriatrics & Gerontology; Clinical Neurology SC Geriatrics & Gerontology; Neurosciences & Neurology GA EB6IP UT WOS:000387485900006 PM 27659393 ER PT J AU Xu, ZZ Proschan, M Lee, S AF Xu, Zhenzhen Proschan, Michael Lee, Shiowjen TI Validity and power considerations on hypothesis testing under minimization SO STATISTICS IN MEDICINE LA English DT Editorial Material C1 [Xu, Zhenzhen; Lee, Shiowjen] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Proschan, Michael] NIAID, Biostat Res Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Xu, ZZ (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM zhenzhen.xu@fda.hhs.gov NR 5 TC 0 Z9 0 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 DEC PY 2016 VL 35 IS 29 BP 5527 EP 5528 DI 10.1002/sim.7037 PG 2 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 EB4QJ UT WOS:000387357400015 PM 27870128 ER PT J AU Rudneva, IA Timofeeva, TA Ignatieva, AV Shilov, AA Ilyushina, NA AF Rudneva, Irina A. Timofeeva, Tatiana A. Ignatieva, Anna V. Shilov, Aleksandr A. Ilyushina, Natalia A. TI Effects of hemagglutinin amino acid substitutions in H9 influenza A virus escape mutants SO ARCHIVES OF VIROLOGY LA English DT Article ID RESPIRATORY DROPLET TRANSMISSION; AVIAN INFLUENZA; HUMAN INFECTION; H5; CHINA; POULTRY; WORKERS; ORIGIN; PATHOGENICITY; SUBTYPES AB We assessed the pH optimum of fusion, HA thermostability, and in vitro replication kinetics of previously obtained influenza H9 escape mutants. The N198S mutation significantly increased the optimum pH of fusion. Four HA changes, S133N, T189A, N198D, and L226Q, were associated with a significant increase in HA thermostability compared to the wild-type virus. HA amino acid changes at positions 116, 133, 135, 157, 162, and 193 significantly decreased the replicative ability of H9 escape mutants in vitro. Monitoring of pleiotropic effects of the HA mutations found in H9 escape mutants is essential for accurate prediction of all possible outcomes of immune selection of H9 influenza A viruses. C1 [Rudneva, Irina A.; Timofeeva, Tatiana A.; Ignatieva, Anna V.; Shilov, Aleksandr A.] Minist Hlth Russian Federat, DI Ivanovsky Inst Virol, Moscow 123098, Russia. [Ilyushina, Natalia A.] US FDA, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Ilyushina, NA (reprint author), US FDA, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Natalia.Ilyushina@fda.hhs.gov NR 37 TC 0 Z9 0 U1 7 U2 7 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 EI 1432-8798 J9 ARCH VIROL JI Arch. Virol. PD DEC PY 2016 VL 161 IS 12 BP 3515 EP 3520 DI 10.1007/s00705-016-3038-x PG 6 WC Virology SC Virology GA DZ7TB UT WOS:000386068400022 PM 27586413 ER PT J AU Doty, AC Hirota, K Olsen, KF Sakamoto, N Ackermann, R Feng, MR Wang, Y Choi, S Qu, W Schwendeman, A Schwendeman, SP AF Doty, Amy C. Hirota, Keiji Olsen, Karl F. Sakamoto, Naoya Ackermann, Rose Feng, Meihua R. Wang, Yan Choi, Stephanie Qu, Wen Schwendeman, Anna Schwendeman, Steven P. TI Validation of a cage implant system for assessing in vivo performance of long-acting, release microspheres SO BIOMATERIALS LA English DT Article DE IVIVC; Controlled release; Cage model; PLGA; Release kinetics ID PLGA MICROSPHERES; DRUG-RELEASE; INVIVO BIOCOMPATIBILITY; LEUPROLIDE ACETATE; POLY(D,L-LACTIDE-CO-GLYCOLIDE) MICROSPHERES; INJECTABLE MICROSPHERES; DELIVERY SYSTEMS; VITRO RELEASE; ACID); PHARMACOKINETICS AB Here we describe development of a silicone rubber/stainless steel mesh cage implant system, much like that used to assess biocompatibility of biomaterials [1], for easy removal of injectable polymer micro spheres in vivo. The sterile cage has a type 316 stainless steel mesh size (38 gm) large enough for cell penetration and free fluid flow in vivo but small enough for microsphere retention, and a silicone rubber shell for injection of the microspheres. Two model drugs, the poorly soluble steroid, triamcinolone acetonide, and the highly water-soluble luteinizing hormone-releasing hormone (LHRH) peptide superagonist, leuprolide, were encapsulated in PLGA microspheres large enough (63-90 mu m) to be restrained' by the cage implant in vivo. The in vitro release from both formulations was followed by ultra performance liquid chromatography (UPLC) with and without the cage in a standard release media, PBS pH 7.4 + 0.02% Tween 80 0.05% sodium azide, at 37 degrees C. Pharmacokinetics (PM) in rats was assessed after SC injection or SC in-cage implantation of microspheres with plasma analysis by LC-MS/MS or EIA. Tr-A and leuprolide in vitro release was largely unaffected after the initial, burst irrespective of the cage or test tube incubation vessel and release was much slower than observed in vivo for both drugs. Moreover, Tr-A and leuprolide pharmacokinetics with and without the cage were highly similar during the 2-3 week release duration before a significant inflammatory response was caused by the cage implant. Hence, the PM-validated cage implant provides a simple means to recover and evaluate the microsphere drug carriers in vivo during a time window of at least a few weeks in order to characterize the polymer microsphere release and erosion behavior in vivo. This approach may facilitate development of mechanism-based in vitro/in vivo correlations and enable development of more accurate and useful in vitro release tests. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Doty, Amy C.; Hirota, Keiji; Olsen, Karl F.; Ackermann, Rose; Feng, Meihua R.; Schwendeman, Anna; Schwendeman, Steven P.] Univ Michigan, Dept Pharmaceut Sci & Biointerfaces Inst, North Campus Res Complex,2800 Plymouth Rd, Ann Arbor, MI 48109 USA. [Sakamoto, Naoya] Univ Michigan, Dept Internal Med, Biomed Sci Res Bldg,109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. [Wang, Yan; Choi, Stephanie; Qu, Wen] US FDA, Ctr Drug Evaluat & Res, Off Gener Drugs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Schwendeman, Steven P.] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. RP Schwendeman, SP (reprint author), Univ Michigan, Dept Pharmaceut Sci & Biointerfaces Inst, North Campus Res Complex,2800 Plymouth Rd, Ann Arbor, MI 48109 USA. EM schwende@umich.edu FU Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation Research (CDER) at the FDA [1U01FD005014] FX This work was financially supported by the Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation Research (CDER) at the FDA (1U01FD005014). This article reflects the views of the authors and should not be construed to represent FDA's views or policies. LC-MS/MS analysis of Tr-A samples was performed by the University of Michigan Pharmacokinetics Core in the College of Pharmacy Department of Pharmaceutical Sciences. Embedding of fixed tissue, sectioning and staining was performed by University of Michigan in vivo Animal Core (IVAC). NR 59 TC 0 Z9 0 U1 24 U2 24 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD DEC PY 2016 VL 109 BP 88 EP 96 DI 10.1016/j.biomaterials.2016.07.041 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA EA2FF UT WOS:000386407500009 PM 27693924 ER PT J AU Mascia, F Schloemann, DT Cataisson, C McKinnon, KM Krymskaya, L Wolcott, KM Yuspa, SH AF Mascia, Francesca Schloemann, Derek T. Cataisson, Christophe McKinnon, Katherine M. Krymskaya, Ludmila Wolcott, Karen M. Yuspa, Stuart H. TI Cell autonomous or systemic EGFR blockade alters the immune-environment in squamous cell carcinomas SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE EGFR; SCC; gefitinib; tumor immune-environment; T regulatory cells ID GROWTH-FACTOR RECEPTOR; CANCER; CARCINOGENESIS; KERATINOCYTES; INHIBITORS; MICE AB Targeting mutations and amplifications in the EGFR has been successful precision therapy for cancers of the lung, oral cavity and gastrointestinal track. However, a systemic immune reaction manifested by dose-limiting inflammation in the skin and gut has been a consistent adverse effect. To address the possibility that intra-tumoral immune changes contribute to the anti-cancer activity of EGFR inhibition, squamous cancers were produced by syngeneic orthografts of either EGFR null or wildtype mouse primary keratinocytes transduced with an oncogenic H-ras retrovirus. Flow cytometric, RNA and Bioplex immunoassay analyses of the tumor immune milieu were performed. Cancers forming from keratinocytes genetically depleted of EGFR were smaller than wildtype cancers and had fewer infiltrating FoxP3 Treg cells, lower Foxp3 RNA and a lower percentage of CD4 PD1 positive cells indicating a tumor cell autonomous regulation of its microenvironment. Hosts bearing wildtype cancers treated with gefitinib for 1 week showed a trend for smaller tumors. In this short term pharmacological model, there was also a trend to reduced FoxP3 cells and FoxP3 RNA in the tumors of treated mice as well as a substantial increase in the ratio of IL-1A/IL-1RA transcripts. These results suggest that relatively brief systemic inhibition of EGFR signaling alters the immune environment of the targeted cancer. Together these data imply that an EGFR dependent Treg function supports the growth of squamous cancers and is a target for the therapeutic activity of EGFR inhibition. What's new? Precision therapy targeting the epidermal growth factor receptor (EGFR) is effective in lung, oral cavity, and gastrointestinal cancer. However, a systemic immune reaction resulting in dose-limiting inflammation in the skin and gut has been a consistent adverse effect. To determine whether immune effectors could contribute to the anti-cancer response, here the authors produced in mice squamous cancers that were either genetically deleted of EGFR or subjected to systemic treatment with gefitinib. Tumor cell autonomous (genetic) or systemic (pharmacologic) inhibition of EGFR signaling reduced tumor growth and Treg infiltration in the microenvironment, suggesting that EGFR-targeted cancer therapy may indeed involve immunomodulation. C1 [Mascia, Francesca; Schloemann, Derek T.; Cataisson, Christophe; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Mascia, Francesca] US FDA, Lab Appl Biochem, Div Biotechnol Res & Review 3, Off Biotechnol Prod,Off Pharmaceut Qual,Ctr Drug, Silver Spring, MD USA. [McKinnon, Katherine M.] NCI, FACS Core Facil, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Krymskaya, Ludmila; Wolcott, Karen M.] NCI, FACS Core Facil, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. RP Yuspa, SH (reprint author), NCI, Lab Canc Biol & Genet, CCR NIH, 37 Convent Dr,Bldg 37 Rm 4068, Bethesda, MD 20892 USA. EM Yuspas@dc37a.Nci.Nih.Gov FU Intramural Research Program of the NIH, NCI, Center for Cancer Research [BC005445-30] FX Grant sponsor: Intramural Research Program of the NIH, NCI, Center for Cancer Research, Project BC005445-30. NR 15 TC 0 Z9 0 U1 31 U2 31 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD DEC 1 PY 2016 VL 139 IS 11 BP 2593 EP 2597 DI 10.1002/ijc.30376 PG 5 WC Oncology SC Oncology GA DX8NQ UT WOS:000384646200021 PM 27509256 ER PT J AU Giufrida, WM Cabral, VF Cardoso, L Conti, DD de Campos, VEB da Rocha, SRP AF Giufrida, Willyan Machado Cabral, Vladimir Ferreira Cardoso-Filho, Lucio Conti, Denise dos Santos de Campos, Vania E. B. da Rocha, Sandro R. P. TI Medroxyprogesterone-encapsulated poly(3-hydroxybutirate-co-3-hydroxyvalerate) nanoparticles using supercritical fluid extraction of emulsions SO JOURNAL OF SUPERCRITICAL FLUIDS LA English DT Article DE PHBV; Nanoparticles; Medroxyprogesterone; Supercritical fluid extraction of emulsions; Drug release; In vitro toxicity of nanoparticles ID BEEF-COWS; IN-VITRO; MOLECULAR-WEIGHT; GROWTH-FACTOR; RELEASE; POLY(3-HYDROXYBUTYRATE-CO-3-HYDROXYVALERATE); PARTICLES; SIZE; PROGESTERONE; MODEL AB In this work, was investigate the effect of the molecular weight of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) on the preparation of medroxyprogesterone acetate (MPA)-encapsulated polymeric nanoparticles (PNPs) using the supercritical fluid extraction of emulsions (SFEE) technique. Particles with diameters between 850 nm-183 nm were obtained using PHBV of molar mass reduced and variable between 210 kDa to 14 kDa, thus establishing a direct relation between the size of the PNPs prepared with SFEE and the molar mass of the polymer. These results were contrasted with those obtained with the conventional emulsion solvent evaporation (ESE) technique. PNPs prepared by SFEE were observed to be smaller than those produced by ESE, for all polymer molecular weights (MW) studied. The encapsulation efficiency (EE%) of MPA in the PNPs prepared with the SFEE technique, and with the lowest MW PHBV was determined to be 70%. The in vitro release kinetics for this system indicated that the mean time for 35% release of MPA was 18 h. Both a first and a second-order kinetics models provide a good fit to the release profile of MPA from the PHBV PNPs. Cellular viability results indicate low toxicity profiles of the PHBV PNPs prepared with the SFEE technique, even at high PNP concentrations. (C) 2016 Elsevier B.V. All rights reserved. C1 [Giufrida, Willyan Machado; Cabral, Vladimir Ferreira; Cardoso-Filho, Lucio] Univ Estadual Maringa, Chem Engn, Ave Colombo 5790,Bloco D-90, BR-87020900 Maringa, Parana, Brazil. [Giufrida, Willyan Machado; Conti, Denise dos Santos; de Campos, Vania E. B.; da Rocha, Sandro R. P.] Wayne State Univ, Coll Engn, Chem Engn & Mat Sci, Detroit, MI 48202 USA. [de Campos, Vania E. B.] Univ Fed Rio de Janeiro, Inst Macromol, Ilha Fundao, POB 68525, BR-21945970 Rio De Janeiro, RJ, Brazil. [Conti, Denise dos Santos] US FDA, Off Gener Drugs, Rockville, MD 20857 USA. RP Cardoso, L (reprint author), Univ Estadual Maringa, Chem Engn, Ave Colombo 5790,Bloco D-90, BR-87020900 Maringa, Parana, Brazil.; da Rocha, SRP (reprint author), Wayne State Univ, Coll Engn, Chem Engn & Mat Sci, Detroit, MI 48202 USA. EM lucio.cardozo@gmail.com; sdr@eng.wayne.edu OI Cardozo-Filho, Lucio/0000-0002-1764-9979 FU NSF (CBET Grant) [0933144]; Nano@WSU; CAPES (Brazilian Foundation) [BEX 0425/11-7, BEX 6328/12-1] FX The authors would like to acknowledge the financial support from NSF (CBET Grant #0933144, S.R.P. da Rocha), Nano@WSU (S.R.P. da Rocha), and CAPES (Brazilian Foundation) for grants to W.M. Giufrida (process number: BEX 0425/11-7)and V.F. Cabral (process number: BEX 6328/12-1). NR 39 TC 1 Z9 1 U1 26 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0896-8446 EI 1872-8162 J9 J SUPERCRIT FLUID JI J. Supercrit. Fluids PD DEC PY 2016 VL 118 BP 79 EP 88 DI 10.1016/j.supflu.2016.07.026 PG 10 WC Chemistry, Physical; Engineering, Chemical SC Chemistry; Engineering GA DW7JO UT WOS:000383827200009 ER PT J AU Cinar, HN Qvarnstrom, Y Wei-Pridgeon, Y Li, W Nascimento, FS Arrowood, MJ Murphy, HR Jang, A Kim, E Kim, R da Silva, A Gopinath, GR AF Cinar, Hediye Nese Qvarnstrom, Yvonne Wei-Pridgeon, Yuping Li, Wen Nascimento, Fernanda S. Arrowood, Michael J. Murphy, Helen R. Jang, AhYoung Kim, Eunje Kim, RaeYoung da Silva, Alexandre Gopinath, Gopal R. TI Comparative sequence analysis of Cyclospora cayetanensis apicoplast genomes originating from diverse geographical regions SO PARASITES & VECTORS LA English DT Article DE Cyclospora cayetanensis; Apicoplast genome; Genomics; Next generation sequencing ID PLASMODIUM-FALCIPARUM; PARASITE; APICOMPLEXAN; EVOLUTION; DNA; METABOLISM; EIMERIIDAE; OUTBREAKS; HUMANS; SPP. AB Background: Cyclospora cayetanensis is an emerging coccidian parasite that causes endemic and epidemic diarrheal disease called cyclosporiasis, and this infection is associated with consumption of contaminated produce or water in developed and developing regions. Food-borne outbreaks of cyclosporiasis have occurred almost every year in the USA since the 1990s. Investigations of these outbreaks are currently hampered due to lack of molecular epidemiological tools for trace back analysis. The apicoplast of C. cayetanensis, a relict non-photosynthetic plastid with an independent genome, provides an attractive target to discover sequence polymorphisms useful as genetic markers for detection and trace back analysis of the parasite. Distinct differences in the apicoplast genomes of C. cayetanensis could be useful in designing advanced molecular methods for rapid detection and, subtyping and geographical source attribution, which would aid outbreak investigations and surveillance studies. Methods: To obtain the genome sequence of the C. cayetanensis apicoplast, we sequenced the C. cayetanensis genomic DNA extracted from clinical stool samples, assembled and annotated a 34,146 bp-long circular sequence, and used this sequence as a reference genome in this study. We compared the genome and the predicted proteome to the data available from other apicomplexan parasites. To initialize the search for genetic markers, we mapped the raw sequence reads from an additional 11 distinct clinical stool samples originating from Nepal, New York, Texas, and Indonesia to the apicoplast reference genome. Results: We identified several high quality single nucleotide polymorphisms (SNPs) and small insertion/deletions spanning the apicoplast genome supported by extensive sequencing reads data, and a 30 bp sequence repeat at the terminal spacer region in a Nepalese sample. The predicted proteome consists of 29 core apicomplexan peptides found in most of the apicomplexans. Cluster analysis of these C. cayetanensis apicoplast genomes revealed a familiar pattern of tight grouping with Eimeria and Toxoplasma, separated from distant species such as Plasmodium and Babesia. Conclusions: SNPs and sequence repeats identified in this study may be useful as genetic markers for identification and differentiation of C. cayetanensis isolates found and could facilitate outbreak investigations. C1 [Cinar, Hediye Nese; Murphy, Helen R.; Jang, AhYoung; Kim, Eunje; Kim, RaeYoung; da Silva, Alexandre; Gopinath, Gopal R.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Qvarnstrom, Yvonne; Wei-Pridgeon, Yuping; Li, Wen; Nascimento, Fernanda S.] Ctr Dis Control & Prevent, Ctr Global Hlth, Div Parasit Dis & Malaria, Atlanta, GA USA. [Arrowood, Michael J.] Ctr Dis Control & Prevent, Natl Ctr Emerging & Zoonot Infect Dis, Div Foodborne Waterborne & Environm Dis, Atlanta, GA USA. RP Cinar, HN (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. EM hediye.cinar@fda.hhs.gov FU CDC's Advanced Molecular Detection and Response to Infectious Disease Outbreaks Initiative; Brazilian National Counsel of Technological and Scientific Development (CNPq) fellowship [236608/2013-4] FX This study was supported by the CDC's Advanced Molecular Detection and Response to Infectious Disease Outbreaks Initiative. Fernanda S. Nascimento was supported by the Brazilian National Counsel of Technological and Scientific Development (CNPq) fellowship (236608/2013-4). NR 51 TC 0 Z9 0 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 NOV 29 PY 2016 VL 9 AR 611 DI 10.1186/s13071-016-1896-4 PG 14 WC Parasitology SC Parasitology GA ED5OY UT WOS:000388902800002 PM 27899155 ER PT J AU Zeng, DX Chen, Z Jiang, Y Xue, F Li, BG AF Zeng, Dexin Chen, Zi Jiang, Yuan Xue, Feng Li, Baoguang TI Advances and Challenges in Viability Detection of Foodborne Pathogens SO FRONTIERS IN MICROBIOLOGY LA English DT Review DE viability detection; foodborne pathogens; propidium monoazide; ethidium monoazide; PMA-qPCR; outbreaks; false positive detection ID REAL-TIME PCR; MEDIATED ISOTHERMAL AMPLIFICATION; POLYMERASE-CHAIN-REACTION; VIABLE ESCHERICHIA-COLI; MONOAZIDE-QUANTITATIVE PCR; LISTERIA-MONOCYTOGENES CELLS; COUPLING PROPIDIUM MONOAZIDE; ETHIDIUM-BROMIDE MONOAZIDE; STAPHYLOCOCCUS-AUREUS; DEAD CELLS AB Foodborne outbreaks area serious public health and food safety concern worldwide. There is a great demand for rapid, sensitive, specific, and accurate methods to detect microbial pathogens in foods. Conventional methods based on cultivation of pathogens have been the gold standard protocols; however, they take up to a week to complete. Molecular assays such as polymerase chain reaction (PCR), sequencing, microarray technologies have been widely used in detection of foodborne pathogens. Among molecular assays, PCR technology [conventional and real-time PGR (qPCR)] is most commonly used in the foodborne pathogen detection because of its high sensitivity and specificity. However, a major drawback of PCR is its inability to differentiate the DNA from dead and viable cells, and this is a critical factor for the food industry, regulatory agencies and the consumer. To remedy this shortcoming, researchers have used biological dyes such as ethidium monoazide and propidium monoazide (PMA) to pretreat samples before DNA extraction to intercalate the DNA of dead cells in food samples, and then proceed with regular DNA preparation and qPCR. By combining PMA treatment with qPCR (PMA-qPCR), scientists have applied this technology to detect viable cells of various bacterial pathogens in foods. The incorporation of PMA into PCR-based assays for viability detection of pathogens in foods has increased significantly in the last decade. On the other hand, some downsides with this approach have been noted, particularly to achieve complete suppression of signal of DNA from the dead cells present in some particular food matrix. Nowadays, there is a tendency of more and more researchers adapting this approach for viability detection; and a few commercial kits based on PMA are available in the market. As time goes on, more scientists apply this approach to a broader range of pathogen detections, this viability approach (PMA or other chemicals such as platinum compound) may eventually become a common methodology for the rapid, sensitive, and accurate detection of foodborne pathogens. In this review, we summarize the development in the field including progress and challenges and give our perspective in this area. C1 [Zeng, Dexin; Chen, Zi; Xue, Feng] Nanjing Agr Univ, Coll Vet Med, Nanjing, Jiangsu, Peoples R China. [Chen, Zi; Jiang, Yuan] Jiangsu Entry Exit Inspect & Quarantine Bur, Anim Quarantine Lab, Nanjing, Jiangsu, Peoples R China. [Jiang, Yuan] Shanghai Entry Exit Inspect & Quarantine Bur, Shanghai, Peoples R China. [Li, Baoguang] US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Xue, F (reprint author), Nanjing Agr Univ, Coll Vet Med, Nanjing, Jiangsu, Peoples R China.; Li, BG (reprint author), US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. EM fengxue1219@aliyun.com; baoguang.li@fda.hhs.gov FU U.S. FDA; National Natural Science Foundation of China [31301460]; National "Youth Top-notch Talent" Support Program; National Science and Technology Support Program [2012BAK17B10]; Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control; Jiangsu Province Science and Technology Support Program [BE20137334] FX The work was done with the support from U.S. FDA and by the National Natural Science Foundation of China (31301460), the National "Youth Top-notch Talent" Support Program, the National Science and Technology Support Program of 2012BAK17B10, Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control and Jiangsu Province Science and Technology Support Program of BE20137334. NR 108 TC 0 Z9 0 U1 22 U2 22 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 NOV 22 PY 2016 VL 7 AR 1833 DI 10.3389/fmicb.2016.01833 PG 12 WC Microbiology SC Microbiology GA ED3OQ UT WOS:000388758800001 PM 27920757 ER PT J AU Mayne, ST Balentine, DA AF Mayne, Susan T. Balentine, Douglas A. TI Revisions to the Nutrition Facts Label SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Mayne, Susan T.; Balentine, Douglas A.] US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr,Room 4B 064,HFS 1, College Pk, MD 20740 USA. RP Mayne, ST (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5001 Campus Dr,Room 4B 064,HFS 1, College Pk, MD 20740 USA. EM susan.mayne@fda.hhs.gov NR 1 TC 0 Z9 0 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD NOV 22 PY 2016 VL 316 IS 20 BP 2152 EP 2153 DI 10.1001/jama.2016.16173 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA ED1XD UT WOS:000388637300026 PM 27893120 ER PT J AU Christensen, CH Barry, KH Andreotti, G Alavanja, MCR Cook, MB Kelly, SP Burdett, LA Yeager, M Freeman, LEB Berndt, SI Koutros, S AF Christensen, Carol H. Barry, Kathryn Hughes Andreotti, Gabriella Alavanja, Michael C. R. Cook, Michael B. Kelly, Scott P. Burdett, Laurie A. Yeager, Meredith Freeman, Laura E. Beane Berndt, Sonja I. Koutros, Stella TI Sex Steroid Hormone Single-Nucleotide Polymorphisms, Pesticide Use, and the Risk of Prostate Cancer: A Nested Case-Control Study within the Agricultural Health Study SO FRONTIERS IN ONCOLOGY LA English DT Article DE prostate cancer; pesticides; sex steroid hormones; single-nucleotide polymorphism; interaction ID DEPLOYMENT-RELATED CHEMICALS; GENOME-WIDE ASSOCIATION; REPAIR PATHWAY GENES; METABOLIC PATHWAY; ANDROGEN RECEPTOR; 3A4 METABOLISM; EXPOSURE; APPLICATORS; VARIANTS; COHORT AB Experimental and epidemiologic investigations suggest that certain pesticides may alter sex steroid hormone synthesis, metabolism or regulation, and the risk of hormone-related cancers. Here, we evaluated whether single-nucleotide polymorphisms (SNPs) involved in hormone homeostasis alter the effect of pesticide exposure on prostate cancer risk. We evaluated pesticide-SNP interactions between 39 pesticides and SNPs with respect to prostate cancer among 776 cases and 1,444 controls nested in the Agricultural Health Study cohort. In these interactions, we included candidate SNPs involved in hormone synthesis, metabolism or regulation (N = 1,100), as well as SNPs associated with circulating sex steroid concentrations, as identified by genome-wide association studies (N = 17). Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Multiplicative SNP-pesticide interactions were calculated using a likelihood ratio test. We translated p-values for interaction into q-values, which reflected the false discovery rate, to account for multiple comparisons. We observed a significant interaction, which was robust to multiple comparison testing, between the herbicide dicamba and rs8192166 in the testosterone metabolizing gene SRD5A1 (p-interaction = 4.0 x 10(-5); q-value = 0.03), such that men with two copies of the wild-type genotype CC had a reduced risk of prostate cancer associated with low use of dicamba (OR = 0.62 95% CI: 0.41, 0.93) and high use of dicamba (OR = 0.44, 95% CI: 0.29, 0.68), compared to those who reported no use of dicamba; in contrast, there was no significant association between dicamba and prostate cancer among those carrying one or two copies of the variant T allele at rs8192166. In addition, interactions between two organophosphate insecticides and SNPs related to estradiol metabolism were observed to result in an increased risk of prostate cancer. While replication is needed, these data suggest both agonistic and antagonistic effects on circulating hormones, due to the combination of exposure to pesticides and genetic susceptibility, may impact prostate cancer risk. C1 [Christensen, Carol H.] US FDA, Off Sci, Ctr Tobacco Prod, Document Control Ctr, Silver Spring, MD USA. [Barry, Kathryn Hughes; Andreotti, Gabriella; Alavanja, Michael C. R.; Freeman, Laura E. Beane; Berndt, Sonja I.; Koutros, Stella] NCI, Occupat & Environm Epidemiol Branch, US Dept HHS, Div Canc Epidemiol & Genet,NIH, Rockville, MD 20850 USA. [Barry, Kathryn Hughes] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Barry, Kathryn Hughes] Univ Maryland, Program Oncol, Marlene & Stewart Greenebaum Comprehens Canc Ctr, Baltimore, MD 21201 USA. [Cook, Michael B.; Kelly, Scott P.] NCI, Metab Epidemiol Branch, US Dept HHS, Div Canc Epidemiol & Genet,NIH, Rockville, MD USA. [Burdett, Laurie A.; Yeager, Meredith] NCI, Canc Genom Res Lab, Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Frederick, MD 21701 USA. RP Koutros, S (reprint author), NCI, Occupat & Environm Epidemiol Branch, US Dept HHS, Div Canc Epidemiol & Genet,NIH, Rockville, MD 20850 USA. EM koutross@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015; Kelly, Scott/D-3195-2013 OI Beane Freeman, Laura/0000-0003-1294-4124; Kelly, Scott/0000-0002-0375-1040 NR 50 TC 0 Z9 0 U1 5 U2 5 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD NOV 21 PY 2016 VL 6 AR 237 DI 10.3389/fonc.2016.00237 PG 8 WC Oncology SC Oncology GA EC6DN UT WOS:000388226800001 PM 27917368 ER PT J AU Yu, H Li, YH Zeng, J Thon, V Nguyen, DM Ly, T Kuang, HY Ngo, A Chen, X AF Yu, Hai Li, Yanhong Zeng, Jie Thon, Vireak Nguyen, Dung M. Ly, Thao Kuang, Hui Yu Ngo, Alice Chen, Xi TI Sequential One-Pot Multienzyme Chemoenzymatic Synthesis of Glycosphingolipid Glycans SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID GLOBO-H HEXASACCHARIDE; SIALYL-LEWIS-X; N-GLYCOLYLNEURAMINIC ACID; ESCHERICHIA-COLI; MONOCLONAL-ANTIBODY; ENZYMATIC-SYNTHESIS; HUMAN-MELANOMA; CANCER VACCINES; CHOLERA-TOXIN; GANGLIOSIDE AB Glycosphingolipids are a diverse family of biologically important glycolipids. In addition to variations on the lipid component, more than 300 glycosphingolipid glycans have been characterized. These glycans are directly involved in various molecular recognition events. Several naturally occurring sialic acid forms have been found in sialic acid-containing glycosphingolipids, namely gangliosides. However, ganglioside glycans containing less common sialic acid forms are currently not available. Herein, highly effective one-pot multienzyme (OPME) systems are used in sequential for high-yield and cost-effective production of glycosphingolipid glycans, including those containing different sialic acid forms such as N-acetylneuraminic acid (Neu5Ac), N-glycolylneuraminic acid (Neu5Gc), 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (Kdn), and 8-0-methyl-N-acetylneuraminic acid (Neu5Ac8OMe). A library of 64 structurally distinct glycosphingolipid glycans belonging to ganglio-series, lacto-/neolacto-series, and globo-/isoglobo-series glycosphingolipid glycans is constructed. These glycans are essential standards and invaluable probes for bioassays and biomedical studies. C1 [Yu, Hai; Li, Yanhong] Glycohub Inc, 4070 Truxel Rd, Sacramento, CA 95834 USA. [Yu, Hai; Li, Yanhong; Zeng, Jie; Thon, Vireak; Nguyen, Dung M.; Ly, Thao; Kuang, Hui Yu; Ngo, Alice; Chen, Xi] Univ Calif Davis, Dept Chem, One Shields Ave, Davis, CA 95616 USA. [Zeng, Jie] Henan Inst Sci & Technol, Sch Food Sci, Xinxiang 453003, Henan, Peoples R China. [Thon, Vireak] US FDA, Lab Bacterial Polysaccharides, Bethesda, MD 20892 USA. [Nguyen, Dung M.] Univ Calif Davis, Ctr Neurosci, Davis, CA 95616 USA. [Kuang, Hui Yu] Touro Univ, Coll Pharm, Vallejo, CA 94592 USA. RP Yu, H (reprint author), Glycohub Inc, 4070 Truxel Rd, Sacramento, CA 95834 USA.; Yu, H; Chen, X (reprint author), Univ Calif Davis, Dept Chem, One Shields Ave, Davis, CA 95616 USA. EM hyu@glycohubusa.com; xiichen@ucdavis.edu FU National Institute of General Medical Sciences; National Cancer Institute of National Institutes of Health [261201300041C] FX This work was supported by the National Institute of General Medical Sciences and the National Cancer Institute of National Institutes of Health Project Number 261201300041C. The plasmid for expressing HiLgtD was a kind gift from Dr. Peng G. Wang in Georgia State University. NR 83 TC 0 Z9 0 U1 5 U2 5 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 NOV 18 PY 2016 VL 81 IS 22 BP 10809 EP 10824 DI 10.1021/acs.joc.6b01905 PG 16 WC Chemistry, Organic SC Chemistry GA EG7SI UT WOS:000391248800021 PM 27736072 ER PT J AU Ottesen, A Ramachandran, P Reed, E White, JR Hasan, N Subramanian, P Ryan, G Jarvis, K Grim, C Daquiqan, N Hanes, D Allard, M Colwell, R Brown, E Chen, Y AF Ottesen, Andrea Ramachandran, Padmini Reed, Elizabeth White, James R. Hasan, Nur Subramanian, Poorani Ryan, Gina Jarvis, Karen Grim, Christopher Daquiqan, Ninalynn Hanes, Darcy Allard, Marc Colwell, Rita Brown, Eric Chen, Yi TI Enrichment dynamics of Listeria monocytogenes and the associated microbiome from naturally contaminated ice cream linked to a listeriosis outbreak SO BMC MICROBIOLOGY LA English DT Article DE Listeria monocytogenes; Enrichment; Ice cream; Microbiota; Co-enriching bacteria; 16S rRNA; Shotgun metagenomics; Next-generation sequencing; NGS; ISO; FDA; USDA; Buffered Listeria enrichment broth (BLEB); Half-Fraser broth (HFB); Fraser broth (FB); University of Vermont modified broth (UVM) ID 16S RIBOSOMAL-RNA; LAG-PHASE; HIGH-THROUGHPUT; UNITED-STATES; TEMPERATURE; ENVIRONMENT; BACTERIUM; ALIGNMENT AB Background: Microbiota that co-enrich during efforts to recover pathogens from foodborne outbreaks interfere with efficient detection and recovery. Here, dynamics of co-enriching microbiota during recovery of Listeria monocytogenes from naturally contaminated ice cream samples linked to an outbreak are described for three different initial enrichment formulations used by the Food and Drug Administration (FDA), the International Organization of Standardization (ISO), and the United States Department of Agriculture (USDA). Enrichment cultures were analyzed using DNA extraction and sequencing from samples taken every 4 h throughout 48 h of enrichment. Resphera Insight and CosmosID analysis tools were employed for high-resolution profiling of 16S rRNA amplicons and whole genome shotgun data, respectively. Results: During enrichment, other bacterial taxa were identified, including Anoxybacillus, Geobacillus, Serratia, Pseudomonas, Erwinia, and Streptococcus spp. Surprisingly, incidence of L. monocytogenes was proportionally greater at hour 0 than when tested 4, 8, and 12 h later with all three enrichment schemes. The corresponding increase in Anoxybacillus and Geobacillus spp. indicated these taxa co-enriched in competition with L. monocytogenes during early enrichment hours. L. monocytogenes became dominant after 24 h in all three enrichments. DNA sequences obtained from shotgun metagenomic data of Listeria monocytogenes at 48 h were assembled to produce a consensus draft genome which appeared to have a similar tracking utility to pure culture isolates of L. monocytogenes. Conclusions: All three methods performed equally well for enrichment of Listeria monocytogenes. The observation of potential competitive exclusion of L. mono by Anoxybacillus and Geobacillus in early enrichment hours provided novel information that may be used to further optimize enrichment formulations. Application of Resphera Insight for high-resolution analysis of 16S amplicon sequences accurately identified L. monocytogenes. Both shotgun and 16S rRNA data supported the presence of three slightly variable genomes of L. monocytogenes. Moreover, the draft assembly of a consensus genome of L. monocytogenes from shotgun metagenomic data demonstrated the potential utility of this approach to expedite trace-back of outbreak-associated strains, although further validation will be needed to confirm this utility. C1 [Ottesen, Andrea; Ramachandran, Padmini; Reed, Elizabeth; Ryan, Gina; Allard, Marc; Brown, Eric; Chen, Yi] Ctr Food Safety & Appl Nutr Food & Drug Adm, Off Regulatory Sci, 5001 Campus Dr, College Pk, MD 20740 USA. [White, James R.] Resphera Biosci, 1529 Lancaster St, Baltimore, MD 21231 USA. [Hasan, Nur; Subramanian, Poorani; Colwell, Rita] CosmosID, 155 Gibbs St, Rockville, MD 20850 USA. [Jarvis, Karen; Grim, Christopher; Daquiqan, Ninalynn; Hanes, Darcy] Ctr Food Safety & Appl Nutr Food & Drug Adm, Off Appl Res & Safety Assessment, 8301 Muirkirk Rd, Laurel, MD 20708 USA. RP Ottesen, A (reprint author), Ctr Food Safety & Appl Nutr Food & Drug Adm, Off Regulatory Sci, 5001 Campus Dr, College Pk, MD 20740 USA. EM Andrea.Ottesen@fda.hhs.gov FU Office of Regulatory Science at the Center for Food Safety and Applied Nutrition FX The work was supported by the Office of Regulatory Science at the Center for Food Safety and Applied Nutrition. NR 38 TC 0 Z9 0 U1 12 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD NOV 16 PY 2016 VL 16 AR 275 DI 10.1186/s12866-016-0894-1 PG 11 WC Microbiology SC Microbiology GA ED5RI UT WOS:000388909600001 PM 27852235 ER PT J AU Zhang, ZH Yin, J Yang, J Shen, WZ Zhang, CY Mou, WJ Luo, JH Yan, H Sun, PQ Luo, YP Tian, YP Xiang, R AF Zhang, Zhuhong Yin, Jing Yang, Jian Shen, Wenzhi Zhang, Chunyan Mou, Wenjun Luo, Jinhua Yan, Hua Sun, Peiqing Luo, Yunping Tian, Yaping Xiang, Rong TI miR-885-5p suppresses hepatocellular carcinoma metastasis and inhibits Wnt/beta-catenin signaling pathway SO ONCOTARGET LA English DT Article DE miR-885-5p; Wnt/beta-catenin HCC; migration; invasion ID MICRORNA EXPRESSION; HEPATITIS-B; CANCER; PROLIFERATION; CELLS; BIOMARKERS; INVASION; TUMORIGENICITY; IDENTIFICATION; PATHOGENESIS AB MicroRNAs (miRNAs) inhibit or improve the malignant progression of hepatocellular carcinoma (HCC). We previously reported that compared to health controls, patients with liver cirrhosis present the highest levels of circulating miR-885-5p, followed by those with chronic hepatitis B and those with HCC. However, the molecular involvement of miR-885-5p in HCC metastasis is presently unclear. Here, we demonstrated that the expression of miR-885-5p negatively correlated with the invasive and metastatic capabilities of human HCC tissue samples and cell lines. We found that miR-885-5p expression levels correlated with the survival of patients with HCC. Overexpression of miR-885-5p decreased metastasis of HCC cells in vitro and in vivo. Inhibition of miR-885-5p improved proliferation of non-metastatic HCC cells. Furthermore, we disclosed that miR-885-5p targeted gene encoding beta-catenin CTNNB1, leading to decreased activity of the Wnt/beta-catenin signaling pathway. The present study indicates that miR-885-5p suppresses the metastasis of HCC and inhibits Wnt/beta-catenin signaling pathway by its CTNNB1 target, which suggests that miR-885-5p to be a promising negative regulator of HCC progression and as a novel therapeutic agent to treat HCC. C1 [Zhang, Zhuhong; Yin, Jing; Yang, Jian; Shen, Wenzhi; Zhang, Chunyan; Mou, Wenjun; Luo, Jinhua; Xiang, Rong] Nankai Univ, Sch Med, Dept Immunol, Tianjin 300071, Peoples R China. [Zhang, Chunyan; Mou, Wenjun; Luo, Jinhua; Tian, Yaping] Chinese Peoples Liberat Army Gen Hosp, Dept Clin Biochem, Beijing 100853, Peoples R China. [Zhang, Zhuhong] Tianjin Med Univ Gen Hosp, Dept Ophthalmol, Tianjin 300052, Peoples R China. [Sun, Peiqing] Scripps Res Inst, La Jolla, CA 92037 USA. [Luo, Yunping] Chinese Acad Med Sci, Inst Basic Med Sci, Dept Immunol, Beijing 100005, Peoples R China. [Luo, Yunping] Peking Union Med Coll, Beijing 100005, Peoples R China. [Zhang, Zhuhong] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Xiang, R (reprint author), Nankai Univ, Sch Med, Dept Immunol, Tianjin 300071, Peoples R China.; Tian, YP (reprint author), Chinese Peoples Liberat Army Gen Hosp, Dept Clin Biochem, Beijing 100853, Peoples R China. EM tianyp@301hospital.com.cn; rxing@nankai.edu.cn RI Yang, Jian/E-1051-2015 FU Major State Basic Research Development Program of China [2013CB967200]; National Natural Science Foundation of China [81273331, 81470354, 81071413, 21375133, 81500743]; National High Technology Research and Development Program of China (863 Program) [2011AA 02A 111]; National Basic Research Program (973) of China [2013CB967202] FX This research was supported by the Major State Basic Research Development Program of China (2013CB967200) to RX, the National Natural Science Foundation of China (81273331 and 81470354) to RX, the National Natural Science Foundation of China (81071413 and 21375133) to YT, the National High Technology Research and Development Program of China (863 Program) (2011AA 02A 111) to YT, the National Natural Science Foundation of China (81500743) to ZZ, and the National Basic Research Program (973) of China (2013CB967202) to YL. NR 36 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 NOV 15 PY 2016 VL 7 IS 46 BP 75038 EP 75051 DI 10.18632/oncotarget.12602 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5GF UT WOS:000389632800048 PM 27738331 ER PT J AU Rui, LX Drennan, AC Ceribelli, M Zhu, F Wright, GW Huang, DW Xiao, WM Li, YG Grindle, KM Lu, L Hodson, DJ Shaffer, AL Zhao, H Xu, WH Yang, YD Staudt, LM AF Rui, Lixin Drennan, Amanda C. Ceribelli, Michele Zhu, Fen Wright, George W. Huang, Da Wei Xiao, Wenming Li, Yangguang Grindle, Kreg M. Lu, Li Hodson, Daniel J. Shaffer, Arthur L. Zhao, Hong Xu, Weihong Yang, Yandan Staudt, Louis M. TI Epigenetic gene regulation by Janus kinase 1 in diffuse large B-cell lymphoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE JAK1; epigenetics; histone modification; lymphoma; oncogene ID NF-KAPPA-B; STAT3; CANCER; MECHANISMS; DISEASE; TRANSCRIPTION; DEREGULATION; SIGNATURES; MUTATIONS; CHROMATIN AB Janus kinases (JAKs) classically signal by activating STAT transcription factors but can also regulate gene expression by epigenetically phosphorylating histone H3 on tyrosine 41 (H3Y41-P). In diffuse large B-cell lymphomas (DLBCLs), JAK signaling is a feature of the activated B-cell (ABC) subtype and is triggered by autocrine production of IL-6 and IL-10. Whether this signaling involves STAT activation, epigenetic modification of chromatin, or both mechanisms is unknown. Here we use genetic and pharmacological inhibition to show that JAK1 signaling sustains the survival of ABC DLBCL cells. Whereas STAT3 contributed to the survival of ABC DLBCL cell lines, forced STAT3 activity could not protect these cells from death following JAK1 inhibition, suggesting epigenetic JAK1 action. JAK1 regulated the expression of nearly 3,000 genes in ABC DLBCL cells, and the chromatin surrounding many of these genes was modified by H3Y41-P marks that were diminished by JAK1 inhibition. These JAK1 epigenetic target genes encode important regulators of ABC DLBCL proliferation and survival, including IRF4, MYD88, and MYC. A small molecule JAK1 inhibitor cooperated with the BTK inhibitor ibrutinib in reducing IRF4 levels and acted synergistically to kill ABC DLBCL cells, suggesting that this combination should be evaluated in clinical trials. C1 [Rui, Lixin; Ceribelli, Michele; Huang, Da Wei; Hodson, Daniel J.; Shaffer, Arthur L.; Zhao, Hong; Xu, Weihong; Yang, Yandan; Staudt, Louis M.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rui, Lixin; Drennan, Amanda C.; Zhu, Fen; Li, Yangguang; Grindle, Kreg M.; Lu, Li] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53705 USA. [Rui, Lixin; Drennan, Amanda C.; Zhu, Fen; Li, Yangguang; Grindle, Kreg M.; Lu, Li] Univ Wisconsin, Sch Med & Publ Hlth, Carbone Canc Ctr, Madison, WI 53705 USA. [Wright, George W.] NCI, Biometr Res Branch, DCTD, NIH, Bethesda, MD 20892 USA. [Xiao, Wenming] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Rui, LX; Staudt, LM (reprint author), NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.; Rui, LX (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53705 USA.; Rui, LX (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Carbone Canc Ctr, Madison, WI 53705 USA. EM lrui@medicine.wisc.edu; lstaudt@mail.nih.gov FU Intramural Research Program of the NIH National Cancer Institute; University of Wisconsin-Madison (UW-Madison) start-up funds; KL2 Scholar Awards [UL1TR0000427, KL2TR000428]; National Cancer Institute [1R01 CA187299]; UW-Madison T32 Hematology Training Award [T32 HL07899] FX This research was supported by the Intramural Research Program of the NIH National Cancer Institute, the University of Wisconsin-Madison (UW-Madison) start-up funds, KL2 Scholar Awards UL1TR0000427 and KL2TR000428, the National Cancer Institute Grant 1R01 CA187299 (to L.R.), and the UW-Madison T32 Hematology Training Award T32 HL07899 (to A.C.D.). NR 40 TC 1 Z9 1 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 NOV 15 PY 2016 VL 113 IS 46 BP E7260 EP E7267 DI 10.1073/pnas.1610970113 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED6MQ UT WOS:000388970100016 PM 27799566 ER PT J AU Kluetz, PG Papadopoulos, EJ Johnson, LL Donoghue, M Kwitkowski, VE Chen, WH Sridhara, R Farrell, AT Keegan, P Kim, G Pazdur, R AF Kluetz, Paul G. Papadopoulos, Elektra J. Johnson, Laura Lee Donoghue, Martha Kwitkowski, Virginia E. Chen, Wen-Hung Sridhara, Rajeshwari Farrell, Ann T. Keegan, Patricia Kim, Geoffrey Pazdur, Richard TI Focusing on Core Patient-Reported Outcomes in Cancer Clinical Trials-Response SO CLINICAL CANCER RESEARCH LA English DT Letter C1 [Kluetz, Paul G.; Donoghue, Martha; Kwitkowski, Virginia E.; Farrell, Ann T.; Keegan, Patricia; Kim, Geoffrey; Pazdur, Richard] US FDA, Off Hematol & Oncol Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Papadopoulos, Elektra J.; Chen, Wen-Hung] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Johnson, Laura Lee; Sridhara, Rajeshwari] US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Kluetz, PG (reprint author), US FDA, Off Hematol & Oncol Prod, 10903 New Hampshire Ave,WO22 Room 2223, Silver Spring, MD 20993 USA. EM paul.kluetz@fda.hhs.gov NR 2 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 15 PY 2016 VL 22 IS 22 BP 5618 EP 5618 DI 10.1158/1078-0432.CCR-16-2140 PG 1 WC Oncology SC Oncology GA ED3IU UT WOS:000388743600027 PM 28151715 ER PT J AU Ramu, J Konak, T Liachenko, S AF Ramu, Jaivijay Konak, Tetyana Liachenko, Serguei TI Magnetic resonance spectroscopic analysis of neurometabolite changes in the developing rat brain at 7 T SO BRAIN RESEARCH LA English DT Article DE Magnetic resonance spectroscopy; Developmental neuroscience; Neurometabolite; Rat ID VIVO H-1-NMR SPECTROSCOPY; DEPOLARIZATION-EVOKED GLUTAMATE; IN-VIVO; NEUROCHEMICAL PROFILE; MOUSE-BRAIN; SHORT-ECHO; PROTON MRS; QUANTIFICATION; H-1; TIME AB We utilized proton magnetic resonance spectroscopy to evaluate the metabolic profile of the hippo campus and anterior cingulate cortex of the developing rat brain from postnatal days 14-70. Measured metabolite concentrations were modeled using linear, exponential, or logarithmic functions and the time point at which the data reached plateau (i.e. when the portion of the data could be fit to horizontal line) was estimated and was interpreted as the time when the brain has reached maturity with respect to that metabolite. N-acetyl-aspartate and myo-inositol increased within the observed period. Gluthathione did not vary significantly, while taurine decreased initially and then stabilized. Phosphocreatine and total creatine had a tendency to increase towards the end of the experiment. Some differences between our data and the published literature were observed in the concentrations and dynamics of phosphocreatine, myo-inositol, and GABA in the hippocampus and creatine, GABA, glutamine, choline and N-acetyl-aspartate in the cortex. Such differences may be attributed to experimental conditions, analysis approaches and animal species. The latter is supported by differences between in-house rat colony and rats from Charles River Labs. Spectroscopy provides a valuable tool for non-invasive brain neurochemical profiling for use in developmental neurobiology research. Special attention needs to be paid to important sources of variation like animal strain and commercial source. Published by Elsevier B.V. C1 [Ramu, Jaivijay; Konak, Tetyana; Liachenko, Serguei] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Liachenko, S (reprint author), US FDA, NCTR, HFT-132,3900 NCTR Rd, Jefferson, AR 72079 USA. EM Serguei.liachenko@fda.hhs.gov FU National Center for Toxicological Research (NCTR)/U.S. Food and Drug Administration (FDA) [protocol P0731] FX This work was supported by the National Center for Toxicological Research (NCTR)/U.S. Food and Drug Administration (FDA), protocol P0731. We thank Merle Paule for substantial help in the project execution and preparation of this manuscript and Elena Liachenko for editorial help. NR 48 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD NOV 15 PY 2016 VL 1651 BP 114 EP 120 DI 10.1016/j.brainres.2016.09.028 PG 7 WC Neurosciences SC Neurosciences & Neurology GA EB6WU UT WOS:000387527100013 PM 27663970 ER PT J AU Wang, X Teferedegne, B Shatzkes, K Tu, W Murata, H AF Wang, Xiao Teferedegne, Belete Shatzkes, Kenneth Tu, Wei Murata, Haruhiko TI Endogenous RNase inhibitor contributes to stability of RNA in crude cell lysates: Applicability to RT-qPCR SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Cell lysate; RNA; RNase; RNase inhibitor; Reverse transcription quantitative PCR; Virus ID RIBONUCLEASE INHIBITOR; QUANTITATIVE PCR; ASSAY AB Crude cell lysates are increasingly used as input for direct analysis by reverse transcription quantitative PCR (RT-qPCR), particularly for high-throughput applications. We previously demonstrated that a simple buffer containing a non-ionic detergent can serve as an inexpensive alternative to commercial cell-lysis reagents for the preparation of RT-qPCR-ready cell lysates; addition of an exogenous RNase inhibitor (RI) to the lysis buffer was found to be unnecessary to maintain RNA stability in cell lysates either freshly prepared or previously stored frozen at -80 degrees C. In the present study, we have demonstrated that the stability of RNA observed in our cell lysates is due to the presence of the endogenous RI. Furthermore, we have established the generalizability and applicability of this phenomenon by evaluating lysates prepared from cell lines commonly used in virology (A549, HeLa, MDCK, and Vero). Awareness of the mechanism underlying RNA stability may engender greater confidence in generating cell lysates for RT-qPCR without relying on addition of exogenous RI (a substantial cost-saving benefit) and encourage appropriate practices for handling and storage of samples. Published by Elsevier Inc. This is an open access article under the CC BY license. C1 [Wang, Xiao; Teferedegne, Belete; Shatzkes, Kenneth; Tu, Wei; Murata, Haruhiko] FDA, CBER, OVRR, Lab DNA Viruses,Div Viral Prod, Silver Spring, MD 20993 USA. [Teferedegne, Belete] FDA, CBER, OVRR, Lab Retrovirus Res,Div Viral Prod, Silver Spring, MD 20993 USA. [Shatzkes, Kenneth] Univ Med & Dent New Jersey, Grad Sch Biomed Sci, Newark, NJ 07103 USA. [Shatzkes, Kenneth] Rutgers Sch Dent Med, Newark, NJ 07103 USA. RP Murata, H (reprint author), Food & Drug Adm, 10903 New Hampshire Ave,Bldg 52-72,Room 1312, Silver Spring, MD 20993 USA. EM haruhiko.murata@fda.hhs.gov OI Shatzkes, Kenneth/0000-0002-1603-5326 FU FDA intramural research funds (CBER Targeted Funding for Modernizing Science and FDA Office of Minority Health Challenge Grant) FX We are grateful to Judy Beeler for reagents and Keith Peden, Andrew M. Lewis Jr., and Clement Meseda for comments on the manuscript. This work was supported by FDA intramural research funds (CBER Targeted Funding for Modernizing Science and FDA Office of Minority Health Challenge Grant). NR 17 TC 0 Z9 0 U1 12 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD NOV 15 PY 2016 VL 513 BP 21 EP 27 DI 10.1016/j.ab.2016.08.011 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DX6RJ UT WOS:000384510500003 PM 27544650 ER PT J AU Ceribelli, M Hou, ZE Kelly, PN Huang, DW Wright, G Ganapathi, K Evbuomwan, MO Pittaluga, S Shaffer, AL Marcucci, G Forman, SJ Xiao, WM Guha, R Zhang, XH Ferrer, M Chaperot, L Plumas, J Jaffe, ES Thomas, CJ Reizis, B Staudt, LM AF Ceribelli, Michele Hou, Zhiying Esther Kelly, Priscilla N. Huang, Da Wei Wright, George Ganapathi, Karthik Evbuomwan, Moses O. Pittaluga, Stefania Shaffer, Arthur L. Marcucci, Guido Forman, Stephen J. Xiao, Wenming Guha, Rajarshi Zhang, Xiaohu Ferrer, Marc Chaperot, Laurence Plumas, Joel Jaffe, Elaine S. Thomas, Craig J. Reizis, Boris Staudt, Louis M. TI A Druggable TCF4-and BRD4-Dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm SO CANCER CELL LA English DT Article ID INTERFERON-PRODUCING CELLS; SELECTIVE-INHIBITION; SEQUENCING REVEALS; FACTOR E2-2; SPI-B; LYMPHOMA; EXPRESSION; MUTATIONS; CANCER; RECURRENT AB Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNAi screening, we identified the E-box transcription factor TCF4 as a master regulator of the BPDCN oncogenic program. TCF4 served as a faithful diagnostic marker of BPDCN, and its downregulation caused the loss of the BPDCN-specific gene expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETis) induced BPDCN apoptosis, which was attributable to disruption of a BPDCN-specific transcriptional network controlled by TCF4-dependent super-enhancers. BETis retarded the growth of BPDCN xenografts, supporting their clinical evaluation in this recalcitrant malignancy. C1 [Ceribelli, Michele; Kelly, Priscilla N.; Huang, Da Wei; Shaffer, Arthur L.; Staudt, Louis M.] NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Hou, Zhiying Esther; Reizis, Boris] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA. [Wright, George] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Ganapathi, Karthik; Evbuomwan, Moses O.; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Marcucci, Guido; Forman, Stephen J.] City Hope Natl Med Ctr, Dept Hematol & Hematopoiet Cell Transplant, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Xiao, Wenming] NCTR FDA, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Guha, Rajarshi; Zhang, Xiaohu; Ferrer, Marc; Thomas, Craig J.] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Chaperot, Laurence; Plumas, Joel] EFS Rhone Alpes Grenoble, R&D Lab, F-38701 La Tronche, France. [Chaperot, Laurence; Plumas, Joel] CNRS, INSERM, Inst Adv Biosci UGA, U1209,UMR 5309, F-38000 Grenoble, France. [Reizis, Boris] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Ganapathi, Karthik] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. RP Staudt, LM (reprint author), NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA.; Reizis, B (reprint author), Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA.; Reizis, B (reprint author), NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. EM boris.reizis@nyumc.org; lstaudt@mail.nih.gov OI Reizis, Boris/0000-0003-1140-7853 FU NIH, National Cancer Institute, Center for Cancer Research; National Human Genome Research Institute; Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E, U54CA143930]; Division of Preclinical Innovation, National Center for Advancing Translational Sciences; Molecular Libraries Initiative of the NIH Roadmap for Medical Research; NIH [AI072571]; Feinberg Lymphoma Research Pilot award FX This research was supported by the Intramural Research Programs of the NIH, National Cancer Institute, Center for Cancer Research, and the National Human Genome Research Institute; the Frederick National Laboratory for Cancer Research, NIH including contract HHSN261200800001E and grant #U54CA143930; the Division of Preclinical Innovation, National Center for Advancing Translational Sciences; the Molecular Libraries Initiative of the NIH Roadmap for Medical Research; and by NIH grant AI072571 and the Feinberg Lymphoma Research Pilot award to B.R. We thank Kathleen Meyer for help with the GEO submission. NR 57 TC 4 Z9 4 U1 4 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD NOV 14 PY 2016 VL 30 IS 5 BP 764 EP 778 DI 10.1016/j.ccell.2016.10.002 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EC3ZE UT WOS:000388064800015 PM 27846392 ER PT J AU Viboud, C Epstein, SL AF Viboud, Cecile Epstein, Suzanne L. TI First flu is forever SO SCIENCE LA English DT Editorial Material ID INFLUENZA VACCINES; INFECTION; IMMUNITY; VIRUS C1 [Viboud, Cecile] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Epstein, Suzanne L.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Viboud, C (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM viboudc@mail.nih.gov NR 10 TC 0 Z9 0 U1 14 U2 14 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD NOV 11 PY 2016 VL 354 IS 6313 BP 706 EP 707 DI 10.1126/science.aak9816 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB4FS UT WOS:000387326300018 PM 27846592 ER PT J AU Pettengill, JB Pightling, AW Baugher, JD Rand, H Strain, E AF Pettengill, James B. Pightling, Arthur W. Baugher, Joseph D. Rand, Hugh Strain, Errol TI Real-Time Pathogen Detection in the Era of Whole-Genome Sequencing and Big Data: Comparison of k-mer and Site-Based Methods for Inferring the Genetic Distances among Tens of Thousands of Salmonella Samples SO PLOS ONE LA English DT Article ID SURVEILLANCE AB The adoption of whole-genome sequencing within the public health realm for molecular characterization of bacterial pathogens has been followed by an increased emphasis on real-time detection of emerging outbreaks (e.g., food-borne Salmonellosis). In turn, large databases of whole-genome sequence data are being populated. These databases currently contain tens of thousands of samples and are expected to grow to hundreds of thousands within a few years. For these databases to be of optimal use one must be able to quickly interrogate them to accurately determine the genetic distances among a set of samples. Being able to do so is challenging due to both biological (evolutionary diverse samples) and computational (petabytes of sequence data) issues. We evaluated seven measures of genetic distance, which were estimated from either k-mer profiles (Jaccard, Euclidean, Manhattan, Mash Jaccard, and Mash distances) or nucleotide sites (NUCmer and an extended multi-locus sequence typing (MLST) scheme). When analyzing empirical data (whole-genome sequence data from 18,997 Salmonella isolates) there are features (e.g., genomic, assembly, and contamination) that cause distances inferred from k-mer profiles, which treat absent data as informative, to fail to accurately capture the distance between samples when compared to distances inferred from differences in nucleotide sites. Thus, site-based distances, like NUCmer and extended MLST, are superior in performance, but accessing the computing resources necessary to perform them may be challenging when analyzing large databases. C1 [Pettengill, James B.; Pightling, Arthur W.; Baugher, Joseph D.; Rand, Hugh; Strain, Errol] US FDA, Biostat & Bioinformat Staff, Ctr Food Safety & Appl Nutr, 5001 Campus Dr, College Pk, MD 20740 USA. RP Strain, E (reprint author), US FDA, Biostat & Bioinformat Staff, Ctr Food Safety & Appl Nutr, 5001 Campus Dr, College Pk, MD 20740 USA. EM errol.strain@fda.hhs.gov FU U.S. Department of Energy; FDA Center for Food Safety and Applied Nutrition; FDA FX This project was supported in part by an appointment to the Research Participation Program at the Center for Food Safety and Applied Nutrition, Office of Foods and Veterinary Medicine, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA.; We thank A. Schpuntoff for assistance with conducting the analyses on the high performance computing cluster and FDA Center for Food Safety and Applied Nutrition for supporting this research. NR 23 TC 0 Z9 0 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 NOV 10 PY 2016 VL 11 IS 11 AR e0166162 DI 10.1371/journal.pone.0166162 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB9ON UT WOS:000387725000070 PM 27832109 ER PT J AU Gamerman, V Guerra, M Shults, J AF Gamerman, Victoria Guerra, Matthew Shults, Justine TI Maximum likelihood based analysis of equally spaced longitudinal count data with first-order antedependence and overdispersion SO SPRINGERPLUS LA English DT Article DE Count data; First-order antedependence; Generalized estimating equations; Markov property; Maximum likelihood estimation; Over-dispersion ID QUASI-NEWTON METHODS; REGRESSION; MODEL AB This manuscript implements a maximum likelihood based approach that is appropriate for equally spaced longitudinal count data with over-dispersion, so that the variance of the outcome variable is larger than expected for the assumed Poisson distribution. We implement the proposed method in the analysis of seizure data and a subset of German Socio-Economic Panel data. To demonstrate the importance of correctly modeling the over-dispersion, we make comparisons with the semi-parametric generalized estimating equations approach that incorrectly ignores any over-dispersion in the data. Our simulations demonstrate that accounting for over-dispersion results in improved small-sample efficiency and appropriate coverage probabilities. We also provide code in R so that readers can implement our approach in their own analyses. C1 [Gamerman, Victoria] Boehringer Ingelheim Pharmaceut Inc, 900 Ridgebury Rd, Ridgefield, CT 06877 USA. [Guerra, Matthew] US FDA, Div Biometr 3, OB, OTS,CDER, Silver Spring, MD 20993 USA. [Shults, Justine] Univ Penn, Dept Biostat, 423 Guardian Dr, Philadelphia, PA 19104 USA. RP Shults, J (reprint author), Univ Penn, Dept Biostat, 423 Guardian Dr, Philadelphia, PA 19104 USA. EM jshults@mail.med.upenn.edu NR 26 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2193-1801 J9 SPRINGERPLUS JI SpringerPlus PD NOV 8 PY 2016 VL 5 AR 1935 DI 10.1186/s40064-016-3564-8 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH5MB UT WOS:000391816100008 PM 27933230 ER PT J AU McDowell, TY Blank, M Lawrence, J Stockbridge, N AF McDowell, Tzu-Yun Blank, Melanie Lawrence, John Stockbridge, Norman TI Food and Drug Administration Analysis of Ticagrelor Using Data From an Enriched Trial to Evaluate Benefit-Risk Difference in an Unstudied Population SO CIRCULATION LA English DT Article DE cardiovascular diseases; clinical trial; myocardial infarction; secondary prevention C1 [McDowell, Tzu-Yun; Blank, Melanie; Stockbridge, Norman] US FDA, Ctr Drug Evaluat & Res, Div Cardiovasc & Renal Prod, Off Drug Evaluat 1,Off New Drugs, Silver Spring, MD USA. [Lawrence, John] US FDA, Ctr Drug Evaluat & Res, Off Translat Sci, Div Biometr 1,Off Biostat, Silver Spring, MD USA. RP McDowell, TY (reprint author), US FDA, 10903 New Hampshire Ave,WO 22,Rm 4185, Silver Spring, MD 20993 USA. EM tzu-yun.mcdowell@fda.hhs.gov NR 3 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 NOV 8 PY 2016 VL 134 IS 19 BP 1500 EP 1502 DI 10.1161/CIRCULATIONAHA.116.024691 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EB4OB UT WOS:000387350100015 PM 27821420 ER PT J AU Goldin, LR McMaster, ML Rotunno, M Herman, SEM Jones, K Zhu, B Boland, J Burdett, L Hicks, B Ravichandran, S Luke, BT Yeager, M Fontaine, L Goldstein, AM Chanock, SJ Tucker, MA Wiestner, A Marti, G Caporaso, NE AF Goldin, Lynn R. McMaster, Mary L. Rotunno, Melissa Herman, Sarah E. M. Jones, Kristine Zhu, Bin Boland, Joseph Burdett, Laurie Hicks, Belynda Ravichandran, Sarangan Luke, Brian T. Yeager, Meredith Fontaine, Laura Goldstein, Alisa M. Chanock, Stephen J. Tucker, Margaret A. Wiestner, Adrian Marti, Gerald Caporaso, Neil E. TI Whole exome sequencing in families with CLL detects a variant in Integrin beta 2 associated with disease susceptibility SO BLOOD LA English DT Letter ID CHRONIC LYMPHOCYTIC-LEUKEMIA; LYMPHOPROLIFERATIVE DISORDERS; EXPRESSION; RISK C1 [Goldin, Lynn R.; McMaster, Mary L.; Goldstein, Alisa M.; Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Rotunno, Melissa] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Herman, Sarah E. M.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Jones, Kristine; Zhu, Bin; Boland, Joseph; Burdett, Laurie; Hicks, Belynda; Yeager, Meredith] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Ravichandran, Sarangan; Luke, Brian T.] Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, Frederick, MD USA. [Fontaine, Laura] Westat Corp, Rockville, MD USA. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Tucker, Margaret A.] NCI, Human Genet Program, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Marti, Gerald] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Goldin, LR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 6E432, Bethesda, MD 20892 USA. EM goldinl@mail.nih.gov NR 13 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD NOV 3 PY 2016 VL 128 IS 18 BP 2261 EP 2263 DI 10.1182/blood-2016-02-697771 PG 3 WC Hematology SC Hematology GA EC4LA UT WOS:000388099600011 PM 27629550 ER PT J AU Si, H Lu, H Yang, X Mattox, A Jang, M Bian, Y Sano, E Viadiu, H Yan, B Yau, C Ng, S Lee, SK Romano, RA Davis, S Walker, RL Xiao, W Sun, H Wei, L Sinha, S Benz, CC Stuart, JM Meltzer, PS Van Waes, C Chen, Z AF Si, H. Lu, H. Yang, X. Mattox, A. Jang, M. Bian, Y. Sano, E. Viadiu, H. Yan, B. Yau, C. Ng, S. Lee, S. K. Romano, R-A Davis, S. Walker, R. L. Xiao, W. Sun, H. Wei, L. Sinha, S. Benz, C. C. Stuart, J. M. Meltzer, P. S. Van Waes, C. Chen, Z. TI TNF-alpha modulates genome-wide redistribution of Delta Np63 alpha/TAp73 and NF-kappa B cREL interactive binding on TP53 and AP-1 motifs to promote an oncogenic gene program in squamous cancer SO ONCOGENE LA English DT Article ID CELL CARCINOMA; C-JUN; TRANSCRIPTION FACTORS; TUMOR SUPPRESSION; SIGNAL PATHWAYS; GROWTH-FACTOR; NECK-CANCER; P53 HOMOLOG; HUMAN HEAD; P63 AB The Cancer Genome Atlas (TCGA) network study of 12 cancer types (PanCancer 12) revealed frequent mutation of TP53, and amplification and expression of related TP63 isoform Delta Np63 in squamous cancers. Further, aberrant expression of inflammatory genes and TP53/p63/p73 targets were detected in the PanCancer 12 project, reminiscent of gene programs comodulated by cREL/Delta Np63/TAp73 transcription factors we uncovered in head and neck squamous cell carcinomas (HNSCCs). However, how inflammatory gene signatures and cREL/p63/p73 targets are comodulated genome wide is unclear. Here, we examined how the inflammatory factor tumor necrosis factor-alpha (TNF-alpha) broadly modulates redistribution of cREL with Delta Np63 alpha/TAp73 complexes and signatures genome wide in the HNSCC model UM-SCC46 using chromatin immunoprecipitation sequencing (ChIP-seq). TNF-alpha enhanced genome-wide co-occupancy of cREL with Delta Np63 alpha on TP53/p63 sites, while unexpectedly promoting redistribution of TAp73 from TP53 to activator protein-1 (AP-1) sites. cREL, Delta Np63 alpha and TAp73 binding and oligomerization on NF-kappa B-, TP53- or AP-1-specific sequences were independently validated by ChIP-qPCR (quantitative PCR), oligonucleotide-binding assays and analytical ultracentrifugation. Function of the binding activity was confirmed using TP53-, AP-1- and NF-kappa B-specific REs or p21, SERPINE1 and IL-6 promoter luciferase reporter activities. Concurrently, TNF-alpha regulated a broad gene network with cobinding activities for cREL, Delta Np63 alpha and TAp73 observed upon array profiling and reverse transcription-PCR. Overlapping target gene signatures were observed in squamous cancer subsets and in inflamed skin of transgenic mice overexpressing Delta Np63 alpha. Furthermore, multiple target genes identified in this study were linked to TP63 and TP73 activity and increased gene expression in large squamous cancer samples from PanCancer 12 TCGA by CircleMap. PARADIGM inferred pathway analysis revealed the network connection of TP63 and NF-kappa B complexes through an AP-1 hub, further supporting our findings. Thus, inflammatory cytokine TNF-a mediates genome-wide redistribution of the cREL/p63/p73, and AP-1 interactome, to diminish TAp73 tumor suppressor function and reciprocally activate NF-kappa B and AP-1 gene programs implicated in malignancy. C1 [Si, H.; Lu, H.; Yang, X.; Mattox, A.; Jang, M.; Bian, Y.; Lee, S. K.; Van Waes, C.; Chen, Z.] NIDCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD USA. [Lu, H.] Zhujiang Hosp Guangzhou, Orthopaed Ctr, Guangzhou, Guangdong, Peoples R China. [Sano, E.] Univ Calif San Diego, Dept Chem & Biochem, San Diego, CA 92103 USA. [Viadiu, H.] Univ Nacl Autonoma Mexico, Inst Quim, Ciudad Univ, Mexico City, DF, Mexico. [Yan, B.] Univ Hong Kong, LKS Fac Med, Hong Kong, Hong Kong, Peoples R China. [Yan, B.] Univ Hong Kong, LKS Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Yan, B.] Univ Hong Kong, Ctr Genome Sci, Hong Kong, Hong Kong, Peoples R China. [Yau, C.; Benz, C. C.] Buck Inst Res Aging, Novato, CA USA. [Ng, S.; Stuart, J. M.] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Romano, R-A; Sinha, S.] SUNY Buffalo, Ctr Excellence Bioinformat & Life Sci, Dept Biochem, Buffalo, NY USA. [Davis, S.; Walker, R. L.] NCI, Canc Genet Branch, Bethesda, MD 20892 USA. [Xiao, W.] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AK USA. [Sun, H.] NIAMSD, Biodata Min & Discovery Sect, Bethesda, MD 20892 USA. [Wei, L.] NEI, Clin Immunol Sect, NIH, Bethesda, MD 20892 USA. [Wei, L.] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou, Guangdong, Peoples R China. RP Van Waes, C (reprint author), NIDCD, NIH, Bldg 10-CRC,4-2732,10 Ctr Dr, Bethesda, MD 20892 USA.; Chen, Z (reprint author), NIDCD, Clin Genom Unit, Head & Neck Surg Branch, NIH, Bldg 10-5D55,10 Ctr Dr, Bethesda, MD 20892 USA. EM vanwaesc@nidcd.nih.gov; chenz@nidcd.nih.gov FU NIH [R01AR049238]; NCI [R01-CA180778, U24-CA143858]; Stand Up to Cancer; Prostate Cancer Foundation; Movember Foundation; [ZIA-DC-000073]; [ZIA-DC-000074] FX We thank Dr Fan Yang (NCI/NIH), Dr Kairong Cui (NHLBI/NIH), Dr Bingmei Zhu (NIDDK/NIH), Jeffery Burnett (NIDCD/NIH), Jamie Coupar (NIDCD/NIH), Guanmei Liang (Thomas Jefferson High School for Science and Technology, Alexandria, VA, USA) and Eric Nicolson (Ithaca High School, Ithaca, New York, NY, USA) for their technical assistance and suggestions. The authors express appreciation to Drs James W Rocco and Leif W Ellisen (Harvard University) for providing Delta Np63 and TAp63 expression vectors, Dr Thomas Gilmore (Boston University) for cRel expression plasmids, Professor Gerry Melino (University of Leicester) for TAp73 alpha expression plasmids, Dr J Silvio Gutkind (NIDCR/NIH) for IL-6 promoter reporter plasmids, Dr Gourisankar Ghosh (UCSD) for the cRel expression plasmid, and Drs Michal Karin (University of California, San Diego), Cheng-Ming Chiang (University of Texas, Southwestern) and Xuan Liu (University of California, Riverside) for critique of and helpful suggestions for the manuscript. HL, HS, XY, AM, MJ, YB, CVW and ZC are supported by intramural projects ZIA-DC-000073, ZIA-DC-000074 and RAR and SS are supported by a grant from NIH (R01AR049238). JMS acknowledges support from NCI (R01-CA180778 and U24-CA143858), Stand Up to Cancer, Prostate Cancer Foundation and the Movember Foundation. NR 55 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 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD NOV 3 PY 2016 VL 35 IS 44 BP 5781 EP 5794 DI 10.1038/onc.2016.112 PG 14 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA EA9XQ UT WOS:000386998400009 PM 27132513 ER PT J AU Perez-Rodriguez, FJ D'Andrea, L de Castellarnau, M Costafreda, MI Guix, S Ribes, E Quer, J Gregori, J Bosch, A Pinto, RM AF Perez-Rodriguez, Francisco J. D'Andrea, Lucia de Castellarnau, Montserrat Isabel Costafreda, Maria Guix, Susana Ribes, Enric Quer, Josep Gregori, Josep Bosch, Albert Pinto, Rosa M. TI Improving virus production through quasispecies genomic selection and molecular breeding SO SCIENTIFIC REPORTS LA English DT Article ID HEPATITIS-A VIRUS; 5 NONTRANSLATED REGION; NONOPTIMAL CODON USAGE; VESICULAR STOMATITIS-VIRUS; INTERNAL INITIATION; ESCHERICHIA-COLI; MUTANT SPECTRUM; RNA VIRUS; TRANSLATION; POPULATIONS AB Virus production still is a challenging issue in antigen manufacture, particularly with slow-growing viruses. Deep-sequencing of genomic regions indicative of efficient replication may be used to identify high-fitness minority individuals suppressed by the ensemble of mutants in a virus quasispecies. Molecular breeding of quasispecies containing colonizer individuals, under regimes allowing more than one replicative cycle, is a strategy to select the fittest competitors among the colonizers. A slow-growing cell culture-adapted hepatitis A virus strain was employed as a model for this strategy. Using genomic selection in two regions predictive of efficient translation, the internal ribosome entry site and the VP1-coding region, high-fitness minority colonizer individuals were identified in a population adapted to conditions of artificially-induced cellular transcription shut-off. Molecular breeding of this population with a second one, also adapted to transcription shut-off and showing an overall colonizer phenotype, allowed the selection of a fast-growing population of great biotechnological potential. C1 [Perez-Rodriguez, Francisco J.; D'Andrea, Lucia; de Castellarnau, Montserrat; Isabel Costafreda, Maria; Guix, Susana; Bosch, Albert; Pinto, Rosa M.] Univ Barcelona, Sch Biol, Dept Genet Microbiol & Stat, Enter Virus Lab, Barcelona, Spain. [Perez-Rodriguez, Francisco J.; D'Andrea, Lucia; de Castellarnau, Montserrat; Isabel Costafreda, Maria; Guix, Susana; Bosch, Albert; Pinto, Rosa M.] Univ Barcelona, Inst Nutr & Food Safety, Enter Virus Lab, Campus Torribera, Santa Coloma De Gramenet, Spain. [Ribes, Enric] Univ Barcelona, Sch Biol, Dept Cell Biol Physiol & Immunol, Enter Virus Lab, Barcelona, Spain. [Quer, Josep; Gregori, Josep] Hosp Univ Vall dHebron, Vall dHebron Inst Recerca, Internal Med Lab Malalties Hepat, Liver Unit, Barcelona, Spain. [Quer, Josep; Gregori, Josep] Inst Salud Carlos III, CIBERehd, Madrid, Spain. [Gregori, Josep] Roche Diagnost SL, Barcelona, Spain. [Isabel Costafreda, Maria] US FDA, Silver Spring, MD USA. RP Pinto, RM (reprint author), Univ Barcelona, Sch Biol, Dept Genet Microbiol & Stat, Enter Virus Lab, Barcelona, Spain.; Pinto, RM (reprint author), Univ Barcelona, Inst Nutr & Food Safety, Enter Virus Lab, Campus Torribera, Santa Coloma De Gramenet, Spain. EM rpinto@ub.edu RI Costafreda, Maria/Q-6953-2016; Guix, Susana/D-4318-2014 OI Costafreda, Maria/0000-0002-3114-3034; Guix, Susana/0000-0002-1588-3198 FU Spanish Ministry of Economy [BIO2011-23461, BIO2014-53285-R]; Generalitat de Catalunya Biotechnology Reference Network (XRB); Spanish Ministry of Science and Innovation; Spanish Ministry of Economy; Spanish Ministry of External Affairs and Cooperation FX This work was supported by Spanish Ministry of Economy projects BIO2011-23461 and BIO2014-53285-R and Generalitat de Catalunya Biotechnology Reference Network (XRB). F.J.P. and M.dC. were recipients of fellowships from the Spanish Ministry of Science and Innovation and Ministry of Economy, respectively. L.dA. was recipient of a fellowship from the Spanish Ministry of External Affairs and Cooperation. NR 50 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 NOV 3 PY 2016 VL 6 AR 35962 DI 10.1038/srep35962 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA7TP UT WOS:000386835500001 PM 27808108 ER EF