FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Katz, LM Valenzuela, C Sadrieh, NK AF Katz, Linda M. Valenzuela, Claudia Sadrieh, Nakissa K. TI Reporting Cosmetic Adverse Events to the US Food and Drug Administration SO DERMATITIS LA English DT Letter C1 [Katz, Linda M.; Valenzuela, Claudia; Sadrieh, Nakissa K.] US FDA, College Pk, MD 20740 USA. RP Katz, LM (reprint author), US FDA, College Pk, MD 20740 USA. EM linda.katz@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1710-3568 EI 2162-5220 J9 DERMATITIS JI Dermatitis PD JUL-AUG PY 2016 VL 27 IS 4 BP 236 EP 237 DI 10.1097/DER.0000000000000195 PG 4 WC Dermatology SC Dermatology GA DR9NY UT WOS:000380224600017 PM 27323232 ER PT J AU Tepper, JS Kuehl, PJ Cracknell, S Nikula, KJ Pei, LQ Blanchard, JD AF Tepper, Jeffrey S. Kuehl, Philip J. Cracknell, Stuart Nikula, Kristen J. Pei, Luqi Blanchard, James D. TI Symposium Summary: "Breathe In, Breathe Out, Its Easy: What You Need to Know About Developing Inhaled Drugs" SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the American-College-of-Toxicology (ACT) / Symposium on Breathe In, Breathe Out, its Easy - What You Need to Know About Developing Inhaled Drugs CY NOV 09-12, 2014 CL Orlando, FL SP Amer Coll Toxicol DE orally inhaled products; respiratory product development; lung pathology; pulmonary function; inhalation toxicology; deposition; dosimetry; safety margins; lung imaging; pharmacokinetics; allometry; safety evaluation ID RESPIRATORY DEPOSITION; INHALATION TOXICOLOGY; INCIDENTAL FINDINGS; AEROSOLS; HISTOPATHOLOGY; TOXICITY; RODENTS; LESIONS; LARYNX; TRACT AB Developing inhaled drugs requires knowledge of lung anatomy, cell biology, respiratory physiology, particle physics, and some plumbing. Although dose makes the poison, in the context of an inhaled drug, the dose is not easily defined. This lack of clarity around dose poses issues and challenges in the design of inhalation toxicology programs. To better understand dose, the influence of ventilation is discussed as are the perturbations in pulmonary function observed with inhalation exposure that can affect dose. Methods for determining inhaled drug deposition to arrive at an estimate of lung dose are examined. Equally important to understanding dose are the techniques used to deliver aerosols to animals. With a better understanding of dose and inhalation exposure, species-specific histopathologic lesions, both common background and toxicologically significant lesions, are reviewed. Finally, insight into how regulators synthesize and evaluate these complex findings to assess clinical safety risks is presented. C1 [Tepper, Jeffrey S.] Tepper Nonclin Consulting, 197 Glasgow Lane, San Carlos, CA 94070 USA. [Kuehl, Philip J.] Lovelace Resp Res Inst, Albuquerque, NM USA. [Cracknell, Stuart] Aerosol Technol, Huntingdon Life Sci, Somerset, NJ USA. [Nikula, Kristen J.] Seventh Wave Labs LLC, Maryland Hts, MO USA. [Pei, Luqi] US FDA, Silver Spring, MD USA. [Blanchard, James D.] Aradigm Corp, Preclin Dev, Hayward, CA USA. RP Tepper, JS (reprint author), Tepper Nonclin Consulting, 197 Glasgow Lane, San Carlos, CA 94070 USA. EM teppertox@gmail.com NR 28 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD JUL-AUG PY 2016 VL 35 IS 4 BP 376 EP 392 DI 10.1177/1091581815624080 PG 17 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DR8AU UT WOS:000380121600002 PM 26857693 ER PT J AU Allamneni, KP Parker, S O'Neill, CA Wright, TL King, S Andrews, L AF Allamneni, Krishna P. Parker, Suezanne O'Neill, Charles A. Wright, Teresa L. King, Sruthi Andrews, Laura TI Workshop Proceedings: Streamlined Development of Safety Assessment Programs Supporting Orphan/Rare Diseases-Are We There Yet? SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Article; Proceedings Paper CT Workshop on Streamlined Development of Safety Assessment Programs Supporting Orphan/Rare Diseases - Are We There Yet held at the 36th Annual Meeting of the American-College-of-Toxicology (ACT) CY NOV 08-11, 2015 CL Summerlin, NV SP Amer Coll Toxicol, Shire, Ultragenyx DE orphan indication; rare disease; safety assessment; enzyme replacement therapy ID METACHROMATIC LEUKODYSTROPHY; MUCOPOLYSACCHARIDOSIS-VI; CYNOMOLGUS MONKEYS; DRUG DEVELOPMENT; IDURSULFASE-IT; RARE DISEASES; MUTATIONS; FREQUENCY; GLYCOSAMINOGLYCANS; ARYLSULFATASE AB A workshop entitled Streamlined Development of Safety Assessment Programs Supporting Orphan/Rare DiseasesAre We There Yet? was held at the 36th Annual Meeting of the American College of Toxicology in Summerlin, Nevada. The workshop was sponsored by Shire and Ultragenyx and was designed to present the nonclinical considerations for the development of various products for rare diseases. A panel of experts from industry and government highlighted the nonclinical considerations in developing toxicology programs supporting rare disease therapeutics, challenges in preclinical safety assessment, reviewed the current guidance, and presented the progress that has been made to date. The main learning from the workshop was that nonclinical testing of therapeutics targeting rare disease warrants special considerations, and early collaboration between sponsors and health authorities may help optimize the scope and timing of the supportive studies. Specific examples for nonclinical development programs for enzyme replacement therapy (ERT) were presented. Although the symposium focused on ERTs, the concepts are broadly applicable. C1 [Allamneni, Krishna P.] Jazz Pharmaceut Inc, Palo Alto, CA 94304 USA. [Parker, Suezanne] Shire, Lexington, MA USA. [O'Neill, Charles A.] BioMarin Pharmaceut Inc, Novato, CA USA. [Wright, Teresa L.] Dimens Therapeut Inc, Cambridge, MA USA. [King, Sruthi] US FDA, Silver Spring, MD USA. [Andrews, Laura] AbbVie Inc Res & Dev Ctr, Worcester, MA USA. RP Allamneni, KP (reprint author), Jazz Pharmaceut Inc, Palo Alto, CA 94304 USA. EM krishna.allamneni@jazzpharma.com NR 77 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 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD JUL-AUG PY 2016 VL 35 IS 4 BP 393 EP 409 DI 10.1177/1091581816644709 PG 17 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DR8AU UT WOS:000380121600003 PM 27272885 ER PT J AU Sharma, AK Morrison, JP Rao, DB Pardo, ID Garman, RH Bolon, B AF Sharma, Alok K. Morrison, James P. Rao, Deepa B. Pardo, Ingrid D. Garman, Robert H. Bolon, Brad TI Toxicologic Pathology Analysis for Translational Neuroscience: Improving Human Risk Assessment Using Optimized Animal Data SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Article DE interspecies extrapolation; nervous system; neuroanatomy; neuropathology; neurotoxicity; neuroscience; translational medicine ID NONCLINICAL GENERAL TOXICITY; MAGNETIC-RESONANCE HISTOLOGY; HUMAN CEREBRAL-CORTEX; DEVELOPMENTAL NEUROTOXICITY; NERVOUS-SYSTEM; RAT-BRAIN; NEUROPATHOLOGY ASSESSMENT; SPECIES-DIFFERENCES; ALZHEIMERS-DISEASE; CORPUS-CALLOSUM AB A half-day American College of Toxicology continuing education course presented key issues often confronted by translational neuroscientists when predicting human risk from animal-derived toxicologic pathology data. Two talks correlated discrete structures with major functions in brains of rodents and nonrodents. The third lecture provided practical advice to obtain highly homologous rodent brain sections for quantitative morphometry in developmental neurotoxicity testing. The last presentation discussed demographic influences (eg, species, strain, sex, age), physiological attributes (eg, body composition, brain vascularity, pharmacokinetic/pharmacodynamic patterns, etc), and husbandry parameters (eg, group housing) recognized to impact the actions of neuroactive chemicals. Speakers described common cases of real-world challenges to animal data interpretation encountered when designing studies or extrapolating biological responses across species. The efficiency of translational neuroscience efforts will likely be enhanced as new methods (eg, high-resolution non-invasive imaging) improve our capability to cross-connect subtle anatomic and/or biochemical lesions with functional changes over time. C1 [Sharma, Alok K.] Covance Inc, Madison, WI USA. [Morrison, James P.] Pathol Associates Inc, Charles River Labs, Durham, NC USA. [Rao, Deepa B.] US FDA, CDER, Silver Spring, MD USA. [Pardo, Ingrid D.] Pfizer Inc, Groton, CT 06340 USA. [Garman, Robert H.] Consultants Vet Pathol Inc, Murrysville, PA USA. [Bolon, Brad] GEMpath Inc, 1100 East 17th Ave,Unit M202, Longmont, CO 80504 USA. RP Bolon, B (reprint author), GEMpath Inc, 1100 East 17th Ave,Unit M202, Longmont, CO 80504 USA. EM bradgempath@aol.com NR 77 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 1091-5818 EI 1092-874X J9 INT J TOXICOL JI Int. J. Toxicol. PD JUL-AUG PY 2016 VL 35 IS 4 BP 410 EP 419 DI 10.1177/1091581816636372 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DR8AU UT WOS:000380121600004 PM 27012643 ER PT J AU Zhang, X Newport, GD Callicott, R Liu, S Thompson, J Berridge, MS Apana, SM Slikker, W Wang, C Paule, MG AF Zhang, X. Newport, G. D. Callicott, R. Liu, S. Thompson, J. Berridge, M. S. Apana, S. M. Slikker, W., Jr. Wang, C. Paule, M. G. TI MicroPET/CT assessment of FDG uptake in brain after long-term methylphenidate treatment in nonhuman primates SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE FDG; Methylphenidate; Nonhuman primates; MicroPET/CT; ADHD; In vivo ID ATTENTION-DEFICIT/HYPERACTIVITY-DISORDER; DEFICIT HYPERACTIVITY DISORDER; VENTRAL TEGMENTAL AREA; ADULT RATS; DOPAMINE TRANSPORTERS; CEREBELLAR NUCLEI; MACACA-MULATTA; BASAL GANGLIA; UNITED-STATES; ADHD AB Methylphenidate (MPH) is a psychostimulant commonly used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Since the long-term effects of this drug on the central nervous system (CNS) are not well understood, we conducted microPET/CT scans on young adult male rhesus monkeys (n = 4/group) to gather information on brain metabolism using the uptake of [F-18]Fluoro-2-deoxy-2-c-glucose (FDG) as a marker. Approximately two-year old, male rhesus monkeys were treated orally with MPH twice per day, five days per week (M F) over a 6-year period. SubjeCts received MPH at either 2.5 or 12.5 mg/kg/dose or vehicle (Prang). To minimize the acute effects of MPH on FDG uptake, microPET/CT scans were scheduled on Mondays before their first daily dosing of the week (approximately 68 h since their last treatment). FDG (370 8.88 MBq) was injected intravenously and 30 min later microPET/CT images were obtained over 60 min. Radiolabeled tracer accumulation in regions of interest (ROIs) in the prefrontal cortex, temporal cortex, striatum and cerebellum were converted into Standard Uptake Values (SUVs). Compared to the control group, the uptake of FDG in the cerebellum was significantly decreased in both the low and high dose groups. These preliminary data demonstrate that microPET imaging is capable of distinguishing differences in retention of FDG in the brains of NHP5 treated chronically with MPH and suggests that this approach may provide a minimally invasive biomarker for exploring the effects of chronic MPH treatment on aspects of brain function. Published by Elsevier Inc. C1 [Zhang, X.; Newport, G. D.; Liu, S.; Thompson, J.; Slikker, W., Jr.; Wang, C.; Paule, M. G.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Callicott, R.] UT Southwestern Med Ctr, Anim Resource Ctr, Dallas, TX USA. [Berridge, M. S.; Apana, S. M.] 3D Imaging LLC, Little Rock, AR 72113 USA. [Berridge, M. S.; Apana, S. M.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. RP Paule, MG (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. FU National Center for Toxicological Research (NCTR)/U.S. Food and Drug Administration (FDA) [NCTR E7234, E7424] FX This work was supported by the National Center for Toxicological Research (NCTR)/U.S. Food and Drug Administration (FDA) (NCTR E7234 and E7424). The authors are grateful for the technical expertise provided by the animal care staff of the Priority One Corporation. NR 65 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 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD JUL-AUG PY 2016 VL 56 SI SI BP 68 EP 74 DI 10.1016/j.ntt.2016.06.005 PG 7 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA DS2QF UT WOS:000380627900009 PM 27307090 ER PT J AU Kuehnert, MJ Epstein, JS AF Kuehnert, Matthew J. Epstein, Jay S. TI Assuring blood safety and availability: Zika virus, the latest emerging infectious disease battlefront SO TRANSFUSION LA English DT Editorial Material C1 [Kuehnert, Matthew J.] Ctr Dis Control & Prevent, Off Blood Organ & Other Tissue Safety, Div Healthcare Qual Promot, Natl Ctr Zoonot & Infect Dis, Atlanta, GA 30333 USA. [Epstein, Jay S.] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Kuehnert, MJ (reprint author), Ctr Dis Control & Prevent, Off Blood Organ & Other Tissue Safety, Div Healthcare Qual Promot, Natl Ctr Zoonot & Infect Dis, Atlanta, GA 30333 USA. EM mkuehnert@cdc.gov NR 0 TC 1 Z9 1 U1 49 U2 50 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUL PY 2016 VL 56 IS 7 BP 1669 EP 1672 DI 10.1111/trf.13673 PG 4 WC Hematology SC Hematology GA DS1NG UT WOS:000380362100001 PM 27389990 ER PT J AU Avonto, C Chittiboyina, AG Wang, M Vasquez, Y Rua, D Khan, IA AF Avonto, Cristina Chittiboyina, Amar G. Wang, Mei Vasquez, Yelkaira Rua, Diego Khan, Ikhlas A. TI In Chemico Evaluation of Tea Tree Essential Oils as Skin Sensitizers: Impact of the Chemical Composition on Aging and Generation of Reactive Species SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID LIMONENE HYDROPEROXIDE ANALOGS; ALLERGIC CONTACT-DERMATITIS; MELALEUCA-ALTERNIFOLIA; ALLYLIC HYDROPEROXIDES; ANTIMICROBIAL ACTIVITY; MASS-SPECTROMETRY; COMPONENTS; VITRO; CAPACITY AB Tea tree oil (TTO) is an essential oil obtained from the leaves of Melaleuca alternifolia, M. linariifolia, or M. dissitiflora. Because of the commercial importance of TTO, substitution or adulteration with other tea tree species (such as cajeput, niaouli, manuka, or kanuka oils) is common and may pose significant risks along with perceived health benefits. The distinctive nature, qualitative and quantitative compositional variation of these oils, is responsible for the various pharmacological as well as adverse effects. Authentic TTOs (especially aged ones) have been identified as potential skin sensitizers, while reports of adverse allergic reactions to the other tea trees essential oils are less frequent. Chemical sensitizers are usually electrophilic compounds, and in chemico methods have been developed to identify skin allergens in terms of their ability to bind to biological nucleophiles. However, little information is available on the assessment of sensitization potential of mixtures, such as essential oils, due to their complexity. In the present study, 10 "tea tree" oils and six major TTO constituents have been investigated for their sensitization potential using a fluorescence in chemico method. The reactivity of authentic TTOs was found to correlate with the age of the oils, while the majority of nonauthentic TTOs were less reactive, even after aging. Further thin-trapping experiments with DCYA and characterization by UHPLC-DAD-MS led to the identification of several possible DCYA-adducts which can be used to deduce the structure of the candidate reactive species. The major TTO components, terpinolene, alpha-terpinene, and terpinene-4-ol, were unstable under accelerated aging conditions, which led to the formation of several DCYA-adducts. C1 [Avonto, Cristina; Chittiboyina, Amar G.; Wang, Mei; Vasquez, Yelkaira; Khan, Ikhlas A.] Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA. [Khan, Ikhlas A.] Univ Mississippi, Sch Pharm, Dept Biomol Sci, Div Pharmacognosy, University, MS 38677 USA. [Rua, Diego] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. RP Khan, IA (reprint author), Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA.; Khan, IA (reprint author), Univ Mississippi, Sch Pharm, Dept Biomol Sci, Div Pharmacognosy, University, MS 38677 USA. EM ikhan@olemiss.edu FU "Science Based Authentication of Dietary Supplements" - Food and Drug Administration [1U01FD004246-04]; United States Department of Agriculture, Agricultural Research Service [58-6408-1-603-06] FX This research is supported in part by "Science Based Authentication of Dietary Supplements" funded by the Food and Drug Administration, grant number 1U01FD004246-04, the United States Department of Agriculture, Agricultural Research Service, Specific Cooperative Agreement No. 58-6408-1-603-06. NR 38 TC 1 Z9 1 U1 7 U2 9 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 JUL PY 2016 VL 29 IS 7 BP 1108 EP 1117 DI 10.1021/acs.chemrestox.5b00530 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA DR8XQ UT WOS:000380182100004 PM 27286037 ER PT J AU Arya, V Kiser, JJ AF Arya, Vikram Kiser, Jennifer J. TI Role of Transporters in Drug Development SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Editorial Material ID MEMBRANE TRANSPORTERS; HEPATIC TRANSPORTERS; PHARMACOKINETICS; POLYMORPHISMS; INFLAMMATION; VARIABILITY; PREDICTION; CLEARANCE; TOXICITY C1 [Arya, Vikram] US FDA, Div Clin Pharmacol 4, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Kiser, Jennifer J.] Skaggs Sch Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Aurora, CO USA. RP Kiser, JJ (reprint author), Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO 80045 USA. EM jennifer.kiser@ucdenver.edu NR 45 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JUL PY 2016 VL 56 SU 7 SI SI BP S7 EP S10 DI 10.1002/jcph.784 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DR6ZW UT WOS:000380050800001 PM 27385180 ER PT J AU Fan, Y Sun, B Agarwal, S Zhang, L AF Fan, Ying Sun, Bo Agarwal, Sheetal Zhang, Lei TI Review of Transporter-Related Postmarketing Requirement or Postmarketing Commitment Studies SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE transporters; new molecular entity (NME); postmarketing requirement (PMR); postmarketing commitment (PMC); drug-drug interaction (DDI); regulatory; labeling ID DRUG-INTERACTION; POLYMORPHISMS; CONSORTIUM AB The objectives of this report are to summarize the content and status of transporter-related postmarketing requirement (PMR)/postmarketing commitment (PMC) studies in new drug applications (NDAs) approved by the U.S. Food and Drug Administration (FDA) and to discuss the reasons for requesting such studies and the impact of PMR/PMC study results on labeling to guide the optimal use of the drugs. Multiple data sources were searched to collect information on transporter-related PMR/PMC studies between January 1999 and May 2015. A total of 40 transporter-related PMR/PMC study requests were issued for 35 NDAs. Among these PMR/PMC studies, 27 requested studies related to P-glycoprotein. As of May 31, 2015, 34 transporter-related PMR/PMC studies (85%) are considered "fulfilled" (per the FDA's PMR/PMC website), and 22 (65%) resulted in labeling updates. The majority of the PMR/PMC studies are for drugs in the therapeutic areas of anti-infectives, oncology, and neurology. The results from PMR/PMC studies are important for dosing optimization and are often included in the updated labeling. Because a significant lag time is anticipated between drug approval and PMR/PMC fulfillment, NDA applicants are encouraged to include transporter-related assessments in clinical drug development programs for drug products. C1 [Fan, Ying; Sun, Bo; Agarwal, Sheetal; Zhang, Lei] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Fan, Ying] US FDA, Off Bioequivalence, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Sun, Bo] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. [Sun, Bo] Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Pharm, Shanghai, Peoples R China. RP Zhang, L (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM leik.zhang@fda.hhs.gov FU National Key Clinical Specialty Construction Project of China FX Dr. Bo Sun was supported in part by an appointment to the research participation program at the CDER administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Dept. of Energy and the U.S. FDA. She was also supported by the National Key Clinical Specialty Construction Project of China. NR 30 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JUL PY 2016 VL 56 SU 7 SI SI BP S193 EP S204 DI 10.1002/jcph.770 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DR6ZW UT WOS:000380050800015 PM 27385175 ER PT J AU Pan, YZ Hsu, V Grimstein, M Zhang, L Arya, V Sinha, V Grillo, JA Zhao, P AF Pan, Yuzhuo Hsu, Vicky Grimstein, Manuela Zhang, Lei Arya, Vikram Sinha, Vikram Grillo, Joseph A. Zhao, Ping TI The Application of Physiologically Based Pharmacokinetic Modeling to Predict the Role of Drug Transporters: Scientific and Regulatory Perspectives SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE transporter; drug-drug interaction; physiologically based pharmacokinetic models; predictive performance ID IN-VIVO EXTRAPOLATION; GASTROINTESTINAL TRANSIT; MEMBRANE TRANSPORTERS; EFFLUX TRANSPORTERS; ABSORPTION PROCESS; RENAL IMPAIRMENT; PART II; P-GP; INHIBITOR; SUBSTRATE AB Transporters play an important role in drug absorption, disposition, and drug action. The evaluation of drug transporters requires a comprehensive understanding of transporter biology and pharmacology. Physiologically based pharmacokinetic (PBPK) models may offer an integrative platform to quantitatively evaluate the role of drug transporters and its interplay with other drug disposition processes such as passive drug diffusion and elimination by metabolizing enzymes. To date, PBPK modeling and simulations integrating drug transporters lag behind that for drug-metabolizing enzymes. In addition, predictive performance of PBPK has not been well established for predicting the role of drug transporters in the pharmacokinetics of a drug. To enhance overall predictive performance of transporter-based PBPK models, it is necessary to have a detailed understanding of transporter biology for proper representation in the models and to have a quantitative understanding of the contribution of transporters in the absorption and metabolism of a drug. This article summarizes PBPK-based submissions evaluating the role of drug transporters to the Office of Clinical Pharmacology of the US Food and Drug Administration. C1 [Pan, Yuzhuo; Hsu, Vicky; Grimstein, Manuela; Zhang, Lei; Arya, Vikram; Sinha, Vikram; Grillo, Joseph A.; Zhao, Ping] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Pan, Yuzhuo] US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Zhao, P (reprint author), WO Bldg 51 Room 3182,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM ping.zhao@fda.hhs.gov NR 51 TC 2 Z9 2 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 JUL PY 2016 VL 56 SU 7 SI SI BP S122 EP S131 DI 10.1002/jcph.740 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DR6ZW UT WOS:000380050800010 PM 27385170 ER PT J AU Vaidyanathan, J Yoshida, K Arya, V Zhang, L AF Vaidyanathan, Jayabharathi Yoshida, Kenta Arya, Vikram Zhang, Lei TI Comparing Various In Vitro Prediction Criteria to Assess the Potential of a New Molecular Entity to Inhibit Organic Anion Transporting Polypeptide 1B1 SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE Transporters; Drug-Drug Interactions; Pharmacokinetics and drug metabolism; Clinical Pharmacology (CPH); Organic Anion Transporting Polypeptide (OATP); Inhibition ID DRUG-DRUG INTERACTIONS; HEPATIC-UPTAKE; CYCLOSPORINE-A; PHARMACOKINETICS; ATORVASTATIN; METABOLISM; HUMANS; CERIVASTATIN; ROSUVASTATIN; ITRACONAZOLE AB Evaluation of organic anion transporting polypeptide (OATP) 1B1-mediated drug-drug interactions (DDIs) is an integral part of drug development and is recommended by regulatory agencies. In this study we compared various prediction methods and cutoff criteria based on in vitro inhibition data to assess the potential of a new molecular entity to inhibit OATP1B1 in vivo. In vitro (eg, IC50, f(u,p)) and in vivo (eg, dose, C-max, change in area under the curve [AUC]) data for 11 substrates and 61 inhibitors for OATP1B1 were obtained from literature and Drugs@FDA, which include 107 clinical (in vivo) DDI studies. Substrate dependency and variability of IC50 values were noted. In addition to the ratio of unbound or total systemic concentration (I-max,I-u and I-max) to IC50, maximum unbound inhibitor concentration at the inlet to the liver (I-u,I-in,I-max) was used for the estimation of "R value" where R = 1 + I-u,I-in,I-max/IC50. Based on our analyses, I-max/K-i >= 0.1, R >= 1.04, or R >= 1.1 seem to be appropriate for reducing the false-negative (FN) predictions. However, as compared with R >= 1.1, I-max/K-i >= 0.1 and R >= 1.04 resulted in higher false positives (FPs) and lower true negatives (TNs). R >= 1.1,I-max,I-u/K-i >= 0.02, and R >= 1.25 alone, or combined criterion of I-max/K-i >= 0.1 and R >= 1.25, were reasonable to determine the need to perform clinical DDI studies with OATP1B1 substrates with similar positive and negative predictive values. Possible reasons of FP or FN from different decision criteria should be considered when interpreting prediction results, and the variability in IC50 determination needs to be understood and minimized. C1 [Vaidyanathan, Jayabharathi; Yoshida, Kenta; Arya, Vikram; Zhang, Lei] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Yoshida, Kenta] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. RP Zhang, L (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM leik.zhang@fda.hhs.gov NR 46 TC 2 Z9 2 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 JUL PY 2016 VL 56 SU 7 SI SI BP S59 EP S72 DI 10.1002/jcph.723 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DR6ZW UT WOS:000380050800005 PM 27385179 ER PT J AU Tempero, M AF Tempero, Margaret TI The Greatest Show on Earth! 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] ASCO Board Directors, Alexandria, VA 22314 USA. [Tempero, Margaret] ASCO, Alexandria, VA 22314 USA. [Tempero, Margaret] ASCO Conquer Canc Fdn Board, Alexandria, VA 22314 USA. [Tempero, Margaret] NCI, Clin Oncol Study Sect, Bethesda, MD 20892 USA. [Tempero, Margaret] NCI, Board Sci Counselors Subcomm, Bethesda, MD 20892 USA. [Tempero, Margaret] Canc Prevent & Res Inst Texas, Clin & Translat Study Sect, Austin, TX 78701 USA. [Tempero, Margaret] FDA, Oncol Drug Advisory Comm, Silver Spring, MD 20993 USA. [Tempero, Margaret] UNMC, Eppley Canc Ctr, Omaha, NE 68198 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 94115 USA. RP Tempero, M (reprint author), UCSF Pancreas Ctr, San Francisco, CA 94143 USA.; Tempero, M (reprint author), ASCO Board Directors, Alexandria, VA 22314 USA.; Tempero, M (reprint author), ASCO, Alexandria, VA 22314 USA.; Tempero, M (reprint author), ASCO Conquer Canc Fdn Board, Alexandria, VA 22314 USA.; Tempero, M (reprint author), NCI, Clin Oncol Study Sect, Bethesda, MD 20892 USA.; Tempero, M (reprint author), NCI, Board Sci Counselors Subcomm, Bethesda, MD 20892 USA.; Tempero, M (reprint author), Canc Prevent & Res Inst Texas, Clin & Translat Study Sect, Austin, TX 78701 USA.; Tempero, M (reprint author), FDA, Oncol Drug Advisory Comm, Silver Spring, MD 20993 USA.; Tempero, M (reprint author), UNMC, Eppley Canc Ctr, Omaha, NE 68198 USA.; 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 94115 USA. NR 0 TC 0 Z9 0 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 JUL 1 PY 2016 VL 14 IS 7 BP 813 EP 813 PG 1 WC Oncology SC Oncology GA DR8VG UT WOS:000380175200001 PM 27407120 ER PT J AU Cunningham, FE Hur, K Dong, DA Miller, DR Zhang, RP Wei, XM McCarren, M Mosholder, AD Graham, DJ Aspinall, SL Good, CB AF Cunningham, Francesca E. Hur, Kwan Dong, Diane Miller, Donald R. Zhang, Rongping Wei, Xiangming McCarren, Madeline Mosholder, Andrew D. Graham, David J. Aspinall, Sherrie L. Good, Chester B. TI A comparison of neuropsychiatric adverse events during early treatment with varenicline or a nicotine patch SO ADDICTION LA English DT Article DE Adverse drug events; mental health disorder; nicotine replacement therapy; varenicline ID RECEPTOR PARTIAL AGONIST; RANDOMIZED CONTROLLED-TRIAL; SUSTAINED-RELEASE BUPROPION; SMOKING-CESSATION; DOUBLE-BLIND; SCHIZOAFFECTIVE DISORDER; PROSPECTIVE COHORT; SUICIDAL-BEHAVIOR; BIPOLAR DISORDER; MAJOR DEPRESSION AB Aims We compared the risk of mental health episodes requiring hospitalization (primary aim) or out-patient clinic visits (secondary aim) associated with varenicline versus the nicotine patch (NP) in an era prior to psychiatric boxed warnings. Design Retrospective cohort. Setting Department of Veterans Affairs (VA), USA. Participants VA patients with or without psychiatric comorbidities and a new prescription for varenicline (15 255) were propensity score-matched (1 : 2) to new users of NP (123 054) between 1 May 2006 and 30 September 2007, resulting in 11 774 and 23 548 patients in the varenicline and NP groups, respectively. Measurements The primary outcomes were hospitalizations with a primary discharge diagnosis of a range of mental health disorders: depression, schizophrenia, bipolar disorder, suicide attempt, post-traumatic stress disorder, other psychosis and drug-induced mental disorders. Secondary outcomes were out-patient clinic visits with a primary diagnosis of the above list of mental health disorders. Findings Background characteristics of the treatment groups were similar after matching. There was no statistically significant difference in risk of hospitalization for any of the studied mental health disorders with varenicline compared with NP. Among secondary outcomes there was an increased risk of out-patient clinic visits for schizophrenia among patients who received varenicline [hazard ratio (HR) = 1.27; 95% confidence interval (CI) = 1.07, 1.51], this increase being evident only in those with a pre-existing mental health disorder. Conclusion In US VA patients studied prior to the boxed warning being implemented, use of varenicline for smoking cessation was not associated with a detectable increase compared with nicotine patches in hospitalization for any mental health outcomes. There was an increased rate of out-patient attendances with a primary diagnosis of schizophrenia amounting to five per 100 person years of treatment. This increase was found only in patients with a pre-existing mental health disorder. C1 [Cunningham, Francesca E.; Hur, Kwan; Dong, Diane; Zhang, Rongping; Wei, Xiangming; McCarren, Madeline; Aspinall, Sherrie L.; Good, Chester B.] VA Ctr Medicat Safety, Hines, IL USA. [Miller, Donald R.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Miller, Donald R.] Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Mosholder, Andrew D.; Graham, David J.] US FDA, Silver Spring, MD USA. [Aspinall, Sherrie L.; Good, Chester B.] VA Pittsburgh Healthcare Syst, VA Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. [Good, Chester B.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Aspinall, Sherrie L.; Good, Chester B.] Univ Pittsburgh, Sch Pharm, Pittsburgh, PA USA. RP Cunningham, FE (reprint author), Ctr Medicat Safety, PBM Serv, Dept Vet Affairs, 1st Ave,1 Block,N Cermak Rd,Bldg 37,Room 139, Hines, IL 60141 USA. EM fran.cunningham@va.gov FU FDA FX Funds from the FDA were used to support this study under an interagency agreement between the FDA and the Veterans Health Administration. The authors do not have a relevant financial interest in this paper or any connections with the tobacco, alcohol, pharmaceutical or gaming industries. The views expressed in this paper are those of the authors, and no official endorsement by the United States Food and Drug Administration, Department of Veteran Affairs or the United States Government is intended or should be inferred. NR 65 TC 1 Z9 1 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD JUL PY 2016 VL 111 IS 7 BP 1283 EP 1292 DI 10.1111/add.13329 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DR5OG UT WOS:000379951700026 PM 26826702 ER PT J AU Yang, SH He, PJ Wang, J Schetter, A Tang, W Funamizu, N Yanaga, K Uwagawa, T Satoskar, AR Gaedcke, J Bernhardt, M Ghadimi, BM Gaida, MM Bergmann, F Werner, J Ried, T Hanna, N Alexander, HR Hussain, SP AF Yang, Shouhui He, Peijun Wang, Jian Schetter, Aaron Tang, Wei Funamizu, Naotake Yanaga, Katsuhiko Uwagawa, Tadashi Satoskar, Abhay R. Gaedcke, Jochen Bernhardt, Markus Ghadimi, B. Michael Gaida, Matthias M. Bergmann, Frank Werner, Jens Ried, Thomas Hanna, Nader Alexander, H. Richard Hussain, S. Perwez TI A Novel MIF Signaling Pathway Drives the Malignant Character of Pancreatic Cancer by Targeting NR3C2 SO CANCER RESEARCH LA English DT Article ID MIGRATION-INHIBITORY FACTOR; DUCTAL ADENOCARCINOMA; TUMOR; INFLAMMATION; EXPRESSION; TUMORIGENESIS; CD74; LINK; AKT AB Pancreatic cancers with aberrant expression of macrophage migration inhibitory factor (MIF) are particularly aggressive. To identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression, we analyzed the expression of coding and noncoding genes in high and low MIF-expressing tumors in multiple cohorts of pancreatic ductal adenocarcinoma (PDAC) patients. The key genes and pathways identified were linked to patient survival and were mechanistically, functionally, and clinically characterized using cell lines, a genetically engineered mouse model, and PDAC patient cohorts. Here, we report evidence of a novel MIF-driven signaling pathway that inhibits the orphan nuclear receptor NR3C2, a previously undescribed tumor suppressor that impacts aggressiveness and survival in PDAC. Mechanistically, MIF upregulated miR-301b that targeted NR3C2 and suppressed its expression. PDAC tumors expressing high levels of MIF displayed elevated levels of miR-301b and reduced levels of NR3C2. In addition, reduced levels of NR3C2 expression correlated with poorer survival in multiple independent cohorts of PDAC patients. Functional analysis showed that NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to the gemcitabine, a chemotherapeutic drug used in PDAC standard of care. Furthermore, genetic deletion of MIF disrupted a MIF-mir-301b-NR3C2 signaling axis, reducing metastasis and prolonging survival in a genetically engineered mouse model of PDAC. Taken together, our results offer a preclinical proof of principle for candidate therapies to target a newly described MIF-miR-301b-NR3C2 signaling axis for PDAC management. (C) 2016 AACR. C1 [Yang, Shouhui; He, Peijun; Wang, Jian; Hussain, S. Perwez] NCI, Pancreat Canc Unit, Bethesda, MD 20892 USA. [Yang, Shouhui; He, Peijun; Wang, Jian; Schetter, Aaron; Tang, Wei; Hussain, S. Perwez] NCI, Lab Human Carcinogenesis, Ctr Canc Res, Bethesda, MD 20892 USA. [Funamizu, Naotake; Yanaga, Katsuhiko; Uwagawa, Tadashi] Jikei Univ, Sch Med, Dept Surg, Tokyo, Japan. [Satoskar, Abhay R.] Ohio State Univ, Dept Pathol & Microbiol, Columbus, OH 43210 USA. [Gaedcke, Jochen; Bernhardt, Markus; Ghadimi, B. Michael] Univ Med, Dept Gen Visceral & Pediat Surg, Gottingen, Germany. [Gaida, Matthias M.; Bergmann, Frank] Heidelberg Univ, Inst Pathol, Heidelberg, Germany. [Werner, Jens] Univ Munich, Dept Surg, Munich, Germany. [Ried, Thomas] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Hanna, Nader; Alexander, H. Richard] Univ Maryland, Sch Med, Div Surg Oncol, Baltimore, MD 21201 USA. [Schetter, Aaron] US FDA, 10903 New Hampshire Ave, Silver Spring, MD USA. RP Hussain, SP (reprint author), NCI, Pancreat Canc Unit, Human Carcinogenesis Lab, NIH, Bldg 37,Room 3044B,37 Convent Dr, Bethesda, MD 20892 USA. EM hussainp@mail.nih.gov FU Intramural NIH HHS [ZIA BC011162-01, ZIA BC011162-02, Z99 CA999999] NR 30 TC 4 Z9 4 U1 4 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2016 VL 76 IS 13 BP 3838 EP 3850 DI 10.1158/0008-5472.CAN-15-2841 PG 13 WC Oncology SC Oncology GA DR7HU UT WOS:000380071400020 PM 27197190 ER PT J AU Chhabra, ES Imon, JS Sauna, Z Schellenberger, V Liu, TY Kulman, J Peters, R AF Chhabra, Ekta Seth Imon, Jonathan S. Sauna, Zuben Schellenberger, Volker Liu, Tongyao Kulman, John Peters, Robert TI Application of in silico antigenicity prediction methods to avoid neo-epitopes during the designing of BIIB073, a next generation long acting recombinant Factor VIII (rFVIII) molecule SO HAEMOPHILIA LA English DT Meeting Abstract C1 [Chhabra, Ekta Seth; Liu, Tongyao; Kulman, John; Peters, Robert] Biogen, Cambridge, MA USA. [Imon, Jonathan S.; Sauna, Zuben] US FDA, Silver Spring, MD USA. [Schellenberger, Volker] Amunix, Mountain View, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-8216 EI 1365-2516 J9 HAEMOPHILIA JI Haemophilia PD JUL PY 2016 VL 22 SU 4 SI SI BP 18 EP 18 PG 1 WC Hematology SC Hematology GA DR5KC UT WOS:000379940900058 ER PT J AU Ai, J Taylor, KM Lisko, JG Tran, H Watson, CH Holman, MR AF Ai, Jiu Taylor, Kenneth M. Lisko, Joseph G. Tran, Hang Watson, Clifford H. Holman, Matthew R. TI Menthol Content in US Marketed Cigarettes SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID SMOKING AB In 2011 menthol cigarettes accounted for 32 percent of the market in the United States, but there are few literature reports that provide measured menthol data for commercial cigarettes. To assess current menthol application levels in the US cigarette market, menthol levels in cigarettes labeled or not labeled to contain menthol was determined for a variety of contemporary domestic cigarette products. We measured the menthol content of 45 whole cigarettes using a validated gas chromatography/mass spectrometry method. In 23 cigarette brands labeled as menthol products, the menthol levels of the whole cigarette ranged from 2.9 to 19.6mg/cigarette, with three products having higher levels of menthol relative to the other menthol products. The menthol levels for 22 cigarette products not labeled to contain menthol ranged from 0.002 to 0.07mg/cigarette. The type of packaging (soft vs. hard pack) for a given cigarette product does not appear to affect menthol levels based on the current limited data. Menthol levels in cigarette products labeled as containing menthol are approximately 50- to 5000-fold higher than those in cigarette products not labeled as containing menthol. In general, menthol content appears to occur within discrete ranges for both mentholated and nonmentholated cigarettes. This study shows that menthol may be present in non-mentholated cigarettes and adds to the understanding of how menthol may be used in cigarette products. It is the first systematic study from the same laboratory which will readily enable comparison among menthol and non-menthol cigarettes. C1 [Ai, Jiu; Taylor, Kenneth M.; Holman, Matthew R.] US FDA, Off Sci, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Lisko, Joseph G.; Tran, Hang; Watson, Clifford H.] Ctr Dis Control & Prevent, Tobacco Prod Lab, Natl Ctr Environm Hlth, Atlanta, GA USA. RP Taylor, KM (reprint author), US FDA, Off Sci, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Kenneth.taylor@fda.hhs.gov FU US Food and Drug Administration, Center for Tobacco Products FX This research was funded by the US Food and Drug Administration, Center for Tobacco Products. NR 17 TC 2 Z9 2 U1 4 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD JUL PY 2016 VL 18 IS 7 BP 1575 EP 1580 DI 10.1093/ntr/ntv162 PG 6 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA DR3TW UT WOS:000379826500005 PM 26259988 ER PT J AU Kong, FH Chen, YF AF Kong, Fanhui Chen, Yeh-Fong TI Testing treatment effect in schizophrenia clinical trials with heavy patient dropout using latent class growth mixture models SO PHARMACEUTICAL STATISTICS LA English DT Article DE missing at random (MAR); missing not at random (MNAR); mixed-effects model for repeated measures (MMRM); latent growth mixture model; schizophrenia clinical trials ID LOCAL INFLUENCE APPROACH; MISSING DATA; SEMIPARAMETRIC REGRESSION; SENSITIVITY-ANALYSIS; NONRANDOM DROPOUT; REPEATED OUTCOMES; INCOMPLETE DATA; BIOMARKER AB By examining the outcome trajectories of the dropout patients with different reasons in the schizophrenia trials, we note that although patients are recruited from the same protocol that have compatible baseline characteristics, they may respond differently even to the same treatment. Some patients show consistent improvement while others only have temporary relief. This creates different patient subpopulations characterized by their response and dropout patterns. At the same time, those who continue to improve seem to be more likely to complete the study while those who only experience temporary relief have a higher chance to drop out. Such phenomenon appears to be quite general in schizophrenia clinical trials. This simultaneous inhomogeneity both in patient response as well as dropout patterns creates a scenario of missing not at random and therefore results in biases when we use the statistical methods based on the missing at random assumption to test treatment efficacy. In this paper, we propose to use the latent class growth mixture model, which is a special case of the latent mixture model, to conduct the statistical analyses in such situation. This model allows us to take the inhomogeneity among subpopulations into consideration to make more accurate inferences on the treatment effect at any visit time. Comparing with the conventional statistical methods such as mixed-effects model for repeated measures, we demonstrate through simulations that the proposed latent mixture model approach gives better control on the Type I error rate in testing treatment effect. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Kong, Fanhui] US FDA, Div Biometr 1, HFD 710,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Chen, Yeh-Fong] US FDA, Div Biometr 3, HFD 710,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Kong, FH (reprint author), US FDA, Div Biometr 1, HFD 710,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Fanhui.kong@fda.hhs.gov FU Regulatory Science and Review Funds [RSR-10-16]; ORISE Fellowship Training Program; Center for Drug Evaluation and Research; U.S. Food and Drug Administration FX The authors are grateful to Dr James Hung and the two reviewers for their valuable and insightful comments and suggestions in the presentation of this article. The authors are also grateful to Dr Gregory Dubitsky for his help in better understanding of the patient dropout process. The authors also wish to thank Dr Xiangmin Zhang for computational assistance during her summer internship in the US Food and Drug Administration in 2013. This research was supported by the Regulatory Science and Review Funds No. RSR-10-16 and the 2012 and 2013 ORISE Fellowship Training Program, granted by the Center for Drug Evaluation and Research, the U.S. Food and Drug Administration. NR 28 TC 0 Z9 0 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 JUL-AUG PY 2016 VL 15 IS 4 SI SI BP 349 EP 361 DI 10.1002/pst.1750 PG 13 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA DR5EL UT WOS:000379925800009 PM 27169874 ER PT J AU Raebel, MA Shetterly, S Lu, CY Flory, J Gagne, JJ Harrell, FE Haynes, K Herrinton, LJ Patorno, E Popovic, J Selvan, M Shoaibi, A Wang, XM Roy, J AF Raebel, Marsha A. Shetterly, Susan Lu, Christine Y. Flory, James Gagne, Joshua J. Harrell, Frank E. Haynes, Kevin Herrinton, Lisa J. Patorno, Elisabetta Popovic, Jennifer Selvan, Mano Shoaibi, Azadeh Wang, Xingmei Roy, Jason TI Methods for using clinical laboratory test results as baseline confounders in multi-site observational database studies when missing data are expected SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE laboratory test results; missing data methods; baseline confounders; observational data; database; Mini-Sentinel; pharmacoepidemiology; pharmacoepidemiology ID ACUTE MYOCARDIAL-INFARCTION; CONVERTING ENZYME-INHIBITORS; HEALTH DATA-NETWORKS; MULTIPLE IMPUTATION; MINI-SENTINEL; DIABETES-MELLITUS; PROPENSITY SCORES; BLOOD-PRESSURE; MORTALITY; RISK AB PurposeOur purpose was to quantify missing baseline laboratory results, assess predictors of missingness, and examine performance of missing data methods. MethodsUsing the Mini-Sentinel Distributed Database from three sites, we selected three exposure-outcome scenarios with laboratory results as baseline confounders. We compared hazard ratios (HRs) or risk differences (RDs) and 95% confidence intervals (CIs) from models that omitted laboratory results, included only available results (complete cases), and included results after applying missing data methods (multiple imputation [MI] regression, MI predictive mean matching [PMM] indicator). ResultsScenario 1 considered glucose among second-generation antipsychotic users and diabetes. Across sites, glucose was available for 27.7-58.9%. Results differed between complete case and missing data models (e.g., olanzapine: HR 0.92 [CI 0.73, 1.12] vs 1.02 [0.90, 1.16]). Across-site models employing different MI approaches provided similar HR and CI; site-specific models provided differing estimates. Scenario 2 evaluated creatinine among individuals starting high versus low dose lisinopril and hyperkalemia. Creatinine availability: 44.5-79.0%. Results differed between complete case and missing data models (e.g., HR 0.84 [CI 0.77, 0.92] vs. 0.88 [0.83, 0.94]). HR and CI were identical across MI methods. Scenario 3 examined international normalized ratio (INR) among warfarin users starting interacting versus noninteracting antimicrobials and bleeding. INR availability: 20.0-92.9%. Results differed between ignoring INR versus including INR using missing data methods (e.g., RD 0.05 [CI -0.03, 0.13] vs 0.09 [0.00, 0.18]). Indicator and PMM methods gave similar estimates. ConclusionMulti-site studies must consider site variability in missing data. Different missing data methods performed similarly. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Raebel, Marsha A.; Shetterly, Susan] Kaiser Permanente Colorado, Inst Hlth Res, POB 378066, Denver, CO 80237 USA. [Raebel, Marsha A.] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO USA. [Lu, Christine Y.; Popovic, Jennifer] Harvard Med Sch, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Flory, James] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Gagne, Joshua J.; Patorno, Elisabetta] Harvard Med Sch, Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Dept Med, Boston, MA USA. [Harrell, Frank E.] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37212 USA. [Haynes, Kevin] HealthCore, Wilmington, DE USA. [Herrinton, Lisa J.] Kaiser Permanente Northern Calif, Oakland, CA USA. [Selvan, Mano] Humana Inc, Comprehens Hlth Insights, Louisville, KY USA. [Shoaibi, Azadeh] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Wang, Xingmei; Roy, Jason] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Raebel, MA (reprint author), Kaiser Permanente Colorado, Inst Hlth Res, POB 378066, Denver, CO 80237 USA. EM Marsha.A.Raebel@kp.org FU Food and Drug Administration from the Department of Health and Human Services [HHSF22301012T-0008, HHSF223020091006I] FX The Mini-Sentinel program is funded by the Food and Drug Administration through contract HHSF22301012T-0008 under Master Agreement HHSF223020091006I from the Department of Health and Human Services. NR 59 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JUL PY 2016 VL 25 IS 7 BP 798 EP 814 DI 10.1002/pds.4015 PG 17 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DR4AF UT WOS:000379843100008 PM 27146273 ER PT J AU Arango, J Chuck, T Ellenberg, SS Foltz, B Gorman, C Hinrichs, H McHale, S Merchant, K Seltzer, J Shapley, S Wild, G AF Arango, Jaime Chuck, Tina Ellenberg, Susan S. Foltz, Bridget Gorman, Colleen Hinrichs, Heidi McHale, Susan Merchant, Kunal Seltzer, Jonathan Shapley, Stephanie Wild, Gretchen TI Good Clinical Practice Training: Identifying Key Elements and Strategies for Increasing Training Efficiency SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Review DE Good Clinical Practice; GCP; clinical trials; clinical research training ID NETWORK AAFP NRN; RESPONSIBLE CONDUCT; RESEARCH ETHICS; NATIONAL-SURVEY; INSTRUCTION; INVESTIGATORS; MISCONDUCT; EXPERIENCE; COMMUNITY; KNOWLEDGE AB Good Clinical Practice (GCP) is an international standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials. The goal of GCP is to ensure the protection of the rights, integrity, and confidentiality of clinical trial participants and to ensure the credibility and accuracy of data and reported results. In the United States, trial sponsors generally require investigators to complete GCP training prior to participating in each clinical trial to foster GCP and as a method to meet regulatory expectations (ie, sponsor's responsibility to select qualified investigators per 21 CFR 312.50 and 312.53(a) for drugs and biologics and 21 CFR 812.40 and 812.43(a) for medical devices). This training requirement is often extended to investigative site staff, as deemed relevant by the sponsor, institution, or investigator. Those who participate in multiple clinical trials are often required by sponsors to complete repeated GCP training, which is unnecessarily burdensome. The Clinical Trials Transformation Initiative convened a multidisciplinary project team involving partners from academia, industry, other researchers and research staff, and government to develop recommendations for streamlining current GCP training practices. Recommendations drafted by the project team, including the minimum key training elements, frequency, format, and evidence of training completion, were presented to a broad group of experts to foster discussion of the current issues and to seek consensus on proposed solutions. C1 [Arango, Jaime] Univ Miami, Collaborat Inst Training Initiat, Miami, FL USA. [Chuck, Tina] Northwell Hlth, Great Neck, NY USA. [Ellenberg, Susan S.] Univ Penn, Philadelphia, PA 19104 USA. [Foltz, Bridget] US FDA, Off Good Clin Practice, Silver Spring, MD USA. [Gorman, Colleen] Pfizer, New York, NY USA. [Hinrichs, Heidi; Wild, Gretchen] St Jude Med, St Paul, MN USA. [McHale, Susan] AstraZeneca, Wilmington, DE USA. [Merchant, Kunal] Clin Trials Transformat Initiat, Durham, NC USA. [Seltzer, Jonathan] ACI Clin, 251 St Asaphs Rd,Suite 402,3 Bala Plaza West, Bala Cynwyd, PA 19004 USA. [Shapley, Stephanie] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Seltzer, J (reprint author), ACI Clin, 251 St Asaphs Rd,Suite 402,3 Bala Plaza West, Bala Cynwyd, PA 19004 USA. EM jseltzer@aciclincial.com FU Food and Drug Administration [R18FD005292, U19FD003800]; CTTI's member organizations FX The authors 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 written materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services, nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government. Partial funding was also provided by pooled membership fees from CTTI's member organizations. NR 41 TC 0 Z9 0 U1 4 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD JUL PY 2016 VL 50 IS 4 BP 480 EP 486 DI 10.1177/2168479016635220 PG 7 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA DR3NA UT WOS:000379808700012 PM 27390628 ER PT J AU Minor, T Parrett, M AF Minor, Travis Parrett, Matt TI A retrospective review of the economic impact of the food and drug administration's proposed egg rule SO AGRICULTURAL ECONOMICS LA English DT Review DE Difference in differences; Egg; Federal regulation; Foodborne illness; Salmonella ID FOODBORNE DISEASE OUTBREAKS; UNITED-STATES; NATURAL EXPERIMENT; EMPLOYMENT AB Using novel 1998-2008 data collected by the Centers for Disease Control and Prevention on foodborne illnesses and outbreaks, we test using a difference-in-differences approach whether the Food and Drug Administration's proposed rule entitled Prevention of Salmonella Enteritidis in Shell Eggs During Production decreased the number of Salmonella illnesses associated with the consumption of shell eggs. We find that this rule led to a reduction in the number of Salmonella illnesses of between 308 and 434 illnesses per year, which we attribute to a reduction in the number of outbreaks associated with egg-containing products rather than a reduction in the average number of illnesses reported in each outbreak. C1 [Minor, Travis; Parrett, Matt] US FDA, Off Commissioner, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. RP Minor, T (reprint author), US FDA, Off Commissioner, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Travis.Minor@fda.hhs.gov OI Minor, Travis/0000-0002-5297-7695 NR 25 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0169-5150 EI 1574-0862 J9 AGR ECON-BLACKWELL JI Agric. Econ. PD JUL PY 2016 VL 47 IS 4 BP 457 EP 464 DI 10.1111/agec.12244 PG 8 WC Agricultural Economics & Policy; Economics SC Agriculture; Business & Economics GA DR5FV UT WOS:000379929800009 ER PT J AU Mahmood, I AF Mahmood, Iftekhar TI Pharmacokinetic Considerations in Designing Pediatric Studies of Proteins, Antibodies, and Plasma-Derived Products SO AMERICAN JOURNAL OF THERAPEUTICS LA English DT Article DE extrapolation; pediatrics; pharmacokinetics; macromolecules ID UNIVERSAL METABOLIC ALLOMETRY; SYSTEMIC CLEARANCE PATHWAYS; MOLECULAR-WEIGHT PROTEINS; RECOMBINANT FACTOR-VIII; LIVER BLOOD-FLOW; PROPHYLACTIC TREATMENT; DRUG CLEARANCE; HEMOPHILIA-A; ENERGY-METABOLISM; SAMPLE-SIZE AB Ignoring the principles of pediatric pharmacology can have serious consequences. Therefore, it is necessary to understand and recognize the impact of developmental processes in children. It is now well recognized that age and the disease state can alter the pharmacokinetics (PKs) of a drug, as a result adjustment in dosing regimen in children as compared with the adults is essential. This review emphasizes on the importance of PK studies in pediatric population for macromolecules. Macromolecules differ from small molecules in many respects, and it is necessary to have a thorough understanding of the behavior of macromolecules in the body across different age groups. The review highlights that like small molecules, the PKs of macromolecules in pediatric population also differ from adults, hence, a PK study is essential in pediatrics for appropriate dose selection in this population. The review also takes a critical look on the many extrapolation techniques to predict PK parameters in pediatrics from adult data. C1 [Mahmood, Iftekhar] US FDA, Div Hematol, Off Blood Review & Res, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Mahmood, I (reprint author), US FDA, Div Hematol, Off Blood Review & Res, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. EM Iftekhar.mahmood@fda.hhs.gov NR 76 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1075-2765 EI 1536-3686 J9 AM J THER JI Am. J. Ther. PD JUL-AUG PY 2016 VL 23 IS 4 BP E1043 EP E1056 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DR1KG UT WOS:000379663800011 PM 27386959 ER PT J AU Derrick, SC Yabe, I Morris, S Cowley, S AF Derrick, Steven C. Yabe, Idalia Morris, Sheldon Cowley, Siobhan TI Induction of Unconventional T Cells by a Mutant Mycobacterium bovis BCG Strain Formulated in Cationic Liposomes Correlates with Protection against Mycobacterium tuberculosis Infections of Immunocompromised Mice SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID BACILLUS-CALMETTE-GUERIN; IMMUNE-RESPONSES; ORAL VACCINATION; IN-VIVO; LYMPHOCYTES; CHALLENGE; VACCINES AB Earlier studies aimed at defining protective immunity induced by Mycobacterium bovis BCG immunization have largely focused on the induction of antituberculosis CD4(+) and CD8(+) T cell responses. Here we describe a vaccine consisting of a BCG Delta mmaA4 deletion mutant formulated in dimethyl dioctadecyl-ammonium bromide (DDA) with D-(+)-trehalose 6,6'-dibehenate (TDB) (DDA/TDB) adjuvant (A4/Adj) that protected TCR delta(-/-) mice depleted of CD4(+), CD8(+), and NK1.1(+) T cells against an aerosol challenge with M. tuberculosis. These mice were significantly protected relative to mice immunized with a nonadjuvanted BCG Delta mmaA4 (BCG-A4) mutant and nonvaccinated controls at 2 months and 9 months postvaccination. In the absence of all T cells following treatment with anti-Thy1.2 antibody, the immunized mice lost the ability to control the infection. These results indicate that an unconventional T cell population was mediating protection in the absence of CD4(+), CD8(+), NK1.1(+), and TCR gamma delta T cells and could exhibit memory. Focusing on CD4(-) CD8(-) double-negative (DN) T cells, we found that these cells accumulated in the lungs postchallenge significantly more in A4/Adj-immunized mice and induced significantly greater frequencies of pulmonary gamma interferon (IFN-gamma)-producing cells than were seen in the nonvaccinated or nonadjuvanted BCG control groups. Moreover, pulmonary DN T cells from the A4/Adj group exhibited significantly higher IFN-gamma integrated median fluorescence intensity (iMFI) values than were seen in the control groups. We also showed that enriched DN T cells from mice immunized with A4/Adj could control mycobacterial growth in vitro significantly better than naive whole-spleen cells. These results suggest that formulating BCG in DDA/TDB adjuvant confers superior protection in immunocompromised mice and likely involves the induction of long-lived memory DN T cells. C1 [Derrick, Steven C.; Morris, Sheldon; Cowley, Siobhan] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Yabe, Idalia] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Derrick, SC (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM steven.derrick@fda.hhs.gov NR 38 TC 0 Z9 0 U1 5 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD JUL PY 2016 VL 23 IS 7 BP 638 EP 647 DI 10.1128/CVI.00232-16 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DQ9GB UT WOS:000379517300013 PM 27226281 ER PT J AU Beger, RD Flynn, TJ AF Beger, Richard D. Flynn, Thomas J. TI Pharmacometabolomics in drug safety and drug-exposome interactions SO METABOLOMICS LA English DT Article DE Pharmacometabolomics; Drug safety; Drug-exposome ID INDUCED LIVER-INJURY; ACETAMINOPHEN-INDUCED HEPATOTOXICITY; MITOCHONDRIAL PERMEABILITY TRANSITION; CYP-MEDIATED BIOACTIVATION; EMBRYONIC STEM-CELLS; MASS-SPECTROMETRY; UNITED-STATES; NONALCOHOLIC STEATOHEPATITIS; UNTARGETED METABOLOMICS; FUNCTIONAL FOODS AB Background Pharmacometabolomics is a relatively new field that measures an individual's metabolome in biofluids to detect prognostic and diagnostic biomarkers of drug response and to provide an effective means to predict variation in a subject's response to drug treatment. Pharmacometabolomics has the potential to help clinicians determine the effectiveness and safety of a drug on an individual basis. Aim of Review To provide information from the current literature in pharmocometabolomics relevant to drug safety including factors besides genetics that can play a role in how a subject responds to a drug treatment. Pharmacometabolomics studies on drug-induced liver toxicity, the use of pharmacometabolomics to detect and predict drug interactions, and future applications of pharmacometabolomics in drug safety are discussed. Key scientific concepts of the review Pharmacometabolomics can play a role in identifying and/or characterizing toxicity at all stages of drug development. These stages include: pharmacokinetics and ADME; initial toxicity; protective mechanisms; adverse events; late injury; and, injury progression or recovery. Pharmacometabolomics also has the ability to detect endogenous metabolites and markers of other exposure factors including alcohol consumption, impact of the gut microbiome, nutrition, other medications (polypharmacy), dietary supplements, and current individual health-to-disease status, all of which could play a role in patient response to a drug. Pharmacometabolomics alone or in combination with pharmacogenomics can be used to develop customized treatment plans for patients (i.e., personalized medicine) that could significantly reduce adverse events that are sometimes associated with the use of pharmaceuticals. C1 [Beger, Richard D.] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. [Flynn, Thomas J.] US FDA, Div Toxicol, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Beger, RD (reprint author), US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA.; Flynn, TJ (reprint author), US FDA, Div Toxicol, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. EM Richard.Beger@fda.hhs.gov; Thomas.Flynn@fda.hhs.gov NR 102 TC 0 Z9 0 U1 14 U2 23 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1573-3882 EI 1573-3890 J9 METABOLOMICS JI Metabolomics PD JUL PY 2016 VL 12 IS 7 AR 123 DI 10.1007/s11306-016-1061-2 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DQ9CR UT WOS:000379508500014 ER PT J AU Kurdekar, A Chunduri, LAA Bulagonda, EP Haleyurgirisetty, MK Kamisetti, V Hewlett, IK AF Kurdekar, Aditya Chunduri, L. A. Avinash Bulagonda, Eswarappa Pradeep Haleyurgirisetty, Mohan Kumar Kamisetti, Venkataramaniah Hewlett, Indira K. TI Comparative performance evaluation of carbon dot-based paper immunoassay on Whatman filter paper and nitrocellulose paper in the detection of HIV infection SO MICROFLUIDICS AND NANOFLUIDICS LA English DT Article ID P24 ANTIGEN-DETECTION; QUANTUM DOTS; IMMUNOSORBENT-ASSAY; NANODOTS SYNTHESIS; DIAGNOSIS; DEVICE; BIOASSAYS; PLASMA; ELISA AB Carbon dots synthesized from citric acid and ethylene diamine by a one-step hydrothermal technique were used to develop a carbon dot-based paper immunoassay (CDPIA) for rapid detection of HIV-1 p24 antigen. In the present study, the 96-well template was hand patterned using a wax pencil, as a prototype method, on two types of paper, (1) Whatman filter paper and (2) nitrocellulose paper. The sandwich immunoassay was performed on both paper microplates for detection of HIV-1 p24 antigen which is an early marker of HIV infection. The detection range was from 10 mu g/mL to 1 ng/mL for the Whatman filter paper while the nitrocellulose paper exhibited a higher range from 10 mu g/mL to 250 pg/mL. CDPIA on the nitrocellulose paper (CDNIA) exhibited a fourfold increase in sensitivity and reduced the assay time by threefold compared with CDPIA on Whatman paper (CDWIA). HIV-negative and HIV-positive plasma samples were tested using CDNIA for the presence of HIV-1 p24 antigen. This immunoassay exhibited no false-positive and false-negative results with the clinical samples tested. This simple and sensitive paper-based HIV-1 p24 antigen assay may be useful in preventing HIV transmission by blood transfusion in resource-limited settings by reducing the antibody negative, infectious window period in blood donors and for early diagnosis of HIV infected individuals where nucleic acid-based testing is not practical or feasible. C1 [Kurdekar, Aditya; Chunduri, L. A. Avinash; Kamisetti, Venkataramaniah] Sri Sathya Sai Inst Higher Learning, Dept Phys, Prasanthinilayam 515134, Puttaparthi, India. [Bulagonda, Eswarappa Pradeep] Sri Sathya Sai Inst Higher Learning, Dept Biosci, Prasanthinilayam 515134, Puttaparthi, India. [Haleyurgirisetty, Mohan Kumar; Hewlett, Indira K.] US FDA, Mol Virol Lab, CBER, Silver Spring, MD USA. RP Kamisetti, V (reprint author), Sri Sathya Sai Inst Higher Learning, Dept Phys, Prasanthinilayam 515134, Puttaparthi, India. EM vrkamisetti@gmail.com FU DST through the DST-INSPIRE Fellowship program, Ministry of Science and Technology, Government of India; UGC, Government of India FX All authors are grateful to Bhagawan Sri Sathya Sai Baba for his constant inspiration and guidance. Aditya Kurdekar thanks DST for their support through the DST-INSPIRE Fellowship program, Ministry of Science and Technology, Government of India. L. A. Avinash Chunduri acknowledges UGC, Government of India for BSR fellowship. We acknowledge with gratitude Prof. S. Sampath for providing the TEM facility for characterization. NR 53 TC 0 Z9 0 U1 20 U2 31 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 JUL PY 2016 VL 20 IS 7 AR 99 DI 10.1007/s10404-016-1763-9 PG 13 WC Nanoscience & Nanotechnology; Instruments & Instrumentation; Physics, Fluids & Plasmas SC Science & Technology - Other Topics; Instruments & Instrumentation; Physics GA DQ8ZJ UT WOS:000379499900005 ER PT J AU Ajit, D Simonyi, A Li, RT Chen, ZH Hannink, M Fritsche, KL Mossine, VV Smith, RE Dobbs, TK Luo, RS Folk, WR Gu, ZZ Lubahn, DB Weisman, GA Sun, GY AF Ajit, Deepa Simonyi, Agnes Li, Runting Chen, Zihong Hannink, Mark Fritsche, Kevin L. Mossine, Valeri V. Smith, Robert E. Dobbs, Thomas K. Luo, Rensheng Folk, William R. Gu, Zezong Lubahn, Dennis B. Weisman, Gary A. Sun, Grace Y. TI Phytochemicals and botanical extracts regulate NF-kappa B and Nrf2/ARE reporter activities in DI TNC1 astrocytes SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE Ashwagandha; Acai; Sutherlandia; Quercetin; ARE reporter; NF-kappa B reporter ID NITRIC-OXIDE PRODUCTION; EUTERPE-OLERACEA MART.; AMAZONIAN PALM BERRY; SUTHERLANDIA-FRUTESCENS; OXIDATIVE STRESS; NEURODEGENERATIVE DISORDERS; MICROGLIAL ACTIVATION; PHOSPHOLIPASE A(2); GENE-EXPRESSION; UP-REGULATION AB The increase in oxidative stress and inflammatory responses associated with neurodegenerative diseases has drawn considerable attention towards understanding the transcriptional signaling pathways involving NF-kappa B (nuclear factor kappa-light-chain-enhancer of activated B cells) and Nrf2 (Nuclear Factor Erythroid 2-like 2). Our recent studies with immortalized murine microglial cells (BV-2) demonstrated effects of botanical polyphenols to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) and enhance Nrf2-mediated antioxidant responses (Sun et al., 2015). In this study, an immortalized rat astrocyte (DI TNC1) cell line expressing a luciferase reporter driven by the NF-kappa B or the Nrf2/Antioxidant Response Element (ARE) promoter was used to assess regulation of these two pathways by phytochemicals such as quercetin, rutin, cyanidin, cyanidin-3-O-glucoside, as well as botanical extracts from Withania somnifera (Ashwagandha), Sutherlandia frutescens (Sutherlandia) and Euterpe oleracea (Acai). Quercetin effectively inhibited LPS-induced NF-kappa B reporter activity and stimulated Nrf2/ARE reporter activity in DI TNC1 astrocytes. Cyanidin and the glycosides showed similar effects but only at much higher concentrations. All three botanical extracts effectively inhibited LPS-induced NF-kappa B reporter activity. These extracts were capable of enhancing ARE activity by themselves and further enhanced ARE activity in the presence of LPS. Quercetin and botanical extracts induced Nrf2 and HO-1 protein expression. Interestingly, Ashwagandha extract was more active in inducing Nrf2 and HO-1 expression in DI TNC1 astrocytes as compared to Sutherlandia and Acai extracts. In summary, this study demonstrated NF-kB and Nrf2/ARE promoter activities in DI TNC1 astrocytes, and further showed differences in ability for specific botanical polyphenols and extracts to down-regulate LPS-induced NF-kappa B and up-regulate the NRF2/ARE activities in these cells. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Ajit, Deepa; Simonyi, Agnes; Li, Runting; Chen, Zihong; Hannink, Mark; Mossine, Valeri V.; Folk, William R.; Lubahn, Dennis B.; Weisman, Gary A.; Sun, Grace Y.] Univ Missouri, Dept Biochem, 117 Schweitzer Hall, Columbia, MO 65211 USA. [Fritsche, Kevin L.] Univ Missouri, Dept Anim Sci, Columbia, MO USA. [Gu, Zezong] Univ Missouri, Dept Pathol & Anat Sci, Columbia, MO USA. [Simonyi, Agnes; Hannink, Mark; Fritsche, Kevin L.; Mossine, Valeri V.; Folk, William R.; Gu, Zezong; Lubahn, Dennis B.; Sun, Grace Y.] Univ Missouri, Ctr Bot Interact Studies, Columbia, MO USA. [Smith, Robert E.; Dobbs, Thomas K.] US FDA, Lenexa, KS USA. [Luo, Rensheng] Univ Missouri, Dept Chem & Biochem, St Louis, MO 63121 USA. RP Sun, GY (reprint author), Univ Missouri, Dept Biochem, 117 Schweitzer Hall, Columbia, MO 65211 USA. EM sung@missouri.edu FU NIH grant from the NCCAM [1P50 AT006273]; NIH grant from ODS [1P50 AT006273]; NIH grant from NCI [1P50 AT006273]; University of Missouri FX The acai was provided by Armando U.O. Sabaa-Srur, from the Federal University of Rio de Janeiro, Brazil. This work is supported by NIH grants from the NCCAM, ODS and NCI [1P50 AT006273] and an Interdisciplinary Intercampus Research Program grant from the University of Missouri. NR 54 TC 0 Z9 1 U1 12 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 EI 1872-9754 J9 NEUROCHEM INT JI Neurochem. Int. PD JUL PY 2016 VL 97 BP 49 EP 56 DI 10.1016/j.neuint.2016.05.004 PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DQ9WC UT WOS:000379559000007 PM 27166148 ER PT J AU Rubin, S Kennedy, R Poland, G AF Rubin, Steven Kennedy, Richard Poland, Gregory TI Emerging Mumps Infection SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Editorial Material ID RUBELLA VACCINE; OUTBREAK C1 [Rubin, Steven] US FDA, Silver Spring, MD 20993 USA. [Kennedy, Richard; Poland, Gregory] Mayo Clin, Rochester, MN USA. RP Rubin, S (reprint author), US FDA, Silver Spring, MD 20993 USA. EM Steven.Rubin@fda.hhs.gov NR 11 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD JUL PY 2016 VL 35 IS 7 BP 799 EP 801 DI 10.1097/INF.0000000000001182 PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA DQ6VY UT WOS:000379344800021 PM 27097351 ER PT J AU Khan, SR Mohammad, A Khan, MA Faustino, PJ AF Khan, Saeed R. Mohammad, Adil Khan, Mansoor A. Faustino, Patrick J. TI Critical Importance and Quality Evaluation of Drug Delivery Autoinjectors in the FDA-DOD Shelf Life Extension Program (SLEP) SO AAPS JOURNAL LA English DT Editorial Material DE auto injector; medical countermeasures (MCM); shelf life extension program (SLEP); strategic national stockpile (SNS) ID STABILITY; AGENTS C1 [Khan, Saeed R.; Mohammad, Adil; Faustino, Patrick J.] US FDA, Div Prod Qual Res, Off Testing & Res, Off Pharmaceut Qual,Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Khan, Mansoor A.] Texas A&M Hlth Sci Ctr, Reynolds Med Bldg,Suite 159, College Stn, TX 77843 USA. RP Khan, SR (reprint author), US FDA, Div Prod Qual Res, Off Testing & Res, Off Pharmaceut Qual,Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM saeed.khan2@fda.hhs.gov NR 12 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 JUL PY 2016 VL 18 IS 4 BP 801 EP 803 DI 10.1208/s12248-016-9910-5 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ2NU UT WOS:000379040000002 PM 27170033 ER PT J AU Xu, J Thakkar, S Gong, BS Tong, WD AF Xu, Joshua Thakkar, Shraddha Gong, Binsheng Tong, Weida TI The FDA's Experience with Emerging Genomics Technologies-Past, Present, and Future SO AAPS JOURNAL LA English DT Review DE big data; genomics; next-generation sequencing; reproducibility; RNA-seq ID RNA-SEQ; GENOTYPING ALGORITHM; ONE-COLOR; MICROARRAY; PERFORMANCE; GWAS; PREDICTION; PLATFORMS; MODELS; INCONSISTENCIES AB The rapid advancement of emerging genomics technologies and their application for assessing safety and efficacy of FDA-regulated products require a high standard of reliability and robustness supporting regulatory decision-making in the FDA. To facilitate the regulatory application, the FDA implemented a novel data submission program, Voluntary Genomics Data Submission (VGDS), and also to engage the stakeholders. As part of the endeavor, for the past 10 years, the FDA has led an international consortium of regulatory agencies, academia, pharmaceutical companies, and genomics platform providers, which was named MicroArray Quality Control Consortium (MAQC), to address issues such as reproducibility, precision, specificity/sensitivity, and data interpretation. Three projects have been completed so far assessing these genomics technologies: gene expression microarrays, whole genome genotyping arrays, and whole transcriptome sequencing (i.e., RNA-seq). The resultant studies provide the basic parameters for fit-for-purpose application of these new data streams in regulatory environments, and the solutions have been made available to the public through peer-reviewed publications. The latest MAQC project is also called the SEquencing Quality Control (SEQC) project focused on next-generation sequencing. Using reference samples with built-in controls, SEQC studies have demonstrated that relative gene expression can be measured accurately and reliably across laboratories and RNA-seq platforms. Besides prediction performance comparable to microarrays in clinical settings and safety assessments, RNA-seq is shown to have better sensitivity for low expression and reveal novel transcriptomic features. Future effort of MAQC will be focused on quality control of whole genome sequencing and targeted sequencing. C1 [Xu, Joshua; Thakkar, Shraddha; Gong, Binsheng; Tong, Weida] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. RP Tong, WD (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. EM Weida.tong@fda.hhs.gov RI Gong, Binsheng/E-2306-2015 OI Gong, Binsheng/0000-0002-8724-5435 FU Intramural FDA HHS [FD999999] NR 30 TC 0 Z9 0 U1 5 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD JUL PY 2016 VL 18 IS 4 BP 814 EP 818 DI 10.1208/s12248-016-9917-y PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ2NU UT WOS:000379040000004 PM 27116022 ER PT J AU Zhang, WP Li, YY Zou, P Wu, M Zhang, ZQ Zhang, T AF Zhang, Wenpeng Li, Yanyan Zou, Peng Wu, Man Zhang, Zhenqing Zhang, Tao TI The Effects of Pharmaceutical Excipients on Gastrointestinal Tract Metabolic Enzymes and Transporters-an Update SO AAPS JOURNAL LA English DT Review DE absorption; metabolic enzyme; pharmaceutical excipient; pharmacokinetics; transporter ID CANCER RESISTANCE PROTEIN; P-GLYCOPROTEIN TRANSPORT; COMMONLY USED EXCIPIENTS; CACO-2 CELL MONOLAYERS; IN-VITRO; DRUG-DELIVERY; MEDIATED EFFLUX; CYTOCHROME-P450 ACTIVITY; INTESTINAL-ABSORPTION; ORAL BIOAVAILABILITY AB Accumulating evidence from the last decade has shown that many pharmaceutical excipients are not pharmacologically inert but instead have effects on metabolic enzymes and/or drug transporters. Hence, the absorption, distribution, metabolism, and elimination (ADME) of active pharmaceutical ingredients (APIs) may be altered due to the modulation of their metabolism and transport by excipients. The impact of excipients is a potential concern for Biopharmaceutics Classification System (BCS)-based biowaivers, particularly as the BCS-based biowaivers have been extended to class 3 drugs in certain dosage forms. The presence of different excipients or varying amounts of excipients between formulations may result in bio-inequivalence. The excipient impact may lead to significant variations in clinical outcomes as well. The aim of this paper is to review the recent findings of excipient effects on gastrointestinal (GI) absorption, focusing on their interactions with the metabolic enzymes and transporters in the GI tract. A wide range of commonly used excipients such as binders, diluents, fillers, solvents, and surfactants are discussed here. We summarized the reported effects of those excipients on GI tract phase I and phase II enzymes, uptake and efflux transporters, and relevant clinical significance. This information can enhance our understanding of excipient influence on drug absorption and is useful in designing pharmacokinetic studies and evaluating the resultant data. C1 [Zhang, Wenpeng; Wu, Man; Zhang, Zhenqing] Beijing Inst Pharmacol & Toxicol, State Key Lab Toxicol & Med Countermeasures, Beijing, Peoples R China. [Li, Yanyan] Husson Univ, Sch Sci & Humanities, Bangor, ME USA. [Zou, Peng] US FDA, CDER OPQ, Silver Spring, MD USA. [Zhang, Tao] Husson Univ, Sch Pharm, Dept Basic Pharmaceut Sci, Bangor, ME USA. RP Zhang, T (reprint author), Husson Univ, Sch Pharm, Dept Basic Pharmaceut Sci, Bangor, ME USA. EM zhangt@husson.edu NR 79 TC 1 Z9 1 U1 7 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD JUL PY 2016 VL 18 IS 4 BP 830 EP 843 DI 10.1208/s12248-016-9928-8 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ2NU UT WOS:000379040000006 PM 27184579 ER PT J AU Martinez, M Mistry, B Lukacova, V Polli, J Hoag, S Dowling, T Kona, R Fahmy, R AF Martinez, Marilyn Mistry, Bipin Lukacova, Viera Polli, Jim Hoag, Stephen Dowling, Thomas Kona, Ravikanth Fahmy, Raafat TI Use of Modeling and Simulation Tools for Understanding the Impact of Formulation on the Absorption of a Low Solubility Compound: Ciprofloxacin SO AAPS JOURNAL LA English DT Article DE ciprofloxacin; IVIVC; mechanistic model; pharmacokinetics ID IMMEDIATE-RELEASE TABLETS; DRUG ABSORPTION; GASTROINTESTINAL-DISEASE; PHARMACOKINETICS; HYDROCHLORIDE; QUALITY; DESIGN AB This study explored the utility of mechanistic absorption models to describe the in vivo performance of a low solubility/low permeability compound in normal healthy subjects. Sixteen healthy human volunteers received three oral formulations and an intravenous infusion in a randomized crossover design. Plasma ciprofloxacin concentrations were estimated by HPLC. In vitro ciprofloxacin release from the oral tablets was tested under a variety of conditions. A mechanistic model was used to explore in vivo dissolution and intestinal absorption. Although dissolution rate influenced the location of drug release, absorption challenges appeared to be associated with permeability limitations in the lower small intestine and colon. The apparent relationship between drug solubilization within the upper small intestinal and formulation overall bioavailability suggested the presence of an intestinal absorption window in many individuals. Failure to absorb drug within this window appeared to be linked with the likelihood of in vivo drug precipitation. Challenges encountered during this modeling exercise included large intersubject variability in product in vivo dissolution and the apparent limitations in ciprofloxacin absorption. Although transporter activity was not included as a model parameter, this evaluation demonstrated how identifying the location of drug absorption across several formulations provided an opportunity to identify factors to consider when formulating similar low solubility/low permeability compounds. The use of mechanistic models was invaluable for our understanding of in vivo product performance and for the assessment of individual profiles rather than means. The latter was essential for understanding the potential challenges that may be encountered when introducing a formulation into a patient population. C1 [Martinez, Marilyn; Mistry, Bipin; Lukacova, Viera; Polli, Jim; Hoag, Stephen; Dowling, Thomas; Kona, Ravikanth; Fahmy, Raafat] US FDA, Rockville, MD 20857 USA. RP Martinez, M (reprint author), US FDA, Rockville, MD 20857 USA. EM marilyn.martinez@fda.hhs.gov NR 22 TC 2 Z9 2 U1 5 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD JUL PY 2016 VL 18 IS 4 BP 886 EP 897 DI 10.1208/s12248-016-9913-2 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ2NU UT WOS:000379040000011 PM 27116024 ER PT J AU Choi, SH Lionberger, RA AF Choi, Stephanie H. Lionberger, Robert A. TI Clinical, Pharmacokinetic, and In Vitro Studies to Support Bioequivalence of Ophthalmic Drug Products SO AAPS JOURNAL LA English DT Article DE bioequivalence; drug release; generic drugs; ophthalmic drugs; physicochemical characterization ID DELIVERY AB For ophthalmic drug products, the determination of bioequivalence can be challenging, as drug concentrations at the site of action cannot always be measured. The FDA has recommended a variety of studies that can be used to demonstrate bioequivalence for different ophthalmic drug products. Product-specific bioequivalence recommendations for 28 ophthalmic products have been posted on FDA's website as of May 2016, outlining the specific tests which should be performed to demonstrate bioequivalence. The type of study that can be used to demonstrate bioequivalence depends on the drug product's active pharmaceutical ingredient(s), dosage form, indication, site of action, mechanism of action, and scientific understanding of drug release/drug availability and drug product characteristics. This article outlines the FDA's current guidance on studies to demonstrate bioequivalence through clinical endpoint studies, pharmacokinetic studies, and in vitro studies for generic ophthalmic drug products. C1 [Choi, Stephanie H.; Lionberger, Robert A.] US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Choi, SH (reprint author), US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Stephanie.Choi@fda.hhs.gov NR 32 TC 0 Z9 0 U1 3 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 JUL PY 2016 VL 18 IS 4 BP 1032 EP 1038 DI 10.1208/s12248-016-9932-z PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ2NU UT WOS:000379040000024 PM 27184578 ER PT J AU Chamkasem, N Harmon, T AF Chamkasem, Narong Harmon, Tiffany TI Direct determination of glyphosate, glufosinate, and AMPA in soybean and corn by liquid chromatography/tandem mass spectrometry SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Glyphosate; Soybean; Corn; LC-MS/MS; Direct determination ID SOLID-PHASE EXTRACTION; AMINOMETHYLPHOSPHONIC ACID; RESIDUE DETERMINATION; WATER; SOIL AB Glyphosate, glufosinate, and aminomethylphosphonic acid (AMPA) are amphoteric, low mass, high water soluble, and do not have chromophore. They are very difficult to be retained on a reversed phase HPLC and detected by UV or fluorescence detectors. A liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed to determine these analytes in soybean and corn using a reversed phase with weak anion-exchange and cation-exchange mixed-mode Acclaim (TM) Trinity (TM) Q1 column. The sample was shaken with water containing ethylenediaminetetraacetic acid disodium salt (Na(2)EDTA) and acetic acid for 10 min to precipitate protein and extract the analytes into the solution. The supernatant was passed thru an Oasis HLB SPE to retain suspended particulates and non-polar interferences. The sample was directly injected and analyzed in 6 min by LC-MS/MS with no sample concentration or derivatization steps. Three isotopically labeled internal standards corresponding to each analyte were used to counter matrix suppression effect. Linearity of the detector response with a minimum coefficient of determination (R (2)) of more than 0.995 was demonstrated in the range of 10 to 1000 ng/mL for each analyte. Accuracy (recovery %) and precision (relative standard deviation or RSD %) were evaluated at the fortification levels of 0.1, 0.5, and 2 mu g/g in seven replicates in both soybean and corn samples. C1 [Chamkasem, Narong; Harmon, Tiffany] US FDA, Southeast Reg Lab, 60 Eighth St NE, Atlanta, GA 30309 USA. RP Chamkasem, N (reprint author), US FDA, Southeast Reg Lab, 60 Eighth St NE, Atlanta, GA 30309 USA. EM narong.chamkasem@fda.hhs.gov FU U.S. Food and Drug Administration FX The authors declare that there is no conflict of interest. Research was funded by U.S. Food and Drug Administration. NR 14 TC 0 Z9 0 U1 35 U2 52 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 JUL PY 2016 VL 408 IS 18 BP 4995 EP 5004 DI 10.1007/s00216-016-9597-6 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DQ1ZI UT WOS:000378999500018 PM 27150204 ER PT J AU Leonard, SR Mammel, MK Rasko, DA Lacher, DW AF Leonard, Susan R. Mammel, Mark K. Rasko, David A. Lacher, David W. TI Hybrid Shiga Toxin-Producing and Enterotoxigenic Escherichia sp Cryptic Lineage 1 Strain 7v Harbors a Hybrid Plasmid SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID COLI STRAINS; COMPARATIVE GENOMICS; FLAGELLIN GENES; EDEMA DISEASE; MULTIPLEX PCR; SEQUENCE; IDENTIFICATION; VIRULENCE; DIARRHEA; EVOLUTION AB Hybrid isolates of Shiga toxin-producing Escherichia coli (STEC) and enterotoxigenic E. coli (ETEC) encoding heat-stable enterotoxin (ST) are being reported with increasing frequency from a variety of sources. However, information regarding the plasmids that these strains harbor is scarce. In this study, we sequence and characterize a plasmid, p7v, from the STEC/ETEC hybrid strain 7v. Whole-genome phylogenetic analyses of STEC/ETEC hybrid strains and prototype E. coli isolates of other pathotypes placed 7v in the Escherichia sp. cryptic lineage 1 (CL1) clade. The complete plasmid, p7v, was determined to be 229,275 bp and encodes putative virulence factors that are typically carried on STEC plasmids as well as those often carried on ETEC plasmids, indicating that the hybrid nature of the strain extends beyond merely encoding the two toxins. Plasmid p7v carries two copies of sta with identical sequences, which were discovered to be divergent from the sta sequences found in the prototype human ETEC strains. Using a nomenclature scheme based on a phylogeny constructed from sta and stb sequences, the sta encoded on p7v is designated STa4. In silico analysis determined that p7v also encodes the K88 fimbria, a colonization factor usually associated with porcine ETEC plasmids. The p7v sequence and the presence of plasmid-encoded virulence factors are compared to those of other STEC/ETEC CL1 hybrid genomes and reveal gene acquisition/loss at the strain level. In addition, the interrogation of 24 STEC/ETEC hybrid genomes for identification of plasmid replicons, colonization factors, Stx and ST subtypes, and other plasmid- encoded virulence genes highlights the diversity of these hybrid strains. IMPORTANCE Hybrid Shiga toxin-producing Escherichia coli/enterotoxigenic Escherichia coli (STEC/ETEC) strains, which have been isolated from environmental, animal, and human clinical samples, may represent an emerging threat as food-borne pathogens. Characterization of these strains is important for assessing virulence potential, aiding in the development of pathogen detection methods, and understanding how the hybrid strains evolve to potentially have a greater impact on public health. This study represents, to our knowledge, both the first characterization of a closed plasmid sequence from a STEC/ETEC hybrid strain and the most comprehensive phylogenetic analysis of available STEC/ETEC hybrid genomes to date. The results demonstrate how the mobility of plasmid-associated virulence genes has resulted in the creation of a diverse plasmid repertoire within the STEC/ ETEC hybrid strains. C1 [Leonard, Susan R.; Mammel, Mark K.; Lacher, David W.] US FDA, Ctr Food Safety & Appl Nutr, Div Mol Biol, Laurel, MD 20708 USA. [Rasko, David A.] Univ Maryland, Sch Med, Inst Genome Sci, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. RP Leonard, SR (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Mol Biol, Laurel, MD 20708 USA. EM susan.leonard@fda.hhs.gov FU Oak Ridge Institute for Science and Education FX S.R.L. was supported by a fellowship appointment administered by Oak Ridge Institute for Science and Education. NR 52 TC 1 Z9 1 U1 4 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD JUL PY 2016 VL 82 IS 14 BP 4309 EP 4319 DI 10.1128/AEM.01129-16 PG 11 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DQ6WB UT WOS:000379345100025 PM 27208138 ER PT J AU Murphy, MV Du, DY Hua, W Cortez, KJ Butler, MG Davis, RL DeCoster, TA Johnson, L Li, LL Nakasato, C Nordin, JD Ramesh, M Schum, M Von Worley, A Zinderman, C Platt, R Klompas, M AF Murphy, Michael V. Du, Dongyi (Tony) Hua, Wei Cortez, Karoll J. Butler, Melissa G. Davis, Robert L. DeCoster, Thomas A. Johnson, Laura Li, Lingling Nakasato, Cynthia Nordin, James D. Ramesh, Mayur Schum, Michael Von Worley, Ann Zinderman, Craig Platt, Richard Klompas, Michael TI Risk Factors for Surgical Site Infections Following Anterior Cruciate Ligament Reconstruction SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID SEPTIC ARTHRITIS; UNITED-STATES; HUMAN TISSUE; ALLOGRAFT; AUTOGRAFT; SURGERY; GRAFT; OUTCOMES; KNEE AB OBJECTIVE. To determine the effect of graft choice (allograft, bone-patellar tendon-bone autograft, or hamstring autograft) on deep tissue infections following anterior cruciate ligament (ACL) reconstructions. DESIGN. Retrospective cohort study. SETTING AND POPULATION. Patients from 6 US health plans who underwent ACL reconstruction from January 1, 2000, through December 31, 2008. METHODS. We identified ACL reconstructions and potential postoperative infections using claims data. A hierarchical stratified sampling strategy was used to identify patients for medical record review to confirm ACL reconstructions and to determine allograft vs autograft tissue implanted, clinical characteristics, and infection status. We estimated infection rates overall and by graft type. We used logistic regression to assess the association between infections and patients' demographic characteristics, comorbidities, and choice of graft. RESULTS. On review of 1,452 medical records, we found 55 deep wound infections. With correction for sampling weights, infection rates varied by graft type: 0.5% (95% CI, 0.3%-0.8%) with allografts, 0.6% (0.1%-1.5%) with bone-patellar tendon-bone autografts, and 2.5% (1.9%-3.1%) with hamstring autograft. After adjusting for potential confounders, we found an increased infection risk with hamstring autografts compared with allografts (odds ratio, 5.9; 95% CI, 2.8-12.8). However, there was no difference in infection risk among bone-patellar tendon-bone autografts vs allografts (odds ratio, 1.2; 95% CI, 0.3-4.8). CONCLUSIONS. The overall risk for deep wound infections following ACL reconstruction is low but it does vary by graft type. Infection risk was highest in hamstring autograft recipients compared with allograft recipients and bone-patellar tendon-bone autograft recipients. C1 [Murphy, Michael V.; Li, Lingling; Platt, Richard; Klompas, Michael] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Murphy, Michael V.; Li, Lingling; Platt, Richard; Klompas, Michael] Harvard Pilgrim Hlth Care Inst, 401 Pk Dr,Ste 401, Boston, MA 02215 USA. [Du, Dongyi (Tony); Hua, Wei; Zinderman, Craig] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Cortez, Karoll J.] US FDA, Off Cellular Tissue & Gene Therapies, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Butler, Melissa G.; Davis, Robert L.] Kaiser Permanentema, Ctr Clin & Outcomes Res, Atlanta, GA USA. [DeCoster, Thomas A.] Univ New Mexico, Sch Med, Dept Orthopaed & Rehabil, Albuquerque, NM 87131 USA. [Johnson, Laura; Ramesh, Mayur] Henry Ford Hlth Syst, Ctr Hlth Serv Res, Detroit, MI USA. [Nakasato, Cynthia] Kaiser Permanente Hawaii, Ctr Hlth Res, Honolulu, HI USA. [Nordin, James D.] HealthPartners Inst Educ & Res, Minneapolis, MN USA. [Schum, Michael; Von Worley, Ann] LCF Res, Hlth Serv Res Div, Albuquerque, NM USA. [Klompas, Michael] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. RP Murphy, MV (reprint author), Harvard Pilgrim Hlth Care Inst, 401 Pk Dr,Ste 401, Boston, MA 02215 USA. EM michael.v.murphy@gmail.com FU US Food and Drug Administration [HHSF223 200810026I/TO6, HHSF22301005T] FX US Food and Drug Administration (HHSF223 200810026I/TO6 and HHSF22301005T). NR 36 TC 0 Z9 1 U1 0 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD JUL PY 2016 VL 37 IS 7 BP 827 EP 833 DI 10.1017/ice.2016.65 PG 7 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DQ3KL UT WOS:000379101100013 PM 27340734 ER PT J AU Wieslander, B Loring, Z Zareba, W McNitt, S Wagner, GS Daubert, JP Strauss, DG AF Wieslander, Bjorn Loring, Zak Zareba, Wojciech McNitt, Scott Wagner, Galen S. Daubert, James P. Strauss, David G. TI Scar burden assessed by Selvester QRS score predicts prognosis, not CRT clinical benefit in preventing heart failure event and death: A MADIT-CRT sub-study SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE Cardiac resynchronization therapy; Myocardial scar; Heart failure; Prognosis; Selvester QRS scoring ID CARDIAC-RESYNCHRONIZATION THERAPY; BUNDLE-BRANCH BLOCK; MAGNETIC-RESONANCE; MYOCARDIAL SCAR; QUANTIFICATION; CARDIOMYOPATHY; DYSSYNCHRONY; CONDUCTION; SURVIVAL; OUTCOMES AB Background: There is a need for improved selection criteria for cardiac resynchronization therapy (CRT). High myocardial scar burden has been associated with worse outcome in CRT patients. However, it is unclear whether high scar burden prevents CRT clinical benefit or is merely predictive of prognosis in heart failure (HF) patients regardless of CRT implantation. We aimed to study the predictive value of scar burden estimated by electrocardiographic Selvester QRS scoring in determining CRT benefit in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) population. Methods: Selvester QRS scoring was performed on all 1820 ECGs of the MADIT-CRT population by a single observer. In both arms and in their respective LBBB subgroups, QRS score was analyzed in comparison to echocardiographic volumes and in relation to time to HF event or death using Cox proportional hazard ratios. To determine effect on CRT clinical benefit, we tested for interaction between the effects of CRT assignment and QRS score on time to HF event or death. Results: In the CRT-D arm, a significant correlation was found between higher continuous QRS score and less increase of left ventricular ejection fraction (LVEF) as well as less decrease of left ventricular end-systolic volume (LVESV) (multivariate -p-values: <0.001). QRS score was significantly correlated with HF event/death in the left bundle branch block (LBBB) subgroup (n = 1037, multivariate HR 1.07 per point, p = 0.046). Scar extent estimated by QRS scoring was neither predictive of CRT clinical benefit in the total study population (interaction -p-value = 0.25) nor in the LBBB subgroup (interaction p-value = 0.86). Conclusion: High scar burden estimated by Selvester QRS score is predictive of adverse overall prognosis in LBBB patients regardless of CRT implantation. However, QRS score does not identify patients who benefit clinically from CRT-D compared to implantation of ICD only. (C) 2016 Elsevier Inc. All rights reserved. C1 [Wieslander, Bjorn] Karolinska Inst, Dept Clin Physiol, Stockholm, Sweden. [Loring, Zak; Strauss, David G.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Zareba, Wojciech] Univ Rochester, Med Ctr, Dept Med, Cardiol Unit, Rochester, NY 14642 USA. [McNitt, Scott] Univ Rochester, Med Ctr, Heart Res Follow Up Program, Rochester, NY 14642 USA. [Wagner, Galen S.] Duke Clin Res Inst, Durham, NC USA. [Daubert, James P.] Duke Univ, Med Ctr, Div Cardiol, Electrophysiol Sect, Durham, NC 27710 USA. [Daubert, James P.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. RP Loring, Z (reprint author), Univ Calif San Francisco, Dept Internal Med, San Francisco, CA 94143 USA. EM zak.loring@ucsf.edu NR 26 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 JUL-AUG PY 2016 VL 49 IS 4 BP 603 EP 609 DI 10.1016/j.jelectrocard.2016.04.008 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DQ1SY UT WOS:000378981900021 PM 27212144 ER PT J AU Hu, JP Hu, ZH Zhang, Y Gou, XJ Mu, Y Wang, LR Xie, XQ AF Hu, Jianping Hu, Ziheng Zhang, Yan Gou, Xiaojun Mu, Ying Wang, Lirong Xie, Xiang-Qun TI Metal binding mediated conformational change of XPA protein: a potential cytotoxic mechanism of nickel in the nucleotide excision repair SO JOURNAL OF MOLECULAR MODELING LA English DT Article DE Cytotoxic mechanism; Nickel ion; Nucleotide excision repair; XPA; Zn-finger ID MOLECULAR-DYNAMICS SIMULATIONS; ZINC-FINGER PROTEINS; PRINCIPAL COMPONENT ANALYSIS; STRANDED-DNA-BINDING; DAMAGED DNA; SECONDARY STRUCTURE; STRUCTURAL INSIGHT; ATOMIC CHARGES; FORCE-FIELD; DOMAIN AB Nucleotide excision repair (NER) is a pivotal life process for repairing DNA nucleotide mismatch caused by chemicals, metal ions, radiation, and other factors. As the initiation step of NER, the xeroderma pigmentosum complementation group A protein (XPA) recognizes damaged DNA molecules, and recruits the replication protein A (RPA), another important player in the NER process. The stability of the Zn2+-chelated Zn-finger domain of XPA center core portion (i.e., XPA(98-210)) is the foundation of its biological functionality, while the displacement of the Zn2+ by toxic metal ions (such as Ni2+, a known human carcinogen and allergen) may impair the effectiveness of NER and hence elevate the chance of carcinogenesis. In this study, we first calculated the force field parameters for the bonded model in the metal center of the XPA(98-210) system, showing that the calculated results, including charges, bonds, angles etc., are congruent with previously reported results measured by spectrometry experiments and quantum chemistry computation. Then, comparative molecular dynamics simulations using these parameters revealed the changes in the conformation and motion mode of XPA(98-210) Zn-finger after the substitution of Zn2+ by Ni2+. The results showed that Ni2+ dramatically disrupted the relative positions of the four Cys residues in the Zn-finger structure, forcing them to collapse from a tetrahedron into an almost planar structure. Finally, we acquired the binding mode of XPA(98-210) with its ligands RPA70N and DNA based on molecular docking and structural alignment. We found that XPA(98-210)'s Zn-finger domain primarily binds to a V-shaped cleft in RPA70N, while the cationic band in its Cterminal subdomain participates in the recognition of damaged DNA. In addition, this article sheds light on the multi-component interaction pattern among XPA, DNA, and other NER-related proteins (i.e., RPA70N, RPA70A, RPA70B, RPA70C, RPA32, and RPA14) based on previously reported structural biology information. Thus, we derived a putative cytotoxic mechanism associated with the nickel ion, where the Ni2+ disrupts the conformation of the XPA Zn-finger, directly weakening its interaction with RPA70N, and thus lowering the effectiveness of the NER process. In sum, this work not only provides a theoretical insight into the multiprotein interactions involved in the NER process and potential cytotoxic mechanism associated with Ni2+ binding in XPA, but may also facilitate rational anticancer drug design based on the NER mechanism. C1 [Hu, Jianping] Leshan Normal Univ, Coll Chem, Leshan 614004, Sichuan, Peoples R China. [Hu, Jianping; Hu, Ziheng; Zhang, Yan; Wang, Lirong; Xie, Xiang-Qun] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15260 USA. [Hu, Jianping; Hu, Ziheng; Zhang, Yan; Wang, Lirong; Xie, Xiang-Qun] Univ Pittsburgh, Sch Pharm, Computat Chem Genom Screening Ctr, Pittsburgh, PA 15260 USA. [Hu, Jianping; Hu, Ziheng; Zhang, Yan; Wang, Lirong; Xie, Xiang-Qun] Univ Pittsburgh, Natl Ctr Excellence Computat Drug Abuse Res, NIH, Pittsburgh, PA 15260 USA. [Hu, Jianping; Hu, Ziheng; Zhang, Yan; Wang, Lirong; Xie, Xiang-Qun] Univ Pittsburgh, Drug Discovery Inst, Pittsburgh, PA 15260 USA. [Hu, Jianping; Hu, Ziheng; Zhang, Yan; Wang, Lirong; Xie, Xiang-Qun] Univ Pittsburgh, Dept Computat Biol & Struct Biol, Sch Med, Pittsburgh, PA 15260 USA. [Hu, Jianping; Gou, Xiaojun] Chengdu Univ, Sch Pharm & Bioengn, Chengdu 610106, Sichuan, Peoples R China. [Hu, Jianping; Gou, Xiaojun] Chengdu Univ, Key Lab Med & Edible Plants Resources Dev, Sch Bioengn, Chengdu 610106, Sichuan, Peoples R China. [Mu, Ying] US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Wang, Lirong; Xie, Xiang-Qun] Univ Pittsburgh, Sch Pharm, 718 Salk Hall, Pittsburgh, PA 15261 USA. RP Wang, LR; Xie, XQ (reprint author), Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15260 USA.; Wang, LR; Xie, XQ (reprint author), Univ Pittsburgh, Sch Pharm, Computat Chem Genom Screening Ctr, Pittsburgh, PA 15260 USA.; Wang, LR; Xie, XQ (reprint author), Univ Pittsburgh, Natl Ctr Excellence Computat Drug Abuse Res, NIH, Pittsburgh, PA 15260 USA.; Wang, LR; Xie, XQ (reprint author), Univ Pittsburgh, Drug Discovery Inst, Pittsburgh, PA 15260 USA.; Wang, LR; Xie, XQ (reprint author), Univ Pittsburgh, Dept Computat Biol & Struct Biol, Sch Med, Pittsburgh, PA 15260 USA.; Wang, LR; Xie, XQ (reprint author), Univ Pittsburgh, Sch Pharm, 718 Salk Hall, Pittsburgh, PA 15261 USA. EM liw30@pitt.edu; xix15@pitt.edu FU NIDA [P30 DA035778A1]; NIH [R01 DA025612]; National Natural Science Foundation of China [11147175, 11247018]; Sichuan Provincial Education Bureau [12ZA066]; Leshan Science and Technology Administration [14GZD022] FX This work was supported by the funding from NIDA (P30 DA035778A1) and NIH (R01 DA025612), and in part by the National Natural Science Foundation of China (11147175, 11247018), the Key Project of Sichuan Provincial Education Bureau (12ZA066), the Project of Leshan Science and Technology Administration (14GZD022). NR 75 TC 1 Z9 1 U1 9 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1610-2940 EI 0948-5023 J9 J MOL MODEL JI J. Mol. Model. PD JUL PY 2016 VL 22 IS 7 AR 156 DI 10.1007/s00894-016-3017-x PG 19 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Multidisciplinary; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Chemistry; Computer Science GA DQ2EM UT WOS:000379014700011 PM 27307058 ER PT J AU Gintant, G Sager, PT Stockbridge, N AF Gintant, Gary Sager, Philip T. Stockbridge, Norman TI Evolution of strategies to improve preclinical cardiac safety testing SO NATURE REVIEWS DRUG DISCOVERY LA English DT Article ID CELL-DERIVED CARDIOMYOCYTES; PLURIPOTENT STEM-CELLS; TORSADES-DE-POINTES; LONG QT SYNDROME; ACTION-POTENTIAL DURATION; RABBIT VENTRICULAR WEDGE; CONTENT SCREENING ASSAY; AUTOMATED PATCH-CLAMP; PROTEIN-KINASE-C; IN-VITRO AB The early and efficient assessment of cardiac safety liabilities is essential to confidently advance novel drug candidates. This article discusses evolving mechanistically based preclinical strategies for detecting drug-induced electrophysiological and structural cardiotoxicity using in vitro human ion channel assays, human-based in silico reconstructions and human stem cell-derived cardiomyocytes. These strategies represent a paradigm shift from current approaches, which rely on simplistic in vitro assays that measure blockade of the K(v)11.1 current (also known as the hERG current or I-Kr) and on the use of non-human cells or tissues. These new strategies have the potential to improve sensitivity and specificity in the early detection of genuine cardiotoxicity risks, thereby reducing the likelihood of mistakenly discarding viable drug candidates and speeding the progression of worthy drugs into clinical trials. C1 [Gintant, Gary] AbbVie, Dept Integrat Pharmacol Integrated Sci & Technol, Dept ZR 13,Bldg AP9 01,1 North Waukegan Rd, N Chicago, IL 60064 USA. [Sager, Philip T.] Stanford Univ, 719 Carolina St, San Francisco, CA 94107 USA. [Stockbridge, Norman] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Gintant, G (reprint author), AbbVie, Dept Integrat Pharmacol Integrated Sci & Technol, Dept ZR 13,Bldg AP9 01,1 North Waukegan Rd, N Chicago, IL 60064 USA. EM gary.gintant@abbvie.com NR 168 TC 13 Z9 14 U1 1 U2 5 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 JUL PY 2016 VL 15 IS 7 BP 457 EP 471 DI 10.1038/nrd.2015.34 PG 15 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA DQ5UH UT WOS:000379270000014 PM 26893184 ER PT J AU Whyte, J AF Whyte, John TI FDA Implements New Labeling for Medications Used During Pregnancy and Lactation SO AMERICAN FAMILY PHYSICIAN LA English DT Editorial Material C1 [Whyte, John] US FDA, Silver Spring, MD 20993 USA. RP Whyte, J (reprint author), US FDA, Silver Spring, MD 20993 USA. EM John.Whyte@fda.hhs.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X EI 1532-0650 J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD JUL 1 PY 2016 VL 94 IS 1 BP 12 EP + PG 2 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA DP7HD UT WOS:000378668900001 PM 27386718 ER PT J AU Brown, C Routon, PW AF Brown, Christian Routon, P. Wesley TI Military Service and the Civilian Labor Force: Time- and Income-Based Evidence SO ARMED FORCES & SOCIETY LA English DT Article DE military service; veterans; civilian earnings; NLSY; quantile regression ID WORLD-WAR-II; QUANTILE REGRESSION; VETERAN STATUS; VIETNAM ERA; SOCIOECONOMIC-STATUS; SCREENING DEVICE; EARNINGS; DRAFT; WAGE; RACE AB The average American military enlistee is likely to differ from the average civilian in employment ambitions and prospects. Current research on veteran wages, however, only examines the effect of military service on average earnings. We employ quantile regression techniques to estimate the effect of military service for the above- and below-average earnings that veterans may experience. We draw data from two longitudinal surveys, one including veterans who served during 1980-1994 and the other including veterans of the early 21st-century wars in Afghanistan and Iraq. For the 21st-century cohort, we find that military service appears to increase wages at and below the median wage but decrease earnings at the high end of the distribution, although these benefits may take several years after service and entry into the civilian labor market to appear. C1 [Brown, Christian] US FDA, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Routon, P. Wesley] Georgia Gwinnett Coll, Econ, Lawrenceville, GA USA. RP Brown, C (reprint author), US FDA, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM christian.brown@fda.hhs.gov NR 42 TC 0 Z9 0 U1 11 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0095-327X EI 1556-0848 J9 ARMED FORCES SOC JI Armed Forces Soc. PD JUL PY 2016 VL 42 IS 3 BP 562 EP 584 DI 10.1177/0095327X15625499 PG 23 WC Political Science; Sociology SC Government & Law; Sociology GA DP3VZ UT WOS:000378425300005 ER PT J AU Mehrotra, N Bhattaram, A Earp, JC Florian, J Krudys, K Lee, JE Lee, JY Liu, J Mulugeta, Y Yu, JY Zhao, P Sinha, V AF Mehrotra, Nitin Bhattaram, Atul Earp, Justin C. Florian, Jeffry Krudys, Kevin Lee, Jee Eun Lee, Joo Yeon Liu, Jiang Mulugeta, Yeruk Yu, Jingyu Zhao, Ping Sinha, Vikram TI Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID ADVERSE DRUG-REACTIONS; REGULATORY SCIENCE; LIVER-CIRRHOSIS; CHILDREN; IMPACT; SIMULATION; PHARMACOKINETICS; PHARMACOMETRICS; DECISIONS; MODEL AB Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twice-daily regimen, different once-daily dosing regimens for treatment-naive human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy. C1 [Mehrotra, Nitin; Bhattaram, Atul; Earp, Justin C.; Florian, Jeffry; Krudys, Kevin; Lee, Jee Eun; Liu, Jiang; Mulugeta, Yeruk; Yu, Jingyu; Zhao, Ping; Sinha, Vikram] US FDA, Div Pharmacometr, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,White Oak Bldg 51,Rm 3199, Silver Spring, MD 20993 USA. [Lee, Joo Yeon] US FDA, Div Biometr 7, Off Biostat, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Mehrotra, N (reprint author), US FDA, Div Pharmacometr, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,White Oak Bldg 51,Rm 3199, Silver Spring, MD 20993 USA. EM nitin.mehrotra@fda.hhs.gov NR 32 TC 2 Z9 2 U1 2 U2 2 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 JUL PY 2016 VL 44 IS 7 BP 924 EP 933 DI 10.1124/dmd.116.069559 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DP7TJ UT WOS:000378701800006 PM 27079249 ER PT J AU Yang, QJ Fan, JH Chen, S Liu, LT Sun, HD Pang, KS AF Yang, Qi Joy Fan, Jianghong Chen, Shu Liu, Lutan Sun, Huadong Pang, K. Sandy TI Metabolite Kinetics: The Segregated Flow Model for Intestinal and Whole Body Physiologically Based Pharmacokinetic Modeling to Describe Intestinal and Hepatic Glucuronidation of Morphine in Rats In Vivo SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID ORAL-DRUG ABSORPTION; 1ST-PASS METABOLISM; P-GLYCOPROTEIN; ESTRADIOL 17-BETA-D-GLUCURONIDE; ENTEROHEPATIC RECIRCULATION; SYSTEMIC AVAILABILITY; LIVER PREPARATION; PORTACAVAL-SHUNT; PBPK MODELS; ENZYMES AB We used the intestinal segregated flow model (SFM) versus the traditional model (TM), nested within physiologically based pharmacokinetic (PBPK) models, to describe the biliary and urinary excretion of morphine 3 beta-glucuronide (MG) after intravenous and intraduodenal dosing of morphine in rats in vivo. The SFM model describes a partial (5%-30%) intestinal blood flow perfusing the transporter- and enzyme-rich enterocyte region, whereas the TM describes 100% flow perfusing the intestine as a whole. For the SFM, drugs entering from the circulation are expected to be metabolized to lesser extents by the intestine due to the segregated flow, reflecting the phenomenon of shunting and route-dependent intestinal metabolism. The poor permeability of MG crossing the liver or intestinal basolateral membranes mandates that most of MG that is excreted into bile is hepatically formed, whereas MG that is excreted into urine originates from both intestine and liver metabolism, since MG is effluxed back to blood. The ratio of MG amounts in urine/bile (A(urine)(MG)/A(bile)(MG)) for intraduodenal/intravenous dosing is expected to exceed unity for the SFM but approximates unity for the TM. Compartmental analysis of morphine and MG data, without consideration of the permeability of MG and where MG is formed, suggests the ratio to be 1 and failed to describe the kinetics of MG. Theobserved intraduodenal/intravenous ratio of A(urine),(MG)(4h)/A(bile,4h)(MG)(2.55 at 4 hours) was better predicted by the SFM-PBPK (2.59 at 4 hours) and not the TM-PBPK (1.0), supporting the view that the SFM is superior for the description of intestinal-livermetabolism of morphine to MG. The SFM-PBPK model predicts an appreciable contribution of the intestine to first pass M metabolism. C1 [Yang, Qi Joy; Fan, Jianghong; Chen, Shu; Liu, Lutan; Sun, Huadong; Pang, K. Sandy] Univ Toronto, Leslie Dan Fac Pharm, Dept Pharmaceut Sci, Toronto, ON M5S 3M2, Canada. [Fan, Jianghong] US FDA, Off Gener Drugs, Silver Spring, MD USA. [Chen, Shu] Apotex Inc, Toronto, ON, Canada. [Sun, Huadong] Bristol Myers Squibb Co, Princeton, NJ USA. RP Pang, KS (reprint author), Univ Toronto, Leslie Dan Fac Pharm, 144 Coll St, Toronto, ON M5S 3M2, Canada. EM ks.pang@utoronto.ca FU Canadian Institutes of Health Research; Ontario Graduate Scholarship Program FX This research was supported by the Canadian Institutes of Health Research [(to K.S.P.)] and the Ontario Graduate Scholarship Program [(to Q.J.Y.)]. NR 59 TC 2 Z9 2 U1 5 U2 8 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 JUL PY 2016 VL 44 IS 7 BP 1123 EP 1138 DI 10.1124/dmd.116.069542 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DP7TJ UT WOS:000378701800030 PM 27098743 ER PT J AU Sarntivijai, S Zhang, S Jagannathan, DG Zaman, S Burkhart, KK Omenn, GS He, YQ Athey, BD Abernethy, DR AF Sarntivijai, Sirarat Zhang, Shelley Jagannathan, Desikan G. Zaman, Shadia Burkhart, Keith K. Omenn, Gilbert S. He, Yongqun Athey, Brian D. Abernethy, Darrell R. TI Linking MedDRA (R)-Coded Clinical Phenotypes to Biological Mechanisms by the Ontology of Adverse Events: A Pilot Study on Tyrosine Kinase Inhibitors SO DRUG SAFETY LA English DT Article ID CARDIOTOXICITY; INFORMATION; DISEASE; INTEGRATION; TERMS; TOOL AB Introduction A translational bioinformatics challenge exists in connecting population and individual clinical phenotypes in various formats to biological mechanisms. The Medical Dictionary for Regulatory Activities (MedDRA (R)) is the default dictionary for adverse event (AE) reporting in the US Food and Drug Administration Adverse Event Reporting System (FAERS). The ontology of adverse events (OAE) represents AEs as pathological processes occurring after drug exposures. Objectives The aim of this work was to establish a semantic framework to link biological mechanisms to phenotypes of AEs by combining OAE with MedDRA (R) in FAERS data analysis. We investigated the AEs associated with tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) targeting tyrosine kinases. The five selected TKIs/mAbs (i.e., dasatinib, imatinib, lapatinib, cetuximab, and trastuzumab) are known to induce impaired ventricular function (non-QT) cardiotoxicity. Results Statistical analysis of FAERS data identified 1053 distinct MedDRA (R) terms significantly associated with TKIs/mAbs, where 884 did not have corresponding OAE terms. We manually annotated these terms, added them to OAE by the standard OAE development strategy, and mapped them to MedDRA (R). The data integration to provide insights into molecular mechanisms of drug-associated AEs was performed by including linkages in OAE for all related AE terms to MedDRA (R) and the existing ontologies, including the human phenotype ontology (HP), Uber anatomy ontology (UBERON), and gene ontology (GO). Sixteen AEs were shared by all five TKIs/mAbs, and each of 17 cardiotoxicity AEs was associated with at least one TKI/mAb. As an example, we analyzed "cardiac failure" using the relations established in OAE with other ontologies and demonstrated that one of the biological processes associated with cardiac failure maps to the genes associated with heart contraction. Conclusion By expanding the existing OAE ontological design, our TKI use case demonstrated that the combination of OAE and MedDRA (R) provides a semantic framework to link clinical phenotypes of adverse drug events to biological mechanisms. C1 [Sarntivijai, Sirarat; Zaman, Shadia; Burkhart, Keith K.; Abernethy, Darrell R.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Zhang, Shelley] Univ Michigan, Coll Literature Sci & Arts, Ann Arbor, MI 48109 USA. [Jagannathan, Desikan G.] Univ Michigan, Coll Engn, Ann Arbor, MI 48109 USA. [He, Yongqun] Univ Michigan, Unit Lab Anim Med, Ann Arbor, MI 48109 USA. [Omenn, Gilbert S.] Univ Michigan, Dept Internal Med & Human Genet, Ann Arbor, MI 48109 USA. [Omenn, Gilbert S.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Sarntivijai, Sirarat; Omenn, Gilbert S.; He, Yongqun; Athey, Brian D.] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Omenn, Gilbert S.; Athey, Brian D.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [He, Yongqun] Univ Michigan, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. [Athey, Brian D.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. RP Sarntivijai, S (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA.; Sarntivijai, S (reprint author), Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. EM siiraa@umich.edu OI Sarntivijai, Sirarat/0000-0002-2548-641X FU Oak Ridge Institute for Science and Education (ORISE); Undergraduate Research Opportunity Program at the University of Michigan; Food and Drug Administration (FDA) Commissioner's Fellowship Program; National Institute of Environmental Health Sciences (NIEHS) [P30ES017885-01A1]; National Institutes of Health (NIH) [U54 DA021529, UL1 TR000433-09]; National Institute of Allergy and Infectious Disease (NIAID) [R01 AI081062] FX This work was supported by the Oak Ridge Institute for Science and Education (ORISE) (Sirarat Sarntivijai), the Undergraduate Research Opportunity Program at the University of Michigan (Shelley Zhang, Desikan Jagannathan, Yongqun He), the Food and Drug Administration (FDA) Commissioner's Fellowship Program (Shadia Zaman), National Institute of Environmental Health Sciences (NIEHS) Grant Number P30ES017885-01A1 (Gilbert Omenn), National Institutes of Health (NIH) Grant Numbers U54 DA021529 and UL1 TR000433-09 (Brian Athey), and National Institute of Allergy and Infectious Disease (NIAID) Grant Number R01 AI081062 (Yongqun He). NR 38 TC 2 Z9 2 U1 1 U2 4 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0114-5916 EI 1179-1942 J9 DRUG SAFETY JI Drug Saf. PD JUL PY 2016 VL 39 IS 7 BP 697 EP 707 DI 10.1007/s40264-016-0414-0 PG 11 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA DP9GR UT WOS:000378805200008 PM 27003817 ER PT J AU Ebel, ED Williams, MS Cole, D Travis, CC Klontz, KC Golden, NJ Hoekstra, RM AF Ebel, Eric D. Williams, Michael S. Cole, Dana Travis, Curtis C. Klontz, Karl C. Golden, Neal J. Hoekstra, Robert M. TI Comparing Characteristics of Sporadic and Outbreak-Associated Foodborne Illnesses, United States, 2004-2011 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID SURVEILLANCE NETWORK FOODNET; DISEASE OUTBREAKS; SITES AB Outbreak data have been used to estimate the proportion of illnesses attributable to different foods. Applying outbreak based attribution estimates to nonoutbreak foodborne illnesses requires an assumption of similar exposure pathways for outbreak and sporadic illnesses. This assumption cannot be tested, but other comparisons can assess its veracity. Our study compares demographic, clinical, temporal, and geographic characteristics of outbreak and sporadic illnesses from Campylobacter, Escherichia colt 0157, Listeria, and Salmonella bacteria ascertained by the Foodborne Diseases Active Surveillance Network (FoodNet). Differences among FoodNet sites in outbreak and sporadic illnesses might reflect differences in surveillance practices. For Campylobacter, Listeria, and Escherichia colt 0157, outbreak and sporadic illnesses are similar for severity, sex, and age. For Salmonella, outbreak and sporadic illnesses are similar for severity and sex. Nevertheless, the percentage of outbreak illnesses in the youngest age category was lower. Therefore, we do not reject the assumption that outbreak and sporadic illnesses are similar. C1 [Ebel, Eric D.; Williams, Michael S.; Golden, Neal J.] US Dept Agr Dist Columbia, Washington, DC USA. [Cole, Dana; Hoekstra, Robert M.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Travis, Curtis C.] Leidos Inc, Reston, VA USA. [Klontz, Karl C.] Food & Drug Adm, College Pk, MD USA. RP Williams, MS (reprint author), Food Safety & Inspect Serv, Risk Assessment & Analyt Div, Off Publ Hlth Sci, USDA, 2150 Ctr Ave,Bldg D, Ft Collins, CO 80526 USA. EM mike.williams@fsis.usda.gov NR 16 TC 0 Z9 0 U1 3 U2 8 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 JUL PY 2016 VL 22 IS 7 BP 1193 EP 1200 DI 10.3201/eid2207.150833 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DP5UR UT WOS:000378563900007 PM 27314510 ER PT J AU Gonzalez-Escalona, N Gavilan, RG Toro, M Zamudio, ML Martinez-Urtaza, J AF Gonzalez-Escalona, Narjol Gavilan, Ronnie G. Toro, Magaly Zamudio, Maria L. Martinez-Urtaza, Jaime TI Outbreak of Vibrio parahaemolyticus Sequence Type 120, Peru, 2009 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID GENOME SEQUENCE; MARYLAND; SEROTYPE; O3-K6 AB In 2009, an outbreak of Vibrio parahaemolyticus occurred in Piura, Cajamarca, Lambayeque, and Lima, Peru. Whole-genome sequencing of clinical and environmental samples from the outbreak revealed a new V. parahaemolyticus clone. All the isolates identified belonged to a single clonal complex described exclusively in Asia before its emergence in Peru. C1 [Gonzalez-Escalona, Narjol] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Gavilan, Ronnie G.; Zamudio, Maria L.] Inst Nacl Salud, Lima, Peru. [Toro, Magaly] Univ Chile, Santiago, Chile. [Martinez-Urtaza, Jaime] Univ Bath, Milner Ctr Evolut, Bath BA2 7AY, Avon, England. RP Martinez-Urtaza, J (reprint author), Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath BA2 7AY, Avon, England. EM j.l.martinez-urtaza@bath.ac.uk RI Toro, Magaly/F-6525-2011 OI Toro, Magaly/0000-0002-6280-2215 FU University of Bath [VB-BB1JMU]; US Food and Drug Administration's Foods Program Intramural Funds FX This project was supported by the University of Bath project VB-BB1JMU and the US Food and Drug Administration's Foods Program Intramural Funds. NR 14 TC 1 Z9 1 U1 2 U2 6 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD JUL PY 2016 VL 22 IS 7 BP 1235 EP 1237 DI 10.3201/eid2207.151896 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DP5UR UT WOS:000378563900013 PM 27315090 ER PT J AU Zhang, Q Rajan, SS Tyner, KM Casey, BJ Dugard, CK Jones, Y Paredes, AM Clingman, CS Howard, PC Goering, PL AF Zhang, Qin Rajan, Sunder S. Tyner, Katherine M. Casey, Brendan J. Dugard, Christopher K. Jones, Yvonne Paredes, Angel M. Clingman, Chekesha S. Howard, Paul C. Goering, Peter L. TI Effects of iron oxide nanoparticles on biological responses and MR imaging properties in human mammary healthy and breast cancer epithelial cells SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS LA English DT Article DE magnetic resonance imaging; contrast agents; iron oxide; nanoparticles; breast epithelial cells ID MODIFIED SUPERPARAMAGNETIC NANOPARTICLES; CONTRAST AGENTS; IN-VITRO; MICROVASCULAR PERMEABILITY; DRUG-DELIVERY; GOLD NANOPARTICLES; OXIDATIVE STRESS; HUMAN MONOCYTES; CELLULAR UPTAKE; TUMOR-TISSUES AB Superparamagnetic iron oxide nanoparticles (SPIONs, diameters >50 nm) have received great attention due to their promising use as magnetic resonance imaging (MRI) contrast agents. In this study, we evaluated the cellular uptake and biological responses in vitro of ultrasmall SPIONs (USPIONs, diameters<50 nm). We compared the cellular responses between breast epithelia isolated from healthy and breast cancer donors after exposure to carboxy-terminated USPIONs (10 and 30 nm PEG-coated, 10 and 30 nm non-PEG-coated). The particles were characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS) and gel electrophoresis. Cellular interactions with USPIONs were assessed by confocal microscopy and TEM. Cellular uptake of USPIONs was quantified using ICP-MS. Cell viability was measured by MTT and neutral red uptake assays. T2* weighted MRI scans were performed using a 7T scanner. Results demonstrated that cell association/internalization of USPIONs was size- and surface coating-dependent (PEG vs. non-PEG), and higher cellular uptake of 10 and 30 nm non-coated particles was observed in both cell types compared with PEG-coated particles. Cell uptake for 10 and 30 nm non-coated particles was higher in cancer cells from two of three tested donors compared to healthy cells from three donors. There was no significant cytotoxicity observed for all tested particles. Significantly enhanced MRI contrast was observed following exposure to 10 and 30 nm non-coated particles compared to PEG-coated particles in both cell types. In comparison, cancer cells showed more enhanced MRI signals when compared to normal cells. The data indicate that cell responses following exposure to USPIONs are dependent on particle properties. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1032-1042, 2016. C1 [Zhang, Qin; Rajan, Sunder S.; Casey, Brendan J.; Goering, Peter L.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Tyner, Katherine M.] US FDA, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Dugard, Christopher K.; Jones, Yvonne; Paredes, Angel M.; Howard, Paul C.] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Clingman, Chekesha S.] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Goering, PL (reprint author), US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM peter.goering@fda.hhs.gov FU US Food and Drug Administration Office of Women's Health [750412CDH] FX Contract grant sponsor: US Food and Drug Administration Office of Women's Health; contract grant number: 750412CDH NR 39 TC 0 Z9 0 U1 8 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4973 EI 1552-4981 J9 J BIOMED MATER RES B JI J. Biomed. Mater. Res. Part B PD JUL PY 2016 VL 104 IS 5 BP 1032 EP 1042 DI 10.1002/jbm.b.33450 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DP6TL UT WOS:000378631600020 PM 26013845 ER PT J AU Linde, PG Archdeacon, P Breyer, MD Ibrahim, T Inrig, JK Kewalramani, R Lee, CC Neuland, CY Roy-Chaudhury, P Sloand, JA Meyer, R Smith, KA Snook, J West, M Falk, RJ AF Linde, Peter G. Archdeacon, Patrick Breyer, Matthew D. Ibrahim, Tod Inrig, Jula K. Kewalramani, Reshma Lee, Celeste Castillo Neuland, Carolyn Y. Roy-Chaudhury, Prabir Sloand, James A. Meyer, Rachel Smith, Kimberly A. Snook, Jennifer West, Melissa Falk, Ronald J. TI Overcoming Barriers in Kidney Health-Forging a Platform for Innovation SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID EVALUATION PROGRAM KEEP; RANDOMIZED CONTROLLED-TRIALS; DISEASE; NEPHROLOGY; QUALITY; DESIGN; CKD AB Innovation in kidney diseases is not commensurate with the effect of these diseases on human health and mortality or innovation in other key therapeutic areas. A primary cause of the dearth in innovation is that kidney diseases disproportionately affect a demographic that is largely disenfranchised, lacking sufficient advocacy, public attention, and funding. A secondary and likely consequent cause is that the existing infrastructure supporting nephrology research pales in comparison with those for other internal medicine specialties, especially cardiology and oncology. Citing such inequities, however, is not enough. Changing the status quo will require a coordinated effort to identify and redress the existing deficits. Specifically, these deficits relate to the need to further develop and improve the following: understanding of the disease mechanisms and pathophysiology, patient engagement and activism, clinical trial infrastructure, and investigational clinical trial designs as well as coordinated efforts among critical stakeholders. This paper identifies potential solutions to these barriers, some of which are already underway through the Kidney Health Initiative. The Kidney Health Initiative is unique and will serve as a current and future platform from which to overcome these barriers to innovation in nephrology. C1 [Linde, Peter G.] AbbVie Inc, Global Pharmaceut Res & Dev, N Chicago, IL USA. [Archdeacon, Patrick] US FDA, Ctr Drug Evaluat & Res, Off Med Policy, Silver Spring, MD USA. [Neuland, Carolyn Y.] US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Div Reprod Gastrorenal & Urol Devices, Silver Spring, MD USA. [Breyer, Matthew D.] Eli Lilly & Co, Biotechnol Discovery Res, Indianapolis, IN 46285 USA. [Ibrahim, Tod; Meyer, Rachel; West, Melissa] Amer Soc Nephrol, Washington, DC 20005 USA. [Inrig, Jula K.] Quintiles Therapeut Sci & Strategy Unit, San Diego, CA USA. [Kewalramani, Reshma] Amgen Inc, Thousand Oaks, CA 91320 USA. [Lee, Celeste Castillo] Vasculitis Fdn, Chapel Hill, NC USA. [Roy-Chaudhury, Prabir] Univ Arizona, Div Nephrol, Tucson, AZ USA. [Sloand, James A.] Baxter Healthcare Corp, Deerfield, IL USA. [Smith, Kimberly A.] Ctr Medicare & Medicaid Serv, Ctr Clin Stand & Qual, Baltimore, MD USA. [Snook, Jennifer] Amer Soc Nephrol, Chicago, IL USA. [Falk, Ronald J.] Univ N Carolina, Dept Med, Div Nephrol, Chapel Hill, NC USA. [Smith, Kimberly A.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Linde, PG; Falk, RJ (reprint author), Amer Soc Nephrol, Kidney Hlth Initiat, 1510 H St NW,Suite 800, Washington, DC 20005 USA. EM peter.linde@abbvie.com; ronald_falk@med.unc.edu FU Kidney Health Initiative (KHI); KHI funds FX This work was supported by the Kidney Health Initiative (KHI), a public-private partnership between the American Society of Nephrology, the US Food and Drug Administration, and >75 member organizations and companies to enhance patient safety and foster innovation in kidney disease. The KHI funds were used to defray costs incurred during the conduct of the project, including project management support. However, there was no honorarium or other financial support provided to the KHI workgroup members. The KHI workgroup, including the authors of this paper, had final review authority and is fully responsible for its content. The KHI makes every effort to avoid actual, potential, or perceived conflicts of interest that may arise as a result of industry relationships or personal interests among the members of the writing committee and work group. More information on the KM, the workgroup, or the conflict of interest policy can be found at www.kidneyhealthinitiative.org. NR 24 TC 3 Z9 3 U1 1 U2 5 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2016 VL 27 IS 7 BP 1902 EP 1910 DI 10.1681/ASN.2015090976 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA DP9OD UT WOS:000378824800007 PM 27127187 ER PT J AU Lash, TL Fox, MP Cooney, D Lu, Y Forshee, RA AF Lash, Timothy L. Fox, Matthew P. Cooney, Darryl Lu, Yun Forshee, Richard A. TI Quantitative Bias Analysis in Regulatory Settings SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID GUILLAIN-BARRE-SYNDROME; DESIGNS AB Nonrandomized studies are essential in the postmarket activities of the US Food and Drug Administration, which, however, must often act on the basis of imperfect data. Systematic errors can lead to inaccurate inferences, so it is critical to develop analytic methods that quantify uncertainty and bias and ensure that these methods are implemented when needed. "Quantitative bias analysis" is an overarching term for methods that estimate quantitatively the direction, magnitude, and uncertainty associated with systematic errors influencing measures of associations. The Food and Drug Administration sponsored a collaborative project to develop tools to better quantify the uncertainties associated with postmarket surveillance studies used in regulatory decision making. We have described the rationale, progress, and future directions of this project. C1 [Lash, Timothy L.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Fox, Matthew P.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Cooney, Darryl] SciMetrika LLC, Durham, NC USA. [Lu, Yun; Forshee, Richard A.] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Lash, TL (reprint author), Rollins Sch Publ Hlth, Dept Epidemiol, 1518 Clifton Rd NE,1518-002-3BB, Atlanta, GA 30322 USA. EM tlash@emory.edu NR 26 TC 0 Z9 0 U1 1 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2016 VL 106 IS 7 BP 1227 EP 1230 DI 10.2105/AJPH.2016.303199 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DO7CL UT WOS:000377939700041 PM 27196652 ER PT J AU Gonzalez-Escalona, N Toro, M Rump, LV Cao, GJ Nagaraja, TG Meng, JH AF Gonzalez-Escalona, Narjol Toro, Magaly Rump, Lydia V. Cao, Guojie Nagaraja, T. G. Meng, Jianghong TI Virulence Gene Profiles and Clonal Relationships of Escherichia coli O26:H11 Isolates from Feedlot Cattle as Determined by Whole-Genome Sequencing SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID UNITED-STATES; EXCISION ENHANCER; ANTIBIOTIC-RESISTANCE; STRAINS; OUTBREAK; BACTERIOPHAGES; DIVERSITY; INFECTION; O157/H7; IDENTIFICATION AB Escherichia coli O26 is the second most important enterohemorrhagic E. coli (EHEC) serogroup worldwide. Serogroup O26 strains are categorized mainly into two groups:enteropathogenic (EPEC) O26, carrying a locus of enterocyte effacement (LEE) and mostly causing mild diarrhea, and Shiga-toxigenic (STEC) O26, which carries the Shiga toxin (STX) gene (stx), responsible for more severe outcomes. stx-negative O26 strains can be further split into two groups. One O26 group differs significantly from O26 EHEC, while the other O26 EHEC-like group shows all the characteristics of EHEC O26 except production of STX. In order to determine the different populations of O26 E. coli present in U.S. cattle, we sequenced 42 O26:H11 strains isolated from feedlot cattle and compared them to 37 O26:H11 genomes available in GenBank. Phylogenetic analysis by whole-genome multilocus sequence typing (wgMLST) showed that O26:H11/H- strains in U.S. cattle were highly diverse. Most strains were sequence type 29 (ST29). By wgMLST, two clear lineages could be distinguished among cattle strains. Lineage 1 consisted of O26:H11 EHEC-like strains (ST29) (4 strains) and O26:H11 EHEC strains (ST21) (2 strains), and lineage 2 (36 strains) consisted of O26: H11 EPEC strains (ST29). Overall, our analysis showed U.S. cattle carried pathogenic (ST21; stx(1)(+) ehxA(+) toxB(+)) and also potentially pathogenic (ST29; ehxA(+) toxB(+)) O26:H11 E. coli strains. Furthermore, in silico analysis showed that 70% of the cattle strains carried at least one antimicrobial resistance gene. Our results showed that whole-genome sequence analysis is a robust and valid approach to identify and genetically characterize E. coli O26:H11, which is of importance for food safety and public health. C1 [Gonzalez-Escalona, Narjol] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Toro, Magaly] Univ Chile, Inst Nutr & Tecnol Alimentos, Santiago, Chile. [Rump, Lydia V.; Cao, Guojie; Meng, Jianghong] Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 USA. [Rump, Lydia V.; Cao, Guojie; Meng, Jianghong] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Nagaraja, T. G.] Kansas State Univ, Coll Vet Med, Dept Diagnost Med & Pathobiol, Manhattan, KS 66506 USA. RP Gonzalez-Escalona, N (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. EM narjol.gonzalez-escalona@fda.hhs.gov RI Toro, Magaly/F-6525-2011 OI Toro, Magaly/0000-0002-6280-2215 FU FDA Food Science and Research Intramural Program; Agriculture and Food Research Initiative from the USDA National Institute of Food and Agriculture [2012-68003-30155] FX This work was supported by the FDA Food Science and Research Intramural Program and was based, in part, upon previous work supported by Agriculture and Food Research Initiative competitive grant 2012-68003-30155 from the USDA National Institute of Food and Agriculture. NR 55 TC 1 Z9 1 U1 3 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD JUL PY 2016 VL 82 IS 13 BP 3900 EP 3912 DI 10.1128/AEM.00498-16 PG 13 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DO8QP UT WOS:000378048800023 PM 27107118 ER PT J AU Johnstone, RH Chang, ETY Bardenet, R de Boer, TP Gavaghan, DJ Pathmanathan, P Clayton, RH Mirams, GR AF Johnstone, Ross H. Chang, Eugene T. Y. Bardenet, Remi de Boer, Teun P. Gavaghan, David J. Pathmanathan, Pras Clayton, Richard H. Mirams, Gary R. TI Uncertainty and variability in models of the cardiac action potential: Can we build trustworthy models? SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Uncertainty quantification; Cardiac electrophysiology; Mathematical model; Probability ID HODGKIN-HUXLEY EQUATIONS; SAFETY ASSESSMENT; ION CHANNELS; ELECTROPHYSIOLOGY; SIMULATIONS; RECONSTRUCTION; MOXIFLOXACIN; MECHANISM; COMPLEX; MCMC AB Cardiac electrophysiology models have been developed for over 50 years, and now include detailed descriptions of individual ion currents and sub-cellular calcium handling. It is commonly accepted that there are many uncertainties in these systems, with quantities such as ion channel kinetics or expression levels being difficult to measure or variable between samples. Until recently, the original approach of describing model parameters using single values has been retained, and consequently the majority of mathematical models in use today provide point predictions, with no associated uncertainty. In recent years, statistical techniques have been developed and applied in many scientific areas to capture uncertainties in the quantities that determine model behaviour, and to provide a distribution of predictions which accounts for this uncertainty. In this paper we discuss this concept, which is termed uncertainty quantification, and consider how it might be applied to cardiac electrophysiology models. We present two case studies in which probability distributions, instead of individual numbers, are inferred from data to describe quantities such as maximal current densities. Then we show how these probabilistic representations of model parameters enable probabilities to be placed on predicted behaviours. We demonstrate how changes in these probability distributions across data sets offer insight into which currents cause beat-to-beat variability in canine APs. We conclude with a discussion of the challenges that this approach entails, and how it provides opportunities to improve our understanding of electrophysiology. (C) 2015 The Authors. Published by Elsevier Ltd. C1 [Johnstone, Ross H.; Gavaghan, David J.; Mirams, Gary R.] Univ Oxford, Dept Comp Sci, Computat Biol, Oxford OX1 3QD, England. [Chang, Eugene T. Y.; Clayton, Richard H.] Univ Sheffield, Insigneo Inst In Silico Med, Sheffield S1 4DP, S Yorkshire, England. [Chang, Eugene T. Y.; Clayton, Richard H.] Univ Sheffield, Dept Comp Sci, Sheffield S1 4DP, S Yorkshire, England. [Bardenet, Remi] Univ Lille, CNRS, F-59651 Villeneuve Dascq, France. [Bardenet, Remi] Univ Lille, CRIStAL, F-59651 Villeneuve Dascq, France. [de Boer, Teun P.] Univ Med Ctr Utrecht, Dept Med Physiol, Div Heart & Lungs, Utrecht, Netherlands. [Pathmanathan, Pras] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Mirams, GR (reprint author), Univ Oxford, Dept Comp Sci, Computat Biol, Oxford OX1 3QD, England.; Clayton, RH (reprint author), Univ Sheffield, Insigneo Inst In Silico Med, Sheffield S1 4DP, S Yorkshire, England.; Clayton, RH (reprint author), Univ Sheffield, Dept Comp Sci, Sheffield S1 4DP, S Yorkshire, England.; Pathmanathan, P (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM pras.pathmanathan@fda.hhs.gov; r.h.clayton@sheffield.ac.uk; gary.mirams@cs.ox.ac.uk RI Mirams, Gary/B-6653-2008; Chang, Eugene/I-5834-2015; OI Mirams, Gary/0000-0002-4569-4312; Chang, Eugene/0000-0002-1097-4189; de Boer, Teun/0000-0002-0561-6491; Clayton, Richard/0000-0002-8438-7518; gavaghan, david/0000-0001-8311-3200 FU Systems Approaches to Biomedical Science Industrial Doctorate Centre studentship [EP/G037280/1]; UK Engineering and Physical Sciences Research Council [EP/K037145/1]; Wellcome Trust [101222/Z/13/Z]; Royal Society [101222/Z/13/Z]; F. Hoffmann-La Roche AG FX RHJ is supported by a Systems Approaches to Biomedical Science Industrial Doctorate Centre studentship (EP/G037280/1) and F. Hoffmann-La Roche AG. RHC and ETYC gratefully acknowledge support from the UK Engineering and Physical Sciences Research Council (www.epsrc.ac.uk) grant number EP/K037145/1. GRM 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). NR 48 TC 4 Z9 4 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUL PY 2016 VL 96 BP 49 EP 62 DI 10.1016/j.yjmcc.2015.11.018 PG 14 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA DP4HW UT WOS:000378458000006 PM 26611884 ER PT J AU Sahin, L Nallani, SC Tassinari, MS AF Sahin, L. Nallani, S. C. Tassinari, M. S. TI Medication Use in Pregnancy and the Pregnancy and Lactation Labeling Rule SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB On 30 June 2015, the US Food and Drug Administration Pregnancy and Lactation Labeling Rule (PLLR) took effect. This rule sets new and improved standards for the inclusion of information about the use of prescription drugs and biological products during pregnancy and lactation. The new labeling requirements have important implications for clinical pharmacology as there is a subheading that is dedicated to inclusion of clinical pharmacology information that inform dosing during pregnancy and the postpartum period, if available. C1 [Sahin, L.; Tassinari, M. S.] US FDA, Div Pediat & Maternal Hlth, Off Drug Evaluat 4, Off New Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Nallani, S. C.] US FDA, Div Clin Pharmacol 2, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Nallani, SC (reprint author), US FDA, Div Clin Pharmacol 2, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Srikanth.Nallani@fda.hhs.gov NR 4 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 JUL PY 2016 VL 100 IS 1 BP 23 EP 25 DI 10.1002/cpt.380 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DO3UK UT WOS:000377707200018 PM 27082701 ER PT J AU Yoshida, K Sun, B Zhang, L Zhao, P Abernethy, DR Nolin, TD Rostami-Hodjegan, A Zineh, I Huang, SM AF Yoshida, K. Sun, B. Zhang, L. Zhao, P. Abernethy, D. R. Nolin, T. D. Rostami-Hodjegan, A. Zineh, I. Huang, S-M TI Systematic and Quantitative Assessment of the Effect of Chronic Kidney Disease on CYP2D6 and CYP3A4/5 SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID CHRONIC-RENAL-FAILURE; HEPATIC-CLEARANCE; DRUG-INTERACTIONS; PROTEIN-BINDING; IN-VITRO; PHARMACOKINETICS; IMPAIRMENT; INSUFFICIENCY; DISPOSITION; METABOLISM AB Recent reviews suggest that chronic kidney disease (CKD) can affect the pharmacokinetics of nonrenally eliminated drugs, but the impact of CKD on individual elimination pathways has not been systematically evaluated. In this study we developed a comprehensive dataset of the effect of CKD on the pharmacokinetics of CYP2D6- and CYP3A4/5-metabolized drugs. Drugs for evaluation were selected based on clinical drug-drug interaction (CYP3A4/5 and CYP2D6) and pharmacogenetic (CYP2D6) studies. Information from dedicated CKD studies was available for 13 and 18 of the CYP2D6 and CYP3A4/5 model drugs, respectively. Analysis of these data suggested that CYP2D6-mediated clearance is generally decreased in parallel with the severity of CKD. There was no apparent relationship between the severity of CKD and CYP3A4/5-mediated clearance. The observed elimination-route dependency in CKD effects between CYP2D6 and CYP3A4/5 may inform the need to conduct clinical CKD studies with nonrenally eliminated drugs for optimal use of drugs in patients with CKD. C1 [Yoshida, K.; Sun, B.; Zhang, L.; Zhao, P.; Abernethy, D. R.; Zineh, I.; Huang, S-M] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Sun, B.] Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Pharm, Shanghai 200030, Peoples R China. [Nolin, T. D.] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Ctr Clin Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Nolin, T. D.] Univ Pittsburgh, Dept Med, Sch Pharm, Renal Electrolyte Div, Pittsburgh, PA USA. [Nolin, T. D.] Univ Pittsburgh, Sch Med, Dept Pharm & Therapeut, Ctr Clin Pharmaceut Sci, Pittsburgh, PA USA. [Nolin, T. D.] Univ Pittsburgh, Sch Med, Dept Med, Renal Electrolyte Div, Pittsburgh, PA 15213 USA. [Rostami-Hodjegan, A.] Univ Manchester, Manchester Pharm Sch, Ctr Appl Pharmaceut Res, Manchester, Lancs, England. [Rostami-Hodjegan, A.] Simcyp, Sheffield, S Yorkshire, England. RP Huang, SM (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM ShiewMei.Huang@fda.hhs.gov FU US Food and Drug Administration's (FDA) Medical Countermeasures initiative; US Department of Energy; FDA FX The authors thank Drs. Aliza Thompson, Karen Rowland-Yeo, Kellie S Reynolds, Martina Sahre, Micheline Piquette-Miller, Rajanikanth Madabushi, and Robert Schuck for helpful discussions and their critical review of this article. This research was supported by the US Food and Drug Administration's (FDA) Medical Countermeasures initiative. Drs. Kenta Yoshida and Bo Sun were supported in part by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA. NR 51 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 JUL PY 2016 VL 100 IS 1 BP 75 EP 87 DI 10.1002/cpt.337 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DO3UK UT WOS:000377707200027 PM 26800425 ER PT J AU Sekine, S Pinnow, EE Wu, E Kurtzig, R Hall, M Dal Pan, GJ AF Sekine, S. Pinnow, E. E. Wu, E. Kurtzig, R. Hall, M. Dal Pan, G. J. TI Assessment of the Impact of Scheduled Postmarketing Safety Summary Analyses on Regulatory Actions SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID UPDATE REPORTS; DRUG; FDA; BIOPHARMACEUTICALS; DEADLINES; APPROVAL AB In addition to standard postmarketing drug safety monitoring, Section 915 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) requires the US Food and Drug Administration (FDA) to conduct a summary analysis of adverse event reports to identify risks of a drug or biologic product 18 months after product approval, or after 10,000 patients have used the product, whichever is later. We assessed the extent to which these analyses identified new safety signals and resultant safety-related label changes. Among 458 newly approved products, 300 were the subjects of a scheduled analysis; a new safety signal that resulted in a safety-related label change was found for 11 of these products. Less than 2% of 713 safety-related label changes were based on the scheduled analyses. Our study suggests that the safety summary analyses provide only marginal value over other pharmacovigilance activities. C1 [Sekine, S.; Pinnow, E. E.; Wu, E.; Kurtzig, R.; Hall, M.; Dal Pan, G. J.] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Sekine, S.] Pharmaceut & Med Devices Agcy, Off Int Programs, Tokyo, Japan. RP Pinnow, EE (reprint author), US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Ellen.Pinnow@fda.hhs.gov FU US Department of Energy; CDER FX This project was supported in part by an appointment to the ORISE Research Participation Program at the CDER administered by the Oak Ridge Institute for Science and Education through an agreement between the US Department of Energy and CDER. Ms. Sekine conducted this research while she was an ORISE fellow in the Office of Surveillance and Epidemiology, Center of Drug Evaluation and Research, US Food and Drug Administration. NR 17 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 JUL PY 2016 VL 100 IS 1 BP 102 EP 108 DI 10.1002/cpt.346 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DO3UK UT WOS:000377707200029 PM 26853718 ER PT J AU Vieira, AR Grass, J Fedorka-Cray, PJ Plumblee, JR Tate, H Cole, DJ AF Vieira, A. R. Grass, J. Fedorka-Cray, P. J. Plumblee, J. R. Tate, H. Cole, D. J. TI Attribution of Salmonella enterica serotype Hadar infections using antimicrobial resistance data from two points in the food supply system SO EPIDEMIOLOGY AND INFECTION LA English DT Article DE Analysis of data; foodborne infections; surveillance ID UNITED-STATES; ANIMAL ORIGIN; DISEASE; SURVEILLANCE; COMMODITIES; MODEL AB A challenge to the development of foodborne illness prevention measures is determining the sources of enteric illness. Microbial subtyping source-attribution models attribute illnesses to various sources, requiring data characterizing bacterial isolate subtypes collected from human and food sources. We evaluated the use of antimicrobial resistance data on isolates of Salmonella enterica serotype Hadar, collected from ill humans, food animals, and from retail meats, in two microbial subtyping attribution models. We also compared model results when either antimicrobial resistance or pulsed-field gel electrophoresis (PFGE) patterns were used to subtype isolates. Depending on the subtyping model used, 68-96% of the human infections were attributed to meat and poultry food products. All models yielded similar outcomes, with 86% [95% confidence interval (CI) 80-91] to 91% (95% CI 88-96) of the attributable infections attributed to turkey, and 6% (95% CI 2-10) to 14% (95% CI 8-20) to chicken. Few illnesses (<3%) were attributed to cattle or swine. Results were similar whether the isolates were obtained from food animals during processing or from retail meat products. Our results support the view that microbial subtyping models are a flexible and robust approach for attributing Salmonella Hadar. C1 [Vieira, A. R.; Grass, J.; Cole, D. J.] Ctr Dis Control & Prevent, Enter Dis Epidemiol Branch, Atlanta, GA USA. [Fedorka-Cray, P. J.; Plumblee, J. R.] USDA ARS, Athens, GA 30613 USA. [Tate, H.] US FDA, Silver Spring, MD USA. RP Vieira, AR (reprint author), Ctr Dis Control & Prevent, Enter Dis Epidemiol Branch, Atlanta, GA USA. EM vht8@cdc.gov NR 20 TC 0 Z9 0 U1 5 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 EI 1469-4409 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD JUL PY 2016 VL 144 IS 9 BP 1983 EP 1990 DI 10.1017/S0950268816000066 PG 8 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DO5JV UT WOS:000377820300023 PM 26838291 ER PT J AU Nahar, K Rashid, J Absar, S Al-Saikhan, FI Ahsan, F AF Nahar, Kamrun Rashid, Jahidur Absar, Shahriar Al-Saikhan, Fahad I. Ahsan, Fakhrul TI Liposomal Aerosols of Nitric Oxide (NO) Donor as a Long-Acting Substitute for the Ultra-Short-Acting Inhaled NO in the Treatment of PAH SO PHARMACEUTICAL RESEARCH LA English DT Article DE CAR peptide; inhalation delivery; nitric oxide donor; peptide link liposomes; pulmonary arterial hypertension; targeted drug delivery ID PULMONARY ARTERIAL-HYPERTENSION; DRUG-DELIVERY SYSTEMS; IN-VITRO; CATIONIC LIPOSOMES; HEPARAN-SULFATE; EX-VIVO; PEPTIDE; FASUDIL; CELLS; LUNG AB This study seeks to develop a liposomal formulation of diethylenetriamine NONOate (DN), a long acting nitric oxide (NO) donor, with a goal to replace inhaled NO (iNO) in the treatment of pulmonary arterial hypertension (PAH). Liposomal formulations were prepared by a lipid film hydration method and modified with a cell penetrating peptide, CAR. The particles were characterized for size, polydispersity index (PDI), zeta potential, entrapment efficiency, storage and nebulization stability, and in-vitro release profiles. The cellular uptake and transport were assessed in rat alveolar macrophages (NR8383) and transforming growth factor beta (TGF-beta) activated rat pulmonary arterial smooth muscle cells (PASMCs). The fraction of the formulation that enters the systemic circulation, after intratracheal administration, was determined in an Isolated Perfused Rat Lung (IPRL) model. The safety of the formulations were assessed using an MTT assay and by measuring injury markers in the bronchoalveolar lavage (BAL) fluid; the pharmacological efficacy was evaluated by monitoring the changes in the mean pulmonary arterial (mPAP) and systemic pressure (mSAP) in a monocrotaline (MCT) induced-PAH rat model Liposome size, zeta potential, and entrapment efficiency were 171 +/- 4 nm, -37 +/- 3 mV, and 46 +/- 5%, respectively. The liposomes released 70 +/- 5% of the drug in 8 h and were stable when stored at 4A degrees C. CAR-conjugated-liposomes were taken up more efficiently by PASMCs than liposomes-without-CAR; the uptake of the formulations by rat alveolar macrophages was minimal. DN-liposomes did not increase lung weight, protein quantity, and levels of injury markers in the BAL fluid. Intratracheal CAR-liposomes reduced the entry of liposomes from the lung to blood; the formulations produced a 40% reduction in mPAP for 180 minutes. This study establishes the proof-of-concept that peptide modified liposomal formulations of long-acting NO donor can be an alternative to short-acting iNO. C1 [Nahar, Kamrun; Rashid, Jahidur; Absar, Shahriar; Ahsan, Fakhrul] Texas Tech Univ, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci, 1300 Coulter St, Amarillo, TX 79106 USA. [Absar, Shahriar] US FDA, Off Gener Drugs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Al-Saikhan, Fahad I.] Prince Sattam Bin Abdulaziz Univ, Coll Pharm, POB 173, Al Kharj 11942, Saudi Arabia. RP Ahsan, F (reprint author), Texas Tech Univ, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci, 1300 Coulter St, Amarillo, TX 79106 USA. EM fakhrul.ahsan@ttuhsc.edu OI Rashid, Jahidur/0000-0002-1769-4067 FU American Recovery and Reinvestment Act Fund, NIH [1R15HL103431, 5 R01 HL114677-02] FX This work was supported in part by an American Recovery and Reinvestment Act Fund, NIH 1R15HL103431 and 5 R01 HL114677-02. NR 52 TC 2 Z9 2 U1 10 U2 17 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 JUL PY 2016 VL 33 IS 7 BP 1696 EP 1710 DI 10.1007/s11095-016-1911-7 PG 15 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DO2NB UT WOS:000377615600014 PM 27048347 ER PT J AU Moussa, EM Kotarek, J Blum, JS Marszal, E Topp, EM AF Moussa, E. M. Kotarek, J. Blum, J. S. Marszal, E. Topp, E. M. TI Physical Characterization and Innate Immunogenicity of Aggregated Intravenous Immunoglobulin (IGIV) in an In Vitro Cell-Based Model SO PHARMACEUTICAL RESEARCH LA English DT Article DE immunogenicity; immunoglobulin; monocytes; protein aggregates ID TRANSGENIC MOUSE MODEL; HUMAN GAMMA-GLOBULIN; ANTIBODY THERAPEUTICS; HUMAN MONOCYTES; AMYLOID-BETA; LINE THP-1; MICE; IGG; PERSPECTIVE; CYTOKINE AB To investigate in vitro the innate immune response to accelerated stress-induced aggregates of intravenous immunoglobulin (IGIV) using a well-defined human cell-line model, and to correlate the innate response to physical properties of the aggregates. IGIV aggregates were prepared by applying various accelerated stress methods, and particle size, count and structure were characterized. Immune cell activation as tracked by inflammatory cytokines released in response to aggregates was evaluated in vitro using peripheral blood mononuclear cells (PBMC), primary monocytes and immortalized human monocyte-like cell lines. IGIV aggregates produced by mechanical stress induced higher cytokine release by PBMC and primary monocytes than aggregates formed by other stresses. Results with the monocytic cell line THP-1 paralleled trends in PBMC and primary monocytes. Effects were dose-dependent, enhanced by complement opsonization, and partially inhibited by blocking toll-like receptors (TLR2 and TLR4) and to a lesser extent by blocking Fc gamma receptors (Fc gamma Rs). Stress-induced IGIV aggregates stimulate a dose-dependent cytokine response in human monocytes and THP-1 cells, mediated in part by TLRs, Fc gamma Rs and complement opsonization. THP-1 cells resemble primary monocytes in many respects with regard to tracking the innate response to IgG aggregates. Accordingly, the measurement of inflammatory cytokines released by THP-1 cells provides a readily accessible assay system to screen for the potential innate immunogenicity of IgG aggregates. The results also highlight the role of aggregate structure in interacting with the different receptors mediating innate immunity. C1 [Moussa, E. M.; Topp, E. M.] Purdue Univ, Coll Pharm, Dept Ind & Phys Pharm, 575 Stadium Mall Dr, W Lafayette, IN 47906 USA. [Kotarek, J.; Marszal, E.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Kotarek, J.] Brand Inst, Rockville, MD USA. [Blum, J. S.] Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. RP Topp, EM (reprint author), Purdue Univ, Coll Pharm, Dept Ind & Phys Pharm, 575 Stadium Mall Dr, W Lafayette, IN 47906 USA. EM topp@purdue.edu FU FDA [HHSF223201310233C] FX The authors gratefully thank Daniela Verthelyi and Jennifer Reed for critically reading the manuscript and providing valuable suggestions and comments. The authors are also thankful to Nancy Eller for useful discussions and to Eunbi Cho for assisting with cell-based assays. This work was funded by FDA contract HHSF223201310233C (PI: E. M. Topp). This project was supported in part by an appointment (JK) to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. The authors have no conflicts of interest to declare. NR 45 TC 1 Z9 1 U1 3 U2 6 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 JUL PY 2016 VL 33 IS 7 BP 1736 EP 1751 DI 10.1007/s11095-016-1914-4 PG 16 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DO2NB UT WOS:000377615600017 PM 27037576 ER PT J AU Filipski, KK Pacanowski, MA Ramamoorthy, A Feero, WG Freedman, AN AF Filipski, Kelly K. Pacanowski, Michael A. Ramamoorthy, Anuradha Feero, William Gregory Freedman, Andrew N. TI Dosing recommendations for pharmacogenetic interactions related to drug metabolism SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE biomarkers; drug labeling; drug-metabolizing enzymes; pharmacogenomics ID EGAPP-WORKING-GROUP; IMPLEMENTATION CONSORTIUM; GUIDELINE AB Objective Pharmacogenomic studies have established the important contribution of drug-metabolizing enzyme genotype toward drug toxicity and treatment failure; however, clinical implementation of pharmacogenomics has been slow. The aim of this study was to systematically review the information on drug-metabolizing enzyme pharmacogenomics available in the US drug labeling, practice guidelines, and recommendations. Methods Drug-metabolizing enzyme genotype and phenotype information was assessed in US FDA drug labeling, clinical practice guidelines, and independent technology assessors to evaluate the consistency in information sources for healthcare providers. Results Eighty four gene-drug pairs were identified as having drug-metabolizing enzyme genotype or phenotype information within the label. The manner in which pharmacogenomic information was presented was heterogeneous both within the label and between clinical practice recommendations. Conclusion For proper implementation of pharmacogenomics in clinical practice, information sources for healthcare providers should relay consistent and clear information for the appropriate use of biomarkers. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Filipski, Kelly K.; Freedman, Andrew N.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Pacanowski, Michael A.; Ramamoorthy, Anuradha] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Feero, William Gregory] Maine Dartmouth Family Med Residency Program, Augusta, ME USA. RP Filipski, KK (reprint author), 9609 Med Ctr Dr Room 4E228, Rockville, MD 20850 USA. EM kelly.filipski@nih.gov FU US Department of Energy; CDER FX A.R. was supported by an appointment to the Oak Ridge Institute for Science and Education (ORISE) Research Participation Program at the Center for Drug Evaluation and Research administered by the ORISE through an agreement between the US Department of Energy and CDER. NR 22 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1744-6872 EI 1744-6880 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD JUL PY 2016 VL 26 IS 7 BP 334 EP 339 DI 10.1097/FPC.0000000000000220 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA DO3MA UT WOS:000377684500003 PM 27058883 ER PT J AU Reiffel, JA Weitz, JI Reilly, P Kaminskas, E Sarich, T Sager, P Seltzer, J AF Reiffel, James A. Weitz, Jeffrey I. Reilly, Paul Kaminskas, Edvardas Sarich, Troy Sager, Philip Seltzer, Jonathan CA Cardiac Safety Res Consortium TI NOAC monitoring, reversal agents, and post-approval safety and effectiveness evaluation: A cardiac safety research consortium think tank SO AMERICAN HEART JOURNAL LA English DT Article ID NONVALVULAR ATRIAL-FIBRILLATION; ACUTE VENOUS THROMBOEMBOLISM; DIRECT ORAL ANTICOAGULANTS; THROMBIN INHIBITOR ASSAY; PARTIAL THROMBOPLASTIN TIME; FACTOR XA INHIBITORS; VITAMIN-K; PERIPROCEDURAL MANAGEMENT; LABORATORY MEASUREMENT; PLASMA-CONCENTRATIONS AB Four non-vitamin K antagonist oral anticoagulants (dabigatran, rivaroxaban, apixaban, and edoxaban) have been approved in the United States for treatment of atrial fibrillation (AF) and venous thromboembolic disease. They have been as or more effective than the prior standards of care, with less fatal or intracranial bleeding, fewer drug and dietary interactions, and greater patient convenience. Nonetheless, the absence of the ability for clinicians to assess compliance or washout with a simple laboratory test (or to adjust dosing with a similar assessment) and the absence of an antidote to rapidly stop major hemorrhage or to enhance safety in the setting of emergent or urgent surgery/procedures have been limitations to greater non-vitamin K antagonist oral anticoagulant usage and better thromboembolic prevention. Accordingly, a Cardiac Research Safety Consortium "think tank" meeting was held in February 2015 to address these concerns. This manuscript reports on the discussions held and the conclusions reached at that meeting. C1 [Reiffel, James A.] Columbia Univ, New York, NY USA. [Weitz, Jeffrey I.] McMaster Univ, Hamilton, ON L8S 4L8, Canada. [Weitz, Jeffrey I.] Thrombosis & Atherosclerosis Res Inst, Hamilton, ON, Canada. [Reilly, Paul] Boehringer Ingelheim Pharmaceut, Ridgefield, CT USA. [Kaminskas, Edvardas] US FDA, Div Hematol Prod, CDER, Silver Spring, MD USA. [Sarich, Troy] Janssen Sci Affairs, Titusville, NJ USA. [Sager, Philip] Stanford Univ, San Francisco, CA USA. [Sager, Philip] Sager Consulting Experts, San Francisco, CA USA. [Seltzer, Jonathan] ACI Clin & Lankenau Heart Inst, Wynnewood, PA USA. RP Reiffel, JA (reprint author), Columbia Univ, 202 Birkdale Lane, Jupiter, FL 33458 USA. EM jar2@cumc.columbia.edu NR 68 TC 2 Z9 2 U1 5 U2 14 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD JUL PY 2016 VL 177 BP 74 EP 86 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO0MN UT WOS:000377473100011 PM 27297852 ER PT J AU Turner, JR Kowey, PR Rodriguez, I Cabell, CH Gintant, G Green, CL Kunz, BL Mortara, J Sager, PT Stockbridge, N Wright, TJ Finkle, J Krucoff, MW AF Turner, J. Rick Kowey, Peter R. Rodriguez, Ignacio Cabell, Christopher H. Gintant, Gary Green, Cynthia L. Kunz, Barbara Lopez Mortara, Justin Sager, Philip T. Stockbridge, Norman Wright, Theressa J. Finkle, John Krucoff, Mitchell W. CA Cardiac Safety Res Consortium TI The Cardiac Safety Research Consortium enters its second decade: An invitation to participate SO AMERICAN HEART JOURNAL LA English DT Article ID REGISTRY INITIATIVE SAFARI; INCUBATOR THINK-TANK; EARLY QT ASSESSMENT; CLINICAL DEVELOPMENT; DRUG DEVELOPMENT; SOCIAL MEDIA; THOROUGH QT; PATH; METHODOLOGIES; PHARMACOLOGY AB The Cardiac Safety Research Consortium (CSRC), a transparent, public-private partnership established in 2005 as a Critical Path Program and formalized in 2006 under a Memorandum of Understanding between the United States Food and Drug Administration and Duke University, is entering its second decade. Our continuing goal is to advance paradigms for more efficient regulatory science related to the cardiovascular safety of new therapeutics, both in the United States and globally, particularly where such safety questions add burden to innovative research and development. Operationally, CSRC brings together a broad base of stakeholders from academia, industry, and government agencies in a collaborative forum focused on identifying barriers and then creating novel solutions through shared data, expertise, and collaborative research. This white paper provides a brief overview of the Consortium's activities in its first decade and a context for some of our current activities and future directions. The growth and success of the CSRC have been primarily driven by members' active participation and the development of goodwill and trust throughout our membership, which have facilitated novel collaborations across traditionally competitive or contentious stakeholder boundaries. The continued expansion of our base of participating academicians, industry experts, and regulators will define the Consortium's success in our second decade. It is our hope that sharing our endeavors to date will stimulate additional participation in the CSRC and also provide a model for other groups starting to develop similar collaborative forums. C1 [Turner, J. Rick; Cabell, Christopher H.] Quintiles, Durham, NC 27703 USA. [Kowey, Peter R.] Lankenau Inst Med Res, Wynnewood, PA USA. [Kowey, Peter R.] Thomas Jefferson Univ, Philadelphia, PA USA. [Rodriguez, Ignacio] Roche, New York, NY USA. [Gintant, Gary] AbbVie, N Chicago, IL USA. [Green, Cynthia L.; Krucoff, Mitchell W.] Duke Univ, Med Ctr, Durham, NC USA. [Green, Cynthia L.; Krucoff, Mitchell W.] Duke Clin Res Inst, Durham, NC USA. [Kunz, Barbara Lopez] DIA, Washington, DC USA. [Mortara, Justin] Mortara Instrument, Milwaukee, WI USA. [Sager, Philip T.] Stanford Univ, Palo Alto, CA 94304 USA. [Stockbridge, Norman] US FDA, White Oak, MD USA. [Wright, Theressa J.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Finkle, John] GlaxoSmithKline, Philadelphia, PA USA. RP Turner, JR (reprint author), Quintiles, Cardiac Safety Serv, 4820 Emperor Blvd, Durham, NC 27703 USA. EM rick.turner@quintiles.com NR 41 TC 0 Z9 0 U1 6 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD JUL PY 2016 VL 177 BP 96 EP 101 DI 10.1016/j.ahj.2016.04.009 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO0MN UT WOS:000377473100013 PM 27297854 ER PT J AU Wang, Y Guan, A Isayeva, I Vorvolakos, K Das, S Li, ZY Phillips, KS AF Wang, Yi Guan, Allan Isayeva, Irada Vorvolakos, Katherine Das, Srilekha Li, Zhenyu Phillips, K. Scott TI Interactions of Staphylococcus aureus with ultrasoft hydrogel biomaterials SO BIOMATERIALS LA English DT Article DE Hydrogel; Medical device; Biofilm; Infection; Bacteria; Plastic surgery ID BACTERIAL ADHESION; BIOFILM FORMATION; MECHANICAL-PROPERTIES; SUBSTRATE STIFFNESS; INJECTABLE FILLERS; SURFACE-TOPOGRAPHY; DERMAL FILLERS; HUMAN SKIN; MESH SIZE; PORE-SIZE AB Ultrasoft biomaterials-polymers, gels, and human soft tissues with an elastic modulus less than similar to 100 kPa-are increasingly used in medical devices. While bacterial interactions (adhesion and biofilm formation) have been extensively studied on stiffer materials, little is known about how bacteria colonize ultrasoft materials as a nidus for infection. The goal of this work was to determine how material properties of ultrasoft hydrogels used for dermal fillers might affect pathogenesis of associated infections. We first synthesized a range of polyacrylamide hydrogels (PAAm) with moduli similar to clinically used dermal fillers and characterized the rheological, morphological and porous properties. We then developed a novel microfabricated insert to contain the PAAm in a flow system for quantification of bacterial adhesion and biofilm formation. The rate of adhesion and numbers of adherent Staphylococcus aureus on the surface of PAAm both decreased as the modulus increased. Adhesion was reduced by 3 logs (from 93 x 10(4)/cm(2) to 0.083 x 10(4)/cm(2)) with increasing modulus (from 17 Pa to 654 Pa). However, the number of bacteria in the bulk was the highest within the stiffest gels. This trend was further amplified in subsequent biofilm studies, where interfacial coverage of biofilm decreased as the modulus increased, while the fraction of biofilm in the bulk was the highest within the stiffest gel. The results show significant differences in bacterial colonization of PAAm based on material properties, and reveal how the injection process may unexpectedly create discontinuities that provide a microenvironmental niche for bacterial colonization. Published by Elsevier Ltd. C1 [Wang, Yi; Isayeva, Irada; Vorvolakos, Katherine; Das, Srilekha; Phillips, K. Scott] US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Biol Chem & Mat Sci, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Guan, Allan; Li, Zhenyu] George Washington Univ, Dept Biomed Engn, Sci & Engn Hall,800 22nd St NW, Washington, DC 20052 USA. RP Phillips, KS (reprint author), US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Biol Chem & Mat Sci, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM kenneth.phillips@fda.hhs.gov RI Phillips, Kenneth/A-2156-2013 OI Phillips, Kenneth/0000-0002-6552-0694 FU FDA Office of Women's Health FX This work was supported by the FDA Office of Women's Health. This project was supported in part by an appointment to the ORISE Research Participation Program at the CDRH, 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/CDRH. NR 75 TC 2 Z9 2 U1 15 U2 42 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 JUL PY 2016 VL 95 BP 74 EP 85 DI 10.1016/j.biomaterials.2016.04.005 PG 12 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DM9PM UT WOS:000376698200007 PM 27131630 ER PT J AU Green, D Rubenstein, A Buffington, D Flemming, R Ghods, M Martin, D AF Green, D. Rubenstein, A. Buffington, D. Flemming, R. Ghods, M. Martin, D. TI Leveraging FDA and CMS collaboration to enhance quality improvement in safe medication use SO RESEARCH IN SOCIAL & ADMINISTRATIVE PHARMACY LA English DT Meeting Abstract C1 [Green, D.; Rubenstein, A.; Buffington, D.; Flemming, R.; Ghods, M.; Martin, D.] US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 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 JUL-AUG PY 2016 VL 12 IS 4 BP E4 EP E4 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DM6CN UT WOS:000376437600009 ER PT J AU Hand, AL Scott, JA Young, PD Stamey, JD Young, DM AF Hand, Austin L. Scott, John A. Young, Phil D. Stamey, James D. Young, Dean M. TI Bayesian adaptive two-stage design for determining person-time in Phase II clinical trials with Poisson data SO JOURNAL OF APPLIED STATISTICS LA English DT Article DE Bayesian predictive distribution; experimental efficacy; conjugate prior; count data; Phase II clinical trials ID SAMPLE-SIZE DETERMINATION; EFFICACY; SAFETY; LIQUID AB Adaptive clinical trial designs can often improve drug-study efficiency by utilizing data obtained during the course of the trial. We present a novel Bayesian two-stage adaptive design for Phase II clinical trials with Poisson-distributed outcomes that allows for person-observation-time adjustments for early termination due to either futility or efficacy. Our design is motivated by the adaptive trial from [9], which uses binomial data. Although many frequentist and Bayesian two-stage adaptive designs for count data have been proposed in the literature, many designs do not allow for person-time adjustments after the first stage. This restriction limits flexibility in the study design. However, our proposed design allows for such flexibility by basing the second-stage person-time on the first-stage observed-count data. We demonstrate the implementation of our Bayesian predictive adaptive two-stage design using a hypothetical Phase II trial of Immune Globulin (Intravenous). C1 [Hand, Austin L.] Quintiles, 4820 Emperor Blvd, Durham, NC USA. [Scott, John A.] Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, Rockville, MD USA. [Young, Phil D.] Baylor Univ, Dept Management Informat Syst, Waco, TX 76798 USA. [Stamey, James D.; Young, Dean M.] Baylor Univ, Dept Stat Sci, Waco, TX 76798 USA. RP Young, PD (reprint author), Baylor Univ, Dept Management Informat Syst, Waco, TX 76798 USA. EM philip_young@baylor.edu OI Scott, John/0000-0002-9116-948X NR 20 TC 0 Z9 0 U1 1 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0266-4763 EI 1360-0532 J9 J APPL STAT JI J. Appl. Stat. PD JUL PY 2016 VL 43 IS 9 BP 1625 EP 1635 DI 10.1080/02664763.2015.1117588 PG 11 WC Statistics & Probability SC Mathematics GA DK6AJ UT WOS:000375002600004 ER PT J AU Chen, HS Ngo, L Petrovskaya, S Gao, YM Laassri, M Rubin, S AF Chen, Huosheng Ngo, Laurie Petrovskaya, Svetlana Gao, Yamei Laassri, Majid Rubin, Steven TI Purification of mumps virus particles of high viability SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE Mumps virus; Potassium tartrate; Purification; Particles; Ultracentrifugation ID CENTRAL-NERVOUS-SYSTEM; PROTEINS; EPIDEMIC AB Mumps is a highly infectious viral disease of humans with a wide array of clinical manifestations ranging from painful swelling of the salivary glands to meningitis and encephalitis. Despite the clinical importance of mumps virus, most of what is known of its biological properties comes from studies using supernatants from virus infected cell cultures, which contain substantial levels of host cell derived debris and biologically active substances such as cytokines, transcription factors and secreted virus proteins. These contaminants complicate interpretation of studies of virus replication, virus-host interactions and in vivo virulence. Here we describe a protocol for concentration of the virus from cell culture supernatants followed by gradient purification, resulting in attainment of high titer live virus of high purity. Published by Elsevier B.V. C1 [Chen, Huosheng; Ngo, Laurie; Petrovskaya, Svetlana; Gao, Yamei; Laassri, Majid; Rubin, Steven] US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Rubin, S (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM steven.rubin@fda.hhs.gov NR 18 TC 0 Z9 0 U1 1 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 JUL PY 2016 VL 233 BP 6 EP 9 DI 10.1016/j.jviromet.2016.03.003 PG 4 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA DL3AK UT WOS:000375506400002 PM 26992653 ER PT J AU Rusconi, B Sanjar, F Koenig, SSK Mammel, MK Tarr, PI Eppinger, M AF Rusconi, Brigida Sanjar, Fatemeh Koenig, Sara S. K. Mammel, Mark K. Tarr, Phillip I. Eppinger, Mark TI Whole Genome Sequencing for Genomics-Guided Investigations of Escherichia coil O157:H7 Outbreaks SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE Escherichia coli; O157:H7; EHEC; phylogenomics; outbreaks; single nucleotide polymorphism; genomic epidemiology; whole genome sequence typing ID HEMOLYTIC-UREMIC-SYNDROME; COLI O157-H7 INFECTIONS; ENTERICA SEROVAR ENTERITIDIS; SPINACH-ASSOCIATED OUTBREAK; FIELD GEL-ELECTROPHORESIS; SHIGA TOXIN PRODUCTION; INSERTION SITES; YERSINIA-PESTIS; PHAGE INSERTION; SEARCH TOOL AB Multi isolate whole genome sequencing (WGS) and typing for outbreak investigations has become a reality in the post-genomics era. We applied this technology to strains from Escherichia coil O157:H7 outbreaks. These include isolates from seven North America outbreaks, as well as multiple isolates from the same patient and from different infected individuals in the same household. Customized high -resolution bioinformatics sequence typing strategies were developed to assess the core genome and mobilome plasticity. Sequence typing was performed using an in-house single nucleotide polymorphism (SNP) discovery and validation pipeline. Discriminatory power becomes of particular importance for the investigation of isolates from outbreaks in which macrogenomic techniques such as pulse -field gel electrophoresis or multiple locus variable number tandem repeat analysis do not differentiate closely related organisms. We also characterized differences in the phage inventory, allowing us to identify plasticity among outbreak strains that is not detectable at the core genome level. Our comprehensive analysis of the mobilome identified multiple plasmids that have not previously been associated with this lineage. Applied phylogenomics approaches provide strong molecular evidence for exceptionally little heterogeneity of strains within outbreaks and demonstrate the value of intra-cluster comparisons, rather than basing the analysis on archetypal reference strains. Next generation sequencing and whole genome typing strategies provide the technological foundation for genomic epidemiology outbreak investigation utilizing its significantly higher sample throughput, cost efficiency, and phylogenetic relatedness accuracy. These phylogenomics approaches have major public health relevance in translating information from the sequence-based survey to support timely and informed countermeasures. Polymorphisms identified in this work offer robust phylogenetic signals that index both short- and long-term evolution and can complement currently employed typing schemes for outbreak ex- and inclusion, diagnostics, surveillance, and forensic studies. C1 [Rusconi, Brigida; Sanjar, Fatemeh; Koenig, Sara S. K.; Eppinger, Mark] Univ Texas Hlth Sci Ctr San Antonio, South Texas Ctr Emerging Infect Dis, San Antonio, TX 78229 USA. [Rusconi, Brigida; Sanjar, Fatemeh; Koenig, Sara S. K.; Eppinger, Mark] Univ Texas Hlth Sci Ctr San Antonio, Dept Biol, San Antonio, TX 78229 USA. [Mammel, Mark K.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD USA. [Tarr, Phillip I.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. RP Eppinger, M (reprint author), Univ Texas Hlth Sci Ctr San Antonio, South Texas Ctr Emerging Infect Dis, San Antonio, TX 78229 USA.; Eppinger, M (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Biol, San Antonio, TX 78229 USA. EM mark.eppinger@utsa.edu FU National Institute of Allergy and Infectious Diseases, National Institute of Health, Department of Health and Human Services [SC2AI120941]; US Department of Homeland Security [2014-ST-062-000058]; Department of Biology; South Texas Center for Emerging Infectious Diseases (STCEID) at the University of Texas at San Antonio; High Performance Computing Center (HPC [2G12RR013646-12]; Swiss National Science Foundation Early Postdoc Mobility Fellowship [P2LAP3-151770]; South Texas Center for Emerging Infectious Diseases (STCEID); UTSA Teaching Fellowship (UTF); [R01DK52081]; [P30DK052574] FX The study was supported by the National Institute of Allergy and Infectious Diseases, National Institute of Health, Department of Health and Human Services under contract SC2AI120941, the US Department of Homeland Security under contract 2014-ST-062-000058, the Department of Biology, the South Texas Center for Emerging Infectious Diseases (STCEID) at the University of Texas at San Antonio, and the High Performance Computing Center (HPC) under contract 2G12RR013646-12. Strain collection and archiving was funded by R01DK52081 and P30DK052574 for the Biobank Core. BR was supported in part by the Swiss National Science Foundation Early Postdoc Mobility Fellowship (P2LAP3-151770). FS was supported in part by the South Texas Center for Emerging Infectious Diseases (STCEID) and through an UTSA Teaching Fellowship (UTF). NR 131 TC 0 Z9 0 U1 8 U2 13 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD JUN 30 PY 2016 VL 7 AR 985 DI 10.3389/fmicb.2016.00985 PG 21 WC Microbiology SC Microbiology GA DP8UW UT WOS:000378774400001 PM 27446025 ER PT J AU Mitra, A Herren, CD Patel, IR Coleman, A Mukhopadhyay, S AF Mitra, Arindam Herren, Christopher D. Patel, Isha R. Coleman, Adam Mukhopadhyay, Suman TI Integration of AI-2 Based Cell-Cell Signaling with Metabolic Cues in Escherichia coli SO PLOS ONE LA English DT Article ID VIRULENCE GENE-EXPRESSION; SALMONELLA-TYPHIMURIUM; RESPONSE REGULATOR; BIOFILM FORMATION; VIBRIO-CHOLERAE; GLOBAL CONTROL; QUORUM; LUXS; PSEUDOMONAS; SYSTEM AB The quorum sensing molecule Autoinducer-2 (AI-2) is generated as a byproduct of activated methyl cycle by the action of LuxS in Escherichia coli. AI-2 is synthesized, released and later internalized in a cell-density dependent manner. Here, by mutational analysis of the genes, uvrY and csrA, we describe a regulatory circuit of accumulation and uptake of AI-2. We constructed a single-copy chromosomal luxS-lacZ fusion in a luxS (+) merodiploid strain and evaluated its relative expression in uvrY and csrA mutants. At the entry of stationary phase, the expression of the fusion and AI-2 accumulation was positively regulated by uvrY and negatively regulated by csrA respectively. A deletion of csrA altered message stability of the luxS transcript and CsrA protein exhibited weak binding to 5' luxS regulatory region. DNA protein interaction and chromatin immunoprecipitation analysis confirmed direct interaction of UvrY with the luxS promoter. Additionally, reduced expression of the fusion in hfq deletion mutant suggested involvement of small RNA interactions in luxS regulation. In contrast, the expression of lsrA operon involved in AI-2 uptake, is negatively regulated by uvrY and positively by csrA in a cell-density dependent manner. The dual role of csrA in AI-2 synthesis and uptake suggested a regulatory crosstalk of cell signaling with carbon regulation in Escherichia coli. We found that the cAMP-CRP mediated catabolite repression of luxS expression was uvrY dependent. This study suggests that luxS expression is complex and regulated at the level of transcription and translation. The multifactorial regulation supports the notion that cell-cell communication requires interaction and integration of multiple metabolic signals. C1 [Mitra, Arindam; Herren, Christopher D.; Patel, Isha R.; Coleman, Adam; Mukhopadhyay, Suman] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Mitra, Arindam] Adamas Univ, Dept Microbiol, Kolkata, W Bengal, India. [Herren, Christopher D.] Kansas State Univ, Div Biol, Manhattan, KS USA. [Patel, Isha R.] US FDA, Div Mol Biol, Off Appl Res & Safety Assessment HFS 025, Ctr Food Safety & Appl Nutr, Laurel, MD USA. [Coleman, Adam] Maryland Dept Hlth & Mental Hyg, Div Newborn & Childhood Screening, Baltimore, MD USA. [Mukhopadhyay, Suman] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD USA. RP Mukhopadhyay, S (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA.; Mukhopadhyay, S (reprint author), NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD USA. EM mukhopadhyays@mail.nih.gov FU USDA-NRI-CSREES Competitive Grant [2004-35204-14749]; USDA-Animal Health [2002-1106-0195318]; Maryland Agriculture Experimental Station grant from the University of Maryland FX This work was in part supported by USDA-NRI-CSREES Competitive Grant 2004-35204-14749, USDA-Animal Health 2002-1106-0195318 and Maryland Agriculture Experimental Station grant from the University of Maryland. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 0 Z9 0 U1 7 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 JUN 30 PY 2016 VL 11 IS 6 AR e0157532 DI 10.1371/journal.pone.0157532 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ0CH UT WOS:000378865200019 PM 27362507 ER PT J AU Upadhyaya, B McCormack, L Fardin-Kia, AR Juenemann, R Nichenametla, S Clapper, J Specker, B Dey, M AF Upadhyaya, Bijaya McCormack, Lacey Fardin-Kia, Ali Reza Juenemann, Robert Nichenametla, Sailendra Clapper, Jeffrey Specker, Bonny Dey, Moul TI Impact of dietary resistant starch type 4 on human gut microbiota and immunometabolic functions SO SCIENTIFIC REPORTS LA English DT Article ID CHAIN FATTY-ACIDS; METABOLIC SYNDROME; RISK-FACTORS; OBESITY; DISEASE; ENERGY; POLYSACCHARIDES; CARBOHYDRATE; CHOLESTEROL; PROTEIN AB Dietary modulation of the gut microbiota impacts human health. Here we investigated the hitherto unknown effects of resistant starch type 4 (RS4) enriched diet on gut microbiota composition and short-chain fatty acid (SCFA) concentrations in parallel with host immunometabolic functions in twenty individuals with signs of metabolic syndrome (MetS). Cholesterols, fasting glucose, glycosylated haemoglobin, and proinflammatory markers in the blood as well as waist circumference and % body fat were lower post intervention in the RS4 group compared with the control group. 16S-rRNA gene sequencing revealed a differential abundance of 71 bacterial operational taxonomic units, including the enrichment of three Bacteroides species and one each of Parabacteroides, Oscillospira, Blautia, Ruminococcus, Eubacterium, and Christensenella species in the RS4 group. Gas chromatography-mass spectrometry revealed higher faecal SCFAs, including butyrate, propionate, valerate, isovalerate, and hexanoate after RS4-intake. Bivariate analyses showed RS4-specific associations of the gut microbiota with the host metabolic functions and SCFA levels. Here we show that dietary RS4 induced changes in the gut microbiota are linked to its biological activity in individuals with signs of MetS. These findings have potential implications for dietary guidelines in metabolic health management. C1 [Upadhyaya, Bijaya; McCormack, Lacey; Juenemann, Robert; Nichenametla, Sailendra; Dey, Moul] S Dakota State Univ, Hlth & Nutr Sci, Box 2203, Brookings, SD 57007 USA. [Fardin-Kia, Ali Reza] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, HFS 717, College Pk, MD 20740 USA. [Clapper, Jeffrey] S Dakota State Univ, Dept Anim Sci, Box 2170, Brookings, SD 57007 USA. [Specker, Bonny] S Dakota State Univ, Ethel Austin Martin Program Human Nutr, Box 506, Brookings, SD 57007 USA. RP Dey, M (reprint author), S Dakota State Univ, Hlth & Nutr Sci, Box 2203, Brookings, SD 57007 USA. EM Moul.Dey@sdstate.edu OI Upadhyaya, Bijaya/0000-0002-8643-0591; Specker, Bonny/0000-0003-4759-9957 FU MGP Ingredients Inc.; Atchison KS [3P2662]; USDA National Institute of Food and Agriculture Hatch Program [1004817]; National Institutes of Health [R00AT4245]; EA Martin Endowment at SDSU FX This work was supported by MGP Ingredients Inc., Atchison KS [3P2662], the USDA National Institute of Food and Agriculture Hatch Program [1004817], National Institutes of Health [R00AT4245] to M.D. and EA Martin Endowment at SDSU to B.S. We are thankful to study participants for their time on the study. Finally, we acknowledge Second Genome for providing paid sequencing services in an efficient and timely manner. The funding agencies had no role in study design, data collection and analyses, or toward any decision related to this manuscript. The opinions expressed in this presentation do not necessarily represent any official policies of the US Food and Drug Administration, or of its' parent organization, the Department of Health and Human Services, and should not be considered as changes in regulatory procedures. Any mention of specific companies or products should not be regarded as endorsements. NR 47 TC 3 Z9 3 U1 12 U2 27 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 JUN 30 PY 2016 VL 6 AR 28797 DI 10.1038/srep28797 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP8SM UT WOS:000378768200001 PM 27356770 ER PT J AU Wei, YS Zhao, MZ Yang, F Mao, Y Xie, H Zhou, QB AF Wei, Yushuang Zhao, Mengzhu Yang, Fang Mao, Yang Xie, Hang Zhou, Qibing TI Iron overload by Superparamagnetic Iron Oxide Nanoparticles is a High Risk Factor in Cirrhosis by a Systems Toxicology Assessment SO SCIENTIFIC REPORTS LA English DT Article ID IN-VITRO; NONALCOHOLIC STEATOHEPATITIS; HEPG2 CELLS; FATTY LIVER; EXPRESSION; TOXICITY; VIVO; METABOLISM; CLEARANCE; FIBROSIS AB Superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent have been widely used in magnetic resonance imaging for tumor diagnosis and theranostics. However, there has been safety concern of SPIONs with cirrhosis related to excess iron-induced oxidative stress. In this study, the impact of iron overload by SPIONs was assessed on a mouse cirrhosis model. A single dose of SPION injection at 0.5 or 5 mg Fe/kg in the cirrhosis group induced a septic shock response at 24 h with elevated serum levels of liver and kidney function markers and extended impacts over 14 days including high levels of serum cholesterols and persistent low serum iron level. In contrast, full restoration of liver functions was found in the normal group with the same dosages over time. Analysis with PCR array of the toxicity pathways revealed the high dose of SPIONs induced significant expression changes of a distinct subset of genes in the cirrhosis liver. All these results suggested that excess iron of the high dose of SPIONs might be a risk factor for cirrhosis because of the marked impacts of elevated lipid metabolism, disruption of iron homeostasis and possibly, aggravated loss of liver functions. C1 [Wei, Yushuang; Zhao, Mengzhu; Yang, Fang; Mao, Yang; Zhou, Qibing] Huazhong Univ Sci & Technol, Natl Engn Res Ctr Nanomed, Dept Nanomed & Biopharmaceut, Wuhan, Hubei, Peoples R China. [Xie, Hang] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Off Vaccines Res & Review, Silver Spring, MD USA. RP Zhou, QB (reprint author), Huazhong Univ Sci & Technol, Natl Engn Res Ctr Nanomed, Dept Nanomed & Biopharmaceut, Wuhan, Hubei, Peoples R China. EM qibingzhou@hust.edu.cn FU National Basic Research Program of China [2011CB933100]; National Natural Science Foundation of China [81372403] FX This work was supported by the National Basic Research Program of China (2011CB933100) and the National Natural Science Foundation of China (81372403). NR 35 TC 2 Z9 2 U1 6 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 30 PY 2016 VL 6 AR 29110 DI 10.1038/srep29110 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP9GI UT WOS:000378804300001 PM 27357559 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 Article DE covariate adaptive randomization; minimization; dynamic allocation; randomization; analyze as you randomize; re-randomization test; permutation test; temporal trend; validity; power ID COVARIATE-ADAPTIVE RANDOMIZATION; TREATMENT ALLOCATION PROCEDURES; BIASED COIN DESIGN; CLINICAL-TRIALS; PROGNOSTIC-FACTORS; BALANCE AB Minimization, a dynamic allocation method, is gaining popularity especially in cancer clinical trials. Aiming to achieve balance on all important prognostic factors simultaneously, this procedure can lead to a substantial reduction in covariate imbalance compared with conventional randomization in small clinical trials. While minimization has generated enthusiasm, some controversy exists over the proper analysis of such a trial. Critics argue that standard testing methods that do not account for the dynamic allocation algorithm can lead to invalid statistical inference. Acknowledging this limitation, the International Conference on Harmonization E9 guideline suggests that 'the complexity of the logistics and potential impact on analyses be carefully evaluated when considering dynamic allocation'. In this article, we investigate the proper analysis approaches to inference in a minimization design for both continuous and time-to-event endpoints and evaluate the validity and power of these approaches under a variety of scenarios both theoretically and empirically. Published 2016. This article is a U.S. Government work and is in the public domain in the USA C1 [Xu, Zhenzhen; Lee, Shiowjen] US FDA, CBER, 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, CBER, Silver Spring, MD 20993 USA. EM Zhenzhen.Xu@fda.hhs.gov NR 32 TC 2 Z9 2 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUN 30 PY 2016 VL 35 IS 14 BP 2315 EP 2327 DI 10.1002/sim.6874 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DP5LB UT WOS:000378537100002 PM 26787557 ER PT J AU Eshwar, AK Tall, B Gangiredla, J Gopinath, GR Patel, IR Neuhauss, SCF Stephan, R Lehner, A AF Eshwar, Athmanya K. Tall, Ben D. Gangiredla, Jayanthi Gopinath, Gopal R. Patel, Isha R. Neuhauss, Stephan C. F. Stephan, Roger Lehner, Angelika TI Linking Genomo- and Pathotype: Exploiting the Zebrafish Embryo Model to Investigate the Divergent Virulence Potential among Cronobacter spp. SO PLOS ONE LA English DT Article ID ENTEROBACTER-SAKAZAKII; CAENORHABDITIS-ELEGANS; NEONATAL MENINGITIS; HUMAN MACROPHAGES; SEQUENCE-ANALYSIS; ESCHERICHIA-COLI; COMB. NOV.; GEN. NOV; TURICENSIS; FOOD AB Bacteria belonging to the genus Cronobacter have been recognized as causative agents of life-threatening systemic infections primarily in premature, low-birth weight and immune compromised neonates. Apparently not all Cronobacter species are linked to infantile infections and it has been proposed that virulence varies among strains. Whole genome comparisons and in silico analysis have proven to be powerful tools in elucidating potential virulence determinants, the presence/absence of which may explain the differential virulence behaviour of strains. However, validation of these factors has in the past been hampered by the availability of a suitable neonatal animal model. In the present study we have used zebrafish embryos to model Cronobacter infections in vivo using wild type and genetically engineered strains. Our experiments confirmed the role of the RepF1B-like plasmids as "virulence plasmids" in Cronobacter and underpinned the importantce of two putative virulence factors-cpa and zpx-in in vivo pathogenesis. We propose that by using this model in vivo infection studies are now possible on a large scale level which will boost the understanding on the virulence strategies employed by these pathogens. C1 [Eshwar, Athmanya K.; Stephan, Roger; Lehner, Angelika] Univ Zurich, Inst Food Safety & Hyg, Zurich, Switzerland. [Tall, Ben D.; Gangiredla, Jayanthi; Gopinath, Gopal R.; Patel, Isha R.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD USA. [Neuhauss, Stephan C. F.] Univ Zurich, Inst Mol Life Sci, Zurich, Switzerland. RP Lehner, A (reprint author), Univ Zurich, Inst Food Safety & Hyg, Zurich, Switzerland. EM lehnera@fsafety.uzh.ch FU Swiss National Science Foundation [310030_138533/1] FX This study was supported by the Swiss National Science Foundation 310030_138533/1 to AE, AL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 0 Z9 0 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 29 PY 2016 VL 11 IS 6 AR e0158428 DI 10.1371/journal.pone.0158428 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ0AM UT WOS:000378859400065 PM 27355472 ER PT J AU Kuehnert, MJ Basavaraju, SV Moseley, RR Pate, LL Galel, SA Williamson, PC Busch, MP Alsina, JO Climent-Peris, C Marks, PW Epstein, JS Nakhasi, HL Hobson, JP Leiby, DA Akolkar, PN Petersen, LR Rivera-Garcia, B AF Kuehnert, Matthew J. Basavaraju, Sridhar V. Moseley, Robin R. Pate, Lisa L. Galel, Susan A. Williamson, Phillip C. Busch, Michael P. Alsina, Jose O. Climent-Peris, Consuelo Marks, Peter W. Epstein, Jay S. Nakhasi, Hira L. Hobson, J. Peyton Leiby, David A. Akolkar, Pradip N. Petersen, Lyle R. Rivera-Garcia, Brenda TI Screening of Blood Donations for Zika Virus Infection - Puerto Rico, April 3-June 11, 2016 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Kuehnert, Matthew J.; Basavaraju, Sridhar V.; Moseley, Robin R.; Petersen, Lyle R.] CDC, Zika Virus Response Blood Safety Team, Atlanta, GA 30333 USA. [Pate, Lisa L.; Galel, Susan A.] Roche Mol Syst Inc, Pleasanton, CA USA. [Williamson, Phillip C.] Creat Testing Solut, Tempe, AZ USA. [Busch, Michael P.] Blood Syst Res Inst, San Francisco, CA USA. [Alsina, Jose O.] Banco Sangre Serv Mutuos, San Juan, PR USA. [Climent-Peris, Consuelo] Banco Sangre Puerto Rico, San Juan, PR USA. [Marks, Peter W.; Epstein, Jay S.; Nakhasi, Hira L.; Hobson, J. Peyton; Leiby, David A.; Akolkar, Pradip N.] US FDA, Silver Spring, MD USA. [Rivera-Garcia, Brenda] Puerto Rico Dept Hlth, San Juan, PR USA. RP Kuehnert, MJ (reprint author), CDC, Zika Virus Response Blood Safety Team, Atlanta, GA 30333 USA. EM eocevent281@cdc.gov NR 6 TC 13 Z9 13 U1 30 U2 35 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 JUN 24 PY 2016 VL 65 IS 24 BP 627 EP 628 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DP2UX UT WOS:000378349900005 PM 27337368 ER PT J AU Park, SI Bisgin, H Ding, HJ Semey, HG Langley, DA Tong, WD Xu, J AF Park, Su Inn Bisgin, Halil Ding, Hongjian Semey, Howard G. Langley, Darryl A. Tong, Weida Xu, Joshua TI Species Identification of Food Contaminating Beetles by Recognizing Patterns in Microscopic Images of Elytra Fragments SO PLOS ONE LA English DT Article ID HISTOGRAMS; FEATURES; CRITERIA AB A crucial step of food contamination inspection is identifying the species of beetle fragments found in the sample, since the presence of some storage beetles is a good indicator of insanitation or potential food safety hazards. The current pratice, visual examination by human analysts, is time consuming and requires several years of experience. Here we developed a species identification algorithm which utilizes images of microscopic elytra fragments. The elytra, or hardened forewings, occupy a large portion of the body, and contain distinctive patterns. In addition, elytra fragments are more commonly recovered from processed food products than other body parts due to their hardness. As a preliminary effort, we chose 15 storage product beetle species frequently detected in food inspection. The elytra were then separated from the specimens and imaged under a microscope. Both global and local characteristics were quantified and used as feature inputs to artificial neural networks for species classification. With leave-one-out cross validation, we achieved overall accuracy of 80% through the proposed global and local features, which indicates that our proposed features could differentiate these species. Through examining the overall and per species accuracies, we further demonstrated that the local features are better suited than the global features for species identification. Future work will include robust testing with more beetle species and algorithm refinement for a higher accuracy. C1 [Park, Su Inn] Texas A&M Univ, Dept Comp Sci, College Stn, TX 77843 USA. [Park, Su Inn; Bisgin, Halil; Tong, Weida; Xu, Joshua] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR USA. [Ding, Hongjian; Semey, Howard G.; Langley, Darryl A.] US FDA, Arkansas Reg Labs, Off Regulatory Affairs, Jefferson, AR USA. [Park, Su Inn] Samsung Austin Semicond LLC, Austin, TX USA. [Bisgin, Halil] Univ Michigan, Dept Comp & Informat Syst, Flint, MI 48503 USA. RP Xu, J (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR USA. EM zhihua.xu@fda.hhs.gov OI Xu, Joshua/0000-0001-5313-5847 FU National Center for Toxicological Research (NCTR) of U.S. Food and Drug Administration (FDA) through the Oak Ridge Institute for Science and Education (ORISE); FDA's Office for Regulatory Affairs [IR01048]; NCTR [Protocol E0759101] FX SIP and HB are grateful to the National Center for Toxicological Research (NCTR) of U.S. Food and Drug Administration (FDA) for the summer research internship program and postdoc research program, respectively, through the Oak Ridge Institute for Science and Education (ORISE). This research was supported in part by internal grants from the FDA's Office for Regulatory Affairs (to HD, Project IR01048) and NCTR (to JX, Protocol E0759101). The views presented in this article do not necessarily reflect those of the FDA. This research was conducted while SIP was a graduate student at Texas A&M University. The funders or SIP's current affiliation (Samsung Austin Semiconductor, LLC) had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the "Author Contributions" section. NR 35 TC 1 Z9 1 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 JUN 24 PY 2016 VL 11 IS 6 AR e0157940 DI 10.1371/journal.pone.0157940 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP3KZ UT WOS:000378393600022 PM 27341524 ER PT J AU Wu, QG Ning, BT Xuan, JK Ren, Z Guo, L Bryant, MS AF Wu, Qiangen Ning, Baitang Xuan, Jiekun Ren, Zhen Guo, Lei Bryant, Matthew S. TI The role of CYP 3A4 and 1A1 in amiodarone-induced hepatocellular toxicity SO TOXICOLOGY LETTERS LA English DT Article DE Amiodarone; Desethylamiodarone; Amiodarone metabolism; Cytochrome P450s (CYPs); HepG2 cells; HepG2 expressing CYP ID GENE-EXPRESSION CHANGES; MASS-SPECTROMETRY; IN-VIVO; DRUG-INTERACTIONS; TREATED PATIENTS; KAVA EXTRACT; HUMAN LIVER; METABOLISM; IDENTIFICATION; PLASMA AB Amiodarone is a widely used potent antiarrhythmic for the treatment of cardiac disease; however, its use is often discontinued due to numerous adverse effects, including hepatotoxicity. To investigate the role of drug metabolism in this liver toxicity, amiodarone and its major metabolite desethylamiodarone were incubated with HepG2 cells overexpressing a series of cytochrome P450 (CYP) isoforms. Significantly higher cytotoxicity of amiodarone was observed in HepG2 cells overexpressing CYP3A4 or CYP1A1, compared with that observed in empty vector transduced control cells. Further, higher levels of the more potent hepatotoxic metabolite desethylamiodarone were detected in CYP3A4 or CYP1A1 expressed cells. The CYP3A4 inhibitor ketoconazole and the CYP1A1 inhibitor a-naphthoflavone drastically inhibited the metabolism of amiodarone to desethylamiodarone. Along with the inhibition of CYP1A1 or CYP3A4, the cytotoxicity of amiodarone was significantly reduced. These data indicate that the metabolism of amiodarone to desethylamiodarone by CYP1A1 or CYP3A4 plays an important role in the hepatocellular toxicity of amiodarone. Published by Elsevier Ireland Ltd. C1 [Wu, Qiangen; Xuan, Jiekun; Ren, Zhen; Guo, Lei; Bryant, Matthew S.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Ning, Baitang] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Guo, L; Bryant, MS (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Lei.Guo@fda.hhs.gov; Matthew.Bryant@fda.hhs.gov NR 35 TC 0 Z9 0 U1 13 U2 21 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 JUN 24 PY 2016 VL 253 BP 55 EP 62 DI 10.1016/j.toxlet.2016.04.016 PG 8 WC Toxicology SC Toxicology GA DL7VM UT WOS:000375848200007 PM 27113703 ER PT J AU Zhao, JC Zhao, JX Mangalam, AK Channappanavar, R Fett, C Meyerholz, DK Agnihothram, S Baric, RS David, CS Perlman, S AF Zhao, Jincun Zhao, Jingxian Mangalam, Ashutosh K. Channappanavar, Rudragouda Fett, Craig Meyerholz, David K. Agnihothram, Sudhakar Baric, Ralph S. David, Chella S. Perlman, Stanley TI Airway Memory CD4(+) T Cells Mediate Protective Immunity against Emerging Respiratory Coronaviruses SO IMMUNITY LA English DT Article ID VIRUS-INFECTION; RECOVERED PATIENTS; BALB/C MICE; RESPONSES; INFLUENZA; RECEPTOR; VACCINE; PROTEIN; GENERATION; DISEASE AB Two zoonotic coronaviruses (CoVs)-SARS-CoV and MERS-CoV-have crossed species to cause severe human respiratory disease. Here, we showed that induction of airway memory CD4(+) T cells specific for a conserved epitope shared by SARS-CoV and MERS-CoV is a potential strategy for developing pan-coronavirus vaccines. Airway memory CD4(+) T cells differed phenotypically and functionally from lung-derived cells and were crucial for protection against both CoVs in mice. Protection was dependent on interferon-gamma and required early induction of robust innate and virus-specific CD8(+) T cell responses. The conserved epitope was also recognized in SARS-CoV- and MERS-CoV-infected human leukocyte antigen DR2 and DR3 transgenic mice, indicating potential relevance in human populations. Additionally, this epitope was cross-protective between human and bat CoVs, the progenitors for many human CoVs. Vaccine strategies that induce airway memory CD4(+) T cells targeting conserved epitopes might have broad applicability in the context of new CoVs and other respiratory virus outbreaks. C1 [Zhao, Jincun] Guangzhou Med Univ, Affiliated Hosp 1, Guangzhou Inst Resp Dis, State Key Lab Resp Dis, Guangzhou 510120, Guangdong, Peoples R China. [Zhao, Jincun; Zhao, Jingxian; Channappanavar, Rudragouda; Fett, Craig; Perlman, Stanley] Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. [Mangalam, Ashutosh K.; Meyerholz, David K.] Univ Iowa, Dept Pathol, Iowa City, IA 52242 USA. [Agnihothram, Sudhakar; Baric, Ralph S.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Agnihothram, Sudhakar; Baric, Ralph S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [David, Chella S.] Mayo Clin, Dept Immunol, Rochester, MN 55905 USA. [Agnihothram, Sudhakar] Natl Ctr Toxicol Res, US FDA, Jefferson, AR 72079 USA. RP Zhao, JC (reprint author), Guangzhou Med Univ, Affiliated Hosp 1, Guangzhou Inst Resp Dis, State Key Lab Resp Dis, Guangzhou 510120, Guangdong, Peoples R China.; Zhao, JC; Perlman, S (reprint author), Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. EM zhaojincun@gird.cn; stanley-perlman@uiowa.edu FU NIH [RO1 AI091322, PO1 AI060699, U19 AI100625]; Thousand Talents Plan Award of China; Municipal Healthcare Joint-Innovation Major Project of Guangzhou (Jincun Zhao) FX Wethank Drs. John Harty and Kevin Legge for critical review of the manuscript. This research was supported in part by grants from the NIH (RO1 AI091322 and PO1 AI060699 to S.P. and U19 AI100625 R.S.B.), the Thousand Talents Plan Award of China 2015, and the Municipal Healthcare Joint-Innovation Major Project of Guangzhou (Jincun Zhao). NR 41 TC 3 Z9 3 U1 5 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUN 21 PY 2016 VL 44 IS 6 BP 1379 EP 1391 DI 10.1016/j.immuni.2016.05.006 PG 13 WC Immunology SC Immunology GA DP2SE UT WOS:000378341200016 PM 27287409 ER PT J AU Fox, ME Mikhailova, MA Bass, CE Takmakov, P Gainetdinov, RR Budygin, EA Wightman, RM AF Fox, Megan E. Mikhailova, Maria A. Bass, Caroline E. Takmakov, Pavel Gainetdinov, Raul R. Budygin, Evgeny A. Wightman, R. Mark TI Cross-hemispheric dopamine projections have functional significance SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE dopamine; voltammetry; synchrony; nucleus accumbens; dorsal striatum ID VENTRAL TEGMENTAL AREA; NUCLEUS-ACCUMBENS; INDUCED DYSKINESIA; STRIATAL NEURONS; RAT; SIGNALS; RELEASE; BRAIN; 6-HYDROXYDOPAMINE; ACTIVATION AB Dopamine signaling occurs on a subsecond timescale, and its dysregulation is implicated in pathologies ranging from drug addiction to Parkinson's disease. Anatomic evidence suggests that some dopamine neurons have cross-hemispheric projections, but the significance of these projections is unknown. Here we report unprecedented interhemispheric communication in the midbrain dopamine system of awake and anesthetized rats. In the anesthetized rats, optogenetic and electrical stimulation of dopamine cells elicited physiologically relevant dopamine release in the contralateral striatum. Contralateral release differed between the dorsal and ventral striatum owing to differential regulation by D2-like receptors. In the freely moving animals, simultaneous bilateral measurements revealed that dopamine release synchronizes between hemispheres and intact, contralateral projections can release dopamine in the midbrain of 6-hydroxydopamine-lesioned rats. These experiments are the first, to our knowledge, to show cross-hemispheric synchronicity in dopamine signaling and support a functional role for contralateral projections. In addition, our data reveal that psychostimulants, such as amphetamine, promote the coupling of dopamine transients between hemispheres. C1 [Fox, Megan E.; Takmakov, Pavel; Wightman, R. Mark] Univ N Carolina, Dept Chem, CB 3290, Chapel Hill, NC 27599 USA. [Fox, Megan E.; Takmakov, Pavel; Wightman, R. Mark] Univ N Carolina, UNC Sch Med, UNC Neurosci Ctr, Chapel Hill, NC 27599 USA. [Mikhailova, Maria A.; Gainetdinov, Raul R.; Budygin, Evgeny A.] St Petersburg State Univ, Inst Translat Biomed, St Petersburg 199034, Russia. [Bass, Caroline E.] Univ Buffalo, Jacobs Sch Med & Biomed Sci, Dept Pharmacol & Toxicol, Buffalo, NY USA. [Budygin, Evgeny A.] Wake Forest Univ, Bowman Gray Sch Med, Dept Neurobiol & Anat, Winston Salem, NC 27157 USA. [Takmakov, Pavel] US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth,White Oak Fed Res Ctr, Silver Spring, MD 20993 USA. RP Wightman, RM (reprint author), Univ N Carolina, Dept Chem, CB 3290, Chapel Hill, NC 27599 USA.; Wightman, RM (reprint author), Univ N Carolina, UNC Sch Med, UNC Neurosci Ctr, Chapel Hill, NC 27599 USA. EM rmw@unc.edu RI Fox, Megan/H-6684-2013; Gainetdinov, Raul/G-5875-2011; OI Fox, Megan/0000-0003-3177-831X; Gainetdinov, Raul/0000-0003-2951-6038; Takmakov, Pavel/0000-0001-6591-0257 FU National Institutes of Health [DA10900, AA022449]; Russian Science Foundation [4-50-00069] FX We thank Michael Bruno for immunohistochemistry assistance and Elyse Dankoski for comments on the manuscript. This work was funded by the National Institutes of Health (Grants DA10900, to R.M.W., and AA022449, to E.A.B.) and the Russian Science Foundation (Grant 4-50-00069, to R.R.G.). NR 56 TC 5 Z9 5 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 21 PY 2016 VL 113 IS 25 BP 6985 EP 6990 DI 10.1073/pnas.1603629113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DP1TN UT WOS:000378272400055 PM 27298371 ER PT J AU Neufeld, E Cassara, AM Montanaro, H Kuster, N Kainz, W AF Neufeld, Esra Cassara, Antonino Mario Montanaro, Hazael Kuster, Niels Kainz, Wolfgang TI Functionalized anatomical models for EM-neuron Interaction modeling SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE functionalized computable human phantom; strength-duration time constant; chronaxie; simulation verification ID ELECTRIC-FIELD STIMULI; NERVE CHRONAXIE TIMES; GRADIENT COIL SAFETY; MRI; SIMULATIONS; DISCREPANCY; THRESHOLDS; RELEVANCE AB The understanding of interactions between electromagnetic (EM) fields and nerves are crucial in contexts ranging from therapeutic neurostimulation to low frequency EM exposure safety. To properly consider the impact of in vivo induced field inhomogeneity on non-linear neuronal dynamics, coupled EM-neuronal dynamics modeling is required. For that purpose, novel functionalized computable human phantoms have been developed. Their implementation and the systematic verification of the integrated anisotropic quasi-static EM solver and neuronal dynamics modeling functionality, based on the method of manufactured solutions and numerical reference data, is described. Electric and magnetic stimulation of the ulnar and sciatic nerve were modeled to help understanding a range of controversial issues related to the magnitude and optimal determination of strength-duration (SD) time constants. The results indicate the importance of considering the stimulation-specific inhomogeneous field distributions (especially at tissue interfaces), realistic models of non-linear neuronal dynamics, very short pulses, and suitable SD extrapolation models. These results and the functionalized computable phantom will influence and support the development of safe and effective neuroprosthetic devices and novel electroceuticals. Furthermore they will assist the evaluation of existing low frequency exposure standards for the entire population under all exposure conditions. C1 [Neufeld, Esra; Cassara, Antonino Mario; Montanaro, Hazael; Kuster, Niels] Fdn Res Informat Technol Soc ITIS, Zeughausstr 43, CH-8004 Zurich, Switzerland. [Montanaro, Hazael; Kuster, Niels] Swiss Fed Inst Technol, CH-8092 Zurich, Switzerland. [Kainz, Wolfgang] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Neufeld, E (reprint author), Fdn Res Informat Technol Soc ITIS, Zeughausstr 43, CH-8004 Zurich, Switzerland. EM neufeld@itis.ethz.ch OI Cassara, Antonino Mario/0000-0003-3375-7440 FU Swiss Commission for Innovation and Technology (CTI) [14930.1 PFLS-LS]; FDA's Critical Path Initiative FX This study was supported by the project CAPITALIS (14930.1 PFLS-LS) of the Swiss Commission for Innovation and Technology (CTI) and FDA's Critical Path Initiative. NR 28 TC 0 Z9 0 U1 2 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUN 21 PY 2016 VL 61 IS 12 BP 4390 EP 4401 DI 10.1088/0031-9155/61/12/4390 PG 12 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DO0AG UT WOS:000377441200008 PM 27224508 ER PT J AU Neufeld, E Oikonomidis, IV Iacono, MI Angelone, LM Kainz, W Kuster, N AF Neufeld, Esra Oikonomidis, Ioannis Vogiatzis Iacono, Maria Ida Angelone, Leonardo M. Kainz, Wolfgang Kuster, Niels TI Investigation of assumptions underlying current safety guidelines on EM-induced nerve stimulation SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE EM exposure safety; coupled EM-neuronal dynamics modeling; MRI gradient coil switching; computable human phantoms; functionalized human phantoms ID VARYING MAGNETIC-FIELDS; ANATOMICAL MODELS; MRI; COILS; BODY AB An intricate network of a variety of nerves is embedded within the complex anatomy of the human body. Although nerves are shielded from unwanted excitation, they can still be stimulated by external electromagnetic sources that induce strongly non-uniform field distributions. Current exposure safety standards designed to limit unwanted nerve stimulation are based on a series of explicit and implicit assumptions and simplifications. This paper demonstrates the applicability of functionalized anatomical phantoms with integrated coupled electromagnetic and neuronal dynamics solvers for investigating the impact of magnetic resonance exposure on nerve excitation within the full complexity of the human anatomy. The impact of neuronal dynamics models, temperature and local hot-spots, nerve trajectory and potential smoothing, anatomical inhomogeneity, and pulse duration on nerve stimulation was evaluated. As a result, multiple assumptions underlying current safety standards are questioned. It is demonstrated that coupled EM-neuronal dynamics modeling involving realistic anatomies is valuable to establish conservative safety criteria. C1 [Neufeld, Esra; Oikonomidis, Ioannis Vogiatzis; Kuster, Niels] Fdn Res Informat Technol Soc ITIS, Zeughausstr 43, CH-8004 Zurich, Switzerland. [Oikonomidis, Ioannis Vogiatzis; Kuster, Niels] Swiss Fed Inst Technol, CH-8092 Zurich, Switzerland. [Iacono, Maria Ida; Angelone, Leonardo M.; Kainz, Wolfgang] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Neufeld, E (reprint author), Fdn Res Informat Technol Soc ITIS, Zeughausstr 43, CH-8004 Zurich, Switzerland. EM neufeld@itis.ethz.ch FU project CAPITALIS of the Swiss Commission for Innovation and Technology (CTI) [14930.1 PFLS-LS]; FDA's Critical Path Initiative FX This study was supported by the project CAPITALIS (14930.1 PFLS-LS) of the Swiss Commission for Innovation and Technology (CTI) and FDA's Critical Path Initiative. We gratefully acknowledge J. Patrick Reilly for carefully reviewing the manuscript and providing valuable feedback. NR 31 TC 2 Z9 2 U1 2 U2 2 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 JUN 21 PY 2016 VL 61 IS 12 BP 4466 EP 4478 DI 10.1088/0031-9155/61/12/4466 PG 13 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DO0AG UT WOS:000377441200013 PM 27223274 ER PT J AU Yang, QR Domesle, KJ Wang, F Ge, BL AF Yang, Qianru Domesle, Kelly J. Wang, Fei Ge, Beilei TI Rapid detection of Salmonella in food and feed by coupling loop-mediated isothermal amplification with bioluminescent assay in real-time SO BMC MICROBIOLOGY LA English DT Article DE LAMP; BART; Salmonella; Food; Feed; Detection ID POLYMERASE-CHAIN-REACTION; IN-GROUND BEEF; FOODBORNE SALMONELLA; ANIMAL FEEDS; PCR; LAMP; SEROVARS; PRODUCE; DNA; CONTAMINATION AB Background: Salmonella is among the most significant pathogens causing food and feed safety concerns. This study examined the rapid detection of Salmonella in various types of food and feed samples by coupling loop-mediated isothermal amplification (LAMP) with a novel reporter, bioluminescent assay in real-time (BART). Performance of the LAMP-BART assay was compared to a conventional LAMP and the commercially available 3M Molecular Detection Assay (MDA) Salmonella. Results: The LAMP-BART assay was 100 % specific among 178 strains (151 Salmonella and 27 non-Salmonella) tested. The detection limits were 36 cells per reaction in pure culture and 10(4) to 10(6) CFU per 25 g in spiked food and feed samples without enrichment, which were comparable to those of the conventional LAMP and 3M MDA Salmonella but 5-10 min faster. Ground turkey showed a strong inhibition on 3M MDA Salmonella, requiring at least 10(8) CFU per 25 g for detection. The correlation between Salmonella cell numbers and LAMP-BART signals was high (R-2 = 0.941-0.962), suggesting good quantification capability. After 24 h enrichment, all three assays accurately detected 1 to 3 CFU per 25 g of Salmonella among five types of food (cantaloupe, ground beef, ground turkey, shell eggs, and tomato) and three types of feed (cattle feed, chicken feed, and dry dog food) examined. However, 10(1) CFU per 25 g was required for cattle feed when tested by 3M MDA Salmonella. Conclusions: The Salmonella LAMP-BART assay was rapid, specific, sensitive, quantitative, and robust. Upon further validation, it may become a valuable tool for routine screening of Salmonella in various types of food and feed samples. C1 [Yang, Qianru; Domesle, Kelly J.; Wang, Fei; Ge, Beilei] US FDA, Ctr Vet Med, Res Off, Div Anim & Food Microbiol, Laurel, MD 20708 USA. [Yang, Qianru] Louisiana State Univ, Ctr Agr, Dept Food Sci, Baton Rouge, LA 70803 USA. [Wang, Fei] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. RP Ge, BL (reprint author), US FDA, Ctr Vet Med, Res Off, Div Anim & Food Microbiol, Laurel, MD 20708 USA. EM beilei.ge@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research FX This study was supported by internal funding from the U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research. NR 41 TC 1 Z9 1 U1 9 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD JUN 17 PY 2016 VL 16 AR 112 DI 10.1186/s12866-016-0730-7 PG 10 WC Microbiology SC Microbiology GA DP9ZL UT WOS:000378856700002 PM 27316515 ER PT J AU Farakos, SMS Pouillot, R Anderson, N Johnson, R Son, I Van Doren, J AF Farakos, Sofia M. Santillana Pouillot, Regis Anderson, Nathan Johnson, Rhoma Son, Insook Van Doren, Jane TI Modeling the survival kinetics of Salmonella in tree nuts for use in risk assessment SO INTERNATIONAL JOURNAL OF FOOD MICROBIOLOGY LA English DT Article DE Low moisture; Predictive microbiology; Fixed effect model; Mixed effect model; Bayesian inference ID ESCHERICHIA-COLI O157/H7; LOW-WATER ACTIVITY; LISTERIA-MONOCYTOGENES; THERMAL INACTIVATION; INOCULATED ALMONDS; METAANALYSIS; TEMPERATURE; UNCERTAINTY; VARIABILITY; KERNELS AB Salmonella has been shown to survive in tree nuts over long periods of time. This survival capacity and its variability are key elements for risk assessment of Salmonella in tree nuts. The aim of-this study was to develop a mathematical model to predict survival of Salmonella in tree nuts at ambient storage temperatures that considers variability and uncertainty separately and can easily be incorporated into a risk assessment model. Data on Salmonella survival on raw almonds, pecans, pistachios and walnuts were collected from the peer reviewed literature. The Weibull model was chosen as the baseline model and various fixed effect and mixed effect models were fit to the data. The best model identified through statistical analysis testing was then used to develop a hierarchical Bayesian model. Salmonella in tree nuts showed slow declines at temperatures ranging from 21 degrees C to 24 degrees C. A high degree of variability in survival was observed across tree nut studies reported in the literature. Statistical analysis results indicated that the best applicable model was a mixed effect model that included a fixed and random variation of 5 per tree nut (which is the time it takes for the first log(10) reduction) and a fixed variation of rho per tree nut (parameter which defines the shape of the curve). Higher estimated survival rates (6) were obtained for Salmonella on pistachios, followed in decreasing order by pecans, almonds and walnuts. The posterior distributions obtained from Bayesian inference were used to estimate the variability in the log(10) decrease levels in survival for each tree nut, and the uncertainty of these estimates. These modeled uncertainty and variability distributions of the estimates can be used to obtain a complete exposure assessment of Salmonella in tree nuts when including time-temperature parameters for storage and consumption data. The statistical approach presented in this study may be applied to any studies that aim to develop predictive models to be implemented in a probabilistic exposure assessment or a quantitative microbial risk assessment. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. C1 [Farakos, Sofia M. Santillana; Pouillot, Regis; Johnson, Rhoma; Son, Insook; Van Doren, Jane] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Anderson, Nathan] US FDA, Ctr Food Safety & Appl Nutr, Bedford Pk, IL USA. RP Farakos, SMS (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. EM sofia.santillanafarakos@fda.hhs.gov FU US Department of Energy; U.S. Food and Drug Administration FX The authors would like to thank Dr. Linda Harris, Dr. Larry Beuchat and Dr. Tyann Blessington for the provision of the raw data. We would also like to thank Dr. Sherri Dennis and Jenny Scott for their thoughtful review of earlier versions of this manuscript. This work was supported, in part, by appointments to the Research Participation Program at the Center for Food Safety and Applied Nutrition administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the U.S. Food and Drug Administration. NR 46 TC 0 Z9 0 U1 14 U2 21 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 JUN 16 PY 2016 VL 227 BP 41 EP 50 DI 10.1016/j.ijfoodmicro.2016.03:014 PG 10 WC Food Science & Technology; Microbiology SC Food Science & Technology; Microbiology GA DM7NF UT WOS:000376546600008 ER PT J AU Patel, PR Sun, W Kim, M Huang, XL Sanderson, PE Tanaka, TQ Mckew, JC Simeonov, A Williamson, KC Zheng, W Huang, WW AF Patel, Paresma R. Sun, Wei Kim, Myunghoon Huang, Xiuli Sanderson, Philip E. Tanaka, Takeshi Q. McKew, John C. Simeonov, Anton Williamson, Kim C. Zheng, Wei Huang, Wenwei TI In vitro evaluation of imidazo[4,5-c]quinolin-2-ones as gametocytocidal antimalarial agents SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Antimalarial; Plasmodium falciparum; Gametocytes; Gametocytocidal; Imidazo[4,5-c]quinolin-2-one ID INHIBITOR; NVP-BEZ235 AB Novel imidazo[4,5-c] quinolin-2-ones were synthesized and evaluated in asexual blood stage and late stage gametocyte assays of Plasmodium falciparum, a major causative agent of malaria. The design of these compounds is based on a recently identified lead compound from a high throughput screen. A concise synthesis was developed that allowed for generation of analogues with substitution around both the quinoline and imidazolidinone rings. Through structure-activity relationship studies, a number of potent compounds were identified that possessed excellent antimalarial activity against both the asexual and sexual stages with minimal cytotoxicity in mammalian cells. This is the first Letter describing SAR and gametocytocidal activity of imidazo[4,5-c] quinolin-2-ones, a new lead series for malaria treatment and prevention. Published by Elsevier Ltd. C1 [Patel, Paresma R.; Sun, Wei; Kim, Myunghoon; Huang, Xiuli; Sanderson, Philip E.; McKew, John C.; Simeonov, Anton; Zheng, Wei; Huang, Wenwei] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Tanaka, Takeshi Q.; Williamson, Kim C.] Loyola Univ, Dept Biol, Chicago, IL 60660 USA. [Patel, Paresma R.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Tanaka, Takeshi Q.] Obihiro Univ Agr & Vet Med, Natl Res Ctr Protozoan Dis, Obihiro, Hokkaido 0808555, Japan. [McKew, John C.] aTyr Pharma Inc, 3545 John Hopkins Court,Suite 250, San Diego, CA 92121 USA. [Williamson, Kim C.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. RP Huang, WW (reprint author), NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. EM huangwe@mail.nih.gov RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU National Center for Advancing Translational Sciences and Public Health Service Grant from the National Institute of Allergy and Infectious Diseases [AI101396] FX The authors would like to thank Paul Shinn, Danielle VanLeer, and Jennifer Bennison for assistance with compound management. This work was supported by the Intramural Research Programs of the National Center for Advancing Translational Sciences and Public Health Service Grant AI101396 from the National Institute of Allergy and Infectious Diseases. T.Q.T. is a JSPS Research Fellow in Biomedical and Behavioral Research at the NIH. NR 15 TC 2 Z9 2 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUN 15 PY 2016 VL 26 IS 12 BP 2907 EP 2911 DI 10.1016/j.bmcl.2016.04.045 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA DN0BA UT WOS:000376728200033 PM 27156776 ER PT J AU Gail, MH Wu, JC Wang, ML Yaun, SS Cook, NR Eliassen, AH McCullough, ML Yu, K Zeleniuch-Jacquotte, A Smith-Warner, SA Ziegler, RG Carroll, RJ AF Gail, Mitchell H. Wu, Jincao Wang, Molin Yaun, Shiaw-Shyuan Cook, Nancy R. Eliassen, A. Heather McCullough, Marjorie L. Yu, Kai Zeleniuch-Jacquotte, Anne Smith-Warner, Stephanie A. Ziegler, Regina G. Carroll, Raymond J. TI Calibration and seasonal adjustment for matched case-control studies of vitamin D and cancer SO STATISTICS IN MEDICINE LA English DT Article DE calibration; seasonal adjustment; measurement error; matched case-control study; molecular epidemiology; biomarkers ID BREAST-CANCER; 25-HYDROXYVITAMIN D; D METABOLITES; SERUM-LEVELS; RISK AB Vitamin D measurements are influenced by seasonal variation and specific assay used. Motivated by multicenter studies of associations of vitamin D with cancer, we formulated an analytic framework for matched case-control data that accounts for seasonal variation and calibrates to a reference assay. Calibration data were obtained from controls sampled within decile strata of the uncalibrated vitamin D values. Seasonal sine-cosine series were fit to control data. Practical findings included the following: (1) failure to adjust for season and calibrate increased variance, bias, and mean square error and (2) analysis of continuous vitamin D requires a variance adjustment for variation in the calibration estimate. An advantage of the continuous linear risk model is that results are independent of the reference date for seasonal adjustment. (3) For categorical risk models, procedures based on categorizing the seasonally adjusted and calibrated vitamin D have near nominal operating characteristics; estimates of log odds ratios are not robust to choice of seasonal reference date, however. Thus, public health recommendations based on categories of vitamin D should also define the time of year to which they refer. This work supports the use of simple methods for calibration and seasonal adjustment and is informing analytic approaches for the multicenter Vitamin D Pooling Project for Breast and Colorectal Cancer. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA. C1 [Gail, Mitchell H.; Yu, Kai; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Wu, Jincao] Food & Drug Adm, Div Biostat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Wang, Molin] Harvard Univ, Dept Biostat, TH Chan Sch Publ Hlth, Boston, MA USA. [Wang, Molin; Cook, Nancy R.; Eliassen, A. Heather; Smith-Warner, Stephanie A.] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA USA. [Yaun, Shiaw-Shyuan; Smith-Warner, Stephanie A.] Harvard Univ, Dept Nutr, TH Chan Sch Publ Hlth, Boston, MA USA. [Cook, Nancy R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. [Eliassen, A. Heather] Brigham & Womens Hosp, Dept Med, Med Network, Channing Div, 75 Francis St, Boston, MA 02115 USA. [Eliassen, A. Heather] Harvard Univ, Sch Med, Boston, MA USA. [McCullough, Marjorie L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Populat Hlth, New York, NY USA. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Perlmutter Canc Ctr, New York, NY USA. [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Carroll, Raymond J.] Univ Technol Sydney, Dept Math & Stat, Sydney, NSW 2007, Australia. RP Gail, MH (reprint author), NCI, Biostat Branch, 9609 Med Ctr Dr,Rm 7E-138, Rockville, MD 20850 USA. EM gailm@mail.nih.gov OI Cook, Nancy/0000-0002-9705-0842; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU Intramural Research Program of the National Cancer Institute, Division of Cancer Epidemiology and Genetics; National Cancer Institute [U01-CA057030, R01-CA098661, UM1-CA182934, P30-CA016087]; National Institute of Environmental Health Sciences [ES000260]; American Cancer Society; [R01-CA152071] FX This work was supported by the Intramural Research Program of the National Cancer Institute, Division of Cancer Epidemiology and Genetics. Carroll's research was supported by a grant from the National Cancer Institute (U01-CA057030). We thank Stephanie Weinstein, Demetrius Albanes, and Michal Freedman for the use of ATBC and PLCO data; the American Cancer Society for use of the CPSII data; Li Cheung for help with R programming; and Mattias Johansson and David Muller for assistance with the sine-cosine method for seasonal adjustment. The American Cancer Society funded the creation, maintenance, and update of the CPSII cohort. The NYUWHS is supported by the National Cancer Institute (grants R01-CA098661, UM1-CA182934, and P30-CA016087) and by the National Institute of Environmental Health Sciences (center grant ES000260). The main Vitamin D Pooling Project was supported by R01-CA152071. NR 10 TC 1 Z9 1 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUN 15 PY 2016 VL 35 IS 13 BP 2133 EP 2148 DI 10.1002/sim.6856 PG 16 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DL4LI UT WOS:000375607200002 PM 27133461 ER PT J AU Pijls, BG Meessen, JMTA Schoones, JW Fiocco, M van der Heide, HJL Sedrakyan, A Nelissen, RGHH AF Pijls, B. G. Meessen, J. M. T. A. Schoones, J. W. Fiocco, M. van der Heide, H. J. L. Sedrakyan, A. Nelissen, R. G. H. H. TI Increased Mortality in Metal-on-Metal versus Non-Metal-on-Metal Primary Total Hip Arthroplasty at 10 Years and Longer Follow-Up: A Systematic Review and Meta-Analysis SO PLOS ONE LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; BONE-MINERAL DENSITY; SERUM-COBALT LEVELS; CLINICAL-TRIAL; BEARING SURFACES; ION LEVELS; DRINKING-WATER; REPLACEMENT; POLYETHYLENE; CANCER AB Importance There are concerns about increased mortality in patients with metal-on-metal bearings in total hip arthroplasty (THA). Objective To determine the mortality and the morbidity in patients with metal-on-metal articulations (MOM THA) compared to patients with non-metal-on-metal articulations (non-MOM THA) after primary total hip arthroplasty. Data Sources Search of PubMed, MEDLINE, EMBASE, Web of Science, Cochrane, CINAHL, Academic-SearchPremier, ScienceDirect, Wiley and clinical trial registers through March 2015, augmented by a hand search of references from the included articles. No language restrictions were applied. Study Selection Two reviewers screened and identified randomised controlled trials and observational studies of primary total hip arthroplasty comparing MOM THA with non-MOM THA. Data Extraction and Synthesis Two reviewers independently extracted study data and assessed risk of bias. Risk differences (RD) were calculated with random effect models. Meta-regression was used to explore modifying factors. Main Outcomes and Measures Difference in mortality and difference in morbidity expressed as revisions and medical complications between patients with MOM THA and non-MOM THA. Results Forty-seven studies were included, comprising 4,000 THA in randomised trials and over 500,000 THA in observational studies. For mortality, random effects analysis revealed a higher pooled RD of 0.7%, 95%, confidence interval (CI) [0.0%, 2.3%], I-square 42%; the heterogeneity was explained by differences in follow-up. When restricted to studies with long term follow-up (i.e. 10 years or more), the RD for mortality was 8.5%, 95%, CI [5.8%, 11.2%]; number needed to treat was 12. Further subgroup analyses and meta-regression random effects models revealed no evidence for other moderator variables (study level covariates, e.g. resurfacing vs. non-resurfacing MOM) than follow-up duration. The quality of the evidence presented in this meta-analysis was characterized as moderate according to the CLEAR-NPT (for non-pharmacological trials) and Cochrane risk of bias Table. Conclusions and Relevance Meta-analysis suggests there may be an increased long-term risk of mortality and revision surgery for patients with MOM THA compared to patients with non-MOM THA. C1 [Pijls, B. G.; Meessen, J. M. T. A.; van der Heide, H. J. L.; Nelissen, R. G. H. H.] Leiden Univ, Med Ctr, Dept Orthopaed, Leiden, Netherlands. [Fiocco, M.] Leiden Univ, Med Ctr, Dept Med Stat, Leiden, Netherlands. [Fiocco, M.] Leiden Univ, Inst Math, NL-2300 RA Leiden, Netherlands. [Schoones, J. W.] Leiden Univ, Med Ctr, Walaeus Lib, Leiden, Netherlands. [Sedrakyan, A.] US FDA, FDA Med Device Epidemiol MDEpiNet Sci & Infrastru, Silver Spring, MD USA. [Sedrakyan, A.] Weill Cornell Med Coll, Dept Healthcare Policy & Res, New York, NY USA. RP Pijls, BG (reprint author), Leiden Univ, Med Ctr, Dept Orthopaed, Leiden, Netherlands. EM b.g.c.w.pijls@lumc.nl RI Schoones, Johannes Wilhelmus/B-2837-2008 OI Schoones, Johannes Wilhelmus/0000-0003-1120-4781 FU Dutch Arthritis Foundation (LRR grant) FX All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available upon request from the corresponding author). RN is a President of the Netherlands Orthopaedic Association. The Leiden University Medical Center (LUMC) Department of Orthopaedics has received grants from the Dutch Arthritis Foundation (LRR grant) and ZonMW during 36 months prior to submittal of the manuscript. All other authors declare that they have no other conflicts of interest. NR 62 TC 0 Z9 0 U1 4 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 13 PY 2016 VL 11 IS 6 AR e0156051 DI 10.1371/journal.pone.0156051 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO5KF UT WOS:000377821300002 PM 27295038 ER PT J AU Zhou, LP Dodd, S Capacci-Daniel, C Garad, S Panicucci, R Sethuraman, V AF Zhou, Liping Dodd, Stephanie Capacci-Daniel, Christina Garad, Sudhakar Panicucci, Riccardo Sethuraman, Vijay TI Co-crystal formation based on structural matching SO EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE Co-crystal; Form; Salt; Solubility; Dissolution; 4-Aminobenzoic acid; Solid state; Hydrogen bond ID COCRYSTALS; SOLUBILITY; ACID; PHARMACOKINETICS; COMPOUND; IMPROVE AB A co-crystal is defined as a single crystalline structure composed of two or more components with no proton transfer which are solid at room temperature. Our group has come up with the following rationale selection of co-formers for initial co-crystal screening: 1) selection of co-formers with the highest potential for hydrogen bonding with the API and 2) selection of co-formers with diversity of secondary structural characteristics. We demonstrate the feasibility of this technique with a Novartis drug candidate A. In the first tier, 20 co-formers were screened and two hits were identified. By examining the two co-formers, which worked from the first round, a second round of screening was undertaken with more focused chemical matter. Nineteen co-crystal formers closely related to the two hits in the first screen were screened in the second tier. From this screen five hits were identified. All the hits were compared for their physical and chemical stability and dissolution profile. Based on the comparison 4-aminobenzoic co-crystal was chosen for in-vivo comparison with the free form. The co-crystal had 12 times higher exposure than the free form thus overcoming the solubility limited exposure. (C) 2016 Elsevier B.V. All rights reserved. C1 [Sethuraman, Vijay] Novartis Pharmaceut, Chem & Pharmaceut Profiling, Tech Res & Dev, Emeryville, CA 94608 USA. [Dodd, Stephanie; Garad, Sudhakar] Novartis Pharmaceut, Chem & Pharmaceut Profiling, Tech Res & Dev, Cambridge, MA 02139 USA. [Zhou, Liping] Ipsen Biosci, 650 E Kendall St, Cambridge, MA 02142 USA. [Capacci-Daniel, Christina] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Panicucci, Riccardo] WuXi App Tech, Suite 1100,222 Third St, Cambridge, MA 02142 USA. RP Sethuraman, V (reprint author), Novartis Pharmaceut, Chem & Pharmaceut Profiling, Tech Res & Dev, Emeryville, CA 94608 USA. NR 23 TC 0 Z9 0 U1 4 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0928-0987 EI 1879-0720 J9 EUR J PHARM SCI JI Eur. J. Pharm. Sci. PD JUN 10 PY 2016 VL 88 BP 191 EP 201 DI 10.1016/j.ejps.2016.02.017 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DM9AI UT WOS:000376655200017 PM 26948852 ER PT J AU Silberstein, E Ulitzky, L Lima, LA Cehan, N Teixeira-Carvalho, A Roingeard, P Taylor, DR AF Silberstein, Erica Ulitzky, Laura Lima, Livia Alves Cehan, Nicoleta Teixeira-Carvalho, Andrea Roingeard, Philippe Taylor, Deborah R. TI HCV-Mediated Apoptosis of Hepatocytes in Culture and Viral Pathogenesis SO PLOS ONE LA English DT Article ID HEPATITIS-C VIRUS; HEPATOCELLULAR-CARCINOMA; GENE-EXPRESSION; LIVER FIBROSIS; CELL-DEATH; SMMC-7721 CELLS; GAMBOGIC ACID; INFECTION; REPLICATION; CASPASE AB Chronic Hepatitis C Virus (HCV) infection is associated with progressive liver injury and subsequent development of fibrosis and cirrhosis. The death of hepatocytes results in the release of cytokines that induce inflammatory and fibrotic responses. The mechanism of liver damage is still under investigation but both apoptosis and immune-mediated processes may play roles. By observing the changes in gene expression patterns in HCV-infected cells, both markers and the causes of HCV-associated liver injury may be elucidated. HCV genotype 1b virus from persistently infected VeroE6 cells induced a strong cytopathic effect when used to infect Huh7.5 hepatoma cells. To determine if this cytopathic effect was a result of apoptosis, ultrastructural changes were observed by electron microscopy and markers of programmed cell death were surveyed. Screening of a human PCR array demonstrated a gene expression profile that contained upregulated markers of apoptosis, including tumor necrosis factor, caspases and caspase activators, Fas, Bcl2-interacting killer (BIK) and tumor suppressor protein, p53, as a result of HCV genotype 1b infection. The genes identified in this study should provide new insights into understanding viral pathogenesis in liver cells and may possibly help to identify novel antiviral and antifibrotic targets. C1 [Silberstein, Erica; Ulitzky, Laura; Lima, Livia Alves; Cehan, Nicoleta; Teixeira-Carvalho, Andrea; Taylor, Deborah R.] CBER FDA, Off Blood Res & Review, Div Emerging Transfus Transmitted Dis, Lab Emerging Pathogens, Silver Spring, MD 20903 USA. [Roingeard, Philippe] Univ Tours, INSERM U966, Tours, France. [Roingeard, Philippe] CHRU Tours, Tours, France. [Lima, Livia Alves] Univ Fed Mato Grosso do Sul, Campo Grande, Brazil. [Cehan, Nicoleta] EMLab P&K, Fairfax, VA 22030 USA. [Teixeira-Carvalho, Andrea] Fundacao Oswaldo Cruz FIOCRUZ, Ctr Pesquisas Rene Rachou, Fundacao Lab Biomarcadores Diagnost & Monitoracao, Grp Integrado Pesquisas Biomarcadores, Belo Horizonte, MG, Brazil. RP Taylor, DR (reprint author), CBER FDA, Off Blood Res & Review, Div Emerging Transfus Transmitted Dis, Lab Emerging Pathogens, Silver Spring, MD 20903 USA. EM Deborah.Taylor@fda.hhs.gov NR 53 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 JUN 9 PY 2016 VL 11 IS 6 AR e0155708 DI 10.1371/journal.pone.0155708 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DO1TW UT WOS:000377563000005 PM 27280444 ER PT J AU Toh, S Hampp, C Reichman, ME Graham, DJ Balakrishnan, S Pucino, F Hamilton, J Lendle, S Iyer, A Rucker, M Pimentel, M Nathwani, N Griffin, MR Brown, NJ Fireman, BH AF Toh, Sengwee Hampp, Christian Reichman, Marsha E. Graham, David J. Balakrishnan, Suchitra Pucino, Frank Hamilton, Jack Lendle, Samuel Iyer, Aarthi Rucker, Malcolm Pimentel, Madelyn Nathwani, Neesha Griffin, Marie R. Brown, Nancy J. Fireman, Bruce H. TI Risk for Hospitalized Heart Failure Among New Users of Saxagliptin, Sitagliptin, and Other Antihyperglycemic Drugs SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID DIPEPTIDYL PEPTIDASE-4 INHIBITORS; RANDOMIZED CLINICAL-TRIALS; ACUTE MYOCARDIAL-INFARCTION; CARDIOVASCULAR OUTCOMES; MINI-SENTINEL; DIABETES-MELLITUS; METAANALYSIS; COHORT; ASSOCIATION; DISEASE AB Background: Recent postmarketing trials produced conflicting results about the risk for hospitalized heart failure (hHF) associated with dipeptidyl peptidase-4 (DPP-4) inhibitors, creating uncertainty about the safety of these antihyperglycemic agents. Objective: To examine the associations of hHF with saxagliptin and sitagliptin. Design: Population-based, retrospective, new-user cohort study. Setting: 18 health insurance and health system data partners in the U.S. Food and Drug Administration's Mini-Sentinel program. Patients: Patients aged 18 years or older with type 2 diabetes who initiated therapy with saxagliptin, sitagliptin, pioglitazone, second-generation sulfonylureas, or long-acting insulin products from 2006 to 2013. Measurements: Hospitalized HF, identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes 402.x1, 404.x1, 404.x3, and 428.xx recorded as the principal discharge diagnosis. Results: 78 553 saxagliptin users and 298 124 sitagliptin users contributed an average of 7 to 9 months of follow-up data to 1 or more pairwise comparisons. The risk for hHF was not higher with DPP-4 inhibitors than with the other study drugs. The hazard ratios from the disease risk score (DRS)-stratified analyses were 0.83 (95% CI, 0.70 to 0.99) for saxagliptin versus sitagliptin, 0.63 (CI, 0.47 to 0.85) for saxagliptin versus pioglitazone, 0.69 (CI, 0.54 to 0.87) for saxagliptin versus sulfonylureas, and 0.61 (CI, 0.50 to 0.73) for saxagliptin versus insulin. The DRS-stratified hazard ratios were 0.74 (CI, 0.64 to 0.85) for sitagliptin versus pioglitazone, 0.86 (CI, 0.77 to 0.95) for sitagliptin versus sulfonylureas, and 0.71 (CI, 0.64 to 0.78) for sitagliptin versus insulin. Results from the 1: 1 propensity score-matched analyses were similar. Results were also similar in subgroups of patients with and without prior cardiovascular disease and in a subgroup defined by the 2 highest DRS deciles. Limitation: Residual confounding and short follow-up. Conclusion: In this large cohort study, a higher risk for hHF was not observed in users of saxagliptin or sitagliptin compared with other selected antihyperglycemic agents. C1 [Toh, Sengwee; Iyer, Aarthi; Rucker, Malcolm; Pimentel, Madelyn; Nathwani, Neesha] Harvard Univ, Sch Med, Dept Populat Med, 401 Pk Dr,Suite 401, Boston, MA 02215 USA. [Toh, Sengwee; Iyer, Aarthi; Rucker, Malcolm; Pimentel, Madelyn; Nathwani, Neesha] Harvard Pilgrim Hlth Care Inst, 401 Pk Dr,Suite 401, Boston, MA 02215 USA. [Hampp, Christian] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, White Oak CDER Off Bldg 22,Room 2441, Silver Spring, MD 20993 USA. [Reichman, Marsha E.] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, White Oak CDER Off Bldg 22,Room 3462, Silver Spring, MD 20993 USA. [Graham, David J.] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, White Oak CDER Off Bldg 22,Room 4314, Silver Spring, MD 20993 USA. [Balakrishnan, Suchitra] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, White Oak CDER Off Bldg 22,Room 3145, Silver Spring, MD 20993 USA. [Pucino, Frank] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, White Oak CDER Off Bldg 22,Room 3204, Silver Spring, MD 20993 USA. [Griffin, Marie R.] Vanderbilt Univ, Med Ctr, Dept Hlth Policy, Suite 2600,1500 21st Ave South, Nashville, TN 37212 USA. [Brown, Nancy J.] Vanderbilt Univ, Sch Med, Dept Hlth Policy, Med Ctr North D3100, Nashville, TN 37232 USA. VA Tennessee Valley Hlth Care Syst, Nashville, TN USA. [Hamilton, Jack; Lendle, Samuel; Fireman, Bruce H.] Kaiser Permanente No Calif, Div Res, 2000 Broadway, Oakland, CA 94612 USA. RP Toh, S (reprint author), Harvard Univ, Sch Med, Dept Populat Med, 401 Pk Dr,Suite 401, Boston, MA 02215 USA.; Toh, S (reprint author), Harvard Pilgrim Hlth Care Inst, 401 Pk Dr,Suite 401, Boston, MA 02215 USA. EM darren_toh@harvardpilgrim.org RI Toh, Sengwee/D-7567-2017; OI Toh, Sengwee/0000-0002-5160-0810; Hamilton, Jack/0000-0001-7544-9388 FU U.S. Department of Health and Human Services [HHSF223200910006I, HHSF22301004T, HHSF22301007T] FX By the FDA through the U.S. Department of Health and Human Services (contract HHSF223200910006I, HHSF22301004T, and HHSF22301007T). NR 36 TC 14 Z9 14 U1 2 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 7 PY 2016 VL 164 IS 11 BP 705 EP + DI 10.7326/M15-2568 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DO1AI UT WOS:000377510100002 PM 27110660 ER PT J AU Wilson, MR Brown, E Keys, C Strain, E Luo, Y Muruvanda, T Grim, C Beaubrun, JJG Jarvis, K Ewing, L Gopinath, G Hanes, D Allard, MW Musser, S AF Wilson, Mark R. Brown, Eric Keys, Chris Strain, Errol Luo, Yan Muruvanda, Tim Grim, Christopher Beaubrun, Junia Jean-Gilles Jarvis, Karen Ewing, Laura Gopinath, Gopal Hanes, Darcy Allard, Marc W. Musser, Steven TI Whole Genome DNA Sequence Analysis of Salmonella subspecies enterica serotype Tennessee obtained from related peanut butter foodborne outbreaks SO PLOS ONE LA English DT Article ID LIMITED GENETIC DIVERSITY; ENTERITIDIS STRAINS; ESCHERICHIA-COLI; HEAT TOLERANCE; TYPHIMURIUM; SCHEME; EVOLUTION; VIRULENCE; PCR AB Establishing an association between possible food sources and clinical isolates requires discriminating the suspected pathogen from an environmental background, and distinguishing it from other closely-related foodborne pathogens. We used whole genome sequencing (WGS) to Salmonella subspecies enterica serotype Tennessee (S. Tennessee) to describe genomic diversity across the serovar as well as among and within outbreak clades of strains associated with contaminated peanut butter. We analyzed 71 isolates of S. Tennessee from disparate food, environmental, and clinical sources and 2 other closely-related Salmonella serovars as outgroups (S. Kentucky and S. Cubana), which were also shot-gun sequenced. A whole genome single nucleotide polymorphism (SNP) analysis was performed using a maximum likelihood approach to infer phylogenetic relationships. Several monophyletic lineages of S. Tennessee with limited SNP variability were identified that recapitulated several food contamination events. S. Tennessee clades were separated from outgroup salmonellae by more than sixteen thousand SNPs. Intra-serovar diversity of S. Tennessee was small compared to the chosen outgroups (1,153 SNPs), suggesting recent divergence of some S. Tennessee clades. Analysis of all 1,153 SNPs structuring an S. Tennessee peanut butter outbreak cluster revealed that isolates from several food, plant, and clinical isolates were very closely related, as they had only a few SNP differences between them. SNP-based cluster analyses linked specific food sources to several clinical S. Tennessee strains isolated in separate contamination events. Environmental and clinical isolates had very similar whole genome sequences; no markers were found that could be used to discriminate between these sources. Finally, we identified SNPs within variable S. Tennessee genes that may be useful markers for the development of rapid surveillance and typing methods, potentially aiding in traceback efforts during future outbreaks. Using WGS can delimit contamination sources for foodborne illnesses across multiple outbreaks and reveal otherwise undetected DNA sequence differences essential to the tracing of bacterial pathogens as they emerge. C1 [Wilson, Mark R.] US FDA, CFSAN, College Pk, MD USA. [Brown, Eric; Keys, Chris; Strain, Errol; Luo, Yan; Muruvanda, Tim; Grim, Christopher; Allard, Marc W.; Musser, Steven] Battelle Mem Inst, Crystal City, VA 22202 USA. [Grim, Christopher; Beaubrun, Junia Jean-Gilles; Jarvis, Karen; Ewing, Laura; Gopinath, Gopal; Hanes, Darcy] US FDA, DVA, VMB, CFSAN,OARSA, Laurel, MD USA. RP Allard, MW (reprint author), Battelle Mem Inst, Crystal City, VA 22202 USA. EM marc.allard@fda.hhs.gov NR 51 TC 3 Z9 3 U1 5 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 3 PY 2016 VL 11 IS 6 AR e0146929 DI 10.1371/journal.pone.0146929 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DN8ZV UT WOS:000377369700002 PM 27258142 ER PT J AU Woodcock, J Ware, JH Miller, PW McMurray, JJV Harrington, DP Drazen, JM AF Woodcock, Janet Ware, James H. Miller, Pamela W. McMurray, John J. V. Harrington, David P. Drazen, Jeffrey M. TI Clinical Trials Series SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Woodcock, Janet] US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [McMurray, John J. V.] Univ Glasgow, Cardiovasc Res Ctr, British Heart Fdn, Glasgow, Lanark, Scotland. [Harrington, David P.] Harvard TH Chan Sch Publ Hlth, Dept Stat, Boston, MA USA. RP Woodcock, J (reprint author), US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. OI mcmurray, john/0000-0002-6317-3975 NR 4 TC 2 Z9 2 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 JUN 2 PY 2016 VL 374 IS 22 BP 2167 EP 2167 DI 10.1056/NEJMe1601510 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EB2RP UT WOS:000387209900012 ER PT J AU Lansdowne, K Strauss, DG Scully, CG AF Lansdowne, Krystal Strauss, David G. Scully, Christopher G. TI Retrospective analysis of pulse oximeter alarm settings in an intensive care unit patient population SO BMC NURSING LA English DT Article DE Pulse oximeter; Patient monitoring; Alarm fatigue; Alarm rates ID FALSE ALARMS; MONITORS AB Background: The cacophony of alerts and alarms in a hospital produced by medical devices results in alarm fatigue. The pulse oximeter is one of the most common sources of alarms. One of the ways to reduce alarm rates is to adjust alarm settings at the bedside. This study is aimed to retrospectively examine individual pulse oximeter alarm settings on alarm rates and inter-and intra-patient variability. Methods: Nine hundred sixty-two previously collected intensive care unit (ICU) patient records were obtained from the Multiparameter Intelligent Monitoring in Intensive Care II Database (Beth Israel Deaconess Medical Center, Boston, MA). Inclusion criteria included patient records that contained SpO(2) trend data sampled at 1 Hz for at least 1 h and a matching clinical record. SpO(2) alarm rates were simulated by applying a range of thresholds (84, 86, 88, and 90 %) and delay times (10 to 60 s) to the SpO(2) data. Patient records with at least 12 h of SpO(2) data were examined for the variability in alarm rate over time. Results: Decreasing SpO(2) thresholds and increasing delay times resulted in decreased alarm rates. A limited number of patient records accounted for most alarms, and this number increased as alarm settings loosened (the top 10 % of patient records were responsible for 57.4 % of all alarms at an SpO(2) threshold of 90 % and 15 s delay and 81.6 % at an SpO(2) threshold of 84 % and 45 s delay). Alarm rates were not consistent over time for individual patients with periods of high and low alarms for all alarm settings. Conclusion: Pulse oximeter SpO(2) alarm rates are variable between patients and over time, and the alarm rate and the extent of inter-and intra-patient variability can be affected by the alarm settings. Personalized alarm settings for a patient's current status may help to reduce alarm fatigue for nurses. C1 [Lansdowne, Krystal; Strauss, David G.; Scully, Christopher G.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Scully, CG (reprint author), US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM christopher.scully@fda.hhs.gov NR 20 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6955 J9 BMC NURS JI BMC Nurs. PD JUN 2 PY 2016 VL 15 AR 36 DI 10.1186/s12912-016-0149-3 PG 8 WC Nursing SC Nursing GA DO1EA UT WOS:000377520100002 PM 27274710 ER PT J AU Schilsky, M Cartiera, K Boga, S Schilsky, S Emre, S Mulligan, D Weinreb, J Israel, G AF Schilsky, M. Cartiera, K. Boga, S. Schilsky, S. Emre, S. Mulligan, D. Weinreb, J. Israel, G. TI Improving the Efficiency, Safety and Cost of Evaluating Living Donor Liver Candidates Using Single Sequence MRI. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY JUN 11-15, 2016 CL Boston, MA C1 [Schilsky, M.; Cartiera, K.; Boga, S.; Emre, S.; Mulligan, D.; Weinreb, J.; Israel, G.] Yale Univ, Yale New Haven Transplantat Ctr, Transplantat & Immunol, Surg, New Haven, CT USA. [Schilsky, M.] Yale Univ, Sect Digest Dis, Med, New Haven, CT USA. [Schilsky, S.] 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 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUN PY 2016 VL 16 SU 3 SI SI MA 240 BP 288 EP 288 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DW1AB UT WOS:000383373902241 ER PT J AU Blumenthal, GM Pazdur, R AF Blumenthal, Gideon M. Pazdur, Richard TI Response Rate as an Approval End Point in Oncology Back to the Future SO JAMA ONCOLOGY LA English DT Editorial Material ID CLINICAL-TRIALS C1 [Blumenthal, Gideon M.] US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. RP Blumenthal, GM (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM gideon.blumenthal@fda.hhs.gov NR 7 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 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JUN PY 2016 VL 2 IS 6 BP 780 EP 781 DI 10.1001/jamaoncol.2015.6352 PG 2 WC Oncology SC Oncology GA DW5RE UT WOS:000383703600015 PM 26913938 ER PT J AU Gaitens, JM Centeno, JA Squibb, KS Condon, M McDiarmid, MA AF Gaitens, Joanna M. Centeno, Jose A. Squibb, Katherine S. Condon, Marian McDiarmid, Melissa A. TI Mobilization of Metal From Retained Embedded Fragments in a Blast-Injured Iraq War Veteran SO MILITARY MEDICINE LA English DT Article ID DEPLETED URANIUM COHORT; FOREIGN-BODY; SURVEILLANCE; CARCINOGENESIS; TOXICITY; RATS AB A frequent comorbidity of traumatic injury due to a blast or explosion, commonly reported in Iraq and Afghanistan veterans, is that of retained embedded fragments typically of unknown content. Because of concerns over both local and systemic health effects related to both the physical presence of and mobilization of materials from embedded fragments, the Department of Veterans Affairs established a surveillance program for this group of veterans. We present here the case of a surveillance-enrolled veteran who submitted: (1) three surgically removed fragments for content analyses, (2) tissue adhered to the fragments for histology and metal concentration evaluation, and (3) pre- and postfragment removal urine samples to assess concentrations of various metals often found in fragments. Results indicate that removed fragments were aluminum-copper alloys. Surrounding tissue analyses revealed elevated concentrations of these metals and evidence of chronic inflammation, but no neoplastic changes. Urine aluminum concentrations, initially elevated compared to normal population values, decreased significantly after fragment removal, illustrating the utility of urine biomonitoring to provide insight into fragment composition. A medical surveillance program integrating fragment composition data, tissue analyses, and repeat urine biomonitoring can help inform the patient-specific medical management of both the local and systemic effects of retained metal fragments. C1 [Gaitens, Joanna M.; Squibb, Katherine S.; Condon, Marian; McDiarmid, Melissa A.] Dept Vet Affairs Med Ctr, 11 North Greene St, Baltimore, MD 21201 USA. [Gaitens, Joanna M.; Squibb, Katherine S.; McDiarmid, Melissa A.] Univ Maryland, Div Occupat & Environm Med, Dept Med, 11 South Paca St,Suite 200, Baltimore, MD 21201 USA. [Centeno, Jose A.] US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 64,Room 4028, Silver Spring, MD 20993 USA. RP Gaitens, JM (reprint author), Dept Vet Affairs Med Ctr, 11 North Greene St, Baltimore, MD 21201 USA.; Gaitens, JM (reprint author), Univ Maryland, Div Occupat & Environm Med, Dept Med, 11 South Paca St,Suite 200, Baltimore, MD 21201 USA. FU U.S. Department of Veterans Affairs; University of Maryland's School of Medicine Institutional Review Board FX This work is supported by the U.S. Department of Veterans Affairs and is approved by the Baltimore VA Medical Center's Office of Research and Development and the University of Maryland's School of Medicine Institutional Review Board. The authors acknowledge the assistance of Michael R. Lewin-Smith, MB, BS, for histopathology and manuscript review.; This work is funded by the U.S. Department of Veterans Affairs. NR 26 TC 0 Z9 0 U1 0 U2 0 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD JUN PY 2016 VL 181 IS 6 BP E625 EP E629 DI 10.7205/MILMED-D-15-00432 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA DW5LO UT WOS:000383686900004 PM 27244078 ER PT J AU Freedman, DM Wu, JC Chen, HL Engels, EA Enewold, LR Freedman, ND Goedert, JJ Kuncl, RW Gail, MH Pfeiffer, RM AF Freedman, D. Michal Wu, Jincao Chen, Honglei Engels, Eric A. Enewold, Lindsey R. Freedman, Neal D. Goedert, James J. Kuncl, Ralph W. Gail, Mitchell H. Pfeiffer, Ruth M. TI Associations between cancer and Parkinson's disease in US elderly adults SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Cancer; Parkinson's disease; Medicare; SEER Program ID REPRODUCTIVE FACTORS; PROSPECTIVE COHORT; MALIGNANT-MELANOMA; MEDICARE DATA; EPIDEMIOLOGY; RISK; DIAGNOSIS; SMOKING; AGE; SURVEILLANCE AB Background: Several studies suggest that cancer is reduced before and after a Parkinson's disease (PD) diagnosis. However, determining relationships among diseases of ageing is challenging due to possible biases in ascertaining disease. This study evaluates the PD and cancer relationship, addressing potential biases. Methods: Using Surveillance, Epidemiology, and End Results-Medicare linked data (1992-2005) of adults >= 65 years, we assessed PD risk after cancer comparing PD in 743 779 cancer patients with PD in a non-cancer group (n = 419 432) in prospective cohort analyses. We also conducted a case-control study of 836 947 cancer cases and 142 869 controls to assess cancer following PD. We applied Cox proportional hazards models to estimate hazards ratios (HRs) for PD after cancer and unconditional logistic regression to estimate odds ratios (ORs) for PD preceding cancer, controlling for physician visits and other factors. To explore biases in ascertaining cancer, we examined relationships between cancer and automobile accident injuries, which we expected to be null. Results: No association was observed between cancer and subsequent PD [ HR = 0.97; 95% confidence interval (CI) = 0.92-1.01] nor between cancer and subsequent automobile injuries (HR = 1.03; 95% CI = 0.98-1.07). One site, lung cancer, was associated with subsequent reduced PD, which may reflect confounding by smoking. In the case-control analysis, PD was associated with reduced subsequent cancer, overall (OR = 0.77; 95% CI = 0.71-0.82) and for several cancer sites. However, the automobile injury/subsequent cancer association was similar (OR = 0.83; 95% CI = 0.78-0.88), suggesting a cancer detection bias after serious health outcomes. Conclusions: In totality, our data do not support a biological relationship between PD and cancer. C1 [Freedman, D. Michal; Wu, Jincao; Engels, Eric A.; Freedman, Neal D.; Goedert, James J.; Gail, Mitchell H.; Pfeiffer, Ruth M.] NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,7E538, Rockville, MD 20850 USA. [Wu, Jincao] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Chen, Honglei] NIEHS, Aging & Neuroepidemiol Grp, POB 12233, Res Triangle Pk, NC 27709 USA. [Enewold, Lindsey R.] NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,7E538, Rockville, MD 20850 USA. [Kuncl, Ralph W.] Univ Redlands, Dept Biol, Redlands, CA 92373 USA. RP Freedman, DM (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,7E538, Rockville, MD 20850 USA. EM freedmam@mail.nih.gov OI Chen, Honglei/0000-0003-3446-7779 FU Intramural Research Program of the National Cancer Institute; National Institute of Environmental Health Sciences, National Institutes of Health; US Public Health Service FX This work was supported by the Intramural Research Program of the National Cancer Institute and the National Institute of Environmental Health Sciences, National Institutes of Health and the US Public Health Service. NR 37 TC 2 Z9 2 U1 4 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2016 VL 45 IS 3 BP 741 EP 751 DI 10.1093/ije/dyw016 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DX8QG UT WOS:000384653200028 PM 26989123 ER PT J AU Winner, TL Lanzarotta, A Sommer, AJ AF Winner, Taryn L. Lanzarotta, Adam Sommer, Andre J. TI Analysis of Counterfeit Coated Tablets and Multi-Layer Packaging Materials Using Infrared Microspectroscopic Imaging SO MICROSCOPY AND MICROANALYSIS LA English DT Article DE ATR; FTIR; counterfeit; packaging; pharmaceuticals ID ATTENUATED TOTAL-REFLECTION; MAPPING MICROSPECTROSCOPY; SPECTROSCOPY; MICROSCOPE AB An effective method for detecting and characterizing counterfeit finished dosage forms and packaging materials is described in this study. Using attenuated total internal reflection Fourier transform infrared spectroscopic imaging, suspect tablet coating and core formulations as well as multi-layered foil safety seals, bottle labels, and cigarette tear tapes were analyzed and compared directly with those of a stored authentic product. The approach was effective for obtaining molecular information from structures as small as 6 mu m. C1 [Winner, Taryn L.; Sommer, Andre J.] Miami Univ, Dept Chem & Biochem, Mol Microspect Lab, Oxford, OH 45056 USA. [Lanzarotta, Adam] US FDA, Forens Chem Ctr, Cincinnati, OH USA. RP Winner, TL (reprint author), Miami Univ, Dept Chem & Biochem, Mol Microspect Lab, Oxford, OH 45056 USA. EM winnertl@miamioh.edu NR 25 TC 0 Z9 0 U1 2 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1431-9276 EI 1435-8115 J9 MICROSC MICROANAL JI Microsc. microanal. PD JUN PY 2016 VL 22 IS 3 BP 649 EP 655 DI 10.1017/S143192761600060X PG 7 WC Materials Science, Multidisciplinary; Microscopy SC Materials Science; Microscopy GA DX4DY UT WOS:000384332600019 PM 27068491 ER PT J AU Chen, HC Chen, JJ AF Chen, Hung-Chia Chen, James J. TI Hybrid Mixture Model for Subpopulation Identification SO STATISTICS IN BIOSCIENCES LA English DT Article DE Cluster analysis; Mixture model; EM algorithm; Personalized medicine; Gene signature ID LIKELIHOOD RATIO TEST; DIFFERENTIAL GENE-EXPRESSION; ACUTE LYMPHOBLASTIC-LEUKEMIA; SUPPORT VECTOR MACHINES; FALSE DISCOVERY RATES; CELL LUNG-CANCER; BREAST-CANCER; COLORECTAL-CANCER; UNEQUAL VARIANCES; COMPONENTS AB Personalized medicine aims to identify those patients who have good or poor prognosis for overall disease outcomes or therapeutic efficacy for a specific treatment. A well-established approach is to identify a set of biomarkers using statistical methods with a classification algorithm to identify patient subgroups for treatment selection. However, there are potential false positives and false negatives in classification resulting in incorrect patient treatment assignment. In this paper, we propose a hybrid mixture model taking uncertainty in class labels into consideration, where the class labels are modeled by a Bernoulli random variable. An EM algorithm was developed to estimate the model parameters, and a parametric bootstrap method was used to test the significance of the predictive variables that were associated with subgroup memberships. Simulation experiments showed that the proposed method averagely had higher accuracy in identifying the subpopulations than the Naive Bayes classifier and logistic regression. A breast cancer dataset was analyzed to illustrate the proposed hybrid mixture model. C1 [Chen, Hung-Chia; Chen, James J.] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 20, Jefferson, AR 72079 USA. RP Chen, JJ (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 20, Jefferson, AR 72079 USA. EM jamesj.chen@fda.hhs.gov NR 52 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1867-1764 EI 1867-1772 J9 STAT BIOSCI JI Stat. Biosci. PD JUN PY 2016 VL 8 IS 1 BP 28 EP 42 DI 10.1007/s12561-015-9131-y PG 15 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DW2IX UT WOS:000383467200003 ER PT J AU Gao, Z Roy, A Tan, M AF Gao, Zhong Roy, Anindya Tan, Ming TI A Two-Stage Adaptive Targeted Clinical Trial Design for Biomarker Performance-Based Sample Size Re-Estimation SO STATISTICS IN BIOSCIENCES LA English DT Article ID EFFICIENCY AB Biomarker-directed targeted clinical trial is aimed at developing pharmaceutical agents for a targeted patient subpopulation sharing a specific disease etiology. Biomarker plays a key role in patient enrichment for targeted trials. Biomarker performance substantially impacts heterogeneity of a targeted study population and consequently trial efficiency, statistical power, information accumulation, and early stopping decision-making (Simon and Maitournam in Clinical Cancer Res 10:6759-6763, 2004; Maitournam and Simon in Stat Med 24:329-339, 2005; Gao et al. in Contemp Clin Trials 42:119-131, 2015). Hence, accurate assessment of biomarker performance is crucial to sample size calculation in planning of targeted trials. However, prior knowledge of biomarker performance is often limited at the planning stage due to inadequacy of biomarker validation, differences between study populations in demographic characteristics and trial settings, etc. Under this circumstance, adaptive design would be useful in updating biomarker performance and re-estimating sample sizes when a targeted trial is ongoing. In this paper, we propose a two-stage adaptive design that provides flexibility in biomarker performance-based sample size adaption for targeted trials. The design can facilitate a targeted trial to achieve planned statistical power by re-assessment of actual biomarker performance and subsequent sample size adaption while preserving desired type-1 error. C1 [Gao, Zhong; Roy, Anindya] Univ Maryland Baltimore Cty, Dept Math & Stat, Baltimore, MD 21250 USA. [Tan, Ming] Georgetown Univ, Dept Biostat Bioinformat & Biomath, Suite 180,Bldg D,4000 Reservoir Rd, Washington, DC 20057 USA. [Gao, Zhong] US FDA, Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Tan, M (reprint author), Georgetown Univ, Dept Biostat Bioinformat & Biomath, Suite 180,Bldg D,4000 Reservoir Rd, Washington, DC 20057 USA. EM Zhong.Gao@fda.hhs.gov; mtt34@georgetown.edu NR 13 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1867-1764 EI 1867-1772 J9 STAT BIOSCI JI Stat. Biosci. PD JUN PY 2016 VL 8 IS 1 BP 66 EP 76 DI 10.1007/s12561-015-9139-3 PG 11 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DW2IX UT WOS:000383467200005 ER PT J AU Wang, SJ Li, MC AF Wang, Sue-Jane Li, Ming-Chung TI Impacts of Predictive Genomic Classifier Performance on Subpopulation-Specific Treatment Effects Assessment SO STATISTICS IN BIOSCIENCES LA English DT Article DE Composite genomic biomarker; Cross-validated machine learning voting algorithm; Pharmacogenomics; Positive or negative predictive value; Prevalence; Subpopulation treatment effect ID ADAPTIVE SIGNATURE DESIGN; CELL LUNG-CANCER; CLINICAL-TRIALS; GENE SIGNATURE AB We consider three (strong, moderate and mild) predictive biomarker scenarios with varying prevalence. As such, there is no treatment effect in the biomarker negative (g(-)) patient subpopulation. Relative to g(-), there is a four-fold profound treatment effect in the biomarker positive (g(+)) patient subpopulation, a strongly predictive scenario; a three-fold large g(+) subpopulation treatment effect, a moderately predictive scenario; and a two-fold modest g(+) subpopulation treatment effect, a mildly predictive scenario. In this paper, we focus on binary endpoint in prescribing treatment effect. Using a Breiman's (Mach. Learn. 24:123-140, 1996) machine learning voting algorithm via a k-fold cross-validated approach applied by Freidlin et al. (Clin. Cancer Res. 16:691-698, 2010), a predictive biomarker may be developed. We consider development or discovery of a genomic biomarker using microarray gene expressions data in randomized controlled trials and validate the biomarker's predictive performance in an independent data set. We investigate the classification performance characteristics of a binary genomic composite biomarker (expected to be predictive of treatment effects) including sensitivity, specificity, accuracy, positive predictive value and negative predictive value as a function of true sensitive prevalence. In doing so, we report the finding based on three representative tuning parameter sets with varying degree of rigor in their choices of the parameters ranging from highly rigorous, moderately rigorous to mildly rigorous. We articulate the rationales on the choices of tuning parameter sets. We also study the impacts of misclassification of genomic biomarker classifiers on their assessment of treatment effects in the positive and negative patient subpopulations, and all-comer patients. We elucidate via simulation studies on approaches to improve sensitivity when a biomarker is highly specific but poorly sensitive, a scenario that is most likely to lead to an incorrect test conclusion of an applicable significant treatment effect in a specific patient subpopulation or both positive and negative subpopulations. We explore when it will be beneficial to develop a binary predictive biomarker and conclude that hypothesis test inferences for the g(+) subpopulation treatment effect in the dual hypotheses setting (all-comer and g(+) alone) cannot be relied upon if the biomarker classifier is only highly specific and poorly sensitive or resulting in poor negative predictive value. The converse dual hypotheses (all-comer and g-alone) have the same concern, viz. highly sensitive and poorly specific or resulting in poor positive predictive value. In addition, we compare the predictive performance of a biomarker classifier between use of direct selection and selection from a candidate pool shedding favorable lights of direct selection approach where biological or mechanistic plausibility can be relied upon. Further research is needed if accurate classifier is required irrespective of prevalence level. C1 [Wang, Sue-Jane] US FDA, CDER, OTS, Off Biostat, Mailstop WO 21,Room 3562,10903 New Hampshire, Silver Spring, MD 20993 USA. [Wang, Sue-Jane] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Off Biostat, Silver Spring, MD USA. [Li, Ming-Chung] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. RP Wang, SJ (reprint author), US FDA, CDER, OTS, Off Biostat, Mailstop WO 21,Room 3562,10903 New Hampshire, Silver Spring, MD 20993 USA. EM suejane.wang@fda.hhs.gov NR 14 TC 3 Z9 3 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1867-1764 EI 1867-1772 J9 STAT BIOSCI JI Stat. Biosci. PD JUN PY 2016 VL 8 IS 1 BP 129 EP 158 DI 10.1007/s12561-013-9092-y PG 30 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DW2IX UT WOS:000383467200008 ER PT J AU Liu, W Zhang, ZW Schroeder, RJ Ho, M Zhang, B Long, C Zhang, H Irony, TZ AF Liu, Wei Zhang, Zhiwei Schroeder, R. Jason Ho, Martin Zhang, Bo Long, Cynthia Zhang, Hui Irony, Telba Z. TI Joint Estimation of Treatment and Placebo Effects in Clinical Trials With Longitudinal Blinding Assessments SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Causal inference; Confounding; Double robustness; G-computation; Inverse probability weighting; Sequential regression; Targeted minimum loss based estimation; Treatmentality ID RANDOMIZED CONTROLLED-TRIAL; CAUSAL INFERENCE; MISSING DATA; MODELS; DISULFIRAM; INDEX AB In some therapeutic areas, treatment evaluation is frequently complicated by a possible placebo effect (i.e., the psychobiological effect of a patient's knowledge or belief of being treated). When a substantial placebo effect is likely to exist, it is important to distinguish the treatment and placebo effects in quantifying the clinical benefit of a new treatment. These causal effects can be formally defined in a joint causal model that includes treatment (e.g., new vs. placebo) and treatmentality (i.e., a patient's belief or mentality about which treatment she or he has received) as separate exposures. Information about the treatmentality exposure can be obtained from blinding assessments, which are increasingly common in clinical trials where blinding success is in question. Assuming that treatmentality has a lagged effect and is measured at multiple time points, this article is concerned with joint evaluation of treatment and placebo effects in clinical trials with longitudinal follow-up, possibly with monotone missing data. We describe and discuss several methods adapted from the longitudinal causal inference literature, apply them to a weight loss study, and compare them in simulation experiments that mimic the weight loss study. Supplementary materials for this article are available online. C1 [Zhang, Zhiwei] US FDA, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Zhang, ZW (reprint author), US FDA, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM zhiwei.zhang@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 35 TC 0 Z9 0 U1 1 U2 1 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 EI 1537-274X J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD JUN PY 2016 VL 111 IS 514 BP 538 EP 548 DI 10.1080/01621459.2015.1130633 PG 11 WC Statistics & Probability SC Mathematics GA DT2QY UT WOS:000381326700008 PM 27110045 ER PT J AU Koonse, B AF Koonse, Brett TI A Summary of the United States Food and Drug Administrations' Food Safety Program for Imported Seafood; One Country's Approach SO FOODS LA English DT Review DE seafood safety; imports food safety; FDA seafood AB It is well known that the vast majority of seafood is captured or farmed in emerging countries and exported to developed countries. This has resulted in seafood being the number one traded food commodity in the world. Food safety is essential to this trade. Exporting countries should understand the regulatory food safety programs of the countries they ship to in order to comply with their applicable laws and regulations to avoid violations and disruptions in trade. The United States (U.S.) imports more seafood than any individual country in the world but the European Union (E.U.) countries, as a block, import significantly more. Each importing country has its own programs and systems in place to ensure the safety of imported seafood. However, most countries that export seafood have regulatory programs in place that comply with the import requirements of the E.U. The purpose of this paper is to describe the United States Food and Drug Administration's (USFDA) imported seafood safety program. The primary audience for the information is foreign government regulators, seafood exporters, and U.S. importers. It can also give consumers confidence that f U.S. seafood is safe no matter which country it originates from. C1 [Koonse, Brett] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Koonse, B (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM brett.koonse@fda.hhs.gov NR 0 TC 2 Z9 2 U1 7 U2 7 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2304-8158 J9 FOODS JI Foods PD JUN PY 2016 VL 5 IS 2 DI 10.3390/foods5020031 PG 9 WC Food Science & Technology SC Food Science & Technology GA DS6RT UT WOS:000380910700011 ER PT J AU Cho, HC Hadjiiski, L Sahiner, B Chan, HP Paramagul, C Helvie, M Nees, AV Cho, HC AF Cho, Hyun-chong Hadjiiski, Lubomir Sahiner, Berkman Chan, Heang-Ping Paramagul, Chintana Helvie, Mark Nees, Alexis V. Cho, Hyun Chin TI A Similarity Study of Interactive Content-Based Image Retrieval Scheme for Classification of Breast Lesions SO IEICE TRANSACTIONS ON INFORMATION AND SYSTEMS LA English DT Article DE computer-aided diagnosis; relevance feedback; content-based image retrieval; breast lesion characterization ID COMPUTER-AIDED DIAGNOSIS; RELEVANCE FEEDBACK; ULTRASOUND IMAGES; BI-RADS; MASSES; FEATURES; PERFORMANCE; SONOGRAPHY; MAMMOGRAMS; BENIGN AB To study the similarity between queries and retrieved masses, we design an interactive CBIR ( Content-based Image Retrieval) CADx ( Computer-aided Diagnosis) system using relevance feedback for the characterization of breast masses in ultrasound ( US) images based on radiologists' visual similarity assessment. The CADx system retrieves masses that are similar to query masses from a reference library based on six computer-extracted features that describe the texture, width-to-height, and posterior shadowing of the mass. The k-NN retrieval with Euclidean distance similarity measure and the Rocchio relevance feedback algorithm ( RRF) are used. To train the RRF parameters, the similarities of 1891 image pairs from 62 ( 31 malignant and 31 benign) masses are rated by 3 MQSA ( Mammography Quality Standards Act) radiologists using a 9-point scale ( 9= most similar). The best RRF parameters are chosen based on 3 observer experiments. For testing, 100 independent query masses ( 49 malignant and 51 benign) and 121 reference masses on 230 ( 79 malignant and 151 benign) images were collected. Three radiologists rated the similarity between the query masses and the computer-retrieved masses. Average similarity ratings without and with RRF were 5.39 and 5.64 for the training set and 5.78 and 6.02 for the test set, respectively. Average AUC values without and with RRF were, respectively, 0.86+/- 0.03 and 0.87+/- 0.03 for the training set and 0.91+/- 0.03 and 0.90+/- 0.03 for the test set. On average, masses retrieved using the CBIR system were moderately similar to the query masses based on radiologists' similarity assessments. RRF improved the similarity of the retrieved masses. C1 [Cho, Hyun-chong] Kangwon Natl Univ, Interdisciplinary Grad Program BIT Med Convergenc, Chunchon, South Korea. [Cho, Hyun-chong] Kangwon Natl Univ, Div Elect & Elect Engn, Chunchon, South Korea. [Hadjiiski, Lubomir; Chan, Heang-Ping; Paramagul, Chintana; Helvie, Mark; Nees, Alexis V.] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Sahiner, Berkman] US FDA, Rockville, MD 20857 USA. [Cho, Hyun Chin] Gyeongsang Natl Univ, Dept Internal Med, Jinju, South Korea. [Cho, Hyun Chin] Gyeongsang Natl Univ, Inst Hlth Sci, Jinju, South Korea. RP Cho, HC (reprint author), Gyeongsang Natl Univ, Dept Internal Med, Jinju, South Korea.; Cho, HC (reprint author), Gyeongsang Natl Univ, Inst Hlth Sci, Jinju, South Korea. EM academic77@naver.com FU USPHS [CA 118305]; Kangwon National University FX This work is supported by USPHS Grant Nos. CA 118305 and 2014 Research Grant from Kangwon National University. NR 24 TC 0 Z9 0 U1 6 U2 6 PU IEICE-INST ELECTRONICS INFORMATION COMMUNICATIONS ENG PI TOKYO PA KIKAI-SHINKO-KAIKAN BLDG, 3-5-8, SHIBA-KOEN, MINATO-KU, TOKYO, 105-0011, JAPAN SN 1745-1361 J9 IEICE T INF SYST JI IEICE Trans. Inf. Syst. PD JUN PY 2016 VL E99D IS 6 BP 1663 EP 1670 DI 10.1587/transinf.2015EDP7207 PG 8 WC Computer Science, Information Systems; Computer Science, Software Engineering SC Computer Science GA DT5ZM UT WOS:000381562200029 ER PT J AU Fisher, R Borio, L AF Fisher, Robert Borio, Luciana TI Ebola Virus Disease: Therapeutic and Potential Preventative Opportunities SO MICROBIOLOGY SPECTRUM LA English DT Article ID HEMORRHAGIC-FEVER; NONHUMAN-PRIMATES; CONVALESCENT PLASMA; POSTEXPOSURE PROTECTION; T-705 FAVIPIRAVIR; UNITED-STATES; WEST-AFRICA; GUINEA-PIGS; RNA INTERFERENCE; CARE MANAGEMENT AB The 2014 Ebola virus disease (EVD) epidemic in West Africa was unprecedented in its geographical distribution, scale, and toll on public health infrastructure. Standard public health measures were rapidly overwhelmed, and many projections on outbreak progression through the region were dire. At the beginning of the outbreak there were no treatments or vaccines that had been shown to be safe and effective for treating or preventing EVD, limiting health care providers to offer supportive care under extremely challenging circumstances and at great risk to themselves. Over time, however, drugs and vaccines in the development pipeline were prioritized based on all available research data and were moved forward for evaluation in clinical trials to demonstrate safety and efficacy. The armamentarium against EVD eventually included biologics such as monoclonal antibodies, convalescent plasma, and vaccines as well as small molecule therapeutics such as small interfering RNAs and nucleoside analogs. This article provides a high-level overview of the interventions and prophylactics considered for use in the outbreak and discusses the challenges faced when attempting to deploy investigational countermeasures in the midst of an evolving epidemic. C1 [Fisher, Robert] US FDA, Off Counterterrorism & Emerging Threats, Silver Spring, MD 20993 USA. [Borio, Luciana] US FDA, Silver Spring, MD 20993 USA. RP Fisher, R (reprint author), US FDA, Off Counterterrorism & Emerging Threats, Silver Spring, MD 20993 USA. EM robert.fisher@fda.hhs.gov NR 126 TC 0 Z9 0 U1 10 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA EI 2165-0497 J9 MICROBIOL SPECTR JI Microbiol. Spectr. PD JUN PY 2016 VL 4 IS 3 AR UNSP EI10-0014-2016 DI 10.1128/microbiolspec.EI10-0014-2016 PG 14 WC Microbiology SC Microbiology GA DT9GD UT WOS:000381803300018 ER PT J AU Park, S Zhang, G Myers, KJ AF Park, Subok Zhang, George Myers, Kyle J. TI Comparison of Channel Methods and Observer Models for the Task-Based Assessment of Multi-Projection Imaging in the Presence of Structured Anatomical Noise SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Channelized Hotelling observer; digital breast tomosynthesis; feature selection; Laguerre Gauss function; multi-projection imaging; partial least squares; task-based image quality assessment ID DIGITAL BREAST TOMOSYNTHESIS; PARTIAL LEAST-SQUARES; PERFORMANCE; OPTIMIZATION; SIMULATION; ALGORITHM; SYSTEM; 3D AB Although Laguerre-Gauss (LG) channels are often used for the task-based assessment of multi-projection imaging, LG channels may not be the most reliable in providing performance trends as a function of system or object parameters for all situations. Partial least squares (PLS) channels are more flexible in adapting to background and signal data statistics and were shown to be more efficient for detection tasks involving 2D non-Gaussian random backgrounds (Witten et al., 2010). In this work, we investigate ways of incorporating spatial correlations in the multi-projection data space using 2D LG channels and two implementations of PLS in the channelized version of the 3D projection Hotelling observer (Park et al., 2010) (3Dp CHO). Our task is to detect spherical and elliptical 3D signals in the angular projections of a structured breast phantom ensemble. The single PLS (sPLS) incorporates the spatial correlation within each projection, whereas the combined PLS (cPLS) incorporates the spatial correlations both within each of and across the projections. The 3Dp CHO-R indirectly incorporates the spatial correlation from the response space (R), whereas the 3Dp CHO-C from the channel space (C). The 3Dp CHO-R-sPLS has potential to be a good surrogate observer when either sample size is small or one training set is used for training both PLS channels and observer. So does the 3Dp CHO-C-cPLS when the sample size is large enough to have a good sized independent set for training PLS channels. Lastly a stack of 2D LG channels used as 3D channels in the CHO-C model showed the capability of incorporating the spatial correlation between the multiple angular projections. C1 [Park, Subok] US FDA, Div Imaging Diagnost & Software Reliabil, Ctr Devices & Radiol Hlth, White Oak, MD 20993 USA. [Zhang, George] Univ Vermont, Sch Med, Burlington, VT 05405 USA. [Myers, Kyle J.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, White Oak, MD 20993 USA. RP Park, S (reprint author), US FDA, Div Imaging Diagnost & Software Reliabil, Ctr Devices & Radiol Hlth, White Oak, MD 20993 USA. EM subok.park@fda.hhs.gov FU Office of Women's Health; Medical Device Fellowship Program of the Center for Devices and Radiological Health at the U.S. Food and Drug Administration FX This work was supported by the Office of Women's Health and the Medical Device Fellowship Program of the Center for Devices and Radiological Health at the U.S. Food and Drug Administration. Asterisk indicates corresponding author. NR 28 TC 1 Z9 1 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 EI 1558-254X J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD JUN PY 2016 VL 35 IS 6 BP 1431 EP 1442 DI 10.1109/TMI.2016.2515027 PG 12 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA DR5GA UT WOS:000379930300006 ER PT J AU Wang, HL Pampati, N McCormick, WM Bhattacharyya, L AF Wang, Hsiaoling Pampati, Nagarani McCormick, William M. Bhattacharyya, Lokesh TI Protein Nitrogen Determination by Kjeldahl Digestion and Ion Chromatography SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE analytical biochemistry; biotechnology; proteins; vaccines; protein nitrogen determination; Kjeldahl digestion; ion chromatography; suppressed conductivity detection; oxalate complexation with copper and aluminum; validation ID SAMPLES; FOOD AB We report development and validation of a simple, rapid, and accurate method for the quantitation of protein nitrogen, which combines Kjeldahl digestion and ion chromatography with suppressed conductivity detection and requires nanomolar amount of nitrogen in samples (>= 10 mu g protein). The mechanism of suppressed conductivity detection does not permit analysis of samples containing copper (present in Kjeldahl digestion solution) and aluminum (present in many vaccines as adjuvants) due to precipitation of their hydroxides within the suppressor. We overcame this problem by including 10 mu M oxalic acid in Kjeldahl digests and in the eluent (30 mM methanesulfonic acid). The chromatography is performed using an IonPac CS-16 cation exchange column by isocratic elution. The method reduces the digestion time to less than 1 h and eliminates the distillation and titration steps of the Kjeldahl method, thereby reducing the analysis time significantly and improving precision and accuracy. To determine protein nitrogen in samples containing non-protein nitrogen, proteins are precipitated by a mixture of deoxycholate and trichloroacetic acid and the precipitates are analyzed after dissolving in KOH. The method is particularly useful for biological samples that are limited and can also be applied to food, environmental, and other materials. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved. C1 [Wang, Hsiaoling; Pampati, Nagarani; McCormick, William M.; Bhattacharyya, Lokesh] Food & Drug Adm, Div Biol Standard & Qual Control, Off Compliance & Biol Qual, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Bhattacharyya, L (reprint author), Food & Drug Adm, Div Biol Standard & Qual Control, Off Compliance & Biol Qual, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM lokesh.bhattacharyya@fda.hhs.gov NR 22 TC 0 Z9 0 U1 21 U2 34 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 JUN PY 2016 VL 105 IS 6 BP 1851 EP 1857 DI 10.1016/j.xphs.2016.03.039 PG 7 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA DT8UB UT WOS:000381770100009 PM 27238484 ER PT J AU Duraiswamy, N Weaver, JD Ekrami, Y Retta, SM Wu, CF AF Duraiswamy, Nandini Weaver, Jason D. Ekrami, Yasamin Retta, Stephen M. Wu, Changfu TI A Parametric Computational Study of the Impact of Non-circular Configurations on Bioprosthetic Heart Valve Leaflet Deformations and Stresses: Possible Implications for Transcatheter Heart Valves SO CARDIOVASCULAR ENGINEERING AND TECHNOLOGY LA English DT Article DE Transcatheter heart valve; THV; TAVR; FEA; Leaflet durability; Non-circular deformation ID MULTISLICE COMPUTED-TOMOGRAPHY; AORTIC-VALVE; FRICTIONAL-PROPERTIES; IN-VITRO; SIMULATION; IMPLANTATION; REPLACEMENT; DEPLOYMENT; GEOMETRY; DESIGN AB Although generally manufactured as circular devices with symmetric leaflets, transcatheter heart valves can become non-circular post-implantation, the impact of which on the long-term durability of the device is unclear. We investigated the effects of five non-circular (EllipMajor, EllipMinor, D-Shape, TriVertex, TriSides) annular configurations on valve leaflet stresses and valve leaflet deformations through finite element analysis. The highest in-plane principal stresses and strains were observed under an elliptical configuration with an aspect ratio of 1.25 where one of the commissures was on the minor axis of the ellipse. In this elliptical configuration (EllipMinor), the maximum principal stress increased 218% and the maximum principal strain increased 80% as compared with those in the circular configuration, and occurred along the free edge of the leaflet whose commissures were not on the minor axis (i.e., the "stretched'' leaflet). The D-Shape configuration was similar to this elliptical configuration, with the degree to which the leaflets were stretched or sagging being less than the EllipMinor configuration. The TriVertex and TriSides configurations had similar leaflet deformation patterns in all three leaflets and similar to the Circular configuration. In the D-Shape, TriVertex, and TriSides configurations, the maximum principal stress was located near the commissures similar to the Circular configuration. In the EllipMinor and EllipMajor configurations, the maximum principal stress occurred near the center of the free edge of the "stretched'' leaflets. These results further affirm recommendations by the International Standards Organization (ISO) that pre-clinical testing should consider non-circular configurations for transcatheter valve durability testing. C1 [Duraiswamy, Nandini; Weaver, Jason D.; Ekrami, Yasamin; Retta, Stephen M.] US FDA, OSEL, DAM, CDRH, Silver Spring, MD 20993 USA. [Wu, Changfu] US FDA, ODE, DCD, CDRH, Silver Spring, MD 20993 USA. RP Duraiswamy, N (reprint author), US FDA, OSEL, DAM, CDRH, Silver Spring, MD 20993 USA. EM nandini.duraiswamy@fda.hhs.gov FU FDA's Office of Women's Health; U.S. Department of Energy; FDA/CDRH FX This work was supported by the FDA's Office of Women's Health and in part by an appointment to the ORISE Research Participation Program at the FDA/CDRH, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA/CDRH. We are thankful to Edwards Life-sciences, for assisting with purchase of the surgical valves and constructive discussions on the results of the study. Special thanks to Michel Labrosse from Univ. of Ottawa and Hyuggun Kim from Univ. of Texas for providing us the initial geometry and experimental data, respectively. NR 23 TC 2 Z9 2 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1869-408X EI 1869-4098 J9 CARDIOVASC ENG TECHN JI Cardiovasc. Eng. Technol. PD JUN PY 2016 VL 7 IS 2 BP 126 EP 138 DI 10.1007/s13239-016-0259-9 PG 13 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA DS1MF UT WOS:000380359100003 PM 26864541 ER PT J AU Custer, B Stramer, SL Glynn, S Williams, AE Anderson, SA AF Custer, Brian Stramer, Susan L. Glynn, Simone Williams, Alan E. Anderson, Steven A. TI Transfusion-transmissible infection monitoring system: a tool to monitor changes in blood safety SO TRANSFUSION LA English DT Editorial Material ID HIV; IMMUNODEFICIENCY; VIRUS C1 [Custer, Brian] UCSF, Blood Syst Res Inst, Epidemiol & Hlth Policy Res Lab Med, San Francisco, CA USA. [Stramer, Susan L.] Amer Red Cross, Sci Affairs, Gaithersburg, MD USA. [Glynn, Simone] NHLBI, Blood Epidemiol & Clin Therapeut Branch, Div Blood Dis & Resources, Bldg 10, Bethesda, MD 20892 USA. [Williams, Alan E.] US FDA, Off Blood Res & Review, CBER, Silver Spring, MD USA. [Anderson, Steven A.] US FDA, Off Biostat & Epidemiol, CBER, Silver Spring, MD USA. RP Custer, B (reprint author), UCSF, Blood Syst Res Inst, Epidemiol & Hlth Policy Res Lab Med, San Francisco, CA USA. EM bcuster@bloodsystems.org NR 13 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUN PY 2016 VL 56 IS 6 SI SI BP 1499 EP 1502 DI 10.1111/trf.13632 PN 2 PG 4 WC Hematology SC Hematology GA DS1NC UT WOS:000380361600003 PM 27295025 ER PT J AU Kourout, M Fisher, C Purkayastha, A Tibbetts, C Winkelman, V Williamson, P Nakhasi, HL Duncan, R AF Kourout, Moussa Fisher, Carolyn Purkayastha, Anjan Tibbetts, Clark Winkelman, Valerie Williamson, Phillip Nakhasi, Hira L. Duncan, Robert TI Multiplex detection and identification of viral, bacterial, and protozoan pathogens in human blood and plasma using a high-density resequencing pathogen microarray platform SO TRANSFUSION LA English DT Article ID DNA MICROARRAYS; HEPATITIS-C; VIRUS; ASSAY; AGENTS; IMPLEMENTATION; VALIDATION; PARASITES; VARIANTS; SAMPLES AB BACKGROUND: The implementation of nucleic acid-based tests for blood donor screening has improved the safety of the blood supply; however, the increasing number of emerging pathogen tests is burdensome. Development of multiplex testing platforms that allow simultaneous screening for different pathogens is a potential solution. STUDY DESIGN AND METHODS: The TessArray resequencing microarray is a platform that allows multiplex detection and identification of 97 different blood-borne pathogens in one single test. The objective was to evaluate the lowest concentration detected in blood or plasma, species discrimination, and applicability of the TessArray microarray platform for testing blood donors. Human blood or plasma spiked with selected pathogens (10,000, 1000, or 100 cells or copies/mL), including three viral, four bacterial, and four protozoan pathogens were each tested on this platform. The nucleic acids were extracted, amplified using multiplexed sets of pooled specific primers, fragmented, labeled, and hybridized to a microarray. Finally, the detected sequences were identified using an automated genomic database alignment algorithm. RESULTS: The performance of this platform demonstrated detection for spiked bacterial and protozoan pathogens of 100 cells/mL and viral pathogens as low as 100 copies/mL. Coded specimens, including spiked and negative controls, were identified correctly for blood specimens (31/32, 97%) and for plasma specimens (20/22, 91%) demonstrating the effectiveness of the platform. CONCLUSION: These results indicated that the TessArray microarray platform could be employed for multiplex detection and identification, with a high level of discriminatory power for numerous blood-borne pathogen targets with potential for use in blood safety. C1 [Kourout, Moussa; Fisher, Carolyn; Nakhasi, Hira L.; Duncan, Robert] US FDA, Div Emerging & Transfus Transmitted Dis, OBRR, CBER, Silver Spring, MD 20993 USA. [Purkayastha, Anjan; Tibbetts, Clark] TessArae LLC, Potomac Falls, VA USA. [Winkelman, Valerie; Williamson, Phillip] Creat Testing Solut, Tempe, AZ USA. RP Duncan, R (reprint author), US FDA, Div Emerging & Transfus Transmitted Dis, OBRR, CBER, Silver Spring, MD 20993 USA. EM robert.duncan@fda.hhs.gov FU FDA Medical Countermeasures Initiative FX This work was supported by a grant from the FDA Medical Countermeasures Initiative. NR 36 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUN PY 2016 VL 56 IS 6 SI SI BP 1537 EP 1547 DI 10.1111/trf.13524 PN 2 PG 11 WC Hematology SC Hematology GA DS1NC UT WOS:000380361600008 PM 26932359 ER PT J AU Mahmood, I AF Mahmood, Iftekhar TI Prediction of Drug Clearance in Premature and Mature Neonates, Infants, and Children <= 2 Years of Age: A Comparison of the Predictive Performance of 4 Allometric Models SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE allometry; clearance; exponents; pediatrics ID METABOLIC-RATES; EXPONENT; PHARMACOKINETICS; PROVIDE; ADULTS; BROWN; WEST; MASS AB The objective of this study was to evaluate the predictive performance of 4 allometric models to predict clearance in pediatric ages ranging from premature neonates to children <= 2 years of age. Four allometric models were used to predict clearances of 28 drugs in children from preterm neonates to 2 years of age (n = 564). The 4 models are (1) basal metabolic rate-dependent model; (2) age-dependent exponent model; (3) an allometric model based on kidney and liver weights as well as kidney and liver blood flow; and (4) an allometric model based on a fixed exponent of 0.75. The predictive performance of these models was evaluated by comparing the predicted clearance of the studied drugs with the observed clearance in an individual child. The results of the study indicated that the 3 new proposed models predicted the mean clearance of the drugs with reasonable accuracy (<= 50% prediction error). On the other hand, the exponent of 0.75 produced substantial prediction error. Predicted individual clearance values were <= 50% in approximately 30% of the children by the proposed 3 methods and 73% by exponent 0.75. The 3 new proposed allometric models can predict mean clearances of drugs in children from premature neonates to <= 2 years of age with reasonable accuracy and are of practical value during pediatric drug development. C1 [Mahmood, Iftekhar] US FDA, Ctr Biol Evaluat & Res, Off Blood Review & Res, Div Hematol Clin Review, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Mahmood, I (reprint author), US FDA, Ctr Biol Evaluat & Res, Off Blood Review & Res, Div Hematol Clin Review, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Iftekhar.mahmood@fda.hhs.gov NR 35 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JUN PY 2016 VL 56 IS 6 BP 733 EP 739 DI 10.1002/jcph.652 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DR6ZQ UT WOS:000380050200010 PM 26437918 ER PT J AU Rasooly, R Bruck, HA Balsam, J Prickril, B Ossandon, M Rasooly, A AF Rasooly, Reuven Bruck, Hugh Alan Balsam, Joshua Prickril, Ben Ossandon, Miguel Rasooly, Avraham TI Improving the Sensitivity and Functionality of Mobile Webcam-Based Fluorescence Detectors for Point-of-Care Diagnostics in Global Health SO DIAGNOSTICS LA English DT Review DE webcams; CCD cameras; mobile phones; fluorescence imaging; flow cytometry; rare cells; resource-poor settings; image enhancement; background subtraction; pixel binning; global health ID STAPHYLOCOCCAL-ENTEROTOXIN-B; LINKED IMMUNOSORBENT ASSAYS; IMAGING FLOW CYTOMETER; ARRAY BIOSENSOR; CELL-PHONE; CHEMILUMINESCENCE DETECTION; ISOTHERMAL AMPLIFICATION; COLORIMETRIC DETECTION; MOLECULAR DIAGNOSTICS; MICROFLUIDIC DEVICE AB Resource-poor countries and regions require effective, low-cost diagnostic devices for accurate identification and diagnosis of health conditions. Optical detection technologies used for many types of biological and clinical analysis can play a significant role in addressing this need, but must be sufficiently affordable and portable for use in global health settings. Most current clinical optical imaging technologies are accurate and sensitive, but also expensive and difficult to adapt for use in these settings. These challenges can be mitigated by taking advantage of affordable consumer electronics mobile devices such as webcams, mobile phones, charge-coupled device (CCD) cameras, lasers, and LEDs. Low-cost, portable multi-wavelength fluorescence plate readers have been developed for many applications including detection of microbial toxins such as C. Botulinum A neurotoxin, Shiga toxin, and S. aureus enterotoxin B (SEB), and flow cytometry has been used to detect very low cell concentrations. However, the relatively low sensitivities of these devices limit their clinical utility. We have developed several approaches to improve their sensitivity presented here for webcam based fluorescence detectors, including (1) image stacking to improve signal-to-noise ratios; (2) lasers to enable fluorescence excitation for flow cytometry; and (3) streak imaging to capture the trajectory of a single cell, enabling imaging sensors with high noise levels to detect rare cell events. These approaches can also help to overcome some of the limitations of other low-cost optical detection technologies such as CCD or phone-based detectors (like high noise levels or low sensitivities), and provide for their use in low-cost medical diagnostics in resource-poor settings. C1 [Rasooly, Reuven] USDA, Western Reg Res Ctr, Agr Res Serv, Albany, CA 94706 USA. [Bruck, Hugh Alan] UMCP, Dept Mech Engn, College Pk, MD 20742 USA. [Balsam, Joshua] FDA, Div Chem & Toxicol Devices, Off Vitro Diagnost & Radiol Hlth, Silver Spring, MD 20993 USA. [Prickril, Ben; Ossandon, Miguel; Rasooly, Avraham] NCI, Rockville, MD 20850 USA. RP Rasooly, A (reprint author), NCI, Rockville, MD 20850 USA. EM reuven.rasooly@ars.usda.gov; bruck@umd.edu; joshua.balsam@fda.hhs.gov; ben.prickril@nih.gov; ossandom@mail.nih.gov; rasoolya@mail.nih.gov NR 151 TC 0 Z9 0 U1 11 U2 15 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2075-4418 J9 DIAGNOSTICS JI Diagnostics PD JUN PY 2016 VL 6 IS 2 AR 19 DI 10.3390/diagnostics6020019 PG 21 WC Medicine, General & Internal SC General & Internal Medicine GA DR6VL UT WOS:000380039300006 ER PT J AU Cai, CZ Carey, KA Nedosekin, DA Menyaev, YA Sarimollaoglu, M Galanzha, EI Stumhofer, JS Zharov, VP AF Cai, Chengzhong Carey, Kai A. Nedosekin, Dmitry A. Menyaev, Yulian A. Sarimollaoglu, Mustafa Galanzha, Ekaterina I. Stumhofer, Jason S. Zharov, Vladimir P. TI In vivo photoacoustic flow cytometry for early malaria diagnosis SO CYTOMETRY PART A LA English DT Article DE in vivo flow cytometry; photoacoustic spectroscopy; fluorescence; label-free detection; malaria; hemozoin; nanobubbles; early diagnosis ID CIRCULATING TUMOR-CELLS; SENSITIVE DETECTION; LIFE-CYCLE; CRYSTALS; SIZE AB In vivo photoacoustic (PA) flow cytometry (PAFC) has already demonstrated a great potential for the diagnosis of deadly diseases through ultrasensitive detection of rare disease-associated circulating markers in whole blood volume. Here, we demonstrate the first application of this powerful technique for early diagnosis of malaria through label-free detection of malaria parasite-produced hemozoin in infected red blood cells (iRBCs) as high-contrast PA agent. The existing malaria tests using blood smears can detect the disease at 0.001-0.1% of parasitemia. On the contrary, linear PAFC showed a potential for noninvasive malaria diagnosis at an extremely low level of parasitemia of 0.0000001%, which is approximate to 10(3) times better than the existing tests. Multicolor time-of-flight PAFC with high-pulse repetition rate lasers at wavelengths of 532, 671, and 820 nm demonstrated rapid spectral and spatial identification and quantitative enumeration of individual iRBCs. Integration of PAFC with fluorescence flow cytometry (FFC) provided real-time simultaneous detection of single iRBCs and parasites expressing green fluorescence proteins, respectively. A combination of linear and nonlinear nanobubble-based multicolor PAFC showed capability to real-time control therapy efficiency by counting of iRBCs before, during, and after treatment. Our results suggest that high-sensitivity, high-resolution ultrafast PAFC-FFC platform represents a powerful research tool to provide the insight on malaria progression through dynamic study of parasite-cell interactions directly in bloodstream, whereas portable hand-worn PAFC device could be broadly used in humans for early malaria diagnosis. (c) 2016 International Society for Advancement of Cytometry C1 [Cai, Chengzhong; Carey, Kai A.; Nedosekin, Dmitry A.; Menyaev, Yulian A.; Sarimollaoglu, Mustafa; Galanzha, Ekaterina I.; Zharov, Vladimir P.] Univ Arkansas Med Sci, Arkansas Nanomed Ctr, 4301 West Markham St 543, Little Rock, AR 72205 USA. [Cai, Chengzhong] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Stumhofer, Jason S.] Univ Arkansas Med Sci, Dept Microbiol & Immunol, Little Rock, AR 72205 USA. RP Zharov, VP (reprint author), Univ Arkansas Med Sci, Arkansas Nanomed Ctr, 4301 West Markham St 543, Little Rock, AR 72205 USA. EM zharovvladimirp@uams.edu OI Menyaev, Yulian/0000-0001-5861-3641 FU National Institutes of Health [EB017217, CA131164]; National Science Foundation [OIA 1457888, DBI 1556068] FX Grant sponsor: National Institutes of Health; Grant numbers: EB017217, CA131164. Grant sponsor: National Science Foundation; Grant numbers: OIA 1457888, DBI 1556068 NR 45 TC 2 Z9 2 U1 10 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 EI 1552-4930 J9 CYTOM PART A JI Cytom. Part A PD JUN PY 2016 VL 89A IS 6 BP 531 EP 542 DI 10.1002/cyto.a.22854 PG 12 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DR0MW UT WOS:000379602600003 PM 27078044 ER PT J AU Fost, N AF Fost, Norman TI Informed Consent Should Be a Required Element for Newborn Screening, Even for Disorders with High Benefit-Risk Ratios SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article ID SODIUM-BICARBONATE; MATERNAL PHENYLKETONURIA; INTRACRANIAL HEMORRHAGE; BILIRUBIN LEVELS; OUTCOMES; INFANTS; PHENYLALANINE; MEDICINE; CHILDREN; THERAPY AB Over-enthusiastic newborn screening has often caused substantial harm and has been imposed on the public without adequate information on benefits and risks and without parental consent. This problem will become worse when genomic screening is implemented. For the past 40 years, there has been broad agreement about the criteria for ethically responsible screening, but the criteria have been systematically ignored by policy makers and practitioners. Claims of high benefit and low risk are common, but they require precise definition and documentation, which has often not occurred, undermining claims that involuntary testing is justified. Even when the benefits and risks are well established, it does not automatically follow that involuntary testing is justified, a position supported by the widespread tolerance for parental refusal of immunizations and newborn screening. C1 [Fost, Norman] Univ Wisconsin, Pediat, Madison, WI 53706 USA. [Fost, Norman] Univ Wisconsin, Bioeth Program, Madison, WI USA. [Fost, Norman] Univ Wisconsin, Child Protect Team, Madison, WI USA. [Fost, Norman] Hosp Eth Comm, Chapel Hill, NC USA. [Fost, Norman] Hlth Sci Inst Review Board, Chapel Hill, NC USA. [Fost, Norman] US FDA, Pediat Advisory Comm, Rockville, MD 20857 USA. [Fost, Norman] NIH, Recombinant DNA Advisory Comm, Bldg 10, Bethesda, MD 20892 USA. RP Fost, N (reprint author), Univ Wisconsin, Pediat, Madison, WI 53706 USA. NR 62 TC 3 Z9 3 U1 4 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-1105 EI 1748-720X J9 J LAW MED ETHICS JI J. Law Med. Ethics PD JUN PY 2016 VL 44 IS 2 BP 241 EP 255 DI 10.1177/1073110516654118 PG 15 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA DR0QI UT WOS:000379611600004 PM 27338600 ER PT J AU Woods, TO Delfino, JG Shein, MJ AF Woods, Terry O. Delfino, Jana G. Shein, Mitchell J. TI Response to Standardized MR Terminology and Reporting of Implants and Devices as Recommended by the American College of Radiology Subcommittee on MR Safety SO RADIOLOGY LA English DT Article AB The U.S. Food and Drug Administration (FDA) continually works toward the goal of safety. For patients with magnetic resonance (MR) Conditional devices, safety is achieved when MR Conditional labeling is clear and accessible and can be unambiguously interpreted and applied. The FDA supports the three facets of standardization listed by the American College of Radiology (ACR) Subcommittee on MR Safety in their special report: (a) standardization in terminology and reporting of spatial gradient magnetic fields associated with MR systems; (b) standardization in reporting of ferromagnetic testing results for implants and devices; and (c) standardization, consistency, and clarity in radiofrequency power deposition guidelines and terminology. While the FDA is in agreement with the ACR Subcommittee on MR Safety that patient safety is of primary concern, the authors disagree with the Subcommittee on several important points and offer a point-by-point response to the Subcommittee's four recommendations. C1 [Woods, Terry O.] US FDA, Off Sci & Engn Labs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Delfino, Jana G.] US FDA, Vitro Diagnost & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Shein, Mitchell J.] US FDA, Device Evaluat, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Woods, TO (reprint author), US FDA, Off Sci & Engn Labs, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM terry.woods@fda.hhs.gov NR 4 TC 0 Z9 1 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUN PY 2016 VL 279 IS 3 BP 906 EP 909 DI 10.1148/radiol.2015151108 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP8AG UT WOS:000378719700029 PM 26599665 ER PT J AU Dye, E Sturgess, A Maheshwari, G May, K Ruegger, C Ramesh, U Tan, H Cockerill, K Groskoph, J Lacana, E Lee, S Miksinski, SP AF Dye, Earl Sturgess, Annie Maheshwari, Gargi May, Kimberly Ruegger, Colleen Ramesh, Usha Tan, Heow Cockerill, Keith Groskoph, John Lacana, Emanuela Lee, Sau Miksinski, Sarah Pope TI Examining Manufacturing Readiness for Breakthrough Drug Development SO AAPS PHARMSCITECH LA English DT Article DE breakthrough therapy; CMC; FDA C1 [Dye, Earl] Genentech Inc, Tech Regulatory Policy, 1399 New York Ave NW,Suite 450, Washington, DC 20005 USA. [Sturgess, Annie] Bristol Myers Squibb Co, Regulatory CMC, New York, NY 10154 USA. [Maheshwari, Gargi] Merck & Co Inc, Biol Proc Dev & Commercializat, Kenilworth, NJ USA. [May, Kimberly] Merck & Co Inc, Biol CMC Regulatory Affairs, Kenilworth, NJ USA. [Ruegger, Colleen] Novartis Pharmaceut, Tech Res & Dev, Hannover, NJ USA. [Ramesh, Usha] Pharmacyclics Inc, CMC, Regulatory Affairs, Sunnyvale, CA USA. [Tan, Heow] Pharmacyclics Inc, Qual & Tech Operat, Sunnyvale, CA USA. [Cockerill, Keith] Amgen Inc, Regulatory Affairs, Thousand Oaks, CA USA. [Groskoph, John] Pfizer Inc, Global Chem Mfg & Controls, New York, NY USA. [Lacana, Emanuela] US FDA, Biosimilars & Biol Policy, Off Biotechnol Prod, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Lee, Sau] US FDA, Off Pharmaceut Qual, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Miksinski, Sarah Pope] US FDA, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Dye, E (reprint author), Genentech Inc, Tech Regulatory Policy, 1399 New York Ave NW,Suite 450, Washington, DC 20005 USA. EM dye.earl@gene.com NR 2 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-9932 J9 AAPS PHARMSCITECH JI AAPS PharmSciTech PD JUN PY 2016 VL 17 IS 3 BP 529 EP 538 DI 10.1208/s12249-015-0455-1 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ1CX UT WOS:000378939800001 PM 26608693 ER PT J AU Korde, N Zhang, Y Loeliger, K Poon, A Simakova, O Zingone, A Costello, R Childs, R Noel, P Silver, S Kwok, M Mo, C Young, N Landgren, O Sloand, E Maric, I AF Korde, Neha Zhang, Yong Loeliger, Kelsey Poon, Andrea Simakova, Olga Zingone, Adriana Costello, Rene Childs, Richard Noel, Pierre Silver, Samuel Kwok, Mary Mo, Clifton Young, Neal Landgren, Ola Sloand, Elaine Maric, Irina TI Monoclonal gammopathy-associated pure red cell aplasia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE anaemia; monoclonal gammopathy of undetermined significance; myeloma; plasmacytosis; pure red cell aplasia ID MULTIPLE-MYELOMA; CYCLOSPORINE-A; ANEMIA; ERYTHROPOIETIN; INHIBITOR; HEPCIDIN; PATIENT; DISEASE; JAPAN AB Pure red cell aplasia (PRCA) is a rare disorder characterized by inhibition of erythroid precursors in the bone marrow and normochromic, normocytic anaemia with reticulocytopenia. Among 51 PRCA patients, we identified 12 (24%) patients having monoclonal gammopathy, monoclonal gammopathy of undetermined significance or smouldering multiple myeloma, with presence of monoclonal protein or abnormal serum free light chains and atypical bone marrow features of clonal plasmacytosis, hypercellularity and fibrosis. Thus far, three patients treated with anti-myeloma based therapeutics have responded with reticulocyte recovery and clinical transfusion independence, suggesting plasma cells play a key role in the pathogenesis of this specific monoclonal gammopathy-associated PRCA. C1 [Korde, Neha; Landgren, Ola] Mem Sloan Kettering Canc Ctr, Myeloma Serv, 1275 York Ave, New York, NY 10065 USA. [Korde, Neha; Zhang, Yong; Zingone, Adriana; Costello, Rene; Landgren, Ola] NCI, Multiple Myeloma Sect, Metab Branch, Silver Spring, MD USA. [Loeliger, Kelsey; Poon, Andrea; Childs, Richard; Young, Neal; Sloand, Elaine] NHLBI, Hematol Branch, Silver Spring, MD 20892 USA. [Simakova, Olga] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Noel, Pierre; Maric, Irina] NIH, Dept Lab Med, Ctr Clin, Ann Arbor, MI USA. [Silver, Samuel] Univ Michigan, Sch Med, Internal Med Hematol Oncol, Ann Arbor, MI USA. [Kwok, Mary; Mo, Clifton] Walter Reed Natl Mil Med Ctr, Murtha Canc Ctr, Bethesda, MD USA. RP Korde, N (reprint author), Mem Sloan Kettering Canc Ctr, Myeloma Serv, 1275 York Ave, New York, NY 10065 USA. EM korden@mskcc.org NR 23 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUN PY 2016 VL 173 IS 6 BP 876 EP 883 DI 10.1111/bjh.14012 PG 8 WC Hematology SC Hematology GA DP6XW UT WOS:000378644100006 PM 26999424 ER PT J AU Sarkar, S Raymick, J Imam, S AF Sarkar, Sumit Raymick, James Imam, Syed TI Neuroprotective and Therapeutic Strategies against Parkinson's Disease: Recent Perspectives SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Review DE Parkinson's disease; dopamine; L-DOPA; striatum; substantia nigra; deep brain timulation; olfaction ID DEEP BRAIN-STIMULATION; SUBTHALAMIC NUCLEUS STIMULATION; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; NITRATED ALPHA-SYNUCLEIN; MIDBRAIN DOPAMINERGIC-NEURONS; LENTIVIRAL VECTOR DELIVERY; NMDA RECEPTOR ANTAGONISTS; IMPROVES MOTOR BEHAVIOR; MESENCHYMAL STEM-CELLS; LEWY BODY DISEASE AB Parkinsonism is a progressive motor disease that affects 1.5 million Americans and is the second most common neurodegenerative disease after Alzheimer's. Typical neuropathological features of Parkinson's disease (PD) include degeneration of dopaminergic neurons located in the pars compacta of the substantia nigra that project to the striatum (nigro-striatal pathway) and depositions of cytoplasmic fibrillary inclusions (Lewy bodies) which contain ubiquitin and alpha-synuclein. The cardinal motor signs of PD are tremors, rigidity, slow movement (bradykinesia), poor balance, and difficulty in walking (Parkinsonian gait). In addition to motor symptoms, non-motor symptoms that include autonomic and psychiatric as well as cognitive impairments are pressing issues that need to be addressed. Several different mechanisms play an important role in generation of Lewy bodies; endoplasmic reticulum (ER) stress induced unfolded proteins, neuroinflammation and eventual loss of dopaminergic neurons in the substantia nigra of mid brain in PD. Moreover, these diverse processes that result in PD make modeling of the disease and evaluation of therapeutics against this devastating disease difficult. Here, we will discuss diverse mechanisms that are involved in PD, neuroprotective and therapeutic strategies currently in clinical trial or in preclinical stages, and impart views about strategies that are promising to mitigate PD pathology. C1 [Sarkar, Sumit; Raymick, James; Imam, Syed] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Bldg 53D,HFT 32, Jefferson, AR 72079 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; James.Raymick@fda.hhs.gov; syed.imam@fda.hhs.gov FU National Center for Toxicological Research/USFDA [E0751201] FX This study was supported by protocol E0751201 National Center for Toxicological Research/USFDA. The entire manuscript was reviewed and edited by Laura Schnackenberg, NCTR/USFDA. NR 304 TC 3 Z9 3 U1 7 U2 13 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD JUN PY 2016 VL 17 IS 6 AR 904 DI 10.3390/ijms17060904 PG 31 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA DP9EK UT WOS:000378799300118 ER PT J AU Agnew-Heard, KA Lancaster, VA Bravo, R Watson, C Walters, MJ Holman, MR AF Agnew-Heard, Kimberly A. Lancaster, Vicki A. Bravo, Roberto Watson, Clifford Walters, Matthew J. Holman, Matthew R. TI Multivariate Statistical Analysis of Cigarette Design Feature Influence on ISO TNCO Yields SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID MAINSTREAM SMOKE CHEMISTRY; CARBON-MONOXIDE YIELDS; MARKET; BRANDS; NICOTINE; TAR; VARIETIES; EXPOSURE; BLOCKING; SAMPLES AB The aim of this study is to explore how differences in cigarette physical design parameters influence tar, nicotine, and carbon monoxide (TNCO) yields in mainstream smoke (MSS) using the International Organization of Standardization (ISO) smoking regimen. Standardized smoking methods were used to evaluate 50 U.S. domestic brand cigarettes and a reference cigarette representing a range of TNCO yields in MSS collected from linear smoking machines using a nonintense smoking regimen. Multivariate statistical methods were used to form dusters of cigarettes based on their ISO TNCO yields and then to explore the relationship between the ISO generated TNCO-yields and the nine cigarette physical design parameters between and within each duster simultaneously. The ISO generated TNCO-yields in MSS are 1.1-17.0 mg tar/cigarette, 0.1-2.2 mg nicotine/cigarette, and 1.6-17.3 mg CO/cigarette. Cluster analysis divided the 51 cigarettes into five discrete dusters based on their ISO TNCO yields. No one physical parameter dominated across all clusters. Predicting ISO machine generated TNCO yields based on these nine physical design parameters is complex due to the correlation among and between the nine physical design parameters and TNCO-yields. From these analyses, it is estimated that approximately 20% of the variability in the ISO generated TNCO yields comes from other parameters (e.g., filter material, filter type, inclusion of expanded or reconstituted tobacco, and tobacco blend composition, along with differences in tobacco leaf origin and stalk positions and added ingredients). A future article will examine the influence of these physical design parameters on TNCO-yields under a Canadian Intense (CI) smoking regimen. Together, these papers will provide a more robust picture of the design features that contribute to TNCO exposure across the range of real world smoking patterns. C1 [Agnew-Heard, Kimberly A.; Lancaster, Vicki A.; Walters, Matthew J.; Holman, Matthew R.] US FDA, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Bravo, Roberto; Watson, Clifford] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, 4770 Buford Highway NE, Atlanta, GA 30341 USA. RP Walters, MJ (reprint author), US FDA, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM matthew.walters@fda.hhs.gov FU Center for Tobacco Products, U.S. Food and Drug Administration FX This research was funded by the Center for Tobacco Products, U.S. Food and Drug Administration. NR 42 TC 0 Z9 0 U1 1 U2 2 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 JUN PY 2016 VL 29 IS 6 BP 1051 EP 1063 DI 10.1021/acs.chemrestox.6b00096 PG 13 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA DP3CJ UT WOS:000378369700013 PM 27222918 ER PT J AU Janne, PA Kim, G Shaw, AT Sridhara, R Pazdur, R McKee, AE AF Janne, Pasi A. Kim, Geoffrey Shaw, Alice T. Sridhara, Rajeshwari Pazdur, Richard McKee, Amy E. TI Dose Finding of Small-Molecule Oncology Drugs: Optimization throughout the Development Life Cycle SO CLINICAL CANCER RESEARCH LA English DT Article ID CONTINUAL REASSESSMENT METHOD; I CLINICAL-TRIALS; CANCER; DESIGN; TOXICITY; OUTCOMES AB In the current era of rapid marketing approval for promising new products in oncology, dose finding and optimization for small-molecule oncology drugs occurs throughout the development cycle and into the postmarketing setting. Many trials that support a regulatory application have high rates of dose reductions and discontinuations, which may result in postmarketing requirements (PMR) to study alternate doses or dosing schedules. Kinase inhibitors particularly have been susceptible to this problem, and among the 31 approved drugs of this class, the approvals of eight have included such PMRs and/or commitments. Thus, the current paradigm for dose finding and optimization could be improved. Newer strategies for dose finding rather than traditional 3 + 3 designs should be considered where feasible, and dose optimization should be continued after phase I and throughout development. Such strategies will increase the likelihood of a right dose for the right drug at the time of regulatory approval. (C) 2016 AACR. C1 [Janne, Pasi A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kim, Geoffrey; Sridhara, Rajeshwari; Pazdur, Richard; McKee, Amy E.] US FDA, Silver Spring, MD USA. [Shaw, Alice T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP McKee, AE (reprint author), US FDA, Off Hematol & Oncol Prod, 10903 New Hampshire Ave, White Oak, MD 20993 USA. EM amy.mckee@fda.hhs.gov FU Astellas Pharma; AstraZeneca FX P.A. Janne reports receiving commercial research grants from Astellas Pharma and AstraZeneca; royalties, through his institution, from LabCorp for intellectual property on EGFR mutations that is owned by Dana-Farber Cancer Institute and licensed to LabCorp; has ownership interest (including patents) in Gatekeeper Pharmaceuticals; and is a consultant/advisory board member for ARIAD Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Chugai Pharma, Merrimack Pharmaceuticals, and Pfizer. A.T. Shaw is a consultant/advisory board member for ARIAD Pharmaceuticals, Daiichi Sankyo, EMD Serono, Genentech, Novartis, Pfizer, Roche, and Taiho Pharmaceutical. No potential conflicts of interest were disclosed by the other authors. NR 22 TC 3 Z9 3 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 JUN 1 PY 2016 VL 22 IS 11 BP 2613 EP 2617 DI 10.1158/1078-0432.CCR-15-2643 PG 5 WC Oncology SC Oncology GA DP2RN UT WOS:000378338200005 PM 27250931 ER PT J AU Dambach, DM Simpson, NE Jones, TW Brennan, RJ Pazdur, R Palmby, TR AF Dambach, Donna M. Simpson, Natalie E. Jones, Thomas W. Brennan, Richard J. Pazdur, Richard Palmby, Todd R. TI Nonclinical Evaluations of Small-Molecule Oncology Drugs: Integration into Clinical Dose Optimization and Toxicity Management SO CLINICAL CANCER RESEARCH LA English DT Article ID INHIBITOR AB Multidisciplinary approaches that incorporate nonclinical pharmacologic and toxicologic characterization of small-molecule oncology drugs into clinical development programs may facilitate improved benefit-risk profiles and clinical toxicity management in patients. The performance of the current nonclinical safety-testing scheme was discussed, highlighting current strengths and areas for improvement. While current nonclinical testing appears to predict the clinical outcome where the prevalence of specific adverse effects are high, nonclinical testing becomes less reliable for predicting clinical adverse effects that occur infrequently, as with some kinase inhibitors. Although adverse effects associated with kinase inhibitors can often be predicted on the basis of target biology, drugs can be promiscuous and inhibit targets with poorly defined function and associated risks. Improvements in adverse effect databases and better characterization of the biologic activities of drug targets may enable better use of computational modeling approaches in predicting adverse effects with kinase inhibitors. Assessing safety of a lead candidate in parallel with other drug properties enables incorporation of a molecule's best features during chemical design, eliminates the worst molecules early, and permits timely investigation/characterization of toxicity mechanisms for identified liabilities. A safety lead optimization and candidate identification strategy that reduces intrinsic toxicity and metabolic risk and enhances selectivity can deliver selective kinase inhibitors that demonstrate on-target adverse effects identified nonclinically. Integrating clinical and nonclinical data during drug development can facilitate better identification and management of oncology drugs. Follow-up nonclinical studies may be used to better understand the risks in a given patient population and minimize or manage these risks more appropriately. C1 [Dambach, Donna M.] Genentech Inc, Dept Safety Assessment, San Francisco, CA USA. [Dambach, Donna M.; Jones, Thomas W.] Int Consortium Innovat & Qual Pharmaceut Dev DruS, Washington, DC USA. [Simpson, Natalie E.; Pazdur, Richard; Palmby, Todd R.] US FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Jones, Thomas W.] Eli Lilly & Co, Toxicol & Pathol, Indianapolis, IN 46285 USA. [Brennan, Richard J.] Sanofi, Preclin Safety, Waltham, MA USA. RP Palmby, TR (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM todd.palmby@fda.hhs.gov NR 12 TC 3 Z9 3 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 JUN 1 PY 2016 VL 22 IS 11 BP 2618 EP 2622 DI 10.1158/1078-0432.CCR-15-2645 PG 5 WC Oncology SC Oncology GA DP2RN UT WOS:000378338200006 PM 27250932 ER PT J AU Nie, L Rubin, EH Mehrotra, N Pinheiro, J Fernandes, LL Roy, A Bailey, S de Alwis, DP AF Nie, Lei Rubin, Eric H. Mehrotra, Nitin Pinheiro, Jose Fernandes, Laura L. Roy, Amit Bailey, Stuart de Alwis, Dinesh P. TI Rendering the 3+3 Design to Rest: More Efficient Approaches to Oncology Dose-Finding Trials in the Era of Targeted Therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID CONTINUAL REASSESSMENT METHOD; I CLINICAL-TRIALS; PHASE-I; PRACTICAL DESIGN; ESCALATION; DECITABINE; APPROVAL; CANCER AB Selection of the maximum tolerated dose (MTD) as the recommended dose for registration trials based on a dose-escalation trial using variations of an MTD/3 + 3 design often occurs in the development of oncology products. The MTD/3 + 3 approach is not optimal and may result in recommended doses that are unacceptably toxic for many patients and in dose reduction/interruptions that might have an impact on effectiveness. Instead of the MTD/3 + 3 approach, the authors recommend an integrated approach. In this approach, typically an adaptive/Bayesian model provides a general framework to incorporate and make decisions for dose escalation based on nonclinical data, such as animal efficacy and toxicity data; clinical data, including pharmacokinetics/pharmacodynamics data; and dose/exposure-response data for efficacy and safety. To improve dose-ranging trials, model-based estimation, rather than hypothesis testing, should be used to maximize and integrate the information gathered across trials and doses. This approach may improve identification of optimal recommended doses, which can then be confirmed in registration trials. C1 [Nie, Lei; Fernandes, Laura L.] US FDA, OB OTS CDER, Div Biometr 5, Silver Spring, MD USA. [Rubin, Eric H.] Merck Res Labs, N Wales, PA USA. [Mehrotra, Nitin] US FDA, OCP OTS CDER, Div Pharmacometr, Silver Spring, MD USA. [Pinheiro, Jose] Johnson & Johnson, Raritan, NJ USA. [Roy, Amit] Bristol Myers Squibb, Princeton, NJ USA. [Bailey, Stuart] Novartis Inst Biomed Res, Cambridge, MA USA. [de Alwis, Dinesh P.] Merck Res Labs, Rahway, NJ USA. RP de Alwis, DP (reprint author), Merck & Co Inc, POB 2000,Mailstop RY34-A500, Rahway, NJ 07065 USA. EM dinesh.de.alwis@merck.com NR 35 TC 5 Z9 5 U1 2 U2 4 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 JUN 1 PY 2016 VL 22 IS 11 BP 2623 EP 2629 DI 10.1158/1078-0432.CCR-15-2644 PG 7 WC Oncology SC Oncology GA DP2RN UT WOS:000378338200007 PM 27250933 ER PT J AU Bullock, JM Rahman, A Liu, Q AF Bullock, Julie M. Rahman, Atiqur Liu, Qi TI Lessons Learned: Dose Selection of Small Molecule-Targeted Oncology Drugs SO CLINICAL CANCER RESEARCH LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; PHASE; EFFICACY; IMATINIB; AGENTS AB Evaluation of dose plays a critical role in a successful oncology development program. Typically for oncology agents, the first-in-man phase I dose-escalation trials are conducted to determine a maximum tolerated dose (MTD). This MTD is taken forward into subsequent trials to establish the safety and efficacy of the drug product. Although this approach was appropriate historically for cytotoxics, the application of MTD as the recommend phase II dose has been problematic for the newer small molecule-targeted oncology agents. Promising alternative approaches using dose and exposure exploration, including lessons learned from recent targeted oncology agent development and approvals, are summarized and discussed. C1 [Bullock, Julie M.] d3 Med LLC, Parsippany, NJ USA. [Rahman, Atiqur; Liu, Qi] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20901 USA. RP Liu, Q (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 51, Silver Spring, MD 20901 USA. EM qi.liu@fda.hhs.gov NR 34 TC 3 Z9 3 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 JUN 1 PY 2016 VL 22 IS 11 BP 2630 EP 2638 DI 10.1158/1078-0432.CCR-15-2646 PG 9 WC Oncology SC Oncology GA DP2RN UT WOS:000378338200008 PM 27250934 ER PT J AU Liu, KC Jinneman, KC Neal-McKinney, J Wu, WH Rice, DH AF Liu, Kun C. Jinneman, Karen C. Neal-McKinney, Jason Wu, Wen-Hsin Rice, Daniel H. TI Genome sequencing and annotation of a Campylobacter coli strain isolated from milk with multidrug resistance SO GENOMICS DATA LA English DT Article DE WGS (Whole Genome Sequencing); C. coli (Campylobacter coli); RAST (Rapid Annotation using Subsystem Technology) ID SUBSYSTEMS TECHNOLOGY; RAST AB As the most prevalent bacterial cause of human gastroenteritis, food-borne Campylobacter infections pose a serious threat to public health. Whole Genome Sequencing (WGS) is a tool providing quick and inexpensive approaches for analysis of food-borne pathogen epidemics. Here we report the WGS and annotation of a Campylobacter coli strain, FNW20G12, which was isolated from milk in the United States in 1997 and carries multidrug resistance. The draft genome of FNW20G12 (DDBJ/ENA/GenBank accession number LWIH00000000) contains 1, 855,435 bp (GC content 31.4%) with 1902 annotated coding regions, 48 RNAs and resistance to aminoglycoside, beta-lactams, tetracycline, as well as fluoroquinolones. There are very few genome reports of C. coli from dairy products with multidrug resistance. Here the draft genome of FNW20G12, a C. coli strain isolated from raw milk, is presented to aid in the epidemiology study of C. coli antimicrobial resistance and role in foodborne outbreak. Published by Elsevier Inc. C1 [Liu, Kun C.; Jinneman, Karen C.; Neal-McKinney, Jason; Wu, Wen-Hsin; Rice, Daniel H.] US FDA, Appl Technol Ctr, Pacific Reg Lab Northwest, 22201 23rd Dr SE, Bothell, WA 98012 USA. RP Liu, KC (reprint author), US FDA, Appl Technol Ctr, Pacific Reg Lab Northwest, 22201 23rd Dr SE, Bothell, WA 98012 USA. EM Kun.liu@fda.hhs.gov NR 9 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-5960 J9 GENOM DATA JI Genom. Data PD JUN PY 2016 VL 8 BP 123 EP 125 DI 10.1016/j.gdata.2016.05.003 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA DO4OF UT WOS:000377761900031 PM 27257607 ER PT J AU Barr, RG Ferraioli, G Palmeri, ML Goodman, ZD Garcia-Tsao, G Rubin, J Garra, B Myers, RP Wilson, SR Rubens, D Levine, D AF Barr, Richard G. Ferraioli, Giovanna Palmeri, Mark L. Goodman, Zachary D. Garcia-Tsao, Guadalupe Rubin, Jonathan Garra, Brian Myers, Robert P. Wilson, Stephanie R. Rubens, Deborah Levine, Deborah TI Elastography Assessment of Liver Fibrosis: Society of Radiologists in Ultrasound Consensus Conference Statement (Reprinted) SO ULTRASOUND QUARTERLY LA English DT Reprint ID RADIATION FORCE IMPULSE; MAGNETIC-RESONANCE ELASTOGRAPHY; CHRONIC HEPATITIS-C; SHEAR-WAVE ELASTOGRAPHY; CHRONIC VIRAL-HEPATITIS; CONTROLLED TRANSIENT ELASTOGRAPHY; 1 BASIC PRINCIPLES; STIFFNESS MEASUREMENT; NONINVASIVE ASSESSMENT; CLINICAL-USE C1 [Barr, Richard G.] Northeastern Ohio Med Univ, Dept Radiol, Rootstown, OH 44272 USA. [Barr, Richard G.] Southwoods Imaging, Boardman, OH USA. [Ferraioli, Giovanna] Univ Pavia, Fdn IRCCS Policlin San Matteo, Dept Infect Dis, Ultrasound Unit, Via Palestro 3, I-27100 Pavia, Italy. [Palmeri, Mark L.] Duke Univ, Dept Biomed Engn, Pratt Sch Engn, Durham, NC 27706 USA. [Goodman, Zachary D.] Inova Fairfax Hosp, Ctr Liver Dis, Falls Church, VA USA. [Garcia-Tsao, Guadalupe] Yale Univ, Dept Med, Sect Digest Dis, New Haven, CO USA. [Garcia-Tsao, Guadalupe] VA Connecticut Healthcare Syst, West Haven, CT USA. [Rubin, Jonathan] Univ Michigan, Med Ctr, Dept Radiol, Ann Arbor, MI 48109 USA. [Garra, Brian] Washington DC VA Med Ctr, Dept Radiol, Washington, DC USA. [Garra, Brian] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Imaging Diagnost & Software Reliabil, Silver Spring, MD USA. [Myers, Robert P.] Univ Calgary, Dept Hepatol, Calgary, AB, Canada. [Wilson, Stephanie R.] Univ Calgary, Dept Radiol, Calgary, AB, Canada. [Rubens, Deborah] Univ Rochester, Med Ctr, Dept Imaging Sci, Rochester, NY 14642 USA. [Rubens, Deborah] Univ Rochester, Med Ctr, Dept Oncol, Rochester, NY 14642 USA. [Rubens, Deborah] Univ Rochester, Med Ctr, Dept Biomed Engn, Rochester, NY 14642 USA. [Levine, Deborah] Beth Israel Deaconess Med Ctr, Dept Radiol, 330 Brookline Ave, Boston, MA 02215 USA. RP Barr, RG (reprint author), Northeastern Ohio Med Univ, Dept Radiol, Rootstown, OH 44272 USA. EM rgbarr@zoominternet.net RI Ferraioli, Giovanna/E-3075-2013 OI Ferraioli, Giovanna/0000-0002-6344-697X NR 116 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0894-8771 EI 1536-0253 J9 ULTRASOUND Q JI Ultrasound Q. PD JUN PY 2016 VL 32 IS 2 BP 94 EP 107 DI 10.1097/RUQ.0000000000000209 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DP3RR UT WOS:000378413100002 PM 27233069 ER PT J AU Ammann, EM Haskins, CB Fillman, KM Ritter, RL Gu, XM Winiecki, SK Carnahan, RM Torner, JC Fireman, BH Jones, MP Chrischilles, EA AF Ammann, Eric M. Haskins, Cole B. Fillman, Kelsey M. Ritter, Rebecca L. Gu, Xiaomei Winiecki, Scott K. Carnahan, Ryan M. Torner, James C. Fireman, Bruce H. Jones, Michael P. Chrischilles, Elizabeth A. TI Intravenous immune globulin and thromboembolic adverse events: A systematic review and meta-analysis of RCTs SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Review ID PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; SECONDARY RECURRENT MISCARRIAGE; PROGRESSIVE MULTIPLE-SCLEROSIS; RENAL-TRANSPLANT RECIPIENTS; IMMUNOGLOBULIN-G THERAPY; DOUBLE-BLIND; IV IMMUNOGLOBULIN; VENOUS THROMBOEMBOLISM; VENOOCCLUSIVE DISEASE AB Prior case reports and observational studies indicate that intravenous immune globulin (IVIg) products may cause thromboembolic events (TEEs), leading the FDA to require a boxed warning in 2013. The effect of IVIg treatment on the risk of serious TEEs (acute myocardial infarction, ischemic stroke, or venous thromboembolism) was assessed using adverse event data reported in randomized controlled trials (RCTs) of IVIg. RCTs of IVIg in adult patients from 1995 to 2015 were identified from Pubmed, Embase, ClinicalTrials.Gov, and two large prior reviews of IVIg's therapeutic applications. Trials at high risk of detection or reporting bias for serious adverse events were excluded. 31 RCTs with a total of 4,129 participants (2,318 IVIg-treated, 1,811 control) were eligible for quantitative synthesis. No evidence was found of increased TEE risk among IVIg-treated patients compared with control patients (odds ratio=51.10, 95% CI: 0.44, 2.88; risk difference50.0%, 95% CI: 20.7%, 0.7%, I-2 = 0%). No significant increase in risk was found when arterial and venous TEEs were analyzed as separate endpoints. Trial publications provided little specific information concerning the methods used to ascertain potential adverse events. Care should be taken in extrapolating the results to patients with higher baseline risks of TEE. (C) 2016 Wiley Periodicals, Inc. C1 [Ammann, Eric M.; Haskins, Cole B.; Fillman, Kelsey M.; Ritter, Rebecca L.; Carnahan, Ryan M.; Torner, James C.; Chrischilles, Elizabeth A.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Gu, Xiaomei] Univ Iowa, Hardin Lib Hlth Sci, Iowa City, IA USA. [Winiecki, Scott K.] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Fireman, Bruce H.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Jones, Michael P.] Univ Iowa, Coll Publ Hlth, Dept Biostat, Iowa City, IA USA. RP Ammann, EM (reprint author), 145 N Riverside Dr,CPHB S400, Iowa City, IA 52242 USA. EM eric-ammann@uiowa.edu OI Carnahan, Ryan/0000-0002-7478-4739 FU NIGMS NIH HHS [T32 GM007337] NR 95 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD JUN PY 2016 VL 91 IS 6 BP 594 EP 605 DI 10.1002/ajh.24358 PG 12 WC Hematology SC Hematology GA DO2CE UT WOS:000377586400021 PM 26973084 ER PT J AU Scully, C Daluwatte, C Marques, N Salsbury, J Enkhbaatar, P Kinsky, M Kramer, G Strauss, D AF Scully, C. Daluwatte, C. Marques, N. Salsbury, J. Enkhbaatar, P. Kinsky, M. Kramer, G. Strauss, D. TI ARTERIAL WAVEFORM DYNAMICS AT VARYING HEMORRHAGE RATES SO SHOCK LA English DT Meeting Abstract CT 39th Annual Conference of the Shock-Society on Shock CY JUN 11-14, 2016 CL Austin, TX SP Shock Soc C1 [Scully, C.; Daluwatte, C.; Strauss, D.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Marques, N.; Salsbury, J.; Enkhbaatar, P.; Kinsky, M.; Kramer, G.] Univ Texas Med Branch, Galveston, TX 77555 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1073-2322 EI 1540-0514 J9 SHOCK JI Shock PD JUN PY 2016 VL 45 IS 6 SU 1 MA P197 BP 120 EP 120 PG 1 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA DO3OX UT WOS:000377692000289 ER PT J AU Skoog, SA Kumar, G Goering, PL Williams, B Stiglich, J Narayan, RJ AF Skoog, Shelby A. Kumar, Girish Goering, Peter L. Williams, Brian Stiglich, Jack Narayan, Roger J. TI Biological Response of Human Bone Marrow-Derived Mesenchymal Stem Cells to Commercial Tantalum Coatings with Microscale and Nanoscale Surface Topographies SO JOM LA English DT Article ID POROUS TANTALUM; OSTEOPROGENITOR RESPONSE; HUMAN OSTEOBLASTS; TITANIUM; DIFFERENTIATION; IMPLANTS; HYDROXYAPATITE; PROLIFERATION; PERFORMANCE; EXPRESSION AB Tantalum is a promising orthopaedic implant coating material due to its robust mechanical properties, corrosion resistance, and excellent biocompatibility. Previous studies have demonstrated improved biocompatibility and tissue integration of surface-treated tantalum coatings compared to untreated tantalum. Surface modification of tantalum coatings with biologically inspired microscale and nanoscale features may be used to evoke optimal tissue responses. The goal of this study was to evaluate commercial tantalum coatings with nanoscale, sub-microscale, and microscale surface topographies for orthopaedic and dental applications using human bone marrow-derived mesenchymal stem cells (hBMSCs). Tantalum coatings with different microscale and nanoscale surface topographies were fabricated using a diffusion process or chemical vapor deposition. Biological evaluation of the tantalum coatings using hBMSCs showed that tantalum coatings promote cellular adhesion and growth. Furthermore, hBMSC adhesion to the tantalum coatings was dependent on surface feature characteristics, with enhanced cell adhesion on sub-micrometer- and micrometer-sized surface topographies compared to hybrid nano-/microstructures. Nanostructured and microstructured tantalum coatings should be further evaluated to optimize the surface coating features to promote osteogenesis and enhance osseointegration of tantalum-based orthopaedic implants. C1 [Skoog, Shelby A.; Narayan, Roger J.] Univ N Carolina, Joint Dept Biomed Engn, Raleigh, NC USA. [Skoog, Shelby A.; Narayan, Roger J.] N Carolina State Univ, Raleigh, NC 27695 USA. [Skoog, Shelby A.; Kumar, Girish; Goering, Peter L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Williams, Brian; Stiglich, Jack] Ultramet Inc, Pacoima, CA USA. RP Narayan, RJ (reprint author), Univ N Carolina, Joint Dept Biomed Engn, Raleigh, NC USA.; Narayan, RJ (reprint author), N Carolina State Univ, Raleigh, NC 27695 USA. EM roger_narayan@msn.com FU NSF [1136330]; State of North Carolina; National Science Foundation FX Shelby Skoog was supported in part by NSF Award #1136330. The authors acknowledge the use of the Analytical Instrumentation Facility (AIF) at North Carolina State University, which is supported by the State of North Carolina and the National Science Foundation. The authors would like to acknowledge Chuck Mooney for assistance with SEM and EDS. NR 29 TC 0 Z9 0 U1 8 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1047-4838 EI 1543-1851 J9 JOM-US JI JOM PD JUN PY 2016 VL 68 IS 6 BP 1672 EP 1678 DI 10.1007/s11837-016-1934-x PG 7 WC Materials Science, Multidisciplinary; Metallurgy & Metallurgical Engineering; Mineralogy; Mining & Mineral Processing SC Materials Science; Metallurgy & Metallurgical Engineering; Mineralogy; Mining & Mineral Processing GA DN9XI UT WOS:000377433600024 ER PT J AU Kar, S Arjunaraja, S Akkoyunlu, M Pier, GB Snapper, CM AF Kar, Swagata Arjunaraja, Swadhinya Akkoyunlu, Mustafa Pier, Gerald B. Snapper, Clifford M. TI Distinct Mechanisms Underlie Boosted Polysaccharide-Specific IgG Responses Following Secondary Challenge with Intact Gram-Negative versus Gram-Positive Extracellular Bacteria SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFLUENZAE TYPE-B; T-CELL HELP; PNEUMOCOCCAL CONJUGATE VACCINE; ANTI-CAPSULAR POLYSACCHARIDE; HUMORAL IMMUNE-RESPONSES; STREPTOCOCCUS-PNEUMONIAE; IN-VIVO; IMMUNOLOGICAL MEMORY; NEISSERIA-MENINGITIDIS; GLYCOCONJUGATE VACCINE AB Priming of mice with intact, heat-killed cells of Gram-negative Neisseria meningitidis, capsular serogroup C (MenC) or Gram-positive group B Streptococcus, capsular type III (GBS-III) bacteria resulted in augmented serum polysaccharide (PS)-specific IgG titers following booster immunization. Induction of memory required CD4(+) T cells during primary immunization. We determined whether PS-specific memory for IgG production was contained within the B cell and/or T cell populations, and whether augmented IgG responses following booster immunization were also dependent on CD4(+) T cells. Adoptive transfer of purified B cells from MenC-or GBS-III-primed, but not naive mice resulted in augmented PS-specific IgG responses following booster immunization. Similar responses were observed when cotransferred CD4(+) T cells were from primed or naive mice. Similarly, primary immunization with unencapsulated MenC or GBS-III, to potentially prime CD4(+) T cells, failed to enhance PS-specific IgG responses following booster immunization with their encapsulated isogenic partners. Furthermore, in contrast to GBS-III, depletion of CD4(+) T cells during secondary immunization with MenC or another Gram-negative bacteria, Acinetobacter baumannii, did not inhibit augmented PS-specific IgG booster responses of mice primed with heat-killed cells. Also, in contrast with GBS-III, booster immunization of MenC-primed mice with isolated MenC-PS, a TI Ag, or a conjugate of MenC-PS and tetanus toxoid elicited an augmented PS-specific IgG response similar to booster immunization with intact MenC. These data demonstrate that memory for augmented PS-specific IgG booster responses to Gram-negative and Grampositive bacteria is contained solely within the B cell compartment, with a differential requirement for CD4(+) T cells for augmented IgG responses following booster immunization. C1 [Kar, Swagata; Snapper, Clifford M.] Uniformed Serv Univ Hlth Sci, Dept Pathol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Arjunaraja, Swadhinya] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Akkoyunlu, Mustafa] US FDA, Lab Bacterial Polysaccharides, Silver Spring, MD 20993 USA. [Pier, Gerald B.] Brigham & Womens Hosp, Dept Med, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. [Pier, Gerald B.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Snapper, CM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Pathol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM clifford.snapper@usuhs.edu OI kar, swagata/0000-0003-3702-6207 FU Uniformed Services University of the Health Sciences Research and Education Endowment Fund FX This work was supported by the Uniformed Services University of the Health Sciences Research and Education Endowment Fund (to C.M.S.). NR 62 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2016 VL 196 IS 11 BP 4614 EP 4621 DI 10.4049/jimmunol.1600082 PG 8 WC Immunology SC Immunology GA DO3IU UT WOS:000377676000021 PM 27183619 ER PT J AU Marks, PW Epstein, JS Borio, LL AF Marks, Peter W. Epstein, Jay S. Borio, Luciana L. TI Maintaining a Safe Blood Supply in an Era of Emerging Pathogens SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE blood safety; donor screening tests; emerging pathogens; pathogen-reduction; Zika virus ID ZIKA VIRUS; TRANSMISSION; TRANSFUSION; STATES; BRAZIL AB Coming shortly after outbreaks of dengue and chikungunya virus in related locations, the recent outbreak of Zika virus in the southern part of the western hemisphere is yet another reminder that infectious pathogens continue to emerge rapidly and can adversely affect public health, including the safety of the blood supply. In response to Zika virus, public health measures that rely largely on donor deferral and sourcing of blood from non-outbreak areas until a blood donor screening test becomes available have been implemented to address the safety of the blood supply in the United States. However, a more universal approach to ensuring blood safety in the setting of rapidly emerging infectious diseases is needed. C1 [Marks, Peter W.; Epstein, Jay S.; Borio, Luciana L.] US FDA, 10903 New Hampshire Ave WO1-3317, Silver Spring, MD 20993 USA. RP Borio, LL (reprint author), US FDA, 10903 New Hampshire Ave WO1-3317, Silver Spring, MD 20993 USA. EM luciana.borio@fda.hhs.gov NR 13 TC 3 Z9 4 U1 3 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2016 VL 213 IS 11 BP 1676 EP 1677 DI 10.1093/infdis/jiw089 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DO0BC UT WOS:000377443400002 PM 26962237 ER PT J AU Mohan, N Shen, Y Endo, Y ElZarrad, MK Wu, WJ AF Mohan, Nishant Shen, Yi Endo, Yukinori ElZarrad, M. Khair Wu, Wen Jin TI Trastuzumab, but Not Pertuzumab, Dysregulates HER2 Signaling to Mediate Inhibition of Autophagy and Increase in Reactive Oxygen Species Production in Human Cardiomyocytes SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID METASTATIC BREAST-CANCER; MITOCHONDRIAL DYSFUNCTION; DILATED CARDIOMYOPATHY; INDUCED CARDIOTOXICITY; MOLECULAR-MECHANISMS; CARDIAC TOLERABILITY; CELLULAR AUTOPHAGY; HEART-FAILURE; ERBB2; PHOSPHORYLATION AB Dysregulation of autophagy has been implicated in various cardiovascular diseases. Trastuzumab, a humanized monoclonal antibody, binds to HER2 domain IV and is approved for the treatment of HER2-positive breast cancer. Trastuzumab therapy is associated with considerable cardiotoxicity, the mechanism of which remains unclear. HER2 signaling plays a pivotal role in cardiomyocyte development and survival and is essential for the prevention of cardiomyopathy. However, a direct link has not been confirmed between trastuzumab-induced cardiomyopathy and impaired HER2 signaling. Our data reveal a novel mechanism by which trastuzumab dysregulates HER2 signaling and impairs basal autophagic process in human primary cardiomyocytes. Specifically, trastuzumab treatment leads to the phosphorylation of HER1-Y845 and HER2-Y1248 and the activation of Erk. This in turn results in upregulation of mTOR signaling pathway and subsequently inhibition of autophagy in primary cardiomyocytes and C57BL/6 mice. Trastuzumab-induced downregulation of autophagy is further supported by the fact that trastuzumab treatment reduces protein levels of autophagosome-associated signaling molecules such as Atg 5-12, Atg 7, Atg 14, and Beclin 1. We further demonstrated that trastuzumab-mediated inhibition of autophagy resulted in the increased production of reactive oxygen species (ROS) in cardiomyocytes. Pertuzumab, another anti-HER2 therapeutic mAb binding to HER2 domain II, fails to modulate HER2 signaling and is unable to inhibit autophagy and to increase ROS production in cardiomyocytes. This study provides novel mechanistic insights into trastuzumab-induced cardiotoxicity, which may assist in formulating novel approaches for clinical management of trastuzumab-induced cardiomyopathy. (C) 2016 AACR. C1 [Mohan, Nishant; Shen, Yi; Endo, Yukinori; ElZarrad, M. Khair; Wu, Wen Jin] US FDA, Div Biotechnol Res & Review 1, Off Biotechnol Prod, Off Pharmaceut Qual,Ctr Evaluat & Res, Silver Spring, MD USA. RP Wu, WJ (reprint author), US FDA, Bldg 52-72,Room 2310,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM wen.wu@fda.hhs.gov FU FDA Office of Women's Health Research Science Program [750912CDR]; Center for Drug Evaluation and Research (CDER); Food and Drug Administration Office of Women's Health; U.S. Food and Drug Administration FX This work was supported by FDA Office of Women's Health Research Science Program award (to W.J. Wu; Project ID: 750912CDR). This project was supported in part by an appointment to the ORISE Research Participation Program at the Center for Drug Evaluation and Research (CDER), 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. Dr. Nishant Mohan is an ORISE research fellow supported by Food and Drug Administration Office of Women's Health. NR 51 TC 2 Z9 2 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUN PY 2016 VL 15 IS 6 BP 1321 EP 1331 DI 10.1158/1535-7163.MCT-15-0741 PG 11 WC Oncology SC Oncology GA DN9VA UT WOS:000377427600017 PM 27197303 ER PT J AU Shapiro, E Bernstein, J Adams, HR Barbier, AJ Buracchio, T Como, P Delaney, KA Eichler, F Goldsmith, JC Hogan, M Kovacs, S Mink, JW Odenkirchen, J Parisi, MA Skrinar, A Waisbren, SE Mulberg, AE AF Shapiro, Elsa Bernstein, Jessica Adams, Heather R. Barbier, Ann J. Buracchio, Teresa Como, Peter Delaney, Kathleen A. Eichler, Florian Goldsmith, Jonathan C. Hogan, Melissa Kovacs, Sarrit Mink, Jonathan W. Odenkirchen, Joanne Parisi, Melissa A. Skrinar, Alison Waisbren, Susan E. Mulberg, Andrew E. TI Neurocognitive clinical outcome assessments for inborn errors of metabolism and other rare conditions SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Inborn errors; Neurocognitive; Clinical outcome assessment; Natural history studies; Rare diseases; Drug development ID LIPOFUSCINOSIS BATTEN-DISEASE; RATING-SCALE; TRIALS AB Well-defined and reliable clinical outcome assessments are essential for determining whether a drug provides clinically meaningful treatment benefit for patients. In 2015, FDA convened a workshop, "Assessing Neurocognitive Outcomes in Inborn Errors of Metabolism." Topics covered included special challenges of clinical studies of inborn errors of metabolism (IEMs) and other rare diseases; complexities of identifying treatment effects in the context of the dynamic processes of child development and disease progression; and the importance of natural history studies. Clinicians, parents/caregivers, and participants from industry, academia, and government discussed factors to consider when developing measures to assess treatment outcomes, as well as tools and methods that may contribute to standardizing measures. Many issues examined are relevant to the broader field of rare diseases in addition to specifics of IEMs. Published by Elsevier Inc. C1 [Shapiro, Elsa; Delaney, Kathleen A.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Shapiro, Elsa; Delaney, Kathleen A.] Shapiro & Delaney LLC, Mendota Hts, MN USA. [Bernstein, Jessica; Buracchio, Teresa; Goldsmith, Jonathan C.; Kovacs, Sarrit; Mulberg, Andrew E.] US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Adams, Heather R.; Mink, Jonathan W.] Univ Rochester, Med Ctr, Dept Neurol, Div Child Neurol, Rochester, NY 14642 USA. [Barbier, Ann J.] Shire, Lexington, MA USA. [Como, Peter] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Eichler, Florian] Harvard Univ, Sch Med, Dept Neurol, Ctr Rare Neurol Dis,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Hogan, Melissa] Saving Case & Friends Inc, Thompsons Stn, TN USA. [Odenkirchen, Joanne] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Parisi, Melissa A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Skrinar, Alison] Ultragenyx Pharmaceut Inc, Clin Outcomes Res & Evaluat, Novato, CA USA. [Waisbren, Susan E.] Harvard Univ, Sch Med, Metab Program, Div Genet & Genom,Boston Childrens Hosp, Boston, MA 02115 USA. [Barbier, Ann J.] Agios Pharmaceut, Cambridge, MA USA. RP Bernstein, J (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM shapi004@umn.edu; jessica.bemstein@fda.hhs.gov; Heather_Adams@URMC.Rochester.edu; annjbarbier@aol.com; teresa.buracchio@fda.hhs.gov; peter.como@fda.hhs.gov; kate.delaney@shapiroanddelaney.com; feichler@partners.org; jonathan.goldsmith@fda.hhs.gov; melissa@savingcase.com; sarrit.kovacs@fda.hhs.gov; Jonathan_Mink@URMC.Rochester.edu; jo21x@nih.gov; parisima@mail.nih.gov; ASkrinar@ultragenyx.com; Susan.Waisbren@childrens.harvard.edu; andrew.mulberg@fda.hhs.gov OI Hogan, Melissa/0000-0003-1249-2164; Shapiro, Elsa/0000-0003-0276-0276 FU NICHD NIH HHS [U54 HD061221] NR 14 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN PY 2016 VL 118 IS 2 BP 65 EP 69 DI 10.1016/j.ymgme.2016.04.006 PG 5 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA DN9TJ UT WOS:000377423300001 PM 27132782 ER PT J AU Szajek, AY Chess, E Johansen, K Gratzl, G Gray, E Keire, D Linhardt, RJ Liu, J Morris, T Mulloy, B Nasr, M Shriver, Z Torralba, P Viskov, C Williams, R Woodcock, J Workman, W Al-Hakim, A AF Szajek, Anita Y. Chess, Edward Johansen, Kristian Gratzl, Gyongyi Gray, Elaine Keire, David Linhardt, Robert J. Liu, Jian Morris, Tina Mulloy, Barbara Nasr, Moheb Shriver, Zachary Torralba, Pearle Viskov, Christian Williams, Roger Woodcock, Janet Workman, Wesley Al-Hakim, Ali TI The US regulatory and pharmacopeia response to the global heparin contamination crisis SO NATURE BIOTECHNOLOGY LA English DT Article ID OVERSULFATED CHONDROITIN SULFATE; ANTITHROMBIN-BINDING OCTASACCHARIDES; ADVERSE CLINICAL EVENTS; MICROPLATE BASED ASSAY; PRODUCTS KEY TESTS; MOLECULAR-WEIGHT; QUALITY-ASSURANCE; MASS-SPECTROMETRY; SODIUM; SPECTROSCOPY AB The contamination of the widely used lifesaving anticoagulant drug heparin in 2007 has drawn renewed attention to the challenges that are associated with the characterization, quality control and standardization of complex biological medicines from natural sources. Heparin is a linear, highly sulfated polysaccharide consisting of alternating glucosamine and uronic acid monosaccharide residues. Heparin has been used successfully as an injectable antithrombotic medicine since the 1930s, and its isolation from animal sources (primarily porcine intestine) as well as its manufacturing processes have not changed substantially since its introduction. The 2007 heparin contamination crisis resulted in several deaths in the United States and hundreds of adverse reactions worldwide, revealing the vulnerability of a complex global supply chain to sophisticated adulteration. This Perspective discusses how the US Food and Drug Administration (FDA), the United States Pharmacopeia! Convention (USP) and international stakeholders collaborated to redefine quality expectations for heparin, thus making an important natural product better controlled and less susceptible to economically motivated adulteration. C1 [Szajek, Anita Y.; Morris, Tina] US Pharmacopeia, Biol & Biotechnol Dept, Rockville, MD USA. [Chess, Edward] Baxter Healthcare Corp, Struct Elucidat Technol Resources, Round Lake, IL 60073 USA. [Johansen, Kristian] Sjolundspk, Hellebaek, Denmark. [Gratzl, Gyongyi] Ben Venue Labs Inc, Boehringer Ingelheim, Bedford, OH USA. [Gray, Elaine; Mulloy, Barbara] Natl Inst Biol Stand & Controls, Potters Bar, Herts, England. [Keire, David] US FDA, Div Pharmaceut Anal, St Louis, MO USA. [Linhardt, Robert J.] Rensselaer Polytech Inst, Ctr Biotechnol & Interdisciplinary Studies, Troy, NY USA. [Liu, Jian] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC USA. [Mulloy, Barbara] Kings Coll London, Inst Pharmaceut Sci, Wilkins Bldg,Waterloo Campus, London, England. [Nasr, Moheb] GlaxoSmithKline, R&D, Collegeville, PA USA. [Shriver, Zachary] MIT, Harvard Mit Div Hlth Sci & Technol, Koch Inst Integrat Canc Res, Dept Biol Engn, Cambridge, MA 02139 USA. [Torralba, Pearle] Fresenius Kabi USA, Prod Dev Analyt Innovat & Dev, Skokie, IL USA. [Viskov, Christian] Sanofi, Vitry Sur Seine, France. [Williams, Roger] US Pharmacopeia, Rockville, MD USA. [Woodcock, Janet; Al-Hakim, Ali] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Workman, Wesley] Pfizer Qual Operat Biotech, Chesterfield, MO USA. RP Al-Hakim, A (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM Ali.Alhakim@fda.hhs.gov FU USP FX The authors appreciate the financial and logistical support provided by USP; the contributions of USP volunteers, the scientific community, and the collaborating laboratories; the public comments; and the collaboration of the FDA, including helpful review and discussion. NR 46 TC 5 Z9 5 U1 8 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUN PY 2016 VL 34 IS 6 BP 625 EP 630 DI 10.1038/nbt.3606 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DO5TT UT WOS:000377846400028 PM 27281424 ER PT J AU Babu, US Harrison, LM Patel, IR Ramirez, GA Williams, KM Pereira, M Balan, KV AF Babu, Uma S. Harrison, Lisa M. Patel, Isha R. Ramirez, Gerardo A. Williams, Kristina M. Pereira, Marion Balan, Kannan V. TI Differential antibacterial response of chicken granulosa cells to invasion by Salmonella serovars SO POULTRY SCIENCE LA English DT Article DE Salmonella enterica serovars; follicles; ovarian granulosa; invasion; antibacterial response ID ENTERICA SEROTYPE ENTERITIDIS; EXPERIMENTALLY INFECTED HENS; OVIDUCT EPITHELIAL-CELLS; LAYING HENS; REPRODUCTIVE-TRACT; EGG CONTAMINATION; PATHOGEN RECOGNITION; GALLUS-DOMESTICUS; GENE-EXPRESSION; INNATE IMMUNITY AB In the United States, Salmonella enterica ser. Enteritidis (SE) is among the leading bacterial cause of foodborne illness via consumption of raw or undercooked eggs. The top Salmonella serovars implicated in U.S. foodborne outbreaks associated with chicken consumption include SE, Typhimurium (ST), Heidelberg (SH), Montevideo, Mbandka, Braenderup, and Newport. While enforcement actions target the eradication of SE from layer hens, there is a growing concern that other serovars could occupy this niche and be a cause of egg-transmitted human salmonellosis. Therefore, we tested the invasion and survival of SE, SH, ST, and Salmonella enterica ser. Hadar (S. Hadar) at 4 and 20 h post infection (hpi) in chicken ovarian granulosa cells (cGC); a cellular layer which surrounds the previtelline layer and central yolk in egg-forming follicles. We also evaluated cGC transcriptional changes, using an antibacterial response PCR array, to assess host response to intracellular Salmonella. We observed that invasion of cGC by SE, SH, and ST was significantly higher than invasion by S. Hadar, with ST showing the highest level of invasion. The Bacterial Survival Index, defined as the ratio of intracellular bacteria at 20 and 4 h, were 18.94, 7.35, and 15.27 for SE, SH, and ST, respectively, with no significant difference in survival between SE or ST compared to SH. Evaluation of cGC anti-Salmonella gene responses indicated that at 4 hpi there was a significant decrease in Toll-like receptor (TLR)-4 mRNA in cGC infected with SE, whereas TLR5 and myeloid differentiation primary response gene 88 were significantly down regulated across all serovars. At 4 hpi, invasion by Salmonella serovars resulted in significant upregulation of several antimicrobial genes, and proinflammatory cytokines and chemokines (PICs). At 20 hpi, all the serovars induced PICs with SH being the strongest inducer. Additionally, SE, SH and ST differentially induced signal transduction pathways. Although only a single strain from each serovar was tested, cGC presents a useful ex vivo cell culture model to assess the virulence potential of Salmonella serovars. C1 [Babu, Uma S.; Harrison, Lisa M.; Patel, Isha R.; Williams, Kristina M.; Pereira, Marion; Balan, Kannan V.] US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. [Ramirez, Gerardo A.] US FDA, Ctr Food Safety & Appl Nutr, Off Food Safety, College Pk, MD 20740 USA. RP Balan, KV (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. EM Kannan.Balan@fda.hhs.gov FU Research Participation Program at the U.S. Food and Drug Administration FX We thank Drs. Alan Johnson and Olga Ocon-Grove, The Pennsylvania State University, for providing training in ovarian granulosa cell isolation, CFSAN Animal Husbandry Unit for support services, and Dr. John Ihrie, CFSAN Office of Analytics and Outreach for excellent statistical analyses. 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 56 TC 0 Z9 0 U1 4 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 JUN PY 2016 VL 95 IS 6 BP 1370 EP 1379 DI 10.3382/ps/pew050 PG 10 WC Agriculture, Dairy & Animal Science SC Agriculture GA DN9VF UT WOS:000377428100018 PM 26944965 ER PT J AU Bellayr, IH Marklein, RA Lo Surdo, JL Bauer, SR Puri, RK AF Bellayr, Ian H. Marklein, Ross A. Lo Surdo, Jessica L. Bauer, Steven R. Puri, Raj K. TI Identification of Predictive Gene Markers for Multipotent Stromal Cell Proliferation SO STEM CELLS AND DEVELOPMENT LA English DT Article ID MESENCHYMAL STEM-CELLS; UMBILICAL-CORD BLOOD; IN-VITRO CULTURE; BONE-MARROW; BREAST-CANCER; REPLICATIVE SENESCENCE; CLINICAL-PRACTICE; THERAPY; EXPRESSION; MODEL AB Multipotent stromal cells (MSCs) are known for their distinctive ability to differentiate into different cell lineages, such as adipocytes, chondrocytes, and osteocytes. They can be isolated from numerous tissue sources, including bone marrow, adipose tissue, skeletal muscle, and others. Because of their differentiation potential and secretion of growth factors, MSCs are believed to have an inherent quality of regeneration and immune suppression. Cellular expansion is necessary to obtain sufficient numbers for use; however, MSCs exhibit a reduced capacity for proliferation and differentiation after several rounds of passaging. In this study, gene markers of MSC proliferation were identified and evaluated for their ability to predict proliferative quality. Microarray data of human bone marrow-derived MSCs were correlated with two proliferation assays. A collection of 24 genes were observed to significantly correlate with both proliferation assays (vertical bar r vertical bar >0.70) for eight MSC lines at multiple passages. These 24 identified genes were then confirmed using an additional set of MSCs from eight new donors using reverse transcription quantitative polymerase chain reaction (RT-qPCR). The proliferative potential of the second set of MSCs was measured for each donor/passage for confluency fraction, fraction of EdU+ cells, and population doubling time. The second set of MSCs exhibited a greater proliferative potential at passage 4 in comparison to passage 8, which was distinguishable by 15 genes; however, only seven of the genes (BIRC5, CCNA2, CDC20, CDK1, PBK, PLK1, and SPC25) demonstrated significant correlation with MSC proliferation regardless of passage. Our analyses revealed that correlation between gene expression and proliferation was consistently reduced with the inclusion of non-MSC cell lines; therefore, this set of seven genes may be more strongly associated with MSC proliferative quality. Our results pave the way to determine the quality of an MSC population for a particular cellular therapy in lieu of an extended in vitro or in vivo assay. C1 [Bellayr, Ian H.; Puri, Raj K.] US FDA, Div Cellular & Gene Therapies, Tumor Vaccines & Biotechnol Branch, Ctr Biol & Evaluat Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Marklein, Ross A.; Lo Surdo, Jessica L.; Bauer, Steven R.] US FDA, Div Cellular & Gene Therapies, Cellular & Tissue Therapies Branch, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Puri, RK (reprint author), US FDA, Div Cellular & Gene Therapies, Tumor Vaccines & Biotechnol Branch, Ctr Biol & Evaluat Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM raj.puri@fda.hhs.gov FU Medical Countermeasures Initiative; FDA Modernizing Science Initiative FX This project is supported by the Medical Countermeasures Initiative and the FDA Modernizing Science Initiative. We would like to thank Drs. Heba Degheidy and Bharat Joshi for reviewing the article. We would like to acknowledge the members of the FDA Modernizing Science Consortium for their discussion of the presented work. NR 66 TC 1 Z9 1 U1 2 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 EI 1557-8534 J9 STEM CELLS DEV JI Stem Cells Dev. PD JUN 1 PY 2016 VL 25 IS 11 BP 861 EP 873 DI 10.1089/scd.2015.0374 PG 13 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA DN9FA UT WOS:000377383700005 PM 27036644 ER PT J AU Yeager, RP Kushman, M Chemerynski, S Weil, R Fu, X White, M Callahan-Lyon, P Rosenfeldt, H AF Yeager, R. Philip Kushman, Mary Chemerynski, Susan Weil, Roxana Fu, Xin White, Marcella Callahan-Lyon, Priscilla Rosenfeldt, Hans TI Proposed Mode of Action for Acrolein Respiratory Toxicity Associated with Inhaled Tobacco Smoke SO TOXICOLOGICAL SCIENCES LA English DT Article DE acrolein; inhalation; tobacco smoke; mode of action; respiratory toxicity ID OBSTRUCTIVE PULMONARY-DISEASE; BRONCHIAL EPITHELIAL-CELLS; INDUCED MUC5AC EXPRESSION; DEATH RECEPTOR PATHWAY; PROTEIN CROSS-LINKING; INDUCED DNA-ADDUCTS; KAPPA-B ACTIVATION; CIGARETTE-SMOKE; OXIDATIVE STRESS; HUMAN LUNG AB This article presents a mode of action (MOA) analysis that identifies key mechanisms in the respiratory toxicity of inhaled acrolein and proposes key acrolein-related toxic events resulting from the inhalation of tobacco smoke. Smoking causes chronic obstructive pulmonary disorder (COPD) and acrolein has been previously linked to the majority of smoking-induced noncancer respiratory toxicity. In contrast to previous MOA analyses for acrolein, this MOA focuses on the toxicity of acrolein in the lower respiratory system, reflecting the exposure that smokers experience upon tobacco smoke inhalation. The key mechanisms of acrolein toxicity identified in this proposed MOA include (1) acrolein chemical reactivity with proteins and other macromolecules of cells lining the respiratory tract, (2) cellular oxidative stress, including compromise of the important anti-oxidant glutathione, (3) chronic inflammation, (4) necrotic cell death leading to a feedback loop where necrosis-induced inflammation leads to more necrosis and oxidative damage and vice versa, (5) tissue remodeling and destruction, and (6) loss of lung elasticity and enlarged lung airspaces. From these mechanisms, the proposed MOA analysis identifies the key cellular processes in acrolein respiratory toxicity that consistently occur with the development of COPD: inflammation and necrosis in the middle and lower regions of the respiratory tract. Moreover, the acrolein exposures that occur as a result of smoking are well above exposures that induce both inflammation and necrosis in laboratory animals, highlighting the importance of the role of acrolein in smoking-related respiratory disease. C1 [Yeager, R. Philip; Kushman, Mary; Chemerynski, Susan; Weil, Roxana; Fu, Xin; Rosenfeldt, Hans] US FDA, Div Nonclin Sci, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [White, Marcella] US FDA, Div Regulatory Project Management, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. [Callahan-Lyon, Priscilla] US FDA, Div Individual Hlth Sci, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. RP Rosenfeldt, H (reprint author), US FDA, Div Nonclin Sci, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM hans.rosenfeldt@fda.hhs.gov NR 158 TC 2 Z9 2 U1 9 U2 14 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 JUN PY 2016 VL 151 IS 2 BP 347 EP 364 DI 10.1093/toxsci/kfw051 PG 18 WC Toxicology SC Toxicology GA DN9WO UT WOS:000377431600013 PM 26969371 ER PT J AU Setty, MKHG Liu, JK Mahtani, P Zhang, PH Du, BC Ragupathy, V Devadas, K Hewlett, IK AF Setty, Mohan Kumar Haleyur Giri Liu, Jikun Mahtani, Prerna Zhang, Panhe Du, Bingchen Ragupathy, Viswanath Devadas, Krishnakumar Hewlett, Indira K. TI Novel Time-Resolved Fluorescence Europium Nanoparticle Immunoassay for Detection of Human Immunodeficiency Virus-1 Group O Viruses Using Microplate and Microchip Platforms SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HIV-1 GROUP-O; TYPE-1 GROUP-O; REVERSE-TRANSCRIPTASE; DIAGNOSTIC WINDOW; UNITED-STATES; P24 ANTIGEN; CAMEROON; SUBTYPE; INFECTIONS; SENSITIVITY AB Accurate detection and quantification of HIV-1 group O viruses have been challenging for currently available HIV assays. We have developed a novel time-resolved fluorescence (TRF) europium nanoparticle immunoassay for HIV-1 group O detection using a conventional microplate enzyme-linked immunosorbent assay (ELISA) and a microchip platform. We screened several antibodies for optimal reactivity with several HIV-1 group O strains and identified antibodies that can detect all the strains of HIV-1 group O that were available for testing. The antibodies were used to develop a conventional ELISA format assay and an in-house developed europium nanoparticle-based assay for sensitivity. The method was evaluated on both microwell plate and microchip platforms. We identified two specific and sensitive antibodies among the six we screened. The antibodies, C65691 and ANT-152, were able to quantify 15 and detect all 17 group O viruses, respectively, as they were broadly cross-reactive with all HIV-1 group O strains and yielded better signals compared with other antibodies. We have developed a sensitive assay that reflects the actual viral load in group O samples by using an appropriate combination of p24 antibodies that enhance group O detection and a highly sensitive TRF-based europium nanoparticle for detection. The combination of ANT-152 and C65690M in the ratio 3:1 was able to give significantly higher signals in our europium-based assay compared with using any single antibody. C1 [Setty, Mohan Kumar Haleyur Giri; Liu, Jikun; Mahtani, Prerna; Zhang, Panhe; Du, Bingchen; Ragupathy, Viswanath; Devadas, Krishnakumar; Hewlett, Indira K.] US FDA, CBER, Mol Virol Lab, Bldg 52-72,New Hampshire Ave, Silver Spring, MD 10903 USA. RP Setty, MKHG; Hewlett, IK (reprint author), US FDA, CBER, Mol Virol Lab, Bldg 52-72,New Hampshire Ave, Silver Spring, MD 10903 USA. EM mohan.haleyurgirisetty@fda.hhs.gov; indira.hewlett@fda.hhs.gov FU NHLBI Nano [IAA-A-HL-12-001]; CBER Intramural grant MOD SCI FX This work was supported by the NHLBI Nano IAA-A-HL-12-001 and a CBER Intramural grant MOD SCI 2014. The authors are thankful to the NIH AIDS Reagent Program for providing HIV 1 group O strains. NR 42 TC 0 Z9 0 U1 11 U2 12 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 JUN PY 2016 VL 32 IS 6 BP 612 EP 619 DI 10.1089/aid.2014.0351 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DN3SI UT WOS:000376983300015 ER PT J AU Sheppard, AE Stoesser, N Wilson, DJ Sebra, R Kasarskis, A Anson, LW Giess, A Pankhurst, LJ Vaughan, A Grim, CJ Cox, HL Yeh, AJ Sifri, CD Walker, AS Peto, TE Crook, DW Mathers, AJ AF Sheppard, Anna E. Stoesser, Nicole Wilson, Daniel J. Sebra, Robert Kasarskis, Andrew Anson, Luke W. Giess, Adam Pankhurst, Louise J. Vaughan, Alison Grim, Christopher J. Cox, Heather L. Yeh, Anthony J. Sifri, Costi D. Walker, A. Sarah Peto, Tim E. Crook, Derrick W. Mathers, Amy J. CA MMM Informatics Grp TI Nested Russian Doll-Like Genetic Mobility Drives Rapid Dissemination of the Carbapenem Resistance Gene bla(KPC) SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID SEQUENCE TYPE 258; KLEBSIELLA-PNEUMONIAE ST258; HYDROLYZING BETA-LACTAMASE; NEW-YORK HOSPITALS; ESCHERICHIA-COLI; MOLECULAR EPIDEMIOLOGY; NEW-JERSEY; ACINETOBACTER-BAUMANNII; ANTIBIOTIC-RESISTANCE; UNITED-STATES AB The recent widespread emergence of carbapenem resistance in Enterobacteriaceae is a major public health concern, as carbapenems are a therapy of last resort against this family of common bacterial pathogens. Resistance genes can mobilize via various mechanisms, including conjugation and transposition; however, the importance of this mobility in short-term evolution, such as within nosocomial outbreaks, is unknown. Using a combination of short-and long-read whole-genome sequencing of 281 blaKPC-positive Enterobacteriaceae isolates from a single hospital over 5 years, we demonstrate rapid dissemination of this carbapenem resistance gene to multiple species, strains, and plasmids. Mobility of bla(KPC) occurs at multiple nested genetic levels, with transmission of bla(KPC) strains between individuals, frequent transfer of bla(KPC) plasmids between strains/ species, and frequent transposition of bla(KPC) transposon Tn4401 between plasmids. We also identify a common insertion site for Tn4401 within various Tn2-like elements, suggesting that homologous recombination between Tn2-like elements has enhanced the spread of Tn4401 between different plasmid vectors. Furthermore, while short-read sequencing has known limitations for plasmid assembly, various studies have attempted to overcome this by the use of reference-based methods. We also demonstrate that, as a consequence of the genetic mobility observed in this study, plasmid structures can be extremely dynamic, and therefore these reference- based methods, as well as traditional partial typing methods, can produce very misleading conclusions. Overall, our findings demonstrate that nonclonal resistance gene dissemination can be extremely rapid, presenting significant challenges for public health surveillance and achieving effective control of antibiotic resistance. C1 [Sheppard, Anna E.; Stoesser, Nicole; Wilson, Daniel J.; Anson, Luke W.; Giess, Adam; Pankhurst, Louise J.; Vaughan, Alison; Walker, A. Sarah; Peto, Tim E.; Crook, Derrick W.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Med, Modernizing Med Microbiol Consortium, Oxford OX3 9DU, England. [Sebra, Robert; Kasarskis, Andrew] Icahn Sch Med, Icahn Inst, New York, NY USA. [Sebra, Robert; Kasarskis, Andrew] Icahn Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Grim, Christopher J.] US FDA, Laurel, MD USA. [Cox, Heather L.; Yeh, Anthony J.; Sifri, Costi D.; Mathers, Amy J.] Univ Virginia Hlth Syst, Dept Med, Div Infect Dis & Int Hlth, Charlottesville, VA USA. [Sifri, Costi D.] Univ Virginia Hlth Syst, Off Hosp Epidemiol, Charlottesville, VA USA. [Crook, Derrick W.] Publ Hlth England, Microbiol Serv, London, England. [Mathers, Amy J.] Univ Virginia Hlth Syst, Dept Pathol, Clin Microbiol, Charlottesville, VA USA. [Giess, Adam] Univ Bergen, Dept Informat, N-5008 Bergen, Norway. [Yeh, Anthony J.] NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Sheppard, AE (reprint author), Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Med, Modernizing Med Microbiol Consortium, Oxford OX3 9DU, England.; Mathers, AJ (reprint author), Univ Virginia Hlth Syst, Dept Med, Div Infect Dis & Int Hlth, Charlottesville, VA USA.; Mathers, AJ (reprint author), Univ Virginia Hlth Syst, Dept Pathol, Clin Microbiol, Charlottesville, VA USA. EM anna.sheppard@ndm.ox.ac.uk; ajm5b@virginia.edu OI Wilson, Daniel/0000-0002-0940-3311; Sheppard, Anna/0000-0002-2913-0920 FU Health Innovation Challenge Fund [HICF-T5-358, WT098615/Z/12/Z]; Department of Health; Wellcome Trust; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford; NIHR Oxford Health Protection Research Unit on Healthcare Associated Infection and Antimicrobial Resistance [HPRU-2012-10041]; Wellcome Trust [101237/Z/13/Z]; Royal Society [101237/Z/13/Z] FX This publication presents independent research commissioned by the Health Innovation Challenge Fund (grants HICF-T5-358 and WT098615/Z/12/Z), a parallel funding partnership of the Department of Health and Wellcome Trust, the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford, and the NIHR Oxford Health Protection Research Unit on Healthcare Associated Infection and Antimicrobial Resistance (HPRU-2012-10041). The views expressed in this publication are those of the authors and not necessarily those of the funders. D.W.C. and T.E.P. are NIHR senior investigators. N.S. was supported by a Wellcome Trust University of Oxford research fellowship during this work. D.J.W. is a Sir Henry Dale Fellow jointly funded by the Wellcome Trust and the Royal Society (grant 101237/Z/13/Z). NR 55 TC 10 Z9 11 U1 3 U2 4 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 JUN PY 2016 VL 60 IS 6 BP 3767 EP 3778 DI 10.1128/AAC.00464-16 PG 12 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DN4PE UT WOS:000377048900060 PM 27067320 ER PT J AU Wang, WD Belosay, A Yang, XJ Hartman, JA Song, HX Iwaniec, UT Turner, RT Churchwell, MI Doerge, DR Helferich, WG AF Wang, Wendan Belosay, Aashvini Yang, Xujuan Hartman, James A. Song, Huaxin Iwaniec, Urszula T. Turner, Russell T. Churchwell, Mona I. Doerge, Daniel R. Helferich, William G. TI Effects of letrozole on breast cancer micro-metastatic tumor growth in bone and lung in mice inoculated with murine 4T1 cells SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Article DE Aromatase inhibitor letrozole; Bioluminescence imaging; Breast cancer; Lung metastases; mu CT; Micro-metastatic bone tumor; Ovariectomy ID AROMATASE INHIBITOR LETROZOLE; SPRAGUE-DAWLEY RATS; POSTMENOPAUSAL WOMEN; IN-VIVO; MARROW MICROMETASTASIS; DISTANT METASTASES; EXPERIMENTAL-MODEL; ENDOCRINE THERAPY; ZOLEDRONIC ACID; ESTROGEN AB Breast cancer (BC) is the leading cancer in women worldwide. Metastasis occurs in stage IV BC with bone and lung being common metastatic sites. Here we evaluate the effects of the aromatase inhibitor letrozole on BC micro-metastatic tumor growth in bone and lung metastasis in intact and ovariectomized (OVX) mice with murine estrogen receptor negative (ER-) BC cells inoculated in tibia. Forty-eight BALB/c mice were randomly assigned to one of four groups: OVX, OVX + Letrozole, Intact, and Intact + Letrozole, and injected with 4T1 cells intra-tibially. Letrozole was subcutaneously injected daily for 23 days at a dose of 1.75 A mu g/g body weight. Tumor progression was monitored by bioluminescence imaging (BLI). Following necropsy, inoculated tibiae were scanned via A mu CT and bone response to tumor was scored from 0 (no ectopic mineralization/osteolysis) to 5 (extensive ectopic mineralization/osteolysis). OVX mice had higher tibial pathology scores indicative of more extensive bone destruction than intact mice, irrespective of letrozole treatment. Letrozole decreased serum estradiol levels and reduced lung surface tumor numbers in intact animals. Furthermore, mice receiving letrozole had significantly fewer tumor colonies and fewer proliferative cells in the lung than OVX and intact controls based on H&E and Ki-67 staining, respectively. In conclusion, BC-inoculated OVX animals had higher tibia pathology scores than BC-inoculated intact animals and letrozole reduced BC metastases to lungs. These findings suggest that, by lowering systemic estrogen level and/or by interacting with the host organ, the aromatase inhibitor letrozole has the potential to reduce ER- BC metastasis to lung. C1 [Wang, Wendan; Belosay, Aashvini; Yang, Xujuan; Hartman, James A.; Helferich, William G.] Univ Illinois, Dept Food Sci & Human Nutr, 574 Bevier Hall,905 South Goodwin Ave, Urbana, IL 61801 USA. [Song, Huaxin] Texas Tech Univ, Hlth Sci Ctr, Sch Nursing, Lubbock, TX 79430 USA. [Iwaniec, Urszula T.; Turner, Russell T.] Oregon State Univ, Coll Publ Hlth & Human Sci, Skeletal Biol Lab, Corvallis, OR 97331 USA. [Iwaniec, Urszula T.; Turner, Russell T.] Oregon State Univ, Ctr Hlth Aging Res, Corvallis, OR 97331 USA. [Churchwell, Mona I.; Doerge, Daniel R.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Helferich, WG (reprint author), Univ Illinois, Dept Food Sci & Human Nutr, 574 Bevier Hall,905 South Goodwin Ave, Urbana, IL 61801 USA. EM helferic@illinois.edu FU DOD Breast Cancer Research Program from U.S. Army Medical Research and Materiel Command [W81XWH-09-1-0689, BC085882]; National Center for Complementary and Integrative Health (NCCIH) [P50AT006268]; Office of Dietary Supplements (ODS); National Cancer Institute (NCI) FX This project was supported by Grant Number W81XWH-09-1-0689; BC085882 (WGH) from DOD Breast Cancer Research Program from U.S. Army Medical Research and Materiel Command and P50AT006268 (WGH) from the National Center for Complementary and Integrative Health (NCCIH), the Office of Dietary Supplements (ODS) and the National Cancer Institute (NCI). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCCIH, ODS, NCI, or the National Institutes of Health. NR 62 TC 0 Z9 0 U1 5 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0262-0898 EI 1573-7276 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD JUN PY 2016 VL 33 IS 5 BP 475 EP 485 DI 10.1007/s10585-016-9792-z PG 11 WC Oncology SC Oncology GA DN4GE UT WOS:000377020900007 PM 27209469 ER PT J AU Teeguarden, JG Twaddle, NC Churchwell, MI Doerge, DR AF Teeguarden, Justin G. Twaddle, Nathan C. Churchwell, Mona I. Doerge, Daniel R. TI Urine and serum biomonitoring of exposure to environmental estrogens I: Bisphenol A in pregnant women SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Bisphenol A; Pharmacokinetics; Exposure; Pregnancy; Biomonitoring; Endocrine disruptors ID SPRAGUE-DAWLEY RATS; ROUTE DEPENDENT DOSIMETRY; TANDEM MASS-SPECTROMETRY; UMBILICAL-CORD BLOOD; ENDOCRINE DISRUPTORS; RHESUS-MONKEYS; PHARMACOKINETIC MODEL; LIQUID-CHROMATOGRAPHY; VIVO EXTRAPOLATION; BPA CONCENTRATIONS AB Despite its very low oral bioavailability and rapid elimination, multiple reports of unexpectedly high bisphenol A (BPA) concentrations in the serum of pregnant mothers or cord blood have raised questions about BPA exposures during pregnancy. Thirty healthy pregnant women recruited to the study were evaluated for total BPA exposure over a 30-h period comprising one-half day in the field and one day in a clinical setting. BPA and its metabolites were measured in serum and total BPA was measured in matching urine samples. The mean total exposure was similar to the 50th percentile of exposure for U.S. women and pregnant women in a large North American cohort. Twenty volunteers had total daily exposures equal to or exceeding the U.S. mean, and six volunteers had exposures exceeding the 75th percentile. Women working as cashiers did not have higher total BPA exposure. BPA was detected in some serum samples (0.25-0.51 ng/ml), but showed no relationship to total BPA in corresponding urine samples, no relationship to total BPA exposure, and had unconjugated BPA fractions of 60-80%, consistent with established criteria for sample contamination. We conclude that typical exposures of North American pregnant women produce internal exposures to BPA in the picomolar range. (C) 2016 Published by Elsevier Ltd. C1 [Teeguarden, Justin G.] Pacific NW Natl Lab, Hlth Effects & Exposure Sci, Richland, WA 99352 USA. [Teeguarden, Justin G.] Oregon State Univ, Dept Environm & Mol Toxicol, Corvallis, OR 97331 USA. [Twaddle, Nathan C.; Churchwell, Mona I.; Doerge, Daniel R.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Teeguarden, JG (reprint author), 902 Battelle Blvd, Richland, WA 99352 USA. EM justin.teeguarden@pnl.gov; nathan.twaddle@fda.hhs.gov; mona.churchwell@fda.hhs.gov; daniel.doerge@fda.hhs.gov FU American Chemistry Council, BPA Global Polycarbonate Group; U.S. Food and Drug Administration FX Funding for this research was provided by a grant from the American Chemistry Council, BPA Global Polycarbonate Group. ACC and member affiliates did not contribute to the study design, data analysis, reporting, or writing and review of the manuscript. The NUR laboratory activities were supported by U.S. Food and Drug Administration funding. The views expressed in this manuscript do not necessarily reflect those of the U.S. Food and Drug Administration. NR 123 TC 3 Z9 3 U1 8 U2 19 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 JUN PY 2016 VL 92 BP 129 EP 142 DI 10.1016/j.fct.2016.03.023 PG 14 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA DN1CR UT WOS:000376804400014 PM 27038865 ER PT J AU Doerge, DR Woodling, KA Churchwell, MI Fleck, SC Helferich, WG AF Doerge, Daniel R. Woodling, Kellie A. Churchwell, Mona I. Fleck, Stefanie C. Helferich, William G. TI Pharmacokinetics of isoflavones from soy infant formula in neonatal and adult rhesus monkeys SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Soy; Genistein; Daidzein; Rhesus monkey; Pharmacokinetics; Mass spectrometry; Neonatal ID SPRAGUE-DAWLEY RATS; ABSOLUTE BIOAVAILABILITY; POSTMENOPAUSAL WOMEN; MARMOSET MONKEYS; BREAST-CANCER; BALB/C MICE; GENISTEIN; DIETARY; GLUCURONIDATION; METABOLISM AB Consumption of soy infant formula represents a unique exposure scenario in which developing children ingest a mixture of endocrine-active isoflavones along with a substantial portion of daily nutrition. Genistein and daidzein were administered as glucoside conjugates to neonatal rhesus monkeys in a fortified commercial soy formula at 5, 35, and 70 days after birth. A single gavage dosing with 10 mg/kg bw genistein and 6 mg/kg bw daidzein was chosen to represent the upper range of typical daily consumption and to facilitate complete pharmacokinetic measurements for aglycone and total isoflavones and equol. Adult monkeys were also gavaged with the same formula solution at 2.8 and 1.6 mg/kg bw genistein and daidzein, respectively, and by IV injection with isoflavone aglycones (5.2 and 3.2 mg/kg bw, respectively) to determine absolute bioavailability. Significant differences in internal exposure were observed between neonatal and adult monkeys, with higher values for dose-adjusted AUC and C-max of the active aglycone isoflavones in neonates. The magnitude and frequency of equol production by the gut microbiome were also significantly greater in adults. These findings are consistent with immaturity of metabolic and/or physiological systems in developing non-human primates that reduces total clearance of soy isoflavones from the body. Published by Elsevier Ltd. C1 [Doerge, Daniel R.; Woodling, Kellie A.; Churchwell, Mona I.; Fleck, Stefanie C.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Helferich, William G.] Univ Illinois, Dept Food Sci & Human Nutr, Urbana, IL 61810 USA. RP Doerge, DR (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM daniel.doerge@fda.hhs.gov FU NIH from National Institute of Aging [P01AG024387]; Office of Dietary Supplements; National Cancer Institute from the National Center for Complementary and Integrative Health [P50AT006268]; National Cancer Institute; German Academic Exchange Service (DAAD); Oak Ridge Institute for Science and Education (ORISE) FX This research was supported in part by NIH Grant Numbers P01AG024387 from National Institute of Aging, the Office of Dietary Supplements, and the National Cancer Institute and P50AT006268 from the National Center for Complementary and Integrative Health, the Office of Dietary Supplements, and the National Cancer Institute (to WGH and DRD). SCF was supported by a fellowship within the postdoctoral program of the German Academic Exchange Service (DAAD). KAW and SCF were supported by the Oak Ridge Institute for Science and Education (ORISE), administered through an interagency agreement between the US. Department of Energy and the U.S. Food and Drug Administration. The assistance of Melissa Ferguson (Alpha Genesis Inc.) in coordinating the monkey procedures is gratefully acknowledged. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the U.S. Food and Drug Administration. The authors have no conflicts of interest to report. NR 49 TC 0 Z9 0 U1 7 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 JUN PY 2016 VL 92 BP 165 EP 176 DI 10.1016/j.fct.2016.04.005 PG 12 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA DN1CR UT WOS:000376804400017 PM 27084109 ER PT J AU Ammann, JR Lovejoy, KS Walters, MJ Holman, MR AF Ammann, Jeffrey R. Lovejoy, Katherine S. Walters, Matthew J. Holman, Matthew R. TI A Survey of N '-Nitrosonornicotine (NNN) and Total Water Content in Select Smokeless Tobacco Products Purchased in the United States in 2015 SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE N '-nitrosonornicotine (NNN); water content; smokeless tobacco products; LC-MS/MS; surveillance ID UN-IONIZED NICOTINE; CHEMICAL-CHARACTERIZATION; UNPROTONATED NICOTINE; CIGARETTE-SMOKING; MOIST SNUFF; NITROSAMINES; PH; SURVEILLANCE; PREVALENCE; ADULTS AB This investigation provides an updated survey measuring the levels of N'-nitrosonornicotine (NNN) and water content of a select number of smokeless tobacco products sold in the United States in 2015. A total of 34 smokeless tobacco products were collected and analyzed for NNN and water content using LC-MS/MS and GC-TCD, respectively. Smokeless tobacco products were chosen to obtain a representative sample of the different types of products on the U.S. market. These smokeless products represent 12 of the 25 top-selling smokeless tobacco products according to 2013 Nielsen net sales data while five of the smokeless tobacco products are of lower selling smokeless tobacco products. The NNN levels and the water content of the smokeless tobacco products were determined and compared to previous studies. Although the range of NNN levels found was broad for the examined smokeless tobacco products (0.64-12.0 mu g/g dry weight), dry snuff had the highest levels of NNN observed (>5 mu g/g dry weight). We observed a general decrease in NNN levels for the same six moist snuff products that were analyzed in 2004 compared to our current 2015 study. The water content of the smokeless tobacco products surveyed ranged from 3.92 to 54.8%. C1 [Ammann, Jeffrey R.; Lovejoy, Katherine S.; Walters, Matthew J.; Holman, Matthew R.] US FDA, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Walters, MJ (reprint author), US FDA, Ctr Tobacco Prod, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM matthew.walters@fda.hhs.gov FU Center for Tobacco Products, U.S. Food and Drug Administration FX The study was funded by the Center for Tobacco Products, U.S. Food and Drug Administration. NR 28 TC 0 Z9 0 U1 5 U2 5 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 JUN 1 PY 2016 VL 64 IS 21 BP 4400 EP 4406 DI 10.1021/acs.jafc.6b00922 PG 7 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA DN5ZQ UT WOS:000377150800025 PM 27192054 ER PT J AU Devarakonda, S Dibaji, SAR Hariharan, P Myers, MR Banerjee, RK AF Devarakonda, Surendra Dibaji, Seyed Ahmad Reza Hariharan, Prasanna Myers, Matthew R. Banerjee, Rupak K. TI Characterization of Focal Location During High-Intensity Focused Ultrasound Ablation in a Tissue Phantom Using Remote Thermocouple Arrays SO JOURNAL OF MEDICAL DEVICES-TRANSACTIONS OF THE ASME LA English DT Article; Proceedings Paper CT University-of-Minnesota's Design of Medical Devices (DMD) Conference CY APR 11-14, 2016 CL Minneapolis, MN SP Univ Minnesota C1 [Devarakonda, Surendra; Dibaji, Seyed Ahmad Reza; Banerjee, Rupak K.] Univ Cincinnati, Dept Mech & Mat Engn, Coll Engn & Appl Sci, Cincinnati, OH 45221 USA. [Hariharan, Prasanna; Myers, Matthew R.] US FDA, Div Solid & Fluid Mech, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Devarakonda, S (reprint author), Univ Cincinnati, Dept Mech & Mat Engn, Coll Engn & Appl Sci, Cincinnati, OH 45221 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 1932-6181 EI 1932-619X J9 J MED DEVICES JI J. Med. Devices PD JUN PY 2016 VL 10 IS 2 AR 020949 DI 10.1115/1.4033243 PG 2 WC Engineering, Biomedical SC Engineering GA DN2ZG UT WOS:000376931100050 ER PT J AU Vesnovsky, O Zhu, L Casamento, JP Grossman, LW Topoleski, LDT AF Vesnovsky, Oleg Zhu, Liang Casamento, Jon P. Grossman, Laurence W. Topoleski, L. D. Timmie TI Evaluating Accuracy of Digital Thermometers Using a Tissue Phantom Mimicking Normal and Fever Environments SO JOURNAL OF MEDICAL DEVICES-TRANSACTIONS OF THE ASME LA English DT Article; Proceedings Paper CT University-of-Minnesota's Design of Medical Devices (DMD) Conference CY APR 11-14, 2016 CL Minneapolis, MN SP Univ Minnesota C1 [Vesnovsky, Oleg; Casamento, Jon P.; Grossman, Laurence W.; Topoleski, L. D. Timmie] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Zhu, Liang; Topoleski, L. D. Timmie] Univ Maryland Baltimore Cty, Dept Mech Engn, Baltimore, MD 21250 USA. RP Vesnovsky, O (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 1932-6181 EI 1932-619X J9 J MED DEVICES JI J. Med. Devices PD JUN PY 2016 VL 10 IS 2 AR 020913 DI 10.1115/1.4033204 PG 3 WC Engineering, Biomedical SC Engineering GA DN2ZG UT WOS:000376931100014 ER PT J AU Spelic, D Hilohi, M Farris, K Eicholtz, G Elee, J Ortego, J Kaus, G AF Spelic, David Hilohi, Mike Farris, Karen Eicholtz, George Elee, Jennifer Ortego, Josephine Kaus, Gary TI The Nationwide Evaluation of X-Ray Trends, Part I: More Than 40 Years of Surveying the US Radiology Practice SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material ID RADIOGRAPHY; CHEST C1 [Spelic, David; Hilohi, Mike] US FDA, Silver Spring, MD USA. [Farris, Karen] Massachusetts Dept Publ Hlth, Boston, MA 02111 USA. [Eicholtz, George] Idaho Dept Hlth, Boise, ID USA. [Elee, Jennifer] Louisiana Dept Environm Qual, Baton Rouge, LA USA. [Ortego, Josephine] Los Angeles Cty Dept Publ Hlth, Los Angeles, CA USA. [Kaus, Gary] South Dakota Dept Hlth, Faulkton, SD USA. RP Spelic, D (reprint author), US FDA, Ctr Devices & Radiol Hlth, WO 66-4534 OIR DRH,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM david.spelic@fda.hhs.gov NR 8 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD JUN PY 2016 VL 13 IS 6 BP 713 EP 715 DI 10.1016/j.jacr.2016.03.013 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DN4QY UT WOS:000377053500023 PM 27262057 ER PT J AU Ahlberg, E Amberg, A Beilke, LD Bower, D Cross, KP Custer, L Ford, KA Van Gompel, J Harvey, J Honma, M Jolly, R Joossens, E Kemper, RA Kenyon, M Kruhlak, N Kuhnke, L Leavitt, P Naven, R Neilan, C Quigley, DP Shuey, D Spirkl, HP Stavitskaya, L Teasdale, A White, A Wichard, J Zwickl, C Myatt, GJ AF Ahlberg, Ernst Amberg, Alexander Beilke, Lisa D. Bower, David Cross, Kevin P. Custer, Laura Ford, Kevin A. Van Gompel, Jacky Harvey, James Honma, Masamitsu Jolly, Robert Joossens, Elisabeth Kemper, Raymond A. Kenyon, Michelle Kruhlak, Naomi Kuhnke, Lara Leavitt, Penny Naven, Russell Neilan, Claire Quigley, Donald P. Shuey, Dana Spirkl, Hans-Peter Stavitskaya, Lidiya Teasdale, Andrew White, Angela Wichard, Joerg Zwickl, Craig Myatt, Glenn J. TI Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: A case study using aromatic amine mutagenicity SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE ICH M7; Pharmaceutical impurities; Mutagenicity; (Q)SAR; Aromatic amines; SAR fingerprint ID DISCRIMINATING STRUCTURAL FEATURES; BUILDING-BLOCKS; NITRENIUM IONS; DNA-BINDING; AMES TEST; CARCINOGENS; POTENCY; MODELS; QSAR; STABILITIES AB Statistical-based and expert rule-based models built using public domain mutagenicity knowledge and data are routinely used for computational (OJSAR assessments of pharmaceutical impurities in line with the approach recommended in the ICH M7 guideline. Knowledge from proprietary corporate mutagenicity databases could be used to increase the predictive performance for selected chemical classes as well as expand the applicability domain of these (Q)SAR models. This paper outlines a mechanism for sharing knowledge without the release of proprietary data. Primary aromatic amine mutagenicity was selected as a case study because this chemical class is often encountered in pharmaceutical impurity analysis and mutagenicity of aromatic amines is currently difficult to predict. As part of this analysis, a series of aromatic amine substructures were defined and the number of mutagenic and non-mutagenic examples for each chemical substructure calculated across a series of public and proprietary mutagenicity databases. This information was pooled across all sources to identify structural classes that activate or deactivate aromatic amine mutagenicity. This structure activity knowledge, in combination with newly released primary aromatic amine data, was incorporated into Leadscope's expert rule-based and statistical-based (Q)SAR models where increased predictive performance was demonstrated. (C) 2016 Elsevier Inc. All rights reserved. C1 [Ahlberg, Ernst] AstraZeneca, Molndal, Sweden. [Amberg, Alexander] Sanofi Aventis Deutschland GmbH, Frankfurt, Germany. [Beilke, Lisa D.] Toxicol Solut, San Diego, CA USA. [Bower, David; Cross, Kevin P.; Myatt, Glenn J.] Leadscope, Columbus, OH USA. [Custer, Laura] Bristol Myers Squibb Co, New Brunswick, NJ USA. [Ford, Kevin A.] Genentech Inc, San Francisco, CA USA. [Van Gompel, Jacky] Janssen Res & Dev, Beerse, Belgium. [Harvey, James; White, Angela] GlaxoSmithKline, Ware, Herts, England. [Honma, Masamitsu] Natl Inst Hlth Sci, Tokyo, Japan. [Jolly, Robert; Zwickl, Craig] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Joossens, Elisabeth] European Commiss, Joint Res Ctr, Ispra, Italy. [Kemper, Raymond A.] Vertex, Boston, MA USA. [Kenyon, Michelle] Pfizer, Groton, CT USA. [Kruhlak, Naomi; Naven, Russell] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Kuhnke, Lara; Wichard, Joerg] Bayer HealthCare, Berlin, Germany. [Neilan, Claire; Shuey, Dana] Incyte Corp, Wilmington, DE USA. [Teasdale, Andrew] AstraZeneca, Macclesfield, Cheshire, England. [Naven, Russell] Takeda, Cambridge, MA USA. [Neilan, Claire] Gilead, Foster City, CA USA. RP Myatt, GJ (reprint author), Leadscope Inc, 1393 Dublin Rd, Columbus, OH 43215 USA. EM gmyatt@leadscope.com NR 39 TC 3 Z9 3 U1 2 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD JUN PY 2016 VL 77 BP 1 EP 12 DI 10.1016/j.yrtph.2016.02.003 PG 12 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA DN1FY UT WOS:000376812900001 PM 26879463 ER PT J AU Amberg, A Beilke, L Bercu, J Bower, D Brigo, A Cross, KP Custer, L Dobo, K Dowdy, E Ford, KA Glowienke, S Van Gompel, J Harvey, J Hasselgren, C Honma, M Jolly, R Kemper, R Kenyon, M Kruhlak, N Leavitt, P Miller, S Muster, W Nicolette, J Plaper, A Powley, M Quigley, DP Reddy, MV Spirkl, HP Stavitskaya, L Teasdale, A Weiner, S Welch, DS White, A Wichard, J Myatt, GJ AF Amberg, Alexander Beilke, Lisa Bercu, Joel Bower, Dave Brigo, Alessandro Cross, Kevin P. Custer, Laura Dobo, Krista Dowdy, Eric Ford, Kevin A. Glowienke, Susanne Van Gompel, Jacky Harvey, James Hasselgren, Catrin Honma, Masamitsu Jolly, Robert Kemper, Raymond Kenyon, Michelle Kruhlak, Naomi Leavitt, Penny Miller, Scott Muster, Wolfgang Nicolette, John Plaper, Andreja Powley, Mark Quigley, Donald P. Reddy, M. Vijayaraj Spirkl, Hans-Peter Stavitskaya, Lidiya Teasdale, Andrew Weiner, Sandy Welch, Dennie S. White, Angela Wichard, Joerg Myatt, Glenn J. TI Principles and procedures for implementation of ICH M7 recommended (Q)SAR analyses SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE ICH M7; Impurities; (Q)SAR; Mutagenic impurities; Ames test; Toxicity databases; Expert review ID POTENTIALLY MUTAGENIC IMPURITIES; CHEMICAL RELATIONAL DATABASES; IN-SILICO SYSTEMS; EXPERT KNOWLEDGE; SALMONELLA ASSAY; TOXICOLOGY; CARCINOGENICITY; GENOTOXICITY; STRATEGIES; PREDICTION AB The ICH M7 guideline describes a consistent approach to identify, categorize, and control DNA reactive, mutagenic, impurities in pharmaceutical products to limit the potential carcinogenic risk related to such impurities. This paper outlines a series of principles and procedures to consider when generating (Q)SAR assessments aligned with the ICH M7 guideline to be included in a regulatory submission. In the absence of adequate experimental data, the results from two complementary (Q)SAR methodologies may be combined to support an initial hazard classification. This may be followed by an assessment of additional information that serves as the basis for an expert review to support or refute the predictions. This paper elucidates scenarios where additional expert knowledge may be beneficial, what such an expert review may contain, and how the results and accompanying considerations may be documented. Furthermore, the use of these principles and procedures to yield a consistent and robust (Q)SAR-based argument to support impurity qualification for regulatory purposes is described in this manuscript. (C) 2016 The Authors. Published by Elsevier Inc. C1 [Amberg, Alexander; Spirkl, Hans-Peter] Sanofi Aventis Deutschland GmbH, Frankfurt, Germany. [Beilke, Lisa] Toxicol Solut, San Diego, CA USA. [Bercu, Joel] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA. [Bower, Dave; Cross, Kevin P.; Hasselgren, Catrin; Miller, Scott; Quigley, Donald P.; Myatt, Glenn J.] Leadscope Inc, 1393 Dublin Rd, Columbus, OH 43215 USA. [Brigo, Alessandro; Muster, Wolfgang] Roche Innovat Ctr, Roche Pharmaceut Res & Early Dev, Pharmaceut Sci, Basel, Switzerland. [Custer, Laura; Leavitt, Penny] Bristol Myers Squibb, New Brunswick, NJ USA. [Dobo, Krista; Kenyon, Michelle] Pfizer, Groton, CT USA. [Ford, Kevin A.] Genentech Inc, San Francisco, CA USA. [Glowienke, Susanne] Novartis Inst Biomed Res, Basel, Switzerland. [Van Gompel, Jacky] Janssen, Beerse, Belgium. [Harvey, James; White, Angela] GlaxoSmithKline, Ware, Herts, England. [Honma, Masamitsu] Natl Inst Hlth Sci, Tokyo, Japan. [Jolly, Robert] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Kemper, Raymond] Vertex, Boston, MA USA. [Kruhlak, Naomi; Powley, Mark; Stavitskaya, Lidiya] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Nicolette, John; Welch, Dennie S.] AbbVie Inc, N Chicago, IL USA. [Plaper, Andreja] KRKA, Novo Mesto, Slovenia. [Reddy, M. Vijayaraj] Merck Res Labs, West Point, PA USA. [Teasdale, Andrew] AstraZeneca, Macclesfield, Cheshire, England. [Weiner, Sandy] Janssen Res Fdn, Spring House, PA 19477 USA. [Wichard, Joerg] Bayer HealthCare, Berlin, Germany. RP Myatt, GJ (reprint author), Leadscope Inc, 1393 Dublin Rd, Columbus, OH 43215 USA. EM gmyatt@leadscope.com NR 46 TC 0 Z9 0 U1 2 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD JUN PY 2016 VL 77 BP 13 EP 24 DI 10.1016/j.yrtph.2016.02.004 PG 12 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA DN1FY UT WOS:000376812900002 PM 26877192 ER PT J AU Solomon, HM Makris, SL Alsaid, H Bermudez, O Beyer, BK Chen, A Chen, CL Chen, Z Chmielewski, G DeLise, AM de Schaepdrijver, L Dogdas, B French, J Harrouk, W Helfgott, J Henkelman, RM Hesterman, J Hew, KW Hoberman, A Lo, CW McDougal, A Minck, DR Scott, L Stewart, J Sutherland, V Tatiparthi, AK Winkelmann, CT Wise, LD Wood, SL Ying, XY AF Solomon, Howard M. Makris, Susan L. Alsaid, Hasan Bermudez, Oscar Beyer, Bruce K. Chen, Antong Chen, Connie L. Chen, Zhou Chmielewski, Gary DeLise, Anthony M. de Schaepdrijver, Luc Dogdas, Belma French, Julian Harrouk, Wafa Helfgott, Jonathan Henkelman, R. Mark Hesterman, Jacob Hew, Kok-Wah Hoberman, Alan Lo, Cecilia W. McDougal, Andrew Minck, Daniel R. Scott, Lelia Stewart, Jane Sutherland, Vicki Tatiparthi, Arun K. Winkelmann, Christopher T. Wise, L. David Wood, Sandra L. Ying, Xiaoyou TI Micro-Cr imaging: Developing criteria for examining fetal skeletons in regulatory developmental toxicology studies - A workshop report SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Concordance criteria; Developmental toxicology; Imaging; Micro-CT; Skeletal evaluation; GLP validation ID ALIZARIN RED S; CT; RABBITS; MOUSE; RATS AB During the past two decades the use and refinements of imaging modalities have markedly increased making it possible to image embryos and fetuses used in pivotal nonclinical studies submitted to regulatory agencies. Implementing these technologies into the Good Laboratory Practice environment requires rigorous testing, validation, and documentation to ensure the reproducibility of data. A workshop on current practices and regulatory requirements was held with the goal of defining minimal criteria for the proper implementation of these technologies and subsequent submission to regulatory agencies. Micro-computed tomography (micro-CT) is especially well suited for high-throughput evaluations, and is gaining popularity to evaluate fetal skeletons to assess the potential developmental toxicity of test agents. This workshop was convened to help scientists in the developmental toxicology field understand and apply micro-CT technology to nonclinical toxicology studies and facilitate the regulatory acceptance of imaging data. Presentations and workshop discussions covered: (1) principles of micro-CT fetal imaging; (2) concordance of findings with conventional skeletal evaluations; and (3) regulatory requirements for validating the system. Establishing these requirements for micro-CT examination can provide a path forward for laboratories considering implementing this technology and provide regulatory agencies with a basis to consider the acceptability of data generated via this technology. Published by Elsevier Inc. C1 [Solomon, Howard M.; Alsaid, Hasan] GlaxoSmithKline, King Of Prussia, PA USA. [Makris, Susan L.] US EPA, Natl Ctr Environm Assessment, Washington, DC 20460 USA. [Bermudez, Oscar; Chen, Connie L.] ILSI Hlth & Environm Sci Inst, Washington, DC USA. [Beyer, Bruce K.] Sanofi US Inc, Bridgewater, NJ USA. [Chen, Antong; Dogdas, Belma] Merck Res Labs, Kenilworth, NJ USA. [Chen, Zhou; Chmielewski, Gary; Harrouk, Wafa; McDougal, Andrew; Minck, Daniel R.] US FDA, Ctr Drug Evaluat & Res, Off New Drugs, Silver Spring, MD USA. [Tatiparthi, Arun K.] Covance Labs, Greenfield, IN USA. [DeLise, Anthony M.] Nova Pharmaceut Corp, E Hanover, NJ USA. [de Schaepdrijver, Luc] Janssen R&D, Beerse, Belgium. [French, Julian] Morphol Consulting Ltd, Stoke On Trent, Staffs, England. [Helfgott, Jonathan] Stage 2 Innovat, Framingham, MI USA. [Henkelman, R. Mark] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Hesterman, Jacob] InviCRO, Boston, MA USA. [Hew, Kok-Wah] Takeda Pharmaceut Co, Deerfield, IL USA. [Hoberman, Alan; Scott, Lelia] Charles River Labs, Preclin Serv, Horsham, PA USA. [Lo, Cecilia W.] Univ Pittsburgh, Pittsburgh, PA USA. [Stewart, Jane] ApconiX, Macclesfield, Cheshire, England. [Sutherland, Vicki] Natl Toxicol Program NIEHS, Res Triangle Pk, NC USA. [Winkelmann, Christopher T.] Pfizer Worldwide Res & Dev, La Jolla, CA USA. [Wood, Sandra L.] Merck Res Labs, Upper Gwynedd, PA USA. [Ying, Xiaoyou] Sanofi US Inc, Cambridge, MA USA. RP Makris, SL (reprint author), 1200 Penn Ave NW,Mailcode 8623P, Washington, DC 20460 USA. EM makris.susan@epa.gov FU HESI's corporate sponsors FX The authors gratefully acknowledge the contributions of the many participants and speakers who supported this workshop with their useful presentations and discussions. The workshop that forms the basis of this publication was primarily supported by in kind contributions of time, expertise, and experimental effort from public and private sector participants from the HESI DART Technical Committee. These contributions are supplemented by direct funding (that largely supports program infrastructure and management) that was provided by HESI's corporate sponsors. A list of supporting organizations (public and private) is available at www.hesiglobal.org. Workshop presentations can also be found online. NR 35 TC 0 Z9 0 U1 2 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD JUN PY 2016 VL 77 BP 100 EP 108 DI 10.1016/j.yrtph.2016.02.018 PG 9 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA DN1FY UT WOS:000376812900012 PM 26930635 ER PT J AU Malik, M Johannesen, L Hnatkova, K Stockbridge, N AF Malik, Marek Johannesen, Lars Hnatkova, Katerina Stockbridge, Norman TI Universal Correction for QT/RR Hysteresis SO DRUG SAFETY LA English DT Article ID SAFETY RESEARCH CONSORTIUM; QT INTERVAL; HEALTHY-SUBJECTS; THOROUGH QT/QTC; DEPENDENCE AB Introduction Clinical pharmacology QT/QTc studies can be smaller if they more efficiently use the data generated. Objective The aim was to use large sets of electrocardiograms (ECGs) deposited at the US Food and Drug Administration to investigate the implications of heart rate measurement on the accuracy of QTc data. Methods Using the data of 80 thorough QT studies, we investigated whether placing study subjects in supine positions during short-term time points stabilizes heart rate (part I, based on 73 studies with 747,912 measured ECGs in 6786 healthy subjects) and whether heart rate measurements different from RR intervals captured simultaneously with QT intervals decrease QTc variability (part II, based on seven studies with 897,570 ECG measurements in 751 healthy subjects). Results In the part I data, when subjects were placed in supine undisturbed positions, heart rate instability (max-min of repeatedly measured heart rates within the same study time point) exceeding 5 beats per minute (bpm) was observed 40 % of the time and exceeded 10 bpm 10 % of the time. In the part II data, even when including QT measurements preceded by variable heart rates, correction of QT durations for RR interval values derived through a simple QT/RR hysteresis model with 95 % adaptation in 120 s led to mean intra-subject standard deviation of QTc (Fridericia formula) of only 7.14 +/- A 1.98 and 6.38 +/- A 1.50 ms in women and men, respectively. Conclusion The QT/RR hysteresis model with 95 % adaptation in 120 s is universally applicable to healthy subjects, providing small QTc variability. Supine positions do not generally stabilize heart rates in healthy subjects. Universally applicable QT/RR hysteresis correction allows clinical QT/QTc studies to include variable heart rate episodes in the time points. C1 [Malik, Marek; Hnatkova, Katerina] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Dovehouse St, London SW3 6LY, England. [Johannesen, Lars] US FDA, Div Biomed Phys, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Johannesen, Lars] Karolinska Inst, Dept Clin Physiol, S-10401 Stockholm, Sweden. [Johannesen, Lars] Karolinska Univ Hosp, Stockholm, Sweden. [Stockbridge, Norman] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Malik, M (reprint author), Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Dovehouse St, London SW3 6LY, England. EM marek.malik@btinternet.com FU British Heart Foundation grants [PG/12/77/29857, PG/13/54/30358] FX The data analysis reported here was supported in part by British Heart Foundation grants PG/12/77/29857 and PG/13/54/30358. NR 20 TC 1 Z9 1 U1 1 U2 1 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0114-5916 EI 1179-1942 J9 DRUG SAFETY JI Drug Saf. PD JUN PY 2016 VL 39 IS 6 BP 577 EP 588 DI 10.1007/s40264-016-0406-0 PG 12 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA DM5UO UT WOS:000376415900008 PM 26968541 ER PT J AU Wilson, RA Yanes, EG Kemppainen, RJ AF Wilson, Robert A. Yanes, Enrique G. Kemppainen, Robert J. TI Iodine speciation in dog foods and treats by high performance liquid chromatography with inductively coupled plasma mass spectrometry detection SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article ID THYROID-HORMONE; ICP-MS; THYROTOXICOSIS; SAMPLES; HYPERTHYROIDISM; CONSUMPTION; IODOTHYRONINES; IODOTYROSINES; THYROGLOBULIN; EXTRACTION AB An analytical method for determination of the iodine species 3-monoiodotyrosine (MIT), iodide, 3,5-diiodotyrosine (DIT), 3,5-diiodothyronine (3, 5-T2),3,5,3'-triiodothyronine (T3), and thyroxine (T4) in dog foods and treats is reported. Iodine speciation was carried out using a HPLC method capable of both anion exchange and reversed-phase retention coupled with inductively coupled plasma mass spectrometry detection (LC-ICP-MS). The method was evaluated by the analysis of the iodine species concentrations in twelve dog foods and treats following enzymatic digestion. The concentrations of MIT, iodide, DIT, T3, and T4 in the samples ranged from 0.64-59.5 mu g/g, 0.86-4.05 mu g/g, 3,000 loci from the Maryland ST8 strains. eBURST analysis comparing these strains with strains of other STs available at the V. parahaemolyticus MLST website showed that the Maryland ST8 strains belonged to a clonal complex endemic to Asia. This indicates that the ST8 isolates from clinical and oyster sources were likely not endemic to Maryland. Finally, this study demonstrates the utility of whole-genome sequencing (WGS) and associated analyses for source-tracking investigations. C1 [Haendiges, Julie; Myers, Robert A.; Mitchell, Clifford S.; Butler, Erin] Dept Hlth & Mental Hyg, Baltimore, MD USA. [Jones, Jessica] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL USA. [Toro, Magaly] Univ Chile, Inst Nutr & Tecnol Alimentos, Santiago, Chile. [Gonzalez-Escalona, Narjol] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Gonzalez-Escalona, N (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. EM narjol.gonzalez-escalona@fda.hhs.gov RI Toro, Magaly/F-6525-2011 OI Toro, Magaly/0000-0002-6280-2215 FU FDA Foods Program intramural funds FX This project was supported by FDA Foods Program intramural funds. NR 36 TC 4 Z9 4 U1 5 U2 8 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 JUN PY 2016 VL 82 IS 11 BP 3208 EP 3216 DI 10.1128/AEM.00096-16 PG 9 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DM2EL UT WOS:000376159400006 PM 26994080 ER PT J AU Patel, IR Gangiredla, J Lacher, DW Mammel, MK Jackson, SA Lampel, KA Elkins, CA AF Patel, Isha R. Gangiredla, Jayanthi Lacher, David W. Mammel, Mark K. Jackson, Scott A. Lampel, Keith A. Elkins, Christopher A. TI FDA Escherichia coli Identification (FDA-ECID) Microarray: a Pangenome Molecular Toolbox for Serotyping, Virulence Profiling, Molecular Epidemiology, and Phylogeny SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; ALTERNATIVE METHODS; GENOMIC DIVERSITY; UNITED STATES; FRESH PRODUCE; OUTBREAK; SEQUENCE; STRAINS; DNA; PATHOGENS AB Most Escherichia coli strains are nonpathogenic. However, for clinical diagnosis and food safety analysis, current identification methods for pathogenic E. coli either are time-consuming and/or provide limited information. Here, we utilized a custom DNA microarray with informative genetic features extracted from 368 sequence sets for rapid and high-throughput pathogen identification. The FDA Escherichia coli Identification (FDA-ECID) platform contains three sets of molecularly informative features that together stratify strain identification and relatedness. First, 53 known flagellin alleles, 103 alleles of wzx and wzy, and 5 alleles of wzm provide molecular serotyping utility. Second, 41,932 probe sets representing the pan-genome of E. coli provide strain-level gene content information. Third, approximately 125,000 single nucleotide polymorphisms (SNPs) of available whole-genome sequences (WGS) were distilled to 9,984 SNPs capable of recapitulating the E. coli phylogeny. We analyzed 103 diverse E. coli strains with available WGS data, including those associated with past foodborne illnesses, to determine robustness and accuracy. The array was able to accurately identify the molecular O and H serotypes, potentially correcting serological failures and providing better resolution for H-nontypeable/nonmotile phenotypes. In addition, molecular risk assessment was possible with key virulence marker identifications. Epidemiologically, each strain had a unique comparative genomic fingerprint that was extended to an additional 507 food and clinical isolates. Finally, a 99.7% phylogenetic concordance was established between microarray analysis and WGS using SNP-level data for advanced genome typing. Our study demonstrates FDA-ECID as a powerful tool for epidemiology and molecular risk assessment with the capacity to profile the global landscape and diversity of E. coli. IMPORTANCE This study describes a robust, state-of-the-art platform developed from available whole-genome sequences of E. coli and Shigella spp. by distilling useful signatures for epidemiology and molecular risk assessment into one assay. The FDA-ECID microarray contains features that enable comprehensive molecular serotyping and virulence profiling along with genome-scale genotyping and SNP analysis. Hence, it is a molecular toolbox that stratifies strain identification and pathogenic potential in the contexts of epidemiology and phylogeny. We applied this tool to strains from food, environmental, and clinical sources, resulting in significantly greater phylogenetic and strain-specific resolution than previously reported for available typing methods. C1 [Patel, Isha R.; Gangiredla, Jayanthi; Lacher, David W.; Mammel, Mark K.; Jackson, Scott A.; Lampel, Keith A.; Elkins, Christopher A.] US FDA, Div Mol Biol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD USA. [Jackson, Scott A.] NIST, Gaithersburg, MD 20899 USA. RP Elkins, CA (reprint author), US FDA, Div Mol Biol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD USA. EM chris.elkins@fda.hhs.gov NR 48 TC 2 Z9 2 U1 5 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD JUN PY 2016 VL 82 IS 11 BP 3384 EP 3394 DI 10.1128/AEM.04077-15 PG 11 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DM2EL UT WOS:000376159400022 PM 27037122 ER PT J AU Green, DJ Mummaneni, P Kim, IW Oh, JM Pacanowski, M Burckart, GJ AF Green, D. J. Mummaneni, P. Kim, I. W. Oh, J. M. Pacanowski, M. Burckart, G. J. TI Pharmacogenomic Information in FDA-Approved Drug Labels: Application to Pediatric Patients SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID THIOPURINE METHYLTRANSFERASE ACTIVITY; DEVELOPMENTAL PHARMACOLOGY; DEVELOPMENT PROGRAMS; TPMT GENOTYPE; CHILDREN; ONTOGENY; CODEINE; POPULATION; INFANTS; GLUCURONIDATION AB Pharmacogenomic (PGx) information is increasingly being incorporated into US Food and Drug Administration-approved drug labels. We reviewed the data source (adults vs. pediatrics) of PGx information in approved drug labels and assessed the suitability of applying adult-derived PGx information and related prescribing recommendations to the care of pediatric patients. We identified 65 drugs with labels containing PGx information and that have also been evaluated in children and found that in the majority of cases (56/65, 86%), the PGx information described was derived from adult studies. The application of PGx information from adults to pediatrics was deemed suitable for 71.4% (n = 40) of the drugs and unclear for 28.6% (n = 16). An ontogeny effect, limited or conflicting data regarding ontogeny of the genetic biomarker, or a difference in the pathophysiology or progression of the adult vs. pediatric disease were the primary reasons for deeming direct application from adults to pediatrics unclear. C1 [Green, D. J.; Burckart, G. J.] US FDA, Pediat Clin Pharmacol Staff, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Mummaneni, P.; Pacanowski, M.] US FDA, Genom & Targeted Therapy Grp, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Kim, I. W.; Oh, J. M.] Seoul Natl Univ, Sch Pharm, Seoul, South Korea. [Kim, I. W.; Oh, J. M.] Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul, South Korea. RP Burckart, GJ (reprint author), US FDA, Pediat Clin Pharmacol Staff, Off Clin Pharmacol, Off Translat Sci,Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM gilbert.burckart@fda.hhs.gov NR 43 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JUN PY 2016 VL 99 IS 6 BP 622 EP 632 DI 10.1002/cpt.330 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DM3KZ UT WOS:000376246600021 PM 26693845 ER PT J AU Ma, LL He, L Wang, L Li, L Lin, XN Pan, GY AF Ma, Leilei He, Lei Wang, Le Li, Li Lin, Xuena Pan, Guoyu TI Altered Expression of Transporters, its Potential Mechanisms and Influences in the Liver of Rodent Models Associated with Diabetes Mellitus and Obesity SO EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS LA English DT Review ID PREGNANE-X-RECEPTOR; ORGANIC ANION TRANSPORTER; CANCER RESISTANCE PROTEIN; HEPATOCYTE NUCLEAR FACTOR-1-ALPHA; CONSTITUTIVE ANDROSTANE RECEPTOR; BLOOD-BRAIN-BARRIER; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; ACTIVATED RECEPTOR; DOWN-REGULATION AB Diabetes mellitus is becoming an increasingly prevalent disease that concerns patients and healthcare professionals worldwide. Among many anti-diabetic agents in clinical uses, numerous reports are available on their altered pharmacokinetics because of changes in the expression of drug transporters and metabolic enzymes under diabetic states. These changes may affect the safety and efficacy of therapeutic agents and/or drug-drug interaction with co-administered agents. Therefore, the changes in transporter expression should be identified, and the underlying mechanisms should be clarified. This review summarizes the progress of recent studies on the alterations in important uptake and efflux transporters in liver of diabetic animals and their regulatory pathways. C1 [Ma, Leilei; Wang, Le; Pan, Guoyu] Chinese Acad Sci, Shanghai Inst Mat Med, Haike Rd 501, Shanghai 201203, Peoples R China. [He, Lei] InCROM CHINA, Quyang Rd 972, Shanghai 200437, Peoples R China. [Li, Li] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, 10903 New Hampshire Ave,Bldg 51,Room 3172, Silver Spring, MD 20993 USA. [Lin, Xuena] Novartis Inst Biomed Res, Metab & Pharmacokinet, Cambridge, MA 02139 USA. RP Pan, GY (reprint author), Chinese Acad Sci, Shanghai Inst Mat Med, Haike Rd 501, Shanghai 201203, Peoples R China. EM guoyupan@hotmail.com FU National Science Foundation of China [81302836, 81573499]; Key Projects of National Science and Technology Program, China [2012ZX09301001-006, 2012ZX09302003, 2012ZX09301001] FX This work was supported by the National Science Foundation of China (Grant No. 81302836 and 81573499), Key Projects of National Science and Technology Program, China (Grant Nos. 2012ZX09301001-006, 2012ZX09302003 and 2012ZX09301001). NR 84 TC 0 Z9 0 U1 3 U2 3 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 JUN PY 2016 VL 41 IS 3 BP 199 EP 210 DI 10.1007/s13318-015-0306-1 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DM3MO UT WOS:000376250700001 PM 26597190 ER PT J AU Eitan, E Hutchison, ER Greig, NH Tweedie, D Celik, H Ghosh, S Fishbein, KW Spencer, RG Sasaki, CY Ghosh, P Das, S Chigurapati, S Raymick, J Sarkar, S Chigurupati, S Seal, S Mattson, MP AF Eitan, Erez Hutchison, Emmette R. Greig, Nigel H. Tweedie, David Celik, Hasan Ghosh, Soumita Fishbein, Kenneth W. Spencer, Richard G. Sasaki, Carl Y. Ghosh, Paritosh Das, Soumen Chigurapati, Susheela Raymick, James Sarkar, Sumit Chigurupati, Srinivasulu Seal, Sudipta Mattson, Mark P. TI Combination therapy with lenalidomide and nanoceria ameliorates CNS autoimmunity (vol 273, pg 151, 2015) SO EXPERIMENTAL NEUROLOGY LA English DT Correction C1 [Eitan, Erez; Hutchison, Emmette R.; Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Greig, Nigel H.; Tweedie, David] NIA, Translat Gerontol Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Celik, Hasan; Ghosh, Soumita; Fishbein, Kenneth W.; Spencer, Richard G.] NIA, Lab Clin Invest, Intramural Res Program, Baltimore, MD 21224 USA. [Das, Soumen] Univ Cent Florida, Mat Sci & Engn Coll Med, Orlando, FL 32816 USA. [Sasaki, Carl Y.; Ghosh, Paritosh] NIA, Immunol Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Chigurapati, Susheela] US FDA, Arkansas Reg Lab, Off Regulatory Affairs, 3900 NCTR Rd,Bldg 26, Jefferson, AR 72079 USA. [Raymick, James; Sarkar, Sumit; Chigurupati, Srinivasulu] Natl Ctr Toxicol Res FDA, Div Neurotoxicol, Jefferson, AR 72079 USA. [Seal, Sudipta] Univ Cent Florida, Adv Mat Proc & Anal Ctr, Nanosci Technol Ctr, Mech Mat Aerosp Engn, Orlando, FL 32816 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov NR 1 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 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2016 VL 280 BP 121 EP 121 DI 10.1016/j.expneurol.2016.02.015 PG 1 WC Neurosciences SC Neurosciences & Neurology GA DL7LK UT WOS:000375822000014 ER PT J AU Shotwell, MS Gray, RA AF Shotwell, Matthew S. Gray, Richard A. TI Estimability Analysis and Optimal Design in Dynamic Multi-scale Models of Cardiac Electrophysiology SO JOURNAL OF AGRICULTURAL BIOLOGICAL AND ENVIRONMENTAL STATISTICS LA English DT Article DE Cardiac cell model; Identifiability; Sensitivity plot; Voltage clamp ID HUXLEY GATING MODEL; IDENTIFIABILITY ANALYSIS; PARAMETER-ESTIMATION; INVERSION AB We present an applied approach to optimal experimental design and estimability analysis for mechanistic models of cardiac electrophysiology, by extending and improving on existing computational and graphical methods. These models are 'multi-scale' in the sense that the modeled phenomena occur over multiple spatio-temporal scales (e.g., single cell vs. whole heart). As a consequence, empirical observations of multi-scale phenomena often require multiple distinct experimental procedures. We discuss the use of conventional optimal design criteria (e.g., D-optimality) in combining experimental observations across multiple scales and multiple experimental modalities. In addition, we present an improved 'sensitivity plot'aEuro"a graphical assessment of parameter estimability-that overcomes a well-known limitation in this context. These techniques are demonstrated using a working Hodgkin-Huxley cell model and three simulated experimental procedures: single-cell stimulation, action potential propagation, and voltage clamp. In light of these assessments, we discuss two model modifications that improve parameter estimability, and show that the choice of optimality criterion has a profound effect on the contribution of each experiment. C1 [Shotwell, Matthew S.] Vanderbilt Univ, Dept Biostat, 2525 West End Ave, Nashville, TN 37203 USA. [Gray, Richard A.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Shotwell, MS (reprint author), Vanderbilt Univ, Dept Biostat, 2525 West End Ave, Nashville, TN 37203 USA. EM matt.shotwell@vanderbilt.edu FU NIH/NHLBI award "Optimal Design of Challenge-Response Experiments in Cardiac Electrophysiology" [1R01HL118392]; National Science Foundation Cyber Physical Systems Frontier Award "Foundation, Compositional, Approximate, and Quantitative Reasoning for Medical Cyber-Physical Systems" [1446832] FX This work was supported by NIH/NHLBI award "Optimal Design of Challenge-Response Experiments in Cardiac Electrophysiology" (1R01HL118392) and National Science Foundation Cyber Physical Systems Frontier Award "Foundation, Compositional, Approximate, and Quantitative Reasoning for Medical Cyber-Physical Systems" (Award Number: 1446832). NR 22 TC 3 Z9 3 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1085-7117 EI 1537-2693 J9 J AGR BIOL ENVIR ST JI J. Agric. Biol. Environ. Stat. PD JUN PY 2016 VL 21 IS 2 BP 261 EP 276 DI 10.1007/s13253-016-0244-7 PG 16 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA DL5YV UT WOS:000375713900003 PM 27330268 ER PT J AU Marasteanu, IJ Jaenicke, EC AF Marasteanu, I. Julia Jaenicke, Edward C. TI The role of US organic certifiers in organic hotspot formation SO RENEWABLE AGRICULTURE AND FOOD SYSTEMS LA English DT Article DE organic agriculture; spatial econometrics; organic certifiers ID COUNTY-LEVEL DETERMINANTS; RURAL-DEVELOPMENT; AUSTRIA; GROWTH; SECTOR; LABOR AB The purpose of this paper is to investigate the formation of hotspots of organic operations (geographically close areas that have positively correlated high numbers of organic operations), paying particular attention to the role of the organic certifying agent. We analyze the association of county-level factors related to policy, economics, demographics and organic certifiers with the probability that a county is in a hotspot or coldspot (geographically close areas that have positively correlated low numbers of organic operations) of organic operations. The results suggest that a high presence of government run organic certifying agents, as well as a high presence of private organic certifying agents who provide outreach services, are both positively associated with the probability that a county belongs to a hotspot. Other factors, such as the level of property taxes and the distance of the county from the nearest interstate, are also significantly correlated with the probability that a county is in a hotspot. Understanding factors associated with organic hotspots is important given the surge in momentum in the organic industry and the concerns that demand for organic products may be outpacing domestic supply. In particular, understanding the role that certifiers play in the formation of organic hotspots is important, as certain services provided by certifiers may be indicative of the level of communication between organic operations and their communities. The results of this paper may encourage public institutions that approve and regulate organic certifiers to provide incentives for offering outreach services, and private institutions interested in promoting organic operations to work more closely with certifying agents as a means to boost organic hotspots. C1 [Marasteanu, I. Julia] US FDA, 5100 Paint Branch Pkwy 1B056, College Pk, MD 20740 USA. [Jaenicke, Edward C.] Penn State Univ, University Pk, PA 16802 USA. RP Marasteanu, IJ (reprint author), US FDA, 5100 Paint Branch Pkwy 1B056, College Pk, MD 20740 USA. EM juliamarasteanu@gmail.com NR 43 TC 0 Z9 0 U1 5 U2 5 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1742-1705 EI 1742-1713 J9 RENEW AGR FOOD SYST JI Renew. Agr. Food Syst. PD JUN PY 2016 VL 31 IS 3 BP 230 EP 245 DI 10.1017/S1742170515000149 PG 16 WC Agriculture, Multidisciplinary SC Agriculture GA DL8CJ UT WOS:000375866700005 ER PT J AU Sauder, CJ Simonyan, V Ngo, L Karagiannis, K Cong, Y Zhang, C Wang, R Wu, WW Malik, T Rubin, SA AF Sauder, Christian J. Simonyan, Vahan Ngo, Laurie Karagiannis, Konstantinos Cong, Yu Zhang, Cheryl Wang, Rong Wu, Wells W. Malik, Tahir Rubin, Steven A. TI Evidence that a polyhexameric genome length is preferred, but not strictly required, for efficient mumps virus replication SO VIROLOGY LA English DT Article DE Mumps virus; Rule of six; Paramyxovirinae; Minigenome; CAT; Full-length cDNA; Nonpolyhexameric genome; Replication; Virus rescue; High throughput sequencing ID NEWCASTLE-DISEASE VIRUS; SENDAI-VIRUS; MESSENGER-RNA; REPORTER GENE; MEASLES-VIRUS; RULE; MUTATIONS; PROPAGATION; MINIGENOME; POLYMERASE AB Mumps virus (MuV) is postulated to adhere to the "rule of six" for efficient replication. To examine the requirement for MuV, minigenomes of nonpolyhexameric length (6n-1 and 6n+1) were analyzed. Expression of the reporter gene CAT was significantly reduced with minigenomes of nonpolyhexameric length compared to the wild type 6n genome, and reduction was more pronounced for the 6n-1 than for the 6n+1 minigenome. That 6n-1 genomes are impacted by nonconformance with the rule of six to a greater degree as compared to 6n+1 genomes was also suggested with MuV derived from cDNA coding for 6n+1 or 6n-1 genomes. While viruses recovered from 6n+1 cDNAs maintained a nonpolyhexameric genome length over multiple replication cycles, viruses rescued from the 6n-1 cDNAs acquired length correcting mutations rapidly following rescue. Our data indicate that polyhexameric genomes are the preferred template for the MuV RNA polymerase, but that this requirement is not absolute. Published by Elsevier Inc. C1 [Sauder, Christian J.; Ngo, Laurie; Cong, Yu; Zhang, Cheryl; Malik, Tahir; Rubin, Steven A.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Simonyan, Vahan; Karagiannis, Konstantinos] US FDA, Off Biostat & Epidemiol, CBER, Silver Spring, MD USA. [Wang, Rong; Wu, Wells W.] US FDA, Facil Biotechnol Resources, CBER, Silver Spring, MD USA. [Cong, Yu] Integrated Res Facil, Frederick, MD USA. [Wang, Rong] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Sauder, CJ (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. EM christian.sauder@fda.hhs.gov FU Oak Ridge Institute for Science and Education FX Salary support for C.Z. and Y.C. was provided by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. We wish to thank Shen Rongfong (FDA/CBER) for helpful discussions about HTS and Luis Santana-Quintero (FDA/CBER) for help using HIVE. We are grateful to Paul Duprex (Boston) for helpful discussions and to Vladimir Lugovtsev and Barry Falgout (FDA/CBER) for critically reading the manuscript. NR 33 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 0042-6822 J9 VIROLOGY JI Virology PD JUN PY 2016 VL 493 BP 173 EP 188 DI 10.1016/j.virol.2016.03.021 PG 16 WC Virology SC Virology GA DL7MH UT WOS:000375824300017 PM 27058764 ER PT J AU Podoplelova, NA Sveshnikova, AN Kurasawa, JH Sarafanov, AG Chambost, H Vasil'ev, SA Demina, IA Ataullakhanov, FI Alessi, MC Panteleev, MA AF Podoplelova, Nadezhda A. Sveshnikova, Anastasia N. Kurasawa, James H. Sarafanov, Andrey G. Chambost, Herve Vasil'ev, Sergey A. Demina, Irina A. Ataullakhanov, Fazly I. Alessi, Marie-Christine Panteleev, Mikhail A. TI Hysteresis-like binding of coagulation factors X/Xa to procoagulant activated platelets and phospholipids results from multistep association and membrane-dependent multimerization SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Review DE Blood platelets; Blood coagulation; Coagulation factor X; Phosphatidylserine; Annexin V; Membrane-dependent reaction ID CELL-BASED MODEL; FACTOR-X; BLOOD-COAGULATION; FACTOR-VIII; COMPLEX; SURFACE; PROTHROMBINASE; HEMOSTASIS; RESONANCE; PROTEINS AB Binding of coagulation factors X (fX) and Xa (fXa) to activated platelets is required for the formation of membrane-dependent enzymatic complexes of intrinsic tenase and prothrombinase. We carried out an in-depth characterization of fX/fXa binding to phospholipids and gel-filtered, thrombin-activated platelets. Flow cytometry, surface plasmon resonance, and computational modeling were used to investigate interactions of fX/fXa with the membranes. Confocal microscopy was employed to study fXa binding to platelet thrombi formed in flowing whole blood under arterial conditions. Binding of DC/fXa to either vesicles or procoagulant platelets did not follow a traditional one-step reversible binding model. Their dissociation was a two-step process resulting in a plateau that was up to 10-fold greater than the saturation value observed in the association experiments. Computational modeling and experimental evidence suggested that this was caused by a combination of two-step association (mainly for DC) and multimerization on the membrane (mainly for fXa). Importantly, DC formed multimers with fXa, thereby improving its retention. The same binding/dissociation hysteresis was observed for annexin V known to form trimers on the membranes. Experiments with platelets from gray syndrome patients showed that alpha-granular factor Va provided an additional high-affinity binding site for fXa that did not affect the hysteresis. Confocal microscopy observation of fXa binding to platelet thrombi in a flow chamber and its wash-out confirmed that this phenomenon persisted under physiologically relevant conditions. This suggests its possible role of "locking" coagulation factors on the membrane and preventing their inhibition in plasma and removal from thrombi by flow. (C) 2016 Published by Elsevier B.V. C1 [Podoplelova, Nadezhda A.; Demina, Irina A.; Ataullakhanov, Fazly I.; Panteleev, Mikhail A.] Fed Res & Clin Ctr Pediat Hematol Oncol & Immunol, Moscow 117198, Russia. [Sveshnikova, Anastasia N.; Ataullakhanov, Fazly I.; Panteleev, Mikhail A.] Ctr Theoret Problems Physicochem Pharmacol, Lab Mol Mech Hemostasis, Moscow 119991, Russia. [Sveshnikova, Anastasia N.; Ataullakhanov, Fazly I.; Panteleev, Mikhail A.] Moscow MV Lomonosov State Univ, Fac Phys, Moscow 119992, Russia. [Kurasawa, James H.; Sarafanov, Andrey G.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Chambost, Herve] Aix Marseille Univ, La Timone Hosp, APHM, Dept Pediat Oncohematol, Marseille, France. [Vasil'ev, Sergey A.] Natl Res Ctr Hematol, Moscow 125167, Russia. [Alessi, Marie-Christine] Aix Marseille Univ, F-13005 Marseille, France. [Panteleev, Mikhail A.] Moscow Inst Phys & Technol, Fac Biol & Med Phys, Dolgoprudnyi 141700, Russia. RP Panteleev, MA (reprint author), Dmitry Rogachev Fed Sci & Clin Ctr Pediat Hematol, Oncol & Immunol, 1 Samory Mashela Str, Moscow 117198, Russia. EM mapanteleev@yandex.ru RI Sveshnikova, Anastasia/J-9945-2015; Panteleev, Mikhail/H-5491-2012 OI Sveshnikova, Anastasia/0000-0003-4720-7319; Panteleev, Mikhail/0000-0002-8128-7757 FU Russian Science Foundation [14-14-00195] FX This study was supported by the Russian Science Foundation grant 14-14-00195. NR 30 TC 3 Z9 3 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 EI 0006-3002 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD JUN PY 2016 VL 1858 IS 6 BP 1216 EP 1227 DI 10.1016/j.bbamem.2016.02.008 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DL0XW UT WOS:000375356900016 PM 26874201 ER PT J AU Parikh, T Sandhu, HK Talele, TT Serajuddin, ATM AF Parikh, Tapan Sandhu, Harpreet K. Talele, Tanaji T. Serajuddin, Abu T. M. TI Characterization of Solid Dispersion of Itraconazole Prepared by Solubilization in Concentrated Aqueous Solutions of Weak Organic Acids and Drying SO PHARMACEUTICAL RESEARCH LA English DT Article DE acid-base interaction; amorphous solid dispersion; Itraconazole; solubilization; stabilization; weak organic acid ID PYRIDINE HYDROGEN-BONDS; POORLY SOLUBLE DRUGS; DIFFERENT SALT FORMS; MODEL BASIC DRUG; PHARMACEUTICAL COCRYSTALS; SUPRAMOLECULAR SYNTHONS; ORAL BIOAVAILABILITY; DICARBOXYLIC-ACIDS; PHYSICAL STABILITY; STATE PROPERTIES AB The purpose of this study was to develop an amorphous solid dispersion (SD) of an extremely water-insoluble and very weakly basic drug, itraconazole (ITZ), by interaction with weak organic acids and then drying that would enhance dissolution rate of drug and physical stability of formulation. Aqueous solubility of ITZ in concentrated solutions of weak organic acids, such as glutaric, tartaric, malic and citric acid, was determined. Solutions with high drug solubility were dried using vacuum oven and the resulting SDs having 2 to 20% drug load were characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. The dissolution of SDs was initially studied in 250 mL of 0.1 N HCl (pH 1.1), and any undissolved solids were collected and analyzed by PXRD. The pH of the dissolution medium was then changed from 1.1 to 5.5, particle size of precipitates were measured, and drug concentrations in solution were determined by filtration through membrane filters of varying pore sizes. The aqueous solubility of ITZ was greatly enhanced in presence of weak acids. While the solubility of ITZ in water was similar to 4 ng/ mL, it increased to 25-40 mg per g of solution at 25A degrees C and 200 mg per g of solution at 65A degrees C at a high acid concentration leading to extremely high solubilization. PXRD of SDs indicated that ITZ was present in the amorphous form, wherein the acid formed a partially crystalline matrix. ATR-FTIR results showed possible weak interactions, such as hydrogen bonding, between drug and acid but there was no salt formation. SDs formed highly supersaturated solutions at pH 1.1 and had superior dissolution rate as compared to amorphous drug and physical mixtures of drug and acids. Following the change in pH from 1.1 to 5.5, ITZ precipitated as mostly nanoparticles, providing high surface area for relatively rapid redissolution. A method of highly solubilizing an extremely water-insoluble drug, ITZ, in aqueous media and converting it into an amorphous form in a physically stable SD was successfully investigated. The dissolution rate and the extent of supersaturation of the drug in dissolution media improved greatly, and any precipitate formed at high pH had very small particle size. C1 [Parikh, Tapan; Talele, Tanaji T.; Serajuddin, Abu T. M.] St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, 8000 Utopia Pkwy, Queens, NY 11439 USA. [Parikh, Tapan] Food & Drug Adm, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. [Sandhu, Harpreet K.] Kashiv Pharma, 440 US Highway 22, Bridgewater, NJ 08807 USA. RP Serajuddin, ATM (reprint author), St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, 8000 Utopia Pkwy, Queens, NY 11439 USA. EM serajuda@stjohns.edu NR 54 TC 4 Z9 4 U1 4 U2 13 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 JUN PY 2016 VL 33 IS 6 BP 1456 EP 1471 DI 10.1007/s11095-016-1890-8 PG 16 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DL2HE UT WOS:000375453600014 PM 26951566 ER PT J AU Zhang, B Liu, W Zhang, H Chen, QH Zhang, ZW AF Zhang, Bo Liu, Wei Zhang, Hui Chen, Qihui Zhang, Zhiwei TI Composite likelihood and maximum likelihood methods for joint latent class modeling of disease prevalence and high-dimensional semicontinuous biomarker data SO COMPUTATIONAL STATISTICS LA English DT Article DE Pseudo-likelihood; Expectation-maximization algorithm; Markov chain Monte Carlo; Shared latent class models; Two-part models ID LINEAR MIXED MODELS; POLYCHLORINATED-BIPHENYLS; BREAST-MILK; EXPOSURE; RISK; ENDOMETRIOSIS; ALGORITHMS; PBDES AB Joint latent class modeling of disease prevalence and high-dimensional semicontinuous biomarker data has been proposed to study the relationship between diseases and their related biomarkers. However, statistical inference of the joint latent class modeling approach has proved very challenging due to its computational complexity in seeking maximum likelihood estimates. In this article, we propose a series of composite likelihoods for maximum composite likelihood estimation, as well as an enhanced Monte Carlo expectation-maximization (MCEM) algorithm for maximum likelihood estimation, in the context of joint latent class models. Theoretically, the maximum composite likelihood estimates are consistent and asymptotically normal. Numerically, we have shown that, as compared to the MCEM algorithm that maximizes the full likelihood, not only the composite likelihood approach that is coupled with the quasi-Newton method can substantially reduce the computational complexity and duration, but it can simultaneously retain comparative estimation efficiency. C1 [Zhang, Bo; Zhang, Zhiwei] US FDA, Ctr Devices & Radiol Hlth, Off Surveillance & Biometr, Div Biostat, Silver Spring, MD 20993 USA. [Liu, Wei] Harbin Inst Technol, Dept Math, Harbin 150001, Peoples R China. [Zhang, Hui] St Jude Childrens Res Hosp, Dept Biostat, 332 N Lauderdale St, Memphis, TN 38105 USA. [Chen, Qihui] China Agr Univ, Coll Econ & Management, Dept Appl Econ, Beijing 100083, Peoples R China. RP Liu, W (reprint author), Harbin Inst Technol, Dept Math, Harbin 150001, Peoples R China. EM Bo.Zhang@fda.hhs.gov; liuwhit@hit.edu.cn RI Zhang, Hui/E-8112-2010; OI Chen, Qihui/0000-0002-0944-0470 NR 28 TC 0 Z9 0 U1 2 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0943-4062 EI 1613-9658 J9 COMPUTATION STAT JI Comput. Stat. PD JUN PY 2016 VL 31 IS 2 BP 425 EP 449 DI 10.1007/s00180-015-0597-3 PG 25 WC Statistics & Probability SC Mathematics GA DJ7EX UT WOS:000374375800002 ER PT J AU Shah, K Ragupathy, V Saga, A Hewlett, I AF Shah, Krishna Ragupathy, Viswanath Saga, Anusha Hewlett, Indira TI High sensitivity detection of HIV-1 using two genomic targets compared with single target PCR SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE HIV NAT assay; primer probe mis match; false negative; dual target; sensitivity ID IMMUNODEFICIENCY-VIRUS TYPE-1; POLYMERASE-CHAIN-REACTION; INFECTION; DIVERSITY; ASSAYS AB The genetic diversity of Human Immunodeficiency Virus type-1(HIV-1) has been shown to affect the performance of Nucleic Acid Testing (NAT) of Human Immunodeficiency Virus type-1. Although, majority NAT assays were designed to detect the conserved regions of HIV-1 mutations at the primer or probe binding regions may lead to false negatives. In this study, we evaluated the feasibility of detecting two genomic targets for enhanced sensitivity. A total of 180 tests using HIV-1 VQA RNA quantitation standard, 240 tests using EQAPOL HIV-1 viral diversity subtype panel, and 30 clinical plasma samples from Cameroon were evaluated. The analysis was based on probit and hit rate. The genomic targets LOD estimated by PROBIT for the gag target was 118cps/ml (95%CI 64cps/ml lower bound), Pol or POL/LTR was at 40cps/ml (95%CI 17, 16cps/ml), LTR 45cps/ml (95%CI 20cps/ml lower bound), and Gag/LTR at 67.8cps/ml (95%CI 32cps/ml lower bound). For HIV-1 subtypes the overall reactivity was 55-100% when tested at 100 and 1000cps/ml and combination of genomic targets detection increased the reactivity to 100%. The plasma samples evaluation showed LTR or pol/LTR combination yielded higher sensitivity for patients with lower viral load (<40cps/ml). We conclude that detection of two HIV-1 genomic targets improved sensitivity for detection of genetically diverse HIV-1 strains. J. Med. Virol. 88:1092-1097, 2016. (c) 2015 Wiley Periodicals, Inc. C1 [Shah, Krishna; Ragupathy, Viswanath; Hewlett, Indira] LMV DETTD OBRR CBER FDA, Bethesda, MD USA. [Shah, Krishna] Northwest High Sch, Voluntary Intern, Germantown, MD USA. [Saga, Anusha] Thomas Jefferson High Sch Sci & Technol, Summer Intern, Alexandria, VA USA. [Shah, Krishna] Univ Maryland, College Pk, MD 20742 USA. RP Ragupathy, V; Hewlett, I (reprint author), CBER FDA, Mol Virol Lab, Bldg 52-72,Room 4230, Silver Spring, MD 20993 USA. EM viswanath.ragupathy@fda.hhs.gov; indira.hewlett@fda.hhs.gov NR 18 TC 0 Z9 0 U1 3 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0146-6615 EI 1096-9071 J9 J MED VIROL JI J. Med. Virol. PD JUN PY 2016 VL 88 IS 6 BP 1092 EP 1097 DI 10.1002/jmv.24431 PG 6 WC Virology SC Virology GA DI6RF UT WOS:000373627000023 PM 26575693 ER PT J AU Korir, RC Parveen, S Hashem, F Bowers, J AF Korir, Robert Cheruiyot Parveen, Salina Hashem, Fawzy Bowers, John TI Microbiological quality of fresh produce obtained from retail stores on the Eastern Shore of Maryland, United States of America SO FOOD MICROBIOLOGY LA English DT Article DE Fresh produce; Total aerobic bacteria; Escherichia coli; E. coli O157:H7; Listeria monocytogenes; Salmonella ID LISTERIA-MONOCYTOGENES; MICROBIAL QUALITY; FOODBORNE ILLNESS; VEGETABLES; PREVALENCE; FOODS; WATER; CONTAMINATION; SALMONELLA; PATHOGENS AB The aim of this study was to investigate the microbiological quality of six types of fresh produce obtained from three retail stores located on the Eastern Shore of Maryland, USA. A total of 414 samples representing basil, cilantro, lettuce, scallion, spinach, and parsley were analyzed for total aerobic bacteria (APC), total coliforms, Escherichia coli, and three pathogenic bacteria (E. coli O157:H7, Listeria monocytogenes, and Salmonella), using standard methods. Presumptive pathogenic isolates were confirmed using BAX Polymerase Chain Reaction. Total aerobic populations varied widely between samples, while 38.41% were positive for total coliforms and only 10.15% for E. coli. Median abundance (log CFU/g) of total coliforms and E. coli were less than the limit of detection and that of APC ranged from 5.78 to 6.61 over the six produce types. There was a statistically significant difference in prevalence of total coliforms among the retail stores, but not for abundance of APC or prevalence of E. coli. E. coli O157: H7 and L. monocytogenes were detected in one spinach sample each, while one parsley and one cilantro sample were positive for Salmonella. There were no statistically significant differences in microbiological quality among produce types. Although the results of this study provided some indices of sanitary and/or spoilage level, no relationship was observed among the total aerobic bacteria, total coliforms, E. coli, and the presence of pathogenic bacteria in the samples tested. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Korir, Robert Cheruiyot; Parveen, Salina; Hashem, Fawzy] Univ Maryland Eastern Shore, Food Sci & Technol PhD Program, Princess Anne, MD 21853 USA. [Bowers, John] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Parveen, S (reprint author), Univ Maryland Eastern Shore, Ctr Food Sci & Technol 2116, Princess Anne, MD 21853 USA. EM sparveen@umes.edu FU Graduate School of University of Maryland Eastern Shore; USDA Evans-Allen FX We sincerely thank Drs. J. Schwarz and L. Marsh, and Chanelle White for helpful suggestions, the Graduate School of University of Maryland Eastern Shore, and USDA Evans-Allen for funding. NR 40 TC 2 Z9 2 U1 7 U2 42 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 JUN PY 2016 VL 56 BP 29 EP 34 DI 10.1016/j.fm.2015.12.003 PG 6 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA DE7IX UT WOS:000370810500004 PM 26919815 ER PT J AU Li, JJ Xue, F Yang, ZQ Zhang, XP Zeng, DX Chao, GX Jiang, Y Li, BG AF Li, Jingjiao Xue, Feng Yang, Zhenquan Zhang, Xiaoping Zeng, Dexin Chao, Guoxiang Jiang, Yuan Li, Baoguang TI Vibrio parahaemolyticus Strains of Pandemic Serotypes Identified from Clinical and Environmental Samples from Jiangsu, China SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE Vibrio parahaemolyticus; serotyping; MLST; virulence genes; TDH-related hemolysin (TRH); pandemic serotypes; epidemiology; phylogeny ID DIARRHEAL PATIENTS; PACIFIC-NORTHWEST; GENETIC-TRAITS; UNITED-STATES; O3-K6 CLONE; VIRULENCE; PCR; SALMONELLA; SEROGROUP; OUTBREAKS AB Vibrio parahaemolyticus has emerged as a major foodborne pathogen in China, Japan, Thailand, and other Asian countries. In this study, 72 strains of V parahaemolyticus were isolated from clinical and environmental samples between 2006 and 2014 in Jiangsu, China. The serotypes and six virulence genes including thermostable direct hemolysin (TDR) and TDR-related hemolysin (TRH) genes were assessed among the isolates. Twenty five serotypes were identified and O3:K6 was one of the dominant serotypes. The genetic diversity was assessed by multilocus sequence typing (MLST) analysis, and 48 sequence types (STs) were found, suggesting this V parahaemolyticus group is widely dispersed and undergoing rapid evolution. A total of 25 strains of pandemic serotypes such as O3:K6, O5:K17, and O1:KUT were identified. It is worth noting that the pandemic serotypes were not exclusively identified from clinical samples, rather, nine strains were also isolated from environmental samples; and some of these strains harbored several virulence genes, which may render those strains pathogenicity potential. Therefore, the emergence of these "environmental" pandemic V parahaernolyticus strains may poses a new threat to the public health in China. Furthermore, six novel serotypes and 34 novel STs were identified among the 72 isolates, indicating that V parahaernolyticus were widely distributed and fast evolving in the environment in Jiangsu, China. The findings of this study provide new insight into the phylogenic relationship between V parahaemolyticus strains of pandemic serotypes from clinical and environmental sources and enhance the MLST database; and our proposed possible O- and K- antigen evolving paths of V parahaemolyticus may help understand how the serotypes of this dispersed bacterial population evolve. C1 [Li, Jingjiao; Xue, Feng; Zeng, Dexin; Jiang, Yuan] Jiangsu Entry Exit Inspect & Quarantine Bur, Anim Quarantine Lab, Nanjing, Jiangsu, Peoples R China. [Li, Jingjiao] Shanghai Jiao Tong Univ, Sch Agr & Biol, Dept Anim Sci, Key Lab Vet Biotechnol, Shanghai 200030, Peoples R China. [Yang, Zhenquan] Yangzhou Univ, Sch Food Sci & Engn, Jiangsu Key Lab Zoonosis, Yangzhou 225009, Jiangsu, Peoples R China. [Zhang, Xiaoping] Beijing Kemufeng Biopharmaceut Co, Beijing, Peoples R China. [Chao, Guoxiang] Yangzhou Key Ctr Dis Control & Prevent, Yangzhou, Jiangsu, Peoples R China. [Li, Baoguang] US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD USA. RP Xue, F; Jiang, Y (reprint author), Jiangsu Entry Exit Inspect & Quarantine Bur, Anim Quarantine Lab, Nanjing, Jiangsu, Peoples R China. EM fengxue1219@aliyun.com; jiango@yeah.net FU National Natural Science Foundation of China [31301460]; National Science and Technology Support Program [2012BAK17B10]; National 10000 Talents Youth Top-Notch Talent Support Program; Jiangsu Province Science and Technology Support Program [BE2013733] FX We would like to thank Yanhong Wan, Lu Gao and Elaibo Zhou for their useful suggestions to this work. The study was supported by the National Natural Science Foundation of China (31301460) the National Science and Technology Support Program of 2012BAK17B10, National 10000 Talents Youth Top-Notch Talent Support Program, and Jiangsu Province Science and Technology Support Program of BE2013733. NR 66 TC 0 Z9 0 U1 4 U2 5 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 MAY 31 PY 2016 VL 7 AR 787 DI 10.3389/fmicb.2016.00787 PG 13 WC Microbiology SC Microbiology GA DN0XJ UT WOS:000376790100001 PM 27303379 ER PT J AU Wu, Y Petrochenko, P Chen, L Wong, SY Absar, M Choi, S Zheng, JW AF Wu, Yong Petrochenko, Peter Chen, Lynn Wong, Sook Yee Absar, Mohammad Choi, Stephanie Zheng, Jiwen TI Core size determination and structural characterization of intravenous iron complexes by cryogenic transmission electron microscopy SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Intravenous iron; Cryo-TEM; Physicochemical characterization; Core size; Nanoscale pharmaceutics ID PHYSICOCHEMICAL PROPERTIES; DEFICIENCY ANEMIA; LABILE IRON; CLINICAL-IMPLICATIONS; ISOMALTOSIDE 1000; CHRONIC DISEASE; NANOPARTICLES; FORMULATIONS; FERUMOXYTOL; METABOLISM AB Understanding physicochemical properties of intravenous (IV) iron drug products is essential to ensure the manufacturing process is consistent and streamlined. The history of physicochemical characterization of IV iron complex formulations stretches over several decades, with disparities in iron core size and particle morphology as the major source of debate. One of the main reasons for this controversy is room temperature sample preparation artifacts, which affect accurate determination of size, shape and agglomeration/aggregation of nanoscale iron particles. The present study is first to report the ultra-fine iron core structures of four IV iron complex formulations, sodium ferric gluconate, iron sucrose, low molecular weight iron dextran and ferumoxytol, using a cryogenic transmission electron microscopy (cryo-TEM) preservation technique, as opposed to the conventional room temperature (RT-TEM) technique. Our results show that room temperature preparation causes nanoparticle aggregation and deformation, while cryo-TEM preserves IV iron colloidal suspension in their native frozen-hydrated and undiluted state. In contrast to the current consensus in literature, all four IV iron colloids exhibit a similar morphology of their iron oxide cores with a spherical shape, narrow size distribution and an average size of 2 nm. Moreover, out of the four tested formulations, ferumoxytol exhibits a cluster-like community of several iron carbohydrate particles which likely accounts for its large hydrodynamic size of 25 nm, measured with dynamic light scattering. Our findings outline a suitable method for identifying colloidal nanoparticle core size in the native state, which is increasingly important for manufacturing and design control of complex drug formulations, such as IV iron drug products. Published by Elsevier B.V. C1 [Wu, Yong; Chen, Lynn; Zheng, Jiwen] US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Petrochenko, Peter; Wong, Sook Yee; Absar, Mohammad; Choi, Stephanie] US FDA, Div Therapeut Performance, Off Res Stand, Off Gener Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Zheng, JW (reprint author), US FDA, Div Biol Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA.; Choi, S (reprint author), US FDA, Div Therapeut Performance, Off Res Stand, Off Gener Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM stephanie.choi@fda.hhs.gov; jiwen.zheng@fda.hhs.gov NR 50 TC 1 Z9 1 U1 4 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD MAY 30 PY 2016 VL 505 IS 1-2 BP 167 EP 174 DI 10.1016/j.ijpharm.2016.03.029 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DM9OP UT WOS:000376695900020 PM 27001529 ER PT J AU Miller, ER Moro, PL Cano, M Lewis, P Bryant-Genevier, M Shimabukuro, TT AF Miller, Elaine R. Moro, Pedro L. Cano, Maria Lewis, Paige Bryant-Genevier, Marthe Shimabukuro, Tom T. TI Post-licensure safety surveillance of 23-valent pneumococcal polysaccharide vaccine in the Vaccine Adverse Event Reporting System (VAERS), 1990-2013 SO VACCINE LA English DT Article DE 23-Valent pneumococcal polysaccharide vaccine; Vaccines; Immunizations; Vaccine safety; Surveillance; Vaccine Adverse Event Reporting System (VAERS) ID IMMUNIZATION PRACTICES ACIP; IMMUNOCOMPROMISING CONDITIONS RECOMMENDATIONS; ADVISORY-COMMITTEE; CONJUGATE VACCINE; UNITED-STATES; ADULTS; CHILDREN; IMMUNOGENICITY; REACTOGENICITY; PREVENTION AB Background: 23-Valent pneumococcal polysaccharide vaccine, trade name Pneumovax (R) 23 (PPSV23), has been used for decades in the Unites States and has an extensive clinical record. However, limited post-licensure safety assessment has been conducted. Objective: To analyze reports submitted to the Vaccine Adverse Event Reporting System (VAERS) following PPSV23 from 1990 to 2013 in order to characterize its safety profile. Methods: We searched the VAERS database for US reports following PPSV23 for persons vaccinated from 1990 to 2013. We assessed safety through: automated analysis of VAERS data, crude adverse event (AE) reporting rates based on PPSV23 doses distributed in the US market, clinical review of death reports and reports involving vaccine administered to pregnant women, and empirical Bayesian data mining to assess for disproportional reporting. Results: During the study period, VAERS received 25,168 PPSV23 reports; 92% were non-serious, 67% were in females and 86% were in adults aged >= 19 years. When PPSV23 was administered alone, fever (43%), injection site erythema (28%) and injection site pain (25%) were the most commonly reported non-serious AEs in children. Injection site erythema (32%), injection site pain (27%) and injection site swelling (23%) were the most commonly reported non-serious AEs in adults. Of serious reports (2129, 8% of total), fever was most commonly reported in both children (69%) and adults (39%). There were 66 reports of death, four in children and 62 in adults. Clinical review of death reports did not reveal any concerning patterns that would suggest a causal association with PPSV23. No disproportional reporting of unexpected AEs was observed in empirical Bayesian data mining. Conclusions: We did not identify any new or unexpected safety concerns for PPSV23. The VAERS data are consistent with safety data from pre-licensure clinical trials and other post-licensure studies. Published by Elsevier Ltd. C1 [Miller, Elaine R.; Moro, Pedro L.; Cano, Maria; Lewis, Paige; Shimabukuro, Tom T.] Ctr Dis Control & Prevent, Immunizat Safety Off, Atlanta, GA USA. [Bryant-Genevier, Marthe] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Miller, ER (reprint author), Ctr Dis Control & Prevent CDC, Immunizat Safety Off, 1600 Clifton Rd,MS D-26, Atlanta, GA 30329 USA. EM EMiller@cdc.gov NR 28 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD MAY 27 PY 2016 VL 34 IS 25 BP 2841 EP 2846 DI 10.1016/j.vaccine.2016.04.021 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DN8GQ UT WOS:000377317600012 PM 27087150 ER PT J AU Bentebibel, SE Khurana, S Schmitt, N Kurup, P Mueller, C Obermoser, G Palucka, AK Albrecht, RA Garcia-Sastre, A Golding, H Ueno, H AF Bentebibel, Salah-Eddine Khurana, Surender Schmitt, Nathalie Kurup, Parvathi Mueller, Cynthia Obermoser, Gerlinde Palucka, A. Karolina Albrecht, Randy A. Garcia-Sastre, Adolfo Golding, Hana Ueno, Hideki TI ICOS+PD-1(+)CXCR3(+) T follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination SO SCIENTIFIC REPORTS LA English DT Article ID MEMORY TFH CELLS; HUMAN BLOOD; RESPONSES; VACCINES; EFFICACY; HUMANS; VIRUS AB The immune mechanism leading to the generation of protective antibody responses following influenza trivalent inactivated vaccine (TIV) vaccinations remains largely uncharacterized. We recently reported that TIV vaccination induced a transient increase of circulating ICOS+PD-1(+)CXCR3(+) T follicular helper (cTfh) cells in blood, which positively correlated with the induction of protective antibody responses measured at day 28. However, whether and how these T cells directly contribute to antibody response remains unclear. In this study, we analyzed the changes after TIV vaccination in the amount and the avidity of the polyclonal antibodies specific for the HA1 subunit of the pandemic H1N1 virus, and analyzed the correlation with the increase of ICOS+PD-1(+)CXCR3(+) cTfh cells. We found that both the amount and the avidity of specific antibodies rapidly increased during the first 7 days after TIV. Importantly, the increase of ICOS+PD-1(+)CXCR3(+) cTfh cells strongly correlated with the increase in the avidity of antibodies, particularly in subjects who did not have high affinity antibodies at baseline. We propose that ICOS+PD-1(+)CXCR3(+) Tfh cells directly contribute to the generation of high-avidity antibodies after TIV vaccinations by selectively interacting with high affinity B cells at extrafollicular sites. C1 [Bentebibel, Salah-Eddine; Schmitt, Nathalie; Kurup, Parvathi; Mueller, Cynthia; Obermoser, Gerlinde; Palucka, A. Karolina; Ueno, Hideki] Baylor Res Inst, Baylor Inst Immunol Res, Dallas, TX 75204 USA. [Khurana, Surender; Golding, Hana] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Albrecht, Randy A.; Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA. [Albrecht, Randy A.; Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Global Hlth & Emerging Pathogens Inst, New York, NY 10029 USA. [Garcia-Sastre, Adolfo] Icahn Sch Med Mt Sinai, Div Infect Dis, Dept Med, New York, NY 10029 USA. [Ueno, Hideki] Icahn Sch Med Mt Sinai, Global Hlth & Emerging Pathogens Inst, Dept Microbiol, New York, NY 10029 USA. RP Ueno, H (reprint author), Baylor Res Inst, Baylor Inst Immunol Res, Dallas, TX 75204 USA.; Ueno, H (reprint author), Icahn Sch Med Mt Sinai, Global Hlth & Emerging Pathogens Inst, Dept Microbiol, New York, NY 10029 USA. EM hideki.ueno@mssm.edu RI Ueno, Hideki/L-1237-2016; OI Ueno, Hideki/0000-0001-7747-0738; Garcia-Sastre, Adolfo/0000-0002-6551-1827 FU NIH [U19-AI089987]; Alliance for Lupus Research; Baylor Health Care System FX This study was supported by NIH grant U19-AI089987, Alliance for Lupus Research, and Baylor Health Care System. NR 26 TC 1 Z9 1 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 MAY 27 PY 2016 VL 6 AR 26494 DI 10.1038/srep26494 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DM9HN UT WOS:000376676200001 PM 27231124 ER PT J AU Prowell, TM Theoret, MR Pazdur, R AF Prowell, Tatiana M. Theoret, Marc R. Pazdur, Richard TI Seamless Oncology-Drug Development SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Prowell, Tatiana M.; Theoret, Marc R.; Pazdur, Richard] Food & Drug Adm, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, Silver Spring, MD USA. [Prowell, Tatiana M.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Breast Canc Program, Baltimore, MD USA. RP Prowell, TM (reprint author), Food & Drug Adm, Ctr Drug Evaluat & Res, Off Hematol & Oncol Prod, Silver Spring, MD USA.; Prowell, TM (reprint author), Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Breast Canc Program, Baltimore, MD USA. NR 4 TC 9 Z9 9 U1 0 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 MAY 26 PY 2016 VL 374 IS 21 BP 2001 EP 2003 DI 10.1056/NEJMp1603747 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DM6EN UT WOS:000376443500001 PM 27074059 ER PT J AU Patel, T Tesfaldet, B Gandotra, C AF Patel, Tejas Tesfaldet, Bereket Gandotra, Charu CA Meta-AnalyTical Interagency Grp MA TI DIPEPTIDYL PEPTIDASE-4 INHIBITORS AND RISK OF HEART FAILURE IN TYPE 2 DIABETES Pooled patient level data are better suited than study level data to investigate the link between dipeptidyl peptidase-4 inhibitors and the risk of heart failure in type 2 diabetes SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Letter ID ACUTE MYOCARDIAL-INFARCTION; CLINICAL-TRIALS; MORTALITY; OUTCOMES; MELLITUS C1 [Patel, Tejas; Tesfaldet, Bereket] US FDA, 10993 New Hampshire Ave, Silver Spring, MD 20993 USA. [Gandotra, Charu] Howard Univ Hosp, Dept Internal Med, Div Cardiovasc Med, Washington, DC USA. RP Patel, T (reprint author), US FDA, 10993 New Hampshire Ave, Silver Spring, MD 20993 USA. EM tejaskumar.patel@fda.hhs.gov NR 12 TC 0 Z9 0 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD MAY 24 PY 2016 VL 353 AR i2920 DI 10.1136/bmj.i2920 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DN3CB UT WOS:000376938800011 PM 27220716 ER PT J AU Wang, CL Wong, S Graham, DJ AF Wang, Cunlin Wong, Sarah Graham, David J. TI Risk of Anaphylaxis With Intravenous Iron Products Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Wang, Cunlin; Graham, David J.] US FDA, Ctr Drug Evaluat & Res, 10903 New Hamshire Ave, Silver Spring, MD 20903 USA. [Wong, Sarah] ACUMEN LLC, Burlingame, CA USA. RP Wang, CL (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hamshire Ave, Silver Spring, MD 20903 USA. EM cunlin.wang@fda.hhs.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 24 PY 2016 VL 315 IS 20 BP 2232 EP 2233 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DM4US UT WOS:000376343000023 PM 27218636 ER PT J AU Carter, JM Lin, A Clotilde, L Lesho, M AF Carter, John M. Lin, Andrew Clotilde, Laurie Lesho, Matthew TI Rapid, Multiplexed Characterization of Shiga Toxin-Producing Escherichia coil (STEC) Isolates Using Suspension Array Technology SO FRONTIERS IN MICROBIOLOGY LA English DT Review DE E. coil; Shiga toxin; immunoassay; PCR; microbead ID MICROBEAD-BASED IMMUNOASSAY; COLI INFECTIONS; UNITED-STATES; IDENTIFICATION; PATHOGENS; O157; VIRULENCE; SAMPLES; CATTLE AB Molecular methods have emerged as the most reliable techniques to detect and characterize pathogenic Escherichia coli. These molecular techniques include conventional single analyte and multiplex PCR, PCR followed by microarray detection, pulsed-field gel electrophoresis (PFGE), and whole genome sequencing. The choice of methods used depends upon the specific needs of the particular study. One versatile method involves detecting serogroup-specific markers by hybridization or binding to encoded microbeads in a suspension array. This molecular serotyping method has been developed and adopted for investigating E. coli outbreaks. The major advantages of this technique are the ability to simultaneously serotype E. coli and detect the presence of virulence and pathogenicity markers. Here, we describe the development of a family of multiplex molecular serotyping methods for Shiga toxin-producing E. colt, compare their performance to traditional serotyping methods, and discuss the cost-benefit balance of these methods in the context of various food safety objectives. C1 [Carter, John M.] ARS, Pacific West Area, Western Reg Res Ctr, Produce Safety & Microbiol Res,USDA, Albany, CA USA. [Lin, Andrew] US FDA, ORA PA FO SAN LB, Off Global Regulatory Operat & Policy, Oceans Reefs & Aquariums,US Dept Hlth & Human Ser, Alameda, CA USA. [Clotilde, Laurie] MagArray Inc, Milpitas, CA USA. [Lesho, Matthew] Luminex Corp, Austin, TX USA. RP Carter, JM (reprint author), ARS, Pacific West Area, Western Reg Res Ctr, Produce Safety & Microbiol Res,USDA, Albany, CA USA. EM mark@safetraces.com FU U.S. Department of Agriculture [108, CRIS 5325-42000-043-00D]; FDA San Francisco Laboratory; FDA Office of Regulatory Science; CFSAN Office of Regulatory Science FX U.S. Department of Agriculture work was funded under National Program 108, Food Safety, CRIS 5325-42000-043-00D. The authors would also like to thank the FDA San Francisco Laboratory, FDA Office of Regulatory Science, and CFSAN Office of Regulatory Science for their support of this research. NR 35 TC 0 Z9 0 U1 7 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 MAY 20 PY 2016 VL 7 AR 439 DI 10.3389/fmicb.2016.00439 PG 6 WC Microbiology SC Microbiology GA DM2AU UT WOS:000376149000001 PM 27242670 ER PT J AU Chen, Y Allard, E Wooten, A Hur, M Sheth, I Laasri, A Hammack, TS Macarisin, D AF Chen, Yi Allard, Emma Wooten, Anna Hur, Minji Sheth, Ishani Laasri, Anna Hammack, Thomas S. Macarisin, Dumitru TI Recovery and Growth Potential of Listeria monocytogenes in Temperature Abused Milkshakes Prepared from Naturally Contaminated Ice Cream Linked to a Listeriosis Outbreak SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE L. monocytogenes; ice cream; milkshake; growth potential; temperature abuse; outbreak ID SMOKED SALMON; INOCULUM SIZE; LAG PHASE; PREVALENCE; BEHAVIOR; KINETICS; SAUSAGE; STORAGE; MILK AB The recovery and growth potential of Listeria monocytogenes was evaluated in three flavors of milkshakes (vanilla, strawberry, and chocolate) that were prepared from naturally contaminated ice cream linked to a listeriosis outbreak in the U.S. in 2015, and were subsequently held at room temperature for 14 h. The average lag phase duration of L. monocytogenes was 9.05 h; the average generation time was 1.67 h; and the average population level increase per sample at 14 h was 1.14 log CFU/g. Milkshake flavors did not significantly affect these parameters. The average lag phase duration of L, monocytogenes in milkshakes with initial contamination levels <= 3 CFU/g (9.50 h) was significantly longer (P < 0.01) than that with initial contamination levels 3 CFU/g (8.60 h). The results highlight the value of using samples that are contaminated with very low levels of L. monocytogenes for recovery and growth evaluations. The behavior of L. monocytogenes populations in milkshakes prepared from naturally contaminated ice cream linked to the listeriosis outbreak should be taken into account when performing risk based analysis using this outbreak as a case study. C1 [Chen, Yi; Sheth, Ishani; Laasri, Anna; Hammack, Thomas S.; Macarisin, Dumitru] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Allard, Emma] Univ New Hampshire, Coll Agr & Life Sci, Durham, NH 03824 USA. [Wooten, Anna] Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 USA. [Hur, Minji] Gachon Univ, Dept Food Sci, Seoul, South Korea. RP Chen, Y (reprint author), US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD USA. EM yi.chen@fda.hhs.gov FU University of Maryland Joint Institute for Food Safety and Applied Nutrition through a cooperative agreement; U.S. Food and Drug Administration (FDA) [EDU001418] 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), #EDU001418, and in part by an appointment to the Research Participation Program at the FDA Center for Food Safety and Applied Nutrition, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. FDA. NR 26 TC 6 Z9 6 U1 3 U2 10 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 MAY 18 PY 2016 VL 7 AR 764 DI 10.3389/fmicb.2016.00764 PG 6 WC Microbiology SC Microbiology GA DL9ZY UT WOS:000376003300001 PM 27242775 ER PT J AU Schaer, CA Deuel, JW Schildknecht, D Mahmoudi, L Garcia-Rubio, I Owczarek, C Schauer, S Kissner, R Banerjee, U Palmer, AF Spahn, DR Irwin, DC Vallelian, F Buehler, PW Schaer, DJ AF Schaer, Christian A. Deuel, Jeremy W. Schildknecht, Daniela Mahmoudi, Leila Garcia-Rubio, Ines Owczarek, Catherine Schauer, Stefan Kissner, Reinhard Banerjee, Uddyalok Palmer, Andre F. Spahn, Donat R. Irwin, David C. Vallelian, Florence Buehler, Paul W. Schaer, Dominik J. TI Haptoglobin Preserves Vascular Nitric Oxide Signaling during Hemolysis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE hemolysis; hemoglobin; extravasation; PIT54; haptoglobin ID CELL-FREE HEMOGLOBIN; RED-BLOOD-CELLS; PULMONARY-HYPERTENSION; GUINEA-PIGS; PLASMA HEMOGLOBIN; INDUCED OXIDATION; STORAGE LESION; DISEASE; TRANSFUSION; COMPLEX AB Rationale: Hemolysis occurs not only in conditions such as sickle cell disease and malaria but also during transfusion of stored blood, extracorporeal circulation, and sepsis. Cell-free Hb depletes nitric oxide (NO) in the vasculature, causing vasoconstriction and eventually cardiovascular complications. We hypothesize that Hb-binding proteins may preserve vascular NO signaling during hemolysis. Objectives: Characterization of an archetypical function by which Hb scavenger proteins could preserve NO signaling during hemolysis. Methods: We investigated NO reaction kinetics, effects on arterial NO signaling, and tissue distribution of cell-free Hb and its scavenger protein complexes. Measurements and Main Results: Extravascular translocation of cell-free Hb into interstitial spaces, including the vascular smooth muscle cell layer of rat and pig coronary arteries, promotes vascular NO resistance. This critical disease process is blocked by haptoglobin. Haptoglobin does not change NO dioxygenation rates of Hb; rather, the large size of the Hb:haptoglobin complex prevents Hb extravasation, which uncouples NO/Hb interaction and vasoconstriction. Size-selective compartmentalization of Hb functions as a substitute for red blood cells after hemolysis and preserves NO signaling in the vasculature. We found that evolutionarily and structurally unrelated Hb-binding proteins, such as PIT54 found in avian species, functionally converged with haptoglobin to protect NO signaling by sequestering cell-free Hb in large protein complexes. Conclusions: Sequential compartmentalization of Hb by erythrocytes and scavenger protein complexes is an archetypical mechanism, which may have supported coevolution of hemolysis and normal vascular function. Therapeutic supplementation of Hb scavengers may restore vascular NO signaling and attenuate disease complications in patients with hemolysis. C1 [Schaer, Christian A.; Deuel, Jeremy W.; Schildknecht, Daniela; Mahmoudi, Leila; Vallelian, Florence; Schaer, Dominik J.] Univ Zurich, Div Internal Med, Zurich, Switzerland. [Schaer, Christian A.; Spahn, Donat R.] Univ Zurich, Inst Anesthesiol, Zurich, Switzerland. [Schauer, Stefan] Univ Zurich, Funct Genom Ctr Zurich, Zurich, Switzerland. [Schaer, Dominik J.] Univ Zurich, Inst Evolutionary Med, Zurich, Switzerland. [Garcia-Rubio, Ines] ETH, Phys Chem Lab, CH-8092 Zurich, Switzerland. [Kissner, Reinhard] ETH, Inst Inorgan Chem, Zurich, Switzerland. [Garcia-Rubio, Ines] Ctr Univ Defensa, Carretera Huesca, Zaragoza, Spain. [Owczarek, Catherine] CSL Ltd, Inst Bio21, Parkville, Vic, Australia. [Banerjee, Uddyalok; Palmer, Andre F.] Ohio State Univ, William G Lowrie Dept Chem & Biomol Engn, Columbus, OH 43210 USA. [Irwin, David C.; Buehler, Paul W.] Univ Colorado Denver, Sch Med, Aurora, CO USA. [Buehler, Paul W.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Schaer, DJ (reprint author), Univ Zurich Hosp, Div Internal Med, CH-8091 Zurich, Switzerland. EM dominik.schaer@usz.ch RI Kissner, Reinhard/C-8799-2016 OI Kissner, Reinhard/0000-0003-4703-1173 FU Swiss National Science Foundation [31003A/138500]; Swiss Federal Commission for Technology and Innovation; Institute of Evolutionary Medicine; Center of Integrative Human Physiology; Ministry of Health (Gesundheitsdirektion) of the Canton of Zurich Project Patient Blood Management; NHLBI [1R01HL125642-01A1] FX Supported by Swiss National Science Foundation grants 31003A/138500 (D.J.S.), Swiss Federal Commission for Technology and Innovation (D.J.S.), the Institute of Evolutionary Medicine (D.J.S.), the Center of Integrative Human Physiology (D.J.S.), the Ministry of Health (Gesundheitsdirektion) of the Canton of Zurich Project Patient Blood Management (D.R.S.), and NHLBI grant 1R01HL125642-01A1 (D.C.I. and P.W.B.). NR 46 TC 5 Z9 5 U1 3 U2 6 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY 15 PY 2016 VL 193 IS 10 BP 1111 EP 1122 DI 10.1164/rccm.201510-2058OC PG 12 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DM0RR UT WOS:000376054000013 PM 26694989 ER PT J AU Li, HF Borrego, F Nagata, S Tolnay, M AF Li, Huifang Borrego, Francisco Nagata, Satoshi Tolnay, Mate TI Fc Receptor-like 5 Expression Distinguishes Two Distinct Subsets of Human Circulating Tissue-like Memory B Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; REGULATORY T-CELLS; PROTEIN; POPULATION; ANTIBODIES; EXPANSION; FCRL4; DIFFERENTIATION; IDENTIFICATION; PROLIFERATION AB Fc receptor-like (FCRL) 5 is a novel IgG binding protein expressed on B cells, with the capacity to regulate Ag receptor signaling. We assessed FCRL5 expression on circulating B cells from healthy donors and found that FCRL5(+) cells are most enriched among atypical CD21(-/lo)/CD27(-) tissue-like memory (TLM) B cells, which are abnormally expanded in several autoimmune and infectious diseases. Using multicolor flow cytometry, FCRL5(+) TLM cells were found to express more CD11c and several inhibitory receptors than did the FCRL5(-) TLM subset. The homing receptor profiles of the two TLM subsets shared features consistent with migration away from lymphoid tissues, but they also displayed distinct differences. Analysis of IgH V regions in single cells indicated that although both subsets are diverse, the FCRL5(+) subset accumulated significantly more somatic mutations. Furthermore, the FCRL5(+) subset had more switched isotype expression and more extensive proliferative history. Microarray analysis and quantitative RT-PCR demonstrated that the two TLM subsets possess distinct gene expression profiles, characterized by markedly different CD11c, SOX5, T-bet, and RTN4R expression, as well as differences in expression of inhibitory receptors. Functional analysis revealed that the FCRL5(+) TLM subset responds poorly to multiple stimuli compared with the FCRL5(-) subset, as reflected by reduced calcium mobilization and blunted cell proliferation. We propose that the FCRL5(+) TLM subset, but not the FCRL5(-) TLM subset, underwent Ag-driven development and is severely dysfunctional. The present study elucidates the heterogeneity of TLM B cells and provides the basis to dissect their roles in the pathogenesis of inflammatory and infectious diseases. C1 [Li, Huifang; Tolnay, Mate] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Borrego, Francisco] BioCruces Hlth Res Inst, Immunopathol Grp, Baracaldo 48903, Spain. [Borrego, Francisco] Ikerbasque, Basque Fdn Sci, Bilbao 48013, Spain. [Nagata, Satoshi] Natl Inst Biomed Innovat Hlth & Nutr, Ctr Drug Design Res, Ibaraki, Osaka 5670085, Japan. RP Tolnay, M (reprint author), US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM mate.tolnay@fda.hhs.gov FU Intramural Research Program of the Center for Drug Evaluation and Research/U.S. Food and Drug Administration; Research Fellowship Program from the Center for Drug Evaluation and Research FX This work was supported by the Intramural Research Program of the Center for Drug Evaluation and Research/U.S. Food and Drug Administration. H.L. was supported by the Research Fellowship Program from the Center for Drug Evaluation and Research administered by the Oak Ridge Associated Universities. NR 45 TC 1 Z9 1 U1 2 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2016 VL 196 IS 10 BP 4064 EP 4074 DI 10.4049/jimmunol.1501027 PG 11 WC Immunology SC Immunology GA DL7OY UT WOS:000375831200009 PM 27076679 ER PT J AU Zhang, Y Zhang, JQ Sheng, W Wang, S Fu, TJ AF Zhang, Yan Zhang, Jieqiong Sheng, Wei Wang, Shuo Fu, Tong-Jen TI Effects of heat and high-pressure treatments on the solubility and immunoreactivity of almond proteins SO FOOD CHEMISTRY LA English DT Article DE Almond protein; Solubility; Immunoreactivity; Heat treatment; High pressure ID PRUNUS-DULCIS; STRUCTURAL-PROPERTIES; FOOD ALLERGENS; CASHEW NUT; AMANDIN; IMPACT; ANTIGENICITY; ISOLATE AB The effects of dry and moist heat, autoclave sterilization and high-pressure treatment on the biochemical characteristics and immunological properties of almond proteins were investigated. Changes in the solubility and immunoreactivity of almond proteins extracted from treated almond flour were evaluated using a total protein assay, indirect competitive inhibition enzyme-linked immunosorbent assay (IC-ELISA), and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Almond proteins were stable during dry-heat treatment at temperatures below 250 degrees C. Dry heat at 400 degrees C, boiling, autoclave sterilization and high-pressure treatment in the presence of water at >= 500 MPa greatly reduced the solubility and immunoreactivity of almond proteins. SDS-PAGE revealed that the protein profiles of almond flour samples treated under these conditions also changed significantly. The synergistic effects of heat, pressure and the presence of water contributed to significant changes in solubility and immunoreactivity of almond proteins. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Zhang, Yan; Zhang, Jieqiong; Sheng, Wei; Wang, Shuo] Tianjin Univ Sci & Technol, Key Lab Food Nutr & Safety, Minist Educ China, Tianjin 300457, Peoples R China. [Zhang, Yan] IIT, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. [Fu, Tong-Jen] US FDA, Div Food Proc Sci & Technol, Bedford Pk, IL 60501 USA. [Zhang, Jieqiong] Acad State Adm Grain, Dept Grain & Oil Safety, Beijing 100037, Peoples R China. RP Zhang, Y (reprint author), Tianjin Univ Sci & Technol, Key Lab Food Nutr & Safety, Minist Educ China, Tianjin 300457, Peoples R China.; Fu, TJ (reprint author), US FDA, Div Food Proc Sci & Technol, Bedford Pk, IL 60501 USA. EM yzhang@tust.edu.cn; tongjen.fu@fda.hhs.gov FU U.S. Food and Drug Administration [5U01FD003801]; IFSH [5U01FD003801]; Ministry of Science and Technology, PR China [2011AA100807] FX The initial phase of this work was conducted at the Institute for Food Safety and Health (IFSH) and was supported by the Cooperative Agreement 5U01FD003801 between the U.S. Food and Drug Administration and IFSH. The latter phase of the work was conducted at the Tianjin University of Science and Technology and was supported by the Ministry of Science and Technology, PR China (Project No. 2011AA100807). We thank Dr. Kristina Williams at the U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition (Laurel, MD) for preparing the anti-amandin antisera used in this study. NR 27 TC 0 Z9 1 U1 9 U2 89 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0308-8146 EI 1873-7072 J9 FOOD CHEM JI Food Chem. PD MAY 15 PY 2016 VL 199 BP 856 EP 861 DI 10.1016/j.foodchem.2015.12.063 PG 6 WC Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics SC Chemistry; Food Science & Technology; Nutrition & Dietetics GA DC2WF UT WOS:000369078600108 PM 26776044 ER PT J AU Wang, X Mbondji-Wonje, C Zhao, JQ Hewlett, I AF Wang, Xue Mbondji-Wonje, Christelle Zhao, Jiangqin Hewlett, Indira TI IL-1 beta and IL-18 inhibition of HIV-1 replication in Jurkat cells and PBMCs SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE IL-1 beta; IL-18; HIV-1; Replication; Caspase-3; Caspase-1 ID CD4 T-CELLS; INTERLEUKIN-18; INFECTION; MECHANISMS; EXPRESSION; DEATH; LINES; AIDS AB HIV-1 infection-induced apoptosis is able to ensure viral replication. The death of some CD4+ T cells residing in lymphoid tissues can be induced by HIV-1 infection through caspase-1 driven pyroptosis with release of cytokine of IL-1 beta and IL-18. It is not well known whether IL-1 beta and IL-18 affect HIV-1 replication in lymphocytic cells. Using susceptible lymphocytic cell line, Jurkat cells, and primary peripheral blood mononuclear cells (PBMCs), we studied the effects of IL-1 beta and IL-18 on HIV-1 replication. We found that treatment with exogenous IL-1 beta protein (rIL-1 beta) and IL-18 protein (rIL-18), or expression of IL-1 beta and IL-18 significantly reduced HIV-1 replication. HIV-1 infection enhanced caspase-3 expression and its activation, and had no effects on caspase-1 activity. Treatment with rIL-1 beta and rIL-18 dramatically lowered caspase-3 activity. IL-1 beta and IL-18 also played roles in diminishing reactivation of viral replication from latency in J1.1 cells. These results indicate that IL-1 beta and IL-18 are able to inhibit HIV-1 replication, and their effects may be due to signaling through apoptosis involved in inactivation of caspase-3 activity. (C) 2016 Elsevier Inc. All rights reserved. C1 [Wang, Xue; Mbondji-Wonje, Christelle; Zhao, Jiangqin; Hewlett, Indira] US FDA, Mol Virol Lab, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Wang, X (reprint author), CBER FDA, Mol Virol Lab, Bldg 72,Rm 4322,10903 New Hampshire Ave, Silver Spring, MD 20993 USA.; Hewlett, I (reprint author), CBER FDA, Mol Virol Lab, Bldg 72,Rm 4308,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM xue.wang@fda.hhs.gov; indira.hewlett@fda.hhs.gov FU internal CBER modernizing science grant FX The authors wish to acknowledge of Dr. Mohan Haleyurgirisetty and Dr. Viswanath Ragupathy for critical review of this manuscript, and acknowledge of the NIH AIDS reagent repository for the reagents. This work was supported by an internal CBER modernizing science grant. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. NR 20 TC 1 Z9 1 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 13 PY 2016 VL 473 IS 4 BP 926 EP 930 DI 10.1016/j.bbrc.2016.03.153 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DL7MB UT WOS:000375823700024 PM 27049306 ER PT J AU Zhao, WZ Chen, JJ Perkins, R Wang, YP Liu, ZC Hong, HX Tong, WD Zou, W AF Zhao, Weizhong Chen, James J. Perkins, Roger Wang, Yuping Liu, Zhichao Hong, Huixiao Tong, Weida Zou, Wen TI A novel procedure on next generation sequencing data analysis using text mining algorithm SO BMC BIOINFORMATICS LA English DT Article DE Data mining; Topic modeling; Next-generation sequencing (NGS); Genetic diversity; Biomarker ID FIELD GEL-ELECTROPHORESIS; LATENT DIRICHLET ALLOCATION; SALMONELLA-SEROTYPES; IDENTIFICATION; ENTERICA; PREDICTION; ALIGNMENT; SYSTEM AB Background: Next-generation sequencing (NGS) technologies have provided researchers with vast possibilities in various biological and biomedical research areas. Efficient data mining strategies are in high demand for large scale comparative and evolutional studies to be performed on the large amounts of data derived from NGS projects. Topic modeling is an active research field in machine learning and has been mainly used as an analytical tool to structure large textual corpora for data mining. Methods: We report a novel procedure to analyse NGS data using topic modeling. It consists of four major procedures: NGS data retrieval, preprocessing, topic modeling, and data mining using Latent Dirichlet Allocation (LDA) topic outputs. The NGS data set of the Salmonella enterica strains were used as a case study to show the workflow of this procedure. The perplexity measurement of the topic numbers and the convergence efficiencies of Gibbs sampling were calculated and discussed for achieving the best result from the proposed procedure. Results: The output topics by LDA algorithms could be treated as features of Salmonella strains to accurately describe the genetic diversity of fliC gene in various serotypes. The results of a two-way hierarchical clustering and data matrix analysis on LDA-derived matrices successfully classified Salmonella serotypes based on the NGS data. The implementation of topic modeling in NGS data analysis procedure provides a new way to elucidate genetic information from NGS data, and identify the gene-phenotype relationships and biomarkers, especially in the era of biological and medical big data. Conclusion: The implementation of topic modeling in NGS data analysis provides a new way to elucidate genetic information from NGS data, and identify the gene-phenotype relationships and biomarkers, especially in the era of biological and medical big data. C1 [Zhao, Weizhong; Chen, James J.; Perkins, Roger; Wang, Yuping; Liu, Zhichao; Hong, Huixiao; Tong, Weida; Zou, Wen] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT-20, Jefferson, AR 72079 USA. [Zhao, Weizhong] Xiangtan Univ, Coll Informat Engn, Xiangtan, Hunan, Peoples R China. RP Zou, W (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT-20, Jefferson, AR 72079 USA. EM wen.zou@fda.hhs.gov FU Oak Ridge Institute for Science and Education; FDA FX This work and the publication were funded by FDA. Dr. Weizhong Zhao acknowledges the support of a fellowship from the Oak Ridge Institute for Science and Education, administered through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. We are grateful to Ms. Beth Juliar and Dr. John Sutherland for critical reading of this manuscript. NR 49 TC 1 Z9 1 U1 15 U2 40 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD MAY 13 PY 2016 VL 17 AR 213 DI 10.1186/s12859-016-1075-9 PG 15 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DL7VW UT WOS:000375849200001 PM 27177941 ER PT J AU Gannavaram, S Bhattacharya, P Ismail, N Kaul, A Singh, R Nakhasi, HL AF Gannavaram, Sreenivas Bhattacharya, Parna Ismail, Nevien Kaul, Amit Singh, Rakesh Nakhasi, Hira L. TI Modulation of innate immune Mechanisms to enhance Leishmania vaccine-induced immunity: Role of Coinhibitory Molecules SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE leishmaniasis; vaccine; coinhibitory molecules; CD200R; PD-L1; CTLA-4; TIM-3; CD200 ID T-CELL EXHAUSTION; EXPERIMENTAL VISCERAL LEISHMANIASIS; ANTIGEN CROSS-PRESENTATION; C VIRUS-INFECTION; DENDRITIC CELLS; MAJOR INFECTION; PROTECTIVE IMMUNITY; DONOVANI INFECTION; IN-VIVO; THERAPEUTIC INTERVENTION AB No licensed human vaccines are currently available against any parasitic disease including leishmaniasis. Several antileishmanial vaccine formulations have been tested in various animal models, including genetically modified live-attenuated parasite vaccines. Experimental infection studies have shown that Leishmania parasites utilize a broad range of strategies to undermine effector properties of host phagocytic cells, i.e., dendritic cells (DCs) and macrophages (MF). Furthermore, Leishmania parasites have evolved strategies to actively inhibit T(H)1 polarizing functions of DCs and to condition the infected MF toward anti-inflammatory/alternative/M2 phenotype. The altered phenotype of phagocytic cells is characterized by decreased production of antimicrobial reactive oxygen, nitrogen molecules, and pro-inflammatory cytokines, such as IFN-gamma, IL-12, and TNF-alpha. These early events limit the activation of T(H)1-effector cells and set the stage for pathogenesis. Furthermore, this early control of innate immunity by the virulent parasites results in substantial alteration in the adaptive immunity characterized by reduced proliferation of CD4(+) and CD8(+) T cells and T(H)2-biased immunity that results in production of anti-inflammatory cytokines, such as TGF-beta, and IL-10. More recent studies have also documented the induction of coinhibitory ligands, such as CTLA-4, PD-L1, CD200, and Tim-3, that induce exhaustion and/or non-proliferation in antigen-experienced T cells. Most of these studies focus on viral infections in chronic phase, thus limiting the direct application of these results to parasitic infections and much less to parasitic vaccines. However, these studies suggest that vaccine-induced protective immunity can be modulated using strategies that enhance the costimulation that might reduce the threshold necessary for T cell activation and conversely by strategies that reduce or block inhibitory molecules, such as PD-L1 and CD200. In this review, we will focus on the polarization of antigen-presenting cells and subsequent role of costimulatory and coinhibitory molecules in mediating vaccine-induced immunity using live-attenuated Leishmania parasites as specific examples. C1 [Gannavaram, Sreenivas; Bhattacharya, Parna; Ismail, Nevien; Kaul, Amit; Nakhasi, Hira L.] US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Silver Spring, MD USA. [Singh, Rakesh] Banaras Hindu Univ, Dept Biochem, Varanasi 221005, Uttar Pradesh, India. RP Gannavaram, S; Nakhasi, HL (reprint author), US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Silver Spring, MD USA. EM sreenivas.gannavaram@fda.hhs.gov; hira.nakhasi@fda.hhs.gov NR 129 TC 1 Z9 1 U1 2 U2 7 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD MAY 13 PY 2016 VL 7 AR UNSP 187 DI 10.3389/fimmu.2016.00187 PG 10 WC Immunology SC Immunology GA DL6WN UT WOS:000375780800002 PM 27242794 ER PT J AU Zhou, WL Wang, PG Wittenberg, JB Rua, D Krynitsky, AJ AF Zhou, Wanlong Wang, Perry G. Wittenberg, James B. Rua, Diego Krynitsky, Alexander J. TI Simultaneous determination of cosmetics ingredients in nail products by fast gas chromatography with tandem mass spectrometry SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Nail products; Cosmetics; GC-MS/MS; Toluene; N-methylpyrrolidone; 2,4-Dihydroxybenzophenone; Diethylene glycol dimethacrylate ID PERFORMANCE LIQUID-CHROMATOGRAPHY; CAPILLARY-ELECTROPHORESIS; PHASE MICROEXTRACTION; WATER SAMPLES; DENTAL RESIN; UV FILTERS; BENZOPHENONES; EXTRACTION; IDENTIFICATION; SALICYLATE AB A rapid and sensitive gas chromatography with tandem mass spectrometry (GC-MS/MS) method has been developed and validated to quantitatively determine cosmetic ingredients, such as toluene, N-methylpyrrolidone, 2,4-dihydroxybenzophenone (benzophenone-1, BP-1), and diethylene glycol dimethacrylate, in nail products. In this procedure, test portions were extracted with acetone, followed by vortexing, sonication, centrifugation, and filtration. During the extraction procedure, BP-1 was derivatized making it amenable to GC-MS analysis, using N,O-bis(trimethylsilyl) trifluoroacetamide. The four ingredients were quantified by GC-MS/MS in an electron ionization mode. Four corresponding stable isotopically labeled analogues were selected as internal standards, which were added at the beginning of the sample preparation to correct for recoveries and matrix effects. The validated method was used to screen 34 commercial nail products for these four cosmetic ingredients. The most common ingredients detected in the nail products were toluene and BP-1. Toluene was detected in 26 products and ranged from 1.36 to 173,000 g/g. BP-1 ranged from 18.3 to 2,370 mu g/g in 10 products. Published by Elsevier B.V. C1 [Zhou, Wanlong; Wang, Perry G.; Wittenberg, James B.; Rua, Diego; Krynitsky, Alexander J.] US FDA, Off Regulatory Sci, CFSAN HFS 717,5100 Paint Branch Pkwy, College Pk, MD 20740 USA. RP Zhou, WL (reprint author), US FDA, Off Regulatory Sci, CFSAN HFS 717,5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Wanlong.zhou@fda.hhs.gov NR 23 TC 1 Z9 1 U1 13 U2 19 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 MAY 13 PY 2016 VL 1446 BP 134 EP 140 DI 10.1016/j.chroma.2016.04.003 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DL3AN UT WOS:000375506700024 PM 27083261 ER PT J AU Zhang, W Hu, SL Yin, JJ He, WW Lu, W Ma, M Gu, N Zhang, Y AF Zhang, Wei Hu, Sunling Yin, Jun-Jie He, Weiwei Lu, Wei Ma, Ming Gu, Ning Zhang, Yu TI Prussian Blue Nanoparticles as Multienzyme Mimetics and Reactive Oxygen Species Scavengers SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID HEART CYTOCHROME-C; INFRARED-SPECTROSCOPY; REDUCTION; PROTEIN; ELECTROCHEMISTRY; OXIDATION; SURFACES; ANALOGS; CANCER; FILMS AB The generation of reactive oxygen species (ROS) is an important mechanism of nanomaterial toxicity. We found that Prussian blue nanoparticles (PBNPs) can effectively scavenge ROS via multienzyme-like activity including peroxidase (POD),. catalase (CAT), and superoxide dismutase (SOD) activity. Instead of producing hydroxyl radicals (center dot OH) through the Fenton reaction, PBNPs were shown to be POD mimetics that can inhibit center dot OH generation. We theorized for the first time that the multienzyme-like activities :of PBNPs were likely caused by the abundant redox potentials of their different forms, making them efficient electron transporters. To study the ROS scavenging ability of PBNPs, a series of in vitro ROS-generating models was established using, chemicals, UV irradiation, oxidized low-density lipoprotein, high glucose contents, and,oxygen glucose deprivation and reperfusion. To demonstrate the ROS scavenging ability of PBNPs, an in vivo inflammation model was established using lipoproteins in Institute for Cancer Research (ICR) mite. The results indicated that PBNPs hold great potential for inhibiting or relieving injury induced by ROS in these pathological processes. electrochemistry, C1 [Zhang, Wei; Hu, Sunling; Ma, Ming; Gu, Ning; Zhang, Yu] Southeast Univ, Sch Biol Sci & Med Engn, Jiangsu Key Lab Biomat & Devices, State Key Lab Bioelect, Nanjing 210096, Jiangsu, Peoples R China. [Zhang, Wei; Hu, Sunling; Ma, Ming; Gu, Ning; Zhang, Yu] Southeast Univ, Collaborat Innovat Ctr Suzhou Nano Sci & Technol, Nanjing 210096, Jiangsu, Peoples R China. [Yin, Jun-Jie; He, Weiwei] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, Div Analyt Chem, College Pk, MD 20740 USA. [Lu, Wei] Nanjing Med Univ, Dept Neurobiol, Nanjing 210096, Jiangsu, Peoples R China. [Lu, Wei] Southeast Univ, Inst Life Sci, Key Lab Dev Genes & Human Dis, Nanjing 210096, Jiangsu, Peoples R China. RP Gu, N; Zhang, Y (reprint author), Southeast Univ, Sch Biol Sci & Med Engn, Jiangsu Key Lab Biomat & Devices, State Key Lab Bioelect, Nanjing 210096, Jiangsu, Peoples R China.; Gu, N; Zhang, Y (reprint author), Southeast Univ, Collaborat Innovat Ctr Suzhou Nano Sci & Technol, Nanjing 210096, Jiangsu, Peoples R China. EM guning@seu.edu.cn; zhangyu@seu.edu.cn RI Yin, Jun Jie /E-5619-2014 FU National Basic Research Program of China [2011CB933503, 2013CB733800]; National Natural Science Foundation of China [31170959, 81571806]; Basic Research Program of Jiangsu Province [BK2011036]; Jiangsu Provincial Technical Innovation Fund for Scientific and Technological Enterprises [SBC201310643]; Jiangsu Provincial Special Program of Medicine Science [BL2013029]; regulatory science grant under the FDA Nanotechnology CORES Program FX This research was supported by the National Basic Research Program of China (Nos. 2011CB933503, 2013CB733800), the National Natural Science Foundation of China (Nos. 31170959, 81571806), the Basic Research Program of Jiangsu Province (No. BK2011036), the Jiangsu Provincial Technical Innovation Fund for Scientific and Technological Enterprises (No. SBC201310643), and the Jiangsu Provincial Special Program of Medicine Science (BL2013029). This work was partially supported by a regulatory science grant under the FDA Nanotechnology CORES Program. This article is not an official U.S. FDA guidance or policy statement. No official support or endorsement by the U.S. FDA is intended or should be inferred. NR 41 TC 14 Z9 14 U1 62 U2 106 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAY 11 PY 2016 VL 138 IS 18 BP 5860 EP 5865 DI 10.1021/jacs.5b12070 PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA DL8JU UT WOS:000375889100027 PM 26918394 ER PT J AU Haber, P Moro, PL Lewis, P Woo, EJ Jankosky, C Cano, M AF Haber, Penina Moro, Pedro L. Lewis, Paige Woo, Emily Jane Jankosky, Christopher Cano, Maria TI Post-licensure surveillance of quadrivalent inactivated influenza (IIV4) vaccine in the United States, Vaccine Adverse Event Reporting System (VAERS), July 1, 2013-May 31, 2015 SO VACCINE LA English DT Article DE Vaccine safety; Post-licensure surveillance; Quadrivalent inactivated influenza vaccines ID GUILLAIN-BARRE-SYNDROME; IMMUNIZATION SAFETY DATA; SEASONAL INFLUENZA; FEBRILE SEIZURES; DATALINK PROJECT; CHILDREN; RISK; ANAPHYLAXIS; SIGNAL; COLLECTION AB Background: Quadrivalent inactivated influenza vaccines (11V4) were first available for use during 2013-14 influenza season for individuals aged >= 6 months. IIV4 is designed to protect against four different flu viruses; two influenza A viruses and two influenza B viruses. Methods: We searched the Vaccine Adverse Event Reporting System (VAERS) for US reports after IIV4 and trivalent inactivated influenza vaccine (IIV3) from 7/1/2013-5/31/2015. Medical records were requested for non-manufacturer reports classified as serious (i.e. death, hospitalization, prolonged hospitalization, life-threatening illness, permanent disability). The review included automated data analysis, clinical review of all serious reports, reports of special interest, and empirical Bayesian data mining. Results: VAERS received 1,838 IIV4 reports; 512 (28%) in persons aged 6 months-17 years of which 42 (8.2%) were serious reports; 1,265 (69%) in persons aged >18 years of which 84(6.6%) were serious reports; two in children <6 months and 59 in persons of unknown age. Injection site erythema (24%), fever (14%) and injection site swelling (17%) were the most frequent adverse events among persons aged 6 months-17 years, while injection site pain (16%), pain (15%) and pain in extremity (13%) were the most frequent among persons aged 18-64 years given the vaccine alone. Among non-death serious reports, injection site reactions, constitutional symptoms, Guillain-Barre syndrome, seizures, and anaphylaxis were the most frequently reported adverse events. Data mining detected disproportional reporting for incorrect vaccine administration with no associated adverse events. Adverse events following IIV4 reported to VAERS were similar to those following IIV3. Conclusions: In our review of VAERS reports, IIV4 had a similar safety profile to IIV3. Most of the reported AEs were non-serious. Our findings are consistent with data from pre-licensure studies of IIV4. Published by Elsevier Ltd. C1 [Haber, Penina; Moro, Pedro L.; Lewis, Paige; Cano, Maria] Ctr Dis Control & Prevent CDC, NCEZID, Div Healthcare Qual Promot, Immunizat Safety Off, 1600 Clifton Rd NE, Atlanta, GA 30329 USA. [Woo, Emily Jane; Jankosky, Christopher] US FDA, Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, Silver Spring, MD USA. RP Haber, P (reprint author), Ctr Dis Control & Prevent CDC, NCEZID, Div Healthcare Qual Promot, Immunizat Safety Off, 1600 Clifton Rd NE, Atlanta, GA 30329 USA. EM PHaber@cdc.gov NR 34 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD MAY 11 PY 2016 VL 34 IS 22 BP 2507 EP 2512 DI 10.1016/j.vaccine.2016.03.048 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DM2XM UT WOS:000376211400008 PM 27015735 ER PT J AU Zerhouni, E Hamburg, M AF Zerhouni, Elias Hamburg, Margaret TI The need for global regulatory harmonization: A public health imperative SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material C1 [Zerhouni, Elias] Sanofi, Global R&D, Paris, France. [Zerhouni, Elias] US Natl Inst Hlth, Bethesda, MD 20892 USA. [Hamburg, Margaret] US Natl Acad Med, Washington, DC 20001 USA. [Hamburg, Margaret] US Food & Drug Adm FDA, Silver Spring, MD 20993 USA. [Hamburg, Margaret] New York City Dept Hlth & Mental Hyg, New York, NY 10013 USA. RP Zerhouni, E (reprint author), Sanofi, Global R&D, Paris, France.; Hamburg, M (reprint author), US Natl Acad Med, Washington, DC 20001 USA. EM Elias.Zerhouni@sanofi.com; Mhamburg@nas.edu NR 3 TC 2 Z9 2 U1 1 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAY 11 PY 2016 VL 8 IS 338 AR 338ed6 DI 10.1126/scitranslmed.aaf1396 PG 2 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DL7PN UT WOS:000375832700001 PM 27169801 ER PT J AU Lowy, N Whyte, J AF Lowy, Naomi Whyte, John TI US Food and Drug Administration and Representation of Older Adults in Clinical Trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Lowy, Naomi; Whyte, John] US FDA, Silver Spring, MD USA. RP Lowy, N (reprint author), US FDA, Silver Spring, MD USA. NR 2 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 10 PY 2016 VL 34 IS 14 BP 1706 EP U263 DI 10.1200/JCO.2015.64.7099 PG 2 WC Oncology SC Oncology GA DL0FZ UT WOS:000375309100025 PM 27001580 ER PT J AU Allman, WR Liu, LH Coleman, AS Akkoyunlu, M AF Allman, Windy R. Liu, Lunhua Coleman, Adam S. Akkoyunlu, Mustafa TI MRL Strains Have a BAFFR Mutation without Functional Consequence SO PLOS ONE LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; AUTOREACTIVE B-CELLS; FAMILY-MEMBER BIM; DISEASE-ACTIVITY; TACI EXPRESSION; MESSENGER-RNA; IPR GENE; MICE; RECEPTOR; AUTOIMMUNITY AB It has been shown that B cell activating factor receptor (BAFFR) is critical for B cell development and survival. In this study, we sought to evaluate the expression and function of BAFFR across multiple stains of mice that vary in their potential to develop systemic autoimmune disease. The inability of a commercial antibody to bind to BAFFR in the autoimmune prone mouse strains, MRL and MRL/Lpr led to the discovery of a mutation in TNFRSF13C gene (encoding BAFFR) that resulted in a Pro44Ser substitution in the N-terminus near the BAFF binding site in these strains. To define the biological consequences of mutant BAFFR, we compared the expression and activity of BAFFR in MRL and MRL/Lpr mice to BALB/c, which express the consensus version of TNFRSF13C. B cells from MRL and MRL/Lpr mice expressed mutant BAFFR on surface and were capable of responding to BAFF as exhibited by BAFF-mediated reduction in apoptosis and NF-kappa B2 activation. Signaling through MAPK ERK1/2 was not significantly induced by BAFF in MRL/Lpr mice; however, MAPK ERK1/2 signaling was intact in MRL mice. The inability of MRL/Lpr B cells to significantly activate ERK1/2 in response to BAFF was due to the high basal activity of the signaling pathway in these cells. In fact, basal activity of ERK1/2 in B cells correlated with the degree of autoimmune susceptibility exhibited by each strain. In addition, aged MRL/Lpr mice with severe autoimmune disease had high BAFF levels, low surface BAFFR, and high basal NF-kappa B2 activation, a pattern which is attributed to the high frequency of antibody secreting cells. We conclude that P44S BAFFR mutation does not hinder BAFFR function or enhance B cell activity in MRL/Lpr and MRL mice and that other susceptibility loci on the MRL background contributed to the hyperactivity of these cells. C1 [Allman, Windy R.; Liu, Lunhua; Coleman, Adam S.; Akkoyunlu, Mustafa] US FDA, Lab Bacterial Polysaccharides, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP Akkoyunlu, M (reprint author), US FDA, Lab Bacterial Polysaccharides, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Mustafa.Akkoyunlu@fda.hhs.gov FU Office of Women's Health, US Food and Drug Administration; Oak Ridge Institute for Science and Education (Oak Ridge, TN) FX This work was supported by funds from the Office of Women's Health, US Food and Drug Administration. W.R.A. and A.S.C. were supported by postdoctoral fellowships from the Oak Ridge Institute for Science and Education (Oak Ridge, TN). NR 53 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 MAY 5 PY 2016 VL 11 IS 5 AR e0154518 DI 10.1371/journal.pone.0154518 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL5KV UT WOS:000375676800037 PM 27149280 ER PT J AU Sullivan, HW Aikin, KJ Chung-Davies, E Wade, M AF Sullivan, Helen W. Aikin, Kathryn J. Chung-Davies, Eunice Wade, Michael TI Prescription Drug Promotion from 2001-2014: Data from the US Food and Drug Administration SO PLOS ONE LA English DT Article ID CONSUMER; TELEVISION; EXPOSURE AB The volume of prescription drug promotion over time is often measured by assessing changes in ad spending. However, this method obscures the fact that some types of advertising are more expensive than others. Another way to measure the changes in prescription drug promotion over time is to assess the number of promotional pieces submitted to the U.S. Food and Drug Administration (FDA). Form FDA 2253 collects information such as the date submitted and the type of material submitted. We analyzed data from Forms FDA 2253 received from 2001-2014. We examined the frequency of submissions by audience (consumer and healthcare professional) and type of promotional material. There was a noted increase in prescription drug promotion submissions across all media in the early 2000s. Although non-Internet promotion submissions have since plateaued, Internet promotion continued to increase. These results can help public health advocates and regulators focus attention and resources. C1 [Sullivan, Helen W.; Aikin, Kathryn J.; Chung-Davies, Eunice; Wade, Michael] US FDA, Silver Spring, MD USA. RP Sullivan, HW (reprint author), US FDA, Silver Spring, MD USA. EM Helen.Sullivan@fda.hhs.gov NR 21 TC 1 Z9 1 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 5 PY 2016 VL 11 IS 5 AR e0155035 DI 10.1371/journal.pone.0155035 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DL5KV UT WOS:000375676800109 PM 27149513 ER PT J AU Lawson, LS Rodriguez, JD AF Lawson, Latevi S. Rodriguez, Jason D. TI Raman Barcode for Counterfeit Drug Product Detection SO ANALYTICAL CHEMISTRY LA English DT Article ID SPECTROSCOPY; IDENTIFICATION; CHEMOMETRICS; MEDICINES; SUPPLEMENTS; TABLETS AB Potential infiltration of counterfeit drug products containing the wrong or no active pharmaceutical ingredient (API) into the bona fide drug supply poses a significant threat to consumers worldwide. Raman spectroscopy offers a rapid, nondestructive avenue to screen a high throughput of samples. Traditional qualitative Raman identification is typically done with spectral correlation methods that compare the spectrum of a reference sample to an unknown. This is often effective for pure materials but is quite challenging when dealing with drug products that contain different formulations of active and inactive ingredients. Typically, reliable identification of drug products using common spectral correlation algorithms can only be made if the specific product under study is present in the library of reference spectra, thereby limiting the scope of products that can be screened. In this paper, we introduce the concept of the Raman barcode for identification of drug products by comparing the known peaks in the API reference spectrum to the peaks present in the finished drug product under study. This method requires the transformation of the Raman spectra of both API and finished drug products into a barcode representation by assigning zero intensity to every spectral frequency except the frequencies that correspond to Raman peaks. By comparing the percentage of nonzero overlap between the expected API barcode and finished drug product barcode, the identity of API present can be confirmed. In this study, 18 approved finished drug products and nine simulated counterfeits were successfully identified with 100% accuracy utilizing this method. C1 [Lawson, Latevi S.; Rodriguez, Jason D.] US FDA, Div Pharmaceut Anal, Ctr Drug Evaluat & Res, 645 South Newstead Ave, St Louis, MO 63110 USA. RP Rodriguez, JD (reprint author), US FDA, Div Pharmaceut Anal, Ctr Drug Evaluat & Res, 645 South Newstead Ave, St Louis, MO 63110 USA. EM Jason.Rodriguez@fda.hhs.gov FU CDER Critical Path and Regulatory Science & Review Enhancement Programs; Center for Drug Evaluation and Research FX This project was supported in part by the CDER Critical Path and Regulatory Science & Review Enhancement Programs. This project was supported in part by an appointment (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. NR 25 TC 1 Z9 1 U1 14 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD MAY 3 PY 2016 VL 88 IS 9 BP 4706 EP 4713 DI 10.1021/acs.analchem.5b04636 PG 8 WC Chemistry, Analytical SC Chemistry GA DR0ZV UT WOS:000379636600019 PM 27043140 ER PT J AU Fratamico, PM DebRoy, C Liu, YH Needleman, DS Baranzoni, GM Feng, P AF Fratamico, Pina M. DebRoy, Chitrita Liu, Yanhong Needleman, David S. Baranzoni, Gian Marco Feng, Peter TI Advances in Molecular Serotyping and Subtyping of Escherichia coli SO FRONTIERS IN MICROBIOLOGY LA English DT Review DE Escherichia coli; molecular serotyping; subtyping; detection; identification; whole genome sequencing; O-group; H-type ID ANTIGEN GENE-CLUSTER; O SEROGROUP IDENTIFICATION; FIELD GEL-ELECTROPHORESIS; REAL-TIME PCR; MULTIPLEX-PCR; H-ANTIGEN; EXTRAINTESTINAL INFECTIONS; NUCLEOTIDE POLYMORPHISMS; SEQUENCING DATA; STRAINS AB Escherichia coli plays an important role as a member of the gut microbiota; however, pathogenic strains also exist, including various diarrheagenic E. coli pathotypes and extraintestinal pathogenic E. coli that cause illness outside of the GI-tract. E. cols have traditionally been serotyped using antisera against the ca. 186 O-antigens and 53 H-flagellar antigens. Phenotypic methods, including bacteriophage typing and O- and H- serotyping for differentiating and characterizing E. coli have been used for many years; however, these methods are generally time consuming and not always accurate. Advances in next generation sequencing technologies have made it possible to develop genetic-based subtyping and molecular serotyping methods for E. coli, which are more discriminatory compared to phenotypic typing methods. Furthermore, whole genome sequencing (WGS) of E. coli is replacing established subtyping methods such as pulsed field gel electrophoresis, providing a major advancement in the ability to investigate food-borne disease outbreaks and for trace-back to sources. A variety of sequence analysis tools and bioinformatic pipelines are being developed to analyze the vast amount of data generated by WGS and to obtain specific information such as O- and H-group determination and the presence of virulence genes and other genetic markers. C1 [Fratamico, Pina M.; Needleman, David S.; Baranzoni, Gian Marco] USDA ARS, Eastern Reg Res Ctr, Wyndmoor, PA USA. [DebRoy, Chitrita] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Feng, Peter] US FDA, Div Microbiol, College Pk, MD USA. RP Fratamico, PM (reprint author), USDA ARS, Eastern Reg Res Ctr, Wyndmoor, PA USA. EM pina.fratamico@ars.usda.gov FU Agricultural Research services (ARS) Research Participation Program; DOE [DE-AC05-060R23100] FX This work was supported in part by an appointment to the Agricultural Research services (ARS) Research Participation Program which is administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy (DOE) and the USDA. ORISE is managed by ORAU under DOE contract number DE-AC05-060R23100. All opinions expressed in this manuscript are the author's and do not necessarily reflect the policies and views of USDA, ARS, DOE, or ORAU/ORISE. NR 94 TC 5 Z9 5 U1 9 U2 20 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 MAY 3 PY 2016 VL 7 AR 644 DI 10.3389/fmicb.2016.00644 PG 8 WC Microbiology SC Microbiology GA DL1MX UT WOS:000375397400001 PM 27199968 ER PT J AU Wittayanukorn, S Babiskin, A Dutcher, S Pu, X Hu, M Zhao, L Lionberger, R AF Wittayanukorn, S. Babiskin, A. Dutcher, S. Pu, X. Hu, M. Zhao, L. Lionberger, R. TI PATTERNS OF BIOEQUIVALENCE RECOMENDATIONS AND TRENDS OF ABBREVIATED NEW DRUG APPLICATIONS APPROVAL OVER TIME SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Wittayanukorn, S.; Babiskin, A.; Dutcher, S.; Pu, X.; Hu, M.; Zhao, L.] US FDA, Div Quantitat Methods & Modeling, Off Res Stand, Off Gener Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Lionberger, R.] US FDA, Off Res Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD MAY PY 2016 VL 19 IS 3 MA PHP166 BP A286 EP A286 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA EL9HP UT WOS:000394931600426 ER PT J AU Etienne, C Califf, R AF Etienne, Carissa Califf, Robert TI Strengthening of regulatory systems for medicines in the Americas SO REVISTA PANAMERICANA DE SALUD PUBLICA-PAN AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Etienne, Carissa] World Hlth Org Amer, Pan Amer Hlth Org, Amer Sanit Bureau, Reg Off, Washington, DC USA. [Califf, Robert] US FDA, Food & Drugs, Washington, DC USA. RP Etienne, C (reprint author), World Hlth Org Amer, Pan Amer Hlth Org, Amer Sanit Bureau, Reg Off, Washington, DC USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU PAN AMER HEALTH ORGANIZATION PI WASHINGTON PA 525 23RD ST NW, WASHINGTON, DC 20037 USA SN 1020-4989 J9 REV PANAM SALUD PUBL JI Rev. Panam. Salud Publica PD MAY PY 2016 VL 39 IS 5 BP 213 EP 214 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EC9FA UT WOS:000388448600001 PM 27706405 ER PT J AU Bolanos, R Bond, K Child, R Coto, JV Cummings, R Dellepiane, N Fitzgerald, J Parker, C Pereira, P Tepoz, JSY Stergachis, A AF Bolanos, Ricardo Bond, Katherine Child, Raquel Vicente Coto, Jose Cummings, Rudolph Dellepiane, Nora Fitzgerald, James Parker, Cathy Pereira, Patricia Sanchez y Tepoz, Julio Stergachis, Andy TI Improving safety, quality and efficacy of medicines in the Americas SO REVISTA PANAMERICANA DE SALUD PUBLICA-PAN AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Bolanos, Ricardo] Adm Nacl Med Alimentos & Tecnol Med ANMAT, Buenos Aires, DF, Argentina. [Bond, Katherine] US Pharmacopeia, Rockville, MD USA. [Bond, Katherine] US FDA, Rockville, MD 20857 USA. [Child, Raquel] Minist Salud, Santiago, Chile. [Vicente Coto, Jose] Direcc Nacl Med, La Libertad, El Salvador. [Cummings, Rudolph] Caribbean Community CARICOM, Georgetown, Guyana. [Dellepiane, Nora] WHO, Geneva, Switzerland. [Fitzgerald, James] Pan Amer Hlth Org, Washington, DC USA. [Parker, Cathy] Hlth Canada, Calgary, AB, Canada. [Pereira, Patricia] Agencia Nacl Vigilincia Sanit ANVISA, Brasilia, DF, Brazil. [Sanchez y Tepoz, Julio] Comis Fed Protecc Riesgos Sanitarios COFEPRIS, Mexico City, CDMX, Mexico. [Stergachis, Andy] Univ Washington, Seattle, WA 98195 USA. RP Bolanos, R (reprint author), Adm Nacl Med Alimentos & Tecnol Med ANMAT, Buenos Aires, DF, Argentina. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PAN AMER HEALTH ORGANIZATION PI WASHINGTON PA 525 23RD ST NW, WASHINGTON, DC 20037 USA SN 1020-4989 J9 REV PANAM SALUD PUBL JI Rev. Panam. Salud Publica PD MAY PY 2016 VL 39 IS 5 BP 215 EP 216 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EC9FA UT WOS:000388448600002 PM 27706408 ER PT J AU Kazandjian, D Suzman, DL Blumenthal, G Mushti, S He, K Libeg, M Keegan, P Pazdur, R AF Kazandjian, Dickran Suzman, Daniel L. Blumenthal, Gideon Mushti, Sirisha He, Kun Libeg, Meredith Keegan, Patricia Pazdur, Richard TI FDA Approval Summary: Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With Progression On or After Platinum-Based Chemotherapy SO ONCOLOGIST LA English DT Article DE Nivolumab; Non-small cell lung carcinoma; PD-1 inhibitor; Immunotherapy ID DOCETAXEL; BLOCKADE; TRIAL AB On October 9, 2015, the U.S. Food and Drug Administration expanded the nivolumab metastatic non-small cell lung cancer (NSCLC) indication to include patients with nonsquamous NSCLC after a 3.25-month review timeline. Approval was based on demonstration of an improvement in overall survival (OS) in an international, multicenter, open-label, randomized trial comparing nivolumab to docetaxel in patients with metastatic nonsquamous NSCLC with progression on or after platinum-based chemotherapy. The CheckMate 057 trial enrolled 582 patients who were randomized (1: 1) to receive nivolumab or docetaxel. Nivolumab demonstrated improved OS compared with docetaxel at the prespecified interim analysis with a hazard ratio (HR) of 0.73 (p = .0015), and a median OS of 12.2 months (95% CI: 9.7-15.0 months) in patients treated with nivolumab compared with 9.4 months (95% CI: 8.0-10.7 months) in patients treated with docetaxel. A statistically significant improvement in objective response rate (ORR) was also observed, with an ORR of 19% (95% CI: 15%-24%) in the nivolumab arm and 12% (95% CI: 9%-17%) in the docetaxel arm. The median duration of response was 17 months in the nivolumab arm and 6 months in the docetaxel arm. Progression-free survival was not statistically different between arms. A prespecified retrospective subgroup analysis suggested that patients with programmed cell death ligand 1-negative tumors treated with nivolumab had similar OS to those treated with docetaxel. The toxicity profile of nivolumab was consistent with the known immune-mediated adverse event profile except for 1 case of grade 5 limbic encephalitis, which led to a postmarketing requirement study to better characterize immune-mediated encephalitis. C1 US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Kazandjian, D (reprint author), US FDA, White Oak Campus,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Dickran.kazandjian@fda.hhs.gov RI Mushti, Sirisha/K-3519-2016 NR 21 TC 14 Z9 15 U1 2 U2 2 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD MAY PY 2016 VL 21 IS 5 BP 634 EP 642 DI 10.1634/theoncologist.2015-0507 PG 9 WC Oncology SC Oncology GA DZ2IB UT WOS:000385664400020 PM 26984449 ER PT J AU Sul, J Blumenthal, GM Jiang, XP He, K Keegan, P Pazdur, R AF Sul, Joohee Blumenthal, Gideon M. Jiang, Xiaoping He, Kun Keegan, Patricia Pazdur, Richard TI FDA Approval Summary: Pembrolizumab for the Treatment of Patients With Metastatic Non-Small Cell Lung Cancer Whose Tumors Express Programmed Death-Ligand 1 SO ONCOLOGIST LA English DT Article DE Lung cancer; Pembrolizumab; Programmed death-ligand 1; US Food and Drug Administration ID TRIAL; CHEMOTHERAPY; DOCETAXEL AB On October 2, 2015, the U.S. Food and Drug Administration (FDA) granted accelerated approval for pembrolizumab, a breakthrough therapy-designated drug, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express programmed death-ligand 1 (PD-L1), as determined by an FDA-approved test, and who have disease progression on or after platinum-containing chemotherapy or targeted therapy against anaplastic lymphoma kinase or epidermal growth factor receptor, if appropriate. This indication was approved concurrently with the PD-L1 immunohistochemistry 22C3 pharmDx, a companion diagnostic test for patient selection based on PD-L1 tumor expression. The accelerated approval was granted based on durable objective response rate (ORR) and an acceptable toxicity profile demonstrated in a multicenter, open-label trial enrolling 550 patients with metastatic NSCLC. The efficacy population comprised 61 patients with tumors identified as strongly positive for PD-L1, and the confirmed ORR as determined by blinded independent central review was 41% (95% confidence interval: 28.6%, 54.3%); all were partial responses. At the time of the analysis, responses were ongoing in 21 of 25 patients (84%), with 11 patients (44%) having response duration of >= 6 months. The most commonly occurring (>= 20%) adverse reactions included fatigue, decreased appetite, dyspnea, and cough. The most frequent (>= 2%) serious adverse drug reactions were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Immune-mediated adverse reactions occurred in 13% of patients and included pneumonitis, colitis, hypophysitis, and thyroid disorders. The accelerated approval regulations describe approval of drugs and biologic products for serious and life-threatening illnesses based on a surrogate endpoint likely to predict clinical benefit. Under these regulations, a confirmatory trial or trials is required to verify and describe the benefit of pembrolizumab for patients with metastatic NSCLC. C1 [Sul, Joohee; Blumenthal, Gideon M.; Jiang, Xiaoping; He, Kun; Keegan, Patricia; Pazdur, Richard] US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,White Oak 22,Room 2331, Silver Spring, MD 20993 USA. RP Sul, J (reprint author), US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,White Oak 22,Room 2331, Silver Spring, MD 20993 USA. EM joohee.sul@fda.hhs.gov NR 11 TC 14 Z9 15 U1 2 U2 2 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD MAY PY 2016 VL 21 IS 5 BP 643 EP 650 DI 10.1634/theoncologist.2015-0498 PG 8 WC Oncology SC Oncology GA DZ2IB UT WOS:000385664400021 PM 27026676 ER PT J AU Cerniglia, CE Pineiro, SA Kotarski, SF AF Cerniglia, Carl E. Pineiro, Silvia A. Kotarski, Susan F. TI An update discussion on the current assessment of the safety of veterinary antimicrobial drug residues in food with regard to their impact on the human intestinal microbiome SO DRUG TESTING AND ANALYSIS LA English DT Article; Proceedings Paper CT SASKVAL 3rd International Workshop on Validation and Regulatory Analysis CY 2015 CL Calgary, CANADA DE antimicrobial agents; drug residues; safety assessment; microbiological effects; acceptable daily intake ID HUMAN COLONIC MICROFLORA; SELECTIVE DECONTAMINATION; GUT MICROBIOME; HUMAN FECES; AGENTS; FLORA; BINDING; MODEL; ENROFLOXACIN; BOWEL AB The human gastrointestinal tract ecosystem consists of complex and diverse microbial communities that have now been collectively termed the intestinal microbiome. Recent scientific breakthroughs and research endeavours have increased our understanding of the important role the intestinal microbiome plays in human health and disease. The use of antimicrobial new animal drugs in food-producing animals may result in the presence of low levels of drug residues in edible foodstuffs. There is concern that antimicrobial new animal drugs in or on animal-derived food products at residue-level concentrations could disrupt the colonization barrier and/or modify the antimicrobial resistance profile of human intestinal bacteria. Therapeutic doses of antimicrobial drugs have been shown to promote shifts in the intestinal microbiome, and these disruptions promote the emergence of antimicrobial-resistant bacteria. To assess the effects of antimicrobial new animal drug residues in food on human intestinal bacteria, many national regulatory agencies and international committees follow a harmonized process, VICH GL36(R), which was issued by a trilateral organization of the European Union, the USA, and Japan called the International Cooperation on Harmonization of Technical Requirements for Veterinary Medicinal Products ( VICH). The guidance describes a general approach currently used by national regulatory agencies and international committees to assess the effects of antimicrobial new animal drug residues in animal-derived food on human intestinal bacteria. The purpose of this review is to provide an overview of this current approach as part of the antimicrobial new animal drug approval process in participating countries, give insights on the microbiological endpoints used in this safety evaluation, and discuss the availability of new information. Copyright (C) 2016 John Wiley & Sons, Ltd. C1 [Cerniglia, Carl E.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Pineiro, Silvia A.] US FDA, Div Human Food Safety, Ctr Vet Med, Rockville, MD 20855 USA. [Kotarski, Susan F.] Zoetis, Vet Med Res & Dev, Kalamazoo, MI 49007 USA. RP Cerniglia, CE (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM carl.cerniglia@fda.hhs.gov NR 48 TC 4 Z9 4 U1 6 U2 6 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 MAY-JUN PY 2016 VL 8 IS 5-6 SI SI BP 539 EP 548 DI 10.1002/dta.2024 PG 10 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA DY0RG UT WOS:000384803300013 PM 27443209 ER PT J AU Park, JE Ramos, VFML Hallett, M AF Park, Jung E. Ramos, Vesper Fe Marie L. Hallett, Mark TI Tremor in a Bassoonist: Tremor in Dystonia or Essential Tremor? SO JOURNAL OF MOVEMENT DISORDERS LA English DT Letter ID TEMPORAL DISCRIMINATION C1 [Park, Jung E.; Ramos, Vesper Fe Marie L.; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 7D42,10 Ctr Dr, Bethesda, MD 20892 USA. [Park, Jung E.] Dongguk Univ, Dept Neurol, Ilsan Hosp, Goyang, South Korea. [Ramos, Vesper Fe Marie L.] US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Div Neurol & Phys Med,Neurodiagnost & Neurosurg D, White Oak, MD USA. RP Park, JE (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 7D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM junge.park@nih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU KOREAN MOVEMENT DISORDERS SOC PI SEOUL PA 2011 MAPO HANWHA OBELISK, 555, DOHWA-DONG, MAPO-GU, SEOUL, 04167, SOUTH KOREA SN 2005-940X EI 2093-4939 J9 J MOV DISORD JI J. Mov. Disord. PD MAY PY 2016 VL 9 IS 2 BP 124 EP 125 DI 10.14802/jmd.15054 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DX8MJ UT WOS:000384642600010 ER PT J AU Kass-Hout, TA Xu, ZH Mohebbi, M Nelsen, H Baker, A Levine, J Johanson, E Bright, RA AF Kass-Hout, Taha A. Xu, Zhiheng Mohebbi, Matthew Nelsen, Hans Baker, Adam Levine, Jonathan Johanson, Elaine Bright, Roselie A. TI OpenFDA: an innovative platform providing access to a wealth of FDA's publicly available data SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE openFDA; drug safety; adverse event; API; application programming interface; open data; open source AB Objective The objective of openFDA is to facilitate access and use of big important Food and Drug Administration public datasets by developers, researchers, and the public through harmonization of data across disparate FDA datasets provided via application programming interfaces (APIs). Materials and Methods Using cutting-edge technologies deployed on FDA's new public cloud computing infrastructure, openFDA provides open data for easier, faster (over 300 requests per second per process), and better access to FDA datasets; open source code and documentation shared on GitHub for open community contributions of examples, apps and ideas; and infrastructure that can be adopted for other public health big data challenges. Results Since its launch on June 2, 2014, openFDA has developed four APIs for drug and device adverse events, recall information for all FDA-regulated products, and drug labeling. There have been more than 20 million API calls (more than half from outside the United States), 6000 registered users, 20,000 connected Internet Protocol addresses, and dozens of new software (mobile or web) apps developed. A case study demonstrates a use of openFDA data to understand an apparent association of a drug with an adverse event. Conclusion With easier and faster access to these datasets, consumers worldwide can learn more about FDA-regulated products. C1 [Kass-Hout, Taha A.; Xu, Zhiheng; Levine, Jonathan; Johanson, Elaine; Bright, Roselie A.] US FDA, Silver Spring, MD USA. [Mohebbi, Matthew; Nelsen, Hans; Baker, Adam] Iodine Inc, 34 Clyde St, San Francisco, CA 94107 USA. RP Xu, ZH (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM zhiheng.xu@fda.hhs.gov OI Kass-Hout, Taha/0000-0002-0123-5157 NR 25 TC 2 Z9 2 U1 6 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAY PY 2016 VL 23 IS 3 BP 596 EP 600 DI 10.1093/jamia/ocv153 PG 5 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DW6SP UT WOS:000383781800023 PM 26644398 ER PT J AU Ding, W Bishop, ME Lyn-Cook, LE Davis, KJ Manjanatha, MG AF Ding, Wei Bishop, Michelle E. Lyn-Cook, Lascelles E. Davis, Kelly J. Manjanatha, Mugimane G. TI In Vivo Alkaline Comet Assay and Enzyme-modified Alkaline Comet Assay for Measuring DNA Strand Breaks and Oxidative DNA Damage in Rat Liver SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Molecular Biology; Issue 111; Genetic toxicology; rat; liver; In vivo alkaline comet assay; Endonuclease III (Endo III); human 8-oxoguanine-DNA-N-glycosylase 1 (hOGG1); DNA strand breaks; oxidative DNA damage ID F344 RATS; GENOTOXICITY; REPAIR AB Unrepaired DNA damage can lead to genetic instability, which in turn may enhance cancer development. Therefore, identifying potential DNA damaging agents is important for protecting public health. The in vivo alkaline comet assay, which detects DNA damage as strand breaks, is especially relevant for assessing the genotoxic hazards of xenobiotics, as its responses reflect the in vivo absorption, tissue distribution, metabolism and excretion (ADME) of chemicals, as well as DNA repair process. Compared to other in vivo DNA damage assays, the assay is rapid, sensitive, visual and inexpensive, and, by converting oxidative DNA damage into strand breaks using specific repair enzymes, the assay can measure oxidative DNA damage in an efficient and relatively artifact-free manner. Measurement of DNA damage with the comet assay can be performed using both acute and subchronic toxicology study designs, and by integrating the comet assay with other toxicological assessments, the assay addresses animal welfare requirements by making maximum use of animal resources. Another major advantage of the assays is that they only require a small amount of cells, and the cells do not have to be derived from proliferating cell populations. The assays also can be performed with a variety of human samples obtained from clinically or occupationally exposed individuals. C1 [Ding, Wei; Bishop, Michelle E.; Lyn-Cook, Lascelles E.; Manjanatha, Mugimane G.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Rockville, MD 20857 USA. [Davis, Kelly J.] US FDA, Toxicol Pathol Associates, Natl Ctr Toxicol Res, Rockville, MD 20857 USA. RP Ding, W (reprint author), US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Rockville, MD 20857 USA. EM wei.ding@fda.hhs.gov FU US Food and Drug Administration FX This work was supported by the US Food and Drug Administration. We acknowledge the original publication of the CPA study by Elsevier B.V.: Ding W, Bishop ME, Peace MG, Davis KJ, White GA, Lyn-Cook LE, Manjanatha MG. Sex-specific dose-response analysis of genotoxicity in cyproterone acetate-treated F344 rats. Mutation Research 774: 1-7, 2014 (PMID: 25440904) NR 24 TC 0 Z9 0 U1 2 U2 2 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD MAY PY 2016 IS 111 AR e53833 DI 10.3791/53833 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS0BJ UT WOS:000380259900031 ER PT J AU Aryankalayil, JB McFarland, HI Rosenberg, AS AF Aryankalayil, Joseph B. McFarland, Hugh I. Rosenberg, Amy S. TI Development of a Therapeutic to Preserve Vaccine Memory Following Ionizing Radiation Exposure SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Aryankalayil, Joseph B.; McFarland, Hugh I.; Rosenberg, Amy S.] US FDA, CDER, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301463 ER PT J AU Cavanaugh, C Gaines, D Pereira, M Williams, K Alam, MS AF Cavanaugh, Christopher Gaines, Dennis Pereira, Marion Williams, Kristina Alam, M. Samiul TI Increased Treg cells and expression of CD39/CD73 during listeriosis in aging mice SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Cavanaugh, Christopher; Gaines, Dennis; Pereira, Marion; Williams, Kristina; Alam, M. Samiul] US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 66.16 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301026 ER PT J AU Deaver, CM Smith, ER Messenheimer, JR Lewandowski, AJ Groesbeck, C Zhang, W Swain, T Chiesa, OA Myers, MJ AF Deaver, Christine M. Smith, Emily R. Messenheimer, Janis R. Lewandowski, Anne J. Groesbeck, Crystal Zhang, Wei Swain, Trevon Chiesa, O. Alberto Myers, Michael J. TI Comparison of serum protein concentrations to clinical observations during lipopolysaccharide (LPS) induced inflammation in swine SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Deaver, Christine M.; Smith, Emily R.; Messenheimer, Janis R.; Lewandowski, Anne J.; Groesbeck, Crystal; Zhang, Wei; Swain, Trevon; Chiesa, O. Alberto; Myers, Michael J.] US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 188.17 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301192 ER PT J AU Lewandowski, A Deaver, C Myers, MJ AF Lewandowski, Annie Deaver, Christine Myers, Michael J. TI Characterization of the inflammatory effects of lambda-carrageenan at the genomic and proteomic levels SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Lewandowski, Annie; Deaver, Christine; Myers, Michael J.] US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 MA 188.18 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301182 ER PT J AU Novatt, H Renn, L Theisen, T Massie, T Massie, T Rabin, RL AF Novatt, Hilary Renn, Lynnsey Theisen, Terence Massie, Tammy Massie, Tristan Rabin, Ronald L. TI Interferon regulatory factor 1 (IRF1) expression patterns by respiratory epithelial cells reveal non-redundancy of type I versus type III interferon. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Novatt, Hilary; Renn, Lynnsey; Theisen, Terence; Massie, Tammy; Massie, Tristan; Rabin, Ronald L.] US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302430 ER PT J AU Rajawat, YS McFarland, H Morgan, R Zhao, YB Rosenberg, AS AF Rajawat, Yogendra Singh McFarland, Hugh Morgan, Richard Zhao, Yangbing Rosenberg, Amy S. TI Development of an Enhanced VETO cells for the generation of Alloantigen-specific Tolerance SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Rajawat, Yogendra Singh; McFarland, Hugh; Rosenberg, Amy S.] US FDA, CDER, Rockville, MD 20857 USA. [Morgan, Richard] Bluebird Bio, Cambridge, MA USA. [Zhao, Yangbing] Univ Penn, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288303288 ER PT J AU Robbins, R Peng, S Moratz, CM AF Robbins, Racheal Peng, Suzette Moratz, Chantal M. TI Mechanisms of Coagulation-Complement pathway interplay in ischemia/reperfusion induced tissue injury. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Robbins, Racheal] WRNMMC, Bethesda, MD USA. [Peng, Suzette] US FDA, Rockville, MD 20857 USA. [Moratz, Chantal M.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301396 ER PT J AU Uehling, M Hillyer, P Shepard, R Sheik, F Luongo, C Buchholz, U Collins, PL Donnelly, RP Rabin, RL AF Uehling, Megan Hillyer, Philippa Shepard, Rachel Sheik, Faruk Luongo, Cindy Buchholz, Ursula Collins, Peter L. Donnelly, Raymond P. Rabin, Ronald L. TI Innate IFNs and pro-inflammatory cytokines in local control of Respiratory Syncytial Virus infection of respiratory epithelial cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Uehling, Megan; Hillyer, Philippa; Shepard, Rachel; Rabin, Ronald L.] US FDA, CBER, Rockville, MD 20857 USA. [Sheik, Faruk; Donnelly, Raymond P.] US FDA, CDER, Rockville, MD 20857 USA. [Luongo, Cindy; Buchholz, Ursula; Collins, Peter L.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 2 WC Immunology SC Immunology GA DS0LX UT WOS:000380288301112 ER PT J AU Xu, H Mills, F Max, EE AF Xu, Hui Mills, Frederick Max, Edward E. TI Intravenous rasburicase-induced immune tolerance is associated with depletion of specific lymphocytes and up-regulation of regulatory T cells SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Immunologists (AAI) CY MAY 13-17, 2016 CL Seattle, WA SP Amer Assoc Immunologists C1 [Xu, Hui; Mills, Frederick; Max, Edward E.] US FDA, CDER, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2016 VL 196 SU 1 PG 1 WC Immunology SC Immunology GA DS0LX UT WOS:000380288302437 ER PT J AU Wang, QZ Cheng, WC Suresh, N Hua, H AF Wang, Quanzeng Cheng, Wei-Chung Suresh, Nitin Hua, Hong TI Development of the local magnification method for quantitative evaluation of endoscope geometric distortion SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE endoscope; local magnification; radial distortion; geometric distortion; picture height distortion; TV distortion ID CAMERA CALIBRATION; ACCURACY; LENSES AB With improved diagnostic capabilities and complex optical designs, endoscopic technologies are advancing. As one of the several important optical performance characteristics, geometric distortion can negatively affect size estimation and feature identification related diagnosis. Therefore, a quantitative and simple distortion evaluation method is imperative for both the endoscopic industry and the medical device regulatory agent. However, no such method is available yet. While the image correction techniques are rather mature, they heavily depend on computational power to process multidimensional image data based on complex mathematical model, i.e., difficult to understand. Some commonly used distortion evaluation methods, such as the picture height distortion (DPH) or radial distortion (DRAD), are either too simple to accurately describe the distortion or subject to the error of deriving a reference image. We developed the basic local magnification (ML) method to evaluate endoscope distortion. Based on the method, we also developed ways to calculate DPH and DRAD. The method overcomes the aforementioned limitations, has clear physical meaning in the whole field of view, and can facilitate lesion size estimation during diagnosis. Most importantly, the method can facilitate endoscopic technology to market and potentially be adopted in an international endoscope standard. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. C1 [Wang, Quanzeng; Cheng, Wei-Chung; Suresh, Nitin] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Suresh, Nitin] Univ Maryland, Dept Elect & Comp Engn, 2410 AV Williams Bldg, College Pk, MD 20742 USA. [Hua, Hong] Univ Arizona, Coll Opt Sci, 1630 East Univ Blvd, Tucson, AZ 85721 USA. RP Wang, QZ (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM quanzeng.wang@fda.hhs.gov NR 23 TC 1 Z9 1 U1 3 U2 3 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 MAY PY 2016 VL 21 IS 5 AR 056003 DI 10.1117/1.JBO.21.5.056003 PG 13 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA DQ6RZ UT WOS:000379334200012 PM 27156717 ER PT J AU Ray, MD Boundy, S Archer, GL AF Ray, M. D. Boundy, S. Archer, G. L. TI Transfer of the methicillin resistance genomic island among staphylococci by conjugation SO MOLECULAR MICROBIOLOGY LA English DT Article ID CASSETTE CHROMOSOME MEC; GRAM-POSITIVE BACTERIA; AUREUS; EPIDERMIDIS; PLASMIDS; ELEMENTS; MOBILIZATION; REPLACEMENT; INTEGRATION; EVOLUTION AB Methicillin resistance creates a major obstacle for treatment of Staphylococcus aureus infections. The resistance gene, mecA, is carried on a large (20 kb to > 60 kb) genomic island, staphylococcal cassette chromosome mec (SCCmec), that excises from and inserts site-specifically into the staphylococcal chromosome. However, although SCCmec has been designated a mobile genetic element, a mechanism for its transfer has not been defined. Here we demonstrate the capture and conjugative transfer of excised SCCmec. SCCmec was captured on pGO400, a mupirocin-resistant derivative of the pGO1/pSK41 staphylococcal conjugative plasmid lineage, and pGO400::SCCmec (pRM27) was transferred by filter-mating into both homologous and heterologous S. aureus recipients representing a range of clonal complexes as well as S. epidermidis. The DNA sequence of pRM27 showed that SCCmec had been transferred in its entirety and that its capture had occurred by recombination between IS257/431 elements present on all SCCmec types and pGO1/pSK41 conjugative plasmids. The captured SCCmec excised from the plasmid and inserted site-specifically into the chromosomal att site of both an isogenic S. aureus and a S. epidermidis recipient. These studies describe a means by which methicillin resistance can be environmentally disseminated and a novel mechanism, IS-mediated recombination, for the capture and conjugative transfer of genomic islands. C1 [Ray, M. D.; Boundy, S.; Archer, G. L.] Virginia Commonwealth Univ, Sch Med, Dept Internal Med, 1101 East Marshall St, Richmond, VA 23298 USA. [Ray, M. D.; Archer, G. L.] Virginia Commonwealth Univ, Dept Microbiol & Immunol, Dept Internal Med, 1101 East Marshall St, Richmond, VA 23298 USA. [Ray, M. D.] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD USA. RP Ray, MD; Archer, GL (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Internal Med, 1101 East Marshall St, Richmond, VA 23298 USA.; Ray, MD; Archer, GL (reprint author), Virginia Commonwealth Univ, Dept Microbiol & Immunol, Dept Internal Med, 1101 East Marshall St, Richmond, VA 23298 USA. EM gordon.archer@vcuhealth.org; garcher3500@gmail.com FU National Institute of Health, National Institute of Allergy and Infectious Diseases [5RO1AI035705-20] FX This work was supported in part by grant 5RO1AI035705-20 from the National Institute of Health, National Institute of Allergy and Infectious Diseases. Whole genome sequencing was performed at UNC Pacific Biosciences High Throughput Sequencing Facility (Chapel Hill, NC). We thank them for their advice and help with sequence assembly. NR 39 TC 6 Z9 6 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD MAY PY 2016 VL 100 IS 4 BP 675 EP 685 DI 10.1111/mmi.13340 PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA DR1SC UT WOS:000379684200007 PM 26822382 ER PT J AU Sahin, L AF Sahin, L. TI Prevalence Reference Rates for Pregnancy Registries and for Labeling SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Sahin, L.] US FDA, Harvard, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2016 VL 106 IS 5 SI SI MA S7 BP 355 EP 355 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA DQ2HT UT WOS:000379024100014 ER PT J AU Ferguson, SA Panos, JJ AF Ferguson, S. A. Panos, J. J. TI Blood-Brain-Barrier Development and Function SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Ferguson, S. A.; Panos, J. J.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2016 VL 106 IS 5 SI SI MA S24 BP 363 EP 363 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA DQ2HT UT WOS:000379024100030 ER PT J AU Vekemans, M Vorhees, CV Tassinari, MS Obican, SG AF Vekemans, M. Vorhees, C. V. Tassinari, M. S. Obican, S. G. TI Student and Postdoctoral Lunch Workshop: Advancing Your Career in Birth Defects Research and Prevention SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Vekemans, M.] Hop Necker Enfants Malad, Paris, France. [Vorhees, C. V.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Tassinari, M. S.] US FDA, Washington, DC 20204 USA. [Obican, S. G.] Univ S Florida, New Tampa, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2016 VL 106 IS 5 SI SI MA W1 BP 378 EP 378 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA DQ2HT UT WOS:000379024100058 ER PT J AU Neal-Kluever, AP Aungst, J Wu, Y Liu, J Shackelford, M Ogungbesan, A Gu, Y Jacobs, K AF Neal-Kluever, A. P. Aungst, J. Wu, Y. Liu, J. Shackelford, M. Ogungbesan, A. Gu, Y. Jacobs, K. TI Regulatory Research to Support Food-Contact Infant Safety Assessment at US Food and Drug Administration SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Neal-Kluever, A. P.; Aungst, J.; Wu, Y.; Shackelford, M.; Ogungbesan, A.; Gu, Y.; Jacobs, K.] US FDA, CFSAN, OFAS, DFCN, College Pk, MD USA. [Liu, J.] Oak Ridge Inst Sci & Educ, Oak Ridge, TN 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 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2016 VL 106 IS 5 SI SI MA P1 BP 404 EP 404 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA DQ2HT UT WOS:000379024100105 ER PT J AU Linnebjerg, H Choi, SL Lam, ECQ Mace, KF Hodgson, TS Sinha, VP AF Linnebjerg, Helle Choi, Siak Leng Lam, Eric Chen Quin Mace, Kenneth F. Hodgson, Teri S. Sinha, Vikram P. TI Pharmacokinetics of the Long-Acting Basal Insulin LY2605541 in Subjects With Varying Degrees of Renal Function SO CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT LA English DT Article DE pharmacokinetics; long-acting basal insulin analogue; renal impairment; insulin peglispro ID DIABETIC-PATIENTS; HEMODIALYSIS; HYPOGLYCEMIA; METABOLISM; IMPACT AB The pharmacokinetics of LY2605541 (basal insulin peglispro), a novel long-acting basal insulin analogue, was evaluated in 5 groups of subjects with varying degrees of renal function based on creatinine clearance: normal renal function (>80 mL/min), mild renal impairment (51-80 mL/min), moderate renal impairment (30-50 mL/min), severe renal impairment (<30 mL/min), or end-stage renal disease (ESRD) requiring hemodialysis. Serial blood samples for pharmacokinetic analyses were collected up to 12 days following a single 0.33 U/kg subcutaneous dose of LY2605541. The apparent clearance (CL/F) and half-life across groups were not affected by renal function. C-max values were lower in subjects with increasing severity of renal impairment; however, the small decrease in C-max did not affect the overall exposure. Regression analysis showed that LY2605541 clearance is independent of renal function (slope = 0.000863; P = .885). The mean fraction of LY2605541 eliminated by a single hemodialysis session was 13% in subjects with ESRD. LY2605541 was generally well tolerated in healthy subjects and those with renal impairment following a single 0.33 U/kg subcutaneous dose. Given these data, no dose adjustment of LY2605541 based on pharmacokinetics is recommended in renal impairment or in patients undergoing hemodialysis. C1 [Linnebjerg, Helle; Mace, Kenneth F.; Hodgson, Teri S.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Choi, Siak Leng; Lam, Eric Chen Quin] Lilly NUS Clin Pharmacol Pte Ltd, Singapore, Singapore. [Sinha, Vikram P.] US FDA, Silver Spring, MD USA. RP Linnebjerg, H (reprint author), Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. EM linnebjerg_helle@lilly.com FU Eli Lilly and Company FX The study was supported by Eli Lilly and Company. NR 19 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2160-7648 J9 CLIN PHARM DRUG DEV JI Clin. Pharmacol. Drug Dev. PD MAY-JUN PY 2016 VL 5 IS 3 BP 216 EP 224 DI 10.1002/cpdd.252 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ3YH UT WOS:000379139500008 PM 27163501 ER PT J AU Parunov, L Surov, S Liang, Y Lee, T Ovanesov, M AF Parunov, L. Surov, S. Liang, Y. Lee, T. Ovanesov, M. TI Calcium chloride reagent regulates thrombin generation response of hemophilia plasma to factor concentrate treatments SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Parunov, L.; Surov, S.; Liang, Y.; Lee, T.; Ovanesov, M.] US FDA, Off Blood Res & Review, 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 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD MAY PY 2016 VL 14 SU 1 SI SI MA FVIII57 BP 62 EP 62 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DQ4HF UT WOS:000379164000153 ER PT J AU Damdinsuren, B Dement-Brown, J Li, HF Tolnay, M AF Damdinsuren, Bazarragchaa Dement-Brown, Jessica Li, Huifang Tolnay, Mate TI B cell receptor induced Fc receptor-like 5 expression is mediated by multiple signaling pathways converging on NF-kappa B and NFAT SO MOLECULAR IMMUNOLOGY LA English DT Article DE Fc receptor-like; Transcriptional regulation; B lymphocytes; B cell antigen receptor; Signal transduction ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; GLYCOGEN-SYNTHASE KINASE-3; CUTTING EDGE; GAMMA-RIIB; T-CELLS; PROTEIN; ACTIVATION; AUTOIMMUNITY; LYMPHOCYTES; FCRL3 AB Fc receptor-like (FCRL) proteins are novel regulators of the B cell response to antigen. Human FCRL5 binds intact IgG and modifies the strength of antigen receptor (BCR) signaling. Altering FCRL5 expression could therefore regulate the B cell response to antigen. In this study, we found that FCRL5 expression is induced specifically upon BCR stimulation and dissected the molecular mechanism. FCRL5 mRNA and cell surface protein expression required prolonged BCR stimulation and de novo protein synthesis. Using chemical inhibitors and activators, we identified roles for several signaling pathways, indicating a complex mechanism. Specifically, the PI3 K/AICT, JNK, PKC and IKK2-dependent classical NF-kappa B pathways were involved in induced FCRL5 expression. Furthermore, induced FCRL5 expression required elevation of intracellular Caz and was partially blocked by cyclosporine A, a calcineurin inhibitor. The importance of the transcription factors NF-kappa B, NFAT and CREB-binding protein was revealed based on sensitivity to inhibitors. Using reporter gene assays, we showed that the core FCRL5 promoter was sufficient to drive induced gene expression. Mutations of two predicted NF-kappa B sites or an NFAT site in the core promoter abrogated induced gene expression, suggesting direct regulation of the FCRL5 gene by NF-kappa B and NFAT. In support, we detected binding of NF-kappa B and NFAT family proteins to oligonucleotides corresponding to the predicted sites. We propose that the identified intricate mechanism serves to ensure that FCRL5 is expressed on B cells at a precise time following antigen encounter, with potential implications regarding regulation of the B cell response. Published by Elsevier Ltd. C1 [Damdinsuren, Bazarragchaa; Dement-Brown, Jessica; Li, Huifang; Tolnay, Mate] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Tolnay, M (reprint author), US FDA, WO Bldg 72,Room 2336,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM mate.tolnay@fda.hhs.gov FU CDER, FDA; FDA FX The authors thank Satoshi Nagata for the FCRL5 Ab, Sean Fitzsimmons and Frederick Mills for suggestions. This work was supported by the Intramural Research Program of CDER, FDA. B.D. was supported by the FDA Commissioner's Fellowship Program. H.F.L. was in part supported through the Research Fellowship Program for CDER administered by the Oak Ridge Associated Universities. NR 42 TC 1 Z9 1 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD MAY PY 2016 VL 73 BP 112 EP 121 DI 10.1016/j.molimm.2016.04.001 PG 10 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA DP7IC UT WOS:000378671400013 PM 27065451 ER PT J AU Klein, MM Treister, R Raij, T Pascual-Leone, A Park, L Nurmikko, T Lenz, F Lefaucheur, JP Lang, M Hallett, M Fox, M Costello, A Carr, DB Ayache, SS Oaklander, AL AF Klein, Max M. Treister, Roi Raij, Tommi Pascual-Leone, Alvaro Park, Lawrence Nurmikko, Turo Lenz, Fred Lefaucheur, Jean-Pascal Lang, Magdalena Hallett, Mark Fox, Michael Costello, Ann Carr, Daniel B. Ayache, Samar S. Oaklander, Anne Louise TI Repetitive transcranial magnetic stimulation for pain: is it too early to standardise repetitive transcranial magnetic stimulation protocols? Reply SO PAIN LA English DT Letter C1 [Klein, Max M.; Treister, Roi; Lang, Magdalena; Fox, Michael; Oaklander, Anne Louise] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA. [Raij, Tommi; Fox, Michael] Northwestern Univ, Feinberg Sch Med, Phys Med & Rehabil, Chicago, IL 60611 USA. [Pascual-Leone, Alvaro; Fox, Michael] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Neurol, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA 02115 USA. [Park, Lawrence] NIMH, US NIH, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. [Nurmikko, Turo] Walton Ctr NHS Fdn Trust, Pain Res Inst, Neurosci Res Ctr, Liverpool, Merseyside, England. [Lenz, Fred] Johns Hopkins Med Inst, Dept Neurosurg, Baltimore, MD 21205 USA. [Lefaucheur, Jean-Pascal; Ayache, Samar S.] Univ Paris Est Creteil, Hop Henri Mondor, Fac Med Creteil, Serv Physiol Explorat Fonct,EA 4391, Creteil, France. [Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Costello, Ann] US FDA, Div Neurol & Phys Med Devices, Off Device Evaluat, Ctr Devices & Radiol Hlth, Bethesda, MD 20014 USA. [Carr, Daniel B.] Tufts Univ, Sch Med, Dept Anesthesiol, Boston, MA 02111 USA. [Carr, Daniel B.] Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. [Carr, Daniel B.] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Oaklander, Anne Louise] Massachusetts Gen Hosp, Dept Pathol Neuropathol, Boston, MA 02114 USA. RP Klein, MM (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA. EM mklein@mgh.harvard.edu NR 1 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 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD MAY PY 2016 VL 157 IS 5 BP 1175 EP 1176 DI 10.1097/j.pain.0000000000000504 PG 3 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA DQ0GA UT WOS:000378875600027 PM 27081841 ER PT J AU Sharma, GM Rallabhandi, P Williams, KM Herrmann, M Sadrieh, N AF Sharma, Girdhari M. Rallabhandi, Prasad Williams, Kristina M. Herrmann, Michelle Sadrieh, Nakissa TI Gluten Quantitation in Cosmetic Products by Enzyme-Linked Immunosorbent Assay SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID WHEAT; IMMUNOASSAY AB The "gluten-free" final rule, published by the U.S. Food and Drug Administration (FDA) in 2013, is intended to provide safe food choices for people suffering from celiac disease. This final rule is not applicable for cosmetic products. As a result, analytical methods for gluten estimation in cosmetics are warranted to aid in the determination of the presence of gluten in these products. A survey of 36 cosmetic products was conducted to measure gluten content by three different ELISAs. None of the nine gluten-free labeled cosmetics included detectable gluten. The gluten content in six cosmetics was 15.2-1453.5 ppm by one competitive ELISA, whereas three cosmetics contained 11.7-572.3 ppm gluten when quantitated with two sandwich ELISAs. Gluten or hydrolyzed wheat protein was found as an ingredient in five cosmetics with detectable gluten levels. A poor recovery of gluten was observed for most of the cosmetics in the foundation/blush/powder category by ELISA kits. This finding warrants a need for improved analytical methods for gluten estimation in cosmetics. C1 [Sharma, Girdhari M.; Rallabhandi, Prasad; Williams, Kristina M.] US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety, 8301 Muirkirk Rd, Laurel, MD 20708 USA. [Herrmann, Michelle; Sadrieh, Nakissa] US FDA, Ctr Food Safety & Appl Nutr, Off Cosmet & Colors, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. RP Sharma, GM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM Girdhari.Sharma@fda.hhs.gov NR 8 TC 0 Z9 0 U1 5 U2 6 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 MAY-JUN PY 2016 VL 99 IS 3 BP 586 EP 590 DI 10.5740/jaoacint.16-0037 PG 5 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA DP0OI UT WOS:000378188700006 ER PT J AU Vega, VA AF Vega, Victor A. TI A Quick Assay for the Quantitation of Fumonisin B-1 and B-2 in Maize Samples by Liquid Chromatography and Mass Spectrometry SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID FUSARIUM-MONILIFORME; WATER ACTIVITY; PROLIFERATUM; TEMPERATURE; GROWTH AB A quick and effective extraction of fumonisin B-1 (FB1) and B-2 (FB2) in corn samples is described. The samples were extracted with an 80% acetonitrile-water solution, followed by a second extraction using an 80% methanol-water solution. The extract was then subjected to an immunoaffinity column for cleanup. Quantitation was then obtained by LC/MS. LC/MS parameters were optimized resulting in a 3 min run time. Corn certified reference materials (CRMs) at three different levels were analyzed. For the lowest level, a corn CRM sample containing 0.6 ppm of FB1 and 0.1 ppm of FB2 was analyzed. For the midlevel, analysis of a corn CRM sample containing 1.2 ppm FB1 and 0.3 ppm FB2 was conducted. A sample containing 3.6 ppm FB1 and 0.8 ppm FB2 was also analyzed. All recoveries were calculated using an external standard curve. Recoveries from all CRM samples ranged from 70 to 110%. Confirmation for both analytes in the sample extracts at each level was accomplished by comparing MS/MS spectra of the samples against those of the standards. This method provides a rapid, specific, robust, and easily controlled assay for the analysis of fumonisin in corn samples. C1 [Vega, Victor A.] US FDA, Southeast Reg Lab, Atlanta, GA 30309 USA. RP Vega, VA (reprint author), US FDA, Southeast Reg Lab, Atlanta, GA 30309 USA. EM victor.vega@fda.hhs.gov NR 6 TC 1 Z9 1 U1 1 U2 2 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 MAY-JUN PY 2016 VL 99 IS 3 BP 717 EP 720 DI 10.5740/jaoacint.15-0266 PG 4 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA DP0OI UT WOS:000378188700020 PM 27297840 ER PT J AU Iha, MH Okada, IA Briganti, RC Mini, CA Trucksess, MW AF Iha, Maria H. Okada, Isaura A. Briganti, Rita C. Mini, Camila A. Trucksess, Mary W. TI Aflatoxins in Brazilian Peanut Confection SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID OCHRATOXIN-A; SAO-PAULO; PRODUCTS; FOOD; REGION; G(1); G(2); B-1 AB The study's objectives were to evaluate a method for the determination of aflatoxins (AFs) in the Brazilian peanut confection "Pacoca" and to apply the method in investigating AF concentrations in Pacoca marketed in Sao Paulo State throughout 2013. Results of another survey conducted between 1994 and 2002 with another method were also reported. The current method consists of immunoaffinity column cleanup, LC with postcolumn derivatization for AF fluorescence enhancement, and fluorescence determination for the toxins. The mean recovery and mean RSDr values were 88.6 and 7.9%, respectively. The LODs for aflatoxin B-1, aflatoxin B-2, aflatoxin G(1), and aflatoxin G(2) were 0.04, 0.01, 0.02, and 0.01 ng/g; and the LOQs were 0.15, 0.04, 0.07, and 0.04 ng/g, respectively. Results of the two survey studies indicate that the contamination of AFs in Pagoca remains a public health problem. In the 2013 survey, 71 of 100 samples (71%) had AFs contamination ranging from 0.3 to 41.8 ng/g, with 12 samples (12%) containing >20 ng/g of the toxins, whereas in the 1994-2002 survey, 73 of 150 samples (51%) had AFs contamination ranging from 9 to 1439 ng/g with 65 samples (45%) containing levels >20 ng/g. C1 [Iha, Maria H.; Okada, Isaura A.; Briganti, Rita C.; Mini, Camila A.] Adolfo Lutz Inst, CLR Ribeirao Preto, Nucleo Ciencias Quim & 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, CLR Ribeirao Preto, Nucleo Ciencias Quim & Bromatol, Rua Minas 877, BR-14085410 Ribeirao Preto, SP, Brazil. EM mhiha@ial.sp.gov.br FU Fundacao de Amparo a Pesquisa do Estado de Salo Paulo FX The authors are grateful to Fundacao de Amparo a Pesquisa do Estado de Salo Paulo for financial support. NR 14 TC 1 Z9 1 U1 2 U2 4 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 EI 1944-7922 J9 J AOAC INT JI J. AOAC Int. PD MAY-JUN PY 2016 VL 99 IS 3 BP 830 EP 833 DI 10.5740/jaoacint.15-0256 PG 4 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA DP0OI UT WOS:000378188700035 ER PT J AU Deshpande, A McMahon, B Daughton, AR Abeyta, EL Hodge, D Anderson, K Pillai, S AF Deshpande, Alina McMahon, Benjamin Daughton, Ashlynn R. Abeyta, Esteban L. Hodge, David Anderson, Kevin Pillai, Segaran TI SURVEILLANCE FOR EMERGING DISEASES WITH MULTIPLEXED POINT-OF-CARE DIAGNOSTICS SO HEALTH SECURITY LA English DT Article ID INFECTIOUS-DISEASES; EBOLA; COUNTRIES; HEALTH; VIRUS AB We present an analysis of the diagnostic technologies that were used to identify historical outbreaks of Ebola virus disease and consider systematic surveillance strategies that may greatly reduce the peak size of future epidemics. We observe that clinical signs and symptoms alone are often insufficient to recognize index cases of diseases of global concern against the considerable background infectious disease burden that is present throughout the developing world. We propose a simple sampling strategy to enrich in especially dangerous pathogens with a low background for molecular diagnostics by targeting blood-borne pathogens in the healthiest age groups. With existing multiplexed diagnostic technologies, such a system could be combined with existing public health screening and reference laboratory systems for malaria, dengue, and common bacteremia or be used to develop such an infrastructure in less-developed locations. Because the needs for valid samples and accurate recording of patient attributes are aligned with needs for global biosurveillance, local public health needs, and improving patient care, co-development of these capabilities appears to be quite natural, flexible, and extensible as capabilities, technologies, and needs evolve over time. Moreover, implementation of multiplexed diagnostic technologies to enhance fundamental clinical lab capacity will increase public health monitoring and biosurveillance as a natural extension. C1 [Deshpande, Alina; Daughton, Ashlynn R.; Abeyta, Esteban L.] Los Alamos Natl Lab, Analyt Intelligence & Technol Div, Los Alamos, NM USA. [McMahon, Benjamin] Los Alamos Natl Lab, Div Theoret, Los Alamos, NM USA. [Hodge, David; Anderson, Kevin] HSARPA, Dept Homeland Secur, Washington, DC USA. [Pillai, Segaran] US FDA, Off Lab Sci & Safety, Off Commissioner, Off Chief Scientist, Washington, DC 20204 USA. RP Deshpande, A (reprint author), Los Alamos Natl Lab, Informat Syst & Modeling, Analyt Intelligence & Technol, A-1,Mail Stop F610, Los Alamos, NM 87545 USA. EM deshpande_a@lanl.gov FU Department of Homeland Security [HSHQPM-14-X-00069] FX This work was supported by an Interagency Agreement with the Department of Homeland Security (HSHQPM-14-X-00069). NR 39 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 2326-5094 EI 2326-5108 J9 HEALTH SECUR JI Health Secur. PD MAY-JUN PY 2016 VL 14 IS 3 SI SI BP 111 EP 121 DI 10.1089/hs.2016.0005 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DO8PU UT WOS:000378046500002 PM 27314652 ER PT J AU Doggett, NA Mukundan, H Lefkowitz, EJ Slezak, TR Chain, PS Morse, S Anderson, K Hodge, DR Pillai, S AF Doggett, Norman A. Mukundan, Harshini Lefkowitz, Elliot J. Slezak, Tom R. Chain, Patrick S. Morse, Stephen Anderson, Kevin Hodge, David R. Pillai, Segaran TI CULTURE-INDEPENDENT DIAGNOSTICS FOR HEALTH SECURITY SO HEALTH SECURITY LA English DT Article ID NUCLEIC-ACID AMPLIFICATION; LATERAL FLOW ASSAY; WHOLE-GENOME AMPLIFICATION; IMMUNOMAGNETIC-ELECTROCHEMILUMINESCENT DETECTION; COMPREHENSIVE LABORATORY EVALUATION; INFECTIOUS-DISEASE-DIAGNOSTICS; IONIZATION MASS-SPECTROMETRY; UNASSEMBLED SEQUENCING DATA; ACUTE RESPIRATORY SYNDROME; REVERSE TRANSCRIPTION-PCR AB The past decade has seen considerable development in the diagnostic application of nonculture methods, including nucleic acid amplification-based methods and mass spectrometry, for the diagnosis of infectious diseases. The implications of these new culture-independent diagnostic tests (CIDTs) include bypassing the need to culture organisms, thus potentially affecting public health surveillance systems, which continue to use isolates as the basis of their surveillance programs and to assess phenotypic resistance to antimicrobial agents. CIDTs may also affect the way public health practitioners detect and respond to a bioterrorism event. In response to a request from the Department of Homeland Security, Los Alamos National Laboratory and the Centers for Disease Control and Prevention cosponsored a workshop to review the impact of CIDTs on the rapid detection and identification of biothreat agents. Four panel discussions were held that covered nucleic acid amplification-based diagnostics, mass spectrometry, antibody-based diagnostics, and next-generation sequencing. Exploiting the extensive expertise available at this workshop, we identified the key features, benefits, and limitations of the various CIDT methods for providing rapid pathogen identification that are critical to the response and mitigation of a bioterrorism event. After the workshop we conducted a thorough review of the literature, investigating the current state of these 4 culture-independent diagnostic methods. This article combines information from the literature review and the insights obtained at the workshop. C1 [Doggett, Norman A.] Los Alamos Natl Lab, Biosci Div, Biosecur & Publ Hlth Grp, Los Alamos, NM USA. [Mukundan, Harshini] Los Alamos Natl Lab, Div Chem, Phys Chem & Appl Spect Grp, Los Alamos, NM USA. [Chain, Patrick S.] Los Alamos Natl Lab, Biosci Div, Bioenergy & Biome Sci Grp, Los Alamos, NM USA. [Lefkowitz, Elliot J.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL USA. [Slezak, Tom R.] Lawrence Livermore Natl Lab, Informat Global Secur Comp Applicat Div, Livermore, CA USA. [Morse, Stephen] Ctr Dis Control & Prevent, Div Select Agents & Toxins, Atlanta, GA USA. [Anderson, Kevin; Hodge, David R.] Homeland Secur Adv Res Projects Agcy, Chem & Biol Def Div, Sci & Technol Directorate, US Dept Homeland Secur, Washington, DC USA. [Pillai, Segaran] US FDA, Off Lab Sci & Safety, Dept Hlth & Human Serv, Off Commissioner,Off Chief Scientist, Silver Spring, MD USA. RP Doggett, NA (reprint author), Los Alamos Natl Lab, Biosci Div, Biosecur & Publ Hlth B 10, POB 1663, Los Alamos, NM 87545 USA. EM doggett@lanl.gov OI Chain, Patrick/0000-0003-3949-3634 FU Department of Homeland Security [HSHQPM-14-X-00069, HSHQPM-15-X-00028] FX This work was supported by Interagency Agreements with the Department of Homeland Security (HSHQPM-14-X-00069 and HSHQPM-15-X-00028). We thank Andrew Bradbury for providing input on immunological assays and recent advances in antibody technologies and Jason Gans for reviewing the manuscript. We would also like to thank the external reviewers for their insightful comments. NR 190 TC 1 Z9 1 U1 7 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2326-5094 EI 2326-5108 J9 HEALTH SECUR JI Health Secur. PD MAY-JUN PY 2016 VL 14 IS 3 SI SI BP 122 EP 142 DI 10.1089/hs.2015.0074 PG 21 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DO8PU UT WOS:000378046500003 PM 27314653 ER PT J AU Negussie, AH Partanen, A Mikhail, AS Xu, S Abi-Jaoudeh, N Maruvada, S Wood, BJ AF Negussie, Ayele H. Partanen, Ari Mikhail, Andrew S. Xu, Sheng Abi-Jaoudeh, Nadine Maruvada, Subha Wood, Bradford J. TI Thermochromic tissue-mimicking phantom for optimisation of thermal tumour ablation SO INTERNATIONAL JOURNAL OF HYPERTHERMIA LA English DT Article DE HIFU; laser; microwave; RF; thermal phantom; thermal therapy; thermal ablation; thermochromic; tissue-mimicking ID INTENSITY FOCUSED ULTRASOUND; HYPERTHERMIA; RADIOFREQUENCY; TEMPERATURE; THERAPY; DELIVERY AB Purpose The purpose of this study was to (1) develop a novel tissue-mimicking thermochromic (TMTC) phantom that permanently changes colour from white to magenta upon heating above ablative temperatures, and (2) assess its utility for specific applications in evaluating thermal therapy devices.Materials and methods Polyacrylamide gel mixed with thermochromic ink was custom made to produce a TMTC phantom that changes its colour upon heating above biological ablative temperatures (> 60 degrees C). The thermal properties of the phantom were characterised, and compared to those of human tissue. In addition, utility of this phantom as a tool for the assessment of laser and microwave thermal ablation was examined.Results The mass density, thermal conductivity, and thermal diffusivity of the TMTC phantom were measured as 10331.0kg/m(3), 0.590 +/- 0.015 W/m.K, and 0.145 +/- 0.002mm(2)/s, respectively, and found to be in agreement with reported values for human soft tissues. Heating the phantom with laser and microwave ablation devices produced clearly demarcated regions of permanent colour change geographically corresponding to regions with temperature elevations above 60 degrees C.Conclusion The TMTC phantom provides direct visualisation of ablation dynamics, including ablation volume and geometry as well as peak absolute temperatures within the treated region post-ablation. This phantom can be specifically tailored for different thermal therapy modalities, such as radiofrequency, laser, microwave, or therapeutic ultrasound ablation. Such modality-specific phantoms may enable better quality assurance, device characterisation, and ablation parameter optimisation, or optimise the study of dynamic heating parameters integral to drug device combination therapies relying upon heat. C1 [Negussie, Ayele H.; Partanen, Ari; Mikhail, Andrew S.; Xu, Sheng; Abi-Jaoudeh, Nadine; Wood, Bradford J.] NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, MSC 1182,Bldg 10,Room 1C341, Bethesda, MD 20892 USA. [Partanen, Ari] Philips, Clin Sci MR Therapy, Andover, MA USA. [Maruvada, Subha] US FDA, Silver Spring, MD USA. RP Wood, BJ (reprint author), NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, MSC 1182,Bldg 10,Room 1C341, Bethesda, MD 20892 USA. EM bwood@nih.gov OI Partanen, Ari/0000-0003-1985-149X FU Philips FX A.H.N., A.S.M., S.X., N.A.-J., S.M. and B.J.W. have no conflict of interest to declare. A. P. is a paid employee of Philips. The authors alone are responsible for the content and writing of the paper. NR 32 TC 1 Z9 1 U1 3 U2 9 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0265-6736 EI 1464-5157 J9 INT J HYPERTHER JI Int. J. Hyperthermia PD MAY PY 2016 VL 32 IS 3 BP 239 EP 243 DI 10.3109/02656736.2016.1145745 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DO4QD UT WOS:000377767000003 PM 27099078 ER PT J AU Dibaji, SAR Banerjee, RK Liu, YB Soneson, JE Myers, MR AF Dibaji, Seyed Ahmad Reza Banerjee, Rupak K. Liu, Yunbo Soneson, Joshua E. Myers, Matthew R. TI Experimental validation of a nonlinear derating technique based upon Gaussian-modal representation of focused ultrasound beams SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID FIELDS; MODEL AB A technique useful for performing derating at acoustic powers where significant harmonic generation occurs is illustrated and validated with experimental measurements. The technique was previously presented using data from simulations. The method is based upon a Gaussian representation of the propagation modes, resulting in simple expressions for the modal quantities, but a Gaussian source is not required. The nonlinear interaction of modes within tissue is estimated from the nonlinear interaction in water, using appropriate amounts of source reduction and focal-point reduction derived from numerical simulations. An important feature of this nonlinear derating method is that focal temperatures can be estimated with little additional effort beyond that required to determine the focal pressure waveforms. Hydrophone measurements made in water were used to inform the derating algorithm, and the resulting pressure waveforms and increases in temperature were compared with values directly measured in tissue phantoms. For a 1.05 MHz focused transducer operated at 80 W and 128 W, the derated pressures (peak positive, peak negative) agreed with the directly measured values to within 11%. Focal temperature rises determined by the derating method agreed with values measured using a remote thermocouple technique with a difference of 17%. C1 [Dibaji, Seyed Ahmad Reza; Banerjee, Rupak K.] Univ Cincinnati, Coll Engn & Appl Sci, Dept Mech & Mat Engn, 2600 Clifton Ave, Cincinnati, OH 45221 USA. [Liu, Yunbo; Soneson, Joshua E.; Myers, Matthew R.] US FDA, Div Appl Mech, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Myers, MR (reprint author), US FDA, Div Appl Mech, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM matthew.myers@fda.hhs.gov FU National Science Foundation [1041508, 1137166, 1403356]; Center for Devices and Radiological Health-US FDA FX Financial support from the National Science Foundation (Grants Nos. 1041508, 1137166, and 1403356) and the Center for Devices and Radiological Health-US FDA are gratefully acknowledged. NR 20 TC 0 Z9 0 U1 1 U2 1 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 EI 1520-8524 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD MAY PY 2016 VL 139 IS 5 BP 2624 EP 2634 DI 10.1121/1.4948607 PG 11 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA DO3XF UT WOS:000377715100045 PM 27250156 ER PT J AU Chiu, K Wagner, L Choe, L Chew, C Kremzner, M AF Chiu, Kimberly Wagner, Lindsay Choe, Lena Chew, Catherine Kremzner, Mary TI Piloting social engagement on a federal agency-administered Facebook page SO JOURNAL OF THE AMERICAN PHARMACISTS ASSOCIATION LA English DT Article ID INFORMATION AB Objectives: To evaluate the impact of a Federal drug information center initiating engagement with stakeholders on a Facebook Page administered by a Federal Agency. Setting: The U.S. Food and Drug Administration (FDA) Facebook page from July 21, 2014, to October 18, 2014. Practice innovation: FDA's Division of Drug Information (DDI) in the Center for Drug Evaluation and Research (CDER) Office of Communications serves as a federal drug information center providing timely, accurate, and useful information on CDER initiatives and CDER-regulated products. We report a 90-day (July 21 to October 18, 2014) pilot during which DDI pharmacists monitored and moderated comments received on FDA's Facebook page to identify those warranting a reply. Once identified, DDI pharmacists replied within 2 business days. Evaluation: Impact was measured by comparing the average number of Likes, Shares, and Reach for Facebook posts before and after the pilot. Additional metrics collected include the number of DDI replies provided to stakeholders' comments and the number of DDI replies provided on time (within 2 business days). Results: During the pilot, DDI contributed 14 posts. On average, each post reached 23,582 more individuals (an increase of 187% compared with pre-pilot posts). On average, each post also received 463 more Likes (450% increase) and 130 more Shares (271% increase). DDI pharmacists replied to 3% (121/3994) and hid 0.58% (23/3994) of Facebook comments received during the 90-day period. All actions were taken within 2 business days. Conclusion: Initiating social engagement had a positive impact on FDA's Facebook page. Published by Elsevier Inc. on behalf of American Pharmacists Association. C1 [Chiu, Kimberly; Wagner, Lindsay; Choe, Lena; Chew, Catherine; Kremzner, Mary] US FDA, Div Drug Informat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Wagner, Lindsay; Choe, Lena; Chew, Catherine; Kremzner, Mary] US PHS, Washington, DC 20201 USA. RP Chiu, K (reprint author), 10001 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Kimberly.Chiu@fda.hhs.gov NR 5 TC 0 Z9 0 U1 1 U2 1 PU AMER PHARMACEUTICAL ASSOC PI WASHINGTON PA 2215 CONSTITUTION AVE NW, WASHINGTON, DC 20037 USA SN 1544-3191 EI 1544-3450 J9 J AM PHARM ASSOC JI J. Am. Pharm. Assoc. PD MAY-JUN PY 2016 VL 56 IS 3 BP 330 EP 337 DI 10.1016/j.japh.2016.01.008 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DO3QX UT WOS:000377697200022 PM 27079138 ER PT J AU Ferguson, SA Panos, JJ AF Ferguson, Sherry A. Panos, John J. TI Blood-Brain-Barrier Development and Function SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 40th Anniversary Annual Meeting of the Developmental-Neurotoxicology-Society Held in Conjunction with the 56th Annual Meeting of the Teratology-Society CY JUN 25-29, 2016 CL San Antonio, TX SP Dev Neurotoxicol Soc, Teratol Soc C1 [Ferguson, Sherry A.; Panos, John J.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 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 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAY-JUN PY 2016 VL 55 MA DNTS 17 BP 66 EP 67 PG 2 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA DO6WC UT WOS:000377923200024 ER PT J AU Paule, M Li, M Zhang, X Liu, SL Hanig, J Slikker, W Wang, C AF Paule, Merle Li, Mi Zhang, Xuan Liu, Shuliang Hanig, Joseph Slikker, William Wang, Cheng TI Long-Lasting Cognitive Deficits in Rhesus Monkeys after Neonatal General Anesthesia Induced by Isoflurane/Nitrous Oxide: Protection by Acetyl-L-carnitine SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 40th Anniversary Annual Meeting of the Developmental-Neurotoxicology-Society Held in Conjunction with the 56th Annual Meeting of the Teratology-Society CY JUN 25-29, 2016 CL San Antonio, TX SP Dev Neurotoxicol Soc, Teratol Soc C1 [Paule, Merle; Li, Mi; Zhang, Xuan; Liu, Shuliang; Slikker, William; Wang, Cheng] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Hanig, Joseph] US FDA, Ctr Drug Evaluat & Res, Silve Spring, MD USA. NR 0 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 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAY-JUN PY 2016 VL 55 MA DNTS 26 BP 69 EP 69 PG 1 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA DO6WC UT WOS:000377923200033 ER PT J AU Grinev, A Chancey, C Volkova, E Anez, G Heisey, DAR Winkelman, V Foster, GA Williamson, P Stramer, SL Rios, M AF Grinev, Andriyan Chancey, Caren Volkova, Evgeniya Anez, German Heisey, Daniel A. R. Winkelman, Valerie Foster, Gregory A. Williamson, Phillip Stramer, Susan L. Rios, Maria TI Genetic Variability of West Nile Virus in US Blood Donors from the 2012 Epidemic Season SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID STATES-OF-AMERICA; UNITED-STATES; EVOLUTIONARY DYNAMICS; PHYLOGENETIC ANALYSIS; SUBURBAN CHICAGO; COMPLETE GENOME; NORTH-AMERICA; NEW-YORK; GENOTYPE; TRANSMISSION AB West Nile virus (WNV) is an arbovirus maintained in nature in a bird-mosquito enzootic cycle which can also infect other vertebrates including humans. WNV is now endemic in the United States (U.S.), causing yearly outbreaks that have resulted in an estimated total of 4-5 million human infections. Over 41,700 cases of West Nile disease, including 18,810 neuroinvasive cases and 1,765 deaths, were reported to the CDC between 1999 and 2014. In 2012, the second largest West Nile outbreak in the U.S. was reported, which caused 5,674 cases and 286 deaths. WNV continues to evolve, and three major WNV lineage I genotypes (NY99, WN02, and SW/WN03) have been described in the U.S. since introduction of the virus in 1999. We report here the WNV sequences obtained from 19 human samples acquired during the 2012 U.S. outbreak and our examination of the evolutionary dynamics in WNV isolates sequenced from 1999-2012. Maximum-likelihood and Bayesian methods were used to perform the phylogenetic analyses. Selection pressure analyses were performed with the HyPhy package using the Datamonkey web-server. Using different codon-based and branch-site selection models, we detected a number of codons subjected to positive pressure in WNV genes. Thirteen of the 19 completely sequenced isolates from 10 U.S. states were genetically similar, sharing up to 55 nucleotide mutations and 4 amino acid substitutions when compared with the prototype isolate WN-NY99. Overall, these analyses showed that following a brief contraction in 2008-2009, WNV genetic divergence in the U.S. continued to increase in 2012, and that closely related variants were found across a broad geographic range of the U.S., coincident with the second-largest WNV outbreak in U.S. history. C1 [Grinev, Andriyan; Chancey, Caren; Volkova, Evgeniya; Anez, German; Heisey, Daniel A. R.; Rios, Maria] US FDA, LEP, DETTD, OBRR,CBER, Silver Spring, MD 20993 USA. [Winkelman, Valerie; Williamson, Phillip] Creat Testing Solut, Tempe, AZ USA. [Foster, Gregory A.; Stramer, Susan L.] Amer Red Cross, Gaithersburg, MD USA. RP Grinev, A (reprint author), US FDA, LEP, DETTD, OBRR,CBER, Silver Spring, MD 20993 USA. EM Andriyan.Grinev@fda.hhs.gov; Maria.Rios@fda.hhs.gov FU U.S. Food and Drug Administration Intramural Program FX This study was supported by the 2013-2015 U.S. Food and Drug Administration Intramural Program. This project was supported in part by an appointment to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 2 Z9 2 U1 2 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD MAY PY 2016 VL 10 IS 5 AR e0004717 DI 10.1371/journal.pntd.0004717 PG 19 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DO4QY UT WOS:000377769300058 PM 27182734 ER PT J AU Sow, SO Muhsen, K Nasrin, D Blackwelder, WC Wu, YK Farag, TH Panchalingam, S Sur, D Zaidi, AKM Faruque, ASG Saha, D Adegbola, R Alonso, PL Breiman, RF Bassat, Q Tamboura, B Sanogo, D Onwuchekwa, U Manna, B Ramamurthy, T Kanungo, S Ahmed, S Qureshi, S Quadri, F Hossain, A Das, SK Antonio, M Hossain, MJ Mandomando, I Nhampossa, T Acacio, S Omore, R Oundo, JO Ochieng, JB Mintz, ED O'Reilly, CE Berkeley, LY Livio, S Tennant, SM Sommerfelt, H Nataro, JP Ziv-Baran, T Robins-Browne, RM Mishcherkin, V Zhang, JX Liu, J Houpt, ER Kotloff, KL Levine, MM AF Sow, Samba O. Muhsen, Khitam Nasrin, Dilruba Blackwelder, William C. Wu, Yukun Farag, Tamer H. Panchalingam, Sandra Sur, Dipika Zaidi, Anita K. M. Faruque, Abu S. G. Saha, Debasish Adegbola, Richard Alonso, Pedro L. Breiman, Robert F. Bassat, Quique Tamboura, Boubou Sanogo, Doh Onwuchekwa, Uma Manna, Byomkesh Ramamurthy, Thandavarayan Kanungo, Suman Ahmed, Shahnawaz Qureshi, Shahida Quadri, Farheen Hossain, Anowar Das, Sumon K. Antonio, Martin Hossain, M. Jahangir Mandomando, Inacio Nhampossa, Tacilta Acacio, Sozinho Omore, Richard Oundo, Joseph O. Ochieng, John B. Mintz, Eric D. O'Reilly, Ciara E. Berkeley, Lynette Y. Livio, Sofie Tennant, Sharon M. Sommerfelt, Halvor Nataro, James P. Ziv-Baran, Tomer Robins-Browne, Roy M. Mishcherkin, Vladimir Zhang, Jixian Liu, Jie Houpt, Eric R. Kotloff, Karen L. Levine, Myron M. TI The Burden of Cryptosporidium Diarrheal Disease among Children < 24 Months of Age in Moderate/High Mortality Regions of Sub-Saharan Africa and South Asia, Utilizing Data from the Global Enteric Multicenter Study (GEMS) SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID DEVELOPING-COUNTRIES; ANTIBODY-RESPONSES; PARVUM INFECTION; YOUNG-CHILDREN; GUINEA-BISSAU; WEST-AFRICA; COMMUNITY; INDIA; EPIDEMIOLOGY; INFANTS AB Background The importance of Cryptosporidium as a pediatric enteropathogen in developing countries is recognized. Methods Data from the Global Enteric Multicenter Study (GEMS), a 3-year, 7-site, case-control study of moderate-to-severe diarrhea (MSD) and GEMS-1A (1-year study of MSD and less-severe diarrhea [LSD]) were analyzed. Stools from 12,110 MSD and 3,174 LSD cases among children aged <60 months and from 21,527 randomly-selected controls matched by age, sex and community were immunoassay-tested for Cryptosporidium. Species of a subset of Cryptosporidium-positive specimens were identified by PCR; GP60 sequencing identified anthroponotic C. parvum. Combined annual Cryptosporidium-attributable diarrhea incidences among children aged < 24 months for African and Asian GEMS sites were extrapolated to sub-Saharan Africa and South Asian regions to estimate region-wide MSD and LSD burdens. Attributable and excess mortality due to Cryptosporidium diarrhea were estimated. Findings Cryptosporidium was significantly associated with MSD and LSD below age 24 months. Among Cryptosporidium-positive MSD cases, C. hominis was detected in 77.8% (95% CI, 73.0%-81.9%) and C. parvum in 9.9%(95% CI, 7.1%-13.6%); 92% of C. parvum tested were anthroponotic genotypes. Annual Cryptosporidium-attributable MSD incidence was 3.48 (95% CI, 2.27-4.67) and 3.18 (95% CI, 1.85-4.52) per 100 child-years in African and Asian infants, respectively, and 1.41 (95% CI, 0.73-2.08) and 1.36 (95% CI, 0.66-2.05) per 100 child-years in toddlers. Corresponding Cryptosporidium-attributable LSD incidences per 100 child-years were 2.52 (95% CI, 0.33-5.01) and 4.88 (95% CI, 0.82-8.92) in infants and 4.04 (95% CI, 0.56-7.51) and 4.71 (95% CI, 0.24-9.18) in toddlers. We estimate 2.9 and 4.7 millio nCryptosporidium-attributable cases annually in children aged < 24 months in the sub-Saharan Africa and India/Pakistan/Bangladesh/Nepal/Afghanistan regions, respectively, and similar to 202,000 Cryptosporidium-attributable deaths (regions combined). similar to 59,000 excess deaths occurred among Cryptosporidium-attributable diarrhea cases over expected if cases had been Cryptosporidium-negative. Conclusions The enormous African/Asian Cryptosporidium disease burden warrants investments to develop vaccines, diagnostics and therapies. C1 [Sow, Samba O.; Tamboura, Boubou; Sanogo, Doh; Onwuchekwa, Uma] Ctr Dev Vaccins, Bamako, Mali. [Muhsen, Khitam; Nasrin, Dilruba; Blackwelder, William C.; Wu, Yukun; Farag, Tamer H.; Panchalingam, Sandra; Berkeley, Lynette Y.; Livio, Sofie; Tennant, Sharon M.; Nataro, James P.; Mishcherkin, Vladimir; Kotloff, Karen L.; Levine, Myron M.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Nasrin, Dilruba; Blackwelder, William C.; Wu, Yukun; Farag, Tamer H.; Berkeley, Lynette Y.; Livio, Sofie; Tennant, Sharon M.; Levine, Myron M.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Wu, Yukun] Emergent Biosolut, Gaithersburg, MD USA. [Sur, Dipika; Ramamurthy, Thandavarayan; Kanungo, Suman] Natl Inst Cholera & Enter Dis, Kolkata, India. [Zaidi, Anita K. M.; Qureshi, Shahida; Quadri, Farheen] Aga Khan Univ, Dept Paediat & Child Hlth, Karachi, Pakistan. [Faruque, Abu S. G.; Ahmed, Shahnawaz; Hossain, Anowar; Das, Sumon K.] Int Ctr Diarrhoeal Dis Res, GPO Box 128, Dhaka 1000, Bangladesh. [Saha, Debasish; Adegbola, Richard; Antonio, Martin; Hossain, M. Jahangir] Med Res Council United Kingdom Unit, Fajara, Gambia. [Saha, Debasish; Adegbola, Richard] GSK Vaccines, Wavre, Belgium. [Alonso, Pedro L.; Bassat, Quique; Mandomando, Inacio; Nhampossa, Tacilta; Acacio, Sozinho] Ctr Invest Saude Manhica, Maputo, Mozambique. [Alonso, Pedro L.; Mandomando, Inacio; Nhampossa, Tacilta; Acacio, Sozinho] Minist Saude, Inst Nacl Saude, Maputo, Mozambique. [Alonso, Pedro L.; Bassat, Quique] Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Barcelona, Spain. [Breiman, Robert F.] Kenya Off US Ctr Dis Control & Prevent, Global Dis Detect Div, Nairobi, Kenya. [Omore, Richard; Oundo, Joseph O.; Ochieng, John B.] Ctr Dis Control & Prevent, Kenya Med Res Inst, Kisumu, Kenya. [Mintz, Eric D.; O'Reilly, Ciara E.] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Atlanta, GA USA. [Sommerfelt, Halvor] Univ Bergen, Ctr Intervent Sci Maternal & Child Hlth, Ctr Int Hlth, Bergen, Norway. [Sommerfelt, Halvor] Norwegian Inst Publ Hlth, Dept Int Publ Hlth, Oslo, Norway. [Muhsen, Khitam; Ziv-Baran, Tomer] Tel Aviv Univ, Dept Epidemiol & Prevent Med, Sch Publ Hlth, Sackler Fac Med, Ramat Aviv, Israel. [Robins-Browne, Roy M.] Univ Melbourne, Murdoch Childrens Res Inst, Dept Microbiol & Immunol, Royal Childrens Hosp, Parkville, Vic, Australia. [Zhang, Jixian; Liu, Jie; Houpt, Eric R.] Univ Virginia, Dept Med, Div Infect Dis & Int Hlth, Charlottesville, VA USA. [Kotloff, Karen L.] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [Farag, Tamer H.; Zaidi, Anita K. M.] Bill & Melinda Gates Fdn, Seattle, WA USA. [Sur, Dipika; Ramamurthy, Thandavarayan] Translat Hlth Sci & Technol Inst, Faridabad, India. [Alonso, Pedro L.] WHO Global Malaria Programme, Geneva, Switzerland. [Breiman, Robert F.] Emory Univ, Global Hlth Inst, Atlanta, GA 30322 USA. [Berkeley, Lynette Y.] US FDA, Silver Spring, MD USA. [Nataro, James P.] Univ Virginia, Sch Med, Dept Pediat, Charlottesville, VA 22908 USA. RP Levine, MM (reprint author), Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA.; Levine, MM (reprint author), Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. EM mlevine@medicine.umaryland.edu RI Bassat, Quique/P-2341-2016 OI Bassat, Quique/0000-0003-0875-7596 FU Bill & Melinda Gates Foundation [38774, OPP1033572] FX This work was supported by grants 38774 and OPP1033572 from the Bill & Melinda Gates Foundation to MML, URL of the funder's website: http://www.gatesfoundation.org/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 3 Z9 3 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD MAY PY 2016 VL 10 IS 5 AR e0004729 DI 10.1371/journal.pntd.0004729 PG 20 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DO4QY UT WOS:000377769300066 PM 27219054 ER PT J AU Verma, A Ngundi, MM Burns, DL AF Verma, Anita Ngundi, Miriam M. Burns, Drusilla L. TI Mechanistic Analysis of the Effect of Deamidation on the Immunogenicity of Anthrax Protective Antigen SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID ALUMINUM-HYDROXIDE GEL; ASPARAGINE DEAMIDATION; RHESUS MACAQUES; VACCINE; TOXIN; MODEL; TRANSLOCATION; ADSORPTION; CHALLENGE; ADJUVANTS AB The spontaneous modification of proteins, such as deamidation of asparagine residues, can significantly affect the immunogenicity of protein-based vaccines. Using a "genetically deamidated" form of recombinant protective antigen (rPA), we have previously shown that deamidation can decrease the immunogenicity of rPA, the primary component of new-generation anthrax vaccines. In this study, we investigated the biochemical and immunological mechanisms by which deamidation of rPA might decrease the immunogenicity of the protein. We found that loss of the immunogenicity of rPA vaccine was independent of the presence of adjuvant. We assessed the effect of deamidation on the immunodominant neutralizing B-cell epitopes of rPA and found that these epitopes were not significantly affected by deamidation. In order to assess the effect of deamidation on T-cell help for antibody production elicited by rPA vaccine, we examined the ability of the wild-type and genetically deamidated forms of rPA to serve as hapten carriers. We found that when wild-type and genetically deamidated rPA were modified to similar extents with 2,4-dinitrophenyl hapten (DNP) and then used to immunize mice, higher levels of anti-DNP antibodies were elicited by wild-type DNP-rPA than those elicited by the genetically deamidated DNP-rPA, indicating that wild-type rPA elicits more T-cell help than the genetically deamidated form of the protein. These results suggest that a decrease in the ability of deamidated rPA to elicit T-cell help for antibody production is a possible contributor to its lower immunogenicity. C1 [Verma, Anita; Ngundi, Miriam M.; Burns, Drusilla L.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Burns, DL (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. EM drusilla.burns@fda.hhs.gov FU Food and Drug Administration Intramural Research Program FX This work was funded by Food and Drug Administration Intramural Research Program. NR 28 TC 1 Z9 1 U1 2 U2 6 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 MAY PY 2016 VL 23 IS 5 BP 396 EP 402 DI 10.1128/CVI.00701-15 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DO0GE UT WOS:000377456600002 PM 26912784 ER PT J AU Devadas, K Biswas, S Haleyurgirisetty, M Ragupathy, V Wang, X Lee, S Hewlett, I AF Devadas, Krishnakumar Biswas, Santanu Haleyurgirisetty, Mohan Ragupathy, Viswanath Wang, Xue Lee, Sherwin Hewlett, Indira TI Identification of Host Micro RNAs That Differentiate HIV-1 and HIV-2 Infection Using Genome Expression Profiling Techniques SO VIRUSES-BASEL LA English DT Article DE host miRNAs; HIV-1 and HIV-2 infection; modulation of host factors ID IMMUNODEFICIENCY-VIRUS TYPE-2; VIRAL LOAD; IMMUNE ACTIVATION; REPLICATION; BINDING; CELLS; PATHOGENESIS; INTEGRASE; APOPTOSIS; EXOSOMES AB While human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2) share many similar traits, major differences in pathogenesis and clinical outcomes exist between the two viruses. The differential expression of host factors like microRNAs (miRNAs) in response to HIV-1 and HIV-2 infections are thought to influence the clinical outcomes presented by the two viruses. MicroRNAs are small non-coding RNA molecules which function in transcriptional and post-transcriptional regulation of gene expression. MiRNAs play a critical role in many key biological processes and could serve as putative biomarker(s) for infection. Identification of miRNAs that modulate viral life cycle, disease progression, and cellular responses to infection with HIV-1 and HIV-2 could reveal important insights into viral pathogenesis and provide new tools that could serve as prognostic markers and targets for therapeutic intervention. The aim of this study was to elucidate the differential expression profiles of host miRNAs in cells infected with HIV-1 and HIV-2 in order to identify potential differences in virus-host interactions between HIV-1 and HIV-2. Differential expression of host miRNA expression profiles was analyzed using the miRNA profiling polymerase chain reaction (PCR) arrays. Differentially expressed miRNAs were identified and their putative functional targets identified. The results indicate that hsa-miR 541-3p, hsa-miR 518f-3p, and hsa-miR 195-3p were consistently up-regulated only in HIV-1 infected cells. The expression of hsa-miR 1225-5p, hsa-miR 18a* and hsa-miR 335 were down modulated in HIV-1 and HIV-2 infected cells. Putative functional targets of these miRNAs include genes involved in signal transduction, metabolism, development and cell death. C1 [Devadas, Krishnakumar; Biswas, Santanu; Haleyurgirisetty, Mohan; Ragupathy, Viswanath; Wang, Xue; Lee, Sherwin; Hewlett, Indira] US FDA, Mol Virol Lab, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Devadas, K; Hewlett, I (reprint author), US FDA, Mol Virol Lab, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Krishnakumar.Devadas@fda.hhs.gov; Santanu.Biswas@fda.hhs.gov; Mohan.Haleyurgirisetty@fda.hhs.gov; Viswanath.Ragupathy@fda.hhs.gov; Xue.Wang@fda.hhs.gov; Sherwin.Lee@fda.hhs.gov; Indira.Hewlett@fda.hhs.gov FU Intramural CBER Modernizing Grant FX We thank Jiangqin Zhao and Krishnamurthy Konduru for critical review of the manuscript. We thank the Facility for Biotechnology Resources ( FBR), CBER for synthesizing the PCR primers used in this study. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: HTLV-IIIMN/H9 from Robert Gallo. This work was funded by an Intramural CBER Modernizing Grant. The findings and conclusions in this research article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent FDA's views or policies. NR 67 TC 0 Z9 0 U1 3 U2 4 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD MAY PY 2016 VL 8 IS 5 AR 121 DI 10.3390/v8050121 PG 25 WC Virology SC Virology GA DN9VU UT WOS:000377429600004 ER PT J AU Gheorghiade, M Larson, CJ Shah, SJ Greene, SJ Cleland, JGF Colucci, WS Dunnmon, P Epstein, SE Kim, RJ Parsey, RV Stockbridge, N Carr, J Dinh, W Krahn, T Kramer, F Wahlander, K Deckelbaum, LI Crandall, D Okada, S Senni, M Sikora, S Sabbah, HN Butler, J AF Gheorghiade, Mihai Larson, Christopher J. Shah, Sanjiv J. Greene, Stephen J. Cleland, John G. F. Colucci, Wilson S. Dunnmon, Preston Epstein, Stephen E. Kim, Raymond J. Parsey, Ramin V. Stockbridge, Norman Carr, James Dinh, Wilfried Krahn, Thomas Kramer, Frank Wahlander, Karin Deckelbaum, Lawrence I. Crandall, David Okada, Shunichiro Senni, Michele Sikora, Sergey Sabbah, Hani N. Butler, Javed TI Developing New Treatments for Heart Failure Focus on the Heart SO CIRCULATION-HEART FAILURE LA English DT Article DE clinical trial; heart failure; growth and development; pharmaceutical preparations; United States Food and Drug Administration ID PRESERVED EJECTION FRACTION; DRUG DEVELOPMENT; CLINICAL-TRIALS; PHASE-II; THERAPIES; HOSPITALIZATION; READMISSIONS; ASSOCIATION; MORTALITY; VIABILITY AB Compared with heart failure (HF) care 20 to 30 years ago, there has been tremendous advancement in therapy for ambulatory HF with reduced ejection fraction with the use of agents that block maladaptive neurohormonal pathways. However, during the past decade, with few notable exceptions, the frequency of successful drug development programs has fallen as most novel therapies have failed to offer incremental benefit or raised safety concerns (ie, hypotension). Moreover, no therapy has been approved specifically for HF with preserved ejection fraction or for worsening chronic HF (including acutely decompensated HF). Across the spectrum of HF, preliminary results from many phase II trials have been promising but are frequently followed by unsuccessful phase III studies, highlighting a disconnect in the translational process between basic science discovery, early drug development, and definitive clinical testing in pivotal trials. A major unmet need in HF drug development is the ability to identify homogeneous subsets of patients whose underlying disease is driven by a specific mechanism that can be targeted using a new therapeutic agent. Drug development strategies should increasingly consider therapies that facilitate reverse remodeling by directly targeting the heart itself rather than strictly focusing on agents that unload the heart or target systemic neurohormones. Advancements in cardiac imaging may allow for more focused and direct assessment of drug effects on the heart early in the drug development process. To better understand and address the array of challenges facing current HF drug development, so that future efforts may have a better chance for success, the Food and Drug Administration facilitated a meeting on February 17, 2015, which was attended by clinicians, researchers, regulators, and industry representatives. The following discussion summarizes the key takeawaydialoguefromthis meeting. C1 [Gheorghiade, Mihai] Northwestern Univ, Northwestern Feinberg Sch Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. [Shah, Sanjiv J.] Northwestern Univ, Northwestern Feinberg Sch Med, Div Cardiol, Chicago, IL 60611 USA. [Larson, Christopher J.; Okada, Shunichiro] Takeda Pharmaceut, Cardiovasc & Metab Dis Drug Discovery Unit, Chicago, IL USA. [Greene, Stephen J.; Kim, Raymond J.] Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. [Cleland, John G. F.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Colucci, Wilson S.] Boston Univ, Sch Med, Cardiovasc Med Sect, Boston, MA 02215 USA. [Colucci, Wilson S.] Boston Med Ctr, Boston, MA USA. [Dunnmon, Preston; Stockbridge, Norman] US FDA, Div Cardiovasc & Renal Prod, Silver Spring, MD USA. [Epstein, Stephen E.] MedStar Washington Hosp Ctr, MedStar Heart & Vasc Inst, Washington, DC USA. [Parsey, Ramin V.] SUNY Stony Brook, Dept Psychiat, Stony Brook, NY USA. [Butler, Javed] SUNY Stony Brook, Div Cardiol, Stony Brook, NY USA. [Carr, James] Stealth Bio Therapeut, Philadelphia, PA USA. [Dinh, Wilfried; Krahn, Thomas; Kramer, Frank] Bayer HealthCare, Global Drug Discovery, Wuppertal, Germany. [Dinh, Wilfried] Univ Witten Herdecke, Dept Cardiol, Witten, Germany. [Wahlander, Karin] Astra Zeneca Res & Dev, Gothenburg, Sweden. [Deckelbaum, Lawrence I.] CSL Behring, Philadelphia, PA USA. [Crandall, David] Sunov Pharmaceut Inc, Marlborough, MA USA. [Senni, Michele] Azienda Osped Papa Giovannni XXIII, Dipartimento Cardiovasc, Bergamo, Italy. [Sikora, Sergey] Cardiocell Inc, San Diego, CA USA. [Sabbah, Hani N.] Henry Ford Hosp, Div Cardiol, Detroit, MI 48202 USA. RP Gheorghiade, M (reprint author), Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, 201 E Huron,Galter 3-150, Chicago, IL 60611 USA. EM m-gheorghiade@northwestern.edu RI Parsey, Ramin/J-8254-2014 FU Bayer; CardioCell; Siemens; LoneStar Heart, Inc.; National Institutes of Health; European Union FX Dr Gheorghiade reports relationships with Abbott, Astellas, AstraZeneca, Bayer, Cardiorentis, CorThera, Cytokinetics, CytoPherx, DebioPharm, Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, INC, Johnson & Johnson, Medtronic, Merck, Novartis, Ono Pharma, Otsuka, Palatin Technologies, Pericor Therapeutics, Protein Design, Sanofi-Aventis, Sigma Tau, Solvay, Sticares InterACT, Takeda, and Trevena Therapeutics. Drs Larson and Okada are employees of Takeda Pharmaceuticals. Dr Shah reports service as an advisory board member for Bayer, Novartis, DC Devices, and the Pulmonary Hypertension Association. Dr Cleland reports consultation with Amgen, Biotronik, GSK, Medtronic, Novartis, Servier, Sorin, an Stealth Biopharma. Dr Colucci is a consultant to Merck, Novartis, Mast, BMS, Johnson and Johnson, and Cardioxyl. Drs Dunnmon and Stockbridge are employees of the US Food and Drug Administration. Dr Epstein reports consultancy and equity interests in CardioCell. Dr Kim is an inventor on a US patent describing delayed-enhancement magnetic resonance imaging that is owned by Northwestern University. and has received grants from Bayer, CardioCell, and Siemens. J. Carr is an employee of Stealth Bio Therapeutics. Drs Dinh, Krahn, and Kramer are employees of Bayer HealthCare AG. Dr Wahlander is an employee of Astra Zeneca Pharmaceuticals. Dr Deckelbaum is an employee of CSL Behring. Dr Crandall is an employee of Sunovion Pharmaceuticals Inc. Dr Senni is a consultant for Bayer, Novartis, and Abbot Vascular. Dr Sikora is an employee of Cardiocell Inc. Dr Sabbah reports research grants from and is a consultant to LoneStar Heart, Inc. Dr Butler reports research support from the National Institutes of Health and European Union and is a consultant to Amgen, Bayer, Boehringer Ingelheim, Cardiocell, Celladon, Novartis, Trevena, Relypsa, Z Pharma, and Zensun. NR 28 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD MAY PY 2016 VL 9 IS 5 AR e002727 DI 10.1161/CIRCHEARTFAILURE.115.002727 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DN0IS UT WOS:000376748200004 ER PT J AU Trinh, KTL Zhang, H Kang, DJ Kahng, SH Tall, B Lee, NY AF Trinh, Kieu The Loan Zhang, Hainan Kang, Dong-Jin Kahng, Sung-Hyun Tall, Ben D. Lee, Nae Yoon TI Fabrication of Polymerase Chain Reaction Plastic Lab-on-a-Chip Device for Rapid Molecular Diagnoses SO INTERNATIONAL NEUROUROLOGY JOURNAL LA English DT Article DE Plastics; Poly(methylmethacrylate); Lab-on-a-Chip Devices; Polymerase Chain Reaction; Diagnosis ID ELECTROPHORESIS MICROCHIPS; MICROFLUIDIC DEVICES; SURFACE MODIFICATION; PCR; AMPLIFICATION; DNA; PMMA; MICRODEVICES; NEURONS; SAMPLES AB Purpose: We aim to fabricate a thermoplastic poly(methylmethacrylate) (PMMA) Lab-on-a-Chip device to perform continuous- flow polymerase chain reactions (PCRs) for rapid molecular detection of foodborne pathogen bacteria. Methods: A miniaturized plastic device was fabricated by utilizing PMMA substrates mediated by poly(dimethylsiloxane) interfacial coating, enabling bonding under mild conditions, and thus avoiding the deformation or collapse of microchannels. Surface characterizations were carried out and bond strength was measured. The feasibility of the Lab-on-a-Chip device for performing on-chip PCR utilizing a lab-made, portable dual heater was evaluated. The results were compared with those obtained using a commercially available thermal cycler. Results: A PMMA Lab-on-a-Chip device was designed and fabricated for conducting PCR using foodborne pathogens as sample targets. A robust bond was established between the PMMA substrates, which is essential for performing miniaturized PCR on plastic. The feasibility of on-chip PCR was evaluated using Escherichia coli O157: H7 and Cronobacter condimenti, two worldwide foodborne pathogens, and the target amplicons were successfully amplified within 25 minutes. Conclusions: In this study, we present a novel design of a low-cost and high-throughput thermoplastic PMMA Lab-on-aChip device for conducting microscale PCR, and we enable rapid molecular diagnoses of two important foodborne pathogens in minute resolution using this device. In this regard, the introduced highly portable system design has the potential to enable PCR investigations of many diseases quickly and accurately. C1 [Trinh, Kieu The Loan; Zhang, Hainan; Lee, Nae Yoon] Gachon Univ, Dept BioNano Technol, 308 Mirae 1 Bldg,1342 Seongnam Daero, Songnam 13120, South Korea. [Kang, Dong-Jin; Kahng, Sung-Hyun] Korea Inst Ocean Sci & Technol, Ansan, South Korea. [Tall, Ben D.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD USA. [Lee, Nae Yoon] Gachon Med Res Inst, Gil Med Ctr, Inchon, South Korea. [Zhang, Hainan] Univ Twente, TNW MCS, Carre Bldg CR 1514,POB 217, NL-7500 AE Enschede, Netherlands. RP Lee, NY (reprint author), Gachon Univ, Dept BioNano Technol, 308 Mirae 1 Bldg,1342 Seongnam Daero, Songnam 13120, South Korea. EM nylee@gachon.ac.kr FU National Research Foundation of Korea (NRF) - Ministry of Science, ICT & Future Planning [2014R1A1A3051319]; Public Welfare & Safety Research program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT & Future Planning [NRF-2012M3A2A1051681] FX This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2014R1A1A3051319) and the Public Welfare & Safety Research program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2012M3A2A1051681). NR 35 TC 0 Z9 0 U1 9 U2 16 PU KOREAN CONTINENCE SOC PI YEONGOTONG-GU PA DEPT UROLOGY, AJOU UNIV COLL MEDICINE, SAN 5 WONCHEN-DONG, YEONGOTONG-GU, SUWON 443-721, SOUTH KOREA SN 2093-4777 EI 2093-6931 J9 INT NEUROUROL J JI Int. Neurourol. J. PD MAY PY 2016 VL 20 SU 1 BP S38 EP S48 DI 10.5213/inj.1632602.301 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA DN3ZN UT WOS:000377002900007 PM 27230459 ER PT J AU Epperly, H Vaughn, FL Mosholder, AD Maloney, EM Rubinson, L AF Epperly, Holly Vaughn, Frances L. Mosholder, Andrew D. Maloney, Elizabeth M. Rubinson, Lewis TI Nonsteroidal Anti-Inflammatory Drug and Aspirin Use, and Mortality among Critically Ill Pandemic H1N1 Influenza Patients: an Exploratory Analysis SO JAPANESE JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID UNITED-STATES; VIRUS AB We explored nonsteroidal anti-inflammatory drug (NSAID) and aspirin (ASA) use and mortality in the U.S. Department of Health and Human Services' registry of 683 adult and 838 pediatric critically ill pandemic 2009 H1N1 influenza (pH1N1) patients. Among adults, 88 (12.9%) and 101 (14.8%) reported pre-admission use of an NSAID and ASA, respectively; mortality was similar (23-24%) regardless of NSAID or ASA use. Mortality among 89 pediatric NSAID users and 749 nonusers did not differ significantly (10.1% and 8.8%, respectively). One of 16 pediatric ASA users died. Among pediatric patients, the adjusted relative risk estimate for NSAID use and 90-day mortality was higher when influenza vaccination was included in the model (risk ratio [RR] = 1.5; 95% confidence interval, 0.7-3.2), although not statistically significant. Among adults, RR estimates did not change appreciably after adjusting for age, sex, health status, or vaccine status. We found no compelling evidence that NSAID or ASA use influenced mortality in severe pH1N1. C1 [Epperly, Holly; Mosholder, Andrew D.; Maloney, Elizabeth M.] US FDA, Div Epidemiol 2, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Vaughn, Frances L.; Rubinson, Lewis] US Dept HHS, Off Assistant Secretary Preparedness & Response A, Washington, DC 20201 USA. RP Mosholder, AD (reprint author), US FDA, Div Epidemiol 2, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM andrew.mosholder@fda.hhs.gov NR 11 TC 0 Z9 0 U1 0 U2 0 PU NATL INST INFECTIOUS DISEASES PI TOKYO PA JPN J INFECT DIS ED OFF NATL INST INFECTIOUS DISEASES TOYAMA 1-23-1, SHINJUKU-KU, TOKYO, 162-8640, JAPAN SN 1344-6304 EI 1884-2836 J9 JPN J INFECT DIS JI Jpn. J. Infect. Dis. PD MAY PY 2016 VL 69 IS 3 BP 248 EP 251 DI 10.7883/yoken.JJID.2014.577 PG 4 WC Infectious Diseases SC Infectious Diseases GA DN7EO UT WOS:000377238300013 PM 26255728 ER PT J AU Tesfamariam, B AF Tesfamariam, Belay TI Bioresorbable vascular scaffolds: Biodegradation, drug delivery and vascular remodeling SO PHARMACOLOGICAL RESEARCH LA English DT Review DE Biodegradable materials; Bioresorbable scaffolds; Kinetic drug release; Endothelial injury; Thrombosis; Vascular remodeling ID DINUCLEOTIDE PHOSPHATE OXIDASE; EVEROLIMUS-ELUTING SCAFFOLD; CORONARY-ARTERY MODEL; IN-VITRO DEGRADATION; COMPOSITE SCAFFOLDS; NEOINTIMA FORMATION; SHEAR-STRESS; FOLLOW-UP; STENT; RELEASE AB The metallic stents with durable polymers have been effective in reducing the need for revascularization, but the permanent presence of the metal and polymer have been associated with persistent inflammation, hypersensitivity reactions and incidence of thrombosis. Recent innovations of bioresorbable polymers are in development which could serve as temporary scaffolds that degrade into molecules and eventually resorb overtime, and leave the artery free of any permanent prosthetic constraints. The transient scaffolding has the advantages of restoring blood vessel to natural state, improve vasomotor tone and increase lumen enlargement because of expansive remodeling following completion of polymer resorption. The success of bioresorbable vascular scaffolds will depend on the degradation timeline, such that the elastic recoil of the blood vessel and negative remodeling which could potentially lead to restenosis are prevented. Bioresorbable scaffolds with bulky backbone and thick struts could lead to prolonged biodegradation, alter blood flow dynamics and increase thrombogenicity. The development of bioresorbable scaffolds is challenging because of the complexity of finding an ideal balance of polymer biodegradation and controlled drug release overtime, such that the fractional drug released achieves optimal inhibitory concentration until the blood vessel remodels to a stable set point. This review discusses the various types of biodegradable materials, factors affecting biodegradation, drug release kinetics, vascular biocompatibility, adaptive vascular remodeling, and challenges in the development of bioresorbable scaffolds to treat vascular restenosis. Published by Elsevier Ltd. C1 [Tesfamariam, Belay] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Tesfamariam, B (reprint author), US FDA, Div Cardiovasc & Renal, CDER, 10903 New Hampshire Ave,Bldg 22,Rm 4176, Silver Spring, MD 20993 USA. EM belay.tesfamariam@fda.hhs.gov NR 51 TC 1 Z9 1 U1 18 U2 35 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD MAY PY 2016 VL 107 BP 163 EP 171 DI 10.1016/j.phrs.2016.03.020 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DN1MB UT WOS:000376829000018 PM 27001225 ER PT J AU Yang, H Anderson, SA Forshee, R Williams, A Epstein, JS Marks, PW AF Yang, H. Anderson, S. A. Forshee, R. Williams, A. Epstein, J. S. Marks, P. W. TI Modeling complete removal of risk assessment questions in the USA predicts the risk of HIV exposure in blood recipients could increase despite the use of nucleic acid testing SO VOX SANGUINIS LA English DT Article DE blood donation testing; blood safety; donors; NAT; residual risk estimation; transfusion medicine ID HUMAN-IMMUNODEFICIENCY-VIRUS; NO EVIDENCE; TRANSFUSION; INFECTION; CRITERIA; DONORS; MEN; SEX AB Background and ObjectivesThe safety of the blood supply in a number of countries is achieved by interventions that include behaviour-based time-limited or indefinite deferrals and screening of donated units for transfusion-transmitted infections. The relatively high sensitivity of nucleic acid testing (NAT) used in blood donor screening has raised the question of whether such time-based deferrals can be eliminated in favour of individual risk assessment. Materials and MethodsData on the annual number of incident human immunodeficiency virus (HIV) infections associated with various behaviours and on the performance characteristics of NAT applied to donor screening were used to model the number of potentially infected units that might escape detection in the worst-case scenario in which individual risk assessment was implemented, but was not effective as a screening tool, and donors did not otherwise self-select for lower risk. ResultsIn the absence of effective individual risk-based screening or donor self-selection, the model predicts that in the United States, an additional 39 (95% CI 35-43) HIV-infected units would escape detection by nucleic acid testing, potentially capable of exposing approximately 68 (95% CI 61-75) individuals to the risk of HIV infection through the administration of prepared blood components. ConclusionDespite some inherent uncertainty, the worst-case scenario of completely ineffective individual risk assessment, absence of donor self-selection and increased reliance on NAT for blood screening is estimated to be associated with an approximately fourfold increase in the risk of HIV exposure through transfusion in the United States. C1 [Yang, H.; Anderson, S. A.; Forshee, R.; Williams, A.; Epstein, J. S.; Marks, P. W.] US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,WO71-7230, Silver Spring, MD 20993 USA. RP Marks, PW (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,WO71-7230, Silver Spring, MD 20993 USA. EM peter.marks@fda.hhs.gov FU Center for Biologics Evaluation and Research of the United States Food and Drug Administration FX This work was funded by the Center for Biologics Evaluation and Research of the United States Food and Drug Administration. All of the authors are United States government employees and have no conflict of interests that could bias this work. NR 13 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0042-9007 EI 1423-0410 J9 VOX SANG JI Vox Sang. PD MAY PY 2016 VL 110 IS 4 BP 324 EP 328 DI 10.1111/vox.12375 PG 5 WC Hematology SC Hematology GA DN6XG UT WOS:000377219200004 PM 26765975 ER PT J AU Haidar, SH Scheibner, KA AF Haidar, Sam H. Scheibner, Kara A. TI Bioanalytical inspections: organizational changes and regulatory perspectives SO BIOANALYSIS LA English DT Editorial Material DE batch acceptance; biosimilars; extract stability; immunogenicity testing; regulatory; US FDA ID VALIDATION C1 [Haidar, Sam H.; Scheibner, Kara A.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Haidar, SH (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM sam.haidar@fda.hhs.gov NR 5 TC 1 Z9 1 U1 0 U2 0 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 MAY PY 2016 VL 8 IS 10 BP 999 EP 1002 DI 10.4155/bio-2016-0052 PG 4 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DM9HT UT WOS:000376676800001 PM 27079934 ER PT J AU Sun, DJ Wen, H Externbrink, A Gao, ZM Keire, D Krauss, G Jiang, WL AF Sun, Dajun Wen, Hong Externbrink, Anna Gao, Zongming Keire, David Krauss, Gregory Jiang, Wenlei TI Ghost-Pill-Buster: A Case Study of Intact Levetiracetam Extended-Release Tablets after Dissolution Testing SO CNS DRUGS LA English DT Article ID ANTIEPILEPTIC DRUGS; FORMULATIONS AB Orally administered medications in extended-release (ER) dosage forms continue to play a pivotal role in the treatment of various central nervous system disorders. For certain ER dosage forms, pharmaceutical scientists have been familiar with the passage of intact tablet-like objects in patients' feces after administration of ER tablets or capsules based on water-insoluble or slowly dissolving excipients. Nevertheless, because of lack of awareness of the "ghost pill" phenomenon, anxiety has ensued among some patients and clinicians, who have less understanding of how drugs are released from these tablets once ingested. It has been brought to the attention of the US Food and Drug Administration (FDA) that epilepsy patients administered with Teva's levetiracetam ER tablets have noticed intact tablets in their stools and been concerned that they were not getting the needed dose of the drug. In response to neurologists' clinical reporting, the FDA has conducted investigations to confirm a minimal risk of incomplete drug release of Teva's drug product. The objective of this study was to evaluate the risks of incomplete drug release associated with the passing of intact levetiracetam ER tablets, by conducting in vitro dissolution testing. Dissolution testing of Teva's drug product was performed in accordance with the US Pharmacopeia monograph for levetiracetam ER tablets in phosphate buffer and bio-relevant buffers at different pH values. In addition, dissolution testing was conducted with split and crushed tablets. At the end of the dissolution testing, all samples were visually inspected for any undissolved pieces. Approximately 90 % of levetiracetam had been released in all dissolution media after 8 h of dissolution. The levetiracetam ER tablets after dissolution testing remained fully intact in all dissolution media. The rates of drug release were significantly faster from split and crushed tablets than that from whole tablets. On the basis of these findings, Teva's levetiracetam ER tablets may appear intact in the stools but have released the drug successfully. The FDA has requested Teva to revise its product labeling to include remarks regarding the potential passing of intact tablets. Since patients who notice ghost pills in their stools may impetuously crush or split the tablets of subsequent doses on their own, healthcare providers should instruct patients to swallow whole tablets throughout the treatment, in accordance with the drug label. C1 [Sun, Dajun; Wen, Hong; Jiang, Wenlei] US FDA, Ctr Drug Evaluat & Res, Off Gener Drugs, Off Res & Stand, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Externbrink, Anna; Gao, Zongming; Keire, David] US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Qual, Off Testing & Res, Silver Spring, MD 20993 USA. [Krauss, Gregory] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. RP Jiang, WL (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Gener Drugs, Off Res & Stand, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM wenlei.jiang@fda.hhs.gov NR 30 TC 0 Z9 0 U1 2 U2 2 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 1172-7047 EI 1179-1934 J9 CNS DRUGS JI CNS Drugs PD MAY PY 2016 VL 30 IS 5 BP 455 EP 460 DI 10.1007/s40263-016-0332-9 PG 6 WC Clinical Neurology; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DM5TW UT WOS:000376414100007 PM 27048352 ER PT J AU Rubin, DB AF Rubin, Daniel B. TI Evaluations of the Optimal Discovery Procedure for Multiple Testing SO INTERNATIONAL JOURNAL OF BIOSTATISTICS LA English DT Article DE optimal discovery procedure; multiple testing; ranking AB The Optimal Discovery Procedure (ODP) is a method for simultaneous hypothesis testing that attempts to gain power relative to more standard techniques by exploiting multivariate structure [1]. Specializing to the example of testing whether components of a Gaussian mean vector are zero, we compare the power of the ODP to a Bonferroni-style method and to the Benjamini-Hochberg method when the testing procedures aim to respectively control certain Type I error rate measures, such as the expected number of false positives or the false discovery rate. We show through theoretical results, numerical comparisons, and two microarray examples that when the rejection regions for the ODP test statistics are chosen such that the procedure is guaranteed to uniformly control a Type I error rate measure, the technique is generally less powerful than competing methods. We contrast and explain these results in light of previously proven optimality theory for the ODP. We also compare the ordering given by the ODP test statistics to the standard rankings based on sorting univariate p-values from smallest to largest. In the cases we considered the standard ordering was superior, and ODP rankings were adversely impacted by correlation. C1 [Rubin, Daniel B.] US FDA, Silver Spring, MD USA. RP Rubin, DB (reprint author), US FDA, Silver Spring, MD USA. EM daniel.rubin@fda.hhs.gov NR 9 TC 0 Z9 0 U1 1 U2 1 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 2194-573X EI 1557-4679 J9 INT J BIOSTAT JI Int. J. Biostat. PD MAY PY 2016 VL 12 IS 1 SI SI BP 21 EP 29 DI 10.1515/ijb-2015-0027 PG 9 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA DM8JV UT WOS:000376609500003 PM 27227716 ER PT J AU Zusterzeel, R O'Callaghan, KM Canos, DA Sanders, WE Marinac-Dabic, D Strauss, DG AF Zusterzeel, Robbert O'Callaghan, Kathryn M. Canos, Daniel A. Sanders, William E. Marinac-Dabic, Danica Strauss, David G. TI Improving the Safety and Effectiveness of Medical Device Therapy in Women SO JOURNAL OF WOMENS HEALTH LA English DT Article ID CARDIAC-RESYNCHRONIZATION THERAPY; HEART-FAILURE; ASSOCIATION; UPDATE AB When not enough women are included in many clinical trials, an information gap on medical device safety and effectiveness exists, which can make it difficult to detect sex-specific results. In this article we discuss potential reasons for the underrepresentation of women and the regulatory research conducted by the U.S. Food and Drug Administration (FDA) used in supporting regulatory decisions. We demonstrate that important differences in cardiovascular device performance between women and men exist. Furthermore, concrete steps are outlined on the possible ways these sex-specific results can be detected and how a recent FDA Action Plan and Guidance Document aim at encouraging female participation in clinical trials and the appropriate analysis thereof. C1 [Zusterzeel, Robbert; O'Callaghan, Kathryn M.; Canos, Daniel A.; Sanders, William E.; Marinac-Dabic, Danica; Strauss, David G.] US FDA, 10903 New Hampshire Ave 62-1111, Silver Spring, MD 20993 USA. RP Zusterzeel, R (reprint author), US FDA, 10903 New Hampshire Ave 62-1111, Silver Spring, MD 20993 USA. EM robbert.zusterzeel@fda.hhs.gov FU U.S. Food and Drug Administration's (FDA) Office of Women's Health; Oak Ridge Institute for Science and Education FX The research included in this report was supported by the U.S. Food and Drug Administration's (FDA) Office of Women's Health and by a research fellowship from the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the FDA. NR 15 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 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD MAY PY 2016 VL 25 IS 5 BP 428 EP 430 DI 10.1089/jwh.2015.5605 PG 3 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA DM6QS UT WOS:000376478100004 PM 27028582 ER PT J AU Guo, XQ Heflich, RH Dial, SL Richter, PA Moore, MM Mei, N AF Guo, Xiaoqing Heflich, Robert H. Dial, Stacey L. Richter, Patricia A. Moore, Martha M. Mei, Nan TI Quantitative analysis of the relative mutagenicity of five chemical constituents of tobacco smoke in the mouse lymphoma assay SO MUTAGENESIS LA English DT Article ID DOSE-RESPONSE RELATIONSHIPS; MAINSTREAM CIGARETTE-SMOKE; RISK-ASSESSMENT; IN-VITRO; GENETIC TOXICOLOGY; IWGT REPORT; GENOTOXICITY; CELLS; CARCINOGENS; CONDENSATE AB Quantifying health-related biological effects, like genotoxicity, could provide a way of distinguishing between tobacco products. In order to develop tools for using genotoxicty data to quantitatively evaluate the risk of tobacco products, we tested five carcinogens found in cigarette smoke, 4-aminobiphenyl (4-ABP), benzo[a]pyrene (BaP), cadmium (in the form of CdCl2), 2-amino-3,4-dimethyl-3H-imidazo[4,5-f]quinoline (MeIQ) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in the mouse lymphoma assay (MLA). The resulting mutagenicity dose responses were analyzed by various quantitative approaches and their strengths and weaknesses for distinguishing responses in the MLA were evaluated. L5178Y/Tk (+/-) 3.7.2C mouse lymphoma cells were treated with four to seven concentrations of each chemical for 4h. Only CdCl2 produced a positive response without metabolic activation (S9); all five chemicals produced dose-dependent increases in cytotoxicity and mutagenicity with S9. The lowest dose exceeding the global evaluation factor, the benchmark dose producing a 10%, 50%, 100% or 200% increase in the background frequency (BMD10, BMD50, BMD100 and BMD200), the no observed genotoxic effect level (NOGEL), the lowest observed genotoxic effect level (LOGEL) and the mutagenic potency expressed as a mutant frequency per micromole of chemical, were calculated for all the positive responses. All the quantitative metrics had similar rank orders for the agents' ability to induce mutation, from the most to least potent as CdCl2(-S9) > BaP(+S9) > CdCl2(+S9) > MeIQ(+S9) > 4-ABP(+S9) > NNK(+S9). However, the metric values for the different chemical responses (i.e. the ratio of the greatest value to the least value) for the different chemicals ranged from 16-fold (BMD10) to 572-fold (mutagenic potency). These results suggest that data from the MLA are capable of discriminating the mutagenicity of various constituents of cigarette smoke, and that quantitative analyses are available that can be useful in distinguishing between the exposure responses. C1 [Guo, Xiaoqing; Heflich, Robert H.; Dial, Stacey L.; Moore, Martha M.; Mei, Nan] Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Richter, Patricia A.] Ctr Tobacco Prod, Silver Spring, MD 20993 USA. [Richter, Patricia A.] Ctr Dis Control & Prevent, 4770 Buford Highway, Atlanta, GA 30341 USA. [Moore, Martha M.] Ramboll Environ, 124 West Capitol Ave,Suite 1890, Little Rock, AR 72201 USA. RP Mei, N (reprint author), Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. EM nan.mei@fda.hhs.gov OI MEI, NAN/0000-0002-3501-9014 FU US Food and Drug Administration (FDA) FX This research was supported by an inter-center agreement within US Food and Drug Administration (FDA) between the Center for Tobacco Products (CTP) and National Center for Toxicological Research (NCTR). This manuscript has been reviewed by the NCTR and the CTP. The information in these materials is not a formal dissemination of information by the US FDA and does not represent agency position or policy. NR 45 TC 1 Z9 1 U1 2 U2 6 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 MAY PY 2016 VL 31 IS 3 BP 287 EP 296 DI 10.1093/mutage/gev039 PG 10 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA DM4GJ UT WOS:000376304600006 PM 26001754 ER PT J AU Dickinson, DM Johnson, SE Coleman, BN Tworek, C Tessman, GK Alexander, J AF Dickinson, Denise M. Johnson, Sarah E. Coleman, Blair N. Tworek, Cindy Tessman, Greta K. Alexander, Jennifer TI The Language of Cigar Use: Focus Group Findings on Cigar Product Terminology SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID UNITED-STATES; AMERICAN YOUTHS; YOUNG-ADULTS; SMOKING; ADOLESCENTS; TOBACCO; MARIJUANA; STUDENTS; GROWTH; BLUNTS AB Introduction: The consumption of cigar products has increased since 2000. The multiple product types within this category, combined with the varied language with which consumers refer to them, present challenges for accurately assessing the prevalence of cigar product use. Surveillance is also complicated by the fact that these products can be used to smoke marijuana, as "blunts"-cigars in which the tobacco is removed and replaced with marijuana. Few studies exist regarding the language and terminology used to describe these products. Methods: Sixteen focus groups were conducted in five cities in the United States between March and May of 2014. Participants (N = 123) included adults who had used cigars, cigarillos, or little cigars in the past 30 days. A semi-structured moderator guide was used to gather data on the terms used to identify cigar product subtypes and the language used to describe the products and their use. Results: Participants used a variety of terms for each product subtype. Brand names were often used, as well as slang terms, including terms describing cigars modified for marijuana use. Some subtypes were less likely than others to be considered "cigars." Participants had mixed opinions about whether users of cigar products are "smokers." Conclusions: Users of cigar products may classify or label products differently from researchers and policy makers, and many refer to their product by brand name or a slang term. These findings have implications for future research, instrument design, and public health messaging about cigar products. Implications: This study adds to the body of evidence highlighting the challenges for measurement and surveillance of non-cigarette tobacco products, including cigars. Findings illustrate the myriad terms used by consumers to describe their use of cigar product subtypes, as well as the complexity of distinguishing between use of cigar products as intended, versus as a vehicle for smoking marijuana. Future research aimed to enhance specificity of cigar use measures will enable policy-makers and public health practitioners to more fully characterize prevalence and patterns of use by cigar subtype. C1 [Dickinson, Denise M.; Alexander, Jennifer] RTI Int, Publ Hlth Res Div, 3040 E Cornwallis Rd, Res Triangle Pk, NC 27709 USA. [Johnson, Sarah E.; Coleman, Blair N.; Tworek, Cindy; Tessman, Greta K.] US FDA, Off Sci, Ctr Tobacco Prod, Silver Spring, MD USA. RP Dickinson, DM (reprint author), RTI Int, Publ Hlth Res Div, 3040 E Cornwallis Rd, Res Triangle Pk, NC 27709 USA. EM ddickinson@rti.org FU US Food and Drug Administration [HHSF223201110005B/HHSF22312003] FX This work was supported by the US Food and Drug Administration under contract number HHSF223201110005B/Order #HHSF22312003. NR 24 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD MAY PY 2016 VL 18 IS 5 BP 850 EP 856 DI 10.1093/ntr/ntv285 PG 7 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA DM4XN UT WOS:000376350700048 PM 26826209 ER PT J AU Winchell, C Raffaelli, RM Roca, R Michele, T AF Winchell, Celia Raffaelli, Ryan M. Roca, Rigoberto Michele, Theresa TI Food and Drug Administration Response to the ATTUD/SRNT Policy Statement on the Labeling of Nicotine Replacement Therapies SO NICOTINE & TOBACCO RESEARCH LA English DT Letter C1 [Winchell, Celia; Raffaelli, Ryan M.; Roca, Rigoberto; Michele, Theresa] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Raffaelli, RM (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Nonprescript Drug Prod, 10903 New Hampshire Ave,WO 22 MS 5411, Silver Spring, MD 20993 USA. EM ryan.raffaelli@fda.hhs.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD MAY PY 2016 VL 18 IS 5 BP 1218 EP 1219 DI 10.1093/ntr/ntv141 PG 2 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA DM4XN UT WOS:000376350700102 PM 26116083 ER PT J AU Sakellaropoulos, T Herod, TJ Alexopoulos, LG Bai, JPF AF Sakellaropoulos, Theodore Herod, Timothy J. Alexopoulos, Leonidas G. Bai, Jane P. F. TI Computed Biological Relations among Five Select Treatment-Related Organ/Tissue Toxicities SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID JOHNSON SYNDROME; EXPRESSION; RHABDOMYOLYSIS; DYSFUNCTION; GENOTYPE; STEVENS; INJURY AB Drug toxicity presents a major challenge in drug development and patient care. We set to build upon previous works regarding select drug-induced toxicities to find common patterns in the mode of action of the drugs associated with these toxicities. In particular, we focused on five disparate organ toxicities, peripheral neuropathy (PN), rhabdomyolysis (RM), Stevens Johnson syndrome/toxic epidermal necrosis (SJS/TEN), lung injury (LI), and heart contraction-related cardiotoxicity (CT), and identified biological commonalities between and among the toxicities in terms of pharmacological targets and nearest neighbors (indirect effects) using the hyper-geometric test and a distance metric of Spearman correlation. There were 20 significant protein targets associated with two toxicities and 0 protein targets associated with three or more toxicities. Per Spearman distance, PN was closest to SJS/TEN compared to other pairs, whereas the pairs involving RM were more different than others excluding RM. The significant targets associated with RM outnumbered those associated with every one of the other four toxicities. Enrichment analysis of drug targets that are expressed in corresponding organ/tissues determined proteins that should be avoided in drug discovery. The identified biological patterns emerging from the mode of action of these drugs are statistically associated with these serious toxicities and could potentially be used as predictors for new drug candidates. The predictive power and usefulness of these biological patterns will increase with the database of these five toxicities. Furthermore, extension: of our approach to all severe adverse reactions will produce useful biological commonalities for reference in drug discovery and development. C1 [Sakellaropoulos, Theodore; Herod, Timothy J.; Bai, Jane P. F.] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Alexopoulos, Leonidas G.] Natl Tech Univ Athens, Sch Mech Engn, Athens, Greece. [Herod, Timothy J.] Univ Virginia, Biomed Engn, Charlottesville, VA 22904 USA. RP Bai, JPF (reprint author), US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM jane.bai@fda.hhs.gov FU U.S. Food and Drug Administration ORISE Fellowships; FDA Critical Path grant FX This work was supported by the U.S. Food and Drug Administration ORISE Fellowships to T.S. and T.J.H. through a 2012 FDA Critical Path grant to J.P.F.B. The views expressed in this article do not represent the views of the U.S. Food and Drug Administration. NR 28 TC 0 Z9 0 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X EI 1520-5010 J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD MAY PY 2016 VL 29 IS 5 BP 914 EP 923 DI 10.1021/acs.chemrestox.6b00060 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA DM1YZ UT WOS:000376144100020 PM 27063352 ER PT J AU Bekele, AZ Gokulan, K Williams, KM Khare, S AF Bekele, Aschalew Z. Gokulan, Kuppan Williams, Katherine M. Khare, Sangeeta TI Dose and Size-Dependent Antiviral Effects of Silver Nanoparticles on Feline Calicivirus, a Human Norovirus Surrogate SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article ID NORWALK VIRUS; IN-VITRO; INACTIVATION; REPLICATION; INHIBITION; INFECTION; PATHOGENS; EXPOSURE AB Objectives: Silver nanoparticles (AgNPs) as antibacterial agents are incorporated in many consumer products, while the use as antiviral agents is an ongoing area of research. We evaluated the antiviral properties of AgNPs of variable sizes (10, 75, and 110nm) and doses (25, 50, and 100g/mL) at different contact time points against feline calicivirus (FCV), a surrogate for norovirus. Materials and Methods: Antiviral effects of the AgNPs were determined by comparing the infectivity of FCV, the appearance of cytopathic effects (CPEs), and the integrity of the viral capsid protein in viral suspension treated with AgNPs with the untreated controls. Results: The 10nm AgNPs at 50 and 100g/mL concentrations inactivated the FCV beyond the limit of detection, resulting in a decrease of up to 6.5log(10) viral titer, prevented development of CPEs, and reduction in the western blot band signal of the viral capsid protein. No significant antiviral effect was observed for the 75 and 110nm AgNPs. Conclusions and Applications: These results demonstrate that the antiviral effects of AgNPs are both size and dose dependent, thus potential applications of AgNPs as antiviral agents to prevent contamination of foodborne viruses need to consider size and dose effects. C1 [Bekele, Aschalew Z.; Gokulan, Kuppan; Williams, Katherine M.; Khare, Sangeeta] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. RP Khare, S (reprint author), US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. EM sangeeta.khare@fda.hhs.gov FU FDA Commissioner Fellowship Program; Oak Ridge Institute for Science and Education FX The authors acknowledge the support provided by Dr. Anil Patri and Dr. Angel Paredes from the NanoCore facility at NCTR for characterizing the nanoparticles used in this study and Drs. Syed Ali, Rajesh Nayak, Marli Azevedo, and Carl Cerniglia for their thoughtful critique of the manuscript. A.Z.B. is supported by the FDA Commissioner Fellowship Program and K.W. and K.G. by the Oak Ridge Institute for Science and Education. NR 35 TC 3 Z9 3 U1 2 U2 5 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 MAY PY 2016 VL 13 IS 5 BP 239 EP 244 DI 10.1089/fpd.2015.2054 PG 6 WC Food Science & Technology SC Food Science & Technology GA DM0CL UT WOS:000376010100002 PM 26938256 ER PT J AU Chon, JW Kim, YJ Kim, HS Kim, DH Jeong, DK Seo, KH AF Chon, Jung-Whan Kim, Young-Ji Kim, Hong-Seok Kim, Dong-Hyeon Jeong, Dong Kwan Seo, Kun-Ho TI Evaluation of Tazobactam-Supplemented, Modified Charcoal-Cefoperazone-Deoxycholate Agar for Qualitative Detection of Campylobacter from Chicken Carcass Rinse SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article ID LACTAMASE INHIBITOR; C. COLI; SPP.; CLAVULANATE; SELECTIVITY; IMPROVEMENT; ENRICHMENT; JEJUNI; BROTH; RAW AB Overgrowth of extended-spectrum -lactamase (ESBL)-producing Escherichia coli on modified charcoal-cefoperazone-deoxycholate agar (mCCDA) is the most common confounding factor for the isolation of Campylobacter from poultry samples. mCCDA modified by supplementation with tazobactam, an ESBL inhibitor, was evaluated for Campylobacter isolation from chicken carcass rinse with regard to isolation rate and selectivity. In total, 120 whole chicken carcasses purchased from retail stores were rinsed with buffered peptone water enriched with 2x blood-free Bolton broth at 42 degrees C for 48h and then inoculated onto mCCDA with and without tazobactam supplementation (mCCDA or T-mCCDA) at 42 degrees C for 48h under microaerobic conditions. Suspect colonies were subcultured and confirmed by colony PCR. Plates with tazobactam exhibited a higher Campylobacter isolation rate (56.7% vs. 30.8%, p<0.05) and selectivity (0.8 vs. 83.3% plates contaminated with non-Campylobacter, p<0.05) than mCCDA. Thus, tazobactam-supplemented mCCDA would be a useful option for qualitative detection of Campylobacter in chicken carcass rinse. C1 [Chon, Jung-Whan] Konkuk Univ, Dept Anim Sci & Technol, Seoul 05029, South Korea. [Kim, Young-Ji; Kim, Hong-Seok; Kim, Dong-Hyeon; Seo, Kun-Ho] Konkuk Univ, Coll Vet Med, Ctr Hlth 1, Seoul 05029, South Korea. [Jeong, Dong Kwan] Kosin Univ, Dept Food & Nutr, Pusan, 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 National Research Foundation of Korea (NRF) - Korean government (MSIP) [2015R1A2A2A05001288] FX This work was supported by the National Research Foundation of Korea (NRF) grant (No. 2015R1A2A2A05001288) funded by the Korean government (MSIP). NR 13 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 MAY PY 2016 VL 13 IS 5 BP 251 EP 254 DI 10.1089/fpd.2015.2062 PG 4 WC Food Science & Technology SC Food Science & Technology GA DM0CL UT WOS:000376010100004 PM 27043031 ER PT J AU Leeters, IPM Davis, A Zusterzeel, R Atwater, B Risum, N Sogaard, P Klem, I Nijveldt, R Wagner, GS Gorgels, APM Kisslo, J AF Leeters, Irene P. M. Davis, Ashlee Zusterzeel, Robbert Atwater, Brett Risum, Niels Sogaard, Peter Klem, Igor Nijveldt, Robin Wagner, Galen S. Gorgels, Anton P. M. Kisslo, Joseph TI Left ventricular regional contraction abnormalities by echocardiographic speckle tracking in combined right bundle branch with left anterior fascicular block compared to left bundle branch block SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE Right bundle branch block; Left anterior fascicular block; Speckle tracking echocardiography; Regional strain; Strain patterns; Dyssynchrony ID CARDIAC-RESYNCHRONIZATION THERAPY; HEART-FAILURE; MYOCARDIAL-INFARCTION; MECHANICAL DYSSYNCHRONY; MAGNETIC-RESONANCE; EJECTION FRACTION; RANDOMIZED-TRIAL; QRS MORPHOLOGY; STRAIN; ACTIVATION AB Background: In contrast to LBBB patients less is known about patients with RBBB + LAFB regarding LV contractile abnormalities and the potential role of CRT. This study investigated whether patients with RBBB + LAFB morphology have echocardiographic mechanical strain abnormalities between the inferior and anterior LV walls, similar to abnormalities between septal and lateral walls in LBBB. Methods and results: Ten healthy volunteers with no-BBB, 28 LBBB and 28 RBBB + LAFB heart failure patients were included in this retrospective study. Two-dimensional regional-strains were obtained by speckle-tracking. Scar was assessed by CMR. Response on echo was defined as normal, classical, borderline or other pattern. The number of classical patterns in LBBB was significantly higher than in RBBB + LAFB and no-BBB groups (p < 0.001 for both). Contrary, the RBBB + LAFB group showed a significantly higher number of borderline patterns compared to other groups (LBBB: p = 0.042, no-block: p = 0.012). In addition, RBBB + LAFB patients had more scar than LBBB patients (9.9% vs 3.4%, p = 0.041), and the average amount of scar in each wall was also higher in RBBB + LAFB (<5% in LBBB and <16% in RBBB + LAFB). Conclusions: Patients with RBBB + LAFB on ECG and clinical HF demonstrate echocardiographic wall motion abnormalities between inferior and anterior LV walls, similar to abnormalities found between septal and lateral LV walls in patients with LBBB and HF. Fewer patients with RBBB + LAFB showed a classical pattern of opposing wall motion compared to LBBB. Factors that might alter strain patterns in RBBB + LAFB, including the detailed presence or absence of LV scar and coexisting block of the central fascicle, should be assessed in future studies. (C) 2016 Elsevier Inc. All rights reserved. C1 [Leeters, Irene P. M.; Gorgels, Anton P. M.] Maastricht Univ, Med Ctr, Dept Cardiol, Postbus 5800, NL-6202 AZ Maastricht, Netherlands. [Davis, Ashlee; Atwater, Brett; Klem, Igor; Wagner, Galen S.; Kisslo, Joseph] Duke Univ, Med Ctr, Dept Cardiol, Durham, NC USA. [Zusterzeel, Robbert] US FDA, Silver Spring, MD USA. [Risum, Niels] Copenhagen Univ Hosp, Dept Cardiol, Copenhagen, Denmark. [Sogaard, Peter] Aalborg Univ Hosp, Ctr Heart, Aalborg, Denmark. [Sogaard, Peter] Aalborg Univ Hosp, Inst Clin, Aalborg, Denmark. [Nijveldt, Robin] Vrije Univ Amsterdam, Med Ctr, Dept Cardiol, Amsterdam, Netherlands. RP Leeters, IPM (reprint author), Maastricht Univ, Med Ctr, Dept Cardiol, Postbus 5800, NL-6202 AZ Maastricht, Netherlands. EM ipm.leeters@student.maastrichtuniversity.nl FU Oak Ridge Institute of Science and Education; ICIN Netherlands Heart Institute, Utrecht, The Netherlands FX Dr. Zusterzeel is supported by a research fellowship from the Oak Ridge Institute of Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. Dr. Nijveldt is supported by a grant from the ICIN Netherlands Heart Institute, Utrecht, The Netherlands. Dr. Kisslo is a speaker for Philips Medical Systems. The other authors report no potential conflicts of interest. NR 31 TC 3 Z9 3 U1 0 U2 3 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD MAY-JUN PY 2016 VL 49 IS 3 BP 353 EP 361 DI 10.1016/j.jelectrocard.2016.02.002 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DM0RI UT WOS:000376053100014 PM 26931516 ER PT J AU Choi, YS Eom, SY Kim, IS Ali, SF Kleinman, MT Kim, YD Kim, H AF Choi, Young-Sook Eom, Sang-Yong Kim, In-Soo Ali, Syed F. Kleinman, Michael T. Kim, Yong-Dae Kim, Heon TI Fucoidan Extracted from Hijiki Protects Brain Microvessel Endothelial Cells Against Diesel Exhaust Particle Exposure-Induced Disruption SO JOURNAL OF MEDICINAL FOOD LA English DT Article DE BBB disruption; bovine brain microvessel endothelial cells (BBMECs); diesel exhaust particles (DEPs); fucoidan; tight junction proteins ID TIGHT JUNCTION PROTEINS; OXIDATIVE STRESS; BARRIER FUNCTION; AIR-POLLUTION; ANTICOAGULANT; MICROGLIA; PATHWAY; GROWTH; ASSAY; VIVO AB This study was performed to evaluate the protective effects of fucoidan against the decreased function of primary cultured bovine brain microvessel endothelial cells (BBMECs) after exposure to diesel exhaust particles (DEPs). BBMECs were extracted from bovine brains and cultured until confluent. To evaluate the function of BBMECs, we performed a permeability test using cell-by-cell equipment and by Western blot analysis for zonular occludens-1 (ZO-1), which is a tight junction protein of BMECs, and evaluated oxidative stress in BBMECs using the DCFH-DA assay and the CUPRAC-BCS assay. The increased oxidative stress in BBMECs following DEP exposure was suppressed by fucoidan. In addition, permeability of BBMECs induced by DEP exposure was decreased by fucoidan treatment. Our results showed that fucoidan protects against BBMEC disruption induced by DEP exposure. This study provides evidence that fucoidan might protect the central nervous system (CNS) against DEP exposure. C1 [Choi, Young-Sook; Eom, Sang-Yong; Kim, In-Soo; Kim, Yong-Dae; Kim, Heon] Chungbuk Natl Univ, Dept Prevent Med, Coll Med, Cheongju 28644, South Korea. [Choi, Young-Sook; Eom, Sang-Yong; Kim, In-Soo; Kim, Yong-Dae; Kim, Heon] Chungbuk Natl Univ, Med Res Inst, Cheongju 28644, South Korea. [Ali, Syed F.] US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Kleinman, Michael T.] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. RP Kim, YD (reprint author), Chungbuk Natl Univ, Dept Prevent Med, Coll Med, Cheongju 28644, South Korea.; Kim, YD (reprint author), Chungbuk Natl Univ, Med Res Inst, Cheongju 28644, South Korea. EM ydkim@chungbuk.ac.kr NR 31 TC 0 Z9 0 U1 5 U2 8 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-620X EI 1557-7600 J9 J MED FOOD JI J. Med. Food PD MAY PY 2016 VL 19 IS 5 BP 466 EP 471 DI 10.1089/jmf.2015.3635 PG 6 WC Chemistry, Medicinal; Food Science & Technology; Nutrition & Dietetics SC Pharmacology & Pharmacy; Food Science & Technology; Nutrition & Dietetics GA DM4AA UT WOS:000376286700005 PM 27152978 ER PT J AU Khurana, T Newman-Lindsay, S Young, PR Slater, JE AF Khurana, Taruna Newman-Lindsay, Shoshana Young, Philip R. Slater, Jay E. TI The NPC2 protein A novel dog allergen SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Article ID FEL D 4; GENE-EXPRESSION; BINDING PROTEIN; C2 DISEASE; F-I; EPIDIDYMIS; EXTRACTS; CAN-F-1; CAT; DEFICIENT AB Background: Dogs are an important source of indoor allergens that cause rhinoconjunctivitis, urticaria, and asthma in sensitized individuals. Can f 1 is reported as a major dog allergen, but other allergens have also been identified. Identification of immunologically important allergens is important for both the diagnosis and treatment of dog allergy. Objective: To identify and characterize the canine NPC2 protein, a novel dog allergen. Methods: We screened commercial and laboratory-generated aqueous dog extracts by 2-dimensional polyacrylamide gel electrophoresis with IgE immunoblotting using human serum samples from 71 dog-allergic individuals. A target of interest was excised from the gel and sequenced. Canine NPC2 sequence was generated, and recombinant proteins expressed in yeast and bacteria were used to determine allergenicity. An IgE enzyme-linked immunosorbent assay was used for screening 71 dog-positive and 30 dog-negative serum samples. Results: A 16-kDa protein (pK = 8.5) in dog allergen extracts was recognized by specific IgE. The protein was identified by sequencing as a CE1 protein or NPC2 protein. Human IgE bound to recombinant protein was expressed in both yeast and bacteria. Ten (14%) of 71 individuals had specific IgE to NPC2 protein from bacteria, and 12 (17%) had IgE to NPC2 protein from yeast. Binding of pooled dog-allergic serum IgE to the dust mite protein Der p 2 was partially inhibited by recombinant NPC2 protein. Conclusion: NPC2 protein, a member of the MD-2-related lipid recognition family, is identified as a dog allergen (Can f 7), with an apparent seroprevalence of 10% to 20%. Published by Elsevier Inc. on behalf of the American College of Allergy, Asthma & Immunology. C1 [Khurana, Taruna; Newman-Lindsay, Shoshana; Young, Philip R.; Slater, Jay E.] US FDA, Lab Immunobiochem, Div Bacterial Parasit & Allergen Prod, Silver Spring, MD USA. RP Slater, JE (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 52-72,Room 3336, Silver Spring, MD 20993 USA. EM jay.slater@fda.hhs.gov FU Center for Biologics Evaluation and Research, US Food and Drug Administration FX This work was supported by intramural funding from the Center for Biologics Evaluation and Research, US Food and Drug Administration. NR 26 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 1081-1206 EI 1534-4436 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD MAY PY 2016 VL 116 IS 5 BP 440 EP + DI 10.1016/j.anai.2016.02.006 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA DL8AB UT WOS:000375860600013 PM 26995145 ER PT J AU Jarow, JP Casak, S Chuk, M Ehrlich, LA Khozin, S AF Jarow, Jonathan P. Casak, Sandra Chuk, Meredith Ehrlich, Lori A. Khozin, Sean TI The Majority of Expedited Investigational New Drug Safety Reports Are Uninformative SO CLINICAL CANCER RESEARCH LA English DT Article AB Sponsors of human drug and biologic products subject to an investigational new drug (IND) application are required to distribute expedited safety reports of serious and unexpected suspected adverse reactions to participating investigators and the FDA to assure the protection of human subjects participating in clinical trials. On September 29, 2010, the FDA issued a final rule amending its regulations governing expedited IND safety reporting requirements that revised the definitions used for reporting and clarified when to submit relevant and useful information to reduce the number of uninformative reports distributed by sponsors. From January 1, 2006, to December 31, 2014, the FDA's Office of Hematology and Oncology Products received an average of 17,686 expedited safety reports per year. An analysis of FDA submissions by commercial sponsors covering this time period suggested a slight increase in the number of expedited safety reports per IND per year after publication of the final rule. An audit of 160 randomly selected expedited safety reports submitted to the FDA's Office of Hematology and Oncology Products in 2015 revealed that only 22 (14%) were informative. The submission of uninformative expedited safety reports by commercial sponsors of INDs continues to be a significant problem that can compromise detection of valid safety signals. (C) 2016 AACR. C1 [Jarow, Jonathan P.; Casak, Sandra; Chuk, Meredith; Ehrlich, Lori A.; Khozin, Sean] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Khozin, S (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 22,Room 2322, Silver Spring, MD 20993 USA. EM sean.khozin@fda.hhs.gov NR 4 TC 3 Z9 3 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 MAY 1 PY 2016 VL 22 IS 9 BP 2111 EP 2113 DI 10.1158/1078-0432.CCR-15-2082 PG 3 WC Oncology SC Oncology GA DL0NG UT WOS:000375329100004 PM 26783289 ER PT J AU Hao, JS Ghosh, P Li, SK Newman, B Kasting, GB Raney, SG AF Hao, Jinsong Ghosh, Priyanka Li, S. Kevin Newman, Bryan Kasting, Gerald B. Raney, Sam G. TI Heat effects on drug delivery across human skin SO EXPERT OPINION ON DRUG DELIVERY LA English DT Review DE dermal clearance; heat effect; heat exposure; patch; skin blood flow; topical drug products; transdermal delivery systems (TDS) ID HUMAN EPIDERMAL MEMBRANE; HIGH AMBIENT-TEMPERATURE; BLOOD-FLOW; PERCUTANEOUS-ABSORPTION; HUMAN THERMOREGULATION; TRANSDERMAL DELIVERY; CUTANEOUS VASODILATION; PLASMA-CONCENTRATIONS; PHYSICAL-EXERCISE; LOCAL TEMPERATURE AB Introduction: Exposure to heat can impact the clinical efficacy and/or safety of transdermal and topical drug products. Understanding these heat effects and designing meaningful in vitro and in vivo methods to study them are of significant value to the development and evaluation of drug products dosed to the skin.Areas covered: This review provides an overview of the underlying mechanisms and the observed effects of heat on the skin and on transdermal/topical drug delivery, thermoregulation and heat tolerability. The designs of several in vitro and in vivo heat effect studies and their results are reviewed.Expert opinion: There is substantial evidence that elevated temperature can increase transdermal/topical drug delivery. However, in vitro and in vivo methods reported in the literature to study heat effects of transdermal/topical drug products have utilized inconsistent study conditions, and in vitro models require better characterization. Appropriate study designs and controls remain to be identified, and further research is warranted to evaluate in vitro-in vivo correlations and the ability of in vitro models to predict in vivo effects. The physicochemical and pharmacological properties of the drug(s) and the drug product, as well as dermal clearance and heat gradients may require careful consideration. C1 [Hao, Jinsong] Marshall Univ, Dept Pharmaceut Sci & Res, Sch Pharm, Huntington, WV 25755 USA. [Ghosh, Priyanka; Newman, Bryan; Raney, Sam G.] US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Li, S. Kevin; Kasting, Gerald B.] Univ Cincinnati, James L Winkle Coll Pharm, Div Pharmaceut Sci, Cincinnati, OH USA. RP Hao, JS (reprint author), Marshall Univ, Sch Pharm, One John Marshall Dr, Huntington, WV 25755 USA. EM haoj@marshall.edu FU U.S. Food and Drug Administration [U01FD004942] FX Funding for this work was made possible, in part, by the U.S. Food and Drug Administration through grant U01FD004942. The views expressed in this manuscript do not reflect the official policies of the U.S. Food and Drug Administration or the U.S. Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government. 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 60 TC 0 Z9 0 U1 12 U2 16 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1742-5247 EI 1744-7593 J9 EXPERT OPIN DRUG DEL JI Expert Opin. Drug Deliv. PD MAY PY 2016 VL 13 IS 5 BP 755 EP 768 DI 10.1517/17425247.2016.1136286 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DK1TA UT WOS:000374696000012 PM 26808472 ER PT J AU Ferguson, CN Gucinski-Ruth, AC AF Ferguson, Carly N. Gucinski-Ruth, Ashley C. TI Evaluation of Ion Mobility-Mass Spectrometry for Comparative Analysis of Monoclonal Antibodies SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article DE Ion mobility-mass spectrometry; Monoclonal antibodies; Higher order structure ID GAS-PHASE CONFORMATIONS; PROTEIN COMPLEXES; CYTOCHROME-C; INTACT; DYNAMICS; EXCHANGE; GUIDE AB Analytical techniques capable of detecting changes in structure are necessary to monitor the quality of monoclonal antibody drug products. Ion mobility mass spectrometry offers an advanced mode of characterization of protein higher order structure. In this work, we evaluated the reproducibility of ion mobility mass spectrometry measurements and mobiligrams, as well as the suitability of this approach to differentiate between and/or characterize different monoclonal antibody drug products. Four mobiligram-derived metrics were identified to be reproducible across a multi-day window of analysis. These metrics were further applied to comparative studies of monoclonal antibody drug products representing different IgG subclasses, manufacturers, and lots. These comparisons resulted in some differences, based on the four metrics derived from ion mobility mass spectrometry mobiligrams. The use of collision-induced unfolding resulted in more observed differences. Use of summed charge state datasets and the analysis of metrics beyond drift time allowed for a more comprehensive comparative study between different monoclonal antibody drug products. Ion mobility mass spectrometry enabled detection of differences between monoclonal antibodies with the same target protein but different production techniques, as well as products with different targets. These differences were not always detectable by traditional collision cross section studies. Ion mobility mass spectrometry, and the added separation capability of collision-induced unfolding, was highly reproducible and remains a promising technique for advanced analytical characterization of protein therapeutics. C1 [Ferguson, Carly N.; Gucinski-Ruth, Ashley C.] US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Qual, Off Testing & Res,Div Pharmaceut Anal, 645 S Newstead Ave, St Louis, MO 63110 USA. [Ferguson, Carly N.] Pfizer Inc, Chesterfield, MO USA. RP Gucinski-Ruth, AC (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Pharmaceut Qual, Off Testing & Res,Div Pharmaceut Anal, 645 S Newstead Ave, St Louis, MO 63110 USA. EM ashley.gucinski@fda.hhs.gov FU U.S. Food and Drug Administration; FDA Center for Drug Evaluation and Research Critical Path Program 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 Engineering and the U.S. Food and Drug Administration for C.N.F. This work was funded by the FDA Center for Drug Evaluation and Research Critical Path Program awarded to A.C.G. The authors thank Michaella Levy from US FDA-DPA for intact mass analysis, and Abby Gelb from the University of Nebraska-Lincoln for useful discussions and suggestions on CCS calculations. NR 36 TC 2 Z9 2 U1 4 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1044-0305 EI 1879-1123 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD MAY PY 2016 VL 27 IS 5 BP 822 EP 833 DI 10.1007/s13361-016-1369-1 PG 12 WC Biochemical Research Methods; Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA DK0BO UT WOS:000374577600007 PM 26988372 ER PT J AU Rohr, J Guo, S Huo, J Bouska, A Lachel, C Li, Y Simone, PD Zhang, W Gong, Q Wang, C Cannon, A Heavican, T Mottok, A Hung, S Rosenwald, A Gascoyne, R Fu, K Greiner, TC Weisenburger, DD Vose, JM Staudt, LM Xiao, W Borgstahl, GEO Davis, S Steidl, C McKeithan, T Iqbal, J Chan, WC AF Rohr, J. Guo, S. Huo, J. Bouska, A. Lachel, C. Li, Y. Simone, P. D. Zhang, W. Gong, Q. Wang, C. Cannon, A. Heavican, T. Mottok, A. Hung, S. Rosenwald, A. Gascoyne, R. Fu, K. Greiner, T. C. Weisenburger, D. D. Vose, J. M. Staudt, L. M. Xiao, W. Borgstahl, G. E. O. Davis, S. Steidl, C. McKeithan, T. Iqbal, J. Chan, W. C. TI Recurrent activating mutations of CD28 in peripheral T-cell lymphomas SO LEUKEMIA LA English DT Article ID FOLLICULAR-HELPER; CRYSTAL-STRUCTURE; GENE-EXPRESSION; MULTIPLE-MYELOMA; CTLA-4 RECEPTORS; COPY NUMBER; RNA-SEQ; BINDING; COSTIMULATION; LANDSCAPE AB Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of mature T-cell neoplasms with a poor prognosis. Recently, mutations in TET2 and other epigenetic modifiers as well as RHOA have been identified in these diseases, particularly in angioimmunoblastic T-cell lymphoma (AITL). CD28 is the major co-stimulatory receptor in T cells which, upon binding ligand, induces sustained T-cell proliferation and cytokine production when combined with T-cell receptor stimulation. We have identified recurrent mutations in CD28 in PTCLs. Two residues-D124 and T195-were recurrently mutated in 11.3% of cases of AITL and in one case of PTCL, not otherwise specified (PTCL-NOS). Surface plasmon resonance analysis of mutations at these residues with predicted differential partner interactions showed increased affinity for ligand CD86 (residue D124) and increased affinity for intracellular adaptor proteins GRB2 and GADS/GRAP2 (residue T195). Molecular modeling studies on each of these mutations suggested how these mutants result in increased affinities. We found increased transcription of the CD28-responsive genes CD226 and TNFA in cells expressing the T195P mutant in response to CD3 and CD86 co-stimulation and increased downstream activation of NF-kappa B by both D124V and T195P mutants, suggesting a potential therapeutic target in CD28-mutated PTCLs. C1 [Rohr, J.; Bouska, A.; Lachel, C.; Zhang, W.; Wang, C.; Cannon, A.; Heavican, T.; Fu, K.; Greiner, T. C.; Iqbal, J.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, 985900 Nebraska Med Ctr, Omaha, NE 68918 USA. [Rohr, J.; Li, Y.; Gong, Q.; Wang, C.; Weisenburger, D. D.; McKeithan, T.; Chan, W. C.] City Hope Natl Med Ctr, Dept Pathol, Familian Sci Bldg,Room 1013, Duarte, CA 91010 USA. [Guo, S.] Fourth Mil Med Univ, Xi Jing Hosp, Dept Pathol, Xian 710032, Shaan Xi Provin, Peoples R China. [Huo, J.; Davis, S.] Univ Oxford, Radcliffe Dept Med, Oxford, England. [Simone, P. D.] Florida Atlantic Univ, Internal Med Residency Program, Coll Med, Boca Raton, FL 33431 USA. [Wang, C.] Shandong Univ, Sch Med, Jinan 250100, Peoples R China. [Mottok, A.; Hung, S.; Gascoyne, R.; Steidl, C.] BC Canc Agcy, Dept Lymphoid Canc Res, Ctr Lymphoid Canc, Vancouver, BC, Canada. [Mottok, A.; Hung, S.; Gascoyne, R.; Steidl, C.] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Rosenwald, A.] Univ Wurzburg, Inst Pathol, Wurzburg, Germany. [Rosenwald, A.] Univ Wurzburg, Comprehens Canc Ctr Mainfranken CCC MF, D-97070 Wurzburg, Germany. [Vose, J. M.] Univ Nebraska Med Ctr, Dept Med, Omaha, NE USA. [Staudt, L. M.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Xiao, W.] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Washington, DC 20204 USA. [Borgstahl, G. E. O.] Univ Nebraska Med Ctr, Eppley Inst Canc Res & Allied Dis, Omaha, NE USA. RP Iqbal, J (reprint author), Univ Nebraska Med Ctr, Dept Pathol & Microbiol, 985900 Nebraska Med Ctr, Omaha, NE 68918 USA.; Chan, WC (reprint author), City Hope Natl Med Ctr, Dept Pathol, Familian Sci Bldg,Room 1013, Duarte, CA 91010 USA. EM jiqbal@unmc.edu; jochan@coh.org OI Gong, Qiang/0000-0001-8502-6813 FU NCI SPECS II [5 UO1 CA157581-01]; NCI SPORE [1P50CA 136411-01 01A1 PP-4]; City of Hope internal funds; Lymphoma Research Foundation [F-263549]; Leukemia and Lymphoma Society [TRP-6129-04]; UNMC Clinical-Translational Research Scholars Program; NCI Eppley Cancer Center Support Grant [P30CA036727]; Dr Mildred-Scheel Cancer Foundation; Michael Smith Foundation for Health Research; National Center for Research Resources [5P20RR016469, 1S10RR027754-01, RR018788-08]; National Institute for General Medical Science [8P20GM103427, GM103471-09]; NCI; NIH [P30CA33572]; Lymphoma SPORE Developmental Research Award [P50 CA107399] FX We thank R Redder and Dr A Dhar and J Eudy of the UNMC sequencing core; V Smith and Dr P Hexley of the UNMC flow cytometry core; and L Brown, N Feng and S Hsueh of the COH Analytical Cytometry Core. We would like to thank Elizabeth Chavez at BCCA for performing the TSCA experiment. Thanks to Dr Francoise Berger of Universite Lyon 1 for contributing several samples to this study. WCC is supported by NCI SPECS II 5 UO1 CA157581-01, NCI SPORE 1P50CA 136411-01 01A1 PP-4 and City of Hope internal funds; JI is supported by the Lymphoma Research Foundation (F-263549), the Leukemia and Lymphoma Society (TRP-6129-04), the UNMC Clinical-Translational Research Scholars Program, and the NCI Eppley Cancer Center Support Grant P30CA036727. AM is supported by the Dr Mildred-Scheel Cancer Foundation and the Michael Smith Foundation for Health Research. Partial support is from NCI Eppley Cancer Center Support Grant P30CA036727, National Center for Research Resources 5P20RR016469, and National Institute for General Medical Science 8P20GM103427 to GB. The University of Nebraska DNA Sequencing Core receives partial support from the National Center for Research Resources (1S10RR027754-01, 5P20RR016469, RR018788-08) and the National Institute for General Medical Science (8P20GM103427, GM103471-09). Research reported in this publication included work performed in the City of Hope Analytical Cytometry Core supported by the NCI and NIH under award number P30CA33572. This publication's contents are the sole responsibility of the authors and do not necessarily represent the official views of the NIH, FDA or NIGMS. WCC is the recipient of a Lymphoma SPORE Developmental Research Award (P50 CA107399). NR 60 TC 6 Z9 6 U1 3 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD MAY PY 2016 VL 30 IS 5 BP 1062 EP 1070 DI 10.1038/leu.2015.357 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA DL5QM UT WOS:000375691800007 PM 26719098 ER PT J AU Yih, WK Kulldorff, M Sandhu, SK Zichittella, L Maro, JC Cole, DV Jin, R Kawai, AT Baker, MA Liu, CF McMahill-Walraven, CN Selvan, MS Platt, R Nguyen, MD Lee, GM AF Yih, Weiling Katherine Kulldorff, Martin Sandhu, Sukhminder K. Zichittella, Lauren Maro, Judith C. Cole, David V. Jin, Robert Kawai, Alison Tse Baker, Meghan A. Liu, Chunfu McMahill-Walraven, Cheryl N. Selvan, Mano S. Platt, Richard Nguyen, Michael D. Lee, Grace M. TI Prospective influenza vaccine safety surveillance using fresh data in the Sentinel System SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE postmarketing product surveillance; sequential analysis; influenza vaccines; vaccine safety; epidemiologic monitoring; research design; pharmacoepidemiology ID GUILLAIN-BARRE-SYNDROME; PROBABILITY RATIO TEST; FEBRILE SEIZURES; UNITED-STATES; H1N1 VACCINE; CHILDREN; RISK; PROJECT; SIGNAL; TIME AB PurposeTo develop the infrastructure to conduct timely active surveillance for safety of influenza vaccines and other medical countermeasures in the Sentinel System (formerly the Mini-Sentinel Pilot), a Food and Drug Administration-sponsored national surveillance system that typically relies on data that are mature, settled, and updated quarterly. MethodsThree Data Partners provided their earliest available (fresh) cumulative claims data on influenza vaccination and health outcomes 3-4 times on a staggered basis during the 2013-2014 influenza season, collectively producing 10 data updates. We monitored anaphylaxis in the entire population using a cohort design and seizures in children 4years of age using both a self-controlled risk interval design (primary) and a cohort design (secondary). After each data update, we conducted sequential analysis for inactivated (IIV) and live (LAIV) influenza vaccines using the Maximized Sequential Probability Ratio Test, adjusting for data-lag. ResultsMost of the 10 sequential analyses were conducted within 6weeks of the last care-date in the cumulative dataset. A total of 6682336 doses of IIV and 782125 doses of LAIV were captured. The primary analyses did not identify any statistical signals following IIV or LAIV. In secondary analysis, the risk of seizures was higher following concomitant IIV and PCV13 than historically after IIV in 6- to 23-month-olds (relative risk=2.7), which requires further investigation. ConclusionsThe Sentinel System can implement a sequential analysis system that uses fresh data for medical product safety surveillance. Active surveillance using sequential analysis of fresh data holds promise for detecting clinically significant health risks early. Limitations of employing fresh data for surveillance include cost and the need for careful scrutiny of signals. (c) 2015 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd. C1 [Yih, Weiling Katherine; Kulldorff, Martin; Zichittella, Lauren; Maro, Judith C.; Cole, David V.; Jin, Robert; Kawai, Alison Tse; Baker, Meghan A.; Platt, Richard; Lee, Grace M.] Harvard Univ, Sch Med, Dept Populat Med, 401 Pk Dr,Suite 401, Boston, MA 02215 USA. [Yih, Weiling Katherine; Kulldorff, Martin; Zichittella, Lauren; Maro, Judith C.; Cole, David V.; Jin, Robert; Kawai, Alison Tse; Baker, Meghan A.; Platt, Richard; Lee, Grace M.] Harvard Pilgrim Hlth Care Inst, Boston, MA 02215 USA. [Sandhu, Sukhminder K.; Nguyen, Michael D.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Liu, Chunfu] HealthCore, Govt & Acad Res, Alexandria, VA USA. [McMahill-Walraven, Cheryl N.] Aetna, Aetna Data Sci, Blue Bell, PA USA. [Selvan, Mano S.] Humana Inc, Comprehens Hlth Insights, Louisville, KY USA. RP Yih, WK; Lee, GM (reprint author), Harvard Univ, Sch Med, Dept Populat Med, 401 Pk Dr,Suite 401, Boston, MA 02215 USA.; Yih, WK; Lee, GM (reprint author), Harvard Pilgrim Hlth Care Inst, Landmark Ctr, 401 Pk Dr,Suite 401, Boston, MA 02215 USA. EM katherine_yih@harvardpilgrim.org; Michael.Nguyen@fda.hhs.gov NR 28 TC 4 Z9 4 U1 3 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD MAY PY 2016 VL 25 IS 5 BP 481 EP 492 DI 10.1002/pds.3908 PG 12 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DL4OA UT WOS:000375615900001 PM 26572776 ER PT J AU Major, JM Zhou, EH Wong, HL Trinidad, JP Pham, TM Mehta, H Ding, YL Staffa, JA Iyasu, S Wang, CL Willy, ME AF Major, Jacqueline M. Zhou, Esther H. Wong, Hui-Lee Trinidad, James P. Pham, Tracy M. Mehta, Hina Ding, Yulan Staffa, Judy A. Iyasu, Solomon Wang, Cunlin Willy, Mary E. TI Trends in rates of acetaminophen-related adverse events in the United States SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE acetaminophen; overdose; emergency department; hospitalizations; pharmacoepidemiology ID POISON CONTROL CENTERS; EMERGENCY-DEPARTMENT VISITS; ACUTE LIVER-FAILURE; AMERICAN ASSOCIATION; DATA SYSTEM; SURVEILLANCE; OVERDOSES; HEPATOTOXICITY; POPULATION; TOXICITY AB PurposeThe goal of this study is to summarize trends in rates of adverse events attributable to acetaminophen use, including hepatotoxicity and mortality. MethodsA comprehensive analysis of data from three national surveillance systems estimated rates of acetaminophen-related events identified in different settings, including calls to poison centers (2008-2012), emergency department visits (2004-2012), and inpatient hospitalizations (1998-2011). Rates of acetaminophen-related events were calculated per setting, census population, and distributed drug units. ResultsRates of poison center calls with acetaminophen-related exposures decreased from 49.5/1000 calls in 2009 to 43.5/1000 calls in 2012. Rates of emergency department visits for unintentional acetaminophen-related adverse events decreased from 58.0/1000 emergency department visits for adverse drug events in 2009 to 50.2/1000 emergency department visits in 2012. Rates of hospital inpatient discharges with acetaminophen-related poisoning decreased from 119.8/100000 hospitalizations in 2009 to 108.6/100000 hospitalizations in 2011. After 2009, population rates of acetaminophen-related events per 1million census population decreased for poison center calls and hospitalizations, while emergency department visit rates remained stable. However, when accounting for drug sales, the rate of acetaminophen-related events (per 1million distributed drug units) increased after 2009. Prior to 2009, the rates of acetaminophen-related hospitalizations had been slowly increasing (p-trend=0.001). ConclusionsAcetaminophen-related adverse events continue to be a public health burden. Future studies with additional time points are necessary to confirm trends and determine whether recent risk mitigation efforts had a beneficial impact on acetaminophen-related adverse events. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Major, Jacqueline M.; Zhou, Esther H.; Wong, Hui-Lee; Trinidad, James P.; Pham, Tracy M.; Mehta, Hina; Ding, Yulan; Staffa, Judy A.; Iyasu, Solomon; Wang, Cunlin; Willy, Mary E.] US FDA, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Major, JM (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 jacqueline.major@fda.hhs.gov NR 26 TC 3 Z9 3 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD MAY PY 2016 VL 25 IS 5 BP 590 EP 598 DI 10.1002/pds.3906 PG 9 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DL4OA UT WOS:000375615900012 PM 26530380 ER PT J AU Winiecki, SK Tejero-Taldo, MI Avant, D Murphy, D McMahon, AW AF Winiecki, Scott K. Tejero-Taldo, M. Isabel Avant, Debbie Murphy, Dianne McMahon, Ann W. TI Pediatric registries at the Food and Drug Administration: design aspects that increase their likelihood of success SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE pediatrics; product surveillance; postmarketing; registries; US Food and Drug Administration; pharmacoepidemiology ID DISORDERS; NETWORKS; DISEASES AB PurposeTo determine aspects of the design of pediatric registries that contribute to the success of registries conducted as a postmarketing study following approval of drugs or biological products by the US Food and Drug Administration. MethodsPediatric registries for drugs and biological products were identified by searching the US Food and Drug Administration Postmarketing Requirements and Commitments database. Based on the recruitment of patients, the meeting of predetermined deadlines, and the submission of data, we classified studies as successful, unsuccessful, or unevaluable. Design aspects of successful and unsuccessful registries were examined for commonalities. ResultsThirty-eight studies were identified, and ten registries met the criteria for successful. Four (40%) successful registries utilized a registry established prior to product approval, and six (60%) were disease-based. Among unsuccessful registries, none were disease-based or utilized a pre-existing registry. ConclusionsCharacteristics identified as more common to successful registries included utilizing a disease-based registry and a registry established prior to product approval. Future studies might examine a larger sample of registries to see if these aspects consistently result in successful studies. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Winiecki, Scott K.] US FDA, Div Epidemiol, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Tejero-Taldo, M. Isabel] US FDA, Div Mfg & Qual, Off Compliance, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Avant, Debbie; Murphy, Dianne; McMahon, Ann W.] US FDA, Off Pediat Therapeut, Silver Spring, MD USA. RP Winiecki, SK (reprint author), Ctr Biol Evaluat & Res, Div Epidemiol, Off Biostat & Epidemiol, 10903 New Hampshire Ave,Bldg 71,Room 1025, Silver Spring, MD 20993 USA. EM scott.winiecki@fda.hhs.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD MAY PY 2016 VL 25 IS 5 BP 602 EP 605 DI 10.1002/pds.3939 PG 4 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DL4OA UT WOS:000375615900014 PM 26687996 ER PT J AU Schuck, RN Grillo, JA AF Schuck, Robert N. Grillo, Joseph A. TI Pharmacogenomic Biomarkers: an FDA Perspective on Utilization in Biological Product Labeling SO AAPS JOURNAL LA English DT Review DE biomarkers; Pharmacogenomics; precision medicine ID MONOCLONAL-ANTIBODIES; CANCER; PHARMACOKINETICS; UPDATE; DRUGS AB Precision medicine promises to improve both the efficacy and safety of therapeutic products by better informing why some patients respond well to a drug, and some experience adverse reactions, while others do not. Pharmacogenomics is a key component of precision medicine and can be utilized to select optimal doses for patients, more precisely identify individuals who will respond to a treatment and avoid serious drug-related toxicities. Since pharmacogenomic biomarker information can help inform drug dosing, efficacy, and safety, pharmacogenomic data are critically reviewed by FDA staff to ensure effective use of pharmacogenomic strategies in drug development and appropriate incorporation into product labels. Pharmacogenomic information may be provided in drug or biological product labeling to inform health care providers about the impact of genotype on response to a drug through description of relevant genomic markers, functional effects of genomic variants, dosing recommendations based on genotype, and other applicable genomic information. The format and content of labeling for biologic drugs will generally follow that of small molecule drugs; however, there are notable differences in pharmacogenomic information that might be considered useful for biologic drugs in comparison to small molecule drugs. Furthermore, the rapid entry of biologic drugs for treatment of rare genetic diseases and molecularly defined subsets of common diseases will likely lead to increased use of pharmacogenomic information in biologic drug labels in the near future. In this review, we outline the general principles of therapeutic product labeling and discuss the utilization of pharmacogenomic information in biologic drug labels. C1 [Schuck, Robert N.; Grillo, Joseph A.] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Silver Spring, MD USA. RP Schuck, RN (reprint author), US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Silver Spring, MD USA. EM Robert.Schuck@fda.hhs.gov NR 21 TC 0 Z9 0 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD MAY PY 2016 VL 18 IS 3 BP 573 EP 577 DI 10.1208/s12248-016-9891-4 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DL2IW UT WOS:000375458700004 PM 26912182 ER PT J AU Suarez-Sharp, S Delvadia, PR Dorantes, A Duan, J Externbrink, A Gao, ZM Ghosh, T Miksinski, SP Seo, P AF Suarez-Sharp, Sandra Delvadia, Poonam R. Dorantes, Angelica Duan, John Externbrink, Anna Gao, Zongming Ghosh, Tapash Miksinski, Sarah Pope Seo, Paul TI Regulatory Perspectives on Strength-Dependent Dissolution Profiles and Biowaiver Approaches for Immediate Release (IR) Oral Tablets in New Drug Applications SO AAPS JOURNAL LA English DT Review DE biowaivers; immediate release oral dosage forms; multi-unit dissolution testing; strength-dependent dissolution acceptance criteria; strength-dependent dissolution profiles AB Dissolution profile comparisons are used by the pharmaceutical industry to assess the similarity in the dissolution characteristics of two formulations to decide whether the implemented changes, usually minor/moderate in nature, will have an impact on the in vitro/in vivo performance of the drug product. When similarity testing is applied to support the approval of lower strengths of the same formulation, the traditional approach for dissolution profile comparison is not always applicable for drug products exhibiting strength-dependent dissolution and may lead to incorrect conclusions about product performance. The objective of this article is to describe reasonable biopharmaceutic approaches for developing a biowaiver strategy for low solubility, proportionally similar/non-proportionally similar in composition immediate release drug products that exhibit strength-dependent dissolution profiles. The paths highlighted in the article include (1) approaches to address biowaiver requests, such as the use of multi-unit dissolution testing to account for sink condition differences between the higher and lower strengths; (2) the use of a single- vs. strength-dependent dissolution method; and (3) the use of single- vs. strength-dependent dissolution acceptance criteria. These approaches are cost- and time-effective and can avoid unnecessary bioequivalence studies. C1 [Suarez-Sharp, Sandra; Delvadia, Poonam R.; Dorantes, Angelica; Duan, John; Ghosh, Tapash; Seo, Paul] US FDA, Div Biopharmaceut, Off New Drug Prod, Off Pharmaceut Qual,Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Externbrink, Anna; Gao, Zongming] US FDA, Div Pharmaceut Anal, Off Testing & Res, Off Pharmaceut Qual,Ctr Drug Evaluat & Res, St Louis, MD USA. [Miksinski, Sarah Pope] US FDA, Off Pharmaceut Qual, Off New Drug Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Suarez-Sharp, S (reprint author), US FDA, Div Biopharmaceut, Off New Drug Prod, Off Pharmaceut Qual,Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM Sandra.Suarez@fda.hhs.gov NR 15 TC 0 Z9 0 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD MAY PY 2016 VL 18 IS 3 BP 578 EP 588 DI 10.1208/s12248-016-9893-2 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DL2IW UT WOS:000375458700005 PM 26928450 ER PT J AU Qiu, JS Martinez, M Tiwari, R AF Qiu, Junshan Martinez, Marilyn Tiwari, Ram TI Evaluating In Vivo-In Vitro Correlation Using a Bayesian Approach SO AAPS JOURNAL LA English DT Article DE IVIVC; MCMC; probability matching prior; tolerance intervals; Weibull distribution ID TOLERANCE INTERVALS; NUMERICAL DECONVOLUTION; METOPROLOL TARTRATE; FORMULATION; TIME; BIOPHARMACEUTICS; SIMULATIONS; DISSOLUTION; VALIDATION; PREDICTION AB A Bayesian approach with frequentist validity has been developed to support inferences derived from a "Level A" in vivo-in vitro correlation (IVIVC). Irrespective of whether the in vivo data reflect in vivo dissolution or absorption, the IVIVC is typically assessed using a linear regression model. Confidence intervals are generally used to describe the uncertainty around the model. While the confidence intervals can describe population-level variability, it does not address the individual-level variability. Thus, there remains an inability to define a range of individual-level drug concentration-time profiles across a population based upon the "Level A" predictions. This individual-level prediction is distinct from what can be accomplished by a traditional linear regression approach where the focus of the statistical assessment is at a marginal rather than an individual level. The objective of this study is to develop a hierarchical Bayesian method for evaluation of IVIVC, incorporating both the individual- and population-level variability, and to use this method to derive Bayesian tolerance intervals with matching priors that have frequentist validity in evaluating an IVIVC. In so doing, we can now generate population profiles that incorporate not only variability in subject pharmacokinetics but also the variability in the in vivo product performance. C1 [Qiu, Junshan; Tiwari, Ram] US FDA, Ctr Drug Evaluat & Res, Off Biostat, Silver Spring, MD USA. [Martinez, Marilyn] US FDA, Ctr Vet Med, Off New Anim Drug Evaluat, Rockville, MD USA. RP Qiu, JS (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Biostat, Silver Spring, MD USA. EM junshan.-qiu@fda.hhs.gov NR 40 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD MAY PY 2016 VL 18 IS 3 BP 619 EP 634 DI 10.1208/s12248-016-9880-7 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DL2IW UT WOS:000375458700009 PM 26896256 ER PT J AU Rajaraman, P Doody, MM Yu, CL Preston, DL Miller, JS Sigurdson, AJ Freedman, DM Alexander, BH Little, MP Miller, DL Linet, MS AF Rajaraman, Preetha Doody, Michele M. Yu, Chu Ling Preston, Dale L. Miller, Jeremy S. Sigurdson, Alice J. Freedman, D. Michal Alexander, Bruce H. Little, Mark P. Miller, Donald L. Linet, Martha S. TI Cancer Risks in US Radiologic Technologists Working With Fluoroscopically Guided Interventional Procedures, 1994-2008 SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE brain; breast; cancer; fluoroscopically guided interventional procedures; interventional radiology; radiologic procedures ID ATOMIC-BOMB SURVIVORS; CENTRAL-NERVOUS-SYSTEM; IONIZING-RADIATION; UNITED-STATES; CARDIOLOGY PROCEDURES; CHILDHOOD-CANCER; POOLED ANALYSIS; BRAIN CANCER; SKIN-CANCER; TUMORS AB OBJECTIVE. The purpose of this study was to examine risks of cancer incidence and mortality among U.S. radiation technologists performing or assisting with fluoroscopically guided interventional procedures. SUBJECTS AND METHODS. A nationwide prospective cohort of 90,957 radiologic technologists, who responded to a 1994-1998 survey that collected information on whether they had ever worked with fluoroscopically guided interventional procedures, was followed through completion of a subsequent cohort survey during 2003-2005 (for cancer incidence) or December 31, 2008 (for cancer mortality). Sex-adjusted hazard ratios (HRs) and 95% CIs were calculated by use of Cox proportional hazards models for incidence and mortality from all cancers other than nonmelanoma skin cancer and for specific cancer outcomes in participants who reported ever performing fluoroscopically guided interventional procedures compared with technologists who never performed these procedures. RESULTS. The analysis showed an approximately twofold increased risk of brain cancer mortality (HR, 2.55; 95% CI, 1.48-4.40) and modest elevations in incidence of melanoma (HR, 1.30; 95% CI, 1.05-1.61) and in breast cancer incidence (HR, 1.16; 95% CI, 1.02-1.32) but not mortality (HR, 1.07; 95% CI, 0.69-1.66) among technologists who performed fluoroscopically guided interventional procedures compared with those who never performed these procedures. Although there was a small suggestive increase in incidence of all cancers combined, excluding nonmelanoma skin cancers (HR, 1.08; 95% CI, 1.00-1.17), mortality from all cancers combined, excluding nonmelanoma skin cancers, was not elevated (HR, 1.00; 95% CI, 0.88-1.14). We similarly observed no elevated risk of cancers of the thyroid, skin other than melanoma, prostate, lung, or colon and rectum or of leukemia that was not chronic lymphocytic leukemia among workers who performed fluoroscopically guided interventional procedures. CONCLUSION. We observed elevated risks of brain cancer, breast cancer, and melanoma among technologists who performed fluoroscopically guided interventional procedures. Although exposure to low-dose radiation is one possible explanation for these increased risks, these results may also be due to chance or unmeasured confounding by nonradiation risk factors. Our results must be confirmed in other studies, preferably with individual radiation dose data. C1 [Rajaraman, Preetha; Doody, Michele M.; Yu, Chu Ling; Sigurdson, Alice J.; Freedman, D. Michal; Little, Mark P.; Linet, Martha S.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept Hlth & Human Serv, 9609 Med Ctr Dr, Rockville, MD 20892 USA. [Rajaraman, Preetha] NCI, Ctr Global Hlth, NIH, US Dept HHS, Rockville, MD 20892 USA. [Preston, Dale L.] Hirosoft Int, Eureka, CA USA. [Miller, Jeremy S.] Informat Management Syst Inc, Calverton, MD USA. [Alexander, Bruce H.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN USA. [Miller, Donald L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Rajaraman, P (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept Hlth & Human Serv, 9609 Med Ctr Dr, Rockville, MD 20892 USA.; Rajaraman, P (reprint author), NCI, Ctr Global Hlth, NIH, US Dept HHS, Rockville, MD 20892 USA. EM rajarama@mail.nih.gov FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services FX Funded by the intramural 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 49 TC 9 Z9 9 U1 3 U2 4 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 MAY PY 2016 VL 206 IS 5 BP 1101 EP 1108 DI 10.2214/AJR.15.15265 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DK4BD UT WOS:000374860500035 PM 26998721 ER PT J AU Mokhtarzadeh, M Eydelman, M Chen, E AF Mokhtarzadeh, Maryam Eydelman, Malvina Chen, Eric TI Challenges and opportunities when developing devices for rare disease populations SO EXPERT OPINION ON ORPHAN DRUGS LA English DT Editorial Material DE Adaptive Clinical Studies; Early Feasibility Studies; Expedited Access Pathway; humanitarian use device (HUD); Orphan Product; Orphan Product Grant Program; Pediatric Device Consortium (PDC) Grant Program; rare disease ID END-POINTS SYMPOSIUM C1 [Mokhtarzadeh, Maryam; Eydelman, Malvina] US FDA, Ctr Devices & Radiol Hlth, Div Ophthalm & Ear Nose & Throat Devices, Silver Spring, MD 20993 USA. [Chen, Eric] US FDA, Off Orphan Prod Dev, 10903 New Hampshire Ave,WO32 Room 5202, Silver Spring, MD 20993 USA. RP Chen, E (reprint author), US FDA, Off Orphan Prod Dev, 10903 New Hampshire Ave,WO32 Room 5202, Silver Spring, MD 20993 USA. EM eric.chen@fda.hhs.gov NR 17 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 2167-8707 J9 EXPERT OPIN ORPHAN D JI Exp. Opin. Orphan Drugs PD MAY PY 2016 VL 4 IS 5 BP 457 EP 459 DI 10.1517/21678707.2016.1166948 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DK5GZ UT WOS:000374949600002 ER PT J AU Blosser, SJ Drake, SK Andrasko, JL Henderson, CM Kamboj, K Antonara, S Mijares, L Conville, P Frank, KM Harrington, SM Balada-Llasat, JM Zelazny, AM AF Blosser, Sara J. Drake, Steven K. Andrasko, Jennifer L. Henderson, Christina M. Kamboj, Kamal Antonara, Stella Mijares, Lilia Conville, Patricia Frank, Karen M. Harrington, Susan M. Balada-Llasat, Joan-Miquel Zelazny, Adrian M. TI Multicenter Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry Study for Identification of Clinically Relevant Nocardia spp. SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID ANTIMICROBIAL SUSCEPTIBILITY; MYCOBACTERIA; TAXONOMY; MEDIA AB This multicenter study analyzed Nocardia spp., including extraction, spectral acquisition, Bruker matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) identification, and score interpretation, using three Nocardia libraries, the Bruker, National Institutes of Health (NIH), and The Ohio State University (OSU) libraries, and compared the results obtained by each center. A standardized study protocol, 150 Nocardia isolates, and NIH and OSU Nocardia MALDI-TOF MS libraries were distributed to three centers. Following standardized culture, extraction, and MALDI-TOF MS analysis, isolates were identified using score cutoffs of >= 2.0 for species/species complex-level identification and >= 1.8 for genus-level identification. Isolates yielding a score of < 2.0 underwent a single repeat extraction and analysis. The overall score range for all centers was 1.3 to 2.7 (average, 2.2 +/- 0.3), with common species generally producing higher average scores than less common ones. Score categorization and isolate identification demonstrated 86% agreement between centers; 118 of 150 isolates were correctly identified to the species/species complex level by all centers. Nine strains (6.0%) were not identified by any center, and six (4.0%) of these were uncommon species with limited library representation. A categorical score discrepancy among centers occurred for 21 isolates (14.0%). There was an overall benefit of 21.2% from repeat extraction of low-scoring isolates and a center-dependent benefit for duplicate spotting (range, 2 to 8.7%). Finally, supplementation of the Bruker Nocardia MALDI-TOF MS library with both the OSU and NIH libraries increased the genus-level and species-level identification by 18.2% and 36.9%, respectively. Overall, this study demonstrates the ability of diverse clinical microbiology laboratories to utilize MALDI-TOF MS for the rapid identification of clinically relevant Nocardia spp. and to implement MALDI-TOF MS libraries developed by single laboratories across institutions. C1 [Blosser, Sara J.; Henderson, Christina M.; Antonara, Stella; Mijares, Lilia; Conville, Patricia; Frank, Karen M.; Zelazny, Adrian M.] NIH, Dept Lab Med, Microbiol Serv, Bldg 10, Bethesda, MD 20892 USA. [Drake, Steven K.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Andrasko, Jennifer L.; Harrington, Susan M.] Cleveland Clin, Pathol & Lab Med Inst, Cleveland, OH 44106 USA. [Kamboj, Kamal; Balada-Llasat, Joan-Miquel] Ohio State Univ, Dept Pathol, Wexner Med Ctr, Columbus, OH 43210 USA. [Blosser, Sara J.] Indiana State Dept Hlth, Div Clin Microbiol & Virol, Indianapolis, IN 46202 USA. [Antonara, Stella] Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH USA. [Mijares, Lilia] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Conville, Patricia] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Zelazny, AM (reprint author), NIH, Dept Lab Med, Microbiol Serv, Bldg 10, Bethesda, MD 20892 USA. EM azelazny@mail.nih.gov FU Intramural Research Program of the NIH Clinical Center, Department of Laboratory Medicine FX The Intramural Research Program of the NIH Clinical Center, Department of Laboratory Medicine, supported this research. NR 18 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 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAY PY 2016 VL 54 IS 5 BP 1251 EP 1258 DI 10.1128/JCM.02942-15 PG 8 WC Microbiology SC Microbiology GA DK5JH UT WOS:000374955700015 PM 26912758 ER PT J AU Ayala, RC Arya, V Younis, IR AF Ayala, Ruben C. Arya, Vikram Younis, Islam R. TI Design Features of Drug-Drug Interaction Trials Between Antivirals and Oral Contraceptives SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE drug-drug interactions; antiviral medications; oral contraceptives; trial design ID WOMEN; METABOLISM; DISEASE; RISK; HIV AB The aim of this work was to explore the major design features of drug-drug interaction trials between antiviral medications (AVs) and oral contraceptives (OCs). Information on these trials (n = 27) was collected from approved drug labels and clinical pharmacology reviews conducted by the U.S. Food and Drug Administration. The primary objective of all trials was to evaluate changes in OC exposure following the coadministration of AVs. In addition, an evaluation of potential pharmacodynamic interaction was performed in 10 of these trials. Twenty-two trials were open label with a fixed-sequence design, and 5 trials used a double-blind crossover design. The trials were conducted using one, two, or three 28-day ovulatory cycles in 10, 8, and 9 trials, respectively. Only 1 trial enrolled HIV-infected women. The median number of women in a trial was 20 (range, 12 to 52). Norethindrone/ethinyl estradiol (EE) combination was the most commonly used OC (n = 16, 59%) followed by norgestimate/EE (n = 9, 33%). Labeling recommendations were based on exposure changes in 25 cases and on safety observations in the trial in 2 cases. In conclusion, a wide variety of trial designs was used, and there is no preferred design. The answer to the exposure question can be achieved using multiple designs. C1 [Ayala, Ruben C.] US FDA, Off Sci Invest, Off Compliance, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Arya, Vikram; Younis, Islam R.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Younis, IR (reprint author), WO 51,Room 2175,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM islam.younis@fda.hhs.gov NR 16 TC 0 Z9 0 U1 3 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 MAY PY 2016 VL 56 IS 5 BP 541 EP 547 DI 10.1002/jcph.637 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DK3VL UT WOS:000374845400003 PM 26384089 ER PT J AU Salazar, JK Carstens, CK Batihja, VM Narula, SS Parish, M Tortorello, ML AF Salazar, Joelle K. Carstens, Christina K. Batihja, Vriddi M. Narula, Sartaj S. Parish, Mickey Tortorello, Mary Lou TI Fate of Listeria monocytogenes in Fresh Apples and Caramel Apples SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Caramel apples; Fresh apples; Growth kinetics; Listeria monocytogenes; Survival ID ESCHERICHIA-COLI O157-H7; CUT CANTALOUPE; RAW FRUITS; GROWTH; INACTIVATION; SURVIVAL; SALMONELLA; BIOCONTROL; WATERMELON; VEGETABLES AB An outbreak of listeriosis in late 2014 and early 2015 associated with caramel apples led to questions about how this product became a vector for Listeria monocytogenes. This investigation aimed to determine information about the survival and growth of L. monocytogenes in both fresh apples and caramel apples, specifically examining the effects of site and level of inoculation, inoculum drying conditions, and storage temperature. At a high inoculation level (7 log CFU per apple), L. monocytogenes inoculated at the stem end proliferated on Gala caramel apples at both 5 and 25 degrees C and on Granny Smith caramel apples at 25 degrees C by as much as 3 to 5 log CFU per apple. Fresh apples and caramel apples inoculated at the equatorial surface supported survival but not growth of the pathogen. Growth rates (mu(max)) for apples inoculated at the stem end, as determined using the Baranyi and Roberts growth model, were 1.64 +/- 0.27 and 1.38 +/- 0.20 log CFU per apple per day for Gala and Granny Smith caramel apples, respectively, stored at 25 degrees C. At a low inoculation level (3 log CFU per apple), L. monocytogenes inoculated at the stem end and the equatorial surface survived but did not grow on fresh Gala and Granny Smith apples stored at 25 degrees C for 49 days; however, on caramel apples inoculated at the stem end, L. monocytogenes had significant growth under the same conditions. Although certain conditions did not support growth, the pathogen was always detectable by enrichment culture. The inoculation procedure had a significant effect on results; when the inoculum was allowed to dry for 24 h at 5 degrees C, growth was significantly slowed compared with inoculum allowed to dry for 2 h at 25 degrees C. Variation in stick materials did affect L. monocytogenes survival, but these differences were diminished once sticks were placed into caramel apples. C1 [Salazar, Joelle K.; Carstens, Christina K.; Tortorello, Mary Lou] US FDA, Div Food Proc Sci & Technol, Bedford Pk, IL 60501 USA. [Batihja, Vriddi M.; Narula, Sartaj S.] Illinois Inst Technol, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. [Parish, Mickey] US FDA, Off Food Safety, College Pk, MD 20740 USA. RP Tortorello, ML (reprint author), US FDA, Div Food Proc Sci & Technol, Bedford Pk, IL 60501 USA. EM mary.tortorello@fda.hhs.gov FU U.S. Food and Drug Administration [U19FD005322]; Oak Ridge Institute for Science and Education Research Participation Program FX The authors sincerely thank Dr. Kathleen Glass for helpful discussions, Tim Monson (Wisconsin State Laboratory of Hygiene) for providing outbreak-associated L. monocytogenes strains, Karl Reineke and Travis Morrissey for help with acquiring apples for experiments, Dr. Yun Wang for laboratory support, and Dr. Don Zink for motivational guidance. This work was supported by grant U19FD005322 from the U.S. Food and Drug Administration to the Illinois Institute of Technology. J. K. Salazar and C. K. Carstens were supported by a Oak Ridge Institute for Science and Education Research Participation Program grant to the U.S. Food and Drug Administration. The sponsors had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 2 Z9 2 U1 12 U2 25 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 MAY PY 2016 VL 79 IS 5 BP 696 EP 702 DI 10.4315/0362-028X.JFP-15-442 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA DL2UM UT WOS:000375490700001 PM 27296414 ER PT J AU Chon, JW Jung, HI Kuk, M Lim, JS Seo, KH Kim, SK AF Chon, Jung-Whan Jung, Hae-In Kuk, Min Lim, Jong-Soo Seo, Kun-Ho Kim, Soo-Ki TI Microbiological Evaluation of Pork and Chicken By-Products in South Korea SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Antibiotic resistance; By-products; Campylobacter; Indicator bacteria; Salmonella ID ANTIMICROBIAL RESISTANCE; CAMPYLOBACTER-JEJUNI; POULTRY GIBLETS; SALMONELLA; PREVALENCE; MEAT; COLI; OPERATIONS; STEPS; BEEF AB In this study, we aimed to evaluate the microbiological risk of pork and chicken by-products by enumerating indicator bacteria (total aerobic bacteria, coliforms, and Escherichia coli) and identifying pathogens such as Campylobacter and Salmonella. The antibiotic resistance of pathogenic isolates was determined, and molecular subtyping was performed using automated repetitive sequence based PCR (rep-PCR). Pork and chicken by-products were collected from 10 processing plants. The mean numbers of total aerobic bacteria, coliforms, and E. coli from 95 pork by-product samples and 64 chicken by-product samples were 5.1, 3.6, and 2.4 log CFU/g and 4.5, 3.0, and 1.8 log CFU/g, respectively. The numbers of indicator bacteria in the gastrointestinal tract (small intestine, large intestine, and gizzard) were significantly higher than those in other organs. Salmonella and Campylobacter species were detected in 3 and 5 of 95 pork by-product samples and in 6 and 3 of 64 chicken by-product samples, respectively. Four of 9 Salmonella isolates examined were resistant to eight antibiotics, and each of these resistant strains produced an extended-spectrum beta-lactamase. Most Campylobacter isolates were resistant to tetracycline (7 of 8 strains) and quinolones (7 of 8 strains). The similarity in rep-PCR patterns among Salmonella isolates was more closely associated with serotype than with the processing plant and type of meat. Conversely, the rep-PCR patterns of Campylobacter isolates were specific to the processing plant. Our findings could help agencies develop regulations for protection from foodborne bacterial infections arising from animal by-products. C1 [Chon, Jung-Whan; Jung, Hae-In; Kuk, Min; Kim, Soo-Ki] Konkuk Univ, Coll Anim Biosci & Biotechnol, Dept Anim Sci & Technol, 120 Neungdong Ro, Seoul 05029, South Korea. [Lim, Jong-Soo; Seo, Kun-Ho] Konkuk Univ, Ctr Hlth 1, Coll Vet Med, 120 Neungdong Ro, Seoul 05029, South Korea. [Chon, Jung-Whan] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Kim, SK (reprint author), Konkuk Univ, Coll Anim Biosci & Biotechnol, Dept Anim Sci & Technol, 120 Neungdong Ro, Seoul 05029, South Korea. EM sookikim@konkuk.ac.kr FU Golden Seed Project [PJ009929]; Ministry of Agriculture, Food and Rural Affairs (MAFRA); Ministry of Oceans and Fisheries (MOF); Rural Development Administration (RDA); Korea Forest Service (KFS) FX This research was supported by Golden Seed Project (PJ009929), Ministry of Agriculture, Food and Rural Affairs (MAFRA), Ministry of Oceans and Fisheries (MOF), Rural Development Administration (RDA) and Korea Forest Service (KFS). NR 38 TC 0 Z9 0 U1 3 U2 3 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD MAY PY 2016 VL 79 IS 5 BP 715 EP 722 DI 10.4315/0362-028X.JFP-15-395 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA DL2UM UT WOS:000375490700004 PM 27296417 ER PT J AU Jackson, KA Stroika, S Katz, LS Beal, J Brandt, E Nadon, C Reimer, A Major, B Conrad, A Tarr, C Jackson, BR Mody, RK AF Jackson, K. A. Stroika, S. Katz, L. S. Beal, J. Brandt, E. Nadon, C. Reimer, A. Major, B. Conrad, A. Tarr, C. Jackson, B. R. Mody, R. K. TI Use of Whole Genome Sequencing and Patient Interviews To Link a Case of Sporadic Listeriosis to Consumption of Prepackaged Lettuce SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Lettuce; Listeriosis; Whole genome sequencing ID UNITED-STATES; MONOCYTOGENES; TRANSMISSION; FOOD AB We report on a case of listeriosis in a patient who probably consumed a prepackaged romaine lettuce-containing product recalled for Listeria monocyto genes contamination. Although definitive epidemiological information demonstrating exposure to the specific recalled product was lacking, the patient reported consumption of a prepackaged romaine lettuce-containing product of either the recalled brand or a different brand. A multinational investigation found that patient and food isolates from the recalled product were indistinguishable by pulsed-field gel electrophoresis and were highly related by whole genome sequencing, differing by four alleles by whole genome multilocus sequence typing and by five high-quality single nucleotide polymorphisms, suggesting a common source. To our knowledge, this is the first time prepackaged lettuce has been identified as a likely source for listeriosis. This investigation highlights the power of whole genome sequencing, as well as the continued need for timely and thorough epidemiological exposure data to identify sources of foodborne infections. C1 [Jackson, K. A.; Stroika, S.; Katz, L. S.; Conrad, A.; Tarr, C.; Jackson, B. R.; Mody, R. K.] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, 1600 Clifton Rd NE, Atlanta, GA 30329 USA. [Beal, J.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Brandt, E.] Ohio Dept Hlth Lab, 8995 East Main St,Bldg 22, Reynoldsburg, OH 43068 USA. [Nadon, C.; Reimer, A.] Publ Hlth Agcy Canada, Natl Microbiol Lab, 1015 Arlington St, Winnipeg, MB R3E 3R2, Canada. [Major, B.] Canadian Food Inspect Agcy, Greater Toronto Area Lab, 2301 Midland Ave, Scarborough, ON M1P 4R7, Canada. [Conrad, A.] Atlanta Res & Educ Fdn, 4 Execut Pk East NE,Suite 355, Atlanta, GA 30329 USA. RP Jackson, KA (reprint author), Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, 1600 Clifton Rd NE, Atlanta, GA 30329 USA. EM KAJackson1@cdc.gov FU Intramural CDC HHS [CC999999] NR 23 TC 0 Z9 0 U1 1 U2 3 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD MAY PY 2016 VL 79 IS 5 BP 806 EP 809 DI 10.4315/0362-028X.JFP-15-384 PG 4 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA DL2UM UT WOS:000375490700016 PM 27296429 ER PT J AU Lanzarotta, A Kelley, CM AF Lanzarotta, Adam Kelley, Caroline Machal TI Forensic Analysis of Human Autopsy Tissue for the Presence of Polydimethylsiloxane (Silicone) and Volatile Cyclic Siloxanes using Macro FT-IR, FT-IR Spectroscopic Imaging and Headspace GC-MS SO JOURNAL OF FORENSIC SCIENCES LA English DT Article DE forensic science; silicone; polydimethylsiloxane; volatile cyclic siloxanes; autopsy tissue; headspace GC-MS; infrared spectroscopic imaging ID MOLECULAR-WEIGHT SILICONES; BREAST IMPLANTS; INFRARED MICROSPECTROSCOPY; THERMAL-DEGRADATION; IDENTIFICATION; VISUALIZATION; SPECIMENS; PLATINUM; BLOOD; WOMEN AB This study describes effective and straightforward primary and secondary methods for the detection of silicone in human autopsy tissue. The primary method is polydimethylsiloxane (PDMS) specific and employs either macro-attenuated total reflection Fourier transform infrared (ATR-FT-IR) spectroscopy for samples with a high PDMS concentration (relative to that of the matrix) or micro-FT-IR spectroscopic imaging in a reflection/absorption modality for samples with a low PDMS concentration. Although the secondary method is not PDMS specific, it employs headspace gas chromatography with mass spectrometric detection (HS/GC-MS) for the detection of low molecular weight volatile cyclic siloxanes (VCS), which are characteristic marker compounds for PDMS. Overall, the combined results from the primary and secondary analyses provide reliable evidence for the presence of silicone. C1 [Lanzarotta, Adam; Kelley, Caroline Machal] US FDA, Forens Chem Ctr, 6751 Steger Dr, Cincinnati, OH 45237 USA. RP Lanzarotta, A (reprint author), US FDA, Forens Chem Ctr, 6751 Steger Dr, Cincinnati, OH 45237 USA. EM adam.lanzarotta@fda.hhs.gov NR 37 TC 1 Z9 1 U1 8 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-1198 EI 1556-4029 J9 J FORENSIC SCI JI J. Forensic Sci. PD MAY PY 2016 VL 61 IS 3 BP 867 EP 874 DI 10.1111/1556-4029.13018 PG 8 WC Medicine, Legal SC Legal Medicine GA DK7AA UT WOS:000375076000046 ER PT J AU Darflinger, R Thompson, LA Zhang, ZW Chao, K AF Darflinger, Robert Thompson, Laura A. Zhang, Zhiwei Chao, Kuo TI Recurrence, retreatment, and rebleed rates of coiled aneurysms with respect to the Raymond-Roy scale: a meta-analysis SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article DE Aneurysm; Coil; Intervention; Statistics; Subarachnoid ID RUPTURED CEREBRAL ANEURYSMS; ENDOVASCULAR TREATMENT; SINGLE-CENTER; OCCLUSION; THERAPY; COILING AB Background and purpose The Raymond-Roy grading scale is used for aneurysm coiling with only limited data on its validity. The scale was developed based on the extent of initial aneurysm occlusion from 1 to 3. However, the model usefulness in evaluating recurrence, retreatment, and rebleeding is unknown. Our goal was to perform a meta-analysis to evaluate the predictiveness of the Raymond scale. Methods We performed a systematic review of the English literature for aneurysm coiling which reported the initial embolization results, based on the Raymond-Roy grading scale, and the respective recurrence rates, retreatment rates, and rebleed rates. This yielded data for 4587 aneurysms. We conducted a Bayesian random effects meta-analysis to evaluate the outcomes with respect to the reported initial embolization results. Results We found the Raymond scale to be predictive of retreatment, with statistically higher rates of retreatment with higher initial Raymond grade. Furthermore, we found a higher probability of rebleeding for initial grades 2 or 3 versus grade 1, which approached significance. The rebleed rates were probably affected by monitoring and treatment of recurrence. However, although there was a trend towards higher recurrence rates with initial grade, this was not statistically significant. Conclusions The modified Raymond-Roy scale appears to provide reasonable predictive value for treated aneurysm, especially for the clinically more important aspects of retreatment and rebleed rates. C1 [Darflinger, Robert; Chao, Kuo] Kaiser Permanente, Med Ctr, Dept Radiol, 1505-B N Edgemont St, Los Angeles, CA 90027 USA. [Thompson, Laura A.; Zhang, Zhiwei] Food & Drug Adm, Ctr Devices & Radiol Hlth, Div Biostat, Washington, DE USA. RP Darflinger, R (reprint author), Kaiser Permanente, Med Ctr, Dept Radiol, 1505-B N Edgemont St, Los Angeles, CA 90027 USA. EM r.darflinger@gmail.com NR 13 TC 1 Z9 1 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 EI 1759-8486 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD MAY PY 2016 VL 8 IS 5 BP 507 EP 511 DI 10.1136/neurintsurg-2015-011668 PG 5 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA DK9SJ UT WOS:000375271300018 PM 25921230 ER PT J AU Bellayr, IH Catalano, JG Puri, RK AF Bellayr, Ian H. Catalano, Jennifer G. Puri, Raj K. TI MicroRNA Expression in Bone Marrow-Derived Human MSCs SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Bellayr, Ian H.; Puri, Raj K.] US FDA, Div Cellular & Gene Therapies, Silver Spring, MD USA. [Catalano, Jennifer G.] US Int Trade Commiss, Off Ind, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 245 BP S96 EP S96 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200242 ER PT J AU Kwilas, AR Ou, W Marino, MP Argaw, T Suzuki, A Joshi, B Husain, SR Puri, RK Reiser, J AF Kwilas, Anna R. Ou, Wu Marino, Michael P. Argaw, Takele Suzuki, Akiko Joshi, Bharat Husain, Syed R. Puri, Raj K. Reiser, Jakob TI Specific Targeting of IL-13 Receptor alpha 2 Expressing Breast Cancer Cells by Paramyxovirus-Pseudotyped Lentiviral Vectors Displaying IL-13 SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Kwilas, Anna R.; Ou, Wu; Marino, Michael P.; Argaw, Takele; Suzuki, Akiko; Joshi, Bharat; Husain, Syed R.; Puri, Raj K.; Reiser, Jakob] US FDA, Div Cellular & Gene Therapies, CBER, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 214 BP S84 EP S84 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200212 ER PT J AU Li, PJ Zou, JZ Morreale, MT Marino, MP Reiser, J AF Li, Pingjuan Zou, Jizhong Morreale, Michael T. Marino, Michael P. Reiser, Jakob TI Targeted Lentiviral Vector Integration Mediated by the AAV Rep78 Protein SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 19th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 04-07, 2016 CL Washington, DC SP Amer Soc Gene & Cell Therapy C1 [Li, Pingjuan; Morreale, Michael T.; Marino, Michael P.; Reiser, Jakob] US FDA, CBER, Silver Spring, MD USA. [Zou, Jizhong] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2016 VL 24 SU 1 MA 566 BP S226 EP S226 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DK9PT UT WOS:000375264200559 ER PT J AU Setse, RW Siberry, GK Moss, WJ Wheeling, J Bohannon, BA Dominguez, KL AF Setse, Rosanna W. Siberry, George K. Moss, William J. Wheeling, John Bohannon, Beverly A. Dominguez, Kenneth L. CA LEGACY Consortium TI Meningococcal Conjugate and Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccination Among HIV-infected Youth SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE HIV; MCV4; Tdap; vaccine coverage ID AGED 13-17 YEARS; HUMAN-IMMUNODEFICIENCY-VIRUS; IMMUNIZATION PRACTICES ACIP; UNITED-STATES; INFLUENZA VACCINATION; HUMAN-PAPILLOMAVIRUS; ADVISORY-COMMITTEE; ADOLESCENT IMMUNIZATION; ANTIBODY-RESPONSE; MULTILEVEL MODELS AB Background: The meningococcal conjugate vaccine (MCV4) and the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) were first recommended for adolescents in the US in 2005. The goal of our study was to determine MCV4 and Tdap vaccines coverage among perinatally and behaviorally HIV-infected adolescents in 2006 and to compare coverage estimates in our study population to similarly aged healthy youth in 2006. Methods: Longitudinal Epidemiologic Study to Gain Insight into HIV/AIDS in Children and Youth (LEGACY) is a retrospective cohort study of HIV-infected youth in 22 HIV specialty clinics across the US. Among LEGACY participants 11 years of age in 2006, we conducted a cross-sectional analysis to determine MCV4, Tdap and MCV4/Tdap vaccine coverage. We compared vaccine coverage among our study population to coverage among similarly aged youth in the 2006 National Immunization Survey for Teens (NIS-Teen Survey). Multivariable mixed effects logistic regression modeling was used to examine associations between MCV4/Tdap vaccination and mode of HIV transmission. Results: MCV4 and Tdap coverage rates among 326 eligible participants were 31.6% and 28.8%, respectively. Among adolescents 13-17 years of age, MCV4 and Tdap coverage was significantly higher among HIV-infected youth than among youth in the 2006 NIS-Teen Survey (P <0.01). In multivariable analysis, perinatally HIV-infected youth were significantly more likely to have received MCV4/Tdap vaccination compared with their behaviorally infected counterparts (adjusted odds ratio: 5.1; 95% confidence interval: 2.0, 12.7). HIV-infected youth with CD4 cell counts of 200-499 cells/L were more likely to have had MCV4/Tdap vaccination compared with those with CD4 counts 500 cells/L (adjusted odds ratio: 2.2; 95% confidence interval: 1.2, 4.3). Participants with plasma HIV RNA viral loads of >400 copies/mL were significantly less likely to have received MCV4/Tdap vaccination (P < 0.05). Conclusions: MCV4 and Tdap coverage among HIV-infected youth was suboptimal but higher than for healthy adolescents in the 2006 NIS-Teen Survey. Perinatal HIV infection was associated with increased likelihood of vaccination. Specific measures are needed to improve vaccine coverage among adolescents in the US. C1 [Setse, Rosanna W.; Moss, William J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent Maternal AIDS Branch, NIH, Bethesda, MD USA. [Wheeling, John] Northrop Grumman Inc, Atlanta, GA USA. [Bohannon, Beverly A.; Dominguez, Kenneth L.; LEGACY Consortium] Ctr Dis Control & Prevent, Epidemiol Branch, Div HIV AIDS Prevent, Ctr HIV Viral Hepatitis STD & TB Prevent, Atlanta, GA USA. [Setse, Rosanna W.] US FDA, Silver Spring, MD USA. RP Setse, RW (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. EM rsetse@hotmail.com FU Centers for Disease Control and Prevention, Atlanta, GA [200-2004-09976] FX The LEGACY project was funded by the Centers for Disease Control and Prevention, Atlanta, GA, contract number 200-2004-09976. This study was approved by the Institutional Review Board (IRB) of the Johns Hopkins School of Medicine, IRB No. NA_00011187. NR 39 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD MAY PY 2016 VL 35 IS 5 BP e152 EP e157 DI 10.1097/INF.0000000000001078 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA DK6PC UT WOS:000375045200004 PM 26855409 ER PT J AU Pham, JC Williams, TL Sparnon, EM Cillie, TK Scharen, HF Marella, WM AF Pham, Julius Cuong Williams, Tamara L. Sparnon, Erin M. Cillie, Tam K. Scharen, Hilda F. Marella, William M. TI Ventilator-Related Adverse Events: A Taxonomy and Findings From 3 Incident Reporting Systems SO RESPIRATORY CARE LA English DT Article DE ventilator; adverse events; human factors; patient safety; public-private partnership; common taxonomy ID INTENSIVE-CARE-UNIT; UNPLANNED EXTUBATIONS; MECHANICAL VENTILATION; QUALITY IMPROVEMENT; RISK-FACTORS; IMPACT AB BACKGROUND: In 2009, researchers from Johns Hopkins University's Armstrong Institute for Patient Safety and Quality; public agencies, including the FDA; and private partners, including the Emergency Care Research Institute and the University HealthSystem Consortium (UHC) Safety Intelligence Patient Safety Organization, sought to form a public-private partnership for the promotion of patient safety (P5S) to advance patient safety through voluntary partnerships. The study objective was to test the concept of the P5S to advance our understanding of safety issues related to ventilator events, to develop a common classification system for categorizing adverse events related to mechanical ventilators, and to perform a comparison of adverse events across different adverse event reporting systems. METHODS: We performed a cross-sectional analysis of ventilator-related adverse events reported in 2012 from the following incident reporting systems: the Pennsylvania Patient Safety Authority's Patient Safety Reporting System, UHC's Safety Intelligence Patient Safety Organization database, and the FDA's Manufacturer and User Facility Device Experience database. Once each organization had its dataset of ventilator-related adverse events, reviewers read the narrative descriptions of each event and classified it according to the developed common taxonomy. RESULTS: A Pennsylvania Patient Safety Authority, FDA, and UHC search provided 252, 274, and 700 relevant reports, respectively. The 3 event types most commonly reported to the UHC and the Pennsylvania Patient Safety Authority's Patient Safety Reporting System databases were airway/breathing circuit issue, human factor issues, and ventilator malfunction events. The top 3 event types reported to the FDA were ventilator malfunction, power source issue, and alarm failure. CONCLUSIONS: Overall, we found that (1) through the development of a common taxonomy, adverse events from 3 reporting systems can be evaluated, (2) the types of events reported in each database were related to the purpose of the database and the source of the reports, resulting in significant differences in reported event categories across the 3 systems, and (3) a public-private collaboration for investigating ventilator-related adverse events under the P5S model is feasible. C1 [Pham, Julius Cuong] Johns Hopkins Univ, Sch Med, Armstrong Inst Patient Safety & Qual, Dept Anesthesia & Crit Care,Dept Emergency Med, Baltimore, MD USA. [Williams, Tamara L.] Univ Hlth Syst Consortium, Chicago, IL USA. [Sparnon, Erin M.; Marella, William M.] Penn Patient Safety Author, Philadelphia, PA USA. [Cillie, Tam K.] US FDA, Ctr Devices & Radiol Hlth, Off Surveillance & Biometr, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Scharen, Hilda F.] US FDA, Ctr Devices & Radiol Hlth, Off Ctr Director, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Scharen, HF (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Hilda.Scharen@fda.hhs.gov NR 23 TC 0 Z9 0 U1 4 U2 5 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD MAY PY 2016 VL 61 IS 5 BP 621 EP 631 DI 10.4187/respcare.04151 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DL0VC UT WOS:000375349700008 PM 26814222 ER PT J AU Thorne, N Malik, N Shah, S Zhao, J Class, B Aguisanda, F Southall, N Xia, MH McKew, JC Rao, M Zheng, W AF Thorne, Natasha Malik, Nasir Shah, Sonia Zhao, Jean Class, Bradley Aguisanda, Francis Southall, Noel Xia, Menghang McKew, John C. Rao, Mahendra Zheng, Wei TI High-Throughput Phenotypic Screening of Human Astrocytes to Identify Compounds That Protect Against Oxidative Stress SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Astrocytes; Neurodegenerative disease; High-throughput screening; Oxidative stress; Stem cells ID PLURIPOTENT STEM-CELLS; FACTOR-KAPPA-B; ANTIOXIDANT RESPONSE; SIGNALING PATHWAY; INDUCED APOPTOSIS; PYRROLIDINE DITHIOCARBAMATE; NEURODEGENERATIVE DISEASES; NEUROLOGICAL DISEASE; CORTICAL ASTROCYTES; NEURONAL DAMAGE AB Astrocytes are the predominant cell type in the nervous system and play a significant role in maintaining neuronal health and homeostasis. Recently, astrocyte dysfunction has been implicated in the pathogenesis of many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Astrocytes are thus an attractive new target for drug discovery for neurological disorders. Using astrocytes differentiated from human embryonic stem cells, we have developed an assay to identify compounds that protect against oxidative stress, a condition associated with many neurodegenerative diseases. This phenotypic oxidative stress assay has been optimized for high-throughput screening in a 1,536-well plate format. From a screen of approximately 4,100 bloactive tool compounds and approved drugs, we identified a set of 22 that acutely protect human astrocytes from the consequences of hydrogen peroxide-induced oxidative stress. Nine of these compounds were also found to be protective of induced pluripotent stem cell-differentiated astrocytes in a related assay. These compounds are thought to confer protection through hormesis, activating stress-response pathways and preconditioning astrocytes to handle subsequent exposure to hydrogen peroxide. In fact, four of these compounds were found to activate the antioxidant response element/nuclear factor-E2-related factor 2 pathway, a protective pathway induced by toxic insults. Our results demonstrate the relevancy and utility of using astrocytes differentiated from human stem cells as a disease model for drug discovery and development. C1 [Thorne, Natasha; Zhao, Jean; Class, Bradley; Aguisanda, Francis; Southall, Noel; Xia, Menghang; McKew, John C.; Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Malik, Nasir; Shah, Sonia] NIAMSD, Lab Stem Cell Biol, NIH, Bethesda, MD 20892 USA. [Rao, Mahendra] NIH, Ctr Regenerat Med, Bldg 10, Bethesda, MD 20892 USA. RP Thorne, N (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 66,Room 5551, Silver Spring, MD 20993 USA.; Zheng, W (reprint author), NIH, NCATS, 9800 Med Ctr Dr,MSC 3375, Bethesda, MD 20892 USA. EM Natasha.Thorne@fda.hhs.gov; wzheng@mail.nih.gov RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU NIH Common Fund; Intramural Research Program of the Therapeutics for Rare and Neglected Diseases/NIH Center for Advancing Translational Sciences; Center for Regenerative Medicine/National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH FX We thank Steve Titus for expert guidance in analyzing data acquired by the InCell2000, Eric Jones for his assistance with robotics used for screening and immunostaining in 1536-well plate format, and Paul Shinn for generating follow-up compound plates. This work was supported by the NIH Common Fund and the Intramural Research Program of the Therapeutics for Rare and Neglected Diseases/NIH Center for Advancing Translational Sciences and the Center for Regenerative Medicine/National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH. NR 97 TC 1 Z9 1 U1 12 U2 29 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD MAY PY 2016 VL 5 IS 5 BP 613 EP 627 DI 10.5966/sctm.2015-0170 PG 15 WC Cell & Tissue Engineering SC Cell Biology GA DK8KS UT WOS:000375176200011 PM 27034412 ER PT J AU Wan, ZM Ye, JQ Sang, JJ Shao, HX Qian, K Jin, WJ Qin, AJ Wan, HQ AF Wan, Zhimin Ye, Jianqiang Sang, Jianjun Shao, Hongxia Qian, Kun Jin, Wenjie Qin, Aijian Wan, Hongquan TI Identification of amino acids in H9N2 influenza virus neuraminidase that are critical for the binding of two mouse monoclonal antibodies SO VETERINARY MICROBIOLOGY LA English DT Article DE H9N2 virus; Neuraminidase; Escape mutant; Amino acid ID A VIRUSES; MOLECULAR CHARACTERIZATION; HUMAN INFECTION; LINKED LECTIN; HONG-KONG; POULTRY; CHINA; CRYSTALLIZATION; GENERATION; RESISTANCE AB Neuraminidase (NA) is one of the major glycoproteins on the surface of influenza virus. It cleaves the linkage between haemagglutinin and cell surface receptors, and thus helps the release and spread of influenza virus. Despite the importance of H9N2 virus in influenza pandemic preparedness, the antigenic characteristics of its surface glycoproteins, especially NA, remains to be investigated. In the present study, we characterized two monoclonal antibodies (mAbs), 1D1 and 1G8, which are against the NA of an H9N2 virus A/Chicken/Jiangsu/Xi/2004 (X1). We examined the inhibitory effect of these mAbs in two NA inhibition assays: enzyme-linked lectin assay (ELLA) and 2'-(4-methylumbelliferyl)-a-D-N-acetylneuraminic acid (Mu-NANA) assay. In ELLA, which uses a large molecule fetuin (molecular weight: 50 kd) as substrate, both antibodies effectively inhibit the NA activity of X1 virus. However, in Mu-NANA assay, which uses the small molecule Mu-NANA (molecular weight: 489 d) as substrate, antibody 1G8 inhibits the NA activity, while antibody 1D1 does not. Three amino acid mutations, at positions 198,199 and 338, respectively, were detected in the NA of escape mutants of X1 virus selected with the two antibodies. Natural mutations at these three positions have occurred, indicative of immune pressure on H9N2 virus in the field. Our findings lay a basis for detailed investigation on the antigenic structure of H9N2 virus NA, which may be helpful for developing NA-based antibody reagents as well as vaccines. (C) 2016 Elsevier B.V. All rights reserved. C1 [Wan, Zhimin; Ye, Jianqiang; Sang, Jianjun; Shao, Hongxia; Qian, Kun; Jin, Wenjie; Qin, Aijian; Wan, Hongquan] Yangzhou Univ, Coll Vet Med, Yangzhou 225009, Jiangsu, Peoples R China. RP Qin, AJ; Wan, HQ (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. EM aijian@yzu.edu.cn; hqwan129@yahoo.com FU Priority Academic Program Development of Jiangsu Province Higher Education Institutions (PAPD); Jiangsu Province Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses FX This study was made possible by the funding from The Priority Academic Program Development of Jiangsu Province Higher Education Institutions (PAPD) and Jiangsu Province Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses. The authors thank Drs. Tian Bai, Jianfang Zhou and Yuelong Shu (Chinese Center for Disease Control and Prevention) for technical assistance in ELLA in the study. NR 39 TC 1 Z9 1 U1 6 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1135 EI 1873-2542 J9 VET MICROBIOL JI Vet. Microbiol. PD MAY 1 PY 2016 VL 187 BP 58 EP 63 DI 10.1016/j.vetmic.2016.03.011 PG 6 WC Microbiology; Veterinary Sciences SC Microbiology; Veterinary Sciences GA DK8IJ UT WOS:000375170100008 PM 27066709 ER PT J AU Viana, SD Fernandes, RC Canas, PM Silva, AM Carvalho, F Ali, SF Ribeiro, CAF Pereira, FC AF Viana, Sofia D. Fernandes, Rosa C. Canas, Paula M. Silva, Andrea M. Carvalho, Felix Ali, Syed F. Fontes Ribeiro, Carlos A. Pereira, Frederico C. TI Presymptomatic MPTP Mice Show Neurotrophic S100B/mRAGE Striatal Levels SO CNS NEUROSCIENCE & THERAPEUTICS LA English DT Article DE MPTP; Presymptomatic; RAGE; S100B; Striatum ID GLYCATION END-PRODUCTS; PARKINSONS-DISEASE; TREATED MICE; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE MPTP; SYMPTOMATIC STAGES; MOUSE MODEL; RAGE; RECEPTOR; S100B; METHAMPHETAMINE AB AimsAstrocytic S100B and receptor for advanced glycation endproducts (RAGE) have been implicated in Parkinson?s disease (PD) pathogenesis through yet unclear mechanisms. This study attempted to characterize S100B/mRAGE (signaling isoform) axis in a dying-back dopaminergic (DAergic) axonopathy setting, which mimics an early event of PD pathology. MethodsC57BL/6 mice were submitted to a chronic MPTP paradigm (20mg/kg i.p., 2 i.d-12h apart, 5days/week for 2weeks) and euthanized 7days posttreatment to assess mRAGE cellular distribution and S100B/mRAGE density in striatum, after probing their locomotor activity (pole test and rotarod). Dopaminergic status, oxidative stress, and gliosis were also measured (HPLC-ED, WB, IHC). ResultsThis MPTP regimen triggered increased oxidative stress (augmented HNE levels), gliosis (GS/Iba1-reactive morphology), loss of DAergic fibers (decreased tyrosine hydroxylase levels), and severe hypodopaminergia. Biochemical deficits were not translated into motor abnormalities, mimicking a presymptomatic PD period. Remarkably, striatal neurotrophic S100B/mRAGE levels and major neuronal mRAGE localization coexist with compensatory responses (3-fold increase in DA turnover), which are important to maintain normal motor function. ConclusionOur findings rule out the involvement of S100B/mRAGE axis in striatal reactive gliosis, DAergic axonopathy and warrant further exploration of its neurotrophic effects in a presymptomatic compensatory PD stage, which is a fundamental period for successful implementation of therapeutic strategies. C1 [Viana, Sofia D.; Fernandes, Rosa C.; Canas, Paula M.; Silva, Andrea M.; Fontes Ribeiro, Carlos A.; Pereira, Frederico C.] Univ Coimbra, Fac Med, IBILI, Lab Pharmacol & Expt Therapeut, Subunit 1 Polo 3,Azinhaga Santa Comba, P-3000548 Coimbra, Portugal. [Viana, Sofia D.; Fernandes, Rosa C.; Canas, Paula M.; Silva, Andrea M.; Fontes Ribeiro, Carlos A.; Pereira, Frederico C.] Univ Coimbra, IBILI, CNC, Subunit 1 Polo 3,Azinhaga Santa Comba, P-3000548 Coimbra, Portugal. [Viana, Sofia D.] ESTESC Coimbra Hlth Sch, Inst Politecn Coimbra, Farm, Oporto, Portugal. [Carvalho, Felix] Univ Porto, Fac Pharm, Dept Biol Sci, UCIBIO REQUIMTE,Lab Toxicol, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [Ali, Syed F.] US FDA, Natl Ctr Toxicol Res, Neurochem Lab, Div Neurotoxicol, Jefferson, AR 72079 USA. RP Pereira, FC (reprint author), Univ Coimbra, Fac Med, IBILI, Lab Pharmacol & Expt Therapeut, Subunit 1 Polo 3,Azinhaga Santa Comba, P-3000548 Coimbra, Portugal. EM fredcp@ci.uc.pt RI Carvalho, Felix/D-4914-2013; OI Carvalho, Felix/0000-0003-3858-3494; Viana, Sofia/0000-0002-1316-1319; Fernandes, Rosa/0000-0001-7828-2296 FU FCT, Portugal [PEst-C/SAU/UI3282/2013, UID/NEU/04539/2013]; COMPETE-FEDER; Fundo Comunitario Europeu (FEDER); Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) [SFRH/BD/78166/2011]; [EXPL/DTP-DES/0104/2013] FX This research was supported by FCT, Portugal, Strategic Project PEst-C/SAU/UI3282/2013, UID/NEU/04539/2013, COMPETE-FEDER, and EXPL/DTP-DES/0104/2013 under the frame of "Programa Operacional Tematico Fatores de Competitividade (COMPETE/QREN)" and "Fundo Comunitario Europeu (FEDER)." SDV is a recipient of a PhD grant from Fundacao para a Ciencia e a Tecnologia (FCT, Portugal, SFRH/BD/78166/2011). The experiments comply with the current laws of Portugal. NR 42 TC 2 Z9 2 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-5930 EI 1755-5949 J9 CNS NEUROSCI THER JI CNS Neurosci. Ther. PD MAY PY 2016 VL 22 IS 5 BP 396 EP 403 DI 10.1111/cns.12508 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DJ7FP UT WOS:000374377600008 PM 26843141 ER PT J AU Fang, JL Vanlandingham, M da Costa, GG Beland, FA AF Fang, Jia-Long Vanlandingham, Michelle da Costa, Goncalo Gamboa Beland, Frederick A. TI Absorption and metabolism of triclosan after application to the skin of B6C3F1 mice SO ENVIRONMENTAL TOXICOLOGY LA English DT Article DE triclosan; toxicokinetics; dermal toxicity; metabolism; excretion; tissue distribution ID PERSONAL CARE PRODUCTS; PERCUTANEOUS-ABSORPTION; 2,4,4'-TRICHLORO-2'-HYDROXYDIPHENYL ETHER; CHLORINATED DERIVATIVES; IRGASAN DP300; WASTE-WATER; SAFETY; PHARMACOKINETICS; TOXICITY; MILK AB Triclosan is used as an antimicrobial agent in personal care products, household items, medical devices, and clinical settings. Humans can receive lifelong exposures to triclosan; however, data on the toxicity and carcinogenicity after topical application are lacking. This study determined the absorption, distribution, metabolism, and excretion of triclosan after application to the skin of B6C3F1 mice. [C-14(U)]triclosan (10 or 100 mg triclosan/kg body weight) was administered topically to mice in two separate experiments: a vehicle selection experiment using propylene glycol, ethanol, and a generic cosmetic cream, and a toxicokinetic experiment. Mice were killed up to 72 h after triclosan administration, and excreta and tissues were analyzed for radioactivity. Ethanol had the best properties of the vehicles evaluated. Maximum absorption was obtained at approximately 12 h after dosing. Radioactivity appeared in the excreta and in all tissues examined, with the highest levels in the gall bladder and the lowest levels in the brain. Triclosan was metabolized to triclosan sulfate, triclosan glucuronide, 2,4-dichlorophenol, and hydroxytriclosan. The metabolite profile was tissue-dependent and the predominant route of excretion was fecal. The AUC(0-) and the C-max of plasma and liver in females were greater than those in males. Slightly lower absorption was observed in mice with Elizabethan collars. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 609-623, 2016. C1 [Fang, Jia-Long; Vanlandingham, Michelle; da Costa, Goncalo Gamboa; Beland, Frederick A.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Fang, JL (reprint author), US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM jia-long.fang@fda.hhs.gov FU National Center for Toxicological Research, U.S. Food and Drug Administration, National Toxicology Program; National Toxicology Program, National Institute of Environmental Health Sciences [NCTR/FDA IAG 224-12-0003, NIH AES12013] FX Contract grant sponsor: National Center for Toxicological Research, U.S. Food and Drug Administration, National Toxicology Program; Contract grant sponsor: National Toxicology Program, National Institute of Environmental Health Sciences.; Contract grant number: NCTR/FDA IAG # 224-12-0003; NIH AES12013 NR 23 TC 1 Z9 1 U1 10 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1520-4081 EI 1522-7278 J9 ENVIRON TOXICOL JI Environ. Toxicol. PD MAY PY 2016 VL 31 IS 5 BP 609 EP 623 DI 10.1002/tox.22074 PG 15 WC Environmental Sciences; Toxicology; Water Resources SC Environmental Sciences & Ecology; Toxicology; Water Resources GA DJ6OM UT WOS:000374332800011 PM 25410937 ER PT J AU Uehara, H Luo, S Aryal, B Levine, RL Rao, VA AF Uehara, Hiroshi Luo, Shen Aryal, Baikuntha Levine, Rodney L. Rao, V. Ashutosh TI Distinct oxidative cleavage and modification of bovine [Cu- Zn]-SOD by an ascorbic acid/Cu(II) system: Identification of novel copper binding site on SOD molecule SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE SOD; Metal catalyzed oxidation; Copper; Ascorbic acid; Carbonylation; Mass spectrometry ID AMYOTROPHIC-LATERAL-SCLEROSIS; METAL-CATALYZED OXIDATION; AMINO-ACID-RESIDUES; SUPEROXIDE-DISMUTASE; CU,ZN-SUPEROXIDE DISMUTASE; AFFINITY CLEAVAGE; PROTEIN OXIDATION; BIOLOGICAL CONSEQUENCES; METHIONINE OXIDATION; HYDROGEN-PEROXIDE AB We investigated the combined effect of ascorbate and copper [Asc/Cu(II)] on the integrity of bovine [Cu-Zn]-superoxide dismutase (bSOD1) as a model system to study the metal catalyzed oxidation (MCO) and fragmentation of proteins. We found Asc/Cu(II) mediates specific cleavage of bSOD1 and generates 12.5 and 3.2 kDa fragments in addition to oxidation/carbonylation of the protein. The effect of other tested transition metals, a metal chelator, and hydrogen peroxide on the cleavage and oxidation indicated that binding of copper to a previously unknown site on SOD1 is responsible for the Asc/Cu(II) specific cleavage and oxidation. We utilized tandem mass spectrometry to identify the specific cleavage sites of Asc/Cu(II)treated bSOD1. Analyses of tryptic- and AspN-peptides have demonstrated the cleavage to occur at Gly31 with peptide bond breakage with Thr30 and Ser32 through diamide and alpha-amidation pathways, respectively. The three-dimensional structure of bSOD1 reveals the imidazole ring of His19 localized within 5 angstrom from the alpha-carbon of Gly31 providing a structural basis that copper ion, most likely coordinated by His19, catalyzes the specific cleavage reaction. Published by Elsevier Inc. C1 [Uehara, Hiroshi; Luo, Shen; Aryal, Baikuntha; Rao, V. Ashutosh] US FDA, Lab Appl Biochem, Div Biotechnol Review & Res 3, Off Biotechnol Prod,Off Pharmaceut Qual,Ctr Drug, White Oak, MD 20993 USA. [Levine, Rodney L.] NHLBI, Biochem Lab, Bldg 10, Bethesda, MD 20892 USA. RP Rao, VA (reprint author), US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Rm 2212, Silver Spring, MD 20993 USA. EM ashutosh.rao@fda.hhs.gov RI Levine, Rodney/D-9885-2011 FU FDA CDER Critical Path Initiative; Intramural Research Program of the National Heart, Lung, and Blood Institute FX This research was supported by the FDA CDER Critical Path Initiative. R.L.L. was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute. NR 54 TC 2 Z9 2 U1 5 U2 14 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 MAY PY 2016 VL 94 BP 161 EP 173 DI 10.1016/j.freeradbiomed.2016.01.020 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DK1AK UT WOS:000374644100016 PM 26872685 ER PT J AU Nishshanka, U Jayasuriya, H Chattopadhaya, C Kijak, PJ Chu, PS Reimschuessel, R Tkachenko, A Ceric, O De Alwis, HG AF Nishshanka, Upul Jayasuriya, Hiranthi Chattopadhaya, Chaitali Kijak, Philip J. Chu, Pak-Sin Reimschuessel, Renate Tkachenko, Andriy Ceric, Olgica De Alwis, Hemakanthi G. TI Screening for toxic phorbol esters in jerky pet treat products using LC-MS SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Jatropha curcas; Phorbol esters; Jerky pet treats; High resolution; Accurate mass; LC-MS method ID JATROPHA-CURCAS; SEED OIL; 12-DEOXY-16-HYDROXYPHORBOL AB Since 2007, the U.S. FDA's Center for Veterinary Medicine (CVM) has been investigating reports of pets becoming ill after consuming jerky pet treats. jerky used in pet treats contains glycerin, which can be made from vegetable oil or as a byproduct of biodiesel production. Because some biodiesel is produced using oil from Jatropha curcas, a plant that contains toxic compounds including phorbol esters, CVM developed a liquid chromatography-mass spectrometry (LC-MS) screening method to evaluate investigational jerky samples for the presence of these toxins. Results indicated that the samples analyzed with the new method did not contain Jatropha toxins at or above the lowest concentration tested. Published by Elsevier B.V. C1 [Nishshanka, Upul; Jayasuriya, Hiranthi; Chattopadhaya, Chaitali; Kijak, Philip J.; Chu, Pak-Sin; De Alwis, Hemakanthi G.] US FDA, Div Residue Chem, Ctr Vet Med, Res Off, 8401 Muirkirk Rd, Laurel, MD 20708 USA. [Reimschuessel, Renate; Tkachenko, Andriy; Ceric, Olgica] US FDA, Vet Lab Invest & Response Network, Ctr Vet Med, Res Off, 8401 Muirkirk Rd, Laurel, MD 20708 USA. RP De Alwis, HG (reprint author), US FDA, Div Residue Chem, Ctr Vet Med, Res Off, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM hemakanthi.dealwis@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration FX This project was supported in part by an appointment to the Research Participation Program at the Center for Veterinary Medicine administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 9 TC 1 Z9 1 U1 3 U2 7 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 MAY 1 PY 2016 VL 1020 BP 90 EP 95 DI 10.1016/j.jchromb.2016.03.023 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DK0UL UT WOS:000374627600013 PM 27038400 ER PT J AU Bell, RL Jarvis, KG Ottesen, AR McFarland, MA Brown, EW AF Bell, Rebecca L. Jarvis, Karen G. Ottesen, Andrea R. McFarland, Melinda A. Brown, Eric W. TI Recent and emerging innovations in Salmonella detection: a food and environmental perspective SO MICROBIAL BIOTECHNOLOGY LA English DT Review ID FLIGHT MASS-SPECTROMETRY; REAL-TIME PCR; ASSISTED-LASER-DESORPTION/IONIZATION; DESORPTION IONIZATION-TIME; 16S RIBOSOMAL-RNA; SUBSP ENTERICA SEROVARS; ESCHERICHIA-COLI; UNITED-STATES; MICROBIAL COMMUNITIES; RAPID IDENTIFICATION AB Salmonella is a diverse genus of Gram-negative bacilli and a major foodborne pathogen responsible for more than a million illnesses annually in the United States alone. Rapid, reliable detection and identification of this pathogen in food and environmental sources is key to safeguarding the food supply. Traditional microbiological culture techniques have been the gold standard' for State and Federal regulators. Unfortunately, the time to result is too long to effectively monitor foodstuffs, especially those with very short shelf lives. Advances in traditional microbiology and molecular biology over the past 25years have greatly improved the speed at which this pathogen is detected. Nonetheless, food and environmental samples possess a distinctive set of challenges for these newer, more rapid methodologies. Furthermore, more detailed identification and subtyping strategies still rely heavily on the availability of a pure isolate. However, major shifts in DNA sequencing technologies are meeting this challenge by advancing the detection, identification and subtyping of Salmonella towards a culture-independent diagnostic framework. This review will focus on current approaches and state-of-the-art next-generation advances in the detection, identification and subtyping of Salmonella from food and environmental sources. C1 [Bell, Rebecca L.; Ottesen, Andrea R.; McFarland, Melinda A.; Brown, Eric W.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Jarvis, Karen G.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD USA. RP Bell, RL (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. EM rebecca.bell@fda.hhs.gov FU U.S. FDA FX All authors are funded by U.S. FDA. NR 113 TC 3 Z9 3 U1 24 U2 46 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1751-7907 EI 1751-7915 J9 MICROB BIOTECHNOL JI Microb. Biotechnol. PD MAY PY 2016 VL 9 IS 3 BP 279 EP 292 DI 10.1111/1751-7915.12359 PG 14 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DK1HH UT WOS:000374662600001 PM 27041363 ER PT J AU Cutler, DM Jessup, AI Kenkel, DS Starr, MA AF Cutler, David M. Jessup, Amber I. Kenkel, Donald S. Starr, Martha A. TI Economic Approaches to Estimating Benefits of Regulations Affecting Addictive Goods SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID WILLINGNESS-TO-PAY; SMOKING-CESSATION; EX-SMOKERS; CONTROLLED-TRIAL; UNITED-STATES; CONSUMPTION; OBESITY; HEALTH; ALCOHOL; ADULTS AB The question of how to evaluate lost consumer surplus in benefit-cost analyses has been contentious. There are clear health benefits of regulations that curb consumption of goods with health risks, such as tobacco products and foods high in fats, calories, sugar, and sodium. Yet, if regulations cause consumers to give up goods, they like, the health benefits they experience may be offset by some utility loss, which benefit-cost analyses of regulations need to take into account. This paper lays out the complications of measuring benefits of regulations aiming to curb consumption of addictive and habitual goods, rooted in the fact that consumers' observed demand for such goods may not be in line with their true preferences. Focusing on the important case of tobacco products, the paper describes four possible approaches for estimating benefits when consumers' preferences may not be aligned with their behavior, and identifies one as having the best feasibility for use in applied benefit-cost analyses in the near term. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine. C1 [Cutler, David M.] Harvard Univ, Dept Econ, Cambridge, MA 02138 USA. [Jessup, Amber I.] US Dept HHS, Off Assistant Secretary Planning & Evaluat, 200 Independence Ave SW, Washington, DC 20201 USA. [Kenkel, Donald S.] Cornell Univ, Dept Policy Anal & Management, Coll Human Ecol, Ithaca, NY USA. [Starr, Martha A.] US FDA, Off Deputy Commissioner Planning Policy & Legisla, Silver Spring, MD USA. RP Jessup, AI (reprint author), US Dept HHS, Off Assistant Secretary Planning & Evaluat, 200 Independence Ave SW, Washington, DC 20201 USA. EM amber.jessup@hhs.gov FU Centers for Disease Control and Prevention; U.S. DHHS; Mathematica Policy Research FX Publication of this article was supported by the Centers for Disease Control and Prevention.; This research was supported by the U.S. DHHS. The work of David Cutler and Donald Kenkel was supported through a subcontract with Mathematica Policy Research. Amber Jessup is employed by the U.S. DHHS. Martha Starr is employed by FDA via an interagency personnel agreement with American University. NR 46 TC 1 Z9 1 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAY PY 2016 VL 50 IS 5 SU 1 BP S20 EP S26 DI 10.1016/j.amepre.2015.12.002 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DJ5VL UT WOS:000374278100005 PM 27102854 ER PT J AU Marrone, AK Shpyleva, S Chappell, G Tryndyak, V Uehara, T Tsuchiya, M Beland, FA Rusyn, I Pogribny, IP AF Marrone, April K. Shpyleva, Svitlana Chappell, Grace Tryndyak, Volodymyr Uehara, Takeki Tsuchiya, Masato Beland, Frederick A. Rusyn, Ivan Pogribny, Igor P. TI Differentially expressed MicroRNAs provide mechanistic insight into fibrosis-associated liver carcinogenesis in mice SO MOLECULAR CARCINOGENESIS LA English DT Article DE liver carcinogenesis; mouse; microRNAs; hepatocellular carcinoma ID TUMOR-INITIATING CELLS; CANCER STEM-CELLS; HEPATOCELLULAR-CARCINOMA; MOLECULAR-MECHANISMS; MOUSE MODELS; CLUSTER; SURVIVAL; EPCAM; HEPATOCARCINOGENESIS; REGENERATION AB Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers, with a rising incidence worldwide. The molecular mechanisms associated with the development of HCC are complex and include multiple interconnected molecular alterations with mounting evidence indicating an important role of microRNAs (miRNAs) in the pathogenesis of HCC. In humans, the development of HCC is commonly associated with liver cirrhosis. To study fibrosis-associated liver carcinogenesis, we used a mouse model designed to emulate the development of HCC in cirrhotic liver. Specifically, we were interested in evaluating the role of miRNAs in the molecular pathogenesis of liver carcinogenesis in male B6C3F1/J mice treated with N-nitrosodiethylamine (DEN) or carbon tetrachloride (CCl4) alone or a combination of DEN and CCl4 and characterized by a differential tumor incidence that increased in the following order: DEN15 mu g/mL, which has previously been associated with successful treatment of Pneumocystis jiroveci pneumonia. AUCt and C-avg did not significantly differ for concurrent ATV/r for 750 mg BID or 1500 mg BID when compared to the group not receiving cART. Nine of 10 subjects not receiving cART, 8 of 10 subjects receiving ATV/r, and 2 of 10 subjects receiving EFV in combination with atovaquone 750 mg BID achieved an atovaquone C-avg >18.5 mu g/mL, a concentration that has previously been associated with successful treatment of Toxoplasma encephalitis (TE). Conclusions. These data suggest that the currently recommended dose of atovaquone 750 mg BID for treatment of mild to moderate PCP may not be adequate in patients receiving concurrent EFV. Furthermore, doses lower than the currently recommended dose of 1500 mg BID may achieve plasma concentrations adequate to treat TE in HIV-infected patients not receiving EFV. C1 [Calderon, Monica M.; Penzak, Scott R.; Kumar, Parag; Alfaro, Raul M.] NIH, Dept Pharm, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Calderon, Monica M.; McManus, Maryellen] NCI, Leidos Biomed Res Inc, Frederick, MD 21701 USA. [Pau, Alice K.] NIAID, NIH, Bethesda, MD USA. [Kovacs, Joseph A.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Calderon, Monica M.] US FDA, Off Safety & Epidemiol, Silver Spring, MD USA. [Penzak, Scott R.] Univ North Texas Syst, Coll Pharm, Dept Pharmacotherapy, 3500 Camp Bowie Blvd,RES 411-A, Ft Worth, TX 76107 USA. RP Penzak, SR (reprint author), Univ North Texas Syst, Coll Pharm, Dept Pharmacotherapy, 3500 Camp Bowie Blvd,RES 411-A, Ft Worth, TX 76107 USA. EM scott.penzak@unthsc.edu FU Intramural NIH HHS; PHS HHS [HHSN2612008000] NR 17 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 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD APR 15 PY 2016 VL 62 IS 8 BP 1036 EP 1042 DI 10.1093/cid/ciw028 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DK7EU UT WOS:000375088500019 PM 26797214 ER PT J AU Tilson, H Hines, LE McEvoy, G Weinstein, DM Hansten, PD Matuszewski, K le Comte, M Higby-Baker, S Hanlon, JT Pezzullo, L Vieson, K Helwig, AL Huang, SM Perre, A Bates, DW Poikonen, J Wittie, MA Grizzle, AJ Brown, M Malone, DC AF Tilson, Hugh Hines, Lisa E. McEvoy, Gerald Weinstein, David M. Hansten, Philip D. Matuszewski, Karl le Comte, Marianne Higby-Baker, Stefanie Hanlon, Joseph T. Pezzullo, Lynn Vieson, Kathleen Helwig, Amy L. Huang, Shiew-Mei Perre, Anthony Bates, David W. Poikonen, John Wittie, Michael A. Grizzle, Amy J. Brown, Mary Malone, Daniel C. TI Recommendations for selecting drug-drug interactions for clinical decision support SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article ID ELECTRONIC HEALTH RECORDS; PHYSICIAN ORDER ENTRY; REDUCE ALERT FATIGUE; AMBULATORY-CARE; SAFETY ALERTS; SYSTEMS; MANAGEMENT; SOFTWARE; RISK; INTERVENTIONS AB Purpose. Recommendations for including drug-drug interactions (DDIs) in clinical decision support (CDS) are presented. Summary. A conference series was conducted to improve CDS for DDIs. A work group consisting of 20 experts in pharmacology, drug information, and CDS from academia, government agencies, health information vendors, and healthcare organizations was convened to address (1) the process to use for developing and maintaining a standard set of DDIs, (2) the information that should be included in a knowledge base of standard DDIs, (3) whether a list of contraindicated drug pairs can or should be established, and (4) how to more intelligently filter DDI alerts. We recommend a transparent, systematic, and evidence-driven process with graded recommendations by a consensus panel of experts and oversight by a national organization. We outline key DDI information needed to help guide clinician decision-making. We recommend judicious classification of DDIs as contraindicated and more research to identify methods to safely reduce repetitive and less-relevant alerts. Conclusion: An expert panel with a centralized organizer or convener should be established to develop and maintain a standard set of DDIs for CDS in the United States. The process should be evidence driven, transparent, and systematic, with feedback from multiple stakeholders for continuous improvement. The scope of the expert panel's work should be carefully managed to ensure that the process is sustainable. Support for research to improve DDI alerting in the future is also needed. Adoption of these steps may lead to consistent and clinically relevant content for interruptive DDIs, thus reducing alert fatigue and improving patient safety. C1 [Tilson, Hugh] Univ N Carolina, Gillings Sch Global Publ Hlth, Publ Hlth Leadership & Epidemiol, Chapel Hill, NC USA. [Hines, Lisa E.; Pezzullo, Lynn] Pharm Qual Alliance, Performance Measurement, Springfield, VA USA. [McEvoy, Gerald] Amer Soc Hlth Syst Pharmacists, Drug Informat, Bethesda, MD USA. [Weinstein, David M.] Lexi Comp, Clin Content, Metab Interact & Genom Grp, Cleveland, OH USA. [Hansten, Philip D.] Univ Washington, Sch Pharm, Dept Pharm, Seattle, WA 98195 USA. [Matuszewski, Karl] First Databank, Clin & Editorial Knowledge Base Serv, San Francisco, CA USA. [le Comte, Marianne] Drug Informat Ctr, Royal Dutch Assoc Adv Pharm, The Hague, Netherlands. [Higby-Baker, Stefanie] Cerner Multum, Denver, CO USA. [Hanlon, Joseph T.] Univ Pittsburgh, Div Geriatr, Pittsburgh, PA USA. [Hanlon, Joseph T.] Univ Pittsburgh, Dept Pharm & Therapeut, Pittsburgh, PA USA. [Vieson, Kathleen] Elsevier Clin Solut, Diag Treatment & Care Decis, Tampa, FL USA. [Helwig, Amy L.] US Dept HHS, Ctr Qual Improvement & Patient Safety, Agcy Healthcare Res & Qual, Washington, DC 20201 USA. [Helwig, Amy L.] Agcy Healthcare Res & Qual, Qual Improvement & Patient Safety, Human Serv, Washington, DC USA. [Huang, Shiew-Mei] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Perre, Anthony] Canc Treatment Ctr Amer, Eastern Reg Med Ctr, New Patient Intake, Philadelphia, PA USA. [Bates, David W.] Harvard Univ, Sch Med, Boston, MA USA. [Poikonen, John] Univ Massachusetts, Lowell, MA USA. [Wittie, Michael A.] US Dept HHS, Off Natl Coordinator Hlth Informat Technol, Washington, DC 20201 USA. [Grizzle, Amy J.] Univ Arizona, Coll Pharm, Ctr Hlth Outcomes & PharmacoEcon Res, Tucson, AZ 85721 USA. [Brown, Mary; Malone, Daniel C.] Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci, Tucson, AZ 85721 USA. RP Malone, DC (reprint author), Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci, Tucson, AZ 85721 USA. EM malone@pharmacy.arizona.edu FU Agency for Healthcare Research and Quality [1R13HS021826-01]; Cerner; Elsevier Clinical Solutions; Epocrates; First Databank; Truven Health Analytics; Wolters-Kluwer; Agency for Healthcare Research and Quality; Epocrates (athenahealth, Inc.); FDB; Wolters Kluwer FX Financial support for this study was provided by the Agency for Healthcare Research and Quality under a grant (1R13HS021826-01) obtained by Dr. Malone. Unrestricted support for this study was provided by Cerner, Elsevier Clinical Solutions, Epocrates, First Databank, Truven Health Analytics, and Wolters-Kluwer. Dr. McEvoy is Assistant Vice President, Drug Information, and Editor in Chief, AHFS Drug Information, ASHP. Dr. Weinstein is an employee of Wolters Kluwer Health. Dr. Matuszewski is an employee of First Databank. Ms. Higby-Baker is an employee of Cerner Multum. Dr. Vieson is an employee of Elsevier Clinical Solutions. Dr. Malone reports grants from the Agency for Healthcare Research and Quality and unrestricted support for this project from Cerner, Elsevier Clinical Solutions, Epocrates (athenahealth, Inc.), FDB, Truven Health Analytics, and Wolters Kluwer. The authors have declared no other conflicts of interest. NR 61 TC 3 Z9 3 U1 8 U2 13 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 APR 15 PY 2016 VL 73 IS 8 BP 576 EP 585 DI 10.2146/ajhp150565 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DJ5VO UT WOS:000374278400017 PM 27045070 ER PT J AU Singh, T Arrazola, RA Corey, CG Husten, CG Neff, LJ Homa, DM King, BA AF Singh, Tushar Arrazola, Rene A. Corey, Catherine G. Husten, Corinne G. Neff, Linda J. Homa, David M. King, Brian A. TI Tobacco Use Among Middle and High School Students - United States, 2011-2015 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Editorial Material C1 [Singh, Tushar; Arrazola, Rene A.; Neff, Linda J.; Homa, David M.; 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. [Corey, Catherine G.; Husten, Corinne G.] Food & Drug Adm, Ctr Tobacco Prod, Atlanta, GA 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 7 TC 50 Z9 50 U1 2 U2 4 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 APR 15 PY 2016 VL 65 IS 14 BP 361 EP 367 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DK0WP UT WOS:000374633200001 PM 27077789 ER PT J AU Huang, JY Henao, OL Griffin, PM Vugia, DJ Cronquist, AB Hurd, S Tobin-D'Angelo, M Ryan, P Smith, K Lathrop, S Zansky, S Cieslak, PR Dunn, J Holt, KG Wolpert, BJ Patrick, ME AF Huang, Jennifer Y. Henao, Olga L. Griffin, Patricia M. Vugia, Duc J. Cronquist, Alicia B. Hurd, Sharon Tobin-D'Angelo, Melissa Ryan, Patricia Smith, Kirk Lathrop, Sarah Zansky, Shelley Cieslak, Paul R. Dunn, John Holt, Kristin G. Wolpert, Beverly J. Patrick, Mary E. TI Infection with Pathogens Transmitted Commonly Through Food and the Effect of Increasing Use of Culture-Independent Diagnostic Tests on Surveillance - Foodborne Diseases Active Surveillance Network, 10 US Sites, 2012-2015 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Editorial Material ID UNITED-STATES; CRYPTOSPORIDIOSIS C1 [Huang, Jennifer Y.; Henao, Olga L.; Griffin, Patricia M.; Patrick, Mary E.] CDC, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Vugia, Duc J.] Calif Dept Publ Hlth, Sacramento, CA USA. [Cronquist, Alicia B.] Colorado Dept Publ Hlth & Environm, Colorado Springs, CO USA. [Hurd, Sharon] Connecticut Dept Publ Hlth, Hartford, CT USA. [Tobin-D'Angelo, Melissa] Georgia Dept Publ Hlth, Atlanta, GA USA. [Ryan, Patricia] Maryland Dept Hlth & Mental Hyg, Baltimore, MD 21201 USA. [Smith, Kirk] Minnesota Dept Hlth, Minneapolis, MN 55414 USA. [Lathrop, Sarah] Univ New Mexico, Albuquerque, NM 87131 USA. [Zansky, Shelley] New York State Dept Hlth, Albany, NY 12237 USA. [Dunn, John] Tennessee Dept Hlth, Memphis, TN USA. [Holt, Kristin G.] USDA, Food Safety & Inspect Serv, Washington, DC USA. [Wolpert, Beverly J.] Food & Drug Adm, Ctr Food Safety & Appl Nutr, Atlanta, GA USA. RP Patrick, ME (reprint author), CDC, Div Foodborne Waterborne & Environm Dis, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. EM mepatrick@cdc.gov NR 8 TC 5 Z9 5 U1 3 U2 7 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD APR 15 PY 2016 VL 65 IS 14 BP 368 EP 371 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DK0WP UT WOS:000374633200002 PM 27077946 ER PT J AU Macura, SL Lathrop, MJ Gui, J Doncel, GF Asin, SN Rollenhagen, C AF Macura, Sherrill L. Lathrop, Melissa J. Gui, Jiang Doncel, Gustavo F. Asin, Susana N. Rollenhagen, Christiane TI Blocking CXCL9 Decreases HIV-1 Replication and Enhances the Activity of Prophylactic Antiretrovirals in Human Cervical Tissues SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV-1 replication; prophylactic microbicides; CXCL9; cervical tissues ID IMMUNODEFICIENCY-VIRUS-INFECTION; COMMERCIAL SEX WORKERS; FEMALE GENITAL-TRACT; CD4(+) T-CELLS; PREEXPOSURE PROPHYLAXIS; TYPE-1 INFECTION; EX-VIVO; GASTROINTESTINAL-TRACT; CERVICOVAGINAL TISSUE; AFRICAN WOMEN AB Objectives: The interferon-gamma-induced chemokine CXCL9 is expressed in a wide range of inflammatory conditions including those affecting the female genital tract. CXCL9 promotes immune cell recruitment, activation, and proliferation. The role of CXCL9 in modulating HIV-1 infection of cervicovaginal tissues, a main portal of viral entry, however, has not been established. We report a link between CXCL9 and HIV-1 replication in human cervical tissues and propose CXCL9 as a potential target to enhance the anti-HIV-1 activity of prophylactic antiretrovirals. Design: Using ex vivo infection of human cervical tissues as a model of mucosal HIV-1 acquisition, we described the effect of CXCL9 neutralization on HIV-1 gene expression and mucosal CD4(+) T-cell activation. The anti-HIV-1 activity of tenofovir, the leading mucosal pre-exposure prophylactic microbicide, alone or in combination with CXCL9 neutralization was also studied. Methods: HIV-1 replication was evaluated by p24 ELISA. HIV-1 DNA and RNA, and CD4, CCR5, and CD38 transcription were evaluated by quantitative real-time polymerase chain reaction. Frequency of activated cervical CD4(+) T cells was quantified using fluorescence-activated cell sorting. Results: Antibody blocking of CXCL9 reduced HIV-1 replication by decreasing mucosal CD4(+) T-cell activation. CXCL9 neutralization in combination with suboptimal concentrations of tenofovir, possibly present in the cervicovaginal tissues of women using the drug inconsistently, demonstrated an earlier and greater decrease in HIV-1 replication compared with tissues treated with tenofovir alone. Conclusions: CXCL9 neutralization reduces HIV-1 replication and may be an effective target to enhance the efficacy of prophylactic antiretrovirals. C1 [Macura, Sherrill L.; Lathrop, Melissa J.; Asin, Susana N.; Rollenhagen, Christiane] VA Med Ctr, Res Serv, White River Jct, VT USA. [Macura, Sherrill L.] US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Silver Spring, MD USA. [Lathrop, Melissa J.] Ctr Dis Control & Prevent, Div Select Agents & Toxins, Atlanta, GA USA. [Gui, Jiang] Geisel Sch Med Dartmouth, Dept Biomed Data Sci, Lebanon, NH USA. [Doncel, Gustavo F.] Eastern Virginia Med Sch, CONRAD, Norfolk, VA 23501 USA. [Asin, Susana N.] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Lebanon, NH USA. [Rollenhagen, Christiane] Geisel Sch Med Dartmouth, Dept Med, Lebanon, NH USA. RP Asin, SN (reprint author), VA Med Ctr, Res Serv, 215 North Main St, Wrj, VT 05009 USA. EM Susana.N.Asin@dartmouth.edu FU United States Agency for International Development [AID-OAA-A-14-00010]; Department of Veterans Affairs, Merit Review Program; Campbell Foundation FX Supported by the United States Agency for International Development (AID-OAA-A-14-00010) (G.F.D.), the Department of Veterans Affairs, Merit Review Program (S.N.A.), and by the Campbell Foundation (C.R.). NR 61 TC 0 Z9 0 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD APR 15 PY 2016 VL 71 IS 5 BP 474 EP 482 DI 10.1097/QAI.0000000000000891 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DG8RC UT WOS:000372350300002 PM 26545124 ER PT J AU Zheng, NY Zeng, JN Manney, A Williams, L Aubry, AF Voronin, K Buzescu, A Zhang, YJ Allentoff, A Xu, C Shen, HW Warner, W Arnold, ME AF Zheng, Naiyu Zeng, Jianing Manney, Amy Williams, Lakenya Aubry, Anne-Francoise Voronin, Kimberly Buzescu, Adela Zhang, Yan J. Allentoff, Alban Xu, Carrie Shen, Hongwu Warner, William Arnold, Mark E. TI Quantitation of a PEGylated protein in monkey serum by UHPLC-HRMS using a surrogate disulfide-containing peptide: A new approach to bioanalysis and in vivo stability evaluation of disulfide-rich protein therapeutics SO ANALYTICA CHIMICA ACTA LA English DT Article DE UHPLC-HRMS; PEGylated protein; Disulfide-containing peptide; Protein quantitation; In vivo stability; Methionine oxidation ID CHROMATOGRAPHY/TANDEM MASS-SPECTROMETRY; LC-MS/MS ASSAY; BIOPHARMACEUTICAL PROTEINS; BIOLOGICAL MATRICES; TRYPSIN DIGESTION; LIGAND-BINDING; INTACT PROTEIN; PLASMA; QUANTIFICATION; MS AB To quantify a therapeutic PEGylated protein in monkey serum as well as to monitor its potential in vivo instability and methionine oxidation, a novel ultra high performance liquid chromatography-high resolution mass spectrometric (UHPLC-HRMS) assay was developed using a surrogate disulfide-containing peptide, DCP(SS), and a confirmatory peptide, CP, a disulfide-free peptide. DCP(SS) was obtained by eliminating the step of reduction/alkylation before trypsin digestion. It contains an intact disulfide linkage between two peptide sequences that are essential for drug function but susceptible to potential in vivo cleavages. HRMS-based single ion monitoring (SIM) on a Q Exactive (TM) mass spectrometer was employed to improve assay specificity and sensitivity for DCP(SS) due to its poor fragmentation and low sensitivity with SRM detection. The assay has been validated for the protein drug in monkey serum using both surrogate peptides with excellent accuracy (within +/- 4.4%Dev) and precision (within 7.5%CV) with a lower limit of quantitation (LLOQ) at 10 ng mL(-1). The protein concentrations in monkey serum obtained from the DCP(SS)-based assay not only provided important pharmacokinetic parameters, but also confirmed in vivo stability of the peptide regions of interest by comparing drug concentrations with those obtained from the CP-based assay or from a ligand-binding assay (LBA). Furthermore, UHPLC-HRMS allowed simultaneous monitoring of the oxidized forms of both surrogate peptides to evaluate potential ex vivo/in vivo oxidation of one methionine present in each of both surrogate peptides. To the best of our knowledge, this is the first report of using a surrogate disulfide-containing peptide for LC-MS bioanalysis of a therapeutic protein. (C) 2016 Elsevier B.V. All rights reserved. C1 [Zheng, Naiyu; Zeng, Jianing; Manney, Amy; Williams, Lakenya; Aubry, Anne-Francoise; Buzescu, Adela; Zhang, Yan J.; Arnold, Mark E.] Bristol Myers Squibb Co, Analyt & Bioanalyt Dev, Princeton, NJ 08543 USA. [Voronin, Kimberly; Allentoff, Alban] Bristol Myers Squibb Co, Discovery Chem, Princeton, NJ 08543 USA. [Xu, Carrie] Bristol Myers Squibb Co, Pharmaceut Candidate Optimizat, Princeton, NJ 08543 USA. [Shen, Hongwu; Warner, William] Bristol Myers Squibb Co, Drug Safety Evaluat, Princeton, NJ 08543 USA. [Shen, Hongwu] US FDA, Off Bioequivalence, Div 2, Off Gener Drugs,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Zheng, NY; Zeng, JN (reprint author), Bristol Myers Squibb Co, Analyt & Bioanalyt Dev, Princeton, NJ 08543 USA. EM naiyu.zheng@bms.com; jianing.zeng@bms.com NR 31 TC 1 Z9 1 U1 5 U2 8 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 APR 15 PY 2016 VL 916 BP 42 EP 51 DI 10.1016/j.aca.2016.02.017 PG 10 WC Chemistry, Analytical SC Chemistry GA DH0RL UT WOS:000372491500006 PM 27016437 ER PT J AU Li, YH Xue, MY Sheng, X Yu, H Zeng, J Thon, V Chen, Y Muthana, MM Wang, PG Chen, X AF Li, Yanhong Xue, Mengyang Sheng, Xue Yu, Hai Zeng, Jie Thon, Vireak Chen, Yi Muthana, Musleh M. Wang, Peng G. Chen, Xi TI Donor substrate promiscuity of bacterial beta 1-3-N-acetylglucosaminyltransferases and acceptor substrate flexibility of beta 1-4-galactosyltransferases SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Carbohydrate; Glycosyltransferase; Donor substrate promiscuity; Acceptor substrate specificity; Enzymatic synthesis; One-pot multienzyme ID ENGINEERED ESCHERICHIA-COLI; HUMAN-MILK OLIGOSACCHARIDES; O-LINKED GLYCANS; NEISSERIA-MENINGITIDIS; CHEMICAL-CHARACTERIZATION; HELICOBACTER-PYLORI; CHEMOENZYMATIC SYNTHESIS; N-ACETYLGLUCOSAMINE; EXPRESSION; BETA-1,4-GALACTOSYLTRANSFERASE AB beta 1-3-N-Acetylglucosaminyltransferases (beta 3GlcNAcTs) and beta 1-4-galactosyltransferases (beta 4GalTs) have been broadly used in enzymatic synthesis of N-acetyllactosamine (LacNAc)-containing oligosaccharides and glycoconjugates including poly-LacNAc, and lacto-N-neotetraose (LNnT) found in the milk of human and other mammals. In order to explore oligosaccharides and derivatives that can be synthesized by the combination of beta 3GlcNAcTs and beta 4GalTs, donor substrate specificity studies of two bacterial beta 3GlcNAcTs from Helicobacter pylori (Hp beta 3GlcNAcT) and Neisseria meningitidis (NmLgtA), respectively, using a library of 39 sugar nucleotides were carried out. The two beta 3GlcNAcTs have complementary donor substrate promiscuity and 13 different trisaccharides were produced. They were used to investigate the acceptor substrate specificities of three beta 4GalTs from Neisseria meningitidis (NmLgtB), Helicobacter pylori (Hp beta 4GalT), and bovine (B beta 4GalT), respectively. Ten of the 13 trisaccharides were shown to be tolerable acceptors for at least one of these beta 4GalTs. The application of NmLgtA in one-pot multienzyme (OPME) synthesis of two trisaccharides including GalNAc beta 1-3Gal beta 1-4Glc beta ProN(3) and Gal beta 1-3Gal beta 1-4Glc was demonstrated. The study provides important information for using these glycosyltransferases as powerful catalysts in enzymatic and chemoenzymatic syntheses of oligosaccharides and derivatives which can be useful probes and reagents. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Li, Yanhong; Xue, Mengyang; Sheng, Xue; Yu, Hai; Zeng, Jie; Thon, Vireak; Chen, Yi; Muthana, Musleh M.; Chen, Xi] Univ Calif Davis, Dept Chem, One Shields Ave, Davis, CA 95616 USA. [Xue, Mengyang; Wang, Peng G.] Shandong Univ, Natl Glycoengn Res Ctr, Jinan 250100, Shandong, Peoples R China. [Xue, Mengyang; Wang, Peng G.] Shandong Univ, Shandong Prov Key Lab Carbohydrate Chem & Glycobi, Jinan 250100, Shandong, Peoples R China. [Zeng, Jie] Henan Inst Sci & Technol, Sch Food Sci, Xinxiang 453003, Henan, Peoples R China. [Thon, Vireak; Wang, Peng G.] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA. [Xue, Mengyang] Shandong Univ, Shandong Prov Key Lab Emergency & Crit Care Med, Jinan 250100, Shandong, Peoples R China. [Sheng, Xue] Univ Calif San Diego, Dept Chem & Biochem, San Diego, CA 92093 USA. [Thon, Vireak] US FDA, Lab Bacterial Polysaccharides, Bethesda, MD 20892 USA. [Muthana, Musleh M.] Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Chen, X (reprint author), Univ Calif Davis, Dept Chem, One Shields Ave, Davis, CA 95616 USA. EM xiichen@ucdavis.edu FU National Science Foundation of the United States [CHE-1300449]; National Institutes of Health of the United States [R01HD065122, R01GM094523]; National Basic Research Program of China 973 Program [2012CB822102]; Key Grant Project of Chinese Ministry of Education [313033] FX This work was supported by National Science Foundation of the United States grant CHE-1300449, National Institutes of Health of the United States grants R01HD065122 and R01GM094523, National Basic Research Program of China 973 Program No. 2012CB822102, and the Key Grant Project of Chinese Ministry of Education No. 313033. NR 55 TC 3 Z9 3 U1 5 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD APR 15 PY 2016 VL 24 IS 8 BP 1696 EP 1705 DI 10.1016/j.bmc.2016.02.043 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DH2CX UT WOS:000372592900012 PM 26968649 ER PT J AU Majewski, MW Tiwari, R Miller, PA Cho, S Franzblau, SG Miller, MJ AF Majewski, Mark W. Tiwari, Rohit Miller, Patricia A. Cho, Sanghyun Franzblau, Scott G. Miller, Marvin J. TI Design, syntheses, and anti-tuberculosis activities of conjugates of piperazino-1,3-benzothiazin-4-ones (pBTZs) with 2,7-dimethylimidazo [1,2-a]pyridine-3-carboxylic acids and 7-phenylacetyl cephalosporins SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Tuberculosis; Benzothiazinones; Imidazopyridine; Cephalosporin ID NONREPLICATING MYCOBACTERIUM-TUBERCULOSIS; BENZOTHIAZINONES; COMBINATION; DERIVATIVES; ASSAY AB Tuberculosis (TB) remains one of the most threatening diseases in the world and the need for development of new therapies is dire. Herein we describe the rationale for the design and subsequent syntheses and studies of conjugates between pBTZ and both the imidazopyridine and cephalosporin scaffolds. Overall some compounds exhibited notable anti-TB activity in the range of 2-0.2 mu M in the Microplate Alamar Blue (MABA) Assay. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Majewski, Mark W.; Tiwari, Rohit; Miller, Patricia A.; Miller, Marvin J.] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. [Cho, Sanghyun; Franzblau, Scott G.] Univ Illinois, Coll Pharm, Inst TB Res, MIC 964,Rm 412, Chicago, IL 60612 USA. [Tiwari, Rohit] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, 10993 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Miller, MJ (reprint author), Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. RI Tiwari, Rohit/D-5692-2013 OI Tiwari, Rohit/0000-0002-7901-3212 FU University of Notre Dame - United States; NIH - United States [NIH-2R01-AI054193] FX We acknowledge the University of Notre Dame - United States, and the NIH - United States (NIH-2R01-AI054193) for support of this work. We acknowledge Nonka Sevova (Mass Spectrometry and Proteomics Facility, UND) for mass spectroscopic analyses and Viktor Krchnak for LC/MS and prep LC assistance. M.W.M. acknowledges an ECK Global Health Fellowship (2014-2015, UND). NR 24 TC 0 Z9 0 U1 2 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD APR 15 PY 2016 VL 26 IS 8 BP 2068 EP 2071 DI 10.1016/j.bmcl.2016.02.076 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA DH0XZ UT WOS:000372509000040 PM 26951749 ER PT J AU Furtak, V Roivainen, M Mirochnichenko, O Zagorodnyaya, T Laassri, M Zaidic, SZ Rehman, L Alam, MM Chizhikov, V Chumakov, K AF Furtak, V. Roivainen, M. Mirochnichenko, O. Zagorodnyaya, T. Laassri, M. Zaidic, S. Z. Rehman, L. Alam, M. M. Chizhikov, V. Chumakov, K. TI Environmental surveillance of viruses by tangential flow filtration and metagenomic reconstruction SO EUROSURVEILLANCE LA English DT Article ID GLOBAL POLIO ERADICATION; HOLLOW-FIBER ULTRAFILTRATION; VACCINE-DERIVED POLIOVIRUSES; PATHOGENIC VIRUSES; WASTE-WATER; RECOVERY; SEWAGE; CIRCULATION; COMMUNITY; ISRAEL AB An approach is proposed for environmental surveillance of poliovirus by concentrating sewage samples with tangential flow filtration (TFF) followed by deep sequencing of viral RNA. Subsequent to testing the method with samples from Finland, samples from Pakistan, a country endemic for poliovirus, were investigated. Genomic sequencing was either performed directly, for unbiased identification of viruses regardless of their ability to grow in cell cultures, or after virus enrichment by cell culture or immunopre-cipitation. Bioinformatics enabled separation and determination of individual consensus sequences. Overall, deep sequencing of the entire viral population identified polioviruses, non-polio enteroviruses, and other viruses. In Pakistani sewage samples, adeno-associated virus, unable to replicate autonomously in cell cultures, was the most abundant human virus. The presence of recombinants of wild polioviruses of serotype 1 (WPV1) was also inferred, whereby currently circulating WPV1 of south-Asian (SOAS) lineage comprised two sub-lineages depending on their non-capsid region origin. Complete genome analyses additionally identified point mutants and intertypic recombinants between attenuated Sabin strains in the Pakistani samples, and in one Finnish sample. The approach could allow rapid environmental surveillance of viruses causing human infections. It creates a permanent digital repository of the entire virome potentially useful for retrospective screening of future discovered viruses. C1 [Furtak, V.; Mirochnichenko, O.; Zagorodnyaya, T.; Laassri, M.; Chizhikov, V.; Chumakov, K.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Roivainen, M.] Natl Inst Hlth & Welf, Helsinki, Finland. [Zaidic, S. Z.; Rehman, L.; Alam, M. M.] Natl Inst Hlth, Dept Virol & Immunol, WHO Reg Reference Lab Polio Eradicat Initiat, Islamabad, Pakistan. RP Chumakov, K (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. EM konstantin.chumakov@fda.hhs.gov FU intramural research program of the US Food and Drug Administration from World Health Organisation FX Authors thank Dr. Humayun Asghar of the World Health Organization for suggestions. This work was funded by the intramural research program of the US Food and Drug Administration and a grant to M.R. from the World Health Organization. NR 28 TC 3 Z9 3 U1 10 U2 17 PU EUR CENTRE DIS PREVENTION & CONTROL PI STOCKHOLM PA TOMTEBODAVAGEN 11A, STOCKHOLM, 171 83, SWEDEN SN 1560-7917 J9 EUROSURVEILLANCE JI Eurosurveillance PD APR 14 PY 2016 VL 21 IS 15 BP 40 EP 50 AR 30193 DI 10.2807/1560-7917.ES.2016.21.15.30193 PG 11 WC Infectious Diseases SC Infectious Diseases GA DJ6LP UT WOS:000374325000006 ER PT J AU Califf, RM Woodcock, J Ostroff, S AF Califf, Robert M. Woodcock, Janet Ostroff, Stephen TI A Proactive Response to Prescription Opioid Abuse SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article C1 [Califf, Robert M.; Woodcock, Janet; Ostroff, Stephen] Food & Drug Adm, Silver Spring, MD USA. RP Califf, RM (reprint author), Food & Drug Adm, Silver Spring, MD USA. FU Amgen; Bayer Healthcare; BMEB Services; Bristol-Myers Squibb; Janssen; Medscape/Heart.org; Merck; Novartis; Regado; Roche; Astra-Zeneca; Genentech; GlaxoSmithKline; Heart.org/Daiichi-Sankyo; Kowa; Servier; Bayer Pharma; CV Sight; DSI-Lilly; Gambro; Gilead Sciences; Heart.org/Bayer; Pfizer; Regeneron; Medicines Company; Nile; Parkview; Amylin; Eli Lilly; Schering-Plough Research Institute; Scios FX Dr. Califf reports receiving consulting fees from Amgen, Bayer Healthcare, BMEB Services, Bristol-Myers Squibb, Janssen, Medscape/Heart.org, Merck, Novartis, Regado, Roche, Astra-Zeneca, Genentech, GlaxoSmithKline, Heart.org/Daiichi-Sankyo, Kowa, Servier, Bayer Pharma, CV Sight, DSI-Lilly, Gambro, Gilead Sciences, Heart.org/Bayer, Pfizer, Regeneron, the Medicines Company, Nile, and Parkview; receiving grant support from Amylin, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novartis, the Schering-Plough Research Institute, Scios, and Parkview; and holding equity in Nitrox/N30 Pharma and Portola, all prior to March 1, 2015. No other potential conflict of interest relevant to this article was reported. NR 11 TC 21 Z9 21 U1 4 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 14 PY 2016 VL 374 IS 15 BP 1480 EP 1485 DI 10.1056/NEJMsr1601307 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA DJ3TD UT WOS:000374128400013 PM 26845291 ER PT J AU Hardison, DR Holland, WC McCall, JR Bourdelais, AJ Baden, DG Darius, HT Chinain, M Tester, PA Shea, D Quintana, HAF Morris, JA Litaker, RW AF Hardison, D. Ransom Holland, William C. McCall, Jennifer R. Bourdelais, Andrea J. Baden, Daniel G. Darius, H. Taiana Chinain, Mireille Tester, Patricia A. Shea, Damian Quintana, Harold A. Flores Morris, James A., Jr. Litaker, R. Wayne TI Fluorescent Receptor Binding Assay for Detecting Ciguatoxins in Fish SO PLOS ONE LA English DT Article ID SENSITIVE SODIUM-CHANNELS; CELL-BASED ASSAY; SITE 5; CIGUATERA; BREVETOXINS; TOXINS; TOXICITY; LIONFISH; PACIFIC; ISLANDS AB Ciguatera fish poisoning is an illness suffered by > 50,000 people yearly after consumption of fish containing ciguatoxins (CTXs). One of the current methodologies to detect ciguatoxins in fish is a radiolabeled receptor binding assay (RBA((R))). However, the license requirements and regulations pertaining to radioisotope utilization can limit the applicability of the RBA((R)) in certain labs. A fluorescence based receptor binding assay (RBA((F))) was developed to provide an alternative method of screening fish samples for CTXs in facilities not certified to use radioisotopes. The new assay is based on competition binding between CTXs and fluorescently labeled brevetoxin-2 (BODIPY (R)-PbTx-2) for voltage-gated sodium channel receptors at site 5 instead of a radiolabeled brevetoxin. Responses were linear in fish tissues spiked from 0.1 to 1.0 ppb with Pacific ciguatoxin-3C (P-CTX-3C) with a detection limit of 0.075 ppb. Carribean ciguatoxins were confirmed in Caribbean fish by LC-MS/MS analysis of the regional biomarker (C-CTX-1). Fish (N = 61) of six different species were screened using the RBA((F)). Results for corresponding samples analyzed using the neuroblastoma cell-based assay (CBA-N2a) correlated well (R-2 = 0.71) with those of the RBA((F)), given the low levels of CTX present in positive fish. Data analyses also showed the resulting toxicity levels of P-CTX-3C equivalents determined by CBA-N2a were consistently lower than the RBA((F)) affinities expressed as% binding equivalents, indicating that a given amount of toxin bound to the site 5 receptors translates into corresponding lower cytotoxicity. Consequently, the RBA((F)), which takes approximately two hours to perform, provides a generous estimate relative to the widely used CBA-N2a which requires 2.5 days to complete. Other RBA((F)) advantages include the long-term(> 5 years) stability of the BODIPY (R)-PbTx-2 and having similar results as the commonly used RBA((R)). The RBA((F)) is cost-effective, allows high sample throughput, and is well-suited for routine CTX monitoring programs. C1 [Hardison, D. Ransom; Holland, William C.; Tester, Patricia A.; Morris, James A., Jr.; Litaker, R. Wayne] NOAA, Ctr Coastal Fisheries & Habitat Res, Beaufort, NC USA. [McCall, Jennifer R.; Bourdelais, Andrea J.; Baden, Daniel G.] Univ N Carolina, MARBIONC CREST Res Pk, Wilmington, NC 28401 USA. [McCall, Jennifer R.] SeaTox Res Inc, UNCW CREST Res Pk, Wilmington, NC USA. [Darius, H. Taiana; Chinain, Mireille] ILM, UMR EIO 241, Lab Tox Microalgae, Papeete, Tahiti, Fr Polynesia. [Tester, Patricia A.] JHT Inc, Orlando, FL USA. [Shea, Damian] N Carolina State Univ, Environm Chem & Toxicol Lab, Raleigh, NC 27695 USA. [Quintana, Harold A. Flores] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL USA. RP Hardison, DR (reprint author), NOAA, Ctr Coastal Fisheries & Habitat Res, Beaufort, NC USA. EM rance.hardison@noaa.gov OI DARIUS, Helene Taiana/0000-0002-1184-7034 FU National Oceanic and Atmospheric Administration's Ecology and Oceanography of Harmful Algae Blooms contribution [843]; National Oceanic and Atmospheric Administration; National Ocean Service; Centers for Coastal Ocean Science; Center for Coastal Fisheries and Habitat Research; Cooperative Institute for Ocean Exploration, Research, and Technology CIOERT [NA14OAR4320260]; NOAA; DOC FX Funding was provided by the National Oceanic and Atmospheric Administration's Ecology and Oceanography of Harmful Algae Blooms contribution #843 - http://coastalscience.noaa.gov/research/habs/ecohab RWL PAT DRH WCH DS. Program funds were provided by the National Oceanic and Atmospheric Administration, National Ocean Service, Centers for Coastal Ocean Science, Center for Coastal Fisheries and Habitat Research-DRH WCH RWL PAT JAM. The UNCW partnership is in part funded through the Cooperative Institute for Ocean Exploration, Research, and Technology CIOERT, award number NA14OAR4320260, NOAA, DOC. Authors associated with this are DGB, AJB, and JRM. NOAA National Marine Fisheries, Office of International Affairs-United States Department of State-JAM. The commercial partner SeaTox Research Inc. was not responsible the design or execution of the project, nor did they provide salary support to any of the collaborators. Their role was limited to providing reagents and running the radioactive receptor binding assay using extracts prepared by DRH and WCH. JHT provided support in the form of salary for PT, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 1 Z9 1 U1 10 U2 20 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 APR 13 PY 2016 VL 11 IS 4 AR e0153348 DI 10.1371/journal.pone.0153348 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ3UC UT WOS:000374131200077 PM 27073998 ER PT J AU Wen, T Wamer, WG Subczynski, WK Hou, S Wu, XC Yin, JJ AF Wen, Tao Wamer, Wayne G. Subczynski, Witold K. Hou, Shuai Wu, Xiaochun Yin, Jun-Jie TI Enhancement of Paramagnetic Relaxation by Photoexcited Gold Nanorods SO SCIENTIFIC REPORTS LA English DT Article ID ELECTRON-SPIN; SINGLET OXYGEN; NANOPARTICLES; EPR; ACTIVATION; RADICALS; GROWTH AB Electron spin resonance (ESR) spectroscopy was used to investigate the switchable, light-dependent effects of gold nanorods (GNRs) on paramagnetic properties of nitroxide spin probes. The photoexcited GNRs enhanced the spin-spin and spin-lattice relaxations of nitroxide spin probes. It was shown that molecular oxygen plays the key role in this process. Our results demonstrate that ESR is a powerful tool for investigating the events following photoexcitation of GNRs. The novel light-controlled effects observed for GNRs on paramagnetic properties and activities of surrounding molecules have a number of significant applications where oxygen sensing and oxygen activity is important. C1 [Wen, Tao; Yin, Jun-Jie] US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Wen, Tao; Hou, Shuai; Wu, Xiaochun] Chinese Acad Sci, Key Lab Standardizat & Measurement Nanotechnol, Natl Ctr Nanosci & Technol, Beijing 100190, Peoples R China. [Wen, Tao] Chinese Acad Med Sci, Inst Basic Med Sci, Beijing 100005, Peoples R China. [Wen, Tao] Peking Union Med Coll, Beijing 100005, Peoples R China. [Wamer, Wayne G.] US FDA, Div Bioanalyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Subczynski, Witold K.] Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. RP Yin, JJ (reprint author), US FDA, Div Analyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA.; Wu, XC (reprint author), Chinese Acad Sci, Key Lab Standardizat & Measurement Nanotechnol, Natl Ctr Nanosci & Technol, Beijing 100190, Peoples R China. EM wuxc@nanoctr.cn; junjie.yin@fda.hhs.gov RI Yin, Jun Jie /E-5619-2014 FU National Natural Science Foundation of China [21173056]; FDA Nanotechnology CORES Program; NIH [P41 EB001980] FX The work was supported by the National Natural Science Foundation of China (Grant No. 21173056), partially supported by a regulatory science grant under the FDA Nanotechnology CORES Program and NIH (Grant P41 EB001980) (W.K.S.). 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 31 TC 0 Z9 0 U1 6 U2 15 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 APR 13 PY 2016 VL 6 AR 24101 DI 10.1038/srep24101 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DJ1LN UT WOS:000373964400001 PM 27071507 ER PT J AU Rahman, Z Yang, Y Korang-Yeboah, M Siddiqui, A Xu, XM Ashraf, M Khan, MA AF Rahman, Ziyaur Yang, Yang Korang-Yeboah, Maxwell Siddiqui, Akhtar Xu, Xiaoming Ashraf, Muhammad Khan, Mansoor A. TI Assessing impact of formulation and process variables on in-vitro performance of directly compressed abuse deterrent formulations SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Abuse deterrence; Sotalol; Hardness; Crush resistance; Extraction; Syringeability and injectability ID OVERDOSE DEATHS; PAIN MANAGEMENT; DRUG OVERDOSE; STATE POLICY; OPIOIDS; RELEASE AB Prescription drug products abuse/misuse is epidemic in United States. Opioids drug forms major portion of prescription drug product abuse. Abuse deterrence formulation (ADF) is one of the many approaches taken by sponsors to tackle this problem. It involves formulating opioids into dosage forms that will be difficult to abuse/misuse. Current investigation focused on evaluating the abuse deterrent properties (ADP) of ADF manufactured by direct compression method. Effect of process and formulation variables on ADP was investigated by statistical design of experiment (fractional factorial design). Independent factors studied were molecular weight of polyethylene oxide (Polyox (TM)), curing time, temperature and method, and antioxidant type. Sotalol hydrochloride was selected as a model drug. ADP investigated were hardness/crush resistance, syringeability and injectability, physical manipulation (reduction into powder) and drug extraction in water and alcohol. Hardness and syringeability are evaluated by newly developed quantitative procedure. Other properties were also investigated such as morphology, crystallinity, assay and dissolution. The hardness and drug extraction was significantly (p < 0.05) affected by curing temperature. Formulations could be powdered in 3 min irrespective of their hardness. Syringeability and injectability were intrinsic properties of the polymer used in the formulation, and were not affected by the investigated factors. Crystallinity of the polymer and drug changed, and was dependent upon curing temperature and time. The dissolution and assay were independent of formulation and process parameters studied. In conclusion, the study indicated some advantages of ADF product compared to non-ADF prepared by direct compression. However, the ADF should not be viewed as abuse proof product rather as incrementally improved product. Published by Elsevier B.V. C1 [Rahman, Ziyaur; Yang, Yang; Korang-Yeboah, Maxwell; Siddiqui, Akhtar; Xu, Xiaoming; Ashraf, Muhammad; Khan, Mansoor A.] Food & Drug Adm, Ctr Drug Evaluat & Res, Div Prod Qual & Res, Bethesda, MD USA. [Khan, Mansoor A.] Texas A&M Hlth Sci, Irma Lerma Rangel Coll Pharm, Dallas, TX USA. RP Khan, MA (reprint author), Reynolds Med Bldg,Suite 159, College Stn, TX 77843 USA. EM mkhan@pharmacy.tamhsc.edu OI Rahman, Ziyaur/0000-0002-0402-825X NR 34 TC 4 Z9 4 U1 3 U2 9 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 APR 11 PY 2016 VL 502 IS 1-2 BP 138 EP 150 DI 10.1016/j.ijpharm.2016.02.029 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DH5GQ UT WOS:000372814700014 PM 26911416 ER PT J AU Garcia, M Misplon, JA Price, GE Lo, CY Epstein, SL AF Garcia, Mayra Misplon, Julia A. Price, Graeme E. Lo, Chia-Yun Epstein, Suzanne L. TI Age Dependence of Immunity Induced by a Candidate Universal Influenza Vaccine in Mice SO PLOS ONE LA English DT Article ID T-CELL REPERTOIRE; A VACCINE; ELDERLY POPULATION; VIRUS-VACCINE; M2 PROTEIN; RESPONSES; NUCLEOPROTEIN; ANTIBODY; PROTECTION; ADENOVIRUS AB Influenza has a major impact on the elderly due to increased susceptibility to infection with age and poor response to current vaccines. We have studied universal influenza vaccine candidates based on influenza A nucleoprotein and matrix 2 (A/NP+M2). Long-lasting protection against influenza virus strains of divergent subtypes is induced, especially with mucosal immunization. Here, we tested universal vaccination in BALB/c mice of different ages. Vaccination used intramuscular DNA priming to A/NP+M2 followed by intranasal (i.n.) boosting with recombinant adenoviruses (rAd) expressing the same antigens, or only A/NP + M2-rAd given i.n. Antigen-specific systemic antibody responses were induced in young, middle-aged, and elderly mice (2, 11-17, and 20 months old, respectively), but decreased with age. Antibody responses in bronchoalveolar lavage (BAL) were detected only in young mice. Antigen-specific T cell responses were seen in young and middle-aged but not elderly mice. A/NP+M2 vaccination by the two regimens above protected against stringent challenge in young and middle-aged mice, but not in elderly mice. However, mice vaccinated with A/NP-rAd or A/M2-rAd during their youth were partially protected against challenge 16 months later when they were elderly. In addition, a regimen of two doses of A/NP+ M2-rAd given i.n. one month apart beginning in old age protected elderly mice against stringent challenge. This study highlights the potential benefit of cross-protective vaccines through middle age, and suggests that their performance might be enhanced in elderly individuals who had been exposed to influenza antigens early in life, as most humans have been, or by a two-dose rAd regimen given later in life. C1 [Garcia, Mayra; Misplon, Julia A.; Price, Graeme E.; Lo, Chia-Yun; Epstein, Suzanne L.] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Garcia, Mayra] US FDA, Div Microbiol Devices, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Epstein, SL (reprint author), US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD USA. EM Suzanne.Epstein@fda.hhs.gov FU FDA, CBER; NIH [HHSN272201300006C] FX This study was supported by FDA, CBER intramural research funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, other than in conducting manuscript clearance.; We acknowledge Dr. Mary Quirion (a former member of this lab) for preliminary experiments that led to this project, and Dr. S. Mark Tompkins (now on the faculty at the University of Georgia) who constructed the pAd/CMV/V5-GW/lacZ vector when he was a member of this lab. We acknowledge the NIH Tetramer Core Facility (contract HHSN272201300006C) for provision of NP147-155-H2-Kd Tetramer-APC. We thank Anthony Ferrine, Mary Belcher and the CBER animal facility staff for expert care of experimental animals; Hang Xie and Zhiping Ye for providing A/Mexico/4108/2009 (H1N1); Maryna Eichelberger for providing aged mice; Howard Mostowski and Heba Degheidy for flow cytometry assistance; and Maryna Eichelberger and Andrew Byrnes for helpful comments on the manuscript. NR 59 TC 1 Z9 1 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 7 PY 2016 VL 11 IS 4 AR e0153195 DI 10.1371/journal.pone.0153195 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI6KO UT WOS:000373608000097 PM 27055234 ER PT J AU Knolhoff, AM Zweigenbaum, JA Croley, TR AF Knolhoff, Ann M. Zweigenbaum, Jerry A. Croley, Timothy R. TI Nontargeted Screening of Food Matrices: Development of a Chemometric Software Strategy To Identify Unknowns in Liquid Chromatography-Mass Spectrometry Data SO ANALYTICAL CHEMISTRY LA English DT Article ID FOODOMICS; MS; CONTAMINANTS; TOOLS AB The ability to identify contaminants or adulterants in diverse, complex sample matrixes is necessary in food safety. Thus, nontargeted screening approaches must be implemented to detect and identify unexpected, unknown hazardous compounds that may be present. Molecular formulas can be generated for detected compounds from high-resolution mass spectrometry data, but analysis can be lengthy when thousands of compounds are detected in a single sample. Efficient data mining methods to analyze these complex data sets are necessary given the inherent chemical diversity and variability of food matrixes. The aim of this work is to determine necessary requirements to successfully apply data analysis strategies to distinguish suspect and control samples. Infant formula and orange juice samples were analyzed with one lot of each matrix containing varying concentrations of a four compound mixture to represent a suspect sample set. Small molecular differences were parsed from the data, where analytes as low as 10 ppb were revealed. This was accomplished, in part, by analyzing a quality control standard, matrix spiked with an analytical standard mixture, technical replicates, a representative number of sample lots, and blanks within the sample sequence; this enabled the development of a data analysis workflow and ensured that the employed method is sufficient for mining relevant molecular features from the data. C1 [Knolhoff, Ann M.; Croley, Timothy R.] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Zweigenbaum, Jerry A.] Agilent Technol, 2850 Centerville Rd, Wilmington, DE 19808 USA. RP Knolhoff, AM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Ann.Knolhoff@fda.hhs.gov NR 19 TC 1 Z9 1 U1 16 U2 29 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD APR 5 PY 2016 VL 88 IS 7 BP 3617 EP 3623 DI 10.1021/acs.analchem.5b04208 PG 7 WC Chemistry, Analytical SC Chemistry GA DI7CI UT WOS:000373656300029 PM 26938581 ER PT J AU Hodson, DJ Shaffer, AL Xiao, WM Wright, GW Schmitz, R Phelan, JD Yang, YD Webster, DE Rui, LX Kohlhammer, H Nakagawa, M Waldmann, TA Staudt, LM AF Hodson, Daniel J. Shaffer, Arthur L. Xiao, Wenming Wright, George W. Schmitz, Roland Phelan, James D. Yang, Yandan Webster, Daniel E. Rui, Lixin Kohlhammer, Holger Nakagawa, Masao Waldmann, Thomas A. Staudt, Louis M. TI Regulation of normal B-cell differentiation and malignant B-cell survival by OCT2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer biology; lymphoma; germinal center ID BINDING TRANSCRIPTION FACTORS; OCTAMER DNA MOTIF; OCA-B; COACTIVATOR OBF-1; UP-REGULATION; IN-VIVO; LYMPHOMA; IMMUNOGLOBULIN; ACTIVATION; EXPRESSION AB The requirement for the B-cell transcription factor OCT2 (octamer-binding protein 2, encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse, but their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This finding led us to examine the role of OCT2 in germinal center-derived lymphomas. shRNA knockdown showed that almost all diffuse large B-cell lymphoma (DLBCL) cell lines are addicted to the expression of OCT2 and its coactivator OCA-B. Genome-wide chromatin immunoprecipitation (ChIP) analysis and gene-expression profiling revealed the broad transcriptional program regulated by OCT2 that includes the expression of STAT3, IL-10, ELL2, XBP1, MYC, TERT, and ADA. Importantly, genetic alteration of OCT2 is not a requirement for cellular addiction in DLBCL. However, we detected amplifications of the POU2F2 locus in DLBCL tumor biopsies and a recurrent mutation of threonine 223 in the DNA-binding domain of OCT2. This neomorphic mutation subtly alters the DNA-binding preference of OCT2, leading to the transactivation of noncanonical target genes including HIF1a and FCRL3. Finally, by introducing mutations designed to disrupt the OCT2-OCA-B interface, we reveal a requirement for this protein-protein interface that ultimately might be exploited therapeutically. Our findings, combined with the predominantly B-cell-restricted expression of OCT2 and the absence of a systemic phenotype in our knockout mice, suggest that an OCT2-targeted therapeutic strategy would be efficacious in both major subtypes of DLBCL while avoiding systemic toxicity. C1 [Hodson, Daniel J.; Shaffer, Arthur L.; Xiao, Wenming; Wright, George W.; Schmitz, Roland; Phelan, James D.; Yang, Yandan; Webster, Daniel E.; Rui, Lixin; Kohlhammer, Holger; Nakagawa, Masao; Waldmann, Thomas A.; Staudt, Louis M.] NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Hodson, Daniel J.] Univ Cambridge, Dept Haematol, Cambridge CB2 0AH, England. [Xiao, Wenming] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Staudt, LM (reprint author), NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Kay Kendall Leukaemia Fund Intermediate Fellowship from the United Kingdom FX We thank the EUCOMM Consortium for the Pou2f2 ES cells. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. D.J.H. was supported by a Kay Kendall Leukaemia Fund Intermediate Fellowship from the United Kingdom. The views presented in this article do not necessarily reflect current or future opinion or policy of the US Food and Drug Administration. Any mention of commercial products is for clarification and not intended as endorsement. NR 50 TC 0 Z9 1 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 5 PY 2016 VL 113 IS 14 BP E2039 EP E2046 DI 10.1073/pnas.1600557113 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI2UI UT WOS:000373354000014 PM 26993806 ER PT J AU Liu, ZC Wang, YP Borlak, J Tong, WD AF Liu, Zhichao Wang, Yuping Borlak, Juergen Tong, Weida TI Mechanistically linked serum miRNAs distinguish between drug induced and fatty liver disease of different grades SO SCIENTIFIC REPORTS LA English DT Article ID PROTEIN-INTERACTION NETWORKS; HEPATIC MICRORNA EXPRESSION; NONALCOHOLIC STEATOHEPATITIS; DOWN-REGULATION; UP-REGULATION; HEPATOCELLULAR-CARCINOMA; ISCHEMIA/REPERFUSION INJURY; CIRCULATING MICRORNAS; LIPID-ACCUMULATION; CHOLINE-DEFICIENT AB Hepatic steatosis is characterised by excessive triglyceride accumulation in the form of lipid droplets (LD); however, mechanisms differ in drug induced (DIS) and/or non-alcoholic fatty liver disease (NAFLD). Here we hypothesized distinct molecular circuits of microRNA/LD-associated target genes and searched for mechanistically linked serum and tissue biomarkers that would distinguish between DIS and human NAFLD of different grades. We analysed > 800 rat hepatic whole genome data for 17 steatotic drugs and identified 157 distinct miRNAs targeting 77 DIS regulated genes. Subsequently, genomic data of N = 105 cases of human NAFLD and N = 32 healthy controls were compared to serum miRNA profiles of N = 167 NAFLD patients. This revealed N = 195 tissue-specific miRNAs being mechanistically linked to LD-coding genes and 24 and 9 miRNAs were commonly regulated in serum and tissue of advanced and mild NAFLD, respectively. The NASH serum regulated miRNAs informed on hepatic inflammation, adipocytokine and insulin signalling, ER-and caveolae associated activities and altered glycerolipid metabolism. Conversely, serum miRNAs associated with blunt steatosis specifically highlighted activity of FOXO1& HNF4a on CPT2, the lipid droplet and ER-lipid-raft associated PLIN3 and Erlin1. Altogether, serum miRNAs informed on the molecular pathophysiology of NAFLD and permitted differentiation between DIS and NAFLD of different grades. C1 [Liu, Zhichao; Wang, Yuping; Tong, Weida] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR USA. [Borlak, Juergen] Hannover Med Sch, Ctr Pharmacol & Toxicol, Hannover, Germany. RP Tong, WD (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR USA.; Borlak, J (reprint author), Hannover Med Sch, Ctr Pharmacol & Toxicol, Hannover, Germany. EM borlak.juergen@mh-hannover.de; weida.tong@fda.hhs.gov FU German Federal Ministry of Education and Research, Virtual Liver Network initiative [031 6154]; ORISE of the FDA FX We thank Hong Fang for comments and discussion. We also thank Dr. Takeki Uehara/Dr. Ikuo Kato and the TGP group for helpful discussions and for expert opinion on histopathology of steatotic livers of treated rats. J Borlak receives funding from the German Federal Ministry of Education and Research as part of the Virtual Liver Network initiative (grant number 031 6154). He is also a recipient of an ORISE stipend of the FDA which is gratefully acknowledged. The views presented in this article do not necessarily reflect current or future opinion or policy of the US Food and Drug Administration. Any mention of commercial products is for clarification and not intended as endorsement. NR 106 TC 3 Z9 3 U1 4 U2 6 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 APR 5 PY 2016 VL 6 AR 23709 DI 10.1038/srep23709 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI3KA UT WOS:000373396300001 PM 27045805 ER PT J AU Dimitrova, M Zenarruzabeitia, O Borrego, F Simhadri, VR AF Dimitrova, Milena Zenarruzabeitia, Olatz Borrego, Francisco Simhadri, Venkateswara R. TI CD300c is uniquely expressed on CD56(bright) Natural Killer Cells and differs from CD300a upon ligand recognition SO SCIENTIFIC REPORTS LA English DT Article ID HUMAN T-CELLS; NK-CELLS; DENDRITIC CELLS; MULTIPLE-SCLEROSIS; INNATE IMMUNITY; LYMPH-NODES; L-SELECTIN; ANNEXIN-V; PHOSPHATIDYLSERINE; RECEPTOR AB Paired receptors on NK cells recognize similar ligands with varied strength of binding ability and perform different functions. The CD300 molecules are emerging as novel immune regulators in health and disease due to their interaction with their lipid-nature ligands. Particularly, the paired receptors CD300c and CD300a have been shown to elicit activating and inhibitory capabilities, respectively. In the current study, we seek to investigate the expression and function of CD300c on human NK cells. We demonstrate that IL-2 and IL-15 treatment significantly induce CD300c expression exclusively on CD56(bright) NK cells. CD300c up-regulation requires STAT5 and its expression is inhibited by IL-4. Consistently, IL-2 secreted from activated CD4(+) T cells specifically induces the expression of CD300c on CD56(bright) NK cells. Crosslinking CD300c with a specific antibody enhances the proficiency of CD56(bright) NK cells to degranulate and induce chemokine and cytokine secretion. We also show the differential binding of CD300a and CD300c to their ligands phosphatidylethanolamine (PE) and phosphatidylserine (PS) and their differential ability to affect CD56(bright) NK cell functions. Our results provide an insight into the novel set of paired receptors CD300a and CD300c that are distinctively expressed on CD56(bright) NK cells with varied effector functions. C1 [Dimitrova, Milena; Simhadri, Venkateswara R.] US FDA, Div Biotechnol Review & Res 1, Off Biotechnol Prod Review & Res, CDER, Rockville, MD 20857 USA. [Zenarruzabeitia, Olatz; Borrego, Francisco] BioCruces Hlth Res Inst, Immunopathol Grp, Baracaldo, Spain. [Zenarruzabeitia, Olatz; Borrego, Francisco] Basque Ctr Transfus & Human Tissues, Immunotherapy Grp, Galdakao, Spain. [Borrego, Francisco] Basque Fdn Sci, Ikerbasque, Bilbao, Spain. RP Simhadri, VR (reprint author), US FDA, Div Biotechnol Review & Res 1, Off Biotechnol Prod Review & Res, CDER, Rockville, MD 20857 USA. EM venkateswara.simhadri@fda.hhs.gov FU Intramural Program of the Food and Drug Administration; ISCIII-Subdireccion de Evaluacion y Fomento de la Investigacion-Fondo Europeo de Desarrollo Regional (FEDER); Plan Estatal de I+D+I [PI13/00889] FX We thank Dr. John E. Coligan for allowing us to use their blood bank services at the National Institute of Health. This work was funded by the Intramural Program of the Food and Drug Administration and Project PI13/00889, integrated into the "Plan Estatal de I+D+I 2013-2016" and funded by the "ISCIII-Subdireccion de Evaluacion y Fomento de la Investigacion-Fondo Europeo de Desarrollo Regional (FEDER)". NR 55 TC 2 Z9 2 U1 1 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 APR 4 PY 2016 VL 6 AR 23942 DI 10.1038/srep23942 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI1QZ UT WOS:000373271900001 PM 27040328 ER PT J AU Zhang, L Luo, S Zhang, BL AF Zhang, Lei Luo, Shen Zhang, Baolin TI The use of lectin microarray for assessing glycosylation of therapeutic proteins SO MABS LA English DT Article DE monoclonal antibodies; therapeutic glycoproteins; lectin microarray; Glycan analysis ID MONOCLONAL-ANTIBODY; MASS-SPECTROMETRY; BANDEIRAEA-SIMPLICIFOLIA; LINKED OLIGOSACCHARIDES; BINDING; CARBOHYDRATE; GLYCOPROTEINS; CHALLENGES; PRODUCTS; ERYTHROPOIETIN AB Glycans or carbohydrates attached to therapeutic glycoproteins can directly affect product quality, safety and efficacy, and therefore must be adequately analyzed and controlled throughout product life cycles. However, the complexity of protein glycosylation poses a daunting analytical challenge. In this study, we evaluated the utility of a lectin microarray for assessing protein glycans. Using commercial lectin chips, which contain 45 lectins toward distinct glycan structures, we were able to determine the lectin binding patterns of a panel of 15 therapeutic proteins, including 8 monoclonal antibodies. Lectin binding signals were analyzed to generate glycan profiles that were generally consistent with the known glycan patterns for these glycoproteins. In particular, the lectin-based microarray was found to be highly sensitive to variations in the terminal carbohydrate structures such as galactose versus sialic acid epitopes. These data suggest that lectin microarray could be used for screening glycan patterns of therapeutic glycoproteins. C1 [Zhang, Lei; Luo, Shen; Zhang, Baolin] Food & Drug Adm, Ctr Drug Evaluat & Res, Off Biotechnol Prod, Silver Spring, MD USA. RP Zhang, BL (reprint author), Food & Drug Adm, Ctr Drug Evaluat & Res, Off Biotechnol Prod, Silver Spring, MD USA. EM baolin.zhang@fda.hhs.gov RI Zhang, Lei/F-5171-2010 FU Intramural FDA HHS [FD999999] NR 43 TC 2 Z9 2 U1 5 U2 9 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1942-0862 EI 1942-0870 J9 MABS-AUSTIN JI mAbs PD APR 2 PY 2016 VL 8 IS 3 BP 524 EP 535 DI 10.1080/19420862.2016.1149662 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DI4XA UT WOS:000373501500009 PM 26918373 ER PT J AU Korang-Yeboah, M Akhtar, S Siddiqui, A Rahman, Z Khan, MA AF Korang-Yeboah, Maxwell Akhtar, Sohail Siddiqui, Akhtar Rahman, Ziyaur Khan, Mansoor A. TI Application of NIR chemometric methods for quantification of the crystalline fraction of warfarin sodium in drug product SO DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY LA English DT Article DE Amorphous warfarin sodium; amorphous quantification; chemometrics; crystalline warfarin sodium; near infrared spectroscopy; partial least square; principal component ID NEAR-INFRARED SPECTROSCOPY; PHARMACEUTICAL APPLICATIONS; PREDICTION; SPECTRA AB Monitoring of the physical state of warfarin sodium (WS) in products is essential for minimizing product quality variability in order to ensure consistent clinical performance. This study reports the development of chemometric models for quantifying the crystalline and amorphous fractions of WS in commercial drug products using NIR spectroscopy. Formulations based on commercially available products with different API to excipient ratio were used for the study. For each content, two formulations containing either lactose monohydrate or lactose anhydrous as the predominant formulation excipient were prepared. Two formulations containing either 100% amorphous WS (AWS) or crystalline WS (CWS) were prepared and mixed in various ratios to obtain sample matrices containing AWS/CWS 0-100%. The uniformity of the samples was confirmed by near infrared chemical imaging. Data were mathematically pretreated by multiplicative signal correction and Savitzky-Golay second derivative. Principal component regression and partial least square regression models were developed from mathematically treated data. All the models showed linear trend for amorphous and crystalline fractions of the WS as indicated by correlation and R-2>0.99 and >0.98, respectively. The models demonstrated good performance parameters with a low-root mean squared error, standard error and bias. The model predicted CWS and AWS contents were in very close agreement with the actual values. The study indicated the utility of NIR chemometric methods in quantification of the crystalline and/or amorphous fraction of WS in its products. C1 [Korang-Yeboah, Maxwell; Akhtar, Sohail; Siddiqui, Akhtar; Rahman, Ziyaur; Khan, Mansoor A.] US FDA, Div Prod Qual Res, Ctr Drug Evaluat & Res, LS Bldg 64,Room 1070,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Khan, MA (reprint author), US FDA, Div Prod Qual Res, Ctr Drug Evaluat & Res, LS Bldg 64,Room 1070,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Mansoor.Khan@fda.hhs.gov OI Rahman, Ziyaur/0000-0002-0402-825X NR 35 TC 0 Z9 0 U1 1 U2 10 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0363-9045 EI 1520-5762 J9 DRUG DEV IND PHARM JI Drug Dev. Ind. Pharm. PD APR 2 PY 2016 VL 42 IS 4 SI SI BP 584 EP 594 DI 10.3109/03639045.2015.1058817 PG 11 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG1FD UT WOS:000371810100010 PM 26161939 ER PT J AU Moolchandani, V Augsburger, LL Gupta, A Khan, MA Langridge, J Hoag, SW AF Moolchandani, Vikas Augsburger, Larry L. Gupta, Abhay Khan, Mansoor A. Langridge, John Hoag, Stephen W. TI To investigate the influence of machine operating variables on formulations derived from lactose types in capsule filling: part 2 SO DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY LA English DT Article DE Capsule filling; drug dissolution; ejection force; formulation development; lactose; machine operating variables; plug crushing strength; plug weight variation ID HARD GELATIN CAPSULES; PLUG FORMATION; DRUG DISSOLUTION; COMPRESSION; COMPACTION; SIZE; PRESSURE; STRENGTH; WEIGHT; SPEED AB This study is the second in a series that examines the characterizing and selection of suitable grades of lactose for capsule formulation development. Based upon the previous study, four grades were selected for further study. The effects of drug load and operational variables on formulations derived from these four lactose types were evaluated for physicochemical and mechanical attributes of plugs and their capsules on an instrumented dosing-disc capsule filling machine (H&H KFM/3) using acetaminophen as a model, highly soluble and poorly compressible drug. The results obtained were as follows: (1) flowability reduced upon increasing drug load; (2) powder bed height (PBH) and compression force (CF) had positive significant effect on plug weight (p<0.05); (3) ejection force was positively and significantly correlated with increasing speed and CF (p<0.05); (4) AL capsule plugs had the highest plug crushing force which was followed by DCL15; (5) the crushing strength of plugs made from DCL11 increased with increasing acetaminophen concentration; (6) higher CF had a significant negative impact on acetaminophen release at 15min time point (p<0.05); (7) at 10% and 40% drug load, formulations containing AL showed the quickest drug release; and (8) increased drug load had a significant negative impact on the release rate at 15 and 45min time points (p<0.05). Overall, the results from this study provides information on risk based assessment of filler selection based on drug load and the range of machine operating variables which will help in defining criteria for meeting key quality attributes for capsule formulation development. C1 [Moolchandani, Vikas; Augsburger, Larry L.; Hoag, Stephen W.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. [Gupta, Abhay; Khan, Mansoor A.] US FDA, Div Prod Qual Res, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Langridge, John] DMV Fonterra Excipients, Goch, Germany. RP Moolchandani, V (reprint author), Nutrilite Hlth Inst Amway, 5600 Beach Blvd, Buena Pk, CA 90622 USA. EM moolchandani.rx@gmail.com FU DMV-Fonterra Excipients (Goch, Germany); University of Maryland Department of Pharmaceutical Sciences FX The views and opinions expressed in this paper are only of the authors, and do not necessarily reflect the views or policies of the FDA. Authors thank the financial support of this research provided by DMV-Fonterra Excipients (Goch, Germany). This work was also supported by University of Maryland Department of Pharmaceutical Sciences predoctoral Dr. Frank J. Slama and H.A.B. Dunning fellowship. NR 51 TC 0 Z9 0 U1 0 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0363-9045 EI 1520-5762 J9 DRUG DEV IND PHARM JI Drug Dev. Ind. Pharm. PD APR 2 PY 2016 VL 42 IS 4 SI SI BP 624 EP 635 DI 10.3109/03639045.2015.1062511 PG 12 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG1FD UT WOS:000371810100014 PM 26165246 ER PT J AU Hammer, DX Lozzi, A Boretsky, A Welle, CG AF Hammer, Daniel X. Lozzi, Andrea Boretsky, Adam Welle, Cristin G. TI Acute insertion effects of penetrating cortical microelectrodes imaged with quantitative optical coherence angiography SO NEUROPHOTONICS LA English DT Article DE optical coherence tomography; angiography; neurophotonics; neurotoxicity; inflammation; cranial window ID BLOOD-FLOW; CRANIAL WINDOW; BRAIN-TISSUE; IN-VIVO; TOMOGRAPHY; IMPLANTATION; MICROSCOPY; DOPPLER; GROWTH; OCT AB The vascular response during cortical microelectrode insertion was measured with amplitude decorrelation-based quantitative optical coherence angiography (OCA). Four different shank-style microelectrode configurations were inserted in murine motor cortex beneath a surgically implanted window in discrete steps while OCA images were collected and processed for angiography and flowmetry. Quantitative measurements included tissue displacement (measured by optical flow), perfused capillary density, and capillary flow velocity. The primary effect of insertion was mechanical perturbation, the effects of which included tissue displacement, arteriolar rupture, and compression of a branch of the anterior cerebral artery causing a global decrease in flow. Other effects observed included local flow drop-out in the region immediately surrounding the microelectrode. The mean basal capillary network velocity for all animals was 0.23 (+/- 0.05 SD) and 0.18 (+/- 0.07 SD) mm/s for capillaries from 100 to 300 mu m and 300 to 500 mu m, respectively. Upon insertion, the 2-shank electrode arrays caused a decrease in capillary flow density and velocity, while the results from other configurations were not different from controls. The proximity to large vessels appears to play a larger role than the array configuration. These results can guide neurosurgeons and electrode designers to minimize trauma and ischemia during microelectrode insertion. (C) The Authors. C1 [Hammer, Daniel X.; Lozzi, Andrea; Boretsky, Adam; Welle, Cristin G.] US FDA, Ctr Devices & Radiol Hlth, Div Biomed Phys, Off Sci & Engn Labs, 20903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Welle, Cristin G.] Univ Colorado Denver, Dept Neurosurg, 12700 East 19th Ave, Aurora, CO 80045 USA. [Welle, Cristin G.] Univ Colorado Denver, Dept Bioengn, 12700 East 19th Ave, Aurora, CO 80045 USA. RP Hammer, DX (reprint author), US FDA, Ctr Devices & Radiol Hlth, Div Biomed Phys, Off Sci & Engn Labs, 20903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM daniel.hammer@fda.hhs.gov NR 43 TC 0 Z9 0 U1 1 U2 1 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 2329-423X EI 2329-4248 J9 NEUROPHOTONICS JI Neurophotonics PD APR-JUN PY 2016 VL 3 IS 2 AR 025002 DI 10.1117/1.NPh.3.2.025002 PG 17 WC Neurosciences; Optics SC Neurosciences & Neurology; Optics GA DV9IH UT WOS:000383253600004 ER PT J AU Vaithianathan, S Haidar, SH Zhang, XY Jiang, WL Avon, C Dowling, TC Shao, CX Kane, M Hoag, SW Flasar, MH Ting, TY Polli, JE AF Vaithianathan, Soundarya Haidar, Sam H. Zhang, Xinyuan Jiang, Wenlei Avon, Christopher Dowling, Thomas C. Shao, Changxing Kane, Maureen Hoag, Stephen W. Flasar, Mark H. Ting, Tricia Y. Polli, James E. TI Reply to "On the Effect of Common Excipients on the Oral Absorption of Class 3 Drugs" SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Editorial Material DE biopharmaceutics classification system; bioequivalence; excipients; oral absorption; permeability; cimetidine; acyclovir ID BIOPHARMACEUTICS CLASSIFICATION-SYSTEM; DOSAGE FORMS; BIOWAIVER MONOGRAPHS; BIOEQUIVALENCE; BIOAVAILABILITY; HYDROCHLORIDE; EXTENT AB We previously concluded that 12 common excipients need not be qualitatively the same and quantitatively very similar to reference for Biopharmaceutics Classification System-based biowaivers. This conclusion for regulatory relief is based upon a series of bioequivalence studies in humans involving cimetidine and acyclovir. Limitations were also discussed. We understand the major concern of Garcia-Arieta et al. is that "results obtained by Vaithianathan et al. should not be extrapolated to other drugs." We understand that individuals conducting their own risk/benefit analysis may reach that conclusion, and we reply to the concerns of Garcia-Arieta et al. We continue to conclude that the 12 common excipients need not be qualitatively the same nor quantitatively very similar to reference, but rather, simply be not more than the quantities studied in our manuscript for cimetidine and acyclovir, and potentially other class 3 drugs with similar properties. (C) 2016 American Pharmacists Association(R). Published by Elsevier Inc. All rights reserved. C1 [Vaithianathan, Soundarya; Avon, Christopher; Shao, Changxing; Kane, Maureen; Hoag, Stephen W.; Polli, James E.] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Haidar, Sam H.; Zhang, Xinyuan; Jiang, Wenlei] US FDA, Ctr Drug Evaluat, Silver Spring, MD 20993 USA. [Dowling, Thomas C.] Ferris State Univ, Dept Pharm Practice, Grand Rapids, MI 49503 USA. [Flasar, Mark H.] Univ Maryland, Dept Gastroenterol & Hepatol, Baltimore, MD 21201 USA. [Ting, Tricia Y.] Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. RP Polli, JE (reprint author), Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. EM jpolli@rx.umaryland.edu NR 21 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 APR PY 2016 VL 105 IS 4 BP 1355 EP 1357 DI 10.1016/j.xphs.2016.02.028 PG 3 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA DT8TX UT WOS:000381769600002 PM 27019956 ER PT J AU Goodarzi, N Morgani, AB Abrahamsson, B Cristofoletti, R Groot, DW Langguth, P Mehta, MU Polli, JE Shah, VP Dressman, JB AF Goodarzi, Navid Morgani, Ahmadreza Barazesh Abrahamsson, Bertil Cristofoletti, Rodrigo Groot, D. W. Langguth, Peter Mehta, Mehul U. Polli, James E. Shah, Vinod P. Dressman, Jennifer B. TI Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Ribavirin SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Editorial Material DE ribavirin; absorption; BCS; biowaiver; permeability; solubility ID CHRONIC HEPATITIS-C; BIOPHARMACEUTICS CLASSIFICATION-SYSTEM; SUSTAINED VIROLOGICAL RESPONSE; INTESTINAL-ABSORPTION; PHARMACOKINETICS; DRUG; BIOEQUIVALENCE; TRANSPORT; THERAPY; VIRUS AB Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing ribavirin are reviewed. Ribavirin is highly soluble, but its permeability characteristics are not well defined. Therefore according to the Biopharmaceutical Classification System, and taking a "worst case" approach, ribavirin should be assigned to class III. As ribavirin is transported across the brush border membrane of the human jejunum by hCNT2, it shows saturable uptake in the intestine. However, no common excipients have been shown to compete for ribavirin absorption, nor have problems with BE of immediate release ribavirin formulations containing different excipients and produced by different manufacturing methods been reported in the open literature. So the risk of bioinequivalence caused by these factors appears to be low. Ribavirin is considered a narrow therapeutic index drug, as judged by comparing the minimum effective concentration and minimum toxic concentrations in blood. Although ribavirin would not be eligible for approval via a Biopharmaceutical Classification System-based biowaiver procedure according to today's guidances due to its narrow therapeutic index, the risks of biowaiving should be weighed against the considerable risks associated with studying BE of ribavirin products in healthy subjects. (C) 2016 American Pharmacists Association(R). Published by Elsevier Inc. All rights reserved. C1 [Goodarzi, Navid] Univ Tehran Med Sci, Fac Pharm, Nanotechnol Res Ctr, Tehran, Iran. [Morgani, Ahmadreza Barazesh] Univ Tehran Med Sci, Dept Pharmaceut, Fac Pharm, Tehran, Iran. [Abrahamsson, Bertil] AstraZeneca R&D, Pharmaceut Dev, Molndal, Sweden. [Cristofoletti, Rodrigo] Brazilian Hlth Surveillance Agcy Anvisa, Div Therapeut Equivalence, Brasilia, DF, Brazil. [Groot, D. W.] RIVM Natl Inst Publ Hlth & Environm, Utrecht, Netherlands. [Langguth, Peter] Johannes Gutenberg Univ Mainz, Inst Pharm, Mainz, Germany. [Mehta, Mehul U.] US FDA, Ctr Drug Evaluat, Silver Spring, MD 20993 USA. [Polli, James E.] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Shah, Vinod P.] FIP, The Hague, Netherlands. [Dressman, Jennifer B.] Goethe Univ Frankfurt, Inst Pharmaceut Technol, Frankfurt, Germany. RP Dressman, JB (reprint author), Goethe Univ Frankfurt, Inst Pharmaceut Technol, Frankfurt, Germany. EM dressman@em.uni-frankfurt.de RI Fachbereich14, Dekanat/C-8553-2015 NR 47 TC 0 Z9 0 U1 0 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 APR PY 2016 VL 105 IS 4 BP 1362 EP 1369 DI 10.1016/j.xphs.2016.01.017 PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA DT8TX UT WOS:000381769600004 PM 26952879 ER PT J AU Scully, CG Daluwatte, C Marques, NR Khan, M Salter, M Wolf, J Nelson, C Salsbury, J Enkhbaatar, P Kinsky, M Kramer, GC Strauss, DG AF Scully, Christopher G. Daluwatte, Chathuri Marques, Nicole R. Khan, Muzna Salter, Michael Wolf, Jordan Nelson, Christina Salsbury, John Enkhbaatar, Perenlei Kinsky, Michael Kramer, George C. Strauss, David G. TI Effect of hemorrhage rate on early hemodynamic responses in conscious sheep SO PHYSIOLOGICAL REPORTS LA English DT Article DE Hemodynamic compensation; hemorrhage; hypovolemia ID BODY NEGATIVE-PRESSURE; HYPOTENSIVE HEMORRHAGE; MULTIPLE HEMORRHAGES; SHOCK; TRAUMA; BLOOD; RESUSCITATION; HYPOVOLEMIA; NACL AB Physiological compensatory mechanisms can mask the extent of hemorrhage in conscious mammals, which can be further complicated by individual tolerance and variations in hemorrhage onset and duration. We assessed the effect of hemorrhage rate on tolerance and early physiologic responses to hemorrhage in conscious sheep. Eight Merino ewes (37.4 +/- 1.1 kg) were subjected to fast (1.25 mL/kg/min) and slow (0.25 mL/kg/min) hemorrhages separated by at least 3 days. Blood was withdrawn until a drop in mean arterial pressure (MAP) of >30 mmHg and returned at the end of the experiment. Continuous monitoring included MAP, central venous pressure, pulmonary artery pressure, pulse oximetry, and tissue oximetry. Cardiac output by thermodilution and arterial blood samples were also measured. The effects of fast versus slow hemorrhage rates were compared for total volume of blood removed and stoppage time (when MAP < 30 mmHg of baseline) and physiological responses during and after the hemorrhage. Estimated blood volume removed when MAP dropped 30 mmHg was 27.0 +/- 4.2% (mean +/- standard error) in the slow and 27.3 +/- 3.2% in the fast hemorrhage (P = 0.47, paired t test between rates). Pressure and tissue oximetry responses were similar between hemorrhage rates. Heart rate increased at earlier levels of blood loss during the fast hemorrhage, but hemorrhage rate was not a significant factor for individual hemorrhage tolerance or hemodynamic responses. In 5/16 hemorrhages MAP stopping criteria was reached with <25% of blood volume removed. This study presents the physiological responses leading up to a significant drop in blood pressure in a large conscious animal model and how they are altered by the rate of hemorrhage. C1 [Scully, Christopher G.; Daluwatte, Chathuri] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Marques, Nicole R.; Khan, Muzna; Salter, Michael; Wolf, Jordan; Nelson, Christina; Salsbury, John; Enkhbaatar, Perenlei; Kinsky, Michael; Kramer, George C.] Univ Texas Med Branch, Dept Anesthesiol, Galveston, TX 77555 USA. [Strauss, David G.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Scully, CG (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 62,Room 1129, Silver Spring, MD 20993 USA. EM Christopher.Scully@fda.hhs.gov NR 32 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2051-817X J9 PHYSIOL REP JI PHYSIOL. REP. PD APR PY 2016 VL 4 IS 7 AR e12739 DI 10.14814/phy2.12739 PG 15 WC Physiology SC Physiology GA DR9UI UT WOS:000380241200001 ER PT J AU Chappell, G Pogribny, IP Guyton, KZ Rusyn, I AF Chappell, Grace Pogribny, Igor P. Guyton, Kathryn Z. Rusyn, Ivan TI Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review SO MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH LA English DT Review DE Epigenetics; Toxicology; Cancer; Genotoxicity; Hazard assessment ID COKE-OVEN WORKERS; POLYCYCLIC AROMATIC-HYDROCARBONS; GLOBAL DNA METHYLATION; MOUSE LUNG-TUMORS; PERIPHERAL-BLOOD LYMPHOCYTES; EXFOLIATED UROTHELIAL CELLS; HISTONE H3 PHOSPHORYLATION; BRONCHIAL EPITHELIAL-CELLS; SISTER-CHROMATID EXCHANGE; MIRNA EXPRESSION PROFILES AB Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as "carcinogenic to humans" (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzo[a]pyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzo[a]pyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments. (C) 2016 Elsevier B.V. All rights reserved. C1 [Chappell, Grace; Rusyn, Ivan] Texas A&M Univ, Dept Vet Integrat Biosci, 4458 TAMU, College Stn, TX 77843 USA. [Pogribny, Igor P.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Guyton, Kathryn Z.] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France. RP Rusyn, I (reprint author), Texas A&M Univ, Dept Vet Integrat Biosci, 4458 TAMU, College Stn, TX 77843 USA. EM irusyn@cvm.tamu.edu RI Rusyn, Ivan/S-2426-2016 FU National Institutes of health [R01 ES023195] FX This work was funded, in part, by a grant from the National Institutes of health (R01 ES023195). The authors thank Andrew Shapiro for his assistance with HAWC. NR 208 TC 4 Z9 4 U1 12 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5742 EI 1388-2139 J9 MUTAT RES-REV MUTAT JI Mutat. Res.-Rev. Mutat. Res. PD APR-JUN PY 2016 VL 768 BP 27 EP 45 DI 10.1016/j.mrrev.2016.03.004 PG 19 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA DP3AT UT WOS:000378365500003 PM 27234561 ER PT J AU Fuentes, S Coyle, EM Beeler, J Golding, H Khurana, S AF Fuentes, Sandra Coyle, Elizabeth M. Beeler, Judy Golding, Hana Khurana, Surender TI Antigenic Fingerprinting following Primary RSV Infection in Young Children Identifies Novel Antigenic Sites and Reveals Unlinked Evolution of Human Antibody Repertoires to Fusion and Attachment Glycoproteins SO PLOS PATHOGENS LA English DT Article ID RESPIRATORY-SYNCYTIAL-VIRUS; MEMORY B-CELLS; G-PROTEIN; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODY; IMMUNOGLOBULIN-G; SECRETING CELLS; INFLUENZA-VIRUS; VACCINE; SERUM AB Respiratory Syncytial Virus (RSV) is the major cause of pneumonia among infants. Here we elucidated the antibody repertoire following primary RSV infection and traced its evolution through adolescence and adulthood. Whole genome-fragment phage display libraries (GFPDL) expressing linear and conformational epitopes in the RSV fusion protein (F) and attachment protein (G) were used for unbiased epitope profiling of infant sera prior to and following RSV infection. F-GFPDL analyses demonstrated modest changes in the anti-F epitope repertoires post-RSV infection, while G-GFPDL analyses revealed 100-fold increase in number of bound phages. The G-reactive epitopes spanned the N- and C-terminus of the G ectodomain, along with increased reactivity to the central conserved domain (CCD). Panels of F and G antigenic sites were synthesized to evaluate sera from young children (<2 yr), adolescents (14-18 yr) and adults (30-45 yr) in SPR real-time kinetics assays. A steady increase in RSV-F epitope repertoires from young children to adults was observed using peptides and F proteins. Importantly, several novel epitopes were identified in pre-fusion F and an immunodominant epitope in the F-p27. In all age groups, antibody binding to pre-fusion F was 2-3 folds higher than to post-fusion form. For RSV-G, antibody responses were high following early RSV infection in children, but declined significantly in adults, using either G proteins or peptides. This study identified unlinked evolution of anti-F and anti G responses and supportive evidence for immune pressure driven evolution of RSV-G. These findings could help development of effective countermeasures including vaccines. C1 [Fuentes, Sandra; Coyle, Elizabeth M.; Beeler, Judy; Golding, Hana; Khurana, Surender] US FDA, Div Viral Prod, CBER, Silver Spring, MD USA. RP Khurana, S (reprint author), US FDA, Div Viral Prod, CBER, Silver Spring, MD USA. EM Surender.Khurana@fda.hhs.gov FU FDA FX This work was supported by FDA intramural funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 2 Z9 2 U1 2 U2 2 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 APR PY 2016 VL 12 IS 4 AR e1005554 DI 10.1371/journal.ppat.1005554 PG 24 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DP0CZ UT WOS:000378156900038 PM 27100289 ER PT J AU Taylor, AD Agurs-Collins, T Persoskie, A Perna, F AF Taylor, Antione D. Agurs-Collins, Tanya Persoskie, Alexander Perna, Frank TI BMI AS A MEDIATOR IN THE RELATION OF DISCRIMINATION AND INFLAMMATION SO PSYCHOSOMATIC MEDICINE LA English DT Meeting Abstract CT 74th Annual Meeting of the American-Psychosomatic-Society CY MAR 09-12, 2015 CL Denver, CO SP Amer Psychosomat Soc C1 [Taylor, Antione D.] Univ Maryland Baltimore Cty, Psychol, Baltimore, MD 21228 USA. [Agurs-Collins, Tanya; Perna, Frank] NCI, Behav Res Program, Rockville, MD USA. [Persoskie, Alexander] US FDA, Populat Hlth Sci Ctr Tobacco Prod, Silver Spring, MD USA. NR 0 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 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD APR PY 2016 VL 78 IS 3 MA 1125 BP A88 EP A88 PG 1 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA DJ1FX UT WOS:000373949800278 ER PT J AU Valdes, KM Sundar, GS Vega, LA Belew, AT Islam, E Binet, R El-Sayed, NM Le Breton, Y McIver, KS AF Valdes, Kayla M. Sundar, Ganesh S. Vega, Luis A. Belew, Ashton T. Islam, Emrul Binet, Rachel El-Sayed, Najib M. Le Breton, Yoann McIver, Kevin S. TI The fruRBA Operon Is Necessary for Group A Streptococcal Growth in Fructose and for Resistance to Neutrophil Killing during Growth in Whole Human Blood SO INFECTION AND IMMUNITY LA English DT Article ID PHOSPHOTRANSFERASE SYSTEM; CARBOHYDRATE UTILIZATION; ESCHERICHIA-COLI; VIRULENCE; GENE; EXPRESSION; PYOGENES; BACTERIA; PROTEIN; IDENTIFICATION AB Bacterial pathogens rely on the availability of nutrients for survival in the host environment. The phosphoenolpyruvate-phosphotransferase system (PTS) is a global regulatory network connecting sugar uptake with signal transduction. Since the fructose PTS has been shown to impact virulence in several streptococci, including the human pathogen Streptococcus pyogenes (the group A Streptococcus [GAS]), we characterized its role in carbon metabolism and pathogenesis in the M1T1 strain 5448. Growth in fructose as a sole carbon source resulted in 103 genes affected transcriptionally, where the fru locus (fruRBA) was the most induced. Reverse transcriptase PCR showed that fruRBA formed an operon which was repressed by FruR in the absence of fructose, in addition to being under carbon catabolic repression. Growth assays and carbon utilization profiles revealed that although the entire fru operon was required for growth in fructose, FruA was the main transporter for fructose and also was involved in the utilization of three additional PTS sugars: cellobiose, mannitol, and N-acetyl-D-galactosamine. The inactivation of sloR, a fruA homolog that also was upregulated in the presence of fructose, failed to reveal a role as a secondary fructose transporter. Whereas the ability of both Delta fruR and Delta fruB mutants to survive in the presence of whole human blood or neutrophils was impaired, the phenotype was not reproduced in murine whole blood, and those mutants were not attenuated in a mouse intraperitoneal infection. Since the Delta fruA mutant exhibited no phenotype in the human or mouse assays, we propose that FruR and FruB are important for GAS survival in a human-specific environment. C1 [Valdes, Kayla M.; Sundar, Ganesh S.; Vega, Luis A.; Belew, Ashton T.; Islam, Emrul; El-Sayed, Najib M.; Le Breton, Yoann; McIver, Kevin S.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Valdes, Kayla M.; Sundar, Ganesh S.; Vega, Luis A.; Belew, Ashton T.; Islam, Emrul; El-Sayed, Najib M.; Le Breton, Yoann; McIver, Kevin S.] Univ Maryland, Maryland Pathogen Res Inst, College Pk, MD 20742 USA. [Binet, Rachel] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [El-Sayed, Najib M.] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. RP Le Breton, Y; McIver, KS (reprint author), Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA.; Le Breton, Y; McIver, KS (reprint author), Univ Maryland, Maryland Pathogen Res Inst, College Pk, MD 20742 USA. EM lebreton@umd.edu; kmciver@umd.edu RI McIver, Kevin/K-9657-2016 OI McIver, Kevin/0000-0002-4769-4463 FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [AI047298, AI100576, AI047298 13S1, AI089621, AI094773] FX HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) provided funding to Kevin S. McIver under grant number AI047298. HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) provided funding to Kayla M. Valdes under fellowship number AI100576. HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) provided supplemental funding to Luis A. Vega and Kevin S. McIver under grant number AI047298 13S1. HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) provided funding to Ganesh S. Sundar under training grant number AI089621. HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) provided funding to Ashton T. Belew and Najib M. El-Sayed under grant number AI094773. NR 68 TC 2 Z9 2 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD APR PY 2016 VL 84 IS 4 BP 1016 EP 1031 DI 10.1128/IAI.01296-15 PG 16 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DN5JV UT WOS:000377103600014 PM 26787724 ER PT J AU De Pascalis, R Mittereder, L Kennett, NJ Elkins, KL AF De Pascalis, Roberto Mittereder, Lara Kennett, Nikki J. Elkins, Karen L. TI Activities of Murine Peripheral Blood Lymphocytes Provide Immune Correlates That Predict Francisella tularensis Vaccine Efficacy SO INFECTION AND IMMUNITY LA English DT Article ID T-CELL RESPONSES; MYCOBACTERIAL GROWTH; PROTECTIVE IMMUNITY; LVS INFECTION; B-CELLS; STRAIN; TULAREMIA; TUBERCULOSIS; ANTIBODIES; SUBPOPULATIONS AB We previously identified potential correlates of vaccine-induced protection against Francisella tularensis using murine splenocytes and further demonstrated that the relative levels of gene expression varied significantly between tissues. In contrast to splenocytes, peripheral blood leukocytes (PBLs) represent a means to bridge vaccine efficacy in animal models to that in humans. Here we take advantage of this easily accessible source of immune cells to investigate cell-mediated immune responses against tularemia, whose sporadic incidence makes clinical trials of vaccines difficult. Using PBLs from mice vaccinated with F. tularensis Live Vaccine Strain (LVS) and related attenuated strains, we combined the control of in vitro Francisella replication within macrophages with gene expression analyses. The in vitro functions of PBLs, particularly the control of intramacrophage LVS replication, reflected the hierarchy of in vivo protection conferred by LVS-derived vaccines. Moreover, several genes previously identified by the evaluation of splenocytes were also found to be differentially expressed in immune PBLs. In addition, more extensive screening identified additional potential correlates of protection. Finally, expression of selected genes in mouse PBLs obtained shortly after vaccination, without ex vivo restimulation, was different among vaccine groups, suggesting a potential tool to monitor efficacious vaccine-induced immune responses against F. tularensis. Our studies demonstrate that murine PBLs can be used productively to identify potential correlates of protection against F. tularensis and to expand and refine a comprehensive set of protective correlates. C1 [De Pascalis, Roberto; Mittereder, Lara; Kennett, Nikki J.; Elkins, Karen L.] US FDA, Lab Mucosal Pathogens & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Mittereder, Lara] NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP De Pascalis, R (reprint author), US FDA, Lab Mucosal Pathogens & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. EM roberto.depascalis@fda.hhs.gov NR 38 TC 2 Z9 2 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD APR PY 2016 VL 84 IS 4 BP 1054 EP 1061 DI 10.1128/IAI.01348-15 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DN5JV UT WOS:000377103600017 PM 26810039 ER PT J AU Roffe, E Marino, APMP Weaver, J Wan, WZ de Araujo, FF Hoffman, V Santiago, HC Murphy, PM AF Roffe, Ester Marino, Ana Paula M. P. Weaver, Joseph Wan, Wuzhou de Araujo, Fernanda F. Hoffman, Victoria Santiago, Helton C. Murphy, Philip M. TI Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice SO INFECTION AND IMMUNITY LA English DT Article ID CHRONIC CHAGAS-DISEASE; CD8(+) T-CELLS; POLYARTERITIS-NODOSA; AMERICAN TRYPANOSOMIASIS; PARASITE PERSISTENCE; SKELETAL-MUSCLE; MYOCARDITIS; INFECTION; INVOLVEMENT; NOMENCLATURE AB Infectious agents are often considered potential triggers of chronic inflammatory disease, including autoimmunity; however, direct evidence is usually lacking. Here we show that following control of acute infection of mice with the myotropic Colombiana strain of Trypanosoma cruzi, parasites persisted in tissue at low levels associated with development of systemic necrotizing vasculitis. Lesions occurred in many but not all organs and tissues, with skeletal muscle arteries being the most severely affected, and were associated with myositis, atrophy, paresis/paralysis, and death. Histopathology showed fibrinoid vascular necrosis, rare amastigote nests within skeletal muscle myocytes, and massive leukocyte infiltrates composed mainly of inflammatory monocytes, F4/80(+) macrophages, and T. cruzi tetramer-specific CD8(+) T lymphocytes capable of producing gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) but not interleukin-17 (IL-17). T. cruzi-specific IgG was detected in sera from infected mice, but antibody deposits and neutrophilic inflammation were not features of the lesions. Thus, T. cruzi infection of mice may be a specific infectious trigger of paralyzing systemic necrotizing vasculitis most severely affecting skeletal muscle, driven by pathogen-specific type I immune responses. C1 [Roffe, Ester; Marino, Ana Paula M. P.; Weaver, Joseph; Wan, Wuzhou; Murphy, Philip M.] NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [de Araujo, Fernanda F.] US FDA, Ctr Biol Evaluat & Res, Div Emerging & Transfus Transmitted Dis, Lab Emerging Pathogens, Silver Spring, MD USA. [Hoffman, Victoria] NIH, Div Vet Resources, Off Res Serv, Off Director, Bethesda, MD USA. [Santiago, Helton C.] NIAID, Helminth Immunol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Roffe, Ester] Fundacao Oswaldo Cruz, Ctr Pesquisas Rene Rachou, Lab Imunol Celular & Mol, Belo Horizonte, MG, Brazil. [Marino, Ana Paula M. P.] Fundacao Oswaldo Cruz, Ctr Pesquisas Rene Rachou, Lab Imunopatol, Belo Horizonte, MG, Brazil. [de Araujo, Fernanda F.] Fundacao Oswaldo Cruz, Ctr Pesquisas Rene Rachou, Lab Biomarcadores Diagnost & Monitoracao, Belo Horizonte, MG, Brazil. [Santiago, Helton C.] Univ Fed Minas Gerais, Dept Bioquim & Imunol, Belo Horizonte, MG, Brazil. RP Murphy, PM (reprint author), NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pmm@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. NR 40 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD APR PY 2016 VL 84 IS 4 BP 1123 EP 1136 DI 10.1128/IAI.01497-15 PG 14 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DN5JV UT WOS:000377103600024 PM 26857570 ER PT J AU Kim, DH Chon, JW Lim, JS Kim, HS Kang, IB Jeong, D Song, KY Kim, H Kim, KY Seo, KH AF Kim, Dong-Hyeon Chon, Jung-Whan Lim, Jong-Soo Kim, Hong-Seok Kang, Il-Byeong Jeong, Dana Song, Kwang-Young Kim, Hyunsook Kim, Kwang-Yup Seo, Kun-Ho TI Establishing Quantitative Standards for Residual Alkaline Phosphatase in Pasteurized Milk SO KOREAN JOURNAL FOR FOOD SCIENCE OF ANIMAL RESOURCES LA English DT Article DE alkaline phosphatase; milk; pasteurization; quantitative criteria; spectrophotometer ID ASSAYS AB The alkaline phosphatase (ALP) assay is a rapid and convenient method for verifying milk pasteurization. Since colorimetric ALP assays rely on subjective visual assessments, their results are especially unreliable near the detection limits. In this study, we attempted to establish quantitative criteria for residual ALP in milk by using a more objective method based on spectrophotometric measurements. Raw milk was heat-treated for 0, 10, 20, 30, and 40 min and then subjected to ALP assays. The quantitative criteria for residual ALP in the milk was determined as 2 mu g phenol/mL of milk, which is just above the ALP value of milk samples heat-treated for 30 min. These newly proposed methodology and criteria could facilitate the microbiological quality control of milk. C1 [Kim, Dong-Hyeon; Lim, Jong-Soo; Kim, Hong-Seok; Kang, Il-Byeong; Jeong, Dana; Song, Kwang-Young; Seo, Kun-Ho] Konkuk Univ, Coll Vet Med, Ctr Hlth 1, Seoul 05029, South Korea. [Chon, Jung-Whan] Konkuk Univ, Dept Anim Sci & Technol, Seoul 05029, South Korea. [Kim, Hyunsook] Hanyang Univ, Coll Human Ecol, Dept Food & Nutr, Seoul 04763, South Korea. [Kim, Kwang-Yup] Chungbuk Natl Univ, Dept Food Sci & Biotechnol, Cheongju 28644, 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, KU Ctr Food Safety, Seoul 05029, South Korea. EM bracstu3@konkuk.ac.kr FU Ministry of Food and Drug Safety [14162KFDA 876]; National Research Foundation of Korea (NRF) - Korea government (MSIP) [2015 R1A2A2A01005017] FX This research was supported by a grant (14162KFDA 876) from Ministry of Food and Drug Safety in 2014, and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2015 R1A2A2A01005017). NR 9 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 2 BP 194 EP 197 DI 10.5851/kosfa.2016.36.2.194 PG 4 WC Food Science & Technology SC Food Science & Technology GA DN3GH UT WOS:000376949900008 PM 27194927 ER PT J AU Nicasio, AM VanScoy, BD Mendes, RE Castanheira, M Bulik, CC Okusanya, OO Bhavnani, SM Forrest, A Jones, RN Friedrich, LV Steenbergen, JN Ambrose, PG AF Nicasio, Anthony M. VanScoy, Brian D. Mendes, Rodrigo E. Castanheira, Mariana Bulik, Catharine C. Okusanya, Olanrewaju O. Bhavnani, Sujata M. Forrest, Alan Jones, Ronald N. Friedrich, Lawrence V. Steenbergen, Judith N. Ambrose, Paul G. TI Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Piperacillin in an In Vitro Infection Model SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID CEFTOLOZANE; MICE AB We have previously demonstrated the pharmacokinetic-pharmacodynamic (PK-PD) index best associated with the efficacy of tazobactam when used in combination with ceftolozane to be the percentage of the dosing interval during which tazobactam concentrations remained above a threshold value (% time>threshold). Using an in vitro infection model and the same isogenic CTX-M-15-producing Escherichia coli triplet set genetically engineered to transcribe different levels of bla(CTX-M-15), herein we describe dose fractionation studies designed to evaluate the PK-PD index associated with tazobactam efficacy, when given in combination with piperacillin, and the impact of the presence of a different beta-lactam agent, or different bla(CTX-M-15) transcription levels, on the magnitude of the tazobactam PK-PD index necessary for efficacy. The recombinant strains demonstrated piperacillin MIC values of 128,>256, and >256 mu g/ml for the low-, moderate-, and high-level CTX-M-15-producing E. coli strains, respectively. The MIC value for piperacillin in the presence of 4 mu g/ml of tazobactam was 2 mu g/ml for all three strains. The PK-PD index associated with tazobactam efficacy was confirmed to be % time>threshold, regardless of beta-lactamase transcription (r(2) = 0.839). The tazobactam concentration thresholds, however, changed with the CTX-M-15 transcription level and were 0.25, 0.5, and 2 mu g/ml for the low-, moderate-, and high-level CTX-M-15-producing strains, respectively (r(2) = 0.921, 0.773, and 0.875, respectively). The % time>threshold values for tazobactam necessary for net bacterial stasis and a 1- and 2-log(10)-unit CFU/ml decrease from baseline at 24 h were 44.9, 62.9, and 84.9%, respectively. In addition to verifying our previous study results, these results also demonstrated that the magnitude of bacterial-cell killing associated with a beta-lactam-beta-lactamase inhibitor combination is dependent on the amount of beta-lactamase produced. These data provide important information for the development of beta-lactam-beta-lactamase inhibitor combination agents. C1 [Nicasio, Anthony M.] Albany Coll Pharm & Hlth Sci, Albany, NY USA. [VanScoy, Brian D.; Bulik, Catharine C.; Okusanya, Olanrewaju O.; Bhavnani, Sujata M.; Forrest, Alan; Ambrose, Paul G.] Inst Clin Pharmacodynam, Latham, NY USA. [Mendes, Rodrigo E.; Castanheira, Mariana; Jones, Ronald N.] JMI Labs, North Liberty, IA USA. [Friedrich, Lawrence V.; Steenbergen, Judith N.] Merck & Co Inc, Kenilworth, NJ USA. [Ambrose, Paul G.] Univ Oxford, Oxford, England. [Okusanya, Olanrewaju O.] US FDA, Silver Spring, MD USA. [Steenbergen, Judith N.] Paratek Pharmaceut, King Of Prussia, PA USA. RP Ambrose, PG (reprint author), Inst Clin Pharmacodynam, Latham, NY USA.; Ambrose, PG (reprint author), Univ Oxford, Oxford, England. EM pambrose@ICPD.com FU Merck Co, Inc.; Merck & Co, Inc., Kenilworth, NJ, USA; Forest Research Institute; Cubist; Achaogen; Astellas; AstraZeneca; Basilea Pharmaceuticals; Bayer HealthCare; Bristol-Meyers Squibb; Cempra Pharmaceuticals; Cerexa; Cubist Pharmaceuticals; Durata Pharmaceuticals; Fedora Pharmaceuticals; Furiex Pharmaceuticals; GlaxoSmithKline; Meiji Seika Pharma; Nabriva Therapeutics; Nimbus; Pfizer; PolyMedix; Rib-X; Roche Bioscience; Rock Therapeutics; Tetraphase Pharmaceuticals; Medicines Company; Actelion; Affinium; American Proficiency Institute (API); AmpliPhi Bio; Anacor; Basilea; BioVersys; Cardeas; Cempra; Daiichi; Dipexium; Durata; Exela; Fedora; Furiex; Genentech; Janssen; Johnson Johnson; Medpace; Meiji Seika Kaisha; Melinta; Merck; Methylgene; Nabriva; Nanosphere; Novartis; Polyphor; Rempex; Roche; Seachaid; Shionogi; Synthes; Medicines Co.; Theravance; Thermo-Fisher; Venatorx; Vertex; Waterloo; Wockhardt FX We thank Kim A. Charpentier from ICPD (Latham, NY, USA) and Lalitagauri M. Deshpande from JMI Laboratories (North Liberty, IA, USA) for manuscript assistance and technical support. Editorial support for the manuscript was provided by PAREXEL and funded by Merck & Co, Inc.; This study was sponsored by Merck & Co, Inc., Kenilworth, NJ, USA. A.M.N. has received research support from Forest Research Institute and Cubist. The Institute for Clinical Pharmacodynamics (B.D.V., C.C.B., O.O.O., S.M.B., A.F., and P.G.A.) has received research support from Achaogen, Astellas, AstraZeneca, Basilea Pharmaceuticals, Bayer HealthCare, Bristol-Meyers Squibb, Cempra Pharmaceuticals, Cerexa, Cubist Pharmaceuticals, Durata Pharmaceuticals, Fedora Pharmaceuticals, Forest Research Institute, Furiex Pharmaceuticals, GlaxoSmithKline, Meiji Seika Pharma, Nabriva Therapeutics, Nimbus, Pfizer, PolyMedix, Rib-X, Roche Bioscience, Rock Therapeutics, Tetraphase Pharmaceuticals, and the Medicines Company. JMI Laboratories, Inc. (R.E.M., M.C., and R.N.J.) received research and educational grants in 2012 to 2014 from Achaogen, Actelion, Affinium, American Proficiency Institute (API), AmpliPhi Bio, Anacor, Astellas, AstraZeneca, Basilea, BioVersys, Cardeas,Cempra, Cerexa, Cubist, Daiichi, Dipexium, Durata, Exela, Fedora, Forest Research Institute, Furiex, Genentech, GlaxoSmithKline, Janssen, Johnson & Johnson, Medpace, Meiji Seika Kaisha, Melinta, Merck, Methylgene, Nabriva, Nanosphere, Novartis, Pfizer, Polyphor, Rempex, Roche, Seachaid, Shionogi, Synthes, the Medicines Co., Theravance, Thermo-Fisher, Venatorx, Vertex, Waterloo, Wockhardt, and other corporations. NR 13 TC 1 Z9 1 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 APR PY 2016 VL 60 IS 4 BP 2075 EP 2080 DI 10.1128/AAC.02747-15 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DM6XL UT WOS:000376496100015 PM 26787689 ER PT J AU Tadesse, DA Singh, A Zhao, SH Bartholomew, M Womack, N Ayers, S Fields, PI McDermott, PF AF Tadesse, Daniel A. Singh, Aparna Zhao, Shaohua Bartholomew, Mary Womack, Niketta Ayers, Sherry Fields, Patricia I. McDermott, Patrick F. TI Antimicrobial Resistance in Salmonella in the United States from 1948 to 1995 SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ESCHERICHIA-COLI; DRUG-RESISTANCE; FOOD ANIMALS; INFECTIONS; TYPHIMURIUM; STRAINS; HUMANS; EMERGENCE; INCREASE AB We conducted a retrospective study of 2,149 clinical Salmonella strains to help document the historical emergence of antimicrobial resistance. There were significant increases in resistance to older drugs, including ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline, which were most common in Salmonella enterica serotype Typhimurium. An increase in multidrug resistance was observed for each decade since the 1950s. These data help show how Salmonella evolved over the past 6 decades, after the introduction of new antimicrobial agents. C1 [Tadesse, Daniel A.; Zhao, Shaohua; Womack, Niketta; Ayers, Sherry; McDermott, Patrick F.] US FDA, Ctr Vet Med, US Dept Hlth & Human Serv, Laurel, MD USA. [Singh, Aparna] NIH, US Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. [Bartholomew, Mary] US FDA, Ctr Vet Med, US Dept Hlth & Human Serv, Rockville, MD 20857 USA. [Fields, Patricia I.] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, US Dept Hlth & Human Serv, Atlanta, GA USA. RP McDermott, PF (reprint author), Ctr Dis Control & Prevent, Ctr Surveillance Epidemiol & Lab Serv, US Dept Hlth & Human Serv, Atlanta, GA USA. EM patrick.mcdermott@fda.hhs.gov FU U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research [223-02-7010] FX The study isolates were collected by American Type Culture Collection (ATCC) through a contract agreement with the U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research (contract 223-02-7010). NR 28 TC 1 Z9 1 U1 2 U2 4 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 APR PY 2016 VL 60 IS 4 BP 2567 EP 2571 DI 10.1128/AAC.02536-15 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DM6XL UT WOS:000376496100082 PM 26856840 ER PT J AU Marklein, RA Lo Surdo, JL Bellayr, IH Godil, SA Puri, RK Bauer, SR AF Marklein, Ross A. Lo Surdo, Jessica L. Bellayr, Ian H. Godil, Saniya A. Puri, Raj K. Bauer, Steven R. TI High Content Imaging of Early Morphological Signatures Predicts Long Term Mineralization Capacity of Human Mesenchymal Stem Cells upon Osteogenic Induction SO STEM CELLS LA English DT Article DE High content imaging; Mesenchymal stem cell; Osteogenesis; Automated microscopy; Morphology ID MARROW STROMAL CELLS; IN-VITRO; CULTURE; BONE; DIFFERENTIATION; FATE; MARKERS; SHAPE; PROLIFERATION; MECHANISMS AB Human bone marrow-derived multipotent mesenchymal stromal cells, often referred to as mesenchymal stem cells (MSCs), represent an attractive cell source for many regenerative medicine applications due to their potential for multi-lineage differentiation, immunomodulation, and paracrine factor secretion. A major complication for current MSC-based therapies is the lack of well-defined characterization methods that can robustly predict how they will perform in a particular in vitro or in vivo setting. Significant advances have been made with identifying molecular markers of MSC quality and potency using multivariate genomic and proteomic approaches, and more recently with advanced techniques incorporating high content imaging to assess high-dimensional single cell morphological data. We sought to expand upon current methods of high dimensional morphological analysis by investigating whether short term cell and nuclear morphological profiles of MSCs from multiple donors (at multiple passages) correlated with long term mineralization upon osteogenic induction. Using the combined power of automated high content imaging followed by automated image analysis, we demonstrated that MSC morphology after 3 days was highly correlated with 35 day mineralization and comparable to other methods of MSC osteogenesis assessment (such as alkaline phosphatase activity). We then expanded on this initial morphological characterization and identified morphological features that were highly predictive of mineralization capacities (>90% accuracy) of MSCs from additional donors and different manufacturing techniques using linear discriminant analysis. Together, this work thoroughly demonstrates the predictive power of MSC morphology for mineralization capacity and motivates further studies into MSC morphology as a predictive marker for additional in vitro and in vivo responses. Stem Cells2016;34:935-947 C1 [Marklein, Ross A.; Lo Surdo, Jessica L.; Bellayr, Ian H.; Godil, Saniya A.; Puri, Raj K.; Bauer, Steven R.] US FDA, Cellular & Tissue Therapies Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Bauer, SR (reprint author), US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave Bldg 72 Rm 3208, Silver Spring, MD 20993 USA. EM steven.bauer@fda.hhs.gov FU Food and Drug Administration Modernizing Science grant program; BARDA grant; Medical Countermeasures Initiative; Division of Cell and Gene Therapies FX The authors would like to acknowledge Eva Rudikoff for her assistance in culturing the MSCs and Drs. John Thomas and Cindy Osborn for reviewing the manuscript. This project was supported in part by Dr. Ross Marklein's appointment to the Research Participation Program at CBER administered by the Oak Ridge Institute for Science and Education through US Department of Education and US Food and Drug Administration. This work was also supported in part by the Food and Drug Administration Modernizing Science grant program, a BARDA grant, a grant from the Medical Countermeasures Initiative and research funds from the Division of Cell and Gene Therapies. NR 53 TC 4 Z9 4 U1 3 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD APR PY 2016 VL 34 IS 4 BP 935 EP 947 DI 10.1002/stem.2322 PG 13 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA DK1TR UT WOS:000374697700012 PM 26865267 ER PT J AU Zhang, JH Li, L Tang, SN Zhang, Y Markiewski, M Xing, CG Jiang, C Lu, JX AF Zhang, Jinhui Li, Li Tang, Suni Zhang, Yong Markiewski, Maciej Xing, Chengguo Jiang, Cheng Lu, Junxuan TI Pyranocoumarin Tissue Distribution, Plasma Metabolome and Prostate Transcriptome Impacts of Sub-Chronic Exposure to Korean Angelica Supplement in Mice SO AMERICAN JOURNAL OF CHINESE MEDICINE LA English DT Article DE Angelica gigas Nakai; Decursin; Decursinol Angelate; Decursinol; Tissue Distribution; Plasma Metabolome; Safety Assessment ID DECURSINOL ANGELATE; TRANSGENIC ADENOCARCINOMA; MOUSE PROSTATE; GIGAS NAKAI; CANCER; CARCINOGENESIS; SURVIVAL; RATS; ANTIANDROGEN; ANTICANCER AB Herbal products containing Korean Angelica gigas Nakai (AGN) root extract are marketed as dietary supplements for memory enhancement, pain killing, and female menopausal symptom relief. We have shown the anticancer activities of AGN supplements in mouse models. To facilitate human anticancer translational research, we characterized the tissue distribution of AGN marker pyranocoumarin compounds decursin (D) and decursinol angelate (DA) (similar to 50% in AGN) and their metabolite decursinol (DOH), assessed the safety of sub-chronic AGN dietary exposure in mice, and explored its impact on plasma aqueous metabolites and the prostate transcriptome. The data show that after a gavage dose, plasma contained readily detectable DOH, but little D and DA, mirroring patterns in the liver. Extrahepatic tissues retained greater levels of DA and D than the liver did. For sub-chronic exposures, male mice were provided ad libitum AIN93M-pellet diets with 0.5 and 1% AGN for six weeks. No adverse effects were observed on the plasma biochemistry markers of liver and kidney integrity in spite of their enlargement. Histopathological examinations of the liver, kidney and other visceral organs did not reveal tissue abnormalities. Metabolomic assessment of plasma from mice fed the 1%-AGN diet suggested metabolic shifts of key amino acids especially in the methionine-cysteine cycle, purine cycle, and glycolysis-citrate cycle. Prostate transcriptomic profiling identified gene signature changes in the metabolisms of drugs, lipids and cellular energetics, neuro-muscular features, immunity and inflammation, and tumor suppressor/oncogene balance. The safety profile was corroborated with a daily i.p. injection of AGN extract (100-300 mg/kg) for four weeks, which resulted in much greater systemic pyranocoumarin exposure than the dietary route did. C1 [Zhang, Jinhui; Li, Li] US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Tang, Suni; Zhang, Yong] Texas Tech Univ, Hlth Sci Ctr, Dept Biomed Sci, Sch Pharm, Amarillo, TX USA. [Markiewski, Maciej] Texas Tech Univ, Hlth Sci Ctr, Dept Immunotherapeut & Biotechnol, Sch Pharm, Amarillo, TX USA. [Xing, Chengguo] Univ Minnesota, Coll Pharm, Dept Med Chem, Minneapolis, MN 55455 USA. [Jiang, Cheng; Lu, Junxuan] Penn State Coll Med, Dept Pharmacol, 500 Univ Dr,POB 850 MC R130, Hershey, PA 17033 USA. [Jiang, Cheng; Lu, Junxuan] Penn State Coll Med, Inst Canc, 500 Univ Dr,POB 850 MC R130, Hershey, PA 17033 USA. RP Zhang, JH (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA.; Lu, JX (reprint author), Penn State Coll Med, Dept Pharmacol, 500 Univ Dr,POB 850 MC R130, Hershey, PA 17033 USA.; Lu, JX (reprint author), Penn State Coll Med, Inst Canc, 500 Univ Dr,POB 850 MC R130, Hershey, PA 17033 USA. EM jinhui.zhang@fda.hhs.gov; junxuanlu@hmc.psu.edu FU NIH National Center for Complementary and Integrative Health grant [AT007395]; Texas Tech University Health Sciences Center Preliminary Data Grant FX This work was supported by NIH National Center for Complementary and Integrative Health grant AT007395 (J. L. C. X.), and Texas Tech University Health Sciences Center Preliminary Data Grant (J. Z.). The authors thank Dr. James Trybus, DVM (Texas A&M Veterinary Medical Diagnostic Laboratory Amarillo Laboratory) for evaluation of tissue specimens for histopathology and Wayne Chee, Pharm. D. and Mr. Debasish Basak for technical assistance. NR 38 TC 0 Z9 0 U1 3 U2 3 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA 5 TOH TUCK LINK, SINGAPORE 596224, SINGAPORE SN 0192-415X EI 1793-6853 J9 AM J CHINESE MED JI Am. J. Chin. Med. PD APR PY 2016 VL 44 IS 2 BP 321 EP 353 DI 10.1142/S0192415X16500191 PG 33 WC Integrative & Complementary Medicine; Medicine, General & Internal SC Integrative & Complementary Medicine; General & Internal Medicine GA DJ9OL UT WOS:000374542700007 PM 27080944 ER PT J AU Jones, CM Lurie, PG Compton, WM AF Jones, Christopher M. Lurie, Peter G. Compton, Wilson M. TI Increase in Naloxone Prescriptions Dispensed in US Retail Pharmacies Since 2013 SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article AB Distribution of naloxone, traditionally through community-based naloxone programs, is a component of a comprehensive strategy to address the epidemic of prescription opioid and heroin overdose deaths in the United States. Recently, there has been increased focus on naloxone prescription in the outpatient setting, particularly through retail pharmacies, yet data on this practice are sparse. We found an 1170% increase in naloxone dispensing from US retail pharmacies between the fourth quarter of 2013 and the second quarter of 2015. These findings suggest that prescribing naloxone in the outpatient setting complements traditional community-based naloxone programs. C1 [Jones, Christopher M.] US Dept Hlth & Human Serv, Off Assistant Secretary Planning & Evaluat, Div Sci Policy, 200 Independence Ave SW, Washington, DC 20201 USA. [Lurie, Peter G.] US FDA, Off Publ Hlth Strategy & Anal, Silver Spring, MD USA. [Compton, Wilson M.] NIDA, NIH, Rockville, MD USA. RP Jones, CM (reprint author), US Dept Hlth & Human Serv, Off Assistant Secretary Planning & Evaluat, Div Sci Policy, 200 Independence Ave SW, Washington, DC 20201 USA. EM christopher.m.jones@fda.hhs.gov NR 8 TC 5 Z9 5 U1 1 U2 3 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 APR PY 2016 VL 106 IS 4 BP 689 EP 690 DI 10.2105/AJPH.2016.303062 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DL8SY UT WOS:000375913000036 PM 26890174 ER PT J AU Bowsher, K Civillico, EF Coburn, J Collinger, J Contreras-Vidal, JL Denison, T Donoghue, J French, J Getzoff, N Hochberg, LR Hoffmann, M Judy, J Kleitman, N Knaack, G Krauthamer, V Ludwig, K Moynahan, M Pancrazio, JJ Peckham, PH Pena, C Pinto, V Ryan, T Saha, D Scharen, H Shermer, S Skodacek, K Takmakov, P Tyler, D Vasudevan, S Wachrathit, K Weber, D Welle, CG Ye, M AF Bowsher, K. Civillico, E. F. Coburn, J. Collinger, J. Contreras-Vidal, J. L. Denison, T. Donoghue, J. French, J. Getzoff, N. Hochberg, L. R. Hoffmann, M. Judy, J. Kleitman, N. Knaack, G. Krauthamer, V. Ludwig, K. Moynahan, M. Pancrazio, J. J. Peckham, P. H. Pena, C. Pinto, V. Ryan, T. Saha, D. Scharen, H. Shermer, S. Skodacek, K. Takmakov, P. Tyler, D. Vasudevan, S. Wachrathit, K. Weber, D. Welle, C. G. Ye, M. TI Brain-computer interface devices for patients with paralysis and amputation: a meeting report SO JOURNAL OF NEURAL ENGINEERING LA English DT Article DE brain-computer interface; neuroprosthetic; regulation; translation; medical device ID PRIORITIES AB Objective. The Food and Drug Administration's (FDA) Center for Devices and Radiological Health (CDRH) believes it is important to help stakeholders (e.g., manufacturers, health-care professionals, patients, patient advocates, academia, and other government agencies) navigate the regulatory landscape for medical devices. For innovative devices involving brain-computer interfaces, this is particularly important. Approach. Towards this goal, on 21 November, 2014, CDRH held an open public workshop on its White Oak, MD campus with the aim of fostering an open discussion on the scientific and clinical considerations associated with the development of brain-computer interface (BCI) devices, defined for the purposes of this workshop as neuroprostheses that interface with the central or peripheral nervous system to restore lost motor or sensory capabilities. Main results. This paper summarizes the presentations and discussions from that workshop. Significance. CDRH plans to use this information to develop regulatory considerations that will promote innovation while maintaining appropriate patient protections. FDA plans to build on advances in regulatory science and input provided in this workshop to develop guidance that provides recommendations for premarket submissions for BCI devices. These proceedings will be a resource for the BCI community during the development of medical devices for consumers. C1 [Bowsher, K.; Getzoff, N.; Hoffmann, M.; Pena, C.; Pinto, V.; Saha, D.; Scharen, H.; Shermer, S.; Skodacek, K.; Wachrathit, K.] US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Silver Spring, MD USA. [Civillico, E. F.; Coburn, J.; Knaack, G.; Krauthamer, V.; Takmakov, P.; Vasudevan, S.; Welle, C. G.; Ye, M.] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD USA. [Collinger, J.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Contreras-Vidal, J. L.] Univ Houston, Elect & Comp Engn, Houston, TX USA. [Denison, T.] Medtronic Inc, Minneapolis, MN USA. [Donoghue, J.; Hochberg, L. R.] Brown Univ, Brown Inst Brain Sci, Sch Engn, Providence, RI 02912 USA. [French, J.] Neurotech Network, Tampa, FL 33623 USA. [Hochberg, L. R.] Ctr Neurorestorat & Neurotechnol, Rehabil R&D Serv, Dept Vet Affairs Med Ctr, Providence, RI USA. [Hochberg, L. R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Judy, J.] Univ Florida, Coll Engn, Nanosci Inst Med & Engn Technol, Gainesville, FL 32611 USA. [Kleitman, N.] Craig H Neilsen Fdn, Encino, CA USA. [Ludwig, K.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Ludwig, K.] Mayo Clin, Dept Neurol Surg, Rochester, MN USA. [Moynahan, M.] Case Western Reserve Univ, Inst Funct Restorat, Cleveland, OH 44106 USA. [Pancrazio, J. J.] Univ Texas Dallas, Bioengn, Dallas, TX 75230 USA. [Peckham, P. H.; Tyler, D.] Case Western Reserve Univ, Sch Engn, Cleveland, OH 44106 USA. [Ryan, T.] Adv Arm Dynam, Redono Beach, CA 90277 USA. [Weber, D.] Def Adv Res Projects Agcy, Biol Technol Off, Arlington, VA USA. RP Bowsher, K (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Silver Spring, MD USA. RI Tyler, Dustin/C-7995-2015; OI Tyler, Dustin/0000-0002-2298-8510; Welle, Cristin/0000-0001-8735-0983; Pancrazio, Joseph/0000-0001-8276-3690; Takmakov, Pavel/0000-0001-6591-0257 NR 21 TC 3 Z9 3 U1 4 U2 7 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 APR PY 2016 VL 13 IS 2 AR 023001 DI 10.1088/1741-2560/13/2/023001 PG 13 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA DL5NM UT WOS:000375683800004 PM 26924826 ER PT J AU Cogan, SF Ludwig, KA Welle, CG Takmakov, P AF Cogan, Stuart F. Ludwig, Kip A. Welle, Cristin G. Takmakov, Pavel TI Tissue damage thresholds during therapeutic electrical stimulation SO JOURNAL OF NEURAL ENGINEERING LA English DT Review DE neural stimulation; tissue damage; electrode; microelectrode; charge injection ID DEEP BRAIN-STIMULATION; CHARGE-INJECTION LIMITS; CHRONICALLY IMPLANTED MICROELECTRODES; CURRENT-DENSITY PROFILES; IRIDIUM OXIDE-FILMS; NEURAL STIMULATION; RETINAL PROSTHESIS; COCHLEAR NUCLEUS; IN-VITRO; AUDITORY-NERVE AB Objective. Recent initiatives in bioelectronic modulation of the nervous system by the NIH (SPARC), DARPA (ElectRx, SUBNETS) and the GlaxoSmithKline Bioelectronic Medicines effort are ushering in a new era of therapeutic electrical stimulation. These novel therapies are prompting a re-evaluation of established electrical thresholds for stimulation-induced tissue damage. Approach. In this review, we explore what is known and unknown in published literature regarding tissue damage from electrical stimulation. Main results. For macroelectrodes, the potential for tissue damage is often assessed by comparing the intensity of stimulation, characterized by the charge density and charge per phase of a stimulus pulse, with a damage threshold identified through histological evidence from in vivo experiments as described by the Shannon equation. While the Shannon equation has proved useful in assessing the likely occurrence of tissue damage, the analysis is limited by the experimental parameters of the original studies. Tissue damage is influenced by factors not explicitly incorporated into the Shannon equation, including pulse frequency, duty cycle, current density, and electrode size. Microelectrodes in particular do not follow the charge per phase and charge density co-dependence reflected in the Shannon equation. The relevance of these factors to tissue damage is framed in the context of available reports from modeling and in vivo studies. Significance. It is apparent that emerging applications, especially with microelectrodes, will require clinical charge densities that exceed traditional damage thresholds. Experimental data show that stimulation at higher charge densities can be achieved without causing tissue damage, suggesting that safety parameters for microelectrodes might be distinct from those defined for macroelectrodes. However, these increased charge densities may need to be justified by bench, non-clinical or clinical testing to provide evidence of device safety. C1 [Cogan, Stuart F.] Univ Texas Dallas, Dept Bioengn, Richardson, TX 75083 USA. [Ludwig, Kip A.] Mayo Clin, Dept Neurol Surg, Rochester, MD USA. [Welle, Cristin G.] US FDA, DBP, OSEL, CDRH, Silver Spring, MD USA. [Takmakov, Pavel] US FDA, DBCMS, OSEL, CDRH, Silver Spring, MD USA. RP Cogan, SF (reprint author), Univ Texas Dallas, Dept Bioengn, Richardson, TX 75083 USA. EM stuart.cogan@utdallas.edu; Ludwig.Kip@mayo.edu; cristin.welle@fda.hhs.gov; pavel.takmakov@fda.hhs.gov OI Welle, Cristin/0000-0001-8735-0983; Takmakov, Pavel/0000-0001-6591-0257 NR 103 TC 6 Z9 7 U1 10 U2 15 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 APR PY 2016 VL 13 IS 2 AR 021001 DI 10.1088/1741-2560/13/2/021001 PG 13 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA DL5NM UT WOS:000375683800002 PM 26792176 ER PT J AU Kleinstreuer, NC Sullivan, K Allen, D Edwards, S Mendrick, DL Embry, M Matheson, J Rowlands, JC Munn, S Maull, E Casey, W AF Kleinstreuer, Nicole C. Sullivan, Kristie Allen, David Edwards, Stephen Mendrick, Donna L. Embry, Michelle Matheson, Joanna Rowlands, J. Craig Munn, Sharon Maull, Elizabeth Casey, Warren TI Adverse outcome pathways: From research to regulation scientific workshop report SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE AOP; Workshop; Toxicology; Pathway; Regulatory; Quantitative; Application; Acceptance; Criteria; Computational ID DILUTION MASS-SPECTROMETRY; EARLY FISH DEVELOPMENT; THYROPEROXIDASE INHIBITION; CONCEPTUAL-FRAMEWORK; VASCULAR DEVELOPMENT; TESTING STRATEGY; DECISION-MAKING; IPCS FRAMEWORK; MODE; CONFIDENCE AB An adverse outcome pathway (AOP) helps to organize existing knowledge on chemical mode of action, starting with a molecular initiating event such as receptor binding, continuing through key events, and ending with an adverse outcome such as reproductive impairment. AOPs can help identify knowledge gaps where more research is needed to understand the underlying mechanisms, aid in chemical hazard characterization, and guide the development of new testing approaches that use fewer or no animals. A September 2014 workshop in Bethesda, Maryland considered how the AOP concept could improve regulatory assessments of chemical toxicity. Scientists from 21 countries, representing industry, academia, regulatory agencies, and special interest groups, attended the workshop, titled Adverse Outcome Pathways: From Research to Regulation. Workshop plenary presentations were followed by breakout sessions that considered regulatory acceptance of AOPs and AOP-based tools, criteria for building confidence in an AOP for regulatory use, and requirements to build quantitative AOPs and AOP networks. Discussions during the closing session emphasized a need to increase transparent and inclusive collaboration, especially with disciplines outside of toxicology. Additionally, to increase impact, working groups should be established to systematically prioritize and develop AOPs. Multiple collaborative projects and follow-up activities resulted from the workshop. (C) 2016 Elsevier Inc. All rights reserved. C1 [Kleinstreuer, Nicole C.; Maull, Elizabeth; Casey, Warren] NIEHS, Natl Toxicol Program, Interagency Ctr Evaluat Alternat Toxicol Methods, POB 12233, Res Triangle Pk, NC 27709 USA. [Sullivan, Kristie] Phys Comm Responsible Med, Washington, DC USA. [Allen, David] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Edwards, Stephen] US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Mendrick, Donna L.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Embry, Michelle] ILSI Hlth & Environm Sci Inst, Washington, DC USA. [Matheson, Joanna] US Consumer Prod Safety Commiss, Rockville, MD USA. [Rowlands, J. Craig] Dow Chem Co USA, Midland, MI 48674 USA. [Munn, Sharon] Commiss European Communities, Joint Res Ctr, I-21020 Ispra, Italy. RP Kleinstreuer, NC (reprint author), POB 13501, Res Triangle Pk, NC 27709 USA. EM Nicole.kleinstreuer@nih.gov OI Kleinstreuer, Nicole/0000-0002-7914-3682 FU federal funds from the NIEHS, NIH [HHSN273201400003C, HHSN273201500010C]; NICEATM FX The authors would like to thank all of the workshop presenters and breakout group moderators, Hristo Aladjov for assisting in creation of Fig. 3, George Daston for his contributions to the workshop steering committee discussions, Catherine Sprankle for editorial comments, NICEATM staff Michael Paris, Steven Morefield, Neepa Choksi, and Catherine Sprankle for assistance with organizing and running the workshop, and PCRM staff Arya Birdie and Mallory Huff for their assistance with organizing the workshop. Nicole Kleinstreuer and David Allen were supported by federal funds from the NIEHS, NIH under Contract Numbers HHSN273201400003C and HHSN273201500010C to Integrated Laboratory Systems, Inc., in support of NICEATM. The views represented in this paper are those of the authors solely, and do not represent the official policy of the U.S. EPA, FDA, NIH, or any other federal government organization. NR 45 TC 6 Z9 6 U1 6 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD APR PY 2016 VL 76 BP 39 EP 50 DI 10.1016/j.yrtph.2016.01.007 PG 12 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA DL3DK UT WOS:000375514200005 PM 26774756 ER PT J AU Mishra, AR Zheng, JW Tang, X Goering, PL AF Mishra, Anurag R. Zheng, Jiwen Tang, Xing Goering, Peter L. TI Silver Nanoparticle-Induced Autophagic-Lysosomal Disruption and NLRP3-Inflammasome Activation in HepG2 Cells Is Size-Dependent SO TOXICOLOGICAL SCIENCES LA English DT Article DE silver nanoparticle; nanomaterials; autophagy; inflammasome; apoptosis; caspase-1 ID ZINC-OXIDE NANOPARTICLES; MEMBRANE PERMEABILIZATION; GOLD NANOPARTICLES; NLRP3 INFLAMMASOME; RAT HEPATOCYTES; KIDNEY-CELLS; TOXICITY; IMPREGNATION; DEGRADATION; DYSFUNCTION AB Silver nanoparticles (AgNPs) are incorporated into medical and consumer products to exploit their excellent antimicrobial properties; however, potential mechanisms of toxicity of AgNPs in mammalian cells are not fully understood. The objective of this study was to determine the mechanism of size- and concentration-dependent cytotoxicity of AgNPs in human liver-derived hepatoma (HepG2) cells. Mechanisms of toxicity were explored at subcytotoxic concentrations (a parts per thousand currency sign10 A mu g/ml AgNPs) and autophagy induction, lysosomal activity, inflammasome-dependent caspase-1 activation, and apoptosis were examined. Using enhanced dark-field light microscopy, hyperspectral imaging, electron microscopy, and energy dispersive X-ray spectroscopy, AgNPs were shown to rapidly accumulate in cytoplasmic vesicles for up to 24 h and 10-nm AgNPs exhibited the highest uptake and accumulation. Autophagy and enhanced lysosomal activity were induced at noncytotoxic concentrations (1 A mu g/ml; primary particle size:10 > 50 > 100 nm), whereas increased caspase-3 activity (associated with apoptosis) was observed at cytotoxic concentrations (10, 25, and 50 A mu g/ml). Subcytotoxic concentrations of AgNPs enhanced expression of LC3B, a pro-autophagic protein, and CHOP, an apoptosis inducing ER-stress protein, and activation of NLRP3-inflammasome (caspase-1, IL-1 beta). Disrupting the autophagy-lysosomal pathway through chloroquine or ATG5-siRNA exacerbated AgNPs-induced caspase-1 activation and lactate dehydrogenase release, suggesting that NLRP3-inflammasome plays an important role in AgNPs-induced cytotoxicity. Overall, 10-nm AgNPs showed the highest cellular responses compared with 50- and 100-nm AgNPs based on equal mass dosimetry. The results indicate the potential of vesicle-engulfed 10-nm AgNPs to induce cytotoxicity by a mechanism involving perturbations in the autophagy-lysosomal system and inflammasome activation. C1 [Mishra, Anurag R.; Zheng, Jiwen; Tang, Xing; Goering, Peter L.] US FDA, Div Biol Chem & Mat Sci, Ctr Devices & Radiol Hlth, Silver Spring, MD 20904 USA. RP Goering, PL (reprint author), US FDA, Div Biol Chem & Mat Sci, CDRH, 10903,New Hampshire Ave,Bldg 64,Rm 4064, Silver Spring, MD 20904 USA. EM Peter.Goering@fda.hhs.gov FU U.S. Food and Drug Administration FX This project was supported in part by an appointment (ARM) 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 work was funded by the U.S. Food and Drug Administration. The authors would like to acknowledge the FDA White Oak Nanotechnology Core Facility and the Flow Cytometry Core Facility for instrument use and technical assistance. NR 53 TC 7 Z9 8 U1 20 U2 40 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 APR PY 2016 VL 150 IS 2 BP 473 EP 487 DI 10.1093/toxsci/kfw011 PG 15 WC Toxicology SC Toxicology GA DJ5ET UT WOS:000374230300019 PM 26801583 ER PT J AU Kovalchuk, A Rodriguez-Juarez, R Ilnytskyy, Y Byeon, B Shpyleva, S Melnyk, S Pogribny, I Kolb, B Kovalchuk, O AF Kovalchuk, Anna Rodriguez-Juarez, Rocio Ilnytskyy, Yaroslav Byeon, Boseon Shpyleva, Svitlana Melnyk, Stepan Pogribny, Igor Kolb, Bryan Kovalchuk, Olga TI Sex-specific effects of cytotoxic chemotherapy agents cyclophosphamide and mitomycin C on gene expression, oxidative DNA damage, and epigenetic alterations in the prefrontal cortex and hippocampus - an aging connection SO AGING-US LA English DT Article DE chemotherapy; chemo brain; epigenetics; DNA methylation; DNA hydroxymethylation; oxidative stress; transcriptome; aging ID COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; DRUG ADRIAMYCIN; BREAST-CANCER; REPAIR GENES; METHYLATION; CHEMOBRAIN; BRAIN; 5-HYDROXYMETHYLCYTOSINE; NEURONS AB Recent research shows that chemotherapy agents can be more toxic to healthy brain cells than to the target cancer cells. They cause a range of side effects, including memory loss and cognitive dysfunction that can persist long after the completion of treatment. This condition is known as chemo brain. The molecular and cellular mechanisms of chemo brain remain obscure. Here, we analyzed the effects of two cytotoxic chemotherapy drugs-cyclophosphamide (CPP) and mitomycin C (MMC) - on transcriptomic and epigenetic changes in the murine prefrontal cortex (PFC) and hippocampal regions. We for the first time showed that CPP and MMC treatments led to profound sex-and brain region-specific alterations in gene expression profiles. Gene expression changes were most prominent in the PFC tissues of female mice 3 weeks after MMC treatment, and the gene expression response was much greater for MCC than CPP exposure. MMC exposure resulted in oxidative DNA damage, evidenced by accumulation of 8-oxo-2'-deoxyguanosine (8-oxodG) and a decrease in the level of 8-oxodG repair protein OGG1 in the PFC of female animals 3 weeks after treatment. MMC treatment decreased global DNA methylation and increased DNA hydroxymethylation in the PFC tissues of female mice. The majority of the changes induced by chemotherapy in the PFC tissues of female mice resembled those that occur during the brain's aging processes. Therefore, our study suggests a link between chemotherapy-induced chemo brain and brain aging, and provides an important roadmap for future analysis. C1 [Kovalchuk, Anna; Kolb, Bryan] Univ Lethbridge, Dept Neurosci, Lethbridge, AB T1K 3M4, Canada. [Rodriguez-Juarez, Rocio; Ilnytskyy, Yaroslav; Byeon, Boseon; Kovalchuk, Olga] Univ Lethbridge, Dept Biol Sci, Lethbridge, AB T1K 3M4, Canada. [Shpyleva, Svitlana; Pogribny, Igor] Natl Ctr Toxicol Res, Food & Drug Adm, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Melnyk, Stepan] Univ Arkansas Med Sci, Dept Phys, Little Rock, AR 72202 USA. [Kolb, Bryan; Kovalchuk, Olga] Alberta Epigenet Network, Calgary, AB T2L 2A6, Canada. [Kolb, Bryan] Canadian Inst Adv Res, Toronto, ON M5G 1Z8, Canada. RP Kolb, B (reprint author), Univ Lethbridge, Dept Neurosci, Lethbridge, AB T1K 3M4, Canada.; Kovalchuk, O (reprint author), Univ Lethbridge, Dept Biol Sci, Lethbridge, AB T1K 3M4, Canada.; Kolb, B; Kovalchuk, O (reprint author), Alberta Epigenet Network, Calgary, AB T2L 2A6, Canada.; Kolb, B (reprint author), Canadian Inst Adv Res, Toronto, ON M5G 1Z8, Canada. EM kolb@uleth.ca; olga.kovalchuk@uleth.ca FU Canadian Institutes of Health Research grant; Alberta Cancer Foundation Dr. Cyril Kay Graduate Scholarship; Alberta Innovates-Health Solutions; CIHR-Canada Graduate Scholarships FX The research has been supported by a Canadian Institutes of Health Research grant held by Olga Kovalchuk and Bryan Kolb. Anna Kovalchuk was a recipient of the Alberta Cancer Foundation Dr. Cyril Kay Graduate Scholarship, Alberta Innovates-Health Solutions and the CIHR-Canada Graduate Scholarships. NR 50 TC 0 Z9 0 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD APR PY 2016 VL 8 IS 4 BP 697 EP 711 PG 15 WC Cell Biology SC Cell Biology GA DL2GN UT WOS:000375451700014 PM 27032448 ER PT J AU Zdanov, S Mandapathil, M Abu Eid, R Adamson-Fadeyi, S Wilson, W Qian, JH Carnie, A Tarasova, N Mkrtichyan, M Berzofsky, JA Whiteside, TL Khleif, SN AF Zdanov, Stephanie Mandapathil, Magis Abu Eid, Rasha Adamson-Fadeyi, Saudat Wilson, Willie Qian, Jiahua Carnie, Andrea Tarasova, Nadya Mkrtichyan, Mikayel Berzofsky, Jay A. Whiteside, Theresa L. Khleif, Samir N. TI Mutant KRAS Conversion of Conventional T Cells into Regulatory T Cells SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID K-RAS; SIGNALING PATHWAYS; TUMOR MICROENVIRONMENT; KINASE INHIBITORS; EPITHELIAL-CELLS; TGF-BETA; C-JUN; MELANOMA; CANCER; ACTIVATION AB Constitutive activation of the KRAS oncogene in human malignancies is associated with aggressive tumor growth and poor prognosis. Similar to other oncogenes, KRAS acts in a cell-intrinsic manner to affect tumor growth or survival. However, we describe here a different, cell-extrinsic mechanism through which mutant KRAS contributes to tumor development. Tumor cells carrying mutated KRAS induced highly suppressive T cells, and silencing KRAS reversed this effect. Overexpression of the mutant KRAS(G12V) gene in wild-type KRAS tumor cells led to regulatory T-cell (Treg) induction. We also demonstrate that mutant KRAS induces the secretion of IL10 and transforming growth factor-beta 1 (both required for Treg induction) by tumor cells through the activation of the MEK-ERK-AP1 pathway. Finally, we report that inhibition of KRAS reduces the infiltration of Tregs in KRAS-driven lung tumorigenesis even before tumor formation. This cell-extrinsic mechanism allows tumor cells harboring a mutant KRAS oncogene to escape immune recognition. Thus, an oncogene can promote tumor progression independent of its transforming activity by increasing the number and function of Tregs. This has a significant clinical potential, in which targeting KRAS and its downstream signaling pathways could be used as powerful immune modulators in cancer immunotherapy. (C) 2016 AACR. C1 [Zdanov, Stephanie; Abu Eid, Rasha; Adamson-Fadeyi, Saudat; Qian, Jiahua; Carnie, Andrea; Mkrtichyan, Mikayel; Khleif, Samir N.] NCI, Canc Vaccine Sect, Vaccine Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Mandapathil, Magis; Whiteside, Theresa L.] Univ Pittsburgh, Dept Pathol, IMPCL, Inst Canc, Pittsburgh, PA USA. [Abu Eid, Rasha; Mkrtichyan, Mikayel; Khleif, Samir N.] Augusta Univ, Georgia Regents Univ, Georgia Canc Ctr, 1120 15th St,CN-2101A, Augusta, GA 30912 USA. [Wilson, Willie] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Tarasova, Nadya] Frederick Natl Lab Canc Res, Canc & Inflammat Program, Frederick, MD USA. [Berzofsky, Jay A.] NIH, Mol Immunogenet & Vac Res Sect, Vaccine Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Adamson-Fadeyi, Saudat] Meharry Med Coll, Dept Canc Biol, Nashville, TN 37208 USA. [Mandapathil, Magis] Univ Marburg, Dept Otorhinolaryngol, Marburg, Germany. [Qian, Jiahua] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Mkrtichyan, Mikayel] FivePrime Therapeut, San Francisco, CA USA. RP Khleif, SN (reprint author), Augusta Univ, Georgia Regents Univ, Georgia Canc Ctr, 1120 15th St,CN-2101A, Augusta, GA 30912 USA. EM SKHLEIF@gru.edu FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (S.N. Khleif). NR 50 TC 1 Z9 1 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD APR PY 2016 VL 4 IS 4 BP 354 EP 365 DI 10.1158/2326-6066.CIR-15-0241 PG 12 WC Oncology; Immunology SC Oncology; Immunology GA DL1RP UT WOS:000375410000010 PM 26880715 ER PT J AU Rosenberg, AS Pariser, AR Diamond, B Yao, L Turka, LA Lacana, E Kishnani, PS AF Rosenberg, A. S. Pariser, A. R. Diamond, B. Yao, L. Turka, L. A. Lacana, E. Kishnani, P. S. TI A role for plasma cell targeting agents in immune tolerance induction in autoimmune disease and antibody responses to therapeutic proteins SO CLINICAL IMMUNOLOGY LA English DT Review DE Autoantibodies; Plasma cells; Immune tolerance; Enzyme replacement therapy ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; THROMBOTIC THROMBOCYTOPENIC PURPURA; INFANTILE POMPE DISEASE; MULTIPLE-MYELOMA; PROTEASOME INHIBITORS; NEUTRALIZING ANTIBODIES; GAUCHER-DISEASE; ENZYME THERAPY; FOLLOW-UP; BORTEZOMIB AB Antibody responses to life saving therapeutic protein products, such as enzyme replacement therapies (ERT) in the setting of lysosomal storage diseases, have nullified product efficacy and caused clinical deterioration and death despite treatment with immune-suppressive therapies. Moreover, in some autoimmune diseases, pathology is mediated by a robust antibody response to endogenous proteins such as is the case in pulmonary alveolar proteinosis, mediated by antibodies to Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). In this work, we make the case that in such settings, when the antibody response is high titered, sustained, and refractory to immune suppressive treatments, the antibody response is mediated by long-lived plasma cells which are relatively unperturbed by immune suppressants including rituximab. However, long-lived plasma cells can be targeted by proteasome inhibitors such as bortezomib. Recent reports of successful reversal of antibody responses with bortezomib in the settings of ERT and Thrombotic Thrombocytopenic Purpura (TTP) argue that the safety and efficacy of such plasma cell targeting agents should be evaluated in larger scale clinical trials to delineate the risks and benefits of such therapies in the settings of antibody-mediated adverse effects to therapeutic proteins and autoantibody mediated pathology. Published by Elsevier Inc. C1 [Rosenberg, A. S.; Lacana, E.] US FDA, Off Biotechnol Prod, CDER, Bldg 71-2238,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Pariser, A. R.] US FDA, Off Translat Sci, CDER, Silver Spring, MD 20993 USA. [Yao, L.] US FDA, Off New Drugs, CDER, Silver Spring, MD 20993 USA. [Turka, L. A.] Massachusetts Gen Hosp, East Transplantat Biol Res Ctr, 13th St,Bldg 149-9019, Boston, MA 02129 USA. [Diamond, B.] Feinstein Inst Med Res, Ctr Autoimmune & Musculoskeletal Dis, 350 Community Dr, Manhasset, NY 11030 USA. [Kishnani, P. S.] Duke Univ, Sch Med, 595 Lasalle St,GSRB 14th Floor,Room 4010, Durham, NC 27710 USA. RP Rosenberg, AS (reprint author), US FDA, Off Biotechnol Prod, CDER, Bldg 71-2238,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. NR 45 TC 2 Z9 2 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 EI 1521-7035 J9 CLIN IMMUNOL JI Clin. Immunol. PD APR PY 2016 VL 165 BP 55 EP 59 DI 10.1016/j.clim.2016.02.009 PG 5 WC Immunology SC Immunology GA DK8KU UT WOS:000375176400011 PM 26928739 ER PT J AU Chen, MJ Suzuki, A Thakkar, S Yu, K Hu, CC Tong, WD AF Chen, Minjun Suzuki, Ayako Thakkar, Shraddha Yu, Ke Hu, Chuchu Tong, Weida TI DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans SO DRUG DISCOVERY TODAY LA English DT Review ID PRIMARY HUMAN HEPATOCYTES; ORAL MEDICATIONS; HEPG2 CELLS; HEPATOTOXICITY; MODELS; TOXICITY; PHARMACEUTICALS; LIPOPHILICITY; PERSPECTIVE; STRATEGY C1 [Chen, Minjun; Thakkar, Shraddha; Yu, Ke; Hu, Chuchu; Tong, Weida] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR USA. [Suzuki, Ayako] Univ Arkansas Med Sci, Dept Med, Little Rock, AR 72205 USA. RP Tong, WD (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR USA. EM weida.tong@fda.hhs.gov NR 46 TC 4 Z9 4 U1 5 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 EI 1878-5832 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD APR PY 2016 VL 21 IS 4 BP 648 EP 653 DI 10.1016/j.drudis.2016.02.015 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DK9HP UT WOS:000375241800015 PM 26948801 ER PT J AU Hong, HX Shen, J Ng, HW Sakkiah, S Ye, H Ge, WG Gong, P Xiao, WM Tong, WD AF Hong, Huixiao Shen, Jie Ng, Hui Wen Sakkiah, Sugunadevi Ye, Hao Ge, Weigong Gong, Ping Xiao, Wenming Tong, Weida TI A Rat alpha-Fetoprotein Binding Activity Prediction Model to Facilitate Assessment of the Endocrine Disruption Potential of Environmental Chemicals SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE model; prediction; alpha-fetoprotein; endocrine; disruption; binding; assessment ID ANDROGEN RECEPTOR ANTAGONISTS; HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-1 INTEGRASE INHIBITORS; ESTROGEN-RECEPTOR; STRUCTURE ELUCIDATION; DECISION FOREST; EXPERT-SYSTEM; MOLECULAR DOCKING; CYTOCHROME-P450 CYP3A4; 4-POINT PHARMACOPHORE AB Endocrine disruptors such as polychlorinated biphenyls (PCBs), diethylstilbestrol (DES) and dichlorodiphenyltrichloroethane (DDT) are agents that interfere with the endocrine system and cause adverse health effects. Huge public health concern about endocrine disruptors has arisen. One of the mechanisms of endocrine disruption is through binding of endocrine disruptors with the hormone receptors in the target cells. Entrance of endocrine disruptors into target cells is the precondition of endocrine disruption. The binding capability of a chemical with proteins in the blood affects its entrance into the target cells and, thus, is very informative for the assessment of potential endocrine disruption of chemicals. alpha-fetoprotein is one of the major serum proteins that binds to a variety of chemicals such as estrogens. To better facilitate assessment of endocrine disruption of environmental chemicals, we developed a model for -fetoprotein binding activity prediction using the novel pattern recognition method (Decision Forest) and the molecular descriptors calculated from two-dimensional structures by Mold(2) software. The predictive capability of the model has been evaluated through internal validation using 125 training chemicals (average balanced accuracy of 69%) and external validations using 22 chemicals (balanced accuracy of 71%). Prediction confidence analysis revealed the model performed much better at high prediction confidence. Our results indicate that the model is useful (when predictions are in high confidence) in endocrine disruption risk assessment of environmental chemicals though improvement by increasing number of training chemicals is needed. C1 [Hong, Huixiao; Shen, Jie; Ng, Hui Wen; Sakkiah, Sugunadevi; Ye, Hao; Ge, Weigong; Xiao, Wenming; Tong, Weida] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Gong, Ping] US Army, Engineer Res & Dev Ctr, Environm Lab, 3909 Halls Ferry Rd, Vicksburg, MS 39180 USA. RP Hong, HX (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. EM Huixiao.Hong@fda.hhs.gov; jieeshen@gmail.com; Huiwen.Ng@fda.hhs.gov; Suguna.Sakkiah@fda.hhs.gov; haoye.ecust@gmail.com; weigong.ge@fda.hhs.gov; Ping.Gong@usace.army.mil; Wenming.Xiao@fda.hhs.gov; Weida.Tong@fda.hhs.gov OI Sakkiah, Suguna Devi/0000-0002-8337-9348 NR 81 TC 2 Z9 2 U1 5 U2 11 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD APR PY 2016 VL 13 IS 4 AR 372 DI 10.3390/ijerph13040372 PG 18 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DK9DR UT WOS:000375231300020 PM 27023588 ER PT J AU Ye, H Ng, HW Sakkiah, S Ge, WG Perkins, R Tong, WD Hong, HX AF Ye, Hao Ng, Hui Wen Sakkiah, Sugunadevi Ge, Weigong Perkins, Roger Tong, Weida Hong, Huixiao TI Pathway Analysis Revealed Potential Diverse Health Impacts of Flavonoids that Bind Estrogen Receptors SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE estrogen receptor; flavonoids; target; gene; pathway analysis ID AMYOTROPHIC-LATERAL-SCLEROSIS; HUMAN-LEUKOCYTE ANTIGENS; BREAST-CANCER CELLS; CARDIOVASCULAR-DISEASE; MOLECULAR DOCKING; ALPHA-FETOPROTEIN; ABC TRANSPORTERS; IN-VITRO; RISK; HORMONE AB Flavonoids are frequently used as dietary supplements in the absence of research evidence regarding health benefits or toxicity. Furthermore, ingested doses could far exceed those received from diet in the course of normal living. Some flavonoids exhibit binding to estrogen receptors (ERs) with consequential vigilance by regulatory authorities at the U.S. EPA and FDA. Regulatory authorities must consider both beneficial claims and potential adverse effects, warranting the increases in research that has spanned almost two decades. Here, we report pathway enrichment of 14 targets from the Comparative Toxicogenomics Database (CTD) and the Herbal Ingredients' Targets (HIT) database for 22 flavonoids that bind ERs. The selected flavonoids are confirmed ER binders from our earlier studies, and were here found in mainly involved in three types of biological processes, ER regulation, estrogen metabolism and synthesis, and apoptosis. Besides cancers, we conjecture that the flavonoids may affect several diseases via apoptosis pathways. Diseases such as amyotrophic lateral sclerosis, viral myocarditis and non-alcoholic fatty liver disease could be implicated. More generally, apoptosis processes may be importantly evolved biological functions of flavonoids that bind ERs and high dose ingestion of those flavonoids could adversely disrupt the cellular apoptosis process. C1 [Ye, Hao; Ng, Hui Wen; Sakkiah, Sugunadevi; Ge, Weigong; Perkins, Roger; Tong, Weida; Hong, Huixiao] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Ye, Hao] WuXi AppTec Co Ltd, Oncol Business Unit, Shanghai 200131, Peoples R China. RP Hong, HX (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. EM haoye.ecust@gmail.com; Huiwen.Ng@fda.hhs.gov; Suguna.Sakkiah@fda.hhs.gov; weigong.ge@fda.hhs.gov; Roger.Perkins@fda.hhs.gov; weida.tong@fda.hhs.gov; Huixiao.Hong@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration FX This research was supported in part by an appointment to the Research Participation Program at the National Center for Toxicological Research (Hao Ye, Hui Wen Ng, Sugunadevi Sakkiah) administered by the Oak Ridge Institute for Science and Education through an inter-agency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 84 TC 0 Z9 0 U1 6 U2 11 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD APR PY 2016 VL 13 IS 4 AR 373 DI 10.3390/ijerph13040373 PG 17 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DK9DR UT WOS:000375231300021 PM 27023590 ER PT J AU Wilkes, JG Stoyanova-Slavova, IB Buzatu, DA AF Wilkes, Jon G. Stoyanova-Slavova, Iva B. Buzatu, Dan A. TI Alignment-independent technique for 3D QSAR analysis SO JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN LA English DT Article DE 3D modeling; Molecular conformation; Spectral data-activity relationship; Quantitative structure-activity relationship ID ANDROGEN RECEPTOR; NEURAL NETWORKS; BINDING; C-13; CHEMICALS AB Molecular biochemistry is controlled by 3D phenomena but structure-activity models based on 3D descriptors are infrequently used for large data sets because of the computational overhead for determining molecular conformations. A diverse dataset of 146 androgen receptor binders was used to investigate how different methods for defining molecular conformations affect the performance of 3D-quantitative spectral data activity relationship models. Molecular conformations tested: (1) global minimum of molecules' potential energy surface; (2) alignment-to-templates using equal electronic and steric force field contributions; (3) alignment using contributions "Best-for-Each" template; (4) non-energy optimized, non-aligned (2D > 3D). Aggregate predictions from models were compared. Highest average coefficients of determination ranged from R (Test) (2) = 0.56 to 0.61. The best model using 2D > 3D (imported directly from ChemSpider) produced R (Test) (2) = 0.61. It was superior to energy-minimized and conformation-aligned models and was achieved in only 3-7 % of the time required using the other conformation strategies. Predictions averaged from models built on different conformations achieved a consensus R (Test) (2) = 0.65. The best 2D > 3D model was analyzed for underlying structure-activity relationships. For the compound strongest binding to the androgen receptor, 10 substructural features contributing to binding were flagged. Utility of 2D > 3D was compared for two other activity endpoints, each modeling a medium sized data set. Results suggested that large scale, accurate predictions using 2D > 3D SDAR descriptors may be produced for interactions involving endocrine system nuclear receptors and other data sets in which strongest activities are produced by fairly inflexible substrates. C1 [Wilkes, Jon G.; Stoyanova-Slavova, Iva B.; Buzatu, Dan A.] Natl Ctr Toxicol Res, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Wilkes, JG (reprint author), Natl Ctr Toxicol Res, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM jon.wilkes@fda.hhs.gov; Iva.Stoyanova-Slavova@fda.hhs.gov; Dan.Buzatu@fda.hhs.gov NR 33 TC 0 Z9 0 U1 2 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-654X EI 1573-4951 J9 J COMPUT AID MOL DES JI J. Comput.-Aided Mol. Des. PD APR PY 2016 VL 30 IS 4 BP 331 EP 345 DI 10.1007/s10822-016-9909-0 PG 15 WC Biochemistry & Molecular Biology; Biophysics; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Computer Science GA DJ7SY UT WOS:000374413900006 PM 27026022 ER PT J AU Myers, MB Banda, M Mckim, KL Wang, YY Powell, MJ Parsons, BL AF Myers, Meagan B. Banda, Malathi Mckim, Karen L. Wang, Yiying Powell, Michael J. Parsons, Barbara L. TI Examined by High-Sensitivity Quantification of PIK3CA, KRAS, HRAS, and BRAF Mutations in Normal Breast and Ductal Carcinomas SO NEOPLASIA LA English DT Article ID COLORECTAL-CANCER; TUMOR; HETEROGENEITY; CELL; CARCINOGENESIS; RESISTANCE; THERAPY; TARGETS; KINASE AB Mutant cancer subpopulations have the potential to derail durable patient responses to molecularly targeted cancer therapeutics, yet the prevalence and size of such subpopulations are largely unexplored. We employed the sensitive and quantitative Allele-specific Competitive Blocker PCR approach to characterize mutant cancer subpopulations in ductal carcinomas (DCs), examining five specific hotspot point mutations (PIK3CA H1047R, KRAS G12D, KRAS G12V, HRAS G12D, and BRAF V600E). As an approach to aid interpretation of the DC results, the mutations were also quantified in normal breast tissue. Overall, the mutations were prevalent in normal breast and DCs, with 9/9 DCs having measureable levels of at least three of the five mutations. HRAS G12D was significantly increased in DCs as compared to normal breast. The most frequent point mutation reported in DC by DNA sequencing, PIK3CA H1047R, was detected in all normal breast tissue and DC samples and was present at remarkably high levels (mutant fractions of 1.1 x 10(-3) to 4.6 x 10(-2)) in 4/10 normal breast samples. In normal breast tissue samples, PIK3CA mutation levels were positively correlated with age. However, the PIK3CA H1047R mutant fraction distributions for normal breast tissues and DCs were similar. The results suggest PIK3CA H1047R mutant cells have a selective advantage in breast, contribute to breast cancer susceptibility, and drive tumor progression during breast carcinogenesis, even when present as only a subpopulation of tumor cells. C1 [Myers, Meagan B.; Banda, Malathi; Mckim, Karen L.; Wang, Yiying; Parsons, Barbara L.] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, HFT-120,3900 NCTR Rd, Jefferson, AR 72079 USA. [Powell, Michael J.] DiaCarta Inc, JOINN Innovat Pk,2600 Hilltop Dr, Richmond, CA 94806 USA. [Wang, Yiying] 102 Kanis Creek Lane, Little Rock, AR 72223 USA. RP Parsons, BL (reprint author), US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, HFT-120,3900 NCTR Rd, Jefferson, AR 72079 USA. EM barbara.parsons@fda.hhs.gov FU National Cancer Institute; National Center for Toxicological Research; U.S. Food and Drug Administration FX The authors thank Dr. Igor Pogribny, Dr. Vasily Dobrovolsky, and Dr. Robert H. Heflich for their helpful review of the manuscript and thank Melanie Raymundo and Larry Pastor for their assistance with the QClamp analysis. Tissue samples were provided by the Cooperative Human Tissue Network which is funded by the National Cancer Institute. Other investigators may have received specimens from the same subjects. This study was supported by the National Center for Toxicological Research and the U.S. Food and Drug Administration. The information in these materials is not a formal dissemination of information by FDA and does not represent agency position or policy. NR 41 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1476-5586 J9 NEOPLASIA JI Neoplasia PD APR PY 2016 VL 18 IS 4 BP 253 EP 263 DI 10.1016/j.neo.2016.03.002 PG 11 WC Oncology SC Oncology GA DK8ET UT WOS:000375160700006 PM 27108388 ER PT J AU Burt, T Yoshida, K Lappin, G Vuong, L John, C de Wildt, SN Sugiyama, Y Rowland, M AF Burt, T. Yoshida, K. Lappin, G. Vuong, L. John, C. de Wildt, S. N. Sugiyama, Y. Rowland, M. TI Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; ACCELERATOR MASS-SPECTROMETRY; PROOF-OF-CONCEPT; HEALTHY-SUBJECTS; PEDIATRIC MICRODOSE; DNA-ADDUCTS; PHARMACOKINETICS; CANCER; PET; TRANSPORTERS C1 [Burt, T.] Burt Consultancy, Durham, NC 27705 USA. [Yoshida, K.; John, C.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Yoshida, K.] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. [Lappin, G.] Lincoln Univ, Sch Pharm, Joseph Banks Labs, Pharmacol, Lincoln LN6 7DL, England. [Vuong, L.] LTV Consulting, Davis, CA USA. [Vuong, L.] BioCore, Seoul, South Korea. [de Wildt, S. N.] Erasmus MC Sophia Childrens Hosp, Intens Care & Pediat Surg, Rotterdam, Netherlands. [Sugiyama, Y.] RIKEN, Innovat Ctr, Sugiyama Lab, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan. [Rowland, M.] Univ Manchester, Ctr Appl Pharmacokinet Res, Manchester M13 9PT, Lancs, England. [Rowland, M.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. RP Burt, T (reprint author), Burt Consultancy, Durham, NC 27705 USA. EM tal.burt@duke.edu RI de Wildt, Saskia/A-9589-2008 OI de Wildt, Saskia/0000-0002-0502-0647 FU Netherlands Organisation for Health Research and Development [13202007] FX K.Y. was supported in part by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA. S.N.W. microdosing research is supported by a grant from the The Netherlands Organisation for Health Research and Development (project number 13202007). NR 93 TC 2 Z9 2 U1 7 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-8054 EI 1752-8062 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD APR PY 2016 VL 9 IS 2 BP 74 EP 88 DI 10.1111/cts.12390 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DJ6NU UT WOS:000374331000002 PM 26918865 ER PT J AU Ye, H Luo, H Ng, HW Meehan, J Ge, WG Tong, WD Hong, HX AF Ye, Hao Luo, Heng Ng, Hui Wen Meehan, Joe Ge, Weigong Tong, Weida Hong, Huixiao TI Applying network analysis and Nebula (neighbor-edges based and unbiased leverage algorithm) to ToxCast data SO ENVIRONMENT INTERNATIONAL LA English DT Article DE ToxCast; Environmental toxicity; Network algorithm; Nebula ID MACHINE LEARNING-METHODS; STRUCTURE ELUCIDATION; EXPERT-SYSTEM; SUBSTRUCTURE CONSTRAINTS; ENVIRONMENTAL CHEMICALS; DEVELOPMENTAL TOXICITY; FUNCTIONAL MODULES; PREDICTIVE MODELS; SPECTRA; ESSESA AB Background: ToxCast data have been used to develop models for predicting in vivo toxicity. To predict the in vivo toxicity of a new chemical using a ToxCast data based model, its ToxCast bioactivity data are needed but not normally available. The capability of predicting ToxCast bioactivity data is necessary to fully utilize ToxCast data in the risk assessment of chemicals. Objectives: We aimed to understand and elucidate the relationships between the chemicals and bioactivity data of the assays in ToxCast and to develop a network analysis based method for predicting ToxCast bioactivity data. Methods: We conducted modularity analysis on a quantitative network constructed from ToxCast data to explore the relationships between the assays and chemicals. We further developed Nebula (neighbor-edges based and unbiased leverage algorithm) for predicting ToxCast bioactivity data. Results: Modularity analysis on the network constructed from ToxCast data yielded seven modules. Assays and chemicals in the seven modules were distinct Leave-one-out cross-validation yielded a Q(2) of 0.5416, indicating ToxCast bioactivity data can be predicted by Nebula. Prediction domain analysis showed some types of ToxCast assay data could be more reliably predicted by Nebula than others. Conclusions: Network analysis is a promising approach to understand ToxCast data. Nebula is an effective algorithm for predicting ToxCast bioactivity data, helping fully utilize ToxCast data in the risk assessment of chemicals. Published by Elsevier Ltd. C1 [Ye, Hao; Luo, Heng; Ng, Hui Wen; Meehan, Joe; Ge, Weigong; Tong, Weida; Hong, Huixiao] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Hong, HX (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM huixiao.hong@fda.hhs.gov RI Luo, Heng/D-3616-2016 OI Luo, Heng/0000-0001-5192-8878 NR 45 TC 1 Z9 1 U1 4 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0160-4120 EI 1873-6750 J9 ENVIRON INT JI Environ. Int. PD APR-MAY PY 2016 VL 89-90 BP 81 EP 92 DI 10.1016/j.envint.2016.01.010 PG 12 WC Environmental Sciences SC Environmental Sciences & Ecology GA DK0LI UT WOS:000374603900010 PM 26826365 ER PT J AU Tesfamariam, B AF Tesfamariam, Belay TI Endothelial Repair and Regeneration Following Intimal Injury SO JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH LA English DT Review DE Endothelial injury/dysfunction; Endothelial regeneration; Endothelial progenitor cells; Stent; Biomarkers ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; DRUG-ELUTING STENTS; PERCUTANEOUS CORONARY INTERVENTION; POTENTIAL PROTHROMBOTIC MECHANISM; DINUCLEOTIDE PHOSPHATE OXIDASE; ANCA-ASSOCIATED VASCULITIS; PROGENITOR CELLS; RE-ENDOTHELIALIZATION; CARDIOVASCULAR DISORDERS; ARTERIAL THROMBOSIS AB Coronary artery intervention using device implants significantly reduce the risk of restenosis and the need for revascularization but are associated with endothelial denudation and impaired function. This may be due to incomplete endothelial recovery as a result of intimal injury, presence of polymer and/or high antiproliferative drug accumulation in the intima. The permanent presence of a metal prosthesis or polymer may impair the proliferation of resident endothelial cells to cover empty areas. Attention has focused on the robust replenishment of endothelial monolayer by recruitment of circulating endothelial progenitor cells derived from the bone marrow to areas of endothelial injury. The balance between endothelial damage and repair is critical for the maintenance of intimal integrity, function, and prevention of thrombotic complications. This review will discuss on the aftereffects of intravascular device implants on endothelial injury and the pathways involved in endothelial repair and regeneration with an emphasis on endothelial progenitor cells. C1 [Tesfamariam, Belay] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 22,Rm 4176, Silver Spring, MD 20993 USA. RP Tesfamariam, B (reprint author), US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 22,Rm 4176, Silver Spring, MD 20993 USA. EM belay.tesfamariam@fda.hhs.gov NR 67 TC 0 Z9 0 U1 4 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1937-5387 EI 1937-5395 J9 J CARDIOVASC TRANSL JI J. Cardiovasc. Transl. Res. PD APR PY 2016 VL 9 IS 2 BP 91 EP 101 DI 10.1007/s12265-016-9677-1 PG 11 WC Cardiac & Cardiovascular Systems; Medicine, Research & Experimental SC Cardiovascular System & Cardiology; Research & Experimental Medicine GA DJ6CN UT WOS:000374297700001 PM 26797874 ER PT J AU Bonate, PL Ahamadi, M Budha, N de la Pena, A Earp, JC Hong, Y Karlsson, MO Ravva, P Ruiz-Garcia, A Struemper, H Wade, JR AF Bonate, Peter L. Ahamadi, Malidi Budha, Nageshwar de la Pena, Amparo Earp, Justin C. Hong, Ying Karlsson, Mats O. Ravva, Patanjali Ruiz-Garcia, Ana Struemper, Herbert Wade, Janet R. TI Methods and strategies for assessing uncontrolled drug-drug interactions in population pharmacokinetic analyses: results from the International Society of Pharmacometrics (ISOP) Working Group SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Editorial Material DE Population pharmacokinetics; Covariate modeling; Drug interactions; Concomitant; Medications ID MODEL; PARAMETERS; TOLCAPONE; IMATINIB; DESIGN AB The purpose of this work was to present a consolidated set of guidelines for the analysis of uncontrolled concomitant medications (ConMed) as a covariate and potential perpetrator in population pharmacokinetic (PopPK) analyses. This white paper is the result of an industry-academia-regulatory collaboration. It is the recommendation of the working group that greater focus be given to the analysis of uncontrolled ConMeds as part of a PopPK analysis of Phase 2/3 data to ensure that the resulting outcome in the PopPK analysis can be viewed as reliable. Other recommendations include: (1) collection of start and stop date and clock time, as well as dose and frequency, in Case Report Forms regarding ConMed administration schedule; (2) prespecification of goals and the methods of analysis, (3) consideration of alternate models, other than the binary covariate model, that might more fully characterize the interaction between perpetrator and victim drug, (4) analysts should consider whether the sample size, not the percent of subjects taking a ConMed, is sufficient to detect a ConMed effect if one is present and to consider the correlation with other covariates when the analysis is conducted, (5) grouping of ConMeds should be based on mechanism (e.g., PGP-inhibitor) and not drug class (e.g., beta-blocker), and (6) when reporting the results in a publication, all details related to the ConMed analysis should be presented allowing the reader to understand the methods and be able to appropriately interpret the results. C1 [Bonate, Peter L.] Astellas, 1 Astellas Way, Northbrook, IL 60062 USA. [Ahamadi, Malidi] Merck & Co Inc, 351 N Sumneytown Pike, N Wales, PA 19454 USA. [Budha, Nageshwar] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA. [de la Pena, Amparo] Eli Lilly & Co Chorus, Lilly Corp Ctr, Indianapolis, IN 46285 USA. [Earp, Justin C.] US FDA, 10903 New Hampshire Ave,Bldg 51,Room 3154, Silver Spring, MD 20993 USA. [Hong, Ying] Novartis Pharmaceut, One Hlth Plaza, E Hanover, NJ 07936 USA. [Karlsson, Mats O.] Uppsala Univ, Box 591, S-75124 Uppsala, Sweden. [Ravva, Patanjali] Boehringer Ingelheim Pharmaceut Inc, 900 Ridgebury Rd, Ridgefield, CT 06877 USA. [Ruiz-Garcia, Ana] Pfizer, 10646 Sci Ctr Dr CB10 Off 2448, San Diego, CA 92121 USA. [Struemper, Herbert] Parexel Int Inc, 2520 Meridian Pkwy, Durham, NC 27713 USA. [Wade, Janet R.] Occams Cooperatie UA, Malandolaan 10, NL-1187 HE Amstelveen, Netherlands. RP Bonate, PL (reprint author), Astellas, 1 Astellas Way, Northbrook, IL 60062 USA.; Earp, JC (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 51,Room 3154, Silver Spring, MD 20993 USA. EM peter.bonate@astellas.com; malidi.ahamadi@merck.com; budha.nageshwar@gene.com; de_la_pena_amparo@lilly.com; justin.earp@fda.hhs.gov; ying.hong@novartis.com; mats.karlsson@farmbio.uu.se; patanjali.ravva@boehringer-ingelheim.com; ana.ruiz@pfizer.com; herbert.struemper@parexel.com; janet.wade@occams.eu OI Wade, Janet/0000-0002-8360-3514; Ruiz-Garcia, Ana/0000-0002-5462-3110 NR 48 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD APR PY 2016 VL 43 IS 2 BP 123 EP 135 DI 10.1007/s10928-016-9464-2 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DK1VW UT WOS:000374704100001 PM 26837775 ER PT J AU Azarbaijani, Y O'Callaghan, K Sanders, W Wu, CF Laschinger, J Dabic, DM Ronk, C Strauss, D Canos, D Zusterzeel, R AF Azarbaijani, Yasameen O'Callaghan, Kathryn Sanders, William Wu, Changfu Laschinger, John Dabic, Danica Marinac Ronk, Christopher Strauss, David Canos, Daniel Zusterzeel, Robbert TI Sex-Differences in Outcomes After Transcatheter Aortic Valve Replacement: A Systematic Literature Review SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Azarbaijani, Yasameen; O'Callaghan, Kathryn; Sanders, William; Wu, Changfu; Laschinger, John; Dabic, Danica Marinac; Ronk, Christopher; Strauss, David; Canos, Daniel; Zusterzeel, Robbert] FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD APR PY 2016 VL 25 IS 4 MA 10 BP A5 EP A5 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA DK1CA UT WOS:000374648800011 ER PT J AU Fadiran, E Wright, H Elahi, M Igun, A Soon, G Chen, A Pariser, A AF Fadiran, Emmanuel Wright, Hilary Elahi, Merina Igun, Ayomide Soon, Greg Chen, Alice Pariser, Anne TI Demographics of Study Participants in Clinical Trials for Oncology Drugs Approved by FDA CDER from January to November 10, 2015 SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Fadiran, Emmanuel; Wright, Hilary; Elahi, Merina; Igun, Ayomide; Soon, Greg; Chen, Alice; Pariser, Anne] 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 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD APR PY 2016 VL 25 IS 4 MA 29 BP A12 EP A12 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA DK1CA UT WOS:000374648800030 ER PT J AU Zusterzeel, R O'Callaghan, K Sanders, W Canos, D Strauss, D AF Zusterzeel, Robbert O'Callaghan, Kathryn Sanders, William Canos, Daniel Strauss, David TI Cardiac Resynchronization Therapy in Women: Meta-Analysis of Clinical Trials and Post-Market Comparative Effectiveness Studies SO JOURNAL OF WOMENS HEALTH LA English DT Meeting Abstract C1 [Zusterzeel, Robbert; O'Callaghan, Kathryn; Sanders, William; Canos, Daniel; Strauss, David] 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 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD APR PY 2016 VL 25 IS 4 MA 90 BP A35 EP A35 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA DK1CA UT WOS:000374648800091 ER PT J AU Vemula, SV Zhao, JQ Liu, JK Wang, X Biswas, S Hewlett, I AF Vemula, Sai Vikram Zhao, Jiangqin Liu, Jikun Wang, Xue Biswas, Santanu Hewlett, Indira TI Current Approaches for Diagnosis of Influenza Virus Infections in Humans SO VIRUSES-BASEL LA English DT Review DE Influenza diagnostics; Immunoassay; Influenza viruses; hemaglutinin; neuraminidase; subtype; next-generation sequencing (NGS) ID MEDIATED ISOTHERMAL AMPLIFICATION; A H1N1 VIRUS; SEQUENCE-BASED AMPLIFICATION; UNITED-STATES; RAPID DIAGNOSIS; PANDEMIC H1N1; H7N9 VIRUS; SUBTYPE IDENTIFICATION; SEASONAL INFLUENZA; CLINICAL SPECIMENS AB Despite significant advancement in vaccine and virus research, influenza continues to be a major public health concern. Each year in the United States of America, influenza viruses are responsible for seasonal epidemics resulting in over 200,000 hospitalizations and 30,000-50,000 deaths. Accurate and early diagnosis of influenza viral infections are critical for rapid initiation of antiviral therapy to reduce influenza related morbidity and mortality both during seasonal epidemics and pandemics. Several different approaches are currently available for diagnosis of influenza infections in humans. These include viral isolation in cell culture, immunofluorescence assays, nucleic acid amplification tests, immunochromatography-based rapid diagnostic tests, etc. Newer diagnostic approaches are being developed to overcome the limitations associated with some of the conventional detection methods. This review discusses diagnostic approaches currently available for detection of influenza viruses in humans. C1 [Vemula, Sai Vikram; Zhao, Jiangqin; Liu, Jikun; Wang, Xue; Biswas, Santanu; Hewlett, Indira] Food & Drug Adm, Ctr Biol Evaluat & Res, Mol Virol Lab, Silver Spring, MD 20993 USA. RP Hewlett, I (reprint author), Food & Drug Adm, Ctr Biol Evaluat & Res, Mol Virol Lab, Silver Spring, MD 20993 USA. EM vikisai@gmail.com; jiangqin.zhao@fda.hhs.gov; Jikun.Liu@fda.hhs.gov; Xue.Wang@fda.hhs.gov; Santanu.Biswas@fda.hhs.gov; Indira.hewlett@fda.hhs.gov OI Zhao, Jiangqin/0000-0003-4672-0735 NR 72 TC 3 Z9 3 U1 14 U2 19 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD APR PY 2016 VL 8 IS 4 AR 96 DI 10.3390/v8040096 PG 15 WC Virology SC Virology GA DK8DQ UT WOS:000375157800010 PM 27077877 ER PT J AU Ahmed, I Roy, BC Subramaniam, D Ganie, SA Kwatra, D Dixon, D Anant, S Zargar, MA Umar, S AF Ahmed, Ishfaq Roy, Badal C. Subramaniam, Dharmalingam Ganie, Showkat Ahmad Kwatra, Deep Dixon, Dan Anant, Shrikant Zargar, Mohammad Afzal Umar, Shahid TI An ornamental plant targets epigenetic signaling to block cancer stem cell-driven colon carcinogenesis SO CARCINOGENESIS LA English DT Article ID WNT/BETA-CATENIN PATHWAY; COLORECTAL-CANCER; BACTERIAL-INFECTION; SELF-RENEWAL; IN-VITRO; NOTCH; APOPTOSIS; RESVERATROL; EXPRESSION; EXTRACT AB Alcea rosea (AR) seed extracts blocked colon cancer cell proliferation, promoted apoptosis, inhibited EZH2 and Notch and Wnt/beta-catenin signaling thereby impeding the growth of tumor xenografts reiterating the notion that plant-derived substances offer an effective preventative/therapeutic strategy to target CRC.Phytochemicals modulate key cellular signaling pathways and have proven anticancer effects. Alcea rosea (AR; Hollyhock) is an ornamental plant with known anti-inflammatory properties. This study explored its role as an anticancer agent. The AR seed extract (AR extract) inhibited proliferation and colony formation in a dose- and time-dependent manner and promoted apoptosis as was evidenced by cleavage of PARP and increased expression of Bax accompanying reduced levels of BCL-xl protein in HCT116 and SW480 cells, respectively. In addition, AR extract-arrested cells at Go/G1 phase of cell cycle and exhibited decreases in Cyclin D1. AR extract-treated cells exhibited reduced number and size of colonospheres in a dose-dependent manner concomitant with decreases in cancer stem cell (CSC) markers ALDH1A1 and Dclk1. Relative levels of beta-catenin, Notch-ICD, Hes1 and EZH2 were also attenuated by AR extract. TOP-flash reporter activity, a measure of Wnt signaling, decreased significantly in response to treatment while overexpression of wild type but not mutant EZH2, reversed the inhibitory effects. Moreover, WIF1 (a Wnt antagonist) promoter activity increased dramatically following treatment with AR extract which phenocopied increases in WIF1 reporter activity following EZH2 knockdown. In vivo, AR extract attenuated tumor growth due probably to reduced levels of EZH2, beta-catenin, CyclinD1 and Ki-67 along with reduced levels of CSC markers. Since partial purification via HPLC yielded a prominent peak, efforts are underway to identify the active ingredient(s). Taken together, the results clearly suggest that AR extract/active component(s) can be an effective preventative/therapeutic agent to target colon cancer. C1 [Ahmed, Ishfaq; Roy, Badal C.; Subramaniam, Dharmalingam; Anant, Shrikant; Umar, Shahid] Univ Kansas, Med Ctr, Dept Mol & Integrat Physiol, Kansas City, KS 66160 USA. [Ganie, Showkat Ahmad; Zargar, Mohammad Afzal] Univ Kashmir, Dept Biochem, Srinagar 190006, Jammu & Kashmir, India. [Kwatra, Deep] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Dixon, Dan] Univ Kansas, Med Ctr, Dept Canc Biol, Kansas City, KS 66160 USA. [Anant, Shrikant; Umar, Shahid] Univ Kansas, Ctr Canc, Kansas City, KS 66160 USA. RP Umar, S (reprint author), Univ Kansas, Med Ctr, Dept Mol & Integrat Physiol, Kansas City, KS 66160 USA.; Umar, S (reprint author), Univ Kansas, Ctr Canc, Kansas City, KS 66160 USA. EM sumar@kumc.edu FU National Cancer Institute [1R01CA185322-01A1]; University of Kansas Cancer Center; University of Kansas Medical Center FX National Cancer Institute (1R01CA185322-01A1 to S.U.); University of Kansas Cancer Center (Pilot project to S.U.); University of Kansas Medical Center (Start-up funds to SU). NR 49 TC 0 Z9 0 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD APR PY 2016 VL 37 IS 4 BP 385 EP 396 DI 10.1093/carcin/bgw009 PG 12 WC Oncology SC Oncology GA DJ5JZ UT WOS:000374245300005 PM 26785732 ER PT J AU Delvadia, RR Wei, XY Longest, PW Venitz, J Byron, PR AF Delvadia, Renishkumar R. Wei, Xiangyin Longest, P. Worth Venitz, Jurgen Byron, Peter R. TI In Vitro Tests for Aerosol Deposition. IV: Simulating Variations in Human Breath Profiles for Realistic DPI Testing SO JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY LA English DT Article DE airflow resistance; dry powder inhaler; in vitro-in vivo correlations; inhalation profiles; patient training; peak inhalation flow rate; realistic inhaler testing ID DRY POWDER INHALERS; PATH SIP MODEL; INSPIRATORY FLOW; REFERENCE VALUES; ADULTS; SPIROMETRY; DISEASE; AIRWAYS; ASTHMA AB Background: The amount of drug aerosol from an inhaler that can pass through an in vitro model of the mouth and throat (MT) during a realistic breath or inhalation flow rate vs. time profile (IP) is designated the total lung dose in vitro, or TLDin vitro. This article describes a clinical study that enabled us to recommend a general method of selecting IPs for use with powder inhalers of known airflow resistance (R) provided subjects followed written instructions either alone or in combination with formal training. Methods: In a drug-free clinical trial, inhaler-naive, nonsmoking healthy adult human volunteers were screened for normal pulmonary function. IPs were collected from each volunteer inhaling through different air flow resistances after different levels of training. IPs were analyzed to determine the distribution of inhalation variables across the population and their dependence on training and airflow resistance. Results: Equations for IP simulation are presented that describe the data including confidence limits at each resistance and training condition. Realistic IPs at upper (90%), median (50%), and lower (10%) confidence limits were functions of R and training. Peak inspiratory flow rates (PIFR) were inversely proportional to R so that if R was assigned, values for PIFR could be calculated. The time of PIFR, T-PIFR, and the total inhaled volume (V) were unrelated to R, but dependent on training. Once R was assigned for a powder inhaler to be tested, a range of simulated IPs could be generated for the different training scenarios. Values for flow rate acceleration and depth of inspiration could also be varied within the population limits of T-PIFR and V. Conclusions: The use of simulated IPs, in concert with realistic in vitro testing, should improve the DPI design process and the confidence with which clinical testing may be initiated for a chosen device. C1 [Delvadia, Renishkumar R.] US FDA, Rockville, MD 20857 USA. [Wei, Xiangyin; Venitz, Jurgen; Byron, Peter R.] Virginia Commonwealth Univ, Sch Pharm, Med Coll Virginia Campus, Richmond, VA 23298 USA. [Longest, P. Worth] Virginia Commonwealth Univ, Sch Engn, Med Coll Virginia Campus, Richmond, VA 23298 USA. RP Byron, PR (reprint author), Virginia Commonwealth Univ, Sch Pharm, Dept Pharmaceut, 410N 12th St,POB 980533, Richmond, VA 23298 USA. EM prbyron@vcu.edu FU Medical College of Virginia Foundation; VCU's Center for Clinical and Translational Research Grant [UL1TR000058]; VCU School of Pharmacy; FDA [1U01FD004570] FX The authors are grateful to Ingmar Medical in Pennsylvania for upgrading and loaning the ASL 5000-XL Breath Simulator and software (needed to simulate large inhaled volumes). The Medical College of Virginia Foundation and VCU's Center for Clinical and Translational Research Grant #UL1TR000058 supported the clinical trial.; RRD and XW acknowledge the support of VCU School of Pharmacy for support as graduate teaching assistants. Data analysis and manuscript preparation were supported in part by FDA grant 1U01FD004570. NR 25 TC 1 Z9 1 U1 0 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1941-2711 EI 1941-2703 J9 J AEROSOL MED PULM D JI J. Aerosol Med. Pulm. Drug Deliv. PD APR 1 PY 2016 VL 29 IS 2 BP 196 EP 206 DI 10.1089/jamp.2015.1215 PG 11 WC Respiratory System SC Respiratory System GA DJ0VP UT WOS:000373922800009 PM 26447531 ER PT J AU Zhuang, LN He, Y Xia, HM Liu, YJ Sy, SKB Derendorf, H AF Zhuang, Luning He, Yang Xia, Huiming Liu, Yajun Sy, Sherwin K. B. Derendorf, Hartmut TI Gentamicin dosing strategy in patients with end-stage renal disease receiving haemodialysis: evaluation using a semi-mechanistic pharmacokinetic/pharmacodynamic model SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; IN-VITRO ACTIVITY; PSEUDOMONAS-AERUGINOSA; POPULATION PHARMACOKINETICS; AMINOGLYCOSIDES; PHARMACODYNAMICS; OPTIMIZATION; ANTIBIOTICS; DIALYSIS; INFANTS AB Gentamicin is widely used in end-stage renal disease (ESRD) patients for the treatment of infections. The goal of this study was to find the most reasonable dosing regimen for gentamicin in ESRD patients receiving haemodialysis. The in vitro antimicrobial activity of gentamicin was evaluated by static and dynamic time-kill experiments against three bacterial strains of MSSA, MRSA and Pseudomonas aeruginosa. A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was established afterwards, allowing the characterization of the antibacterial effect of gentamicin in the human body. The model was utilized to assess dosing regimens of gentamicin in ESRD patients receiving haemodialysis, taking both efficacy and safety into account. The PK/PD model was capable of describing the bacterial response to gentamicin exposure in all three strains. Simulation based on the PK/PD model showed that pre-dialysis and post-dialysis dosing would bring comparable benefit to the ESRD patient regardless of whether the PK/PD target (fC(max)/MIC > 8-fold) was achieved, while the post-dialysis dosing resulted in a significantly lower trough concentration. The result of simulated dose fractionation demonstrated that both fC(max)/MIC and fAUC(0-24)/MIC are strong predictors of drug effectiveness, but the PK/PD model would provide a more precise prediction of antibacterial activity as well as valuable information on dose selection in ESRD patients receiving haemodialysis. Our study supports the original FDA label with regard to the dosing regimen of gentamicin in ESRD patients, which offers adequate clinical benefit as well as an acceptable safety profile. C1 [Zhuang, Luning; Sy, Sherwin K. B.; Derendorf, Hartmut] Univ Florida, Coll Pharm, Dept Pharmaceut, Gainesville, FL 32610 USA. [Zhuang, Luning] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Div Pharmacometr, Silver Spring, MD USA. [He, Yang] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA. [Xia, Huiming] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Div Clin Pharmacol 4, Silver Spring, MD USA. [Liu, Yajun] US FDA, Ctr Drug Evaluat & Res, Off Gener Drugs, Div Bioequivalence 2, Silver Spring, MD USA. [Sy, Sherwin K. B.] Univ Estadual Maringa, Dept Stat, Postgrad Program Biostat, BR-87020 Maringa, Parana, Brazil. RP Derendorf, H (reprint author), 1345 Ctr Dr,Room P3-20,POB 100494, Gainesville, FL 32610 USA. EM hartmut@ufl.edu OI Sy, Sherwin/0000-0001-6405-9130 FU University of Florida FX This study was supported by internal funding from the University of Florida. NR 29 TC 3 Z9 3 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 EI 1460-2091 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD APR PY 2016 VL 71 IS 4 BP 1012 EP 1021 DI 10.1093/jac/dkv428 PG 10 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA DJ5FP UT WOS:000374232500023 PM 26702923 ER PT J AU Fiebelkorn, AP Coleman, LA Belongia, EA Freeman, SK York, D Bi, DL Kulkarni, A Audet, S Mercader, S McGrew, M Hickman, CJ Bellini, WJ Shivakoti, R Griffin, DE Beeler, J AF Fiebelkorn, Amy Parker Coleman, Laura A. Belongia, Edward A. Freeman, Sandra K. York, Daphne Bi, Daoling Kulkarni, Ashwin Audet, Susette Mercader, Sara McGrew, Marcia Hickman, Carole J. Bellini, William J. Shivakoti, Rupak Griffin, Diane E. Beeler, Judith TI Measles Virus Neutralizing Antibody Response, Cell-Mediated Immunity, and Immunoglobulin G Antibody Avidity Before and After Receipt of a Third Dose of Measles, Mumps, and Rubella Vaccine in Young Adults SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE measles; third dose of measles; mumps; rubella (MMR) vaccine; measles vaccine immunogenicity; vaccine-preventable disease; immunization; cell-mediated immunity; measles virus antibody avidity ID RHESUS MACAQUES; FOLLOW-UP; PERSISTENCE; OUTBREAK; IMMUNIZATION; INDIVIDUALS; CHILDREN; ASSAY AB Background. Two doses of measles, mumps, and rubella (MMR) vaccine are 97% effective against measles, but waning antibody immunity to measles and failure of the 2-dose vaccine occur. We administered a third MMR dose (MMR3) to young adults and assessed immunogenicity over 1 year. Methods. Measles virus (MeV) neutralizing antibody concentrations, cell-mediated immunity (CMI), and immunoglobulin G (IgG) antibody avidity were assessed at baseline and 1 month and 1 year after MMR3 receipt. Results. Of 662 subjects at baseline, 1 (0.2%) was seronegative for MeV-neutralizing antibodies (level, < 8 mIU/mL), and 23 (3.5%) had low antibody levels (8-120 mIU/mL). One month after MMR3 receipt, 1 subject (0.2%) was seronegative, and 6 (0.9%) had low neutralizing antibodies, with only 21 of 662 (3.2%) showing a a parts per thousand yen4-fold rise in neutralizing antibodies. One year after MMR3 receipt, no subject was seronegative, and 10 of 617 (1.6%) had low neutralizing antibody levels. CMI analyses showed low levels of spot-forming cells after stimulation, suggesting the presence of T-cell memory, but the response was minimal after MMR3 receipt. MeV IgG avidity did not correlate with findings of neutralization analyses. Conclusions. Most subjects were seropositive before MMR3 receipt, and very few had a secondary immune response after MMR3 receipt. Similarly, CMI and avidity analyses showed minimal qualitative improvements in immune response after MMR3 receipt. We did not find compelling data to support a routine third dose of MMR vaccine. C1 [Fiebelkorn, Amy Parker; Bi, Daoling; Mercader, Sara; McGrew, Marcia; Hickman, Carole J.; Bellini, William J.] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. [Coleman, Laura A.; Belongia, Edward A.; Freeman, Sandra K.; York, Daphne] Marshfield Clin Res Fdn, Marshfield, WI USA. [Kulkarni, Ashwin; Audet, Susette; Beeler, Judith] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Shivakoti, Rupak; Griffin, Diane E.] Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Coleman, Laura A.] Abbott Nutr, Columbus, OH USA. [Shivakoti, Rupak] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. RP Fiebelkorn, AP (reprint author), CDC, NCIRD, 1600 Clifton Rd,MS A-34, Atlanta, GA 30333 USA. EM afiebelkorn@cdc.gov FU CDC FX This work was supported by the CDC (funding to the Marshfield Clinic Research Foundation). NR 31 TC 1 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD APR 1 PY 2016 VL 213 IS 7 BP 1115 EP 1123 DI 10.1093/infdis/jiv555 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DJ4OP UT WOS:000374186300010 PM 26597262 ER PT J AU Stewart, A Yeik, GD Casey, L Swider, MG Heckman, NM Clemens, R AF Stewart, Aura Yeik, Glenn D. Casey, Lewie Swider, Marlene Garcia Heckman, Niedre M. Clemens, Roger TI Scorecard Tool Assists with FSMA Compliance SO FOOD TECHNOLOGY LA English DT Article C1 [Stewart, Aura] Nutripromise LLC, Austin, TX 78733 USA. [Yeik, Glenn D.] Trimedyne Inc, Irvine, CA 92618 USA. [Casey, Lewie] MEIRxRS, Glendale, CA 91203 USA. [Swider, Marlene Garcia] US FDA, Los Angeles Dist Off, Irvine, CA 92612 USA. [Heckman, Niedre M.] Baxalta US Inc, Global Regulatory Affairs, Westlake Village, CA 91362 USA. [Clemens, Roger] Univ So Calif, Sch Pharm, Los Angeles, CA 90089 USA. RP Stewart, A (reprint author), Nutripromise LLC, Austin, TX 78733 USA.; Yeik, GD (reprint author), Trimedyne Inc, Irvine, CA 92618 USA.; Casey, L (reprint author), MEIRxRS, Glendale, CA 91203 USA.; Swider, MG (reprint author), US FDA, Los Angeles Dist Off, Irvine, CA 92612 USA.; Heckman, NM (reprint author), Baxalta US Inc, Global Regulatory Affairs, Westlake Village, CA 91362 USA.; Clemens, R (reprint author), Univ So Calif, Sch Pharm, Los Angeles, CA 90089 USA. EM aura.stewart@outlook.com; gyeik@trimedyne.com; lcasey@meirxrs.com; marlene.swider@fda.hhs.gov; niedre.heckman@baxalta.com; clemens@usc.edu NR 7 TC 0 Z9 0 U1 0 U2 0 PU INST FOOD TECHNOLOGISTS PI CHICAGO PA 525 WEST VAN BUREN, STE 1000, CHICAGO, IL 60607-3814 USA SN 0015-6639 J9 FOOD TECHNOL-CHICAGO JI Food Technol. PD APR PY 2016 VL 70 IS 4 BP 52 EP 55 PG 4 WC Food Science & Technology SC Food Science & Technology GA DJ3DN UT WOS:000374085100013 ER PT J AU Johnson, SA Javurek, AB Painter, MS Ellersieck, MR Welsh, TH Camacho, L Lewis, SM Vanlandingham, MM Ferguson, SA Rosenfeld, CS AF Johnson, Sarah A. Javurek, Angela B. Painter, Michele S. Ellersieck, Mark R. Welsh, Thomas H., Jr. Camacho, Luisa Lewis, Sherry M. Vanlandingham, Michelle M. Ferguson, Sherry A. Rosenfeld, Cheryl S. TI Effects of developmental exposure to bisphenol A on spatial navigational learning and memory in rats: A CLARITY-BPA study SO HORMONES AND BEHAVIOR LA English DT Article DE Endocrine disrupting chemicals; Estrogens; DOHaD; Rodents; Barnes maze; Behavioral testing; Testosterone ID SPRAGUE-DAWLEY RATS; ADULT MALE RATS; MICE PEROMYSCUS-LEUCOPUS; SEXUALLY SELECTED TRAITS; DENDRITIC SPINE DENSITY; WATER-MAZE; MATERNAL-BEHAVIOR; SEX-DIFFERENCES; PERINATAL EXPOSURE; ANDROGEN RECEPTOR AB Bisphenol A (BPA) is a ubiquitous industrial chemical used in the production of a wide variety of items. Previous studies suggest BPA exposure may result in neuro-disruptive effects; however, data are inconsistent across animal and human studies. As part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), we sought to determine whether female and male rats developmentally exposed to BPA demonstrated later spatial navigational learning and memory deficits. Pregnant NCTR Sprague-Dawley rats were orally dosed from gestational day 6 to parturition, and offspring were directly orally dosed until weaning (postnatal day 21). Treatment groups included a vehicle control, three BPA doses (2.5 mu g/kg body weight (bw)/day-[2.5], 25 mu g/kg bw/day-[25), and 2500 mu g/kg bw/day-[2500]) and a 0.5 mu g/kg/day ethinyl estradiol (EE)-reference estrogen dose. At adulthood, 1/sex/litter was tested for seven days in the Barnes maze. The 2500 BPA group sniffed more incorrect holes on day 7 than those in the control, 2.5 BPA, and EE groups. The 2500 BPA females were less likely than control females to locate the escape box in the allotted time (p value = 0.04). Although 2.5 BPA females exhibited a prolonged latency, the effect did not reach significance (p value = 0.06), whereas 2.5 BPA males showed improved latency compared to control males (p value = 0.04), although the significance of this result is uncertain. No differences in serum testosterone concentration were detected in any male or female treatment groups. Current findings suggest developmental exposure of rats to BPA may disrupt aspects of spatial navigational learning and memory. (C) 2015 Elsevier Inc. All rights reserved. C1 [Johnson, Sarah A.; Javurek, Angela B.; Painter, Michele S.; Rosenfeld, Cheryl S.] Univ Missouri, Bond Life Sci Ctr, 440F Bond Life Sci Ctr,1201 E Rollins Rd, Columbia, MO 65211 USA. [Johnson, Sarah A.; Javurek, Angela B.; Painter, Michele S.; Rosenfeld, Cheryl S.] Univ Missouri, Biomed Sci, 440F Bond Life Sci Ctr,1201 E Rollins Rd, Columbia, MO 65211 USA. [Ellersieck, Mark R.] Univ Missouri, Agr Expt Stn Stat, Columbia, MO 65211 USA. [Welsh, Thomas H., Jr.] Texas A&M Univ, Dept Anim Sci, College Stn, TX 77843 USA. [Camacho, Luisa; Vanlandingham, Michelle M.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Lewis, Sherry M.] US FDA, Natl Ctr Toxicol Res, Off Sci Coordinat, Jefferson, AR 72079 USA. [Ferguson, Sherry A.] US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. [Rosenfeld, Cheryl S.] Univ Missouri, Genet Area Program, Columbia, MO 65211 USA. [Rosenfeld, Cheryl S.] Univ Missouri, Thompson Ctr Autism & Neurobehav Disorders, Columbia, MO 65211 USA. RP Rosenfeld, CS (reprint author), Univ Missouri, Bond Life Sci Ctr, 440F Bond Life Sci Ctr,1201 E Rollins Rd, Columbia, MO 65211 USA.; Rosenfeld, CS (reprint author), Univ Missouri, Biomed Sci, 440F Bond Life Sci Ctr,1201 E Rollins Rd, Columbia, MO 65211 USA. EM rosenfeldc@missouri.edu FU NIEHS [U01 ES020929, AES12013 (FDA IAG 224-12-0003)]; NIEHS FX This study is part of the NIEHS CLARITY-BPA Consortium supported by NIEHS grant U01 ES020929 to C.S.R., and the animal portion of this study is supported by NIEHS Interagency Agreement AES12013 (FDA IAG 224-12-0003). NR 118 TC 7 Z9 7 U1 5 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0018-506X EI 1095-6867 J9 HORM BEHAV JI Horm. Behav. PD APR PY 2016 VL 80 BP 139 EP 148 DI 10.1016/j.yhbeh.2015.09.005 PG 10 WC Behavioral Sciences; Endocrinology & Metabolism SC Behavioral Sciences; Endocrinology & Metabolism GA DJ3DF UT WOS:000374084300016 PM 26436835 ER PT J AU Coelho, SG Patri, AK Wokovich, AM McNeil, SE Howard, PC Miller, SA AF Coelho, Sergio G. Patri, Anil K. Wokovich, Anna M. McNeil, Scott E. Howard, Paul C. Miller, Sharon A. TI Repetitive Application of Sunscreen Containing Titanium Dioxide Nanoparticles on Human Skin SO JAMA DERMATOLOGY LA English DT Letter ID PERCUTANEOUS-ABSORPTION; STRATUM-CORNEUM; TIO2 C1 [Coelho, Sergio G.] NCI, Cell Biol Lab, NIH, Bldg 37,Room 2132, Bethesda, MD 20892 USA. [Patri, Anil K.; McNeil, Scott E.] Frederick Natl Lab Canc Res, Nanotechnol Characterizat Lab, Canc Res Technol Program, Leidos Biomed Res Inc, Frederick, MD USA. [Wokovich, Anna M.] US FDA, Div Pharmaceut Anal, Off Testing & Res, Off Pharmaceut Sci,Ctr Drug Evaluat & Res, St Louis, MO USA. [Howard, Paul C.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Miller, Sharon A.] US FDA, Div Radiol Hlth, Off In Vitro Diagnost & Radiol Hlth, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Coelho, SG (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Room 2132, Bethesda, MD 20892 USA. EM sergio.coelho@fda.hhs.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 NR 6 TC 1 Z9 1 U1 3 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD APR PY 2016 VL 152 IS 4 BP 470 EP 472 DI 10.1001/jamadermatol.2015.5944 PG 3 WC Dermatology SC Dermatology GA DJ0TF UT WOS:000373916600024 PM 26913928 ER PT J AU Eydelman, MB Nguyen, T Green, JA AF Eydelman, Malvina B. Tieuvi Nguyen Green, J. Angelo TI The US Food and Drug Administration's New Regulatory Toolkit to Bring Medical Device Innovation Back to the United States SO JAMA OPHTHALMOLOGY LA English DT Editorial Material C1 [Eydelman, Malvina B.; Tieuvi Nguyen; Green, J. Angelo] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Eydelman, MB (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM malvina.eydelman@fda.hhs.gov NR 7 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD APR PY 2016 VL 134 IS 4 BP 353 EP 354 DI 10.1001/jamaophthalmol.2015.5943 PG 2 WC Ophthalmology SC Ophthalmology GA DJ1UA UT WOS:000373988900006 PM 26846511 ER PT J AU Xu, S Shetterly, S Cook, AJ Raebel, MA Goonesekera, S Shoaibi, A Roy, J Fireman, B AF Xu, Stanley Shetterly, Susan Cook, Andrea J. Raebel, Marsha A. Goonesekera, Sunali Shoaibi, Azadeh Roy, Jason Fireman, Bruce TI Evaluation of propensity scores, disease risk scores, and regression in confounder adjustment for the safety of emerging treatment with group sequential monitoring SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE propensity score; disease risk score; matching; stratification; group sequential analyses; pharmacoepidemiology ID MULTIPLE CONFOUNDERS; PERFORMANCE; BIAS AB PurposeThe objective of this study was to evaluate regression, matching, and stratification on propensity score (PS) or disease risk score (DRS) in a setting of sequential analyses where statistical hypotheses are tested multiple times. MethodsIn a setting of sequential analyses, we simulated incident users and binary outcomes with different confounding strength, outcome incidence, and the adoption rate of treatment. We compared Type I error rate, empirical power, and time to signal using the following confounder adjustments: (i) regression; (ii) treatment matching (1:1 or 1:4) on PS or DRS; and (iii) stratification on PS or DRS. We estimated PS and DRS using lookwise and cumulative methods (all data up to the current look). We applied these confounder adjustments in examining the association between non-steroidal anti-inflammatory drugs and bleeding. ResultsPropensity score and DRS methods had similar empirical power and time to signal. However, DRS methods yielded Type I error rates up to 17% for 1:4 matching and 15.3% for stratification methods when treatment and outcome were common and confounding strength with treatment was stronger. When treatment and outcome were not common, stratification on PS and DRS and regression yielded 8-10% Type I error rates and inflated empirical power. However, when outcome and treatment were common, both regression and stratification on PS outperformed other matching methods with Type I error rates close to 5%. ConclusionsWe suggest regression and stratification on PS when the outcomes and/or treatment is common and use of matching on PS with higher ratios when outcome or treatment is rare or moderately rare. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Xu, Stanley; Shetterly, Susan; Raebel, Marsha A.] Kaiser Permanente Colorado, Inst Hlth Res, POB 378066, Denver, CO 80237 USA. [Cook, Andrea J.] Grp Hlth Res Inst, Biostat Unit, Seattle, WA USA. [Goonesekera, Sunali] Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Goonesekera, Sunali] Harvard Univ, Sch Med, Boston, MA USA. [Shoaibi, Azadeh] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Roy, Jason] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Fireman, Bruce] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. RP Xu, S (reprint author), Kaiser Permanente Colorado, Inst Hlth Res, POB 378066, Denver, CO 80237 USA. EM stan.xu@kp.org FU NCATS NIH HHS [KL2 TR001080, UL1 TR001082]; NCRR NIH HHS [UL1 RR025780]; PHS HHS [HHSF223200910006I] NR 18 TC 1 Z9 1 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD APR PY 2016 VL 25 IS 4 BP 453 EP 461 DI 10.1002/pds.3983 PG 9 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DJ1ZI UT WOS:000374003100014 PM 26875591 ER PT J AU Claycamp, HG Kona, R Fahmy, R Hoag, SW AF Claycamp, H. Gregg Kona, Ravikanth Fahmy, Raafat Hoag, Stephen W. TI Quality-by-Design II: Application of Quantitative Risk Analysis to the Formulation of Ciprofloxacin Tablets SO AAPS PHARMSCITECH LA English DT Article DE Bayesian Monte Carlo simulation; ciprofloxacin hydrochloride; ciprofloxacin and granulation; roller compaction; quality-by-design (QbD); qualitative risk assessment ID IMMEDIATE-RELEASE TABLETS; MAGNESIUM STEARATE; COMPRESSED TABLETS; LUBRICATION; SPACE AB Qualitative risk assessment methods are often used as the first step to determining design space boundaries; however, quantitative assessments of risk with respect to the design space, i.e., calculating the probability of failure for a given severity, are needed to fully characterize design space boundaries. Quantitative risk assessment methods in design and operational spaces are a significant aid to evaluating proposed design space boundaries. The goal of this paper is to demonstrate a relatively simple strategy for design space definition using a simplified Bayesian Monte Carlo simulation. This paper builds on a previous paper that used failure mode and effects analysis (FMEA) qualitative risk assessment and Plackett-Burman design of experiments to identity the critical quality attributes. The results show that the sequential use of qualitative and quantitative risk assessments can focus the design of experiments on a reduced set of critical material and process parameters that determine a robust design space under conditions of limited laboratory experimentation. This approach provides a strategy by which the degree of risk associated with each known parameter can be calculated and allocates resources in a manner that manages risk to an acceptable level. C1 [Claycamp, H. Gregg] US FDA, Ctr Drug Evaluat & Res, Off Compliance, Silver Spring, MD USA. [Kona, Ravikanth; Hoag, Stephen W.] Univ Maryland, Dept Pharmaceut Sci, Sch Pharm, Baltimore, MD 21201 USA. [Claycamp, H. Gregg; Fahmy, Raafat] US FDA, Off New Anim Drug Evaluat, Rockville, MD 20857 USA. RP Hoag, SW (reprint author), Univ Maryland, Dept Pharmaceut Sci, Sch Pharm, Baltimore, MD 21201 USA. EM shoag@rx.umaryland.edu FU FDA; CIPET FX The authors would like to acknowledge the financial assistance from the FDA and CIPET. Drs. Bancha Chuasuwan, Ramesh Dandu, and Walter Xie for their technical assistance with the CIP assay. Thanks to Gary Hollenbeck for his assistance with roller compaction work at UPM Inc. NR 41 TC 0 Z9 0 U1 5 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-9932 J9 AAPS PHARMSCITECH JI AAPS PharmSciTech PD APR PY 2016 VL 17 IS 2 BP 233 EP 244 DI 10.1208/s12249-015-0349-2 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DI2TN UT WOS:000373351900001 PM 26202064 ER PT J AU Courtney, CR Agyingi, L Fokou, A Christie, S Asaah, B Meli, J Ngai, J Hewlett, I Nyambi, PN AF Courtney, Colleen R. Agyingi, Lucy Fokou, Arlette Christie, Stephanie Asaah, Bladine Meli, Josephine Ngai, Johnson Hewlett, Indira Nyambi, Phillipe N. TI Monitoring HIV-1 Group M Subtypes in Yaounde, Cameroon Reveals Broad Genetic Diversity and a Novel CRF02_AG/F2 Infection SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID RECOMBINANT FORMS; STRAINS; SEQUENCES; EVOLUTION AB Broad HIV-1 genetic diversity in Cameroon provides a unique opportunity to monitor HIV-1 evolution and allows the detection of novel strains. We have genetically characterized the HIV-1 subtypes found in 156 samples from 90 drug-naive subjects in Yaounde, Cameroon collected from 2011 to 2013, using phylogenetic analysis of regions in gag and pol. We identified subtypes CRF02_AG (64.9%), CRF22_01A1 (7.1%), D (4.5%), F2 (3.9%), G (3.2%), CRF18_cpx (3.2%), CRF37_cpx (3.2%), CRF11_cpx (2.6%), CRF13_cpx (1.9%), A1 (1.3%), CRF01_AE (1.3%), CRF09_cpx (1.3%), A2 (0.6%), and H (0.6%). Sequence data for both the gag and pol regions were obtained from 62 subjects; for 59 of these subjects the two regions were identified as the same viral subtype while three subjects were discordant, A1/CRF02_AG (subject MDC006), CRF02_AG/F2 (subject MDC179), and a dual infection with CRF02_AG/F2 (subject MDC131). Longitudinal sequence data were obtained for 28 of these 62 subjects and confirmed the cross-sectional results. These data update subtype information for this area and highlight the necessity of such studies due to the numerous circulating subtypes, the ongoing superinfection, and the risk of emerging novel recombinant viruses. C1 [Courtney, Colleen R.] NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. [Agyingi, Lucy] Univ Dschang, Fac Sci, Dschang, Cameroon. [Agyingi, Lucy; Asaah, Bladine; Meli, Josephine; Ngai, Johnson] Med Diagnost Ctr, Yaounde, Cameroon. [Fokou, Arlette] Sch Lab Technicians, Yaounde, Cameroon. [Christie, Stephanie] Icahn Sch Med Mt Sinai, Dept Biophys & Syst Pharmacol, New York, NY 10029 USA. [Meli, Josephine] Gen Hosp, Yaounde, Cameroon. [Hewlett, Indira] Food & Drug Adm, Ctr Biol Evaluat & Res, Div Emerging & Transmiss Transmitted Dis, Lab Mol Virol,Off Blood Review & Res, Silver Spring, MD USA. [Nyambi, Phillipe N.] NYU, Sch Med, Dept Pathol, New York, NY USA. [Nyambi, Phillipe N.] Vet Affairs New York Harbor Healthcare Syst, New York, NY USA. RP Nyambi, PN (reprint author), NYU, Sch Med, Dept Pathol, VA Med Ctr, 423 East 23rd St,Room 18124N, New York, NY 10010 USA. EM phillipe.nyambi@nyumc.org FU National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Health (NIH) [AI083142, AI07647]; National Cancer Institute (NCI) Grant [CA153726]; Fogarty International Center Grant [TW009604] FX The authors would like to thank Dr. Luzia Mayr, Sonal Soni, Dr. Ralf Duerr, Dr. Aubin Nanfack, and Dr. Viswanath Ragupathy for their support and laboratory expertise. We are grateful to the volunteers who have provided the samples for this study. Funding has been provided by the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Health (NIH) Grants AI083142 and AI07647, National Cancer Institute (NCI) Grant CA153726, and Fogarty International Center Grant TW009604. NR 15 TC 1 Z9 1 U1 1 U2 2 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 APR 1 PY 2016 VL 32 IS 4 BP 381 EP 385 DI 10.1089/aid.2015.0286 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DI5JE UT WOS:000373533900013 PM 26681241 ER PT J AU Bjornsdottir-Butler, K McCarthy, SA Dunlap, PV Benner, RA AF Bjornsdottir-Butler, K. McCarthy, S. A. Dunlap, P. V. Benner, R. A., Jr. TI Photobacterium angustum and Photobacterium kishitanii, Psychrotrophic High-Level Histamine-Producing Bacteria Indigenous to Tuna SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID HISTIDINE-DECARBOXYLASE GENES; DNA-DNA HYBRIDIZATION; FORMING BACTERIA; MARINE BACTERIUM; SP-NOV.; GENUS BENECKEA; FISH; GROWTH; IDENTIFICATION; TAXONOMY AB Scombrotoxin fish poisoning (SFP) remains the main contributor of fish poisoning incidents in the United States, despite efforts to control its spread. Psychrotrophic histamine-producing bacteria (HPB) indigenous to scombrotoxin-forming fish may contribute to the incidence of SFP. We examined the gills, skin, and anal vents of yellowfin (n = 3), skipjack (n = 1), and albacore (n = 6) tuna for the presence of indigenous HPB. Thirteen HPB strains were isolated from the anal vent samples from albacore (n = 3) and yellowfin (n = 2) tuna. Four of these isolates were identified as Photobacterium kishitanii and nine isolates as Photobacterium angustum; these isolates produced 560 to 603 and 1,582 to 2,338 ppm histamine in marine broth containing 1% histidine (25 degrees C for 48 h), respectively. The optimum growth temperatures and salt concentrations were 26 to 27 degrees C and 1% salt for P. kishitanii and 30 to 32 degrees C and 2% salt for P. angustum in Luria 70% seawater (LSW-70). The optimum activity of the HDC enzyme was at 15 to 30 degrees C for both species. At 5 degrees C, P. kishitanii and P. angustum had growth rates of 0.1 and 0.2 h(-1\), respectively, and the activities of histidine decarboxylase (HDC) enzymes were 71% and 63%, respectively. These results show that indigenous HPB in tuna are capable of growing at elevated and refrigeration temperatures. These findings demonstrate the need to examine the relationships between the rate of histamine production at refrigeration temperatures, seafood shelf life, and regulatory limits. C1 [Bjornsdottir-Butler, K.; McCarthy, S. A.; Benner, R. A., Jr.] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL USA. [Dunlap, P. V.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. RP Bjornsdottir-Butler, K (reprint author), US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL USA. EM kristin.butler@fda.hhs.gov NR 56 TC 0 Z9 0 U1 7 U2 9 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 APR PY 2016 VL 82 IS 7 BP 2167 EP 2176 DI 10.1128/AEM.02833-15 PG 10 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DI2QV UT WOS:000373342400020 PM 26826233 ER PT J AU Rhoads, DD Mathison, BA Bishop, HS da Silva, AJ Pantanowitz, L AF Rhoads, Daniel D. Mathison, Blaine A. Bishop, Henry S. da Silva, Alexandre J. Pantanowitz, Liron TI Review of Telemicrobiology SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Review ID BLOOD SMEARS; COMPUTER VISION; IMAGE-ANALYSIS; MICROSCOPY; DIAGNOSIS; MALARIA; TELEPATHOLOGY; PATHOLOGY; URINE; TELEMEDICINE AB Context.-Microbiology laboratories are continually pursuing means to improve quality, rapidity, and efficiency of specimen analysis in the face of limited resources. One means by which to achieve these improvements is through the remote analysis of digital images. Telemicrobiology enables the remote interpretation of images of microbiology specimens. To date, the practice of clinical tele-microbiology has not been thoroughly reviewed. Objective.-To identify the various methods that can be employed for telemicrobiology, including emerging technologies that may provide value to the clinical laboratory. Data Sources.-Peer-reviewed literature, conference proceedings, meeting presentations, and expert opinions pertaining to telemicrobiology have been evaluated. Conclusions.-A number of modalities have been employed for telemicroscopy, including static capture techniques, whole slide imaging, video telemicroscopy, mobile devices, and hybrid systems. Telemicrobiology has been successfully implemented for several applications, including routine primary diagnosis, expert teleconsultation, and proficiency testing. Emerging areas of telemicrobiology include digital plate reading of bacterial cultures, mobile health applications, and computer-augmented analysis of digital images. To date, static image capture techniques have been the most widely used modality for telemicrobiology, despite newer technologies being available that may produce better quality interpretations. Telemicrobiology adds value, quality, and efficiency to the clinical microbiology laboratory, and increased adoption of telemicrobiology is anticipated. C1 [Rhoads, Daniel D.; Pantanowitz, Liron] Univ Pittsburgh, Dept Pathol, Med Ctr, Pittsburgh, PA USA. [Mathison, Blaine A.; Bishop, Henry S.; da Silva, Alexandre J.] Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Ctr Global Hlth, Atlanta, GA USA. [da Silva, Alexandre J.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD USA. [Rhoads, Daniel D.] Cleveland Clin, Dept Lab Med, 9500 Euclid Ave,LL1-123, Cleveland, OH 44195 USA. RP Rhoads, DD (reprint author), Cleveland Clin, Dept Lab Med, 9500 Euclid Ave,LL1-123, Cleveland, OH 44195 USA. EM danrhoads@gmail.com FU Intramural CDC HHS [CC999999] NR 58 TC 0 Z9 0 U1 2 U2 4 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 APR PY 2016 VL 140 IS 4 BP 362 EP 370 DI 10.5858/arpa.2015-0116-RA PG 9 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA DI7TJ UT WOS:000373704600015 PM 26317376 ER PT J AU Kluetz, PG Slagle, A Papadopoulos, EJ Johnson, LL Donoghue, M Kwitkowski, VE Chen, WH Sridhara, R Farrell, AT Keegan, P Kim, G Pazdur, R AF Kluetz, Paul G. Slagle, Ashley 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: Symptomatic Adverse Events, Physical Function, and Disease-Related Symptoms SO CLINICAL CANCER RESEARCH LA English DT Article ID QUALITY-OF-LIFE; VALIDATION AB Cancer clinical trials have relied on overall survival and measures of tumor growth or reduction to assess the efficacy of a drug. However, benefits are often accompanied by significant symptomatic toxicities. The degree to which a therapy improves disease symptoms and introduces symptomatic toxicity affects how patients function in their daily lives. These concepts are important contributors to health-related quality of life (HRQOL). In this article, we discuss patient-reported outcome (PRO) assessment in cancer trials and challenges relying solely on static multi-item HRQOL instruments. We propose focusing on three separate measures of well-defined concepts: symptomatic adverse events, physical function, and disease-related symptoms, which are key contributors to the effect of a therapy on HRQOL. Separate measures of these three concepts may facilitate the incorporation of emerging contemporary instruments that can tailor the PRO assessment strategy to different trial contexts. Irrespective of the PRO measures used, continued improvement in trial design and conduct is crucial to decrease missing data and optimize the quality of PRO information. International stakeholder collaboration and continued research into optimal practices for PRO and other clinical outcome assessments are necessary to advance a common framework for generating and reporting rigorous patient-centered data from cancer clinical trials. (C) 2016 AACR. 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 20993 USA. [Slagle, Ashley; Papadopoulos, Elektra J.; Chen, Wen-Hung] US FDA, Clin Outcome Assessment Staff, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Johnson, Laura Lee; Sridhara, Rajeshwari] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Kluetz, PG (reprint author), US FDA, 10903 New Hampshire Ave,WO22 Room 2223, Silver Spring, MD 20993 USA. EM paul.kluetz@fda.hhs.gov NR 22 TC 9 Z9 9 U1 5 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 1 PY 2016 VL 22 IS 7 BP 1553 EP 1558 DI 10.1158/1078-0432.CCR-15-2035 PG 6 WC Oncology SC Oncology GA DI2WT UT WOS:000373360600003 PM 26758559 ER PT J AU Thayer, KA Taylor, KW Garantziotis, S Schurman, SH Kissling, GE Hunt, D Herbert, B Church, R Jankowich, R Churchwell, MI Scheri, RC Birnbaum, LS Bucher, JR AF Thayer, Kristina A. Taylor, Kyla W. Garantziotis, Stavros Schurman, Shepherd H. Kissling, Grace E. Hunt, Dawn Herbert, Brenda Church, Rebecca Jankowich, Rachael Churchwell, Mona I. Scheri, Richard C. Birnbaum, Linda S. Bucher, John R. TI Bisphenol A, Bisphenol S, and 4-Hydroxyphenyl 4-Isoprooxyphenylsulfone (BPSIP) in Urine and Blood of Cashiers SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID THERMAL PAPER RECEIPTS; SPRAGUE-DAWLEY RATS; UNITED-STATES; HUMAN EXPOSURE; SERUM; PRODUCTS; ANALOGS; PENETRATION; PROFILES; CHINA AB BACKGROUND: Bisphenol A (BPA) is a high-production-volume chemical associated with a wide range of health outcomes in animal and human studies. BPA is used as a developer in thermal paper products, including cash register receipt paper; however, little is known about exposure of cashiers to BPA and alternative compounds in receipt paper. OBJECTIVE: We determined whether handling receipt paper results in measurable absorption of BPA or the BPA alternatives bisphenol S (BPS) and 4-hydroxyphenyl 4-isoprooxyphenylsulfone (BPSIP). METHODS: Cashiers (n = 77) and non-cashiers (n = 25) were recruited from the Raleigh-Durham-Chapel Hill region of North Carolina during 2011-2013. Receipts were analyzed for the presence of BPA or alternatives considered for use in thermal paper. In cashiers, total urine and serum BPA, BPS, and BPSIP levels in post-shift samples (collected <= 2 hr after completing a shift) were compared with pre-shift samples. Levels of these compounds in urine from cashiers were compared to levels in urine from non-cashiers. RESULTS: Each receipt contained 1-2% by weight of the paper of BPA, BPS, or BPSIP. The post-shift geometric mean total urinary BPS concentration was significantly higher than the pre-shift mean in 33 cashiers who handled receipts containing BPS. The mean urine BPA concentrations in 31 cashiers who handled BPA receipts were as likely to decrease as to increase after a shift, but the mean post-shift concentrations were significantly higher than those in non-cashiers. BPSIP was detected more frequently in the urine of cashiers handling BPSIP receipts than in the urine of noncashiers. Only a few cashiers had detectable levels of total BPA or BPS in serum, whereas BPSIP tended to be detected more frequently. CONCLUSIONS: Thermal receipt paper is a potential source of occupational exposure to BPA, BPS, and BPSIP. C1 [Thayer, Kristina A.; Taylor, Kyla W.; Bucher, John R.] NIEHS, Div Natl Toxicol Program, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Garantziotis, Stavros; Schurman, Shepherd H.; Hunt, Dawn; Herbert, Brenda; Church, Rebecca; Jankowich, Rachael] NIEHS, Clin Res Unit, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Churchwell, Mona I.; Scheri, Richard C.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Birnbaum, Linda S.] NCI, NIH, DHHS, Res Triangle Pk, NC USA. RP Thayer, KA (reprint author), NIEHS, POB 12233,MD K2-04, Res Triangle Pk, NC 27709 USA. EM thayer@niehs.nih.gov RI Garantziotis, Stavros/A-6903-2009; OI Garantziotis, Stavros/0000-0003-4007-375X; Schurman, Shepherd/0000-0002-9133-7906 FU intramural research programs of the NIEHS; National Cancer Institute (NCI), NIH FX This research was supported by the intramural research programs of the NIEHS and the National Cancer Institute (NCI), NIH. NR 37 TC 10 Z9 11 U1 18 U2 54 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2016 VL 124 IS 4 BP 437 EP 444 DI 10.1289/ehp.1409427 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DI9OU UT WOS:000373833100017 PM 26309242 ER PT J AU Ikejimba, L Lo, JY Chen, YC Oberhofer, N Kiarashi, N Samei, E AF Ikejimba, Lynda Lo, Joseph Y. Chen, Yicheng Oberhofer, Nadia Kiarashi, Nooshin Samei, Ehsan TI A quantitative metrology for performance characterization of five breast tomosynthesis systems based on an anthropomorphic phantom SO MEDICAL PHYSICS LA English DT Article DE tomosynthesis; breast phantom; image rendition; image quality; adipose variability ID SOFTWARE PHANTOM; IMAGING-SYSTEMS; X-RAY; MAMMOGRAPHY; SIMULATION; MODEL; OPTIMIZATION; IMAGES; CT AB Purpose: In medical imaging systems, proper rendition of anatomy is essential in discerning normal tissue from disease. Currently, digital breast tomosynthesis (DBT) systems are evaluated using subjective evaluation of lesion visibility in uniform phantoms. This study involved the development of a new methodology to objectively measure the rendition of a 3D breast model by an anthropomorphic breast phantom, and its implementation on five clinical DBT systems of different makes and models. Methods: A 3D, patient-based breast phantom was fabricated based on XCAT breast models. This phantom was imaged on representative breast tomosynthesis systems. The ability of tomosynthesis systems to accurately reproduce the 3D structure of the breast was assessed by computational analysis of the resultant images in terms of three groups of indices: contrast index (CI), reflective of local difference between adipose and glandular material; adipose variability index (AVI), reflective of contributions of noise and artifacts within uniform adipose regions; and contrast detectability, which describes contrast against local background variability and is described by contrast variability index (CVI), coefficient of variation (COV), contrast to adipose variability index (CAVI), and contrast to noise ratio index (CNRI). The indices were obtained by comparing the image data to the gold standard 3D distribution of breast tissue in the model. Corresponding indices were measured within variable region of interest (ROI) sizes ranging from 10 to 37 mm. The characterization was performed on five tomosynthesis systems: Fuji Aspire Crystal, GE Essential, Hologic Dimension, IMS Giotto, and Siemens Inspiration, all evaluated at a fixed dose of 1.5 mGy average glandular dose, anonymized in random order from A to E. Results: Results are provided as a function of ROI size. The systems ranked orders in terms of CI with values of 7.4%, 7.0%, 6.9%, 6.4%, and 5.2% for systems A-E, respectively. This system ranking was identical for CNRI. Both CI and CNRI were constant over ROI size. The ranking was similar for CVI. The COV also changed little with ROI size and was similar across systems. For 10 mm ROIs, the average system COV was 0.7, which reduced to 0.5 with 37 mm ROIs. Two systems (A and B) exhibited highest AVI values when measured in 10 mm ROIs. This, however, was ROI-size-dependent with the three other systems (C-E) yielding higher AVI values when measured with 37 mm ROIs. Two systems (B and E) showed inferior CAVI compared to others. Conclusions: The quality of rendition tracked with differences in image appearance across systems. The findings illustrate that the anthropomorphic phantom can be used as a basis to extract quantitative values of image attributes in DBT. (C) 2016 American Association of Physicists in Medicine. C1 [Ikejimba, Lynda; Lo, Joseph Y.] Duke Univ, Dept Radiol, Med Phys Grad Program, Carl E Ravin Adv Imaging Labs, Durham, NC 27705 USA. [Lo, Joseph Y.] Duke Univ, Dept Elect & Comp Engn, Med Phys Grad Program, Carl E Ravin Adv Imaging Labs, Durham, NC 27705 USA. Duke Univ, Dept Biomed Engn, Med Phys Grad Program, Carl E Ravin Adv Imaging Labs, Durham, NC 27705 USA. [Chen, Yicheng] Tsinghua Univ, Dept Engn Phys, Beijing 100084, Peoples R China. [Oberhofer, Nadia] Hlth Serv South Tyrol, I-30100 Bolzano, Italy. [Kiarashi, Nooshin] Duke Univ, Carl E Ravin Adv Imaging Labs, Dept Radiol, Durham, NC 27705 USA. [Kiarashi, Nooshin] Duke Univ, Carl E Ravin Adv Imaging Labs, Dept Elect & Comp Engn, Durham, NC 27705 USA. [Samei, Ehsan] Duke Univ, Carl E Ravin Adv Imaging Labs, Dept Radiol, Clin Imaging Phys Grp,Med Phys Grad Program, Durham, NC 27705 USA. [Samei, Ehsan] Duke Univ, Carl E Ravin Adv Imaging Labs, Dept Elect & Comp Engn, Clin Imaging Phys Grp,Med Phys Grad Program, Durham, NC 27705 USA. [Samei, Ehsan] Duke Univ, Carl E Ravin Adv Imaging Labs, Dept Biomed Engn, Clin Imaging Phys Grp,Med Phys Grad Program, Durham, NC 27705 USA. [Samei, Ehsan] Duke Univ, Carl E Ravin Adv Imaging Labs, Dept Phys, Clin Imaging Phys Grp,Med Phys Grad Program, Durham, NC 27705 USA. [Ikejimba, Lynda] US FDA, Div Imaging Diagnost & Software Reliabil, Off Sci & Engn Labs, Ctr Diagnost & Radiol Hlth, Silver Spring, MD 20993 USA. RP Ikejimba, L (reprint author), Duke Univ, Dept Radiol, Med Phys Grad Program, Carl E Ravin Adv Imaging Labs, Durham, NC 27705 USA. EM lci@duke.edu NR 36 TC 3 Z9 3 U1 1 U2 4 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD APR PY 2016 VL 43 IS 4 BP 1627 EP 1638 DI 10.1118/1.4943373 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DI7VV UT WOS:000373711000006 PM 27036562 ER PT J AU Xin, KZ Chang, WC Ovanesov, MV AF Xin, Kevin Z. Chang, William C. Ovanesov, Mikhail V. TI Interconnectedness of global hemostasis assay parameters in simultaneously evaluated thrombin generation, fibrin generation and clot lysis in normal plasma SO THROMBOSIS RESEARCH LA English DT Article DE Thrombin generation; Fibrin generation; Fibrinolysis; Global hemostasis assay; Overall hemostasis potential; Tissue plasminogen activator; Tissue factor; TAFI ID RECOMBINANT FACTOR VIIA; CALIBRATED AUTOMATED THROMBOGRAPHY; PROTEASE INHIBITORS DX-9065A; CORN TRYPSIN-INHIBITOR; TISSUE FACTOR; DIFFERENT MODES; CONTACT FACTOR; WHOLE-BLOOD; IN-VITRO; HEMOPHILIA AB Background: Fluorogenic thrombin generation (TG) assays and turbidity-based fibrin generation (FG)- and fibrinolysis (FL)-resistance assays have been sought to assess bleeding and clotting disorders. Theoretically, TG, FG and FL tests should provide overlapping information because thrombin is responsible for FG and induces protection from FL. The relationships between TG, FG and FL parameters remain poorly investigated, partly because existing experimental systems do not permit simultaneous detection of both TG and FG in the same sample of plasma, and are instead tested in separate experiments. Objectives and methods: We evaluated the potential benefits of a combined TG/FG/FL assay by testing responses of normal plasma to a wide range of tissue factor (TF) and tissue plasminogen activator (tPA) concentrations. Correlations between multiple parameters extracted from the TG and FG/FL curves were also compared. Results: Rate of FG correlated well with TG peak height at all TF concentrations, but correlations between TG and FL parameters depended on the TF concentration. Without thrombomodulin, all FG/FL parameters at high TF could be predicted from TG parameters and no FL protection was observed. With thrombomodulin and high TF, TF-dependent FL protection did not correlate with TF-dependent TG. The fluorogenic thrombin substrate did not interfere with optical density readings, and meaningful tPA concentrations did not interfere with TG readings. Conclusions: In normal plasma, TG, FG and FL parameters may provide interchangeable information. Evaluation of FL-resistance may provide additional data under special assay conditions, but the value of this information should be studied under disease conditions. Published by Elsevier Ltd. C1 [Xin, Kevin Z.; Chang, William C.; Ovanesov, Mikhail V.] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Ovanesov, MV (reprint author), US FDA, 10903 New Hampshire Ave,WO52-72-4206, Silver Spring, MD 20993 USA. EM mikhail.ovanesov@fda.hhs.gov FU Oak Ridge Institute for Science and Education (ORISE) FX This study was supported in part by a Postgraduate and Postbaccalaureate Research Fellowship Award to W.C.C. 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 (FDA). This paper is an informal communication and represents authors' best judgment. These comments do not bind or obligate FDA. NR 31 TC 0 Z9 0 U1 3 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PD APR PY 2016 VL 140 BP 132 EP 139 DI 10.1016/j.thromres.2015.11.023 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DI8DX UT WOS:000373732600021 PM 26632515 ER PT J AU Obuchowski, NA Buckler, A Kinahan, P -Mayer, HC Petrick, N Barboriak, DP Bullen, J Barnhart, H Sullivan, DC AF Obuchowski, Nancy A. Buckler, Andrew Kinahan, Paul -Mayer, Heather Chen Petrick, Nicholas Barboriak, Daniel P. Bullen, Jennifer Barnhart, Huiman Sullivan, Daniel C. TI Statistical Issues in Testing Conformance with the Quantitative Imaging Biomarker Alliance (QIBA) Profile Claims SO ACADEMIC RADIOLOGY LA English DT Article DE QIBA; quantitative imaging biomarker; precision; repeatability; bias; total deviation index; linearity ID TECHNICAL PERFORMANCE AB A major initiative of the Quantitative Imaging Biomarker Alliance is to develop standards-based documents called "Profiles," which describe one or more technical performance claims for a given imaging modality. The term "actor" denotes any entity (device, software, or person) whose performance must meet certain specifications for the claim to be met. The objective of this paper is to present the statistical issues in testing actors' conformance with the specifications. In particular, we present the general rationale and interpretation of the claims, the minimum requirements for testing whether an actor achieves the performance requirements, the study designs used for testing conformity, and the statistical analysis plan. We use three examples to illustrate the process: apparent diffusion coefficient in solid tumors measured by MRI, change in Perc 15 as a biomarker for the progression of emphysema, and percent change in solid tumor volume by computed tomography as a biomarker for lung cancer progression. C1 [Obuchowski, Nancy A.; Bullen, Jennifer] Cleveland Clin Fdn, Quantitat Hlth Sci, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Buckler, Andrew] Elucid Bioimaging Inc, Wenham, MA USA. [Kinahan, Paul] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [-Mayer, Heather Chen] NIST, Gaithersburg, MD 20899 USA. [Petrick, Nicholas] US FDA, CDRH, Silver Spring, MD USA. [Barboriak, Daniel P.; Barnhart, Huiman; Sullivan, Daniel C.] Duke Univ, Sch Med, Durham, NC USA. RP Obuchowski, NA (reprint author), Cleveland Clin Fdn, Quantitat Hlth Sci, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM obuchon@ccf.org RI Barboriak, Daniel/M-4414-2015; OI Barboriak, Daniel/0000-0002-2536-6266; Buckler, Andrew/0000-0002-0786-4835 FU NIBIB [HHSN268201300071C] FX This work was supported by a grant from NIBIB (no. HHSN268201300071C). QIBA is indebted to the many volunteers who participated in the QIBA metrology workshops for their contributions to the statistical groundwork for the claims. NR 13 TC 0 Z9 0 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD APR PY 2016 VL 23 IS 4 BP 496 EP 506 DI 10.1016/j.acra.2015.12.020 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DH8HM UT WOS:000373034100014 PM 26898527 ER PT J AU Dickert, NW Brown, J Cairns, CB Eaves-Leanos, A Goldkind, SF Kim, SYH Nichol, G O'Conor, KJ Scott, JD Sinert, R Wendler, D Wright, DW Silbergleit, R AF Dickert, Neal W. Brown, Jeremy Cairns, Charles B. Eaves-Leanos, Aaliyah Goldkind, Sara F. Kim, Scott Y. H. Nichol, Graham O'Conor, Katie J. Scott, Jane D. Sinert, Richard Wendler, David Wright, David W. Silbergleit, Robert TI Confronting Ethical and Regulatory Challenges of Emergency Care Research With Conscious Patients SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; INFORMED-CONSENT; COMMUNITY CONSULTATION; PATIENTS PERCEPTIONS; CLINICAL-RESEARCH; CARDIAC-ARREST; TRIAL; ENROLLMENT; EXCEPTION; SURVIVAL AB Barriers to informed consent are ubiquitous in the conduct of emergency care research across a wide range of conditions and clinical contexts. They are largely unavoidable; can be related to time constraints, physical symptoms, emotional stress, and cognitive impairment; and affect patients and surrogates. US regulations permit an exception from informed consent for certain clinical trials in emergency settings, but these regulations have generally been used to facilitate trials in which patients are unconscious and no surrogate is available. Most emergency care research, however, involves conscious patients, and surrogates are often available. Unfortunately, there is neither clear regulatory guidance nor established ethical standards in regard to consent in these settings. In this report the result of a workshop convened by the National Institutes of Health Office of Emergency Care Research and Department of Bioethics to address ethical challenges in emergency care research we clarify potential gaps in ethical understanding and federal regulations about research in emergency care in which limited involvement of patients or surrogates in enrollment decisions is possible. We propose a spectrum of approaches directed toward realistic ethical goals and a research and policy agenda for addressing these issues to facilitate clinical research necessary to improve emergency care. C1 [Dickert, Neal W.] Emory Univ, Sch Med, Dept Med, Atlanta, GA USA. [Wright, David W.] Emory Univ, Sch Med, Dept Emergency Med, Atlanta, GA USA. [Dickert, Neal W.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Brown, Jeremy] Natl Inst Gen Med Sci, Off Emergency Care Res, Bethesda, MD USA. [Cairns, Charles B.] Univ Arizona, Coll Med, Tucson, AZ USA. [Eaves-Leanos, Aaliyah] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Goldkind, Sara F.] US FDA, Off Commissioner, Silver Spring, MD USA. [Goldkind, Sara F.] St Louis Univ, Res & Clin Bioeth Consultant, St Louis, MO 63103 USA. [Eaves-Leanos, Aaliyah] St Louis Univ, Albert Gnaegi Ctr Hlth Care Eth, St Louis, MO 63103 USA. [Kim, Scott Y. H.; Wendler, David] NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. [Nichol, Graham] Univ Washington, Harborview Ctr Prehospital Emergency Care, Seattle, WA 98195 USA. [O'Conor, Katie J.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Scott, Jane D.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Sinert, Richard] Suny Downstate Med Ctr, Dept Emergency Med, New York, NY USA. [Silbergleit, Robert] Univ Michigan, Sch Med, Dept Emergency Med, Ann Arbor, MI USA. RP Dickert, NW (reprint author), Emory Univ, Sch Med, Dept Med, Atlanta, GA USA.; Dickert, NW (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. EM njr@emory.edu FU National Institutes of Health Office (NIH) of Emergency Care Research and Department of Bioethics FX By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist and provided the following details: This workshop was supported by the National Institutes of Health Office (NIH) of Emergency Care Research and Department of Bioethics. Drs. Brown, Goldkind, Kim, Scott, and Wendler and Ms. Eaves-Leanos were federal employees during this workshop (NIH and Food and Drug Administration [FDA]). NR 40 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 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD APR PY 2016 VL 67 IS 4 BP 538 EP 545 DI 10.1016/j.annemergmed.2015.10.026 PG 8 WC Emergency Medicine SC Emergency Medicine GA DI1FK UT WOS:000373241800022 PM 26707358 ER PT J AU Avonto, C Wang, YH Avula, B Wang, M Rua, D Khan, IA AF Avonto, C. Wang, Y. -H. Avula, B. Wang, M. Rua, D. Khan, I. A. TI Comparative studies on the chemical and enzymatic stability of alpha- and beta-arbutin SO INTERNATIONAL JOURNAL OF COSMETIC SCIENCE LA English DT Article DE chemical analysis; formulation/stability; hydroquinone; whitening cosmetics; alpha-arbutin; beta-arbutin ID PERFORMANCE LIQUID-CHROMATOGRAPHY; FIRE BLIGHT; LIGHTENING AGENTS; PYRUS-COMMUNIS; HYDROQUINONE; PEAR; PHOTOSTABILITY; GLUCOSIDASE; PEROXIDASE; MECHANISMS AB OBJECTIVES: The aim of this study was to establish a comparative analysis of the chemical and enzymatic stability of - and -arbutins as potential sources of the substance of concern hydroquinone (HQ). The study was performed using an array of techniques including HPLC-PDA, nuclear magnetic resonance (NMR) and optical rotation (OR). Both arbutins are emerging as popular and effective skin whiteners, acting as tyrosinase inhibitors in a fashion similar to the popular whitening agent HQ. Due to their structural similarity to the regulated agent HQ, both arbutins may be regarded as potential sources of the active aglycone after chemical or metabolic conversion. METHODS: Various cosmetic formulations including creams, sera, gels and lotions were analysed by HPLC-PDA for their arbutin and HQ content in freshly opened and aged samples stored for 16 months. Solutions of pure compounds were also aged and periodically checked for degradation products using 1D and 2D NMR experiments and OR measurements. The metabolic stability was investigated using pear peels as a biological model. RESULTS: Both arbutins were found to be stable in water and methanol solutions in the absence of buffer or stabilizers. Their stability in cosmetic formulations, however, was found to depend on the type of formulation and pH. Both compounds were unstable under strong hydrolytic conditions, with consequent release of HQ. Enzymatic instability of both arbutins was also observed, although no formation of HQ was observed under the chosen experimental conditions. CONCLUSION: Both arbutins were found to possess similar stability profiles, and to be more prone to in vivo rather than in chemico degradation, although no HQ was found after enzymatic hydrolysis. Also, no epimerization was observed in any of the tested conditions. Diverse experimental approaches can be applied to analyse the chemical and enzymatic stability of arbutins in regard to the potential release of HQ in different types of preparations. These result showed the potential use of NMR and OR as complementary investigative tools for the stability and safety assessment of arbutin along with more established HPLC methods. C1 [Avonto, C.; Wang, Y. -H.; Avula, B.; Wang, M.; Khan, I. A.] Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA. [Rua, D.] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Khan, I. A.] Univ Mississippi, Sch Pharm, Dept BioMol Sci, Div Pharmacognosy, University, MS 38677 USA. [Khan, I. A.] King Saud Univ, Coll Pharm, Dept Pharmacognosy, Riyadh, Saudi Arabia. RP Khan, IA (reprint author), Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA.; Khan, IA (reprint author), Univ Mississippi, Natl Ctr Nat Prod Res, University, MS 38677 USA. EM ikhan@olemiss.edu OI Avonto, Cristina/0000-0002-8209-6813 FU 'Science Based Authentication of Dietary Supplements' - Food and Drug Administration [5U01FD004246]; United States Department of Agriculture, Agricultural Research Service [58-6408-02-1-162] FX This research is supported in part by 'Science Based Authentication of Dietary Supplements' funded by the Food and Drug Administration Grant Number 5U01FD004246, and the United States Department of Agriculture, Agricultural Research Service, Specific Cooperative Agreement No. 58-6408-02-1-162. The authors are thankful to Prof. J. F. Parcher for the patience and diligence in reviewing this manuscript. NR 37 TC 0 Z9 0 U1 7 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0142-5463 EI 1468-2494 J9 INT J COSMETIC SCI JI Int. J. Cosmetic Sci. PD APR PY 2016 VL 38 IS 2 BP 187 EP 193 DI 10.1111/ics.12275 PG 7 WC Chemistry, Applied; Dermatology SC Chemistry; Dermatology GA DH3BE UT WOS:000372661200010 PM 26352830 ER PT J AU Dong, M Fisher, C Anez, G Rios, M Nakhasi, HL Hobson, JP Beanan, M Hockman, D Grigorenko, E Duncan, R AF Dong, M. Fisher, C. Anez, G. Rios, M. Nakhasi, H. L. Hobson, J. P. Beanan, M. Hockman, D. Grigorenko, E. Duncan, R. TI Standardized methods to generate mock (spiked) clinical specimens by spiking blood or plasma with cultured pathogens SO JOURNAL OF APPLIED MICROBIOLOGY LA English DT Article DE blood-borne; mock specimens; molecular quantification; pathogen spiking; standardized methods ID MODIFIER PROTEIN UFM1; LEISHMANIA-DONOVANI; EXPRESSION; PARASITE; DELETION; GROWTH AB AimsTo demonstrate standardized methods for spiking pathogens into human matrices for evaluation and comparison among diagnostic platforms. Methods and ResultsThis study presents detailed methods for spiking bacteria or protozoan parasites into whole blood and virus into plasma. Proper methods must start with a documented, reproducible pathogen source followed by steps that include standardized culture, preparation of cryopreserved aliquots, quantification of the aliquots by molecular methods, production of sufficient numbers of individual specimens and testing of the platform with multiple mock specimens. Results are presented following the described procedures that showed acceptable reproducibility comparing in-house real-time PCR assays to a commercially available multiplex molecular assay. ConclusionsA step by step procedure has been described that can be followed by assay developers who are targeting low prevalence pathogens. Significance and Impact of the StudyThe development of diagnostic platforms for detection of low prevalence pathogens such as biothreat or emerging agents is challenged by the lack of clinical specimens for performance evaluation. This deficit can be overcome using mock clinical specimens made by spiking cultured pathogens into human matrices. To facilitate evaluation and comparison among platforms, standardized methods must be followed in the preparation and application of spiked specimens. C1 [Dong, M.; Fisher, C.; Anez, G.; Rios, M.; Nakhasi, H. L.; Duncan, R.] US FDA, CBER, Div Emerging & Transfus Transmitted Dis, Lab Emerging Pathogens, Silver Spring, MD 20993 USA. [Hobson, J. P.] US FDA, CDRH, Div Microbiol Devices, Off In Vitro Diagnost & Radiol Hlth OIR, Silver Spring, MD 20993 USA. [Beanan, M.] NIAID, DMID, Off Biodef Res Resources & Translat Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hockman, D.; Grigorenko, E.] Diatherix Lab, Huntsville, AL USA. [Anez, G.] Sanofi Pasteur, Swiftwater, PA USA. RP Duncan, R (reprint author), US FDA, Bldg 52-72,Room 4312,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Robert.duncan@fda.hhs.gov RI Hockman, Donna/D-7237-2017; Duncan, Robert/I-8168-2015; OI Hockman, Donna/0000-0002-1790-0895; Duncan, Robert/0000-0001-8409-2501; Anez, German/0000-0001-5361-3001 FU NIAID [AAI13005-001] FX We wish to acknowledge that this work was supported by NIAID through an Interagency Agreement AAI13005-001 awarded to CBER/FDA. Members of the NIAID/Office of Biodefense, Research Resources, and Translational Research, Division of Microbiology and Infectious Diseases aided in the editing of the text. Yukiko Kozaki LEP/DETTD/CBER graciously assisted with statistical analysis. Healthy human blood and plasma was obtained thanks to the NIH Clinical Center, Department of Transfusion Medicine. NR 18 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1364-5072 EI 1365-2672 J9 J APPL MICROBIOL JI J. Appl. Microbiol. PD APR PY 2016 VL 120 IS 4 BP 1119 EP 1129 DI 10.1111/jam.13082 PG 11 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DH9IW UT WOS:000373110800027 PM 26835651 ER PT J AU Welle, CG Contreras, D AF Welle, Cristin G. Contreras, Diego TI Sensory-driven and spontaneous gamma oscillations engage distinct cortical circuitry SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE gamma oscillation; visual cortex; cortical column; spontaneous activity; GABA(A) receptor ID PRIMARY VISUAL-CORTEX; LOCAL-FIELD POTENTIALS; RECEPTIVE-FIELDS; AUDITORY-CORTEX; BAND ACTIVITY; HZ OSCILLATIONS; CEREBRAL-CORTEX; AWAKE MONKEY; RESPONSES; NEURONS AB Gamma oscillations are a robust component of sensory responses but are also part of the background spontaneous activity of the brain. To determine whether the properties of gamma oscillations in cortex are specific to their mechanism of generation, we compared in mouse visual cortex in vivo the laminar geometry and single-neuron rhythmicity of oscillations produced during sensory representation with those occurring spontaneously in the absence of stimulation. In mouse visual cortex under anesthesia (isoflurane and xylazine), visual stimulation triggered oscillations mainly between 20 and 50 Hz, which, because of their similar functional significance to gamma oscillations in higher mammals, we define here as gamma range. Sensory representation in visual cortex specifically increased gamma oscillation amplitude in the supragranular (L2/3) and granular (L4) layers and strongly entrained putative excitatory and inhibitory neurons in infragranular layers, while spontaneous gamma oscillations were distributed evenly through the cortical depth and primarily entrained putative inhibitory neurons in the infragranular (L5/6) cortical layers. The difference in laminar distribution of gamma oscillations during the two different conditions may result from differences in the source of excitatory input to the cortex. In addition, modulation of superficial gamma oscillation amplitude did not result in a corresponding change in deep-layer oscillations, suggesting that superficial and deep layers of cortex may utilize independent but related networks for gamma generation. These results demonstrate that stimulus-driven gamma oscillations engage cortical circuitry in a manner distinct from spontaneous oscillations and suggest multiple networks for the generation of gamma oscillations in cortex. C1 [Welle, Cristin G.] US FDA, Div Biomed Phys, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Welle, Cristin G.; Contreras, Diego] Univ Penn, Sch Med, Dept Neurosci, 211 CRB, Philadelphia, PA 19106 USA. RP Contreras, D (reprint author), Univ Penn, Sch Med, Dept Neurosci, 211 CRB, Philadelphia, PA 19106 USA. EM diegoc@upenn.edu OI Welle, Cristin/0000-0001-8735-0983 FU National Institutes of Health [R01 EY-020765]; Conte Center [P50 MH-064045]; Vision Training Grant [T32 EY-00735] FX This work was supported by National Institutes of Health Grant R01 EY-020765, Conte Center P50 MH-064045, and Vision Training Grant T32 EY-00735. NR 83 TC 4 Z9 4 U1 6 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD APR PY 2016 VL 115 IS 4 BP 1821 EP 1835 DI 10.1152/jn.00137.2015 PG 15 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA DI3BX UT WOS:000373374300008 PM 26719085 ER PT J AU Ferlin, KM Kaplan, DS Fisher, JP AF Ferlin, Kimberly M. Kaplan, David S. Fisher, John P. TI Separation of Mesenchymal Stem Cells Through a Strategic Centrifugation Protocol SO TISSUE ENGINEERING PART C-METHODS LA English DT Article ID HUMAN BONE-MARROW; IN-VITRO; LINEAGE COMMITMENT; ADHESION STRENGTH; STROMAL CELLS; DIFFERENTIATION; CULTURE; ASSAY; ADIPOGENESIS; CYTOSKELETAL AB Despite great promise surrounding mesenchymal stem cells (MSCs), their implementation for tissue engineering strategies remains in the development phases. Many of the concerns regarding the clinical use of MSCs originate from population heterogeneity, during both isolation and differentiation. In this study, we utilize our previously developed centrifugation cell adhesion protocol for the separation of MSCs. Our findings reveal that MSCs can be isolated from whole bone marrow using a 200 g (700 pN) centrifugal force after 24 h of culture on polystyrene with cell surface marker expression equivalent to positive controls. During differentiation, a centrifugation protocol with identical force parameters could be applied 14 days into chondrogenic differentiation to isolate differentiated chondrocytes, which exhibited increased expression of chondrogenic markers compared to controls. In summary, the use of our developed centrifugation cell adhesion protocol has proven to be an effective means to separate MSC populations, decreasing the heterogeneity of subsequent cell therapy products. C1 [Ferlin, Kimberly M.; Fisher, John P.] Univ Maryland, Fischell Dept Bioengn, 3238 Jeong H Kim Engn Bldg, College Pk, MD 20742 USA. [Kaplan, David S.] US FDA, CDRH, Silver Spring, MD USA. RP Fisher, JP (reprint author), Univ Maryland, Fischell Dept Bioengn, 3238 Jeong H Kim Engn Bldg, College Pk, MD 20742 USA. EM jpfisher@umd.edu FU National Science Foundation/Food and Drug Administration Scholar-in-Residence Program [CBET 1238398] FX Research reported in this publication was supported by the National Science Foundation/Food and Drug Administration Scholar-in-Residence Program (CBET 1238398). The authors wish to thank Dr. Girish Kumar for his technical assistance with the flow cytometry experiments. NR 31 TC 0 Z9 0 U1 4 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3384 EI 1937-3392 J9 TISSUE ENG PART C-ME JI Tissue Eng. Part C-Methods PD APR 1 PY 2016 VL 22 IS 4 BP 348 EP 359 DI 10.1089/ten.tec.2015.0408 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA DI1EA UT WOS:000373237600006 PM 26797048 ER PT J AU Chen, YL Sakamuru, S Huang, RL Reese, DH Xia, MH AF Chen, Yanling Sakamuru, Srilatha Huang, Ruili Reese, David H. Xia, Menghang TI Identification of compounds that modulate retinol signaling using a cell-based qHTS assay SO TOXICOLOGY IN VITRO LA English DT Article DE Retinol signaling; Developmental toxicant; High-throughput screening; Stem cell; LOPAC; Tox21 ID EMBRYONAL CARCINOMA-CELLS; VITAMIN-A; STEM-CELLS; NUCLEAR RECEPTORS; CANCER-CELLS; HL-60 CELLS; NEURONAL DIFFERENTIATION; ENVIRONMENTAL CHEMICALS; GENE-EXPRESSION; ACID RECEPTORS AB In vertebrates, the retinol (vitamin A) signaling pathway (RSP) controls the biosynthesis and catabolism of all trans retinoic acid (atRA), which regulates transcription of genes essential for embryonic development. Chemicals that interfere with the RSP to cause abnormal intracellular levels of atRA are potential developmental toxicants. To assess chemicals for the ability to interfere with retinol signaling, we have developed a cell-based RARE (Retinoic Acid Response Element) reporter gene assay to identify RSP disruptors. To validate this assay in a quantitative high-throughput screening (qHTS) platform, we screened the Library of Pharmacologically Active Compounds (LOPAC) in both agonist and antagonist modes. The screens detected known RSP agonists, demonstrating assay reliability, and also identified novel RSP agonists including kenpaullone, niclosamide, PD98059 and SU4312, and RSP antagonists including Bay 11-7085, LY294002, 3,4-Methylenedioxy-beta-nitrostyrene, and topoisomerase inhibitors (camptothecin, topotecan, amsacrine hydrochloride, and idarubicin). When evaluated in the P19 pluripotent cell, these compounds were found to affect the expression of the Hoxa1 gene that is essential for embryo body patterning. These results show that the RARE assay is an effective qHTS approach for screening large compound libraries to identify chemicals that have the potential to adversely affect embryonic development through interference with retinol signaling. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Chen, Yanling; Reese, David H.] US FDA, Div Mol Biol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Sakamuru, Srilatha; Huang, Ruili; Xia, Menghang] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. RP Chen, YL (reprint author), US FDA, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM yanling.chen@fda.hhs.gov FU National Institute of Environmental Health Sciences/Division of the National Toxicology Program [NTR 12003] FX This work was supported in part through the interagency agreement IAG #NTR 12003 from the National Institute of Environmental Health Sciences/Division of the National Toxicology Program to the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH). This project was also supported in part by the appointment of Dr. Yanling Chen to the Research Participation Program at the Center for Food Safety and Applied Nutrition administrated by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration (U.S. FDA). This research does not necessarily reflect the statements, opinions, views, conclusions, or policies of the NCATS, the NIH, U.S. FDA, or the United States government. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. NR 83 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 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD APR PY 2016 VL 32 BP 287 EP 296 DI 10.1016/j.tiv.2016.01.011 PG 10 WC Toxicology SC Toxicology GA DH4MU UT WOS:000372760900032 PM 26820057 ER PT J AU Wu, YF Beland, FA Fang, JL AF Wu, Yuanfeng Beland, Frederick A. Fang, Jia-Long TI Effect of triclosan, triclocarban, 2,2 ',4 ',-tetrabromodiphenyl ether, and bisphenol A on the iodide uptake, thyroid peroxidase activity, and expression of genes involved in thyroid hormone synthesis SO TOXICOLOGY IN VITRO LA English DT Article DE Thyroid disruptors; Iodide uptake; Thyroid hormone synthesis; Thyroid peroxidase ID POLYBROMINATED DIPHENYL ETHERS; IN-VIVO EXPOSURE; SODIUM/IODIDE SYMPORTER; FLAME RETARDANTS; CELL-LINE; VITAMIN-A; RAT; THYROXINE; SERUM; DISRUPTION AB Triclosan, triclocarban, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), and bisphenol A (BPA) have been reported to disturb thyroid hormone (TH) homeostasis. We have examined the effects of these chemicals on sodium/iodide symporter (NIS)-mediated iodide uptake and the expression of genes involved in TH synthesis in rat thyroid follicular FRTL-5 cells, and on the activity of thyroid peroxidase (TPO) using rat thyroid microsomes. All four chemicals inhibited NIS-mediated iodide uptake in a concentration-dependent manner. A decrease in the iodide uptake was also observed in the absence of sodium iodide. Kinetic studies showed that all four chemicals were non-competitive inhibitors of NIS, with the order of K-i values being triclosan < triclocarban < BDE-47 < BPA. The transcriptional expression of three genes involved in TH synthesis, Slc5a5, Tpo, and Tgo, and three thyroid transcription factor genes, Pax8, Foxe1, and Nkx2-1, was examined using quantitative real-time PCR. No significant changes in the expression of any genes were observed with triclosan or triclocarban. BDE-47 decreased the level of Tpo, while BPA altered the expression of all six genes. Triclosan and triclocarban inhibited the activity of TPO at 166 and >300 mu M, respectively. Neither BDE-47 nor BPA affected TPO activity. In conclusion, triclosan, triclocarban, BDE-47, and BPA inhibited iodide uptake, but had differential effects on the expression of TH synthesis-related genes and the activity of TPO. Published by Elsevier Ltd. C1 [Wu, Yuanfeng; Beland, Frederick A.; Fang, Jia-Long] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Fang, JL (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM jia-long.fang@fda.hhs.gov FU National Center for Toxicological Research, U.S. Food and Drug Administration (FDA) [FDA IAG: 224-07-0007, NIH Y1ES1027]; National Toxicology Program, National Institute of Environmental Health Sciences [FDA IAG: 224-07-0007, NIH Y1ES1027] FX This research was supported through an interagency agreement between the National Center for Toxicological Research, U.S. Food and Drug Administration (FDA) and the National Toxicology Program, National Institute of Environmental Health Sciences. (FDA IAG: 224-07-0007; NIH Y1ES1027). NR 56 TC 4 Z9 4 U1 4 U2 14 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 APR PY 2016 VL 32 BP 310 EP 319 DI 10.1016/j.tiv.2016.01.014 PG 10 WC Toxicology SC Toxicology GA DH4MU UT WOS:000372760900034 PM 26827900 ER PT J AU Shan, J Alam, SK Garra, B Zhang, YT Ahmed, T AF Shan, Juan Alam, S. Kaisar Garra, Brian Zhang, Yingtao Ahmed, Tahira TI COMPUTER-AIDED DIAGNOSIS FOR BREAST ULTRASOUND USING COMPUTERIZED BI-RADS FEATURES AND MACHINE LEARNING METHODS SO ULTRASOUND IN MEDICINE AND BIOLOGY LA English DT Article DE Breast cancer; Computer-aided diagnosis; Computerized features; Breast Imaging Reporting and Data System; BI-RADS; Machine learning; Receiver operating characteristic; Tissue characterization; Tumor classification; Ultrasonic imaging ID SUPPORT VECTOR MACHINES; MASSES; CANCER; BENIGN; IMAGES; DIFFERENTIATION; CLASSIFICATION; SONOGRAPHY; STATISTICS; LESIONS AB This work identifies effective computable features from the Breast Imaging Reporting and Data System (BI-RADS), to develop a computer-aided diagnosis (CAD) system for breast ultrasound. Computerized features corresponding to ultrasound BI-RADs categories were designed and tested using a database of 283 pathology-proven benign and malignant lesions. Features were selected based on classification performance using a "bottom-up'' approach for different machine learning methods, including decision tree, artificial neural network, random forest and support vector machine. Using 10-fold cross-validation on the database of 283 cases, the highest area under the receiver operating characteristic (ROC) curve (AUC) was 0.84 from a support vector machine with 77.7% overall accuracy; the highest overall accuracy, 78.5%, was from a random forest with the AUC 0.83. Lesion margin and orientation were optimum features common to all of the different machine learning methods. These features can be used in CAD systems to help distinguish benign from worrisome lesions. (E-mail: jshan@pace.edu) (C) 2016 World Federation for Ultrasound in Medicine & Biology. C1 [Shan, Juan] Pace Univ, Seidenberg Sch Comp Sci & Informat Syst, Dept Comp Sci, 163 William St, New York, NY 10038 USA. [Alam, S. Kaisar] Improlabs Pte Ltd, Valley Point, Singapore. [Alam, S. Kaisar] Rutgers State Univ, Computat Biomed Imaging & Modeling Ctr CBIM, Piscataway, NJ USA. [Alam, S. Kaisar] Islamic Univ Technol, Dept Elect & Elect Engn, Gazipur, Bangladesh. [Garra, Brian] US FDA, Silver Spring, MD USA. [Garra, Brian; Ahmed, Tahira] Washington DC Vet Affairs Med Ctr, Washington, DC USA. [Zhang, Yingtao] Harbin Inst Technol, Sch Comp Sci & Technol, Harbin 150006, Peoples R China. RP Shan, J (reprint author), Pace Univ, Seidenberg Sch Comp Sci & Informat Syst, Dept Comp Sci, 163 William St, New York, NY 10038 USA. EM jshan@pace.edu NR 23 TC 1 Z9 1 U1 7 U2 13 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 APR PY 2016 VL 42 IS 4 BP 980 EP 988 DI 10.1016/j.ultrasmedbio.2015.11.016 PG 9 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA DI3FT UT WOS:000373384700017 PM 26806441 ER PT J AU Mays, D Arrazola, RA Tworek, C Rolle, IV Neff, LJ Portnoy, DB AF Mays, Darren Arrazola, Rene A. Tworek, Cindy Rolle, Italia V. Neff, Linda J. Portnoy, David B. TI Openness to Using Non-cigarette Tobacco Products Among US Young Adults SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID HARM PERCEPTIONS; COLLEGE-STUDENTS; UNITED-STATES; SMOKING; PREVALENCE; AWARENESS; USERS AB Introduction: National data indicate that the prevalence of non-cigarette tobacco product use is highest among young adults; however, little is known about their openness to use these products in the future and associated risk factors. This study sought to characterize openness to using non cigarette tobacco products and associated factors among U.S. young adults. Methods: In 2014, National Adult Tobacco Survey data (2012-2013) were analyzed to characterize openness to using the following tobacco products among all young adults aged 18-29 years (N=5,985): cigars; electronic cigarettes ("e-cigarettes"); hookah; pipe tobacco; chew, snuff, or dip; snus; and dissolvables. Among those who were not current users of each product, multivariable logistic regression was used to examine associations between demographics, cigarette smoking status, lifetime use of other non-cigarette products, perceived harm and addictiveness of smoking, and receipt of tobacco industry promotions and openness to using each product. Results: Among all young adults, openness to using non-cigarette tobacco products was greatest for hookah (28.2%); e-cigarettes (25.5%); and cigars (19.1%). In multivariable analyses, which included non-current users of each product, non-current ever, current, and former smokers were more likely than never smokers to be open to using most examined products, as were men and adults aged 18-24 years. Receipt of tobacco industry promotions was associated with openness to using e-cigarettes; chew, snuff, or dip; and snus. Conclusions: There is substantial openness to trying non-cigarette tobacco products among U.S. young adults. Young adults are an important population to consider for interventions targeting non-cigarette tobacco product use. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Mays, Darren] US FDA, Tobacco Regulatory Sci Fellowship Program, Silver Spring, MD 20993 USA. [Mays, Darren] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Arrazola, Rene A.; Rolle, Italia V.; Neff, Linda J.] CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Tworek, Cindy; Portnoy, David B.] US FDA, Off Sci, Ctr Tobacco Prod, 10903 New Hampshire Ave,Bldg 71,Room G335, Silver Spring, MD 20993 USA. RP Portnoy, DB (reprint author), US FDA, Off Sci, Ctr Tobacco Prod, 10903 New Hampshire Ave,Bldg 71,Room G335, Silver Spring, MD 20993 USA. EM david.portnoy@fda.hhs.gov OI Portnoy, David/0000-0003-2175-9457 FU U.S. Food and Drug Administration (FDA) Center for Tobacco Products; U.S. CDC Office on Smoking and Health FX The 2012-2013 National Adult Tobacco Survey was supported by the U.S. Food and Drug Administration (FDA) Center for Tobacco Products and the U.S. CDC Office on Smoking and Health. The findings and conclusions in this report are those of the authors and do not necessarily represent the official positions or policies of the FDA or CDC. The information in this article is not a formal dissemination of information by either the FDA or CDC. The authors thank Dr. Sean Hu (CDC); Lieutenant Kimberly Nguyen (CDC); Dr. Bridget Ambrose (FDA); Dr. Hannah Day (FDA); and Mr. Enver Holder-Hayes (FDA) for their assistance in data stewardship of the 2012-2013 National Adult Tobacco Survey. NR 26 TC 2 Z9 2 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD APR PY 2016 VL 50 IS 4 BP 528 EP 534 DI 10.1016/j.amepre.2015.08.015 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DH1RP UT WOS:000372562900012 PM 26549502 ER PT J AU McKinnon, RA Siddiqi, SM Chaloupka, FJ Mancino, L Prasad, K AF McKinnon, Robin A. Siddiqi, Sameer M. Chaloupka, Frank J. Mancino, Lisa Prasad, Kislaya TI Obesity-Related Policy/Environmental Interventions A Systematic Review of Economic Analyses SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID NUTRITION EDUCATION-PROGRAM; BODY-MASS INDEX; COST-EFFECTIVENESS; PREVENTION PROGRAM; EXPANDED FOOD; NATURAL EXPERIMENT; PHYSICAL-ACTIVITY; UNITED-STATES; CARE COSTS; HEALTH AB Context: Policy and environmental changes to support and encourage individual-level nutrition and physical activity behavior are underway in many parts of the U.S. and around the world at national, state, and local levels. Yet, to the authors' knowledge, no summary of the cost-benefit or cost-effectiveness studies of obesity-related policy/environmental interventions exists. Evidence acquisition: The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta Analyses) statement guidelines were followed to identify, screen, and describe the protocols used in this systematic review. In 2014, a unique search was conducted of titles and abstracts in MEDLINE, EconLit, SCOPUS, and Web of Science databases that were published from January 2002 through January 2014 in English-language, peer-reviewed journals. The search terms described obesity, physical activity, and diet in combination with economic evaluation. Evidence synthesis: In 2014 and 2015, the results were analyzed. A total of 27 studies met the inclusion criteria, of which 26 described separate interventions. Of the 27 included studies, eight focused on the community and built environment, seven assessed nutrition-related changes, nine reported on the school environment, and three evaluated social marketing and media interventions. The vast majority of included studies reported beneficial economic outcomes of the interventions. Conclusions: Given the large and growing literature on the health and behavioral outcomes of policy and environmental interventions, the relatively low number of located cost-beneft and cost-effectiveness economic assessments appears to indicate a prime opportunity for the research community to address. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [McKinnon, Robin A.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [McKinnon, Robin A.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Siddiqi, Sameer M.] Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Chaloupka, Frank J.] Univ Illinois, Inst Hlth Res & Policy, Ctr Hlth Policy, Chicago, IL USA. [Mancino, Lisa] Econ Res Serv, USDA, Washington, DC USA. [Prasad, Kislaya] Univ Maryland, Robert H Smith Sch Business, College Pk, MD 20742 USA. RP McKinnon, RA (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM robin.mckinnon@fda.hhs.gov FU Robert Wood Johnson Foundation FX The authors are grateful to Penny Randall-Levy for expert referencing support. Funding for Frank J. Chaloupka's time was supported by the Robert Wood Johnson Foundation's grant to the University of Illinois at Chicago for the Bridging the Gap program. NR 56 TC 1 Z9 1 U1 9 U2 33 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 APR PY 2016 VL 50 IS 4 BP 543 EP 549 DI 10.1016/j.amepre.2015.10.021 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DH1RP UT WOS:000372562900014 PM 26707464 ER PT J AU Park, M Deck, J Foley, SL Nayak, R Songer, JG Seibel, JR Khan, SA Rooney, AP Hecht, DW Rafii, F AF Park, Miseon Deck, Joanna Foley, Steven L. Nayak, Rajesh Songer, J. Glenn Seibel, Janice R. Khan, Saeed A. Rooney, Alejandro P. Hecht, David W. Rafii, Fatemeh TI Diversity of Clostridium perfringens isolates from various sources and prevalence of conjugative plasmids SO ANAEROBE LA English DT Article DE Clostridium perfringens; Plasmid; Epidemiology; Diversity; PFGE ID TOXIN PLASMIDS; GEL-ELECTROPHORESIS; GENETIC DIVERSITY; STRAINS AB Clostridium perfringens is an important pathogen, causing food poisoning and other mild to severe infections in humans and animals. Some strains of C. perfringens contain conjugative plasmids, which may carry antimicrobial resistance and toxin genes. We studied genomic and plasmid diversity of 145 C. perfringens type A strains isolated from soils, foods, chickens, clinical samples, and domestic animals (porcine, bovine and canine), from different geographic areas in the United States between 1994 and 2006, using multiple-locus variable-number tandem repeat analysis (MLVA) and/or pulsed-field gel electrophoresis (PFGE). MLVA detected the genetic diversity in a majority of the isolates. PFGE, using SmaI and KspI, confirmed the MLVA results but also detected differences among the strains that could not be differentiated by MLVA. All of the PFGE profiles of the strains were different, except for a few of the epidemiologically related strains, which were identical. The PFGE profiles of strains isolated from the same domestic animal species were clustered more closely with each other than with other strains. However, a variety of C. perfringens strains with distinct genetic backgrounds were found among the clinical isolates. Variation was also observed in the size and number of plasmids in the strains. Primers for the internal fragment of a conjugative tcpH gene of C. perfringens plasmid pCPF4969 amplified identical size fragments from a majority of strains tested; and this gene hybridized to the various-sized plasmids of these strains. The sequences of the PCR-amplified tcpH genes from 12 strains showed diversity among the tcpH genes. Regardless of the sources of the isolates, the genetic diversity of C. perfringens extended to the plasmids carrying conjugative genes. Published by Elsevier Ltd. C1 [Park, Miseon; Deck, Joanna; Foley, Steven L.; Nayak, Rajesh; Khan, Saeed A.; Rafii, Fatemeh] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Songer, J. Glenn] Univ Arizona, Tucson, AZ 85721 USA. [Seibel, Janice R.] Iowa State Univ, Ames, IA 50011 USA. [Rooney, Alejandro P.] ARS, Crop Protect Res Unit, Natl Ctr Agr Utilizat Res, USDA, Peoria, IL 61604 USA. [Hecht, David W.] Loyola Univ, Med Ctr, Div Infect Dis, Maywood, IL 60126 USA. RP Rafii, F (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM fatemeh.rafii@fda.hhs.gov NR 31 TC 1 Z9 2 U1 1 U2 12 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 APR PY 2016 VL 38 BP 25 EP 35 DI 10.1016/j.anaerobe.2015.11.003 PG 11 WC Microbiology SC Microbiology GA DG9FG UT WOS:000372387600005 PM 26608548 ER PT J AU Wagner, C Pan, YZ Hsu, V Sinha, V Zhao, P AF Wagner, Christian Pan, Yuzhuo Hsu, Vicky Sinha, Vikram Zhao, Ping TI Predicting the Effect of CYP3A Inducers on the Pharmacokinetics of Substrate Drugs Using Physiologically Based Pharmacokinetic (PBPK) Modeling: An Analysis of PBPK Submissions to the US FDA SO CLINICAL PHARMACOKINETICS LA English DT Article ID INDUCTION DATA AB Background and Objective We recently published analyses regarding the predictive performance of physiologically based pharmacokinetic (PBPK) models, submitted to the US Food and Drug Administration (FDA), for the effect of cytochrome P450 (CYP) inhibitors on the pharmacokinetics of substrate drugs. We now analyze and summarize the predictive performance of PBPK models for the effect of CYP3A inducers on a substrate's pharmacokinetics. Methods This analysis was based on 11 substrate PBPK models, developed by six sponsors, using a commercial PBPK software, with 13 clinical interaction studies. Four CYP3A inducers were used: rifampicin, rifabutin, carbamazepine, and efavirenz. Sponsors either directly used the software-provided inducer models or verified these models' induction magnitude prior to use. The metric for assessing predictive performance was the R-predicted/observed value [R-predicted/observed = (predicted mean exposure ratio)/(observed mean exposure ratio)], with the exposure ratio defined as maximum plasma concentration (C-max) or area under the plasma concentration-time curve (AUC) with and without an inducer. Results In 77 % (10/13; AUCR) and 83 % (10/12; C-max R) of the cases, the R-predicted/observed values were within 1.25-fold of the observed data. Cases with R-predicted/observed values >1.25-fold (>twofold for all three AUCR) were under-predictions as a result of using the PBPK software's default rifampicin model. Improved predictions were observed when the rifampicin model was modified by increasing the induction potency. Conclusion Based on submissions to the FDA, and similar to our previous findings for CYP inhibition, we observed good agreement between PBPK-predicted and observed effect of CYP3A inducers on substrate pharmacokinetics. Verification of the inducer model appears to be crucial for improved predictive performance. C1 [Wagner, Christian; Hsu, Vicky; Sinha, Vikram; Zhao, Ping] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Pan, Yuzhuo] US FDA, Off Bioequivalence, Div 2, Off Gener Drugs,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Zhao, P (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM ping.zhao@fda.hhs.gov NR 7 TC 8 Z9 8 U1 0 U2 1 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 APR PY 2016 VL 55 IS 4 BP 475 EP 483 DI 10.1007/s40262-015-0330-y PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DH1FI UT WOS:000372529400006 PM 26369776 ER PT J AU Sertkaya, A Wong, HH Jessup, A Beleche, T AF Sertkaya, Aylin Wong, Hui-Hsing Jessup, Amber Beleche, Trinidad TI Key cost drivers of pharmaceutical clinical trials in the United States SO CLINICAL TRIALS LA English DT Article DE Clinical trial cost; cost drivers; clinical procedure costs; site retention costs; site monitoring costs; administrative staff costs ID DRUG DEVELOPMENT; PROTOCOL DESIGN AB Background: The increasing cost of clinical research has significant implications for public health, as it affects drug companies' willingness to undertake clinical trials, which in turn limits patient access to novel treatments. Thus, gaining a better understanding of the key cost drivers of clinical research in the United States is important. Purpose: The study which is based on a report prepared by Eastern Research Group, Inc., for the US Department of Health and Human Services, examined different factors, such as therapeutic area, patient recruitment, administrative staff, and clinical procedure expenditures, and their contribution to pharmaceutical clinical trial costs in the United States by clinical trial phase. Methods: The study used aggregate data from three proprietary databases on clinical trial costs provided by Medidata Solutions. We evaluated per-study costs across therapeutic areas by aggregating detailed (per patient and per site) cost information. We also compared average expenditures on cost drivers with the use of weighted mean and standard deviation statistics. Results: Therapeutic area was an important determinant of clinical trial costs by phase. The average cost of a Phase 1 study conducted at a US site ranged from US$1.4million (pain and anesthesia) to US$6.6million (immunomodulation), including estimated site overhead and monitoring costs of the sponsoring organization. A Phase 2 study cost from US$7.0million (cardiovascular) to US$19.6million (hematology), whereas a Phase 3 study cost ranged from US$11.5million (dermatology) to US$52.9 (pain and anesthesia) on average. Across all study phases and excluding estimated site overhead costs and costs for sponsors to monitor the study, the top three cost drivers of clinical trial expenditures were clinical procedure costs (15%-22% of total), administrative staff costs (11%-29% of total), and site monitoring costs (9%-14% of total). Limitations: The data were from 2004 through 2012 and were not adjusted for inflation. Additionally, the databases used represented a convenience, that is, non-probability, sample and did not allow for statistically valid estimates of cost drivers. Finally, the data were from trials funded by the global pharmaceutical and biotechnology industry only. Hence, our study findings are limited to that segment. Conclusion: Therapeutic area being studied as well as number and types of clinical procedures involved were the key drivers of direct costs in Phase 1 through Phase 3 studies. Research shows that strategies exist for reducing the price tag of some of these major direct cost components. Therefore, to increase clinical trial efficiency and reduce costs, gaining a better understanding of the key direct cost drivers is an important step. C1 [Sertkaya, Aylin] Eastern Res Grp Inc, 110 Hartwell Ave, Lexington, MA 02421 USA. [Wong, Hui-Hsing; Jessup, Amber] US Dept Hlth & Human Serv, Off Sci & Data Policy, Off Assistant Secretary Planning & Evaluat, Washington, DC USA. [Beleche, Trinidad] US FDA, Off Commissioner, Dept Hlth & Human Serv, Silver Spring, MD USA. RP Sertkaya, A (reprint author), Eastern Res Grp Inc, 110 Hartwell Ave, Lexington, MA 02421 USA. EM aylin.sertkaya@erg.com FU US Department of Health and Human Services Office of the Assistant Secretary for Planning and Evaluation [HHSP23320095634WC, HHSP23337007T] FX The funding for this study was provided by the US Department of Health and Human Services Office of the Assistant Secretary for Planning and Evaluation (Contract No. HHSP23320095634WC Task Order No. HHSP23337007T). NR 28 TC 5 Z9 5 U1 9 U2 14 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 APR PY 2016 VL 13 IS 2 BP 117 EP 126 DI 10.1177/1740774515625964 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DG8AY UT WOS:000372306000001 PM 26908540 ER PT J AU Levin, G AF Levin, Gregory TI Avoiding bias and incorrect confidence interval coverage in prescription drug labeling SO CLINICAL TRIALS LA English DT Article DE Clinical trials; prescription drug labeling; regulation; estimation; bias; confidence interval AB Background: The primary purpose of prescription drug labeling is to give healthcare professionals the information needed to prescribe drugs appropriately. Therefore, labeling typically reports the effects that the treatment might be expected to have on several efficacy measures, including not only the primary endpoint used to establish effectiveness but also a number of key secondary endpoints that are important to practitioners and patients. Methods: One possible regulatory approach to drug labeling is to include results on important secondary efficacy endpoints in labeling only if there is statistical evidence of a treatment effect and a clinically meaningful estimated effect. We evaluate the statistical consequences of this approach by deriving and discussing the potential bias in point estimates and deviation from nominal coverage in confidence intervals that are reported in labeling. Results: Such an approach can lead to substantial conditional bias in point estimates (toward spuriously greater effects than the truth) and undercoverage in confidence intervals. Conclusion: These statistical properties may have important and undesirable regulatory and public health implications. We discuss an alternative approach to include results in labeling for a selected set of reliably ascertained, clinically important endpoints whether or not there is evidence of a treatment effect. C1 [Levin, Gregory] US FDA, Silver Spring, MD 20993 USA. RP Levin, G (reprint author), US FDA, Silver Spring, MD 20993 USA. EM Gregory.Levin@fda.hhs.gov NR 8 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 APR PY 2016 VL 13 IS 2 BP 199 EP 204 DI 10.1177/1740774515615097 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DG8AY UT WOS:000372306000010 PM 26572563 ER PT J AU Williams, M Backhaus, T Bowe, C Choi, K Connors, K Hickmann, S Hunter, W Kookana, R Marfil-Vega, R Verslycke, T AF Williams, Mike Backhaus, Thomas Bowe, Craig Choi, Kyungho Connors, Kristin Hickmann, Silke Hunter, Wesley Kookana, Rai Marfil-Vega, Ruth Verslycke, Tim TI PHARMACEUTICALS IN THE ENVIRONMENT: AN INTRODUCTION TO THE ET&C SPECIAL ISSUE SO ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY LA English DT Editorial Material ID PERSONAL CARE PRODUCTS; VETERINARY MEDICINES; PIMEPHALES-PROMELAS; AQUATIC TOXICITY; RISK-ASSESSMENT; DRINKING-WATER; FISH; EXPOSURE; POPULATION; SERTRALINE C1 [Williams, Mike; Kookana, Rai] CSIRO Land & Water, Floreat, SA, Australia. [Backhaus, Thomas] Univ Gothenburg, Dept Biol & Environm Sci, Gothenburg, Sweden. [Bowe, Craig] Ohio Univ, Dept Sci, Ironton, OH USA. [Choi, Kyungho] Seoul Natl Univ, Sch Publ Hlth, Seoul, South Korea. [Connors, Kristin] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. [Hickmann, Silke] German Environm Agcy, Environm Risk Assessment Pharmaceut, Dessau Rosslau, Germany. [Hunter, Wesley] US FDA, Ctr Vet Med, Rockville, MD 20857 USA. [Marfil-Vega, Ruth] Amer Water, Belleville, IL USA. [Verslycke, Tim] Gradient, Cambridge, MA USA. RP Williams, M (reprint author), CSIRO Land & Water, Floreat, SA, Australia. EM mike.williams@csiro.au RI Williams, Mike/I-1724-2013; Kookana, Rai/A-5170-2012; OI Kookana, Rai/0000-0002-0477-3284; Connors, Kristin/0000-0002-4887-8408 NR 54 TC 0 Z9 0 U1 6 U2 22 PU WILEY-BLACKWELL 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 APR PY 2016 VL 35 IS 4 BP 763 EP 766 DI 10.1002/etc.3394 PG 4 WC Environmental Sciences; Toxicology SC Environmental Sciences & Ecology; Toxicology GA DH0RB UT WOS:000372490300001 PM 27003718 ER PT J AU Sokolic, R Iyengar, S Scalchunes, C Mangurian, C Albert, M Varni, JW Cowan, M AF Sokolic, Rob Iyengar, Sumathi Scalchunes, Christopher Mangurian, Christina Albert, Michael Varni, James W. Cowan, Morton TI QUALITY OF LIFE (QOL) IN PATIENTS WITH WISKOTT-ALDRICH SYNDROME (WAS) SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Sokolic, Rob] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Iyengar, Sumathi] Wiskott Aldrich Fdn, Smyrna, GA USA. [Scalchunes, Christopher] Immune Deficiency Fdn, Towson, MD USA. [Mangurian, Christina] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Albert, Michael] Univ Childrens Hosp, Munich, Germany. [Varni, James W.] Texas A&M Univ, Dept Pediat, College Stn, TX USA. [Cowan, Morton] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4215 BP 237 EP 237 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300014 ER PT J AU Rosen, LB Glowinski, RM Berger, M Browne, SK Holland, SM AF Rosen, Lindsey B. Glowinski, Rebecca M. Berger, Melvin Browne, Sarah K. Holland, Steven M. TI CHARACTERIZATION OF ANTICYTOKINE AUTOANTIBODIES IN INTRAVENOUS IMMUNOGLOBULIN (IVIG) PREPARATIONS SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Rosen, Lindsey B.; Glowinski, Rebecca M.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Berger, Melvin] CSL Behring LLC, Immunol R&D, King Of Prussia, PA USA. [Browne, Sarah K.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4457 BP 270 EP 271 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300096 ER PT J AU Uzel, G Ouyang, W Pittaluga, S Schindler, M Su, H Koneti, R Su, HC Agharahimi, A Hussey, AA Hsu, AP Meffre, E Holland, SM AF Uzel, Gulbu Ouyang, Weiming Pittaluga, Stefania Schindler, Matthew Su, Hua Koneti, Rao Su, Helen C. Agharahimi, Anahita Hussey, Ashleigh A. Hsu, Amy P. Meffre, Eric Holland, Steven M. TI MANY FACES OF CTLA-4 HAPLOINSUFFICIENCY; EXPANDING DISEASE SPECTRUM WITH PATHOLOGIC, IMMUNOLOGIC AND MOLECULAR FINDINGS IN A LARGE COHORT SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Uzel, Gulbu] NIAID, Lab Clin Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ouyang, Weiming] US FDA, Lab Cell Biol, Div Monoclonal Antibodies, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Pittaluga, Stefania] NIH, Hematopathol Sect, Bldg 10, Bethesda, MD 20892 USA. [Schindler, Matthew] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Su, Hua; Koneti, Rao; Hussey, Ashleigh A.; Hsu, Amy P.; Holland, Steven M.] NIAID, NIH, LCID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Su, Helen C.] NIAID, Lab Host Def, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Agharahimi, Anahita] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Meffre, Eric] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4683 BP 332 EP 332 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300234 ER PT J AU Andrade, SE Toh, S Houstoun, M Mott, K Pitts, M Kieswetter, C Ceresa, C Haffenreffer, K Reichman, ME AF Andrade, Susan E. Toh, Sengwee Houstoun, Monika Mott, Katrina Pitts, Marilyn Kieswetter, Caren Ceresa, Carrie Haffenreffer, Katherine Reichman, Marsha E. TI Surveillance of Medication Use During Pregnancy in the Mini-Sentinel Program SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Pregnancy; Prescription medications; Surveillance ID PRESCRIPTION DRUG-USE; WOMEN AB Objectives Mini-Sentinel is a pilot project sponsored by the U.S. Food and Drug Administration to create an active surveillance system to monitor the safety of FDA-regulated medical products. We assessed the capability of the Mini-Sentinel pilot to provide prevalence rates of medication use among pregnant women delivering a liveborn infant. Methods An algorithm was developed to identify pregnancies for a reusable analytic tool to be executed against the Mini-Sentinel Distributed Database. Diagnosis and procedure codes were used to identify women ages 10-54 years delivering a liveborn infant between April 2001 and December 2012. A comparison group of age- and date-matched nonpregnant women was identified. The analytic code was distributed to all 18 Mini-Sentinel data partners. The use of specific medications, selected because of concerns about their safe use during pregnancy, was identified from outpatient dispensing data. We determined the frequency of pregnancy episodes and nonpregnant episodes exposed to medications of interest, any time during the pregnant/matched nonpregnant period, and during each trimester. Results The analytic tool successfully identified 1,678,410 live birth deliveries meeting the eligibility criteria. The prevalence of use at any time during pregnancy was 0.38 % for angiotensin-converting enzyme inhibitors and 0.22 % for statins. For a parts per thousand currency sign0.05 % of pregnancy episodes, the woman was dispensed warfarin, methotrexate, ribavirin, or mycophenolate. Conclusions The analytic tool developed for this study can be used to assess the use of medications during pregnancy as safety issues arise, and is adaptable to include different medications, observation periods, pre-existing conditions, and enrollment criteria. C1 [Andrade, Susan E.] Reliant Med Grp, Fallon Community Hlth Plan, Meyers Primary Care Inst, 630 Plantat St, Worcester, MA 01605 USA. [Andrade, Susan E.] Univ Massachusetts, Sch Med, Meyers Primary Care Inst, 630 Plantat St, Worcester, MA 01605 USA. [Toh, Sengwee; Haffenreffer, Katherine] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA 02115 USA. [Toh, Sengwee; Haffenreffer, Katherine] Harvard Pilgrim Hlth Care Inst, Boston, MA 02115 USA. [Houstoun, Monika; Mott, Katrina; Pitts, Marilyn; Kieswetter, Caren; Ceresa, Carrie; Reichman, Marsha E.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Andrade, SE (reprint author), Reliant Med Grp, Fallon Community Hlth Plan, Meyers Primary Care Inst, 630 Plantat St, Worcester, MA 01605 USA.; Andrade, SE (reprint author), Univ Massachusetts, Sch Med, Meyers Primary Care Inst, 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] FX This study was supported through funding from contract HHSF223200910006I, Task Order No. HHSF22301007T 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 results interpretation 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 19 TC 2 Z9 2 U1 1 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD APR PY 2016 VL 20 IS 4 BP 895 EP 903 DI 10.1007/s10995-015-1878-8 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG6BR UT WOS:000372167700019 PM 26645616 ER PT J AU Privitera, MD Welty, TE Gidal, BE Diaz, FJ Krebill, R Szaflarski, JP Dworetzky, BA Pollard, JR Elder, EJ Jiang, WL Jiang, XH Berg, M AF Privitera, Michael D. Welty, Timothy E. Gidal, Barry E. Diaz, Francisco J. Krebill, Ron Szaflarski, Jerzy P. Dworetzky, Barbara A. Pollard, John R. Elder, Edmund J., Jr. Jiang, Wenlei Jiang, Xiaohui Berg, Michel TI Generic-to-generic lamotrigine switches in people with epilepsy: the randomised controlled EQUIGEN trial SO LANCET NEUROLOGY LA English DT Article ID ANTIEPILEPTIC DRUGS; SUBSTITUTION; BIOEQUIVALENCE; FORMULATION; COMPASS; EVENTS AB Background Patients and clinicians share concerns that generic drug substitution might lead to loss of efficacy or emergence of adverse events. In this trial, we assessed US Food and Drug Administration (FDA) bioequivalence standards by studying the effects of switching between two disparate generic immediate-release lamotrigine products in patients with epilepsy. Methods The Equivalence among Generic Antiepileptic Drugs (EQUIGEN) chronic-dose study was a randomised, double-blind, crossover study that enrolled adults (aged >= 18 years) with epilepsy from six epilepsy centres at academic institutions across the USA who were receiving immediate-release lamotrigine dosed at 100 mg, 200 mg, 300 mg, or 400 mg twice daily. Eligible patients were randomly allocated (1:1) to one of two treatment sequences (sequence 1 or sequence 2), comprising four study periods of 14 days each. During each 14-day treatment period, patients received balanced doses of an oral generic lamotrigine product every 12 h (200-800 mg total, identical to lamotrigine dose prior to study enrolment); after each 14-day period, patients were crossed over to receive the other generic product. Computer-based randomisation was done using random permuted blocks of size two or four for each site to prevent sequence predictability. Both patients and study personnel were masked to the generic products selected, their predicted exposure (ie, "high" vs "low"), and their group allocation. The primary outcome of this trial was bioequivalence between the generic products, which was assessed at the end of the study through a comparison of maximum plasma concentration (C-max) and area under the concentration-time curve (AUC) for each product in the analysis population (all patients who completed all four treatment periods). Bioequivalence was established if the 90% CIs of the ratios of these two parameters for the two products were within equivalence limits (80-125%) in the analysis population. This study is registered with ClinicalTrials.gov, number NCT01713777. Findings Between April 25, 2013, and Aug 12, 2014, 35 eligible patients were enrolled and randomly assigned to treatment sequence 1 (n=15) or treatment sequence 2 (n=20). 33 patients completed all four treatment periods and were included in the primary outcome analysis. The 90% CIs of the ratios of both C-max and AUC were within equivalence limits (AUC 90% CI 98-103, C-max 90% CI 99-105), showing that lamotrigine exposures were equivalent between the generic products. No significant changes in seizure frequency or adverse events were recorded. No deaths, study-related serious adverse events, or changes in clinical laboratory values or vital signs occurred during this study. Interpretation Disparate generic lamotrigine products in patients with epilepsy showed bioequivalence with no detectable difference in clinical effects, confirming that US Food and Drug Administration bioequivalence standards are appropriate. C1 [Privitera, Michael D.] Univ Cincinnati, Med Ctr, Cincinnati, OH 45267 USA. [Welty, Timothy E.] Drake Univ, Coll Pharm & Hlth Sci, Des Moines, IA 50311 USA. [Gidal, Barry E.] Univ Wisconsin, Sch Pharm, 425 N Charter St, Madison, WI 53706 USA. [Gidal, Barry E.] Univ Wisconsin, Dept Neurol, 425 N Charter St, Madison, WI 53706 USA. [Diaz, Francisco J.; Krebill, Ron] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66103 USA. [Szaflarski, Jerzy P.] Univ Alabama Birmingham, Dept Neurol, UAB Stn, Birmingham, AL 35294 USA. [Dworetzky, Barbara A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurol, Boston, MA USA. [Pollard, John R.] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Elder, Edmund J., Jr.] Univ Wisconsin, Zeeh Pharmaceut Expt Stn, Madison, WI USA. [Jiang, Wenlei; Jiang, Xiaohui] Food & Drug Adm, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Berg, Michel] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA. RP Privitera, MD (reprint author), Univ Cincinnati, Med Ctr 0525, 260 Stetson St,Suite 2300, Cincinnati, OH 45267 USA. EM privitmd@ucmail.uc.edu FU American Epilepsy Society; Epilepsy Foundation; US Food and Drug Administration FX American Epilepsy Society, Epilepsy Foundation, and US Food and Drug Administration. NR 26 TC 12 Z9 12 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD APR PY 2016 VL 15 IS 4 BP 365 EP 372 DI 10.1016/S1474-4422(16)00014-4 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DG3MP UT WOS:000371974000016 PM 26875743 ER PT J AU Zhu, M Yancy, HF Deaver, C Jones, YL Myers, MJ AF Zhu, M. Yancy, H. F. Deaver, C. Jones, Y. L. Myers, M. J. TI Loperamide-induced expression of immune and inflammatory genes in Collies associated with ivermectin sensitivity SO JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS LA English DT Article ID BLOOD-BRAIN-BARRIER; P-GLYCOPROTEIN; MULTIDRUG SENSITIVITY; INTERLEUKIN-8 IL-8; BREED DISTRIBUTION; MUTATION; CHEMOKINES; FREQUENCY; SAMPLE; BIOMARKERS AB This study evaluated the impact of the ABCB1-1 mutation in Collies which exhibited toxicity toward ivermectin, on changes in gene expression when given the unrelated ABCB1 substrate loperamide, to identify potential biomarkers predictive of drug safety. Thirty-two healthy intact Collies consisting of dogs with either a wild-type, heterozygous mutant, or homozygous mutant genotype were used. Whole blood samples were collected from Collies at 0or 5h following administration of loperamide at a dose of 0.10mg/kg. Whole-genome gene expression microarray was conducted to examine for changes in gene expression. Microarray analysis identified loperamide-induced changes in gene expression which were specifically associated with ivermectin-sensitive phenotypes in Collies possessing the ABCB1-1 mutation. Gene pathway analysis further demonstrated that the altered genes are involved in immunological disease, cell death and survival, and cellular development. Thirteen genes, including CCL8 and IL-8, were identified. Collie dogs harboring ABCB1-1 mutation which also exhibited toxicity toward ivermectin demonstrated systematic responses following loperamide treatment exhibited by altered expression of genes involved in immune and inflammatory signaling pathways. Genes such as CCL8 and IL-8 are potential biomarkers in whole blood that may predict the safety of loperamide in dogs with ABCB1-1 mutation associated with ivermectin sensitivity. C1 [Zhu, M.; Yancy, H. F.; Deaver, C.; Jones, Y. L.; Myers, M. J.] US FDA, Ctr Vet Med, Res Off, 8401 Muirkirk Rd, Laurel, MD 20708 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 NR 28 TC 0 Z9 0 U1 0 U2 4 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 APR PY 2016 VL 39 IS 2 BP 131 EP 137 DI 10.1111/jvp.12268 PG 7 WC Pharmacology & Pharmacy; Veterinary Sciences SC Pharmacology & Pharmacy; Veterinary Sciences GA DG0DR UT WOS:000371733600003 PM 26471945 ER PT J AU Chiesa, OA Feng, S Kijak, P Smith, EA Li, H Qiu, J AF Chiesa, O. A. Feng, S. Kijak, P. Smith, E. A. Li, H. Qiu, J. TI Plasma pharmacokinetics of ceftiofur metabolite desfuroylceftiofur cysteine disulfide in holstein steers: application of nonlinear mixed-effects modeling SO JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS LA English DT Article ID LIQUID-CHROMATOGRAPHY; CATTLE; SODIUM; SERUM; MILK; RESIDUE; COWS AB Eight clinically normal and drug-naive Holstein steers were dosed with ceftiofur sodium at 2.2mg/kg body weight intramuscularly. Doses were given at 24-h intervals for 5days. Prior to the first dose and after all injections, blood samples were collected serially for determination of plasma concentrations of one of ceftiofur's main metabolites, desfuroylceftiofur cysteine disulfide (DCCD). A nonlinear mixed-effect model was used to analyze the plasma concentration data. A stochastic approximation expectation maximization (SAEM) algorithm in MONOLIX version 4.2.2 was used to approximate the likelihood of the nonlinear mixed-effect model and to estimate the population parameters. In addition, simulation studies were conducted to justify the model and demonstrate how to interpret the model parameters given different scenarios. C1 [Chiesa, O. A.; Smith, E. A.] US FDA, Ctr Vet Med, Div Appl Vet Res, Res Off, 8401 Muirkirk Rd, Laurel, MD 20708 USA. [Feng, S.; Kijak, P.; Li, H.] US FDA, Ctr Vet Med, Div Residue Chem, Res Off, Laurel, MD 20708 USA. [Qiu, J.] US FDA, Ctr Drug Evaluat & Res, Div 1, Off Biostat, Silver Spring, MD USA. RP Chiesa, OA (reprint author), US FDA, Ctr Vet Med, Div Appl Vet Res, Res Off, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM oscar.chiesa@fda.hhs.gov NR 15 TC 0 Z9 0 U1 5 U2 11 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 APR PY 2016 VL 39 IS 2 BP 149 EP 156 DI 10.1111/jvp.12245 PG 8 WC Pharmacology & Pharmacy; Veterinary Sciences SC Pharmacology & Pharmacy; Veterinary Sciences GA DG0DR UT WOS:000371733600006 PM 26112893 ER PT J AU Sahu, SC Njoroge, J Bryce, SM Zheng, JW Ihrie, J AF Sahu, Saura C. Njoroge, Joyce Bryce, Steven M. Zheng, Jiwen Ihrie, John TI Flow cytometric evaluation of the contribution of ionic silver to genotoxic potential of nanosilver in human liver HepG2 and colon Caco2 cells SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE nanosilver; nanoparticles; genotoxicity; ionic silver; silver acetate; HepG2 cells; Caco2 cells; micronucleus; flow cytometry ID VITRO MICRONUCLEUS ASSAY; NANOPARTICLE-PROTEIN CORONA; IN-VITRO; FOOD-INDUSTRY; CYTOTOXICITY; TOXICITY; APOPTOSIS; MODEL; MITOCHONDRIAL; DISSOLUTION AB Exposure to nanosilver found in food- and cosmetics-related consumer products is of public concern because of the lack of information about its safety. In this study, two widely used in vitro cell culture models, human liver HepG2 and colon Caco2 cells, and the flow cytometric micronucleus (FCMN) assay were evaluated as tools for rapid predictive screening of the potential genotoxicity of nanosilver. Recently, we reported the genotoxicity of 20 nm nanosilver using these systems. In the current study presented here, we tested the hypothesis that the nanoparticle size and cell types were critical determinants of its genotoxicity. To test this hypothesis, we used the FCMN assay to evaluate the genotoxic potential of 50 nm nanosilver of the same shape, composition, surface charge and obtained from the same commercial source using the same experimental conditions and in vitro models (HepG2 and Caco2) as previously tested for the 20 nm silver. Results of our study show that up to the concentrations tested in these cultured cell test systems, the smaller (20 nm) nanoparticle is genotoxic to both the cell types by inducing micronucleus (MN). However, the larger (50 nm) nanosilver induces MN only in HepG2 cells, but not in Caco2 cells. Also in this study, we evaluated the contribution of ionic silver to the genotoxic potential of nanosilver using silver acetate as the representative ionic silver. The MN frequencies in HepG2 and Caco2 cells exposed to the ionic silver in the concentration range tested are not statistically significant from the control values except at the top concentrations for both the cell types. Therefore, our results indicate that the ionic silver may not contribute to the MN-forming ability of nanosilver in HepG2 and Caco2 cells. Also our results suggest that the HepG2 and Caco2 cell cultures and the FCMN assay are useful tools for rapid predictive screening of a genotoxic potential of food- and cosmetics-related chemicals including nanosilver. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Recently, we reported the genotoxicity of 20 nm nanosilver evaluated by the FCMN assay. In this study, we evaluated the genotoxic potential of 50 nm nanosilver of the same shape, composition, surface charge and obtained from the same commercial source using the same experimental conditions, human-derived cells (HepG2 and Caco2) and genotoxic endpoint (FCMN) used for the 20 nm silver. Also, in this study, we evaluated the contribution of ionic silver to the genotoxic potential of nanosilver using silver acetate as the representative ionic silver. C1 [Sahu, Saura C.; Njoroge, Joyce] US FDA, Ctr Food Safety & Appl Nutr, Div Toxicol, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. [Bryce, Steven M.] Litron Labs, Rochester, NY 14623 USA. [Zheng, Jiwen] US FDA, Ctr Devices & Radiol Hlth, Div Chem & Mat Sci, Off Sci & Engn Lab, Silver Spring, MD 20993 USA. [Ihrie, John] US FDA, Ctr Food Safety & Appl Nutr, Div Publ Hlth Informat & Analyt, Off Analyt & Outreach, Silver Spring, MD 20993 USA. RP Sahu, SC (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Toxicol, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. EM saura.sahu@fda.hhs.gov NR 60 TC 4 Z9 4 U1 5 U2 24 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 APR PY 2016 VL 36 IS 4 BP 521 EP 531 DI 10.1002/jat.3276 PG 11 WC Toxicology SC Toxicology GA DD8CT UT WOS:000370152900004 PM 26732652 ER PT J AU Sahu, SC Roy, S Zheng, JW Ihrie, J AF Sahu, Saura C. Roy, Shambhu Zheng, Jiwen Ihrie, John TI Contribution of ionic silver to genotoxic potential of nanosilver in human liver HepG2 and colon Caco2 cells evaluated by the cytokinesis-block micronucleus assay SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE nanosilver; silver nanoparticles; nanoparticles; genotoxicity; micronucleus; HepG2; Caco2; cytokinesis-block micronucleus; in vitro micronucleus ID NANOPARTICLE-PROTEIN CORONA; ABERRATIONS IN-VITRO; FOOD-INDUSTRY; CYTOTOXICITY; TOXICITY; SIZE; MODEL; DISSOLUTION; PARTICLES; IMPACT AB Extensive human exposure to food- and cosmetics-related consumer products containing nanosilver is of public concern because of the lack of information about their safety. Genotoxicity is an important endpoint for the safety and health hazard assessment of regulated products including nanomaterials. The in vitro cytokinesis-block micronucleus (CBMN) assay is a very useful test for predictive genotoxicity testing. Recently, we have reported the genotoxicity of 20nm nanosilver in human liver HepG2 and colon Caco2 cells evaluated using the CBMN assay. The objective of our present study was three-fold: (i) to evaluate if HepG2 and Caco2 cells are valuable in vitro models for rapid genotoxicity screening of nanosilver; (ii) to test the hypothesis that the nanoparticle size and cell types are critical determinants of its genotoxicity; and (iii) to determine if ionic silver contributes to the nanosilver genotoxicity. With these objectives in mind, we evaluated the genotoxic potential of 50nm nanosilver of the same shape, composition, surface charge, obtained from the same commercial source, under the same experimental conditions and the same genotoxic CBMN endpoint used for the previously tested 20nm silver. The ionic silver (silver acetate) was also evaluated under the same conditions. Results of our study show that up to the concentrations tested in these cell types, the smaller (20nm) nanosilver induces micronucleus formation in both the cell types but the larger (50nm) nanosilver and the ionic silver provide a much weaker response compared with controls under the same conditions. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Recently, we have reported the genotoxicity of 20nm nanosilver evaluated using the in vitro cytokinesis-block micronucleus (CBMN) assay. In this study, we evaluated the genotoxic potential of 50nm nanosilver of the same shape, composition, surface charge, obtained from the same commercial source, under the same experimental conditions and the same genotoxic CBMN endpoint used for the previously tested 20nm silver. The ionic silver (silver acetate) was also evaluated under the same conditions. Results of our study show that up to the concentrations tested in these cell types, the smaller (20nm) nanosilver induces micronucleus formation in both the cell types but the larger (50nm) nanosilver and the ionic silver provide much weaker response compared with controls under the same conditions. C1 [Sahu, Saura C.] US FDA, Ctr Food Safety & Appl Nutr, Div Toxicol, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. [Roy, Shambhu] Bioreliance Corp, Rockville, MD 20850 USA. [Zheng, Jiwen] US FDA, Ctr Devices & Radiol Hlth, Div Chem & Mat Sci, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Ihrie, John] US FDA, Ctr Food Safety & Appl Nutr, Div Publ Hlth Informat & Analyt, Off Analyt & Outreach, Silver Spring, MD 20740 USA. RP Sahu, SC (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Toxicol, Off Appl Res & Safety Assessment, Laurel, MD 20708 USA. EM saura.sahu@fda.hhs.gov NR 60 TC 0 Z9 0 U1 0 U2 16 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 APR PY 2016 VL 36 IS 4 BP 532 EP 542 DI 10.1002/jat.3279 PG 11 WC Toxicology SC Toxicology GA DD8CT UT WOS:000370152900005 PM 26813850 ER PT J AU Teisl, MF Lando, AM Levy, AS Noblet, CL AF Teisl, Mario F. Lando, Amy M. Levy, Alan S. Noblet, Caroline L. TI Importance of cohorts in analyzing trends in safe at-home food-handling practices SO FOOD CONTROL LA English DT Article DE Birth cohort; Safe food handling; Trends ID SELF-REPORTED BEHAVIORS; CROSS-SECTION SURVEYS; VERBAL TEST-SCORES; UNITED-STATES; FOODBORNE ILLNESS; YOUNG-ADULTS; CONSUMER PERCEPTIONS; SOCIOECONOMIC-STATUS; MODELS APPLICATIONS; KNOWLEDGE AB Safe in-home food preparation is the last line of defense for preventing foodborne illness. The Food Safety Survey assessing consumers' food handling behavior has been conducted every 3-5 years (1993, 1998, 2001, 2006, 2010) using a random digit telephone sample of United States adult consumers. Sample sizes ranged from 1620 to 4547. A previous analysis of this data has examined trends in safe food handling (as measured by washing hands and/or cutting boards after touching/cutting raw meat or chicken and by washing hands after cracking eggs). We continue and expand this analysis by modeling the unique effects of age, survey period (year) and birth cohort on safe food handling. We find that age, period, and cohort effects are relevant in measuring changes in food handling behavior; however, the effects are not similar in size or apparent mediating process. The strongest effect is period, followed by age and cohort. Thus it appears contemporaneous changes in information activity can make relatively large short-run improvements, whereas changes in one's maturation and accumulated experience have quadratic effects, and the unique shared experience of cohort leaves its own definite long-lasting imprint. We propose that the birth cohort effects can be explained by the food safety environment during young adulthood. Those who were young adults in two critical time periods - before 1940 when there were widespread foodborne infections and immediately after the 1993 outbreak of Escherichia coli O157:H7 - have better food handling behaviors. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Teisl, Mario F.; Noblet, Caroline L.] Univ Maine, Sch Econ, Orono, ME 04469 USA. [Lando, Amy M.; Levy, Alan S.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Teisl, MF (reprint author), Univ Maine, Sch Econ, 5782 Winslow Hall, Orono, ME 04469 USA. EM teisl@maine.edu OI teisl, mario/0000-0002-2021-9208 NR 94 TC 1 Z9 1 U1 6 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 APR PY 2016 VL 62 BP 381 EP 389 DI 10.1016/j.foodcont.2015.10.040 PG 9 WC Food Science & Technology SC Food Science & Technology GA DB0TI UT WOS:000368220000053 ER PT J AU Shi, Q Yang, X AF Shi, Qiang Yang, Xi TI Circulating MicroRNA and Long Noncoding RNA as Biomarkers of Cardiovascular Diseases SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Review ID ACUTE MYOCARDIAL-INFARCTION; HEART-FAILURE; CARDIAC-HYPERTROPHY; MESSENGER-RNAS; EXPRESSION; CANCER; EVOLUTION; SURVIVAL; MOUSE AB Although >85% of the human genome is transcribed, only <2% is transcribed into protein-coding RNA (messenger RNA, mRNA). Many thousands of noncoding RNAs are transcribed and recognized as functional RNAs with diverse sizes, structures, and biological functions. Based on size, noncoding RNA can be generally divided into two subgroups: short noncoding RNA (<200 nucleotides including microRNA or miRNA) and long noncoding RNA (lncRNA, >200 nucleotides). It is now clear that these RNAs fulfil critical roles as transcriptional and post-transcriptional regulators and as guides of chromatin-modifying complexes. Although not translated into protein, noncoding RNAs can regulate cardiac function through diverse mechanisms and their dysregulation is increasingly linked with cardiovascular pathophysiology. Furthermore, a series of recent studies have discovered that noncoding RNAs can be found in the bloodstream and some species are remarkably stable. This has raised the possibility that such noncoding RNAs may be measured in body fluids and serve as novel diagnostic biomarkers. Here, we summarize the current knowledge of noncoding RNAs' function and biomarker potential in cardiac diseases, concentrating mainly on circulating miRNAs and lncRNAs. (C) 2015 Wiley Periodicals, Inc. C1 [Shi, Qiang; Yang, Xi] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. RP Yang, X (reprint author), US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. EM xi.yang@fda.hhs.gov NR 52 TC 4 Z9 4 U1 0 U2 67 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9541 EI 1097-4652 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD APR PY 2016 VL 231 IS 4 BP 751 EP 755 DI 10.1002/jcp.25174 PG 5 WC Cell Biology; Physiology SC Cell Biology; Physiology GA DB1NE UT WOS:000368274100001 PM 26308238 ER PT J AU Williams, PA O'Donoghue, AC Sullivan, HW Willoughby, JF Squire, C Parvanta, S Betts, KR AF Williams, Pamela A. O'Donoghue, Amie C. Sullivan, Helen W. Willoughby, Jessica Fitts Squire, Claudia Parvanta, Sarah Betts, Kevin R. TI Communicating efficacy information based on composite scores in direct-to-consumer prescription drug advertising SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE United States; Direct-to-consumer (DTC) advertisements; Prescription drugs; Marketing; Communication; Composite scores ID ADVERTISEMENTS; RISK AB Objective: Drug efficacy can be measured by composite scores, which consist of two or more symptoms or other clinical components of a disease. We evaluated how individuals interpret composite scores in direct-to-consumer (DTC) prescription drug advertising. Methods: We conducted an experimental study of seasonal allergy sufferers (n = 1967) who viewed a fictitious print DTC ad that varied by the type of information featured (general indication, list of symptoms, or definition of composite scores) and the presence or absence of an educational intervention about composite scores. We measured composite score recognition and comprehension, and perceived drug efficacy and risk. Results: Ads that featured either (1) the composite score definition alone or (2) the list of symptoms or general indication information along with the educational intervention improved composite score comprehension. Ads that included the composite score definition or the educational intervention led to lower confidence in the drug's benefits. The composite score definition improved composite score recognition and lowered drug risk perceptions. Conclusion: Adding composite score information to DTC print ads may improve individuals' comprehension of composite scores and affect their perceptions of the drug. Practice implications: Providing composite score information may lead to more informed patient-provider prescription drug decisions. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Williams, Pamela A.; Willoughby, Jessica Fitts; Squire, Claudia; Parvanta, Sarah] RTI Int, Res Triangle Pk, NC USA. [O'Donoghue, Amie C.; Sullivan, Helen W.; Betts, Kevin R.] US FDA, Off Prescript Drug Promot, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Willoughby, Jessica Fitts] Washington State Univ, Edward R Murrow Coll Commun, Pullman, WA 99164 USA. RP Williams, PA (reprint author), RTI Int, Social Policy Hlth & Econ Res Unit, 3040 East Cornwallis Rd,POB 12194, Res Triangle Pk, NC 27709 USA. EM pamwilliams@rti.org; jessica.willoughby@wsu.edu OI Williams, Pamela/0000-0002-6040-6972; Willoughby, Jessica/0000-0002-1118-9502 FU Center for Drug Evaluation and Research, Food and Drug Administration (FDA) FX The Center for Drug Evaluation and Research, Food and Drug Administration (FDA) provided research funding for this study. The authors thank Chelsea Burfeind of RTI International for research assistance and Kayla Gray and Maria Ashbaugh of RTI International for their assistance with stimuli development. NR 27 TC 1 Z9 1 U1 2 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD APR PY 2016 VL 99 IS 4 BP 583 EP 590 DI 10.1016/j.pec.2015.10.019 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA DH7IE UT WOS:000372965900014 PM 26589655 ER PT J AU Srivastava, HK Wolfgang, S Rodriguez, JD AF Srivastava, Hirsch K. Wolfgang, Steven Rodriguez, Jason D. TI Expanding the analytical toolbox for identity testing of pharmaceutical ingredients: Spectroscopic screening of dextrose using portable Raman and near infrared spectrometers SO ANALYTICA CHIMICA ACTA LA English DT Article DE Excipient screening; Raman spectroscopy; Near infrared spectroscopy; Identification tests; Adulteration AB In the pharmaceutical industry, dextrose is used as an active ingredient in parenteral solutions and as an inactive ingredient (excipient) in tablets and capsules. In order to address the need for more sophisticated analytical techniques, we report our efforts to develop enhanced identification methods to screen pharmaceutical ingredients at risk for adulteration or substitution using field-deployable spectroscopic screening. In this paper, we report our results for a study designed to evaluate the performance of field-deployable Raman and near infrared (NIR) methods to identify dextrose samples. We report a comparison of the sensitivity of the spectroscopic screening methods against current compendial identification tests that rely largely on a colorimetric assay. Our findings indicate that NIR and Raman spectroscopy are both able to distinguish dextrose by hydration state and from other sugar substitutes with 100% accuracy for all methods tested including spectral correlation based library methods, principal component analysis and classification methods. Published by Elsevier B.V. C1 [Srivastava, Hirsch K.; Wolfgang, Steven; 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 Critical Path Program; CDER Regulatory Science & Review Enhancement Program; Center for Drug Evaluation and Research FX This project was supported in part by the CDER Critical Path and Regulatory Science & Review Enhancement Programs. This project was supported in part by an appointment (H.K.S) to the Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 19 TC 0 Z9 0 U1 3 U2 18 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 31 PY 2016 VL 914 BP 91 EP 99 DI 10.1016/j.aca.2016.01.061 PG 9 WC Chemistry, Analytical SC Chemistry GA DF4UY UT WOS:000371348100010 PM 26965331 ER PT J AU Holmes, DR Shuren, J Califf, R Zuckerman, B Abel, D Farb, A Leon, M Mack, M AF Holmes, David R., Jr. Shuren, Jeff Califf, Robert Zuckerman, Bram Abel, Dorothy Farb, Andrew Leon, Martin Mack, Michael TI Clinical Perspective-Early Feasibility Device Medical Studies in the United States Time for More Than Regulatory Reform SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material C1 [Holmes, David R., Jr.] Mayo Clin, Dept Cardiovasc Dis, Rochester, MN 55905 USA. [Shuren, Jeff; Zuckerman, Bram; Abel, Dorothy; Farb, Andrew] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Califf, Robert] US FDA, Off Commissioner, Silver Spring, MD USA. [Leon, Martin] Columbia Univ, Med Ctr, Div Cardiol, NY Presbyterian Hosp, New York, NY USA. [Mack, Michael] Baylor Scott & White Hlth, Dept Cardiovasc Surg, Plano, TX USA. RP Holmes, DR (reprint author), Mayo Clin, Dept Cardiol, 200 First St SW, Rochester, MN 55905 USA. EM holmes.david@mayo.edu NR 5 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 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD MAR 28 PY 2016 VL 9 IS 6 BP 626 EP 628 DI 10.1016/j.jcin.2016.02.004 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DH3WQ UT WOS:000372717900026 PM 27013168 ER PT J AU Gaczynska, M Karpowicz, P Stuart, CE Norton, MG Teckman, JH Marszal, E Osmulski, PA AF Gaczynska, Maria Karpowicz, Przemyslaw Stuart, Christine E. Norton, Malgorzata G. Teckman, Jeffrey H. Marszal, Ewa Osmulski, Pawel A. TI AFM Imaging Reveals Topographic Diversity of Wild Type and Z Variant Polymers of Human alpha(1)-Proteinase Inhibitor SO PLOS ONE LA English DT Article ID LOOP-SHEET POLYMERIZATION; ALPHA(1)-ANTITRYPSIN DEFICIENCY; SERPIN POLYMERIZATION; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; ALPHA-1-ANTITRYPSIN DEFICIENCY; CONFORMATIONAL DISEASE; ENDOPLASMIC-RETICULUM; MASS-SPECTROMETRY; MOLECULAR-BASIS AB alpha(1)-Proteinase inhibitor (antitrypsin) is a canonical example of the serpin family member that binds and inhibits serine proteases. The natural metastability of serpins is crucial to carry out structural rearrangements necessary for biological activity. However, the enhanced metastability of the mutant Z variant of antitrypsin, in addition to folding defect, may substantially contribute to its polymerization, a process leading to incurable serpinopathy. The metastability also impedes structural studies on the polymers. There are no crystal structures of Z monomer or any kind of polymers larger than engineered wild type (WT) trimer. Our understanding of polymerization mechanisms is based on biochemical data using in vitro generated WT oligomers and molecular simulations. Here we applied atomic force microscopy (AFM) to compare topography of monomers, in vitro formed WT oligomers, and Z type polymers isolated from transgenic mouse liver. We found the AFM images of monomers closely resembled an antitrypsin outer shell modeled after the crystal structure. We confirmed that the Z variant demonstrated higher spontaneous propensity to dimerize than WT monomers. We also detected an unexpectedly broad range of different types of polymers with periodicity and topography depending on the applied method of polymerization. Short linear oligomers of unit arrangement similar to the Z polymers were especially abundant in heat-treated WT preparations. Long linear polymers were a prominent and unique component of liver extracts. However, the liver preparations contained also multiple types of oligomers of topographies undistinguishable from those found in WT samples polymerized with heat, low pH or guanidine hydrochloride treatments. In conclusion, we established that AFM is an excellent technique to assess morphological diversity of antitrypsin polymers, which is important for etiology of serpinopathies. These data also support previous, but controversial models of in vivo polymerization showing a surprising diversity of polymer topography. C1 [Gaczynska, Maria; Karpowicz, Przemyslaw; Osmulski, Pawel A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. [Stuart, Christine E.; Norton, Malgorzata G.; Marszal, Ewa] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Teckman, Jeffrey H.] St Louis Univ, Sch Med, Cardinal Glennon Childrens Med Ctr, Dept Pediat & Biochem, St Louis, MO USA. [Karpowicz, Przemyslaw] Univ Gdansk, Dept Med Chem, PL-80952 Gdansk, Poland. RP Osmulski, PA (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. EM Osmulski@uthscsa.edu FU Alpha-1 Foundation; Texas Higher Education Coordinating Board Norman Hackerman Advanced Research Program; Morrison Foundation; Research Participation Program at the Center for Biologics Evaluation and Research; U.S. Department of Energy; U.S. Food and Drug Administration FX The research was supported by the Alpha-1 Foundation Pilot Grant to MG and EM (alpha-1foundation.org), the Texas Higher Education Coordinating Board Norman Hackerman Advanced Research Program (www.arpatp.com) and the Morrison Foundation to PAO, and in part by the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration to CES. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 0 Z9 0 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 23 PY 2016 VL 11 IS 3 AR e0151902 DI 10.1371/journal.pone.0151902 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3QJ UT WOS:000372701200073 PM 27008547 ER PT J AU Cho, JH Katsumata, R Zhou, SX Bin Kim, C Dulaney, AR Janes, DW Ellison, CJ AF Cho, Joon Hee Katsumata, Reika Zhou, Sunshine X. Bin Kim, Chae Dulaney, Austin R. Janes, Dustin W. Ellison, Christopher J. TI Ultrasmooth Polydopamine Modified Surfaces for Block Copolymer Nanopatterning on Flexible Substrates SO ACS APPLIED MATERIALS & INTERFACES LA English DT Article DE block copolymer (BCP); polydopamine (PDA); surface modification; flexible substrates; conformal coating; solution deposition; self-assembly; nanopatterning ID THIN-FILMS; LITHOGRAPHY; DOPAMINE; TRANSISTORS; FABRICATION; GRAPHENE; NANOPARTICLES; ELECTRONICS; ORIENTATION; MECHANICS AB Nature has engineered universal, catechol-containing adhesives which can be synthetically mimicked in the form of polydopamine (PDA). In this study, PDA was exploited to enable the formation of block copolymer (BCP) nanopatterns on a variety of soft material surfaces. While conventional PDA coating times (1 h) produce a layer too rough for most applications of BCP nanopatterning, we found that these substrates could be polished by bath sonication in a weakly basic solution to form a conformal, smooth (root-mean-square roughness similar to 0.4 nm), and thin (3 nm) layer free of large prominent granules. This chemically functionalized, biomimetic layer served as a reactive platform for subsequently grafting a surface neutral layer of poly(styrene-random-methyl methacrylate-random-glycidyl methacrylate) to perpendicularly orient lamellae-forming poly(styrene-block-methyl methacrylate) BCP. Moreover, scanning electron microscopy observations confirmed that a BCP nanopattem on a poly(ethylene terephthalate) substrate was not affected by bending with a radius of similar to 0.5 cm. This procedure enables nondestructive, plasma-free surface modification of chemically inert, low-surface energy soft materials, thus overcoming many current chemical and physical limitations that may impede high throughput, roll-to-roll nanomanufacturing. C1 [Cho, Joon Hee; Katsumata, Reika; Zhou, Sunshine X.; Bin Kim, Chae; Dulaney, Austin R.; Ellison, Christopher J.] Univ Texas Austin, McKetta Dept Chem Engn, 200 East Dean Keeton St, Austin, TX 78712 USA. [Janes, Dustin W.] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Ellison, CJ (reprint author), Univ Texas Austin, McKetta Dept Chem Engn, 200 East Dean Keeton St, Austin, TX 78712 USA. EM ellison@che.utexas.edu FU Welch Foundation [F-1709]; DuPont Young Professor Award; 3M Nontenured Faculty Award; Norman Hackerman Advanced Research Program [ARP- 003658-0037-2011]; LG Chem Graduate Research Fellowship; Graduate Dean's Prestigious Fellowship Supplement; Takenaka Scholarship Foundation; Dr. Thomas F. Edgar Endowed Graduate Fellowship in Chemical Engineering FX C.J.E. thanks the Welch Foundation (grant # F-1709), DuPont Young Professor Award, 3M Nontenured Faculty Award and the Norman Hackerman Advanced Research Program (grant # ARP- 003658-0037-2011) for partial financial support. J.H.C. acknowledges partial financial support from LG Chem Graduate Research Fellowship and Graduate Dean's Prestigious Fellowship Supplement. R.K. thanks the Takenaka Scholarship Foundation and Dr. Thomas F. Edgar Endowed Graduate Fellowship in Chemical Engineering for financial support. The findings and conclusions in this paper have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any agency determination or policy. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. NR 53 TC 2 Z9 2 U1 13 U2 47 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1944-8244 J9 ACS APPL MATER INTER JI ACS Appl. Mater. Interfaces PD MAR 23 PY 2016 VL 8 IS 11 BP 7456 EP 7463 DI 10.1021/acsami.6b00626 PG 8 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA DH7BQ UT WOS:000372946600080 PM 26942554 ER PT J AU Paseiro-Cerrato, R Noonan, GO Begley, TH AF Paseiro-Cerrato, Rafael Noonan, Gregory O. Begley, Timothy H. TI Evaluation of Long-Term Migration Testing from Can Coatings into Food Simulants: Polyester Coatings SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE food packaging can coatings; polyesters; oligomers; terephthalic acid; isophthalic acid; nadic acid; long-term migration; stability; hydrolysis; HPLC-DAD/CAD; HPLC-MS/MS ID POLYETHYLENE TEREPHTHALATE PET; OLIGOMERS AB FDA guidance for food contact substances recommends that for food packaging intended for use at sterilized, high temperature processed, or retorted conditions, a migration test with a retort step at 121 degrees C for 2 h followed by a 10 day migration test at 40 degrees C should be performed. These conditions are in intended to simulate processing and long-term storage. However, can coatings may be in contact with food for years, and there are very few data evaluating if this short-term testing accurately simulates migration over extended time periods. A long-term migration test at 40 degrees C with retorted and non-retorted polyester cans using several food simulants (water, 3% acetic acid, 10% ethanol, 50% ethanol, and isooctane) was conducted to verify whether traditional migration testing protocols accurately predict migration from food contact materials used for extended time periods. Time points were from 1 day to 515 days. HPLC-MS/MS was used to analyze polyester monomers, and oligomer migration was monitored using HPLC-DAD/CAD and HPLC-MS. Concentrations of monomers and oligomers increased during the migration experiments, especially in ethanol food simulants. The data suggest that current FDA migration protocols may need to be modified to address changes in migrants as a result of long-term storage conditions. C1 [Paseiro-Cerrato, Rafael; Noonan, Gregory O.; Begley, Timothy H.] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. RP Paseiro-Cerrato, R (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Rafael.Cerrato@fda.hhs.gov NR 15 TC 3 Z9 3 U1 3 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD MAR 23 PY 2016 VL 64 IS 11 BP 2377 EP 2385 DI 10.1021/acs.jafc.5b05880 PG 9 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA DH5TH UT WOS:000372854300023 PM 26917426 ER PT J AU Ramachandran, G Tennant, SM Boyd, MA Wang, JY Tulapurkar, ME Pasetti, MF Levine, MM Simon, R AF Ramachandran, Girish Tennant, Sharon M. Boyd, Mary A. Wang, Jin Y. Tulapurkar, Mohan E. Pasetti, Marcela F. Levine, Myron M. Simon, Raphael TI Functional Activity of Antibodies Directed towards Flagellin Proteins of Non-Typhoidal Salmonella SO PLOS ONE LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; INVASIVE NONTYPHOIDAL SALMONELLA; ELECTRON CRYOMICROSCOPY; CONJUGATE VACCINE; ATOMIC MODEL; INFECTION; PROTECTION; FEVER; VIRULENCE; MACROPHAGES AB Non-typhoidal Salmonella (NTS) serovars Typhimurium and Enteritidis are major causes of invasive bacterial infections in children under 5 years old in sub-Saharan Africa, with case fatality rates of similar to 20%. There are no licensed NTS vaccines for humans. Vaccines that induce antibodies against a Salmonella Typhi surface antigen, Vi polysaccharide, significantly protect humans against typhoid fever, establishing that immune responses to Salmonella surface antigens can be protective. Flagella proteins, abundant surface antigens in Salmonella serovars that cause human disease, are also powerful immunogens, but the functional capacity of elicited anti-flagellar antibodies and their role in facilitating bacterial clearance has been unclear. We examined the ability of anti-flagellar antibodies to mediate microbial killing by immune system components in-vitro and assessed their role in protecting mice against invasive Salmonella infection. Polyclonal (hyperimmune sera) and monoclonal antibodies raised against phase 1 flagellin proteins of S. Enteritidis and S. Typhimurium facilitated bacterial uptake and killing of the homologous serovar pathogen by phagocytes. Polyclonal anti-flagellar antibodies accompanied by complement also achieved direct bacterial killing. Serum bactericidal activity was restricted to Salmonella serovars expressing the same flagellin used as immunogen. Notably, individual anti-flagellin monoclonal antibodies with complement were not bactericidal, but this biological activity was restored when different monoclonal anti-flagellin antibodies were combined. Passive transfer immunization with a monoclonal IgG antibody specific for phase 1 flagellin from S. Typhimurium protected mice against lethal challenge with a representative African invasive S. Typhimurium strain. These findings have relevance for the use of flagellin proteins in NTS vaccines, and confirm the role of anti-flagellin antibodies as mediators of protective immunity. C1 [Ramachandran, Girish; Tennant, Sharon M.; Boyd, Mary A.; Wang, Jin Y.; Pasetti, Marcela F.; Levine, Myron M.; Simon, Raphael] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Ramachandran, Girish; Tennant, Sharon M.; Wang, Jin Y.; Tulapurkar, Mohan E.; Levine, Myron M.; Simon, Raphael] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Boyd, Mary A.; Pasetti, Marcela F.; Levine, Myron M.] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [Tulapurkar, Mohan E.] Univ Maryland, Sch Med, Div Pulm & Crit Care, Baltimore, MD 21201 USA. [Boyd, Mary A.] US FDA, Silver Spring, MD USA. RP Simon, R (reprint author), Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA.; Simon, R (reprint author), Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. EM rsimon@medicine.umaryland.edu RI tulapurkar, mohan/F-1926-2015 OI tulapurkar, mohan/0000-0002-2476-5417 FU Middle Atlantic RCE Program, NIAID/NIH [2 U54 AI057168]; UK Wellcome Trust FX This work was supported by Middle Atlantic RCE Program, NIAID/NIH 2 U54 AI057168 and a Strategic Translation Grant from the UK Wellcome Trust (MML PI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 2 Z9 2 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 21 PY 2016 VL 11 IS 3 AR e0151875 DI 10.1371/journal.pone.0151875 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3NW UT WOS:000372694700077 PM 26998925 ER PT J AU Wang, SH Ding, YJ Zhao, WZ Huang, YH Perkins, R Zou, W Chen, JJ AF Wang, Shi-Heng Ding, Yijun Zhao, Weizhong Huang, Yung-Hsiang Perkins, Roger Zou, Wen Chen, James J. TI Text mining for identifying topics in the literatures about adolescent substance use and depression SO BMC PUBLIC HEALTH LA English DT Article DE Topic model; Text mining; Adolescent; Substance use; Depression ID ALCOHOL-USE; INFORMATION-RETRIEVAL; YOUNG ADULTHOOD; USE DISORDERS; SYMPTOMS; PREDICTORS; KNOWLEDGE; TRAJECTORIES; DISCOVERY; SMOKING AB Background: Both adolescent substance use and adolescent depression are major public health problems, and have the tendency to co-occur. Thousands of articles on adolescent substance use or depression have been published. It is labor intensive and time consuming to extract huge amounts of information from the cumulated collections. Topic modeling offers a computational tool to find relevant topics by capturing meaningful structure among collections of documents. Methods: In this study, a total of 17,723 abstracts from PubMed published from 2000 to 2014 on adolescent substance use and depression were downloaded as objects, and Latent Dirichlet allocation (LDA) was applied to perform text mining on the dataset. Word clouds were used to visually display the content of topics and demonstrate the distribution of vocabularies over each topic. Results: The LDA topics recaptured the search keywords in PubMed, and further discovered relevant issues, such as intervention program, association links between adolescent substance use and adolescent depression, such as sexual experience and violence, and risk factors of adolescent substance use, such as family factors and peer networks. Using trend analysis to explore the dynamics of proportion of topics, we found that brain research was assessed as a hot issue by the coefficient of the trend test. Conclusions: Topic modeling has the ability to segregate a large collection of articles into distinct themes, and it could be used as a tool to understand the literature, not only by recapturing known facts but also by discovering other relevant topics. C1 [Wang, Shi-Heng; Ding, Yijun; Zhao, Weizhong; Perkins, Roger; Zou, Wen; Chen, James J.] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT-20, Jefferson, AR 72079 USA. [Wang, Shi-Heng] China Med Univ, Grad Inst Biostat, 91 Xueshi Rd, Taichung 40402, Taiwan. [Huang, Yung-Hsiang] Natl Ctr High Performance Comp, Natl Appl Res Labs, 7,R&D 6th Rd,Hsinchu Sci Pk, Hsinchu 30076, Taiwan. RP Zou, W; Chen, JJ (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT-20, Jefferson, AR 72079 USA. EM wen.zou@fda.hhs.gov; jamesj.chen@fda.hhs.gov NR 51 TC 0 Z9 0 U1 4 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD MAR 19 PY 2016 VL 16 AR 279 DI 10.1186/s12889-016-2932-1 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DH0TB UT WOS:000372495900001 PM 26993983 ER PT J AU Simonyan, V Chumakov, K Dingerdissen, H Faison, W Goldweber, S Golikov, A Gulzar, N Karagiannis, K Lam, PVN Maudru, T Muravitskaja, O Osipova, E Pan, Y Pschenichnov, A Rostovtsev, A Santana-Quintero, L Smith, K Thompson, EE Tkachenko, V Torcivia-Rodriguez, J Voskanian, A Wan, Q Wang, J Wu, TJ Wilson, C Mazumder, R AF Simonyan, Vahan Chumakov, Konstantin Dingerdissen, Hayley Faison, William Goldweber, Scott Golikov, Anton Gulzar, Naila Karagiannis, Konstantinos Phuc Vinh Nguyen Lam Maudru, Thomas Muravitskaja, Olesja Osipova, Ekaterina Pan, Yang Pschenichnov, Alexey Rostovtsev, Alexandre Santana-Quintero, Luis Smith, Krista Thompson, Elaine E. Tkachenko, Valery Torcivia-Rodriguez, John Voskanian, Alin Wan, Quan Wang, Jing Wu, Tsung-Jung Wilson, Carolyn Mazumder, Raja TI High-performance integrated virtual environment (HIVE): a robust infrastructure for next-generation sequence data analysis SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID ALIGNMENT; POLIOMYELITIS; ERADICATION; BIOLOGY AB The High-performance Integrated Virtual Environment (HIVE) is a distributed storage and compute environment designed primarily to handle next-generation sequencing (NGS) data. This multicomponent cloud infrastructure provides secure web access for authorized users to deposit, retrieve, annotate and compute on NGS data, and to analyse the outcomes using web interface visual environments appropriately built in collaboration with research and regulatory scientists and other end users. Unlike many massively parallel computing environments, HIVE uses a cloud control server which virtualizes services, not processes. It is both very robust and flexible due to the abstraction layer introduced between computational requests and operating system processes. The novel paradigm of moving computations to the data, instead of moving data to computational nodes, has proven to be significantly less taxing for both hardware and network infrastructure. The honeycomb data model developed for HIVE integrates metadata into an object-oriented model. Its distinction from other object-oriented databases is in the additional implementation of a unified application program interface to search, view and manipulate data of all types. This model simplifies the introduction of new data types, thereby minimizing the need for database restructuring and streamlining the development of new integrated information systems. The honeycomb model employs a highly secure hierarchical access control and permission system, allowing determination of data access privileges in a finely granular manner without flooding the security subsystem with a multiplicity of rules. HIVE infrastructure will allow engineers and scientists to perform NGS analysis in a manner that is both efficient and secure. HIVE is actively supported in public and private domains, and project collaborations are welcomed. C1 [Simonyan, Vahan; Chumakov, Konstantin; Dingerdissen, Hayley; Goldweber, Scott; Golikov, Anton; Karagiannis, Konstantinos; Phuc Vinh Nguyen Lam; Maudru, Thomas; Muravitskaja, Olesja; Osipova, Ekaterina; Pschenichnov, Alexey; Rostovtsev, Alexandre; Santana-Quintero, Luis; Smith, Krista; Thompson, Elaine E.; Tkachenko, Valery; Torcivia-Rodriguez, John; Voskanian, Alin; Wang, Jing; Wilson, Carolyn] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Dingerdissen, Hayley; Faison, William; Goldweber, Scott; Gulzar, Naila; Karagiannis, Konstantinos; Pan, Yang; Smith, Krista; Torcivia-Rodriguez, John; Wan, Quan; Wu, Tsung-Jung; Mazumder, Raja] George Washington Univ, Dept Biochem & Mol Biol, Med Ctr, Washington, DC 20037 USA. RP Simonyan, V (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM vahan.simonyan@fda.hhs.gov OI Pan, Yang/0000-0003-3487-7233 FU Food and Drug Administration Medical Countermeasures Initiative FX This research was supported in part by the Food and Drug Administration Medical Countermeasures Initiative. 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 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD MAR 17 PY 2016 AR baw022 DI 10.1093/database/baw022 PG 16 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DJ3FQ UT WOS:000374090600001 ER PT J AU Xu, XM Gupta, A Al-Ghabeish, M Calderon, SN Khan, MA AF Xu, Xiaoming Gupta, Abhay Al-Ghabeish, Manar Calderon, Silvia N. Khan, Mansoor A. TI Risk based in vitro performance assessment of extended release abuse deterrent formulations SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Abuse deterrent formulation; Opioid analgesics; Evaluation matrix; Drug abuse; manipulation; Mode of abuse; Syringeability; Injectability ID PRESCRIPTION OPIOID ABUSE; IMMPACT RECOMMENDATIONS; LABORATORY ASSESSMENT; MORPHINE-SULFATE; UNITED-STATES; ATTRACTIVENESS; LIABILITY; CAPSULES; MISUSE; PAIN AB High strength extended release opioid products, which are indispensable tools in the management of pain, are associated with serious risks of unintentional and potentially fatal overdose, as well as of misuse and abuse that might lead to addiction. The issue of drug abuse becomes increasingly prominent when the dosage forms can be readily manipulated to release a high amount of opioid or to extract the drug in certain products or solvents. One approach to deter opioid drug abuse is by providing novel abuse deterrent formulations (ADF), with properties that may be viewed as barriers to abuse of the product. However, unlike regular extended release formulations, assessment of ADF technologies are challenging, in part due to the great variety of formulation designs available to achieve deterrence of abuse by oral, parenteral, nasal and respiratory routes. With limited prior history or literature information, and lack of compendial standards, evaluation and regulatory approval of these novel drug products become increasingly difficult. The present article describes a risk-based standardized in-vitro approach that can be utilized in general evaluation of abuse deterrent features for all ADF products. Published by Elsevier B.V. C1 [Xu, Xiaoming; Gupta, Abhay; Al-Ghabeish, Manar; Khan, Mansoor A.] US FDA, Div Prod Qual Res, Off Testing & Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Calderon, Silvia N.] US FDA, Ctr Drug Evaluadon & Res, Silver Spring, MD 20993 USA. [Khan, Mansoor A.] Texas A&M Hlth Sci Ctr, Irma Lerma Rangel Coll Pharm, Reynolds Med Bldg,Suite 159, College Stn, TX 77843 USA. RP Khan, MA (reprint author), Texas A&M Hlth Sci Ctr, Irma Lerma Rangel Coll Pharm, Reynolds Med Bldg,Suite 159, College Stn, TX 77843 USA. EM mkhan@pharmacy.tamhsc.edu FU Intramural FDA HHS [FD999999] NR 40 TC 2 Z9 2 U1 2 U2 4 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 MAR 16 PY 2016 VL 500 IS 1-2 BP 255 EP 267 DI 10.1016/j.ijpharm.2016.01.031 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DD6QX UT WOS:000370049900026 PM 26784976 ER PT J AU Ho, WS Feldman, MJ Maric, D Amable, L Hall, MD Feldman, GM Ray-Chaudhury, A Lizak, MJ Vera, JC Robison, RA Zhuang, ZP Heiss, JD AF Ho, Winson S. Feldman, Michael J. Maric, Dragan Amable, Lauren Hall, Matthew D. Feldman, Gerald M. Ray-Chaudhury, Abhik Lizak, Martin J. Vera, Juan-Carlos Robison, R. Aaron Zhuang, Zhengping Heiss, John D. TI PP2A inhibition with LB100 enhances cisplatin cytotoxicity and overcomes cisplatin resistance in medulloblastoma cells SO ONCOTARGET LA English DT Article DE medulloblastoma; PP2A; LB100; STAT3; cisplatin ID PROTEIN PHOSPHATASE 2A; MITOTIC CATASTROPHE; GROWTH ARREST; BRAIN-TUMORS; STAT3; CANCER; PHOSPHORYLATION; TARGET; CHEMOTHERAPY; CARBOPLATIN AB The protein phosphatase 2A (PP2A) inhibitor, LB100, has been shown in pre-clinical studies to be an effective chemo- and radio-sensitizer for treatment of various cancers. We investigated effects associated with LB100 treatment alone and in combination with cisplatin for medulloblastoma (MB) in vitro and in vivo in an intracranial xenograft model. We demonstrated that LB100 had a potent effect on MB cells. By itself, LB100 inhibited proliferation and induced significant apoptosis in a range of pediatric MB cell lines. It also attenuated MB cell migration, a pre-requirement for invasion. When used in combination, LB100 enhanced cisplatin-mediated cytotoxic effects. Cell viability in the presence of 1 uM cisplatin alone was 61% (DAOY), 100% (D341), and 58% (D283), but decreased with the addition of 2 mu M of LB100 to 26% (DAOY), 67% (D341), and 27% (D283), (p < 0.005). LB100 suppressed phosphorylation of the STAT3 protein and several STAT3 downstream targets. Also, LB100 directly increased cisplatin uptake and overcame cisplatin-resistance in vitro. Finally, LB100 exhibited potent in vivo anti-neoplastic activity in combination with cisplatin in an intracranial xenograft model. C1 [Ho, Winson S.; Feldman, Michael J.; Ray-Chaudhury, Abhik; Zhuang, Zhengping; Heiss, John D.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, NINDS Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. [Amable, Lauren] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD 20892 USA. [Hall, Matthew D.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Feldman, Gerald M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Lizak, Martin J.] NINDS, In Vivo NMR Ctr, NIH, Bethesda, MD 20892 USA. [Vera, Juan-Carlos] Tulane Univ, Sch Med, New Orleans, LA 70112 USA. [Robison, R. Aaron] Univ So Calif, Childrens Hosp Los Angeles, Div Neurosurg, Los Angeles, CA 90027 USA. RP Zhuang, ZP; Heiss, JD (reprint author), NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. EM zhuangp@ninds.nih.gov; HeissJ@ninds.nih.gov OI Robison, Richard Aaron/0000-0001-8014-9451 FU NINDS of the National Institutes of Health; NIMHD of the National Institutes of Health; NCATS of the National Institutes of Health FX This research was supported by the Intramural Research Programs of NINDS, NIMHD and NCATS of the National Institutes of Health. NR 41 TC 1 Z9 1 U1 5 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 15 PY 2016 VL 7 IS 11 BP 12447 EP 12463 PG 17 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5LW UT WOS:000375679600054 PM 26799670 ER PT J AU Kazandjian, D Blumenthal, GM Yuan, W He, K Keegan, P Pazdur, R AF Kazandjian, Dickran Blumenthal, Gideon M. Yuan, Weishi He, Kun Keegan, Patricia Pazdur, Richard TI FDA Approval of Gefitinib for the Treatment of Patients with Metastatic EGFR Mutation-Positive Non-Small Cell Lung Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID PREVIOUSLY TREATED PATIENTS; TYROSINE KINASE INHIBITORS; PHASE-III TRIAL; OPEN-LABEL; CARBOPLATIN-PACLITAXEL; 1ST-LINE TREATMENT; CHEMOTHERAPY; SURVIVAL; ALK; ADENOCARCINOMA AB On July 13, 2015, the FDA approved gefitinib (Iressa; AstraZeneca UK Limited) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Concurrently, a labeling expansion of the therascreen EGFR RGQ PCR Kit (Qiagen) as a companion diagnostic test was approved. The approval was based on the results of a multicenter, single-arm, open-label clinical study of 106 treatment-naive patients with metastatic EGFR mutation-positive NSCLC who received gefitinib, 250 mg daily, until disease progression or intolerable toxicity. The major efficacy outcome was RECIST v1.1 objective response rate (ORR). The blinded independent central review (BICR) ORR was 50% [95% confidence interval (CI), 41-59] with a median duration of response (DoR) of 6.0 months. Efficacy results were supported by a retrospective exploratory analysis of a subset of a randomized, multicenter, open-label trial on 1,217 patients with metastatic NSCLC. Of the patients randomized, 186 (15%) were retrospectively determined to be EGFR positive and evaluable for a BICR assessment. The HR for progression-free survival (PFS) was 0.54 (95% CI, 0.38-0.79), favoring gefitinib over platinum-doublet chemotherapy. The most common (>= 20%) adverse reactions were skin reactions, increased aspartate and alanine aminotransferase, proteinuria, and diarrhea. Approximately 5% of patients discontinued treatment due to an adverse reaction. Given the safety profile and clinically meaningful ORR, DoR, and PFS, the benefit-risk analysis was deemed favorable for FDA approval. (C) 2016 AACR. C1 [Kazandjian, Dickran; Blumenthal, Gideon M.; Keegan, Patricia; Pazdur, Richard] US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Yuan, Weishi; He, Kun] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Kazandjian, D (reprint author), 10903 New Hampshire Ave,WO22 2320, Silver Spring, MD 20993 USA. EM Dickran.kazandjian@fda.hhs.gov NR 34 TC 6 Z9 7 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2016 VL 22 IS 6 BP 1307 EP 1312 DI 10.1158/1078-0432.CCR-15-2266 PG 6 WC Oncology SC Oncology GA DI2WD UT WOS:000373358900003 PM 26980062 ER PT J AU Robb, MA McInnes, PM Califf, RM AF Robb, Melissa A. McInnes, Pamela M. Califf, Robert M. TI Biomarkers and Surrogate Endpoints Developing Common Terminology and Definitions SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Robb, Melissa A.] US FDA, Off Med Policy, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,White Oak,Bldg 51,Rm 6360, Silver Spring, MD 20993 USA. [McInnes, Pamela M.] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Califf, Robert M.] US FDA, Silver Spring, MD USA. RP Robb, MA (reprint author), US FDA, Off Med Policy, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,White Oak,Bldg 51,Rm 6360, Silver Spring, MD 20993 USA. EM melissa.robb@fda.hhs.gov NR 6 TC 5 Z9 5 U1 0 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 15 PY 2016 VL 315 IS 11 BP 1107 EP 1108 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DG5ZB UT WOS:000372159800011 PM 26978201 ER PT J AU Xie, YL Rosen, LB Sereti, I Barber, DL Chen, RY Hsu, DC Qasba, SS Zerbe, CS Holland, SM Browne, SK AF Xie, Yingda L. Rosen, Lindsey B. Sereti, Irini Barber, Daniel L. Chen, Ray Y. Hsu, Denise C. Qasba, S. Sonia Zerbe, Christa S. Holland, Steven M. Browne, Sarah K. TI Severe Paradoxical Reaction During Treatment of Disseminated Tuberculosis in a Patient With Neutralizing Anti-IFN gamma Autoantibodies SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE paradoxical reaction; autoantibodies; interferon-gamma; disseminated tuberculosis; IRIS ID RECONSTITUTION INFLAMMATORY SYNDROME; CD4(+) T-CELLS; INTERFERON-GAMMA; MYCOBACTERIAL INFECTION; PULMONARY TUBERCULOSIS; THERAPY; DISEASE; SUSCEPTIBILITY; RESPONSES AB Interferon-gamma (IFN gamma) neutralizing autoantibodies are associated with disseminated nontuberculous mycobacterial infections. We report a previously healthy Thai woman with disseminated tuberculosis and high-titer IFN gamma-neutralizing autoantibodies, who developed a severe inflammatory reaction during anti-tuberculosis treatment. IFN gamma contributes to host control of tuberculosis but appears inessential for tuberculosis paradoxical reactions. C1 [Xie, Yingda L.; Rosen, Lindsey B.; Chen, Ray Y.; Zerbe, Christa S.; Holland, Steven M.; Browne, Sarah K.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sereti, Irini; Hsu, Denise C.] NIAID, Lab Immunoregulat, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Barber, Daniel L.] NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Qasba, S. Sonia] Montgomery Cty Hlth Dept, Silver Spring, MD USA. [Browne, Sarah K.] FDA, Ctr Biol Evaluat & Res, Div Vaccines & Related Prod Applicat, Silver Spring, MD USA. RP Holland, SM (reprint author), Bldg 10-CRC,Rm B3-4141 MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health [ZO1-AI00647-06] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (ZO1-AI00647-06). S. K. B. is currently in the FDA/CBER (Food and Drug Administration/Center for Biologics Evaluation and Research). NR 22 TC 3 Z9 3 U1 2 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 15 PY 2016 VL 62 IS 6 BP 770 EP 773 DI 10.1093/cid/civ995 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DF9XU UT WOS:000371716700014 PM 26646678 ER PT J AU Cope, JR Conrad, DA Cohen, N Cotilla, M DaSilva, A Jackson, J Visvesvara, GS AF Cope, Jennifer R. Conrad, Dennis A. Cohen, Naiomi Cotilla, Manuel DaSilva, Alexandre Jackson, Jonathan Visvesvara, Govinda S. TI Use of the Novel Therapeutic Agent Miltefosine for the Treatment of Primary Amebic Meningoencephalitis: Report of 1 Fatal and 1 Surviving Case SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE primary amebic meningoencephalitis; Naegleria fowleri; miltefosine ID NAEGLERIA-FOWLERI; TAP WATER AB Primary amebic meningoencephalitis (PAM) is a fulminant central nervous system infection caused by the thermophilic free-living ameba Naegleria fowleri. Few survivals have been documented and adequate treatment is lacking. We report 2 PAM cases, 1 fatal and 1 surviving, treated with the novel antiparasitic agent miltefosine. C1 [Cope, Jennifer R.; DaSilva, Alexandre; Jackson, Jonathan; Visvesvara, Govinda S.] Ctr Dis Control & Prevent, 1600 Clifton Rd NE,MS C-09, Atlanta, GA 30329 USA. [Conrad, Dennis A.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Cohen, Naiomi; Cotilla, Manuel] Miami Childrens Hosp, Miami, FL USA. [DaSilva, Alexandre] US FDA, Laurel, MD USA. RP Cope, JR (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd NE,MS C-09, Atlanta, GA 30329 USA. EM jcope@cdc.gov FU Intramural CDC HHS [CC999999] NR 11 TC 5 Z9 5 U1 4 U2 7 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 2016 VL 62 IS 6 BP 774 EP 776 DI 10.1093/cid/civ1021 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DF9XU UT WOS:000371716700015 PM 26679626 ER PT J AU Vijay, V Moland, CL Han, T Fuscoe, JC Lee, T Herman, EH Jenkins, GR Lewis, SM Cummings, CA Gao, Y Cao, ZJ Yu, LR Desai, VG AF Vijay, Vikrant Moland, Carrie L. Han, Tao Fuscoe, James C. Lee, Taewon Herman, Eugene H. Jenkins, G. Ronald Lewis, Sherry M. Cummings, Connie A. Gao, Yuan Cao, Zhijun Yu, Li-Rong Desai, Varsha G. TI Early transcriptional changes in cardiac mitochondria during chronic doxorubicin exposure and mitigation by dexrazoxane in mice SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Doxorubicin; Dexrazoxane; Mitochondria; Biomarkers; Cardiotoxicity ID ANTHRACYCLINE-INDUCED CARDIOTOXICITY; ADRIAMYCIN-INDUCED CARDIOMYOPATHY; ACUTE LYMPHOBLASTIC-LEUKEMIA; INDUCED MYOCARDIAL DAMAGE; FATTY-ACID-METABOLISM; GENE-EXPRESSION; MOUSE MODEL; NADH DEHYDROGENASE; ENERGY-METABOLISM; SKELETAL-MUSCLE AB Identification of early biomarkers of cardiotoxicity could help initiate means to ameliorate the cardiotoxic actions of clinically useful drugs such as doxorubicin (DOX). Since DOX has been shown to target mitochondria, transcriptional levels of mitochondria-related genes were evaluated to identify early candidate biomarkers in hearts of male B6C3F(1) mice given a weekly intravenous dose of 3 mg/kg DOX or saline (SAL) for 2, 3, 4, 6, or 8 weeks (6, 9, 12, 18, or 24 mg/kg cumulative DOX doses, respectively). Also, a group of mice was pretreated (intraperitoneally) with the cardio-protectant, dexrazoxane (DXZ; 60 mg/kg) 30 min before each weekly dose of DOX or SAL. At necropsy a week after the last dose, increased plasma concentrations of cardiac troponin T (cTnT) were detected at 18 and 24 mg/kg cumulative DOX doses, whereas myocardial alterations were observed only at the 24 mg/kg dose. Of 1019 genes interrogated, 185, 109, 140, 184, and 451 genes were differentially expressed at 6, 9, 12, 18, and 24 mg/kg cumulative DOX doses, respectively, compared to concurrent SAL-treated controls. Of these, expression of 61 genes associated with energy metabolism and apoptosis was significantly altered before and after occurrence of myocardial injury, suggesting these as early genomics markers of cardiotoxicity. Much of these DOX-induced transcriptional changes were attenuated by pretreatment of mice with DXZ. Also, DXZ treatment significantly reduced plasma cTnT concentration and completely ameliorated cardiac alterations induced by 24 mg/kg cumulative DOX. This information on early transcriptional changes during DOX treatment may be useful in designing cardioprotective strategies targeting mitochondria. Published by Elsevier Inc. C1 [Vijay, Vikrant; Moland, Carrie L.; Han, Tao; Fuscoe, James C.; Jenkins, G. Ronald; Desai, Varsha G.] US FDA, Personalized Med Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Lee, Taewon] Korea Univ, Dept Math, Sejong, South Korea. [Herman, Eugene H.] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Lewis, Sherry M.] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Cummings, Connie A.] UltraPath Imaging, 2228 Page Rd, Durham, NC 27703 USA. [Gao, Yuan; Cao, Zhijun; Yu, Li-Rong] US FDA, Biomarkers & Alternat Models Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Desai, VG (reprint author), US FDA, Personalized Med Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM varsha.desai@fda.hhs.gov RI Vijay, Vikrant/E-7651-2010 OI Vijay, Vikrant/0000-0001-8425-1285 NR 88 TC 3 Z9 3 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAR 15 PY 2016 VL 295 BP 68 EP 84 DI 10.1016/j.taap.2016.02.003 PG 17 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DG3DT UT WOS:000371950400007 PM 26873546 ER PT J AU Menachery, VD Yount, BL Sims, AC Debbink, K Agnihothram, SS Gralinski, LE Graham, RL Scobey, T Plante, JA Royal, SR Swanstrom, J Sheahan, TP Pickles, RJ Corti, D Randell, SH Lanzavecchia, A Marasco, WA Baric, RS AF Menachery, Vineet D. Yount, Boyd L., Jr. Sims, Amy C. Debbink, Kari Agnihothram, Sudhakar S. Gralinski, Lisa E. Graham, Rachel L. Scobey, Trevor Plante, Jessica A. Royal, Scott R. Swanstrom, Jesica Sheahan, Timothy P. Pickles, Raymond J. Corti, Davide Randell, Scott H. Lanzavecchia, Antonio Marasco, Wayne A. Baric, Ralph S. TI SARS-like WIV1-CoV poised for human emergence SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE SARS; CoV; emergence; Spike; WIV1 ID ACUTE RESPIRATORY SYNDROME; HUMAN MONOCLONAL-ANTIBODIES; CROSS-SPECIES TRANSMISSION; SYNDROME CORONAVIRUS; NEUTRALIZATION; DETERMINANTS; DISEASE; CELLS; HOST; MICE AB Outbreaks from zoonotic sources represent a threat to both human disease as well as the global economy. Despite a wealth of metagenomics studies, methods to leverage these datasets to identify future threats are underdeveloped. In this study, we describe an approach that combines existing metagenomics data with reverse genetics to engineer reagents to evaluate emergence and pathogenic potential of circulating zoonotic viruses. Focusing on the severe acute respiratory syndrome (SARS)-like viruses, the results indicate that the WIV1-coronavirus (CoV) cluster has the ability to directly infect and may undergo limited transmission in human populations. However, in vivo attenuation suggests additional adaptation is required for epidemic disease. Importantly, available SARS monoclonal antibodies offered success in limiting viral infection absent from available vaccine approaches. Together, the data highlight the utility of a platform to identify and prioritize prepandemic strains harbored in animal reservoirs and document the threat posed by WIV1-CoV for emergence in human populations. C1 [Menachery, Vineet D.; Yount, Boyd L., Jr.; Sims, Amy C.; Debbink, Kari; Gralinski, Lisa E.; Graham, Rachel L.; Scobey, Trevor; Plante, Jessica A.; Royal, Scott R.; Swanstrom, Jesica; Sheahan, Timothy P.; Baric, Ralph S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Debbink, Kari] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Agnihothram, Sudhakar S.; Pickles, Raymond J.; Baric, Ralph S.] Natl Ctr Toxicol Res, Div Microbiol, Food & Drug Adm, Jefferson, AR 72079 USA. [Pickles, Raymond J.; Randell, Scott H.] Univ N Carolina, Dept Cell Biol & Physiol, Cyst Fibrosis Ctr, Chapel Hill, NC 27599 USA. [Pickles, Raymond J.; Randell, Scott H.] Univ N Carolina, Marsico Lung Inst, Cyst Fibrosis Ctr, Chapel Hill, NC 27599 USA. [Corti, Davide; Lanzavecchia, Antonio] Inst Biomed Res, Bellinzona, Switzerland. [Corti, Davide; Lanzavecchia, Antonio] ETH, Inst Microbiol, CH-8092 Zurich, Switzerland. [Corti, Davide] Humabs BioMed SA, Bellinzona, Switzerland. [Marasco, Wayne A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS,Dept Med, 44 Binney St, Boston, MA 02115 USA. RP Baric, RS (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA.; Baric, RS (reprint author), Natl Ctr Toxicol Res, Div Microbiol, Food & Drug Adm, Jefferson, AR 72079 USA. EM rbaric@email.unc.edu FU National Institute of Allergy and Infectious Disease; National Institute of Aging of the NIH [U19AI109761, U19AI107810, AI1085524, F32AI102561, K99AG049092]; National Institute of Diabetes and Digestive and Kidney Disease [NIH DK065988]; NIH [AI076159, AI079521] FX We thank Dr. Zhengli-Li Shi of the Wuhan Institute of Virology for access to bat CoV sequences and plasmid of WIV1-CoV spike protein. Research was supported by the National Institute of Allergy and Infectious Disease and the National Institute of Aging of the NIH under Awards U19AI109761 and U19AI107810 (to R.S.B.), AI1085524 (to W.A.M.), and F32AI102561 and K99AG049092 (to V.D.M.). Human airway epithelial cell cultures were supported by the National Institute of Diabetes and Digestive and Kidney Disease under Award NIH DK065988 (to S.H.R.). Support for the generation of the mice expressing human ACE2 was provided by NIH Grants AI076159 and AI079521 (to A.C.S.). NR 27 TC 9 Z9 9 U1 3 U2 6 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 MAR 15 PY 2016 VL 113 IS 11 BP 3048 EP 3053 DI 10.1073/pnas.1517719113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG4BF UT WOS:000372014200070 PM 26976607 ER PT J AU Fowlkes, AL Witte, D Beeler, J Audet, SA Broadhead, R Bellini, WJ Cutts, F Helfand, RF AF Fowlkes, Ashley L. Witte, Desiree Beeler, Judy Audet, Susette A. Broadhead, Robin Bellini, William J. Cutts, Felicity Helfand, Rita F. TI Supplemental measles vaccine antibody response among HIV-infected and -uninfected children in Malawi after 1-and 2-dose primary measles vaccination schedules SO VACCINE LA English DT Article DE Measles vaccine; HIV; Supplementary immunization activity; Antibody response; Neutralizing antibody ID EDMONSTON-ZAGREB; AGE; IMMUNOGENICITY; INFANTS; TRIAL AB Background: The long-term antibody response to measles vaccine (MV) administered at age 6 months with or without subsequent doses is not well documented. Methods: Measles serum antibody responses were evaluated after a supplemental dose of measles vaccine (sMV) administered at a median age of 20 months among Malawian children who had previously received 2 doses of measles vaccine (MV) at ages 6 and 9 months (HIV-infected and random sample of HIV-uninfected) or 1 dose at age 9 months (random sample of HIV-uninfected). We compared measles antibody seropositivity between groups by enzyme linked immunoassay and seroprotection by plaque reduction neutralization geometric mean concentrations. Results: Of 1756 children enrolled, 887 (50.5%) received a sMV dose following MV at 9 months of age and had specimens available after sMV receipt, including 401 HIV-uninfected children who received one MV dose at 9 months, 464 HIV-uninfected and 22 HIV-infected children who received two doses of MV at ages 6 and 9 months. Among HIV-uninfected children, protective levels of antibody were found post sMV in 90-99% through ages 24-36 months and were not affected by MV schedule. Geometric mean concentration levels of measles antibody were significantly increased post-sMV among those HIV-uninfected children previously non-responsive to vaccination. Among HIV-infected children, the proportion seroprotected increased initially but by 9 months post-sMV was no higher than pre-sMV. Conclusions: Our findings support early 2-dose MV to provide measles immunity for young infants without risk of interference with antibody responses to subsequent MV doses administered as part of SIAs. Published by Elsevier Ltd. C1 [Fowlkes, Ashley L.; Bellini, William J.; Helfand, Rita F.] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Witte, Desiree; Broadhead, Robin] Univ Malawi, Coll Med, Blantyre, Malawi. [Beeler, Judy; Audet, Susette A.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Cutts, Felicity] London Sch Hyg & Trop Med, London WC1, England. RP Fowlkes, AL (reprint author), MPH, 1600 Clifton Rd NE,Mailstop A-32, Atlanta, GA 30329 USA. EM afowlkes@cdc.gov FU World Health Organization [V21/181/130]; Centers for Disease Control and Prevention; Berna Biotech FX World Health Organization (grant V21/181/130 to R.B.); Centers for Disease Control and Prevention; Berna Biotech (formerly Swiss Serum and Vaccine Institute; donation of measles vaccine). NR 17 TC 0 Z9 0 U1 6 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD MAR 14 PY 2016 VL 34 IS 12 BP 1459 EP 1464 DI 10.1016/j.vaccine.2016.01.055 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DG9EG UT WOS:000372385000007 PM 26873052 ER PT J AU Forry, SP Madonna, MC Lopez-Perez, D Lin, NJ Pasco, MD AF Forry, Samuel P. Madonna, Megan C. Lopez-Perez, Daneli Lin, Nancy J. Pasco, Madeleine D. TI Automation of antimicrobial activity screening SO AMB EXPRESS LA English DT Article DE Antimicrobial activity screening; Automation; Performance assessment ID ORAL MICROBIAL ECOLOGY; TOTAL LABORATORY AUTOMATION; TUMOR-CELL-LINES; STREPTOCOCCUS-MUTANS; ANTIBACTERIAL ACTIVITY; DENTAL PLAQUE; BIOFILM; COMMUNITIES; SUSCEPTIBILITY; IMMUNOLOGY AB Manual and automated methods were compared for routine screening of compounds for antimicrobial activity. Automation generally accelerated assays and required less user intervention while producing comparable results. Automated protocols were validated for planktonic, biofilm, and agar cultures of the oral microbe Streptococcus mutans that is commonly associated with tooth decay. Toxicity assays for the known antimicrobial compound cetylpyridinium chloride (CPC) were validated against planktonic, biofilm forming, and 24 h biofilm culture conditions, and several commonly reported toxicity/antimicrobial activity measures were evaluated: the 50 % inhibitory concentration (IC50), the minimum inhibitory concentration (MIC), and the minimum bactericidal concentration (MBC). Using automated methods, three halide salts of cetylpyridinium (CPC, CPB, CPI) were rapidly screened with no detectable effect of the counter ion on antimicrobial activity. C1 [Forry, Samuel P.; Madonna, Megan C.; Lopez-Perez, Daneli; Lin, Nancy J.; Pasco, Madeleine D.] NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. [Lopez-Perez, Daneli] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Forry, SP (reprint author), NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. EM sam.forry@nist.gov FU NRC; NIST SURF program FX The NIST SURF program provided support for MCM. DLP was supported through an NRC Postdoctoral Fellowship. NR 48 TC 1 Z9 1 U1 1 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2191-0855 J9 AMB EXPRESS JI AMB Express PD MAR 12 PY 2016 VL 6 AR 20 DI 10.1186/s13568-016-0191-2 PG 10 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DG3IH UT WOS:000371962200001 PM 26970766 ER PT J AU Bowyer, JF Sarkar, S Tranter, KM Hanig, JP Miller, DB O'Callaghan, JP AF Bowyer, John F. Sarkar, Sumit Tranter, Karen M. Hanig, Joseph P. Miller, Diane B. O'Callaghan, James P. TI Vascular-directed responses of microglia produced by methamphetamine exposure: indirect evidence that microglia are involved in vascular repair? SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Microglia; Vascular damage; Methamphetamine; Amphetamine; Neurotoxicity; Hyperthermia; Hypertension ID CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; NEURONAL DEGENERATION; INDUCED NEUROTOXICITY; IMMUNE-SYSTEM; ADULT BRAIN; RAT-BRAIN; AMPHETAMINE; ACTIVATION; HYPERTHERMIA AB Background: Brain microglial activations and damage responses are most commonly associated with neurodegeneration or systemic innate immune system activation. Here, we used histological methods to focus on microglial responses that are directed towards brain vasculature, previously undescribed, after a neurotoxic exposure to methamphetamine. Methods: Male rats were given doses of methamphetamine that produce pronounced hyperthermia, hypertension, and toxicity. Identification of microglia and microglia-like cells (pericytes and possibly perivascular cells) was done using immunoreactivity to allograft inflammatory factor 1 (Aif1 a.k.a Iba1) and alpha M integrin (Itgam a.k.a. Cd11b) while vasculature endothelium was identified using rat endothelial cell antigen 1 (RECA-1). Regions of neuronal, axonal, and nerve terminal degeneration were determined using Fluoro-Jade C. Results: Dual labeling of vasculature (RECA-1) and microglia (Iba1) showed a strong association of hypertrophied cells surrounding and juxtaposed to vasculature in the septum, medial dorsal hippocampus, piriform cortex, and thalamus. The Iba1 labeling was more pronounced in the cell body while Cd11b more so in the processes of activated microglia. These regions have been previously identified to have vascular leakage after neurotoxic methamphetamine exposure. Dual labeling with Fluoro-Jade C and Iba1 indicated that there was minimal or no evidence of neuronal damage in the septum and hippocampus where many hypertrophied Iba1-labeled cells were found to be associated with vasculature. Although microglial activation around the prominent neurodegeneration was found in the thalamus, there were also many examples of activated microglia associated with vasculature. Conclusions: The data implicate microglia, and possibly related cell types, in playing a major role in responding to methamphetamine-induced vascular damage, and possibly repair, in the absence of neurodegeneration. Identifying brain regions with hypertrophied/activated microglial-like cells associated with vasculature has the potential for identifying regions of more subtle examples of vascular damage and BBB compromise. C1 [Bowyer, John F.; Sarkar, Sumit; Tranter, Karen M.] US FDA, Div Neurotoxicol, Natl Ctr Toxicol, Jefferson, AR 72079 USA. [Hanig, Joseph P.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Miller, Diane B.; O'Callaghan, James P.] NIOSH, Hlth Effects Lab Div, Ctr Dis Control & Prevent, Morgantown, WV 26505 USA. [Bowyer, John F.] US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT-132, Jefferson, AR 72079 USA. RP Bowyer, JF (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol, Jefferson, AR 72079 USA.; Bowyer, JF (reprint author), US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT-132, Jefferson, AR 72079 USA. EM John.Bowyer@fda.hhs.gov FU FDA [E7519] FX This study was supported by FDA protocol E7519. NR 54 TC 1 Z9 1 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD MAR 12 PY 2016 VL 13 AR 64 DI 10.1186/s12974-016-0526-6 PG 15 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DG0VJ UT WOS:000371783500001 PM 26970737 ER PT J AU Troche, JR Mayne, ST Freedman, ND Shebl, FM Guertin, KA Cross, AJ Abnet, CC AF Troche, Jose Ramon Mayne, Susan T. Freedman, Neal D. Shebl, Fatma M. Guertin, Kristin A. Cross, Amanda J. Abnet, Christian C. TI Alcohol Consumption-Related Metabolites in Relation to Colorectal Cancer and Adenoma: Two Case-Control Studies Using Serum Biomarkers SO PLOS ONE LA English DT Article ID DOSE-RESPONSE METAANALYSIS; CIGARETTE-SMOKING; UNITED-STATES; RISK; EPIDEMIOLOGY; COHORT; METABOLOMICS; MORTALITY; MIGRANTS; TOBACCO AB Alcohol is a known carcinogen that may be associated with colorectal cancer. However, most epidemiologic studies assess alcoholic beverage consumption using self-reported data, leading to potential exposure misclassification. Biomarkers of alcohol consumption may provide an alternative, complementary approach that reduces misclassification and incorporates individual differences in alcohol metabolism. Therefore, we evaluated the relationship between previously identified alcohol consumption-related metabolites and colorectal cancer and adenoma using serum metabolomics data from two studies. Data on colorectal cancer were obtained from a nested case-control study of 502 US adults (252 cases, 250 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Data on colorectal adenoma were obtained from a case-control study of 197 US adults (120 cases, 77 controls) from the Navy Colon Adenoma Study. Unconditional multivariable logistic regression models were fit to calculate odds ratios (OR) and 95% confidence intervals (CI) for eight alcohol consumption-related metabolites identified in a previous analysis: ethyl glucuronide; 4-androstene-3beta, 17beta-diol disulfate 1; 5-alpha-androstan-3beta, 17beta-diol disulfate; 16-hydroxypalmitate; bilirubin (E, Z or Z, E); cyclo (-leu-pro); dihomo-linoleate (20: 2n6); and palmitoleate (16: 1n7). We found no clear association between these alcohol consumption-related metabolites and either endpoint. However, we did observe an inverse association between cyclo (-leu-pro) and colorectal adenoma that was only observed in the highest metabolite quantile (OR4th vs. 1st Quantile = 0.30, 95% CI: 0.12-0.78; P-trend = 0.047), but no association for colorectal cancer. In conclusion, there were no adverse associations between alcohol consumption-related metabolites and colorectal cancer or adenoma. C1 [Troche, Jose Ramon; Mayne, Susan T.; Shebl, Fatma M.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Troche, Jose Ramon; Freedman, Neal D.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Mayne, Susan T.; Shebl, Fatma M.] Yale Canc Ctr, New Haven, CT USA. [Guertin, Kristin A.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Cross, Amanda J.] Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Epidemiol & Biostat, Sch Publ Hlth, St Marys Campus,Norfolk Pl, London, England. [Mayne, Susan T.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Troche, JR (reprint author), Yale Univ, Sch Publ Hlth, New Haven, CT USA.; Troche, JR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. EM joseramon.troche@yale.edu RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health; National Institutes of Health [T32 CA105666] FX This work was partially supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health (http://www.cancer.gov/research/nci-role/intramural) and the National Institutes of Health (http://www.nih.gov/), grant T32 CA105666. NR 47 TC 0 Z9 0 U1 7 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 11 PY 2016 VL 11 IS 3 AR e0150962 DI 10.1371/journal.pone.0150962 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3SC UT WOS:000371989200024 PM 26967509 ER PT J AU Kasar, S Underbayev, C Hassan, M Ilev, I Degheidy, H Bauer, S Marti, G Lutz, C Raveche, E Batish, M AF Kasar, Siddha Underbayev, Chingiz Hassan, Moinuddin Ilev, Ilko Degheidy, Heba Bauer, Steven Marti, Gerald Lutz, Carol Raveche, Elizabeth Batish, Mona TI Alterations in the mir-15a/16-1 Loci Impairs Its Processing and Augments B-1 Expansion in De Novo Mouse Model of Chronic Lymphocytic Leukemia (CLL) SO PLOS ONE LA English DT Article ID B-CELL LYMPHOCYTOSIS; ZEALAND BLACK MOUSE; SIDE POPULATION; INFRARED-SPECTROSCOPY; DROSHA-DGCR8 COMPLEX; PRIMARY MICRORNA; MATURE MICRORNA; PROGRESSION; EXPRESSION; IDENTIFICATION AB New Zealand Black (NZB) mice, a de novo model of CLL, share multiple characteristics with CLL patients, including decreased expression of miR-15a/16-1. We previously discovered a point mutation and deletion in the 3' flanking region of mir-16-1 of NZB and a similar mutation has been found in a small number of CLL patients. However, it was unknown whether the mutation is the cause for the reduced miR-15a/16-1 expression and CLL development. Using PCR and in vitro microRNA processing assays, we found that the NZB sequence alterations in the mir-15a/16-1 loci result in deficient processing of the precursor forms of miR-15a/16-1, in particular, we observe impaired conversion of pri-miR-15a/16-1 to pre-miR-15a/16-1. The in vitro data was further supported by derivation of congenic strains with replaced mir-15a/16-1 loci at one or both alleles: NZB congenic mice (NmiR+/-) and DBA congenic mice (DmiR-/-). The level of miR-15a/16-1 reflected the configuration of the mir-15a/16-1 loci with DBA congenic mice (DmiR-/-) showing reduced miR-15a levels compared to homozygous wild-type allele, while the NZB congenic mice (NmiR+/-) showed an increase in miR-15a levels relative to homozygous mutant allele. Similar to Monoclonal B-cell Lymphocytosis (MBL), the precursor stage of the human disease, an overall expansion of the B-1 population was observed in DBA congenic mice (DmiR-/-) relative to wild-type (DmiR+/+). These studies support our hypothesis that the mutations in the mir-15a/16-1 loci are responsible for decreased expression of this regulatory microRNA leading to B-1 expansion and CLL development. C1 [Kasar, Siddha; Underbayev, Chingiz; Lutz, Carol; Raveche, Elizabeth; Batish, Mona] Rutgers State Univ, New Jersey Med Sch, Newark, NJ 07103 USA. [Hassan, Moinuddin; Ilev, Ilko; Marti, Gerald] US FDA, OSEL, CDRH, White Oak, MD USA. [Degheidy, Heba; Bauer, Steven] US FDA, CBER, White Oak, MD USA. [Kasar, Siddha] Dana Faber Canc Inst, Boston, MA USA. RP Batish, M (reprint author), Rutgers State Univ, New Jersey Med Sch, Newark, NJ 07103 USA. EM batishmo@njms.rutgers.edu FU NIH [R01CA12926]; NIH Director's Early Independence Award [DP5OD012160-01]; UMDNJ-NJMS Flow Cytometry Core, Molecular Resource Facility; Transgenic Core FX This work was supported by NIH R01CA12926 (ESR) and NIH Director's Early Independence Award DP5OD012160-01 (MB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This work was supported by NIH R01CA12926 (ESR) and NIH Director's Early Independence Award DP5OD012160-01 (MB). We thank the UMDNJ-NJMS Flow Cytometry Core, Molecular Resource Facility and the Transgenic Core for their support. NR 50 TC 1 Z9 1 U1 1 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 MAR 9 PY 2016 VL 11 IS 3 AR e0149331 DI 10.1371/journal.pone.0149331 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3TF UT WOS:000371992300009 PM 26959643 ER PT J AU Erlandson, KJ Bisht, H Weisberg, AS Hyun, SI Hansen, BT Fischer, ER Hinshaw, JE Moss, B AF Erlandson, Karl J. Bisht, Himani Weisberg, Andrea S. Hyun, Seong-In Hansen, Bryan T. Fischer, Elizabeth R. Hinshaw, Jenny E. Moss, Bernard TI Poxviruses Encode a Reticulon-Like Protein that Promotes Membrane Curvature SO CELL REPORTS LA English DT Article ID TUBULAR ENDOPLASMIC-RETICULUM; VACCINIA VIRUS MORPHOGENESIS; A17L ENVELOPE PROTEIN; INTERMEDIATE COMPARTMENT; IMMATURE VIRIONS; RNA-POLYMERASE; TOPOLOGY; RECOMBINANT; BIOGENESIS; EXPRESSION AB Poxviruses are enveloped DNA viruses that replicate within the cytoplasm. The first viral structures are crescents and spherical particles, with a lipoprotein membrane bilayer, that are thought to be derived from the ER. We determined that A17, a conserved viral transmembrane protein essential for crescent formation, forms homo-oligomers and shares topological features with cellular reticulon-like proteins. The latter cell proteins promote membrane curvature and contribute to the tubular structure of the ER. When the purified A17 protein was incorporated into liposomes, 25 nm diameter vesicles and tubules formed at low and high A17 concentrations, respectively. In addition, intracellular expression of A17 in the absence of other viral structural proteins transformed the ER into aggregated three-dimensional (3D) tubular networks. We suggest that A17 is a viral reticulon-like protein that contributes to curvature during biogenesis of the poxvirus membrane. C1 [Erlandson, Karl J.; Bisht, Himani; Weisberg, Andrea S.; Hyun, Seong-In; Moss, Bernard] NIAID, Lab Viral Dis, NIH, Bethesda, MD 20892 USA. [Hansen, Bryan T.; Fischer, Elizabeth R.] NIAID, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Hinshaw, Jenny E.] NIDDK, Struct Cell Biol Sect, NIH, Bethesda, MD 20892 USA. [Bisht, Himani] US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. RP Moss, B (reprint author), NIAID, Lab Viral Dis, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, NIAID; NIGMS PRAT fellowship FX Support was from the Division of Intramural Research, NIAID. K.J.E. received support from an NIGMS PRAT fellowship. NR 27 TC 1 Z9 1 U1 3 U2 7 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 MAR 8 PY 2016 VL 14 IS 9 BP 2084 EP 2091 DI 10.1016/j.celrep.2016.01.075 PG 8 WC Cell Biology SC Cell Biology GA DF6LJ UT WOS:000371466900006 PM 26923595 ER PT J AU Burall, LS Grim, CJ Mammel, MK Datta, AR AF Burall, Laurel S. Grim, Christopher J. Mammel, Mark K. Datta, Atin R. TI Whole Genome Sequence Analysis Using JSpecies Tool Establishes Clonal Relationships between Listeria monocytogenes Strains from Epidemiologically Unrelated Listeriosis Outbreaks SO PLOS ONE LA English DT Article ID MULTIPLEX PCR; UNITED-STATES; SEROTYPE 4B; PHYLOGENIES; SALMONELLA; ISOLATE; SCHEME AB In an effort to build a comprehensive genomic approach to food safety challenges, the FDA has implemented a whole genome sequencing effort, GenomeTrakr, which involves the sequencing and analysis of genomes of foodborne pathogens. As a part of this effort, we routinely sequence whole genomes of Listeria monocytogenes (Lm) isolates associated with human listeriosis outbreaks, as well as those isolated through other sources. To rapidly establish genetic relatedness of these genomes, we evaluated tetranucleotide frequency analysis via the JSpecies program to provide a cursory analysis of strain relatedness. The JSpecies tetranucleotide (tetra) analysis plots standardized (z-score) tetramer word frequencies of two strains against each other and uses linear regression analysis to determine similarity (r(2)). This tool was able to validate the close relationships between outbreak related strains from four different outbreaks. Included in this study was the analysis of Lm strains isolated during the recent caramel apple outbreak and stone fruit incident in 2014. We identified that many of the isolates from these two outbreaks shared a common 4b variant (4bV) serotype, also designated as IVb-v1, using a qPCR protocol developed in our laboratory. The 4bV serotype is characterized by the presence of a 6.3 Kb DNA segment normally found in serotype 1/2a, 3a, 1/2c and 3c strains but not in serotype 4b or 1/2b strains. We decided to compare these strains at a genomic level using the JSpecies Tetra tool. Specifically, we compared several 4bV and 4b isolates and identified a high level of similarity between the stone fruit and apple 4bV strains, but not the 4b strains co-identified in the caramel apple outbreak or other 4b or 4bV strains in our collection. This finding was further substantiated by a SNP-based analysis. Additionally, we were able to identify close relatedness between isolates from clinical cases from 1993-1994 and a single case from 2011 as well as links between two isolates from over 30 years ago. The identification of these potential links shows that JSpecies Tetra analysis can be a useful tool in rapidly assessing genetic relatedness of Lm isolates during outbreak investigations and for comparing historical isolates. Our analyses led to the identification of a highly related clonal group involved in two separate outbreaks, stone fruit and caramel apple, and suggests the possibility of a new genotype that may be better adapted for certain foods and/or environment. C1 [Burall, Laurel S.; Grim, Christopher J.; Mammel, Mark K.; Datta, Atin R.] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD USA. RP Burall, LS; Datta, AR (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD USA. EM Laurel.Burall@fda.hhs.gov; Atin.Datta@fda.hhs.gov FU U.S. Food and Drug Administration; U.S. Department of Energy; FDA FX This project was supported in part by an appointment to the Internship/Research Participation Program at the Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy and FDA (http://orise.orau.gov/). This funding supported the appointment of CJG. ORISE had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. All other funding came from the U.S. Food and Drug Administration. NR 35 TC 2 Z9 2 U1 4 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 7 PY 2016 VL 11 IS 3 AR e0150797 DI 10.1371/journal.pone.0150797 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3SL UT WOS:000371990100063 PM 26950338 ER PT J AU Hung, HMJ Wang, SJ Yang, PL AF Hung, H. M. James Wang, Sue-Jane Yang, Peiling TI Rejoinder to Dr. Cyrus R. Mehta SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Editorial Material C1 [Hung, H. M. James; Yang, Peiling] FDA, Div Biometr 1, OB OTS CDER, Silver Spring, MD USA. [Wang, Sue-Jane] FDA, Off Biostat, OTS CDER, Silver Spring, MD USA. RP Hung, HMJ (reprint author), FDA, Div Biometr 1, OB OTS CDER, Silver Spring, MD USA. EM hsienming.hung@fda.hhs.gov NR 2 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. PD MAR 3 PY 2016 VL 26 IS 2 BP 405 EP 405 DI 10.1080/10543406.2015.1099542 PG 1 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA DI8CG UT WOS:000373728000016 PM 26467176 ER PT J AU Lago, MA Ackerman, LK AF Lago, Miguel A. Ackerman, Luke K. TI Identification of print-related contaminants in food packaging SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE Food packaging; photoinitiators; set-off; photo-scission; print-contaminant; DART-MS ID CHROMATOGRAPHY-MASS SPECTROMETRY; SOLID-PHASE MICROEXTRACTION; GAS-CHROMATOGRAPHY; CONTACT MATERIALS; LIQUID-CHROMATOGRAPHY; AMINE SYNERGISTS; INK PHOTOINITIATORS; DRY FOODS; SET-OFF; ISOPROPYLTHIOXANTHONE ITX AB Since the UV ink photoinitiator (PI) isopropylthioxanthone (ITX) was discovered in packaged milk, studies of print contamination have focused primarily on PIs but have also included amine synergists. Many other substances are used or formed during the print process, yet their identity and set-off properties have yet to be catalogued in food packaging. Three different techniques: direct analysis in real-time high-resolution mass spectrometry (DART-HRMS), gas chromatography-mass spectrometry (GC-MS) and ultra-high-pressure liquid chromatography electrospray ionisation/HRMS (UHPLC/ESI-HRMS) were used to detect and identify print-related molecules from the food-contact and print surfaces of three different packages with under-cured prints. This approach tentatively identified or confirmed 110 compounds, including 35 print-related molecules. The majority of compounds identified on food-contact surfaces were packaging monomers/byproducts, solvents/plasticisers, antioxidants/degradants or slip agents/lubricants. Of these, 28 showed evidence of set-off. The identities of 16 PIs, seven known scission products and five probable PI degradants were confirmed, most showing signs of set-off. Of the print-related molecules, at least five are novel print contaminants such as 4-morpholin-4-yl-benzaldehyde or 3-phenyl-2-benzofuran-1(3H)-one. C1 [Lago, Miguel A.; Ackerman, Luke K.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Lago, Miguel A.] Univ Santiago de Compostela, Dept Analyt Chem Nutr & Food Sci, Fac Pharm, Santiago De Compostela, Spain. RP Ackerman, LK (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM Luke.Ackerman@fda.hhs.gov RI Lago, Miguel A./D-7839-2016 OI Lago, Miguel A./0000-0002-6459-3023 FU Ministerio de Economia y Competitividad through the pre-doctoral fellowships FPI [BES-2012-051993]; EEBB [EEBB-I-14-08151] FX This work was supported by the Ministerio de Economia y Competitividad through the pre-doctoral fellowships FPI (reference number BES-2012-051993) and EEBB (EEBB-I-14-08151) awarded to Miguel A. Lago. NR 49 TC 1 Z9 1 U1 6 U2 19 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PD MAR 3 PY 2016 VL 33 IS 3 BP 518 EP 529 DI 10.1080/19440049.2015.1136435 PG 12 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA DG4KM UT WOS:000372041100013 PM 26789986 ER PT J AU Wang, ZF Jablonski, JE AF Wang, Zhengfang Jablonski, Joseph E. TI Targeted and non-targeted detection of lemon juice adulteration by LC-MS and chemometrics SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE Lemon juice; adulteration; LC-MS; Orbitrap; principal component analysis; chemometrics ID PERFORMANCE LIQUID-CHROMATOGRAPHY; SPECTROMETRY CHEMICAL PROFILES; QUADRUPOLE MASS-SPECTROMETRY; FRUIT JUICES; PHENOLIC-COMPOUNDS; ISOTOPE RATIOS; ELECTROSPRAY-IONIZATION; HAZELNUT ALLERGENS; SPANISH CULTIVARS; CITRIC-ACID AB Economically motivated adulteration (EMA) of lemon juice was detected by LC-MS and principal component analysis (PCA). Twenty-two batches of freshly squeezed lemon juice were adulterated by adding an aqueous solution containing 5% citric acid and 6% sucrose to pure lemon juice to obtain 30%, 60% and 100% lemon juice samples. Their total titratable acidities, degrees Brix and pH values were measured, and then all the lemon juice samples were subject to LC-MS analysis. Concentrations of hesperidin and eriocitrin, major phenolic components of lemon juice, were quantified. The PCA score plots for LC-MS datasets were used to preview the classification of pure and adulterated lemon juice samples. Results showed a large inherent variability in the chemical properties among 22 batches of 100% lemon juice samples. Measurement or quantitation of one or several chemical properties (targeted detection) was not effective in detecting lemon juice adulteration. However, by using the LC-MS datasets, including both chromatographic and mass spectrometric information, 100% lemon juice samples were successfully differentiated from adulterated samples containing 30% lemon juice in the PCA score plot. LC-MS coupled with chemometric analysis can be a complement to existing methods for detecting juice adulteration. C1 [Wang, Zhengfang; Jablonski, Joseph E.] US FDA, Ctr Food Safety & Appl Nutr, Div Food Proc Sci & Technol, Bedford Pk, IL USA. RP Jablonski, JE (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Food Proc Sci & Technol, Bedford Pk, IL USA. EM Joseph.Jablonski@fda.hhs.gov NR 43 TC 0 Z9 0 U1 5 U2 16 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 EI 1944-0057 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PD MAR 3 PY 2016 VL 33 IS 3 BP 560 EP 573 DI 10.1080/19440049.2016.1138547 PG 14 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA DG4KM UT WOS:000372041100017 PM 26807674 ER PT J AU Li, M Zhao, Y Humar, A Tevar, AD Hughes, C Venkataramanan, R AF Li, Mi Zhao, Yang Humar, Abhinav Tevar, Amit D. Hughes, Christopher Venkataramanan, Raman TI Pharmacokinetics of drugs in adult living donor liver transplant patients: regulatory factors and observations based on studies in animals and humans SO EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY LA English DT Review DE drug metabolism; liver resection; liver transplant; drug transporter; Cytochromes P450; pro-inflammatory cytokine ID REGENERATING RAT-LIVER; FOR-SIZE SYNDROME; PARTIAL-HEPATECTOMY; HEPATIC REGENERATION; MYCOPHENOLIC-ACID; THEOPHYLLINE PHARMACOKINETICS; POPULATION PHARMACOKINETICS; INFLAMMATORY MEDIATORS; TRANSPORTER REGULATION; HUMAN HEPATOCYTES AB Introduction: Limited information is available on the pharmacokinetics of drugs in the donors and recipients following adult living donor liver transplantation (LDLT). Given that both the donors and recipients receive multiple drug therapies, it is important to assess the pharmacokinetics of drugs used in these patients. Areas covered: Pathophysiological changes that occur post-surgery and regulatory factors that may influence pharmacokinetics of drugs, especially hepatic drug metabolism and transport in both LDLT donors and the recipients are discussed. Pharmacokinetic data in animals with partial hepatectomy are presented. Clinical pharmacokinetic data of certain drugs in LDLT recipients are further reviewed. Expert opinion: It takes up to six months for the liver volume to return to normal after LDLT surgery. In the LDLT recipients, drug exposure generally is higher with lower clearance during early period post-transplant; lower initial dosages of immunosuppressants are used than deceased donor liver transplant recipients during the first six months post-transplantation. In animals, the activities of hepatic drug metabolizing enzymes and transporters are known to be altered differentially during liver regeneration. Future studies on the actual hepatic function with reference to drug metabolism, drug transport, and biliary secretion in both LDLT donors and recipients are required. C1 [Li, Mi; Zhao, Yang; Venkataramanan, Raman] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Li, Mi] Tsinghua Univ, Sch Med, Beijing 100084, Peoples R China. [Zhao, Yang] US FDA, Off Pharmaceut Qual, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Humar, Abhinav; Tevar, Amit D.; Hughes, Christopher; Venkataramanan, Raman] Sch Med, Thomas Starzl Transplantat Inst, Dept Surg, Pittsburgh, PA USA. [Venkataramanan, Raman] Magee Womens Res Inst, Pittsburgh, PA USA. [Venkataramanan, Raman] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. RP Venkataramanan, R (reprint author), Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. EM rv@pitt.edu NR 86 TC 3 Z9 3 U1 0 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1742-5255 EI 1744-7607 J9 EXPERT OPIN DRUG MET JI Expert Opin. Drug Metab. Toxicol. PD MAR 3 PY 2016 VL 12 IS 3 BP 231 EP 243 DI 10.1517/17425255.2016.1139575 PG 13 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA DE6NX UT WOS:000370751900001 PM 26809188 ER PT J AU Patro, JN Ramachandran, P Barnaba, T Mammel, MK Lewis, JL Elkins, CA AF Patro, Jennifer N. Ramachandran, Padmini Barnaba, Tammy Mammel, Mark K. Lewis, Jada L. Elkins, Christopher A. TI Culture-Independent Metagenomic Surveillance of Commercially Available Probiotics with High-Throughput Next-Generation Sequencing SO MSPHERE LA English DT Article DE Probiotics; dietary supplements; metagenomics; whole-genome sequencing; lactic acid bacteria ID LACTOBACILLUS-RHAMNOSUS; INTESTINAL MICROBIOTA; MICROARRAY; ACCURACY; PRODUCTS; QUALITY; MARKET; CASEI AB Millions of people consume dietary supplements either following a doctor's recommendation or at their own discretion to improve their overall health and well-being. This is a rapidly growing trend, with an associated and expanding manufacturing industry to meet the demand for new health-related products. In this study, we examined the contents and microbial viability of several popular probiotic products on the United States market. Culture-independent methods are proving ideal for fast and efficient analysis of foodborne pathogens and their associated microbial communities but may also be relevant for analyzing probiotics containing mixed microbial constituents. These products were subjected to next-generation whole-genome sequencing and analyzed by a custom in-house-developed k-mer counting method to validate manufacturer label information. In addition, the batch variability of respective products was examined to determine if any changes in their formulations and/or the manufacturing process occurred. Overall, the products we tested adhered to the ingredient claims and lot-to-lot differences were minimal. However, there were a few discrepancies in the naming of closely related Lactobacillus and Bifidobacterium species, whereas one product contained an apparent Enterococcus contaminant in two of its three lots. With the microbial contents of the products identified, we used traditional PCR and colony counting methods to comparatively assess our results and verify the viability of the microbes in these products with regard to the labeling claims. Of all the supplements examined, only one was found to be inaccurate in viability. Our use of next-generation sequencing as an analytical tool clearly demonstrated its utility for quickly analyzing commercially available products containing multiple microbes to ensure consumer safety. IMPORTANCE The rapidly growing supplement industry operates without a formal premarket approval process. Consumers rely on product labels to be accurate and true. Those products containing live microbials report both identity and viability on most product labels. This study used next-generation sequencing technology as an analytical tool in conjunction with classic culture methods to examine the validity of the labels on supplement products containing live microbials found in the United States marketplace. Our results show the importance of testing these products for identity, viability, and potential contaminants, as well as introduce a new cultureindependent diagnostic approach for testing these products. C1 [Patro, Jennifer N.; Ramachandran, Padmini; Barnaba, Tammy; Mammel, Mark K.; Lewis, Jada L.; Elkins, Christopher A.] US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Elkins, CA (reprint author), US FDA, Div Mol Biol, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. EM chris.elkins@fda.hhs.gov FU Oak Ridge Institute for Science Education FX Padmini Ramachandran was supported by a fellowship appointment administered by the Oak Ridge Institute for Science Education. NR 34 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2379-5042 J9 MSPHERE JI mSphere PD MAR-APR PY 2016 VL 1 IS 2 AR UNSP e00057-16 DI 10.1128/mSphere.00057-16 PG 12 WC Microbiology SC Microbiology GA EI6DH UT WOS:000392584700019 ER PT J AU Wright, PF Hoen, AG Ilyushina, NA Brown, EP Ackerman, ME Wieland-Alter, W Connor, RI Jegaskanda, S Rosenberg-Hasson, Y Haynes, BC Luke, CJ Subbarao, K Treanor, JJ AF Wright, Peter F. Hoen, Anne G. Ilyushina, Natalia A. Brown, Eric P. Ackerman, Margaret E. Wieland-Alter, Wendy Connor, Ruth I. Jegaskanda, Sinthujan Rosenberg-Hasson, Yael Haynes, Brenda C. Luke, Catherine J. Subbarao, Kanta Treanor, John J. TI Correlates of Immunity to Influenza as Determined by Challenge of Children with Live, Attenuated Influenza Vaccine SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE humoral immunity; influenza vaccine; mucosal immunity; vaccine ID WILD-TYPE VIRUS; YOUNG-CHILDREN; IMMUNIZATION PRACTICES; ADVISORY-COMMITTEE; UNITED-STATES; COLD; RESISTANCE; RECOMMENDATIONS; PREVENTION; ANTIBODIES AB Background. The efficacy of live, attenuated live attenuated influenza vaccine(LAIV) and inactivated influenza vaccine(IIV) is poorly explained by either single or composite immune responses to vaccination. Protective biomarkers were therefore studied in response to LAIV or IIV followed by LAIV challenge in children. Methods. Serum and mucosal responses to LAIV or IIV were analyzed using immunologic assays to assess both quantitative and functional responses. Cytokines and chemokines were measured in nasal washes collected before vaccination, on days 2, 4, and 7 after initial LAIV, and again after LAIV challenge using a 63-multiplex Luminex panel. Results. Patterns of immunity induced by LAIV and IIV were significantly different. Serum responses induced by IIV, including hemagglutination inhibition, did not correlate with detection or quantitation of LAIV on subsequent challenge. Modalities that induced sterilizing immunity seen after LAIV challenge could not be defined by any measurements of mucosal or serum antibodies induced by the initial LAIV immunization. No single cytokine or chemokine was predictive of protection. Conclusions. The mechanism of protective immunity observed after LAIV could not be defined, and traditional measurements of immunity to IIV did not correlate with protection against an LAIV challenge. C1 [Wright, Peter F.; Ilyushina, Natalia A.] Geisel Sch Med Dartmouth, Dept Pediat, Lebanon, NH USA. [Hoen, Anne G.] Geisel Sch Med Dartmouth, Dept Epidemiol, Lebanon, NH USA. [Wieland-Alter, Wendy; Haynes, Brenda C.] Geisel Sch Med Dartmouth, Dept Med, Lebanon, NH USA. [Connor, Ruth I.] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Lebanon, NH USA. [Brown, Eric P.; Ackerman, Margaret E.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. [Jegaskanda, Sinthujan; Luke, Catherine J.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Rosenberg-Hasson, Yael] Stanford Univ, Inst Immun Transplantat & Infect, Human Immune Monitoring Ctr, Palo Alto, CA 94304 USA. [Treanor, John J.] Univ Rochester, Dept Med, New York, NY USA. [Ilyushina, Natalia A.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Wright, PF (reprint author), Geisel Sch Med Dartmouth, Div Infect Dis & Int Med, One Med Ctr Dr, Lebanon, NH 03756 USA. EM peter.f.wright@dartmouth.edu NR 25 TC 4 Z9 4 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD SPR PY 2016 VL 3 IS 2 DI 10.1093/ofid/ofw108 PG 8 WC Infectious Diseases SC Infectious Diseases GA EC3IR UT WOS:000388020200061 ER PT J AU Martinez-Urtaza, J Trinanes, J Gonzalez-Escalona, N Baker-Austin, C AF Martinez-Urtaza, Jaime Trinanes, Joaquin Gonzalez-Escalona, Narjol Baker-Austin, Craig TI Is El Nino a long-distance corridor for waterborne disease? SO NATURE MICROBIOLOGY LA English DT Editorial Material ID CHOLERA; VIBRIO; DISSEMINATION; EMERGENCE; AMERICA AB The apparent emergence of new and devastating Vibrio diseases in Latin America during significant El Nino events is striking. New microbiological, genomic and bioinformatic tools are providing us with evidence that El Nino may represent a long-distance corridor for waterborne diseases into the Americas from Asia. C1 [Martinez-Urtaza, Jaime] Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath BA2 7AY, Somerset, 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, Rosenstiel Sch Marine & Atmospher Sci, Cooperat Inst Marine & Atmospher Studies, 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. [Baker-Austin, Craig] CEFAS, Weymouth DT4 8UB, Dorset, England. RP Martinez-Urtaza, J (reprint author), Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath BA2 7AY, Somerset, England. EM J.L.Martinez-Urtaza@bath.ac.uk NR 16 TC 3 Z9 3 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND EI 2058-5276 J9 NAT MICROBIOL JI NAT. MICROBIOL PD MAR PY 2016 VL 1 IS 3 AR 16018 DI 10.1038/NMICROBIOL.2016.18 PG 3 WC Microbiology SC Microbiology GA DW4HU UT WOS:000383604600013 PM 27572176 ER PT J AU Duggirala, HJ Tonning, JM Smith, E Bright, RA Baker, JD Ball, R Bell, C Bright-Ponte, SJ Botsis, T Bouri, K Boyer, M Burkhart, K Condrey, GS Chen, JJ Chirtel, S Filice, RW Francis, H Jiang, HY Levine, J Martin, D Oladipo, T O'Neill, R Palmer, LAM Paredes, A Rochester, G Sholtes, D Szarfman, A Wong, HL Xu, ZH Kass-Hout, T AF Duggirala, Hesha J. Tonning, Joseph M. Smith, Ella Bright, Roselie A. Baker, John D. Ball, Robert Bell, Carlos Bright-Ponte, Susan J. Botsis, Taxiarchis Bouri, Khaled Boyer, Marc Burkhart, Keith Condrey, G. Steven Chen, James J. Chirtel, Stuart Filice, Ross W. Francis, Henry Jiang, Hongying Levine, Jonathan Martin, David Oladipo, Taiye O'Neill, Rene Palmer, Lee Anne M. Paredes, Antonio Rochester, George Sholtes, Deborah Szarfman, Ana Wong, Hui-Lee Xu, Zhiheng Kass-Hout, Taha TI Use of data mining at the Food and Drug Administration SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE data mining; pharmacovigilance; disproportionality analysis ID EVENT REPORTING SYSTEM; ADVERSE EVENTS; MEDICAL DEVICE; SIGNAL-DETECTION; PHARMACOVIGILANCE; HEPATOTOXICITY; SURVEILLANCE; VACCINE; VAERS AB Objectives This article summarizes past and current data mining activities at the United States Food and Drug Administration (FDA). Target audience We address data miners in all sectors, anyone interested in the safety of products regulated by the FDA (predominantly medical products, food, veterinary products and nutrition, and tobacco products), and those interested in FDA activities. Scope Topics include routine and developmental data mining activities, short descriptions of mined FDA data, advantages and challenges of data mining at the FDA, and future directions of data mining at the FDA. C1 [Duggirala, Hesha J.; Baker, John D.; Bright-Ponte, Susan J.; Palmer, Lee Anne M.] US FDA, Ctr Vet Med, Rockville, MD 20857 USA. [Tonning, Joseph M.; Bell, Carlos; Burkhart, Keith; Francis, Henry; Szarfman, Ana] US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Smith, Ella; Boyer, Marc; Chirtel, Stuart; Oladipo, Taiye] US FDA, Ctr Food Safety & Appl Nutr, Rockville, MD 20857 USA. [Bright, Roselie A.; Bouri, Khaled; Filice, Ross W.; Levine, Jonathan; Kass-Hout, Taha] US FDA, Off Commissioner, Rockville, MD 20857 USA. [Ball, Robert; Botsis, Taxiarchis; Martin, David] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Condrey, G. Steven] US FDA, Off Regulatory Affairs, Rockville, MD 20857 USA. [Chen, James J.] US FDA, Natl Ctr Toxicol Res, Rockville, MD 20857 USA. [Jiang, Hongying; O'Neill, Rene; Wong, Hui-Lee; Xu, Zhiheng] US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. [Paredes, Antonio; Rochester, George; Sholtes, Deborah] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Duggirala, HJ (reprint author), 7519 Standish Pl,HFV 200, Rockville, MD 20855 USA. EM Hesha.Duggirala@fda.hhs.gov OI Kass-Hout, Taha/0000-0002-0123-5157 NR 53 TC 1 Z9 1 U1 9 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAR PY 2016 VL 23 IS 2 BP 428 EP 434 DI 10.1093/jamia/ocv063 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DW6SN UT WOS:000383781600027 PM 26209436 ER PT J AU Lyn-Cook, B Word, B Joseph, S Hammons, G AF Lyn-Cook, Beverly Word, Beverly Joseph, Stancy Hammons, Goorge TI Epigenetics and pancreatic cancer: The role of nutrigenomics in cancer health disparities SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [Lyn-Cook, Beverly; Word, Beverly; Joseph, Stancy; Hammons, Goorge] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2016 VL 25 IS 3 SU S MA C26 DI 10.1158/1538-7755.DISP15-C26 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300085 ER PT J AU Kotarek, J Stuart, C De Paoli, SH Simak, J Lin, TL Gao, YM Ovanesov, M Liang, YD Scott, D Brown, J Bai, Y Metcalfe, DD Marszal, E Ragheb, JA AF Kotarek, Joseph Stuart, Christine De Paoli, Silvia H. Simak, Jan Lin, Tsai-Lien Gao, Yamei Ovanesov, Mikhail Liang, Yideng Scott, Dorothy Brown, Janice Bai, Yun Metcalfe, Dean D. Marszal, Ewa Ragheb, Jack A. TI Subvisible Particle Content, Formulation, and Dose of an Erythropoietin Peptide Mimetic Product Are Associated With Severe Adverse Postmarketing Events SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE particle sizing; formulation; peptides; protein aggregation ID MAST-CELL ACTIVATION; POLYETHYLENE-GLYCOL; ANTIBODIES; RI AB Peginesatide (Omontys (R); Affymax, Inc., Cupertino, CA) was voluntarily withdrawn from the market less than a year after the product launch. Although clinical trials had demonstrated the drug to be safe and efficacious, 49 cases of anaphylaxis, including 7 fatalities, were reported not long after market introduction. Commercialization was initiated with a multiuse vial presentation, which differs in formulation from the single-use vial presentation used in phase 3 studies. Standard physical and chemical testing did not indicate any deviation from product specifications in either formulation. However, an analysis of subvisible particulates using nanoparticle tracking analysis and flow imaging revealed a significantly higher concentration of subvisible particles in the multiuse vial presentation linked to the hypersensitivity cases. Although it is unknown whether the elevated particulate content is causally related to these serious adverse events, this report illustrates the utility of characterizing subvisible particulates not captured by conventional light obscuration. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved. C1 [Kotarek, Joseph; Stuart, Christine; De Paoli, Silvia H.; Simak, Jan; Ovanesov, Mikhail; Liang, Yideng; Scott, Dorothy; Marszal, Ewa] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Lin, Tsai-Lien] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Gao, Yamei] US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Brown, Janice] US FDA, Off New Drug Qual Assessment, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Bai, Yun; Metcalfe, Dean D.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ragheb, Jack A.] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Marszal, E (reprint author), US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA.; Ragheb, JA (reprint author), US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Ewa.Marszal@fda.hhs.gov; Jack.Ragheb@fda.hhs.gov FU US Department of Energy; US FDA; Division of Intramural Research, NIAID FX This project was supported in part by an appointment to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US FDA. Additionally, portions of this work were supported by the Division of Intramural Research, NIAID. We thank David Frucht and Raymond Yin for generously donating the anti-PEG antibodies used in the study and the Takeda Pharmaceutical Company Ltd for providing product-related materials. We also acknowledge the numerous contributions of the entire FDA Omontys Task Force. NR 17 TC 6 Z9 6 U1 3 U2 5 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 MAR PY 2016 VL 105 IS 3 BP 1023 EP 1027 DI 10.1016/S0022-3549(15)00180-X PG 5 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA DT8TT UT WOS:000381769100001 PM 26886324 ER PT J AU Raben, JS Hariharan, P Robinson, R Malinauskas, R Vlachos, PP AF Raben, Jaime S. Hariharan, Prasanna Robinson, Ronald Malinauskas, Richard Vlachos, Pavlos P. TI Time-Resolved Particle Image Velocimetry Measurements with Wall Shear Stress and Uncertainty Quantification for the FDA Nozzle Model SO CARDIOVASCULAR ENGINEERING AND TECHNOLOGY LA English DT Article DE Particle image velocimetry (PIV); Medical device; Validation; Nozzle flow model; Uncertainty ID INDUCED PLATELET ACTIVATION; MECHANICAL HEART-VALVES; IN-STENT RESTENOSIS; SINGLE-PIXEL RESOLUTION; PHASE-CORRELATION; DIGITAL PIV; MICRO-PIV; FLOW; ACCURACY; HYPERPLASIA AB We present advanced particle image velocimetry (PIV) processing, post-processing, and uncertainty estimation techniques to support the validation of computational fluid dynamics analyses of medical devices. This work is an extension of a previous FDA-sponsored multi-laboratory study, which used a medical device mimicking geometry referred to as the FDA benchmark nozzle model. Experimental measurements were performed using time-resolved PIV at five overlapping regions of the model for Reynolds numbers in the nozzle throat of 500, 2000, 5000, and 8000. Images included a twofold increase in spatial resolution in comparison to the previous study. Data was processed using ensemble correlation, dynamic range enhancement, and phase correlations to increase signal-to-noise ratios and measurement accuracy, and to resolve flow regions with large velocity ranges and gradients, which is typical of many blood-contacting medical devices. Parameters relevant to device safety, including shear stress at the wall and in bulk flow, were computed using radial basis functions. In addition, in-field spatially resolved pressure distributions, Reynolds stresses, and energy dissipation rates were computed from PIV measurements. Velocity measurement uncertainty was estimated directly from the PIV correlation plane, and uncertainty analysis for wall shear stress at each measurement location was performed using a Monte Carlo model. Local velocity uncertainty varied greatly and depended largely on local conditions such as particle seeding, velocity gradients, and particle displacements. Uncertainty in low velocity regions in the sudden expansion section of the nozzle was greatly reduced by over an order of magnitude when dynamic range enhancement was applied. Wall shear stress uncertainty was dominated by uncertainty contributions from velocity estimations, which were shown to account for 90-99% of the total uncertainty. This study provides advancements in the PIV processing methodologies over the previous work through increased PIV image resolution, use of robust image processing algorithms for near-wall velocity measurements and wall shear stress calculations, and uncertainty analyses for both velocity and wall shear stress measurements. The velocity and shear stress analysis, with spatially distributed uncertainty estimates, highlights the challenges of flow quantification in medical devices and provides potential methods to overcome such challenges. C1 [Raben, Jaime S.] Virginia Tech, Sch Biomed Engn & Sci, Blacksburg, VA USA. [Hariharan, Prasanna; Robinson, Ronald; Malinauskas, Richard] US FDA, Silver Spring, MD USA. [Vlachos, Pavlos P.] Purdue Univ, Sch Mech Engn, 585 Purdue Mall, W Lafayette, IN 47906 USA. RP Vlachos, PP (reprint author), Purdue Univ, Sch Mech Engn, 585 Purdue Mall, W Lafayette, IN 47906 USA. EM pvlachos@purdue.edu FU National Science Foundation Scholar-in-Residence program at the Food and Drug Administration, NSF-SIR Award [1239265] FX This work was supported by the National Science Foundation Scholar-in-Residence program at the Food and Drug Administration, NSF-SIR Award Number 1239265. Additionally, the authors would like to acknowledge contributions from Dr. Steven Day (Rochester Institute of Technology), Matthew Giarra (Virginia Tech), and Dr. Sandy Stewart (FDA). Dr. Changfu Wu (FDA), Dr. Rachel Neubrander (FDA), and Dr. Matthew Myers (FDA) provided helpful feedback on the manuscript. NR 53 TC 2 Z9 2 U1 8 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1869-408X EI 1869-4098 J9 CARDIOVASC ENG TECHN JI Cardiovasc. Eng. Technol. PD MAR PY 2016 VL 7 IS 1 BP 7 EP 22 DI 10.1007/s13239-015-0251-9 PG 16 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA DS1MB UT WOS:000380358700002 PM 26628081 ER PT J AU Madenjian, JJ Regensberg, P Caterino, M AF Madenjian, James J. Regensberg, Pamela Caterino, Michael TI CERACIS CALIFORNICUS (CASEY) (COLEOPTERA: CIIDAE): NEWLY RECOGNIZED HERBARIUM PEST SO COLEOPTERISTS BULLETIN LA English DT Editorial Material C1 [Madenjian, James J.] US FDA, 19701 Fairchild, Irvine, CA 92612 USA. [Regensberg, Pamela] Denver Bot Gardens, 909 York St, Denver, CO 80206 USA. [Caterino, Michael] Clemson Univ, E-143 Poole Agr Ctr, Clemson, SC 29634 USA. RP Madenjian, JJ (reprint author), US FDA, 19701 Fairchild, Irvine, CA 92612 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU COLEOPTERISTS SOC PI ATHENS PA UNIV GEORGIA, 413 BIOLOGICAL SCIENCES BUILDING, ATHENS, GA 30602-2603 USA SN 0010-065X EI 1938-4394 J9 COLEOPTS BULL JI Coleopt. Bull. PD MAR PY 2016 VL 70 IS 1 BP 137 EP 141 PG 5 WC Entomology SC Entomology GA DO8YN UT WOS:000378071600017 ER PT J AU Kremzner, M AF Kremzner, Mary TI Food and Drug Administration: Helping pharmacists ensure that patients receive high-quality medicines SO JOURNAL OF THE AMERICAN PHARMACISTS ASSOCIATION LA English DT Editorial Material AB Objectives: Ensuring that the drugs patients take are safe and effective is critical to the Food and Drug Administration (FDA) mission and a major reason for testing an active pharmaceutical ingredient or currently marketed drug product. To address gaps in the assessment of drug quality, FDA's Center for Drug Evaluation and Research (CDER) has created the Office of Pharmaceutical Quality (OPQ). Summary: This newly formed "super-office" within CDER launched a concerted new strategy that enhances the surveillance of drug manufacturing and will bring a comprehensive approach to quality oversight. Conclusion: With OPQ and these new performance measures in place, FDA can sharpen its focus on issues critical to quality and can identify and respond to manufacturing issues before they become major systemic problems. Published by Elsevier, Inc. on behalf of the American Pharmacists Association C1 [Kremzner, Mary] US PHS, Silver Spring, MD USA. [Kremzner, Mary] US FDA, Div Drug Informat, Off Communicat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Kremzner, M (reprint author), 10001 New Hampshire Ave,Hillandale Bldg,Room 4150, Silver Spring, MD 20993 USA. EM mary.kremzner@fda.hhs.gov NR 4 TC 0 Z9 0 U1 1 U2 1 PU AMER PHARMACEUTICAL ASSOC PI WASHINGTON PA 2215 CONSTITUTION AVE NW, WASHINGTON, DC 20037 USA SN 1544-3191 EI 1544-3450 J9 J AM PHARM ASSOC JI J. Am. Pharm. Assoc. PD MAR-APR PY 2016 VL 56 IS 2 BP 201 EP 202 DI 10.1016/j.japh.2015.12.012 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DO3QK UT WOS:000377695900015 PM 27000171 ER PT J AU Khajanchi, BK Odeh, E Gao, LH Jacobs, MB Philipp, MT Lin, T Norris, SJ AF Khajanchi, Bijay K. Odeh, Evelyn Gao, Lihui Jacobs, Mary B. Philipp, Mario T. Lin, Tao Norris, Steven J. TI Phosphoenolpyruvate Phosphotransferase System Components Modulate Gene Transcription and Virulence of Borrelia burgdorferi SO INFECTION AND IMMUNITY LA English DT Article ID LYME-DISEASE SPIROCHETE; PSEUDOMONAS-AERUGINOSA; ADENYLYL-CYCLASE; VIBRIO-CHOLERAE; CAENORHABDITIS-ELEGANS; CARBON METABOLISM; ESCHERICHIA-COLI; INFECTIOUS CYCLE; EXPRESSION; PROTEIN AB The phosphoenolpyruvate phosphotransferase system (PEP-PTS) and adenylate cyclase (AC) IV (encoded by BB0723 [cyaB]) are well conserved in different species of Borrelia. However, the functional roles of PEP-PTS and AC in the infectious cycle of Borrelia have not been characterized previously. We examined 12 PEP-PTS transporter component mutants by needle inoculation of mice to assess their ability to cause mouse infection. Transposon mutants with mutations in the EIIBC components (ptsG) (BB0645, thought to be involved in glucose-specific transport) were unable to cause infection in mice, while all other tested PEPPTS mutants retained infectivity. Infectivity was partially restored in an in trans-complemented strain of the ptsG mutant. While the ptsG mutant survived normally in unfed as well as fed ticks, it was unable to cause infection in mice by tick transmission, suggesting that the function of ptsG is essential to establish infection by either needle inoculation or tick transmission. In Gram-negative organisms, the regulatory effects of the PEP-PTS are mediated by adenylate cyclase and cyclic AMP (cAMP) levels. A recombinant protein encoded by B. burgdorferi BB0723 (a putative cyaB homolog) was shown to have adenylate cyclase activity in vitro; however, mutants with mutations in this gene were fully infectious in the tick-mouse infection cycle, indicating that its function is not required in this process. By transcriptome analysis, we demonstrated that the ptsG gene may directly or indirectly modulate gene expression of Borrelia burgdorferi. Overall, the PEP-PTS glucose transporter PtsG appears to play important roles in the pathogenesis of B. burgdorferi that extend beyond its transport functions. C1 [Khajanchi, Bijay K.; Odeh, Evelyn; Gao, Lihui; Lin, Tao; Norris, Steven J.] Univ Texas Hlth Sci Ctr Houston, Sch Med, Dept Pathol & Lab Med, Houston, TX 77030 USA. [Norris, Steven J.] Univ Texas Hlth Sci Ctr Houston, Sch Med, Dept Microbiol & Mol Genet, Houston, TX 77030 USA. [Jacobs, Mary B.; Philipp, Mario T.] Tulane Univ, Hlth Sci Ctr, Tulane Natl Primate Res Ctr, Div Bacteriol & Parasitol, Covington, LA USA. [Khajanchi, Bijay K.] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. RP Khajanchi, BK (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Med, Dept Pathol & Lab Med, Houston, TX 77030 USA.; Khajanchi, BK (reprint author), US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. EM Bijay.K.Khajanchi@uth.tmc.edu OI Norris, Steven/0000-0002-2501-8034 FU NIAID, NIH [R01 AI059048]; Jeane B Kempner Postdoctoral Fellowships, UTMB; National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01 AI059048] FX NIAID, NIH provided funding to Steven J Norris under grant number R01 AI059048. Jeane B Kempner Postdoctoral Fellowships, UTMB provided funding to Bijay Khajanchi.; Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R01 AI059048. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 60 TC 6 Z9 6 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD MAR PY 2016 VL 84 IS 3 BP 754 EP 764 DI 10.1128/IAI.00917-15 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DN5JS UT WOS:000377103300014 PM 26712207 ER PT J AU Senior, JR AF Senior, John R. TI Can Rechallenge Be Done Safely After Mild or Moderate Drug-Induced Liver Injury? SO HEPATOLOGY LA English DT Editorial Material ID RISK C1 [Senior, John R.] US FDA, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res,Dept Hlth & Human Serv, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Senior, JR (reprint author), US FDA, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res,Dept Hlth & Human Serv, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM john.senior@fda.hhs.gov NR 10 TC 0 Z9 0 U1 1 U2 2 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 MAR PY 2016 VL 63 IS 3 BP 691 EP 693 DI 10.1002/hep.28353 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DJ8WF UT WOS:000374493200004 PM 26597733 ER PT J AU Aikin, KJ O'Donoghue, AC Squire, CM Sullivan, HW Betts, KR AF Aikin, Kathryn J. O'Donoghue, Amie C. Squire, Claudia M. Sullivan, Helen W. Betts, Kevin R. TI An Empirical Examination of the FDAAA-Mandated Toll-Free Statement for Consumer Reporting of Side Effects in Direct-to-Consumer Television Advertisements SO JOURNAL OF PUBLIC POLICY & MARKETING LA English DT Article DE direct-to-consumer; prescription drugs; advertisements; toll-free statement; Food and Drug Administration Amendments Act ID INFORMATION; RECENCY; RECALL; MEMORY; PERSPECTIVES; INVOLVEMENT; JUDGMENTS; EFFICACY; MEDWATCH; PRINT AB This research investigates how the inclusion of the "toll-free statement" (a message about a toll-free number by which consumers can report drug side effects to the U.S. Food and Drug Administration) in direct-to-consumer (DTC) television advertisements for prescription drugs affects consumers' comprehension of product risks and benefits, as well as their comprehension and memory of the toll-free statement. Participants viewed one of nine mock television advertisements across which elements of the toll-free statement varied. Presenting the statement in both text and audio resulted in better processing of the statement than text-only presentations. When the statement was shown in text alone, presenting it during the entire advertisement or after the statement of risks resulted in better processing than a placement before the risk information. The placement, duration, and prominence of the statement did not affect risk or benefit comprehension. These findings suggest that the toll-free statement can be added to DTC television advertisements without significantly affecting risk and benefit comprehension and that certain presentations are preferable for communicating the statement. The appropriate inclusion of the toll-free statement in DTC television advertisements may increase the visibility of the adverse event reporting system, without cost to the understanding of benefits or risks. C1 [Aikin, Kathryn J.; O'Donoghue, Amie C.; Sullivan, Helen W.; Betts, Kevin R.] US FDA, Rockville, MD 20857 USA. [Squire, Claudia M.] RTI Int, Res Triangle Pk, NC 27709 USA. RP Aikin, KJ; O'Donoghue, AC; Sullivan, HW; Betts, KR (reprint author), US FDA, Rockville, MD 20857 USA.; Squire, CM (reprint author), RTI Int, Res Triangle Pk, NC 27709 USA. EM Kathryn.Aikin@fda.hhs.gov; Amie.Odonoghue@fda.hhs.gov; cms@rti.org; Helen.Sullivan@fda.hhs.gov; Kevin.Betts@fda.hhs.gov FU Office of Prescription Drug Promotion, U.S. Food and Drug Administration FX This research was funded by the Office of Prescription Drug Promotion, U.S. Food and Drug Administration, and received an exemption from the FDA's Research Involving Human Subjects Committee. The authors thank John Quinn, Office of Safety Evaluation, FDA, for his help in obtaining the MedWatch direct report numbers and Jack Swasy, American University, for his assistance with study design. Janet Hoek served as associate editor for this article. NR 49 TC 0 Z9 0 U1 3 U2 3 PU AMER MARKETING ASSOC PI CHICAGO PA 311S WACKER DR, STE 5800, CHICAGO, IL 60606-6629 USA SN 0743-9156 EI 1547-7207 J9 J PUBLIC POLICY MARK JI J. Public Policy Mark. PD SPR PY 2016 VL 35 IS 1 BP 108 EP 123 DI 10.1509/jppm.14.077 PG 16 WC Business SC Business & Economics GA DL8EY UT WOS:000375874600008 ER PT J AU Lanzarotta, A AF Lanzarotta, Adam TI Analysis of Forensic Casework Utilizing Infrared Spectroscopic Imaging dagger SO SENSORS LA English DT Article DE infrared spectroscopic imaging; adulteration; dietary supplement; forensic science; melamine cyanurate ID ANTIMALARIAL TABLETS; ARRAY DETECTOR; CYANURIC ACID; IDENTIFICATION; FINGERPRINTS; MELAMINE AB A search of the current scientific literature yields a limited number of studies that describe the use of Fourier transform infrared (FT-IR) spectroscopic imaging for the analysis of forensic casework, which is likely due to the fact that these instruments are fairly new commodities to the field of analytical chemistry and are therefore not yet commonplace in forensic laboratories. This report describes recent forensic case studies that have used the technique for determining the composition of a wide variety of multi-component sample types, including animal tissue sections for toxic inclusions, drugs/dietary supplements, an antibiotic with an active pharmaceutical ingredient (API) present as several different salt forms, an adulterated bulk API, unknown trace powders for illicit drugs and an ophthalmic solution suspected of being adulterated with bleach. C1 [Lanzarotta, Adam] US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. RP Lanzarotta, A (reprint author), US FDA, Forens Chem Ctr, Cincinnati, OH 45237 USA. EM adam.lanzarotta@fda.hhs.gov NR 30 TC 1 Z9 1 U1 6 U2 12 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1424-8220 J9 SENSORS-BASEL JI Sensors PD MAR PY 2016 VL 16 IS 3 DI 10.3390/s16030278 PG 12 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation SC Chemistry; Electrochemistry; Instruments & Instrumentation GA DI7WV UT WOS:000373713600098 PM 26927101 ER PT J AU Yu, LX Akseli, I Allen, B Amidon, G Bizjak, TG Boam, A Caulk, M Doleski, D Famulare, J Fisher, AC Furness, S Hasselbalch, B Havel, H Hoag, SW Iser, R Johnson, BD Ju, R Katz, P Lacana, E Lee, SL Lostritto, R McNally, G Mehta, M Mohan, G Nasr, M Nosal, R Oates, M O'Connor, T Polli, J Raju, GK Ramanadham, M Randazzo, G Rosencrance, S Schwendeman, A Selen, A Seo, P Shah, V Sood, R Thien, MP Tong, T Trout, BL Tyner, K Vaithiyalingam, S VanTrieste, M Walsh, F Wesdyk, R Woodcock, J Wu, G Wu, L Yu, L Zezza, D AF Yu, Lawrence X. Akseli, Ilgaz Allen, Barbara Amidon, Gregory Bizjak, Tara Gooen Boam, Ashley Caulk, Margaret Doleski, David Famulare, Joseph Fisher, Adam C. Furness, Scott Hasselbalch, Brian Havel, Henry Hoag, Stephen W. Iser, Robert Johnson, Bruce D. Ju, Robert Katz, Paula Lacana, Emanuela Lee, Sau L. Lostritto, Richard McNally, Grace Mehta, Mehul Mohan, Ganapathy Nasr, Moheb Nosal, Roger Oates, Mary O'Connor, Thomas Polli, Jim Raju, G. K. Ramanadham, Mahesh Randazzo, Giuseppe Rosencrance, Susan Schwendeman, Anna Selen, Arzu Seo, Paul Shah, Vinod Sood, Ramesh Thien, Michael P. Tong, Tony Trout, Bernhardt L. Tyner, Katherine Vaithiyalingam, Siva VanTrieste, Martin Walsh, Fionnuala Wesdyk, Russell Woodcock, Janet Wu, Geoffrey Wu, Larisa Yu, Louis Zezza, Diane TI Advancing Product Quality: a Summary of the Second FDA/PQRI Conference SO AAPS JOURNAL LA English DT Article ID PHARMACEUTICAL QUALITY; DISSOLUTION; TRIBOLOGY; RHEOLOGY; TEXTURE; DRUG C1 [Yu, Lawrence X.; Bizjak, Tara Gooen; Boam, Ashley; Caulk, Margaret; Doleski, David; Fisher, Adam C.; Furness, Scott; Hasselbalch, Brian; Iser, Robert; Katz, Paula; Lacana, Emanuela; Lee, Sau L.; Lostritto, Richard; McNally, Grace; Mehta, Mehul; O'Connor, Thomas; Ramanadham, Mahesh; Randazzo, Giuseppe; Rosencrance, Susan; Selen, Arzu; Seo, Paul; Sood, Ramesh; Tyner, Katherine; Wesdyk, Russell; Woodcock, Janet; Wu, Geoffrey; Wu, Larisa] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Akseli, Ilgaz] Boehringer Ingelheim Pharmaceut Inc, 90 E Ridge POB 368, Ridgefield, CT 06877 USA. [Allen, Barbara; Walsh, Fionnuala] Eli Lilly & Co, Indianapolis, IN 46225 USA. [Amidon, Gregory; Schwendeman, Anna] Univ Michigan, Ann Arbor, MI 48109 USA. [Famulare, Joseph] Genentech Roche, 1 DNA Way, San Francisco, CA 94080 USA. [Havel, Henry] Havel Biopharma LLC, Nanomed Alliance, Indianapolis, IN 46220 USA. [Hoag, Stephen W.; Polli, Jim] Univ Maryland, Baltimore, MD 21201 USA. [Johnson, Bruce D.] Perrigo Co Plc, Allegan, MI 49010 USA. [Ju, Robert; Yu, Louis] Abbvie, N Chicago, IL 60064 USA. [Mohan, Ganapathy; Thien, Michael P.] Merck & Co Inc, West Point, PA 19486 USA. [Nasr, Moheb] GlaxoSmithKline, Washington, DC 20001 USA. [Nosal, Roger; Oates, Mary] Pfizer Inc, Eastern Point Rd, Groton, CT 06340 USA. [Raju, G. K.] Light Pharma Inc, Cambridge, MA 02142 USA. [Shah, Vinod] PQRI, Arlington, VA USA. [Tong, Tony] Teva Pharmaceut USA, 223 Quaker Rd, Pomona, NY 10970 USA. [Trout, Bernhardt L.] MIT, Cambridge, MA 02139 USA. [Vaithiyalingam, Siva] Teva Pharmaceut USA, 425 Privet Rd, Horsham, PA 19044 USA. [VanTrieste, Martin] Amgen Inc, One Amgen Ctr Dr, Thousand Oaks, CA 91320 USA. [Zezza, Diane] Novartis, E Hanover, NJ 07936 USA. RP Yu, LX (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM lawrence.yu@fda.hhs.gov FU NIGMS NIH HHS [R01 GM113832] NR 33 TC 1 Z9 1 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD MAR PY 2016 VL 18 IS 2 BP 528 EP 543 DI 10.1208/s12248-016-9874-5 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DL2JN UT WOS:000375460900005 PM 26860627 ER PT J AU Walker, BN James, RH Song, S Calogero, D Ilev, IK AF Walker, Bennett N. James, Robert H. Song, Samuel Calogero, Don Ilev, Ilko K. TI Confocal laser method for quantitative evaluation of critical optical properties of toric intraocular lenses SO JOURNAL OF CATARACT AND REFRACTIVE SURGERY LA English DT Article ID CORRECTING ASTIGMATISM; POWER MEASUREMENT; CATARACT PATIENTS; EYES; IMPLANTS AB PURPOSE: To present a proof-of-concept study on the development and implementation of an innovative confocal laser method platform for precise quantitative evaluation of critical optical properties unique to toric intraocular lenses (IOLs). SETTING: U.S. Food and Drug Administration, Optical Therapeutics and Medical Nanophotonics Laboratory, Silver Spring, Maryland, USA. DESIGN: Experimental study. METHODS: The optical properties of hydrophobic toric IOLs were evaluated with a confocal laser method that was modified to isolate the 2 planes of focus that are observed with toric IOLs. RESULTS: The results show the confocal laser method has the potential to measure the orthogonally separated optical powers and then calculate them to the commonly referenced spherical equivalent and cylinder powers of toric IOLs with high accuracy (<= 1 mu m of focal length measurement). Furthermore, the proposed confocal laser method design includes a new component for precise differentiation of the 2 focal planes and isolation of the 2 focal points, and thus for accurate measurement of the anterior cylinder axis of toric IOLs. CONCLUSION: The modifications to the confocal laser method platform enabled the quantitative evaluation of optical properties attributed to toric IOLs. Published by Elsevier Inc. on behalf of ASCRS and ESCRS. C1 [Walker, Bennett N.; James, Robert H.; Song, Samuel; Ilev, Ilko K.] US FDA, Ctr Devices & Radiol Hlth, Opt Therapeut & Med Nanophoton, Silver Spring, MD USA. [Walker, Bennett N.; Calogero, Don] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Silver Spring, MD USA. [Walker, Bennett N.; Calogero, Don] US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Silver Spring, MD USA. RP Walker, BN (reprint author), US FDA, 10906 New Hampshire Ave, White Oak, MD 20993 USA. EM bennett.walker@fda.hhs.gov NR 28 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0886-3350 EI 1873-4502 J9 J CATARACT REFR SURG JI J. Cataract. Refract. Surg. PD MAR PY 2016 VL 42 IS 3 BP 455 EP 461 DI 10.1016/j.jcrs.2015.09.031 PG 7 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA DK6HG UT WOS:000375022700015 PM 27063527 ER PT J AU Jin, YQ Wang, HM Han, W Lu, J Chu, P Han, SJ Ni, X Ning, BT Yu, DK Guo, YL AF Jin, Yaqiong Wang, Huanmin Han, Wei Lu, Jie Chu, Ping Han, Shujing Ni, Xin Ning, Baitang Yu, Dianke Guo, Yongli TI Single nucleotide polymorphism rs11669203 in TGFBR3L is associated with the risk of neuroblastoma in a Chinese population SO TUMOR BIOLOGY LA English DT Article DE MYCN; Neuroblastoma; Single nucleotide polymorphisms; TGFBR3L ID MYCN-AMPLIFIED NEUROBLASTOMA; N-MYC; GENOMIC INSTABILITY; TUMOR INITIATION; BETA-BINDING; EXPRESSION; CANCER; GENE; DIFFERENTIATION; SUSCEPTIBILITY AB With a primary mortality, neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Amplification of the MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog) oncogene is observed in 20-30 % of NB cases, a feature which also characterizes a highly aggressive subtype of the disease. However, the systematic study of association between single nucleotide polymorphisms (SNPs) in MYCN-regulated genes and the risk of NB has not been investigated. In the current study, we scanned a set of 16 SNPs located within known or predicted MYCN binding sites in a cohort of 247 patients of Chinese origin with neuroblastic family tumors, including neuroblastoma (NB), ganglioneuroma (GN), and ganglioneuroblastoma (GNB), and in 290 cancer-free controls to determine whether any of the tested SNPs are associated with neuroblastic family tumors. We found that the rs11669203 G > C polymorphism, located in TGFBR3L promoter, is significantly associated with the risk of NB. Further, we found that this association is site specific to adrenal NB compared to non-adrenal NB. In addition, transcriptome analysis indicated that increased expression of TGFBR3L is strongly correlated with poor survival. The SNP rs11669203 located at the MYCN binding site of TGFBR3L is significantly associated with elevated risk of NB, and abnormal MYCN-regulated TGFBR3L expression may contribute to NB oncogenesis. C1 [Jin, Yaqiong; Lu, Jie; Chu, Ping; Han, Shujing; Ni, Xin; Guo, Yongli] Capital Med Univ, Beijing Childrens Hosp, Beijing Pediat Res Inst, Beijing Key Lab Pediat Dis Otolaryngol Head & Nec, Beijing, Peoples R China. [Wang, Huanmin; Han, Wei] Capital Med Univ, Beijing Childrens Hosp, Dept Surg Oncol, Beijing, Peoples R China. [Ni, Xin] Capital Med Univ, Beijing Childrens Hosp, Dept Head & Neck Surg, Beijing, Peoples R China. [Ning, Baitang; Yu, Dianke] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Guo, YL (reprint author), Capital Med Univ, Beijing Childrens Hosp, Beijing Pediat Res Inst, Beijing Key Lab Pediat Dis Otolaryngol Head & Nec, Beijing, Peoples R China.; Yu, DK (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Dianke.Yu@fda.hhs.gov; guoyongli@bch.com.cn OI Jin, Ya-Qiong/0000-0002-9318-6531 FU National Natural Science Foundation of China [81472369]; Clinical Research Special Foundation by Wu Jieping Medical Foundation [320. 6750. 12398] FX Supported by National Natural Science Foundation of China (81472369) and Clinical Research Special Foundation by Wu Jieping Medical Foundation (320. 6750. 12398). NR 49 TC 4 Z9 4 U1 3 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1010-4283 EI 1423-0380 J9 TUMOR BIOL JI Tumor Biol. PD MAR PY 2016 VL 37 IS 3 BP 3739 EP 3747 DI 10.1007/s13277-015-4192-6 PG 9 WC Oncology SC Oncology GA DK4QJ UT WOS:000374903500099 PM 26468016 ER PT J AU Argaw, T Colon-Moran, W Wilson, C AF Argaw, Takele Colon-Moran, Winston Wilson, Carolyn TI Susceptibility of porcine endogenous retrovirus to anti-retroviral inhibitors SO XENOTRANSPLANTATION LA English DT Article DE anti-retroviral; porcine endogenous retrovirus; xenotransplantation ID CROSS-SPECIES TRANSMISSION; HUMAN-CELLS; LEUKEMIA-VIRUS; NO EVIDENCE; ISLET XENOTRANSPLANTATION; REVERSE-TRANSCRIPTASE; PERV INFECTION; IDENTIFICATION; REPLICATION; PIGS AB BackgroundPorcine endogenous retrovirus (PERV) is an endogenous retrovirus that poses a risk of iatrogenic transmission in the context of pig-to-human xenotransplantation. The lack of a means to control PERV infection in the context of pig-to-human xenotransplantation is a major concern in the field. In this study, we set out to evaluate the ability of currently licensed anti-HIV drugs, and other types of anti-retroviral compounds, to inhibit PERV infection in vitro. MethodsWe used target cells stably expressing one of the known PERV viral receptors, an infectious molecular clone, PERV-A 14/220, and at least one drug from each class of anti-retroviral inhibitors as well as off-label drugs shown to have anti-viral activities. The susceptibility of PERV-A 14/220 LacZ to the anti-retroviral drugs was determined from infected cells by histochemical staining. ResultsWe extend the results of previous studies by showing that, in addition to raltegravir, dolutegravir is found to have a potent inhibitory activity against PERV replication (IC50 8.634 0.336 and IC50 3.06 +/- 0.844 nM, respectively). The anti-HIV drug zidovudine (AZT) showed considerable anti-PERV activity with IC50 of 1.923 +/- 0.691 M as well. ConclusionsThe study results indicate that some of the licensed anti-retroviral drugs may be useful for controlling PERV infection. However, the efficacy at nanomolar concentrations put forward integrase inhibitors as a drug that has the potential to be useful in the event that xenotransplantation recipients have evidence of PERV transmission and replication. C1 [Argaw, Takele; Colon-Moran, Winston; Wilson, Carolyn] US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Gene Transfer & Immunogen Branch, Silver Spring, MD USA. RP Wilson, C (reprint author), 10903 New Hampshire Ave,Bldg 71,Rm 6316, Silver Spring, MD 20993 USA. EM carolyn.wilson@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 48 TC 1 Z9 1 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X EI 1399-3089 J9 XENOTRANSPLANTATION JI Xenotransplantation PD MAR-APR PY 2016 VL 23 IS 2 BP 151 EP 158 DI 10.1111/xen.12230 PG 8 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA DK2VI UT WOS:000374772100006 PM 27028725 ER PT J AU Swann, JP AF Swann, John P. TI The history of efforts to regulate dietary supplements in the USA SO DRUG TESTING AND ANALYSIS LA English DT Review DE regulation; FDA; supplements; history; vitamins; botanicals ID VITAMIN AB This review examines the emergence of dietary supplements and how the Food and Drug Administration (FDA) attempted to regulate these, beginning with the arrival of vitamins and how these were managed under the 1906 Food and Drugs Act, and ending with the seismic influence of the 1994 Dietary Supplement Health and Education Act (DSHEA). Included are the impact of major laws, key court decisions, and the construction of the FDA's supplement actions and rules from the 1920s to the 1990s for products that were neither drugs nor typical foods. Stiff resistance to the regulations by supplement manufacturers, trade associations, politicians, and especially the public at large is an important part of this story. The paper closes with the passage of DSHEA and how it literally changed the definition and parameters of control of dietary supplements. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Swann, John P.] US FDA, Hist Off, White Oak Bldg 1,Rm 1206,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Swann, JP (reprint author), US FDA, Hist Off, White Oak Bldg 1,Rm 1206,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM john.swann@fda.hhs.gov NR 99 TC 2 Z9 2 U1 8 U2 13 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 MAR-APR PY 2016 VL 8 IS 3-4 SI SI BP 271 EP 282 DI 10.1002/dta.1919 PG 12 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA DJ5NP UT WOS:000374255900001 PM 26593452 ER PT J AU Liu, YT Santillo, MF AF Liu, Yitong Santillo, Michael F. TI Cytochrome P450 2D6 and 3A4 enzyme inhibition by amine stimulants in dietary supplements SO DRUG TESTING AND ANALYSIS LA English DT Article DE CYP2D6; CYP3A4; enzyme inhibition; stimulants; dietary supplements ID CYP2D6; AMPHETAMINE; DERIVATIVES; OXIDATION; PROBES AB A number of dietary supplements used for weight loss and athletic performance enhancement have been recently shown to contain a variety of stimulants, for which there is a lack of pharmacological and toxicological information. One concern for these emerging compounds is their potential to inhibit metabolic enzymes in the liver such as cytochromes P450 (CYP), which can lead to unexpected interactions among dietary supplements, drugs, and other xenobiotics. In this study, inhibition of human recombinant CYP2D6 and CYP3A4 by 27 amine stimulants associated with dietary supplements and their analogs was evaluated by luminescence assays. The strongest CYP2D6 inhibitors were coclaurine (IC50=0.14 +/- 0.01M) and N-benzylphenethylamine (IC50=0.7 +/- 0.2M), followed by several other relatively strong inhibitors (IC50, 2-12M) including -methylphenethylamine, N,-dimethylphenethylamine (phenpromethamine), 1,3-dimethylamylamine (DMAA), N,-diethylphenethylamine, higenamine (norcoclaurine) and N,N-diethylphenethylamine. Only nine compounds inhibited CYP3A4 by 20-55% at 100M. Results of this study illustrate that several amine stimulants associated with dietary supplements inhibit CYP2D6 and CYP3A4 in vitro, and these compounds may participate in adverse drug-dietary supplement interactions in vivo. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Liu, Yitong; Santillo, Michael F.] US FDA, Div Toxicol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, 8301 Muirkirk Rd, Laurel, MD 20708 USA. RP Liu, YT (reprint author), US FDA, Div Toxicol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM yitong.liu@fda.hhs.gov RI Santillo, Michael/B-5081-2009; OI Santillo, Michael/0000-0001-8087-5859; Liu, Yitong/0000-0002-4300-4349 FU US Food and Drug Administration (FDA) FX This research was supported by the US Food and Drug Administration (FDA). NR 26 TC 0 Z9 0 U1 2 U2 6 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 MAR-APR PY 2016 VL 8 IS 3-4 SI SI BP 307 EP 310 DI 10.1002/dta.1863 PG 4 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA DJ5NP UT WOS:000374255900006 PM 26360628 ER PT J AU Johnston, DI Chang, A Viray, M Chatham-Stephens, K He, H Taylor, E Wong, LL Schier, J Martin, C Fabricant, D Salter, M Lewis, L Park, SY AF Johnston, David I. Chang, Arthur Viray, Melissa Chatham-Stephens, Kevin He, Hua Taylor, Ethel Wong, Linda L. Schier, Joshua Martin, Colleen Fabricant, Daniel Salter, Monique Lewis, Lauren Park, Sarah Y. TI Hepatotoxicity associated with the dietary supplement OxyELITE Pro (TM) Hawaii, 2013 SO DRUG TESTING AND ANALYSIS LA English DT Article DE toxic hepatitis; dietary supplements ID ACUTE LIVER-FAILURE; HERBAL HEPATOTOXICITY; WEIGHT-LOSS; CAUSALITY ASSESSMENT; INJURY; HEPATITIS AB Dietary supplements are increasingly marketed to and consumed by the American public for a variety of purported health benefits. On 9 September 2013, the Hawaii Department of Health (HDOH) was notified of a cluster of acute hepatitis and fulminant hepatic failure among individuals with exposure to the dietary supplement OxyELITE Pro (OEP). HDOH conducted an outbreak investigation in collaboration with federal partners. Physicians were asked to report cases, defined as individuals with acute onset hepatitis of unknown etiology on or after 1 April 2013, a history of weight-loss/muscle-building dietary supplement use during the 60 days before illness onset, and residence in Hawaii during the period of exposure. Reported cases' medical records were reviewed, questionnaires were administered, and a product investigation, including chemical analyses and traceback, was conducted. Of 76 reports, 44 (58%) met case definition; of these, 36 (82%) reported OEP exposure during the two months before illness. No other common supplements or exposures were observed. Within the OEP-exposed subset, two patients required liver transplantation, and a third patient died. Excessive product dosing was not reported. No unique lot numbers were identified; there were multiple mainland distribution points, and lot numbers common to cases in Hawaii were also identified in continental states. Product analysis found consumed products were consistent with labeled ingredients; the mechanism of hepatotoxicity was not identified. We report one of the largest statewide outbreaks of dietary supplement-associated hepatotoxicity. The implicated product was OEP. The increasing popularity of dietary supplements raises the potential for additional clusters of dietary supplement-related adverse events. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Johnston, David I.; Viray, Melissa; He, Hua; Park, Sarah Y.] Hawaii Dept Hlth, Dis Outbreak Control Div, Honolulu, HI USA. [Chang, Arthur; Chatham-Stephens, Kevin; Taylor, Ethel; Schier, Joshua; Martin, Colleen; Lewis, Lauren] Ctr Dis Control & Prevent, Hlth Studies Branch, Natl Ctr Environm Hlth, Atlanta, GA USA. [Wong, Linda L.] Queens Med Ctr, Honolulu, HI USA. [Fabricant, Daniel] Nat Prod Assoc, Washington, DC USA. [Salter, Monique] US FDA, Off Foods & Vet Med, Coordinated Outbreak Response & Evaluat Network, Rockville, MD 20857 USA. RP Johnston, DI (reprint author), 1250 Punchbowl St, Honolulu, HI 96813 USA. EM david.johnston@doh.hawaii.gov FU Intramural CDC HHS [CC999999]; NIH HHS [T35 OD010991] NR 36 TC 9 Z9 9 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 MAR-APR PY 2016 VL 8 IS 3-4 SI SI BP 319 EP 327 DI 10.1002/dta.1894 PG 9 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA DJ5NP UT WOS:000374255900009 PM 26538199 ER PT J AU Zhang, ZW Nie, L Soon, GX Hu, ZH AF Zhang, Zhiwei Nie, Lei Soon, Guoxing Hu, Zonghui TI New Methods for Treatment Effect Calibration, with Applications to Non-Inferiority Trials SO BIOMETRICS LA English DT Article DE Active control; Conditional constancy; Covariate adjustment; Double robustness; Indirect comparison; Structural nested model ID RESISTANT HIV-1 INFECTION; RANDOMIZED-TRIALS; CLINICAL-TRIALS; MEAN MODELS; RALTEGRAVIR; ESTIMATOR; INFERENCE; EFFICIENT AB In comparative effectiveness research, it is often of interest to calibrate treatment effect estimates from a clinical trial to a target population that differs from the study population. One important application is an indirect comparison of a new treatment with a placebo control on the basis of two separate randomized clinical trials: a non-inferiority trial comparing the new treatment with an active control and a historical trial comparing the active control with placebo. The available methods for treatment effect calibration include an outcome regression (OR) method based on a regression model for the outcome and a weighting method based on a propensity score (PS) model. This article proposes new methods for treatment effect calibration: one based on a conditional effect (CE) model and two doubly robust (DR) methods. The first DR method involves a PS model and an OR model, is asymptotically valid if either model is correct, and attains the semiparametric information bound if both models are correct. The second DR method involves a PS model, a CE model, and possibly an OR model, is asymptotically valid under the union of the PS and CE models, and attains the semiparametric information bound if all three models are correct. The various methods are compared in a simulation study and applied to recent clinical trials for treating human immunodeficiency virus infection. C1 [Zhang, Zhiwei] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Nie, Lei] US FDA, Div Biometr 5, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Soon, Guoxing] US FDA, Div Biometr 4, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Hu, Zonghui] NIAID, Biostat Res Branch, Div Clin Res, NIH, Rockville, MD USA. RP Zhang, ZW (reprint author), US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. EM zhiwei.zhang@fda.hhs.gov NR 30 TC 0 Z9 0 U1 4 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD MAR PY 2016 VL 72 IS 1 BP 20 EP 29 DI 10.1111/biom.12388 PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA DJ0SM UT WOS:000373914700002 PM 26363775 ER PT J AU Avigan, MI Mozersky, RP Seeff, LB AF Avigan, Mark I. Mozersky, Robert P. Seeff, Leonard B. TI Scientific and Regulatory Perspectives in Herbal and Dietary Supplement Associated Hepatotoxicity in the United States SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Review DE challenges in assessing herbal hepatotoxicity; herbal supplement contamination; regulation; herbal supplement adulteration; drug induced liver injury; herbal supplement epidemiology; Dietary Supplement Health and Education Act (DSHEA); US Food and Drug Administration ID INDUCED LIVER-INJURY; ANABOLIC-ANDROGENIC STEROIDS; WEIGHT-LOSS SUPPLEMENTS; TRADITIONAL CHINESE MEDICINE; MULTIPLE HEPATIC ADENOMAS; VENO-OCCLUSIVE DISEASE; OF-THE-LITERATURE; HEPATOCELLULAR-CARCINOMA; PELIOSIS-HEPATIS; USNIC ACID AB In the United States (US), the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food and Drug Administration (FDA) as a special category of foods. Under this designation, regulatory scientists do not routinely evaluate the efficacy of these products prior to their marketing, despite the content variability and phytochemical complexity that often characterizes them. Nonetheless, there has been notable progress in the development of advanced scientific methods to qualitatively and quantitatively measure ingredients and screen for contaminants and adulterants in botanical products when hepatotoxicity is recognized. C1 [Avigan, Mark I.] US FDA, Off Pharmacovigilance & Epidemiol, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Mozersky, Robert P.] Ctr Food Safety & Appl Nutr, Off Dietary Supplement Prod, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [Seeff, Leonard B.] 6403 Hillmead Rd, Bethesda, MD 20817 USA. RP Seeff, LB (reprint author), 6403 Hillmead Rd, Bethesda, MD 20817 USA. EM mark.avigan@fda.hhs.gov; robert.mozersky@fda.hhs.gov; mahler68@hotmail.com NR 180 TC 4 Z9 4 U1 6 U2 10 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD MAR PY 2016 VL 17 IS 3 AR 331 DI 10.3390/ijms17030331 PG 30 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA DI7WN UT WOS:000373712800056 PM 26950122 ER PT J AU Yan, HH Endo, Y Shen, Y Rotstein, D Dokmanovic, M Mohan, N Mukhopadhyay, P Gao, B Pacher, P Wu, WJ AF Yan, Haoheng Endo, Yukinori Shen, Yi Rotstein, David Dokmanovic, Milos Mohan, Nishant Mukhopadhyay, Partha Gao, Bin Pacher, Pal Wu, Wen Jin TI Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID ACUTE MYELOID-LEUKEMIA; NECROSIS-FACTOR-ALPHA; HER2-POSITIVE BREAST-CANCER; INDUCED LIVER-INJURY; GEMTUZUMAB OZOGAMICIN; CLINICAL-PRACTICE; PHASE-I; DRUG; ANTIBODY; MECHANISMS AB Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2-positive metastatic breast cancer. It consists of trastuzumab, a humanized mAb directed against HER2, and a microtubule inhibitor, DM1, conjugated to trastuzumab via a thioether linker. Hepatotoxicity is one of the serious adverse events associated with T-DM1 therapy. Mechanisms underlying T-DM1-induced hepatotoxicity remain elusive. Here, we use hepatocytes and mouse models to investigate the mechanisms of T-DM1-induced hepatotoxicity. We show that T-DM1 is internalized upon binding to cell surface HER2 and is colocalized with LAMP1, resulting in DM1-associated cytotoxicity, including disorganized microtubules, nuclear fragmentation/multiple nuclei, and cell growth inhibition. We further demonstrate that T-DM1 treatment significantly increases the serum levels of aspartate aminotransferase, alanine amino-transferase, and lactate dehydrogenase in mice and induces inflammation and necrosis in liver tissues, and that T-DM1-induced hepatotoxicity is dose dependent. Moreover, the gene expression of TNF alpha in liver tissues is significantly increased in mice treated with T-DM1 as compared with those treated with trastuzumab or vehicle. We propose that T-DM1-induced upregulation of TNFa enhances the liver injury that may be initially caused by DM1-mediated intracellular damage. Our proposal is underscored by the fact that T-DM1 induces the outer mitochondrial membrane rupture, a typical morphologic change in the mitochondrial-dependent apoptosis, and mitochondrial membrane potential dysfunction. Our work provides mechanistic insights into T-DM1-induced hepatotoxicity, which may yield novel strategies to manage liver injury induced by T-DM1 or other ADCs. (C) 2015 AACR. C1 [Yan, Haoheng; Endo, Yukinori; Shen, Yi; Dokmanovic, Milos; Mohan, Nishant; Wu, Wen Jin] US FDA, Div Biotechnol Review & Res 1, Off Biotechnol Prod, Off Pharmaceut Qual,Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Yan, Haoheng] NCI, Bethesda, MD 20892 USA. [Rotstein, David] US FDA, Div Compliance, Off Surveillance & Compliance, Ctr Vet Med, Derwood, MD USA. [Mukhopadhyay, Partha; Pacher, Pal] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. [Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. RP Wu, WJ (reprint author), US FDA, Bldg 52-72,Room 2310,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM wen.wu@fda.hhs.gov FU Interagency Oncology Task Force Joint Fellowship Program - FDA; Interagency Oncology Task Force Joint Fellowship Program - NCI; Food and Drug Administration Office of Women's Health FX This study is supported by the Interagency Oncology Task Force Joint Fellowship Program sponsored by the FDA and NCI. This work was also supported by the Food and Drug Administration Office of Women's Health and in part by an appointment to the ORISE Research Participation Program at the Center for Drug Evaluation and Research, FDA, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA. Dr. Nishant Mohan is an ORISE research fellow supported by Food and Drug Administration Office of Women's Health. NR 47 TC 4 Z9 4 U1 3 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAR PY 2016 VL 15 IS 3 BP 480 EP 490 DI 10.1158/1535-7163.MCT-15-0580 PG 11 WC Oncology SC Oncology GA DI6FW UT WOS:000373595600014 PM 26712117 ER PT J AU Robinson, BL Dumas, M Cuevas, E Gu, Q Paule, MG Ali, SF Kanungo, J AF Robinson, Bonnie L. Dumas, Melanie Cuevas, Elvis Gu, Qiang Paule, Merle G. Ali, Syed F. Kanungo, Jyotshna TI Distinct effects of ketamine and acetyl L-carnitine on the dopamine system in zebrafish SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Ketamine; Zebrafish; Acetyl L-carnitine; Dopamine; Tyrosine hydroxylase; MAO ID SH-SY5Y NEUROBLASTOMA-CELLS; MONOAMINE-OXIDASE ACTIVITY; TYROSINE-HYDROXYLASE; GENE-EXPRESSION; SUBANESTHETIC KETAMINE; INDUCED NEUROTOXICITY; SEROTONERGIC SYSTEM; PSYCHOTIC SYMPTOMS; ADULT ZEBRAFISH; RHESUS-MONKEY AB Ketamine, a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist is commonly used as a pediatric anesthetic. We have previously shown that acetyl L-carnitine (ALCAR) prevents ketamine toxicity in zebrafish embryos. In mammals, ketamine is known to modulate the dopaminergic system. NMDA receptor antagonists are considered as promising anti-depressants, but the exact mechanism of their function is unclear. Here, we measured the levels of dopamine (DA) and its metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the zebrafish embryos exposed to ketamine in the presence and absence of 0.5 mM ALCAR. Ketamine, at lower doses (0.1-03 mM), did not produce significant changes in DA, DOPAC or HVA levels in 52 h post-fertilization embryos treated for 24 h. In these embryos, tyrosine hydroxylase (TH) mRNA expression remained unchanged. However, 2 mM ketamine (internal embryo exposure levels equivalent to human anesthetic plasma concentration) significantly reduced DA level and TH mRNA indicating that DA synthesis was adversely affected. In the presence or absence of 2 mM ketamine, ALCAR showed similar effects on DA level and TH mRNA, but increased DOPAC level compared to control. ALCAR reversed 2 mM ketamine-induced reduction in HVA levels. With ALCAR alone, the expression of genes encoding the DA metabolizing enzymes, MAO (monoamine oxidase) and catechol-O-methyltransferase (COMT), was not affected. However, ketamine altered MAO mRNA expression, except at the 0.1 mM dose. COMT transcripts were reduced in the 2 mM ketamine-treated group. These distinct effects of ketamine and ALCAR on the DA system may shed some light on the mechanism on how ketamine can work as an anti-depressant, especially at sub-anesthetic doses that do not affect DA metabolism and suppress MAO gene expression. Published by Elsevier Inc. C1 [Robinson, Bonnie L.; Dumas, Melanie; Cuevas, Elvis; Gu, Qiang; Paule, Merle G.; Ali, Syed F.; Kanungo, Jyotshna] US FDA, Div Neurotoxicol, 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 95 TC 1 Z9 1 U1 3 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAR-APR PY 2016 VL 54 BP 52 EP 60 DI 10.1016/j.ntt.2016.02.004 PG 9 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA DI5QE UT WOS:000373552900008 PM 26898327 ER PT J AU Chappell, G Silva, GO Uehara, T Pogribny, IP Rusyn, I AF Chappell, Grace Silva, Grace O. Uehara, Takeki Pogribny, Igor P. Rusyn, Ivan TI Characterization of copy number alterations in a mouse model of fibrosis-associated hepatocellular carcinoma reveals concordance with human disease SO CANCER MEDICINE LA English DT Article DE Chromosomal instability; cirrhosis; copy number alterations; fibrosis; hepatocellular carcinoma ID BREAST-CANCER; MOLECULAR-MECHANISMS; GENETIC INSTABILITY; LIVER-CANCER; HEPATOCARCINOGENESIS; LANDSCAPE; MICE; CARCINOGENESIS; EXPRESSION; DISCOVERY AB Hepatocellular carcinoma (HCC) is a prevalent human cancer with rising incidence worldwide. Human HCC is frequently associated with chronic liver inflammation and cirrhosis, pathophysiological processes that are a consequence of chronic viral infection, disturbances in metabolism, or exposure to chemical toxicants. To better characterize the pathogenesis of HCC, we used a human disease-relevant mouse model of fibrosis-associated hepatocarcinogenesis. In this model, marked liver tumor response caused by the promutagenic chemical N-nitrosodiethylamine in the presence of liver fibrosis was associated with epigenetic events indicative of genomic instability. Therefore, we hypothesized that DNA copy number alterations (CNAs), a feature of genomic instability and a common characteristic of cancer, are concordant between human HCC and mouse models of fibrosis-associated hepatocarcinogenesis. We evaluated DNA CNAs and changes in gene expression in the mouse liver (normal, tumor, and nontumor fibrotic tissues). Additionally, we compared our findings to DNA CNAs in human HCC cases (tumor and nontumor cirrhotic/fibrotic tissues) using publicly available data from The Cancer Genome Atlas (TCGA). We observed that while fibrotic liver tissue is largely devoid of DNA CNAs, highly frequently occurring DNA CNAs are found in mouse tumors, which is indicative of a profound increase in chromosomal instability in HCC. The cross-species gene-level comparison of CNAs identified shared regions of CNAs between human fibrosis- and cirrhosis-associated liver tumors and mouse fibrosis-associated HCC. Our results suggest that CNAs most commonly arise in neoplastic tissue rather than in fibrotic or cirrhotic liver, and demonstrate the utility of this mouse model in replicating the molecular features of human HCC. C1 [Chappell, Grace; Rusyn, Ivan] Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. [Chappell, Grace; Uehara, Takeki] Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. [Silva, Grace O.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Silva, Grace O.] Univ N Carolina, Curriculum Bioinformat & Computat Biol, Chapel Hill, NC 27599 USA. [Silva, Grace O.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Pogribny, Igor P.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Rusyn, I (reprint author), Texas A&M Univ, Vet Integrat Biosci, 4458 TAMU, College Stn, TX 77843 USA. EM IRusyn@cvm.tamu.edu RI Rusyn, Ivan/S-2426-2016 FU National Institutes of Health [P42 ES005948] FX This work was supported, in part, by National Institutes of Health grant P42 ES005948. NR 53 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD MAR PY 2016 VL 5 IS 3 BP 574 EP 585 DI 10.1002/cam4.606 PG 12 WC Oncology SC Oncology GA DI0QW UT WOS:000373203000019 PM 26778414 ER PT J AU Degheidy, H Abbasi, F Mostowski, H Gaigalas, AK Marti, G Bauer, S Wang, LL AF Degheidy, Heba Abbasi, Fatima Mostowski, Howard Gaigalas, Adolfas K. Marti, Gerald Bauer, Steven Wang, Lili TI Consistent, multi-instrument single tube quantification of CD20 in antibody bound per cell based on CD4 reference SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article DE flow cytometry; CD20 quantification; instrument characterization and standardization; mean; geometric mean fluorescence intensity; antibody bound per cell ID CHRONIC LYMPHOCYTIC-LEUKEMIA; QUANTITATIVE FLOW-CYTOMETRY; ASSAYS PRACTICE GUIDELINES; ANTI-CD4 FITC ANTIBODY; B-CELLS; HLA-DR; EXPRESSION; FLUORESCEIN; VALIDATION; VARIABLES AB Detecting changes in the expression levels of cell antigens could provide critical information for the diagnosis of many diseases, for example, leukemia, lymphoma, and immunodeficiency diseases, detecting minimal residual disease, monitoring immunotherapies and discovery of meaningful clinical disease markers. One of the most significant challenges in flow cytometry is how to best ensure measurement quality and generate consistent and reproducible inter-laboratory and intra-laboratory results across multiple cytometer platforms and locations longitudinally over time. In a previous study, we developed a procedure for instrument standardization across four different flow cytometer platforms from the same manufacturer. CD19 quantification was performed on three of the standardized instruments relative to CD4 expression on T lymphocytes with a known amount of antibody bound per cell (ABC) as a quantification standard. Consistent and reliable measures of CD19 expression were obtained independent of fluorochrome used demonstrating the utility of this approach. In the present investigation, quantification of CD20 relative to CD4 reference marker was implemented within a single tube containing both antibodies. Relative quantification of CD20 was performed using anti-CD20 antibody (clone L27) in three different fluorochromes relative to anti-CD4 antibody (clone SK3). Our results demonstrated that cell surface marker quantification can be performed robustly using the single tube assay format with novel gating strategies. The ABC values obtained for CD20 expression levels using PE, APC, or PerCP Cy5.5 are consistent over the five different instrument platforms for any given apparently healthy donor independent of the fluorochrome used. (c) 2015 International Clinical Cytometry Society C1 [Degheidy, Heba; Abbasi, Fatima; Mostowski, Howard; Bauer, Steven] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Gaigalas, Adolfas K.; Wang, Lili] NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. [Marti, Gerald] FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Wang, LL (reprint author), NIST, 100 Bur Dr,Stop 8312, Gaithersburg, MD 20899 USA.; Bauer, S (reprint author), FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Steven.bauer@fda.hhs.gov; lili.wang@nist.gov FU DCGT; OCTGT; CBER; BBD; MML; NIST FX Grant sponsor: DCGT.; Grant sponsor: OCTGT.; Grant sponsor: CBER.; Grant sponsor: BBD.; Grant sponsor: MML.; Grant sponsor: NIST. NR 27 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4949 EI 1552-4957 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD MAR PY 2016 VL 90 IS 2 SI SI BP 159 EP 167 DI 10.1002/cyto.b.21253 PG 9 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA DI3EE UT WOS:000373380400007 PM 26013593 ER PT J AU Rentsendorj, O Zhang, XY Williams, MC Buehler, PW D'Agnillo, F AF Rentsendorj, Otgonchimeg Zhang, Xiaoyuan Williams, Matthew C. Buehler, Paul W. D'Agnillo, Felice TI Transcriptional Suppression of Renal Antioxidant Enzyme Systems in Guinea Pigs Exposed to Polymerized Cell-Free Hemoglobin SO TOXICS LA English DT Article DE hemoglobin-based oxygen carrier (HBOC); kidney; oxidative stress; antioxidants; DNA methylation ID OXIDATIVE STRESS; CPG-ISLANDS; METABOLIC SYNDROME; BLOOD SUBSTITUTES; BREAST-CANCER; METHYLATION; DNA; HYPERMETHYLATION; SUSCEPTIBILITY; EXPRESSION AB Hemoglobin-based oxygen carriers (HBOCs) are being developed as oxygen and plasma volume-expanding therapeutics though their potential to promote oxidative tissue injury has raised safety concerns. Using a guinea pig exchange transfusion model, we examined the effects of polymerized bovine hemoglobin (HbG) on the transcriptional regulation, activity, and expression of the renal antioxidant enzymes; superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). HbG infusion downregulated the mRNA levels for genes encoding SOD isoforms 1-3, GPx1, GPx3, GPx4, and CAT. This transcriptional suppression correlated with decreased enzymatic activities for SOD, CAT, and GPx. Immunostaining revealed decreased protein expression of SOD1, CAT, and GPx1 primarily in renal cortical tubules. DNA methylation analyses identified CpG hypermethylation in the gene promoters for SOD1-3, GPx1, GPx3, and GPx4, suggesting an epigenetic-based mechanism underlying the observed gene repression. HbG also induced oxidative stress as evidenced by increased renal lipid peroxidation end-products and 4-HNE immunostaining, which could be the result of the depleted antioxidant defenses and/or serve as a trigger for increased DNA methylation. Together, these findings provide evidence that the renal exposure to HbG suppresses the function of major antioxidant defense systems which may have relevant implications for understanding the safety of hemoglobin-based products. C1 [Rentsendorj, Otgonchimeg; Zhang, Xiaoyuan; Williams, Matthew C.; Buehler, Paul W.; D'Agnillo, Felice] US FDA, Lab Biochem & Vasc Biol, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. RP D'Agnillo, F (reprint author), US FDA, Lab Biochem & Vasc Biol, Div Hematol Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM otgonchimeg.rentsendorj@fda.hhs.gov; xiaoyuan.zhang@fda.hhs.gov; matthew.williams@fda.hhs.gov; paul.buehler@fda.hhs.gov; felice.dagnillo@fda.hhs.gov NR 43 TC 1 Z9 1 U1 5 U2 8 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2305-6304 J9 Toxics JI Toxics PD MAR PY 2016 VL 4 IS 1 DI 10.3390/toxics4010006 PG 14 WC Toxicology SC Toxicology GA DI2EW UT WOS:000373309500005 ER PT J AU Jones, CM Lurie, PG Throckmorton, DC AF Jones, Christopher M. Lurie, Peter G. Throckmorton, Douglas C. TI Effect of US Drug Enforcement Administration's Rescheduling of Hydrocodone Combination Analgesic Products on Opioid Analgesic Prescribing SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Jones, Christopher M.] US Dept HHS, Off Assistant Secretary Planning & Evaluat, Washington, DC 20201 USA. [Throckmorton, Douglas C.] US FDA, Off Commissioner, Silver Spring, MD USA. RP Jones, CM (reprint author), US Dept HHS, Off Assistant Secretary Planning & Evaluat, Washington, DC 20201 USA. EM christopher.jones@hhs.gov NR 6 TC 7 Z9 7 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAR PY 2016 VL 176 IS 3 BP 399 EP + DI 10.1001/jamainternmed.2015.7799 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DG7ZP UT WOS:000372302500029 PM 26809459 ER PT J AU Elahi, M Eshera, N Bambata, N Barr, H Lyn-Cook, B Beitz, J Rios, M Taylor, DR Lightfoote, M Hanafi, N DeJager, L Wiesenfeld, P Scott, PE Fadiran, EO Henderson, MB AF Elahi, Merina Eshera, Noha Bambata, Nkosazana Barr, Helen Lyn-Cook, Beverly Beitz, Julie Rios, Maria Taylor, Deborah R. Lightfoote, Marilyn Hanafi, Nada DeJager, Lowri Wiesenfeld, Paddy Scott, Pamela E. Fadiran, Emmanuel O. Henderson, Marsha B. TI The Food and Drug Administration Office of Women's Health: Impact of Science on Regulatory Policy: An Update SO JOURNAL OF WOMENS HEALTH LA English DT Article ID CARDIAC RESYNCHRONIZATION THERAPY; MOLECULAR ENTITY DRUGS; PHASE CLINICAL-TRIALS; RAT UTERINE GROWTH; SEX-DIFFERENCES; BREAST-CANCER; CORONARY-ANGIOGRAPHY; POSTMENOPAUSAL WOMEN; PREDICT DISPOSITION; CELIAC-DISEASE AB The U.S. Food and Drug Administration Office of Women's Health (FDA OWH) has supported women's health research for similar to 20 years, funding more than 300 studies on women's health issues, including research on diseases/conditions that disproportionately affect women in addition to the evaluation of sex differences in the performance of and response to medical products. These important women's health issues are studied from a regulatory perspective, with a focus on improving and optimizing medical product development and the evaluation of product safety and efficacy in women. These findings have influenced industry direction, labeling, product discontinuation, safety notices, and clinical practice. In addition, OWH-funded research has addressed gaps in the knowledge about diseases and medical conditions that impact women across the life span such as cardiovascular disease, pregnancy, menopause, osteoporosis, and the safe use of numerous medical products. C1 [Elahi, Merina; Eshera, Noha; Bambata, Nkosazana; Scott, Pamela E.; Fadiran, Emmanuel O.; Henderson, Marsha B.] US FDA, Off Womens Hlth, WO Bldg 32,Room 2312,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Barr, Helen; Lightfoote, Marilyn; Hanafi, Nada] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Lyn-Cook, Beverly] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Beitz, Julie] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Rios, Maria; Taylor, Deborah R.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [DeJager, Lowri; Wiesenfeld, Paddy] US FDA, Ctr Food Safety & Appl Nutr, Silver Spring, MD 20993 USA. RP Fadiran, EO (reprint author), US FDA, Off Womens Hlth, WO Bldg 32,Room 2312,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM emmanuel.fadiran@fda.hhs.gov NR 128 TC 0 Z9 0 U1 2 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD MAR 1 PY 2016 VL 25 IS 3 BP 222 EP 234 DI 10.1089/jwh.2015.5671 PG 13 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA DG6DU UT WOS:000372173200005 PM 26871618 ER PT J AU Adesanya, MR Bailey, W Belcher, DC Beltran, M Branch, T Brand, MK Craft, EM Donahue, AH Dye, BA Thornton-Evans, G Garcia, I Hyman, F Joskow, R Lester, AM Makrides, NS Manski, RJ Mehegan, M Mouden, LD Nelson, D Norris, L O'Hara, J Cherry-Peppers, G Ricks, TL Rollins, R AF Adesanya, Margo R. Bailey, William Belcher, Donald C. Beltran, Marco Branch, Tracy Brand, Marcia K. Craft, Edwin M. Donahue, Agnes H. Dye, Bruce A. Thornton-Evans, Gina Garcia, Isabel Hyman, Frederick Joskow, Renee Lester, Arlene M. Makrides, Nicholas S. Manski, Richard J. Mehegan, Marian Mouden, Lynn Douglas Nelson, Danielle Norris, Laurie O'Hara, Jessica Cherry-Peppers, Gail Ricks, Timothy L. Rollins, Rochelle CA US Dept Hlth Human Serv TI US Department of Health and Human Services Oral Health Strategic Framework, 2014-2017 SO PUBLIC HEALTH REPORTS LA English DT Editorial Material ID DENTAL-CARE; CARIES C1 [Adesanya, Margo R.] Natl Inst Dent & Craniofacial Res, NIH, Off Sci Policy & Anal, Rockville, MD USA. [Bailey, William] Ctr Dis Control & Prevent, Atlanta, GA USA. [Belcher, Donald C.] US Coast Guard, Qual & Performance Improvement, Washington, DC USA. [Beltran, Marco; Rollins, Rochelle] Adm Children & Families, Washington, DC USA. [Branch, Tracy; Lester, Arlene M.] OS Off Minor Hlth, Washington, DC USA. [Brand, Marcia K.; Joskow, Renee] Hlth Resources & Serv Adm, Rockville, MD USA. [Craft, Edwin M.] Subst Abuse & Mental Hlth Serv Adm, Rockville, MD USA. [Donahue, Agnes H.] OS Off Assistant Secretary Hlth, OASH Intergovt Affairs RHA, Washington, DC USA. [Dye, Bruce A.] Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Thornton-Evans, Gina] Ctr Dis Control & Prevent, Div Oral Hlth, Atlanta, GA USA. [Garcia, Isabel] Natl Inst Dent & Craniofacial Res, NIH, Rockville, MD USA. [Hyman, Frederick] US FDA, Ctr Drug Evaluat & Res, Div Dermatol & Dent Prod, Silver Spring, MD USA. [Makrides, Nicholas S.] Fed Bur Prisons, Washington, DC USA. [Manski, Richard J.] Agcy Healthcare Res & Qual, Rockville, MD USA. [Mehegan, Marian] Off Assistant Secretary Hlth, Off Womens Hlth, Washington, DC USA. [Mouden, Lynn Douglas] Ctr Medicare & Medicaid Serv, Div Qual Evaluat & Hlth Outcomes, Children & Adults Hlth Programs Grp, Washington, DC USA. [Nelson, Danielle] Adm Community Living, Washington, DC USA. [Norris, Laurie] Ctr Medicare & Medicaid Serv, Oral Hlth Initiat, Div Qual Evaluat & Hlth Outcomes, Washington, DC USA. [O'Hara, Jessica] Off Secretary, Off Assistant Secretary Planning & Evaluat, Washington, DC USA. [Cherry-Peppers, Gail] US FDA, Ctr Tobacco Prod, Off Sci, Silver Spring, MD USA. [Ricks, Timothy L.] Indian Hlth Serv, Nashville Area Off Publ Hlth, Nashville, TN USA. RP Adesanya, MR (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Off Sci Policy & Anal, Rockville, MD USA. NR 56 TC 0 Z9 0 U1 2 U2 2 PU ASSOC SCHOOLS PUBLIC HEALTH PI WASHINGTON PA 1900 M ST NW, STE 710, WASHINGTON, DC 20036 USA SN 0033-3549 J9 PUBLIC HEALTH REP JI Public Health Rep. PD MAR-APR PY 2016 VL 131 IS 2 BP 242 EP 257 PG 16 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DG9HH UT WOS:000372392900007 ER PT J AU de Moraes, IVM Ribeiro, PRV Schmidt, FL Canuto, KM Zocolo, GJ de Brito, ES Luo, RS Richards, KM Tran, K Smith, RE AF Machado de Moraes, Ingrid Vieira Vasconcelos Ribeiro, Paulo Riceli Schmidt, Flavio Luis Canuto, Kirley Marques Zocolo, Guilherme Juliao de Brito, Edy Sousa Luo, Rensheng Richards, Kristy M. Tran, Kevin Smith, Robert E. TI UPLC-QTOF-MS and NMR analyses of graviola (Annona muricata) leaves SO REVISTA BRASILEIRA DE FARMACOGNOSIA-BRAZILIAN JOURNAL OF PHARMACOGNOSY LA English DT Article DE Graviola; Annona muricata; UPLC-QTOF-MS; Parkinson's disease; NMR ID ASIMINA-TRILOBA FRUIT; FRENCH-WEST-INDIES; ATYPICAL PARKINSONISM; AQUEOUS EXTRACT; DIABETIC-RATS; ACETOGENINS AB Graviola leaves (Annona muricata L., Annonaceae) are used by some people to try to treat or even cure cancer, even though over-consumption of the fruit, which contains the neurotoxins annonacin and squamocin has caused an atypical form of Parkinson's disease. In previous analyses, the fruits were extracted with methanol under ambient conditions before analyses. In the present study, UPLC-QTOF-MS and NMR were used to analyze freeze-dried graviola leaves that were extracted using dry methanol and ethanol at 100 degrees C and 10 MPa (100 atm) pressure in a sealed container. Methanol solubilized 33% of the metabolites in the lyophilized leaves. Ethanol solubilized 41% of metabolites in the lyophilized leaves. The concentrations of total phenolic compounds were 100.3 +/- 2.8 and 93.2 +/- 2.0 mg gallic acid equivalents per g of sample, for the methanolic and ethanolic extracts, respectively. Moreover, the toxicophore (unsaturated gamma-lactone) that is present in neurotoxic acetogenins was found in the lipophilic portion of this extract. The concentrations of the neurotoxins annonacin and squamocin were found by UPLC-QTOF-MS to be 305.6 +/- 28.3 and 17.4 +/- 0.89 mu g/g-dw, respectively, in the dried leaves. Pressurized methanol solubilized more annonacin and squamocin than ethanol. On the other hand, a hot, aqueous infusion solubilized only 0.213% of the annonacin and too little of the squamocin to be detected. So, graviola leaves contain significant amounts of the neurotoxins annonacin and squamocin, as well as some potentially healthy phenolic compounds. Finally, the potential neurotoxicity of whole leaves in dietary supplements could be much higher than that of a tea (hot aqueous infusion) that is made from them. (C) 2015 Sociedade Brasileira de Farmacognosia. Published by Elsevier Editora Ltda. All rights reserved. C1 [Machado de Moraes, Ingrid Vieira; Vasconcelos Ribeiro, Paulo Riceli; Canuto, Kirley Marques; Zocolo, Guilherme Juliao; de Brito, Edy Sousa] Embrapa Agroind Trop, Fortaleza, Ceara, Brazil. [Schmidt, Flavio Luis] Univ Estadual Campinas, Fac Engn Alimentos, Dept Tecnol Alimentos, Campinas, SP, Brazil. [Luo, Rensheng] Univ Missouri, St Louis, MO 63121 USA. [Richards, Kristy M.; Tran, Kevin; Smith, Robert E.] US FDA, Lenexa, KS USA. RP Smith, RE (reprint author), US FDA, Lenexa, KS USA. EM Robert.smith@fda.hhs.gov NR 24 TC 0 Z9 0 U1 5 U2 17 PU SOC BRASILEIRA FARMACOGNOSIA PI CURITIBA-PR PA C/O PROF CID AIMBIRE DE MORAES SANTOS, UFPR-LAB FARM, RUA PREF LOTHARIO MEISSNER, 632-JD BOTANICO, CURITIBA-PR, 80210-170, BRAZIL SN 0102-695X J9 REV BRAS FARMACOGN JI Rev. Bras. Farmacogn.-Braz. J. Pharmacogn. PD MAR-APR PY 2016 VL 26 IS 2 BP 174 EP 179 DI 10.1016/j.bjp.2015.12.001 PG 6 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DH2DM UT WOS:000372594400005 ER PT J AU Wu, B Li, JJ Wang, YH AF Wu, Benjamin Li, Jinjiang Wang, Yahong TI Evaluation of the Microcentrifuge Dissolution Method as a Tool for Spray-Dried Dispersion SO AAPS JOURNAL LA English DT Article DE centrifuge parameters; filtration; hydroxypropyl methylcellulose acetate succinate (HPMC-AS); indomethacin; ketoconazole; microcentrifuge dissolution; polyvinylpyrrolidone (PVP); SDD; supernatant ID METHYLCELLULOSE ACETATE SUCCINATE; AMORPHOUS SOLID DISPERSIONS; PERMEABILITY; PERFORMANCE; SOLUBILITY; SYSTEMS AB Although using spray-dried dispersions (SDDs) to improve the bioavailability of poorly water-soluble compounds has become a common practice in supporting the early phases of clinical studies, their performance evaluation, whether in solid dosage forms or alone, still presents significant challenges. A microcentrifuge dissolution method has been reported to quickly assess the dissolution performance of SDDs. While the microcentrifuge dissolution method has been used in the SDD community, there is still a need to understand the mechanisms about the molecular species present in supernatant after centrifugation, the molecular nature of active pharmaceutical ingredients (APIs), as well as the impact of experimental conditions. In this paper, we aim to assess the effect of API and polymer properties on the dissolution behavior of SDDs along with centrifuging parameters, and for this, two poorly water-soluble compounds (indomethacin and ketoconazole) and two commonly used polymers in the pharmaceutical industry (PVP and HPMC-AS) were chosen to prepare SDDs. A typical microcentrifuge dissolution procedure as reported in the publication (Curatolo et al., Pharm Res 26: 1419-1431, 2009) was followed. In addition, after separation of the supernatant from precipitation, some of the samples were filtered through filters of various sizes to investigate the particulate nature (particle size) of the supernatant. Furthermore, the centrifuge speed was varied to study sedimentation of API, SDD, or polymer particles. The results indicated that for the SDDs of four drug-polymer pairs, microcentrifuge dissolution exhibited varied behaviors, depending on the polymer and the drug used. The SDDs of indomethacin with either PVP or HPMC-AS showed a reproducible dissolution with minimum variability even after filtration and subjecting to varied centrifugation speed, suggesting that the supernatant behaved solution-like. However, ketoconazole-PVP and ketoconazole-HPMC-AS SDDs displayed a significant variation in concentration as the speed of centrifugation and the pore sizes of filters were altered, indicating that their supernatant was heterogeneous with the presence of particulates. In conclusion, microcentrifuge dissolution method was more suitable for indomethacin-PVP and indomethacin-HPMC-AS systems compared with ketoconazole-PVP and ketoconazole-HPMC-AS. Therefore, the use of microcentrifuge dissolution method depends on both compounds and polymers selected, which should be examined case by case. C1 [Wu, Benjamin; Wang, Yahong] Bristol Myers Squibb Co, Analyt & Bioanalyt Dev, Res & Dev, New Brunswick, NJ 08903 USA. [Li, Jinjiang] Bristol Myers Squibb Co, Drug Prod Sci & Technol, Res & Dev, New Brunswick, NJ 08903 USA. [Wang, Yahong] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Li, JJ (reprint author), Bristol Myers Squibb Co, Drug Prod Sci & Technol, Res & Dev, New Brunswick, NJ 08903 USA. EM jinjiang.li@bms.com FU Bristol-Myers Squibb FX All financial support for the studies reported herein was provided by Bristol-Myers Squibb. The authors have no financial involvement with any other organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. NR 16 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD MAR PY 2016 VL 18 IS 2 BP 346 EP 353 DI 10.1208/s12248-016-9872-7 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG3NV UT WOS:000371977400008 PM 26831250 ER PT J AU Wang, YMC Wang, J Hon, YY Zhou, L Fang, LY Ahn, HY AF Wang, Yow-Ming C. Wang, Jie Hon, Yuen Yi Zhou, Lin Fang, Lanyan Ahn, Hae Young TI Evaluating and Reporting the Immunogenicity Impacts for Biological Products-a Clinical Pharmacology Perspective SO AAPS JOURNAL LA English DT Article DE clinical pharmacology assessment; immunogenicity data for approved biological products; impact on clinical pharmacokinetics and efficacy; incidence of anti-drug antibodies and neutralizing antibodies ID INFLAMMATORY-BOWEL-DISEASE; REGULATORY CONSIDERATIONS; THERAPEUTIC PROTEINS; ANTIDRUG ANTIBODIES; INFLIXIMAB LEVELS; METAANALYSIS; VALIDATION; PATIENT; ARTICLE; ASSAYS AB Immunogenicity assessment is important for biological products due to potential impacts of immunogenicity on safety and efficacy. We reviewed the prescribing information and the FDA's clinical pharmacology review of 121 approved biological products for evaluating and reporting of immunogenicity data. Of the 121 products, 89% (n = 108) reported the incidence of immunogenicity and 49% (n = 59) reported immunogenicity impact on efficacy. However, only 26% (n = 31) reported whether the immunogenicity affected pharmacokinetics. A subset of 16 products reported effects of anti-drug antibodies (ADA) on both systemic clearance and efficacy; 8 of 16 products had increased systemic clearance coinciding with reduced efficacy, and 6 of 16 products had no changes in either clearance or efficacy. Factors contributing to infrequent reporting of the ADA effect on exposure and methods for determining the effect of ADA on exposure are summarized. Measuring ADA and drug concentrations concurrently over time enables the evaluation of ADA impact on pharmacokinetics. Within-subject comparison of concentration data (before vs. after ADA formation) is a useful alternative to between-subject (ADA+ vs. ADA-) comparison when sample size is limited or when the majority of subjects developed ADA. The biological complexity of immune responses presents challenges to quantifying the ADA impact on pharmacokinetics using model-based methods. Our findings support that pharmacokinetic exposure is more sensitive than efficacy endpoints for evaluating ADA effects. A decrease in drug concentration due to formation of ADA during treatment can serve as an early indicator for potential reduced efficacy occurring at a later time. C1 [Wang, Yow-Ming C.; Wang, Jie; Hon, Yuen Yi; Zhou, Lin; Fang, Lanyan; Ahn, Hae Young] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Wang, YMC (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM yowming.wang@fda.hhs.gov NR 22 TC 0 Z9 0 U1 1 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 MAR PY 2016 VL 18 IS 2 BP 395 EP 403 DI 10.1208/s12248-015-9857-y PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG3NV UT WOS:000371977400013 PM 26721560 ER PT J AU Mahmood, I Staschen, CM AF Mahmood, Iftekhar Staschen, Carl-Michael TI Prediction of Human Glomerular Filtration Rate from Preterm Neonates to Adults: Evaluation of Predictive Performance of Several Empirical Models SO AAPS JOURNAL LA English DT Article DE allometry; GFR; pediatrics ID INULIN-CLEARANCE; RENAL CLEARANCE; CYSTIC-FIBROSIS; DRUG CLEARANCE; PHARMACOKINETICS; CHILDREN; EXPONENT; AGE; INFANTS; LIFE AB The objective of this study was to evaluate the predictive performance of several allometric empirical models (body weight dependent, age dependent, fixed exponent 0.75, a data-dependent single exponent, and maturation models) to predict glomerular filtration rate (GFR) in preterm and term neonates, infants, children, and adults without any renal disease. In this analysis, the models were developed from GFR data obtained from inulin clearance (preterm neonates to adults; n = 93) and the predictive performance of these models were evaluated in 335 subjects (preterm neonates to adults). The primary end point was the prediction of GFR from the empirical allometric models and the comparison of the predicted GFR with measured GFR. A prediction error within +/- 30% was considered acceptable. Overall, the predictive performance of the four models (BDE, ADE, and two maturation models) for the prediction of mean GFR was good across all age groups but the prediction of GFR in individual healthy subjects especially in neonates and infants was erratic and may be clinically unacceptable. C1 [Mahmood, Iftekhar; Staschen, Carl-Michael] US FDA, Div Hematol Clin Review Branch, OBRR, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Mahmood, I (reprint author), US FDA, Div Hematol Clin Review Branch, OBRR, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Iftekhar.mahmood@fda.hhs.gov NR 58 TC 1 Z9 1 U1 1 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 MAR PY 2016 VL 18 IS 2 BP 445 EP 454 DI 10.1208/s12248-016-9868-3 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG3NV UT WOS:000371977400018 PM 26801317 ER PT J AU Toerner, JG Cox, E AF Toerner, Joseph G. Cox, Edward TI A Collaborative Model for Endpoint Development: Advancing the Science of Antibacterial Drug Clinical Trials SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material DE antibacterial drug development; non-inferiority trial design; clinical endpoints ID SKIN-STRUCTURE INFECTIONS; ACUTE BACTERIAL SKIN C1 [Toerner, Joseph G.; Cox, Edward] US FDA, Ctr Drug Evaluat & Res, Off Antimicrobial Prod, Silver Spring, MD USA. RP Cox, E (reprint author), FDA OMPT CDER Off New Drugs, Off Antimicrobial Prod, White Oak Bldg 22,Rm 6212,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM edward.cox@fda.hhs.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 1 PY 2016 VL 62 IS 5 BP 608 EP 609 DI 10.1093/cid/civ1007 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DF9XK UT WOS:000371715600019 PM 26668336 ER PT J AU Lee, SK Choi, D Chon, JW Seo, KH AF Lee, Soo Kyoung Choi, Dasom Chon, Jung Whan Seo, Kun Ho TI Resistance of Strains Producing Extended-Spectrum beta-Lactamases Among Salmonella from Duck Carcasses at Slaughterhouses in Three Major Provinces of South Korea SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article ID ESCHERICHIA-COLI; ANTIMICROBIAL RESISTANCE; KLEBSIELLA-PNEUMONIAE; RETAIL CHICKEN; PUBLIC-HEALTH; FOOD ANIMALS; PREVALENCE; HUMANS; GENES; FARM AB The current study was carried out to estimate Salmonella spp. contamination of duck carcasses and to determine the antibiotic susceptibility profiles and serotype distribution of the isolates. Salmonella spp. was detected in 21.7% (26/120) of fresh raw duck carcasses sampled at different slaughterhouses in South Korea. Eight Salmonella serovars were identified; the most prevalent serovar was S. Typhimurium (34.6%), followed by S. Virchow (30.8%). All isolates were resistant to at least one antibiotic, and five remarkable isolates were resistant to more than 10 antibiotics, including third- and fourth-generation cephalosporins. Additional phenotypic and genetic characterization demonstrated that these isolates harbored resistance genes to broad-spectrum -lactams, blaCTX-M-15 and blaCMY-2 genes, among the most prevalent -lactamase enzymes worldwide. Based on molecular subtyping performed using the DiversiLab automated repetitive-sequence-based PCR system, isolates were classified into cluster A and cluster B. Among -lactamase-producing Salmonellas, the isolate showing >98% similarity in their repetitive-sequence-based PCR banding pattern seemed to have acquired the resistance gene (bla(CMY-2)) and thus a distinct multiresistance profile. Given that antibiotic-resistant genes might be transferred by plasmid-mediated conjugation, periodic microbiological assessment within slaughterhouses is recommended for pathogens not to be transmitted through cross-contamination during slaughtering and dressing. C1 [Lee, Soo Kyoung; Choi, Dasom; Seo, Kun Ho] Konkuk Univ, KU Ctr Food Safety, Coll Vet Med, 120 Neungdong Ro, Seoul 05029, South Korea. [Chon, Jung Whan] Konkuk Univ, Dept Anim Sci & Technol, Seoul 05029, South Korea. [Chon, Jung Whan] US FDA, Natl Ctr Toxicol Res, Div Microbiol, Jefferson, AR 72079 USA. RP Seo, KH (reprint author), Konkuk Univ, KU Ctr Food Safety, Coll Vet Med, 120 Neungdong Ro, Seoul 05029, South Korea. EM bracstu3@konkuk.ac.kr FU Konkuk University FX This paper was supported by Konkuk University in 2013. NR 29 TC 1 Z9 1 U1 1 U2 3 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 MAR 1 PY 2016 VL 13 IS 3 BP 135 EP 141 DI 10.1089/fpd.2015.2042 PG 7 WC Food Science & Technology SC Food Science & Technology GA DG2FN UT WOS:000371882100004 PM 26885565 ER PT J AU Miller, KL Lanthier, M AF Miller, Kathleen L. Lanthier, Michael TI Trends In Orphan New Molecular Entities, 1983-2014: Half Were First In Class, And Rare Cancers Were The Most Frequent Target SO HEALTH AFFAIRS LA English DT Article ID DRUG DEVELOPMENT AB The Orphan Drug Act was enacted in 1983 to stimulate drug development for rare diseases. How well this law has accomplished that goal is an important public health question. This study examined the characteristics of the 209 orphan drugs approved as new molecular entities in the period 1983-2014. As a whole, these drugs were highly innovative and provided substantial gains in reducing unmet medical needs for rare diseases: Over 50 percent of the drugs were first in class, and 78 percent received a priority review. Drugs approved as either therapeutic or supportive therapies for rare cancers represented the highest proportion of these drugs (35 percent). Additionally, in 2010-14 large companies became a strong presence in developing orphan new molecular entities for oncology indications. Overall, new orphan drugs appeared to be highly innovative and provided important advances in care for patients with rare diseases. C1 [Miller, Kathleen L.; Lanthier, Michael] US FDA, Off Planning, Silver Spring, MD USA. [Miller, Kathleen L.] Univ N Carolina, Dept Hlth Policy & Management, Chapel Hill, NC USA. RP Miller, KL (reprint author), US FDA, Off Planning, Silver Spring, MD USA. EM kathleen.miller@fda.hhs.gov NR 10 TC 2 Z9 2 U1 3 U2 4 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD MAR PY 2016 VL 35 IS 3 BP 464 EP 470 DI 10.1377/hlthaff.2015.0921 PG 7 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DG1KA UT WOS:000371825000014 PM 26953301 ER PT J AU Butler, MG Zhou, EH Zhang, F Wu, YT Wu, AC Levenson, MS Wu, PS Seymour, S Toh, S Iyer, A Iyasu, S Baker, MA AF Butler, Melissa G. Zhou, Esther H. Zhang, Fang Wu, Yu-te Wu, Ann Chen Levenson, Mark S. Wu, Pingsheng Seymour, Sally Toh, Sengwee Iyer, Aarthi Iyasu, Solomon Baker, Meghan A. TI Changing patterns of asthma medication use related to US Food and Drug Administration long-acting beta(2)-agonist regulation from 2005-2011 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Long-acting beta(2)-agonist; asthma; US Food and Drug Administration; medication use; drug safety ID INTERRUPTED TIME-SERIES; RANDOMIZED CONTROLLED TRIAL; PERSISTENT ASTHMA; UNITED-STATES; SALMETEROL; CHILDREN; THERAPY; EXACERBATIONS; INTERVENTIONS; MONOTHERAPY AB Background: Safety concerns associated with long-acting beta(2)-agonists (LABAs) have led to many US Food and Drug Administration (FDA) regulatory activities for this class of drugs. Little is known about the effect of these regulatory activities on use of LABA-containing agents or other asthma medications. Methods: We created rolling cohorts of pediatric and adult asthmatic patients in the Mini-Sentinel Distributed Database between January 2005 and June 2011. The proportions of asthmatic patients using LABA-containing products, inhaled corticosteroids (ICSs), leukotriene modifiers, short-acting b2-agonists, oral corticosteroids, other bronchodilators, and no medications were measured on a monthly basis, and the changes were evaluated by using interrupted time series with segmented regression analysis. Results: When the 2005 regulatory activity was announced, there were statistically significant decreases in the use of fixed-dose ICS-LABA agents in children (-0.98 percentage points) and adults (-1.24 percentage points). Increased use of ICSs and leukotriene modifiers was observed just after the regulatory activities were announced in both children and adults. Although of smaller magnitude, continued favorable changes in the use of LABA agents were observed after the 2010 FDA regulatory activity. Conclusion: The 2005 and 2010 FDA regulatory activities might have contributed to reduced use of LABA agents, as intended; however, their effect, independent of other factors, cannot be determined. Use of other classes of asthma medications was similarly affected. C1 [Butler, Melissa G.] Kaiser Permanente Georgia, Ctr Clin & Outcomes Res, Atlanta, GA USA. [Butler, Melissa G.] Evidence Space, Hamilton, Bermuda. [Zhou, Esther H.; Iyasu, Solomon] US FDA, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Wu, Yu-te; Levenson, Mark S.] US FDA, Off Biostat, Silver Spring, MD USA. [Seymour, Sally] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Zhang, Fang; Wu, Ann Chen; Toh, Sengwee; Iyer, Aarthi; Baker, Meghan A.] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Zhang, Fang; Wu, Ann Chen; Toh, Sengwee; Iyer, Aarthi; Baker, Meghan A.] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Wu, Pingsheng] Vanderbilt Univ, Sch Med, Dept Med & Biostat, Nashville, TN 37212 USA. [Baker, Meghan A.] Brigham & Womens Hosp, Dept Med, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. RP Baker, MA (reprint author), Dept Populat Med, 133 Brookline Ave,6th Floor, Boston, MA 02215 USA. EM meghan_baker@harvardpilgrim.org RI Toh, Sengwee/D-7567-2017 OI Toh, Sengwee/0000-0002-5160-0810 FU US Food and Drug Administration (FDA) through the Department of Health and Human Resources [HHSF223200910006I]; FDA; Sentinel System FX Mini-Sentinel is funded by the US Food and Drug Administration (FDA) through the Department of Health and Human Resources ( contract HHSF223200910006I). Mini-Sentinel is a pilot project sponsored by the FDA to inform and facilitate development of a fully operational active surveillance system, the Sentinel System, for monitoring the safety of FDA-regulated medical products. Mini-Sentinel is one piece of the Sentinel Initiative, a multifaceted effort by the FDA to develop a national electronic system that will complement existing methods of safety surveillance. Mini-Sentinel Collaborators include Data and Academic Partners that provide access to health care data and ongoing scientific, technical, methodological, and organizational expertise. NR 29 TC 2 Z9 2 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2016 VL 137 IS 3 BP 710 EP 717 DI 10.1016/j.jaci.2015.09.057 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA DG2LB UT WOS:000371897500012 PM 26725997 ER PT J AU Sharma, GM Rallabhandi, P Williams, KM Pahlavan, A AF Sharma, Girdhari M. Rallabhandi, Prasad Williams, Kristina M. Pahlavan, Autusa TI Characterization of Antibodies for Grain-Specific Gluten Detection SO JOURNAL OF FOOD SCIENCE LA English DT Article DE antibodies; gluten; grain-specific; immunoassay ID EXERCISE-INDUCED ANAPHYLAXIS; PROLAMIN STORAGE PROTEINS; CELIAC-DISEASE; UNITED-STATES; FOOD ALLERGY; WHEAT GLUTEN; BARLEY; GLIADIN; ELISA; OATS AB Gluten ingestion causes immunoglobulin E (IgE)-mediated allergy or celiac disease in sensitive individuals, and a strict gluten-free diet greatly limits food choices. Immunoassays such as enzyme-linked immunosorbent assay (ELISA) are used to quantify gluten to ensure labeling compliance of gluten-free foods. Anti-gluten antibodies may not exhibit equal affinity to gluten from wheat, rye, and barley. Moreover, because wheat gluten is commonly used as a calibrator in ELISA, accurate gluten quantitation from rye and barley contaminated foods may be compromised. Immunoassays utilizing grainspecific antibodies and calibrators may help improve gluten quantitation. In this study, polyclonal antibodies raised against gluten-containing grain-specific peptides were characterized for their immunoreactivity to gluten from different grain sources. Strong immunoreactivity to multiple gluten polypeptides from wheat, rye, and barley was observed in the range 34 to 43 kDa with anti-gliadin, 11 to 15 and 72 to 95 kDa with anti-secalin, and 30 to 43 kDa with anti-hordein peptide antibodies, respectively. Minimal or no cross-reactivity with gluten from other grains was observed among these antibodies. The anti-consensus peptide antibody raised against a repetitive amino acid sequence of proline and glutamine exhibited immunoreactivity to gluten from wheat, rye, barley, and oat. The antibodies exhibited similar immunoreactivity with most of the corresponding grain cultivars by ELISA. The high specificity and minimal cross-reactivity of grain-specific antibodies suggest their potential use in immunoassays for accurate gluten quantitation. C1 [Sharma, Girdhari M.; Rallabhandi, Prasad; Williams, Kristina M.] US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Immunobiol Branch, 8301 Muirkirk Rd, Laurel, MD 20708 USA. [Pahlavan, Autusa] Univ Maryland, Joint Inst Food Safety & Appl Nutr, 5201 Paint Branch Pkwy, College Pk, MD 20742 USA. RP Sharma, GM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Immunobiol Branch, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM Girdhari.Sharma@fda.hhs.gov FU U.S. FDA Office of Women's Health (OWH) grant FX The authors thank Dr. Carmen Diaz-Amigo for help with the selection of amino acid sequences used for antibody production. This work was partly supported by a U.S. FDA Office of Women's Health (OWH) grant (to PR). NR 27 TC 0 Z9 0 U1 8 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-1147 EI 1750-3841 J9 J FOOD SCI JI J. Food Sci. PD MAR PY 2016 VL 81 IS 3 BP T810 EP T816 DI 10.1111/1750-3841.13241 PG 7 WC Food Science & Technology SC Food Science & Technology GA DG5VW UT WOS:000372148400034 PM 26878584 ER PT J AU Minor, T Ali, MM Rizzo, JA AF Minor, Travis Ali, Mir M. Rizzo, John A. TI Body Weight and Suicidal Behavior in Adolescent Females: The Role of Self-Perceptions SO JOURNAL OF MENTAL HEALTH POLICY AND ECONOMICS LA English DT Article ID PERCEIVED WEIGHT; MASS INDEX; OBESITY; ASSOCIATIONS; PREVALENCE; DISORDERS; OUTCOMES AB Background: Suicide is the third leading cause of death among adolescents and recent data indicate that the suicide rate, particularly for young girls, is increasing. Excess body weight among adolescents has also been documented widely over the last two decades and is considered one of the most pressing public health concerns today. Previous literature has examined the relationship between actual body weight and suicidal behavior, but there is little evidence on self-perception of weight and suicidal behaviors. Aim of the Study: This study examines the relationship between body weight and suicidal behaviors using a rich longitudinal data set of a large nationally-representative sample of female adolescents to account for a number of confounding factors. The study explores the relationship, not only between actual weight status and suicidal behaviors, but also between self-perception of weight and suicidal behaviors. Method: Using data from a nationally-representative sample of adolescents in the United States, the study ascertains the effect of body weight status on suicidal behaviors by estimating endogeneity-corrected models including school-level fixed effects to account for bi-directionality and unobserved confounders. Actual body weight status was calculated using interviewer-measured height and weight. The study also used a measure of self-perceived weight status to compare how actual versus self-perceived weight status affects suicidal behavior. Thinking about committing suicide and attempting to commit suicide in the past 12 months were utilized as dichotomous measures of suicidal behaviors. Potential mediators between suicidal behaviors and weight status such as family history of suicide, participation in risky health behaviors and parental characteristics were also controlled for in the analysis. The analytical sample consists of 5,430 adolescent females aged 11 to 18. Results: The results suggest that both self-perceived and measured weight status (overweight or obese) increase a female adolescent's probability of suicidal ideation, with self-perceived weight status causing a larger increase in suicidal ideation. There is some evidence that body weight status affects suicide attempts, but these results are much less robust. Finally, endogeneity bias is shown to be of concern in all estimates, and failing to account for this bias is likely to understate any estimated effect. Implications for Health Policy: The results have important implications for the design of public health programs to prevent adolescent suicide, especially among female adolescents. Understanding the mechanisms through which adolescents are motivated to take such dire actions will help to allocate resources into the treatment areas which are most effective in stemming the rise of suicidal behaviors. This study identifies one key factor, self perception of weight, which may be an avenue for mental health care providers to continue exploring. Implications for Future Research: Further research on this topic could include not only studying the impact of body weight on suicidal behaviors, but also examining the relationships between body weight and other important mental health outcomes such as psychological distress and major depressive episodes. C1 [Minor, Travis] US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20910 USA. [Ali, Mir M.] Subst Abuse & Mental Hlth Serv Adm, Ctr Behav Hlth Stat & Qual, Rockville, MD USA. [Rizzo, John A.] SUNY Stony Brook, Dept Econ, Stony Brook, NY 11794 USA. [Rizzo, John A.] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. RP Minor, T (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20910 USA. EM Travis.Minor@fda.hhs.gov FU National Institute of Child Health and Human Development [P01- HD31921] FX The views expressed in this paper are solely those of the authors and do not necessarily reflect the views of the FDA or SAMHSA. This research uses data from Add Health, a program project designed by J. Richard Udry, Peter S.Bearman, and Kathleen Mullan Harris, and funded by a grant P01- HD31921 from the National Institute of Child Health and Human Development, with cooperative funding from 17 other agencies. Special acknowledgment is due Ronald R. Rindfuss and Barbara Entwisle for assistance in the original design. Persons interested in obtaining data files from Add Health should contact Add Health, Carolina Population Center, 123 W. Franklin Street, Chapel Hill, NC 27516-2524 (addhealth@unc.edu). NR 18 TC 0 Z9 0 U1 4 U2 6 PU INT CTR MENTAL HEALTH POLICY & ECONOMICS-ICMPE PI MILANO PA VIA DANIELE CRESPI 7, MILANO, 20123, ITALY SN 1091-4358 J9 J MENT HEALTH POLICY JI J. Ment. Health Policy Econ. PD MAR PY 2016 VL 19 IS 1 BP 21 EP 31 PG 11 WC Health Policy & Services; Psychiatry SC Health Care Sciences & Services; Psychiatry GA DG6QP UT WOS:000372211500003 PM 27084791 ER PT J AU Lin, ZC Healey, S Wu, ZY AF Lin, Zhichao Healey, Stephanie Wu, Zhongyu TI Rapid and simultaneous detection of alpha/beta radioactivity in food by solid phase extraction liquid scintillation counting SO JOURNAL OF RADIOANALYTICAL AND NUCLEAR CHEMISTRY LA English DT Article; Proceedings Paper CT 10th International Conference on Methods and Applications of Radioanalytical Chemistry (MARC) CY APR 12-17, 2015 CL Kailua Kona, HI DE Food contamination; Rapid screening method; Alpha and beta radioactivity; Liquid scintillation counting; Radiological emergency response; Extraction resin ID ACTINIDES; SAMPLES; TH-232; U-238 AB The purpose of this study was to develop a practical radioanalytical method suitable for screening for beta- and alpha-emitting radioactive contamination in a large number and wide variety of foods in the event of a nuclear or radiological emergency. Simple and rapid solid-phase extraction was used to overcome matrix and radiometric interferences that occurred during food analysis. Benefiting from discriminative liquid scintillation counting, simultaneous detection of alpha and beta radioactivity was achieved with negligible quench effects and similar to 95 % counting efficiencies. Method limits of detection were similar to 0.06 Bq/kg for alpha and similar to 0.4 Bq/kg for beta radioactivity and the results were within +/- 20 % of the known values. C1 [Lin, Zhichao; Healey, Stephanie; Wu, Zhongyu] US FDA, Winchester Engn & Analyt Ctr, 109 Holton St, Winchester, MA 01890 USA. RP Lin, ZC (reprint author), US FDA, Winchester Engn & Analyt Ctr, 109 Holton St, Winchester, MA 01890 USA. EM zhichao.lin@fda.hhs.gov NR 19 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0236-5731 EI 1588-2780 J9 J RADIOANAL NUCL CH JI J. Radioanal. Nucl. Chem. PD MAR PY 2016 VL 307 IS 3 BP 1987 EP 1994 DI 10.1007/s10967-015-4531-5 PG 8 WC Chemistry, Analytical; Chemistry, Inorganic & Nuclear; Nuclear Science & Technology SC Chemistry; Nuclear Science & Technology GA DG1ER UT WOS:000371808900069 ER PT J AU Tempero, M AF Tempero, Margaret TI Promising the Moon! SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Tempero, Margaret] UCSF Pancreas Ctr, Med, San Francisco, CA USA. [Tempero, Margaret] ASCO, Alexandria, VA 22314 USA. [Tempero, Margaret] AACR ASCO, Alexandria, VA 22314 USA. [Tempero, Margaret] NCI, Clin Oncol Study Sect, Bethesda, MD 20892 USA. [Tempero, Margaret] Mayo Clin, Pancreas SPOREs, Rochester, MN 55905 USA. [Tempero, Margaret] UAB Minnesota, Minneapolis, MN 55401 USA. [Tempero, Margaret] Univ Arizona, GI SPORE, Tucson, AZ 85721 USA. [Tempero, Margaret] Lustgarten Fdn, Bethpage, NY 66873 USA. [Tempero, Margaret] Pancreat Canc Act Network, Manhattan Beach, CA 90266 USA. [Tempero, Margaret] V Fdn, Cary, NC 27513 USA. [Tempero, Margaret] Alberta Canada Canc Board, Edmonton, AB, Canada. [Tempero, Margaret] EORTC, Brussels, Belgium. [Tempero, Margaret] US FDA, Oncol Drug Advisory Comm, Rockville, MD 20857 USA. [Tempero, Margaret] UNMC Eppley Canc Ctr, Omaha, NE 68198 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 USA.; Tempero, M (reprint author), ASCO, Alexandria, VA 22314 USA.; Tempero, M (reprint author), AACR ASCO, Alexandria, VA 22314 USA.; Tempero, M (reprint author), NCI, Clin Oncol Study Sect, Bethesda, MD 20892 USA.; Tempero, M (reprint author), Mayo Clin, Pancreas SPOREs, Rochester, MN 55905 USA.; Tempero, M (reprint author), UAB Minnesota, Minneapolis, MN 55401 USA.; Tempero, M (reprint author), Univ Arizona, GI SPORE, Tucson, AZ 85721 USA.; Tempero, M (reprint author), Lustgarten Fdn, Bethpage, NY 66873 USA.; Tempero, M (reprint author), Pancreat Canc Act Network, Manhattan Beach, CA 90266 USA.; Tempero, M (reprint author), V Fdn, Cary, NC 27513 USA.; Tempero, M (reprint author), Alberta Canada Canc Board, Edmonton, AB, Canada.; Tempero, M (reprint author), EORTC, Brussels, Belgium.; Tempero, M (reprint author), US FDA, Oncol Drug Advisory Comm, Rockville, MD 20857 USA.; Tempero, M (reprint author), UNMC Eppley Canc Ctr, Omaha, NE 68198 USA.; 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 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 MAR PY 2016 VL 14 IS 3 BP 237 EP 237 PG 1 WC Oncology SC Oncology GA DG3VF UT WOS:000371997900003 PM 26957609 ER PT J AU Charkhkar, H Knaack, GL McHail, DG Mandal, HS Peixoto, N Rubinson, JF Dumas, TC Pancrazio, JJ AF Charkhkar, Hamid Knaack, Gretchen L. McHail, Daniel G. Mandal, Himadri S. Peixoto, Nathalia Rubinson, Judith F. Dumas, Theodore C. Pancrazio, Joseph J. TI Chronic intracortical neural recordings using microelectrode arrays coated with PEDOT-TFB SO ACTA BIOMATERIALIA LA English DT Article DE Neural recording; Brain computer interface; Microelectrode arrays; Conductive polymers; PEDOT; Bio-impedance modeling ID POLY(3,4-ETHYLENEDIOXYTHIOPHENE) PEDOT; CONDUCTING POLYMERS; ELECTROCHEMICAL CHARACTERIZATION; TISSUE-RESPONSE; OHMIC BEHAVIOR; IN-VIVO; INTERFACES; ELECTRODES; POLYMERIZATION; PROBES AB Microelectrode arrays have been extensively utilized to record extracellular neuronal activity for brain machine interface applications. Modifying the microelectrodes with conductive polymers such as poly(3,4-ethylenedioxythiophene) (PEDOT) has been reported to be advantageous because it increases the effective surface area of the microelectrodes, thereby decreasing impedance and enhancing charge transfer capacity. However, the long term stability and integrity of such coatings for chronic recordings remains unclear. Previously, our group has demonstrated that use of the smaller counter ion tetrafluoroborate (TFB) during electrodeposition increased the stability of the PEDOT coatings in vitro compared to the commonly used counter ion poly(styrenesulfonate) (PSS). In the current work, we examined the long-term in vivo performance of PEDOT TFB coated microelectrodes. To do so, we selectively modified half of the microelectrodes on NeuroNexus single shank probes with PEDOT TFB while the other half of the microelectrodes were modified with gold as a control. The modified probes were then implanted into the primary motor cortex of rats. Single unit recordings were observed on both PEDOT TFB and gold control microelectrodes for more than 12 weeks. Compared to the gold-coated microelectrodes, the PEDOT TFB coated microelectrodes exhibited an overall significantly lower impedance and higher number of units per microelectrode specifically for the first four weeks. The majority of PEDOT TFB microelectrodes with activity had an impedance magnitude lower than 400 kl at 1 kHz. Our equivalent circuit modeling of the impedance data suggests stability in the polymer-related parameters for the duration of the study. In addition, when comparing PEDOT TFB microelectrodes with and without long-term activity, we observed a distinction in certain circuit parameters for these microelectrodes derived from equivalent circuit modeling prior to implantation. This observation may prove useful in qualifying PEDOT TFB microelectrodes with a greater likelihood of registering long-term activity. Overall, our findings confirm that.PEDOT TFB is a chronically stable coating for microelectrodes to enable neural recording. Statement of significance Microelectrode arrays have been extensively utilized to record extracellular neuronal activity for brain - machine interface applications. Poly(3,4-ethylenedioxythiophene) (PEDOT) has gained interest because of its unique electrochemical characteristics and its excellent intrinsic electrical conductivity. However, the long-term stability of the PEDOT film, especially for chronic neural applications, is unclear. In this manuscript, we report for the first time the use of highly stable PEDOT doped with tetrafluoroborate (TFB) for long-term neural recordings. We show that PEDOT TFB coated microelectrodes on average register more units compared to control gold microelectrodes for at least first four weeks post implantation. We collected the in vivo impedance data over a wide frequency spectrum and developed an equivalent circuit model which helped us determine certain parameters to distinguish between PEDOT TFB microelectrodes with and without long-term activity. Our findings suggest that PEDOT-TFB is a chronically stable coating for neural recording microelectrodes. As such, PEDOT-TFB could facilitate chronic recordings with ultra-small and high-density neural arrays. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. C1 [Charkhkar, Hamid; Peixoto, Nathalia] George Mason Univ, Dept Elect & Comp Engn, Fairfax, VA 22030 USA. [Knaack, Gretchen L.] US FDA, Div Biomed Phys, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [McHail, Daniel G.; Dumas, Theodore C.] George Mason Univ, Krasnow Inst Adv Study, Dept Mol Neurosci, Fairfax, VA 22030 USA. [Mandal, Himadri S.] Blackrock Microsyst, Salt Lake City, UT USA. [Rubinson, Judith F.] Georgetown Univ, Dept Chem, Washington, DC 20057 USA. [Pancrazio, Joseph J.] George Mason Univ, Dept Bioengn, Fairfax, VA 22030 USA. [Charkhkar, Hamid] APT Ctr, 10701 East Blvd 151 W, Cleveland, OH 44106 USA. RP Charkhkar, H (reprint author), 4400 Univ Dr,MSN 1G5, Fairfax, VA 22030 USA. EM hamid.charkhkar@case.edu OI Charkhkar, Hamid/0000-0001-5485-5969; Pancrazio, Joseph/0000-0001-8276-3690 FU MRI program at NSF [CHE-0959546]; Defense Advanced Research Projects Agency (DARPA) MTO through the Space and Naval Warfare Systems Center, Pacific Grant [N66001-12-1-4026] FX The authors would like to acknowledge Ms. Jemika Kastee and Ms. Susheela Meyyeppan for their assistance in this study. The authors also wish to thank Ms. Haydee Dalafu (Georgetown University) for assistance with X-ray diffraction experiments. X-ray powder diffraction data was obtained using an instrument purchased with support from the MRI program at NSF (CHE-0959546). This work was sponsored by the Defense Advanced Research Projects Agency (DARPA) MTO under the auspices of Dr. Jack Judy through the Space and Naval Warfare Systems Center, Pacific Grant/Contract No. N66001-12-1-4026 - Biocompatibility of Advanced Materials for Brain Machine Interfaces. NR 56 TC 3 Z9 3 U1 8 U2 23 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1742-7061 EI 1878-7568 J9 ACTA BIOMATER JI Acta Biomater. PD MAR 1 PY 2016 VL 32 BP 57 EP 67 DI 10.1016/j.actbio.2015.12.022 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DF8ZF UT WOS:000371649100006 PM 26689462 ER PT J AU Ferlin, KM Prendergast, ME Miller, ML Kaplan, DS Fisher, JP AF Ferlin, Kimberly M. Prendergast, Margaret E. Miller, Makenzie L. Kaplan, David S. Fisher, John P. TI Influence of 3D printed porous architecture on mesenchymal stem cell enrichment and differentiation SO ACTA BIOMATERIALIA LA English DT Article DE 3D printing; Biomaterial; Mesenchymal stem cell; Differentiation; Scaffold architecture ID MARROW STROMAL CELLS; POLY(PROPYLENE FUMARATE); PORE-SIZE; SCAFFOLDS; BIOMATERIALS; REGENERATION; CULTURE; DESIGN; PERMEABILITY; LINEAGES AB The interactions between cells and an underlying biomaterial are important for the promotion of cell adhesion, proliferation, and function. Mesenchymal stem cells (MSCs) have great clinical potential as they are an adult stem cell population capable of multilineage differentiation. The relationship between MSC behavior and several material properties including substrate stiffness and pore size are well investigated, but there has been little research on the influence of porous architecture in a three-dimensional scaffold with a well-controlled architecture. Here, we investigate the impact of two different three-dimensionally printed, pore geometries on the enrichment and differentiation of MSCs. 3D printed scaffolds with ordered cubic pore geometry were supportive of MSC enrichment from unprocessed bone marrow, resulting in cell surface marker expression that was comparable to typical adhesion to tissue culture polystyrene, the gold standard for MSC culture. Results also show that scaffolds fabricated with ordered cubic pores significantly increase the gene expression of MSCs undergoing adipogenesis and chondrogenesis, when compared to scaffolds with ordered cylindrical pores. However, at the protein expression level, these differences were modest. For MSCs undergoing osteogenesis, gene expression results suggest that cylindrical pores may initially increase early osteogenic marker expression, while protein level expression at later timepoints is increased for scaffolds with ordered cubic pores. Taken together, these results suggest that 3D printed scaffolds with ordered cubic pores could be a suitable culture system for single-step MSC enrichment and differentiation. Statement of Significance Mesenchymal stem cells (MSCs) have great therapeutic potential, as they are capable of multilineage differentiation. MSC behavior, including lineage commitment, may be influenced by biomaterial properties including substrate stiffness and pore size. With three-dimensional (3D) printing, we can investigate these relationships in 3D culture systems. Here, we fabricated scaffolds with two different well controlled pore geometries, and investigated the impact on MSC enrichment and differentiation. Results show that scaffolds with ordered cubic pore geometry were supportive of both MSC enrichment from unprocessed bone marrow as well as MSC differentiation, resulting in increased gene expression during adipogenesis and chondrogenesis. These results suggest that 3D printed scaffolds with ordered cubic pores could be a suitable culture system for single-step MSC enrichment and differentiation. (C) 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. C1 [Ferlin, Kimberly M.; Prendergast, Margaret E.; Miller, Makenzie L.; Fisher, John P.] Univ Maryland, Fischell Dept Bioengn, 3238 Jeong H Kim Engn Bldg, College Pk, MD 20742 USA. [Kaplan, David S.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Fisher, JP (reprint author), Univ Maryland, Fischell Dept Bioengn, 3238 Jeong H Kim Engn Bldg, College Pk, MD 20742 USA. EM jpfisher@umd.edu FU National Science Foundation/Food and Drug Administration Scholar-in-Residence Program [CBET 1238398] FX Research reported in this publication was supported by the National Science Foundation/Food and Drug Administration Scholar-in-Residence Program (CBET 1238398). The authors wish to thank Dr. Srinidhi Nagaraja for his technical assistance obtaining and analyzing the results of mu CT and Dr. Girish Kumar for his technical assistance with the flow cytometry experiments. NR 38 TC 4 Z9 4 U1 11 U2 47 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1742-7061 EI 1878-7568 J9 ACTA BIOMATER JI Acta Biomater. PD MAR 1 PY 2016 VL 32 BP 161 EP 169 DI 10.1016/j.actbio.2016.01.007 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DF8ZF UT WOS:000371649100016 PM 26773464 ER PT J AU Petersen, T Townsend, K Gordon, LA Sidharthan, S Silk, R Nelson, A Gross, C Calderon, M Proschan, M Osinusi, A Polis, MA Masur, H Kottilil, S Kohli, A AF Petersen, Tess Townsend, Kerry Gordon, Lori A. Sidharthan, Sreetha Silk, Rachel Nelson, Amy Gross, Chloe Calderon, Monica Proschan, Michael Osinusi, Anu Polis, Michael A. Masur, Henry Kottilil, Shyam Kohli, Anita TI High adherence to all-oral directly acting antiviral HCV therapy among an inner-city patient population in a phase 2a study SO HEPATOLOGY INTERNATIONAL LA English DT Article DE HCV; DAA; Adherence; MEMS ID HEPATITIS-C VIRUS; GENOTYPE 1; TREATMENT-NAIVE; LEDIPASVIR; SOFOSBUVIR; RIBAVIRIN; COMBINATION; MEDICATION; INFECTION; CIRRHOSIS AB As treatment for chronic hepatitis C (HCV) virus has evolved to all-oral, interferon-free directly acting antiviral (DAA) therapy, the impact of these improvements on patient adherence has not been described. Medication adherence was measured in 60 HCV, genotype-1, treatment-na < ve participants enrolled in a phase 2a clinical trial at the National Institutes of Health and community clinics. Participants received either ledipasvir/sofosbuvir (LDV/SOF) (90 mg/400 mg) (one pill) daily for 12 weeks, LDV/SOF + GS-9451 (80 mg/day) (two pills) daily for 6 weeks, or LDV/SOF + GS-9669 (500 mg twice daily; three pills, two in the morning, one in the evening) for 6 weeks. Adherence was measured using medication event monitoring system (MEMS) caps, pill counts and patient report. Overall adherence to DAAs was high. Adherence declined over the course of the 12-week treatment (p = 0.04). While controlled psychiatric disease or symptoms of depression did not influence adherence, recent drug use was a risk factor for non-adherence to 12-week (p = 0.01), but not 6-week regimens. Adherence as measured by MEMS was lower than by patient report. Adherence to short courses of DAA therapy with 1-3 pills a day was excellent in an urban population with multiple risk factors for non-adherence. C1 [Petersen, Tess; Sidharthan, Sreetha; Silk, Rachel; Masur, Henry; Kohli, Anita] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Townsend, Kerry; Osinusi, Anu; Polis, Michael A.; Kottilil, Shyam] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Gordon, Lori A.] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. [Gordon, Lori A.] Xavier Univ Louisiana, New Orleans, LA USA. [Silk, Rachel; Nelson, Amy; Gross, Chloe; Osinusi, Anu; Kottilil, Shyam] Univ Maryland, Inst Human Virol, Div Infect Dis, Baltimore, MD 21201 USA. [Gross, Chloe; Calderon, Monica; Kohli, Anita] SAIC Frederick Inc, Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program,Frederick Natl Lab Ca, Frederick, MD USA. [Calderon, Monica] US FDA, Silver Spring, MD USA. [Proschan, Michael] NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Osinusi, Anu] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA. [Kohli, Anita] Creighton Univ, St Josephs Hosp, Div Hepatol, Phoenix, AZ USA. [Kohli, Anita] Creighton Univ, Med Ctr, Sch Med, Phoenix, AZ USA. [Kottilil, Shyam] Univ Maryland, Sch Med, Inst Human Virol, Div Clin Care & Res, N222,725 West Lombard St,Room S222, Baltimore, MD 21201 USA. RP Kottilil, S (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA.; Kottilil, S (reprint author), Univ Maryland, Inst Human Virol, Div Infect Dis, Baltimore, MD 21201 USA.; Kottilil, S (reprint author), Univ Maryland, Sch Med, Inst Human Virol, Div Clin Care & Res, N222,725 West Lombard St,Room S222, Baltimore, MD 21201 USA. EM SKottilil@ihv.umaryland.edu FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases; NIH; Gilead Sciences FX The 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. ClinicalTrials.gov no. NCT01805882. The research was supported in part by the National Institute of Allergy and Infectious Diseases. Study medications were provided by Gilead Sciences, Inc., and the study was partially funded by a Collaborate Research and Development Agreement between NIH and Gilead Sciences. The study involves human subjects, and all subjects signed informed consent approved by the NIAID IRB. We would like to acknowledge the contributions of Colleen Kotb, NP, Colleen Hadigan, MD, and Senora Mitchell for their clinic support. NR 31 TC 5 Z9 5 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1936-0533 EI 1936-0541 J9 HEPATOL INT JI Hepatol. Int. PD MAR PY 2016 VL 10 IS 2 BP 310 EP 319 DI 10.1007/s12072-015-9680-7 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DG0YM UT WOS:000371792100010 PM 26612014 ER PT J AU Bergholz, PW Strawn, LK Ryan, GT Warchocki, S Wiedmann, M AF Bergholz, Peter W. Strawn, Laura K. Ryan, Gina T. Warchocki, Steven Wiedmann, Martin TI Spatiotemporal Analysis of Microbiological Contamination in New York State Produce Fields following Extensive Flooding from Hurricane Irene, August 2011 SO JOURNAL OF FOOD PROTECTION LA English DT Article DE Escherichia coli; Farm; Flood; Salmonella; Soil; Water ID ESCHERICHIA-COLI O157-H7; FRESH-WATER BEACHES; POPULATION-STRUCTURE; SALMONELLA-ENTERICA; PATHOGENIC BACTERIA; BORNE PATHOGENS; SURFACE WATERS; NEW-ORLEANS; PERSISTENCE; SUBTYPES AB Although flooding introduces microbiological, chemical, and physical hazards onto croplands, few data are available on the spatial extent, patterns, and development of contamination over time postflooding. To address this paucity of information, we conducted a spatially explicit study of Escherichia coli and Salmonella contamination prevalence and genetic diversity in produce fields after the catastrophic flooding that occurred in New England during 2011. Although no significant differences were detected between the two participating farms, both random forest and logistic regression revealed changes in the spatial pattern of E. coli contamination in drag swab samples over time. Analyses also indicated that E. coli detection was associated with changes in farm management to remediate the land after flooding. In particular, E. coli was widespread in drag swab samples at 21 days postflooding, but the spatial pattern changed by 238 days postflooding such that E. coli was then most prevalent in close proximity to surface water features. The combined results of several population genetics analyses indicated that over time postflooding E. coli populations on the farms (i) changed in composition and (ii) declined overall. Salmonella was primarily detected in surface water features, but some Salmonella strains were isolated from soil and drag swab samples at 21 and 44 days postflooding. Although postflood contamination and land management responses should always be evaluated in the context of each unique farm landscape, our results provide quantitative data on the general patterns of contamination after flooding and support the practice of establishing buffer zones between flood-contaminated cropland and harvestable crops in produce fields. C1 [Bergholz, Peter W.] N Dakota State Univ, Dept Vet & Microbiol Sci, Fargo, ND 58108 USA. [Bergholz, Peter W.; Strawn, Laura K.; Ryan, Gina T.; Warchocki, Steven; Wiedmann, Martin] Cornell Univ, Dept Food Sci, Ithaca, NY 14803 USA. [Strawn, Laura K.] Virginia Polytech Inst & State Univ, Dept Food Sci & Technol, Eastern Shore Agr Res & Extens Ctr, Painter, VA 23420 USA. [Ryan, Gina T.] US FDA, College Pk, MD 20740 USA. RP Bergholz, PW (reprint author), N Dakota State Univ, Dept Vet & Microbiol Sci, Fargo, ND 58108 USA.; Bergholz, PW (reprint author), Cornell Univ, Dept Food Sci, Ithaca, NY 14803 USA. EM peter.bergholz@ndsu.edu RI Wiedmann, Martin/A-9683-2008; OI Wiedmann, Martin/0000-0002-4168-5662; Strawn, Laura/0000-0002-9523-0081 FU Hatch Act Federal Formula Funds [NYC-143462]; National Institute of Food and Agriculture, Agriculture and Food Research Initiative competitive predoctoral grant [NYC-143531] FX This work was made possible by Cornell Cooperative Extension agents Charles Bornt, Laura McDermott, and Crystal Stewart, who arranged study sites and aided field sampling excursions. Two privately owned and operated produce farms generously participated in this study. We thank Sana Mujahid, Rachel Pfuntner, Kitiya Vongkamjan, and Courtenay Simmons for their assistance on field excursions. This work was supported by Hatch Act Federal Formula Funds directed to M. Wiedmann (project NYC-143462) and a National Institute of Food and Agriculture, Agriculture and Food Research Initiative competitive predoctoral grant to L. K. Strawn (project NYC-143531). NR 45 TC 0 Z9 0 U1 3 U2 8 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD MAR PY 2016 VL 79 IS 3 BP 384 EP 391 DI 10.4315/0362-028X.JFP-15-334 PG 8 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA DF7SF UT WOS:000371557200005 PM 26939648 ER PT J AU Miller, S Bergman, R Duffy, M Gross, D Jackson, A James, R Kotrebai, M Lamontagne, A Lyon, T Yandek, E Sliney, D AF Miller, Sharon Bergman, Rolf Duffy, Mark Gross, David Jackson, Andrew James, Robert Kotrebai, Mihaly Lamontagne, Andre Lyon, Terry Yandek, Edward Sliney, David TI Interlaboratory Evaluation of Ultraviolet Radiation Emissions from Compact Fluorescent Lamps SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID ENERGY-SAVING LAMPS; OPTICAL RADIATION; INDIVIDUALS; EXPOSURE; IMPACT AB There have been many recent reports regarding the potential risks of UV emissions from compact fluorescent lamps (CFLs). In some of these reports, the robustness of the measurements was difficult to discern. We conducted round-robin measurements, involving three lamp manufacturers and two government research laboratories to gather reliable data on the UV emissions from commercially available CFLs. The initial sample of lamps consisted of 71 spiral-shaped CFLs purchased from local retailers. From the initial sample, 14 high UV emitting CFLs were chosen for further evaluation. We compared the UV emissions at a distance of 20cm with the UV exposure limits (ELs) published by the International Commission on Non-ionizing Radiation Protection (ICNIRP). We found that the allowable exposure time for measured lamps ranged from 21 to 415h. This indicates that the emissions would not exceed the short-term ELs that have been established by the ICNIRP for healthy individuals. We also evaluated the potential long-term risk and found it to be insignificant. There was a large variation in the UV emissions found, even for lamps from a single package, indicating that it is impossible to predict the UV output of a CFL based on its physical appearance and model designation. C1 [Miller, Sharon; James, Robert] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Duffy, Mark; Kotrebai, Mihaly] Gen Elect Lighting, Cleveland, OH USA. [Gross, David] Osram Sylvania, Beverly, MA USA. [Jackson, Andrew] Philips Lighting, Salina, KS USA. [Lamontagne, Andre] US FDA, Winchester Engn & Analyt Ctr, Winchester, MA USA. [Sliney, David] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Div Environm Hlth Engn, Baltimore, MD USA. RP Miller, S (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. EM sharona.miller@fda.hhs.gov NR 16 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0031-8655 EI 1751-1097 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD MAR-APR PY 2016 VL 92 IS 2 BP 348 EP 354 DI 10.1111/php.12573 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DF6YR UT WOS:000371504900017 ER PT J AU Fisher, W Wang, J George, NI Gearhart, JM McLanahan, ED AF Fisher, W. Wang, Jian George, Nysia I. Gearhart, Jeffery M. McLanahan, Eva D. TI Dietary Iodine Sufficiency and Moderate Insufficiency in the Lactating Mother and Nursing Infant: A Computational Perspective SO PLOS ONE LA English DT Article ID THYROID-HORMONE LEVELS; DOSE-RESPONSE MODEL; BREAST-MILK IODINE; TRANSIENT HYPOTHYROXINEMIA; MATERNAL HYPOTHYROXINEMIA; PRETERM INFANTS; STIMULATING HORMONE; PREGNANT-WOMEN; CHILDREN BORN; PBPK MODELS AB The Institute of Medicine recommends that lactating women ingest 290 mu g iodide/d and a nursing infant, less than two years of age, 110 mu g/d. The World Health Organization, United Nations Children's Fund, and International Council for the Control of Iodine Deficiency Disorders recommend population maternal and infant urinary iodide concentrations >= 100 mu g/L to ensure iodide sufficiency. For breast milk, researchers have proposed an iodide concentration range of 150-180 mu g/L indicates iodide sufficiency for the mother and infant, however no national or international guidelines exist for breast milk iodine concentration. For the first time, a lactating woman and nursing infant biologically based model, from delivery to 90 days postpartum, was constructed to predict maternal and infant urinary iodide concentration, breast milk iodide concentration, the amount of iodide transferred in breast milk to the nursing infant each day and maternal and infant serum thyroid hormone kinetics. The maternal and infant models each consisted of three sub-models, iodide, thyroxine (T4), and triiodothyronine (T3). Using our model to simulate a maternal intake of 290 mu g iodide/d, the average daily amount of iodide ingested by the nursing infant, after 4 days of life, gradually increased from 50 to 101 mu g/day over 90 days postpartum. The predicted average lactating mother and infant urinary iodide concentrations were both in excess of 100 mu g/L and the predicted average breast milk iodide concentration, 157 mu g/L. The predicted serum thyroid hormones (T4, free T4 (fT4), and T3) in both the nursing infant and lactating mother were indicative of euthyroidism. The model was calibrated using serum thyroid hormone concentrations for lactating women from the United States and was successful in predicting serum T4 and fT4 levels (within a factor of two) for lactating women in other countries. T3 levels were adequately predicted. Infant serum thyroid hormone levels were adequately predicted for most data. For moderate iodide deficient conditions, where dietary iodide intake may range from 50 to 150 mu g/d for the lactating mother, the model satisfactorily described the iodide measurements, although with some variation, in urine and breast milk. Predictions of serum thyroid hormones in moderately iodide deficient lactating women (50 mu g/d) and nursing infants did not closely agree with mean reported serum thyroid hormone levels, however, predictions were usually within a factor of two. Excellent agreement between prediction and observation was obtained for a recent moderate iodide deficiency study in lactating women. Measurements included iodide levels in urine of infant and mother, iodide in breast milk, and serum thyroid hormone levels in infant and mother. A maternal iodide intake of 50 mu g/d resulted in a predicted 29-32% reduction in serum T4 and fT4 in nursing infants, however the reduced serum levels of T4 and fT4 were within most of the published reference intervals for infant. This biologically based model is an important first step at integrating the rapid changes that occur in the thyroid system of the nursing newborn in order to predict adverse outcomes from exposure to thyroid acting chemicals, drugs, radioactive materials or iodine deficiency. C1 [Fisher, W.; George, Nysia I.] US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. [Wang, Jian] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Gearhart, Jeffery M.] Henry M Jackson Fdn Adv Mil Med, 2729 R St,Bldg 837, Wright Patterson AFB, OH 43433 USA. [Gearhart, Jeffery M.] Wright State Univ, Boonshoft Sch Med, Dayton, OH 45435 USA. [McLanahan, Eva D.] CDC ATSDR, Div Community Hlth Invest, 4770 Buford HWY NE, Atlanta, GA 30341 USA. RP Fisher, W (reprint author), US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Jeffrey.Fisher@fda.hhs.gov FU NCTR FX Funding was provided by NCTR. NR 82 TC 2 Z9 2 U1 5 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 1 PY 2016 VL 11 IS 3 AR e0149300 DI 10.1371/journal.pone.0149300 PG 25 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF5ZW UT WOS:000371434500024 PM 26930410 ER PT J AU Fang, JL Wu, YF da Costa, GG Chen, S Chitranshi, P Beland, FA AF Fang, Jia-Long Wu, Yuanfeng da Costa, Goncalo Gamboa Chen, Si Chitranshi, Priyanka Beland, Frederick A. TI Human Sulfotransferases Enhance the Cytotoxicity of Tolvaptan SO TOXICOLOGICAL SCIENCES LA English DT Article DE tolvaptan; sulfation; cytotoxicity; drug efflux transporters; metabolism ID POLYCYSTIC KIDNEY-DISEASE; NONPEPTIDE AVP ANTAGONIST; HEALTHY-SUBJECTS; PHARMACODYNAMICS; PHARMACOKINETICS; BIOACTIVATION; METABOLISM AB Tolvaptan, a vasopressin receptor 2 antagonist used to treat hyponatremia, has recently been reported to be associated with liver injury. Sulfotransferases (SULTs) have been implicated as important detoxifying and/or activating enzymes for numerous xenobiotics, drugs, and endogenous compounds. To characterize better the role of SULTs in tolvaptan metabolism, HEK293 cells stably overexpressing 12 human SULTs were generated. Using these cell lines, the extent of tolvaptan sulfate formation was assessed by reversed-phase high-performance liquid chromatography through comparison to a synthetic standard. Of the 12 known human SULTs, no detectable sulfation of tolvaptan was observed with SULT1A1, SULT1A2, SULT1A3, SULT1C2, SULT1C4, SULT4A1, or SULT6B1. The affinity of individual SULT isozymes, as determined by K-m analysis, was SULT1C3 >> SULT2A1 > SULT2B1 similar to SULT1B1 > SULT1E1. The half inhibitory concentration of tolvaptan on cell growth in HEK293/SULT1C3 cells and HEK293/CYP3A4 & SULT1C3 cells was significantly lower than that in the corresponding HEK293/vector cells or HEK293/CYP3A4 & SULT vector cells. Moreover, exposing cells to tolvaptan in the presence of cyclosporine A, an inhibitor of the drug efflux transporters, significantly increased the intracellular levels of tolvaptan sulfate and decreased the cell viability in HEK293/SULT1C3 cells. These data indicate that sulfation increased the cytotoxicity of tolvaptan. C1 [Fang, Jia-Long; Wu, Yuanfeng; da Costa, Goncalo Gamboa; Chen, Si; Chitranshi, Priyanka; Beland, Frederick A.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Food & Drug Adm, Jefferson, AR 72079 USA. RP Fang, JL (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Food & Drug Adm, Jefferson, AR 72079 USA. EM jia-long.fang@fda.hhs.gov FU U.S. Department of Energy; U.S. FDA FX Yuanfeng Wu, Si Chen, and Priyanka Chitranshi were supported by an appointment to the Postgraduate Research in the Division of Biochemical Toxicology at the National Center for Toxicological Research administered by Oak Ridge Institute for Science Education through an interagency agreement between the U.S. Department of Energy and the U.S. FDA. The authors declare that there are no conflicts of interest. NR 22 TC 1 Z9 1 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD MAR PY 2016 VL 150 IS 1 BP 27 EP 39 DI 10.1093/toxsci/kfv311 PG 13 WC Toxicology SC Toxicology GA DF8NS UT WOS:000371615300004 PM 26660633 ER PT J AU Lee, M Huang, RL Tong, WD AF Lee, Mikyung Huang, Ruili Tong, Weida TI Discovery of Transcriptional Targets Regulated by Nuclear Receptors Using a Probabilistic Graphical Model SO TOXICOLOGICAL SCIENCES LA English DT Article DE nuclear receptor; transcriptional regulation; Tox21; toxicogenomics project; author-topic model; integrative analysis ID BREAST-CANCER; RETINOIC ACID; PPAR-GAMMA; X RECEPTOR; EXPRESSION; APOPTOSIS; CELLS; PROMOTER; COMPLEX; BINDING AB Nuclear receptors (NRs) are ligand-activated transcriptional regulators that play vital roles in key biological processes such as growth, differentiation, metabolism, reproduction, and morphogenesis. Disruption of NRs can result in adverse health effects such as NR-mediated endocrine disruption. A comprehensive understanding of core transcriptional targets regulated by NRs helps to elucidate their key biological processes in both toxicological and therapeutic aspects. In this study, we applied a probabilistic graphical model to identify the transcriptional targets of NRs and the biological processes they govern. The Tox21 program profiled a collection of approximate 10 000 environmental chemicals and drugs against a panel of human NRs in a quantitative high-throughput screening format for their NR disruption potential. The Japanese Toxicogenomics Project, one of the most comprehensive efforts in the field of toxicogenomics, generated large-scale gene expression profiles on the effect of 131 compounds (in its first phase of study) at various doses, and different durations, and their combinations. We applied author-topic model to these 2 toxicological datasets, which consists of 11 NRs run in either agonist and/or antagonist mode (18 assays total) and 203 in vitro human gene expression profiles connected by 52 shared drugs. As a result, a set of clusters (topics), which consists of a set of NRs and their associated target genes were determined. Various transcriptional targets of the NRs were identified by assays run in either agonist or antagonist mode. Our results were validated by functional analysis and compared with TRANSFAC data. In summary, our approach resulted in effective identification of associated/affected NRs and their target genes, providing biologically meaningful hypothesis embedded in their relationships. C1 [Lee, Mikyung; Huang, Ruili] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Tong, Weida] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Tong, WD (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Weida.tong@fda.hhs.gov FU U.S. Food and Drug Administration; National Center for Advancing Translational Sciences, National Institutes of Health FX This work was supported by the U.S. Food and Drug Administration and the National Center for Advancing Translational Sciences, National Institutes of Health. We would also like to thank Dr. Rajarshi Guha for helpful discussion. The views expressed in this article are those of the authors and do not necessarily reflect the statements, opinions, views, conclusions, or policies of the National Center for Advancing Translational Sciences, National Institutes of Health, U.S. Food and Drug Administration, or the United States government. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. NR 26 TC 0 Z9 0 U1 0 U2 5 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 2016 VL 150 IS 1 BP 64 EP 73 DI 10.1093/toxsci/kfv261 PG 10 WC Toxicology SC Toxicology GA DF8NS UT WOS:000371615300007 PM 26643261 ER PT J AU Boudreau, MD Imam, MS Paredes, AM Bryant, MS Cunningham, CK Felton, RP Jones, MY Davis, KJ Olson, GR AF Boudreau, Mary D. Imam, Mohammed S. Paredes, Angel M. Bryant, Matthew S. Cunningham, Candice K. Felton, Robert P. Jones, Margie Y. Davis, Kelly J. Olson, Greg R. TI Differential Effects of Silver Nanoparticles and Silver Ions on Tissue Accumulation, Distribution, and Toxicity in the Sprague Dawley Rat Following Daily Oral Gavage Administration for 13 Weeks SO TOXICOLOGICAL SCIENCES LA English DT Article DE silver; nanoparticle; silver acetate; exposure assessment; accumulation; distribution; in vivo; oral administration; rodent; transmission electron microscopy ID BASEMENT-MEMBRANE; NANO-SILVER; EXPOSURE; CARCINOGENICITY; MICROSCOPY; KINETICS; MUCOSA; TESTS; MICE; SIZE AB There are concerns within the regulatory and research communities regarding the health impact associated with consumer exposure to silver nanoparticles (AgNPs). This study evaluated particulate and ionic forms of silver and particle size for differences in silver accumulation, distribution, morphology, and toxicity when administered daily by oral gavage to Sprague Dawley rats for 13 weeks. Test materials and dose formulations were characterized by transmission electron microscopy (TEM), dynamic light scattering, and inductively coupled mass spectrometry (ICP-MS). Seven-week-old rats (10 rats per sex per group) were randomly assigned to treatments: AgNP (10, 75, and 110 nm) at 9, 18, and 36 mg/kg body weight (bw); silver acetate (AgOAc) at 100, 200, and 400 mg/kg bw; and controls (2 mM sodium citrate (CIT) or water). At termination, complete necropsies were conducted, histopathology, hematology, serum chemistry, micronuclei, and reproductive system analyses were performed, and silver accumulations and distributions were determined. Rats exposed to AgNP did not show significant changes in body weights or intakes of feed and water relative to controls, and blood, reproductive system, and genetic tests were similar to controls. Differences in the distributional pattern and morphology of silver deposits were observed by TEM: AgNP appeared predominantly within cells, while AgOAc had an affinity for extracellular membranes. Significant dose-dependent and AgNP size-dependent accumulations were detected in tissues by ICP-MS. In addition, sex differences in silver accumulations were noted for a number of tissues and organs, with accumulations being significantly higher in female rats, especially in the kidney, liver, jejunum, and colon. C1 [Boudreau, Mary D.; Imam, Mohammed S.; Bryant, Matthew S.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd,HFT-110, Jefferson, AR 72079 USA. [Paredes, Angel M.; Cunningham, Candice K.; Jones, Margie Y.] US FDA, Natl Ctr Toxicol Res, NCTR ORA Nanotechnol Core Facil, Jefferson, AR USA. [Felton, Robert P.] US FDA, Natl Ctr Toxicol Res, Bioinformat & Biostat Div, Jefferson, AR USA. [Davis, Kelly J.; Olson, Greg R.] Jefferson Labs, Toxicol Pathol Associates, Jefferson, AR USA. RP Boudreau, MD (reprint author), US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd,HFT-110, Jefferson, AR 72079 USA. EM mary.boudreau@fda.hhs.gov RI Ke, daming/Q-1036-2015 OI Ke, daming/0000-0002-0065-2135 FU US Food and Drug Administration/National Center for Toxicological Research, US Department of Health and Human Services; National Institute of Environmental Health Sciences/National Toxicology Program, National Institutes of Health [FDA IAG] [224-12-003]; National Institute of Environmental Health Sciences/National Toxicology Program, National Institutes of Health [NIEHS IAG] [AES12013] FX This work was supported by an Interagency Agreement (IAG) between the US Food and Drug Administration/National Center for Toxicological Research, US Department of Health and Human Services and the National Institute of Environmental Health Sciences/National Toxicology Program, National Institutes of Health [FDA IAG no. 224-12-003/NIEHS IAG no. AES12013]. NR 51 TC 4 Z9 5 U1 9 U2 39 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD MAR PY 2016 VL 150 IS 1 BP 131 EP 160 DI 10.1093/toxsci/kfv318 PG 30 WC Toxicology SC Toxicology GA DF8NS UT WOS:000371615300013 PM 26732888 ER PT J AU Hutsell, BA Cheng, KJ Rice, KC Negus, SS Banks, ML AF Hutsell, Blake A. Cheng, Kejun Rice, Kenner C. Negus, Sidney Stevens Banks, Matthew L. TI Effects of the kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI) on cocaine versus food choice and extended-access cocaine intake in rhesus monkeys SO ADDICTION BIOLOGY LA English DT Article DE Addiction; choice; cocaine; kappa opioid receptor; nor-binaltorphimine; rhesus monkey ID BASAL EXTRACELLULAR DOPAMINE; NUCLEUS-ACCUMBENS; ENVIRONMENTAL MANIPULATIONS; ALTERNATIVE REINFORCER; MESSENGER-RNA; AGONIST; RATS; NEUROCHEMISTRY; HUMANS; PHENDIMETRAZINE AB The dynorphin/kappa opioid receptor (KOR) system has been implicated as one potential neurobiological modulator of the abuse-related effects of cocaine and as a potential target for medications development. This study determined effects of the KOR antagonist nor-binaltorphimine (nor-BNI) on cocaine self-administration under a novel procedure that featured two daily components: (1) a 2-hour choice' component (9:00-11:00 am) when monkeys could choose between food pellets and cocaine injections (0-0.1mg/kg per injection, intravenous) and (2) a 20-hour extended-access' component (noon to 8:00 am) when cocaine (0.1mg/kg per injection) was available under a fixed-ratio schedule to promote high daily cocaine intakes. Rhesus monkeys (n=4) were given 14 days of exposure to the choice+extended-access procedure then treated with nor-BNI (3.2 or 10.0mg/kg, intramuscular), and cocaine choice and extended-access cocaine intake were evaluated for an additional 14 days. Consistent with previous studies, cocaine maintained both a dose-dependent increase in cocaine choice during choice components and a high level of cocaine intake during extended-access components. Neither 3.2 nor 10mg/kg nor-BNI significantly altered cocaine choice or extended-access cocaine intake. In two additional monkeys, nor-BNI also had no effect on cocaine choice or extended-access cocaine intake when it was administered at the beginning of exposure to the extended-access components. Overall, these results do not support a major role for the dynorphin/KOR system in modulating cocaine self-administration under these conditions in non-human primates nor do they support the clinical utility of KOR antagonists as a pharmacotherapeutic strategy for cocaine addiction. C1 [Hutsell, Blake A.; Negus, Sidney Stevens; Banks, Matthew L.] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, 410 North 12th St,POB 980613, Richmond, VA 23298 USA. [Negus, Sidney Stevens; Banks, Matthew L.] Virginia Commonwealth Univ, Inst Drug & Alcohol Abuse Studies, Med Coll Virginia Campus, Richmond, VA 23298 USA. [Cheng, Kejun; Rice, Kenner C.] NIAAA, Chem Biol Branch, NIH, Bethesda, MD USA. [Cheng, Kejun] US FDA, Off Pharmaceut Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Banks, ML (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, 410 North 12th St,POB 980613, Richmond, VA 23298 USA. EM mbanks7@vcu.edu RI Banks, Matthew/K-4429-2014 OI Banks, Matthew/0000-0003-4949-5246 FU National Institute on Drug Abuse of the National Institutes of Health [R01 DA026946, T32 DA007027] FX Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under award numbers R01 DA026946 and T32 DA007027. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health and the Food and Drug Administration. We thank Jennifer Gough and Crystal Reyns for technical assistance and Kevin Costa for writing the original computer program version. NR 60 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 EI 1369-1600 J9 ADDICT BIOL JI Addict. Biol. PD MAR PY 2016 VL 21 IS 2 BP 360 EP 373 DI 10.1111/adb.12206 PG 14 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA DF2CW UT WOS:000371148700013 PM 25581305 ER PT J AU Nandy, P Lucas, AD Gonzalez, EA Hitchins, VM AF Nandy, Poulomi Lucas, Anne D. Gonzalez, Elizabeth A. Hitchins, Victoria M. TI Efficacy of commercially available wipes for disinfection of pulse oximeter sensors SO AMERICAN JOURNAL OF INFECTION CONTROL LA English DT Article DE Hospital-acquired infection (HAI); Disinfection; Pulse oximeter sensor; Test soil; Noncritical device ID HOSPITAL-ACQUIRED INFECTION; MEDICAL DEVICES; MICROORGANISMS; SURFACE; CARE AB Background: This study examined the effectiveness of commercially available disinfecting wipes and cosmetic wipes in disinfecting pulse oximeter sensors contaminated with pathogenic bacterial surrogates. Methods: Surrogates of potential biological warfare agents and bacterial pathogens associated with hospital-acquired infections (HAIs) were spotted on test surfaces, with and without an artificial test soil (sebum), allowed to dry, and then cleaned with different commercially available cleaning and disinfecting wipes or sterile gauze soaked in water, bleach (diluted 1:10), or 70% isopropanol. The percentage of microbial survival and an analytical estimation of remaining test soil on devices were determined. Results: Wipes containing sodium hypochlorite as the active ingredient and gauze soaked in bleach (1:10) were the most effective in removing both vegetative bacteria and spores. In the presence of selective disinfectants, sebum had a protective effect on vegetative bacteria, but not on spores. Conclusions: The presence of sebum reduces the cleaning efficiency of some commercially available wipes for some select microbes. Various commercial wipes performed significantly better than the designated cleaning agent (70% isopropanol) in disinfecting the oximetry sensor. Cosmetic wipes were not more effective than the disinfecting wipes in removing sebum. Copyright (C) 2016 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved. C1 [Nandy, Poulomi; Lucas, Anne D.; Gonzalez, Elizabeth A.; Hitchins, Victoria M.] US FDA, Lab Microbiol & Infect Control, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Nandy, P (reprint author), US FDA, Lab Microbiol & Infect Control, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM poulomi.nandy@fda.hhs.gov FU US Food and Drug Administration's Medical Countermeasures Initiative; US Department of Energy; US Food and Drug Administration 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. This project was also funded by the US Food and Drug Administration's Medical Countermeasures Initiative. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. NR 24 TC 0 Z9 0 U1 0 U2 3 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 MAR 1 PY 2016 VL 44 IS 3 BP 304 EP 310 DI 10.1016/j.ajic.2015.09.028 PG 7 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DF4CS UT WOS:000371295500015 PM 26589998 ER PT J AU Matanock, A Katz, LS Jackson, KA Kucerova, Z Conrad, AR Glover, WA Nguyen, V Mohr, MC Marsden-Haug, N Thompson, D Dunn, JR Stroika, S Melius, B Tarr, C Dietrich, SE Kao, AS Kornstein, L Li, Z Maroufi, A Marder, EP Meyer, R Perez-Osorio, AC Reddy, V Reporter, R Carleton, H Tweeten, S Waechter, H Yee, LM Wise, ME Davis, K Jackson, BR AF Matanock, Almea Katz, Lee S. Jackson, Kelly A. Kucerova, Zuzana Conrad, Amanda R. Glover, William A. Von Nguyen Mohr, Marika C. Marsden-Haug, Nicola Thompson, Deborah Dunn, John R. Stroika, Steven Melius, Beth Tarr, Cheryl Dietrich, Stephen E. Kao, Annie S. Kornstein, Laura Li, Zhen Maroufi, Azarnoush Marder, Ellyn P. Meyer, Rebecca Perez-Osorio, Ailyn C. Reddy, Vasudha Reporter, Roshan Carleton, Heather Tweeten, Samantha Waechter, HaeNa Yee, Lisa M. Wise, Matthew E. Davis, Kim Jackson, Brendan R. TI Two Listeria monocytogenes Pseudo-outbreaks Caused by Contaminated Laboratory Culture Media SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article AB Listeriosis is a serious foodborne infection that disproportionately affects elderly adults, pregnant women, newborns, and immunocompromised individuals. Diagnosis is made by culturing Listeria monocytogenes from sterile body fluids or from products of conception. This report describes the investigations of two listeriosis pseudo-outbreaks caused by contaminated laboratory media made from sheep blood. C1 [Matanock, Almea; Katz, Lee S.; Jackson, Kelly A.; Kucerova, Zuzana; Conrad, Amanda R.; Von Nguyen; Stroika, Steven; Tarr, Cheryl; Carleton, Heather; Jackson, Brendan R.] US Ctr Dis Control & Prevent, Atlanta, GA USA. [Matanock, Almea] Epidem Intelligence Serv, Atlanta, GA USA. [Conrad, Amanda R.] Atlanta Res & Educ Fdn, Decatur, GA USA. [Glover, William A.; Marsden-Haug, Nicola; Melius, Beth; Li, Zhen; Perez-Osorio, Ailyn C.] Washington State Dept Hlth, Shoreline, WA USA. [Mohr, Marika C.] Ohio Dept Hlth, Columbus, OH 43266 USA. [Thompson, Deborah] New Mexico Dept Hlth, Santa Fe, NM USA. [Dunn, John R.; Marder, Ellyn P.] Tennessee Dept Hlth, Nashville, TN USA. [Dietrich, Stephen E.] Michigan Dept Hlth & Human Serv, Lansing, MI USA. [Kao, Annie S.] Cty San Diego Hlth & Human Serv Agcy, San Diego, CA USA. [Kornstein, Laura; Reddy, Vasudha; Waechter, HaeNa] New York City Dept Hlth & Mental Hyg, New York, NY USA. [Meyer, Rebecca] Georgia Dept Publ Hlth, Atlanta, GA USA. [Maroufi, Azarnoush; Reporter, Roshan; Tweeten, Samantha; Yee, Lisa M.] Los Angeles Cty Dept Publ Hlth, Los Angeles, CA USA. [Davis, Kim] US FDA, Silver Spring, MD USA. RP Matanock, A (reprint author), US Ctr Dis Control & Prevent, Atlanta, GA USA. EM xdf2@cdc.gov NR 5 TC 0 Z9 0 U1 1 U2 3 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 MAR PY 2016 VL 54 IS 3 BP 768 EP 770 DI 10.1128/JCM.02035-15 PG 3 WC Microbiology SC Microbiology GA DF2EC UT WOS:000371152200040 PM 26699704 ER PT J AU Odia, Y Iwamoto, FM Moustakas, A Fraum, TJ Salgado, CA Li, AG Kreisl, TN Sul, J Butman, JA Fine, HA AF Odia, Yazmin Iwamoto, Fabio M. Moustakas, Argirios Fraum, Tyler J. Salgado, Carlos A. Li, Aiguo Kreisl, Teri N. Sul, Joohee Butman, John A. Fine, Howard A. TI A phase II trial of enzastaurin (LY317615) in combination with bevacizumab in adults with recurrent malignant gliomas SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Enzastaurin; Bevacizumab; Trial; Glioma; Glioblastoma ID PROTEIN-KINASE-C; ENDOTHELIAL GROWTH-FACTOR; RECURSIVE PARTITIONING ANALYSIS; SINGLE-AGENT BEVACIZUMAB; CENTRAL-NERVOUS-SYSTEM; GLIOBLASTOMA-MULTIFORME; CELL-GROWTH; IN-VIVO; SELECTIVE INHIBITOR; ANAPLASTIC GLIOMA AB We evaluated the efficacy of combination enzastaurin (LY317615) and bevacizumab for recurrent malignant gliomas and explored serologic correlates. We enrolled 81 patients with glioblastomas (GBM, n = 40) and anaplastic gliomas (AG, n = 41). Patients received enzastaurin as a loading dose of 1125 mg, followed by 500 or 875 mg daily for patients on non-enzyme-inducing or enzyme-inducing antiepileptics, respectively. Patients received bevacizumab 10 mg/kg intravenously biweekly. Clinical evaluations were repeated every 4 weeks. Magnetic resonance imaging was obtained at baseline and every 8 weeks from treatment onset. Phosphorylated glycogen synthase kinase (GSK)-3 levels from peripheral blood mononuclear cells (PBMCs) were checked with each MRI. Median overall survival was 7.5 and 12.4 months for glioblastomas and anaplastic glioma cohorts, with median progression-free survivals of 2.0 and 4.4 months, respectively. Of GBM patients, 3/40 (7.5 %) were not evaluable, while 8/37 (22 %) had partial or complete response and 20/37 (54 %) had stable disease for 2+ months. Of the 39 evaluable AG patients, 18 (46 %) had an objective response, and 16 (41 %) had stable disease for 2+ months. The most common grade 3+ toxicities were lymphopenia (15 %), hypophosphatemia (8.8 %) and thrombotic events (7.5 %). Two (2.5 %) GBM patients died suddenly; another death (1.3 %) occurred from intractable seizures. Phosphorylated GSK-3 levels from PBMCs did not correlate with treatment response. A minimally important improvement in health-related quality of life was self-reported in 7-9/24 (29.2-37.5 %). Early response based on Levin criteria was significantly associated with significantly longer progression free survival for glioblastomas. Enzastaurin (LY317615) in combination with bevacizumab for recurrent malignant gliomas is well-tolerated, with response and progression-free survival similar to bevacizumab monotherapy. C1 [Odia, Yazmin; Iwamoto, Fabio M.; Kreisl, Teri N.] Columbia Univ Coll Phys & Surg, Neurooncol Div, Neurol Inst New York, 710 West 168th St,9th Floor,NI 9-017, New York, NY 10032 USA. [Moustakas, Argirios] Univ Vermont, Med Ctr, 89 South Williams St, Burlington, VT 05401 USA. [Fraum, Tyler J.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, Campus Box 8131,510 S Kingshighway Blvd, St Louis, MO 63110 USA. [Salgado, Carlos A.] Univ Maryland, Sch Med, 655 West Baltimore St, Baltimore, MD 21201 USA. [Li, Aiguo] NCI, Ctr Canc Res, Bldg 37,Room 1142, Bethesda, MD USA. [Sul, Joohee] Fed Drug Adm, 10903 New Hampshire Ave,Bldg WO22 Rm 2331, Silver Spring, MD 20993 USA. [Butman, John A.] NIH, Ctr Clin, Dept Radiol, Bldg 10,Clinical Ctr 10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. [Fine, Howard A.] New York Presbyterian Hospital, Weill Cornell Med Ctr, Brain Tumor Ctr, Div Neurooncol, 1305 York Ave,9th Floor, New York, NY 10021 USA. RP Odia, Y (reprint author), Columbia Univ Coll Phys & Surg, Neurooncol Div, Neurol Inst New York, 710 West 168th St,9th Floor,NI 9-017, New York, NY 10032 USA. EM yo2240@cumc.columbia.edu FU National Cancer Institute Intramural Research Program FX National Cancer Institute Intramural Research Program. NR 43 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD MAR PY 2016 VL 127 IS 1 BP 127 EP 135 DI 10.1007/s11060-015-2020-x PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DF6HF UT WOS:000371455800014 PM 26643807 ER PT J AU Stultz, BG Mcginnis, K Thompson, EE Lo Surdo, JL Bauer, SR Hursh, DA AF Stultz, Brian G. Mcginnis, Kathleen Thompson, Elaine E. Lo Surdo, Jessica L. Bauer, Steven R. Hursh, Deborah A. TI Chromosomal stability of mesenchymal stromal cells during in vitro culture SO CYTOTHERAPY LA English DT Article DE genomic stability; mesenchymal stromal cells; MSC; SKY; spectral karyotyping ID EMBRYONIC STEM-CELLS; MALIGNANT-TRANSFORMATION; ABERRATIONS; THERAPY; DIFFERENTIATION; ACQUISITION; INSTABILITY; LYMPHOCYTES; ANEUPLOIDY; SENESCENCE AB Background aims. Mesenchymal stromal cells (MSCs) are being investigated for use in cell therapy. The extensive in vitro expansion necessary to obtain sufficient cells for clinical use increases the risk that genetically abnormal cells will arise and be propagated during cell culture. Genetic abnormalities may lead to transformation and poor performance in clinical use, and are a critical safety concern for cell therapies using MSCs. Methods. We used spectral karyotyping (SKY) to investigate the genetic stability of human MSCs from ten donors during passaging. Results. Our data indicate that chromosomal abnormalities exist in MSCs at early passages and can be clonally propagated. The karyotypic abnormalities observed during our study diminished during passage. Conclusions. Karyotyping of MSCs reveals characteristics which may be valuable in deciding the suitability of cells for further use. Karyotypic analysis is useful for monitoring the genetic stability of MSCs during expansion. C1 [Stultz, Brian G.; Mcginnis, Kathleen; Thompson, Elaine E.; Lo Surdo, Jessica L.; Bauer, Steven R.; Hursh, Deborah A.] US FDA, Ctr Biol Evaluat & Res, Div Cell & Gene Therapies, 10903 New Hampshire Ave,Bldg 72,Room 3216, Silver Spring, MD 20993 USA. RP Hursh, DA (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Cell & Gene Therapies, 10903 New Hampshire Ave,Bldg 72,Room 3216, Silver Spring, MD 20993 USA. EM deborah.hursh@fda.hhs.gov FU Food and Drug Administration (FDA) Modernizing Science Initiative; Medical Countermeasures Initiative; Center of Biologics Evaluation and Research, FDA FX The authors thank Dr. Lei Huang for help in developing the metaphase spread protocol and Dr. Thomas Ried and his laboratory for advice in the initial stages of this project. We thank Drs. Jiang Hu and Estelle Russek-Cohen for providing early statistical advice. Elaine Thompson and Kathleen McGinnis were supported by appointments to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. We thank Drs. Cheng-Hong Wei, Brent McCright, Haritha Vallabhaneni, Patrick Lynch and Mark Mortin for comments that improved the manuscript. This work was supported by grants from the Food and Drug Administration (FDA) Modernizing Science Initiative, the Medical Countermeasures Initiative, and research funds from the Center of Biologics Evaluation and Research, FDA. NR 43 TC 5 Z9 5 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD MAR PY 2016 VL 18 IS 3 BP 336 EP 343 DI 10.1016/j.jcyt.2015.11.017 PG 8 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA DE8VM UT WOS:000370914800004 PM 26780865 ER PT J AU Lebrec, H Brennan, PR Haggerty, H Herzyk, D Kamperschroer, C Maier, CC Ponce, R Preston, BD Weinstock, D Mellon, RD AF Lebrec, H. Brennan, P. R. Haggerty, H. Herzyk, D. Kamperschroer, C. Maier, C. C. Ponce, R. Preston, B. D. Weinstock, D. Mellon, R. D. TI HESI/FDA workshop on immunomodulators and cancer risk assessment: Building blocks for a weight-of -evidence approach SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Immunotoxicology; Immunotoxicity; Immunomodulation; Immunosuppression; Carcinogenicity; Cancer; Risk assessment ID RANDOMIZED CONTROLLED-TRIALS; ANTITUMOR IMMUNE-RESPONSE; NECROSIS FACTOR THERAPY; RHEUMATOID-ARTHRITIS; VIRAL-INFECTIONS; CHRONIC INFLAMMATION; GENERAL-POPULATION; UNITED-STATES; CELL LYMPHOMA; MOUSE MODELS AB Profound immunosuppression (e.g., AIDS, transplant therapy) is epidemiologically associated with an increased cancer risk, and often with oncogenic viruses. It is currently unclear how broadly this association translates to therapeutics that modulate immunity. A workshop co-sponsored by the FDA and HESI examined how perturbing the immune system may contribute to carcinogenesis, and highlighted priorities for improving non-clinical risk assessment of targeted immunomodulatory therapies. Conclusions from the workshop were as follows. 1) While profound altered immunity can promote tumorigenesis, not all components of the immune system are equally important in defense against or promotion of cancer and a similar cancer risk for all immunomodulatory molecules should not be assumed. 2) Rodent carcinogenicity studies have limitations and are generally not reliable predictors of cancer risk associated with immunosuppression. 3) Cancer risk needs to be evaluated based on mechanism-based weight-of-evidence, including data from immune function tests most relevant to tumor immunosurveillance or promotion. 4) Information from nonclinical experiments, clinical epidemiology and immunomodulatory therapeutics show that immunosurveillance involves a complex network of cells and mediators. To support a weight-of-evidence approach, an increased focus on understanding the quantitative relationship between changes in relevant immune function tests and cancer risk is needed. (C) 2015 Published by Elsevier Inc. C1 [Lebrec, H.; Ponce, R.; Preston, B. D.] Amgen Inc, 1120 Vet Blvd, San Francisco, CA 94080 USA. [Brennan, P. R.] UCB Celltech, 208 Bath Rd, Slough SL1 3WE, Berks, England. [Haggerty, H.] Bristol Myers Squibb Co, 1 Squibb Dr, New Brunswick, NJ 08903 USA. [Herzyk, D.] Merck & Co Inc, 770 Sumneytown Pike,POB 4,MS WP45-233, West Point, PA USA. [Kamperschroer, C.] Pfizer Inc, Eastern Point Rd, Groton, CT USA. [Maier, C. C.] GlaxoSmithKline, 709 Swedeland Rd, King Of Prussia, PA 19406 USA. [Weinstock, D.] Janssen Res & Dev LLC, Welsh & McKean Rd, Spring House, PA 19477 USA. [Mellon, R. D.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Lebrec, H (reprint author), Amgen Inc, 1120 Vet Blvd, San Francisco, CA 94080 USA. EM hlebrec@amgen.com NR 74 TC 0 Z9 0 U1 3 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD MAR PY 2016 VL 75 BP 72 EP 80 DI 10.1016/j.yrtph.2015.12.018 PG 9 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA DE5NF UT WOS:000370677000009 PM 26743742 ER PT J AU Aikin, KJ O'Donoghue, AC Sullivan, HW Betts, KR Squire, C AF Aikin, Kathryn J. O'Donoghue, Amie C. Sullivan, Helen W. Betts, Kevin R. Squire, Claudia TI Who Said It Better? A Test of Wording Differences in the MedWatch "Toll-Free Statement" for Consumer Reporting of Side Effects in Direct-to-Consumer Television Advertisements SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE DTC; prescription drugs; advertisements; toll-free statement; Food and Drug Administration Amendments Act AB Background: A toll-free statement alerting consumers how to report side effects to the US Food and Drug Administration (FDA) is required for both prescription drug labeling and direct-to-consumer (DTC) print ads. Because of different regulatory requirements between these materials (the Toll-free Number for Reporting Adverse Events on Labeling for Human Drug Products Rule [TFNR] versus the FDA Amendments Act [FDAAA], respectively), the wording of this statement differs. We studied how statement wording for reporting side effects to FDA in DTC television ads affects comprehension of product risks and benefits, comprehension of and memory for the toll-free statement, and perceived statement clarity. Methods: Participants viewed 1 of 8 mock prescription drug television ads that varied the wording and placement of the toll-free statement, and then responded to a questionnaire. Results: The FDAAA statement was more noticeable, clear, and more participants were able to recall and recognize its correct purpose. Comprehension of product risk and benefit information did not differ based on statement wording. Conclusions: Findings suggest that the FDAAA toll-free statement wording is superior to that of the TFNR. C1 [Aikin, Kathryn J.; O'Donoghue, Amie C.; Sullivan, Helen W.; Betts, Kevin R.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Squire, Claudia] RTI Int, Durham, NC USA. RP Aikin, KJ (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Kathryn.Aikin@fda.hhs.gov FU Office of Prescription Drug Promotion, Center for Drug Evaluation and Research, Food and Drug Administration FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was funded by the Office of Prescription Drug Promotion, Center for Drug Evaluation and Research, Food and Drug Administration. NR 4 TC 3 Z9 3 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD MAR PY 2016 VL 50 IS 2 BP 169 EP 173 DI 10.1177/2168479015596023 PG 5 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA DE9MC UT WOS:000370960700004 ER PT J AU Mihalcik, LM Bausman, M Brown, P Everds, N Feldmann, J Henck, J Potenta, D Sims, J Zandee, J AF Mihalcik, Lauren Murphree Bausman, Megan Brown, Paul Everds, Nancy Feldmann, Jennifer Henck, Judith Potenta, Dan Sims, John Zandee, Joyce TI Community Opinions on the Collection and Use of Historical Control Data in Nonclinical Toxicity Studies SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE historical control data; nonclinical toxicity studies; survey AB Background: Access and use of historical control data was identified as a top stakeholder concern across organizations according to results of a survey of needs and challenges related to nonclinical data conducted by the FDA/PhUSE Nonclinical Working Group in 2011. There is a perception there may be additional ways to capitalize on historical control data to enhance studies or submissions across industry, academia, and government. During the working sessions of the FDA/PhUSE Computational Sciences Symposium in March 2012, a Historical Control subgroup of the FDA/PhUSE Nonclinical Working Group was formed to investigate how the industry might more effectively harness the vast amount of data from untreated/vehicle control animals. The subgroup includes broad representation of stakeholders with interest in nonclinical data. Methods: This paper describes progress to date and includes results of a second survey to determine how organizations use and would like to use historical control data. Results: Respondents to the survey strongly support that historical control data are useful and should be in an accessible format. Four potential project options were posed in the survey, with an overall positive response; also, several write-in options were suggested by respondents. Conclusions: Community-supported projects to increase the availability of well-annotated and scientifically curated collections of historical control data appear to be of most interest. C1 [Mihalcik, Lauren Murphree; Brown, Paul] US FDA, Off New Drugs, Silver Spring, MD USA. [Bausman, Megan] Covance Labs, 3301 Kinsman Blvd, Madison, WI 53704 USA. [Mihalcik, Lauren Murphree; Everds, Nancy] Amgen Inc, San Francisco, CA USA. [Feldmann, Jennifer] Instem, Conshohocken, PA USA. [Henck, Judith] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Potenta, Dan] Novartis Pharmaceut, E Hanover, NJ USA. [Sims, John] Pfizer, Pearl River, NY USA. [Zandee, Joyce] Integrated Nonclin Dev Solut, Ann Arbor, MI USA. RP Bausman, M (reprint author), Covance Labs, 3301 Kinsman Blvd, Madison, WI 53704 USA. EM megan.bausman@covance.com FU FDA/PhUSE; Instem; Covance FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by an FDA/PhUSE Collaboration with in-kind support from Instem and Covance. NR 4 TC 1 Z9 1 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD MAR PY 2016 VL 50 IS 2 BP 174 EP 187 DI 10.1177/2168479015600203 PG 14 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA DE9MC UT WOS:000370960700005 ER PT J AU Lin, M Lee, S Zhen, BG Scott, J Horne, A Solomon, G Russek-Cohen, E AF Lin, Min Lee, Shiowjen Zhen, Boguang Scott, John Horne, Amelia Solomon, Ghideon Russek-Cohen, Estelle TI CBER's Experience With Adaptive Design Clinical Trials SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE adaptive design; FDA; clinical trial; survey; biologics ID SAMPLE-SIZE; PRODUCT DEVELOPMENT; CONDITIONAL POWER; 2-STAGE DESIGNS; INTERIM; OPPORTUNITIES; REASSESSMENT; BARRIERS; VACCINE; CANCER AB There is considerable interest among pharmaceutical and other medical product developers in adaptive clinical trials, in which knowledge learned during the course of a trial affects ongoing conduct or analysis of the trial. When the FDA released a draft Guidance document on adaptive design clinical trials in early 2010, expectations were high that it would lead to an increase in regulatory submissions involving adaptive design features, particularly for confirmatory trials. A 6-year (2008-2013) retrospective survey was performed within the Center for Biologics Evaluation and Research (CBER) at the FDA to gather information regarding the submission and evaluation of adaptive design trial proposals. We present an up-to-date summary of adaptive design proposals seen in CBER and provide an overview of our experiences. We share our concerns regarding the statistical issues and operational challenges raised during the review process for adaptive design trials. We also provide general recommendations for developing proposals for such trials. Our motivation in writing this paper was to encourage the best study design proposals to be submitted to CBER. Sometimes these can be adaptive, and sometimes a simpler design is most efficient. C1 [Lin, Min; Lee, Shiowjen; Zhen, Boguang; Scott, John; Horne, Amelia; Solomon, Ghideon; Russek-Cohen, Estelle] US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Lin, M (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM min.lin@fda.hhs.gov NR 36 TC 2 Z9 2 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD MAR PY 2016 VL 50 IS 2 BP 195 EP 203 DI 10.1177/2168479015604181 PG 9 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA DE9MC UT WOS:000370960700007 ER PT J AU Tang, R Pennello, G AF Tang, Rong Pennello, Gene TI Validation of Prognostic Marker Tests: Statistical Lessons Learned From Regulatory Experience SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Review DE prospective study; retrospective study; case-cohort; nested case-control; risk categorization ID LOGISTIC-REGRESSION ANALYSIS; CLINICAL-TRIAL DESIGNS; BREAST-CANCER; RISK PREDICTION; HEART-FAILURE; TUMOR-MARKER; CASE-COHORT; EPIDEMIOLOGIC COHORT; COVARIATE DATA; SELECTION AB Despite concerted efforts to discover and validate prognostic biomarkers or signatures, few medical tests indicated for prognostic uses have been widely accepted by the clinical community. Even fewer, perhaps, are covered by public or private health plans. We were able to identify 6 prognostic marker tests that have been approved or cleared by the US Food and Drug Administration. The pivotal clinical studies for these prognostic marker tests exhibited a wide variety of designs and statistical analyses. From these experiences, we develop statistical points to consider for design, conduct, and analysis of successful clinical validation studies of prognostic tests. In particular, we review broad themes regarding prospective and retrospective study designs, sample size, clinical performance evaluation, and handling of missing data. Our review emphasizes the distinction between a prognostic biomarker and the medical test used to measure it. For this purpose, a section on test measurement validation is also provided. C1 [Tang, Rong; Pennello, Gene] US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Tang, R (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Rong.tang@fda.hhs.gov NR 87 TC 0 Z9 0 U1 2 U2 5 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 MAR PY 2016 VL 50 IS 2 BP 241 EP 252 DI 10.1177/2168479015601721 PG 12 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA DE9MC UT WOS:000370960700013 ER PT J AU Durmowicz, EL Rudy, SF Chen, IL AF Durmowicz, Elizabeth L. Rudy, Susan F. Chen, Ii-Lun TI Electronic cigarettes: analysis of FDA adverse experience reports in non-users SO TOBACCO CONTROL LA English DT Letter C1 [Durmowicz, Elizabeth L.; Rudy, Susan F.; Chen, Ii-Lun] US FDA, Ctr Tobacco Prod, Off Sci, WO 75-Room 5476,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Durmowicz, EL (reprint author), US FDA, Ctr Tobacco Prod, Off Sci, WO 75-Room 5476,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Elizabeth.durmowicz@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 3 TC 3 Z9 3 U1 0 U2 4 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 MAR PY 2016 VL 25 IS 2 BP 242 EP 242 DI 10.1136/tobaccocontrol-2015-052235 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DE7YH UT WOS:000370852500019 PM 25908596 ER PT J AU Willemin, ME Sophie, DC Le Grand, R Lestremau, F Zeman, FA Leclerc, E Moesch, C Brochot, C AF Willemin, Marie-Emilie Desmots, Sophie Le Grand, Rozenn Lestremau, Francois Zeman, Florence A. Leclerc, Eric Moesch, Christian Brochot, Celine TI PBPK modeling of the cis- and trans-permethrin isomers and their major urinary metabolites in rats SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE PBPK model; cis/trans-Permethrin; 3-Phenoxybenzoic acid; cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid; Bayesian calibration; Metabolites ID IN-VITRO METABOLISM; ADULT MALE-MOUSE; PYRETHROID INSECTICIDES; PHARMACOKINETIC MODEL; MASS-SPECTROMETRY; CLINICAL-MANIFESTATIONS; REPRODUCTIVE TOXICITY; SYNTHETIC PYRETHROIDS; SEMEN QUALITY; EXPOSURE AB Permethrin, a pyrethroid insecticide, is suspected to induce neuronal and hormonal disturbances in humans. The widespread exposure of the populations has been confirmed by the detection of the urinary metabolites of permethrin in biomonitoring studies. Permethrin is a chiral molecule presenting two forms, the cis and the trans isomers. Because in vitro studies indicated a metabolic interaction between the trans and cis isomers of permethrin, we adapted and calibrated a PBPK model for trans- and cis-permethrin separately in rats. The model also describes the toxicokinetics of three urinary metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1cyclopropane) carboxylic acid (cis- and trans-DCCA), 3-phenoxybenzoic acid (3-PBA) and 4'OH-phenoxybenzoic acid (4'-OH-PBA). In vivo experiments performed in Sprague-Dawley rats were used to calibrate the PBPK model in a Bayesian framework. The model captured well the toxicokinetics of permethrin isomers and their metabolites including the rapid absorption, the accumulation in fat, the extensive metabolism of the parent compounds, and the rapid elimination of metabolites in urine. Average hepatic clearances in rats were estimated to be 2.4 and 5.7 L/h/kg for cis- and trans-permethrin, respectively. High concentrations of the metabolite 4'-OH-PBA were measured in urine compared to cis- and trans-DCCA and 3-PBA. The confidence in the extended PBPK model was then confirmed by good predictions of published experimental data obtained using the isomers mixture. The extended PBPK model could be extrapolated to humans to predict the internal dose of exposure to permethrin from biomonitoring data in urine. (C) 2016 Elsevier Inc. All rights reserved. C1 [Willemin, Marie-Emilie; Zeman, Florence A.; Brochot, Celine] Inst Natl Environm Ind & Risques INERIS, Unite Modeles Ecotoxicol & Toxicol METO, Parc ALATA BP2, F-60550 Verneuil En Halatte, France. [Willemin, Marie-Emilie; Leclerc, Eric] Univ Technol Compiegne, Univ Paris 04, Ctr Rech Royallieu CS 60319, CNRS,Biomech & Bioengn UMR 7338, F-60203 Compiegne, France. [Desmots, Sophie] Inst Natl Environnement Ind & Risques INERIS, Unite Toxicol Expt TOXI, Parc ALATA BP2, F-60550 Verneuil En Halatte, France. [Le Grand, Rozenn; Moesch, Christian] Ctr Hosp Univ Limoges, Serv Pharmacol & Toxicol Pharmacovigilance, 2 Ave Martin Luther King, F-87042 Limoges, France. [Lestremau, Francois] Inst Natl Environm Ind & Risques INERIS, Unite Innovat Mesure NOVA, Parc ALATA BP2, F-60550 Verneuil En Halatte, France. [Willemin, Marie-Emilie] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Brochot, C (reprint author), Inst Natl Environm Ind & Risques INERIS, Unite Modeles Ecotoxicol & Toxicol METO, Parc ALATA BP2, F-60550 Verneuil En Halatte, France. EM celine.brochot@ineris.fr RI Brochot, Celine/O-5099-2014; Zeman, Florence/O-1135-2015 FU Foundation of Universite de Technologie de Compiegne "La Fondation UTC pour l'Innovation" [ToxOnChip project]; French Ministry of Ecology and Sustainable Development [190] FX This work was supported by the Foundation of Universite de Technologie de Compiegne "La Fondation UTC pour l'Innovation" [ToxOnChip project] and the French Ministry of Ecology and Sustainable Development [Program 190]. NR 63 TC 2 Z9 2 U1 10 U2 16 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 2016 VL 294 BP 65 EP 77 DI 10.1016/j.taap.2016.01.011 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DE9UQ UT WOS:000370985300007 PM 26802525 ER PT J AU Gonzalez, C Rosas-Hernandez, H Ramirez-Lee, MA Salazar-Garcia, S Ali, SF AF Gonzalez, Carmen Rosas-Hernandez, Hector Alejandro Ramirez-Lee, Manuel Salazar-Garcia, Samuel Ali, Syed F. TI Role of silver nanoparticles (AgNPs) on the cardiovascular system SO ARCHIVES OF TOXICOLOGY LA English DT Review DE Silver nanoparticles; Cardiovascular system; Endothelium; Blood vessels; Toxicity ID BLOOD-BRAIN-BARRIER; NITRIC-OXIDE SYNTHASE; SPRAGUE-DAWLEY RATS; RETINAL ENDOTHELIAL-CELLS; IN-VITRO; DIABETIC-RETINOPATHY; ULTRAFINE PARTICLES; OXIDATIVE STRESS; ENGINEERED NANOPARTICLES; VASCULAR-PERMEABILITY AB With the advent of nanotechnology, the use and applications of silver nanoparticles (AgNPs) have increased, both in consumer products as well as in medical devices. However, little is known about the effects of these nanoparticles on human health, more specific in the cardiovascular system, since this system represents an important route of action in terms of distribution, bioaccumulation and bioavailability of the different circulating substances in the bloodstream. A collection of studies have addressed the effects and applications of different kinds of AgNPs (shaped, sized, coated and functionalized) in several components of the cardiovascular system, such as endothelial cells, isolated vessels and organs as well as integrative animal models, trying to identify the underlying mechanisms involved in their actions, to understand their implication in the field of biomedicine. The purpose of the present review is to summarize the most relevant studies to date of AgNPs effects in the cardiovascular system and provide a broader picture of the potential toxic effects and exposure risks, which in turn will allow pointing out the directions of further research as well as new applications of these versatile nanomaterials. C1 [Gonzalez, Carmen; Rosas-Hernandez, Hector; Alejandro Ramirez-Lee, Manuel; Salazar-Garcia, Samuel] Univ Autonoma San Luis Potosi, Fac Ciencias Quim, Av Manuel Nava 6, San Luis Potosi 78210, Slp, Mexico. [Gonzalez, Carmen; Ali, Syed F.] Natl Ctr Toxicol Res, Neurochem Lab, Div Neurotoxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. RP Gonzalez, C (reprint author), Univ Autonoma San Luis Potosi, Fac Ciencias Quim, Av Manuel Nava 6, San Luis Potosi 78210, Slp, Mexico. EM cgonzalez.uaslp@gmail.com OI Rosas-Hernandez, Hector/0000-0002-2736-8302 NR 106 TC 2 Z9 2 U1 8 U2 36 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 2016 VL 90 IS 3 BP 493 EP 511 DI 10.1007/s00204-014-1447-8 PG 19 WC Toxicology SC Toxicology GA DE0VJ UT WOS:000370343000001 PM 25543135 ER PT J AU Woo, EJ AF Woo, Emily Jane TI CORR Insights(A (R)): What Are the 30-day Readmission Rates Across Orthopaedic Subspecialties? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Editorial Material C1 [Woo, Emily Jane] US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Woo, EJ (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jane.woo@fda.hhs.gov NR 0 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 MAR PY 2016 VL 474 IS 3 BP 848 EP 849 DI 10.1007/s11999-015-4621-2 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DD8BV UT WOS:000370150000043 PM 26552803 ER PT J AU Ball, R Robb, M Anderson, SA Dal Pan, G AF Ball, R. Robb, M. Anderson, S. A. Dal Pan, G. TI The FDA's Sentinel Initiative-A Comprehensive Approach to Medical Product Surveillance SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB In May 2008, the Department of Health and Human Services announced the launch of the Sentinel Initiative by the US Food and Drug Administration (FDA) to create the Sentinel System, a national electronic system for medical product safety surveillance.(1,2) This system complements existing FDA surveillance capabilities that track adverse events reported after the use of FDA regulated products by allowing the FDA to proactively assess the safety of these products. C1 [Ball, R.; Robb, M.; Dal Pan, G.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Anderson, S. A.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Ball, R (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM Robert.Ball@fda.hhs.gov NR 0 TC 6 Z9 6 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2016 VL 99 IS 3 BP 265 EP 268 DI 10.1002/cpt.320 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DE5LH UT WOS:000370672000012 PM 26667601 ER PT J AU Revollo, JR Crabtree, NM Pearce, MG Pacheco-Martinez, MM Dobrovolsky, VN AF Revollo, Javier R. Crabtree, Nathaniel M. Pearce, Mason G. Monserrat Pacheco-Martinez, M. Dobrovolsky, Vasily N. TI Mutation analysis with random DNA identifiers (MARDI) catalogs Pig-a mutations in heterogeneous pools of CD48-deficient T cells derived from DMBA-treated rats SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE NGS; flow cytometry; glycosylphosphatidylinositol (GPI) anchor; cell sorting ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; GENETIC-DISEASE; LYMPHOCYTES; QPCR AB Identification of mutations induced by xenotoxins is a common task in the field of genetic toxicology. Mutations are often detected by clonally expanding potential mutant cells and genotyping each viable clone by Sanger sequencing. Such a clone-by-clone approach requires significant time and effort, and sometimes is even impossible to implement. Alternative techniques for efficient mutation identification would greatly benefit both basic and regulatory genetic toxicology research. Here, we report the development of Mutation Analysis with Random DNA Identifiers (MARDI), a novel high-fidelity Next Generation Sequencing (NGS) approach that circumvents clonal expansion and directly catalogs mutations in pools of mutant cells. MARDI uses oligonucleotides carrying Random DNA Identifiers (RDIs) to tag progenitor DNA molecules before PCR amplification, enabling clustering of descendant DNA molecules and eliminating NGS- and PCR-induced sequencing artifacts. When applied to the Pig-a cDNA analysis of heterogeneous pools of CD48-deficient T cells derived from DMBA-treated rats, MARDI detected nearly all Pig-a mutations that were previously identified by conventional clone-by-clone analysis and discovered many additional ones consistent with DMBA exposure: mostly A to T transversions, with the mutated A located on the non-transcribed DNA strand. Environ. Mol. Mutagen. 57:114-124, 2016. (c) 2015 Wiley Periodicals, Inc. C1 [Revollo, Javier R.; Pearce, Mason G.; Dobrovolsky, Vasily N.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Crabtree, Nathaniel M.] Univ Arkansas, UALR UAMS Joint Bioinformat Program, Little Rock, AR 72204 USA. [Monserrat Pacheco-Martinez, M.] Univ Autonoma Metropolitana Iztapalapa, Dept Ciencias Salud, Mexico City 09340, DF, Mexico. RP Revollo, JR (reprint author), 3900 NCTR Rd,HFT 120, Jefferson, AR 72079 USA. EM Javier.revollo@fda.hhs.gov NR 13 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD MAR PY 2016 VL 57 IS 2 BP 114 EP 124 DI 10.1002/em.21992 PG 11 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA DE0SB UT WOS:000370333500002 PM 26683280 ER PT J AU Schmeisser, F Jing, XH Joshi, M Vasudevan, A Soto, J Li, X Choudhary, A Baichoo, N Resnick, J Ye, ZP McCormick, W Weir, JP AF Schmeisser, Falko Jing, Xianghong Joshi, Manju Vasudevan, Anupama Soto, Jackeline Li, Xing Choudhary, Anil Baichoo, Noel Resnick, Josephine Ye, Zhiping McCormick, William Weir, Jerry P. TI A novel approach for preparation of the antisera reagent for potency determination of inactivated H7N9 influenza vaccines SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article DE Influenza vaccine reagents; influenza vaccines; single-radial immunodiffusion assay; vaccine potency assay ID SINGLE-RADIAL-IMMUNODIFFUSION; RANDOMIZED CLINICAL-TRIAL; VIRUS; HEMAGGLUTININ; CANDIDATE; ASSAY AB BackgroundThe potency of inactivated influenza vaccines is determined using a single-radial immunodiffusion (SRID) assay and requires standardized reagents consisting of a Reference Antigen and an influenza strain-specific antiserum. Timely availability of reagents is a critical step in influenza vaccine production, and the need for backup approaches for reagent preparation is an important component of pandemic preparedness. ObjectivesWhen novel H7N9 viruses emerged in China in 2013, candidate inactivated H7N9 influenza vaccines were developed for evaluation in clinical trials, and reagents were needed to measure vaccine potency. MethodsWe previously described an alternative approach for generating strain-specific potency antisera, utilizing modified vaccinia virus Ankara vectors to produce influenza hemagglutinin (HA)-containing virus-like particles (VLPs) for immunization. Vector-produced HA antigen is not dependent upon the success of the traditional bromelain-digestion and HA purification. ResultsAntiserum for H7N9 vaccines, produced after immunization of sheep with preparations of bromelain-HA (br-HA), was not optimal for the SRID assay, and the supply of antiserum was limited. However, antiserum obtained from sheep boosted with VLPs containing H7 HA greatly improved the ring quality in the SRID assay. Importantly, this antiserum worked well with both egg- and cell-derived antigen and was distributed to vaccine manufacturers. ConclusionsUtilizing a previously developed approach for preparing vaccine potency antiserum, we have addressed a major bottleneck encountered in preparation of H7N9 vaccine reagents. The combination of br-HA and mammalian VLPs for sequential immunization represents the first use of an alternative approach for producing an influenza vaccine potency antiserum. C1 [Schmeisser, Falko; Vasudevan, Anupama; Weir, Jerry P.] US FDA, Ctr Biol Evaluat & Res, Lab DNA Viruses, Div Viral Prod, Silver Spring, MD USA. [Jing, Xianghong; Soto, Jackeline; Li, Xing; Ye, Zhiping] US FDA, Lab Resp Viral Dis, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Joshi, Manju; Choudhary, Anil; Baichoo, Noel; Resnick, Josephine; McCormick, William] US FDA, Div Biol Stand & Qual Control, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Weir, JP (reprint author), Div Viral Prod, Lab DNA Viruses, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jerry.weir@fda.hhs.gov FU Biomedical Advanced Research and Development Authority; Department of Health and Human Services FX This work was supported in part by the Biomedical Advanced Research and Development Authority, Department of Health and Human Services. Vaccine samples were provided by ID Biomedical Corp. of Quebec d/b/a/GSK Biologicals and Sanofi Pasteur Inc. We thank Limei Chen (CDC) and Othmar Engelhardt (NIBSC, UK) for H7 candidate vaccine viruses RG32A and NIBRG-60, respectively. Anupama Vasudevan was a participant in the Oak Ridge Institute for Science and Education program at CBER. NR 22 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 EI 1750-2659 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD MAR PY 2016 VL 10 IS 2 BP 134 EP 140 DI 10.1111/irv.12365 PG 7 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA DD9CA UT WOS:000370222100010 PM 26616263 ER PT J AU Hampp, C Greene, P Pinheiro, SP AF Hampp, Christian Greene, Patty Pinheiro, Simone P. TI Use of Prescription Drug Samples in the USA: A Descriptive Study with Considerations for Pharmacoepidemiology SO DRUG SAFETY LA English DT Article ID EXPOSURE MISCLASSIFICATION; CLAIMS DATABASES; PHYSICIANS; RECIPIENTS; BEHAVIOR; COHORT; IMPACT AB Introduction Free prescription drug samples provided in physician offices can lead to exposure misclassification in pharmacoepidemiologic studies that rely on pharmacy claims data. Methods We quantified drug-specific sample provision rates based on nationally projected data from a survey of over 3200 US office-based physicians for 1993-2013. Results Between 2009 and 2013, a total of 44.7 % of newly initiated brand-only sitagliptin but only 3.6 % of generically available metformin therapy was provided as samples. We observed similar discrepancies between newly initiated rosuvastatin and simvastatin, dabigatran and warfarin, atomoxetine and methylphenidate, and between oral antibiotic drugs. During continued therapy, sample use was still present though to a lesser extent (sitagliptin 17.0 %, rosuvastatin 23.9 %), and remained high for some oral contraceptives (norethindrone 55.8 %). Oral contraceptives had the longest average days of sample supply (levonorgestrel, continued use 85.1 days). The average days of supply for all other chronically used study drugs ranged from 13.4 (dabigatran, new use) to 25.3 (exenatide, continued use) per sample provided. From 1993 to 2013, we found pronounced drops in sample provisions over time coinciding with more recent generic approval dates. Conclusions We observed markedly differential exposure to medication samples between branded and generic drugs. This can introduce bias in pharmacoepidemiologic studies, especially when adverse events that occur soon after drug initiation are of interest. C1 [Hampp, Christian; Pinheiro, Simone P.] US FDA, Off Surveillance & Epidemiol, Off Pharmacovigilance & Epidemiol, Div Epidemiol 1,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. [Greene, Patty] US FDA, Ctr Drug Evaluat & Res, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol,Div Epidemiol 2, Silver Spring, MD 20993 USA. RP Hampp, C (reprint author), US FDA, Off Surveillance & Epidemiol, Off Pharmacovigilance & Epidemiol, Div Epidemiol 1,Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM christian.hampp@fda.hhs.gov OI Hampp, Christian/0000-0002-1094-6364 FU Intramural FDA HHS [FD999999] NR 25 TC 1 Z9 1 U1 1 U2 6 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0114-5916 EI 1179-1942 J9 DRUG SAFETY JI Drug Saf. PD MAR PY 2016 VL 39 IS 3 BP 261 EP 270 DI 10.1007/s40264-015-0382-9 PG 10 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA DD8JH UT WOS:000370172200008 PM 26798052 ER PT J AU Minor, T MacEwan, JP AF Minor, Travis MacEwan, Joanna P. TI A comparison of diagnosed and undiagnosed diabetes patients and labor supply SO ECONOMICS & HUMAN BIOLOGY LA English DT Article DE Diabetes; Labor supply; Undiagnosed ID EMPLOYMENT; IMPACT; PRODUCTIVITY; PREVALENCE; HEALTH; HYPERGLYCEMIA; DURATION; EARNINGS; DISEASE; WAGES AB Using data from four waves of the National Health and Nutrition Examination Survey, we examine the difference between individuals with diagnosed and undiagnosed cases of type 2 diabetes and their labor supply decisions. We show that a diagnosis of type 2 diabetes is significantly associated with a reduction in both male and female employment probability by 11 and 19 percentage points, respectively. Additionally, hours worked by individuals with diagnosed type 2 diabetes are 7 h lower per week for males and 8 h lower per week for females. Further, individuals with undiagnosed type 2 diabetes experience a drop in labor supply somewhat smaller but similar to their diagnosed counterparts. This association may be driven by the similarities between undiagnosed and very recently diagnosed type 2 diabetes. In all estimations, we consistently find that type 1 diabetes has a different effect than either diagnosed or undiagnosed type 2 diabetes. Published by Elsevier B.V. C1 [Minor, Travis] US FDA, CFSAN, CPK1 HFS-020,5100 Paint Branch Pkwy, College Pk, MD 20740 USA. [MacEwan, Joanna P.] Precis Hlth Econ, 11100 Santa Monica Blvd, Los Angeles, CA 90025 USA. RP Minor, T (reprint author), US FDA, CFSAN, CPK1 HFS-020,5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Travis.Minor@fda.hhs.gov; Joanna.MacEwan@precisionhealtheconomics.com NR 28 TC 1 Z9 1 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-677X EI 1873-6130 J9 ECON HUM BIOL JI Econ. Hum. Biol. PD MAR PY 2016 VL 20 BP 14 EP 25 DI 10.1016/j.ehb.2015.10.003 PG 12 WC Economics; Public, Environmental & Occupational Health SC Business & Economics; Public, Environmental & Occupational Health GA DC4MV UT WOS:000369195900002 PM 26650918 ER PT J AU Williams, KS Killebrew, DA Clary, GP Meeker, RB AF Williams, Kimberly S. Killebrew, Deirdre A. Clary, Gillian P. Meeker, Rick B. TI Opposing Effects of NGF and proNGF on HIV Induced Macrophage Activation SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Article DE Inflammation; Neuroprotection; Calcium; Actin; p75 neurotrophin receptor; TrkA ID NERVE GROWTH-FACTOR; MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; MATRIX METALLOPROTEINASES; NEUROTROPHIC FACTOR; SMALL-MOLECULE; CEREBROSPINAL-FLUID; NEURONAL APOPTOSIS; PROTEIN; NEURODEGENERATION AB Macrophage and microglial activation by HIV in the central nervous system (CNS) triggers the secretion of soluble factors which damage neurons. Therapeutic approaches designed to restore cognitive function by suppressing this inflammatory activity have not yet been successful. Recent studies have indicated that the phenotype of macrophages is differentially controlled by the mature and pro form of nerve growth factor. These cells therefore may be highly responsive to the imbalance in pro versus mature neurotrophins often associated with neurodegenerative diseases. In this study we evaluated the interactions between neurotrophins and HIV induced macrophage activation. HIV stimulation of macrophages induced a neurotoxic phenotype characterized by the expression of podosomes, suppression of calcium spiking and increased neurotoxin production. The secretome of the activated macrophages revealed a bias toward anti-angiogenic like activity and increased secretion of MMP-9. Co-stimulation with NGF and HIV suppressed neurotoxin secretion, increased calcium spiking, suppressed podosome expression and reversed 86 % of the proteins secreted in response to HIV, including MMP-9 and many growth factors. In contrast, co-stimulation of macrophages with proNGF not only failed to reverse the effects of HIV but increased the neurotoxic phenotype. These differential effects of proNGF and NGF on HIV activation provide a potential novel therapeutic avenue for controlling macrophage activation in response to HIV. C1 [Williams, Kimberly S.; Killebrew, Deirdre A.; Clary, Gillian P.; Meeker, Rick B.] Univ N Carolina, Dept Neurol, CB 7025, 6109F Neurosci Res Bldg,115 Mason Farm Rd, Chapel Hill, NC 27599 USA. [Williams, Kimberly S.; Meeker, Rick B.] Univ N Carolina, Neurobiol Curriculum, Chapel Hill, NC 27599 USA. [Killebrew, Deirdre A.] SUNY Stony Brook, Ctr Sci & Math Educ, Stony Brook, NY 11794 USA. [Clary, Gillian P.] US FDA, Rockville, MD 20852 USA. RP Meeker, RB (reprint author), Univ N Carolina, Dept Neurol, CB 7025, 6109F Neurosci Res Bldg,115 Mason Farm Rd, Chapel Hill, NC 27599 USA.; Meeker, RB (reprint author), Univ N Carolina, Neurobiol Curriculum, Chapel Hill, NC 27599 USA. EM meekerr@neurology.unc.edu FU NIH [F31 MH101019, R01 MH085606, R01 NS083164] FX This research was supported by NIH grants: F31 MH101019, R01 MH085606 and R01 NS083164. NR 54 TC 2 Z9 2 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 EI 1557-1904 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD MAR PY 2016 VL 11 IS 1 BP 98 EP 120 DI 10.1007/s11481-015-9631-z PG 23 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DC9CU UT WOS:000369519400009 PM 26420421 ER PT J AU Ahmed, R Arfin, R Rubel, MH Islam, KK Jia, CX Metaxas, D Garra, BS Alam, SK AF Ahmed, Rifat Arfin, Rishad Rubel, Monir Hossan Islam, Kazi Khairul Jia, Congxian Metaxas, Dimitris Garra, Brian S. Alam, S. Kaisar TI Comparison of windowing effects on elastography images: Simulation, phantom and in vivo studies SO ULTRASONICS LA English DT Article DE Elastography; Data window; Spectral leakage; Strain; Ultrasound ID NONSTATIONARY STRAIN FILTER; TO-NOISE RATIO; CROSS-CORRELATION; ULTRASOUND ELASTOGRAPHY; AXIAL RESOLUTION; ELASTICITY; TRACKING; ESTIMATORS; ALGORITHM; CONTRAST AB In this paper, we have evaluated the use of smooth windows for ultrasound elastography. In ultrasound elastography, local tissue strain is estimated using operations such as cross-correlation on local segments of RF data. In this process, local data segments are selected by multiplying the RF data by a rectangular window. Such data truncation causes non-ideal spectral behavior, which can be mitigated by using smooth windows. Accordingly, we hypothesize that the use of smooth windows may improve the elastographic signal-to-noise ratio (SNRe) and contrast-to-noise ratio (CNRe) of strain images. The effects of using smooth windows have not been fully characterized for time-domain strain estimators. Thus, we have compared the elastographic performance of rectangular, Hanning, Gaussian, and Chebyshev windows used in conjunction with cross-correlation based algorithm and adaptive stretching algorithm using finite element method (FEM) simulation, experimental phantom, and in vivo data. Smooth windows are found to improve the SNRe by up to 3.94 for FEM data and by up to 1.76 for phantom data which represent 76% and 60.52% improvements, respectively. CNRe improves by up to 12.23 for FEM simulated data and by up to 4.28 for phantom data which represent 213.07% and 248.2% improvements, respectively. Mean structural similarity (MSSIM) was used for assessing the image perceptual quality and smooth windows improved it by up to 0.22 (85.98% improvement) for simulated data. We have evaluated these parameters at 1-6% applied strains for the experimental phantom and at 1%, 2%, 4%, 6%, 8%, and 12% applied strains for FEM simulation. We observed a maximum deterioration in axial resolution of 0.375 mm (which is on the order of the wavelength, 0.3 mm) due to smooth windows. "Salt-and-pepper" noise from false-peak errors has also been reduced. Smooth windows increased the lesion-to-background contrast (by increasing the CNRe by 213.07%) of a low contrast lesion (10-dB). For the in vivo cases, use of smooth windows resulted in better depiction of lesions, which is important for lesion classification. In this work, we have used an ATL Ultramark 9 scanner with an L10-5 (7.5 MHz) probe for the phantom experiment and a Sonix SP500 scanner with an L14-5/38 probe (10 MHz) for in vivo data collection. (C) 2015 Elsevier B.V. All rights reserved. C1 [Alam, S. Kaisar] Improlabs Pte Ltd, Singapore, Singapore. [Metaxas, Dimitris; Alam, S. Kaisar] Rutgers State Univ, CBIM, Piscataway, NJ USA. [Ahmed, Rifat; Rubel, Monir Hossan; Islam, Kazi Khairul; Alam, S. Kaisar] Islamic Univ Technol, Dept Elect & Elect Engn, Gazipur, Bangladesh. [Arfin, Rishad] South East Univ, Dhaka, Bangladesh. [Jia, Congxian; Garra, Brian S.] US FDA, Silver Spring, MD USA. [Garra, Brian S.] Washington DC Vet Affairs Med Ctr, Washington, DC USA. RP Alam, SK (reprint author), Improlabs Pte Ltd, Singapore, Singapore. EM kaisar.alam@ieee.org FU Susan G. Komen for the Cure [KG081601]; Fulbright Scholar award FX This work has been supported in part by Susan G. Komen for the Cure Grant KG081601 and a Fulbright Scholar award. The elastography phantom used in this study was custom-built by CIRS, Inc. (Norfolk, VA). The phantom data were acquired by Sarayu Ramachandran, Andy Kalisz, and Shreedevi Dasgupta, formerly of Riverside Research, New York, NY. In vivo breast data were acquired by Louise M. Mobbs and Dr. Brian S. Garra at Department of Radiology, Fletcher Allen Health Care, Burlington, VT. We are indebted to Roz Raskin, also of Riverside Research, for her valuable editorial help. NR 57 TC 0 Z9 0 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0041-624X EI 1874-9968 J9 ULTRASONICS JI Ultrasonics PD MAR PY 2016 VL 66 BP 140 EP 153 DI 10.1016/j.ultras.2015.11.001 PG 14 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA DA4TY UT WOS:000367795100007 PM 26647169 ER PT J AU Lloret, E Picouet, PA Trbojevich, R Fernandez, A AF Lloret, Elsa Picouet, Pierre A. Trbojevich, Raul Fernandez, Avelina TI Colour stability of cooked ham packed under modified atmospheres in polyamide nanocomposite blends SO LWT-FOOD SCIENCE AND TECHNOLOGY LA English DT Article DE Nylon; Cooked ham; Nanoclays; Oxygen permeation; Colour; Exfoliation; MAP ID TRANSPORT-PROPERTIES; OXIDATIVE STABILITY; SLICED HAM; SHELF-LIFE; CLASSIFICATION; QUALITY; STORAGE; LIGHT; FILMS; WATER AB Two novel blends containing a low-density polyethylene (LDPE) and a neat polyamide (PA) or a polyamide nanocomposite (PAN) layers were fabricated and their technological potential was evaluated during the refrigeration of cooked ham in modified atmospheres (MAP). Nanoclays were homogeneously distributed and nearly exfoliated, and they lowered significantly the oxygen transmission rate (OTR) of the PAN films. Due to the lower OTR, the headspace oxygen level in PAN pouches do not rise above 0.26% but it approached 2% in PA pouches at day 20. The residual oxygen levels were key for colour change during MAP storage of cooked ham. Cooked ham redness and reflectivity were stable during 27 days in PAN pouches while a strong colour deterioration took place after day 7 in PA pouches. Other parameters such as moisture content and water activity remained unaltered, and pH development was related to microbial growth and independent of the packaging polymer. The evolution of cooked ham colour in PAN was comparable to a high-barrier commercial polymer, and was acceptable for commercial sale for 27 days, showing excellent perspectives for polyamide nanocomposites in the storage of cooked ham. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Lloret, Elsa; Picouet, Pierre A.] IRTA, Dept Tecnol Dels Aliments, Monells, Girona, Spain. [Trbojevich, Raul] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Fernandez, Avelina] Inst Fis Corpuscular CSIC UVEG, Valencia, Spain. RP Fernandez, A (reprint author), Inst Fis Corpuscular CSIC UVEG, Parc Cient, Valencia, Spain. EM velifdez@ific.uv.es RI Fernandez Garcia, Avelina/A-1471-2009 FU Spanish Comision Interministerial de Ciencia y Tecnologia (Ministerio de Ciencia e Innovacion) [AGL07-65936-C02]; National Center for Toxicological Research [E0736801]; U.S. Food and Drug Administration FX Financial support from the Spanish Comision Interministerial de Ciencia y Tecnologia (Ministerio de Ciencia e Innovacion) under contract AGL07-65936-C02 is acknowledged. R. Trbojevich is grateful to project #E0736801 from the National Center for Toxicological Research and U.S. Food and Drug Administration. Authors are grateful to Dr. Frederick Be land and Dr. Matthew Bryant for assistance in the review of this manuscript. NR 30 TC 1 Z9 1 U1 12 U2 32 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0023-6438 EI 1096-1127 J9 LWT-FOOD SCI TECHNOL JI LWT-Food Sci. Technol. PD MAR PY 2016 VL 66 BP 582 EP 589 DI 10.1016/j.lwt.2015.11.012 PG 8 WC Food Science & Technology SC Food Science & Technology GA CZ9JF UT WOS:000367413200079 ER PT J AU Zhang, B Liu, W Zhang, H Chen, QH Zhang, ZW AF Zhang, Bo Liu, Wei Zhang, Hui Chen, Qihui Zhang, Zhiwei TI A note on misspecification in joint modeling of correlated data with informative cluster sizes SO JOURNAL OF STATISTICAL PLANNING AND INFERENCE LA English DT Article DE Joint random-effects model; Nonignorable cluster size; Information matrix test; Model combining ID SUBUNIT-SPECIFIC OUTCOMES; LINEAR MIXED MODELS; MISSING DATA; INFERENCE; TRIALS AB Clustered data are commonly generated in biomedical, economic, and social science studies. When cluster sizes are correlated with primary outcomes, data are identified as correlated data with "informative cluster sizes". For such data, standard data analysis methods do not apply because of induced biases. Joint modeling approach has been proposed as one of the strategies to analyze informative cluster size data. However, cluster size model misspecification may affect the reliability of joint modeling approach in statistical inference. This article focuses on the joint modeling approach that combines generalized linear mixed models and cluster size models. It reveals the prodigious impact of cluster size model misspecification on the statistical inferences in joint models and offers solutions to this misspecification problem. A modified information matrix test and a sandwich estimator test are adopted, and their effectiveness as diagnostic tools in detecting cluster size model misspecification is demonstrated. Numerical studies show that the two diagnostic tests are highly favorable, but they might inflate Type I errors when the sample size is small. We also recommend an alternative approach to draw inferences by using frequentist model averaging if there is strong confidence that the suitable model is included in the pool of candidate cluster size models. This article reviews a set of related theorems as well as complements them with comprehensive numerical studies, which together provide a methodological solution to the cluster size model misspecification in joint modeling. Published by Elsevier B.V. C1 [Zhang, Bo; Zhang, Zhiwei] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Liu, Wei] Harbin Inst Technol, Dept Math, Harbin 150001, Peoples R China. [Zhang, Hui] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA. [Chen, Qihui] China Agr Univ, Coll Econ & Management, Dept Appl Econ, Beijing 100083, Peoples R China. RP Zhang, B (reprint author), US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM Bo.Zhang@fda.hhs.gov RI Zhang, Hui/E-8112-2010; OI Chen, Qihui/0000-0002-0944-0470 NR 26 TC 0 Z9 0 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-3758 EI 1873-1171 J9 J STAT PLAN INFER JI J. Stat. Plan. Infer. PD MAR PY 2016 VL 170 BP 46 EP 63 DI 10.1016/j.jspi.2015.09.005 PG 18 WC Statistics & Probability SC Mathematics GA CZ0EL UT WOS:000366777800004 ER PT J AU Zhu, L Ruan, JQ Li, N Fu, PP Ye, Y Lin, G AF Zhu, Lin Ruan, Jian-Qing Li, Na Fu, Peter P. Ye, Yang Lin, Ge TI A novel ultra-performance liquid chromatography hyphenated with quadrupole time of flight mass spectrometry method for rapid estimation of total toxic retronecine-type of pyrrolizidine alkaloids in herbs without requiring corresponding standards SO FOOD CHEMISTRY LA English DT Article DE Food safety; Hepatotoxic; Pyrrolizidine alkaloids; Retronecine type; UHPLC-MS ID N-OXIDES; METABOLIC-ACTIVATION; SENECIO-SCANDENS; DNA-ADDUCTS; HPLC-MS; PLANTS; TUMORIGENICITY; IDENTIFICATION; QIANLIGUANG; INTERFACE AB Nearly 50% of naturally-occurring pyrrolizidine alkaloids (PAs) are hepatotoxic, and the majority of hepatotoxic PM are retronecine-type PM (RET-PAs). However, quantitative measurement of PM in herbs/foodstuffs is often difficult because most of reference PM are unavailable. In this study, a rapid, selective, and sensitive UHPLC-QTOF-MS method was developed for the estimation of RET-PAs in herbs without requiring corresponding standards. This method is based on our previously established characteristic and diagnostic mass fragmentation patterns and the use of retrorsine for calibration. The use of a single RET-PA retrorsine) for construction of calibration was based on high similarities with no significant differences demonstrated by the calibration curves constructed by peak areas of extract ion chromatograms of fragment ion at m/z 120.0813 or 138.0919 versus concentrations of five representative RET-PAs. The developed method was successfully applied to measure a total content of toxic RET-PAs of diversified structures in fifteen potential PA-containing herbs. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Zhu, Lin; Ruan, Jian-Qing; Lin, Ge] Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Hong Kong, Hong Kong, Peoples R China. [Zhu, Lin; Ruan, Jian-Qing; Ye, Yang; Lin, Ge] Chinese Univ Hong Kong, Chinese Acad Sci, Shanghai Inst Mat Med, Joint Res Lab Promoting Globalizat Tradit Chinese, Hong Kong, Hong Kong, Peoples R China. [Fu, Peter P.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Li, Na] Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Macau Inst Appl Res Med & Hlth, Taipa, Macau, Peoples R China. [Ye, Yang] Chinese Acad Sci, Shanghai Inst Mat Med, Dept Chem, State Key Lab Drug Res & Nat Prod, Beijing 100864, Peoples R China. RP Lin, G (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Hong Kong, Hong Kong, Peoples R China. EM gelin@cuhk.edu.hk FU Research Grant Council of Hong Kong (GRF) [471013, 469712] FX This research is supported by Research Grant Council of Hong Kong (GRF Grants No. 471013 and 469712). 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 39 TC 4 Z9 4 U1 7 U2 66 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 2016 VL 194 BP 1320 EP 1328 DI 10.1016/j.foodchem.2014.11.093 PG 9 WC Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics SC Chemistry; Food Science & Technology; Nutrition & Dietetics GA CV4PL UT WOS:000364248900170 PM 26471688 ER PT J AU Korang-Yeboah, M Rahman, Z Shah, D Mohammad, A Wu, SY Siddiqui, A Khan, MA AF Korang-Yeboah, Maxwell Rahman, Ziyaur Shah, Dhaval Mohammad, Adil Wu, Suyang Siddiqui, Akhtar Khan, Mansoor A. TI Impact of formulation and process variables on solid-state stability of theophylline in controlled release formulations SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Solid-state stability; Dissolution; Pseudopolymorphic transition; Theophylline ID ANHYDROUS THEOPHYLLINE; QUANTITATIVE-DETERMINATION; PHASE-TRANSFORMATION; PSEUDO-POLYMORPHISM; CRYSTAL NUCLEATION; DRUG APPLICATIONS; HYDRATE FORMATION; WET GRANULATION; TABLETS; CRYSTALLIZATION AB Understanding the impact of pharmaceutical processing, formulation excipients and their interactions on the solid-state transitions of pharmaceutical solids during use and in storage is critical in ensuring consistent product performance. This study reports the effect of polymer viscosity, diluent type, granulation and granulating fluid (water and isopropanol) on the pseudopolymorphic transition of theophylline anhydrous (THA) in controlled release formulations as well as the implications of this transition on critical quality attributes of the tablets. Accordingly, 12 formulations were prepared using a full factorial screening design and monitored over a 3 month period at 40 degrees C and 75%. Physicochemical characterization revealed a drastic drop in tablet hardness accompanied by a very significant increase in moisture content and swelling of all formulations. Spectroscopic analysis (ssNMR, Raman, NIR and PXRD) indicated conversion of THA to theophylline monohydrate (TMO) in all formulations prepared by aqueous wet granulation in as early as two weeks. Although all freshly prepared formulations contained THA, the hydration-dehydration process induced during aqueous wet granulation hastened the pseudopolymorphic conversion of theophylline during storage through a cascade of events. On the other hand, no solid state transformation was observed in directly compressed formulations and formulations in which isopropanol was employed as a granulating fluid even after the twelve weeks study period. The transition of THA to TMO resulted in a decrease in dissolution while an increase in dissolution was observed in directly compressed and IPA granulated formulation. Consequently, the impact of pseudopolymorphic transition of theophylline on dissolution in controlled release formulations may be the net result of two opposing factors: swelling and softening of the tablets which tend to favor an increase in drug dissolution and hydration of theophylline which decreases the drug dissolution. Published by Elsevier B.V. C1 [Korang-Yeboah, Maxwell; Rahman, Ziyaur; Shah, Dhaval; Mohammad, Adil; Wu, Suyang; Siddiqui, Akhtar; Khan, Mansoor A.] Ctr Drug Evaluat & Res Food & Drug Adm, Div Prod Qual Res, Silver Spring, MD 20993 USA. [Khan, Mansoor A.] Rangel Coll Pharm, Texas A&M Hlth Sci Ctr, Reynolds Med Bldg,Suite 159, College Stn, TX 77843 USA. RP Khan, MA (reprint author), Ctr Drug Evaluat & Res Food & Drug Adm, Div Prod Qual Res, Silver Spring, MD 20993 USA.; Khan, MA (reprint author), Rangel Coll Pharm, Texas A&M Hlth Sci Ctr, Reynolds Med Bldg,Suite 159, College Stn, TX 77843 USA. EM mkhan@pharmacy.tamhsc.edu RI SHAH, DHAVAL/L-5439-2016; OI Shah, Dhaval/0000-0002-3631-6125; Rahman, Ziyaur/0000-0002-0402-825X NR 41 TC 1 Z9 1 U1 6 U2 16 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 29 PY 2016 VL 499 IS 1-2 BP 20 EP 28 DI 10.1016/j.ijpharm.2015.11.046 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DD6QI UT WOS:000370048300003 PM 26688036 ER PT J AU Ghosh, S Ghosh, S Tiwari, RC AF Ghosh, Samiran Ghosh, Santu Tiwari, Ram C. TI Bayesian approach for assessing non-inferiority in a three-arm trial with pre-specified margin SO STATISTICS IN MEDICINE LA English DT Article DE assay sensitivity; Bayesian Method; Jeffreys' prior; Markov chain Monte Carlo; non-inferiority margin ID SEQUENTIAL CLINICAL-TRIALS; DESIGN; NONINFERIORITY; MULTIPLE; POWER AB Non-inferiority trials are becoming increasingly popular for comparative effectiveness research. However, inclusion of the placebo arm, whenever possible, gives rise to a three-arm trial which has lesser burdensome assumptions than a standard two-arm non-inferiority trial. Most of the past developments in a three-arm trial consider defining a pre-specified fraction of unknown effect size of reference drug, that is, without directly specifying a fixed non-inferiority margin. However, in some recent developments, a more direct approach is being considered with pre-specified fixed margin albeit in the frequentist setup. Bayesian paradigm provides a natural path to integrate historical and current trials' information via sequential learning. In this paper, we propose a Bayesian approach for simultaneous testing of non-inferiority and assay sensitivity in a three-arm trial with normal responses. For the experimental arm, in absence of historical information, non-informative priors are assumed under two situations, namely when (i) variance is known and (ii) variance is unknown. A Bayesian decision criteria is derived and compared with the frequentist method using simulation studies. Finally, several published clinical trial examples are reanalyzed to demonstrate the benefit of the proposed procedure. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Ghosh, Samiran] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Ghosh, Samiran; Ghosh, Santu] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Ghosh, Santu] Georgia Regents Univ, Dept Biostat & Epidemiol, Augusta, GA USA. [Tiwari, Ram C.] US FDA, Off Biostat, CDER, Silver Spring, MD USA. RP Ghosh, S (reprint author), Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA.; Ghosh, S (reprint author), Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. EM sghos@med.wayne.edu FU PCORI [ME-1409-21410]; NIH [P30-ES020957] FX The research of first author is partly supported by PCORI contract number ME-1409-21410 and NIH grant number P30-ES020957. Authors would also like to thank an anonymous referee and the editorial team, whose comments provided additional insights and have greatly improved the scope and presentation of the paper. NR 31 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD FEB 28 PY 2016 VL 35 IS 5 BP 695 EP 708 DI 10.1002/sim.6746 PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DC0YW UT WOS:000368945000004 PM 26434554 ER PT J AU Batson, JS Bempong, DK Lukulay, PH Ranieri, N Satzger, RD Verbois, L AF Batson, JaCinta S. Bempong, Daniel K. Lukulay, Patrick H. Ranieri, Nicola Satzger, R. Duane Verbois, Leigh TI Assessment of the effectiveness of the CD3+tool to detect counterfeit and substandard anti-malarials SO MALARIA JOURNAL LA English DT Article DE Anti-malarials; Counterfeit medicines; Medicine quality screening; Substandard medicines ID DRUGS; ARTESUNATE AB Background: The US FDA recently developed CD3+, a counterfeit detection tool that is based on sample illumination at specific wavelengths of light and visual comparison of suspect sample and packaging materials to an authentic sample. To test performance of the CD3+ in field conditions, a study was conducted in Ghana which compared the CD3+ side-by-side with two existing medicine quality screening technologies-TruScan (TM) Portable Raman spectrometer and GPHF Minilab (R). Methods: A total of 84 anti-malarial test samples comprising artemether-lumefantrine tablets and artesunate-amodiaquine tablets were used. The technologies were evaluated for sensitivity in determining counterfeit/substandard (The term counterfeit or falsified is used in this article to refer to medicines that carry a false representation of identity or source or both. The term substandard is used to refer to medicines that do not meet the quality specifications given in the accepted pharmacopeia.) medicines, specificity in determining authentic products, and reliability of the results. Authentic samples obtained from manufacturers were used as reference standards. HPLC analysis data was used as the "gold standard" for decisions regarding a sample being authentic or substandard/counterfeit. Results: CD3+ had a sensitivity of 1.00 in detecting counterfeit/substandard products compared to Minilab (0.79) and TruScan (0.79). CD3+ had a lower specificity (0.53) in determining authentic products compared to the specificities reached by Minilab (0.99) and TruScan (1.00). High sensitivity in this context means that the technology is effective in identifying substandard/counterfeit products whereas the low specificity means that the technique can sometimes mischaracterize good products as substandard/counterfeit. Examination of dosage units only (and not packaging) using CD3+ yielded improved specificity 0.64. When only assessment of sample identification was done, the TruScan provided sensitivity (1.00) and specificity (0.99); and the Minilab provided sensitivity (1.00) and specificity (1.00). All three technologies demonstrated 100 % reliability when used to analyse the same set of samples over 3 days by a single analyst and also when used to determine the same set of samples by three different analysts. Eight of the field samples were confirmed to be counterfeits with no active pharmaceutical ingredient content. All three technologies identified these samples as counterfeits. Conclusions: The study revealed the relative effectiveness of the technologies as quality control tools. Using a combination of CD3+, with either the Minilab or TruScan, to screen for medicine quality will allow for complete examination of both the dosage units and the packaging to decide whether it is authentic or counterfeit. C1 [Bempong, Daniel K.; Lukulay, Patrick H.] US Pharmacopeial Convent Inc, 12601 Twinbrook Pkwy, Rockville, MD 20852 USA. [Batson, JaCinta S.; Ranieri, Nicola; Satzger, R. Duane] Forens Chem Ctr, Food & Drug Adm, 6751 Steger Dr, Cincinnati, OH 45237 USA. [Verbois, Leigh] Food & Drug Adm, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Bempong, DK (reprint author), US Pharmacopeial Convent Inc, 12601 Twinbrook Pkwy, Rockville, MD 20852 USA. EM DKB@usp.org FU Skoll Global Threats Fund FX Collaborative partners in this study were: United States Pharmacopeial Convention (USP); United States Food and Drug Administration (US FDA); United States Agency for International Development (USAID); President's Malaria Initiative (PMI); Centers for Disease Control and Prevention (CDC); National Institutes of Health (NIH); Ghana Food and Drug Authority (Ghana FDA); USP Center for Pharmaceutical Advancement and Training (CePAT). This research was funded in part by the Skoll Global Threats Fund (http://www.skollglobalthreats.org). NR 9 TC 1 Z9 1 U1 2 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD FEB 25 PY 2016 VL 15 AR 119 DI 10.1186/s12936-016-1180-2 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DF3CL UT WOS:000371221200002 PM 26917250 ER PT J AU Xue, Y Wilkes, JG Moskal, TJ Williams, AJ Cooper, WM Nayak, R Rafii, F Buzatu, DA AF Xue, Yong Wilkes, Jon G. Moskal, Ted J. Williams, Anna J. Cooper, Willie M. Nayak, Rajesh Rafii, Fatemeh Buzatu, Dan A. TI Development of a Flow Cytometry-Based Method for Rapid Detection of Escherichia coli and Shigella Spp. Using an Oligonucleotide Probe SO PLOS ONE LA English DT Article ID FOOD MATRIX INTERFERENCE; MICROBIAL-POPULATIONS; COMBINATION; CONSUMPTION; OUTBREAK; O157/H7; PROTEIN AB Standard methods to detect Escherichia coli contamination in food use the polymerase chain reaction (PCR) and agar culture plates. These methods require multiple incubation steps and take a long time to results. An improved rapid flow-cytometry based detection method was developed, using a fluorescence-labeled oligonucleotide probe specifically binding a16S rRNA sequence. The method positively detected 51 E. coli isolates as well as 4 Shigella species. All 27 non-E. coli strains tested gave negative results. Comparison of the new genetic assay with a total plate count (TPC) assay and agar plate counting indicated similar sensitivity, agreement between cytometry cell and colony counts. This method can detect a small number of E. coli cells in the presence of large numbers of other bacteria. This method can be used for rapid, economical, and stable detection of E. coli and Shigella contamination in the food industry and other contexts. C1 [Xue, Yong; Wilkes, Jon G.; Williams, Anna J.; Cooper, Willie M.; Buzatu, Dan A.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Nayak, Rajesh; Rafii, Fatemeh] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Xue, Y (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR USA. EM Yong.Xue@fda.hhs.gov FU US federal government FX This work was supported by the US federal government. NR 23 TC 1 Z9 1 U1 5 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 25 PY 2016 VL 11 IS 2 AR e0150038 DI 10.1371/journal.pone.0150038 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF2LW UT WOS:000371175700048 PM 26913737 ER PT J AU Noel, A Xiao, R Perveen, Z Zaman, HM Rouse, RL Paulsen, DB Penn, AL AF Noel, A. Xiao, R. Perveen, Z. Zaman, H. M. Rouse, R. L. Paulsen, D. B. Penn, A. L. TI Incomplete lung recovery following sub-acute inhalation of combustion-derived ultrafine particles in mice SO PARTICLE AND FIBRE TOXICOLOGY LA English DT Article DE Inhalation; Particulate matter; Combustion-derived ultrafine particles; Lung recovery; Inflammation; Oxidative stress; Biotransformation; Gene expression; Particle-laden macrophage biomarker ID PARTICULATE AIR-POLLUTION; DIESEL EXHAUST PARTICLES; LOWER-RESPIRATORY SYMPTOMS; LONG-TERM EXPOSURE; OIL FLY-ASH; CARBON-BLACK; OXIDATIVE STRESS; GENE-EXPRESSION; FINE PARTICLES; INFLAMMATORY RESPONSE AB Background: Particulate matter (PM) is one of the six criteria pollutant classes for which National Ambient Air Quality Standards have been set by the United States Environmental Protection Agency. Exposures to PM have been correlated with increased cardio-pulmonary morbidity and mortality. Butadiene soot (BDS), generated from the incomplete combustion of 1,3-butadiene (BD), is both a model PM mixture and a real-life example of a petrochemical product of incomplete combustion. There are numerous events, including wildfires, accidents at refineries and tank car explosions that result in sub-acute exposure to high levels of airborne particles, with the people exposed facing serious health problems. These real-life events highlight the need to investigate the health effects induced by short-term exposure to elevated levels of PM, as well as to assess whether, and if so, how well these adverse effects are resolved over time. In the present study, we investigated the extent of recovery of mouse lungs 10 days after inhalation exposures to environmentally-relevant levels of BDS aerosols had ended. Methods: Female BALB/c mice exposed to either HEPA-filtered air or to BDS (5 mg/m(3) in HEPA filtered air, 4 h/day, 21 consecutive days) were sacrificed immediately, or 10 days after the final BDS exposure. Bronchoalveolar lavage fluid (BALF) was collected for cytology and cytokine analysis. Lung proteins and RNA were extracted for protein and gene expression analysis. Lung histopathology evaluation also was performed. Results: Sub-acute exposures of mice to hydrocarbon-rich ultrafine particles induced: (1) BALF neutrophil elevation; (2) lung mucosal inflammation, and (3) increased BALF IL-1 beta concentration; with all three outcomes returning to baseline levels 10 days post-exposure. In contrast, (4) lung connective tissue inflammation persisted 10 days post-exposure; (5) we detected time-dependent up-regulation of biotransformation and oxidative stress genes, with incomplete return to baseline levels; and (6) we observed persistent particle alveolar load following 10 days of recovery. Conclusion: These data show that 10 days after a 21-day exposure to 5 mg/m(3) of BDS has ended, incomplete lung recovery promotes a pro-biotransformation, pro-oxidant, and pro-inflammatory milieu, which may be a starting point for potential long-term cardio-pulmonary effects. C1 [Noel, A.; Perveen, Z.; Zaman, H. M.; Penn, A. L.] Louisiana State Univ, Sch Vet Med, Dept Comparat Biomed Sci, Skip Bertman Dr, Baton Rouge, LA 70803 USA. [Paulsen, D. B.] Louisiana State Univ, Sch Vet Med, Dept Pathobiol Sci, Baton Rouge, LA 70803 USA. [Xiao, R.] Columbia Univ, Dept Anesthesiol, Med Ctr, New York, NY USA. [Rouse, R. L.] US FDA, Silver Spring, MD USA. RP Penn, AL (reprint author), Louisiana State Univ, Sch Vet Med, Dept Comparat Biomed Sci, Skip Bertman Dr, Baton Rouge, LA 70803 USA. EM apenn1@lsu.edu FU Louisiana Governor's Biotechnology Initiative GBI-BOR [013]; Fonds de Recherche Quebec Sante (FRQS) FX The authors thank Dr. William Polk and Ms. Lindsey Clemones of the Louisiana State University School of Veterinary Medicine and Ms. Paula Polk of the Louisiana State University Health Sciences Center (Shreveport) for excellent technical assistance. This study was supported by a grant (Arthur L. Penn) from the Louisiana Governor's Biotechnology Initiative GBI-BOR#013. Alexandra Noel is a recipient of a post-doctoral fellowship from the Fonds de Recherche Quebec Sante (FRQS). NR 93 TC 1 Z9 1 U1 8 U2 30 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-8977 J9 PART FIBRE TOXICOL JI Part. Fibre Toxicol. PD FEB 24 PY 2016 VL 13 AR 10 DI 10.1186/s12989-016-0122-z PG 20 WC Toxicology SC Toxicology GA DE7CG UT WOS:000370791000001 PM 26911867 ER PT J AU Morozov, GI Zhao, HY Mage, MG Boyd, LF Jiang, JS Dolan, MA Venna, R Norcross, MA McMurtrey, CP Hildebrand, W Schuck, P Natarajan, K Margulies, DH AF Morozov, Giora I. Zhao, Huaying Mage, Michael G. Boyd, Lisa F. Jiang, Jiansheng Dolan, Michael A. Venna, Ramesh Norcross, Michael A. McMurtrey, Curtis P. Hildebrand, William Schuck, Peter Natarajan, Kannan Margulies, David H. TI Interaction of TAPBPR, a tapasin homolog, with MHC-I molecules promotes peptide editing SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antigen presentation; peptide loading; major histocompatibility complex; protein interactions; SAXS ID MAJOR HISTOCOMPATIBILITY COMPLEX; ANTIGEN PRESENTATION; ENDOPLASMIC-RETICULUM; BIOLOGICAL MACROMOLECULES; PRESENTATION PATHWAY; SOLUTION SCATTERING; ESCHERICHIA-COLI; HEAVY-CHAIN; TRANSPORTER; BETA(2)-MICROGLOBULIN AB Peptide loading of major histocompatibility complex class I (MHC-I) molecules is central to antigen presentation, self-tolerance, and CD8(+) T-cell activation. TAP binding protein, related (TAPBPR), a widely expressed tapasin homolog, is not part of the classical MHC-I peptide-loading complex (PLC). Using recombinant MHC-I molecules, we show that TAPBPR binds HLA-A*02:01 and several other MHC-I molecules that are either peptide-free or loaded with low-affinity peptides. Fluorescence polarization experiments establish that TAPBPR augments peptide binding by MHC-I. The TAPBPR/MHC-I interaction is reversed by specific peptides, related to their affinity. Mutational and small-angle X-ray scattering (SAXS) studies confirm the structural similarities of TAPBPR with tapasin. These results support a role of TAPBPR in stabilizing peptide-receptive conformation(s) of MHC-I, permitting peptide editing. C1 [Morozov, Giora I.; Mage, Michael G.; Boyd, Lisa F.; Jiang, Jiansheng; Natarajan, Kannan; Margulies, David H.] NIAID, Mol Biol Sect, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Zhao, Huaying; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromolecular Biophys, NIH, Bethesda, MD 20892 USA. [Dolan, Michael A.] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Venna, Ramesh; Norcross, Michael A.] US FDA, Ctr Drug Evaluat & Res, Immunol Lab, Silver Spring, MD 20993 USA. [McMurtrey, Curtis P.; Hildebrand, William] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. RP Margulies, DH (reprint author), NIAID, Mol Biol Sect, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dhm@nih.gov RI ID, BioCAT/D-2459-2012; OI Morozov, Giora/0000-0002-2605-6075 FU DOE Office of Science [DE-AC02-06CH11357]; National Institute of General Medical Sciences of the National Institutes of Health [9 P41 GM103622]; National Institute of Allergy and Infectious Diseases [AI0000394]; National Institute of Biomedical Imaging and Bioengineering/National Institutes of Health [EB000008]; Center for Drug Evaluation and Review/Federal Drug Administration [1617] FX We thank Drs. David Garboczi [National Institute of Allergy and Infectious Diseases (NIAID)] and Rick Willis and John Altman of the NIAID tetramer facility for plasmids used for generating some MHC constructs; Drs. Ted Hansen, Rose Mage, Nathan May, and Rajat Varma for comments on the manuscript; and Robert Tampe for discussion. We appreciate the help of Dr. Tengchuan Jin with fluorescence polarization. Drs. Srinivas Chakravarthy and Weifeng Shang at Bio-CAT/APS (18IDD) assisted with small-angle X-ray scattering (SAXS) data collection. SAXS research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357, a project supported by Grant 9 P41 GM103622 from the National Institute of General Medical Sciences of the National Institutes of Health. Our research was supported by the intramural research programs of the National Institute of Allergy and Infectious Diseases (Project AI0000394) and National Institute of Biomedical Imaging and Bioengineering (Project EB000008)/National Institutes of Health and the Center for Drug Evaluation and Review/Federal Drug Administration (Project 1617). NR 51 TC 3 Z9 3 U1 2 U2 5 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 23 PY 2016 VL 113 IS 8 BP E1006 EP E1015 DI 10.1073/pnas.1519894113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DE4SK UT WOS:000370620300011 PM 26869717 ER EF